Pregabalin versus tramadol for postoperative pain management in patients undergoing lumbar laminectomy: a randomized, double-blinded, placebo-controlled study

PubMed Central

Kumar, Koramutla Pradeep; Kulkarni, Dilip Kumar; Gurajala, Indira; Gopinath, Ramachandran

2013-01-01

Prevention and treatment of postoperative pain continues to be a major challenge in postoperative care. Opioid analgesics, with their well-known side effects, continue to represent a cornerstone in postoperative pain control. Anticonvulsant medications are established treatments for neuropathic pain. Pregabalin (S-[+]-3-isobutylgaba), a structural analog of gamma-Aminobutyric acid, has been used for the treatment of various neuropathic pain and also as an adjunctive therapy for adults with partial onset seizures. This study was thus taken up to primarily assess and compare the analgesic and anxiolytic effects of administering pregabalin and tramadol preoperatively for patients undergoing elective decompressive lumbar laminectomy. The study group included 75 patients between the ages of 20–60 years belonging to American Society of Anesthesiology-1 (ASA) and ASA-2 patients. The patients were randomly allocated into three groups of 25 patients each. The placebo group received a placebo capsule, the tramadol group received a 100 mg capsule, while the pregabalin group received a 150 mg capsule orally 1 hour before anesthetic induction. Pregabalin showed statistically significant analgesic effects compared to placebo, but the effect was found to be less prevalent compared to tramadol. The need for rescue analgesia was the least prevalent in tramadol patients followed by pregabalin patients, and reached a maximum in the control group. Pregabalin showed statistically significant anxiolytic effects compared to placebo, and this was associated with less sedation in comparison to tramadol. Pregabalin had fewer numbers of postoperative complications of nausea, vomiting, and drowsiness in comparison to tramadol. The results of this study support the clinical use of pregabalin in the postsurgical setting for pain relief, as it is well tolerated, and usually presents with transient adverse effects. PMID:23837006

Pregabalin for the Prevention of Oxaliplatin-Induced Painful Neuropathy: A Randomized, Double-Blind Trial.

PubMed

de Andrade, Daniel Ciampi; Jacobsen Teixeira, Manoel; Galhardoni, Ricardo; Ferreira, Karine S L; Braz Mileno, Paula; Scisci, Nathalia; Zandonai, Alexandra; Teixeira, William G J; Saragiotto, Daniel F; Silva, Valquíria; Raicher, Irina; Cury, Rubens Gisbert; Macarenco, Ricardo; Otto Heise, Carlos; Wilson Iervolino Brotto, Mario; Andrade de Mello, Alberto; Zini Megale, Marcelo; Henrique Curti Dourado, Luiz; Mendes Bahia, Luciana; Lilian Rodrigues, Antonia; Parravano, Daniella; Tizue Fukushima, Julia; Lefaucheur, Jean-Pascal; Bouhassira, Didier; Sobroza, Evandro; Riechelmann, Rachel P; Hoff, Paulo M; Valério da Silva, Fernanda; Chile, Thais; Dale, Camila S; Nebuloni, Daniela; Senna, Luiz; Brentani, Helena; Pagano, Rosana L; de Souza, Ângela M

2017-10-01

Pregabalin is a medication that can decrease neuronal hyperexcitability, relieve neuropathic pain, and reach stable plasma levels after a titration period of only a few days.Its use during oxaliplatin infusions was not able to decrease the incidence of chronic, oxalipaltin-related neuropathic pain, compared with placebo. Patients with colorectal cancer (CRC) receiving oxaliplatin (OXA) develop acute and chronic painful oxaliplatin-induced peripheral neuropathy (OXAIPN). Acute and chronic OXA-related neuropathies have different pathophysiological bases, but both lead to a common phenomenon: central sensitization (CS) of nociceptive neuronal networks, leading to increased sensitivity (hyperlgesia, allodynia) in the somatosensory system, the common ground of chronic neuropathic pain. Because CS is related to increased risk of painful OXAIPN, we hypothesized that preemptive use of the anti-hyperalgesic drug pregabaline (known to decrease CS) during OXA infusions would decrease the incidence of chronic OXAIPN. Pain-free, chemotherapy-naïve CRC patients receiving at least one cycle of modified-FLOX [5-FU(500 mg/m 2 )+leucovorin(20 mg/m 2 )/week for] 6 weeks+oxaliplatin(85 mg/m 2 ) at weeks 1-3-5 every 8 weeks] were randomized (1:1) into the study. Patients received either pregabalin or placebo for 3 days before and 3 days after each OXA infusion and were followed for up to 6 months. Clinical assessments were performed at baseline, at the end of chemotherapy, and after the follow-up period. The main outcome was average pain at the last visit assessed by the visual analogic scale (0-10) item of the Brief Pain Inventory (BPI). Secondary endpoints were presence of neuropathic pain according to the Douleur Neuropathique-4 (DN-4), pain dimensions (short- form McGill Pain Questionnaire [MPQ]), Neuropathic Pain Symptom Inventory (NPSI), and changes in nerve conduction studies (NCS) and side effect profile. One hundred ninety-nine patients (57.0 ± 10.7 years old, 98 female, 101 male) were randomized. Data from 56 patients were not included in the analyses (as they did not receive at least one full cycle of modified FLOX). Data from 78 patients in the pregabalin group and 65 patients in the placebo group were retained for analyses. At the last visit, pain intensity in the pregabalin group was 1.03 (95% confidence interval [CI] = 0.79-1.26), and 0.85 (95% CI = 0.64-1.06) in the placebo group, which did not reach significance. Scores from the BPI, MPQ, DN-4, NPSI, and NCS and side-effect profiles and incidence of death did not differ between groups. Quality of life (QoL) score did not differ between groups (placebo = 76.9 ± 23.1, pregabalin group 79.4 ± 20.6). Mood scores were not significantly different between groups (placebo 9.7 [8.1-11.2]; pregabalin 6.8 [5.6-8.0]). The preemptive use of pregabalin during OXA infusions was safe, but did not decrease the incidence of chronic pain related to OXAIPN. ©AlphaMedPress; the data published online to support this summary is the property of the authors.

Duloxetine, Pregabalin, and Duloxetine Plus Gabapentin for Diabetic Peripheral Neuropathic Pain Management in Patients With Inadequate Pain Response to Gabapentin: An Open-Label, Randomized, Noninferiority Comparison

PubMed Central

Tanenberg, Robert J.; Irving, Gordon A.; Risser, Richard C.; Ahl, Jonna; Robinson, Michael J.; Skljarevski, Vladimir; Malcolm, Sandra K.

2011-01-01

OBJECTIVE: To determine whether duloxetine is noninferior to (as good as) pregabalin in the treatment of pain associated with diabetic peripheral neuropathy. PATIENTS AND METHODS: We performed a 12-week, open-label study of patients with diabetic peripheral neuropathic pain who had been treated with gabapentin (≥900 mg/d) and had an inadequate response (defined as a daily pain score of ≥4 on a numerical rating scale [0-10 points]). The first patient was enrolled on September 28, 2006, and the last patient visit occurred on August 26, 2009. Patients were randomized to duloxetine monotherapy (n=138), pregabalin monotherapy (n=134), or a combination of duloxetine and gabapentin (n=135). The primary objective was a noninferiority comparison between duloxetine and pregabalin on improvement in the weekly mean of the diary-based daily pain score (0- to 10-point scale) at end point. Noninferiority would be declared if the mean improvement for duloxetine was no worse than the mean improvement for pregabalin, within statistical variability, by a margin of –0.8 unit. RESULTS: The mean change in the pain rating at end point was –2.6 for duloxetine and –2.1 for pregabalin. The 97.5% lower confidence limit was a –0.05 difference in means, establishing noninferiority. As to adverse effects, nausea, insomnia, hyperhidrosis, and decreased appetite were more frequent with duloxetine than pregabalin; insomnia, more frequent with duloxetine than duloxetine plus gabapentin; peripheral edema, more frequent with pregabalin than with duloxetine; and nausea, hyperhidrosis, decreased appetite, and vomiting, more frequent with duloxetine plus gabapentin than with pregabalin. CONCLUSION: Duloxetine was noninferior to pregabalin for the treatment of pain in patients with diabetic peripheral neuropathy who had an inadequate pain response to gabapentin. Trial Registration: clinicaltrials.gov Identifier: NCT00385671 PMID:21719618

The Effects of Pregabalin and the Glial Attenuator Minocycline on the Response to Intradermal Capsaicin in Patients with Unilateral Sciatica

PubMed Central

Sumracki, Nicole M.; Hutchinson, Mark R.; Gentgall, Melanie; Briggs, Nancy; Williams, Desmond B.; Rolan, Paul

2012-01-01

Background Patients with unilateral sciatica have heightened responses to intradermal capsaicin compared to pain-free volunteers. No studies have investigated whether this pain model can screen for novel anti-neuropathic agents in patients with pre-existing neuropathic pain syndromes. Aim This study compared the effects of pregabalin (300 mg) and the tetracycline antibiotic and glial attenuator minocycline (400 mg) on capsaicin-induced spontaneous pain, flare, allodynia and hyperalgesia in patients with unilateral sciatica on both their affected and unaffected leg. Methods/Results Eighteen patients with unilateral sciatica completed this randomised, double-blind, placebo-controlled, three-way cross-over study. Participants received a 10 µg dose of capsaicin into the middle section of their calf on both their affected and unaffected leg, separated by an interval of 75 min. Capsaicin-induced spontaneous pain, flare, allodynia and hyperalgesia were recorded pre-injection and at 5, 20, 40, 60 and 90 min post-injection. Minocycline tended to reduce pre-capsaicin injection values of hyperalgesia in the affected leg by 28% (95% CI 0% to 56%). The area under the effect time curves for capsaicin-induced spontaneous pain, flare, allodynia and hyperalgesia were not affected by either treatment compared to placebo. Significant limb differences were observed for flare (AUC) (−38% in affected leg, 95% CI for difference −19% to −52%). Both hand dominance and sex were significant covariates of response to capsaicin. Conclusions It cannot be concluded that minocycline is unsuitable for further evaluation as an anti-neuropathic pain drug as pregabalin, our positive control, failed to reduce capsaicin-induced neuropathic pain. However, the anti-hyperalgesic effect of minocycline observed pre-capsaicin injection is promising pilot information to support ongoing research into glial-mediated treatments for neuropathic pain. The differences in flare response between limbs may represent a useful biomarker to further investigate neuropathic pain. Inclusion of a positive control is imperative for the assessment of novel therapies for neuropathic pain. PMID:22685578

Pregabalin as mono- or add-on therapy for patients with refractory chronic neuropathic pain: a post-marketing prescription-event monitoring study.

PubMed

Lampl, Christian; Schweiger, Christine; Haider, Bernhard; Lechner, Anita

2010-08-01

This observational study examined the outcome of two different therapeutic strategies in the treatment of chronic neuropathic pain by including pregabalin (PGB) as mono- or add-on therapy in one of two treatment options. Patients with a pain score of > or =4, refractory to usual care for neuropathic pain for at least 6 months, were allocated consecutively to one of two treatment strategies according to the decision of the physician: complete switch to a flexible-dosage, monotherapeutic or add-on therapy with pregabalin (PGB group), or change established doses and combinations of pre-existing mono- or combination therapy without pregabalin (non-PGB group). After 4 weeks (primary endpoint) a significant improvement in pain reduction was documented in both intention-to treat (ITT) analysis (PGB group, n = 85: mean pain score reduction of 3.53, SD 2.03, p < 0.001; non-PGB group, n = 102; mean pain score reduction of 2.83, SD 2.23, p < 0.001) and per-protocol (PP) analysis (PGB group, n = 79: mean pain score reduction 3.53 vs. 2.83, p < 0.05; non-PGB group, n = 81; 3.5 vs. 2.9, p < 0.05) compared to baseline. Comparison of the results observed in the two groups shows that patients in the PGB group achieved significantly greater pain reduction. These results demonstrate that PGB administered twice daily is superior to treatment regimes without PGB in reducing pain and pain-related interference in quality of life.

Standard analgesics reverse burrowing deficits in a rat CCI model of neuropathic pain, but not in models of type 1 and type 2 diabetes-induced neuropathic pain.

PubMed

Rutten, Kris; Gould, Stacey A; Bryden, Luke; Doods, Henri; Christoph, Thomas; Pekcec, Anton

2018-09-17

Burrowing is a rodent behavior validated as a robust and reproducible outcome measure to infer the global effect of pain in several inflammatory pain models. However, less is known about the effect of analgesics on burrowing in neuropathic pain models and no studies have determined burrowing performance in models of diabetes-associated neuropathic pain. To compare the sensitivity of the burrowing assay in different neuropathic pain models: mononeuropathic pain and diabetic polyneuropathy. Burrowing performance was determined by the amount of substrate left in a hollow tube by rats with chronic constriction injury (CCI). In addition, burrowing performance, locomotion and pain development was assessed in the Zucker diabetic fatty (ZDF) rat model, resembling type-2 diabetes. Efficacy of clinically-active reference drugs (opioids, gabapentin and/or pregabalin) were investigated in these models. Burrowing behavior was additionally assessed in a second model, induced by streptozotocin (STZ) treatment, resembling type-1 diabetes. In the CCI model, moderate but consistent burrowing deficits were observed that persisted over a period of ≥20 days. Systemic administration of morphine, pregabalin and gabapentin reversed this deficit. In contrast, none of the reference drugs improved marked burrowing deficits detected in ZDF rats, and pregabalin did not reverse severe burrowing deficits observed in STZ rats. Burrowing performance cannot necessarily be used as pain-related readout across pain models and largely depends on the model used, at least in models of neuropathy. Specifically, analgesic drug effects might be masked by general diabetes-associated alteration of the animals' well-being, resulting in false negative outcomes. Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.

Cost of treatment of peripheral neuropathic pain with pregabalin or gabapentin in routine clinical practice: impact of their loss of exclusivity

PubMed Central

Rejas‐Gutiérrez, Javier; Pérez‐Páramo, María; Navarro‐Artieda, Ruth

2016-01-01

Abstract To analyze the effect of loss of exclusivity of data on the cost of treatment of peripheral neuropathic pain (PNP) with pregabalin or gabapentin in routine clinical practice. A retrospective observational study, with electronic medical records for patients enrolled at primary care centers managed by the health care provider Badalona Serveis Assistencials, who initiated treatment of PNP with pregabalin or gabapentin. The analysis used drugs and resources prices for year 2015. The 1163 electronic medical records (pregabalin; N = 764, gabapentin; N = 399) for patients (62.2% women) with a mean (standard deviation) age of 59.2 (14.7) years were analyzed. Treatment duration was slightly shorter with pregabalin than with gabapentin (5.2 vs 5.5 months; P = 0.124), with mean doses of 227.4 (178.6) mg and 900.0 (443.4) mg, respectively. The average study drug cost per patient was higher for pregabalin than for gabapentin; €214.6 (206.3) vs €157.4 (181.9), P < 0.001, although the cost of concomitant analgesic medication was lower; €176.5 (271.8) vs €306.7 (529.2), P < 0.001. The adjusted average total cost per patient was lower in those treated with pregabalin than in those treated with gabapentin; €2,413 (2119‐2708) vs €3201 (2806–3.597); P = 0.002, owing to significantly lower health care costs; €1307 (1247‐1367) vs €1538 (1458‐1618), P < 0.001, and also non‐health care costs; €1106 (819‐1393) vs €1663 (1279‐2048), P = 0.023, that was caused by a significantly lower use of concomitant medication, fewer medical visits to primary care, and fewer days of sick leave. After loss of exclusivity of both drugs, pregabalin continued to show lower health care and non‐health care costs than gabapentin in the treatment of PNP in routine clinical practice. PMID:27671223

Five Patients With Burning Mouth Syndrome in Whom an Antidepressant (Serotonin-Noradrenaline Reuptake Inhibitor) Was Not Effective, but Pregabalin Markedly Relieved Pain.

PubMed

Ito, Mikiko; Tokura, Tatsuya; Yoshida, Keizo; Nagashima, Wataru; Kimura, Hiroyuki; Umemura, Eri; Tachibana, Masako; Miyauchi, Tomoya; Kobayashi, Yuka; Arao, Munetaka; Ozaki, Norio; Kurita, Kenichi

2015-01-01

Burning mouth syndrome (BMS) causes idiopathic pain or a burning sensation in clinically normal oral mucosa. Burning mouth syndrome is a chronic disease with an unknown etiology. Burning mouth syndrome is also idiopathic, and a consensus regarding diagnosis/treatment has not been reached yet. Recent studies have supported the suggestion that BMS is a neuropathic pain disorder in which both the peripheral and central nervous systems are involved. Tricyclic antidepressants (nortriptyline and amitriptyline), serotonin-noradrenaline reuptake inhibitors (SNRIs) (duloxetine and milnacipran), and antiepileptic drugs, potential-dependent calcium channel α2δ subunit ligands (gabapentine and pregabalin), are currently recommended as the first-choice drugs for neuropathic pain. In this study, we report 5 patients with BMS in whom there was no response to SNRI (milnacipran or duloxetine), or administration was discontinued because of adverse reactions, but in whom pregabalin therapy markedly reduced or led to the disappearance of pain in a short period. Pregabalin, whose mechanism of action differs from that of SNRIs, may become a treatment option for BMS patients who are not responsive to or are resistant to SNRIs.

Cost-effectiveness modeling for neuropathic pain treatments: investigating the relative importance of parameters using an open-source model.

PubMed

Hirst, Matthew; Bending, Matthew W; Baio, Gianluca; Yesufu-Udechuku, Amina; Dunlop, William C N

2018-06-08

The study objective was to develop an open-source replicate of a cost-effectiveness model developed by National Institute for Health and Care (NICE) in order to explore uncertainties in health economic modeling of novel pharmacological neuropathic pain treatments. The NICE model, consisting of a decision tree with branches for discrete levels of pain relief and adverse event (AE) severities, was replicated using R and used to compare a hypothetical neuropathic pain drug to pregabalin. Model parameters were sourced from NICE's clinical guidelines and associated with probability distributions to account for underlying uncertainty. A simulation-based scenario analysis was conducted to assess how uncertainty in efficacy and AEs affected the net monetary benefit (NMB) for the hypothetical treatment at a cost-effectiveness threshold of £20,000 per QALY. Relative to pregabalin, an increase in efficacy was associated with greater NMB than an improvement in tolerability. A greater NMB was observed when efficacy was marginally higher than that of pregabalin while maintaining the same level of AEs than when efficacy was equivalent to pregabalin but with a more substantial reduction in AEs. In the latter scenario, the NMB was only positive at a low cost-effectiveness threshold. The replicate model shares the limitations described in the NICE guidelines. There is a lack of support in scientific literature for the assumption that increased efficacy is associated with a greater reduction in tolerability. The replicate model also included a single comparator, unlike the NICE model. Pain relief is a stronger driver of NMB than tolerability at a cost-effectiveness threshold of £20,000 per QALY. Health technology assessment decisions which are influenced by NICE's model may reward efficacy gains even if they are associated with more severe AEs. This contrasts with recommendations from clinical guidelines for neuropathic pain which place more equal weighting on improvements in efficacy and tolerability as value drivers.

Pregabalin abuse among opiate addicted patients.

PubMed

Grosshans, Martin; Lemenager, Tagrid; Vollmert, Christian; Kaemmerer, Nina; Schreiner, Rupert; Mutschler, Jochen; Wagner, Xenija; Kiefer, Falk; Hermann, Derik

2013-12-01

Pregabalin is a novel GABA-analogue approved for the treatment of partial onset seizures, neuropathic pain, and general anxiety disorder. Pregabalin has been classified as a Schedule V drug with a low risk of inflicting abuse or addiction. However, some publications have indicated that pregabalin may have a potential for abuse among patients with past or current opiate addiction. Thus, we hypothesized that pregabalin might be abused by patients who were undergoing an opiate replacement therapy and never had an indication for taking pregabalin on medical grounds. Urine specimens from 124 patients with opiate dependency syndrome and from 111 patients with other addiction disorders (alcohol, benzodiazepines, cannabis, amphetamines) were screened for pregabalin by means of a mass spectrometer analysis. We found 12.1 % of all urine specimens from patients with opiate addiction to be positive for pregabalin. None of the patients concerned had a medical indication for using pregabalin. In the control group, 2.7 % of the patients were tested positively for pregabalin, due to their taking it regularly for chronic pain or general anxiety. Our data suggest that pregabalin is liable to be abused among individuals with opiate dependency syndrome Thus, vigilance and caution are called for when patients with a past or current opiate dependency are exposed to treatment with pregabalin.

Neuronal hyperexcitability in the ventral posterior thalamus of neuropathic rats: modality selective effects of pregabalin.

PubMed

Patel, Ryan; Dickenson, Anthony H

2016-07-01

Neuropathic pain represents a substantial clinical challenge; understanding the underlying neural mechanisms and back-translation of therapeutics could aid targeting of treatments more effectively. The ventral posterior thalamus (VP) is the major termination site for the spinothalamic tract and relays nociceptive activity to the somatosensory cortex; however, under neuropathic conditions, it is unclear how hyperexcitability of spinal neurons converges onto thalamic relays. This study aimed to identify neural substrates of hypersensitivity and the influence of pregabalin on central processing. In vivo electrophysiology was performed to record from VP wide dynamic range (WDR) and nociceptive-specific (NS) neurons in anesthetized spinal nerve-ligated (SNL), sham-operated, and naive rats. In neuropathic rats, WDR neurons had elevated evoked responses to low- and high-intensity punctate mechanical stimuli, dynamic brushing, and innocuous and noxious cooling, but less so to heat stimulation, of the receptive field. NS neurons in SNL rats also displayed increased responses to noxious punctate mechanical stimulation, dynamic brushing, noxious cooling, and noxious heat. Additionally, WDR, but not NS, neurons in SNL rats exhibited substantially higher rates of spontaneous firing, which may correlate with ongoing pain. The ratio of WDR-to-NS neurons was comparable between SNL and naive/sham groups, suggesting relatively few NS neurons gain sensitivity to low-intensity stimuli leading to a "WDR phenotype." After neuropathy was induced, the proportion of cold-sensitive WDR and NS neurons increased, supporting the suggestion that changes in frequency-dependent firing and population coding underlie cold hypersensitivity. In SNL rats, pregabalin inhibited mechanical and heat responses but not cold-evoked or elevated spontaneous activity. Copyright © 2016 the American Physiological Society.

Pregabalin for painful HIV neuropathy

PubMed Central

Simpson, D. M.; Schifitto, G.; Clifford, D. B.; Murphy, T. K.; Durso-De Cruz, E.; Glue, P.; Whalen, E.; Emir, B.; Scott, G. N.; Freeman, R.

2010-01-01

Objective: Pregabalin is effective in several neuropathic pain syndromes. This trial evaluated its efficacy, safety, and tolerability for treatment of painful HIV-associated neuropathy. Methods: This randomized, double-blind, placebo-controlled, parallel-group trial included a 2-week double-blind dose-adjustment (150–600 mg/day BID) phase, a 12-week double-blind maintenance phase, and an optional 3-month open label extension phase. The primary efficacy measure was the mean Numeric Pain Rating Scale (NPRS) score, an 11-point numeric rating scale. Secondary measures included Patient Global Impression of Change (PGIC) and sleep measurements. Results: Baseline mean NPRS score was 6.93 for patients randomized to pregabalin (n = 151) and 6.72 for those to placebo (n = 151). Pregabalin average daily dosage (SD) was 385.7 (160.3) mg/d. At endpoint, pregabalin and placebo showed substantial reductions in mean NPRS score from baseline: −2.88 vs −2.63, p = 0.3941. Pregabalin had greater improvements in NPRS score relative to placebo at weeks 1 (−1.14 vs −0.69, p = 0.0131) and 2 (−1.92 vs −1.43, p = 0.0393), and at weeks 7 (−3.22 vs −2.53 p = 0.0307) and 8 (−3.33 vs −2.53, p = 0.0156). At all other time points, differences between groups were not significant. Sleep measurements and 7-item PGIC did not differ among treatment groups; however, collapsed PGIC scores showed 82.8% of pregabalin and 66.7% of placebo patients rated themselves in 1 of the 3 “improved” categories (p = 0.0077). Somnolence and dizziness were the most common adverse events with pregabalin. Conclusions: Pregabalin was well-tolerated, but not superior to placebo in the treatment of painful HIV neuropathy. Factors predicting analgesic response in HIV neuropathy warrant additional research. Classification of Evidence: This Class II trial showed that pregabalin is not more effective than placebo in treatment of painful HIV neuropathy. GLOSSARY AE = adverse events; ANCOVA = analysis of covariance; ARF = activity region finder; ARV = antiretroviral; GPS = Gracely Pain Scale; HADS = Hospital Anxiety and Depression Scale; HIV-DSP = HIV-associated distal sensory polyneuropathy; LOCF = last observation carried forward; mBPI-sf = modified Brief Pain Inventory–short form; NPRS = Numeric Pain Rating Scale; NPSI = Neuropathic Pain Symptom Inventory; NRS = Numeric Rating Scale; PGIC = Patient Global Impression of Change; VAS = visual analog scale. PMID:20124207

Neuronal hyperexcitability in the ventral posterior thalamus of neuropathic rats: modality selective effects of pregabalin

PubMed Central

Dickenson, Anthony H.

2016-01-01

Neuropathic pain represents a substantial clinical challenge; understanding the underlying neural mechanisms and back-translation of therapeutics could aid targeting of treatments more effectively. The ventral posterior thalamus (VP) is the major termination site for the spinothalamic tract and relays nociceptive activity to the somatosensory cortex; however, under neuropathic conditions, it is unclear how hyperexcitability of spinal neurons converges onto thalamic relays. This study aimed to identify neural substrates of hypersensitivity and the influence of pregabalin on central processing. In vivo electrophysiology was performed to record from VP wide dynamic range (WDR) and nociceptive-specific (NS) neurons in anesthetized spinal nerve-ligated (SNL), sham-operated, and naive rats. In neuropathic rats, WDR neurons had elevated evoked responses to low- and high-intensity punctate mechanical stimuli, dynamic brushing, and innocuous and noxious cooling, but less so to heat stimulation, of the receptive field. NS neurons in SNL rats also displayed increased responses to noxious punctate mechanical stimulation, dynamic brushing, noxious cooling, and noxious heat. Additionally, WDR, but not NS, neurons in SNL rats exhibited substantially higher rates of spontaneous firing, which may correlate with ongoing pain. The ratio of WDR-to-NS neurons was comparable between SNL and naive/sham groups, suggesting relatively few NS neurons gain sensitivity to low-intensity stimuli leading to a “WDR phenotype.” After neuropathy was induced, the proportion of cold-sensitive WDR and NS neurons increased, supporting the suggestion that changes in frequency-dependent firing and population coding underlie cold hypersensitivity. In SNL rats, pregabalin inhibited mechanical and heat responses but not cold-evoked or elevated spontaneous activity. PMID:27098028

The clinician impact and financial cost to the NHS of litigation over pregabalin: a cohort study in English primary care.

PubMed

Croker, Richard; Smyth, Darren; Walker, Alex J; Goldacre, Ben

2018-06-07

Following litigation over pregabalin's second-use medical patent for neuropathic pain, National Health Service (NHS) England was required by the court to instruct general practitioners (GPs) to prescribe the branded form (Lyrica) for pain. Pfizer's patent was found invalid in 2015, a ruling subject to ongoing appeals. If the Supreme Court appeal in February 2018, whose judgement is awaited, is unsuccessful, the NHS can seek to reclaim excess prescribing costs. We set out to describe the variation in prescribing of pregabalin as branded Lyrica, geographically and over time; to determine how clinicians responded to the NHS England instruction to GPs; and to model excess costs to the NHS attributable to the legal judgements. English primary care. English general practices. Variation in prescribing of branded Lyrica across the country before and after the NHS England instruction, by practice and by Clinical Commissioning Group; excess prescribing costs. The proportion of pregabalin prescribed as Lyrica increased from 0.3% over 6 months before the NHS England instruction (September 2014 to February 2015) to 25.7% afterwards (April to September 2015). Although 70% of pregabalin is estimated to be for pain, including neuropathic pain, only 11.6% of practices prescribed Lyrica at this level; the median proportion prescribed as Lyrica was 8.8% (IQR 1.1%-41.9%). If pregabalin had come entirely off patent in September 2015, and Pfizer had not appealed, we estimate the NHS would have spent £502 million less on pregabalin to July 2017. NHS England instructions to GPs regarding branded prescription of pregabalin were widely ignored and have created much debate around clinical independence in prescribing. Protecting revenue from 'skinny labels' will pose a challenge. If Pfizer's final appeal on the patent is unsuccessful, the NHS can seek reimbursement of excess pregabalin prescribing costs, potentially £502 million. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

[The alpha2delta subunit of the voltage-dependent calcium channel. A new pharmaceutical target for psychiatry and neurology].

PubMed

Wedekind, D; Bandelow, B

2005-07-01

Calcium channel blockers are substances used for treating high blood pressure and coronary heart disease. New medications have been developed that modulate calcium channels but also show promise in psychiatric and neurologic applications. Gabapentin and pregabalin bind to a subunit of calcium channels--the alpha2delta receptors--thereby reducing calcium influx to neurons. As a result, less glutamate is released from nerve endings that use excitatory amino acids as transmitters. This in turn reduces substance P-related activation of AMPA heteroreceptors on noradrenergic synapses, total transmitter release, and finally neuronal activity. That mechanism is the probable explanation for gabapentin's and pregabalin's usefulness in the treatment of neuropathic pain but also their possible anticonvulsive and anxiolytic effects.

Pregabalin in the treatment of inferior alveolar nerve paraesthesia following overfilling of endodontic sealer

PubMed Central

Alonso-Ezpeleta, Oscar; Martín, Pablo J.; López-López, José; Castellanos-Cosano, Lizett; Martín-González, Jenifer; Segura-Egea, Juan J.

2014-01-01

A case of orofacial pain and inferior alveolar nerve (IAN) paraesthesia after extrusion of endodontic sealer within the mandibular canal treated with prednisone and pregabalin is described. A 36-year-old woman underwent root canal treatment of the mandibular second right premolar tooth. Post-operative panoramic radiograph revealed the presence of radiopaque canal sealer in the mandibular canal. Damage to IAN consecutive to extrusion of endodontic sealer was diagnosed. Non-surgical management was decided, including: 1 mg/kg/day prednisone 2 times/day, once-daily regimen, and 150 mg/day pregabalin, two doses per day, monitoring the progress with periodic follow-up visits. Six weeks after the incident the signs and symptoms were gone. The complete resolution of paraesthesia and the control of pain achieved suggest that a non-surgical approach, combining prednisone and the GABA analogue pregabalin, is a good option in the management of the IAN damage subsequent to endodontic sealer extrusion. Key words:Endodontics, inferior alveolar nerve, neuropathic pain, orofacial pain, paraesthesia, pregabalin. PMID:24790724

Use of Pregabalin - A Nationwide Pharmacoepidemiological Drug Utilization Study with Focus on Abuse Potential.

PubMed

Schjerning, O; Pottegård, A; Damkier, P; Rosenzweig, M; Nielsen, J

2016-07-01

Pregabalin is currently approved for the treatment of epilepsy, generalized anxiety disorder and neuropathic pain with a licensed dosage range of 150 mg to 600 mg/day. Growing concern about the abuse potential of pregabalin is partly based on reports of pregabalin being used in dosages that exceed the approved therapeutic range. To identify predictors of pregabalin use above recommended dosage, we conducted a pharmacoepidemological drug utilization study using the Danish nationwide registers. We deployed 4 measures of abuse: high use (≥600 mg/day) or very high use (≥1 200 mg/day) over a 6- or 12-month period, respectively. Multiple logistic regression was used to identify patient and treatment characteristics that were associated with either abuse marker. Out of 42 520 pregabalin users 4 090 (9.6%) were treated with more than 600 mg/day for 6 months and 2 765 (6.5%) for more than 12 months. Male gender and prescription of antipsychotics and benzodiazepines were associated with increased risk of use of above the recommended dosage. Use of pregabalin above recommended dosages was rare but abuse may occur in susceptible patients. © Georg Thieme Verlag KG Stuttgart · New York.

Combined antiallodynic effect of Neurotropin® and pregabalin in rats with L5-spinal nerve ligation.

PubMed

Okazaki, Ryohei; Namba, Hiroyoshi; Yoshida, Hiroyuki; Okai, Hisashi; Taguchi, Kazuki; Kawamura, Minoru

2013-03-12

In this study, we investigated the combined effect of Neurotropin® and pregabalin for L5-spinal nerve ligation (L5-SNL) model in rats and thiopental-induced sleep in mice. The left fifth lumbar nerve of rats was tightly ligated with silk sutures under pentobarbital anesthesia. The hindpaw withdrawal threshold was measured by application of von Frey filaments. Thiopental sodium was intravenously administered in mice and sleeping time was measured. In L5-SNL rats, an isobolographic analysis was performed to clarify the combined antiallodynic effect of Neurotropin and pregabalin 14 days after ligation in rats. In isobolographic analysis and thiopental-induced sleep test, Neurotropin and pregabalin were orally administered to coincide with the timing of the peak effect of each drug. Neurotropin (50-200 NU/kg) and pregabalin (2.5-10mg/kg) showed a dose-dependent antiallodynic action in L5-SNL rats. The antiallodynic effect of pregabalin was reversed by intrathecal injection of yohimbine or ondansetron. Isobolographic analysis suggested that the combined antiallodynic effect of Neurotropin and pregabalin in L5-SNL rats may have been more than a mere additive effect. Neurotropin (50-400 NU/kg) had no effect on thiopental-induced sleeping time whereas pregabalin (30-100mg/kg) significantly prolonged it. When the dose of pregabalin was 30 mg/kg, Neurotropin (50-400 NU/kg) did not further exacerbate the prolongation effect of pregabalin on thiopental-induced sleep. It was suggested that when Neurotropin was administered in combination with pregabalin, it might provide more effective pain relief than that obtained with each agent alone in neuropathic pain without aggravating adverse effects of pregabalin. Copyright © 2013 Elsevier Inc. All rights reserved.

GC-MS/MS detects potential pregabalin abuse in susceptible subjects' hair.

PubMed

Ianni, Federica; Aroni, Kyriaki; Gili, Alessio; Sardella, Roccaldo; Bacci, Mauro; Lancia, Massimo; Natalini, Benedetto; Gambelunghe, Cristiana

2018-06-01

Pregabalin, a GABA analogue, binds to the alpha 2 delta subunit of voltage-dependent calcium channels. It is recognised as efficacious in pathologies such as epilepsy, neuropathic pain, and anxiety disorders. Since pregabalin prescriptions have increased worldwide, reports of its abuse have been accumulating, mainly in patients with opioid abuse disorders. The present study investigated potential pregabalin abuse by means of hair analysis, a matrix that provides valuable retrospective information. Half of the pool of 280 susceptible patients had been occasional drug users and were being monitored for driving licence renewals. The other 140 patients had a history of opiate dependency and were monitored to assess compliance with methadone therapy. In view of determining pregabalin in hair samples, it was extracted in methanol, successfully derivatised to give the ethyl chloroformate derivative, and finally pregabalin was analysed by gas chromatography-tandem mass spectrometry. Selectivity, linearity, limit of detection, limit of quantification, recovery, intra- and inter-day precision, and accuracy of the quantification procedure were appraised. Pregabalin limits of detection and quantification were 30 pg/mg and 50 pg/mg, respectively. We found 10.7% of hair samples from methadone patients and 4.29% from occasional drug users were positive to pregabalin without medical prescription. The mean pregabalin concentration in hair was higher than in consumers with medical indications (1.45 ng/mg vs 0.74 ng/mg). These results suggest that pregabalin possesses a significant abuse potential particularly among individuals attending opiate dependence services and that pregabalin abuse is a serious emerging issue, which should be carefully monitored. Copyright © 2017 John Wiley & Sons, Ltd.

Short-term incubation of gabapentin or pregabalin does not affect chemically induced injury in neuronal cell models in vitro

PubMed Central

Baldewig, Malte; Goldbaum, Olaf; Richter-Landsberg, Christiane; Weyland, Andreas; Bantel, Carsten

2018-01-01

Purpose Gabapentinoids are currently the mainstay of pharmacological treatments for patients with neuropathic pain. Little is known about the effects of this therapy on the integrity of neuronal networks, especially in patients with an already-damaged nervous system. Since gabapentinoids can worsen cognitive functions and recent studies have shown alterations in the brains of patients with neuropathic pain, it may be possible that these drugs have neurotoxic effects. Methods Rat clonal PC12 pheochromocytoma (autonomic) and primary sensory dorsal-root ganglion (DRG) neurons from newborn Wistar rats were employed for this study. To mimic neuronal damage, cells were exposed to cytotoxins using either hydrogen peroxide (H2O2) or vincristine. Results No direct cytotoxic effects were observed after incubating PC12 cells for 24 hours with increasing concentrations of gabapentin or pregabalin using MTT cytotoxicity assays. Even a 7-day incubation did not cause cellular damage. Furthermore, in preinjured PC12 and DRG neurons, neither gabapentin nor pregabalin prevented or enhanced the cytotoxic effects of H2O2 or vincristine after incubation for 24 hours and 7 days, respectively. Cell morphology and integrity of the cytoskeleton assessed by employing immunostaining of cytoskeletal proteins (α-tubulin, neurofilament L) remained intact and were not altered by gabapentinoids. Conclusion Based on these results, gabapentinoids are unlikely to be neurotoxic in cultured autonomic (PC12) and sensory DRG cells, even when cells are preinjured. These results are of high clinical relevance, as it seems unlikely that the morphological changes recently observed in the brains of neuropathic pain patients are caused or worsened by gabapentinoids.

Pregabalin: in the treatment of postherpetic neuralgia.

PubMed

Frampton, James E; Foster, Rachel H

2005-01-01

Pregabalin, the pharmacologically active S-enantiomer of 3-aminomethyl-5-methyl-hexanoic acid, has a similar pharmacological profile to that of its developmental predecessor gabapentin, but showed greater analgesic activity in rodent models of neuropathic pain. The exact mechanism of action of pregabalin is unclear, although it may reduce excitatory neurotransmitter release by binding to the alpha2-delta protein subunit of voltage-gated calcium channels. Oral pregabalin 150-600 mg/day, administered twice or three times daily, was superior to placebo in relieving pain and improving pain-related sleep interference in three randomised, double-blind, placebo-controlled, multicentre studies of 8-13 weeks' duration in a total of 776 evaluable patients with postherpetic neuralgia (PHN). Weekly mean pain scores (primary endpoint; assessed in all three studies) and weekly mean sleep interference scores (assessed in two studies) were significantly improved at 1 week. In two studies, significant improvements in daily mean pain scores were apparent on the first or second day of treatment with pregabalin administered three times daily. Pregabalin was generally well tolerated when force-titrated over 1 week to fixed dosages (maximum 600 mg/day) in clinical trials that enrolled most elderly PHN patients. Dizziness, somnolence and peripheral oedema of mild-to-moderate intensity were the most common adverse events.

Ameliorative potential of Vernonia cinerea on chronic constriction injury of sciatic nerve induced neuropathic pain in rats.

PubMed

Thiagarajan, Venkata R K; Shanmugam, Palanichamy; Krishnan, Uma M; Muthuraman, Arunachalam

2014-09-01

The aim of the present study is to investigate the ameliorative potential of ethanolic extract of whole plant of Vernonia cinerea in the chronic constriction injury (CCI) of sciatic nerve induced neuropathic pain in rats. Behavioral parameters such as a hot plate, acetone drop, paw pressure, Von Frey hair and tail immersion tests were performed to assess the degree of thermal, chemical and mechanical hyperalgesia and allodynia. Biochemical changes in sciatic nerve tissue were ruled out by estimating thiobarbituric acid reactive substances (TBARS), reduced glutathione (GSH) and total calcium levels. Ethanolic extract of Vernonia cinerea and pregabalin were administered for 14 consecutive days starting from the day of surgery. CCI of sciatic nerve has been shown to induce significant changes in behavioral, biochemical and histopathological assessments when compared to the sham control group. Vernonia cinerea attenuated in a dose dependent manner the above pathological changes induced by CCI of the sciatic nerve, which is similar to attenuation of the pregabalin pretreated group. The ameliorating effect of ethanolic extract of Vernonia cinerea against CCI of sciatic nerve induced neuropathic pain may be due to the presence of flavonoids and this effect is attributed to anti-oxidative, neuroprotective and calcium channel modulator actions of these compounds.

Ameliorative potential of Vernonia cinerea on chronic constriction injury of sciatic nerve induced neuropathic pain in rats.

PubMed

Thiagarajan, Venkata R K; Shanmugam, Palanichamy; Krishnan, Uma M; Muthuraman, Arunachalam

2014-08-29

The aim of the present study is to investigate the ameliorative potential of ethanolic extract of whole plant of Vernonia cinerea in the chronic constriction injury (CCI) of sciatic nerve induced neuropathic pain in rats. Behavioral parameters such as a hot plate, acetone drop, paw pressure, Von Frey hair and tail immersion tests were performed to assess the degree of thermal, chemical and mechanical hyperalgesia and allodynia. Biochemical changes in sciatic nerve tissue were ruled out by estimating thiobarbituric acid reactive substances (TBARS), reduced glutathione (GSH) and total calcium levels. Ethanolic extract of Vernonia cinerea and pregabalin were administered for 14 consecutive days starting from the day of surgery. CCI of sciatic nerve has been shown to induce significant changes in behavioral, biochemical and histopathological assessments when compared to the sham control group. Vernonia cinerea attenuated in a dose dependent manner the above pathological changes induced by CCI of the sciatic nerve, which is similar to attenuation of the pregabalin pretreated group. The ameliorating effect of ethanolic extract of Vernonia cinerea against CCI of sciatic nerve induced neuropathic pain may be due to the presence of flavonoids and this effect is attributed to anti-oxidative, neuroprotective and calcium channel modulator actions of these compounds.

A hydro-ethanolic extract of Synedrella nodiflora (L.) Gaertn ameliorates hyperalgesia and allodynia in vincristine-induced neuropathic pain in rats.

PubMed

Amoateng, Patrick; Adjei, Samuel; Osei-Safo, Dorcas; Ameyaw, Elvis Ofori; Ahedor, Believe; N'guessan, Benoit Banga; Nyarko, Alexander Kwadwo

2015-07-01

The hydro-ethanolic extract of Synedrella nodiflora (L.) Gaertn whole plant has demonstrated analgesic effects in acute pain models. The extract has also demonstrated anticonvulsant effects in murine models of experimental epilepsy. The present study illustrates an evaluation of the hydro-ethanolic extract of the plant for possible analgesic properties in hyperalgesia and allodynia associated with vincristine-induced neuropathy in rats. Neuropathic pain was induced in Sprague-Dawley rats by injecting 100 μg/kg of vincristine sulphate on alternative days for 6 days (days 0, 2, 4, 8, 10 and 12). Vincristine-induced cold allodynia, mechanical hyperalgesia and thermal hyperalgesia were measured pre-vincristine administration and on days 15, 17 and 19 post-vincristine administration. The rats were then treated with S. nodiflora extract (SNE) (100, 300 and 1000 mg/kg), pregabalin (10, 30 and 100 mg/kg) and distilled water as vehicle daily for 5 days and pain thresholds were measured on alternate days for 3 days. SNE and pregabalin produced analgesic properties observed as increased paw withdrawal latencies to mechanical, tactile, cold water stimuli and thermal hyperalgesic tests during the 5 days of treatment. The findings suggest that hydro-ethanolic extract of S. nodiflora possesses anti-hyperalgesic and anti-allodynic effects in vincristine-induced neuropathic pain in rats.

Effects of S 38093, an antagonist/inverse agonist of histamine H3 receptors, in models of neuropathic pain in rats.

PubMed

Chaumette, T; Chapuy, E; Berrocoso, E; Llorca-Torralba, M; Bravo, L; Mico, J A; Chalus, M; Eschalier, A; Ardid, D; Marchand, F; Sors, A

2018-01-01

Histamine H3 receptors are mainly expressed on CNS neurons, particularly along the nociceptive pathways. The potential involvement of these receptors in pain processing has been suggested using H3 receptor inverse agonists. The antinociceptive effect of S 38093, a novel inverse agonist of H3 receptors, has been evaluated in several neuropathic pain models in rat and compared with those of gabapentin and pregabalin. While S 38093 did not change vocalization thresholds to paw pressure in healthy rats, it exhibited a significant antihyperalgesic effect in the Streptozocin-induced diabetic (STZ) neuropathy model after acute and chronic administration and, in the chronic constriction injury (CCI) model only after chronic administration, submitted to the paw-pressure test. Acute S 38093 administration at all doses tested displayed a significant cold antiallodynic effect in a model of acute or repeated administration of oxaliplatin-induced neuropathy submitted to cold tail immersion, cold allodynia being the main side effect of oxaliplatin in patients. The effect of S 38093 increased following chronic administration (i.e. twice a day during 5 days) in the CCI and STZ models except in the oxaliplatin models where its effect was already maximal from the first administration The kinetics and size of effect of S 38093 were similar to gabapentin and/or pregabalin. Finally, the antinociceptive effect of S 38093 could be partially mediated by α2 adrenoreceptors desensitization in the locus coeruleus. These results highlight the interest of S 38093 to relieve neuropathic pain and warrant clinical trials especially in chemotherapeutic agent-induced neuropathic pain. S 38093, a new H3 antagonist/inverse agonist, displays antiallodynic and antihyperalgesic effect in neuropathic pain, especially in oxaliplatin-induced neuropathy after chronic administration. This effect of S 38093 in neuropathic pain could be partly mediated by α2 receptors desensitization in the locus coeruleus. © 2017 European Pain Federation - EFIC®.

Comparative Analgesic Efficacy of Pregabalin Administered According to Either a Prevention Protocol or an Intervention Protocol in Rats with Cisplatin-induced Peripheral Neuropathy.

PubMed

Han, F Y; Kuo, A; Nicholson, J R; Corradinni, L; Smith, M T

2018-05-21

Chemotherapy-induced peripheral neuropathy (CIPN) is a type of peripheral neuropathic pain that may be dose-limiting in patients administered potentially curative cancer chemotherapy dosing regimens. In cancer survivors, persistent CIPN adversely affects patient quality of life and so adjuvant drugs (anticonvulsants e.g. pregabalin or antidepressants e.g. amitriptyline) are recommended for the relief of CIPN. However, most studies in rodent models of CIPN involve administration of single bolus doses of adjuvant drugs to assess pain-relieving efficacy. Hence this study was designed to assess the efficacy of pregabalin administered to CIPN-rats according to either a prevention or an intervention protocol. Groups of male Sprague-Dawley rats received four single intraperitoneal bolus doses of cisplatin at 3 mg/kg at once-weekly intervals to induce CIPN. For the prevention protocol, oral pregabalin (or vehicle) was administered to CIPN-rats once-daily for 21 consecutive days from day 0 to day 20 inclusive. For the intervention protocol, oral pregabalin was administered once-daily for 21 consecutive days from day 28 to day 48 inclusive. Mechanical allodynia and mechanical hyperalgesia in the bilateral hindpaws were assessed just prior to each dose of cisplatin and at least once-weekly until study completion (day 27, prevention protocol; or day 48, intervention protocol). Mechanical allodynia and mechanical hyperalgesia were also determined at the time of peak effect at ~2 h post- pregabalin/vehicle administration once-weekly until study completion. For the prevention protocol in CIPN-rats, pregabalin alleviated mechanical hyperalgesia but not mechanical allodynia. For the intervention protocol, pregabalin alleviated both mechanical allodynia and mechanical hyperalgesia in the hindpaws. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Elucidating the mechanism of action of pregabalin: α(2)δ as a therapeutic target in anxiety.

PubMed

Micó, Juan-Antonio; Prieto, Rita

2012-08-01

This review provides a brief summary of what is known about the anxiolytic mechanism of action of pregabalin, a highly selective, high-affinity ligand of the P/Q type of voltage-gated calcium channel (CaV). Evidence from in vivo models of neuronal hyperexcitability suggests that pregabalin reduces synaptic release of neurotransmitters in selected CNS regions including the cortex, olfactory bulb, hypothalamus, amygdala, hippocampus, cerebellum and dorsal horn of the spinal cord. Release of neurotransmitters from the synaptic vesicle, and propagation of neurotransmission, requires the vesicle to fuse with the presynaptic membrane. Pregabalin binding to the α(2)δ type 1 protein of the P/Q type CaV reduces the availability of Ca2+ required for membrane fusion and exocytosis of neurotransmitters. Evidence that the anxiolytic mechanism of action of pregabalin is mediated by binding to the α(2)δ type 1 protein comes from animal models, which have demonstrated a structure-activity relationship between the affinity of ligands for the α(2)δ type 1 protein and their potency in models of anxiety such as the Vogel conflict test. Furthermore, the anxiolytic activity of pregabalin is lost in transgenic mice with specific point mutations in the CaV α(2)δ type 1 protein. Pregabalin-mediated reduction in calcium currents has also been shown to result in a significant inhibition of the release of neurotransmitters implicated in pathological anxiety such as glutamate and monoamine neurotransmitters. However, further research is needed to confirm that these effects contribute to the anxiolytic mechanism of action of pregabalin. Finally, pregabalin may also act by inhibiting synaptogenesis of excitatory neurons formed in response to chronic stress or anxiety, or more acutely inhibit the trafficking of CaV to the plasma membrane.

Trial of Pregabalin for Acute and Chronic Sciatica.

PubMed

Mathieson, Stephanie; Maher, Christopher G; McLachlan, Andrew J; Latimer, Jane; Koes, Bart W; Hancock, Mark J; Harris, Ian; Day, Richard O; Billot, Laurent; Pik, Justin; Jan, Stephen; Lin, C-W Christine

2017-03-23

Sciatica can be disabling, and evidence regarding medical treatments is limited. Pregabalin is effective in the treatment of some types of neuropathic pain. This study examined whether pregabalin may reduce the intensity of sciatica. We conducted a randomized, double-blind, placebo-controlled trial of pregabalin in patients with sciatica. Patients were randomly assigned to receive either pregabalin at a dose of 150 mg per day that was adjusted to a maximum dose of 600 mg per day or matching placebo for up to 8 weeks. The primary outcome was the leg-pain intensity score on a 10-point scale (with 0 indicating no pain and 10 the worst possible pain) at week 8; the leg-pain intensity score was also evaluated at week 52, a secondary time point for the primary outcome. Secondary outcomes included the extent of disability, back-pain intensity, and quality-of-life measures at prespecified time points over the course of 1 year. A total of 209 patients underwent randomization, of whom 108 received pregabalin and 101 received placebo; after randomization, 2 patients in the pregabalin group were determined to be ineligible and were excluded from the analyses. At week 8, the mean unadjusted leg-pain intensity score was 3.7 in the pregabalin group and 3.1 in the placebo group (adjusted mean difference, 0.5; 95% confidence interval [CI], -0.2 to 1.2; P=0.19). At week 52, the mean unadjusted leg-pain intensity score was 3.4 in the pregabalin group and 3.0 in the placebo group (adjusted mean difference, 0.3; 95% CI, -0.5 to 1.0; P=0.46). No significant between-group differences were observed with respect to any secondary outcome at either week 8 or week 52. A total of 227 adverse events were reported in the pregabalin group and 124 in the placebo group. Dizziness was more common in the pregabalin group than in the placebo group. Treatment with pregabalin did not significantly reduce the intensity of leg pain associated with sciatica and did not significantly improve other outcomes, as compared with placebo, over the course of 8 weeks. The incidence of adverse events was significantly higher in the pregabalin group than in the placebo group. (Funded by the National Health and Medical Research Council of Australia; PRECISE Australian and New Zealand Clinical Trials Registry number, ACTRN12613000530729 .).

DDD-028: a potent potential non-opioid, non-cannabinoid analgesic for neuropathic and inflammatory pain.

PubMed

Rajagopalan, Parthasarathi; Tracey, Heather; Chen, Zhoumou; Bandyopadhyaya, Acintya; Veeraraghavan, Sridhar; Rajagopalan, Desikan R; Salvemini, Daniela; McPhee, Ian; Viswanadha, Srikant; Rajagopalan, Raghavan

2014-07-15

DDD-028 (4), a novel pentacyclic pyridoindolobenzazepine derivative was evaluated in vitro for receptor binding affinity and in vivo for analgesic activity using rodent models of neuropathic and inflammatory pain. DDD-028 does not bind to opioid, cannabinoid, dopamine, or histamine receptors. DDD-028 is very active even at the low oral dose of 1-5 mg/kg in both neuropathic, (spinal nerve ligation and chronic constriction injury) and inflammatory (Complete Freund's Adjuvant Induced) models of pain. DDD-028 appears to be about 6-fold more potent than pregabalin and indomethacin. Visual observation of all the animals used in these studies indicated that DDD-028 is well tolerated without any sedation. Thus, DDD-028 seems to be a promising candidate for the treatment of neuropathic and inflammatory pain without the possible side effects or abuse potential associated with opioid or cannabinoid activities. Copyright © 2014 Elsevier Ltd. All rights reserved.

Recommendations for the Pharmacological Management of Neuropathic Pain: An Overview and Literature Update

PubMed Central

Dworkin, Robert H.; O'Connor, Alec B.; Audette, Joseph; Baron, Ralf; Gourlay, Geoffrey K.; Haanpää, Maija L.; Kent, Joel L.; Krane, Elliot J.; LeBel, Alyssa A.; Levy, Robert M.; Mackey, Sean C.; Mayer, John; Miaskowski, Christine; Raja, Srinivasa N.; Rice, Andrew S. C.; Schmader, Kenneth E.; Stacey, Brett; Stanos, Steven; Treede, Rolf-Detlef; Turk, Dennis C.; Walco, Gary A.; Wells, Christopher D.

2010-01-01

The Neuropathic Pain Special Interest Group of the International Association for the Study of Pain recently sponsored the development of evidence-based guidelines for the pharmacological treatment of neuropathic pain. Tricyclic antidepressants, dual reuptake inhibitors of serotonin and norepinephrine, calcium channel α2-δ ligands (ie, gabapentin and pregabalin), and topical lidocaine were recommended as first-line treatment options on the basis of the results of randomized clinical trials. Opioid analgesics and tramadol were recommended as second-line treatments that can be considered for first-line use in certain clinical circumstances. Results of several recent clinical trials have become available since the development of these guidelines. These studies have examined botulinum toxin, high-concentration capsaicin patch, lacosamide, selective serotonin reuptake inhibitors, and combination therapies in various neuropathic pain conditions. The increasing number of negative clinical trials of pharmacological treatments for neuropathic pain and ambiguities in the interpretation of these negative trials must also be considered in developing treatment guidelines. The objectives of the current article are to review the Neuropathic Pain Special Interest Group guidelines for the pharmacological management of neuropathic pain and to provide a brief overview of these recent studies. PMID:20194146

Adverse drug event profile associated with pregabalin among patients with and without cancer: analysis of a spontaneous reporting database.

PubMed

Kose, Eiji

2018-03-25

Pregabalin is used for the relief of neuropathic pain in patients with and without cancer. However, no report has examined whether there is a difference in the adverse drug event (ADE) profile of pregabalin in each context. We aimed to establish whether pregabalin's ADE profile was different between patients with and without cancer. This study was based on the Japanese Adverse Drug Event Report (JADER) database, which is a spontaneous reporting database. Reports obtained from the JADER database were analysed from April 2004 to December 2016 for ADEs, using reporting odds ratios (RORs), a method of disproportionality analysis. We evaluated the association between the RORs and ADEs of pregabalin and compared the age, dosage and time at which ADEs occurred in patients with and without cancer. The primary outcome was RORs. Secondary outcomes were expression age and time-to-onset of ADE among patients with and without cancer. In total, 426 216 reports from the JADER database were analysed. The major side effects associated with pregabalin among both patient groups were interstitial pneumonia, renal failure, liver failure, altered consciousness, heart failure and rhabdomyolysis. The pregabalin dose was significantly higher in patients with cancer than in those without cancer. Furthermore, the times to reporting of interstitial pneumonia, altered consciousness and liver failure were significantly shorter in patients with cancer than in those without cancer. The ADE profiles of pregabalin were broadly similar among patients with and without cancer, but time-to-onset and type of some ADEs may be different. © 2018 John Wiley & Sons Ltd.

Treatment of painful diabetic neuropathy

PubMed Central

Petropoulos, Ioannis N.; Alam, Uazman; Malik, Rayaz A.

2015-01-01

Painful diabetic neuropathy (PDN) is a debilitating consequence of diabetes that may be present in as many as one in five patients with diabetes. The objective assessment of PDN is difficult, making it challenging to diagnose and assess in both clinical practice and clinical trials. No single treatment exists to prevent or reverse neuropathic changes or to provide total pain relief. Treatment of PDN is based on three major approaches: intensive glycaemic control and risk factor management, treatments based on pathogenetic mechanisms, and symptomatic pain management. Clinical guidelines recommend pain relief in PDN through the use of antidepressants such as amitriptyline and duloxetine, the γ-aminobutyric acid analogues gabapentin and pregabalin, opioids and topical agents such as capsaicin. Of these medications, duloxetine and pregabalin were approved by the US Food and Drug Administration (FDA) in 2004 and tapentadol extended release was approved in 2012 for the treatment of PDN. Proposed pathogenetic treatments include α-lipoic acid (stems reactive oxygen species formation), benfotiamine (prevents vascular damage in diabetes) and aldose-reductase inhibitors (reduces flux through the polyol pathway). There is a growing need for studies to evaluate the most potent drugs or combinations for the management of PDN to maximize pain relief and improve quality of life. A number of agents are potential candidates for future use in PDN therapy, including Nav 1.7 antagonists, N-type calcium channel blockers, NGF antibodies and angiotensin II type 2 receptor antagonists. PMID:25553239

Pregabalin for the Treatment of Men With Chronic Prostatitis/Chronic Pelvic Pain Syndrome

PubMed Central

Pontari, Michel A.; Krieger, John N.; Litwin, Mark S.; White, Paige C.; Anderson, Rodney U.; McNaughton-Collins, Mary; Nickel, J. Curtis; Shoskes, Daniel A.; Alexander, Richard B.; O'Leary, Michael; Zeitlin, Scott; Chuai, Shannon; Landis, J. Richard; Cen, Liyi; Propert, Kathleen J.; Kusek, John W.; Nyberg, Leroy M.; Schaeffer, Anthony J.

2013-01-01

Background Evidence suggests that the urogenital pain of chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) may be neuropathic. Methods This randomized, double-blind, placebo-controlled trial was conducted across 10 tertiary care centers in North America to determine whether pregabalin, which has been proved effective in other chronic pain syndromes, is effective in reducing CP/CPPS symptoms. In 2006–2007, 324 men with pelvic pain for at least 3 of the previous 6 months were enrolled in this study. Men were randomly assigned to receive pregabalin or placebo in a 2:1 ratio and were treated for 6 weeks. Pregabalin dosage was increased from 150 to 600 mg/d during the first 4 weeks. The primary outcome was a 6-point decrease in the National Institutes of Health Chronic Prostatitis Symptom Index (NIH-CPSI) total score. Multiple secondary outcomes were assessed. Results Of 218 men assigned to receive pregabalin, 103 (47.2%) reported at least a 6-point decrease in the NIHCPSI total score at 6 weeks compared with 35.8% (38 of 106 men) assigned to receive placebo (P = .07, exact Mantel-Haenszel test, adjusting for clinical sites). Compared with the placebo group, men assigned to receive pregabalin experienced reductions in the NIH-CPSI total score and sub-scores (P < .05), a higher Global Response Assessment response rate (31.2% and 18.9%; P = .02), and improvement in total McGill Pain Questionnaire score (P = .01). Results for the other outcomes did not differ between groups. Conclusion Pregabalin therapy for 6 weeks was not superior to placebo use in the rate of a 6-point decrease (improvement) in the NIH-CPSI total score in men with CP/CPPS. Trial Registration clinicaltrials.gov Identifier: NCT00371033 PMID:20876412

Pregabalin Suppresses Spinal Neuronal Hyperexcitability and Visceral Hypersensitivity in the Absence of Peripheral Pathophysiology

PubMed Central

Bannister, Kirsty; Sikandar, Shafaq; Bauer, Claudia S.; Dolphin, Annette C.; Porreca, Frank; Dickenson, Anthony H.

2011-01-01

Background Opioid induced hyperalgesia is recognised in the laboratory and the clinic, generating central hyperexcitability in the absence of peripheral pathology. We investigated pregabalin, indicated for neuropathic pain, and ondansetron, a drug that disrupts descending serotonergic processing in the central nervous system, on spinal neuronal hyperexcitability and visceral hypersensitivity in a rat model of opioid induced hyperalgesia. Methods Sprague-Dawley rats (180-200 g) were implanted with morphine (90μg · μl−1 · hr−1) or saline (0.9% w/v) filled osmotic mini-pumps. On days 7-10 in isoflurane anaesthetized animals we evaluated the effects of (a) systemic pregabalin on spinal neuronal and visceromotor responses and (b) spinal ondansetron on dorsal horn neuronal responses. The messenger RNA levels of α2δ-1, 5HT3A and mu-opioid receptor in the dorsal root ganglia of all animals were analysed. Results In morphine-treated animals the evoked spinal neuronal responses were enhanced to a sub-set of thermal and mechanical stimuli. This activity was attenuated by pregabalin (by at least 71%) and ondansetron (37%), and the visceromotor response to a sub-set of colorectal distension pressures was attenuated by pregabalin (52.8%) (n = 8 for all measures, P < 0.05). Messenger RNA levels were unchanged. Conclusions The inhibitory action of pregabalin in opioid induced hyperalgesia animals is not neuropathy-dependent nor reliant on up-regulation of the α2δ-1 subunit of voltage gated calcium channels, mechanisms proposed essential for pregabalin’s efficacy in neuropathy. In opioid induced hyperalgesia, which extends to colonic distension, a serotonergic facilitatory system may be upregulated creating an environment that’s permissive for pregabalin-mediated analgesia without peripheral pathology. PMID:21602662

Diagnosis and management of neuropathic pain: review of literature and recommendations of the Polish Association for the study of pain and the Polish Neurological Society - part one.

PubMed

Szczudlik, Andrzej; Dobrogowski, Jan; Wordliczek, Jerzy; Stępień, Adam; Krajnik, Małgorzata; Leppert, Wojciech; Woroń, Jarosław; Przeklasa-Muszyńska, Anna; Kocot-Kępska, Magdalena; Zajączkowska, Renata; Janecki, Marcin; Adamczyk, Anna; Malec-Milewska, Małgorzata

2014-01-01

Neuropathic pain still present a major diagnostic and therapeutic challenge despite considerable progress in understanding of its mechanisms and publication of number of studies which assessed the efficacy and safety of drugs used in the symptomatic treatment. In practice, it is diagnosed less frequently than recognised in the epidemiological studies, and many patients do not achieve satisfactory outcomes of treatment. A multidisciplinary team of Polish experts, commissioned by the Polish Association for the Study of Pain and the Polish Neurological Society, has reviewed the literature on neuropathic pain, with special focus on the published international recommendations, and formulated recommendations on neuropathic pain diagnosis and treatment, in accordance with the principles of evidence-based medicine. The paper presents also background information on the neuropathic pain definition, epidemiology, pathomechanism and method of assessment. The diagnosis of neuropathic pain may be established based on medical history and physical examination including special assessment of the somatosensory system. First-line drugs used in pharmacological management of neuropathic pain are: tricyclic antidepressants, serotonin and norepinephrine reuptake inhibitors, gabapentin, pregabalin, opioids and lidocaine patches. Copyright © 2014 Polish Neurological Society. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

Predictive Modeling of Response to Pregabalin for the Treatment of Neuropathic Pain Using 6-Week Observational Data: A Spectrum of Modern Analytics Applications.

PubMed

Emir, Birol; Johnson, Kjell; Kuhn, Max; Parsons, Bruce

2017-01-01

This post hoc analysis used 11 predictive models of data from a large observational study in Germany to evaluate potential predictors of achieving at least 50% pain reduction by week 6 after treatment initiation (50% pain response) with pregabalin (150-600 mg/d) in patients with neuropathic pain (NeP). The potential predictors evaluated included baseline demographic and clinical characteristics, such as patient-reported pain severity (0 [no pain] to 10 [worst possible pain]) and pain-related sleep disturbance scores (0 [sleep not impaired] to 10 [severely impaired sleep]) that were collected during clinic visits (baseline and weeks 1, 3, and 6). Baseline characteristics were also evaluated combined with pain change at week 1 or weeks 1 and 3 as potential predictors of end-of-treatment 50% pain response. The 11 predictive models were linear, nonlinear, and tree based, and all predictors in the training dataset were ranked according to their variable importance and normalized to 100%. The training dataset comprised 9187 patients, and the testing dataset had 6114 patients. To adjust for the high imbalance in the responder distribution (75% of patients were 50% responders), which can skew the parameter tuning process, the training set was balanced into sets of 1000 responders and 1000 nonresponders. The predictive modeling approaches that were used produced consistent results. Baseline characteristics alone had fair predictive value (accuracy range, 0.61-0.72; κ range, 0.17-0.30). Baseline predictors combined with pain change at week 1 had moderate predictive value (accuracy, 0.73-0.81; κ range, 0.37-0.49). Baseline predictors with pain change at weeks 1 and 3 had substantial predictive value (accuracy, 0.83-0.89; κ range, 0.54-0.71). When variable importance across the models was estimated, the best predictor of 50% responder status was pain change at week 3 (average importance 100.0%), followed by pain change at week 1 (48.1%), baseline pain score (14.1%), baseline depression (13.9%), and using pregabalin as a monotherapy (11.7%). The finding that pain changes by week 1 or weeks 1 and 3 are the best predictors of pregabalin response at 6 weeks suggests that adhering to a pregabalin medication regimen is important for an optimal end-of-treatment outcome. Regarding baseline predictors alone, considerable published evidence supports the importance of high baseline pain score and presence of depression as factors that can affect treatment response. Future research would be required to elucidate why using pregabalin as a monotherapy also had more than a 10% variable importance as a potential predictor. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Risk of heart failure and edema associated with the use of pregabalin: a systematic review.

PubMed

Ho, Joanne M; Tricco, Andrea C; Perrier, Laure; Chen, Maggie; Juurlink, David N; Straus, Sharon E

2013-05-04

Pregabalin is used in the treatment of postherpetic neuralgia, diabetic neuropathic pain, partial seizures, anxiety disorders and fibromyalgia. Recognized adverse effects associated with its use include cognitive impairment, somnolence and dizziness. Heart failure associated with pregabalin has been described, however the strength of this association has not been well characterized. To examine this further, we will conduct a systematic review of the risk of heart failure and edema associated with use of pregabalin. We will include all studies (experimental, quasi-experimental, observational, case series/reports, drug regulatory reports) that examine the use of pregabalin compared to placebo, gabapentin or conventional care. Our primary outcome is heart failure and the secondary outcomes include edema and weight gain. We will search electronic databases (MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials), and grey literature sources (trial registries, conference abstracts) to identify relevant studies. To ensure literature saturation, we will contact drug manufacturers, conduct forward citation searching, and scan the reference lists of key articles and included studies. We will not restrict inclusion by language or publication status.Two reviewers will screen citations (titles and abstracts) and full-text articles, conduct data abstraction, and appraise risk of bias. Random-effects meta-analysis will be conducted if the studies are deemed heterogeneous in terms of clinical, statistical and methodological factors but still suitable for meta-analysis. The results of this review will assist physicians to better appreciate pregabalin's risk for edema or congestive heart failure and will be pertinent to the thousands of patients worldwide who are administered this medication.Our protocol was registered in the PROSPERO database (CRD42012002948).

PRECISE - pregabalin in addition to usual care for sciatica: study protocol for a randomised controlled trial.

PubMed

Mathieson, Stephanie; Maher, Christopher G; McLachlan, Andrew J; Latimer, Jane; Koes, Bart W; Hancock, Mark J; Harris, Ian; Day, Richard O; Pik, Justin; Jan, Stephen; Billot, Laurent; Lin, Chung-Wei Christine

2013-07-11

Sciatica is a type of neuropathic pain that is characterised by pain radiating into the leg. It is often accompanied by low back pain and neurological deficits in the lower limb. While this condition may cause significant suffering for the individual, the lack of evidence supporting effective treatments for sciatica makes clinical management difficult. Our objectives are to determine the efficacy of pregabalin on reducing leg pain intensity and its cost-effectiveness in patients with sciatica. PRECISE is a prospectively registered, double-blind, randomised placebo-controlled trial of pregabalin compared to placebo, in addition to usual care. Inclusion criteria include moderate to severe leg pain below the knee with evidence of nerve root/spinal nerve involvement. Participants will be randomised to receive either pregabalin with usual care (n = 102) or placebo with usual care (n = 102) for 8 weeks. The medicine dosage will be titrated up to the participant's optimal dose, to a maximum 600 mg per day. Follow up consultations will monitor individual progress, tolerability and adverse events. Usual care, if deemed appropriate by the study doctor, may include a referral for physical or manual therapy and/or prescription of analgesic medication. Participants, doctors and researchers collecting participant data will be blinded to treatment allocation. Participants will be assessed at baseline and at weeks 2, 4, 8, 12, 26 and 52. The primary outcome will determine the efficacy of pregabalin in reducing leg pain intensity. Secondary outcomes will include back pain intensity, disability and quality of life. Data analysis will be blinded and by intention-to-treat. A parallel economic evaluation will be conducted from health sector and societal perspectives. This study will establish the efficacy of pregabalin in reducing leg pain intensity in patients with sciatica and provide important information regarding the effect of pregabalin treatment on disability and quality of life. The impact of this research may allow the future development of a cost-effective conservative treatment strategy for patients with sciatica. ClinicalTrial.gov, ACTRN 12613000530729.

Are there different predictors of analgesic response between antidepressants and anticonvulsants in painful diabetic neuropathy?

PubMed

Marchettini, P; Wilhelm, S; Petto, H; Tesfaye, S; Tölle, T; Bouhassira, D; Freynhagen, R; Cruccu, G; Lledó, A; Choy, E; Kosek, E; Micó, J A; Späth, M; Skljarevski, V; Lenox-Smith, A; Perrot, S

2016-03-01

To investigate baseline demographics and disease characteristics as predictors of the analgesic effect of duloxetine and pregabalin on diabetic peripheral neuropathic pain (DPNP). Based on data from the COMBO-DN study, a multinational clinical trial in DPNP, the potential impact of baseline characteristics on pain relief after 8-week monotherapy with 60 mg/day duloxetine or 300 mg/day pregabalin was assessed using analyses of covariance. Subgroups of interest were characterized regarding their baseline characteristics and efficacy outcomes. A total of 804 patients were evaluated at baseline. A significant interaction with treatment was observed in the mood symptom subgroups with a larger pain reduction in duloxetine-treated patients having no mood symptoms [Hospital Anxiety and Depression Scale (HADS) depression or anxiety subscale score <11; -2.33 (duloxetine); -1.52 (pregabalin); p = 0.024]. There were no significant interactions between treatment for subgroups by age (<65 or ≥65 years), gender, baseline pain severity [Brief Pain Inventory Modified Short Form (BPI-MSF) average pain <6 or ≥6], diabetic neuropathy duration (≤2 or >2 years), baseline haemoglobin A1c (HbA1c) (<8% or ≥8%), presence of comorbidities and concomitant medication use. Our analyses suggest that the efficacy of duloxetine and pregabalin for initial 8-week treatment in DPNP was consistent across examined subgroups based on demographics and disease characteristics at baseline except for the presence of mood symptoms. Duloxetine treatment appeared to be particularly beneficial in DPNP patients having no mood symptoms. © 2015 European Pain Federation - EFIC®

Neuropathic low back pain in clinical practice.

PubMed

Baron, R; Binder, A; Attal, N; Casale, R; Dickenson, A H; Treede, R-D

2016-07-01

Low back pain (LBP) is one of the most common chronic pain conditions. This paper reviews the available literature on the role of neuropathic mechanisms in chronic LBP and discusses implications for its clinical management, with a particular focus on pharmacological treatments. Literature searches were performed in PubMed, key pain congresses and ProQuest Dialog to identify published evidence on neuropathic back pain and its management. All titles were assessed for relevant literature. Chronic LBP comprises both nociceptive and neuropathic components, however, the neuropathic component appears under-recognized and undertreated. Neuropathic pain (NP) is challenging to manage. Many patients with chronic LBP have pain that is refractory to existing treatments. Typically, less than half of patients experience clinically meaningful analgesia with oral pharmacotherapies; these are also associated with risks of adverse effects. Paracetamol and NSAIDs, although widely used for LBP, are unlikely to ameliorate the neuropathic component and data on the use of NP medications such as antidepressants and gabapentin/pregabalin are limited. While there is an unmet need for improved treatment options, recent data have shown tapentadol to have efficacy in the neuropathic component of LBP, and studies suggest that the capsaicin 8% patch and lidocaine 5% medicated plaster, topical analgesics available for the treatment of peripheral NP, may be a valuable additional approach for the management of neuropathic LBP. Chronic LBP often has an under-recognized neuropathic component, which can be challenging to manage, and requires improved understanding and better diagnosis and treatment. WHAT DOES THIS REVIEW ADD?: Increased recognition and improved understanding of the neuropathic component of low back pain raises the potential for the development of mechanism-based therapies. Open and retrospective studies suggest that agents like tapentadol and topical analgesics - such as the capsaicin 8% patch and the lidocaine 5% medicated plaster - may be effective options for the treatment of neuropathic low back pain in defined patient groups. © 2016 The Authors. European Journal of Pain published by John Wiley & Sons Ltd on behalf of European Pain Federation - EFIC®.

Sedative effects of oral pregabalin premedication on intravenous sedation using propofol target-controlled infusion.

PubMed

Karube, Noriko; Ito, Shinichi; Sako, Saori; Hirokawa, Jun; Yokoyama, Takeshi

2017-08-01

The sedative effects of pregabalin during perioperative period have not been sufficiently characterized. The aim of this study was to verify the sedative effects of premedication with pregabalin on intravenous sedation (IVS) using propofol and also to assess the influences of this agent on circulation, respiration, and postanesthetic complications. Ten healthy young volunteers underwent 1 h of IVS using propofol, three times per subject, on separate days (first time, no pregabalin; second time, pregabalin 100 mg; third time, pregabalin 200 mg). The target blood concentration (C T ) of propofol was increased in a stepwise fashion based on the bispectral index (BIS) value. Ramsay's sedation score (RSS) was determined at each propofol C T . Propofol C T was analyzed at each sedation level. Circulation and respiration during IVS and complications were also verified. Propofol C T was reduced at BIS values of 60 and 70 in both premedicated groups (100 mg: p = 0.043 and 0.041; 200 mg: p = 0.004 and 0.016, respectively) and at a BIS value of 80 in the pregabalin 200 mg group (p < 0.001). Propofol C T was decreased at RSS 4-6 in the pregabalin 100 mg group (RSS 4: p = 0.047; RSS 5: p = 0.007; RSS 6: p = 0.014), and at RSS 3-6 in the pregabalin 200 mg group (RSS 3-5: p < 0.001; RSS 6: p = 0.002). We conclude that oral premedication with pregabalin reduces the amount of propofol required to obtain an acceptable and adequate sedation level.

PRECISE - pregabalin in addition to usual care for sciatica: study protocol for a randomised controlled trial

PubMed Central

2013-01-01

Background Sciatica is a type of neuropathic pain that is characterised by pain radiating into the leg. It is often accompanied by low back pain and neurological deficits in the lower limb. While this condition may cause significant suffering for the individual, the lack of evidence supporting effective treatments for sciatica makes clinical management difficult. Our objectives are to determine the efficacy of pregabalin on reducing leg pain intensity and its cost-effectiveness in patients with sciatica. Methods/Design PRECISE is a prospectively registered, double-blind, randomised placebo-controlled trial of pregabalin compared to placebo, in addition to usual care. Inclusion criteria include moderate to severe leg pain below the knee with evidence of nerve root/spinal nerve involvement. Participants will be randomised to receive either pregabalin with usual care (n = 102) or placebo with usual care (n = 102) for 8 weeks. The medicine dosage will be titrated up to the participant’s optimal dose, to a maximum 600 mg per day. Follow up consultations will monitor individual progress, tolerability and adverse events. Usual care, if deemed appropriate by the study doctor, may include a referral for physical or manual therapy and/or prescription of analgesic medication. Participants, doctors and researchers collecting participant data will be blinded to treatment allocation. Participants will be assessed at baseline and at weeks 2, 4, 8, 12, 26 and 52. The primary outcome will determine the efficacy of pregabalin in reducing leg pain intensity. Secondary outcomes will include back pain intensity, disability and quality of life. Data analysis will be blinded and by intention-to-treat. A parallel economic evaluation will be conducted from health sector and societal perspectives. Discussion This study will establish the efficacy of pregabalin in reducing leg pain intensity in patients with sciatica and provide important information regarding the effect of pregabalin treatment on disability and quality of life. The impact of this research may allow the future development of a cost-effective conservative treatment strategy for patients with sciatica. Trial registration ClinicalTrial.gov, ACTRN 12613000530729 PMID:23845078

Pharmacotherapy for neuropathic pain in adults: systematic review, meta-analysis and updated NeuPSIG recommendations

PubMed Central

Finnerup, Nanna B; Attal, Nadine; Haroutounian, Simon; McNicol, Ewan; Baron, Ralf; Dworkin, Robert H; Gilron, Ian; Haanpaa, Maija; Hansson, Per; Jensen, Troels S; Kamerman, Peter R; Lund, Karen; Moore, Andrew; Raja, Srinivasa N; Rice, Andrew SC; Rowbotham, Michael; Sena, Emily; Siddall, Philip; Smith, Blair H; Wallace, Mark

2015-01-01

Summary Background Neuropathic pain is difficult to treat. New treatments, clinical trials and standards of quality for assessing evidence justify an update of evidence-based recommendations for its pharmacological treatment. Methods The Neuropathic Pain Special Interest Group (NeuPSIG) of the International Association for the Study of Pain conducted a systematic review of randomised double-blind studies of oral and topical pharmacotherapy for neuropathic pain, including unpublished trials (retrieved from clinicaltrials.gov and pharmaceutical websites). Meta-analysis used Numbers Needed to Treat (NNT) for 50 % pain relief as primary measure and assessed publication bias. Recommendations used the Grading of Recommendations Assessment, Development, and Evaluation (GRADE). Findings In total 229 studies were included. Analysis of publication bias suggested a 10% overstatement of treatment effects. Studies published in peer-review journals reported greater effects than online studies (R2=9·3%, p<0·01). Trial outcomes were generally modest even for effective drugs : in particular NNTs were 3·6 (95 % CI 3·0–4·4) for tricyclic antidepressants (TCAs), 6·4 (95 % CI 5·2–8·4) for serotonin- noradrenaline reuptake inbibitor (SNRI) antidepressants duloxetine and venlafaxine, 7·7 (95 % CI 6·5–9·4) for pregabalin and 6·3 (95 % CI 5·0–8·3) for gabapentin. NNTs were higher for gabapentin ER/enacarbil and capsaicin high concentration patches, lower for opioids and botulinum toxin A (BTX-A) and undetermined for lidocaine patches. Final quality of evidence was lower for lidocaine patches and BTX-A. Tolerability/safety and values/preferences were high for lidocaine patches and lower for opioids and TCAs. This permitted a strong GRADE recommendation for use and proposal as first line for TCAs, SNRIs, pregabalin, gabapentin and gabapentin ER/enacarbil in neuropathic pain, a weak recommendation for use and proposal as second line for lidocaine patches, capsaicin patches and tramadol, and a weak recommendations for use and proposal as third line for strong opioids (particularly oxycodone and morphine) and BTX-A. Data for cannabinoids, tapentadol, drug combinations, and several other antiepileptics, antidepressants and topical drugs were inconclusive. Interpretation Limited efficacy, large placebo responses, inadequate diagnostic criteria and poor phenotypic profiling probably account for modest trial outcomes and should be taken into account in future studies. Funding This study was funded by NeuPSIG. PMID:25575710

Oral pregabalin for postoperative pain relief after third molar extraction: a randomized controlled clinical trial.

PubMed

Olmedo-Gaya, Maria Victoria; Manzano-Moreno, Francisco J; Galvez-Mateos, Rafael; González-Rodriguez, Maria Paloma; Talero-Sevilla, Cristina; Vallecillo-Capilla, Manuel

2016-09-01

The aim of this randomized controlled clinical trial was to evaluate the efficacy and safety of pregabalin administered pre- and postoperatively in patients with pain and swelling due to the surgical removal of impacted lower third molars. The final study sample comprised 60 volunteers (23 males and 37 females). Group 1 (n = 30) received 75 mg oral pregabalin 1 h before surgery and 1 h after surgery. Group 2 (n = 30) served as a control group and received no pregabalin. Both groups were administered with 650 mg paracetamol every 8 h for 2 days. Postoperative pain intensity and swelling were measured using a visual analog scale (VAS); pain relief experienced was reported using a four-point verbal rating scale (VRS); the rescue medication requirement, adverse effects, and global impression of the medication were also recorded. No significant difference in pain intensity (VAS) was observed between the groups. However, fewer rescue medication tablets were needed by pregabalin-treated patients than by controls (p = 0.021). The frequency and intensity of adverse effects were significantly higher in pregabalin-treated patients (p < 0.001), although no serious adverse events occurred. No significant difference in the degree of swelling was observed in any measurement except that from mandibular angle to lip junction, which showed lesser inflammation in the pregabalin group at 24 h post-surgery (p = 0.011). The global opinion on the medication received was more positive in the pregabalin group (p = 0.042). The administration of pregabalin reduces the requirement for rescue medication after third molar surgery and results in a more constant pain level, with fewer peaks of pain intensity. These findings suggest that pregabalin may be useful to control acute postoperative pain. Adverse effects are known to be reduced at the low pregabalin dose used in our study.

The evidence for pharmacological treatment of neuropathic pain.

PubMed

Finnerup, Nanna Brix; Sindrup, Søren Hein; Jensen, Troels Staehelin

2010-09-01

Randomized, double-blind, placebo-controlled trials on neuropathic pain treatment are accumulating, so an updated review of the available evidence is needed. Studies were identified using MEDLINE and EMBASE searches. Numbers needed to treat (NNT) and numbers needed to harm (NNH) values were used to compare the efficacy and safety of different treatments for a number of neuropathic pain conditions. One hundred and seventy-four studies were included, representing a 66% increase in published randomized, placebo-controlled trials in the last 5 years. Painful poly-neuropathy (most often due to diabetes) was examined in 69 studies, postherpetic neuralgia in 23, while peripheral nerve injury, central pain, HIV neuropathy, and trigeminal neuralgia were less often studied. Tricyclic antidepressants, serotonin noradrenaline reuptake inhibitors, the anticonvulsants gabapentin and pregabalin, and opioids are the drug classes for which there is the best evidence for a clinical relevant effect. Despite a 66% increase in published trials only a limited improvement of neuropathic pain treatment has been obtained. A large proportion of neuropathic pain patients are left with insufficient pain relief. This fact calls for other treatment options to target chronic neuropathic pain. Large-scale drug trials that aim to identify possible subgroups of patients who are likely to respond to specific drugs are needed to test the hypothesis that a mechanism-based classification may help improve treatment of the individual patients. Copyright (c) 2010 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

Neuropathic cancer pain: What we are dealing with? How to manage it?

PubMed Central

Esin, Ece; Yalcin, Suayib

2014-01-01

Cancer pain is a serious health problem, and imposes a great burden on the lives of patients and their families. Pain can be associated with delay in treatment, denial of treatment, or failure of treatment. If the pain is not treated properly it may impair the quality of life. Neuropathic cancer pain (NCP) is one of the most complex phenomena among cancer pain syndromes. NCP may result from direct damage to nerves due to acute diagnostic/therapeutic interventions. Chronic NCP is the result of treatment complications or malignancy itself. Although the reason for pain is different in NCP and noncancer neuropathic pain, the pathophysiologic mechanisms are similar. Data regarding neuropathic pain are primarily obtained from neuropathic pain studies. Evidence pertaining to NCP is limited. NCP due to chemotherapeutic toxicity is a major problem for physicians. In the past two decades, there have been efforts to standardize NCP treatment in order to provide better medical service. Opioids are the mainstay of cancer pain treatment; however, a new group of therapeutics called coanalgesic drugs has been introduced to pain treatment. These coanalgesics include gabapentinoids (gabapentin, pregabalin), antidepressants (tricyclic antidepressants, duloxetine, and venlafaxine), corticosteroids, bisphosphonates, N-methyl-D-aspartate antagonists, and cannabinoids. Pain can be encountered throughout every step of cancer treatment, and thus all practicing oncologists must be capable of assessing pain, know the possible underlying pathophysiology, and manage it appropriately. The purpose of this review is to discuss neuropathic pain and NCP in detail, the relevance of this topic, clinical features, possible pathology, and treatments of NCP. PMID:24790459

Synthesis and biological evaluation of 3,7-diazabicyclo[4.3.0]nonan-8-ones as potential nootropic and analgesic drugs.

PubMed

Martini, Elisabetta; Di Cesare Mannelli, Lorenzo; Bartolucci, Gianluca; Bertucci, Carlo; Dei, Silvia; Ghelardini, Carla; Guandalini, Luca; Manetti, Dina; Scapecchi, Serena; Teodori, Elisabetta; Romanelli, Maria Novella

2011-04-14

A series of cis and trans 3,7-diazabicyclo[4.3.0]nonan-8-ones has been synthesized and tested for their ability to revert scopolamine-induced amnesia in the mouse passive-avoidance test. The racemates of the most potent compounds 4 and 7 were separated and tested, but no enantioselectivity was found for the nootropic activity. Compounds 4 and 7 and their enantiomers displayed interesting antihyperalgesic activity in two models of neuropathic pain (streptozotocin-induced and oxalilplatin-induced neuropathy) in comparison with pregabalin.

Pregabalin and gabapentin for the treatment of sciatica.

PubMed

Robertson, Kelvin; Marshman, Laurence A G; Plummer, David

2016-04-01

Whilst pregabalin (PGB) and gabapentin (GBP) are both used to treat neuropathic pain, their relative role in sciatica is unclear. Our aim was to extensively review the roles of PGB and GBP in treating sciatica. The efficacy, side effects (SE) profile and cost of PGB and GBP in neuropathic pain states were reviewed with special reference to sciatica. Eleven articles matched the criteria: seven systematic reviews, one retrospective cross-sectional study, one placebo-controlled-crossover study, one randomized placebo-controlled double-blind study and one case report. GBP and PGB appeared to demonstrate comparable efficacy and SE. However, the amount and quality of evidence was low, and only indirect comparisons were available. Importantly, no direct "head-to-head" study existed. Globally, costs varied widely (by up to 31 times) and unpredictably (PGB cheaper than GBP, or vice versa). Formulary regulator rulings were globally disparate; however, many exclusively favoured the more expensive drug (whether GBP or PGB). No studies assessed PGB-GBP interchange. Weak evidence suggests that efficacy and SE with GBP and PGB are probably similar; however, firm conclusions are precluded. Despite weak data, and having cited minor titration, but definite cost, advantages, UK National Institute for Health and Clinical Excellence favoured PGB over GBP. Given that no evidence supports unhindered PGB-GBP interchange, neither drug should probably be favoured. Prospective "head-to-head" studies are urgently required to provide robust evidence-based knowledge for choice of GBP or PGB in sciatica. Copyright © 2015 Elsevier Ltd. All rights reserved.

Pregabalin beneficial effects on sleep quality or health-related quality of life are poorly correlated with reduction on pain intensity after an 8-week treatment course.

PubMed

Perez-Lloret, Santiago; Rojas, Gloria Meza; Menoni, Maria Celia; Ruiz, Gabriela; Velásquez, Carolina; Rodriguez, Hernán; Rey, María Verónica; Cardinali, And Daniel P

2012-01-01

Pregabalin (PGB) has been shown to improve sleep quality and health-related quality of life (HRQoL) as well as pain intensity in patients with neuropathic pain. The objective of the study was to explore the magnitude of the correlations between changes in pain intensity, sleep quality, and HRQoL after PGB treatment. One hundred thirty-eight patients with neuropathic pain of any origin and without an adequate response to analgesics received an 8-week treatment course of PGB in an open-label fashion. Pain intensity, sleep quality, and HRQoL outcomes were evaluated at baseline and at week 8 by means of an 11-point (0-10) numerical rating scale (NRS), the Pittsburgh Sleep Quality Index (PSQI), and the EuroQol health-state visuoanalogic scale (EQ-5D VAS) score, respectively. At week 8, mean PGB dose was 166.7 ± 7.8 mg/d. Pain intensity NRS score, PSQI total score, and EQ-5D VAS score were improved by 66.5% ± 1.9%, 40.0% ± 3.6%, and 26.4% ± 4.7% (all P < 0.01), respectively. Correlations between percent change from baseline in pain NRS score and PSQI total score or EQ-5D VAS scores were r = 0.36 (P < 0.01, R = 0.11) and r = -0.20 (P < 0.02, R = 0.05), respectively. A multivariate logistic regression analysis disclosed that PSQI score change below the median (ie, a better outcome) was related to higher EQ-5D VAS score change (odds ratio, 2.15; 95% confidence interval, 1.09-4.25), whereas pain intensity NRS score change below the median was not (odds ratio, 1.58; 95% confidence interval,0.78-3.23). In our study, PGB-related improvements in sleep quality and HRQoL were marginally related to reductions in pain intensity in patients with neuropathic pain. Improvement in sleep quality was a significant predictor of better HRQoL, whereas pain intensity reduction was not.

Mechanical Conflict System: A Novel Operant Method for the Assessment of Nociceptive Behavior

PubMed Central

Harte, Steven E.; Meyers, Jessica B.; Donahue, Renee R.; Taylor, Bradley K.; Morrow, Thomas J.

2016-01-01

A new operant test for preclinical pain research, termed the Mechanical Conflict System (MCS), is presented. Rats were given a choice either to remain in a brightly lit compartment or to escape to a dark compartment by crossing an array of height-adjustable nociceptive probes. Latency to escape the light compartment was evaluated with varying probe heights (0, .5, 1, 2, 3, and 4 mm above compartment floor) in rats with neuropathic pain induced by constriction nerve injury (CCI) and in naive control rats. Escape responses in CCI rats were assessed following intraperitoneal administration of pregabalin (10 and 30 mg/kg), morphine (2.5 and 5 mg/kg), and the tachykinin NK1 receptor antagonist, RP 67580 (1 and 10 mg/kg). Results indicate that escape latency increased as a function of probe height in both naive and CCI rats. Pregabalin (10 and 30 mg/kg) and morphine (5 mg/kg), but not RP 67580, decreased latency to escape in CCI rats suggesting an antinociceptive effect. In contrast, morphine (10 mg/kg) but not pregabalin (30 mg/kg) increased escape latency in naive rats suggesting a possible anxiolytic action of morphine in response to light-induced fear. No order effects following multiple test sessions were observed. We conclude that the MCS is a valid method to assess behavioral signs of affective pain in rodents. PMID:26915030

Management of chronic spinal cord dysfunction.

PubMed

Abrams, Gary M; Ganguly, Karunesh

2015-02-01

Both acute and chronic spinal cord disorders present multisystem management problems to the clinician. This article highlights key issues associated with chronic spinal cord dysfunction. Advances in symptomatic management for chronic spinal cord dysfunction include use of botulinum toxin to manage detrusor hyperreflexia, pregabalin for management of neuropathic pain, and intensive locomotor training for improved walking ability in incomplete spinal cord injuries. The care of spinal cord dysfunction has advanced significantly over the past 2 decades. Management and treatment of neurologic and non-neurologic complications of chronic myelopathies ensure that each patient will be able to maximize their functional independence and quality of life.

Mechanisms of the gabapentinoids and α 2 δ-1 calcium channel subunit in neuropathic pain.

PubMed

Patel, Ryan; Dickenson, Anthony H

2016-04-01

The gabapentinoid drugs gabapentin and pregabalin are key front-line therapies for various neuropathies of peripheral and central origin. Originally designed as analogs of GABA, the gabapentinoids bind to the α 2 δ-1 and α 2 δ-2 auxiliary subunits of calcium channels, though only the former has been implicated in the development of neuropathy in animal models. Transgenic approaches also identify α 2 δ-1 as key in mediating the analgesic effects of gabapentinoids, however the precise molecular mechanisms remain unclear. Here we review the current understanding of the pathophysiological role of the α 2 δ-1 subunit, the mechanisms of analgesic action of gabapentinoid drugs and implications for efficacy in the clinic. Despite widespread use, the number needed to treat for gabapentin and pregabalin averages from 3 to 8 across neuropathies. The failure to treat large numbers of patients adequately necessitates a novel approach to treatment selection. Stratifying patients by sensory profiles may imply common underlying mechanisms, and a greater understanding of these mechanisms could lead to more direct targeting of gabapentinoids.

Different underlying pain mechanisms despite identical pain characteristics: a case report of a patient with spinal cord injury.

PubMed

Westermann, Andrea; Krumova, Elena K; Pennekamp, Werner; Horch, Christoph; Baron, Ralf; Maier, Christoph

2012-07-01

Pain following spinal cord injury has been classified as nociceptive (musculoskeletal, visceral) or neuropathic (above, at, below level). There is no clear relation between the etiology and reported symptoms. Thus, due to different underlying mechanisms, the treatment is often ineffective. We report on a patient with spinal cord injury with neurological level of injury at T8 suffering from bilateral burning and prickling pain in the T9-11 dermatomes bilaterally (at-level pain), as well as diffusely in both legs from below the torso (below-level pain), accompanied by musculoskeletal low back pain. Bilateral comparison of quantitative sensory testing (QST) and skin biopsy revealed completely different findings in the dermatome T9 despite identical at-level pain characteristics. On the right side, QST revealed a normal sensory profile; the intraepidermal nerve fiber density (IENFD) was reduced, but not as severe as the contralateral side. On the left side there was a severe sensory loss with a stronger reduction of the IENDF, similar to the areas below the neurological level. These findings were significantly related to the treatment results. Pregabalin induced unilateral pain relief only in the area with remaining sensory function, whereas the left-sided at-level pain was unchanged. Thus, 2 different underlying mechanisms leading to bilaterally neuropathic pain with identical symptoms and with different treatment success were demonstrated in a single patient. The at-level pain in areas with remaining sensory function despite IENFD reduction could be relieved by pregabalin. Thus, in an individual case, QST may be helpful to better understand pain-generating mechanisms and to initiate successful treatment. Copyright © 2012 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

Ameliorative effect of Vernonia cinerea in vincristine-induced painful neuropathy in rats.

PubMed

Thiagarajan, Venkata Rathina Kumar; Shanmugam, Palanichamy; Krishnan, Uma Maheswari; Muthuraman, Arunachalam

2014-10-01

The present study was designed to investigate the antinociceptive potential of Vernonia cinerea (VC) on vincristine-induced painful neuropathy in rats. A chemotherapeutic agent, vincristine (50 μg/kg intraperitoneally for 10 consecutive days), was administered for the induction of neuropathic pain in rats. The painful behavioral changes were assessed using hot plate, acetone drop, paw pressure, Von Frey hair and tail immersion tests to assess the degree of hyperalgesic and allodynic pain sensation in paw and tail. Tissue biomarker changes including thiobarbituric acid reactive substances (TBARSs), reduced glutathione (GSH) and total calcium levels were estimated in sciatic nerve tissue samples to assess the degree of oxidative stress. Histopathological changes were also observed in transverse sections of rat sciatic nerve tissue. Ethanolic extract of VC leaves and pregabalin were administered for 14 consecutive days from day 0 (day of surgery). Pregabalin served as a positive control in the present study. Vincristine administration resulted in a significant reduction in painful behavioral changes along with a rise in the levels of TBARS, total calcium and decrease in GSH levels when compared with the normal control group. Furthermore, significant histopathological changes were also observed. Pretreatment with VC significantly attenuated vincristine-induced development of painful behavioral, biochemical and histological changes in a dose-dependent manner, which is similar to that of pregabalin-pretreated group. The attenuating effect of VC in vincristine-induced nociceptive painful sensation may be due to its potential of antioxidative, neuroprotective and calcium channel inhibitory action. © The Author(s) 2012.

Investigation of the predictive validity of laser-EPs in normal, UVB-inflamed and capsaicin-irritated skin with four analgesic compounds in healthy volunteers.

PubMed

Schaffler, Klaus; Nicolas, Laurent B; Borta, Andreas; Brand, Tobias; Reitmeir, Peter; Roebling, Robert; Scholpp, Joachim

2017-07-01

The aim of the present study was to assess the predictivity of laser-(radiant-heat)-evoked potentials (LEPs) from the vertex electroencephalogram, using an algesimetric procedure, testing the anti-nociceptive/anti-hyperalgesic effects of single oral doses of four marketed analgesics (of different compound classes) vs. placebo, in healthy volunteers with three skin types. This was a randomized, placebo-controlled, single-blind, five-way-crossover trial. Twenty-five healthy male/female Caucasians were included (receiving celecoxib 200 mg, pregabalin 150 mg, duloxetine 60 mg, lacosamide 100 mg or placebo) in a Williams design, with CO 2 laser-induced painful stimuli to normal, ultraviolet (UV) B-inflamed and capsaicin-irritated skin. LEPs and visual analogue scale ratings were taken at baseline and hourly for 6 h postdose from all three skin types. In normal skin, the averaged postdose LEP peak-to-peak-(PtP)-amplitudes were reduced by pregabalin (-2.68 μV; 95% confidence interval (CI) -4.16, 1.19) and duloxetine (-1.73 μV; 95% CI -3.21, -0.26) but not by lacosamide and celecoxib vs. placebo. On UVB-irradiated skin, reflecting inflammatory pain, celecoxib induced a pronounced reduction in LEP PtP amplitudes vs. placebo (-6.2 μV; 95% CI -7.88, -4.51), with a smaller reduction by duloxetine (-4.54 μV; 95% CI -6.21, -2.87) and pregabalin (-3.72 μV; 95% CI -5.40, -2.04), whereas lacosamide was inactive. LEP PtP amplitudes on capsaicin-irritated skin, reflecting peripheral/spinal sensitization, as in neuropathic pain, were reduced by pregabalin (-3.78 μV; 95% CI -5.31, -2.25) and duloxetine (-2.32 μV; 95% CI -3.82, -0.82) but not by celecoxib or lacosamide vs. placebo, which was in agreement with known clinical profiles. Overall, PtP amplitude reductions were in agreement with subjective ratings. LEP algesimetry is sensitive to analgesics with different modes of action and may enable the effects of novel analgesics to be assessed during early clinical development. © 2017 The British Pharmacological Society.

Severe eosinophilic colitis caused by neuropathic agents in a patient with chronic fatigue syndrome and functional abdominal pain: case report and review of the literature.

PubMed

Fragkos, Konstantinos C; Barragry, John; Fernando, Charisma Shahi; Novelli, Marco; Begent, Joanna; Zárate-Lopez, Natalia

2018-06-01

Eosinophilic colitis is a rare clinical condition that belongs to the group of eosinophilic gastrointestinal disorders. Its occurrence can be primary or secondary to infection, medications, or autoimmune/hematological conditions. We present a case of a young female adult with severe chronic fatigue syndrome, widespread chronic pain, including functional abdominal pain, who developed severe eosinophilic colitis following successive treatments with gabapentin and pregabalin. On both occasions, symptoms manifested as abdominal pain, diarrhea, and eosinophilia and improved upon discontinuation of the medications. Magnetic resonance imaging of the small bowel demonstrated an ascending colon colitis, and endoscopic investigations confirmed florid colitis mainly in the ascending colon with biopsies demonstrating a dense eosinophilic infiltrate with micro-abscesses. Serum eosinophil counts correlated well with the timing of the agents' administration. There was no other organ involvement. Symptoms improved upon discontinuation of the drugs and steroid administration. Eosinophilic colitis is an exceptionally rare entity and its mechanism of action is still unclear. Suspicion of eosinophilic colitis should be raised if a patient presents with abdominal pain, diarrhea, and peripheral eosinophilia following treatment with pregabalin or gabapentin. © Georg Thieme Verlag KG Stuttgart · New York.

Anti-allodynic and Anti-hyperalgesic effects of an ethanolic extract and xylopic acid from the fruits of Xylopia aethiopica in murine models of neuropathic pain.

PubMed

Ameyaw, Elvis O; Woode, Eric; Boakye-Gyasi, Eric; Abotsi, Wonder K M; Kyekyeku, James Oppong; Adosraku, Reimmel K

2014-04-01

Fruit extracts of Xylopia aethiopica are used traditionally in the management of pain disorders including headache and neuralgia. An animal model of vincristine-induced sensory neuropathy was developed after repeated intraperitoneal injection in rats and used in the present work to study the effects of the ethanolic extract of X. aethiopica (XAE) and its diterpene xylopic acid (XA) in vincristine-induced neuropathic pain. Vincristine (0.1 mg kg(-1) day(-1)) was administered during two cycles of five consecutive days to induce chemotherapy-induced neuropathic pain. Static tactile anti-allodynic, anti-hyperalgesic, and cold anti-allodynic effects of XAE (30-300 mg kg(-1)) and XA (10-100 mg kg(-1)) were assessed using Von Frey filaments of bending forces of 4, 8, and 15 g, the Randall-Selitto paw pressure test, and cold water (4.5°C), respectively. Administration of vincristine caused the development of allodynia and hyperalgesia with no significant motor deficit, spontaneous pain, and foot deformity. XAE (30-300 mg kg(-1)) and XA (10-100 mg kg(-1)) exhibited anti-hyperalgesic, tactile, and cold anti-allodynic properties with XA exhibiting greater potency than XAE. Pregabalin (10-100 mg kg(-1)) used as control produced similar effect. These findings establish the anti-allodynic and anti-hyperalgesic effects of the ethanolic fruit XAE and its major diterpene XA in vincristine-induced neuropathtic pain.

Pharmacokinetics of pregabalin controlled-release in healthy volunteers: effect of food in five single-dose, randomized, clinical pharmacology studies.

PubMed

Chew, Marci L; Plotka, Anna; Alvey, Christine W; Pitman, Verne W; Alebic-Kolbah, Tanja; Scavone, Joseph M; Bockbrader, Howard N

2014-09-01

The pharmacokinetic properties of the immediate-release (IR) and the recently developed controlled-release (CR) formulation of pregabalin are dose proportional. Pregabalin IR can be taken with or without food. This analysis characterizes the effect of food on pregabalin CR. The objectives of this analysis were: (1) to evaluate the effect of administration time and fat or caloric content of an accompanying meal on the pharmacokinetic properties of a single dose of pregabalin CR (330 mg) relative to a single dose of pregabalin IR (300 mg); (2) to evaluate the pharmacokinetic properties of a single dose of pregabalin CR administered fasted relative to a single dose of pregabalin CR administered immediately after food; and (3) to determine the safety and tolerability of single-dose administration of pregabalin CR and IR with and without food. The effect of food on the pharmacokinetic properties of pregabalin CR was determined in five phase I, open-label, single-dose, crossover studies (24-28 participants/study). Caloric and fat content of meals were varied and treatments were administered in the morning, at midday, or in the evening. Blood samples were collected up to 48 h post-dose. Pharmacokinetic parameters were estimated from plasma concentration-time data using standard noncompartmental methods. Adverse events were monitored throughout all studies. One hundred and twenty-eight healthy participants (19-54 years of age) received pregabalin. Peak plasma concentrations (C max) were lower for CR than the respective pregabalin IR doses, and time to C max occurred later. When pregabalin CR was administered with food at midday or in the evening, total exposures [area under the plasma concentration-time curve from time zero extrapolated to infinite time (AUC∞)] were equivalent for pregabalin CR and IR formulations regardless of fat or caloric content. When pregabalin CR was administered with an 800-1,000 calorie medium-fat breakfast, AUC∞ was equivalent for pregabalin CR and IR. Bioequivalence criteria for comparison of pregabalin CR after a low- or medium-calorie breakfast relative to pregabalin IR were not met; however, bioavailability of the pregabalin CR vs. IR formulation was relatively high (75-86 %). When pregabalin CR was administered fasted, the AUC∞ was 70-78 % of the AUC∞ of pregabalin CR administered with food and bioequivalence criteria were not met. Additionally, the AUC∞ of the pregabalin CR formulation administered fasted was 62-69 % of that of pregabalin IR administered fasted and bioequivalence criteria were not met. Single-dose pregabalin CR and IR were well tolerated in all studies, with no serious or severe adverse events reported. Time of day of administration and the fat and caloric content of the accompanying meal had minimal overall effect on the pharmacokinetic properties and bioavailability of the pregabalin CR formulation.

New targets for neuropathic pain therapeutics.

PubMed

Kinloch, Ross A; Cox, Peter J

2005-08-01

Neuropathic pain (NeP) is initiated by a lesion or dysfunction in the nervous system. Unlike physiological pain it serves no useful purpose and is usually sustained and chronic. NeP encompasses a wide range of pain syndromes of diverse aetiologies which together account for > 12 million sufferers in the US. Currently, there are a number of therapies available for NeP, including gabapentin, pregabalin, anticonvulsants (tiagabine HCl), tricyclic antidepressants (amitriptyline, nortriptyline) and acetaminophen/opioid combination products (Vicodin, Tylenol #3). However, these products do not provide sufficient pain relief and a significant proportion of sufferers are refractory (60%). Therefore, there is a need for new therapies that provide more predictable efficacy in all patients with improved tolerability. Over the last decade, understanding of the basic mechanisms contributing to the generation of NeP in preclinical animal models has greatly improved. Together with the completion of the various genome sequencing projects and significant advances in microarray and target validation strategies, new therapeutic approaches are being rigourously pursued. This article reviews the rationale behind a number of these mechanism-based approaches, briefly discusses specific challenges that they face, and finally, speculates on the potential of emerging technologies as alternative therapeutic strategies to the traditional 'small-molecule' approach.

[Efficacy of tramadol/acetaminophen medication for central post-stroke pain].

PubMed

Tanei, Takafumi; Kajita, Yasukazu; Noda, Hiroshi; Takebayashi, Shigenori; Hirano, Masaki; Nakahara, Norimoto; Wakabayashi, Toshihiko

2013-08-01

Central post-stroke pain(CPSP)is the most difficult type of central neuropathic pain to control with medical treatment. Opioids are commonly used for chronic neuropathic pain, but their efficacy in treating central neuropathic pain, particularly CPSP, is not clear. Tramadol is an opioid analgesic that, in combination with acetaminophen, has been approved since 2011 for the treatment of non-cancer pain in Japan. In this study we evaluated the efficacy of tramadol/acetaminophen medication for CPSP. We retrospectively reviewed nine cases of CPSP that received oral tramadol/acetaminophen medication. All cases received tramadol/acetaminophen medication after first taking pregabalin then antidepressant medication. Pain levels were assessed before tramadol/acetaminophen medication began and one month after a maintenance dose was reached, using a visual analogue scale(VAS)and the McGill pain questionnaire(MPQ). The mean dose of tramadol was 121±61.6 mg/day. Tramadol/acetaminophen medication was effective in reducing pain in seven of nine cases(77.8%). The VAS improved 32.9±13.8% from pre-to post-medication, and the MPQ improved from 15.4±9.1 pre-medication to 8.1±4.7 post-medication(p<0.05). These effects continued 9.3±4.5 months during follow up periods. Side effects were observed in six cases(one severe, one moderate, two mild, two transient), but medication was continued in eight cases. Oral tramadol/acetaminophen medication was effective at reducing pain levels in patients with CPSP, and is a medication option for the treatment of CPSP.

Anti-allodynic and Anti-hyperalgesic effects of an ethanolic extract and xylopic acid from the fruits of Xylopia aethiopica in murine models of neuropathic pain

PubMed Central

Ameyaw, Elvis O.; Woode, Eric; Boakye-Gyasi, Eric; Abotsi, Wonder K.M.; Kyekyeku, James Oppong; Adosraku, Reimmel K.

2014-01-01

Background: Fruit extracts of Xylopia aethiopica are used traditionally in the management of pain disorders including headache and neuralgia. An animal model of vincristine-induced sensory neuropathy was developed after repeated intraperitoneal injection in rats and used in the present work to study the effects of the ethanolic extract of X. aethiopica (XAE) and its diterpene xylopic acid (XA) in vincristine-induced neuropathic pain. Materials and Methods: Vincristine (0.1 mg kg-1 day-1) was administered during two cycles of five consecutive days to induce chemotherapy-induced neuropathic pain. Static tactile anti-allodynic, anti-hyperalgesic, and cold anti-allodynic effects of XAE (30-300 mg kg-1) and XA (10-100 mg kg-1) were assessed using Von Frey filaments of bending forces of 4, 8, and 15 g, the Randall-Selitto paw pressure test, and cold water (4.5°C), respectively. Results: Administration of vincristine caused the development of allodynia and hyperalgesia with no significant motor deficit, spontaneous pain, and foot deformity. XAE (30-300 mg kg-1) and XA (10-100 mg kg-1) exhibited anti-hyperalgesic, tactile, and cold anti-allodynic properties with XA exhibiting greater potency than XAE. Pregabalin (10-100 mg kg-1) used as control produced similar effect. Conclusion: These findings establish the anti-allodynic and anti-hyperalgesic effects of the ethanolic fruit XAE and its major diterpene XA in vincristine-induced neuropathtic pain. PMID:24761123

Clinical, Electrophysiological, and Serological Evaluation of Patients with Cramp-Fasciculation Syndrome.

PubMed

Poyraz, Mürüvvet; Matur, Zeliha; Aysal, Fikret; Tüzün, Erdem; Hanoğlu, Lütfü; Öge, A Emre

2017-06-01

Cramp-fasciculation syndrome (CFS) is a rare peripheral nerve hyperexcitability syndrome. There are only a few reports on clinical and serological profile of a CFS cohort that was followed up by a single outpatient clinic. Clinical, electrophysiological, and serological features of 6 CFS patients (5 men, 1 woman; 27-65 years old) were investigated. All patients presented with cramps, fasciculations, muscle pain, and autonomic symptoms, and 2 also reported numbness and burning sensation in limbs, suggestive of neuropathic pain. Antibodies to uncharacterized voltage-gated potassium channel (VGKC)-complex proteins were found in 2 patients and to contactin-associated protein-like 2 (CASPR2) in 1 patient. None of the patients had a tumor. Most of the patients revealed prolonged after-discharges following tibial nerve stimulation. Nerve conduction studies and R-R interval variability tests were normal, whereas sympathetic skin responses were increased in amplitude in 3 seronegative patients. Five patients showed favorable response to carbamazepine or pregabalin treatment, whereas 1 VGKC-antibody-positive patient was resistant to carbamazepine and immunosuppressant treatment. Neuropathic pain and VGKC-complex antibodies may be encountered in CFS patients. Although autonomic symptoms are commonly found in CFS, routine autonomic system tests which are done in electrophysiology laboratories might yield normal results.

The antinociceptive effect and mechanisms of action of pregabalin in mice.

PubMed

Kaygisiz, Bilgin; Kilic, Fatma Sultan; Senguleroglu, Nuri; Baydemir, Canan; Erol, Kevser

2015-02-01

Pregabalin, a potent anticonvulsant agent, is used in treatment-resistant epileptic patients. It is reported that pregabalin also has analgesic effect in different pain syndromes. However, there is limited data on its antinociceptive mechanisms of action. We aimed to investigate the central and peripheral antinociceptive effects of pregabalin and the contribution of nitrergic, serotonergic, and opioidergic pathways in mice. We used tail flick, tail clip and hot plate tests to investigate the central antinociceptive effects and acetic acid-induced writhing test to assess peripheral antinociceptive effects of pregabalin (10, 30, 100mg/kg). We also combined pregabalin (100mg/kg) with, a nonspecific nitric oxide synthase inhibitor l-NAME (100mg/kg), a serotonin receptor antagonist cyproheptadine (50 μg/kg), and an opioid receptor antagonist naloxone (1mg/kg). Pregabalin 30 mg/kg enhanced the percentage of maximal possible effect (% MPE) in tail flick test. Pregabalin 100mg/kg significantly increased % MPE in tail clip and tail flick tests and decreased the number of writhings. Pregabalin made no significant alteration in hot plate test at all doses. The combined use of pregabalin 100mg/kg with l-NAME, cyproheptadine, and naloxone showed that % MPE was reduced only in the combination of pregabalin with naloxone and solely in tail clip test while no significant difference was observed in writhing test. We suggest that pregabalin (30 and 100mg/kg) presents central spinal but not central supraspinal antinociceptive effect and pregabalin 100mg/kg shows peripheral antinociceptive effect. The opioidergic pathway seems to mediate the central spinal antinociceptive effect of pregabalin while nitrergic and serotonergic pathways are not involved. Copyright © 2014 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

DNA methyltransferase DNMT3a contributes to neuropathic pain by repressing Kcna2 in primary afferent neurons

PubMed Central

Zhao, Jian-Yuan; Liang, Lingli; Gu, Xiyao; Li, Zhisong; Wu, Shaogen; Sun, Linlin; Atianjoh, Fidelis E.; Feng, Jian; Mo, Kai; Jia, Shushan; Lutz, Brianna Marie; Bekker, Alex; Nestler, Eric J.; Tao, Yuan-Xiang

2017-01-01

Nerve injury induces changes in gene transcription in dorsal root ganglion (DRG) neurons, which may contribute to nerve injury-induced neuropathic pain. DNA methylation represses gene expression. Here, we report that peripheral nerve injury increases expression of the DNA methyltransferase DNMT3a in the injured DRG neurons via the activation of the transcription factor octamer transcription factor 1. Blocking this increase prevents nerve injury-induced methylation of the voltage-dependent potassium (Kv) channel subunit Kcna2 promoter region and rescues Kcna2 expression in the injured DRG and attenuates neuropathic pain. Conversely, in the absence of nerve injury, mimicking this increase reduces the Kcna2 promoter activity, diminishes Kcna2 expression, decreases Kv current, increases excitability in DRG neurons and leads to spinal cord central sensitization and neuropathic pain symptoms. These findings suggest that DNMT3a may contribute to neuropathic pain by repressing Kcna2 expression in the DRG. PMID:28270689

Conversion from thrice- to twice-daily pregabalin dosing for pain: Economic and clinical outcomes in a veteran population.

PubMed

Okolo, Chike; Malmstrom, Robert; Duncan, Karsten; Lopez, Julio

2015-09-01

Results of a study analyzing economic and clinical outcomes one year after conversion from thrice- to twice-daily pregabalin dosing for pain are presented. A retrospective chart review was conducted at two Veterans Affairs facilities. The analyzed population included all patients receiving pregabalin for pain whose dosing was converted from thrice- to twice-daily pregabalin dosing during a one-year period. The primary endpoint was the economic impact of the conversion. Secondary endpoints included reversion to thrice-daily pregabalin dosing, pregabalin discontinuation, addition of medications for pain, and unscheduled neuropathy-related visits. Among the 57 patients included in the data analysis, 41 continued to take pregabalin twice daily, 10 had pregabalin discontinued, and 6 had dosing reverted to thrice daily. The mean age of patients and the distribution of add-on pain medications did not differ significantly between patients whose pregabalin dosing frequency remained at twice daily and patients whose frequency reverted to thrice daily. The costs associated with pregabalin therapy differed significantly between the preconversion and postconversion periods. A savings of $115,867 was realized from this conversion for both facilities combined over the course of one year. In patients receiving pregabalin for pain, conversion from thrice- to twice-daily pregabalin dosing-while maintaining the same daily dose-resulted in substantial cost savings while having little effect on clinical outcomes. Copyright © 2015 by the American Society of Health-System Pharmacists, Inc. All rights reserved.

A long noncoding RNA contributes to neuropathic pain by silencing Kcna2 in primary afferent neurons

PubMed Central

Zhao, Xiuli; Tang, Zongxiang; Zhang, Hongkang; Atianjoh, Fidelis E.; Zhao, Jian-Yuan; Liang, Lingli; Wang, Wei; Guan, Xiaowei; Kao, Sheng-Chin; Tiwari, Vinod; Gao, Yong-Jing; Hoffman, Paul N.; Cui, Hengmi; Li, Min; Dong, Xinzhong; Tao, Yuan-Xiang

2013-01-01

Neuropathic pain is a refractory disease characterized by maladaptive changes in gene transcription and translation within the sensory pathway. Long noncoding RNAs (lncRNAs) are emerging as new players in gene regulation, but how lncRNAs operate in the development of neuropathic pain is unclear. Here we identify a conserved lncRNA for Kcna2 (named Kcna2 antisense RNA) in first-order sensory neurons of rat dorsal root ganglion (DRG). Peripheral nerve injury increases Kcna2 antisense RNA expression in injured DRG through activation of myeloid zinc finger protein 1, a transcription factor that binds to Kcna2 antisense RNA gene promoter. Mimicking this increase downregulates Kcna2, reduces total Kv current, increases excitability in DRG neurons, and produces neuropathic pain symptoms. Blocking this increase reverses nerve injury-induced downregulation of DRG Kcna2 and attenuates development and maintenance of neuropathic pain. These findings suggest native Kcna2 antisense RNA as a new therapeutic target for the treatment of neuropathic pain. PMID:23792947

A 52-year-old woman with disabling peripheral neuropathy: review of diabetic polyneuropathy.

PubMed

Rutkove, Seward B

2009-10-07

Ms Q is a 52-year-old woman who has had progressive polyneuropathy in the setting of diabetes for the past 8 years. Ms Q's major disability is that of increasingly severe neuropathic pain and cramps that have been poorly responsive to a variety of therapies, including gabapentin and topiramate. The diagnosis of and differential diagnosis for diabetic polyneuropathy are reviewed herein. In general, treatment options for diabetic polyneuropathy remain primarily symptomatic. Improving the metabolic profile through weight loss, exercise, and if necessary, medications may help slow neuropathy progression. Many medications are effective in reducing pain, and newly developed ones, such as pregabalin and duloxetine, while specifically marketed for diabetic neuropathy, are likely to be no better and are considerably more expensive than older ones. Alpha-lipoic acid appears to be effective as well.

The absorption profile of pregabalin in chronic pancreatitis.

PubMed

Olesen, Anne E; Olofsen, Erik; Olesen, Søren S; Staahl, Camilla; Andresen, Trine; Dahan, Albert; Drewes, Asbjørn M

2012-12-01

It was recently shown that pregabalin decreased pain associated with chronic pancreatitis. It is well known that pancreatitis patients suffer from fat malabsorption with accompanying diarrhoea because of loss of exocrine pancreatic enzyme production. This may lead to changes in the mucosal surface in the small intestine and possibly affect the absorption of pregabalin. The pharmacokinetics of pregabalin has never been investigated in patients suffering from chronic pancreatitis. The aim of this study was to develop a population pharmacokinetic model of pregabalin administered to patients with chronic pancreatitis. The pregabalin population pharmacokinetic analysis was conducted on data from fifteen patients with chronic pancreatitis. Each patient received 75 mg of pregabalin (oral capsule). Pregabalin concentrations were measured using a validated liquid chromatographic method. Data analysis was performed using non-linear mixed effects modelling methodology as implemented by NONMEM. A one-compartment model with first-order absorption and elimination adequately described pregabalin pharmacokinetics. Time to maximum observed plasma concentration (T(max) ) was 1.53 (95% CI 1.09-2.05). The maximum plasma concentration (C(max) ) was 1.98 μg/ml (95% CI 1.69-2.34), and area under the plasma concentration-time profile (area under the curve) was 18.2 μg*hr/ml (95% CI 14.7-26.3). Pregabalin is well absorbed in patients with chronic pancreatitis, and the pharmacokinetic profile of pregabalin is not extensively affected by chronic pancreatitis. © 2012 The Authors Basic & Clinical Pharmacology & Toxicology © 2012 Nordic Pharmacological Society.

Antiepileptic drugs for chronic non-cancer pain in children and adolescents.

PubMed

Cooper, Tess E; Wiffen, Philip J; Heathcote, Lauren C; Clinch, Jacqui; Howard, Richard; Krane, Elliot; Lord, Susan M; Sethna, Navil; Schechter, Neil; Wood, Chantal

2017-08-05

Pain is a common feature of childhood and adolescence around the world, and for many young people, that pain is chronic. The World Health Organization (WHO) guidelines for pharmacological treatments for children's persisting pain acknowledge that pain in children is a major public health concern of high significance in most parts of the world. While in the past, pain was largely dismissed and was frequently left untreated, views on children's pain have changed over time, and relief of pain is now seen as importantWe designed a suite of seven reviews on chronic non-cancer pain and cancer pain (looking at antidepressants, antiepileptic drugs, non-steroidal anti-inflammatory drugs, opioids, and paracetamol) in order to review the evidence for children's pain utilising pharmacological interventions in children and adolescents.As the leading cause of morbidity in the world today, chronic disease (and its associated pain) is a major health concern. Chronic pain (that is pain lasting three months or longer) can occur in the paediatric population in a variety of pathophysiological classifications (nociceptive, neuropathic, or idiopathic) relating to genetic conditions, nerve damage pain, chronic musculoskeletal pain, and chronic abdominal pain, and for other unknown reasons.Antiepileptic (anticonvulsant) drugs, which were originally developed to treat convulsions in people with epilepsy, have in recent years been used to provide pain relief in adults for many chronic painful conditions and are now recommended for the treatment of chronic pain in the WHO list of essential medicines. Known side effects of antiepileptic drugs range from sweating, headache, elevated temperature, nausea, and abdominal pain to more serious effects including mental or motor function impairment. To assess the analgesic efficacy and adverse events of antiepileptic drugs used to treat chronic non-cancer pain in children and adolescents aged between birth and 17 years, in any setting. We searched the Cochrane Central Register of Controlled Trials (CENTRAL) via the Cochrane Register of Studies Online, MEDLINE via Ovid, and Embase via Ovid from inception to 6 September 2016. We also searched the reference lists of retrieved studies and reviews as well as online clinical trial registries. Randomised controlled trials, with or without blinding, by any route, treating chronic non-cancer pain in children and adolescents, comparing any antiepileptic drug with placebo or an active comparator. Two review authors independently assessed studies for eligibility. We planned to use dichotomous data to calculate risk ratio and number needed to treat for one additional event, using standard methods if data were available. We assessed the evidence using GRADE and created two 'Summary of findings' tables. We included two studies with a total of 141 participants (aged 7 to 18 years) with chronic neuropathic pain, complex regional pain syndrome type 1 (CRPS-I), or fibromyalgia. One study investigated pregabalin versus placebo in participants with fibromyalgia (107 participants), and the other study investigated gabapentin versus amitriptyline in participants with CRPS-I or neuropathic pain (34 participants). We were unable to perform any quantitative analysis.Risk of bias for the two included studies varied, due to issues with randomisation (low to unclear risk), blinding of outcome assessors (low to unclear risk), reporting bias (low to unclear risk), the size of the study populations (high risk), and industry funding in the 'other' domain (low to unclear risk). We judged the remaining domains of sequence generation, blinding of participants and personnel, and attrition as low risk of bias. Primary outcomesOne study (gabapentin 900 mg/day versus amitriptyline 10 mg/day, 34 participants, for 6 weeks) did not report our primary outcomes (very low-quality evidence).The second study (pregabalin 75 to 450 mg/day versus placebo 75 to 450 mg/day, 107 participants, for 15 weeks) reported no significant change in pain scores for pain relief of 30% or greater between pregabalin 18/54 (33.3%), and placebo 16/51 (31.4%), P = 0.83 (very low-quality evidence). This study also reported Patient Global Impression of Change, with the percentage of participants feeling "much or very much improved" with pregabalin 53.1%, and placebo 29.5% (very low-quality evidence).We downgraded the evidence by three levels to very low for one of two reasons: due to the fact that there was no evidence to support or refute the use of the intervention, or that there were too few data and the number of events was too small to be meaningful. Secondary outcomesIn one small study, adverse events were uncommon: gabapentin 2 participants (2 adverse events); amitriptyline 1 participant (1 adverse event) (6-week trial). The second study reported a higher number of adverse events: pregabalin 38 participants (167 adverse events); placebo 34 participants (132 adverse events) (15-week trial) (very low-quality evidence).Withdrawals due to adverse events were infrequent in both studies: pregabalin (4 participants), placebo (4 participants), gabapentin (2 participants), and amitriptyline (1 participant) (very low-quality evidence).Serious adverse events were reported in both studies. One study reported only one serious adverse event (cholelithiasis and major depression resulting in hospitalisation in the pregabalin group) and the other study reported no serious adverse events (very low-quality evidence).There were few or no data for our remaining secondary outcomes (very low-quality evidence).We downgraded the evidence by three levels to very low due to too few data and the fact that the number of events was too small to be meaningful. This review identified only two small studies, with insufficient data for analysis.As we could undertake no meta-analysis, we were unable to comment about efficacy or harm from the use of antiepileptic drugs to treat chronic non-cancer pain in children and adolescents. Similarly, we could not comment on our remaining secondary outcomes: Carer Global Impression of Change; requirement for rescue analgesia; sleep duration and quality; acceptability of treatment; physical functioning; and quality of life.We know from adult randomised controlled trials that some antiepileptics, such as gabapentin and pregabalin, can be effective in certain chronic pain conditions.We found no evidence to support or refute the use of antiepileptic drugs to treat chronic non-cancer pain in children and adolescents.

Clinical, Electrophysiological, and Serological Evaluation of Patients with Cramp-Fasciculation Syndrome

PubMed Central

POYRAZ, Mürüvvet; MATUR, Zeliha; AYSAL, Fikret; TÜZÜN, Erdem; HANOĞLU, Lütfü; ÖGE, A. Emre

2017-01-01

Introduction Cramp-fasciculation syndrome (CFS) is a rare peripheral nerve hyperexcitability syndrome. There are only a few reports on clinical and serological profile of a CFS cohort that was followed up by a single outpatient clinic. Methods Clinical, electrophysiological, and serological features of 6 CFS patients (5 men, 1 woman; 27–65 years old) were investigated. Results All patients presented with cramps, fasciculations, muscle pain, and autonomic symptoms, and 2 also reported numbness and burning sensation in limbs, suggestive of neuropathic pain. Antibodies to uncharacterized voltage-gated potassium channel (VGKC)-complex proteins were found in 2 patients and to contactin-associated protein-like 2 (CASPR2) in 1 patient. None of the patients had a tumor. Most of the patients revealed prolonged after-discharges following tibial nerve stimulation. Nerve conduction studies and R-R interval variability tests were normal, whereas sympathetic skin responses were increased in amplitude in 3 seronegative patients. Five patients showed favorable response to carbamazepine or pregabalin treatment, whereas 1 VGKC-antibody-positive patient was resistant to carbamazepine and immunosuppressant treatment. Conclusion Neuropathic pain and VGKC-complex antibodies may be encountered in CFS patients. Although autonomic symptoms are commonly found in CFS, routine autonomic system tests which are done in electrophysiology laboratories might yield normal results. PMID:28680318

Effect of pregabalin on fear-based conditioned avoidance learning and spatial learning in a mouse model of scopolamine-induced amnesia.

PubMed

Sałat, Kinga; Podkowa, Adrian; Malikowska, Natalia; Trajer, Jędrzej

2017-03-01

Cognitive deficits are one of the frequent symptoms accompanying epilepsy or its treatment. In this study, the effect on cognition of intraperitoneally administered antiepileptic drug, pregabalin (10 mg/kg), was investigated in scopolamine-induced memory-impaired mice in the passive avoidance task and Morris water maze task. The effect of scopolamine and pregabalin on animals' locomotor activity was also studied. In the retention phase of the passive avoidance task, pregabalin reversed memory deficits induced by scopolamine (p < 0.05). During the acquisition phase of the Morris water maze pregabalin-treated memory-impaired mice performed the test with longer escape latencies than the vehicle-treated mice (significant at p < 0.05 on Day 5, and at p < 0.001 on Day 6). There were no differences in this parameter between the scopolamine-treated control group and pregabalin-treated memory-impaired mice, which indicated that pregabalin had no influence on spatial learning in this task. During the probe trial a significant difference (p < 0.05) was observed in terms of the mean number of target crossings between vehicle-treated mice and pregabalin-treated memory-impaired mice but there was no difference between the scopolamine-treated control group and mice treated with pregabalin + scopolamine. Pregabalin did not influence locomotor activity increased by scopolamine. In passive avoidance task, pregabalin reversed learning deficits induced by scopolamine. In the Morris water maze, pregabalin did not influence spatial learning deficits induced by scopolamine. These results are relevant for epileptic patients treated with pregabalin and those who use it for other therapeutic indications (anxiety, pain).

The topical 5% lidocaine medicated plaster in localized neuropathic pain: a reappraisal of the clinical evidence

PubMed Central

de León-Casasola, Oscar A; Mayoral, Victor

2016-01-01

Topical 5% lidocaine medicated plasters represent a well-established first-line option for the treatment of peripheral localized neuropathic pain (LNP). This review provides an updated overview of the clinical evidence (randomized, controlled, and open-label clinical studies, real-life daily clinical practice, and case series). The 5% lidocaine medicated plaster effectively provides pain relief in postherpetic neuralgia, and data from a large open-label controlled study indicate that the 5% lidocaine medicated plaster is as effective as systemic pregabalin in postherpetic neuralgia and painful diabetic polyneuropathy but with an improved tolerability profile. Additionally, improved analgesia and fewer side effects were experienced by patients treated synchronously with the 5% lidocaine medicated plaster, further demonstrating the value of multimodal analgesia in LNP. The 5% lidocaine medicated plaster provides continued benefit after long-term (≤7 years) use and is also effective in various other LNP conditions. Minor application-site reactions are the most common adverse events associated with the 5% lidocaine medicated plaster; there is minimal risk of systemic adverse events and drug–drug interactions. Although further well-controlled studies are warranted, the 5% lidocaine medicated plaster is efficacious and safe in LNP and may have particular clinical benefit in elderly and/or medically compromised patients because of the low incidence of adverse events. PMID:26929664

Gene Therapy for Neuropathic Pain by Silencing of TNF-α Expression with Lentiviral Vectors Targeting the Dorsal Root Ganglion in Mice

PubMed Central

Ogawa, Nobuhiro; Kawai, Hiromichi; Terashima, Tomoya; Kojima, Hideto; Oka, Kazuhiro; Chan, Lawrence; Maegawa, Hiroshi

2014-01-01

Neuropathic pain can be a debilitating condition. Many types of drugs that have been used to treat neuropathic pain have only limited efficacy. Recent studies indicate that pro-inflammatory mediators including tumor necrosis factor α (TNF-α) are involved in the pathogenesis of neuropathic pain. In the present study, we engineered a gene therapy strategy to relieve neuropathic pain by silencing TNF-α expression in the dorsal root ganglion (DRG) using lentiviral vectors expressing TNF short hairpin RNA1-4 (LV-TNF-shRNA1-4) in mice. First, based on its efficacy in silencing TNF-α in vitro, we selected shRNA3 to construct LV-TNF-shRNA3 for in vivo study. We used L5 spinal nerve transection (SNT) mice as a neuropathic pain model. These animals were found to display up-regulated mRNA expression of activating transcription factor 3 (ATF3) and neuropeptide Y (NPY), injury markers, and interleukin (IL)-6, an inflammatory cytokine in the ipsilateral L5 DRG. Injection of LV-TNF-shRNA3 onto the proximal transected site suppressed significantly the mRNA levels of ATF3, NPY and IL-6, reduced mechanical allodynia and neuronal cell death of DRG neurons. These results suggest that lentiviral-mediated silencing of TNF-α in DRG relieves neuropathic pain and reduces neuronal cell death, and may constitute a novel therapeutic option for neuropathic pain. PMID:24642694

Update on neuropathic pain treatment for trigeminal neuralgia

PubMed Central

Al-Quliti, Khalid W.

2015-01-01

Trigeminal neuralgia is a syndrome of unilateral, paroxysmal, stabbing facial pain, originating from the trigeminal nerve. Careful history of typical symptoms is crucial for diagnosis. Most cases are caused by vascular compression of the trigeminal root adjacent to the pons leading to focal demyelination and ephaptic axonal transmission. Brain imaging is required to exclude secondary causes. Many medical and surgical treatments are available. Most patients respond well to pharmacotherapy; carbamazepine and oxcarbazepine are first line therapy, while lamotrigine and baclofen are considered second line treatments. Other drugs such as topiramate, levetiracetam, gabapentin, pregabalin, and botulinum toxin-A are alternative treatments. Surgical options are available if medications are no longer effective or tolerated. Microvascular decompression, gamma knife radiosurgery, and percutaneous rhizotomies are most promising surgical alternatives. This paper reviews the medical and surgical therapeutic options for the treatment of trigeminal neuralgia, based on available evidence and guidelines. PMID:25864062

Early improvement with pregabalin predicts endpoint response in patients with generalized anxiety disorder: an integrated and predictive data analysis.

PubMed

Montgomery, Stuart A; Lyndon, Gavin; Almas, Mary; Whalen, Ed; Prieto, Rita

2017-01-01

Generalized anxiety disorder (GAD), a common mental disorder, has several treatment options including pregabalin. Not all patients respond to treatment; quickly determining which patients will respond is an important treatment goal. Patient-level data were pooled from nine phase II and III randomized, double-blind, short-term, placebo-controlled trials of pregabalin for the treatment of GAD. Efficacy outcomes included the change from baseline in the Hamilton Anxiety Scale (HAM-A) total score and psychic and somatic subscales. Predictive modelling assessed baseline characteristics and early clinical responses to determine those predictive of clinical improvement at endpoint. A total of 2155 patients were included in the analysis (1447 pregabalin, 708 placebo). Pregabalin significantly improved the HAM-A total score compared with the placebo at endpoint, treatment difference (95% confidence interval), -2.61 (-3.21 to -2.01), P<0.0001. Pregabalin significantly improved HAM-A psychic and somatic scores compared with placebo, -1.52 (-1.85 to -1.18), P<0.0001, and -1.10 (-1.41 to -0.80), P<0.0001, respectively. Response to pregabalin in the first 1-2 weeks (≥20 or ≥30% improvement in HAM-A total, psychic or somatic score) was predictive of an endpoint greater than or equal to 50% improvement in the HAM-A total score. Pregabalin is an effective treatment option for patients with GAD. Patients with early response to pregabalin are more likely to respond significantly at endpoint.

Effects of pregabalin on brain edema, neurologic and histologic outcomes in experimental traumatic brain injury.

PubMed

Shamsi Meymandi, Manzumeh; Soltani, Zahra; Sepehri, Gholamreza; Amiresmaili, Sedigheh; Farahani, Fatemeh; Moeini Aghtaei, Mohammadmehdi

2018-05-03

Brain edema and increased intracranial pressure (ICP) are among the main causes of neurological disturbance and mortality following traumatic brain injury (TBI). Since pregabalin neuroprotective effects have been shown, this study was performed to evaluate the possible neuroprotective effects of pregabalin in experimental TBI of male rats. Adult male Wistar rats were divided into 4 groups: sham, vehicle, pregabalin 30 mg/kg and pregabalin 60 mg/kg. TBI was induced in vehicle and pregabalin groups by Marmarou method. Pregabalin was administered 30 min after TBI. Sham and vehicle groups received saline. Brain water and Evans blue content and histopathological changes were evaluated 24, 5 and 24 h after TBI, respectively. The ICP and neurological outcomes (veterinary coma scale, VCS) were recorded before, 1 h and 24 h post TBI. The results showed a significant reduction in brain water content and ICP, and a significant increase in VCS of pregabalin group (60 mg/kg) as compared to vehicle group (P < 0.05). Also, pregabalin reduced brain edema and apoptosis score as compared to vehicle group. Post TBI pregabalin administration revealed a delayed but significant improvement in ICP and neurological outcomes in experimental TBI. The underlying mechanism(s) was not determined and needs further investigation. Copyright © 2018 Elsevier Inc. All rights reserved.

Endogenous analgesic effect of pregabalin: A double-blind and randomized controlled trial.

PubMed

Sugimine, S; Saito, S; Araki, T; Yamamoto, K; Obata, H

2017-07-01

Conditioned pain modulation (CPM) is widely used to measure endogenous analgesia, and a recent study indicated that drugs that act on endogenous analgesia are more effective in individuals with lower CPM. Recent animal studies have indicated that pregabalin activates endogenous analgesia by stimulating the descending pain inhibitory system. The present study examined whether the analgesic effect of pregabalin is greater in individuals with lower original endogenous analgesia using CPM. Fifty-nine healthy subjects were randomly assigned to either a pregabalin group or a placebo group, and 50 of them completed the study. CPM was measured before and after pregabalin or placebo administration. The correlation of initial CPM to change in CPM was compared between the pregabalin and placebo groups. Initial CPM was significantly correlated with the change in CPM in the pregabalin group (r = -0.73, p < 0.0001) but not in the placebo group (p = 0.56) (difference in correlation coefficients between groups; p = 0.004). Furthermore, the initial CPM significantly affected the change in CPM in the pregabalin group but not in the placebo group (pregabalin group: adj R 2  = 0.51, p < 0.001, y = -0.54x + 2.98; placebo group: p = 0.56, significant difference in regression slopes; p = 0.015). These results indicate that pregabalin has a higher endogenous analgesic effect in individuals with lower original endogenous analgesia. The analgesic effect of pregabalin depends on the original endogenous analgesia status. Its effect on conditioned pain modulation (CPM) was stronger for subjects with lower original endogenous analgesia, suggesting that the mechanism of pregabalin involves the improvement of endogenous analgesia. © 2017 European Pain Federation - EFIC®.

Safety and efficacy of pregabalin in adolescents with fibromyalgia: a randomized, double-blind, placebo-controlled trial and a 6-month open-label extension study.

PubMed

Arnold, Lesley M; Schikler, Kenneth N; Bateman, Lucinda; Khan, Tahira; Pauer, Lynne; Bhadra-Brown, Pritha; Clair, Andrew; Chew, Marci L; Scavone, Joseph

2016-07-30

Fibromyalgia (FM) is a common pain condition characterized by widespread musculoskeletal pain and tenderness. Pregabalin is an approved treatment for adults in the United States, but there are no approved treatments for adolescents with FM. This was a 15-week, randomized, double-blind, placebo-controlled study and 6-month open-label safety trial of flexible-dose pregabalin (75-450 mg/day) for the treatment of adolescents (12-17 years) with FM. Primary outcome was change in mean pain score at endpoint (scored from 0-10, with 24-h recall). Secondary outcomes included global assessments and measures of pain, sleep, and FM impact. A total of 107 subjects were randomized to treatment (54 pregabalin, 53 placebo) and 80 completed the study (44 pregabalin, 36 placebo). Improvement in mean pain score at endpoint with pregabalin versus placebo was not statistically significant, treatment difference (95 % CI), -0.66 (-1.51, 0.18), P = 0.121. There were significant improvements with pregabalin versus placebo in secondary outcomes of change in pain score by week (P < 0.05 for 10 of 15 weeks); change in pain score at week 15 (1-week recall), treatment difference (95 % CI), -0.87 (-1.68, -0.05), P = 0.037; and patient global impression of change, 53.1 % versus 29.5 % very much or much improved (P = 0.013). Trends toward improvement with pregabalin in other secondary outcomes measuring pain, sleep, and FM impact were not significant. Safety was consistent with the known profile of pregabalin in adults with FM. Pregabalin did not significantly improve the mean pain score in adolescents with FM. There were significant improvements in secondary outcomes measuring pain and impression of change. NCT01020474 ; NCT01020526 .

Pregabalin Improves Pain Scores in Patients with Fibromyalgia Irrespective of Comorbid Osteoarthritis.

PubMed

Argoff, Charles E; Emir, Birol; Whalen, Ed; Ortiz, Marie; Pauer, Lynne; Clair, Andrew

2016-11-01

Fibromyalgia (FM) is a chronic pain disorder with patients frequently suffering from comorbid conditions, including osteoarthritis (OA). Data on how FM patients with comorbid OA respond to recommended therapies (such as pregabalin) could help their treatment. This was a pooled exploratory analysis of three randomized placebo-controlled clinical trials of pregabalin in FM patients to assess the impact of comorbid OA on the response to pregabalin. Patients were divided into those with and without comorbid OA. Difference in change in least squares (LS) mean pain score at endpoint (assessed by 0-10 numeric rating scale, controlled for baseline pain score) with pregabalin (300 mg/day and 450 mg/day) vs placebo was assessed. Changes in Patient Global Impression of Change (PGIC) responders and Fibromyalgia Impact Questionnaire (FIQ) total score were also assessed. There were 1665 patients in the analysis set (558, placebo; 552, pregabalin 300 mg/day; 555, pregabalin 450 mg/day), including 296 with comorbid OA. Pregabalin 450 mg/day significantly improved the LS mean (95% confidence interval) difference in pain score vs placebo in patients with (0.99 [0.44, 1.55], P < 0.001), and without (0.64 [0.39, 0.89], P < 0.001) OA. Improvements with pregabalin 300 mg/day with (0.31 [-0.25, 0.86], P = 0.276) and without (0.51 [0.25, 0.76], P < 0.001) OA were not consistently significant. Improvements in PGIC and FIQ total score were observed in patients with and without comorbid OA. FM patients with or without comorbid OA respond to treatment with pregabalin 450mg/day with significant improvements in pain intensity scores. These data could provide guidance to healthcare professionals treating these patients. © 2016 American Academy of Pain Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Pregabalin Versus Pramipexole: Effects on Sleep Disturbance in Restless Legs Syndrome

PubMed Central

Garcia-Borreguero, Diego; Patrick, Jeffrey; DuBrava, Sarah; Becker, Philip M.; Lankford, Alan; Chen, Crystal; Miceli, Jeffrey; Knapp, Lloyd; Allen, Richard P.

2014-01-01

Study Objectives: To compare pregabalin versus placebo and pramipexole for reducing restless legs syndrome (RLS)-related sleep disturbance. Design: Randomized, double-blinded, crossover trial. Setting: Twenty-three US sleep centers. Participants: Eighty-five individuals with moderate to severe idiopathic RLS and associated sleep disturbance. Interventions: Participants were randomized across 6 treatment sequences comprising three 4-week periods on pregabalin 300 mg/day (n = 75), pramipexole 0.5 mg/day (n = 76), or placebo (n = 73). Measurements and Results: Polysomnography was conducted over 2 nights at the end of each period. Primary (wake after sleep onset [WASO], pregabalin vs placebo) and key secondary endpoints were analyzed for statistical significance, with descriptive statistics for other endpoints. Pregabalin improved sleep maintenance, demonstrated by reductions in WASO (-27.1 min vs placebo [P < 0.0001]; -26.9 vs pramipexole) and number of awakenings after sleep onset (-2.7 vs placebo; -7.9 vs pramipexole [P < 0.0001]) by polysomnography, and an increase in subjective total sleep time (30.8 min vs placebo [P < 0.0001]; 26.8 vs pramipexole). Pregabalin also increased slow wave sleep duration (20.9 min vs placebo; 32.1 vs pramipexole [P < 0.0001]). Reduction in periodic limb movement arousal index (PLMAI) with pregabalin was similar to pramipexole and greater than placebo (-3.7 PLMA/h [P < 0.0001]), although reduction in total PLM in sleep was less than for pramipexole. Conclusions: This study demonstrated improvements in objective and subjective measures of sleep maintenance and sleep architecture with pregabalin compared with placebo and pramipexole. Effects of pregabalin on periodic limb movement arousal index were comparable to pramipexole. Trial Registration: ClinicalTrials.gov identifier, NCT00991276; http://clinicaltrials.gov/show/NCT00991276 Citation: Garcia-Borreguero D; Patrick J; DuBrava S; Becker PM; Lankford A; Chen C; Miceli J; Knapp L; Allen RP. Pregabalin versus pramipexole: effects on sleep disturbance in restless legs syndrome. SLEEP 2014;37(4):635-643. PMID:24899755

Pharmacological kynurenine 3-monooxygenase enzyme inhibition significantly reduces neuropathic pain in a rat model.

PubMed

Rojewska, Ewelina; Piotrowska, Anna; Makuch, Wioletta; Przewlocka, Barbara; Mika, Joanna

2016-03-01

Recent studies have highlighted the involvement of the kynurenine pathway in the pathology of neurodegenerative diseases, but the role of this system in neuropathic pain requires further extensive research. Therefore, the aim of our study was to examine the role of kynurenine 3-monooxygenase (Kmo), an enzyme that is important in this pathway, in a rat model of neuropathy after chronic constriction injury (CCI) to the sciatic nerve. For the first time, we demonstrated that the injury-induced increase in the Kmo mRNA levels in the spinal cord and the dorsal root ganglia (DRG) was reduced by chronic administration of the microglial inhibitor minocycline and that this effect paralleled a decrease in the intensity of neuropathy. Further, minocycline administration alleviated the lipopolysaccharide (LPS)-induced upregulation of Kmo mRNA expression in microglial cell cultures. Moreover, we demonstrated that not only indirect inhibition of Kmo using minocycline but also direct inhibition using Kmo inhibitors (Ro61-6048 and JM6) decreased neuropathic pain intensity on the third and the seventh days after CCI. Chronic Ro61-6048 administration diminished the protein levels of IBA-1, IL-6, IL-1beta and NOS2 in the spinal cord and/or the DRG. Both Kmo inhibitors potentiated the analgesic properties of morphine. In summary, our data suggest that in neuropathic pain model, inhibiting Kmo function significantly reduces pain symptoms and enhances the effectiveness of morphine. The results of our studies show that the kynurenine pathway is an important mediator of neuropathic pain pathology and indicate that Kmo represents a novel pharmacological target for the treatment of neuropathy. Copyright © 2015 Elsevier Ltd. All rights reserved.

Pregabalin- and azithromycin-induced rhabdomyolysis with purpura: An unrecognized interaction: A case report.

PubMed

Kato, Kazuya; Iwasaki, Yoshiaki; Onodera, Kazuhiko; Higuchi, Mineko; Kato, Kimitaka; Kato, Yurina; Tsutsui, Masato; Taniguchi, Masahiko; Furukawa, Hiroyuki

2016-01-01

Rhabdomyolysis associated with the use of pregabalin or azithromycin has been demonstrated to be a rare but potentially life-threatening adverse event. Here, we report an extremely rare case of rhabdomyolysis with purpura in a patient who had used pregabalin and azithromycin. We present the case of a 75-year-old woman with a history of fibromyalgia who was admitted with mild limb weakness and lower abdominal purpura. She was prescribed pregabalin (75mg, twice daily) for almost 3 months to treat chronic back pain. Her medical history revealed that 3days before admission, she began experiencing acute bronchitis and was treated with a single dose of azithromycin (500mg). She had developed rapid onset severe myalgia, mild whole body edema, muscle weakness leading to gait instability, abdominal purpura and tender purpura on the lower extremities. Laboratory values included a white blood cell count of 25,400/mL and a creatinine phosphokinase (CPK) concentration of 1250 IU/L. Based on these findings and the patient's clinical history, a diagnosis of pregabalin- and azithromycin-induced rhabdomyolysis was made. The long-term use of pregabalin and the initiation azithromycin therapy followed by a rapid onset of rhabdomyolysis is indicative of a drug interaction between pregabalin and azithromycin. We report an extremely rare case of rhabdomyolysis with purpura caused by a drug interaction between pregabalin and azithromycin. However, the mechanisms of the interactions between azithromycin on the pregabalin are still unknown. Copyright © 2016 The Author(s). Published by Elsevier Ltd.. All rights reserved.

Mechanisms and Management of Diabetic Painful Distal Symmetrical Polyneuropathy

PubMed Central

Tesfaye, Solomon; Boulton, Andrew J.M.; Dickenson, Anthony H.

2013-01-01

Although a number of the diabetic neuropathies may result in painful symptomatology, this review focuses on the most common: chronic sensorimotor distal symmetrical polyneuropathy (DSPN). It is estimated that 15–20% of diabetic patients may have painful DSPN, but not all of these will require therapy. In practice, the diagnosis of DSPN is a clinical one, whereas for longitudinal studies and clinical trials, quantitative sensory testing and electrophysiological assessment are usually necessary. A number of simple numeric rating scales are available to assess the frequency and severity of neuropathic pain. Although the exact pathophysiological processes that result in diabetic neuropathic pain remain enigmatic, both peripheral and central mechanisms have been implicated, and extend from altered channel function in peripheral nerve through enhanced spinal processing and changes in many higher centers. A number of pharmacological agents have proven efficacy in painful DSPN, but all are prone to side effects, and none impact the underlying pathophysiological abnormalities because they are only symptomatic therapy. The two first-line therapies approved by regulatory authorities for painful neuropathy are duloxetine and pregabalin. α-Lipoic acid, an antioxidant and pathogenic therapy, has evidence of efficacy but is not licensed in the U.S. and several European countries. All patients with DSPN are at increased risk of foot ulceration and require foot care, education, and if possible, regular podiatry assessment. PMID:23970715

Guidelines in the management of diabetic nerve pain: clinical utility of pregabalin.

PubMed

Vinik, Aaron I; Casellini, Carolina M

2013-01-01

Diabetic peripheral neuropathy is a common complication of diabetes. It presents as a variety of syndromes for which there is no universally accepted unique classification. Sensorimotor polyneuropathy is the most common type, affecting about 30% of diabetic patients in hospital care and 25% of those in the community. Pain is the reason for 40% of patient visits in a primary care setting, and about 20% of these have had pain for greater than 6 months. Chronic pain may be nociceptive, which occurs as a result of disease or damage to tissue with no abnormality in the nervous system. In contrast, neuropathic pain is defined as "pain arising as a direct consequence of a lesion or disease affecting the somatosensory system." Persistent neuropathic pain interferes significantly with quality of life, impairing sleep and recreation; it also significantly impacts emotional well-being, and is associated with depression, anxiety, and noncompliance with treatment. Painful diabetic peripheral neuropathy is a difficult-to-manage clinical problem, and patients with this condition are more apt to seek medical attention than those with other types of diabetic neuropathy. Early recognition of psychological problems is critical to the management of pain, and physicians need to go beyond the management of pain per se if they are to achieve success. This evidence-based review of the assessment of the patient with pain in diabetes addresses the state-of-the-art management of pain, recognizing all the conditions that produce pain in diabetes and the evidence in support of a variety of treatments currently available. A search of the full Medline database for the last 10 years was conducted in August 2012 using the terms painful diabetic peripheral neuropathy, painful diabetic peripheral polyneuropathy, painful diabetic neuropathy and pain in diabetes. In addition, recent reviews addressing this issue were adopted as necessary. In particular, reports from the American Academy of Neurology and the Toronto Consensus Panel on Diabetic Neuropathy were included. Unfortunately, the results of evidence-based studies do not necessarily take into account the presence of comorbidities, the cost of treatment, or the role of third-party payers in decision-making. Thus, this review attempts to give a more balanced view of the management of pain in the diabetic patient with neuropathy and in particular the role of pregabalin.

Pregabalin Use Among Users of Illicit Drugs: A Cross-Sectional Survey in Southern Germany.

PubMed

Snellgrove, Brendan J; Steinert, Tilman; Jaeger, Susanne

2017-10-01

The antiepileptic drug pregabalin is one of the best-selling pharmaceutical products worldwide. There are increasing concerns about its potential for misuse and dependence especially among patients with former or current substance use disorders (SUDs). Our objective was to clarify the extent and pattern of pregabalin use as well as motives and predictors in this population. We conducted a cross-sectional study with patients on a detoxification ward for illicit drugs at the Center for Psychiatry, Südwürttemberg, Ravensburg in southern Germany from August 2012 until July 2013. We used an extensive questionnaire, part of the Structured Clinical Interview for DSM-IV (Diagnostic and Statistical Manual of Mental Disorders, 4th edition) Axis I Disorders (SCID-I) and urine samples. Of the 253 participating patients, 56% had used pregabalin at least once. Of these, 92% had acquired it at least in part from illegal sources. The main motives for the use of pregabalin were the attenuation of opioid withdrawal symptoms, the augmentation of other psychotropic substances, and the psychotropic effects of pregabalin itself. Predictors for pregabalin use were opioid and sedative use as well as younger age. The criteria of dependency according to DSM-IV was met by 11% of pregabalin users and 13% of urine samples were positive for pregabalin. Use of pregabalin is common among users of illicit drugs in large parts of southern Germany, with motives for use, acquisition, and mode of use suggesting misuse. The mode of use, especially intake of high doses and concomitant use of other drugs, poses a serious risk to this population, including the development of dependency.

Rapamycin suppresses microglial activation and reduces the development of neuropathic pain after spinal cord injury.

PubMed

Tateda, Satoshi; Kanno, Haruo; Ozawa, Hiroshi; Sekiguchi, Akira; Yahata, Kenichiro; Yamaya, Seiji; Itoi, Eiji

2017-01-01

Rapamycin is an inhibitor of the mammalian target of rapamycin (mTOR) signaling pathway, plays an important role in multiple cellular functions. Our previous study showed rapamycin treatment in acute phase reduced the neural tissue damage and locomotor impairment after spinal cord injury (SCI). However, there has been no study to investigate the therapeutic effect of rapamycin on neuropathic pain after SCI. In this study, we examined whether rapamycin reduces neuropathic pain following SCI in mice. We used a mouse model of thoracic spinal cord contusion injury, and divided the mice into the rapamycin-treated and the vehicle-treated groups. The rapamycin-treated mice were intraperitoneally injected with rapamycin (1 mg/kg) 4 h after SCI. The rapamycin treatment suppressed phosphorylated-p70S6K in the injured spinal cord that indicated inhibition of mTOR. The rapamycin treatment significantly improved not only locomotor function, but also mechanical and thermal hypersensitivity in the hindpaws after SCI. In an immunohistochemical analysis, Iba-1-stained microglia in the lumbar spinal cord was significantly decreased in the rapamycin-treated mice. In addition, the activity of p38 MAPK in the lumbar spinal cord was significantly attenuated by rapamycin treatment. Furthermore, phosphorylated-p38 MAPK-positive microglia was relatively decreased in the rapamycin-treated mice. These results indicated rapamycin administration in acute phase to reduce secondary neural tissue damage can contribute to the suppression of the microglial activation in the lumbar spinal cord and attenuate the development of neuropathic pain after SCI. The present study first demonstrated that rapamycin has significant therapeutic potential to reduce the development of neuropathic pain following SCI. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:93-103, 2017. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.

Once daily controlled-release pregabalin in the treatment of patients with fibromyalgia: a phase III, double-blind, randomized withdrawal, placebo-controlled study.

PubMed

Arnold, Lesley M; Arsenault, Pierre; Huffman, Cynthia; Patrick, Jeffrey L; Messig, Michael; Chew, Marci L; Sanin, Luis; Scavone, Joseph M; Pauer, Lynne; Clair, Andrew G

2014-10-01

Safety and efficacy of a once daily controlled-released (CR) formulation of pregabalin was evaluated in patients with fibromyalgia using a placebo-controlled, randomized withdrawal design. This multicenter study included 6 week single-blind pregabalin CR treatment followed by 13 week double-blind treatment with placebo or pregabalin CR. The starting dose of 165 mg/day was escalated during the first 3 weeks, up to 495 mg/day based on efficacy and tolerability. Patients with ≥50% reduction in average daily pain score at the end of the single-blind phase were randomized to continue pregabalin CR at the optimized dose (330-495 mg/day) or to placebo. The primary endpoint was time to loss of therapeutic response (LTR), defined as <30% pain reduction relative to single-blind baseline or discontinuation owing to lack of efficacy or adverse event (AE). Secondary endpoints included measures of pain severity, global assessment, functional status, tiredness/fatigue, and sleep. ClinicalTrials.gov NCT01271933. A total of 441 patients entered the single-blind phase, and 63 were randomized to pregabalin CR and 58 to placebo. The median time to LTR (Kaplan-Meier analysis) was significantly longer in the pregabalin CR group than placebo (58 vs. 22 days, p = 0.02). By trial end, 34/63 (54.0%) pregabalin CR and 41/58 (70.7%) placebo patients experienced LTR. Significantly more patients reported 'benefit from treatment' (Benefit, Satisfaction, and Willingness to Continue Scale) in the pregabalin CR group; no other secondary endpoints were statistically significant. Most AEs were mild to moderate in severity (most frequent: dizziness, somnolence). The percentage of pregabalin CR patients discontinuing because of AEs was 12.2% and 4.8% in the single-blind and double-blind phases, respectively (placebo, 0%). Time to LTR was significantly longer with pregabalin CR versus placebo in fibromyalgia patients who initially showed improvement with pregabalin CR, indicating maintenance of response. Pregabalin CR was well tolerated in most patients. Generalizability may be limited by study duration and selective population.

Guidelines in the management of diabetic nerve pain: clinical utility of pregabalin

PubMed Central

Vinik, Aaron I; Casellini, Carolina M

2013-01-01

Diabetic peripheral neuropathy is a common complication of diabetes. It presents as a variety of syndromes for which there is no universally accepted unique classification. Sensorimotor polyneuropathy is the most common type, affecting about 30% of diabetic patients in hospital care and 25% of those in the community. Pain is the reason for 40% of patient visits in a primary care setting, and about 20% of these have had pain for greater than 6 months. Chronic pain may be nociceptive, which occurs as a result of disease or damage to tissue with no abnormality in the nervous system. In contrast, neuropathic pain is defined as “pain arising as a direct consequence of a lesion or disease affecting the somatosensory system.” Persistent neuropathic pain interferes significantly with quality of life, impairing sleep and recreation; it also significantly impacts emotional well-being, and is associated with depression, anxiety, and noncompliance with treatment. Painful diabetic peripheral neuropathy is a difficult-to-manage clinical problem, and patients with this condition are more apt to seek medical attention than those with other types of diabetic neuropathy. Early recognition of psychological problems is critical to the management of pain, and physicians need to go beyond the management of pain per se if they are to achieve success. This evidence-based review of the assessment of the patient with pain in diabetes addresses the state-of-the-art management of pain, recognizing all the conditions that produce pain in diabetes and the evidence in support of a variety of treatments currently available. A search of the full Medline database for the last 10 years was conducted in August 2012 using the terms painful diabetic peripheral neuropathy, painful diabetic peripheral polyneuropathy, painful diabetic neuropathy and pain in diabetes. In addition, recent reviews addressing this issue were adopted as necessary. In particular, reports from the American Academy of Neurology and the Toronto Consensus Panel on Diabetic Neuropathy were included. Unfortunately, the results of evidence-based studies do not necessarily take into account the presence of comorbidities, the cost of treatment, or the role of third-party payers in decision-making. Thus, this review attempts to give a more balanced view of the management of pain in the diabetic patient with neuropathy and in particular the role of pregabalin. PMID:23467255

Pregabalin role in inhibition of morphine analgesic tolerance and physical dependency in rats.

PubMed

Hasanein, Parisa; Shakeri, Saeed

2014-11-05

Pregabalin is recently proposed as analgesic or adjuvant in pain management. While previous preclinical investigations have evaluated pregabalin-opioid interactions, the effect of pregabalin on opioid tolerance and dependency has not yet been studied. Here we evaluated the effects of different doses of pregabalin (50, 100 and 200mg/kg, s.c.) on morphine-induced tolerance and dependency in rats. Adult male Wistar rats were rendered tolerant to analgesic effect of morphine by injection of morphine (10mg/kg, s.c.) twice daily for 7 days. To develop morphine dependence, rats were given escalating doses of morphine. To determine the effect of pregabalin on the development of morphine tolerance and dependence, different doses of pregabalin were administrated before morphine. The tail-flick and naloxone precipitation withdrawal tests were used to evaluate the degree of tolerance and dependence, respectively. Chronic morphine-injected rats showed significant decrements in the percentage maximum possible effect (%MPE) of morphine on the days 5 and 7 (32.5%±3.5, 21.5%±4, respectively) compared to the first day (100%) which showed morphine tolerance. Pregabalin 200mg/kg completely prevented the development of morphine tolerance. In addition, concomitant treatment of morphine with pregabalin attenuated almost all of the naloxone-induced withdrawal signs which include weight loss, jumping, penis licking, teeth chattering, wet dog shakes, rearing, standing, sniffing, face grooming and paw tremor. These data show that pregabaline has a potential anti-tolerant/anti-dependence property against chronic usage of morphine. Therefore, pregabalin appears to be a promising candidate for the treatment of opioid addiction after confirming by future clinical studies. Copyright © 2014 Elsevier B.V. All rights reserved.

Effects of new fluorinated analogues of GABA, pregabalin bioisosters, on the ambient level and exocytotic release of [3H]GABA from rat brain nerve terminals.

PubMed

Borisova, T; Pozdnyakova, N; Shaitanova, E; Gerus, I; Dudarenko, M; Haufe, G; Kukhar, V

2017-01-15

Recently, we have shown that new fluorinated analogues of γ-aminobutyric acid (GABA), bioisosters of pregabalin (β-i-Bu-GABA), i.e. β-polyfluoroalkyl-GABAs (FGABAs), with substituents: β-CF 3 -β-OH (1), β-CF 3 (2); β-CF 2 CF 2 H (3), are able to increase the initial rate of [ 3 H]GABA uptake by isolated rat brain nerve terminals (synaptosomes), and this effect is higher than that of pregabalin. So, synthesized FGABAs are structural but not functional analogues of GABA. Herein, we assessed the effects of synthesized FGABAs (100μM) on the ambient level and exocytotic release of [ 3 H]GABA in nerve terminals and compared with those of pregabalin (100μM). It was shown that FGABAs 1-3 did not influence the ambient level of [ 3 H]GABA in the synaptosomal preparations, and this parameter was also not altered by pregabalin. During blockage of GABA transporters GAT1 by specific inhibitor NO-711, FGABAs and pregabalin also did not change ambient [ 3 H]GABA in synaptosomal preparations. Exocytotic release of [ 3 H]GABA from synaptosomes decreased in the presence of FGABAs 1-3 and pregabalin, and the effects of FGABAs 1 &3 were more significant than those of FGABAs 2 and pregabalin. FGABAs 1-3/pregabalin-induced decrease in exocytotic release of [ 3 H]GABA from synaptosomes was not a result of changes in the potential of the plasma membrane. Therefore, new synthesized FGABAs 1 &3 were able to decrease exocytotic release of [ 3 H]GABA from nerve terminals more effectively in comparison to pregabalin. Absence of unspecific side effects of FGABAs 1 &3 on the membrane potential makes these compounds perspective for medical application. Copyright © 2016 Elsevier Ltd. All rights reserved.

Results from clinical trials of a selective ionotropic glutamate receptor 5 (iGluR5) antagonist, LY5454694 tosylate, in 2 chronic pain conditions.

PubMed

Chappell, Amy S; Iyengar, Smriti; Lobo, Evelyn D; Prucka, William R

2014-06-01

This article reports results of 2 studies investigating LY545694 in pain due to osteoarthritis (OA) of the knee and diabetic peripheral neuropathic pain (DPNP). Study I randomized patients to either of 2 doses of LY545694 or to placebo, and study II randomized patients to either of 3 doses of LY545694, to pregabalin, or to placebo. No significant differences between LY545694 groups and placebo were observed on the primary (average pain severity) or secondary efficacy measures in either study. Notably, study I lacked an active control, and, in study II, pregabalin, did not separate from placebo. Treatment-emergent nausea, vomiting, and dizziness were significantly more frequent in the LY545694 groups in both trials (P⩽.05), and significantly more LY545694-treated patients discontinued because of adverse events (P<.001). Steady-state concentrations of LY545694 were comparable in patients in both studies but were lower than exposures required for efficacy in animal models of pain behavior. Because the active control did not separate from placebo in the DPNP study, the study was potentially failed, rather than negative. Without an active control, it is unknown whether the OA study was negative or failed. Consequently, efficacy of selective ionotropic glutamate receptor antagonism in chronic pain conditions may warrant further investigation. Future trials should consider different pain conditions, contain a positive control with larger patient numbers per arm, and be conducted within a single region. Copyright © 2014 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

An evidence-based review of pregabalin for the treatment of fibromyalgia.

PubMed

Arnold, Lesley M; Choy, Ernest; Clauw, Daniel J; Oka, Hiroshi; Whalen, Ed; Semel, David; Pauer, Lynne; Knapp, Lloyd

2018-04-16

Pregabalin, an α2-δ agonist, is approved for the treatment of fibromyalgia (FM) in the United States, Japan, and 37 other countries. The purpose of this article was to provide an in-depth, evidence-based summary of pregabalin for FM as demonstrated in randomized, placebo-controlled clinical studies, including open-label extensions, meta-analyses, combination studies and post-hoc analyses of clinical study data. PubMed was searched using the term "pregabalin AND fibromyalgia" and the Cochrane Library with the term "pregabalin". Both searches were conducted on 2 March 2017 with no other date limits set. Eleven randomized, double-blind, placebo-controlled clinical studies were identified including parallel group, two-way crossover and randomized withdrawal designs. One was a neuroimaging study. Five open-label extensions were also identified. Evidence of efficacy was demonstrated across the studies identified with significant and clinically relevant improvements in pain, sleep quality and patient status. The safety and tolerability profile of pregabalin is consistent across all the studies identified, including in adolescents, with dizziness and somnolence the most common adverse events reported. These efficacy and safety data are supported by meta-analyses (13 studies). Pregabalin in combination with other pharmacotherapies (7 studies) is also efficacious. Post-hoc analyses have demonstrated the onset of pregabalin efficacy as early as 1-2 days after starting treatment, examined the effect of pregabalin on other aspects of sleep beyond quality, and shown it is effective irrespective of the presence of a wide variety of patient demographic and clinical characteristics. Pregabalin is a treatment option for FM; its clinical utility has been comprehensively demonstrated.

Effect of Pregabalin on Cardiovascular Responses to Exercise and Postexercise Pain and Fatigue in Fibromyalgia: A Randomized, Double-Blind, Crossover Pilot Study

PubMed Central

White, Andrea T.; Light, Kathleen C.; Bateman, Lucinda; Hughen, Ronald W.; Vanhaitsma, Timothy A.; Light, Alan R.

2015-01-01

Pregabalin, an approved treatment for fibromyalgia (FM), has been shown to decrease sympathetic nervous system (SNS) activity and inhibit sympathetically maintained pain, but its effects on exercise responses have not been reported. Methods. Using a randomized double-blind crossover design, we assessed the effect of 5 weeks of pregabalin (versus placebo) on acute cardiovascular and subjective responses to moderate exercise in 19 FM patients. Blood pressure (BP), heart rate (HR), and ratings of perceived exertion (RPE) during exercise and ratings of pain, physical fatigue, and mental fatigue before, during, and for 48 hours after exercise were compared in patients on pregabalin versus placebo and also versus 18 healthy controls. Results. On placebo, exercise RPE and BP were significantly higher in FM patients than controls (p < 0.04). Pregabalin responders (n = 12, defined by patient satisfaction and symptom changes) had significantly lower exercise BP, HR, and RPE on pregabalin versus placebo (p < 0.03) and no longer differed from controls (p > 0.26). Cardiovascular responses of nonresponders (n = 7) were not altered by pregabalin. In responders, pregabalin improved ratings of fatigue and pain (p < 0.04), but negative effects on pain and fatigue were seen in nonresponders. Conclusions. These preliminary findings suggest that pregabalin may normalize cardiovascular and subjective responses to exercise in many FM patients. PMID:27026828

Effect of Perioperative Pregabalin on Postoperative Quality of Recovery in Patients Undergoing Off-Pump Coronary Artery Bypass Grafting (OPCABG): A Prospective, Randomized, Double-Blind Trial.

PubMed

Borde, Deepak Prakash; Futane, Savani Sameer; Asegaonkar, Balaji; Apsingekar, Pramod; Khade, Sujeet; Khodve, Bapu; Puranik, Manish; George, Antony; Joshi, Shreedhar

2017-08-01

Use of pregabalin is increasing in cardiac surgical patients. However, studies using comprehensive scoring systems are lacking on the drug's impact on postoperative recovery. The authors tested the hypothesis that perioperative oral pregabalin improves the postoperative quality of recovery as assessed using the Quality of Recovery (QoR-40) questionnaire in patients undergoing off-pump coronary artery bypass grafting (OPCABG). This was a randomized, double-blind, placebo-controlled study. Tertiary-care hospital. Patients undergoing OPCABG. Patients were assigned randomly to the following 2 groups: the pregabalin group (those who received pregabalin, 150 mg capsule orally, 1 hour before surgery and 2 days postoperatively [75 mg twice a day] starting after extubation; n = 37); and the control group (those who received 2 similar-looking multivitamin capsules at similar times; n = 34). The QoR-40 scores were noted preoperatively and 24 hours after extubation. Both groups were comparable in terms of preoperative patient characteristics and baseline QoR-40 scores. Global scores were significantly improved in the pregabalin group compared with the control group in the postoperative period (177±9 v 170±9; p = 0.002). QoR-40 values in the dimensions of emotional state (p = 0.005), physical comfort (p = 0.04), and pain (p = 0.02) were improved in the pregabalin group. Perioperative pregabalin improved postoperative quality of recovery as assessed using the QoR-40 questionnaire in patients undergoing OPCABG. Perioperative pregabalin offered advantages beyond better pain control, such as improved physical comfort and better emotional state; therefore, the drug's use in the perioperative period is recommended. Copyright © 2017 Elsevier Inc. All rights reserved.

Time to improvement of pain and sleep quality in clinical trials of pregabalin for the treatment of fibromyalgia.

PubMed

Arnold, Lesley M; Emir, Birol; Pauer, Lynne; Resnick, Malca; Clair, Andrew

2015-01-01

To determine the time to immediate and sustained clinical improvement in pain and sleep quality with pregabalin in patients with fibromyalgia. A post hoc analysis of four 8- to 14-week phase 2-3, placebo-controlled trials of fixed-dose pregabalin (150-600 mg/day) for fibromyalgia, comprising 12 pregabalin and four placebo treatment arms. A total of 2,747 patients with fibromyalgia, aged 18-82 years. Pain and sleep quality scores, recorded daily on 11-point numeric rating scales (NRSs), were analyzed to determine time to immediate improvement with pregabalin, defined as the first of ≥2 consecutive days when the mean NRS score was significantly lower for pregabalin vs placebo in those treatment arms with a significant improvement at endpoint, and time to sustained clinical improvement with pregabalin, defined as a ≥1-point reduction of the baseline NRS score of patient responders who had a ≥30% improvement on the pain NRS, sleep NRS, or Fibromyalgia Impact Questionnaire (FIQ) from baseline to endpoint, or who reported "much improved" or "very much improved" on the Patient Global Impression of Change (PGIC) at endpoint. Significant improvements in pain and sleep quality scores at endpoint vs placebo were seen in 8/12 and 11/12 pregabalin treatment arms, respectively (P < 0.05). In these arms, time to immediate improvements in pain or sleep occurred by day 1 or 2. Time to sustained clinical improvement occurred significantly earlier in pain, sleep, PGIC, and FIQ responders (P < 0.02) with pregabalin vs placebo. Both immediate and sustained clinical improvements in pain and sleep quality occurred faster with pregabalin vs placebo. Wiley Periodicals, Inc.

Pregabalin versus pramipexole: effects on sleep disturbance in restless legs syndrome.

PubMed

Garcia-Borreguero, Diego; Patrick, Jeffrey; DuBrava, Sarah; Becker, Philip M; Lankford, Alan; Chen, Crystal; Miceli, Jeffrey; Knapp, Lloyd; Allen, Richard P

2014-04-01

To compare pregabalin versus placebo and pramipexole for reducing restless legs syndrome (RLS)-related sleep disturbance. Randomized, double-blinded, crossover trial. Twenty-three US sleep centers. Eighty-five individuals with moderate to severe idiopathic RLS and associated sleep disturbance. Participants were randomized across 6 treatment sequences comprising three 4-week periods on pregabalin 300 mg/day (n = 75), pramipexole 0.5 mg/day (n = 76), or placebo (n = 73). Polysomnography was conducted over 2 nights at the end of each period. Primary (wake after sleep onset [WASO], pregabalin vs placebo) and key secondary endpoints were analyzed for statistical significance, with descriptive statistics for other endpoints. Pregabalin improved sleep maintenance, demonstrated by reductions in WASO (-27.1 min vs placebo [P < 0.0001]; -26.9 vs pramipexole) and number of awakenings after sleep onset (-2.7 vs placebo; -7.9 vs pramipexole [P < 0.0001]) by polysomnography, and an increase in subjective total sleep time (30.8 min vs placebo [P < 0.0001]; 26.8 vs pramipexole). Pregabalin also increased slow wave sleep duration (20.9 min vs placebo; 32.1 vs pramipexole [P < 0.0001]). Reduction in periodic limb movement arousal index (PLMAI) with pregabalin was similar to pramipexole and greater than placebo (-3.7 PLMA/h [P < 0.0001]), although reduction in total PLM in sleep was less than for pramipexole. This study demonstrated improvements in objective and subjective measures of sleep maintenance and sleep architecture with pregabalin compared with placebo and pramipexole. Effects of pregabalin on periodic limb movement arousal index were comparable to pramipexole. ClinicalTrials.gov identifier, NCT00991276; http://clinicaltrials.gov/show/NCT00991276.

Pregabalin misuse in methadone maintenance treatment patients in Israel: Prevalence and risk factors.

PubMed

Sason, Anat; Adelson, Miriam; Schreiber, Shaul; Peles, Einat

2018-05-29

Drug users reportedly abuse pregabalin, and its combination with opiates was related to fatalities. We aimed to estimate the prevalence of pregabalin misuse and risk factors among patients in methadone maintenance treatment (MMT). A cross-sectional study included all current MMT patients (n = 300) after excluding 9 with prescriptions, from a large tertiary medical center university-affiliated MMT clinic in Israel. Pregabalin was tested in one of the routine urine tests for other substances in December 2017. Data on urine results and patients' characteristics were retrieved from the patients' records. Pregabalin was detected among 53 (17.7%) patients. The group had higher depressive symptoms severity score (21-HAM-D) (11.1 ± 8.4 vs. 8.3 ± 7.8, p = 0.03), a higher prevalence of sero-positive HIV (13.7% vs. 4.2%, p = 0.02), sero-positive hepatitis C (66.7% vs. 50.4%, p = 0.04), DSM-IV-TR Axis I psychiatric diagnosis (54.0% vs. 41.7%, p = 0.03), and positive urine for opiates (22.6% vs. 8.9%, p = 0.008), cannabis (39.6% vs. 4.0 p < 0.0005) benzodiazepine (BDZ) (77.4% vs. 18.2%, p < 0.0005) and oxycodone (11.3% vs. 0.4%, p < 0.0005). Logistic regression found pregabalin group as more likely to be urine positive to BDZ (OR = 12.8 95%CI 5.0-32.5) cannabis (OR = 22.7, 95%CI 6.3-81.6) and oxycodone (OR = 43.9, 95%CI 3.6-541.4), with higher 21-HAM-D scores (OR = 1.1, 95%CI 1.04-1.2) and hepatitis C sera-positive (OR = 4.1, 95% CI 1.5-11.4). Unexpectedly, 13.2% of the pregabalin group had take-home dose privileges, which are rewards to non-drug abusers. High prevalence of pregabalin misuse among both BDZ abusers and non-abusers and patients with depressive symptoms supports both the inclusion of routine monitoring for pregabalin and intervention in MMT population. Copyright © 2018. Published by Elsevier B.V.

Diabetic Peripheral Neuropathy: Epidemiology, Diagnosis, and Pharmacotherapy.

PubMed

Iqbal, Zohaib; Azmi, Shazli; Yadav, Rahul; Ferdousi, Maryam; Kumar, Mohit; Cuthbertson, Daniel J; Lim, Jonathan; Malik, Rayaz A; Alam, Uazman

2018-06-01

Diabetic peripheral neuropathy (DPN) is the commonest cause of neuropathy worldwide, and its prevalence increases with the duration of diabetes. It affects approximately half of patients with diabetes. DPN is symmetric and predominantly sensory, starting distally and gradually spreading proximally in a glove-and-stocking distribution. It causes substantial morbidity and is associated with increased mortality. The unrelenting nature of pain in this condition can negatively affect a patient's sleep, mood, and functionality and result in a poor quality of life. The purpose of this review was to critically review the current literature on the diagnosis and treatment of DPN, with a focus on the treatment of neuropathic pain in DPN. A comprehensive literature review was undertaken, incorporating article searches in electronic databases (EMBASE, PubMed, OVID) and reference lists of relevant articles with the authors' expertise in DPN. This review considers seminal and novel research in epidemiology; diagnosis, especially in relation to novel surrogate end points; and the treatment of neuropathic pain in DPN. We also consider potential new pharmacotherapies for painful DPN. DPN is often misdiagnosed and inadequately treated. Other than improving glycemic control, there is no licensed pathogenetic treatment for diabetic neuropathy. Management of painful DPN remains challenging due to difficulties in personalizing therapy and ascertaining the best dosing strategy, choice of initial pharmacotherapy, consideration of combination therapy, and deciding on defining treatment for poor analgesic responders. Duloxetine and pregabalin remain first-line therapy for neuropathic pain in DPN in all 5 of the major published guidelines by the American Association of Clinical Endocrinologists, American Academy of Neurology, European Federation of Neurological Societies, National Institute of Clinical Excellence (United Kingdom), and the American Diabetes Association, and their use has been approved by the US Food and Drug Administration. Clinical recognition of DPN is imperative for allowing timely symptom management to reduce the morbidity associated with this condition. Copyright © 2018 Elsevier HS Journals, Inc. All rights reserved.

Developmental Toxicity Studies with Pregabalin in Rats: Significance of Alterations in Skull Bone Morphology.

PubMed

Morse, Dennis C; Henck, Judith W; Bailey, Steven A

2016-04-01

Pregabalin was administered to pregnant Wistar rats during organogenesis to evaluate potential developmental toxicity. In an embryo-fetal development study, compared with controls, fetuses from pregabalin-treated rats exhibited increased incidence of jugal fused to maxilla (pregabalin 1250 and 2500 mg/kg) and fusion of the nasal sutures (pregabalin 2500 mg/kg). The alterations in skull development occurred in the presence of maternal toxicity (reduced body weight gain) and developmental toxicity (reduced fetal body weight and increased skeletal variations), and were initially classified as malformations. Subsequent investigative studies in pregnant rats treated with pregabalin during organogenesis confirmed the advanced jugal fused to maxilla, and fusion of the nasal sutures at cesarean section (gestation day/postmating day [PMD] 21) in pregabalin-treated groups. In a study designed to evaluate progression of skull development, advanced jugal fused to maxilla and fusion of the nasal sutures was observed on PMD 20-25 and PMD 21-23, respectively (birth occurs approximately on PMD 22). On postnatal day (PND) 21, complete jugal fused to maxilla was observed in the majority of control and 2500 mg/kg offspring. No treatment-related differences in the incidence of skull bone fusions occurred on PND 21, indicating no permanent adverse outcome. Based on the results of the investigative studies, and a review of historical data and scientific literature, the advanced skull bone fusions were reclassified as anatomic variations. Pregabalin was not teratogenic in rats under the conditions of these studies. © 2016 Wiley Periodicals, Inc.

IL-10 mediated by herpes simplex virus vector reduces neuropathic pain induced by HIV gp120 combined with ddC in rats.

PubMed

Zheng, Wenwen; Huang, Wan; Liu, Shue; Levitt, Roy C; Candiotti, Keith A; Lubarsky, David A; Hao, Shuanglin

2014-07-30

HIV-associated sensory neuropathy affects over 50% of HIV patients and is a common peripheral nerve complication of HIV infection and highly active antiretroviral therapy (HAART). Evidence shows that painful HIV sensory neuropathy is influenced by neuroinflammatory events that include the proinflammatory molecules, MAP Kinase, tumor necrosis factor-α (TNFα), stromal cell-derived factor 1-α (SDF1α), and C-X-C chemokine receptor type 4 (CXCR4). However, the exact mechanisms of painful HIV sensory neuropathy are not known, which hinders our ability to develop effective treatments. In this study, we investigated whether inhibition of proinflammatory factors reduces the HIV-associated neuropathic pain state. Neuropathic pain was induced by peripheral HIV coat protein gp120 combined with 2',3'-dideoxycytidine (ddC, one of the nucleoside reverse transcriptase inhibitors (NRTIs)). Mechanical threshold was tested using von Frey filament fibers. Non-replicating herpes simplex virus (HSV) vectors expressing interleukin 10 (IL10) were inoculated into the hindpaws of rats. The expression of TNFα, SDF1α, and CXCR4 in the lumbar spinal cord and L4/5 dorsal root ganglia (DRG) was examined using western blots. IL-10 expression mediated by the HSV vectors resulted in a significant elevation of mechanical threshold. The anti-allodynic effect of IL-10 expression mediated by the HSV vectors lasted more than 3 weeks. The area under the effect-time curves (AUC) in mechanical threshold in rats inoculated with the HSV vectors expressing IL-10, was increased compared with the control vectors, indicating antinociceptive effect of the IL-10 vectors. The HSV vectors expressing IL-10 also concomitantly reversed the upregulation of p-p38, TNFα, SDF1α, and CXCR4 induced by gp120 in the lumbar spinal dorsal horn and/or the DRG at 2 and/or 4 weeks. The blocking of the signaling of these proinflammatory molecules is able to reduce HIV-related neuropathic pain, which provide a novel mechanism-based approach to treating HIV-associated neuropathic pain using gene therapy.

Hepatitis C-related cryoglobulinemic neuropathy: potential role of oxcarbazepine for pain control.

PubMed

Moretti, Rita; Caruso, Paola; Dal Ben, Matteo; Gazzin, Silvia; Tiribelli, Claudio

2018-01-25

Peripheral neuropathy is one most common, limiting and invalidating neurological symptom in subjects with hepatitis C virus and mixed cryoglobulinemia. Notably, the medical therapy proposed to eradicate HCV, can frequently exacerbate the painful neuropathy. Therefore, neuropathy therapies are insufficient and inadequate, and comprise immunosuppressive drugs, such as steroid or cyclosporine, intravenous immunoglobulin or plasma exchange. These have shown variable success in case reports, with a presumably temporary effect, but with major side effects. We assessed the effects of oxcarbazepine treatment in 67 cases of cryoglobulinemia related neuropathy, who did not respond to either steroid or Gabapentin, or Pregabalin. Oxcarbazepine was chosen based on the promising preliminary results. Patients treated with Oxcarbazepine showed a rapid, discrete and persistent relief of polyneuropathic signs, without consistent side effects, and with a limited interaction with concomitant drugs. These data favor the use of oxcarbazepine as a useful tool in the management of neuropathic pain associated with Hepatitis-C cryoglobulin neuropathy.

Efficacy and Safety of Pregabalin in the Treatment of Patients With Painful Diabetic Peripheral Neuropathy and Pain on Walking.

PubMed

Huffman, Cynthia; Stacey, Brett R; Tuchman, Michael; Burbridge, Claire; Li, Chunming; Parsons, Bruce; Pauer, Lynne; Scavone, Joseph M; Behar, Regina; Yurkewicz, Lorraine

2015-11-01

This randomized, double-blind, placebo-controlled, multicenter, 2-period crossover study (two 6-week treatment periods separated by a 2-week washout period) evaluated the efficacy and safety of pregabalin (150 to 300 mg/d) for treatment of pain and pain on walking in patients with painful diabetic peripheral neuropathy (DPN) who experienced pain while walking. Co-primary efficacy endpoints were: (1) mean pain score (last 7 daily pain diary scores, 0 to 10 numeric rating scale at end of each treatment period) and (2) DPN pain on walking (0 to 10 numeric rating scale immediately after walking 50 feet [15.2 m] on flat surface). Secondary endpoints included other pain parameters, patient-reported sleep, health-related quality of life, and safety measures. Two hundred three patients were treated (pregabalin, n=198; placebo, n=186), with no statistically significant treatment difference for pregabalin versus placebo in the co-primary efficacy endpoints, mean DPN pain (P=0.0656) and mean DPN pain on walking (P=0.412). A carryover effect was observed. Analysis of co-primary endpoints for period 1 showed significant treatment difference for DPN pain (P=0.034) and DPN pain on walking (P=0.001). Treatment with pregabalin resulted in significant improvements versus placebo on prespecified patient global impression of change (end of period 1; P=0.002), and sleep interference rating scale (end of period 2; P=0.011). Adverse events were more frequent with pregabalin than with placebo and caused discontinuation in 13 (6.6%) pregabalin patients versus 5 (2.7%) placebo patients. Failure to meet the co-primary objectives may be related to carryover effect from period 1 to period 2, lower pregabalin dose (150 to 300 mg/d), and/or placebo response in painful DPN.

IL-10 mediated by herpes simplex virus vector reduces neuropathic pain induced by HIV gp120 combined with ddC in rats

PubMed Central

2014-01-01

Background HIV-associated sensory neuropathy affects over 50% of HIV patients and is a common peripheral nerve complication of HIV infection and highly active antiretroviral therapy (HAART). Evidence shows that painful HIV sensory neuropathy is influenced by neuroinflammatory events that include the proinflammatory molecules, MAP Kinase, tumor necrosis factor-α (TNFα), stromal cell-derived factor 1-α (SDF1α), and C-X-C chemokine receptor type 4 (CXCR4). However, the exact mechanisms of painful HIV sensory neuropathy are not known, which hinders our ability to develop effective treatments. In this study, we investigated whether inhibition of proinflammatory factors reduces the HIV-associated neuropathic pain state. Results Neuropathic pain was induced by peripheral HIV coat protein gp120 combined with 2′,3′-dideoxycytidine (ddC, one of the nucleoside reverse transcriptase inhibitors (NRTIs)). Mechanical threshold was tested using von Frey filament fibers. Non-replicating herpes simplex virus (HSV) vectors expressing interleukin 10 (IL10) were inoculated into the hindpaws of rats. The expression of TNFα, SDF1α, and CXCR4 in the lumbar spinal cord and L4/5 dorsal root ganglia (DRG) was examined using western blots. IL-10 expression mediated by the HSV vectors resulted in a significant elevation of mechanical threshold. The anti-allodynic effect of IL-10 expression mediated by the HSV vectors lasted more than 3 weeks. The area under the effect-time curves (AUC) in mechanical threshold in rats inoculated with the HSV vectors expressing IL-10, was increased compared with the control vectors, indicating antinociceptive effect of the IL-10 vectors. The HSV vectors expressing IL-10 also concomitantly reversed the upregulation of p-p38, TNFα, SDF1α, and CXCR4 induced by gp120 in the lumbar spinal dorsal horn and/or the DRG at 2 and/or 4 weeks. Conclusion The blocking of the signaling of these proinflammatory molecules is able to reduce HIV-related neuropathic pain, which provide a novel mechanism-based approach to treating HIV-associated neuropathic pain using gene therapy. PMID:25078297

Indications of newer and older anti-epileptic drug use: findings from a southern Italian general practice setting from 2005–2011

PubMed Central

Italiano, Domenico; Capuano, Annalisa; Alibrandi, Angela; Ferrara, Rosarita; Cannata, Angelo; Trifirò, Gianluca; Sultana, Janet; Ferrajolo, Carmen; Tari, Michele; Tari, Daniele Ugo; Perrotta, Margherita; Pagliaro, Claudia; Rafaniello, Concita; Spina, Edoardo; Arcoraci, Vincenzo

2015-01-01

Aims The aim of the study was to analyze the prescribing pattern of both newer and older AEDs. Methods A population of almost 150 000 individuals registered with 123 general practitioners was included in this study. Patients who received at least one AED prescription over 2005–2011 were identified. The 1 year prevalence and cumulative incidence of AED use, by drug class and individual drug, were calculated over the study period. Potential predictors of starting therapy with newer AEDs were also investigated. Results The prevalence of use per 1000 inhabitants of older AEDs increased from 10.7 (95% CI10.1, 11.2) in 2005 to 13.0 (95% CI12.4, 13.6) in 2011, while the incidence remained stable. Newer AED incidence decreased from 9.4 (95% CI 8.9, 9.9) in 2005 to 7.0 (95% CI 6.6, 7.5) in 2011, with a peak of 15.5 (95% CI 14.8, 16.1) in 2006. Phenobarbital and valproic acid were the most commonly prescribed AEDs as starting therapy for epilepsy. Gabapentin and pregabalin accounted for most new pain-related prescriptions, while valproic acid and lamotrigine were increasingly used for mood disorders. Female gender (OR 1.36, 95% CI 1.20, 1.53), age ranging between 45–54 years (OR 1.39, 95% CI 1.16, 1.66) and pain as an indication (OR 16.7, 95% CI, 13.1, 21.2) were associated with newer AEDs starting therapy. Conclusions Older AEDs were mainly used for epileptic and mood disorders, while newer drugs were preferred for neuropathic pain. Gender, age, indication of use and year of starting therapy influenced the choice of AED type. The decrease of newer AED use during 2007 is probably related to the restricted reimbursement criteria for gabapentin and pregabalin. PMID:25556909

Attenuating effect of Acorus calamus extract in chronic constriction injury induced neuropathic pain in rats: an evidence of anti-oxidative, anti-inflammatory, neuroprotective and calcium inhibitory effects

PubMed Central

2011-01-01

Background Acorus calamus (family: Araceae), is an indigenous plant, traditionally it is used as an ingredient of various cocktail preparations and for the management of severe inflammatory disorders in Indian system of medicine. Present study investigated the attenuating role of Acorus calamus plant extract in chronic constriction injury (CCI) of sciatic nerve induced peripheral neuropathy in rats. Methods Hot plate, plantar, Randall Selitto, Von Frey Hair, pin prick, acetone drop, photoactometer and rota-rod tests were performed to assess degree of thermal, radiant, mechanical, chemical sensation, spontaneous motor activity and motor co-ordination changes respectively, at different time intervals i.e., day 0, 1, 3, 6, 9, 12, 15, 18 and 21. Tissue myeloperoxidase, superoxide anion and total calcium levels were determined after 21st day to assess biochemical alterations. Histopathological evaluations were also performed. Hydroalcoholic extract of Acorus calamus (HAE-AC, 100 and 200 mg/kg, p.o.) and pregabalin (10 mg/kg, p.o.) were administered from the day of surgery for 14 days. Results CCI of sciatic nerve significantly induced thermal, radiant, mechanical hyperalgesia and thermal, chemical, tactile allodynia, along with increase in the levels of superoxide anion, total calcium and myeloperoxidase activity. Moreover significant histological changes were also observed. HAE-AC attenuated CCI induced development of painful behavioural, biochemical and histological changes in a dose dependent manner similar to that of pregabalin serving as positive control. Conclusions Acorus calamus prevented CCI induced neuropathy which may be attributed to its multiple actions including anti-oxidative, anti-inflammatory, neuroprotective and calcium inhibitory actions. PMID:21426568

Efficacy of Pregabalin in Acute Postoperative Pain Under Different Surgical Categories

PubMed Central

Lam, David M.H.; Choi, Siu-Wai; Wong, Stanley S.C.; Irwin, Michael G.; Cheung, Chi-Wai

2015-01-01

Abstract The efficacy of pregabalin in acute postsurgical pain has been demonstrated in numerous studies; however, the analgesic efficacy and adverse effects of using pregabalin in various surgical procedures remain uncertain. We aim to assess the postsurgical analgesic efficacy and adverse events after pregabalin administration under different surgical categories using a systematic review and meta-analysis of randomized controlled trials. A search of the literature was performed between August 2014 to April 2015, using PubMed, Ovid via EMBASE, Google Scholar, and ClinicalTrials.gov with no limitation on publication year or language. Studies considered for inclusion were randomized controlled trials, reporting on relevant outcomes (2-, 24-hour pain scores, or 24 hour morphine-equivalent consumption) with treatment with perioperative pregabalin. Seventy-four studies were included. Pregabalin reduced pain scores at 2 hours in all categories: cardiothoracic (Hedge's g and 95%CI, −0.442 [−0.752 to −0.132], P = 0.005), ENT (Hedge g and 95%CI, −0.684 [−1.051 to −0.316], P < 0.0001), gynecologic (Hedge g, 95%CI, −0.792 [−1.235 to −0.350], P < 0.0001), laparoscopic cholecystectomy (Hedge g, 95%CI, –0.600 [–0.989 to –0.210], P = 0.003), orthopedic (Hedge g, 95%CI, −0.507 [−0.812 to −0.202], P = 0.001), spine (Hedge g, 95%CI, −0.972 [−1.537 to −0.407], P = 0.001), and miscellaneous procedures (Hedge g, 95%CI, −1.976 [−2.654 to −1.297], P < 0.0001). Pregabalin reduced 24-hour morphine consumption in gynecologic (Hedge g, 95%CI, −1.085 [−1.582 to −0.441], P = 0.001), laparoscopic cholecystectomy (Hedge g, 95%CI, –0.886 [–1.652 to –0.120], P = 0.023), orthopedic (Hedge g, 95%CI, −0.720 [−1.118 to −0.323], P < 0.0001), spine (Hedge g, 95%CI, −1.016 [−1.732 to −0.300], P = 0.005), and miscellaneous procedures (Hedge g, 95%CI, −1.329 [−2.286 to −0.372], P = 0.006). Pregabalin resulted in significant sedation in all surgical categories except ENT, laparoscopic cholecystectomy, and gynecologic procedures. Postoperative nausea and vomiting was only significant after pregabalin in miscellaneous procedures. Analgesic effects and incidence of adverse effects of using pregabalin are not equal in different surgical categories. PMID:26579802

Administering of pregabalin and acetaminophen on management of postoperative pain in patients with nasal polyposis undergoing functional endoscopic sinus surgery.

PubMed

Rezaeian, Ahmad

2017-12-01

Management of postoperative pain is a common problem in endoscopic sinus surgery. The objective of this study is the evaluation of pregabalin and acetaminophen effects on the management of postoperative pain in patients with nasal polyposis undergoing functional endoscopic sinus surgery (FESS). In this clinical trial, double-blinded study, 70 patients with nasal polyposis who have indication of FESS were enrolled to this study. After operation, patients were divided randomly into pregabalin and acetaminophen therapy groups. The pregabalin group (n = 35) was treated under pregabalin 50 mg TDS and the acetaminophen group (n = 35) was treated under tablet acetaminophen 500 mg/6 h. Each group was administered for 3 d. The visual analogue scale (VAS) was measured in onset, 12, 24, 48 and 72 h after surgery. All data were entered into SPSS software (SPSS Inc., Chicago, IL) and appropriate statistical tests were assessed to every relation. In this study, there was no significant difference between two groups according to VAS in onset (p = .37); however, VAS in 12, 24, 48 and 72 h after operation was significantly lower in the pregabalin group compared with the acetaminophen group (p < .0001, for every four). Also in the pregabalin group, adverse effects were significantly lower than the acetaminophen group (p < .03). Pregabalin has more effect, safely and usefully than acetaminophen on the management of postoperative pain in the patients with nasal polyposis undergoing functional endoscopic sinus surgery.

Anticonvulsants for fibromyalgia.

PubMed

Üçeyler, Nurcan; Sommer, Claudia; Walitt, Brian; Häuser, Winfried

2013-10-16

Fibromyalgia (FM) is a clinically well-defined chronic condition of unknown aetiology characterised by chronic widespread pain that often co-exists with sleep problems and fatigue. People often report high disability levels and poor health-related quality of life (HRQoL). Drug therapy focuses on reducing key symptoms and disability, and improving HRQoL. Anticonvulsants (antiepileptic drugs) are drugs frequently used for the treatment of chronic pain syndromes. To assess the benefits and harms of anticonvulsants for treating FM symptoms. We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (Issue 8, 2013), MEDLINE (1966 to August 2013), PsycINFO (1966 to August 2013), SCOPUS (1980 to August 2013) and the reference lists of reviewed articles for published studies and www.clinicaltrials.gov (to August 2013) for unpublished trials. We selected randomised controlled trials of any formulation of anticonvulsants used for the treatment of people with FM of any age. Two review authors independently extracted the data of all included studies and assessed the risks of bias of the studies. We resolved discrepancies by discussion. We included eight studies: five with pregabalin and one study each with gabapentin, lacosamide and levetiracetam. A total of 2480 people were included into anticonvulsants groups and 1099 people in placebo groups. The median therapy phase of the studies was 13 weeks. The amount and quality of evidence were insufficient to draw definite conclusions on the efficacy and safety of gabapentin, lacosamide and levetiracetam in FM. The amount and quality of evidence was sufficient to draw definite conclusions on the efficacy and safety of pregabalin in FM. Therefore, we focused on our interpretation of the evidence for pregabalin due to our greater certainty about its effects and its greater relevance to clinical practice. All pregabalin studies had a low risk of bias. Reporting a 50% or greater reduction in pain was more frequent with pregabalin use than with a placebo (risk ratio (RR) 1.59; 95% confidence interval (CI) 1.33 to 1.90; number needed to treat for an additional beneficial outcome (NNTB) 12; 95% CI 9 to 21). The number of people who reported being 'much' or 'very much' improved was higher with pregabalin than with placebo (RR 1.38; 95% CI 1.23 to 1.55; NNTB 9; 95% CI 7 to 15). Pregabalin did not substantially reduce fatigue (SMD -0.17; 95% CI -0.25 to -0.09; 2.7% absolute improvement on a 1 to 50 scale) compared with placebo. Pregabalin had a small benefit over placebo in reducing sleep problems by 6.2% fewer points on a scale of 0 to 100 (standardised mean difference (SMD) -0.35; 95% CI -0.43 to -0.27). The dropout rate due to adverse events was higher with pregabalin use than with placebo use (RR 1.68; 95% CI 1.36 to 2.07; number needed to treat for an additional harmful outcome (NNTH) 13; 95% CI 9 to 23). There was no significant difference in serious adverse events between pregabalin and placebo use (RR 1.03; 95% CI 0.71 to 1.49). Dizziness was reported as an adverse event more frequently with pregabalin use than with placebo use (RR 3.77; 95% CI 3.06 to 4.63; NNTH 4; 95% CI 3 to 5). The anticonvulsant, pregabalin, demonstrated a small benefit over placebo in reducing pain and sleep problems. Pregabalin use was shown not to substantially reduce fatigue compared with placebo. Study dropout rates due to adverse events were higher with pregabalin use compared with placebo. Dizziness was a particularly frequent adverse event seen with pregabalin use. At the time of writing this review, pregabalin is the only anticonvulsant drug approved for treating FM in the US and in 25 other non-European countries. However, pregabalin has not been approved for treating FM in Europe. The amount and quality of evidence were insufficient to draw definite conclusions on the efficacy and safety of gabapentin, lacosamide and levetiracetam in FM.

Adjunctive pregabalin in partial responders with major depressive disorder and residual anxiety.

PubMed

Vitali, Mario; Tedeschini, Enrico; Mistretta, Martino; Fehling, Kiki; Aceti, Franca; Ceccanti, Mauro; Fava, Maurizio

2013-02-01

Anxiety symptoms in depression result often in treatment resistance, residual symptoms, and persistent functional impairment. To assess the effectiveness and safety of adjunctive pregabalin to antidepressants for residual anxiety in patients with major depressive disorder (MDD). A retrospective chart review was conducted to identify partial responders among patients with MDD with residual anxiety. Twenty such patients (age, 58.4 ± 11.2 years; 15 women; baseline Hamilton Depression Rating Scale [HDRS], 17.1 ± 3.5) who received adjunctive pregabalin for residual anxiety were included. Antidepressants augmented were the selective serotonin reuptake inhibitors (n = 12), mirtazapine (n = 2), and selective serotonin-norepinephrine reuptake inhibitors (n = 6). Twenty patients received at least 4 weeks of pregabalin treatment after 8 weeks of antidepressant therapy. At week 1 (9 weeks after initiating treatment), pregabalin was prescribed at a mean ± SD dose of 71.2 ± 31.7 mg, and the mean maximum pregabalin dose prescribed was 156.2 ± 76.5 mg (range, 75-300 mg). At week 8, there were 13 responders (13/20 [65%]), and 7 of these 13 patients achieved remission (HDRS17 < 8). There were significant decreases in HDRS scores (13.5 ± 3.1 vs 9.1 ± 2.9, P < 0.000), and HDRS anxiety/somatization subscale scores (6.3 ± 2 to 3.6 ± 1.7, P < 0.000). Adverse effects included somnolence (n = 7), weight gain (n = 3), dizziness (n = 4), dry mouth (n = 6), edema (n = 3), blurred vision (n = 3), difficulty with concentration/attention (n = 8), headache (n = 6), and diarrhea (n = 5). The results suggest a possible augmentation role for pregabalin when used in conjunction with conventional antidepressants for residual anxiety in MDD.

Direct medical costs and medication compliance among fibromyalgia patients: duloxetine initiators vs. pregabalin initiators.

PubMed

Sun, Peter; Peng, Xiaomei; Sun, Steve; Novick, Diego; Faries, Douglas E; Andrews, Jeffrey S; Wohlreich, Madelaine M; Wu, Andrew

2014-01-01

To assess and compare direct medical costs and medication compliance between patients with fibromyalgia who initiated duloxetine and patients with fibromyalgia who initiated pregabalin in 2008. A retrospective cohort study design was used based on a large US national commercial claims database (2006 to 2009). Patients with fibromyalgia aged 18 to 64 who initiated duloxetine or pregabalin in 2008 and who had continuous health insurance 1 year preceding and 1 year following the initiation were selected into duloxetine cohort or pregabalin cohort based on their initiated agent. Medication compliance was measured by total supply days, medication possession ratio (MPR), and proportion of patients with MPR ≥ 0.8. Direct medical costs were measured by annual costs per patient and compared between the cohorts in the year following the initiation. Propensity score stratification and bootstrapping methods were used to adjust for distribution bias, as well as cross-cohort differences in demographic, clinical and economic characteristics, and medication history prior to the initiation. Both the duloxetine (n = 3,033) and pregabalin (n = 4,838) cohorts had a mean initiation age around 49 years, 89% were women. During the postindex year, compared to the pregabalin cohort, the duloxetine cohort had higher totally annual supply days (273.5 vs. 176.6, P < 0.05), higher MPR (0.7 vs. 0.5, P < 0.05), and more patients with MPR ≥ 0.8 (45.1% vs. 29.4%, P < 0.05). Further, relative to pregabalin cohort, duloxetine cohort had lower inpatient costs ($2,994.9 vs. $4,949.6, P < 0.05), lower outpatient costs ($8,259.6 vs. $10,312.2, P < 0.05), similar medication costs ($5,214.6 vs. $5,290.8, P > 0.05), and lower total medical costs ($16,469.1 vs. $20,552.6, P < 0.05) in the postinitiation year. In a real-world setting, patients with fibromyalgia who initiated duloxetine in 2008 had better medication compliance and consumed less inpatient, outpatient, and total medical costs than those who initiated pregabalin. © 2013 The Authors Pain Practice © 2013 World Institute of Pain.

Influence of arachidonyl-2'-chloroethylamide, a selective cannabinoid CB1 receptor agonist, on the anticonvulsant and acute side-effect potentials of clobazam, lacosamide, and pregabalin in the maximal electroshock-induced seizure model and chimney test in mice.

PubMed

Florek-Luszczki, Magdalena; Zagaja, Miroslaw; Luszczki, Jarogniew J

2015-08-01

The influence of arachidonyl-2'-chloroethylamide (ACEA - a selective cannabinoid CB1 receptor agonist) on the anticonvulsant potency and acute adverse-effect potentials of clobazam, lacosamide, and pregabalin was determined in the maximal electroshock-induced seizure model and chimney test in mice. ACEA (2.5 mg/kg, i.p.) significantly enhanced the anticonvulsant potency of pregabalin in the mouse maximal electroshock-induced seizure model by decreasing the median effective dose (ED50 ) of pregabalin from 125.39 to 78.06 mg/kg (P < 0.05). In contrast, ACEA (2.5 mg/kg) had no significant impact on the anticonvulsant potency of clobazam and lacosamide in the mouse maximal electroshock-induced seizure model. On the other hand, ACEA (2.5 mg/kg) did not affect acute adverse effects of clobazam, lacosamide or pregabalin, and the median toxic doses (TD50 ) for the studied anti-epileptic drugs in combination with ACEA did not differ from the TD50 values as determined for the drugs administered alone in the chimney test. In conclusion, ACEA ameliorates the pharmacological profile of pregabalin, when considering both the anticonvulsant and the acute adverse effects of the drug in preclinical study on animals. The combination of pregabalin with ACEA can be of pivotal importance for patients with epilepsy as a potentially advantageous combination if the results from this study translate into clinical settings. © 2015 Société Française de Pharmacologie et de Thérapeutique.

Pain Reduces Sexual Motivation in Female But Not Male Mice

PubMed Central

Farmer, Melissa A.; Leja, Alison; Foxen-Craft, Emily; Chan, Lindsey; MacIntyre, Leigh C.; Niaki, Tina; Chen, Mengsha; Mapplebeck, Josiane C.S.; Tabry, Vanessa; Topham, Lucas; Sukosd, Melissa; Binik, Yitzchak M.; Pfaus, James G.

2014-01-01

Chronic pain is often associated with sexual dysfunction, suggesting that pain can reduce libido. We find that inflammatory pain reduces sexual motivation, measured via mounting behavior and/or proximity in a paced mating paradigm, in female but not male laboratory mice. Pain was produced by injection of inflammogens zymosan A (0.5 mg/ml) or λ-carrageenan (2%) into genital or nongenital (hind paw, tail, cheek) regions. Sexual behavior was significantly reduced in female mice experiencing pain (in all combinations); male mice similarly treated displayed unimpeded sexual motivation. Pain-induced reductions in female sexual behavior were observed in the absence of sex differences in pain-related behavior, and could be rescued by the analgesic, pregabalin, and the libido-enhancing drugs, apomorphine and melanotan-II. These findings suggest that the well known context sensitivity of the human female libido can be explained by evolutionary rather than sociocultural factors, as female mice can be similarly affected. PMID:24760835

Impact of a Novel Cost-Saving Pharmacy Program on Pregabalin Use and Health Care Costs.

PubMed

Martin, Carolyn; Odell, Kevin; Cappelleri, Joseph C; Bancroft, Tim; Halpern, Rachel; Sadosky, Alesia

2016-02-01

Pharmacy cost-saving programs often aim to reduce costs for members and payers by encouraging use of lower-tier or generic medications and lower-cost sales channels. In 2010, a national U.S. health plan began a novel pharmacy program directed at reducing pharmacy expenditures for targeted medications, including pregabalin. The program provided multiple options to avoid higher cost sharing: use mail order pharmacy or switch to a lower-cost alternative medication via mail order or retail. Members who did not choose any option eventually paid the full retail cost of pregabalin. To evaluate the impact of the pharmacy program on pregabalin and alternative medication use, health care costs, and health care utilization. This retrospective analysis of claims data included adult commercial health plan members with a retail claim for pregabalin in the first 13 months of the pharmacy program (identification [ID] period: February 1, 2010-February 28, 2011). Members whose benefit plan included the pharmacy program were assigned to the program cohort; all others were assigned to the nonprogram cohort. The program cohort index date was the first retail pregabalin claim during the ID period and after the program start; the nonprogram cohort index date was the first retail pregabalin claim during the ID period. All members were continuously enrolled for 12 months pre- and post-index and had at least 1 inpatient claim or ≥ 2 ambulatory visit claims for a pregabalin-indicated condition. Cohorts were propensity score matched (PSM) 1:1 with logistic regression on demographic and pre-index characteristics, including mail order and pregabalin use, comorbidity, health care costs, and health care utilization. Pregabalin, gabapentin and other alternative medication use, health care costs, and health care utilization were measured. The program cohort was also divided into 2 groups: members who changed to gabapentin post-index and those who did not. A difference-in-differences (DiD) analysis was used to compare the between-cohort change in pregabalin and alternative medication use patterns, health care costs, and health care resource utilization from pre- to post-index. The within-cohort change from pre- to post-index was analyzed by McNemar's test (categorical variables) or paired t-test (continuous variables). The Rao-Scott chi-square test (categorical) and general estimating equations (continuous) were used to analyze between-cohort differences at each time point. Differences in program member characteristics of those who changed versus those who did not change to gabapentin post-index were assessed by traditional chi-square test (categorical) or two-sample t-test (continuous variables). A total of 1,218 members in each cohort were PSM. Mean age was 51 years, 76.7% were women, and the most common pregabalin-indicated condition was fibromyalgia (77.6%). After the program start, the mean number of pregabalin claims from mail order and retail combined decreased in the program cohort from 4.7 pre-index to 3.8 post-index, and increased in the nonprogram cohort from 4.7 pre-index to 6.2 post-index (DiD, P < 0.001). Pregabalin mail order use increased from 3.1% to 48.1% of program members versus 2.8% to 9.4% of nonprogram members (DiD, P < 0.001). Program members were also more likely to change to the anticonvulsant gabapentin post-index than were nonprogram members (31.0% vs. 15.9%, P < 0.001). Mean total health care costs were similar between cohorts, and the pre- to post-index change did not differ between cohorts (DiD, P = 0.474). However, mean total pharmacy costs rose from pre-index to post-index by $820 and $790 in the program and nonprogram cohorts, respectively (both P < 0.001); the increase was similar between cohorts (DiD, P = 0.888). Program members who changed to gabapentin had a higher mean comorbidity score (P = 0.001) and greater post-index use of opioids, alternative medications, and health care resources (P < 0.050) than program members who did not change to gabapentin. The pharmacy program increased mail order use of pregabalin but reduced pregabalin claims from any venue. Program members were more likely to change to gabapentin than were nonprogram members, and those who changed had higher comorbidity, use of alternative medication, and health care resources. Despite increased mail order use for pregabalin and greater change to gabapentin by program members, the pharmacy program was not cost saving with respect to mean pharmacy or total health care costs.

Preemptive multimodal pain regimen reduces opioid analgesia for patients undergoing robotic-assisted laparoscopic radical prostatectomy.

PubMed

Trabulsi, Edouard J; Patel, Jitesh; Viscusi, Eugene R; Gomella, Leonard G; Lallas, Costas D

2010-11-01

Minimally invasive surgical techniques have many benefits, including reduced postoperative pain. Despite this, most patients require opioid analgesia, which can have significant side effects and toxicity. We report the first urologic study using multimodal analgesia with pregabalin, a gabapentinoid. The present retrospective study included 60 patients who underwent robotic-assisted laparoscopic radical prostatectomy. Of the 60 patients, 30 received multimodal treatment with pregabalin 150 mg, acetaminophen 975 mg, and celecoxib 400 mg orally 2 hours before the start of the procedure and continued postoperatively. These patients were compared with 30 consecutive previous patients, who had received a standard postoperative analgesic regimen with intravenous ketorolac 15 mg every 6 hours with oxycodone 5 mg and acetaminophen 325 mg, 1 to 2 tablets, every 4 hours as needed for pain. The patients in the multimodal treatment group had a significantly reduced intraoperative opioid requirement, as measured by the mean morphine equivalent dose administered (38.4 ± 2.73 mg vs 49.1 ± 2.65 mg; P < .01). The mean postoperative opioid use was also significantly reduced (10.7 ± 2.82 mg vs 26.2 ± 6.56 mg; P = .034), as was the mean total morphine equivalent dose administered (49.1 ± 2.7 mg vs 75.3 ± 4.6 mg; P < .001). The operative time, estimated operative blood loss, antiemetic use, postoperative creatinine and hemoglobin levels, and length of stay were similar in the 2 groups. No operative or treatment complications occurred in either group. The present retrospective review has indicated that a multimodal analgesic approach with pregabalin and celecoxib administered preoperatively decreases intraoperative and postoperative opioid use in patients undergoing robotic-assisted laparoscopic radical prostatectomy. Copyright © 2010 Elsevier Inc. All rights reserved.

Virtual reality-augmented neurorehabilitation improves motor function and reduces neuropathic pain in patients with incomplete spinal cord injury.

PubMed

Villiger, Michael; Bohli, Dominik; Kiper, Daniel; Pyk, Pawel; Spillmann, Jeremy; Meilick, Bruno; Curt, Armin; Hepp-Reymond, Marie-Claude; Hotz-Boendermaker, Sabina; Eng, Kynan

2013-10-01

Neurorehabilitation interventions to improve lower limb function and neuropathic pain have had limited success in people with chronic, incomplete spinal cord injury (iSCI). We hypothesized that intense virtual reality (VR)-augmented training of observed and executed leg movements would improve limb function and neuropathic pain. Patients used a VR system with a first-person view of virtual lower limbs, controlled via movement sensors fitted to the patient's own shoes. Four tasks were used to deliver intensive training of individual muscles (tibialis anterior, quadriceps, leg ad-/abductors). The tasks engaged motivation through feedback of task success. Fourteen chronic iSCI patients were treated over 4 weeks in 16 to 20 sessions of 45 minutes. Outcome measures were 10 Meter Walking Test, Berg Balance Scale, Lower Extremity Motor Score, Spinal Cord Independence Measure, Locomotion and Neuropathic Pain Scale (NPS), obtained at the start and at 4 to 6 weeks before intervention. In addition to positive changes reported by the patients (Patients' Global Impression of Change), measures of walking capacity, balance, and strength revealed improvements in lower limb function. Intensity and unpleasantness of neuropathic pain in half of the affected participants were reduced on the NPS test. Overall findings remained stable 12 to 16 weeks after termination of the training. In a pretest/posttest, uncontrolled design, VR-augmented training was associated with improvements in motor function and neuropathic pain in persons with chronic iSCI, several of which reached the level of a minimal clinically important change. A controlled trial is needed to compare this intervention to active training alone or in combination.

Modulation of serum BDNF levels in postherpetic neuralgia following pulsed radiofrequency of intercostal nerve and pregabalin.

PubMed

Saxena, Ashok Kumar; Lakshman, Kavitha; Sharma, Tusha; Gupta, Neha; Banerjee, Basu Dev; Singal, Archana

2016-01-01

To study the modulation of serum BDNF levels following integrated multimodal intervention in postherpetic neuralgia (PHN). A randomized, double-blind controlled study was undertaken among patients of thoracic PHN where 30 patients received pregabalin with pulsed radiofrequency and 30 controls received pregabalin with sham treatment. Pain intensity (visual analog scale) was reduced earlier in intervention group (15.3 ± 5.7 at the fourth week) compared with control group (16.3 ± 6.6 at the eighth week). Serum BDNF level increased with time in both the groups with overall increase more pronounced in intervention group. Integrated multimodal therapy using minimally invasive pulsed radiofrequency and pregabalin in PHN was effective in early pain reduction with elevated serum BDNF levels.

A protocol for a systematic review for perioperative pregabalin use.

PubMed

Eipe, Naveen; Penning, John; Ansari, Mohammed; Yazdi, Fatemeh; Ahmadzai, Nadera

2012-09-13

Perioperative pain management has recently been revolutionized with the recognition of novel mechanisms and introduction of newer drugs. Many randomized trials have studied the use of the gabapentinoid anti-epileptic, pregabalin, in acute pain. Published systematic reviews suggest that using pregabalin for perioperative pain management may decrease analgesic requirements and pain scores, at the expense of troublesome side effects. A major limitation of the extant reviews is the lack of rigorous investigation of clinical characteristics that would maximize the benefit harms ratio in favor of surgical patients. We posit that effects of pregabalin for perioperative pain management vary by the type of surgical pain model and propose this systematic review protocol to update previous systematic reviews and investigate the heterogeneity in findings across subgroups of surgical pain models. Using a peer-reviewed search strategy, we will search key databases for clinical trials on perioperative pregabalin use in adults. The electronic searches will be supplemented by scanning the reference lists of included studies. No limits of language, country or year will be imposed. Outcomes will include pain; use of co-analgesia, particularly opioids; enhanced recovery; and drug-related harms. We will focus on the identification of surgical models and patient characteristics that have shown benefit and adverse effects from pregabalin.Two clinical experts will independently screen the studies for inclusion using eligibility criteria established a priori. Data extracted by the reviewers will then be verified. Publication bias will be assessed, as will risk of bias using the Cochrane Risk of Bias tool. Meta-analysis and meta-regression are planned if the studies are deemed statistically, methodologically and clinically homogenous. Evidence will be graded for its strength for a select number of outcomes. We will explore the findings of perioperative clinical trials studying the use of pregabalin for acute pain. We will comment on the implications of the findings and provide further direction for the appropriate use of pregabalin in acute pain. This protocol will attempt to bridge the growing gap between clinical experience and emerging evidence, and has the potential to aid future guideline development in the perioperative use of pregabalin. PROSPERO registration number CRD42012002078.

Defining success in clinical trials--profiling pregabalin, the newest AED.

PubMed

Ryvlin, P

2005-11-01

The efficacy and safety of pregabalin as adjunctive therapy for patients with partial epilepsy with or without secondary generalization has been established by four randomized, 12-week, double-blind, placebo-controlled trials (n = 1396) and four long-term open-label studies (n = 1480). Patients in the three fixed-dose trials were >/=12 years of age, had >/=6 partial seizures and no 4-week seizure-free period during the 8-week baseline period. Seventy-three per cent of patients were taking >/=2 concomitant antiepileptic drugs. Responder rates across the effective doses (150-600 mg/day) ranged from 14% to 51% and demonstrated a significant dose-response relationship. The most common adverse events were central nervous system related, generally mild or moderate, transient, and tended to be dose related. The fourth placebo-controlled trial compared a fixed dose of pregabalin 600 mg/day with a flexible-dose regimen (150-600 mg/day). Responder rates were greater for both the fixed dose (45.3%, P < 0.001) and flexible dose (31.3%, P < 0.001) when compared with placebo (11.0%). Compared with the fixed-dose group, the flexible-dose patients had a lower incidence of adverse events and study discontinuations. In long-term open-label trials, the efficacy of pregabalin was maintained with respect to 50% responder rates suggesting no obvious tolerance developing over 2 years. Seizure-free rates were 8.9% and 5.8% for the last 6 months and 1 year of pregabalin treatment, respectively. Long-term open-label pregabalin treatment was well tolerated.

Long-term add-on pregabalin treatment in patients with partial-onset epilepsy: pooled analysis of open-label clinical trials.

PubMed

Uthman, Basim M; Bazil, Carl W; Beydoun, Ahmad; Schulze-Bonhage, Andreas; Benabou, Reina; Whalen, Ed; Emir, Birol; Griesing, Teresa; Leon, Teresa

2010-06-01

To evaluate the safety, tolerability, and efficacy of long-term pregabalin as add-on therapy for patients with poorly controlled partial seizures. Analysis of data from six long-term clinical trials involving 2,061 patients receiving open-label pregabalin 75-600 mg/day adjunctive therapy for partial onset epilepsy refractory to multiple antiepileptic drugs. Total pregabalin exposure was 3,877 person-years. The mean duration of pregabalin treatment was 534 days (range 0.3-8 years) and 59% completed 1 year. One-third of patients discontinued for lack of efficacy. The most common dose was >or=300 mg/day; over half took >or=450 mg/day. There was a mean reduction in the 28-day seizure rate of 25-40%, and more than 40% of all patients had a >or=50% reduction in seizures from baseline during the last 3 months of treatment. Twelve percent of all patients had a 6-month period continuously free of seizures. In the last year, 6% were seizure-free for the entire year. Pregabalin was generally well-tolerated and the safety profile favorable in patients treated for up to several years, with an adverse event (AE) profile similar to short-term placebo-controlled trials. Common AEs included CNS symptoms (dizziness, somnolence, headache, and asthenia), accidental injury, and weight gain. CNS AEs tended to be mild and transient. Rates of sudden unexpected death in epilepsy (SUDEP), mortality, cancer, and status epilepticus were within the expected range for this population. Adjunctive pregabalin was effective, generally well tolerated, and safe in the long-term treatment of partial seizures, and provided clinically meaningful seizure reduction and freedom without evidence of tolerance over 2 years of follow-up.

The analgesic effect of pregabalin in patients with chronic pain is reflected by changes in pharmaco-EEG spectral indices

PubMed Central

Graversen, Carina; Olesen, Søren S; Olesen, Anne E; Steimle, Kristoffer; Farina, Dario; Wilder-Smith, Oliver H G; Bouwense, Stefan A W; van Goor, Harry; Drewes, Asbjørn M

2012-01-01

AIM To identify electroencephalographic (EEG) biomarkers for the analgesic effect of pregabalin in patients with chronic visceral pain. METHODS This was a double-blind, placebo-controlled study in 31 patients suffering from visceral pain due to chronic pancreatitis. Patients received increasing doses of pregabalin (75 mg–300 mg twice a day) or matching placebo during 3 weeks of treatment. Pain scores were documented in a diary based on a visual analogue scale. In addition, brief pain inventory-short form (BPI) and quality of life questionnaires were collected prior to and after the study period. Multi-channel resting EEG was recorded before treatment onset and at the end of the study. Changes in EEG spectral indices were extracted, and individual changes were classified by a support vector machine (SVM) to discriminate the pregabalin and placebo responses. Changes in individual spectral indices and pain scores were correlated. RESULTS Pregabalin increased normalized intensity in low spectral indices, most prominent in the theta band (3.5–7.5 Hz), difference of −3.18, 95% CI −3.57, −2.80; P = 0.03. No changes in spectral indices were seen for placebo. The maximum difference between pregabalin and placebo treated patients was seen in the parietal region, with a classification accuracy of 85.7% (P = 0.009). Individual changes in EEG indices were correlated with changes in pain diary (P = 0.04) and BPI pain composite scores (P = 0.02). CONCLUSIONS Changes in spectral indices caused by slowing of brain oscillations were identified as a biomarker for the central analgesic effect of pregabalin. The developed methodology may provide perspectives to assess individual responses to treatment in personalized medicine. PMID:21950372

Pregabalin monotherapy in patients with partial-onset seizures

PubMed Central

Kwan, Patrick; Fakhoury, Toufic; Pitman, Verne; DuBrava, Sarah; Knapp, Lloyd; Yurkewicz, Lorraine

2014-01-01

Objective: To assess pregabalin monotherapy for partial-onset seizures using a historical-controlled conversion-to-monotherapy design. Methods: Adults with inadequately controlled partial-onset seizures while receiving 1 or 2 antiepileptic drugs during an 8-week prospective baseline were randomized to double-blind monotherapy with pregabalin 600 or 150 mg/d (4:1) for 20 weeks (8-week conversion and 12-week monotherapy period). The primary endpoint was the seizure-related exit rate for pregabalin 600 mg/d, based on discontinuations due to predefined criteria. Efficacy was declared if the upper limit of the 95% confidence interval for the exit rate was below a historical-control threshold of 74%, with stepwise evaluation using a threshold of 68%. Results: The trial was stopped early for positive efficacy after an interim analysis in 125 patients. The full study population included 161 patients, with 148 evaluable for efficacy. The mean time since epilepsy diagnosis was 14 years. Overall, 54.3% (600 mg/d) and 46.9% (150 mg/d) of patients completed 20 weeks of double-blind treatment. Seizure-related exit rate in the 600 mg/d group (27.5%; 95% confidence interval, 17.8%–37.2%) was significantly below the 74% and 68% thresholds (p < 0.001 for both). Eight patients on 600 mg/d and 2 on 150 mg/d were seizure-free throughout pregabalin monotherapy. Pregabalin's overall safety profile was consistent with prior trials. Conclusions: Pregabalin monotherapy was safe and efficacious for patients with inadequately controlled partial-onset seizures. Classification of evidence: This study provides Class III evidence that patients with inadequately controlled partial-onset seizures switched to pregabalin monotherapy have fewer seizure-related exit events compared with historical controls switched to pseudo-placebo monotherapy. PMID:24415567

Effect of Pregabalin and Dexamethasone on Postoperative Analgesia after Septoplasty

PubMed Central

Demirhan, Abdullah; Akkaya, Akcan; Tekelioglu, Umit Yasar; Apuhan, Tayfun; Bilgi, Murat; Yurttas, Veysel; Bayir, Hakan; Yildiz, Isa; Gok, Uzeyir; Kocoglu, Hasan

2014-01-01

Objectives. The aim of this study was to explore effect of a combination of pregabalin and dexamethasone on pain control after septoplasty operations. Methods. In this study, 90 patients who were scheduled for septoplasty under general anesthesia were randomly assigned into groups that received either placebo (Group C), pregabalin (Group P), or pregabalin and dexamethasone (Group PD). Preoperatively, patients received either pregabalin 300 mg one hour before surgery, dexamethasone 8 mg intravenously during induction, or placebo according to their allocation. Postoperative pain treatment included tramadol and diclofenac sodium 30 minutes before the end of the operation. Numeric rating scale (NRS) for pain assessment, side effects, and consumption of tramadol, pethidine, and ondansetron were recorded. Results. The median NRS score at the postoperative 0 and the 2nd h was significantly higher in Group C than in Group P and Group PD (P ≤ 0.004 for both). The 24 h tramadol and pethidine, consumptions were significantly reduced in Groups P and PD compared to Group C (P < 0.001 and P < 0.001). The incidence of blurred vision was significantly higher in Group PD compared to Group C within both 0–2 h and 0–24 h periods (P = 0.002 and P < 0.001, resp.). Conclusions. We conclude that administration of 300 mg pregabalin preoperatively may be an adequate choice for pain control after septoplasty. Addition of dexamethasone does not significantly reduce pain in these patients. PMID:24876957

Quantitative Sensory Testing Predicts Pregabalin Efficacy in Painful Chronic Pancreatitis

PubMed Central

Olesen, Søren S.; Graversen, Carina; Bouwense, Stefan A. W.; van Goor, Harry; Wilder-Smith, Oliver H. G.; Drewes, Asbjørn M.

2013-01-01

Background A major problem in pain medicine is the lack of knowledge about which treatment suits a specific patient. We tested the ability of quantitative sensory testing to predict the analgesic effect of pregabalin and placebo in patients with chronic pancreatitis. Methods Sixty-four patients with painful chronic pancreatitis received pregabalin (150–300 mg BID) or matching placebo for three consecutive weeks. Analgesic effect was documented in a pain diary based on a visual analogue scale. Responders were defined as patients with a reduction in clinical pain score of 30% or more after three weeks of study treatment compared to baseline recordings. Prior to study medication, pain thresholds to electric skin and pressure stimulation were measured in dermatomes T10 (pancreatic area) and C5 (control area). To eliminate inter-subject differences in absolute pain thresholds an index of sensitivity between stimulation areas was determined (ratio of pain detection thresholds in pancreatic versus control area, ePDT ratio). Pain modulation was recorded by a conditioned pain modulation paradigm. A support vector machine was used to screen sensory parameters for their predictive power of pregabalin efficacy. Results The pregabalin responders group was hypersensitive to electric tetanic stimulation of the pancreatic area (ePDT ratio 1.2 (0.9–1.3)) compared to non-responders group (ePDT ratio: 1.6 (1.5–2.0)) (P = 0.001). The electrical pain detection ratio was predictive for pregabalin effect with a classification accuracy of 83.9% (P = 0.007). The corresponding sensitivity was 87.5% and specificity was 80.0%. No other parameters were predictive of pregabalin or placebo efficacy. Conclusions The present study provides first evidence that quantitative sensory testing predicts the analgesic effect of pregabalin in patients with painful chronic pancreatitis. The method can be used to tailor pain medication based on patient’s individual sensory profile and thus comprises a significant step towards personalized pain medicine. PMID:23469256

α2δ-1 Gene Deletion Affects Somatosensory Neuron Function and Delays Mechanical Hypersensitivity in Response to Peripheral Nerve Damage

PubMed Central

Patel, Ryan; Bauer, Claudia S.; Nieto-Rostro, Manuela; Margas, Wojciech; Ferron, Laurent; Chaggar, Kanchan; Crews, Kasumi; Ramirez, Juan D.; Bennett, David L. H.; Schwartz, Arnold; Dickenson, Anthony H.

2013-01-01

The α2δ-1 subunit of voltage-gated calcium channels is upregulated after sensory nerve injury and is also the therapeutic target of gabapentinoid drugs. It is therefore likely to play a key role in the development of neuropathic pain. In this study, we have examined mice in which α2δ-1 gene expression is disrupted, to determine whether α2δ-1 is involved in various modalities of nociception, and for the development of behavioral hypersensitivity after partial sciatic nerve ligation (PSNL). We find that naive α2δ-1−/− mice show a marked behavioral deficit in mechanical and cold sensitivity, but no change in thermal nociception threshold. The lower mechanical sensitivity is mirrored by a reduced in vivo electrophysiological response of dorsal horn wide dynamic range neurons. The CaV2.2 level is reduced in brain and spinal cord synaptosomes from α2δ-1−/− mice, and α2δ-1−/− DRG neurons exhibit lower calcium channel current density. Furthermore, a significantly smaller number of DRG neurons respond to the TRPM8 agonist menthol. After PSNL, α2δ-1−/− mice show delayed mechanical hypersensitivity, which only develops at 11 d after surgery, whereas in wild-type littermates it is maximal at the earliest time point measured (3 d). There is no compensatory upregulation of α2δ-2 or α2δ-3 after PSNL in α2δ-1−/− mice, and other transcripts, including neuropeptide Y and activating transcription factor-3, are upregulated normally. Furthermore, the ability of pregabalin to alleviate mechanical hypersensitivity is lost in PSNL α2δ-1−/− mice. Thus, α2δ-1 is essential for rapid development of mechanical hypersensitivity in a nerve injury model of neuropathic pain. PMID:24133248

Characteristics, resource utilization and safety profile of patients prescribed with neuropathic pain treatments: a real-world evidence study on general practices in Europe - the role of the lidocaine 5% medicated plaster.

PubMed

Katz, Pablo; Pegoraro, Valeria; Liedgens, Hiltrud

2017-08-01

To identify characteristics, resource utilization, and safety profile of patients prescribed with lidocaine 5% medicated plaster, pregabalin, gabapentin, amitriptyline and duloxetine when experiencing pain in the real-world setting of general practitioners (GPs) in Europe. Retrospective analysis on real world data from IMS Health Longitudinal Patient Database. Patients with at least one prescription of the drugs of interest during 2014 were selected and those with a non-neuropathic pain-related diagnosis were excluded. Patients' demographic and clinical characteristics, resource utilization data and adverse drug reactions (ADRs) as described in the leaflet were extracted. The association between treatments and ADR occurrence was evaluated applying multivariate logistic models. A total of 70,515 patients were selected from Italy, Germany, the UK, Spain and Belgium. Lidocaine 5% medicated plaster patients were the oldest in Italy, the UK and Spain and the most health impaired in Italy, Spain and Belgium. No relevant differences in the number of co-prescriptions, specialist visits, examinations and hospitalizations were found. Significantly less lidocaine 5% plasters patients experienced ADRs, with odds ratios in favor of lidocaine 5% medicated plasters ranging from 3.41 (p = .036) to 52.33 (p < .001). Evidence from daily clinical practice in GP settings agrees with the findings from more controlled clinical-trial settings, with lidocaine 5% medicated plaster patients showing a better safety profile, but also a comparable level of resource utilization. A possible re-evaluation of the scientific value coming from this retrospective study in building up a diagnostic as well as a therapeutic algorithm is suggested.

Reduction of central neuropathic pain with ketamine infusion in a patient with Ehlers-Danlos syndrome: a case report.

PubMed

Lo, Tony Chung Tung; Yeung, Stephen Tung; Lee, Sujin; Skavinski, Kira; Liao, Solomon

2016-01-01

Ehlers-Danlos syndrome frequently causes acute and chronic pain because of joint subluxations and dislocations secondary to hypermobility. Current treatments for pain related to Ehlers-Danlos syndrome and central pain syndrome are inadequate. This case report discusses the therapeutic use of ketamine intravenous infusion as an alternative. A 27-year-old Caucasian female with a history of Ehlers-Danlos syndrome and spinal cord ischemic myelopathy resulting in central pain syndrome, presented with severe generalized body pain refractory to multiple pharmacological interventions. After a 7-day course of ketamine intravenous infusion under controlled generalized sedation in the intensive care unit, the patient reported a dramatic reduction in pain levels from 7-8 out of 10 to 0-3 out of 10 on a numeric rating scale and had a significant functional improvement. The patient tolerated a reduction in her pain medication regimen, which originally included opioids, gabapentin, pregabalin, tricyclic antidepressants, and nonsteroidal anti-inflammatory drugs. Ketamine infusion treatment has been used in various pain syndromes, including central neuropathic pain, ischemic pain, and regional pain syndrome. Reports have suggested that ketamine modulates pain by the regression of N-methyl-D-aspartate receptor to a resting state. As such, propagation of nociceptive signal to brain is interrupted allowing for the restoration of physiological balance between pain inhibition and facilitation. The present report shows that this treatment option can be used in patients with refractory central pain syndrome in the setting of spinal cord myelopathy secondary to Ehlers-Danlos syndrome. In addition, as seen in this case, this protocol can potentially decrease the chronic use of pain medication, such as opioids.

Comparative Efficacy of Newer Antidepressants in Combination with Pregabalin for Fibromyalgia Syndrome: A Controlled, Randomized Study.

PubMed

Ramzy, Eiad A

2017-01-01

This controlled, randomized study investigated the hypothesis that the combined use of pregabalin plus paroxetine for fibromyalgia management would be associated with comparable Somatic Symptoms Scale-8 (SSS-8) and Center for Epidemiological Studies Depression Scale (CESDS) scores, but higher tolerability than the combined use of pregabalin plus either amitriptyline or venlafaxine. After institutional ethics committee approval, 75 female subjects diagnosed with fibromyalgia and in receipt of pregabalin (75 mg/day) were randomly allocated to concurrently receive amitriptyline (25 mg/day; n = 24), venlafaxine (75 mg/day; n = 25), or paroxetine (25 mg/day; n = 26). All patients were assessed bimonthly for 6 consecutive months for changes in SSS-8 and CESDS scores, life satisfaction, mood, sleep quality, fatigue, medication tolerability, and adverse events. Compared with pregabalin plus amitriptyline or venlafaxine, the combined use of pregabalin plus paroxetine in fibromyalgia patients resulted in significantly lower SSS-8 and CESDS scores from 18 (P < 0.05) and 10 weeks (P < 0.001) after the initiation of study medications, respectively; higher medication tolerability (P < 0.001); improved life satisfaction, mood, and sleep quality at most observation times (P < 0.05); and fewer instances of dry mouth and elevated blood pressure (P < 0.02). Medication termination due to poor tolerability was observed most frequently in the venlafaxine group (P < 0.05), while drowsiness, dizziness, blurred vision, abnormal taste, hunger, hallucination, urination problems, and sexual dysfunction were observed most frequently in the amitriptyline group (P < 0.02). The combined use of pregabalin plus paroxetine offers an effective method with increased tolerability to reduce the somatic and depressive symptoms of fibromyalgia and to enhance the quality of life in affected individuals. © 2016 World Institute of Pain.

Brief post-stressor treatment with pregabalin in an animal model for PTSD: short-term anxiolytic effects without long-term anxiogenic effect.

PubMed

Zohar, Joseph; Matar, Michael A; Ifergane, Gal; Kaplan, Zeev; Cohen, Hagit

2008-09-01

The short- and long-term behavioral effects of a brief course of pregabalin, an antiepileptic structural analogue of alpha-aminobyturic acid with analgesic and anxiolytic effects, were assessed in an animal model of post-traumatic stress disorder (PTSD). Two-hundred thirty-three adult male Sprague-Dawley rats were employed. Behavioral responses to traumatic stress exposure (predator urine scent) were assessed immediately after (1 h) and 30 days after treatment with saline or pregabalin (at doses of 30, 100 and 300 mg/kg) in terms of behavior in the elevated plus maze (EPM) and the acoustic startle response (ASR) paradigms. At day 31 the freezing response to a trauma cue (clean cat litter) was assessed. The same treatment regimen initiated at day 7 was assessed at day 30 and in response to the trauma cue on day 31 in a separate experiment. In the short term, doses of 100 mg/kg and 300 mg/kg of pregabalin effectively attenuated anxiety-like behaviors. In the longer-term, pregabalin did not attenuate the onset of PTSD-like behaviors or the prevalence rates of severe cue-responses, for either the immediate or the delayed treatment regimens. Pregabalin may present an alternative compound for acute anxiolytic treatment after exposure to trauma, but has no long-term protective/preventive effects.

Pregabalin for the treatment of generalized anxiety disorder: an update

PubMed Central

Baldwin, David S; Ajel, Khalil; Masdrakis, Vasilios G; Nowak, Magda; Rafiq, Rizwan

2013-01-01

A previous review summarized what was then known about the potential role of pregabalin in the treatment of patients with generalized anxiety disorder (GAD): this review provides an update on its pharmacological properties and presumed mechanism of action, the liability for abuse, and efficacy and tolerability in patients with GAD. Pregabalin has a similar molecular structure to the inhibitory neurotransmitter gamma amino butyric acid (GABA) but its mechanism of action does not appear to be mediated through effects on GABA. Instead, its anxiolytic effects may arise through high-affinity binding to the alpha-2-delta sub-unit of the P/Q type voltage-gated calcium channel in “over-excited” presynaptic neurons, thereby reducing the release of excitatory neurotransmitters such as glutamate. The findings of randomized controlled trials and meta-analyses together indicate that pregabalin is efficacious in both acute treatment and relapse prevention in GAD, with some evidence of an early onset of effect, and broad efficacy in reducing the severity of psychological and physical symptoms of anxiety. It also has efficacy as an augmenting agent after non-response to antidepressant treatment in GAD. Continuing vigilance is needed in assessing its potential abuse liability but the tolerability profile of pregabalin may confer some advantages over other pharmacological treatments in the short term for treatment in patients with GAD. PMID:23836974

R-Flurbiprofen Reduces Neuropathic Pain in Rodents by Restoring Endogenous Cannabinoids

PubMed Central

Marian, Claudiu; Häussler, Annett; Wijnvoord, Nina; Ziebell, Simone; Metzner, Julia; Koch, Marco; Myrczek, Thekla; Bechmann, Ingo; Kuner, Rohini; Costigan, Michael; Dehghani, Faramarz; Geisslinger, Gerd; Tegeder, Irmgard

2010-01-01

Background R-flurbiprofen, one of the enantiomers of flurbiprofen racemate, is inactive with respect to cyclooxygenase inhibition, but shows analgesic properties without relevant toxicity. Its mode of action is still unclear. Methodology/Principal Findings We show that R-flurbiprofen reduces glutamate release in the dorsal horn of the spinal cord evoked by sciatic nerve injury and thereby alleviates pain in sciatic nerve injury models of neuropathic pain in rats and mice. This is mediated by restoring the balance of endocannabinoids (eCB), which is disturbed following peripheral nerve injury in the DRGs, spinal cord and forebrain. The imbalance results from transcriptional adaptations of fatty acid amide hydrolase (FAAH) and NAPE-phospholipase D, i.e. the major enzymes involved in anandamide metabolism and synthesis, respectively. R-flurbiprofen inhibits FAAH activity and normalizes NAPE-PLD expression. As a consequence, R-Flurbiprofen improves endogenous cannabinoid mediated effects, indicated by the reduction of glutamate release, increased activity of the anti-inflammatory transcription factor PPARγ and attenuation of microglia activation. Antinociceptive effects are lost by combined inhibition of CB1 and CB2 receptors and partially abolished in CB1 receptor deficient mice. R-flurbiprofen does however not cause changes of core body temperature which is a typical indicator of central effects of cannabinoid-1 receptor agonists. Conclusion Our results suggest that R-flurbiprofen improves the endogenous mechanisms to regain stability after axonal injury and to fend off chronic neuropathic pain by modulating the endocannabinoid system and thus constitutes an attractive, novel therapeutic agent in the treatment of chronic, intractable pain. PMID:20498712

Cauda equina syndrome following an uneventful spinal anesthesia in a patient undergoing drainage of the Bartholin abscess: A case report.

PubMed

Merino-Urrutia, Waldo; Villagrán-Schmidt, Milca; Ulloa-Vásquez, Priscilla; Carrasco-Moyano, Rubén; Uribe, Alberto; Stoicea, Nicoleta; Bergese, Sergio D

2018-05-01

Neuraxial anesthesia is a commonly used type of regional anesthesia. Cauda equina syndrome is an unusual and severe complication of neuraxial anesthesia, and is caused by damage to the sacral roots of the neural canal. We present a case of cauda equina syndrome following spinal anesthesia in a patient who underwent Bartholin abscess drainage. A 23-year old female scheduled to undergo surgical drainage of Bartholin abscess. Spinal anesthesia was performed with bupivacaine and fentanyl. There were no perioperative adverse events reported. On postoperative day 1, the patient went to the emergency department describing bilateral weakness and pain of the lower extremities (LE). Lumbar magnetic resonance imaging showed increased gadolinium accumulation in the neural sheath at the level of the cauda equina tracts, consistent with the diagnosis of arachnoiditis and the diagnosis of cauda equina was established. The patient received the following emergent treatment: 75 mg pregabalin (oral) every 12 hours, 20 mg (8 drops) tramadol (oral) every 8 hours, and 4 mg dexamethasone (intravenous) every 6 hours. On postoperative day 4, the patient still experienced bilateral flaccid paraparesis (accentuated in the left side), neuropathic pain in low extremities, and left brachial monoparesis. Hence, dexamethasone was instantly replaced with 1 g methylprednisolone (intravenous) for 5 days. After completing 5 days of methylprednisolone, on postoperative day 9, the patient experienced less pain in left extremities, osteotendinous reflexes were slightly diminished, and she was able to walk with difficulty for 3 to 5 minutes. Greater mobility was evidenced, with right proximal and distal low extremities Medical Research Council Scale grades of 2 and 3 and left proximal and distal low extremities Medical Research Council Scale grades 1 and 2, respectively. Oral prednisone was restarted. Consequently, she was discharged home in stable conditions on postoperative day 25 with a prescription for sertraline, clonazepam, pregabalin, paracetamol, and prednisone. The early detection and treatment of complications after neuraxial anesthesia is essential to minimize the risk of permanent damage.

Development and evaluation of in situ gel of pregabalin

PubMed Central

Madan, Jyotsana R; Adokar, Bhushan R; Dua, Kamal

2015-01-01

Aim and Background: Pregabalin (PRG), an analog of gamma-aminobutyric acid, reduces the release of many neurotransmitters, including glutamate, and noradrenaline. It is used for the treatment of epilepsy; simple and complex partial convulsion. The present research work aims to ensure a high drug absorption by retarding the advancement of PRG formulation through the gastrointestinal tract. The work aims to design a controlled release PRG formulation which is administered as liquid and further gels in the stomach and floats in gastric juice. Materials and Methods: In situ gelling formulations were prepared using sodium alginate, calcium chloride, sodium citrate, hydroxypropyl methylcellulose (HPMC) K100M, and sodium bicarbonate. The prepared formulations were evaluated for solution viscosity, drug content, in vitro gelling studies, gel strength, and in vitro drug release. The final formulation was optimized using a 32 full factorial design. Results: The formulation containing 2.5% w/v sodium alginate and 0.2% w/v calcium chloride were considered optimum since it showed minimum floating lag time (18 s), optimum viscosity (287.3 cps), and gel strength (4087.17 dyne/cm2). The optimized formulation follows Korsmeyer-Peppas kinetic model with n value 0.3767 representing Fickian diffusion mechanism of drug release. Conclusion: Floating in situ gelling system of PRG can be formulated using sodium alginate as a gelling polymer and calcium chloride as a complexing agent to control the drug release for about 12 h for the treatment of epilepsy. PMID:26682193

Pregabalin for decreasing pancreatic pain in chronic pancreatitis.

PubMed

Gurusamy, Kurinchi Selvan; Lusuku, Charnelle; Davidson, Brian R

2016-02-02

Chronic abdominal pain is one of the major symptoms in people with chronic pancreatitis. The role of pregabalin in people with chronic pancreatic pain due to chronic pancreatitis is uncertain. To assess the benefits and harms of pregabalin in people with chronic abdominal pain due to chronic pancreatitis. We searched the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library 2015, issue 6, and MEDLINE, EMBASE, Science Citation Index Expanded, trials registers until June 2015. We also searched the references of included trials to identify further trials. We considered only randomised controlled trials (RCT) performed in people with chronic pancreatic pain due to chronic pancreatitis, irrespective of language, blinding, or publication status for inclusion in the review. Two review authors independently identified trials and independently extracted data. We calculated the risk ratio (RR) or mean difference (MD) with 95% confidence intervals (CI) with RevMan 5, based on intention-to-treat analysis. Only one study, funded by Pfizer, met the inclusion criteria for the review. A total of 64 participants (with chronic pain due to chronic pancreatitis) were randomly assigned to receive escalating doses of pregabalin (150 mg per day to 600 mg per day; 34 participants) or matching placebo (30 participants). Participants received pregabalin or placebo for three weeks on an outpatient basis; the outcomes were measured at the end of the treatment (i.e. three weeks from commencement of treatment). Potential participants taking concomitant analgesic medication and expected to stay on a stable regime during the trial were allowed to enter the study. This trial was at low risk of bias. The overall quality of evidence was low or moderate.Only the short-term outcomes were available in this trial. The medium and long-term outcomes, number of work days lost, and length of hospital stay due to admissions for pain control were not available. This trial found that the changes in opiate use (MD -26.00 mg; 95% CI -47.36 to -4.64; participants = 64; moderate-quality evidence), and pain score percentage changes from baseline (MD -12.00; 95% CI -21.82 to -2.18; participants = 64; moderate-quality evidence) were better in participants taking pregabalin compared to those taking placebo. This trial also found that there were more adverse events in participants taking pregabalin compared to those taking placebo (RR 1.71; 95% CI 1.20 to 2.43; participants = 64). The differences between pregabalin and placebo were imprecise for short-term health-related quality of life measured with the EORTC CLQ-30 questionnaire (MD 11.40; 95% CI -3.28 to 26.08; participants = 64; moderate-quality evidence), proportion of people with serious adverse events (RR 1.76; 95% CI 0.35 to 8.96; participants = 64; low-quality evidence), and proportion of people requiring hospital admissions (RR 0.44; 95% CI 0.04 to 4.62; participants = 64; low quality evidence). Based on low- to moderate-quality evidence, short-term use of pregabalin decreases short-term opiate use, and short-term pain scores, but increases the adverse events compared to placebo, in people with chronic pain due to chronic pancreatitis. The clinical implication of the decreases in short-term opiate use and short-term pain scores is not known.Future trials assessing the role of pregabalin in decreasing chronic pain in chronic pancreatitis should assess the medium- or long-term effects of pregabalin and should include outcomes such as, quality of life, treatment-related adverse events, number of work days lost, number of hospital admissions, and the length of hospital stay, in addition to pain scores, to assess the clinical and socioeconomic impact.

Impact of pregabalin treatment on synaptic plasticity and glial reactivity during the course of experimental autoimmune encephalomyelitis

PubMed Central

Silva, Gleidy A A; Pradella, Fernando; Moraes, Adriel; Farias, Alessandro; dos Santos, Leonilda M B; de Oliveira, Alexandre L R

2014-01-01

Background Multiple sclerosis (MS) is an autoimmune and neurodegenerative disease that affects young adults. It is characterized by generating a chronic demyelinating autoimmune inflammation in the central nervous system. An experimental model for studying MS is the experimental autoimmune encephalomyelitis (EAE), induced by immunization with antigenic proteins from myelin. Aims The present study investigated the evolution of EAE in pregabalin treated animals up to the remission phase. Methods and results The results demonstrated a delay in the onset of the disease with statistical differences at the 10th and the 16th day after immunization. Additionally, the walking track test (CatWalk) was used to evaluate different parameters related to motor function. Although no difference between groups was obtained for the foot print pressure, the regularity index was improved post treatment, indicating a better motor coordination. The immunohistochemical analysis of putative synapse preservation and glial reactivity revealed that pregabalin treatment improved the overall morphology of the spinal cord. A preservation of circuits was depicted and the glial reaction was downregulated during the course of the disease. qRT-PCR data did not show immunomodulatory effects of pregabalin, indicating that the positive effects were restricted to the CNS environment. Conclusions Overall, the present data indicate that pregabalin is efficient for reducing the seriousness of EAE, delaying its course as well as reducing synaptic loss and astroglial reaction. PMID:25365796

Synergistic anticonvulsant effects of pregabalin and amlodipine on acute seizure model of epilepsy in mice.

PubMed

Qureshi, Itefaq Hussain; Riaz, Azra; Khan, Rafeeq Alam; Siddiqui, Afaq Ahmed

2017-08-01

Status epilepticus is a life threatening neurological medical emergency. It may cause serious damage to the brain and even death in many cases if not treated properly. There is limited choice of drugs for the short term and long term management of status epilepticus and the dugs recommended for status epilepticus possess various side effects. The present study was designed to investigate synergistic anticonvulsant effects of pregabalin with amlodipine on acute seizure model of epilepsy in mice. Pentylenetetrazole was used to induce acute seizures which mimic status epilepticus. Pregabalin and amlodipine were used in combination to evaluate synergistic anti-seizure effects on acute seizure model of epilepsy in mice. Diazepam and valproate were used as reference dugs. The acute anti-convulsive activity of pregabalin with amlodipine was evaluated in vivo by the chemical induced seizures and their anti-seizure effects were compared with pentylenetetrazole, reference drugs and to their individual effects. The anti-seizure effects of tested drugs were recorded in seconds on seizure characteristics such as latency of onset of threshold seizures, rearing and fallings and Hind limbs tonic extensions. The seizure protection and mortality to the animals exhibited by the drugs were recorded in percentage. Combination regimen of pregabalin with amlodipine exhibited dose dependent significant synergistic anticonvulsant effects on acute seizures which were superior to their individual effects and equivalent to reference drugs.

Efficacy of Pregabalin in Childhood Refractory Partial Seizure

PubMed Central

Zamani, Gholamreza; Tavasoli, Alireza; Zare-Shahabadi, Ameneh; Rezaei, Nima; Ahmadvand, Alireza

2014-01-01

Objective: About one third of partial seizures are refractory to treatment. Several anticonvulsant drugs have entered the market in recent decades but concerns about intolerance, drug interactions, and the safety of the drug are notable. One of these new anticonvulsants is pregabalin, a safe drug with almost no interaction with other antiepileptic drugs. Methods: In this open label clinical trial study, pregabalin was used for evaluation of its efficacy on reducing seizure frequency in 29 children suffering from refractory partial seizures. Average daily and weekly seizure frequency of the patients was recorded during a 6-week period (baseline period). Then, during a period of 2 weeks (titration period), pregabalin was started with a dose of 25-75 mg/d, using method of flexible dose, and was brought to maximum dose of drug that was intended in this study (450 mg/d) based on clinical response of the patients and seizure frequency. Then the patients were given the drug for 12 weeks and the average frequency of daily and weekly seizures were recorded again (treatment period). Findings : Reduction in seizure frequency in this study was 36% and the responder rate or number of patients who gained more than 50% reduction in seizure frequency was 51.7%. Conclusion: This study showed that pregabalin can be used with safety and an acceptable efficacy in treatment of childhood refractory partial seizures. PMID:25793053

Galectin-3 Inhibition Is Associated with Neuropathic Pain Attenuation after Peripheral Nerve Injury

PubMed Central

Ai, Zisheng; Zheng, Yongjun

2016-01-01

Neuropathic pain remains a prevalent and persistent clinical problem because it is often poorly responsive to the currently used analgesics. It is very urgent to develop novel drugs to alleviate neuropathic pain. Galectin-3 (gal3) is a multifunctional protein belonging to the carbohydrate-ligand lectin family, which is expressed by different cells. Emerging studies showed that gal3 elicits a pro-inflammatory response by recruiting and activating lymphocytes, macrophages and microglia. In the study we investigated whether gal3 inhibition could suppress neuroinflammation and alleviate neuropathic pain following peripheral nerve injury. We found that L5 spinal nerve ligation (SNL) increases the expression of gal3 in dorsal root ganglions at the mRNA and protein level. Intrathecal administration of modified citrus pectin (MCP), a gal3 inhibitor, reduces gal3 expression in dorsal root ganglions. MCP treatment also inhibits SNL-induced gal3 expression in primary rat microglia. SNL results in an increased activation of autophagy that contributes to microglial activation and subsequent inflammatory response. Intrathecal administration of MCP significantly suppresses SNL-induced autophagy activation. MCP also inhibits lipopolysaccharide (LPS)-induced autophagy in cultured microglia in vitro. MCP further decreases LPS-induced expression of proinflammatory mediators including IL-1β, TNF-α and IL-6 by regulating autophagy. Intrathecal administration of MCP results in adecreased mechanical and cold hypersensitivity following SNL. These results demonstrated that gal3 inhibition is associated with the suppression of SNL-induced inflammatory process andneurophathic pain attenuation. PMID:26872020

Early transcutaneous electrical nerve stimulation reduces hyperalgesia and decreases activation of spinal glial cells in mice with neuropathic pain.

PubMed

Matsuo, Hideaki; Uchida, Kenzo; Nakajima, Hideaki; Guerrero, Alexander Rodriguez; Watanabe, Shuji; Takeura, Naoto; Sugita, Daisuke; Shimada, Seiichiro; Nakatsuka, Terumasa; Baba, Hisatoshi

2014-09-01

Although transcutaneous electrical nerve stimulation (TENS) is widely used for the treatment of neuropathic pain, its effectiveness and mechanism of action in reducing neuropathic pain remain uncertain. We investigated the effects of early TENS (starting from the day after surgery) in mice with neuropathic pain, on hyperalgesia, glial cell activation, pain transmission neuron sensitization, expression of proinflammatory cytokines, and opioid receptors in the spinal dorsal horn. Following nerve injury, TENS and behavioral tests were performed every day. Immunohistochemical, immunoblot, and flow cytometric analysis of the lumbar spinal cord were performed after 8 days. Early TENS reduced mechanical and thermal hyperalgesia and decreased the activation of microglia and astrocytes (P<0.05). In contrast, the application of TENS at 1 week (TENS-1w) or 2 weeks (TENS-2w) after injury was ineffective in reducing hyperalgesia (mechanical and thermal) or activation of microglia and astrocytes. Early TENS decreased p-p38 within microglia (P<0.05), the expression levels of protein kinase C (PKC-γ), and phosphorylated anti-phospho-cyclic AMP response element-binding protein (p-CREB) in the superficial spinal dorsal horn neurons (P<0.05), mitogen-activated protein (MAP) kinases, and proinflammatory cytokines, and increased the expression levels of opioid receptors (P<0.05). The results suggested that the application of early TENS relieved hyperalgesia in our mouse model of neuropathic pain by inhibiting glial activation, MAP kinase activation, PKC-γ, and p-CREB expression, and proinflammatory cytokines expression, as well as maintenance of spinal opioid receptors. The findings indicate that TENS treatment is more effective when applied as early after nerve injury as possible. Copyright © 2014 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

[On the risk of dependence on gabapentinoids].

PubMed

Bonnet, Udo; Scherbaum, Norbert

2018-02-01

In the last ten years, the prescriptions of the gabapentinoids gabapentin and pregabalin increased largely also in Germany. Since several national and international pharmacovigilance-databases have warned for abuse liabilities and overdose fatalities in association with both gabapentinoids, which moreover, became to be sold on internet and black-markets, their addictive power has been subject to an ongoing clinical debate. As pre- and post-approval clinical trials did not reveal significant signs of dependence on gabapentin or pregabalin, we systematically searched in PubMed and Scopus for clinical studies and case reports being associated with abuse of and dependence on these drugs. We found 14 clinical-epidemiologic studies and 38 case reports/series. These were evaluated for i) fulfilled dependence criteria according to ICD-10, ii) non-medical self-administration and their duration, iii) relapses, iv) social sequels, and v) cases seeking treatment for misusing gabapentin or pregabalin. Mostly, the cases of abuse of and dependence on gabapentinoids appeared to be associated with other substance dependencies, primarily opiate dependence and polyvalent drug use. Drug users preferred pregabalin citing a faster and stronger euphoria ("liking") than achievable with oral gabapentin. Both gabapentinoids were anxiolytic in therapeutic doses, stimulating in lower and sedating along with increasing doses. Fatalities have been described mainly in the population of opiate dependents and polyvalent drug users, predominantly together with excessive pregabalin overdosing. It is debated whether the gabapentinoids were indeed the main cause of death in these cases or whether gabapentin and pregabalin had been only bystanders. Tolerance and withdrawal symptoms (physical dependence) of gabapentinoids appeared to be common in medical and non-medical use of gabapentinoids. There were only 4 persons who had fulfilled behavioral dependence criteria of gabapentinoids (all had used pregabalin) and had no association with other substance use disorders (apart from nicotine). Regarding the transitions from prescription to non-medical self-administration, the frequency and duration of self-administrations as well as the number of reported relapses, pregabalin appeared also to be more addictive than gabapentin. However, all these events were reported rather infrequently compared with traditional substances of abuse. We did not find a case with social sequalea due to the use of gabapentinoids or a person who sought treatment for his gabapentin or pregabalin use. Therefore, the gabapentinoids were assumed to possess a lower "wanting" in consideration of Berridge's and Robinsons's incentive-sensitization theory of addiction. Also, anti-adverse selection of gabapentinoids is discussed to be present in the population of opioid and multi-drug users. Based upon all these results and assumptions, we have estimated the relative risk of dependence on gabapentinoids by using an algorithm which was previously developed by Griffith and Johnson for evaluation of the abuse liabilities of sedatives. Overall, the risk of harm and dependence on gabapentinoids appeared to be lower than that of other sedatives (and stimulants). In addition, pregabalin appeared to be somewhat riskier than gabapentin. We think that in patients with current or past substance use disorders, the treatment with gabapentinoids should be avoided or if indispensable, these drugs should be administered exclusively over a limited time span with caution by using a therapeutic and prescription monitoring. Georg Thieme Verlag KG Stuttgart · New York.

Chronic pancreatitis.

PubMed

DiMagno, Matthew J; DiMagno, Eugene P

2012-09-01

We review important new clinical observations in chronic pancreatitis reported in 2011. Smoking increases the risk of nongallstone acute pancreatitis and the progression of acute pancreatitis to chronic pancreatitis. Binge drinking during Oktoberfest did not associate with increased hospital admissions for acute pancreatitis. The unfolded protein response is an adaptive mechanism to maintain pancreatic health in response to noxious stimuli such as alcohol. Onset of diabetes mellitus in chronic pancreatitis is likely due to progressive disease rather than individual variables. Insufficient pancreatic enzyme dosing is common for treatment of pancreatic steatorrhea; 90 000 United States Pharmacopeia units of lipase should be given with meals. Surgical drainage provides sustained, superior pain relief compared with endoscopic treatment in patients advanced chronic pancreatitis with a dilated main duct ± pancreatic stones. The central acting gabapentoid pregabalin affords a modest 12% pain reduction in patients with chronic pancreatitis but approximately 30% of patients have significant side effects. Patients with nongallstone-related acute pancreatitis or chronic pancreatitis of any cause should cease smoking. Results of this year's investigations further elucidated the pancreatic pathobiology due to alcohol, onset of diabetes mellitus in chronic pancreatitis, and the mechanisms and treatment of neuropathic pain in chronic pancreatitis.

Influence of xanthotoxin (8-methoxypsoralen) on the anticonvulsant activity of various novel antiepileptic drugs against maximal electroshock-induced seizures in mice.

PubMed

Zagaja, Mirosław; Andres-Mach, Marta; Patrzylas, Paweł; Pyrka, Daniel; Szpringer, Monika; Florek-Łuszczki, Magdalena; Żółkowska, Dorota; Skalicka-Woźniak, Krystyna; Łuszczki, Jarogniew J

2016-12-01

The aim of this study was to determine the effects of xanthotoxin (8-methoxypsoralen) on the protective action of 5 various second- and third-generation antiepileptic drugs (i.e., lacosamide, lamotrigine, oxcarbazepine, pregabalin and topiramate) in the mouse maximal electroshock-induced seizure model. Seizure activity was evoked in adult male albino Swiss mice by a current (25mA, 500V, 0.2s stimulus duration) delivered via auricular electrodes. Drug-related adverse effects were determined in the chimney, grip-strength and passive avoidance tests. Total brain antiepileptic drug concentrations were measured to confirm pharmacodynamic nature of observed interactions with xanthotoxin. Results indicate that xanthotoxin (100mg/kg, i.p.) significantly enhanced the anticonvulsant action of lacosamide (P<0.01), oxcarbazepine (P<0.05), pregabalin (P<0.01), and topiramate (P<0.001), but not that of lamotrigine in the maximal electroshock-induced seizure test. Moreover, xanthotoxin (50mg/kg) still significantly potentiated the anticonvulsant action of lacosamide (P<0.05), pregabalin (P<0.05), and topiramate (P<0.001) in this seizure test. Xanthotoxin had no significant impact on total brain concentrations of the studied antiepileptic drugs in mice. Furthermore, combinations of xanthotoxin with oxcarbazepine or topiramate produced no adverse effects. However, xanthotoxin in combination with lacosamide, lamotrigine or pregabalin significantly reduced muscular strength in mice in the grip-strength test. In the chimney test, only the combinations of xanthotoxin with pregabalin significantly impaired motor coordination in mice. In conclusion, the combinations of xanthotoxin with oxcarbazepine and topiramate produce beneficial anticonvulsant pharmacodynamic interactions in the maximal electroshock-induced seizure test. A special caution is advised when combining xanthotoxin with pregabalin due to appearance of acute adverse effects. Copyright © 2016 Elsevier B.V. All rights reserved.

Clinical characteristics, pharmacotherapy and healthcare resource use among patients with fibromyalgia newly prescribed gabapentin or pregabalin.

PubMed

Gore, Mugdha; Sadosky, Alesia Beth; Zlateva, Gergana; Clauw, Daniel J

2009-01-01

To characterize comorbidities, pain-related pharmacotherapy, and healthcare resource use among patients with fibromyalgia (FM) newly prescribed pregabalin or gabapentin in clinical practice. Using the PharMetrics Database, FM patients (International Classification of Diseases, Ninth Revision, Clinical Modification code 729.1X) newly prescribed pregabalin (n = 1,606; mean age 49.9 +/- 9.6 years; 87.9% female) and gabapentin (n = 930; mean age 49.5 +/- 9.6 years; 86.6% female) on/after July 1, 2007 were identified. Prevalence of comorbidities, pharmacotherapy, and healthcare resource use/costs (pharmacy, outpatient, inpatient, total) were examined during the 6 months preceding (preindex) and following (postindex) the date of their first pregabalin or gabapentin (index) prescription. Patients in both cohorts had a variety of comorbidities and used multiple medications. There were significant decreases (P values < 0.05) in the use of nonsteroidal anti-inflammatory drugs (32.1% vs. 29.5%), anticonvulsants (27.0% vs. 22.0%), and combination therapies in the pregabalin cohort in the postindex period. There were significant increases (all P values < 0.05) in use of short-acting opioids (58.8% vs. 63.7%), any opioids (61.5% vs. 65.6%), serotonin-norepinephrine reuptake inhibitors (22.5% vs. 24.5%), anticonvulsants (16.3% vs. 26.2%), benzodiazepines (33.2% vs. 36.6%), topical agents (6.6% vs. 9.0%), and combination therapies in the gabapentin cohort. Although there were no changes in units of healthcare resources used, there were increases in the postindex period in hospitalization, medications, and total costs for pregabalin, and office visits and medication costs for gabapentin (all P values < 0.05). Results suggest a high comorbidity and medication use burden in FM patients in this study. Further evaluation is warranted to clarify differences in resource utilization/costs observed with these two anticonvulsants.

Orofacial neuropathic pain reduces spontaneous burrowing behavior in rats.

PubMed

Deseure, K; Hans, G

2018-07-01

It was recently reported that spontaneous burrowing behavior is decreased after tibial nerve transection, spinal nerve transection and partial sciatic nerve ligation. It was proposed that spontaneous burrowing could be used as a measure of the impact of neuropathic pain after peripheral nerve injury. It has remained unclear whether the reduction in burrowing behavior is caused directly by pain or hypersensitivity in the affected limbs, making it more difficult to perform burrowing, or by a pain induced decrease in the general wellbeing, thus reducing the motivation to burrow. We studied burrowing behavior after infraorbital nerve injury, a model of orofacial neuropathic pain that does not affect the limbs. Burrowing behavior was significantly reduced after infraorbital nerve injury. Isolated face grooming and responsiveness to mechanical von Frey stimulation of the infraorbital nerve territory were significantly increased after infraorbital nerve injury, indicative, respectively, of spontaneous pain and mechanical allodynia. It is concluded that spontaneous burrowing may provide a measure of the global impact of pain on the animal's wellbeing after peripheral nerve injury and incorporation of this behavioral assay in preclinical drug testing may improve the predictive validity of currently used pain models. Copyright © 2018 Elsevier Inc. All rights reserved.

Impairment of VGLUT2 but not VGLUT1 signaling reduces neuropathy-induced hypersensitivity.

PubMed

Leo, Sandra; Moechars, Dieder; Callaerts-Vegh, Zsuzsanna; D'Hooge, Rudi; Meert, Theo

2009-11-01

Glutamate is the major excitatory neurotransmitter in the central nervous system with an important role in nociceptive processing. Storage of glutamate into vesicles is controlled by vesicular glutamate transporters (VGLUT). Null mutants for VGLUT1 and VGLUT2 were poorly viable, thus, pain-related behavior was presently compared between heterozygote VGLUT1 and VGLUT2 mice and their respective wild-type littermates using a test battery that included a variety of assays for thermal and mechanical acute nociception, and inflammatory and neuropathic pain syndromes. Behavioral analysis of VGLUT1 mutant mice did not show important behavioral changes in the pain conditions tested. Reduction of VGLUT2 also resulted in unaltered acute nociceptive and inflammatory-induced pain behavior. Interestingly, VGLUT2 heterozygote mice showed an attenuation or absence of some typical neuropathic pain features (e.g., absence of mechanical and cold allodynia after spared nerve injury). Chronic constriction injury in VGLUT2 heterozygote mice showed also reduced levels of cold allodynia, but had no impact on mechanical thresholds. Together, these data suggest that VGLUT2, but not VGLUT1, plays a role in neuropathy-induced allodynia and hypersensitivity, and might be a therapeutic target to prevent and/or treat neuropathic pain.

Mode of action associated with development of hemangiosarcoma in mice given pregabalin and assessment of human relevance.

PubMed

Criswell, Kay A; Cook, Jon C; Wojcinski, Zbigniew; Pegg, David; Herman, James; Wesche, David; Giddings, John; Brady, Joseph T; Anderson, Timothy

2012-07-01

Pregabalin increased the incidence of hemangiosarcomas in carcinogenicity studies of 2-year mice but was not tumorigenic in rats. Serum bicarbonate increased within 24 h of pregabalin administration in mice and rats. Rats compensated appropriately, but mice developed metabolic alkalosis and increased blood pH. Local tissue hypoxia and increased endothelial cell proliferation were also confirmed in mice alone. The combination of hypoxia and sustained increases in endothelial cell proliferation, angiogenic growth factors, dysregulated erythropoiesis, and macrophage activation is proposed as the key event in the mode of action (MOA) for hemangiosarcoma formation. Hemangiosarcomas occur spontaneously in untreated control mice but occur only rarely in humans. The International Programme on Chemical Safety and International Life Sciences Institute developed a Human Relevance Framework (HRF) analysis whereby presence or absence of key events can be used to assess human relevance. The HRF combines the MOA with an assessment of biologic plausibility in humans to assess human relevance. This manuscript compares the proposed MOA with Hill criteria, a component of the HRF, for strength, consistency, specificity, temporality, and dose response, with an assessment of key biomarkers in humans, species differences in response to disease conditions, and spontaneous incidence of hemangiosarcoma to evaluate human relevance. Lack of key biomarker events in the MOA in rats, monkeys, and humans supports a species-specific process and demonstrates that the tumor findings in mice are not relevant to humans at the clinical dose of pregabalin. Based on this collective dataset, clinical use of pregabalin would not pose an increased risk for hemangiosarcoma to humans.

The use of a battery of pain models to detect analgesic properties of compounds: a two-part four-way crossover study.

PubMed

Okkerse, Pieter; van Amerongen, Guido; de Kam, Marieke L; Stevens, Jasper; Butt, Richard P; Gurrell, Rachel; Dahan, Albert; van Gerven, Joop M; Hay, Justin L; Groeneveld, Geert Jan

2017-05-01

The aim was to investigate the ability of a battery of pain models to detect analgesic properties of commonly used analgesics in healthy subjects. The battery consisted of tests eliciting electrical, mechanical and thermal (contact heat and cold pressor)-pain and included a UVB model, the thermal grill illusion and a paradigm of conditioned pain modulation. Subjects were administered fentanyl 3 μg kg -1 , phenytoin 300 mg, (S)-ketamine 10 mg and placebo (part I), or imipramine 100 mg, pregabalin 300 mg, ibuprofen 600 mg and placebo (part II). Pain measurements were performed at baseline and up to 10 h post-dose. Endpoints were analysed using a mixed model analysis of variance. Sixteen subjects (8 female) completed each part. The pain tolerance threshold (PTT) for electrical stimulation was increased (all P < 0.05) compared to placebo for (S)-ketamine (+10.1%), phenytoin (+8.5%) and pregabalin (+10.8%). The PTT for mechanical pain was increased by pregabalin (+14.1%). The cold pressor PTT was increased by fentanyl (+17.1%) and pregabalin (+46.4%). Normal skin heat pain detection threshold was increased by (S)-ketamine (+3.3%), fentanyl (+2.8%) and pregabalin (+4.1%). UVB treated skin pain detection threshold was increased by fentanyl (+2.6%) and ibuprofen (+4.0%). No differences in conditioned pain modulation were observed. This study shows that these pain models are able to detect changes in pain thresholds after administration of different classes of analgesics in healthy subjects. The analgesic compounds all showed a unique profile in their effects on the pain tasks administered. © 2016 The British Pharmacological Society.

Intracellular mGluR5 plays a critical role in neuropathic pain

PubMed Central

Vincent, Kathleen; Cornea, Virginia M.; Jong, Yuh-Jiin I.; Laferrière, André; Kumar, Naresh; Mickeviciute, Aiste; Fung, Jollee S. T.; Bandegi, Pouya; Ribeiro-da-Silva, Alfredo; O'Malley, Karen L.; Coderre, Terence J.

2016-01-01

Spinal mGluR5 is a key mediator of neuroplasticity underlying persistent pain. Although brain mGluR5 is localized on cell surface and intracellular membranes, neither the presence nor physiological role of spinal intracellular mGluR5 is established. Here we show that in spinal dorsal horn neurons >80% of mGluR5 is intracellular, of which ∼60% is located on nuclear membranes, where activation leads to sustained Ca2+ responses. Nerve injury inducing nociceptive hypersensitivity also increases the expression of nuclear mGluR5 and receptor-mediated phosphorylated-ERK1/2, Arc/Arg3.1 and c-fos. Spinal blockade of intracellular mGluR5 reduces neuropathic pain behaviours and signalling molecules, whereas blockade of cell-surface mGluR5 has little effect. Decreasing intracellular glutamate via blocking EAAT-3, mimics the effects of intracellular mGluR5 antagonism. These findings show a direct link between an intracellular GPCR and behavioural expression in vivo. Blockade of intracellular mGluR5 represents a new strategy for the development of effective therapies for persistent pain. PMID:26837579

Does Pregabalin Have Neuropsychotropic Effects?: A Short Perspective

PubMed Central

Marks, David M.; Patkar, Ashwin A.; Masand, Prakash S.

2009-01-01

Pregabalin is a newly developed synthetic gamma-aminobutyric acid (GABA) that is approved for the treatment of fibromyalgia and several neuropathy. It has been proven to show analgesic, anxiolytic, anticonvulsant and sleep enhancement effects, which could be applicable in the treatment of a variety of psychiatric disorders. There have been consistent reports that unexplained somatic symptoms (i.e., pain) may be a part of psychiatric disorders such as major depressive disorder (MDD) and anxiety disorders. Previous researches have also suggested the possible therapeutic potential of anticonvulsants as augmentation therapy or monotherapy in the treatment of mood disorders and anxiety disorders. Hence this short perspective tries to prompt and facilitate a shifting of researchers' attention to potential neuropsychotropic drug role of pregabalin to treat a wide range of neuropsychiatric disorders. PMID:20046375

Integrating data from randomized controlled trials and observational studies to predict the response to pregabalin in patients with painful diabetic peripheral neuropathy.

PubMed

Alexander, Joe; Edwards, Roger A; Savoldelli, Alberto; Manca, Luigi; Grugni, Roberto; Emir, Birol; Whalen, Ed; Watt, Stephen; Brodsky, Marina; Parsons, Bruce

2017-07-20

More patient-specific medical care is expected as more is learned about variations in patient responses to medical treatments. Analytical tools enable insights by linking treatment responses from different types of studies, such as randomized controlled trials (RCTs) and observational studies. Given the importance of evidence from both types of studies, our goal was to integrate these types of data into a single predictive platform to help predict response to pregabalin in individual patients with painful diabetic peripheral neuropathy (pDPN). We utilized three pivotal RCTs of pregabalin (398 North American patients) and the largest observational study of pregabalin (3159 German patients). We implemented a hierarchical cluster analysis to identify patient clusters in the Observational Study to which RCT patients could be matched using the coarsened exact matching (CEM) technique, thereby creating a matched dataset. We then developed autoregressive moving average models (ARMAXs) to estimate weekly pain scores for pregabalin-treated patients in each cluster in the matched dataset using the maximum likelihood method. Finally, we validated ARMAX models using Observational Study patients who had not matched with RCT patients, using t tests between observed and predicted pain scores. Cluster analysis yielded six clusters (287-777 patients each) with the following clustering variables: gender, age, pDPN duration, body mass index, depression history, pregabalin monotherapy, prior gabapentin use, baseline pain score, and baseline sleep interference. CEM yielded 1528 unique patients in the matched dataset. The reduction in global imbalance scores for the clusters after adding the RCT patients (ranging from 6 to 63% depending on the cluster) demonstrated that the process reduced the bias of covariates in five of the six clusters. ARMAX models of pain score performed well (R 2 : 0.85-0.91; root mean square errors: 0.53-0.57). t tests did not show differences between observed and predicted pain scores in the 1955 patients who had not matched with RCT patients. The combination of cluster analyses, CEM, and ARMAX modeling enabled strong predictive capabilities with respect to pain scores. Integrating RCT and Observational Study data using CEM enabled effective use of Observational Study data to predict patient responses.

Effect of curcumin in mice model of vincristine-induced neuropathy.

PubMed

Babu, Anand; Prasanth, K G; Balaji, Bhaskar

2015-06-01

Curcumin exhibits a wide spectrum of biological activities which include neuroprotective, antinociceptive, anti-inflammatory, and antioxidant activity. The present study evaluates the effect of curcumin in vincristine-induced neuropathy in a mice model. Vincristine sulfate (0.1 mg/kg, i.p. for 10 consecutive days) was administered to mice to induce neuropathy. Pain behavior was assessed at different days, i.e., 0, 7, 10, and 14 d. Sciatic nerve total calcium, superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), reduced glutathione (GSH), nitric oxide (NO), and lipid peroxidation (LPO) were also estimated after the 14th day of study. Pregabalin (10 mg/kg, p.o.) and curcumin (15, 30, and 60 mg/kg, p.o.) were administered for 14 consecutive days. Curcumin at 60 mg/kg significantly attenuated the vincristine-induced neuropathic pain manifestations in terms of thermal hyperalgesia (p < 0.001) and allodynia (p < 0.001); mechanical hyperalgesia (p < 0.001); functional loss (p < 0.001); and in the delayed phase of formalin test (p < 0.001). Curcumin at 30 and 60 mg/kg exhibited significant changes (p < 0.001) in antioxidant levels and in total calcium levels in vincristine-injected mice. Curcumin at 30 and 60 mg/kg dose levels significantly attenuated vincristine-induced neuropathy which may be due to its multiple actions including antinociceptive, calcium inhibitory, and antioxidant effect.

Adding pregabalin to a multimodal analgesic regimen does not reduce pain scores following cosmetic surgery: a randomized trial.

PubMed

Chaparro, Luis Enrique; Clarke, Hance; Valdes, Paola A; Mira, Mauricio; Duque, Lorena; Mitsakakis, Nicholas

2012-12-01

Multimodal analgesia increases the chance of successful discharge and pain control after surgery, and pregabalin is being promoted as an effective analgesic, based on placebo-controlled studies. We investigated whether adding pregabalin improved pain control and reduced opioid requests when it was added to a multimodal analgesic regimen for cosmetic surgery. One hundred and ten women who underwent same-day cosmetic surgery were randomized to receive oral pregabalin, 75 mg q12 h for five consecutive days starting the night before surgery, or identical placebos. Participants, outcomes assessors, and the statistician were blinded. The primary outcome was postoperative numerical movement-evoked pain scores at 2, 24, 48, 72, and 96 h after surgery. The secondary outcomes included pain scores at rest; incidence of moderate to severe pain; and analgesic and antiemetic requirements; as well as the incidence of nausea, vomiting, and somnolence. Based on 99 patients who completed the study, we found no difference between the groups in the primary outcome; 72 h after surgery, movement-evoked median pain scores were <4/10 in both groups. We found no differences in opioid requirements (p = 0.95) or anti-inflammatory requirements (p = 0.45), and no difference in opioid-related adverse events. Perioperative pregabalin 75 mg twice a day does not increase benefit when it is added to an already multimodal analgesic regimen for patients undergoing cosmetic surgery. Several factors could explain our findings, including the possibility of publication bias in the current literature.

Oxycodone-induced tolerance to respiratory depression: reversal by ethanol, pregabalin and protein kinase C inhibition.

PubMed

Hill, Rob; Dewey, William L; Kelly, Eamonn; Henderson, Graeme

2018-06-01

Oxycodone, a prescription opioid, is a major drug of abuse, especially in the USA, and contributes significantly to opioid overdose deaths each year. Overdose deaths result primarily from respiratory depression. We have studied respiratory depression by oxycodone and have characterized how tolerance develops on prolonged exposure to the drug. We have investigated the role of PKC in maintaining tolerance and have examined whether ethanol or pregabalin reverses oxycodone-induced tolerance. Respiration was measured in male CD-1 mice by whole-body plethysmography. Mice were preinjected with oxycodone then implanted with mini-pumps (s.c.) delivering 20, 45 or 120 mg·kg -1 ·day -1 oxycodone for 6 days and subsequently challenged with oxycodone (3 mg·kg -1 , i.p.) or morphine (10 mg·kg -1 , i.p.) to assess the level of tolerance. Oxycodone-treated mice developed tolerance to oxycodone and cross tolerance to morphine-induced respiratory depression. Tolerance was less with 20 mg·kg -1 ·day -1 than with 45 or 120 mg·kg -1 ·day -1 oxycodone treatment. At doses that do not depress respiration, ethanol (0.3 g·kg -1 ), pregabalin (20 mg·kg -1 ) and calphostin C (45 μg·kg -1 ) all reversed oxycodone-induced tolerance resulting in significant respiratory depression. Reversal of tolerance was less in mice treated with oxycodone (120 mg·kg -1 ·day -1 ). In mice receiving ethanol and calphostin C or ethanol and pregabalin, there was no greater reversal of tolerance than seen with either drug alone. These data suggest that oxycodone-induced tolerance is mediated by PKC and that reversal of tolerance by ethanol or pregabalin may be a contributory factor in oxycodone overdose deaths. © 2018 The British Pharmacological Society.

Effects of WIN 55,212-2 mesylate on the anticonvulsant action of lamotrigine, oxcarbazepine, pregabalin and topiramate against maximal electroshock-induced seizures in mice.

PubMed

Luszczki, Jarogniew J; Wlaz, Aleksandra; Karwan, Slawomir; Florek-Luszczki, Magdalena; Czuczwar, Stanislaw J

2013-11-15

The aim of this study was to determine the effect of WIN 55,212-2 mesylate (WIN - a non-selective cannabinoid CB1 and CB2 receptor agonist) on the protective action of four second-generation antiepileptic drugs (lamotrigine, oxcarbazepine, pregabalin and topiramate) in the mouse maximal electroshock seizure model. Tonic hind limb extension (seizure activity) was evoked in adult male albino Swiss mice by a current (sine-wave, 25 mA, 500 V, 50 Hz, 0.2s stimulus duration) delivered via auricular electrodes. Drug-related adverse effects were ascertained by use of the chimney test (evaluating motor performance), the step-through passive avoidance task (assessing long-term memory) and the grip-strength test (evaluating skeletal muscular strength). Total brain concentrations of antiepileptic drugs were measured by high-pressure liquid chromatography to ascertain any pharmacokinetic contribution to the observed antiseizure effect. Results indicate that WIN (5mg/kg, i.p.) significantly enhanced the anticonvulsant action of lamotrigine (P<0.05), pregabalin (P<0.001) and topiramate (P<0.05), but not that of oxcarbazepine in the maximal electroshock-induced tonic seizure test in mice. Furthermore, none of the investigated combinations of WIN with antiepileptic drugs were associated with any concurrent adverse effects with regards to motor performance, long-term memory or muscular strength. Pharmacokinetic characterization revealed that WIN had no impact on total brain concentrations of lamotrigine, oxcarbazepine, pregabalin and topiramate in mice. These preclinical data would suggest that WIN in combination with lamotrigine, pregabalin and topiramate is associated with beneficial anticonvulsant pharmacodynamic interactions in the maximal electroshock-induced tonic seizure test. © 2013 Published by Elsevier B.V.

A Decade of Gabapentinoid Misuse: An Analysis of the European Medicines Agency's 'Suspected Adverse Drug Reactions' Database.

PubMed

Chiappini, Stefania; Schifano, Fabrizio

2016-07-01

The gabapentinoids pregabalin and gabapentin are being increasingly prescribed for a range of clinical conditions. Recently, although gabapentinoids at therapeutic dosages may present with low addictive liability levels, cases of misuse and rising numbers of related fatalities have been reported. The aim of the study was to identify and assess cases of gabapentinoid misuse or dependence as reported to the European Medicines Agency's EudraVigilance database, to identify the magnitude of this problem and the characteristics of these reactions. All spontaneous reports of both gabapentin- (2004-2015) and pregabalin- (2006-2015) related misuse/abuse/dependence were retrieved. A descriptive analysis by source, sex, age, and type of report was performed. From the EudraVigilance database 7639 (6.6 % of a total of 115,616) and 4301 (4.8 % of 90,166) adverse drug reaction reports of misuse/abuse/dependence were, respectively, associated with pregabalin and gabapentin, with an overall reporting frequency increasing over time. For both molecules, subjects typically involved were female adults. A total of 27 and 86 fatalities, respectively, associated with pregabalin and gabapentin, and mostly in combination with opioids, were identified. Analysis of proportional reporting ratios for drug abuse/dependence/intentional product misuse values seem to indicate that these adverse drug reactions were more frequently reported for pregabalin (1.25, 1.39, and 1.58, respectively) compared with gabapentin. Despite data collection/methodological approach limitations, the present data seem to suggest that gabapentinoid misuse may be a cause for concern, especially in patients with a history of substance misuse. Hence, healthcare professionals should be vigilant when prescribing these molecules.

The use of a battery of pain models to detect analgesic properties of compounds: a two‐part four‐way crossover study

PubMed Central

Okkerse, Pieter; van Amerongen, Guido; de Kam, Marieke L.; Stevens, Jasper; Butt, Richard P.; Gurrell, Rachel; Dahan, Albert; van Gerven, Joop M.; Hay, Justin L.

2017-01-01

Aim The aim was to investigate the ability of a battery of pain models to detect analgesic properties of commonly used analgesics in healthy subjects. Methods The battery consisted of tests eliciting electrical, mechanical and thermal (contact heat and cold pressor)‐pain and included a UVB model, the thermal grill illusion and a paradigm of conditioned pain modulation. Subjects were administered fentanyl 3 μg kg–1, phenytoin 300 mg, (S)‐ketamine 10 mg and placebo (part I), or imipramine 100 mg, pregabalin 300 mg, ibuprofen 600 mg and placebo (part II). Pain measurements were performed at baseline and up to 10 h post‐dose. Endpoints were analysed using a mixed model analysis of variance. Results Sixteen subjects (8 female) completed each part. The pain tolerance threshold (PTT) for electrical stimulation was increased (all P < 0.05) compared to placebo for (S)‐ketamine (+10.1%), phenytoin (+8.5%) and pregabalin (+10.8%). The PTT for mechanical pain was increased by pregabalin (+14.1%). The cold pressor PTT was increased by fentanyl (+17.1%) and pregabalin (+46.4%). Normal skin heat pain detection threshold was increased by (S)‐ketamine (+3.3%), fentanyl (+2.8%) and pregabalin (+4.1%). UVB treated skin pain detection threshold was increased by fentanyl (+2.6%) and ibuprofen (+4.0%). No differences in conditioned pain modulation were observed. Conclusion This study shows that these pain models are able to detect changes in pain thresholds after administration of different classes of analgesics in healthy subjects. The analgesic compounds all showed a unique profile in their effects on the pain tasks administered. PMID:27862179

Single Administration of Melatonin Modulates the Nitroxidergic System at the Peripheral Level and Reduces Thermal Nociceptive Hypersensitivity in Neuropathic Rats.

PubMed

Borsani, Elisa; Buffoli, Barbara; Bonazza, Veronica; Reiter, Russel J; Rezzani, Rita; Rodella, Luigi F

2017-10-14

Neuropathic pain is a severe condition with unsatisfactory treatments. Melatonin, an indolamine, seems to be a promising molecule suitable for this purpose due to its well-known anti-inflammatory, analgesic, and antioxidant effects, as well as its modulation of the nitroxidergic system. Nevertheless, the data on its mechanism of action and potentialities are currently insufficient in this pathology, especially at the peripheral level. Thus, this work evaluated the effect of a single administration of melatonin in an established mononeuropathy pain model that monitors the behaviour and the changes in the nitroxidergic system in dorsal root ganglia and skin, which are affected by nervous impairment. Experiments were carried out on Sprague Dawley rats subdivided into the sham operated (control) and the chronic constriction injured animals, a model of peripheral neuropathic pain on sciatic nerve. Single administrations of melatonin (5-10 mg/kg) or vehicle were injected intraperitoneally on the 14th day after surgery, when the mononeuropathy was established. The animals were behaviourally tested for thermal hyperalgesia. The dorsal root ganglia and the plantar skin of the hind-paws were removed and processed for the immunohistochemical detection of neuronal and inducible nitric oxide synthases. The behavioural results showed an increase of withdrawal latency during the plantar test as early as 30 min after melatonin administration. The immunohistochemical results indicated a modulation of the nitroxidergic system both at dorsal root ganglia and skin level, permitting speculate on a possible mechanism of action. We showed that melatonin may be a possible therapeutic strategy in neuropathic pain.

Targeting the S1P Axis and Development of a Novel Therapy for Obesity Related Triple Negative Breast Cancer

DTIC Science & Technology

2017-09-01

neuropathic pain associated with chemotherapy. Moreover, our recent 7 work shows that targeting the S1P/S1PR1 axis by treatment with FTY720 greatly...reduces cancer-induced bone pain and neuroinflammation (Grenald et al., 2017) and supports potential fast-track clinical application of the FDA...approved drug, FTY720, as a therapeutic avenue for cancer-induced bone pain . 4.3. The Impact on Technology Transfer Nothing to report 4.4. The impact on

Intrathecal transplantation of neuroblastoma cells decreases heat hyperalgesia and cold allodynia in a rat model of neuropathic pain.

PubMed

De la Calle, J L; Mena, M A; González-Escalada, J R; Paíno, C L

2002-11-30

Intrathecal grafting of cells as biological pumps to deliver monoamines, endorphins, and/or trophic factors, has been shown to be effective in treating chronic pain both in experimental animals and in clinical trials. We have tested whether intrathecal implantation of neuroblastoma cells reduces heat hyperalgesia and cold allodynia in a rat model of neuropathic pain induced by chronic constriction injury (CCI) of the sciatic nerve. Behavioral tests and cerebrospinal fluid (CSF) collection were performed before CCI, 1 week later (after which, vehicle or NB69 cells were intrathecally injected) and at 4, 7, and 14 days post-injection. Both CSF sampling and injection of the cells were performed by direct lumbar puncture. Intrathecal grafting of 4 x 10(6) NB69 neuroblastoma cells reduced to basal levels the nociceptive response to heat in nerve-injured hindpaws, while the response of control limbs remained unchanged. Similarly, the allodynic response to cold elicited by acetone evaporation decreased in the animals implanted with NB69 cells. An increase in the concentrations of dopamine and serotonin metabolites of around 150% was observed in the CSF of animals that received grafts of NB69 cells. These data suggest that the monoamines released by NB69 cells in the intrathecal space produce analgesia to neuropathic pain in rats. Copyright 2002 Elsevier Science Inc.

A Rat Model of Full Thickness Thermal Injury Characterized by Thermal Hyperalgesia, Mechanical Allodynia, Pronociceptive Peptide Release and Tramadol Analgesia

DTIC Science & Technology

2014-01-01

tramadol reduces acute, postoperative, neuropathic and cancer pain [9,10,12 14] and may have a lower propensity to induce addiction [15] with little to...opioid systems simultaneously, we next examined whether tramadol could attenuate burn evoked pain behaviors in our rat model of full thickness thermal...injury. Tramadol attenuated thermal hyperalgesia when administered one week following thermal injury, a time point when pain behaviors peak in this

Cerebral Biochemical Effect of Pregabalin in Patients with Painful Diabetic Neuropathy: A Randomized Controlled Trial.

PubMed

De Jaeger, Mats; Goudman, Lisa; Van Schuerbeek, Peter; De Mey, Johan; Keymeulen, Bart; Brouns, Raf; Moens, Maarten

2018-06-27

With the development of new neuroimaging tools it has become possible to assess neurochemical alterations in patients experiencing chronic pain and to determine how these factors change during pharmacological treatment. The goal of this study was to examine the exact neurochemical mechanism underlying pregabalin treatment, utilizing magnetic resonance spectroscopy ( 1 H-MRS), in a population of patients with painful diabetic polyneuropathy (PDN), with the overall aim to ultimately objectify the clinical effect of pregabalin. A double blind, randomized, placebo-controlled study was conducted. A total of 27 patients with PDN were enrolled in the study, of whom 13 received placebo treatment (control group) and 14 received pregabalin (intervention group). Pregabalin treatment consisted of stepwise dose escalation over the study period from 75 mg daily ultimately to 600 mg daily. 1 H-MRS was performed at 3T on four regions of interest in the brain: the rostral anterior cingulate cortex (rACC), left and right thalamus and prefrontal cortex. The absolute concentrations of N-acetyl aspartate, glutamate, glutamine, gamma-amino-butyric-acid (GABA), glucose (Glc) and myo-inositol (mINS) were determined using LCModel. The concentration of most neurometabolites in the placebo and pregabalin group did not significantly differ over time, with only a small significant difference in Glc level in the left thalamus (p = 0.049). Comparison of the effects of the different doses revealed significant differences for mINS in the rACC (baseline 2.42 ± 1.21 vs. 450 mg 1.58 ± 0.94; p = 0.022) and dorsolateral prefrontal cortex (75 mg 2.38 ± 0.89 vs. 450 mg 1.59 ± 0.85; p = 0.042) and also for GABA in the rACC (75 mg 0.53 ± 0.51 vs. 225 mg 0.28 ± 0.19; p = 0.014). No differences were found in metabolite concentrations between the placebo (control) and intervention groups, but some differences, although small, were found between the different doses. This study is registered at ClinicalTrials.gov (NCT01180608). Lyrica Independent Investigator Research Award (LIIRA) 2010 (Pfizer) funded the study.

Chronic ibuprofen administration reduces neuropathic pain but does not exert neuroprotection after spinal cord injury in adult rats.

PubMed

Redondo-Castro, Elena; Navarro, Xavier

2014-02-01

Ibuprofen is commonly used as an anti-inflammatory analgesic drug, although it is not amongst the first-line treatments for neuropathic pain. Its main effects are mediated by non-specific inhibition of COX enzymes, but it also exerts some COX-independent effects, such as the inhibition of RhoA signaling and the modulation of glial activity. These effects have boosted the use of ibuprofen as a tool to promote axonal regeneration and to increase functional recovery after neural injuries, although with controversial results showing positive and negative outcomes of ibuprofen treatment in several experimental models. We have evaluated the effects of ibuprofen administered at 60 mg/kg twice a day to rats subjected to a mild spinal cord contusion. Our results indicate that ibuprofen ameliorates mechanical hyperalgesia in rats by reducing central hyperexcitability, but failed to produce improvements in the recovery of locomotion. Despite an early effect on reducing microglial reactivity, the ibuprofen treatment did not provide histological evidence of neuroprotection; indeed the volume of cord tissue spared rostral to the lesion was decreased in ibuprofen treated rats. In summary, the early modulation of neuroinflammation produced by the administration of ibuprofen seems to eventually lead to a worse resolution of detrimental events occurring in the secondary injury phase, but also to reduce the development of neuropathic pain. Copyright © 2013 Elsevier Inc. All rights reserved.

Activation of Corticostriatal Circuitry Relieves Chronic Neuropathic Pain

PubMed Central

Lee, Michelle; Manders, Toby R.; Eberle, Sarah E.; Su, Chen; D'amour, James; Yang, Runtao; Lin, Hau Yueh; Deisseroth, Karl; Froemke, Robert C.

2015-01-01

Neural circuits that determine the perception and modulation of pain remain poorly understood. The prefrontal cortex (PFC) provides top-down control of sensory and affective processes. While animal and human imaging studies have shown that the PFC is involved in pain regulation, its exact role in pain states remains incompletely understood. A key output target for the PFC is the nucleus accumbens (NAc), an important component of the reward circuitry. Interestingly, recent human imaging studies suggest that the projection from the PFC to the NAc is altered in chronic pain. The function of this corticostriatal projection in pain states, however, is not known. Here we show that optogenetic activation of the PFC produces strong antinociceptive effects in a rat model (spared nerve injury model) of persistent neuropathic pain. PFC activation also reduces the affective symptoms of pain. Furthermore, we show that this pain-relieving function of the PFC is likely mediated by projections to the NAc. Thus, our results support a novel role for corticostriatal circuitry in pain regulation. PMID:25834050

Pharmacodynamic response profiles of anxiolytic and sedative drugs.

PubMed

Chen, Xia; Broeyer, Freerk; de Kam, Marieke; Baas, Joke; Cohen, Adam; van Gerven, Joop

2017-05-01

Centrally-acting acutely anxiolytic drugs, such as benzodiazepines, barbiturates and gabapentinoids, affect various central nervous system (CNS) functions, which reflects not only their anxiolytic effects but also neuropsychological side-effects. To validate the pharmacodynamic biomarkers for GABA-ergic anxiolytics, this study determined the pharmacodynamics of two anxiolytics and a nonanxiolytic control, and linked them to their anxiolytic and sedative effects, during an anxiety-challenge study day. Twenty healthy volunteers were randomized in this placebo-controlled, double-blind, four-way cross-over study with single-dose alprazolam (1 mg), diphenhydramine (50 mg), pregabalin (200 mg) or placebo. The Neurocart was used between repeated fear-potentiated startle assessments. Thus, the potential influence of anxiety on CNS pharmacodynamic markers could be examined. Compared to placebo, VAS calmness increased with alprazolam (2.0 mm) and pregabalin (2.5 mm) but not with diphenhydramine. Saccadic peak velocity (SPV) declined after alprazolam (-57 ° s -1 ) and pregabalin (-28 ° s -1 ), more than with diphenhydramine (-14 ° s -1 ); so did smooth pursuit. The average responses of SPV and smooth pursuit were significantly correlated with the drug-induced increases in VAS calmness . The SPV-relative responses of VAS alertness , body-sway and adaptive-tracking also differed among alprazolam, pregabalin and diphenhydramine. Compared with the antihistaminergic sedative diphenhydramine, alprazolam and pregabalin caused larger SPV reduction, which was correlated with simultaneous improvement of subjective calmness, during a study day in which anxiety was stimulated repeatedly. The different effect profiles of the three drugs are in line with their pharmacological distinctions. These findings corroborate the profiling of CNS effects to demonstrate pharmacological selectivity, and further support SPV as biomarker for anxiolysis involving GABA-ergic neurons. The study also supports the use of prolonged mild threat to demonstrate anxiolytic effects in healthy volunteers. © 2016 The British Pharmacological Society.

The effect of a single dose of preemptive pregabalin administered with COX-2 inhibitor: a trial in total knee arthroplasty.

PubMed

Lee, Jin Kyu; Chung, Kyu-Sung; Choi, Choong Hyeok

2015-01-01

We sought to compare a group (Group L) (n=21) of patients that underwent total knee arthroplasty and received a single preoperative dose of pregabalin combined with a COX-2 inhibitor with a control group (Group C) (n=20) that only received a COX-2 inhibitor in terms of (1) acute postoperative pain intensity, (2) analgesic consumption, and (3) functional recovery. Mean cumulative fentanyl consumption during the first 48 hours was lower in Group L than in Group C (P<0.05). The pain scores at rest were lower in Group L at 6 and 12 hours after surgery (P<0.05). No significant intergroup difference was noted in functional recovery. The addition of pregabalin led to an additive reduction in early postoperative pain and analgesic consumption. Copyright © 2014 Elsevier Inc. All rights reserved.

An Improved LC-ESI-MS/MS Method to Quantify Pregabalin in Human Plasma and Dry Plasma Spot for Therapeutic Monitoring and Pharmacokinetic Applications.

PubMed

Dwivedi, Jaya; Namdev, Kuldeep K; Chilkoti, Deepak C; Verma, Surajpal; Sharma, Swapnil

2018-06-06

Therapeutic drug monitoring (TDM) of anti-epileptic drugs provides a valid clinical tool in optimization of overall therapy. However, TDM is challenging due to the high biological samples (plasma/blood) storage/shipment costs and the limited availability of laboratories providing TDM services. Sampling in the form of dry plasma spot (DPS) or dry blood spot (DBS) is a suitable alternative to overcome these issues. An improved, simple, rapid, and stability indicating method for quantification of pregabalin in human plasma and DPS has been developed and validated. Analyses were performed on liquid chromatography tandem mass spectrometer under positive ionization mode of electrospray interface. Pregabain-d4 was used as internal standard, and the chromatographic separations were performed on Poroshell 120 EC-C18 column using an isocratic mobile phase flow rate of 1 mL/min. Stability of pregabalin in DPS was evaluated under simulated real-time conditions. Extraction procedures from plasma and DPS samples were compared using statistical tests. The method was validated considering the FDA method validation guideline. The method was linear over the concentration range of 20-16000 ng/mL and 100-10000 ng/mL in plasma and DPS, respectively. DPS samples were found stable for only one week upon storage at room temperature and for at least four weeks at freezing temperature (-20 ± 5 °C). Method was applied for quantification of pregabalin in over 600 samples of a clinical study. Statistical analyses revealed that two extraction procedures in plasma and DPS samples showed statistically insignificant difference and can be used interchangeably without any bias. Proposed method involves simple and rapid steps of sample processing that do not require a pre- or post-column derivatization procedure. The method is suitable for routine pharmacokinetic analysis and therapeutic monitoring of pregabalin.

The Relationship Between Gabapentin and Pregabalin and Posttraumatic Stress Disorder in Burned Servicemembers

DTIC Science & Technology

2012-10-01

Gabapentin and pregabalin are anticonvulsant drugs that limited evidence suggests may also be effective treatments for some psychological disorders. This...inclusion in numerous review articles about alternative pharmacologic treatments for PTSD and other psychological disorders, there is a dearth of...perform the Wil- coxon’s signed-rank test and the χ2 test to examine differences between the two groups. The Spearman correlation test was used to

Cost-effectiveness analysis of pharmacologic treatment of fibromyalgia in Mexico.

PubMed

Arreola Ornelas, Héctor; Rosado Buzzo, Alfonso; García, Lourdes; Dorantes Aguilar, Javier; Contreras Hernández, Iris; Mould Quevedo, Joaquín F

2012-01-01

To identify, from the Mexican Public Health System perspective, which would be the most cost-effective treatment for patients with Fibromyalgia (FM). A Markov model including three health states, divided by pain intensity (absence or presence of mild, moderate or severe pain) and considering three-month cycles; costs and effectiveness were estimated for amitriptyline (50mg/day), fluoxetine (80 mg/day), duloxetine (120 mg/day), gabapentin (900 mg/day), pregabalin (450 mg/day), tramadol/acetaminophen (150 mg/1300 mg/día) and amitriptyline/fluoxetine (50mg/80 mg/día) for the treatment of FM. The clinical outcome considered was the annual rate of pain control. Probabilities assigned to the model were collected from published literature. Direct medical costs for FM treatment were retrieved from the 2006 data of the Mexican Institute of Social Security (IMSS) databases and were expressed in 2010 Mexican Pesos. Probabilistic Sensitivity Analyses were conducted. The best pain control rate was obtained with pregabalin (44.8%), followed by gabapentin (38.1%) and duloxetine (34.2%). The lowest treatment costs was for amitriptyline ($ 9047.01), followed by fluoxetine ($ 10,183.89) and amitriptyline/fluoxetine ($ 10,866.01). By comparing pregabalin vs amitriptyline, additional annual cost per patient for pain control would be around $ 50.000 and $ 75.000 and would result cost-effective in 70% and 80% of all cases. Among all treatment options for FM, pregabalin achieved the highest pain control and was cost-effective in 80% of patients of the Mexican Public Health System. Copyright © 2011 Elsevier España, S.L. All rights reserved.

Quantitation of pregabalin in dried blood spots and dried plasma spots by validated LC-MS/MS methods.

PubMed

Kostić, Nađa; Dotsikas, Yannis; Jović, Nebojša; Stevanović, Galina; Malenović, Anđelija; Medenica, Mirjana

2015-05-10

In this paper, novel LC-MS/MS methods for the determination of antiepileptic drug pregabalin in dried matrix spots (DMS) are presented. This attractive technique of sample collection in micro amount was utilized in the form of dried blood spots (DBS) and dried plasma spots (DPS). Following a pre-column derivatization procedure, using n-propyl chloroformate in the presence of n-propanol, and consecutive liquid-liquid extraction, derivatized pregabalin and its internal standard, 4-aminocyclohexanecarboxylic acid, were detected in positive ion mode by applying two SRM transitions per analyte. A YMC-Pack Octyl column (50mm×4.0mm, 3μm particle size) maintained at 30°C, was utilized with running mobile phase composed of acetonitrile: 0.15% formic acid (85:15, v/v). Flow rate was 550μL/min and total run time 2min. Established methods were fully validated over the concentration range of 0.200-20.0μg/mL for DBS and 0.400-40.0μg/mL for DPS, respectively, while specificity, accuracy, precision, recovery, matrix-effect, stability, dilution integrity and spot homogeneity were found within acceptance criteria. Validated methods were applied for the determination of pregabalin levels in dried blood and plasma samples obtained from patients with epilepsy, after per os administration of commercial capsules. Comparison of drug level in blood and plasma, as well as correction steps undertaken in order to overcome hematocrit issue, when analyzing DBS, are also given. Copyright © 2015 Elsevier B.V. All rights reserved.

The Antinociceptive and Antiinflammatory Properties of 3-furan-2-yl-N-p-tolyl-acrylamide, a Positive Allosteric Modulator of α7 Nicotinic Acetylcholine Receptors in Mice

PubMed Central

Bagdas, Deniz; Targowska-Duda, Katarzyna M.; López, Jhon J.; Perez, Edwin G.; Arias, Hugo R.; Damaj, M. Imad

2016-01-01

BACKGROUND Positive allosteric modulators (PAMs) facilitate endogenous neurotransmission and/or enhance the efficacy of agonists without directly acting on the orthosteric binding sites. In this regard, selective α7 nicotinic acetylcholine receptor type II PAMs display antinociceptive activity in rodent chronic inflammatory and neuropathic pain models. This study investigates whether 3-furan-2-yl-N-p-tolyl-acrylamide (PAM-2), a new putative α7-selective type II PAM, attenuates experimental inflammatory and neuropathic pains in mice. METHODS We tested the activity of PAM-2 after intraperitoneal administration in 3 pain assays: the carrageenan-induced inflammatory pain, the complete Freund adjuvant induced inflammatory pain, and the chronic constriction injury–induced neuropathic pain in mice. We also tested whether PAM-2 enhanced the effects of the selective α7 agonist choline in the mouse carrageenan test given intrathecally. Because the experience of pain has both sensory and affective dimensions, we also evaluated the effects of PAM-2 on acetic acid–induced aversion by using the conditioned place aversion test. RESULTS We observed that systemic administration of PAM-2 significantly reversed mechanical allodynia and thermal hyperalgesia in inflammatory and neuropathic pain models in a dose- and time-dependent manner without motor impairment. In addition, by attenuating the paw edema in inflammatory models, PAM-2 showed antiinflammatory properties. The antinociceptive effect of PAM-2 was inhibited by the selective competitive antagonist methyllycaconitine, indicating that the effect is mediated by α7 nicotinic acetylcholine receptors. Furthermore, PAM-2 enhanced the antiallodynic and antiinflammatory effects of choline, a selective α7 agonist, in the mouse carrageenan test. PAM-2 was also effective in reducing acetic acid induced aversion in the conditioned place aversion assay. CONCLUSIONS These findings suggest that the administration of PAM-2, a new α7-selective type II PAM, reduces the neuropathic and inflammatory pain sensory and affective behaviors in the mouse. Thus, this drug may have therapeutic applications in the treatment and management of chronic pain. PMID:26280585

Subcutaneous, intrathecal and periaqueductal grey administration of asimadoline and ICI-204448 reduces tactile allodynia in the rat.

PubMed

Caram-Salas, Nadia L; Reyes-García, Gerardo; Bartoszyk, Gerd D; Araiza-Saldaña, Claudia I; Ambriz-Tututi, Mónica; Rocha-González, Héctor I; Arreola-Espino, Rosaura; Cruz, Silvia L; Granados-Soto, Vinicio

2007-11-14

The purpose of this study was to assess the possible antiallodynic effect of asimadoline ([N-methyl-N-[1S)-1-phenyl)-2-(13S))-3-hydroxypyrrolidine-1-yl)-ethyl]-2,2-diphenylacetamide HCl]) and ICI-20448 ([2-[3-(1-(3,4-Dichlorophenyl-N-methylacetamido)-2-pyrrolidinoethyl)-phenoxy]acetic acid HCl]), two peripheral selective kappa opioid receptor agonists, after subcutaneous, spinal and periaqueductal grey administration to neuropathic rats. Twelve days after spinal nerve ligation tactile allodynia was observed, along with an increase in kappa opioid receptor mRNA expression in dorsal root ganglion and dorsal horn spinal cord. A non-significant increase in periaqueductal grey was also seen. Subcutaneous (s.c.) administration of asimadoline and ICI-204448 (1-30 mg/kg) dose-dependently reduced tactile allodynia. This effect was partially blocked by s.c., but not intrathecal, naloxone. Moreover, intrathecal administration of asimadoline or ICI-204448 (1-30 mug) reduced tactile allodynia in a dose-dependent manner and this effect was completely blocked by intrathecal naloxone. Microinjection of both kappa opioid receptor agonists (3-30 mug) into periaqueductal grey also produced a naloxone-sensitive antiallodynic effect in rats. Our results indicate that systemic, intrathecal and periaqueductal grey administration of asimadoline and ICI-204448 reduces tactile allodynia. This effect may be a consequence of an increase in kappa opioid receptor mRNA expression in dorsal root ganglion, dorsal horn spinal cord and, to some extent, in periaqueductal grey. Finally, our data suggest that these drugs could be useful to treat neuropathic pain in human beings.

Neuropathic pain in leprosy: symptom profile characterization and comparison with neuropathic pain of other etiologies

PubMed Central

Raicher, Irina; Stump, Patrick Raymond Nicolas Andre Ghislain; Harnik, Simone Bega; de Oliveira, Rodrigo Alves; Baccarelli, Rosemari; Marciano, Lucia H.S.C.; Ura, Somei; Virmond, Marcos C.L.; Teixeira, Manoel Jacobsen; de Andrade, Daniel Ciampi

2018-01-01

Abstract Introduction: Previous studies reported a high prevalence of neuropathic pain in leprosy, being especially present in “pharmacologically cured” patients. The presence of neuropathic pain in leprosy poses a supplementary burden in patient's quality of life, daily activities, and mood. Objectives: The aim of this study was to assess whether neuropathic pain in leprosy has similar symptom profile as neuropathic pain of other etiologies and to retrospectively assess the efficacy of neuropathic pain medications regularly prescribed to leprosy. Methods: Leprosy and nonleprosy patients had their neuropathic pain characterized by the neuropathic pain symptom inventory (NPSI, ranges from 0 to 100, with 100 being the maximal neuropathic pain intensity) in a first visit. In a second visit, leprosy patients who had significant pain and received pharmacological treatment in the first evaluation were reassessed (NPSI) and had their pain profile and treatment response further characterized, including information on drugs prescribed for neuropathic pain and their respective pain relief. Results: The pain characteristics based on NPSI did not significantly differ between leprosy and nonleprosy neuropathic pain patients in visit 1 after correction for multiple analyses, and cluster analyses confirmed these findings (ie, no discrimination between leprosy and nonleprosy groups; Pearson χ2 = 0.072, P = 0.788). The assessment of pain relief response and the drugs taken by each patient, linear regression analysis showed that amitriptyline, when effective, had the highest percentage of analgesic relief. Conclusions: Neuropathic pain in leprosy is as heterogeneous as neuropathic pain of other etiologies, further supporting the concept that neuropathic pain is a transetiological entity. Neuropathic pain in leprosy may respond to drugs usually used to control pain of neuropathic profile in general, and amitriptiline may constitute a potential candidate drug for future formal clinical trials aimed at controlling neuropathic pain in leprosy. PMID:29756085

Inferior ST-Elevation Acute Myocardial Infarction or an Inferior-Lead Brugada-like Electrocardiogram Pattern Associated With the Use of Pregabalin and Quetiapine?

PubMed

Brunetti, Natale D; Ieva, Riccardo; Correale, Michele; Cuculo, Andrea; Santoro, Francesco; Guaricci, Andrea I; De Gennaro, Luisa; Gaglione, Antonio; Di Biase, Matteo

2016-01-01

The Brugada electrocardiogram pattern is characterized by coved-type ST-elevation (>2 mm) in the right precordial leads. We report the case of a 62-year-old man, with bipolar disorder, admitted to the emergency department because of dyspnea and chest discomfort. The patient was on treatment with pregabalin and quetiapine. Unexpectedly, electrocardiogram at admission showed diffuse ST-elevation, more evident in inferior leads, where a Brugada-like pattern was present. The patient underwent coronary angiography with a diagnosis of suspected acute coronary syndrome. Coronary angiography, however, showed mild coronary artery disease not requiring coronary angioplasty. Echocardiography did not reveal left ventricular dysfunction or pericardial effusion. Troponin levels remained normal over serial controls. Eventually, chest radiography showed lung opacities and consolidation suggestive for pneumonia. To the best of our knowledge, this is one of the first cases showing a transient Brugada-like electrocardiogram pattern in inferior leads, probably amplified by the administration of pregabalin and quetiapine.

Neuropathic pain in leprosy: symptom profile characterization and comparison with neuropathic pain of other etiologies.

PubMed

Raicher, Irina; Stump, Patrick Raymond Nicolas Andre Ghislain; Harnik, Simone Bega; de Oliveira, Rodrigo Alves; Baccarelli, Rosemari; Marciano, Lucia H S C; Ura, Somei; Virmond, Marcos C L; Teixeira, Manoel Jacobsen; de Andrade, Daniel Ciampi

2018-03-01

Previous studies reported a high prevalence of neuropathic pain in leprosy, being especially present in "pharmacologically cured" patients. The presence of neuropathic pain in leprosy poses a supplementary burden in patient's quality of life, daily activities, and mood. The aim of this study was to assess whether neuropathic pain in leprosy has similar symptom profile as neuropathic pain of other etiologies and to retrospectively assess the efficacy of neuropathic pain medications regularly prescribed to leprosy. Leprosy and nonleprosy patients had their neuropathic pain characterized by the neuropathic pain symptom inventory (NPSI, ranges from 0 to 100, with 100 being the maximal neuropathic pain intensity) in a first visit. In a second visit, leprosy patients who had significant pain and received pharmacological treatment in the first evaluation were reassessed (NPSI) and had their pain profile and treatment response further characterized, including information on drugs prescribed for neuropathic pain and their respective pain relief. The pain characteristics based on NPSI did not significantly differ between leprosy and nonleprosy neuropathic pain patients in visit 1 after correction for multiple analyses, and cluster analyses confirmed these findings (ie, no discrimination between leprosy and nonleprosy groups; Pearson χ2 = 0.072, P = 0.788). The assessment of pain relief response and the drugs taken by each patient, linear regression analysis showed that amitriptyline, when effective, had the highest percentage of analgesic relief. Neuropathic pain in leprosy is as heterogeneous as neuropathic pain of other etiologies, further supporting the concept that neuropathic pain is a transetiological entity. Neuropathic pain in leprosy may respond to drugs usually used to control pain of neuropathic profile in general, and amitriptiline may constitute a potential candidate drug for future formal clinical trials aimed at controlling neuropathic pain in leprosy.

Demonstration of an anti-hyperalgesic effect of a novel pan-Trk inhibitor PF-06273340 in a battery of human evoked pain models.

PubMed

Loudon, Peter; Siebenga, Pieter; Gorman, Donal; Gore, Katrina; Dua, Pinky; van Amerongen, Guido; Hay, Justin L; Groeneveld, Geert Jan; Butt, Richard P

2018-02-01

Inhibitors of nerve growth factor (NGF) reduce pain in several chronic pain indications. NGF signals through tyrosine kinase receptors of the tropomyosin-related kinase (Trk) family and the unrelated p75 receptor. PF-06273340 is a small molecule inhibitor of Trks A, B and C that reduces pain in nonclinical models, and the present study aimed to investigate the pharmacodynamics of this first-in-class molecule in humans. A randomized, double-blind, single-dose, placebo- and active-controlled five-period crossover study was conducted in healthy human subjects (NCT02260947). Subjects received five treatments: PF-06273340 50 mg, PF-06273340 400 mg, pregabalin 300 mg, ibuprofen 600 mg and placebo. The five primary endpoints were the pain detection threshold for the thermal pain tests and the pain tolerance threshold for the cold pressor, electrical stair and pressure pain tests. The trial had predefined decision rules based on 95% confidence that the PF-06273340 effect was better than that of placebo. Twenty subjects entered the study, with 18 completing all five periods. The high dose of PF-06273340 met the decision rules on the ultraviolet (UV) B skin thermal pain endpoint [least squares (LS) mean vs. placebo: 1.13, 95% confidence interval: 0.64-1.61], but not on the other four primary endpoints. The low dose did not meet the decision criteria for any of the five primary endpoints. Pregabalin (cold pressor and electrical stair tests) and ibuprofen (UVB thermal pain) showed significant analgesic effects on expected endpoints. The study demonstrated, for the first time, the translation of nonclinical effects into man in an inflammatory pain analgesic pharmacodynamic endpoint using a pan-Trk inhibitor. © 2017 The British Pharmacological Society.

Frutalin reduces acute and neuropathic nociceptive behaviours in rodent models of orofacial pain.

PubMed

Damasceno, Marina B M V; de Melo Júnior, José de Maria A; Santos, Sacha Aubrey A R; Melo, Luana T M; Leite, Laura Hévila I; Vieira-Neto, Antonio E; Moreira, Renato de A; Monteiro-Moreira, Ana Cristina de O; Campos, Adriana R

2016-08-25

Orofacial pain is a highly prevalent clinical condition, yet difficult to control effectively with available drugs. Much attention is currently focused on the anti-inflammatory and antinociceptive properties of lectins. The purpose of this study was to evaluate the antinociceptive effect of frutalin (FTL) using rodent models of inflammatory and neuropathic orofacial pain. Acute pain was induced by formalin, glutamate or capsaicin (orofacial model) and hypertonic saline (corneal model). In one experiment, animals were pretreated with l-NAME and naloxone to investigate the mechanism of antinociception. The involvement of the lectin domain in the antinociceptive effect of FTL was verified by allowing the lectin to bind to its specific ligand. In another experiment, animals pretreated with FTL or saline were submitted to the temporomandibular joint formalin test. In yet another, animals were submitted to infraorbital nerve transection to induce chronic pain, followed by induction of thermal hypersensitivity using acetone. Motor activity was evaluated with the rotarod test. A molecular docking was performed using the TRPV1 channel. Pretreatment with FTL significantly reduced nociceptive behaviour associated with acute and neuropathic pain, especially at 0.5 mg/kg. Antinociception was effectively inhibited by l-NAME and d-galactose. In line with in vivo experiments, docking studies indicated that FTL may interact with TRPV1. Our results confirm the potential pharmacological relevance of FTL as an inhibitor of orofacial nociception in acute and chronic pain mediated by TRPA1, TRPV1 and TRPM8 receptor. Copyright © 2016. Published by Elsevier Ireland Ltd.

A human trial of HSV mediated gene transfer for the treatment of chronic pain

PubMed Central

Wolfe, Darren; Mata, Marina; Fink, David J.

2009-01-01

Gene transfer to the dorsal root ganglion using replication defective herpes simplex virus (HSV)-based vectors reduces pain related behaviors in rodent models of inflammatory pain, neuropathic pain, and pain caused by cancer in bone. HSV vectors engineered to produce inhibitory neurotransmitters including the delta opioid agonist peptide enkephalin, the mu opioid agonist peptide endomorphin-2 and glutamic acid decarboxylase (GAD) to effect the release of gamma amino butyric acid (GABA) act to inhibit nociceptive neurotransmission at the first synapse between primary nociceptive and second-order neuron in the dorsal horn of spinal cord. HSV vectors engineered to release anti-inflammatory peptides including interleukin (IL)-4, IL-10 and the p55 soluble tumor necrosis factor α (TNFα) receptor reduce neuroimmune activation in the spinal dorsal horn. The path leading from preclinical animal studies to the ongoing phase 1 human trial of the enkephalin-producing vector in patients with pain from cancer, and plans for an efficacy trial with an opioid producing vector in inflammatory pain and an efficacy trial with a GAD producing vector in diabetic neuropathic pain are outlined. PMID:19242524

Effects of centrally acting analgesics on spinal segmental reflexes and wind-up.

PubMed

Mazo, I; Roza, C; Zamanillo, D; Merlos, M; Vela, J M; Lopez-Garcia, J A

2015-08-01

The spinal cord is a prime site of action for analgesia. Here we characterize the effects of established analgesics on segmental spinal reflexes. The aim of the study was to look for the pattern of action or signature of analgesic effects on these reflexes. We used a spinal cord in vitro preparation of neonate mice to record ventral root responses to dorsal root stimulation. Pregabalin, clonidine, morphine and duloxetine and an experimental sigma-1 receptor antagonist (S1RA) were applied to the preparation in a cumulative concentration protocol. Drug effects on the wind-up produced by repetitive stimulation of C-fibres and on responses to single A- and C-fibre intensity stimuli were analysed. All compounds produced a concentration-dependent inhibition of total spikes elicited by repetitive stimulation. Concentrations producing ∼50% reduction in this parameter were (in μM) clonidine (0.01), morphine (0.1), pregabalin (1), duloxetine (10) and S1RA (30). At these concentrations clonidine, pregabalin and S1RA had significant effects on the wind-up index and little depressant effects on responses to single stimuli. Morphine and duloxetine did not depress wind-up index and showed large effects on responses to single stimuli. None of the compounds had strong effects on the amplitude of the non-nociceptive monosynaptic reflex. morphine and duloxetine had general depressant effects on spinal reflexes, whereas the effects of clonidine, pregabalin and S1RA appeared to be restricted to signals originated by strong repetitive activation of C-fibres. Results are discussed in the context of reported behavioural effects of the compounds studied. © 2014 European Pain Federation - EFIC®

Neuropathic pain in people with cancer (part 2): pharmacological and non-pharmacological management.

PubMed

Taverner, Tarnia

2015-08-01

The aim of this paper is to provide an overview of the management of neuropathic pain associated with cancer and to provide helpful clinical advice for nurses working with patients who may have neuropathic pain. While cancer pain is a mixed-mechanism pain, this article will focus only on neuropathic pain management. The impact of neuropathic pain on patients' quality of life is great and while many patients recover from their cancer, a significant number continue to suffer from a neuropathic pain syndrome. Management of neuropathic pain is significantly different from management of nociceptive pain with respect to pharmacological and non-pharmacological strategies. Neuropathic pain is complex, and as such requires complex management using pharmacological as well as non-pharmacological approaches. Specific drugs for neuropathic pain may be effective for some patients, but not all; therefore, ongoing and comprehensive assessment and management are required. Furthermore, these patients may require trials of several drugs before they find one that works for them. It is important for nurses to understand neuropathic pain, its manifestation, impact on quality of life and management when nursing patients with neuropathic pain associated with cancer.

Blockade of anoctamin-1 in injured and uninjured nerves reduces neuropathic pain.

PubMed

García, Guadalupe; Martínez-Rojas, Vladimir A; Oviedo, Norma; Murbartián, Janet

2018-06-02

The aim of this study was to determine the participation of anoctamin-1 in 2 models of neuropathic pain in rats (L5/L6 spinal nerve ligation [SNL] and L5 spinal nerve transection [SNT]). SNL and SNT diminished withdrawal threshold in rats. Moreover, SNL up-regulated anoctamin-1 protein expression in injured L5 and uninjured L4 DRG whereas that it enhanced activating transcription factor 3 (ATF-3) and caspase-3 expression only in injured L5 DRG. In marked contrast, SNT enhanced ATF-3 and caspase-3, but not anoctamin-1, expression in injured L5 DRG but it did not modify anoctamin-1, ATF-3 nor caspase-3 expression in uninjured L4 DRG. Accordingly, repeated (3 times) intrathecal injection of the anoctamin-1 blocker T16A inh-A01 (0.1-1 µg) or MONNA (1-10 µg) partially reverted SNL-induced mechanical allodynia in a dose-dependent manner. In contrast, anoctamin-1 blockers only produced a modest effect in SNT-induced mechanical allodynia. Interestingly, intrathecal injection of T16A inh-A01 (1 µg) or MONNA (10 µg) prevented SNL-induced up-regulation of anoctamin-1, ATF-3 and caspase-3 in injured L5 DRG. Repeated intrathecal injection of T16A inh-A01 or MONNA also reduced SNT-induced up-regulation of ATF-3 in injured L5 DRG. In contrast, T16A inh-A01 and MONNA did not affect SNT-induced up-regulation of caspase-3 expression in L5 DRG. Likewise, gabapentin (100 µg) diminished SNL-induced up-regulation of anoctamin-1, ATF-3 and caspase-3 expression in injured L5 DRG. These data suggest that spinal anoctamin-1 in injured and uninjured DRG participates in the maintenance of neuropathic pain in rats. Our data also indicate that expression of anoctamin-1 in DRG is differentially regulated depending on the neuropathic pain model. Copyright © 2018. Published by Elsevier B.V.

Ketamine Does Not Produce Relief of Neuropathic Pain in Mice Lacking the β-Common Receptor (CD131)

PubMed Central

Swartjes, Maarten; Niesters, Marieke; Heij, Lara; Dunne, Ann; Aarts, Leon; Hand, Carla Cerami; Kim, Hyung-Suk; Brines, Michael; Cerami, Anthony; Dahan, Albert

2013-01-01

Neuropathic pain (NP) is a debilitating condition associated with traumatic, metabolic, autoimmune and neurological etiologies. Although the triggers for NP are diverse, there are common underlying pathways, including activation of immune cells in the spinal cord and up-regulation of the N-methyl-D-aspartate receptor (NMDAR). Ketamine, a well-known NDMAR antagonist, reduces neuropathic pain in a sustained manner. Recent study has shown that the novel 11-amino acid peptide erythropoietin derivative ARA290 produces a similar, long-lasting relief of NP. Here, we show that both drugs also have similar effects on the expression of mRNA of the NMDAR, as well as that of microglia, astrocytes and chemokine (C-C motif) ligand 2, all-important contributors to the development of NP. Although the effects of ketamine and ARA 290 on NP and its molecular mediators suggest a common mechanism of action, ARA 290 has no affinity for the NMDAR and acts specifically via the innate repair receptor (IRR) involved in tissue protection. We speculated therefore, that the IRR might be critically involved in the action of ketamine on neuropathic pain. To evaluate this, we studied the effects of ketamine and ARA 290 on acute pain, side effects, and allodynia following a spared nerve injury model in mice lacking the β-common receptor (βcR), a structural component of the IRR. Ketamine (50 mg/kg) and ARA 290 (30 µg/kg) produced divergent effects on acute pain: ketamine produced profound antinociception accompanied with psychomotor side effects, but ARA290 did not, in both normal and knock out mice. In contrast, while both drugs were antiallodynic in WT mice, they had no effect on NP in mice lacking the βcR. Together, these results show that an intact IRR is required for the effective treatment of NP with either ketamine or ARA 290, but is not involved in ketamine’s analgesic and side effects. PMID:23936499

Comparative efficacy and safety of six antidepressants and anticonvulsants in painful diabetic neuropathy: a network meta-analysis.

PubMed

Rudroju, Neelima; Bansal, Dipika; Talakokkula, Shiva Teja; Gudala, Kapil; Hota, Debasish; Bhansali, Anil; Ghai, Babita

2013-01-01

Anticonvulsants and antidepressants are mostly used in management of painful diabetic neuropathy (PDN). However there are few direct comparisons between drugs of these classes, making evidence-based decision-making in the treatment of painful diabetic neuropathy difficult. This study aimed to perform a network meta-analysis and benefit-risk analysis to evaluate the comparative efficacy and safety of these drugs in PDN treatment. Comparative effectiveness study. Medical Education and Research facility in India. A comprehensive data search was done in PubMed, Cochrane, and Embase up to August 2012. We then systematically reviewed the studies which compared any of 6 drugs for the management of PDN: amitriptyline, duloxetine, gabapentin, pregabalin, valproate, and venlafaxine or any of their combinations. We performed a random-effects network meta-analysis to rank treatments in terms of efficacy and safety. We chose the number of patients experiencing = 50% reduction in pain and number of patient withdrawals due to adverse events (AE) as primary outcomes for efficacy and safety, respectively. We also performed benefit-risk analysis, taking efficacy outcome as benefit and safety outcome as risk. Analysis was intention-to-treat. We included 21 published trials in the analysis. Duloxetine, gabapentin, pregabalin, and venlafaxine were shown to be significantly efficacious compared to placebo with odds ratios (OR) of 2.12, 3.98, 2.78, and 4.43, respectively. Amitriptyline (OR: 7.03, 95% confidence interval [CI]: 1.87, 29.05) and duloxetine (OR: 3.26, 95% CI: 1.04, 9.97) caused more withdrawals than gabapentin. The ranking order of efficacy was gabapentin, venlafaxine, pregabalin, duloxetine/gabapentin, duloxetine, amitriptyline, and placebo and the ranking order of safety was placebo, gabapentin, pregabalin, venlafaxine, duloxetine/gabapentin combination, duloxetine, and amitriptyline. Benefit-risk balance favored the order: gabapentin, venlafaxine, pregabalin, duloxetine/gabapentin combination, duloxetine, placebo, and amitriptyline. We could not include valproate in our analysis owing to the lack of studies reporting the dichotomous efficacy and safety outcomes. Gabapentin was found to be most efficacious and amitriptyline to be least safe among the treatments included in the study. Gabapentin showed most favorable balance between efficacy and safety.

Gabapentin enacarbil, pregabalin and rotigotine are equally effective in restless legs syndrome: a comparative meta-analysis.

PubMed

Iftikhar, I H; Alghothani, L; Trotti, L M

2017-12-01

To synthesize evidence from available randomized controlled trials (RCT) to compare the efficacies of dopaminergic drugs (pramipexole, ropinirole and rotigotine) and α-2-δ ligands (gabapentin enacarbil and pregabalin) for the treatment of restless legs syndrome (RLS). We searched PubMed for all eligible RCTs. Network meta-analysis using frequentist methodology with random effect models was performed for mean changes in scores on the International RLS Study Group Rating Scale (IRLS) and for responder rates on Clinical Global Impressions-Improvement (CGI-I); analyzed as odds ratio (OR). Network meta-analysis of mean changes in IRLS data from 35 studies with 7333 participants showed that all treatments, in specific gabapentin enacarbil, followed by pregabalin and rotigotine were superior to placebo [mean reduction in IRLS scores: -5.31 (-6.74 to -3.87), -5.20 (-6.91 to -3.49), 5.17 (3.73-6.61), respectively] but there were no significant differences between active treatments. Network meta-analysis of 5137 participants from 24 studies showed that gabapentin enacarbil and rotigotine were associated with the highest CGI-I response rates [ORs: 5.68; (95% CI, 4.14-7.21); and 4.68 (2.87-6.49), compared to placebo, respectively]. No significant inter-treatment differences exist, except for that between gabapentin enacarbil and ropinirole. Based on IRLS scores and CGI-I response rates, while gabapentin enacarbil, pregabalin and rotigotine stand out as the most efficacious of all examined drugs, it is noteworthy that no significant inter-treatment differences exist, except for that between gabapentin enacarbil and ropiniriole (for CGI-I response rates). © 2017 EAN.

Dose Titration of Pregabalin in Patients with Painful Diabetic Peripheral Neuropathy: Simulation Based on Observational Study Patients Enriched with Data from Randomized Studies.

PubMed

Alexander, Joe; Edwards, Roger A; Manca, Luigi; Grugni, Roberto; Bonfanti, Gianluca; Emir, Birol; Whalen, Edward; Watt, Stephen; Parsons, Bruce

2018-03-01

Achieving a therapeutic response to pregabalin in patients with painful diabetic peripheral neuropathy (pDPN) requires adequate upward dose titration. Our goal was to identify relationships between titration and response to pregabalin in patients with pDPN. Data were integrated from nine randomized, placebo-controlled clinical trials as well as one 6-week open-label observational study conducted by 5808 physicians (2642 patients with pDPN) in standard outpatient settings in Germany. These studies evaluated pregabalin for treatment of pDPN. Using these data, we examined "what if" scenarios using a microsimulation platform that integrates data from randomized and observational sources as well as autoregressive-moving-average with exogenous inputs models that predict pain outcomes, taking into account weekly changes in pain, sleep interference, dose, and other patient characteristics that were unchanging. Final pain levels were significantly different depending on dose changes (P < 0.0001), with greater proportions improving with upward titration regardless of baseline pain severity. Altogether, 78.5% of patients with pDPN had 0-1 dose change, and 15.2% had ≥ 2 dose changes. Simulation demonstrated that the 4.8% of inadequately titrated patients who did not improve/very much improve their pain levels would have benefited from ≥ 2 dose changes. Patient satisfaction with tolerability (range 90.3-96.2%) was similar, regardless of baseline pain severity, number of titrations, or extent of improvement, suggesting that tolerability did not influence treatment response patterns. Upward dose titration reduced pain in patients with pDPN who actually received it. Simulation also predicted pain reduction in an inadequately titrated nonresponder subgroup of patients had they actually received adequate titration. The decision not to uptitrate must have been driven by factors other than tolerability. Pfizer, Inc.

Cytisine inhibits the protective activity of various classical and novel antiepileptic drugs against 6 Hz-induced psychomotor seizures in mice.

PubMed

Tutka, Piotr; Kondrat-Wróbel, Maria W; Zaluska, Katarzyna; Żółkowska, Dorota; Florek-Łuszczki, Magdalena; Łuszczki, Jarogniew J

2017-01-01

Cytisine (CYT) is a partial agonist of brain α4β2 nicotinic acetylcholine receptors widely used in Central/Eastern Europe for smoking cessation. This study evaluated the effect of CYT on the ability of classical and novel antiepileptic drugs to prevent seizures evoked by the 6-Hz test, a model of psychomotor seizures in mice thought as a model of drug-resistant seizures. CYT administered intraperitoneally (i.p.) in a dose of 2 mg kg -1 significantly inhibited the anticonvulsant activity of lacosamide, levetiracetam, and pregabalin, increasing their median effective doses 50 (ED 50 ) values from 6.88 to 10.52 mg kg -1 (P < 0.05) for lacosamide, from 22.08 to 38.26 mg kg -1 (P < 0.05) for levetiracetam, and from 40.48 to 64.61 mg kg -1 (P < 0.01) for pregabalin, respectively. There were no significant changes in total brain concentrations of lacosamide, levetiracetam, and pregabalin following CYT i.p. administration. CYT administered in a dose of 2 mg kg -1 failed to change the protective action of clobazam, clonazepam, phenobarbital, tiagabine, and valproate in the 6-Hz test. Neither CYT (2 mg kg -1 ) alone nor its combination with the anticonvulsant drugs (at their ED 50 values from the 6-Hz test) affected motor coordination; skeletal muscular strength and long-term memory, as determined in the chimney; and grip strength and passive avoidance tests, respectively. CYT-evoked alterations in the protection provided by some antiepileptic drugs against seizures can be of serious concern for epileptic smokers, who might demonstrate therapeutic failure to lacosamide, levetiracetam, and pregabalin, resulting in possible breakthrough seizure attacks.

Multi-Modal Preemptive Analgesia With Pregabalin, Acetaminophen, Naproxen, and Dextromethorphan in Radical Neck Dissection Surgery: A Randomized Clinical Trial

PubMed Central

Amiri, Hamid Reza; Mirzaei, Mojtaba; Beig Mohammadi, Mohammad Taghi; Tavakoli, Farhad

2016-01-01

Background Preemptive analgesia may be considered as a method not only to alleviate postoperative pain but also to decrease analgesic consumption. Different regimens are suggested, but there is currently no standard. Objectives The aim was to measure the efficacy of preemptive analgesia with pregabalin, acetaminophen, naproxen, and dextromethorphan in radical neck dissection surgery for reducing the intensity of pain and morphine consumption. Patients and Methods This study was conducted as a randomized double-blind clinical trial. Eighty adult patients (18 to 60 years of age) under the American society of anesthesiologists (ASA) physical status I and II undergoing elective radical neck dissection were enrolled. Patients were randomized into two groups of 40 with a simple randomization method. The case group received a combination of 15 mg/kg acetaminophen, 2.5 mg/kg pregabalin, 7 mg/kg naproxen, and 0.3 mg/kg dextromethorphan administered orally one hour prior to surgery. Postoperative pain was assessed with the universal pain assessment tool (UPAT) at 0, 2, 4, 6, 12, and 24 hours after surgery. Subjects received morphine based on postoperative pain control protocol. Total administered morphine doses were noted. Results Postoperative pain rates at 0, 2, 4, 6, 12, and 24 hours after surgery were significantly lower for the case group than the control group (P values = 0.014, 0.003, 0.00, 0.00, and 0.00, respectively). Total morphine doses for the preemptive analgesia group were 45% lower than those of the other group. Side effects were similar for both groups. Conclusions A single preoperative oral dose of pregabalin, acetaminophen, dextromethorphan, and naproxen one hour before surgery is an effective method for reducing postoperative pain and morphine consumption in patients undergoing radical neck dissection. PMID:27843771

Magnesium enhances opioid-induced analgesia - What we have learnt in the past decades?

PubMed

Bujalska-Zadrożny, Magdalena; Tatarkiewicz, Jan; Kulik, Kamila; Filip, Małgorzata; Naruszewicz, Marek

2017-03-01

Opioids are increasingly used in alleviating pain, including cancer-related pain and postoperative pain. Unfortunately, the development of tolerance, the resistance of neuropathic pain on opioid analgesia or other undesirable effects may limit their utility. In order to reduce opioid doses, and thereby to avoid the risk of side effects and sudden deaths due to overdosing, attempts have been made to introduce co-analgesics. Due to an increasing amount of data concerning a potential enhance of opioid analgesia by the physiological antagonist of N-methyl-d-aspartate receptors, magnesium ions (Mg 2+ ), a concomitant use of such a combination seems to be interesting from a clinical point of view. Therefore, the aim of this review is to provide an analysis of existing preclinical and clinical studies in the context of the benefits of using this combination in clinical practice. A potential mechanism of magnesium - opioid interaction is also suggested. The potential influence of Mg on opioid adverse/side effects as well as conclusions on the safety of combined administration of magnesium and opioid drugs were also summarized. Data from animal studies indicate that magnesium increases opioid analgesia in chronic (e.g., neuropathic, inflammatory) as well as acute pain. In clinical trials, most authors confirmed that magnesium reduces opioid consumption and alleviates postoperative pain scores while not increasing the risk of side effects after opioids. However, more clinical studies are needed concerning an influence of Mg on opioid activity in other difficult to treat types of pain, especially neuropathic and inflammatory. Copyright © 2016 Elsevier B.V. All rights reserved.

Prevalence of neuropathic pain in knee or hip osteoarthritis: A systematic review and meta-analysis.

PubMed

French, Helen P; Smart, Keith M; Doyle, Frank

2017-08-01

Discordance between radiographic and pain severity in osteoarthritis (OA) has led researchers to investigate other pain mechanisms, including neuropathic pain. Accurate identification of any neuropathic pain in hip or knee OA is important for appropriate management, but neuropathic pain prevalence is unknown. We aimed to obtain an overall prevalence estimate by systematically reviewing and meta-analysing the prevalence of neuropathic pain in people with hip or knee OA. Observational studies which measured neuropathic pain in people aged 18 years and older with hip or knee OA were considered for inclusion. Electronic databases were searched up to February 2016. Two reviewers independently identified eligible studies and assessed methodological quality. Prevalence estimates and 95% confidence intervals were calculated using random effects meta-analytic techniques. Nine studies met the inclusion criteria. Study samples were from general population, hospital and community settings and all used self-report questionnaires to determine neuropathic pain. The overall prevalence estimate was 23% (95% CI: 10-39%), with considerable heterogeneity (I 2 = 97.9%, p < 0.001). This estimate was largely unchanged with subgroup analyses based on index joint, questionnaire type, setting and consideration of other potential causes of neuropathic pain. However, the estimate for two studies that excluded other potential causes of neuropathic pain was substantially higher (32%, 95% CI: 29-35%). Neuropathic pain prevalence in people with knee or hip OA is considerable at 23%, and may be higher after other potential causes of neuropathic pain are excluded. Concerns regarding the validity of neuropathic pain questionnaires, selection bias, methodological quality and study heterogeneity suggest caution with interpretation of these findings. Prevalence studies using standardised criteria for neuropathic pain are required. Copyright © 2017 Elsevier Inc. All rights reserved.

Two cases of painful gynecomastia and lower extremity pain in association with pregabalin therapy.

PubMed

Málaga, Ignacio; Sanmarti, Francesc X

2006-09-01

We report two patients with refractory epilepsy who developed unilateral painful gynecomastia and lower extremity pain (one of them localized and the other one diffuse), shortly after receiving Pregabalin (PGB). Neither of them had previous endocrinologic problems or complaints about pain on their medical history. PGB was stopped in one patient and reduced in the other one, with complete disparition of the symptoms in the following weeks in both patients. This supports the hypothesis that gynecomastia could be a drug-induced and easy to manage secondary effect of PGB, with a higher incidence than observed on previous clinical trials.

Neuropathic sensory symptoms: association with pain and psychological factors

PubMed Central

Shaygan, Maryam; Böger, Andreas; Kröner-Herwig, Birgit

2014-01-01

Background A large number of population-based studies of chronic pain have considered neuropathic sensory symptoms to be associated with a high level of pain intensity and negative affectivity. The present study examines the question of whether this association previously found in non-selected samples of chronic pain patients can also be found in chronic pain patients with underlying pathology of neuropathic sensory symptoms. Methods Neuropathic sensory symptoms in 306 patients with chronic pain diagnosed as typical neuropathic pain, radiculopathy, fibromyalgia, or nociceptive back pain were assessed using the Pain DETECT Questionnaire. Two separate cluster analyses were performed to identify subgroups of patients with different levels of self-reported neuropathic sensory symptoms and, furthermore, to identify subgroups of patients with distinct patterns of neuropathic sensory symptoms (adjusted for individual response bias regarding specific symptoms). Results ANOVA (analysis of variance) results in typical neuropathic pain, radiculopathy, and fibromyalgia showed no significant differences between the three levels of neuropathic sensory symptoms regarding pain intensity, pain chronicity, pain catastrophizing, pain acceptance, and depressive symptoms. However, in nociceptive back pain patients, significant differences were found for all variables except pain chronicity. When controlling for the response bias of patients in ratings of symptoms, none of the patterns of neuropathic sensory symptoms were associated with pain and psychological factors. Conclusion Neuropathic sensory symptoms are not closely associated with higher levels of pain intensity and cognitive-emotional evaluations in chronic pain patients with underlying pathology of neuropathic sensory symptoms. The findings are discussed in term of differential response bias in patients with versus without verified neuropathic sensory symptoms by clinical examination, medical tests, or underlying pathology of disease. Our results lend support to the importance of using adjusted scores, thereby eliminating the response bias, when investigating self-reported neuropathic symptoms by patients. PMID:24899808

An Observational Longitudinal Study Investigating the Effectiveness of 75 mg Pregabalin Post-Hemodialysis among Uremic Pruritus Patients.

PubMed

Khan, Tahir Mehmood; Wu, David Bin-Chia; Goh, Bey-Hing; Lee, Learn-Han; Alhafez, Abdul Aziz; Syed Sulaiman, Syed Azhar

2016-11-08

A prospective, observational, longitudinal study was conducted to assess the effectiveness of 75 mg pregabalin (PG) post-hemodialysis (pHD) for treatment-resistant uremic pruritus (UP). A total of forty-five patients completed the entire six week follow-up. At the baseline assessment, the majority of the patients were distressed by the UP frequency and intensity. Sleep (mean = 3.30 ± 1.1), leisure/social activities (mean = 2.90 ± 0.80) and distribution (mean = 2.92 ± 0.34) were the three domains that were primarily effected by the UP. Overall, further reduction in the 5D-itching scale (IS) was noted at day 42, which confirmed a sustained (B = -12.729, CI -13.257 to -12.201, p < 0.001) relief of pruritus severity among patients with treatment-resistant pruritus. Patients with a higher serum calcium level had a score difference of +1 from the other patients (B = 1.010, p = 0.061). There was a reduction of 12 points compared to the baseline 5D-IS for each patient on day 42 after using pregabalin 75 mg PD pHD for 42 days, which represented major relief. Among the demographic factors, only gender was significantly associated with the 5D-IS score.

Opioids for neuropathic pain.

PubMed

Katz, Nathaniel; Benoit, Christine

2005-06-01

Whether opioids are effective for neuropathic pain has been a matter of controversy for decades. Within limits, it is clear that opioids in general are effective for neuropathic pain. Furthermore, there is no evidence that opioids are any less effective for neuropathic pain than for non-neuropathic pain, no evidence that opioids are less effective for neuropathic pain than are other medications, and no evidence that one opioid is any more effective than another for neuropathic pain. It remains uncertain whether opioids are effective for central pain, although they may have a role. Although some patients appear to enjoy long-term benefits, most studies have been short-term. Opioids have an important role in the treatment of neuropathic pain; however, skillful opioid use balances the benefits with management of side effects and prevention and treatment of abuse and addiction.

Food-Derived Natural Compounds for Pain Relief in Neuropathic Pain.

PubMed

Lim, Eun Yeong; Kim, Yun Tai

2016-01-01

Neuropathic pain, defined as pain caused by a lesion or disease of the somatosensory nervous system, is characterized by dysesthesia, hyperalgesia, and allodynia. The number of patients with this type of pain has increased rapidly in recent years. Yet, available neuropathic pain medicines have undesired side effects, such as tolerance and physical dependence, and do not fully alleviate the pain. The mechanisms of neuropathic pain are still not fully understood. Injury causes inflammation and immune responses and changed expression and activity of receptors and ion channels in peripheral nerve terminals. Additionally, neuroinflammation is a known factor in the development and maintenance of neuropathic pain. During neuropathic pain development, the C-C motif chemokine receptor 2 (CCR2) acts as an important signaling mediator. Traditional plant treatments have been used throughout the world for treating diseases. We and others have identified food-derived compounds that alleviate neuropathic pain. Here, we review the natural compounds for neuropathic pain relief, their mechanisms of action, and the potential benefits of natural compounds with antagonistic effects on GPCRs, especially those containing CCR2, for neuropathic pain treatment.

Neuropathic pain.

PubMed

Colloca, Luana; Ludman, Taylor; Bouhassira, Didier; Baron, Ralf; Dickenson, Anthony H; Yarnitsky, David; Freeman, Roy; Truini, Andrea; Attal, Nadine; Finnerup, Nanna B; Eccleston, Christopher; Kalso, Eija; Bennett, David L; Dworkin, Robert H; Raja, Srinivasa N

2017-02-16

Neuropathic pain is caused by a lesion or disease of the somatosensory system, including peripheral fibres (Aβ, Aδ and C fibres) and central neurons, and affects 7-10% of the general population. Multiple causes of neuropathic pain have been described and its incidence is likely to increase owing to the ageing global population, increased incidence of diabetes mellitus and improved survival from cancer after chemotherapy. Indeed, imbalances between excitatory and inhibitory somatosensory signalling, alterations in ion channels and variability in the way that pain messages are modulated in the central nervous system all have been implicated in neuropathic pain. The burden of chronic neuropathic pain seems to be related to the complexity of neuropathic symptoms, poor outcomes and difficult treatment decisions. Importantly, quality of life is impaired in patients with neuropathic pain owing to increased drug prescriptions and visits to health care providers, as well as the morbidity from the pain itself and the inciting disease. Despite challenges, progress in the understanding of the pathophysiology of neuropathic pain is spurring the development of new diagnostic procedures and personalized interventions, which emphasize the need for a multidisciplinary approach to the management of neuropathic pain.

Neuropathic Pain and Psychological Morbidity in Patients with Treated Leprosy: A Cross-Sectional Prevalence Study in Mumbai

PubMed Central

Lasry-Levy, Estrella; Hietaharju, Aki; Pai, Vivek; Ganapati, Ramaswamy; Rice, Andrew S. C.; Haanpää, Maija; Lockwood, Diana N. J.

2011-01-01

Background Neuropathic pain has been little studied in leprosy. We assessed the prevalence and clinical characteristics of neuropathic pain and the validity of the Douleur Neuropathique 4 questionnaire as a screening tool for neuropathic pain in patients with treated leprosy. The association of neuropathic pain with psychological morbidity was also evaluated. Methodology/Principal Findings Adult patients who had completed multi-drug therapy for leprosy were recruited from several Bombay Leprosy Project clinics. Clinical neurological examination, assessment of leprosy affected skin and nerves and pain evaluation were performed for all patients. Patients completed the Douleur Neuropathique 4 and the 12-item General Health Questionnaire to identify neuropathic pain and psychological morbidity. Conclusions/Significance One hundred and one patients were recruited, and 22 (21.8%) had neuropathic pain. The main sensory symptoms were numbness (86.4%), tingling (68.2%), hypoesthesia to touch (81.2%) and pinprick (72.7%). Neuropathic pain was associated with nerve enlargement and tenderness, painful skin lesions and with psychological morbidity. The Douleur Neuropathique 4 had a sensitivity of 100% and specificity of 92% in diagnosing neuropathic pain. The Douleur Neuropathique 4 is a simple tool for the screening of neuropathic pain in leprosy patients. Psychological morbidity was detected in 15% of the patients and 41% of the patients with neuropathic pain had psychological morbidity. PMID:21408111

Construct validity of an instrument to measure neuropathic pain in women with bladder pain syndrome.

PubMed

Arya, Lily A; Harvie, Heidi S; Andy, Uduak U; Cory, Lori; Propert, Kathleen J; Whitmore, Kristene

2013-06-01

To determine the construct validity of an instrument to measure neuropathic pain in women with bladder pain syndrome (BPS). Our hypothesis is that neuropathic, bladder, and bowel pain represent different constructs in women with BPS. Secondary planned analysis of a prospective cross-sectional study of 150 women with BPS. The relationship between neuropathic pain, urinary, and bowel symptoms was assessed. The correlation of the total neuropathic pain score with total urinary and bowel symptom scores was low to moderate (r = 0.28-0.49). The correlation of specific neuropathic pain items with bladder and bowel pain was also low to moderate (r = 0.12-0.36). Women with neuropathic pain had significantly higher scores for urinary urgency, bladder pain, abdominal pain, diarrhea, and constipation than women with non-neuropathic pain (all P < 0.0001). Somatosensory neuropathic pain and "visceral" bladder and bowel pain represent separate but related constructs in women with BPS. Copyright © 2012 Wiley Periodicals, Inc.

A PROMIS Measure of Neuropathic Pain Quality

PubMed Central

Askew, Robert L.; Cook, Karon F.; Keefe, Francis J.; Nowinski, Cindy J; Cella, David; Revicki, Dennis A.; DeWitt, Esi M. Morgan; Michaud, Kaleb; Trence, Dace L.; Amtmann, Dagmar

2016-01-01

Objectives Neuropathic pain is a consequence of many chronic conditions. This study aimed to develop a unidimensional neuropathic pain scale whose scores represent levels of neuropathic pain and distinguish between individuals with neuropathic and non-neuropathic pain conditions. Methods A candidate item pool of 42 pain quality descriptors was administered to participants with osteoarthritis, rheumatoid arthritis, diabetic neuropathy, and cancer chemotherapy-induced peripheral neuropathy. A subset of pain quality descriptors (items) that best distinguished between participants with and those without neuropathic pain conditions were identified. Dimensionality of pain descriptors was evaluated in a development sample and cross-validated in a hold-out sample. Item responses were calibrated using an item response theory model, and scores were generated on a T-score metric. Neuropathic pain scale scores were evaluated in terms of reliability, validity, and the ability to distinguish between participants with and without conditions typically associated with neuropathic pain. Results Of the 42 initial items, 5 were identified for the Patient Reported Outcome Measurement Information System (PROMIS) Neuropathic Pain Quality scale (PROMIS-PQ-Neuro). The IRT-generated T-scores exhibited good discriminatory ability based on receiver operator characteristic analysis. Score thresholds were identified that optimize sensitivity and specificity. Construct, criterion, and discriminant validity, and reliability of scale scores were supported. Conclusions The 5-item PROMIS PQ-Neuro is a short and practical measure that can be used to identify patients more likely to have neuropathic pain and to distinguish levels of neuropathic pain. The data collected will support future research that targets other unidimensional pain quality domains (e.g., nociceptive pain). PMID:27565279

Neuropathic pain

PubMed Central

Colloca, Luana; Ludman, Taylor; Bouhassira, Didier; Baron, Ralf; Dickenson, Anthony H.; Yarnitsky, David; Freeman, Roy; Truini, Andrea; Attal, Nadine; Finnerup, Nanna B.; Eccleston, Christopher; Kalso, Eija; Bennett, David L.; Dworkin, Robert H.; Raja, Srinivasa N.

2017-01-01

Neuropathic pain is caused by a lesion or disease of the somatosensory system, including peripheral fibres (Aβ, Aδ and C fibres) and central neurons, and affects 7–10% of the general population. Multiple causes of neuropathic pain have been described and its incidence is likely to increase owing to the ageing global population, increased incidence of diabetes mellitus and improved survival from cancer after chemotherapy. Indeed, imbalances between excitatory and inhibitory somatosensory signalling, alterations in ion channels and variability in the way that pain messages are modulated in the central nervous system all have been implicated in neuropathic pain. The burden of chronic neuropathic pain seems to be related to the complexity of neuropathic symptoms, poor outcomes and difficult treatment decisions. Importantly, quality of life is impaired in patients with neuropathic pain owing to increased drug prescriptions and visits to health care providers, as well as the morbidity from the pain itself and the inciting disease. Despite challenges, progress in the understanding of the pathophysiology of neuropathic pain is spurring the development of new diagnostic procedures and personalized interventions, which emphasize the need for a multidisciplinary approach to the management of neuropathic pain. PMID:28205574

Gene Transfer of Glutamic Acid Decarboxylase 67 by Herpes Simplex Virus Vectors Suppresses Neuropathic Pain Induced by Human Immunodeficiency Virus gp120 Combined with ddC in Rats.

PubMed

Kanao, Megumi; Kanda, Hirotsugu; Huang, Wan; Liu, Shue; Yi, Hyun; Candiotti, Keith A; Lubarsky, David A; Levitt, Roy C; Hao, Shuanglin

2015-06-01

Human immunodeficiency virus (HIV)-related painful sensory neuropathies primarily consist of the HIV infection-related distal sensory polyneuropathy and antiretroviral toxic neuropathies. Pharmacotherapy provides only partial relief of pain in patients with HIV/acquired immune deficiency syndrome because little is known about the exact neuropathological mechanisms for HIV-associated neuropathic pain (NP). Hypofunction of γ-aminobutyric acid (GABA) GABAergic inhibitory mechanisms has been reported after peripheral nerve injury. In this study, we tested the hypothesis that HIV gp120 combined with antiretroviral therapy reduces spinal GABAergic inhibitory tone and that restoration of GABAergic inhibitory tone will reduce HIV-related NP in a rat model. The application of recombinant HIV-1 envelope protein gp120 into the sciatic nerve plus systemic ddC (one antiretroviral drug) induced mechanical allodynia. The hind paws of rats were inoculated with replication-defective herpes simplex virus (HSV) vectors genetically encoding gad1 gene to express glutamic acid decarboxylase 67 (GAD67), an enzyme that catalyzes the decarboxylation of glutamate to GABA. Mechanical threshold was tested using von Frey filaments before and after treatments with the vectors. The expression of GAD67 in both the lumbar spinal cord and the L4-5 dorsal root ganglia was examined using western blots. The expression of mitochondrial superoxide in the spinal dorsal horn was examined using MitoSox imaging. The immunoreactivity of spinal GABA, pCREB, and pC/EBPβ was tested using immunohistochemistry. In the gp120 with ddC-induced neuropathic pain model, GAD67 expression mediated by the HSV vector caused an elevation of mechanical threshold that was apparent on day 3 after vector inoculation. The antiallodynic effect of the single HSV vector inoculation expressing GAD67 lasted >28 days. The area under the time-effect curves in the HSV vector expressing GAD67 was increased compared with that in the control vectors (P = 0.0005). Intrathecal GABA-A/B agonists elevated mechanical threshold in the pain model. The HSV vectors expressing GAD67 reversed the lowered GABA immunoreactivity in the spinal dorsal horn in the neuropathic rats. HSV vectors expressing GAD67 in the neuropathic rats reversed the increased signals of mitochondrial superoxide in the spinal dorsal horn. The vectors expressing GAD67 reversed the upregulated immunoreactivity expression of pCREB and pC/EBPβ in the spinal dorsal horn in rats exhibiting NP. Based on our results, we suggest that GAD67 mediated by HSV vectors acting through the suppression of mitochondrial reactive oxygen species and transcriptional factors in the spinal cord decreases pain in the HIV-related neuropathic pain model, providing preclinical evidence for gene therapy applications in patients with HIV-related pain states.

Food-Derived Natural Compounds for Pain Relief in Neuropathic Pain

PubMed Central

Lim, Eun Yeong

2016-01-01

Neuropathic pain, defined as pain caused by a lesion or disease of the somatosensory nervous system, is characterized by dysesthesia, hyperalgesia, and allodynia. The number of patients with this type of pain has increased rapidly in recent years. Yet, available neuropathic pain medicines have undesired side effects, such as tolerance and physical dependence, and do not fully alleviate the pain. The mechanisms of neuropathic pain are still not fully understood. Injury causes inflammation and immune responses and changed expression and activity of receptors and ion channels in peripheral nerve terminals. Additionally, neuroinflammation is a known factor in the development and maintenance of neuropathic pain. During neuropathic pain development, the C-C motif chemokine receptor 2 (CCR2) acts as an important signaling mediator. Traditional plant treatments have been used throughout the world for treating diseases. We and others have identified food-derived compounds that alleviate neuropathic pain. Here, we review the natural compounds for neuropathic pain relief, their mechanisms of action, and the potential benefits of natural compounds with antagonistic effects on GPCRs, especially those containing CCR2, for neuropathic pain treatment. PMID:27891521

Duloxetine for the treatment of painful diabetic peripheral neuropathy in Venezuela: economic evaluation.

PubMed

Carlos, Fernando; Espejel, Luis; Novick, Diego; López, Rubén; Flores, Daniel

2015-09-25

Painful diabetic peripheral neuropathy affects 40-50% of patients with diabetic neuropathy, leading to impaired quality of life and substantial costs. Duloxetine and pregabalin have evidence-based support, and are formally approved for controlling painful diabetic peripheral neuropathy. We used a 12-week decision model for examining painful diabetic peripheral neuropathy first-line therapy with daily doses of duloxetine 60mg or pregabalin 300mg, under the perspective of the Instituto Venezolano de los Seguros Sociales. We gathered model parameters from published literature and expert´s opinion, focusing on the magnitude of pain relief, the presence of adverse events, the possibility of withdrawal owing to intolerable adverse events or due to lack of efficacy, and the quality-adjusted life years expected in each strategy. We analyzed direct medical costs (which are expressed in Bolívares Fuertes, BsF) comprising drug acquisition besides additional care devoted to treatment of adverse events and poor pain relief. We conducted both deterministic and probabilistic sensitivity analyses. Total expected costs per 1000 patients were BsF 1 046 146 (26%) lower with duloxetine than with pregabalin. Most of these savings (91%) corresponds to the difference in the acquisition’s cost of each medication. duloxetine also provided 23 more patients achieving good pain relief and a gain of about two quality-adjusted life years per 1000 treated. Model was robust to plausible changes in main parameters. Duloxetine remained the preferred option in 93.9% of the second-order Monte Carlo simulations. This study suggests duloxetine dominates (i.e., is more effective and lead to gains in quality-adjusted life years), remaining less costly than pregabalin for treatment of painful diabetic peripheral neuropathy.

Chronic Neuropathic Pain in Mice Reduces μ-Opioid Receptor-Mediated G-protein Activity in the Thalamus

PubMed Central

Hoot, Michelle R.; Sim-Selley, Laura J.; Selley, Dana E.; Scoggins, Krista L.; Dewey, William L.

2011-01-01

Neuropathic pain is a debilitating condition that is often difficult to treat using conventional pharmacological interventions and the exact mechanisms involved in the establishment and maintenance of this type of chronic pain have yet to be fully elucidated. The present studies examined the effect of chronic nerve injury on μ-opioid receptors and receptor-mediated G-protein activity within the supraspinal brain regions involved in pain processing of mice. Chronic constriction injury (CCI) reduced paw withdrawal latency, which was maximal at 10 days post-injury. [d-Ala2,(N-Me)Phe4, Gly5-OH] enkephalin (DAMGO)-stimulated [35S]GTPγS binding was then conducted at this time point in membranes prepared from the rostral ACC (rACC), thalamus and periaqueductal grey (PAG) of CCI and sham-operated mice. Results showed reduced DAMGO-stimulated [35S]GTPγS binding in the thalamus and PAG of CCI mice, with no change in the rACC. In thalamus, this reduction was due to decreased maximal stimulation by DAMGO, with no difference in EC50 values. In PAG, however, DAMGO Emax values did not significantly differ between groups, possibly due to the small magnitude of the main effect. [3H]Naloxone binding in membranes of the thalamus showed no significant differences in Bmax values between CCI and sham-operated mice, indicating that the difference in G-protein activation did not result from differences in μ-opioid receptor levels. These results suggest that CCI induced a region-specific adaptation of μ-opioid receptor-mediated G-protein activity, with apparent desensitization of the μ-opioid receptor in the thalamus and PAG and could have implications for treatment of neuropathic pain. PMID:21762883

[Prevalence and aetiopathogenesis of neuropathic pain in elderly cancer patients].

PubMed

Cabezón-Gutiérrez, Luis; Custodio-Cabello, Sara; Khosravi-Shahi, Parham

2016-01-01

The prevalence of neuropathic pain is difficult to estimate as most studies evaluating chronic pain do not differentiate neuropathic from nociceptive pain. There are only a few studies of neuropathic pain in the elderly, specifically in the oncology population. This article is a non-systematic review of the relevant evidence on the prevalence and aetiopathogenesis of neuropathic cancer pain in the elderly. Copyright © 2015 SEGG. Published by Elsevier Espana. All rights reserved.

Identifying neuropathic pain in patients with multiple sclerosis: a cross-sectional multicenter study using highly specific criteria.

PubMed

Solaro, Claudio; Cella, M; Signori, Alessio; Martinelli, Vittorio; Radaelli, Marta; Centonze, D; Sica, F; Grasso, M G; Clemenzi, A; Bonavita, S; Esposito, S; Patti, F; D'Amico, E; Cruccu, G; Truini, A

2018-04-01

Pain is a common and heterogeneous complication of multiple sclerosis (MS). In this multicenter, cross sectional study, we aimed at investigating the prevalence of pain in MS using highly specific criteria for distinguishing the different types of pain. After a structured interview, in patients with pain, clinical examination and DN4 questionnaire were used for distinguishing neuropathic and nociceptive pain. In subjects with neuropathic pain, the Neuropathic Pain Symptom Inventory was used for differentiating neuropathic pain symptoms. We enrolled 1249 participants (832 F, 417 M, mean age 33.9 years, mean disease duration 8 years, mean EDSS 3.2); based on clinical evaluation and DN4 score 429 patients (34.34%) were classified with pain (470 pain syndromes): 286 nociceptive pain syndromes and 184 neuropathic pain syndromes. Multivariate analysis showed that pain was associated with age, gender and disease severity and that neuropathic pain was distinctly associated with EDSS. Our study, providing definite information on the prevalence, characteristics and variables associated with neuropathic pain due to MS, shows that a more severe disease course is associated with a higher risk of neuropathic pain. Our findings might, therefore, provide a basis for improving the clinical management of this common MS complication.

Transient urinary retention and chronic neuropathic pain associated with genital herpes simplex virus infection.

PubMed

Haanpää, Maija; Paavonen, Jorma

2004-10-01

Genital herpes (GH) causes genital ulcer disease, severe transient pain, and often paresthesias. Whether or not GH can cause urinary retention or chronic neuropathic pain is not well known. We present two immunocompetent patients with GH associated with neuropathic symptoms. We also review the literature on GH and associated neurologic problems. Patient 1 had primary herpes simplex virus (HSV)-2 infection with transient urinary retention and chronic bilateral neuropathic pain in the sacral area. Patient 2 had recurrent HSV-1 associated with unitaleral chronic neuropathic pain in the sacral area. Although transient urinary retention associated with GH is not uncommon, chronic neuropathic pain has not been reported previously. Our cases show that chronic neuropathic pain, that is "pain initiated or caused by a primary lesion or dysfunction in the nervous system," can follow genital HSV infection.

Impact of a pregabalin step therapy policy among medicare advantage beneficiaries.

PubMed

Suehs, Brandon T; Louder, Anthony; Udall, Margarita; Cappelleri, Joseph C; Joshi, Ashish V; Patel, Nick C

2014-06-01

Managed healthcare organizations often utilize formulary management strategies such as prior authorization and step therapy to guide appropriate medication use and to control medication expenditures. The objective of this study was to examine clinical and economic outcomes associated with implementation of a pregabalin step therapy (ST) policy among Medicare Advantage Prescription Drug (MAPD) members. Pharmacy and medical claims data from Humana (restricted cohort; ST policy implemented 01/01/2009) and Thomson Reuters MarketScan(®) (unrestricted cohort) were analyzed for MAPD members aged 65 to 89 years receiving treatment for painful diabetic peripheral neuropathy (pDPN), postherpetic neuralgia (PHN) or fibromyalgia (FM). Difference-in-differences (DID) was used to examine year-over-year changes in disease-related and all-cause utilization and costs. Regression analyses examined medication utilization and healthcare expenditures after controlling for between-group compositional differences. We identified 13,911 members in the restricted cohort and matched to members from unrestricted health plans. FM (51.0%) and pDPN (41.8%) were the most common diagnoses. Members in the unrestricted cohort were older and had a greater level of comorbidity than members in the restricted cohort. The restricted cohort demonstrated greater year-over-year decrease in pregabalin utilization and increase in year-over-year gabapentin utilization compared with the unrestricted cohort. ST restriction was associated with an increase in disease-related pharmacy costs and a decrease in total medical costs for the restricted cohort compared with the unrestricted cohort. There was no difference between cohorts in total healthcare cost. After controlling for differences in age and comorbidity burden between the groups, implementation of a pregabalin ST restriction was associated with increased disease-related pharmacy costs and decreased total medical costs; however, there was no net difference in total healthcare cost or total pharmacy cost. © 2013 Pfizer Inc and Humana, Inc. Pain Practice © 2013 World Institute of Pain.

Alternative treatment strategies for neuropathic pain: Role of Indian medicinal plants and compounds of plant origin-A review.

PubMed

Singh, Hasandeep; Bhushan, Sakshi; Arora, Rohit; Singh Buttar, Harpal; Arora, Saroj; Singh, Balbir

2017-08-01

Neuropathic pain is a complex, chronic pain state accompanied by tissue injury and nerve damage. This important health issue constitutes a challenge for the modern medicine worldwide. The management of neuropathic pain remains a major clinical challenge, pertaining to an inadequate understanding of pathophysiological mechanisms of neuropathic pain. Various classes of drugs have been reported effective for the management of neuropathic pain viz. opiates, tricyclic antidepressants, and antiepileptic agents. However, association of adverse effects with these drugs hinders their confident prescription in people with neuropathic pain. Recently, various medicinal plants have been reported effective for the management of neuropathic pain. So, it may be prudent to look beyond synthetic drugs pertaining to their unprecedented pharmacotherapeutic effects with lesser adverse effects. The extensive literature review has been carried out from databases such as Science direct, Scifinder, Wiley online library, PubMed, Research gate, Google scholar and Chemical Abstracts. The list of Traditional Indian Medicinal plants (TIMPs) and isolated compounds have been compiled which have been reported effective as an alternative therapy for the management of neuropathic pain. This helps the researchers to discover some novel therapeutic agents against neuropathic pain. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Gait analysis and weight bearing in pre-clinical joint pain research.

PubMed

Ängeby Möller, Kristina; Svärd, Heta; Suominen, Anni; Immonen, Jarmo; Holappa, Johanna; Stenfors, Carina

2018-04-15

There is a need for better joint pain treatment, but development of new medication has not been successful. Pre-clinical models with readouts that better reflect the clinical situation are needed. In patients with joint pain, pain at rest and pain at walking are two major complaints. We describe a new way of calculating results from gait analysis using the CatWalk™ setup. Rats with monoarthritis induced by injection of Complete Freund's Adjuvant (CFA) intra-articularly into the ankle joint of one hind limb were used to assess gait and dynamic weight bearing. The results show that dynamic weight bearing was markedly reduced for the injected paw. Gait parameters such as amount of normal step sequences, walking speed and duration of step placement were also affected. Treatment with naproxen (an NSAID commonly used for inflammatory pain) attenuated the CFA-induced effects. Pregabalin, which is used for neuropathic pain, had no effect. Reduced dynamic weight bearing during locomotion, assessed and calculated in the way we present here, showed a dose-dependent and lasting normalization after naproxen treatment. In contrast, static weight bearing while standing (Incapacitance tester) showed a significant effect for a limited time only. Mechanical sensitivity (von Frey Optihairs) was completely normalized by naproxen, and the window for testing pharmacological effect disappeared. Objective and reproducible effects, with an endpoint showing face validity compared to pain while walking in patients with joint pain, are achieved by a new way of calculating dynamic weight bearing in monoarthritic rats. Copyright © 2017 Elsevier B.V. All rights reserved.

A Systematic Review of NMDA Receptor Antagonists for Treatment of Neuropathic Pain in Clinical Practice.

PubMed

Aiyer, Rohit; Mehta, Neel; Gungor, Semih; Gulati, Amitabh

2018-05-01

To investigate the efficacy of N-methyl-D-aspartate receptor (NMDAR) antagonists for neuropathic pain (NeuP) and review literature to determine if specific pharmacologic agents provide adequate NeuP relief. Literature was reviewed on PubMed using a variety of key words for 8 NMDAR antagonists. These key words include: "Ketamine and Neuropathy," "Ketamine and Neuropathic Pain," "Methadone and Neuropathy," "Methadone and Neuropathic Pain," "Memantine and Neuropathic pain," "Memantine and Neuropathy," "Amantadine and Neuropathic Pain," "Amantadine and Neuropathy," "Dextromethorphan and Neuropathic Pain," "Dextromethorphan and Neuropathy," "Carbamazepine and Neuropathic Pain," "Carbamazepine and Neuropathy," "Valproic Acid and Neuropathy," "Valproic Acid and Neuropathic Pain," "Phenytoin and Neuropathy," and "Phenytoin and Neuropathic Pain." With the results, the papers were reviewed using the PRISMA (Preferred Reporting in Systematic and Meta-Analyses) guideline. A total of 58 randomized controlled trials were reviewed among 8 pharmacologic agents, which are organized by date and alphabetical order. Of the trials for ketamine, 15 showed some benefit for analgesia. Methadone had 3 positive trials, while amantadine and memantine each only had 2 trials showing NeuP analgesic properties. Dextromethorphan and valproic acid both had 4 randomized controlled trials that showed some NeuP treatment benefit while carbamazepine had over 8 trials showing efficacy. Finally, phenytoin only had 1 trial that showed clinical response in treatment. There are a variety of NMDAR antagonist agents that should be considered for treatment of NeuP. Nevertheless, continued and further investigation of the 8 pharmacologic agents is needed to continue to evaluate their efficacy for treatment of NeuP.

Neuropathic symptoms, quality of life, and clinician perception of patient care in medical oncology outpatients with colorectal, breast, lung, and prostate cancer.

PubMed

Jones, Desiree; Zhao, Fengmin; Brell, Joanna; Lewis, Mark A; Loprinzi, Charles L; Weiss, Matthias; Fisch, Michael J

2015-03-01

We investigated how treatment-induced neuropathic symptoms are associated with patients' quality of life (QOL) and clinician-reported difficulty in caring for patients. Data were obtained from 3,106 outpatients with colorectal, breast, lung, or prostate cancer on numbness/tingling (N/T), neuropathic pain, and QOL. Clinicians reported the degree of difficulty in caring for patients' physical and psychological symptoms. For all patients, moderate to severe N/T was associated with poor QOL (OR = 1.82, 95% CI = 1.47-2.26, P < 0.001) but neuropathic pain was not (OR = 1.31, 95% CI = 0.94-1.83, P = 0.114). Moderate to severe N/T and neuropathic pain were associated with increased care difficulty (OR = 1.49, 95% CI = 1.27-1.74, P < 0.001 for N/T, and OR = 1.46, 95% CI = 1.15-1.84, P = 0.002 for neuropathic pain). The association of neuropathic pain with care difficulty was most significant in patients with colorectal cancer (CRC) (OR = 2.32, 95% CI = 1.41-3.83, P = 0.001). Baseline neuropathic pain was associated with declining QOL in CRC patients (OR = 2.08, 95% CI = 1.21-3.58, P = 0.008). Clinicians may experience increased care difficulty for patients of all cancer types with moderate to severe N/T or neuropathic pain; care difficulty due to neuropathic pain may be higher for CRC patients. Nearly half the patients of all cancer types with moderate to severe N/T may expect poor short-term QOL; CRC-but not other-patients with baseline neuropathic pain are likely to experience declining QOL. About half of patients with moderate to severe N/T (any cancer type) may expect poor QOL in the short term; CRC patients with baseline neuropathic pain in particular may experience declining QOL.

Diagnosis and treatment of neuropathic pain.

PubMed

Chong, M Sam; Bajwa, Zahid H

2003-05-01

Currently, no consensus on the optimal management of neuropathic pain exists and practices vary greatly worldwide. Possible explanations for this include difficulties in developing agreed diagnostic protocols and the coexistence of neuropathic, nociceptive and, occasionally, idiopathic pain in the same patient. Also, neuropathic pain has historically been classified according to its etiology (e.g., painful diabetic neuropathy, trigeminal neuralgia, spinal cord injury) without regard for the presumed mechanism(s) underlying the specific symptoms. A combined etiologic/mechanistic classification might improve neuropathic pain management. The treatment of neuropathic pain is largely empirical, often relying heavily on data from small, generally poorly-designed clinical trials or anecdotal evidence. Consequently, diverse treatments are used, including non-invasive drug therapies (antidepressants, antiepileptic drugs and membrane stabilizing drugs), invasive therapies (nerve blocks, ablative surgery), and alternative therapies (e.g., acupuncture). This article reviews the current and historical practices in the diagnosis and treatment of neuropathic pain, and focuses on the USA, Europe and Japan.

Topical amitriptyline and ketamine for the treatment of neuropathic pain.

PubMed

Mercadante, Sebastiano

2015-01-01

A neuropathy is a disturbance of function or pathological change in nerves. In some cases, peripheral neuropathic pain may occur due to a lesion or disease of the peripheral somatosensory nervous system. Efficacy of different agents for peripheral neuropathic pain conditions is less than optimal. The administration of topical analgesics might be an option, due to the potential of reduced adverse effects and increased patient compliance. There is major interest in compounding topical analgesics for peripheral neuropathic pain, but several challenges remain for this approach. Topical analgesics have the potential to be a valuable additional approach for the management of peripheral neuropathic pain. Topical amitriptyline-ketamine combination (AK) is a promising agent for peripheral neuropathic pain conditions. Some studies have shown its efficacy in neuropathic pain conditions. However, this data was not uniformely obtained and its role remains still controversial. Efficacy may depend on many factors, including the choice of the vehicle, the concentration, the pain site, and specific diseases. More studies are necessary to support the use of AK in clinical practice.

Treating chronic non-cancer pain in older people--more questions than answers?

PubMed

Gaskell, Helen; Derry, Sheena; Moore, R Andrew

2014-09-01

There is little evidence specifically relating to drug treatments for pain in older people, but much can be extrapolated from what we already know. The evidence about drug treatments for chronic non-cancer pain is changing, driven by major improvements in understanding of clinical trial analysis and by the adoption of patient-centered outcomes of proven economic benefit. There is clear evidence of lack of useful effect, or insufficient evidence of effect for a number of commonly used drugs, including paracetamol, topical rubefacients, low concentration topical capsaicin, and for strong opioids in chronic non-cancer pain. In musculoskeletal pain there is evidence of efficacy for NSAIDs, tramadol, and tapentadol, and in neuropathic pain for duloxetine, pregabalin, and gabapentin, with weak evidence for amitriptyline. The new perspective is of drugs that work well in a minority of patients, but hardly at all in the remainder. The goal of treatment is large reductions in pain, by 50% or more. This outcome, and only this outcome, is associated with large benefits in terms of improved sleep, reduced depression, and large gains in function and quality of life. It is not possible to predict which patient will benefit from which drug, but early success or failure appears to be predictive of long-term success or failure. The emphasis is on stopping treatments that do not work and switching to other drugs in the same or different class, so that any potential future risk of treatment is balanced by very large and immediate benefit. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Can treatment success with 5% lidocaine medicated plaster be predicted in cancer pain with neuropathic components or trigeminal neuropathic pain?

PubMed Central

Kern, Kai-Uwe; Nalamachu, Srinivas; Brasseur, Louis; Zakrzewska, Joanna M

2013-01-01

An expert group of 40 pain specialists from 16 countries performed a first assessment of the value of predictors for treatment success with 5% lidocaine-medicated plaster in the management of cancer pain with neuropathic components and trigeminal neuropathic pain. Results were based on the retrospective analysis of 68 case reports (sent in by participants in the 4 weeks prior to the conference) and the practical experience of the experts. Lidocaine plaster treatment was mostly successful for surgery or chemotherapy-related cancer pain with neuropathic components. A dose reduction of systemic pain treatment was observed in at least 50% of all cancer pain patients using the plaster as adjunct treatment; the presence of allodynia, hyperalgesia or pain quality provided a potential but not definitively clear indication of treatment success. In trigeminal neuropathic pain, continuous pain, severe allodynia, hyperalgesia, or postherpetic neuralgia or trauma as the cause of orofacial neuropathic pain were perceived as potential predictors of treatment success with lidocaine plaster. In conclusion, these findings provide a first assessment of the likelihood of treatment benefits with 5% lidocaine-medicated plaster in the management of cancer pain with neuropathic components and trigeminal neuropathic pain and support conducting large, well-designed multicenter studies. PMID:23630431

ANALGESIC EFFECT OF INTRATHECAL BACLOFEN BOLUS ON NEUROPATHIC PAIN IN SPINAL CORD INJURY PATIENTS.

PubMed

Kumru, Hatice; Benito-Penalva, Jesus; Kofler, Markus; Vidal, Joan

2018-05-18

GABA-ergic neurons are widely distributed throughout the central nervous system, including the spinal cord which is important for the transmission of pain impulses to the brain. Here we hypothesized that intrathecal baclofen (ITB) which is a GABA analogue might exert analgesic effects on neuropathic pain, which could be related to subtypes of pain in spinal cord injury (SCI). SCI patients with a cervical or thoracic lesion and neuropathic pain were randomized to receive either a single ITB bolus or placebo. Numerical Rating Scale (NRS), Neuropathic Pain Symptom Inventory (NPSI), and Brief Pain Inventory (BPI) were obtained for assessment of neuropathic pain. Spasticity was assessed using Modified Ashworth Scale and visual analogue scale. Evaluations were performed at baseline, and 4, 8, and 24 hours after application of ITB or placebo. Eight patients received ITB, 5 placebo. Neuropathic pain improved significantly in the ITB group based on NRS, BPI, and NPSI, which revealed an effect on all subtypes of pain. Spasticity declined significantly. In the placebo group, there was neither significant change in pain nor in spasticity. An ITB bolus exerted a significant analgesic effect on all subtypes of neuropathic pain in SCI patients. ITB has analgesic effects on all subtypes of neuropathic pain and can improve interference of neuropathic pain with activities of daily living. ITB might be a promising analgesic treatment to control neuropathic pain. Copyright © 2018. Published by Elsevier Inc.

DOE Optimization of Nano-based Carrier of Pregabalin as Hydrogel: New Therapeutic & Chemometric Approaches for Controlled Drug Delivery Systems

PubMed Central

Arafa, Mona G.; Ayoub, Bassam M.

2017-01-01

Niosomes entrapping pregabalin (PG) were prepared using span 60 and cholesterol in different molar ratios by hydration method, the remaining PG from the hydrating solution was separated from vesicles by freeze centrifugation. Optimization of nano-based carrier of pregabalin (PG) was achieved. Quality by Design strategy was successfully employed to obtain PG-loaded niosomes with the desired properties. The optimal particle size, drug release and entrapment efficiency were attained by Minitab® program using design of experiment (DOE) that predicted the best parameters by investigating the combined effect of different factors simultaneously. Pareto chart was used in the screening step to exclude the insignificant variables while response surface methodology (RSM) was used in the optimization step to study the significant factors. Best formula was selected to prepare topical hydrogels loaded with niosomal PG using HPMC and Carbopol 934. It was verified, by means of mechanical and rheological tests, that addition of the vesicles to the gel matrix affected significantly gel network. In vitro release and ex vivo permeation experiments were carried out. Delivery of PG molecules followed a Higuchi, non Fickian diffusion. The present work will be of interest for pharmaceutical industry as a controlled transdermal alternative to the conventional oral route. PMID:28134262

DOE Optimization of Nano-based Carrier of Pregabalin as Hydrogel: New Therapeutic & Chemometric Approaches for Controlled Drug Delivery Systems

NASA Astrophysics Data System (ADS)

Arafa, Mona G.; Ayoub, Bassam M.

2017-01-01

Niosomes entrapping pregabalin (PG) were prepared using span 60 and cholesterol in different molar ratios by hydration method, the remaining PG from the hydrating solution was separated from vesicles by freeze centrifugation. Optimization of nano-based carrier of pregabalin (PG) was achieved. Quality by Design strategy was successfully employed to obtain PG-loaded niosomes with the desired properties. The optimal particle size, drug release and entrapment efficiency were attained by Minitab® program using design of experiment (DOE) that predicted the best parameters by investigating the combined effect of different factors simultaneously. Pareto chart was used in the screening step to exclude the insignificant variables while response surface methodology (RSM) was used in the optimization step to study the significant factors. Best formula was selected to prepare topical hydrogels loaded with niosomal PG using HPMC and Carbopol 934. It was verified, by means of mechanical and rheological tests, that addition of the vesicles to the gel matrix affected significantly gel network. In vitro release and ex vivo permeation experiments were carried out. Delivery of PG molecules followed a Higuchi, non Fickian diffusion. The present work will be of interest for pharmaceutical industry as a controlled transdermal alternative to the conventional oral route.

Long-term outcome of Cavalier King Charles spaniel dogs with clinical signs associated with Chiari-like malformation and syringomyelia.

PubMed

Plessas, I N; Rusbridge, C; Driver, C J; Chandler, K E; Craig, A; McGonnell, I M; Brodbelt, D C; Volk, H A

2012-11-17

The disease complex Chiari-like malformation (CM) and syringomyelia (SM) has been associated with the development of neuropathic pain (NeP), and commonly affects Cavalier King Charles spaniels (CKCS). This prospective cohort study followed 48 CKCSs with CM and/or SM and clinical signs suggestive of NeP for a period of 39 (±14.3) months from diagnosis. At the end of the study, 36 dogs were still alive; five dogs died of an unrelated or unknown cause, and seven were euthanased due to severe clinical signs suggestive of NeP. During the follow-up period, the clinical signs of scratching, facial rubbing behaviour, vocalisation and exercise ability were evaluated. Nine out of 48 dogs stopped scratching (P<0.001), but there was no statistically significant change in the number of dogs exhibiting exercise intolerance, vocalisation or facial rubbing behaviour. The overall severity of clinical signs based on a visual analogue scale (VAS) (0 mm: no clinical signs 100 mm: severe clinical signs) increased (from median 75 mm (interquartile ranges (IQR) 68-84) to 84 mm (IQR 71.5-91), P<0.001). A quarter of the dogs were static or improved. In general, the majority of the owners felt that the quality of life of their dogs was acceptable. Medical treatments received were gabapentin or pregabalin and/or intermittently, carprofen. The owner's perception of their animal's progress, and progress based on VAS, had strong positive correlation (Spearman's rank correlation (s(r)) 0.74, P<0.001). Overall, this study suggests that clinical signs suggestive of NeP progress in three-quarters of CKCSs with CM and/or SM.

The potential role of neuropathic mechanisms in dry eye syndromes.

PubMed

Mcmonnies, Charles W

Dry eye syndromes can involve both nociceptive and neuropathic symptoms. Nociceptive symptoms are the normal physiological responses to noxious stimuli. Neuropathic symptoms are caused by a lesion or disease of the somatosensory nervous system and can be the result of hypersensitisation of peripheral or central corneal and conjunctival somatosensory nerves. For example, inflammation could induce neuroplastic peripheral sensitisation of the ocular surface or lid wiper and exacerbate nociceptive symptoms. Neuropathic symptoms may explain the incommensurate relation between signs and symptoms in some dry eye syndromes although absence of signs of a dry eye syndrome may also be a consequence of inappropriate methods used when examining for them. Involvement of neuropathic mechanisms may also help explain dry eye symptoms which occur in association with reduced corneal sensitivity. This review includes a discussion of the potential for ocular symptoms involving neuropathic mechanisms to contribute to psychosocial problems such as depression, stress, anxiety and sleep disorders as well as for these types of psychosocial problems to contribute to neuropathic mechanisms and dry eye syndromes. Failure to consider the possibility that neuropathic mechanisms can contribute to dry eye syndromes may reduce accuracy of diagnosis and the suitability of treatment provided. Dry eye symptoms in the absence of commensurate evidence of tear dysfunction, and unsatisfactory response to tear dysfunction therapies should prompt consideration of neuropathic mechanisms being involved. Symptoms which persist after local anaesthetic instillation are more likely to be neuropathic in origin. Reducing inflammation may help limit any associated neuroplastic hypersensitivity. Copyright © 2016 Spanish General Council of Optometry. Published by Elsevier España, S.L.U. All rights reserved.

Peripheral neuropathy may increase the risk for asymptomatic otic barotrauma during hyperbaric oxygen therapy: research report.

PubMed

Mozdzanowski, Christopher; Perdrizet, George A

2014-01-01

Otic barotrauma (OBT) is an adverse event seen in patients receiving hyperbaric oxygen (HBO2) therapy. After encountering a case of painless tympanic perforation during HBO2 therapy of a diabetic patient with the diagnosis of neuropathic Wagner Grade III foot ulcer, we hypothesized that peripheral neuropathy of the lower extremity may be associated with an increased risk of asymptomatic OBT during HBO2 therapy. The medical records of all HBO2 patients during a one-year period of time were reviewed. Subjects were selected based on otoscopic documentation of OBT and divided into two groups based on the presence or absence of lower extremity peripheral neuropathy. Time to therapeutic compression, presence or absence of ear-related symptoms and modified Teed (mTeed) scores were compared between the two groups. A total of 38 patients with OBT, 18 neuropathic and 20 non-neuropathic, were identified. Asymptomatic OBT occurred more frequently in the neuropathic vs. non-neuropathic group (56% vs. 5%, p < 0.001). mTeed scores were significantly greater in the neuropathic vs. non-neuropathic group (mTeed 1, 30% vs. 61%; mTeed 2, 65% vs. 36%; mTeed 3, 4% vs. 3%; p = 0.032). Mean compression times were shorter in the neuropathic vs. non-neuropathic group (10. 5 +/- 1.8 vs. 14.4 +/- 3.3 minutes, p < 0.001). The presence of peripheral neuropathy of the lower extremity may be associated with a significantly greater incidence of asymptomatic otic barotrauma during HBO2 therapy.

Prevalence of Neuropathic Pain in Patients with Traumatic Brachial Plexus Injury: A Multicenter Prospective Hospital-Based Study.

PubMed

Ciaramitaro, Palma; Padua, Luca; Devigili, Grazia; Rota, Eugenia; Tamburin, Stefano; Eleopra, Roberto; Cruccu, Giorgio; Truini, Andrea

2017-12-01

Prevalence and clinical characteristics of neuropathic pain due to traumatic brachial plexus injury. Observational epidemiological study. Hospital-based multicenter study. One hundred seven prospectively enrolled patients with brachial plexus injury. All the patients underwent clinical examination and neurophysiological testing for a definitive diagnosis of the brachial plexus lesion. The DN4 questionnaire was used to identify neuropathic pain, and the Neuropathic Pain Symptom Inventory (NPSI) to evaluate the different symptoms of neuropathic pain. The SF36 questionnaire and the Beck Depression Inventory (BDI) were used to assess quality of life and mood disturbances in patients with neuropathic pain. Of the 107 enrolled patients, 74 had pain (69%); neuropathic pain, as assessed by means of the DN4, was identified in 60 (56%) of these patients. According to the NPSI, the most frequent and severe pain type was the spontaneous burning pain. Clinical and neurophysiological findings showed that pain is unrelated to age but is associated with the severity of peripheral nerve damage. The SF36 questionnaire and BDI showed that neuropathic pain impairs quality of life and causes depression. Our study provides information on the prevalence, characteristics, and variables associated with neuropathic pain due to traumatic brachial plexus injuries that might provide a basis for improving the clinical management of this condition. © 2017 American Academy of Pain Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com

Dendritic spine remodeling following early and late Rac1 inhibition after spinal cord injury: evidence for a pain biomarker

PubMed Central

Zhao, Peng; Hill, Myriam; Liu, Shujun; Chen, Lubin; Bangalore, Lakshmi; Waxman, Stephen G.

2016-01-01

Neuropathic pain is a significant complication following spinal cord injury (SCI) with few effective treatments. Drug development for neuropathic pain often fails because preclinical studies do not always translate well to clinical conditions. Identification of biological characteristics predictive of disease state or drug responsiveness could facilitate more effective clinical translation. Emerging evidence indicates a strong correlation between dendritic spine dysgenesis and neuropathic pain. Because dendritic spines are located on dorsal horn neurons within the spinal cord nociceptive system, dendritic spine remodeling provides a unique opportunity to understand sensory dysfunction after SCI. In this study, we provide support for the postulate that dendritic spine profiles can serve as biomarkers for neuropathic pain. We show that dendritic spine profiles after SCI change to a dysgenic state that is characteristic of neuropathic pain in a Rac1-dependent manner. Suppression of the dysgenic state through inhibition of Rac1 activity is accompanied by attenuation of neuropathic pain. Both dendritic spine dysgenesis and neuropathic pain return when inhibition of Rac1 activity is lifted. These findings suggest the utility of dendritic spines as structural biomarkers for neuropathic pain. PMID:26936986

Acetaminophen and non-steroidal anti-inflammatory drugs interact with morphine and tramadol analgesia for the treatment of neuropathic pain in rats.

PubMed

Shinozaki, Tomonari; Yamada, Toshihiko; Nonaka, Takahiro; Yamamoto, Tatsuo

2015-06-01

Although non-steroidal anti-inflammatory drugs and acetaminophen have no proven efficacy against neuropathic pain, they are frequently prescribed for neuropathic pain patients. We examined whether the combination of opioids (tramadol and morphine) with indomethacin or acetaminophen produce favorable effects on neuropathic pain and compared the efficacy for neuropathic pain with that for inflammatory pain. The carrageenan model was used as the inflammatory pain model while the tibial neuroma transposition (TNT) model was used as the neuropathic pain model. The tibial nerve is transected in the TNT model, with the tibial nerve stump then transpositioned to the lateral aspect of the hindlimb. Neuropathic pain (mechanical allodynia and neuroma pain) is observed after TNT injury. Drugs were administered orally. In the carrageenan model, all drugs produced anti-allodynic effects and all drug combinations, but not tramadol + indomethacin combination, produced synergistic anti-allodynic effects. In the TNT model, tramadol and morphine, but not acetaminophen and indomethacin, produced anti-neuropathic pain effects. In the combination, with the exception of morphine + acetaminophen combination, both acetaminophen and indomethacin reduced the 50% effective dose (ED50) of tramadol and morphine as compared with the ED50s for the single drug study in the TNT model. The ED50s of tramadol and morphine in the carrageenan combination test were not statistically significantly different from the ED50s in the TNT model combination study. The combination of opioids with indomethacin or acetaminophen produced a synergistic analgesic effect both in inflammatory and neuropathic pain with some exceptions. The efficacy of these combinations for neuropathic pain was not different from that for inflammatory pain.

Diagnosis and management of neuropathic pain: a balanced approach to treatment.

PubMed

Nicholson, Bruce D

2003-12-01

To provide nurse practitioners with a conceptual framework from which to diagnose and manage chronic neuropathic pain, specifically postherpetic neuralgia (PHN). A current review of the available treatment options for the management of neuropathic pain and PHN is provided. A comprehensive literature review was conducted. Clinical articles, meta-analyses, and reviews were selected for their relevance to the diagnosis and management of chronic neuropathic pain and PHN. Managing patients with chronic neuropathic pain is a common clinical challenge due to variability in individual symptoms, mechanisms, and treatment responses. In patients with PHN, a balanced treatment approach focusing on efficacy, safety, and tolerability is recommended. With appropriate treatment, most patients are able to achieve clinically significant relief from neuropathic pain. Diagnosis and management of neuropathic pain syndromes is challenging. Because of the complexity of chronic pain, successful long-term treatment can be especially difficult (Nicholson, 2003b). While most acute pain is nociceptive (i.e., a response to noxious stimuli), chronic pain can be nociceptive, neuropathic, or of mixed origin. PHN is a chronic pain syndrome that can last for years, causing physical and social disability and psychological distress (Kanazi, 2000). Despite major recent advances in the treatment of PHN, many patients remain refractory to current therapy (Dworkin, 2003). For practicing clinicians, including nurse practitioners, viewing pain as a disease rather than a symptom is the first step towards its successful management. Understanding the pathophysiology of chronic pain and emerging treatment paradigms for the management of neuropathic pain and PHN is critical to optimal care.

Non-stereoselective reversal of neuropathic pain by naloxone and naltrexone

PubMed Central

Hutchinson, Mark R.; Zhang, Yingning; Brown, Kimberley; Coats, Benjamen D.; Shridhar, Mitesh; Sholar, Paige W.; Patel, Sonica J.; Crysdale, Nicole Y.; Harrison, Jacqueline A.; Maier, Steven F.; Rice, Kenner C.; Watkins, Linda R.

2008-01-01

Although activated spinal cord glia contribute importantly to neuropathic pain, how nerve injury activates glia remains controversial. It has recently been proposed, on the basis of genetic approaches, that toll-like receptor 4 (TLR4) may be a key receptor for initiating microglial activation following L5 spinal nerve injury. The present studies extend this idea pharmacologically by showing that TLR4 is key for maintaining neuropathic pain following sciatic nerve chronic constriction injury (CCI). Established neuropathic pain was reversed by intrathecally delivered TLR4 receptor antagonists derived from lipopolysaccharide. Additionally, (+)-naltrexone, (+)-naloxone, and (-))-naloxone, which we show here to be TLR4 antagonists in vitro on both stably transfected HEK293-TLR4 and microglial cell lines, suppressed neuropathic pain with complete reversal upon chronic infusion. Immunohistochemical analyses of spinal cords following chronic infusion revealed suppression of CCI-induced microglial activation by (+)-naloxone and (-))-naloxone, paralleling reversal of neuropathic pain. Together, these CCI data support the conclusion that neuron-to-glia signaling through TLR4 is important not only for initiating neuropathic pain, as suggested previously, but also for maintaining established neuropathic pain. Furthermore, these studies suggest that the novel TLR4 antagonists (+)-naloxone and (-))-naloxone can each fully reverse established neuropathic pain upon multi-day administration. This finding with (+)-naloxone is of potential clinical relevance. This is because (+)-naloxone is an antagonist that is inactive at the (-))-opioid selective receptors on neurons that produce analgesia. Thus, these data suggest that (+)-opioid antagonists such as (+)-naloxone may be useful clinically to suppress glial activation, yet (-))-opioid agonists suppress pain. PMID:18662331

Pharmacologic management of chronic neuropathic pain

PubMed Central

Mu, Alex; Weinberg, Erica; Moulin, Dwight E.; Clarke, Hance

2017-01-01

Abstract Objective To provide family physicians with a practical clinical summary of the Canadian Pain Society (CPS) revised consensus statement on the pharmacologic management of neuropathic pain. Quality of evidence A multidisciplinary interest group within the CPS conducted a systematic review of the literature on the current treatments of neuropathic pain in drafting the revised consensus statement. Main message Gabapentinoids, tricyclic antidepressants, and serotonin-norepinephrine reuptake inhibitors are the first-line agents for treating neuropathic pain. Tramadol and other opioids are recommended as second-line agents, while cannabinoids are newly recommended as third-line agents. Other anticonvulsants, methadone, tapentadol, topical lidocaine, and botulinum toxin are recommended as fourth-line agents. Conclusion Many pharmacologic analgesics exist for the treatment of neuropathic pain. Through evidence-based recommendations, the CPS revised consensus statement helps guide family physicians in the management of patients with neuropathic pain. PMID:29138154

Slack channels expressed in sensory neurons control neuropathic pain in mice.

PubMed

Lu, Ruirui; Bausch, Anne E; Kallenborn-Gerhardt, Wiebke; Stoetzer, Carsten; Debruin, Natasja; Ruth, Peter; Geisslinger, Gerd; Leffler, Andreas; Lukowski, Robert; Schmidtko, Achim

2015-01-21

Slack (Slo2.2) is a sodium-activated potassium channel that regulates neuronal firing activities and patterns. Previous studies identified Slack in sensory neurons, but its contribution to acute and chronic pain in vivo remains elusive. Here we generated global and sensory neuron-specific Slack mutant mice and analyzed their behavior in various animal models of pain. Global ablation of Slack led to increased hypersensitivity in models of neuropathic pain, whereas the behavior in models of inflammatory and acute nociceptive pain was normal. Neuropathic pain behaviors were also exaggerated after ablation of Slack selectively in sensory neurons. Notably, the Slack opener loxapine ameliorated persisting neuropathic pain behaviors. In conclusion, Slack selectively controls the sensory input in neuropathic pain states, suggesting that modulating its activity might represent a novel strategy for management of neuropathic pain. Copyright © 2015 the authors 0270-6474/15/351125-11$15.00/0.

Pharmacologic management of chronic neuropathic pain: Review of the Canadian Pain Society consensus statement.

PubMed

Mu, Alex; Weinberg, Erica; Moulin, Dwight E; Clarke, Hance

2017-11-01

To provide family physicians with a practical clinical summary of the Canadian Pain Society (CPS) revised consensus statement on the pharmacologic management of neuropathic pain. A multidisciplinary interest group within the CPS conducted a systematic review of the literature on the current treatments of neuropathic pain in drafting the revised consensus statement. Gabapentinoids, tricyclic antidepressants, and serotonin-norepinephrine reuptake inhibitors are the first-line agents for treating neuropathic pain. Tramadol and other opioids are recommended as second-line agents, while cannabinoids are newly recommended as third-line agents. Other anticonvulsants, methadone, tapentadol, topical lidocaine, and botulinum toxin are recommended as fourth-line agents. Many pharmacologic analgesics exist for the treatment of neuropathic pain. Through evidence-based recommendations, the CPS revised consensus statement helps guide family physicians in the management of patients with neuropathic pain. Copyright© the College of Family Physicians of Canada.

An Algorithm for Neuropathic Pain Management in Older People.

PubMed

Pickering, Gisèle; Marcoux, Margaux; Chapiro, Sylvie; David, Laurence; Rat, Patrice; Michel, Micheline; Bertrand, Isabelle; Voute, Marion; Wary, Bernard

2016-08-01

Neuropathic pain frequently affects older people, who generally also have several comorbidities. Elderly patients are often poly-medicated, which increases the risk of drug-drug interactions. These patients, especially those with cognitive problems, may also have restricted communication skills, making pain evaluation difficult and pain treatment challenging. Clinicians and other healthcare providers need a decisional algorithm to optimize the recognition and management of neuropathic pain. We present a decisional algorithm developed by a multidisciplinary group of experts, which focuses on pain assessment and therapeutic options for the management of neuropathic pain, particularly in the elderly. The algorithm involves four main steps: (1) detection, (2) evaluation, (3) treatment, and (4) re-evaluation. The detection of neuropathic pain is an essential step in ensuring successful management. The extent of the impact of the neuropathic pain is then assessed, generally with self-report scales, except in patients with communication difficulties who can be assessed using behavioral scales. The management of neuropathic pain frequently requires combination treatments, and recommended treatments should be prescribed with caution in these elderly patients, taking into consideration their comorbidities and potential drug-drug interactions and adverse events. This algorithm can be used in the management of neuropathic pain in the elderly to ensure timely and adequate treatment by a multidisciplinary team.

Use of a Novel High-Resolution Magnetic Resonance Neurography Protocol to Detect Abnormal Dorsal Root Ganglia in Sjögren Patients With Neuropathic Pain

PubMed Central

Birnbaum, Julius; Duncan, Trisha; Owoyemi, Kristie; Wang, Kenneth C.; Carrino, John; Chhabra, Avneesh

2014-01-01

Abstract The diagnosis and treatment of patients with Sjögren syndrome (SS) with neuropathic pain pose several challenges. Patients with SS may experience unorthodox patterns of burning pain not conforming to a traditional “stocking-and-glove” distribution, which can affect the face, torso, and proximal extremities. This distribution of neuropathic pain may reflect mechanisms targeting the proximal-most element of the peripheral nervous system—the dorsal root ganglia (DRG). Skin biopsy can diagnose such a small-fiber neuropathy and is a surrogate marker of DRG neuronal cell loss. However, SS patients have been reported who have similar patterns of proximal neuropathic pain, despite having normal skin biopsy studies. In such cases, DRGs may be targeted by mechanisms not associated with neuronal cell loss. Therefore, alternative approaches are warranted to help characterize abnormal DRGs in SS patients with proximal neuropathic pain. We performed a systematic review of the literature to define the frequency and spectrum of SS peripheral neuropathies, and to better understand the attribution of SS neuropathic pain to peripheral neuropathies. We found that the frequency of SS neuropathic pain exceeded the prevalence of peripheral neuropathies, and that painful peripheral neuropathies occurred less frequently than neuropathies not always associated with pain. We developed a novel magnetic resonance neurography (MRN) protocol to evaluate DRG abnormalities. Ten SS patients with proximal neuropathic pain were evaluated by this MRN protocol, as well as by punch skin biopsies evaluating for intraepidermal nerve fiber density (IENFD) of unmyelinated nerves. Five patients had radiographic evidence of DRG abnormalities. Patients with MRN DRG abnormalities had increased IENFD of unmyelinated nerves compared to patients without MRN DRG abnormalities (30.2 [interquartile range, 4.4] fibers/mm vs. 11.0 [4.1] fibers/mm, respectively; p = 0.03). Two of these 5 SS patients whose neuropathic pain resolved with intravenous immunoglobulin (IVIg) therapy had improvement of MRN DRG abnormalities. We have developed a novel MRN protocol that can detect DRG abnormalities in SS patients with neuropathic pain who do not have markers of peripheral neuropathy. We found that SS patients with MRN DRG abnormalities had statistically significant, increased IENFD on skin biopsy studies, which may suggest a relationship between trophic mediators and neuropathic pain. Given that our literature review has demonstrated that many SS neuropathic pain patients do not have a neuropathy, our findings suggest an important niche for this MRN DRG technique in the evaluation of broader subsets of SS neuropathic pain patients who may not have underlying neuropathies. The improvement of MRN DRG abnormalities in patients with IVIg-induced remission of neuropathic pain suggests that our MRN protocol may be capturing reversible, immune-mediated mechanisms targeting the DRG. PMID:24797167

Understanding Neuropathic Corneal Pain-Gaps and Current Therapeutic Approaches

PubMed Central

Goyal, Sunali; Hamrah, Pedram

2017-01-01

The richly innervated corneal tissue is one of the most powerful pain generator in the body. Corneal neuropathic pain results from dysfunctional nerves causing perceptions such as burning, stinging, eye-ache and pain. Various inflammatory diseases, neurological diseases, and surgical interventions can be the underlying cause of corneal neuropathic pain. Recent efforts have been made by the scientific community to elucidate the pathophysiology and neurobiology of pain resulting from initially protective physiological reflexes, to a more persistent chronic state. The goal of this clinical review is to briefly summarize the pathophysiology of neuropathic corneal pain, describe how to systematically approach the diagnosis of these patients, and finally summarizing our experience with current therapeutic approaches for the treatment of corneal neuropathic pain. PMID:26959131

[Gabapentin mitigates neuropathic pain in cancer patients--a case report].

PubMed

Okada, Masakuni; Shinjo, Takuya

2007-08-01

A 64-year-old male underwent low anterior resection of the rectum for rectal cancer. Five years later, he suffered neuropathic cancer pain on the left-posterior surface of his thigh caused by sacral invasion of the recurrence site. His neuropathic pain was not sufficiently responsive to the combination therapy of opioids, non-steroidal antiinflammatory drugs (NSAIDs), continuous infusion of subcutaneous ketamine and oral mexiletine. Gabapentin, which has been suggested as an adjuvant analgesic for neuropathic pain introduced orally, rapidly and significantly alleviated his pain and we could subsequently dispense with ketamine and mexiletine. No adverse effect was seen during this treatment. The present case indicates that gabapentin would be one of the most effective adjuvant analgesics for neuropathic cancer pain.

Tramadol and Propentofylline Coadministration Exerted Synergistic Effects on Rat Spinal Nerve Ligation-Induced Neuropathic Pain

PubMed Central

Wang, Huan; Wang, Wei; Zhang, Hui; Liu, Rui; Xu, Li-Xian; Mei, Xiao-Peng

2013-01-01

Neuropathic pain is an intractable clinical problem. Drug treatments such as tramadol have been reported to effectively decrease neuropathic pain by inhibiting the activity of nociceptive neurons. It has also been reported that modulating glial activation could also prevent or reverse neuropathic pain via the administration of a glial modulator or inhibitor, such as propentofylline. Thus far, there has been no clinical strategy incorporating both neuronal and glial participation for treating neuropathic pain. Therefore, the present research study was designed to assess whether coadministration of tramadol and propentofylline, as neuronal and glial activation inhibitors, respectively, would exert a synergistic effect on the reduction of rat spinal nerve ligation (SNL)-induced neuropathic pain. Rats underwent SNL surgery to induce neuropathic pain. Pain behavioral tests were conducted to ascertain the effect of drugs on SNL-induced mechanical allodynia with von-Frey hairs. Proinflammatory factor interleukin-1β (IL-1β) expression was also detected by Real-time RT-PCR. Intrathecal tramadol and propentofylline administered alone relieved SNL-induced mechanical allodynia in a dose-dependent manner. Tramadol and propentofylline coadministration exerted a more potent effect in a synergistic and dose dependent manner than the intrathecal administration of either drug alone. Real-time RT-PCR demonstrated IL-1β up-expression in the ipsilateral spinal dorsal horn after the lesion, which was significantly decreased by tramadol and propentofylline coadministration. Inhibiting proinflammatory factor IL-1β contributed to the synergistic effects of tramadol and propentofylline coadministration on rat peripheral nerve injury-induced neuropathic pain. Thus, our study provided a rationale for utilizing a novel strategy for treating neuropathic pain by blocking the proinflammatory factor related pathways in the central nervous system. PMID:24009718

Identification of key genes and pathways associated with neuropathic pain in uninjured dorsal root ganglion by using bioinformatic analysis.

PubMed

Chen, Chao-Jin; Liu, De-Zhao; Yao, Wei-Feng; Gu, Yu; Huang, Fei; Hei, Zi-Qing; Li, Xiang

2017-01-01

Neuropathic pain is a complex chronic condition occurring post-nervous system damage. The transcriptional reprogramming of injured dorsal root ganglia (DRGs) drives neuropathic pain. However, few comparative analyses using high-throughput platforms have investigated uninjured DRG in neuropathic pain, and potential interactions among differentially expressed genes (DEGs) and pathways were not taken into consideration. The aim of this study was to identify changes in genes and pathways associated with neuropathic pain in uninjured L4 DRG after L5 spinal nerve ligation (SNL) by using bioinformatic analysis. The microarray profile GSE24982 was downloaded from the Gene Expression Omnibus database to identify DEGs between DRGs in SNL and sham rats. The prioritization for these DEGs was performed using the Toppgene database followed by gene ontology and pathway enrichment analyses. The relationships among DEGs from the protein interactive perspective were analyzed using protein-protein interaction (PPI) network and module analysis. Real-time polymerase chain reaction (PCR) and Western blotting were used to confirm the expression of DEGs in the rodent neuropathic pain model. A total of 206 DEGs that might play a role in neuropathic pain were identified in L4 DRG, of which 75 were upregulated and 131 were downregulated. The upregulated DEGs were enriched in biological processes related to transcription regulation and molecular functions such as DNA binding, cell cycle, and the FoxO signaling pathway. Ctnnb1 protein had the highest connectivity degrees in the PPI network. The in vivo studies also validated that mRNA and protein levels of Ctnnb1 were upregulated in both L4 and L5 DRGs. This study provides insight into the functional gene sets and pathways associated with neuropathic pain in L4 uninjured DRG after L5 SNL, which might promote our understanding of the molecular mechanisms underlying the development of neuropathic pain.

Neuropathic pain phenotyping by international consensus (NeuroPPIC) for genetic studies: a NeuPSIG systematic review, Delphi survey, and expert panel recommendations

PubMed Central

van Hecke, Oliver; Kamerman, Peter R.; Attal, Nadine; Baron, Ralf; Bjornsdottir, Gyda; Bennett, David L.H.; Bennett, Michael I.; Bouhassira, Didier; Diatchenko, Luda; Freeman, Roy; Freynhagen, Rainer; Haanpää, Maija; Jensen, Troels S.; Raja, Srinivasa N.; Rice, Andrew S.C.; Seltzer, Ze'ev; Thorgeirsson, Thorgeir E.; Yarnitsky, David; Smith, Blair H.

2015-01-01

Abstract For genetic research to contribute more fully to furthering our knowledge of neuropathic pain, we require an agreed, valid, and feasible approach to phenotyping, to allow collaboration and replication in samples of sufficient size. Results from genetic studies on neuropathic pain have been inconsistent and have met with replication difficulties, in part because of differences in phenotypes used for case ascertainment. Because there is no consensus on the nature of these phenotypes, nor on the methods of collecting them, this study aimed to provide guidelines on collecting and reporting phenotypes in cases and controls for genetic studies. Consensus was achieved through a staged approach: (1) systematic literature review to identify all neuropathic pain phenotypes used in previous genetic studies; (2) Delphi survey to identify the most useful neuropathic pain phenotypes and their validity and feasibility; and (3) meeting of experts to reach consensus on the optimal phenotype(s) to be collected from patients with neuropathic pain for genetic studies. A basic “entry level” set of phenotypes was identified for any genetic study of neuropathic pain. This set identifies cases of “possible” neuropathic pain, and controls, and includes: (1) a validated symptom-based questionnaire to determine whether any pain is likely to be neuropathic; (2) body chart or checklist to identify whether the area of pain distribution is neuroanatomically logical; and (3) details of pain history (intensity, duration, any formal diagnosis). This NeuroPPIC “entry level” set of phenotypes can be expanded by more extensive and specific measures, as determined by scientific requirements and resource availability. PMID:26469320

Cardioprotection induced in a mouse model of neuropathic pain via anterior nucleus of paraventricular thalamus.

PubMed

Cheng, Yi-Fen; Chang, Ya-Ting; Chen, Wei-Hsin; Shih, Hsi-Chien; Chen, Yen-Hui; Shyu, Bai-Chuang; Chen, Chien-Chang

2017-10-10

Myocardial infarction is the leading cause of death worldwide. Restoration of blood flow rescues myocardium but also causes ischemia-reperfusion injury. Here, we show that in a mouse model of chronic neuropathic pain, ischemia-reperfusion injury following myocardial infarction is reduced, and this cardioprotection is induced via an anterior nucleus of paraventricular thalamus (PVA)-dependent parasympathetic pathway. Pharmacological inhibition of extracellular signal-regulated kinase activation in the PVA abolishes neuropathic pain-induced cardioprotection, whereas activation of PVA neurons pharmacologically, or optogenetic stimulation, is sufficient to induce cardioprotection. Furthermore, neuropathic injury and optogenetic stimulation of PVA neurons reduce the heart rate. These results suggest that the parasympathetic nerve is responsible for this unexpected cardioprotective effect of chronic neuropathic pain in mice.Various forms of preconditioning can prevent ischemic-reperfusion injury after myocardial infarction. Here, the authors show that in mice, the presence of chronic neuropathic pain can have a cardioprotective effect, and that this is dependent on neural activation in the paraventricular thalamus.

TNF α is involved in neuropathic pain induced by nucleoside reverse transcriptase inhibitor in rats

PubMed Central

Zheng, Xuexing; Ouyang, Handong; Liu, Shue; Mata, Marina; Fink, David J.; Hao, Shuanglin

2011-01-01

In patients with HIV/AIDS, neuropathic pain is a common neurological complication. Infection with the HIV itself may lead to neuropathic pain, and painful symptoms are enhanced when patients are treated with nucleoside reverse transcriptase inhibitors (NRTI). The mechanisms by which NRTIs contribute to the development of neuropathic pain are not known. In the current studies, we tested the role of TNFα in antiretroviral drug-induced neuropathic pain. We administered 2′,3′-dideoxycytidine (ddC, one of the NRTIs) systemically to induce mechanical allodynia. We found that ddC induced overexpression of both mRNA and proteins of GFAP and TNFα in the spinal dorsal horn. TNFα was colocalized with GFAP in the spinal dorsal horn and with NeuN in the DRG. Knockdown of TNFα with siRNA blocked the mechanical allodynia induced by ddC. Intrathecal administration of glial inhibitor or recombinant TNF soluble receptor, reversed mechanical allodynia induced by ddC. These results suggest that TNFα is involved in NRTI-induced neuropathic pain. PMID:21741472

Neuropathic pain, depressive symptoms, and C-reactive protein in sciatica patients.

PubMed

Uher, Tomas; Bob, Petr

2013-03-01

There is evidence that neuropathic pain component in low back pain (LBP) patients is associated with higher ratings of comorbidities such as depression and anxiety disorders. In line with current findings, the purpose of this clinical study is to examine a hypothesis regarding a relationship of neuropathic pain component, depression, and other psychopathological symptoms in a specific group of LBP patients with sciatica pain. With respect to findings that depression is related to inflammatory changes, and inflammatory mediators may play a role in neuropathic pain generation, we have assessed also serum C-reactive protein (CRP). Results of the present study show that increased neuropathic pain component in sciatica patients is associated with elevated levels of depression, anxiety, alexithymia, and serum CRP levels. In conclusion, results of this study indicate that CRP levels in sciatica patients are closely associated with neuropathic pain.

Botulinum Toxin for the Treatment of Neuropathic Pain

PubMed Central

Park, JungHyun; Park, Hue Jung

2017-01-01

Botulinum toxin (BoNT) has been used as a treatment for excessive muscle stiffness, spasticity, and dystonia. BoNT for approximately 40 years, and has recently been used to treat various types of neuropathic pain. The mechanism by which BoNT acts on neuropathic pain involves inhibiting the release of inflammatory mediators and peripheral neurotransmitters from sensory nerves. Recent journals have demonstrated that BoNT is effective for neuropathic pain, such as postherpetic neuralgia, trigeminal neuralgia, and peripheral neuralgia. The purpose of this review is to summarize the experimental and clinical evidence of the mechanism by which BoNT acts on various types of neuropathic pain and describe why BoNT can be applied as treatment. The PubMed database was searched from 1988 to May 2017. Recent studies have demonstrated that BoNT injections are effective treatments for post-herpetic neuralgia, diabetic neuropathy, trigeminal neuralgia, and intractable neuropathic pain, such as poststroke pain and spinal cord injury. PMID:28837075

Revised definition of neuropathic pain and its grading system: an open case series illustrating its use in clinical practice.

PubMed

Geber, Christian; Baumgärtner, Ulf; Schwab, Rainer; Müller, Harald; Stoeter, Peter; Dieterich, Marianne; Sommer, Clemens; Birklein, Frank; Treede, Rolf-Detlef

2009-10-01

The definition of neuropathic pain has recently been revised by an expert committee of the Neuropathic Pain Special Interest Group of the International Association for the Study of Pain (NeuPSIG) as "pain arising as direct consequence of a lesion or disease affecting the somatosensory system," and a grading system of "definite," "probable," and "possible" neuropathic pain has been introduced. This open case series of 5 outpatients (3 men, 2 women; mean age 48 +/- 12 years) demonstrates how the grading system can be applied, in combination with appropriate confirmatory testing, to diagnosis neuropathic conditions in clinical practice. The proposed grading system includes a dynamic algorithm that enhances the physician's ability to determine with a greater level of certainty whether a pain condition is neuropathic. Its clinical use should be further validated in prospective studies.

Predictors of pain medication selection among patients diagnosed with fibromyalgia.

PubMed

Boulanger, Luke; Wu, Ning; Chen, Shih-Yin; Nagar, Saurabh; Fraser, Kimberly; Bernauer, Mark J; Zhao, Zhenxiang; Zhao, Yang

2012-04-01

Several pharmacologic therapies have been recommended for managing fibromyalgia. However, the factors associated with each treatment initiation have not been well established. This study assessed factors that were associated with the use of duloxetine vs. other pain medications among patients with fibromyalgia. Administrative claims from a large, U.S. commercially insured population were analyzed using a retrospective cohort design. Patients with fibromyalgia who were 18 to 64 years old and initiated duloxetine vs. selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants (TCAs), venlafaxine, gabapentin, pregabalin, tramadol, or nontramadol opioids between January 1, 2007 and December 12, 2008 were selected. Treatment initiation was defined as no access to the same medication over the previous 90 days, with the most recent initiation date as the index date. All patients selected had at least one fibromyalgia diagnosis (ICD-9-CM: 729.1) in the 12 months prior to initiation of each study medication. Multiple logistic regression models were estimated to assess the predictors of initiating duloxetine vs. each of the other medications. The study included 117,305 patients with fibromyalgia (48 years of age on average; 76% women) who initiated duloxetine (n = 5,827), SSRIs (n = 8,620), TCAs (n = 5,424), venlafaxine (n = 2,038), gabapentin (n = 5,733), pregabalin (n = 11,152), tramadol (n = 7,312), or nontramadol opioids (n = 71,199). Common fibromyalgia-related comorbidities were low back pain (31% to 49%), osteoarthritis (14% to 21%), and sleep disturbance (10% to 15%). Controlling for demographic and clinical characteristics, patients who received pregabalin in the prior 12-month period were more likely to initiate duloxetine. Patients from other treatment cohorts, except for those in the pregabalin and nontramadol opioid cohorts, were more likely to re-initiate the same prior medication than to begin treatment with duloxetine. Other predictors of duloxetine initiation included history of rheumatoid and sleep disturbance. The presence of select comorbidities and prior use of certain medications were associated with the duloxetine initiation among working-age, commercially insured patients with fibromyalgia. © 2011 The Authors. Pain Practice © 2011 World Institute of Pain.

Prevalence and associations of neuropathic pain in a cohort of multi-ethnic Asian low back pain patients.

PubMed

Kew, Yueting; Tan, Cheng-Yin; Ng, Chong-Jing; Thang, Sue-Sien; Tan, Leong-Hooi; Khoo, Yvonne Khaii; Lim, Jun-Ni; Ng, Jia-Hui; Chan, Chris Yin-Wei; Kwan, Mun-Keong; Goh, Khean-Jin

2017-04-01

The prevalence of neuropathic low back pain differs in different ethnic populations. The aims of the study are to determine its frequency and associations in a multi-ethnic cohort of Asian low back pain patients. This was a cross-sectional study of low back patients seen at the University of Malaya Medical Centre, Kuala Lumpur, Malaysia. Neuropathic low back pain patients were identified using the painDETECT questionnaire and compared with non-neuropathic (unclear or nociceptive) low back pain patients, in terms of socio-demographic and clinical factors, pain severity (numerical pain rating scale, NPRS), disability (Roland Morris Disability Questionnaire, RMDQ), as well as anxiety and depression (Hospital Anxiety and Depression Scale, HADS). Of 210 patients, 26 (12.4%) have neuropathic low back pain. Neuropathic pain is associated with non-Chinese ethnicity, higher body mass index and pain radiation below the knee. Patients with neuropathic pain have significantly higher NPRS and RMDQ scores, and there are more subjects with anxiety on HADS. However, there are no differences between the groups in age, gender, pain duration or underlying diagnosis of low back pain. The prevalence of neuropathic low back pain in a multi-ethnic Malaysian cohort is lower than previously reported in other populations with possible differences between ethnic groups. It is associated with greater pain severity, disability and anxiety.

Treatments of traumatic neuropathic pain: a systematic review

PubMed Central

Yao, Chenglun; Zhou, Xijie; Zhao, Bin; Sun, Chao; Poonit, Keshav; Yan, Hede

2017-01-01

Traumatic neuropathic pain caused by traumatic neuroma has long been bothering both doctors and patients, the mechanisms of traumatic neuropathic pain are widely discussed by researchers and the treatment is challenging. Clinical treatment of painful neuroma is unclear. Numerous treatment modalities have been introduced by experts in this field. However, there is still no single standard recognized treatment. Different forms of treatments have been tested in animals and humans, but pharmacotherapies (antidepressants, antiepileptics) remain the basis of traumatic neuropathic pain management. For intractable cases, nerve stump transpositions into a muscle, vein or bone are seen as traditional surgical procedures which provide a certain degree of efficacy. Novel surgical techniques have emerged in recent years, such as tube guided nerve capping, electrical stimulation and adipose autograft have substantially enriched the abundance of the treatment for traumatic neuropathic pain. Several treatments show advantages over the others in terms of pain relief and prevention of neuroma formation, making it difficult to pick out a single modality as the reference. An effective and standardized treatment for traumatic neuropathic pain would provide better choice for researchers and clinical workers. In this review, we summarized current knowledge on the treatment of traumatic neuropathic pain, and found a therapeutic strategy for this intractable pain. We tried to provide a useful guideline for choosing the right modality in management of traumatic neuropathic pain. PMID:28915703

The neurosurgical treatment of neuropathic facial pain.

PubMed

Brown, Jeffrey A

2014-04-01

This article reviews the definition, etiology and evaluation, and medical and neurosurgical treatment of neuropathic facial pain. A neuropathic origin for facial pain should be considered when evaluating a patient for rhinologic surgery because of complaints of facial pain. Neuropathic facial pain is caused by vascular compression of the trigeminal nerve in the prepontine cistern and is characterized by an intermittent prickling or stabbing component or a constant burning, searing pain. Medical treatment consists of anticonvulsant medication. Neurosurgical treatment may require microvascular decompression of the trigeminal nerve. Copyright © 2014 Elsevier Inc. All rights reserved.

Recent developments in research and treatment for social phobia (social anxiety disorder).

PubMed

Cottraux, Jean

2005-01-01

This review covers three themes of research that brought fresh data useful for clinical practice in a handicapping anxiety disorder: social phobia. Recent findings deriving from basic biological research, new forms of psychological therapies, and recent psychopharmacology controlled trials are reviewed. The basic neuroimaging research suggests that greater activation of the amygdala to novel versus familiar faces may be an underlying trait marker for social phobia. Social phobia may represent a phenotype that expresses a genetically driven trait of social withdrawal, which may be related to infantile inhibited temperament (Kagan's syndrome). The development of virtual reality therapy as therapeutic tool for social phobia appeared promising in one controlled, but not randomized, study. A controlled study suggests that social phobias in children can be effectively treated with cognitive behavioural therapy. This represents an extension of the work done with adults. Venlafaxine appears an effective short-term treatment for social anxiety disorder in two controlled studies. A new compound, pregabalin, appeared clearly effective in a positive controlled study. This trial marks the advent of a new pharmacological lineage for social phobia. Both venlafaxine and pregabalin, however, have been studied in short-term studies. Longer follow-up and relapse prevention studies are warranted. Neuroimaging research points to a temperamental basis for social phobia. Virtual reality therapy is an emerging tool to carry out exposure treatment. Group cognitive behavioural therapy can be extended successfully to children. Venlafaxine and pregabalin have a proven short-term effectiveness in social phobia.

Emerging drugs for diabetic peripheral neuropathy and neuropathic pain.

PubMed

Papanas, Nikolaos; Ziegler, Dan

2016-12-01

Diabetic sensorimotor polyneuropathy (DSPN) is a common complication of diabetes. Areas covered: In this review, the authors discuss the emerging drugs for DSPN, which aim either at improving alleviation of neuropathic pain or addressing the putative mechanisms underlying diabetic neuropathy. Expert Opinion: Current treatment does not address the sensory deficits and pathogenesis underlying DSPN, so there is an unmet need for treatment options targeting the natural history of the condition. Some of these pathogenetic therapies have demonstrated clinically relevant improvements in neuropathic endpoints in recent randomised controlled trials. Since any effective analgesic monotherapy is known to induce a clinically meaningful response in only some 50% of the patients, there remains a substantial unmet need in patients with neuropathic pain. Advanced knowledge in the neurobiology of neuropathic pain and improved phenotypic profiling have led to a burst of research into novel pharmaceutical approaches. An array of promising molecular entities have reached the clinical stage of development, which should improve our therapeutic armamentarium in the fight against DSPN and neuropathic pain in the foreseeable future.

Oral 2-hydroxyoleic acid inhibits reflex hypersensitivity and open-field-induced anxiety after spared nerve injury.

PubMed

Avila-Martin, G; Galan-Arriero, I; Ferrer-Donato, A; Busquets, X; Gomez-Soriano, J; Escribá, P V; Taylor, J

2015-01-01

Recently, fatty acids have been shown to modulate sensory function in animal models of neuropathic pain. In this study, the antinociceptive effect of 2-hydroxyoleic acid (2-OHOA) was assessed following spared nerve injury (SNI) with reflex and cerebrally mediated behavioural responses. Initial antinociceptive behavioural screening of daily administration of 2-OHOA (400 mg/kg, p.o.) was assessed in Wistar rats by measuring hindlimb reflex hypersensitivity to von Frey and thermal plate stimulation up to 7 days after SNI, while its modulatory effect on lumbar spinal dorsal horn microglia reactivity was assessed with OX-42 immunohistochemistry. In vitro the effect of 2-OHOA (120 μM) on cyclooxygenase protein expression (COX-2/COX-1 ratio) in lipopolysaccharide-activated macrophage cells was tested with Western blot analysis. Finally, the effects of 2-OHOA treatment on the place escape aversion paradigm (PEAP) and the open-field-induced anxiety test were tested at 21 days following nerve injury compared with vehicle-treated sham and pregabalin-SNI (30 mg/kg, p.o.) control groups. Oral 2-OHOA significantly reduced ipsilateral mechanical and thermal hypersensitivity up to 7 days after SNI. Additionally 2-OHOA decreased the COX-2/COX-1 ratio in lipopolysaccharide-activated macrophage cells and OX-42 expression within the ipsilateral lumbar spinal dorsal horn 7 days after SNI. 2-OHOA significantly restored inner-zone exploration in the open-field test compared with the vehicle-treated sham group at 21 days after SNI. Oral administration of the modified omega 9 fatty acid, 2-OHOA, mediates antinociception and prevents open-field-induced anxiety in the SNI model in Wistar rats, which is mediated by an inhibition of spinal dorsal horn microglia activation. © 2014 European Pain Federation - EFIC®

The effect of exercise frequency on neuropathic pain and pain-related cellular reactions in the spinal cord and midbrain in a rat sciatic nerve injury model

PubMed Central

Sumizono, Megumi; Otsuka, Shotaro; Terashi, Takuto; Nakanishi, Kazuki; Ueda, Koki; Takada, Seiya; Kikuchi, Kiyoshi

2018-01-01

Background Exercise regimens are established methods that can relieve neuropathic pain. However, the relationship between frequency and intensity of exercise and multiple cellular responses of exercise-induced alleviation of neuropathic pain is still unclear. We examined the influence of exercise frequency on neuropathic pain and the intracellular responses in a sciatic nerve chronic constriction injury (CCI) model. Materials and methods Rats were assigned to four groups as follows: CCI and high-frequency exercise (HFE group), CCI and low-frequency exercise (LFE group), CCI and no exercise (No-Ex group), and naive animals (control group). Rats ran on a treadmill, at a speed of 20 m/min, for 30 min, for 5 (HFE) or 3 (LFE) days a week, for a total of 5 weeks. The 50% withdrawal threshold was evaluated for mechanical sensitivity. The activation of glial cells (microglia and astrocytes), expression of brain-derived neurotrophic factor (BDNF) and μ-opioid receptor in the spinal dorsal horn and endogenous opioid in the midbrain were examined using immunohistochemistry. Opioid receptor antagonists (naloxone) were administered using intraperitoneal injection. Results The development of neuropathic pain was related to the activation of glial cells, increased BDNF expression, and downregulation of the μ-opioid receptor in the ipsilateral spinal dorsal horn. In the No-Ex group, neuropathic pain showed the highest level of mechanical hypersensitivity at 2 weeks, which improved slightly until 5 weeks after CCI. In both exercise groups, the alleviation of neuropathic pain was accelerated through the regulation of glial activation, BDNF expression, and the endogenous opioid system. The expression of BDNF and endogenous opioid in relation to exercise-induced alleviation of neuropathic pain differed in the HFE and LFE groups. The effects of exercise-induced alleviation of mechanical hypersensitivity were reversed by the administration of naloxone. Conclusion The LFE and HFE program reduced neuropathic pain. Our findings indicated that aerobic exercise-induced alleviated neuropathic pain through the regulation of glial cell activation, expression of BDNF in the ipsilateral spinal dorsal horn, and the endogenous opioid system. PMID:29445295

Expression profiling of genes modulated by minocycline in a rat model of neuropathic pain

PubMed Central

2014-01-01

Background The molecular mechanisms underlying neuropathic pain are constantly being studied to create new opportunities to prevent or alleviate neuropathic pain. The aim of our study was to determine the gene expression changes induced by sciatic nerve chronic constriction injury (CCI) that are modulated by minocycline, which can effectively diminish neuropathic pain in animal studies. The genes associated with minocycline efficacy in neuropathic pain should provide insight into the etiology of neuropathic pain and identify novel therapeutic targets. Results We screened the ipsilateral dorsal part of the lumbar spinal cord of the rat CCI model for differentially expressed genes. Out of 22,500 studied transcripts, the abundance levels of 93 transcripts were altered following sciatic nerve ligation. Percentage analysis revealed that 54 transcripts were not affected by the repeated administration of minocycline (30 mg/kg, i.p.), but the levels of 39 transcripts were modulated following minocycline treatment. We then selected two gene expression patterns, B1 and B2. The first transcription pattern, B1, consisted of 10 mRNA transcripts that increased in abundance after injury, and minocycline treatment reversed or inhibited the effect of the injury; the B2 transcription pattern consisted of 7 mRNA transcripts whose abundance decreased following sciatic nerve ligation, and minocycline treatment reversed the effect of the injury. Based on the literature, we selected seven genes for further analysis: Cd40, Clec7a, Apobec3b, Slc7a7, and Fam22f from pattern B1 and Rwdd3 and Gimap5 from pattern B2. Additionally, these genes were analyzed using quantitative PCR to determine the transcriptional changes strongly related to the development of neuropathic pain; the ipsilateral DRGs (L4-L6) were also collected and analyzed in these rats using qPCR. Conclusion In this work, we confirmed gene expression alterations previously identified by microarray analysis in the spinal cord and analyzed the expression of selected genes in the DRG. Moreover, we reviewed the literature to illustrate the relevance of these findings for neuropathic pain development and therapy. Further studies are needed to elucidate the roles of the individual genes in neuropathic pain and to determine the therapeutic role of minocycline in the rat neuropathic pain model. PMID:25038616

Tramadol and propentofylline coadministration exerted synergistic effects on rat spinal nerve ligation-induced neuropathic pain.

PubMed

Zhang, Jin; Wu, Dan; Xie, Cheng; Wang, Huan; Wang, Wei; Zhang, Hui; Liu, Rui; Xu, Li-Xian; Mei, Xiao-Peng

2013-01-01

Neuropathic pain is an intractable clinical problem. Drug treatments such as tramadol have been reported to effectively decrease neuropathic pain by inhibiting the activity of nociceptive neurons. It has also been reported that modulating glial activation could also prevent or reverse neuropathic pain via the administration of a glial modulator or inhibitor, such as propentofylline. Thus far, there has been no clinical strategy incorporating both neuronal and glial participation for treating neuropathic pain. Therefore, the present research study was designed to assess whether coadministration of tramadol and propentofylline, as neuronal and glial activation inhibitors, respectively, would exert a synergistic effect on the reduction of rat spinal nerve ligation (SNL)-induced neuropathic pain. Rats underwent SNL surgery to induce neuropathic pain. Pain behavioral tests were conducted to ascertain the effect of drugs on SNL-induced mechanical allodynia with von-Frey hairs. Proinflammatory factor interleukin-1β (IL-1β) expression was also detected by Real-time RT-PCR. Intrathecal tramadol and propentofylline administered alone relieved SNL-induced mechanical allodynia in a dose-dependent manner. Tramadol and propentofylline coadministration exerted a more potent effect in a synergistic and dose dependent manner than the intrathecal administration of either drug alone. Real-time RT-PCR demonstrated IL-1β up-expression in the ipsilateral spinal dorsal horn after the lesion, which was significantly decreased by tramadol and propentofylline coadministration. Inhibiting proinflammatory factor IL-1β contributed to the synergistic effects of tramadol and propentofylline coadministration on rat peripheral nerve injury-induced neuropathic pain. Thus, our study provided a rationale for utilizing a novel strategy for treating neuropathic pain by blocking the proinflammatory factor related pathways in the central nervous system.

Combination Drug Therapy for Pain following Chronic Spinal Cord Injury

PubMed Central

Hama, Aldric; Sagen, Jacqueline

2012-01-01

A number of mechanisms have been elucidated that maintain neuropathic pain due to spinal cord injury (SCI). While target-based therapeutics are being developed based on elucidation of these mechanisms, treatment for neuropathic SCI pain has not been entirely satisfactory due in part to the significant convergence of neurological and inflammatory processes that maintain the neuropathic pain state. Thus, a combination drug treatment strategy, wherein several pain-related mechanism are simultaneously engaged, could be more efficacious than treatment against individual mechanisms alone. Also, by engaging several targets at once, it may be possible to reduce the doses of the individual drugs, thereby minimizing the potential for adverse side effects. Positive preclinical and clinical studies have demonstrated improved efficacy of combination drug treatment over single drug treatment in neuropathic pain of peripheral origin, and perhaps such combinations could be utilized for neuropathic SCI pain. At the same time, there are mechanisms that distinguish SCI from peripheral neuropathic pain, so novel combination therapies will be needed. PMID:22550581

Deep brain stimulation of the dorsal anterior cingulate cortex for the treatment of chronic neuropathic pain.

PubMed

Russo, Jennifer F; Sheth, Sameer A

2015-06-01

Chronic neuropathic pain is estimated to affect 3%-4.5% of the worldwide population. It is associated with significant loss of productive time, withdrawal from the workforce, development of mood disorders such as depression and anxiety, and disruption of family and social life. Current medical therapeutics often fail to adequately treat chronic neuropathic pain. Deep brain stimulation (DBS) targeting subcortical structures such as the periaqueductal gray, the ventral posterior lateral and medial thalamic nuclei, and the internal capsule has been investigated for the relief of refractory neuropathic pain over the past 3 decades. Recent work has identified the dorsal anterior cingulate cortex (dACC) as a new potential neuromodulation target given its central role in cognitive and affective processing. In this review, the authors briefly discuss the history of DBS for chronic neuropathic pain in the United States and present evidence supporting dACC DBS for this indication. They review existent literature on dACC DBS and summarize important findings from imaging and neurophysiological studies supporting a central role for the dACC in the processing of chronic neuropathic pain. The available neurophysiological and empirical clinical evidence suggests that dACC DBS is a viable therapeutic option for the treatment of chronic neuropathic pain and warrants further investigation.

Interference with work in fibromyalgia: effect of treatment with pregabalin and relation to pain response.

PubMed

Straube, Sebastian; Moore, R Andrew; Paine, Jocelyn; Derry, Sheena; Phillips, Ceri J; Hallier, Ernst; McQuay, Henry J

2011-06-03

Clinical trials in chronic pain often collect information about interference with work as answers to component questions of commonly used questionnaires but these data are not normally analysed separately. We performed a meta-analysis of individual patient data from four large trials of pregabalin for fibromyalgia lasting 8-14 weeks. We analysed data on interference with work, inferred from answers to component questions of Fibromyalgia Impact Questionnaire (FIQ), Short Form 36 Health Survey, Sheehan Disability Scale, and Multidimensional Assessment of Fatigue, including "How many days in the past week did you miss work, including housework, because of fibromyalgia?" from FIQ. Analyses were performed according to randomised treatment group (pregabalin 150-600 mg daily or placebo), pain improvement (0-10 numerical pain rating scale scores at trial beginning vs. end), and end of trial pain state (100 mm visual analogue pain scale [VAS]). Comparing treatment group average outcomes revealed modest improvement over the duration of the trials, more so with active treatment than with placebo. For the 'work missed' question from FIQ the change for patients on placebo was from 2.2 (standard deviation [SD] 2.3) days of work lost per week at trial beginning to 1.9 (SD 2.1) days lost at trial end (p < 0.01). For patients on 600 mg pregabalin the change was from 2.1 (SD 2.2) days to 1.6 (SD 2.0) days (p < 0.001). However, the change in days of work lost was substantial in patients with a good pain response: from 2.0 (SD 2.2) days to 0.97 (SD 1.6) days (p < 0.0001) for those experiencing >/= 50% pain improvement and from 1.9 (SD 2.2) days to 0.73 (SD 1.4) days (p < 0.0001) for those achieving a low level of pain at trial end (<30 mm on the VAS). Patients achieving both >/= 50% pain improvement and a pain score <30 mm on the VAS had the largest improvement, from 2.0 (SD 2.2) days to 0.60 (SD 1.3) days (p < 0.0001). Analysing answers to the other questions yielded qualitatively similar results. Effective pain treatment goes along with benefit regarding work. A reduction in time off work >1 day per week can be achieved in patients with good pain responses.

Effect of the spider toxin Tx3-3 on spinal processing of sensory information in naive and neuropathic rats: an in vivo electrophysiological study.

PubMed

Dalmolin, Gerusa D; Bannister, Kirsty; Gonçalves, Leonor; Sikandar, Shafaq; Patel, Ryan; Cordeiro, Marta do Nascimento; Gomez, Marcus Vinícius; Ferreira, Juliano; Dickenson, Anthony H

2017-07-01

Drugs that counteract nociceptive transmission in the spinal dorsal horn preferentially after nerve injury are being pursued as possible neuropathic pain treatments. In a previous behavioural study, the peptide toxin Tx3-3, which blocks P/Q- and R-type voltage-gated calcium channels, was effective in neuropathic pain models. In the present study, we aimed to investigate the effect of Tx3-3 on dorsal horn neuronal responses in rats under physiological conditions and neuropathic pain condition induced by spinal nerve ligation (SNL). In vivo electrophysiological recordings of dorsal horn neuronal response to electrical and natural (mechanical and thermal) stimuli were made in rats under normal physiological state (naive rats) or after the SNL model of neuropathic pain. Tx3-3 (0.3-100 pmol/site) exhibited greater inhibitory effect on electrical-evoked neuronal response of SNL rats than naive rats, inhibiting nociceptive C-fibre and Aδ-fibre responses only in SNL rats. The wind-up of neurones, a measurement of spinal cord hyperexcitability, was also more susceptible to a dose-related inhibition by Tx3-3 after nerve injury. Moreover, Tx3-3 exhibited higher potency to inhibit mechanical- and thermal-evoked neuronal response in conditions of neuropathy. Tx3-3 mediated differential inhibitory effect under physiological and neuropathic conditions, exhibiting greater potency in conditions of neuropathic pain.

MiR-19a targets suppressor of cytokine signaling 1 to modulate the progression of neuropathic pain.

PubMed

Wang, Conghui; Jiang, Qi; Wang, Min; Li, Dong

2015-01-01

We aimed to investigate whether miR-19a is associated with neuropathic pain and elucidate the underlying regulatory mechanism. We established a neuropathic pain model of bilateral chronic constriction injury (bCCI). Then bCCI rats were injected with mo-miR-19a, siR-SOCS1 or blank expression vector through a microinjection syringe via an intrathecal catheter on 3 day before surgery and after surgery. Behavioral tests, such as mechanical allodynia, thermal hyperalgesia and acetone induced cold allodynia, were performed to evaluate the pain threshold. Besides, quantitative real-time polymerase chain reaction (qRT-PCR) was performed to determine the expression of miR-19a and western blotting was carried out to measure the expression of SOCS1. miR-19a expression levels were markedly increased in neuropathic pain models. Moreover, miR-19a significantly attenuated mechanical allodynia and thermal hyperalgesia, and similar results were obtained after knockdown of SOCS1 expression. However, miR-19a markedly increased the times that the rats appeared a sign of cold allodynia, and knockdown of SOCS1 expression had similar effects. Besides, the results of bioinformatics analysis and western blotting analysis were all confirmed that SOCS1 was a direct target of miR-19a in neuropathic pain models. Our finding indicate that SOCS1 is a direct target of miR-19a in neuropathic pain rats and miR-19a may play a critical role in regulating of neuropathic pain via targeting SOCS1.

Analgesic effect of piracetam on peripheral neuropathic pain induced by chronic constriction injury of sciatic nerve in rats.

PubMed

Mehta, Ashish K; Bhati, Yogendra; Tripathi, Chakra D; Sharma, Krishna K

2014-08-01

Despite immense advances in the treatment strategies, management of neuropathic pain remains unsatisfactory. Piracetam is a prototype of nootropic drugs, used to improve cognitive impairment. The present study was designed to investigate the effect of piracetam on peripheral neuropathic pain in rats. Neuropathic pain was induced by the chronic constriction injury of the sciatic nerve. Following this, piracetam was intraperitoneally administered for 2 weeks in doses of 50, 100 and 200 mg/kg, and pain was assessed by employing the behavioural tests for thermal hyperalgesia (hot plate and tail flick tests) and cold allodynia (acetone test). After the induction of neuropathic pain, significant development of thermal hyperalgesia and cold allodynia was observed. The administration of piracetam (50 mg/kg) did not have any significant effect on all the behavioural tests. Further, piracetam (100 mg/kg) also had no effect on the hot plate and tail flick tests; however it significantly decreased the paw withdrawal duration in the acetone test. Piracetam in a dose of 200 mg/kg significantly modulated neuropathic pain as observed from the increased hot plate and tail flick latencies, and decreased paw withdrawal duration (in acetone test). Therefore, the present study suggests the potential use of piracetam in the treatment of neuropathic pain, which merits further clinical investigation.

Tramadol reduces anxiety-related and depression-associated behaviors presumably induced by pain in the chronic constriction injury model of neuropathic pain in rats.

PubMed

Caspani, Ombretta; Reitz, Marie-Céline; Ceci, Angelo; Kremer, Andreas; Treede, Rolf-Detlef

2014-09-01

Depression and anxiety are common comorbidities of neuropathic pain (NP). Pharmacological preclinical studies on NP have given abundant information on the effects of drugs on reflex measures of stimulus-evoked pain. However, few preclinical studies focus on relief of comorbidities evoked by NP. In this study, we investigated the effects of tramadol on nociceptive reflex, depression-associated and anxiety-related behaviors in a NP model in rats. We used chronic constriction injury (CCI) of the sciatic nerve as an animal model of neuropathic pain. We performed electronic von Frey tests (evF) to measure mechanical sensitivity, elevated plus maze tests (EPM) to record anxiety-related behaviors and forced swimming tests (FST) to evaluate depression-associated behaviors. In the evF, CCI rats showed a decrease of 82% of the paw withdrawal threshold (PWT) compared to sham (P<0.001). Tramadol increased the PWT by 336% in CCI rats (P<0.001) and by 16% in sham (P<0.05). On the EPM, CCI rats spent 45% less time than sham on the open arms of the maze (P<0.05). Tramadol increased the time spent on the open arms of CCI rats by 67% (P<0.05) and had no significant effect on sham. During the FST, CCI rats showed 28% longer immobility than sham (P<0.01). Tramadol reduced the immobility time in CCI rats by 22% (P<0.001), while having no effect on sham. Tramadol reversed the changes in mechanical sensitivity as well as anxiety-related and depression-associated behaviors that are caused by injury of the sciatic nerve with only minor effects in the absence of injury. These data suggest that tramadol relieves chronic pain and its indirect consequences and comorbidities, and that this study also is a model for pharmacological studies seeking to investigate the effect of drugs on the major disabling symptoms of NP. Copyright © 2014 Elsevier Inc. All rights reserved.

Intravenous Acetaminophen Does Not Decrease Persistent Surgical Pain After Cardiac Surgery.

PubMed

Turan, Alparslan; Karimi, Nika; Zimmerman, Nicole M; Mick, Stephanie L; Sessler, Daniel I; Mamoun, Negmeldeen

2017-12-01

The authors investigated the hypothesis that perioperative acetaminophen reduces incisional pain at 30 and 90 days. This was a prospective, randomized, double-blind trial. Tertiary-care hospital (single center) cardiac surgery unit. Patients undergoing cardiac surgery via median sternotomy. Patients were assigned randomly to intravenous (IV) acetaminophen or IV placebo. Patients were given 4 doses of 1 g of IV acetaminophen or an equal volume of saline placebo over 15 minutes every 6 hours for 24 hours starting in the operating room after sternal closure. Study participants were assessed by phone for incisional pain severity 30 and 90 days after surgery. Those reporting any incisional pain were asked to complete the Neuropathic Pain Questionnaire-Short Form and the modified Brief Pain Inventory. Patients were compared on 30- and 90-day incisional pain severity using separate multivariable linear regression models. IV acetaminophen had no effect on 30- and 90-day incisional pain, with an estimated difference in means (confidence interval) of 0.06 (-0.87 to 0.99) at 30 days (p = 0.88) and 0.07 (-0.71 to 0.86) at 90 days (p = 0.83). Low pain severity, neuropathic pain, and interference at both 30 and 90 days after surgery, regardless of treatment group, were observed. IV acetaminophen did not reduce the incidence or intensity of incisional pain at 30 days and 90 days after surgery. Copyright © 2017 Elsevier Inc. All rights reserved.

Orofacial neuropathic pain induced by oxaliplatin: downregulation of KCNQ2 channels in V2 trigeminal ganglion neurons and treatment by the KCNQ2 channel potentiator retigabine.

PubMed

Ling, Jennifer; Erol, Ferhat; Viatchenko-Karpinski, Viacheslav; Kanda, Hirosato; Gu, Jianguo G

2017-01-01

Neuropathic pain induced by chemotherapy drugs such as oxaliplatin is a dose-limiting side effect in cancer treatment. The mechanisms underlying chemotherapy-induced neuropathic pain are not fully understood. KCNQ2 channels are low-threshold voltage-gated K+ channels that play a role in controlling neuronal excitability. Downregulation of KCNQ2 channels has been proposed to be an underlying mechanism of sensory hypersensitivity that leads to neuropathic pain. However, it is currently unknown whether KCNQ channels may be downregulated by chemotherapy drugs in trigeminal ganglion neurons to contribute to the pathogenesis of chemotherapy-induced orofacial neuropathic pain. In the present study, mechanical sensitivity in orofacial regions is measured using the operant behavioral test in rats treated with oxaliplatin. Operant behaviors in these animals show the gradual development of orofacial neuropathic pain that manifests with orofacial mechanical allodynia. Immunostaining shows strong KCNQ2 immunoreactivity in small-sized V2 trigeminal ganglion neurons in controls, and the numbers of KCNQ2 immunoreactivity positive V2 trigeminal ganglion neurons are significantly reduced in oxaliplatin-treated animals. Immunostaining is also performed in brainstem and shows strong KCNQ2 immunoreactivity at the trigeminal afferent central terminals innervating the caudal spinal trigeminal nucleus (Vc) in controls, but the KCNQ2 immunoreactivity intensity is significantly reduced in oxaliplatin-treated animals. We further show with the operant behavioral test that oxaliplatin-induced orofacial mechanical allodynia can be alleviated by the KCNQ2 potentiator retigabine. Taken together, these findings suggest that KCNQ2 downregulation may be a cause of oxaliplatin-induced orofacial neuropathic pain and KCNQ2 potentiators may be useful for alleviating the neuropathic pain.

Fyn kinase-mediated phosphorylation of NMDA receptor NR2B subunit at Tyr1472 is essential for maintenance of neuropathic pain.

PubMed

Abe, Tetsuya; Matsumura, Shinji; Katano, Tayo; Mabuchi, Tamaki; Takagi, Kunio; Xu, Li; Yamamoto, Akitsugu; Hattori, Kotaro; Yagi, Takeshi; Watanabe, Masahiko; Nakazawa, Takanobu; Yamamoto, Tadashi; Mishina, Masayoshi; Nakai, Yoshihide; Ito, Seiji

2005-09-01

Despite abundant evidence implicating the importance of N-methyl-D-aspartate (NMDA) receptors in the spinal cord for pain transmission, the signal transduction coupled to NMDA receptor activation is largely unknown for the neuropathic pain state that lasts over periods of weeks. To address this, we prepared mice with neuropathic pain by transection of spinal nerve L5. Wild-type, NR2A-deficient, and NR2D-deficient mice developed neuropathic pain; in addition, phosphorylation of NR2B subunits of NMDA receptors at Tyr1472 was observed in the superficial dorsal horn of the spinal cord 1 week after nerve injury. Neuropathic pain and NR2B phosphorylation at Tyr1472 were attenuated by the NR2B-selective antagonist CP-101,606 and disappeared in mice lacking Fyn kinase, a Src-family tyrosine kinase. Concomitant with the NR2B phosphorylation, an increase in neuronal nitric oxide synthase activity was visualized in the superficial dorsal horn of neuropathic pain mice by NADPH diaphorase histochemistry. Electron microscopy showed that the phosphorylated NR2B was localized at the postsynaptic density in the spinal cord of mice with neuropathic pain. Indomethacin, an inhibitor of prostaglandin (PG) synthesis, and PGE receptor subtype EP1-selective antagonist reduced the NR2B phosphorylation in these mice. Conversely, EP1-selective agonist stimulated Fyn kinase-dependent nitric oxide formation in the spinal cord. The present study demonstrates that Tyr1472 phosphorylation of NR2B subunits by Fyn kinase may have dual roles in the retention of NMDA receptors in the postsynaptic density and in activation of nitric oxide synthase, and suggests that PGE2 is involved in the maintenance of neuropathic pain via the EP1 subtype.

Therapeutic Drug Monitoring of the Newer Anti-Epilepsy Medications

PubMed Central

Krasowski, Matthew D.

2010-01-01

In the past twenty years, 14 new antiepileptic drugs have been approved for use in the United States and/or Europe. These drugs are eslicarbazepine acetate, felbamate, gabapentin, lacosamide, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, rufinamide, stiripentol, tiagabine, topiramate, vigabatrin and zonisamide. In general, the clinical utility of therapeutic drug monitoring has not been established in clinical trials for these new anticonvulsants, and clear guidelines for drug monitoring have yet to be defined. The antiepileptic drugs with the strongest justifications for drug monitoring are lamotrigine, oxcarbazepine, stiripentol, and zonisamide. Stiripentol and tiagabine are strongly protein bound and are candidates for free drug monitoring. Therapeutic drug monitoring has lower utility for gabapentin, pregabalin, and vigabatrin. Measurement of salivary drug concentrations has potential utility for therapeutic drug monitoring of lamotrigine, levetiracetam, and topiramate. Therapeutic drug monitoring of the new antiepileptic drugs will be discussed in managing patients with epilepsy. PMID:20640233

Ion channel blockers for the treatment of neuropathic pain.

PubMed

Colombo, Elena; Francisconi, Simona; Faravelli, Laura; Izzo, Emanuela; Pevarello, Paolo

2010-05-01

Neuropathic pain, a severe chronic pain condition characterized by a complex pathophysiology, is a largely unmet medical need. Ion channels, which underlie cell excitability, are heavily implicated in the biological mechanisms that generate and sustain neuropathic pain. This review highlights the biological evidence supporting the involvement of voltage-, proton- and ligand-gated ion channels in the neuropathic pain setting. Ion channel modulators at different research or development stages are reviewed and referenced. Ion channel modulation is one of the main avenues to achieve novel, improved neuropathic pain treatments. Voltage-gated sodium and calcium channel and glutamate receptor modulators are likely to produce new, improved agents in the future. Rationally targeting subtypes of known ion channels, tackling recently discovered ion channel targets or combining drugs with different mechanism of action will be primary sources of new drugs in the longer term.

Linguistic adaptation, validation and comparison of 3 routinely used neuropathic pain questionnaires.

PubMed

Li, Jun; Feng, Yi; Han, Jisheng; Fan, Bifa; Wu, Dasheng; Zhang, Daying; Du, Dongping; Li, Hui; Lim, Jian; Wang, Jiashuang; Jin, Yi; Fu, Zhijian

2012-01-01

Neuropathic pain questionnaires are efficient diagnostic tools for neuropathic pain and play an important role in neuropathic pain epidemiologic studies in China. No comparison data was available in regards to the Leeds Assessment of Neuropathic Symptoms and Signs (LANSS), the Neuropathic Pain Questionnaire (NPQ) and ID Pain within and among the same population. To achieve a linguistic adaptation, validation, and comparison of Chinese versions of the 3 neuropathic pain questionnaires (LANSS, NPQ and ID Pain). A nonrandomized, controlled, prospective, multicenter trial. Ten pain centers in China. Two forward translations followed by comparison and reconciliation of the translations. Comparison of the 2 backward translations with the original version was made to establish consistency and accuracy of the translations. Pilot testing and pain specialists' evaluations were also required. A total of 140 patients were enrolled in 10 centers throughout China: 70 neuropathic pain patients and 70 nociceptive pain patients. Reliability (Cronbach's alpha coefficients and Guttman split-half coefficients) and validity (sensitivity, specificity, positive and negative predictive values, receiver operating characteristic [ROC] curves and the area under the ROC curves) of the 3 questionnaires were determined. ROC curves and the area under the ROC curves of the 3 questionnaires were also compared. Chinese versions of LANSS, NPQ and ID Pain had a good reliability (Cronbach's alpha coefficients and Guttman split-half coefficients were greater than 0.7). Sensitivity, specificity, positive and negative predictive values of the Chinese versions of LANSS and ID Pain were considerably high ( > 80%). The area under the ROC curves of LANSS and ID Pain was significantly higher than that of NPQ (P < 0.05). There was no statistically significant difference between the area under the ROC curves of LANSS and ID Pain (P > 0.05). The study was based on patients with a high school degree or above, which limited the application of the 3 neuropathic pain questionnaires to patients with lower educational levels. The Chinese versions of LANSS and ID Pain developed and validated by this study can be used as a diagnostic tool in differentiating neuropathic pain in patients whose native language is Chinese (Mandarin).

The prevalence of neuropathic pain is high after treatment for breast cancer: a systematic review.

PubMed

Ilhan, Emre; Chee, Edwin; Hush, Julia; Moloney, Niamh

2017-11-01

Pain is common, but often poorly managed after breast cancer treatment. Screening questionnaires and the Neuropathic Pain Special Interest Group (NeuPSIG) criteria are 2 clinical approaches used to determine whether pain has neuropathic components, which may enable better pain management. The aims of this review were (1) to synthesise data from the literature on neuropathic pain prevalence in women after breast cancer treatment; (2) to investigate whether the prevalence of neuropathic pain differed between studies using screening questionnaires and the NeuPSIG criteria. We searched for studies that administered a validated neuropathic pain screening questionnaire and/or the NeuPSIG criteria to women treated for early-stage (I-III) breast cancer. Thirteen studies using screening questionnaires (N = 3792) and 3 studies using components of the NeuPSIG criteria (N = 621) were included. Meta-analyses were conducted for questionnaire data but not for NeuPSIG criteria data because of inadequate homogeneity. Among all participants treated for early-stage breast cancer, pooled prevalence estimates (95% confidence interval) ranged between 14.2% (8.3-21.4) and 27.2% (24.7-88.4) for studies using screening questionnaires; studies using NeuPSIG criteria reported prevalence rates from 24.1% to 31.3%. Among those who reported pain after treatment, the pooled prevalence estimate (95% confidence interval) of neuropathic pain from screening questionnaires ranged from 32.6% (24.2-41.6) to 58.2% (24.7-88.4); studies using NeuPSIG criteria reported prevalence rates from 29.5% to 57.1%. These prevalence estimates are higher than those reported for other types of cancer, and emphasise the need to assess the contribution of neuropathic pain after breast cancer treatment. PROSPERO registration CRD42015029987.

Differential pain modulation in patients with peripheral neuropathic pain and fibromyalgia.

PubMed

Gormsen, Lise; Bach, Flemming W; Rosenberg, Raben; Jensen, Troels S

2017-12-29

Background The definition of neuropathic pain has recently been changed by the International Association for the Study of Pain. This means that conditions such as fibromyalgia cannot, as sometimes discussed, be included in the neuropathic pain conditions. However, fibromyalgia and peripheral neuropathic pain share common clinical features such as spontaneous pain and hypersensitivity to external stimuli. Therefore, it is of interest to directly compare the conditions. Material and methods In this study we directly compared the pain modulation in neuropathic pain versus fibromyalgia by recording responses to a cold pressor test in 30 patients with peripheral neuropathic pain, 28 patients with fibromyalgia, and 26 pain-free age-and gender-matched healthy controls. Patients were asked to rate their spontaneous pain on a visual analog scale (VAS (0-100 mm) immediately before and immediately after the cold pressor test. Furthermore the duration (s) of extremity immersion in cold water was used as a measure of the pain tolerance threshold, and the perceived pain intensity at pain tolerance on the VAS was recorded on the extremity in the water after the cold pressor test. In addition, thermal (thermo tester) and mechanical stimuli (pressure algometer) were used to determine sensory detection, pain detection, and pain tolerance thresholds in different body parts. All sensory tests were done by the same examiner, in the same room, and with each subject in a supine position. The sequence of examinations was the following: (1) reaction time, (2) pressure thresholds, (3) thermal thresholds, and (4) cold pressor test. Reaction time was measured to ensure that psychomotoric inhibitions did not influence pain thresholds. Results Pain modulation induced by a cold pressor test reduced spontaneous pain by 40% on average in neuropathic pain patients, but increased spontaneous pain by 2.6% in fibromyalgia patients. This difference between fibromyalgia and neuropathic pain patients was significant (P < 0.002). Fibromyalgia patients withdrew their extremity from the cold water significantly earlier than neuropathic pain patients and healthy controls; however, they had a higher perceived pain intensity on the VAS than neuropathic pain patients and control subjects. Furthermore, neuropathic pain patients had a localized hypersensitivity to mechanical and thermal stimuli in the affected area of the body. In contrast, fibromyalgia patients displayed a general hypersensitivity to mechanical and thermal stimuli when the stimuli were rated by the VAS, and hypersensitivity to some of the sensory stimuli. Conclusions These findings are the first to suggest that a conditioning stimulus evoked by a cold pressor test reduced spontaneous ongoing pain in patients with peripheral neuropathic pain, but not in fibromyalgia patients when directly compared. The current study supports the notion that fibromyalgia and neuropathic pain are distinct pain conditions with separate sensory patterns and dysfunctions in pain-modulating networks. Fibromyalgia should therefore not, as sometimes discussed, be included in NP conditions. Implications On the basis of the findings, it is of interest to speculate on the underlying mechanisms. The results are consistent with the idea that peripheral neuropathic pain is primarily driven from damaged nerve endings in the periphery, while chronic fibromyalgia pain may be a central disorder with increased activity in pain-facilitating systems.

A longitudinal study of painless and painful intercostobrachial neuropathy after breast cancer surgery.

PubMed

La Cesa, S; Sammartino, P; Mollica, C; Cascialli, G; Cruccu, G; Truini, A; Framarino-Dei-Malatesta, M

2018-04-29

Intercostobrachial neuropathy, often resulting in neuropathic pain, is a common complication of breast cancer surgery. In this 1-year longitudinal study, we aimed at seeking information on the frequency, clinical features, and course of painless and painful intercostobrachial neuropathy. We enrolled 40 women previously undergoing breast cancer surgery. In these patients, we collected, at 3, 6 and 12 months after surgery, clinical and quantitative sensory testing (QST) variables to diagnose intercostobrachial neuropathy, DN4 questionnaire to identify neuropathic pain, Neuropathic Pain Symptom Inventory to assess the different neuropathic pain symptoms, the Beck Depression Inventory to assess depressive symptoms, and SF36 to assess quality of life and Patient Global Impression of Change. Clinical and QST examination showed an intercostobrachial neuropathy in 23 patients (57.5%). Out of the 23 patients, five experienced neuropathic pain, as assessed with clinical examination and DN4. Axillary surgery clearance was associated with an increased risk of intercostobrachial neuropathy. Whereas sensory disturbances improved during the 1-year observation, neuropathic pain did not. Nevertheless, Beck Depression Inventory, SF36, and the Patient Global Impression of Change scores significantly improved over time. Our study shows that although intercostobrachial neuropathy is a common complication of breast cancer surgery, neuropathic pain affects only a minor proportion of patients. After 1 year, sensory disturbances partially improve and have only a mild impact on mood and quality of life.

MiR-19a targets suppressor of cytokine signaling 1 to modulate the progression of neuropathic pain

PubMed Central

Wang, Conghui; Jiang, Qi; Wang, Min; Li, Dong

2015-01-01

Purpose: we aimed to investigate whether miR-19a is associated with neuropathic pain and elucidate the underlying regulatory mechanism. Methods: We established a neuropathic pain model of bilateral chronic constriction injury (bCCI). Then bCCI rats were injected with mo-miR-19a, siR-SOCS1 or blank expression vector through a microinjection syringe via an intrathecal catheter on 3 day before surgery and after surgery. Behavioral tests, such as mechanical allodynia, thermal hyperalgesia and acetone induced cold allodynia, were performed to evaluate the pain threshold. Besides, quantitative real-time polymerase chain reaction (qRT-PCR) was performed to determine the expression of miR-19a and western blotting was carried out to measure the expression of SOCS1. Results: miR-19a expression levels were markedly increased in neuropathic pain models. Moreover, miR-19a significantly attenuated mechanical allodynia and thermal hyperalgesia, and similar results were obtained after knockdown of SOCS1 expression. However, miR-19a markedly increased the times that the rats appeared a sign of cold allodynia, and knockdown of SOCS1 expression had similar effects. Besides, the results of bioinformatics analysis and western blotting analysis were all confirmed that SOCS1 was a direct target of miR-19a in neuropathic pain models. Conclusions: Our finding indicate that SOCS1 is a direct target of miR-19a in neuropathic pain rats and miR-19a may play a critical role in regulating of neuropathic pain via targeting SOCS1. PMID:26617805

In vitro study of the neuropathic potential of the organophosphorus compounds trichlorfon and acephate.

PubMed

Fernandes, Laís S; Emerick, Guilherme L; dos Santos, Neife Aparecida G; de Paula, Eloísa Silva; Barbosa, Fernando; dos Santos, Antonio Cardozo

2015-04-01

Organophosphorus-induced delayed neuropathy (OPIDN) is a central and peripheral distal axonopathy characterized by ataxia and paralysis. Trichlorfon and acephate are two organophosphorus compounds (OPs) used worldwide as insecticide and which cause serious effects to non-target species. Despite that, the neuropathic potential of these OPs remains unclear. The present study addressed the neurotoxic effects and the neuropathic potential of trichlorfon and acephate in SH-SY5Y human neuroblastoma cells, by evaluating inhibition and aging of neuropathy target esterase (NTE), inhibition of acetylcholinesterase (AChE), neurite outgrowth, cytotoxicity and intracellular calcium. Additionally, the effects observed were compared to those of two well-studied OPs: mipafox (known as neuropathic) and paraoxon (known as non-neuropathic). Trichlorfon and mipafox presented the lowest percentage of reactivation of inhibited NTE and the lowest ratio IC50 NTE/IC50 AChE. Moreover, they caused inhibition and aging of at least 70% of the activity of NTE at sub-lethal concentrations. All these effects have been associated with induction of OPIDN. When assayed at these concentrations, trichlorfon and mipafox reduced neurite outgrowth and increased intracellular calcium, events implicated in the development of OPIDN. Acephate caused effects similar to those caused by paraoxon (non-neuropathic OP) and was only able to inhibit 70% of NTE activity at lethal concentrations. These findings suggest that trichlorfon is potentially neuropathic, whereas acephate is not. Copyright © 2015 Elsevier Ltd. All rights reserved.

Identification of an adenylyl cyclase inhibitor for treating neuropathic and inflammatory pain.

PubMed

Wang, Hansen; Xu, Hui; Wu, Long-Jun; Kim, Susan S; Chen, Tao; Koga, Kohei; Descalzi, Giannina; Gong, Bo; Vadakkan, Kunjumon I; Zhang, Xuehan; Kaang, Bong-Kiun; Zhuo, Min

2011-01-12

Neuropathic pain, often caused by nerve injury, is commonly observed among patients with different diseases. Because its basic mechanisms are poorly understood, effective medications are limited. Previous investigations of basic pain mechanisms and drug discovery efforts have focused mainly on early sensory neurons such as dorsal root ganglion and spinal dorsal horn neurons, and few synaptic-level studies or new drugs are designed to target the injury-related cortical plasticity that accompanies neuropathic pain. Our previous work has demonstrated that calcium-stimulated adenylyl cyclase 1 (AC1) is critical for nerve injury-induced synaptic changes in the anterior cingulate cortex. Through rational drug design and chemical screening, we have identified a lead candidate AC1 inhibitor, NB001, which is relatively selective for AC1 over other adenylate cyclase isoforms. Using a variety of behavioral tests and toxicity studies, we have found that NB001, when administered intraperitoneally or orally, has an analgesic effect in animal models of neuropathic pain, without any apparent side effects. Our study thus shows that AC1 could be a productive therapeutic target for neuropathic pain and describes a new agent for the possible treatment of neuropathic pain.

Adverse event assessment and reporting in trials of newer treatments for post-operative pain.

PubMed

Hoffer, D; Smith, S M; Parlow, J; Allard, R; Gilron, I

2016-08-01

Assessment and reporting of adverse events (AEs) in studies of perioperative interventions is critical given the potential for unintended and preventable iatrogenic morbidity and mortality. This focused review evaluated the quality of AE assessment and reporting in acute post-operative pain treatment trials. Since older analgesics (e.g., opioids, NSAIDs) already have a well-characterized safety profile, we concentrated on trials of pregabalin and gabapentin as a representative sample of studies where the perioperative safety profile was relatively unknown. We reviewed primary reports of trials of pregabalin and gabapentin for treatment of acute post-operative pain for: (1) adherence to the 10 recommendations from the 'CONSORT Extension for Harms,' (2) AE assessment method, (3) timing of AE assessment and reporting, and (4) assessment and reporting of AE severity. We identified 31 trials of pregabalin and 59 of gabapentin. The median number of CONSORT harms recommendations that were satisfied was 7 of 10. The most common (41%) method of AE assessment was direct questioning about specific AEs by investigators. However, AE assessment method was not described in 18% of trials. AE assessments were reported for specified perioperative time points in only 24% of trials. Of greatest concern, no AE data were reported whatsoever in 8 of the included publications. Considerable widespread improvements are needed in AE reporting for post-operative pain treatment trials. In addition to heightened awareness among clinical investigators, mandatory journal editorial policies may further facilitate improvements in safety assessment and reporting. © 2016 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.

A systematic review of cost-effectiveness modeling of pharmaceutical therapies in neuropathic pain: variation in practice, key challenges, and recommendations for the future.

PubMed

Critchlow, Simone; Hirst, Matthew; Akehurst, Ron; Phillips, Ceri; Philips, Zoe; Sullivan, Will; Dunlop, Will C N

2017-02-01

Complexities in the neuropathic-pain care pathway make the condition difficult to manage and difficult to capture in cost-effectiveness models. The aim of this study is to understand, through a systematic review of previous cost-effectiveness studies, some of the key strengths and limitations in data and modeling practices in neuropathic pain. Thus, the aim is to guide future research and practice to improve resource allocation decisions and encourage continued investment to find novel and effective treatments for patients with neuropathic pain. The search strategy was designed to identify peer-reviewed cost-effectiveness evaluations of non-surgical, pharmaceutical therapies for neuropathic pain published since January 2000, accessing five key databases. All identified publications were reviewed and screened according to pre-defined eligibility criteria. Data extraction was designed to reflect key data challenges and approaches to modeling in neuropathic pain and based on published guidelines. The search strategy identified 20 cost-effectiveness analyses meeting the inclusion criteria, of which 14 had original model structures. Cost-effectiveness modeling in neuropathic pain is established and increasing across multiple jurisdictions; however, amongst these studies, there is substantial variation in modeling approach, and there are common limitations. Capturing the effect of treatments upon health outcomes, particularly health-related quality-of-life, is challenging, and the health effects of multiple lines of ineffective treatment, common for patients with neuropathic pain, have not been consistently or robustly modeled. To improve future economic modeling in neuropathic pain, further research is suggested into the effect of multiple lines of treatment and treatment failure upon patient outcomes and subsequent treatment effectiveness; the impact of treatment-emergent adverse events upon patient outcomes; and consistent and appropriate pain measures to inform models. The authors further encourage transparent reporting of inputs used to inform cost-effectiveness models, with robust, comprehensive and clear uncertainty analysis and, where feasible, open-source modeling is encouraged.

Presynaptic GABAergic inhibition regulated by BDNF contributes to neuropathic pain induction

PubMed Central

Chen, Jeremy Tsung-chieh; Guo, Da; Campanelli, Dario; Frattini, Flavia; Mayer, Florian; Zhou, Luming; Kuner, Rohini; Heppenstall, Paul A.; Knipper, Marlies; Hu, Jing

2014-01-01

The gate control theory proposes the importance of both pre- and post-synaptic inhibition in processing pain signal in the spinal cord. However, although postsynaptic disinhibition caused by brain-derived neurotrophic factor (BDNF) has been proved as a crucial mechanism underlying neuropathic pain, the function of presynaptic inhibition in acute and neuropathic pain remains elusive. Here we show that a transient shift in the reversal potential (EGABA) together with a decline in the conductance of presynaptic GABAA receptor result in a reduction of presynaptic inhibition after nerve injury. BDNF mimics, whereas blockade of BDNF signalling reverses, the alteration in GABAA receptor function and the neuropathic pain syndrome. Finally, genetic disruption of presynaptic inhibition leads to spontaneous development of behavioural hypersensitivity, which cannot be further sensitized by nerve lesions or BDNF. Our results reveal a novel effect of BDNF on presynaptic GABAergic inhibition after nerve injury and may represent new strategy for treating neuropathic pain. PMID:25354791

Neuropathic pain in the orofacial region: The role of pain history. A retrospective study.

PubMed

Dieb, W; Moreau, N; Chemla, I; Descroix, V; Boucher, Y

2017-06-01

Orofacial neuropathic pain is often difficult to treat, mostly because of still unclear underlying mechanisms. The occurrence of such neuropathic pain varies depending on different factors, of which preexisting preoperative pain seems to be of high importance. The aim of this study was thus to test the hypothesis that prior history of pain could indeed be considered a risk factor for the development of orofacial neuropathic pain in the same region. The study was performed in the dental department of the Groupe Hospitalier Pitié-Salpêtrière (GHPS) in Paris, France. We investigated the presence of prior inflammatory pain before development of orofacial neuropathic pain in 56 patients. For each patient file, the following items were collected: age, gender; medical history; diagnosis; description of the pain (at time of consultation); presence or absence of prior dental treatment; date and type of dental treatment received. 41 patients (73%) of orofacial neuropathic pain patients had a history of pain compatible with an inflammatory condition; 4% (n=2) did not report any prior pain and 23% (n=13) could not remember. Among the patients with documented history of pain prior to neuropathy, 88% (n=36) received surgical treatment; 61%, (n=25) endodontic treatment and 22%, (n=9) restorative treatment. All eventually received endodontic treatment or tooth extraction. These dental treatments are compatible with the hypothesis of prior inflammatory pain in these patients. These results support the hypothesis that prior inflammatory pain could favor the development of orofacial neuropathic pain. Prevention and treatment of inflammatory trigeminal pain may therefore play a key role in preventing future neuropathic pain development. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Molecular Hydrogen Attenuates Neuropathic Pain in Mice

PubMed Central

Kawaguchi, Masanori; Satoh, Yasushi; Otsubo, Yukiko; Kazama, Tomiei

2014-01-01

Neuropathic pain remains intractable and the development of new therapeutic strategies are urgently required. Accumulating evidence indicates that overproduction of oxidative stress is a key event in the pathogenesis of neuropathic pain. However, repeated intra-peritoneal or intrathecal injections of antioxidants are unsuitable for continuous use in therapy. Here we show a novel therapeutic method against neuropathic pain: drinking water containing molecular hydrogen (H2) as antioxidant. The effect of hydrogen on neuropathic pain was investigated using a partial sciatic nerve ligation model in mice. As indicators of neuropathic pain, temporal aspects of mechanical allodynia and thermal hyperalgesia were analysed for 3 weeks after ligation. Mechanical allodynia and thermal hyperalgesia were measured using the von Frey test and the plantar test, respectively. When mice were allowed to drink water containing hydrogen at a saturated level ad libitum after ligation, both allodynia and hyperalgesia were alleviated. These symptoms were also alleviated when hydrogen was administered only for the induction phase (from day 0 to 4 after ligation). When hydrogen was administered only for the maintenance phase (from day 4 to 21 after ligation), hyperalgesia but not allodynia was alleviated. Immunohistochemical staining for the oxidative stress marker, 4-hydroxy-2-nonenal and 8-hydroxydeoxyguanosine, showed that hydrogen administration suppressed oxidative stress induced by ligation in the spinal cord and the dorsal root ganglion. In conclusion, oral administration of hydrogen water may be useful for alleviating neuropathic pain in a clinical setting. PMID:24941001

[Transcranial magnetic stimulation and motor cortex stimulation in neuropathic pain].

PubMed

Mylius, V; Ayache, S S; Teepker, M; Kappus, C; Kolodziej, M; Rosenow, F; Nimsky, C; Oertel, W H; Lefaucheur, J P

2012-12-01

Non-invasive and invasive cortical stimulation allows the modulation of therapy-refractory neuropathic pain. High-frequency repetitive transcranial magnetic stimulation (rTMS) of the contralateral motor cortex yields therapeutic effects at short-term and predicts the benefits of epidural motor cortex stimulation (MCS). The present article summarizes the findings on application, mechanisms and therapeutic effects of cortical stimulation in neuropathic pain.

Social acceptance and quality of life of leprosy patient

NASA Astrophysics Data System (ADS)

Eyanoer, P. C.

2018-03-01

Some of the leprosy patients facing problems in many aspects such as social, economic, cultural and national security. Both the debilitating effects and disfigurements of leprosy, the society tends to stigmatize negatively those suffering from leprosy. The impact of negative stigma on society causes depression and problems in workplace cause difficulty in patient’s daily life. Neuropathic pain disturbs the quality of life of leprosy patients which could become so severe and significant. The neuropathic pain will lower their productivity which later caused difficulties in finding a job. This study was an analytical observational study to identify the correlation between neuropathic pain and quality of life in Leprosy Hospital of Scanning in Medan Belawan. The result showed that there is a correlation between neuropathic pain and disruption of quality of life (p=0.017). In conclusion, the milder the neuropathic pain experienced by persons with leprosy, the less the quality of life will be disturbed.

Agmatine attenuates neuropathic pain in sciatic nerve ligated rats: modulation by hippocampal sigma receptors.

PubMed

Kotagale, Nandkishor Ramdas; Shirbhate, Saurabh Haridas; Shukla, Pradeep; Ugale, Rajesh Ramesh

2013-08-15

Present study investigated the influence of the sigma (σ₁ and σ₂) receptors within hippocampus on the agmatine induced antinociception in neuropathic rats. Animals were subjected to sciatic nerve ligation for induction of neuropathic pain and observed the paw withdrawal latency in response to thermal hyperalgesia, cold allodynia and the mechanical hyperalgesia. Intrahippocampal (i.h.) as well as intraperitoneal (i.p.) administration of agmatine attenuated neuropathic pain in sciatic nerve ligated rats. Intrahippocampal administration of σ₁ agonist (+)-pentazocine or σ₂ agonist PB28 sensitized whereas, σ₁ antagonist BD1063 or σ₂ antagonist SM21 potentiated antinociceptive effect of agmatine. The behavioral effects correlated with hippocampal tumor necrosis factor-α (TNF-α) levels observed by western blot analysis. These results suggest that both the σ₁ and σ₂ receptor subunits within hippocampus play an important role in antinociceptive action of agmatine against neuropathic pain. © 2013 Elsevier B.V. All rights reserved.

Development of neuropathic pain is affected by bedding texture in two models of peripheral nerve injury in rats.

PubMed

Robinson, Ian; Dowdall, Tom; Meert, Theo F

2004-09-16

It has long been known that there are numerous genetic and environmental factors that affect the in vivo research of neuropathic pain. In this letter, we describe the impact that bedding material can have on the development of neuropathic pain behaviors in rodents. In two models of neuropathic pain, the Chronic Constriction Injury (CCI) and the partial axotomy, we demonstrated that features of the sawdust on which the animals are housed during experimentation have a clear effect on the development of mechanical hyperalgesia and chemical hypersensitivity. Rats housed on coarse sawdust presented with a much-reduced response to a pinprick and acetone test compared to counterparts housed on fine sawdust. It is therefore concluded that the development of specific stimulus modalities of neuropathic pain behavior following peripheral nerve injury can be influenced in part by environmental factors, in this case bedding texture.

Emerging drugs for neuropathic pain.

PubMed

Gilron, Ian; Dickenson, Anthony H

2014-09-01

Neuropathic pain is a costly and disabling condition, which affects up to 8% of the population. Available therapies often provide incomplete pain relief and treatment-related side effects are common. Preclinical neuropathic pain models have facilitated identification of several promising targets, which have progressed to human clinical phases of evaluation. A systematic database search yielded 25 new molecular entities with specified pharmacological mechanisms that have reached Phase II or III clinical trials. These include calcium channel antagonists, vanilloid receptor antagonists, potassium channel agonists, NMDA antagonists, novel opioid receptor agonists, histamine H3 receptor antagonists, a novel sodium channel antagonist, serotonin modulators, a novel acetylcholine receptor agonist, α-2b adrenoreceptor agonist, cannabinoid CB2 receptor agonist, nitric oxide synthase inhibitor, orexin receptor antagonist, angiotensin II 2 antagonist, imidazoline I2 receptor agonist, apoptosis inhibitor and fatty acid amide hydrolase inhibitor. Although the diversity of pharmacological mechanisms of interest emphasise the complexity of neuropathic pain transmission, the considerable number of agents under development reflect a continued enthusiasm in drug development for neuropathic pain. Ongoing enhancements in methodology of both preclinical and clinical research and closer translation in both directions are expected to more efficiently identify new agents, which will improve the management of neuropathic pain.

MiR-155 modulates the progression of neuropathic pain through targeting SGK3.

PubMed

Liu, Shaoxing; Zhu, Bo; Sun, Yan; Xie, Xianfeng

2015-01-01

This study aimed to illustrate the potential effects of miR-155 in neuropathic pain and its potential mechanism. Spragure-Dawley (SD) rats were used for neuropathic pain model of bilateral chronic constriction injury (bCCI) construction. Effects of miR-155 expression on pain threshold of mechanical stimuli (MWT), paw withdrawal threshold latency (PMTL) and cold threshold were analyzed. Target for miR-155 was analyzed using bioinformatics methods. Moreover, effects of miR-155 target gene expression on pain thresholds were also assessed. Compared with the controls and sham group, miR-155 was overexpressed in neuropathic pain rats (P<0.05), but miR-155 slicing could significantly decreased the pain thresholds (P<0.05). Serum and glucocorticoid regulated protein kinase 3 (SGK3) was predicted as the target gene for miR-155, and miR-155 expression was negatively correlated to SGK3 expression. Furthermore, SGK3 overexpression could significantly decreased the pain thresholds which was the same as miR-155 (P<0.05). Moreover, miR-155 slicing and SGK3 overexpression could significantly decrease the painthreshold. The data presented in this study suggested that miR-155 slicing could excellently alleviate neuropathic pain in rats through targeting SGK3 expression. miR-155 may be a potential therapeutic target for neuropathic pain treatment.

Systemic Inflammatory and Th17 Immune Activation among Patients Treated for Lumbar Radiculopathy Exceeds that of Patients Treated for Persistent Postoperative Neuropathic Pain.

PubMed

Shamji, Mohammed F; Guha, Daipayan; Paul, Darcia; Shcharinsky, Alina

2017-09-01

The pathophysiology of lumbar radiculopathy includes both mechanical compression and biochemical irritation of apposed neural elements. Inflammatory and immune cytokines have been implicated, induced by systemic exposure of immune-privileged intervertebral disc tissue. Surgical intervention provides improved symptoms and quality of life, but persistent postoperative neuropathic pain (PPNP) afflicts a significant fraction of patients. To compare the inflammatory and immune phenotypes among patients undergoing structural surgery for lumbar radiculopathy and spinal cord stimulation for neuropathic pain. Consecutive patients undergoing surgical intervention for lumbar radiculopathy or neuropathic pain were studied. Demographic data included age, gender, and VAS and neuropathic pain scores. Serum was evaluated for cytokine levels (IL-6, Il-17, TNF-α) and cellular content [white blood cell (WBC)/differential, lymphocyte subtypes]. The primary analysis differentiated molecular and cellular profiles between radiculopathy and neuropathic pain patients. Subgroup analysis within the surgical radiculopathy population compared those patients achieving relief of symptoms and those with PPNP. Heightened IL-6, Il-17, and TNF-α levels were observed for the lumbar radiculopathy group compared with the neuropathic pain group. This was complemented by higher WBC count and a greater fraction of Th17 lymphocytes among radiculopathy patients. In the lumbar discectomy subgroup, pain relief was seen among patients with preoperatively elevated IL-17 levels. Those patients with PPNP refractory to surgical discectomy exhibited normal cytokine levels. Differences in Th17 immune activation are seen among radiculopathy and neuropathic pain patients. These cellular and molecular profiles may be translated into biomarkers to improve patient selection for structural spine surgery. Copyright © 2017 by the Congress of Neurological Surgeons

Behavioral effects of antiepileptic drugs in rats: Are the effects on mood and behavior detectable in open-field test?

PubMed

Zimcikova, Eva; Simko, Julius; Karesova, Iva; Kremlacek, Jan; Malakova, Jana

2017-11-01

Behavioral side effects of antiepileptic drugs (AEDs) are common including both positive and negative effects on mood, anxiety, depression, and psychosis. We aimed to evaluate behavioral patterns in rats after administration of lamotrigine, levetiracetam, phenytoin, topiramate, carbamazepine, gabapentin, pregabalin, and zonisamide. The open-field test was performed and locomotion, rearing, grooming, central latency and defecation were recorded over a 5min interval for each rat (8 rats in each group receiving AED and 16 controls). Kruskal-Wallis nonparametric test or ANOVA were used to assess differences among the groups. The experimental groups did not differ in latency to enter the center compartment, neither in the decline of locomotor activity in the 1st and the 5th minute of the observation, nor in number of rears. Significant differences among groups were observed in the total number of lines crossed, grooming, as well in the number of fecal pellets. Locomotor activity was significantly increased in lamotrigine, if compared with gabapentin and pregabalin (ANOVA; p <0.05). Rats exposed to topiramate displayed a significantly increased number of grooming (when compared to pregabalin: p<0.01). Defecation (the number of fecal pellets) significantly increased in the gabapentin and carbamazepine group. There are significant differences between AEDs in terms of their behavioral profile. It is of great importance to evaluate these effects in clinical practice to bring more clear insight into these positive or negative side effects of AEDs. Copyright © 2017 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.

The CanPain SCI Clinical Practice Guidelines for Rehabilitation Management of Neuropathic Pain after Spinal Cord: screening and diagnosis recommendations.

PubMed

Mehta, S; Guy, S D; Bryce, T N; Craven, B C; Finnerup, N B; Hitzig, S L; Orenczuk, S; Siddall, P J; Widerström-Noga, E; Casalino, A; Côté, I; Harvey, D; Kras-Dupuis, A; Lau, B; Middleton, J W; Moulin, D E; O'Connell, C; Parrent, A G; Potter, P; Short, C; Teasell, R; Townson, A; Truchon, C; Wolfe, D; Bradbury, C L; Loh, E

2016-08-01

Clinical practice guidelines. To develop the first Canadian clinical practice guidelines for screening and diagnosis of neuropathic pain in people with spinal cord injury (SCI). The guidelines are relevant for inpatient and outpatient SCI rehabilitation settings in Canada. The CanPainSCI Working Group reviewed evidence to address clinical questions regarding screening and diagnosis of neuropathic pain after SCI. A consensus process was followed to achieve agreement on recommendations and clinical considerations. Twelve recommendations, based on expert consensus, were developed for the screening and diagnosis of neuropathic pain after SCI. The recommendations address methods for assessment, documentation tools, team member accountability, frequency of screening and considerations for diagnostic investigation. Important clinical considerations accompany each recommendation. The expert Working Group developed recommendations for the screening and diagnosis of neuropathic pain after SCI that should be used to inform practice.

Pregabalin Modulation of Neurotransmitter Release Is Mediated by Change in Intrinsic Activation/Inactivation Properties of Cav2.1 Calcium ChannelsS⃞

PubMed Central

Di Guilmi, Mariano N.; Urbano, Francisco J.; Inchauspe, Carlota Gonzalez

2011-01-01

In this work, we studied the effects of the anticonvulsant and analgesic drug pregabalin (PGB) on excitatory postsynaptic currents (EPSCs) at principal neurons of the mouse medial nucleus of the trapezoid body and on presynaptic calcium currents at the calyx of Held. We found that the acute application of PGB reduced the amplitude of EPSCs in a dose-dependent manner with a maximal blocking effect of approximately 30%. A clinical high-concentration dose of PGB (e.g., 500 μM) blocked Cav2.1 channel-mediated currents and decreased their facilitation during a 100-Hz train, without changing their voltage-dependent activation. Furthermore, PGB also removed the inactivation of Cav2.1 channels at a clinically relevant low concentration of 100 μM. These results suggest novel modulatory mechanisms mediated by the acute administration of PGB on fast excitatory synaptic transmission and might contribute to better understanding PGB anticonvulsant/analgesic clinical effects. PMID:21177783

Orthotic management of the neuropathic foot: an interdisciplinary care perspective.

PubMed

Robinson, Christopher; Major, Matthew J; Kuffel, Charles; Hines, Kevin; Cole, Pamela

2015-02-01

Clinical management of the patient with neuropathic foot is becoming commonplace in orthotic clinics worldwide. The presentations that can result from neuropathic foot are diverse, requiring clinicians to understand the pathomechanics of ulceration, infection, and Charcot joint arthropathy to provide effective interventions. The purpose of this clinical perspective is to provide a review of the literature regarding clinical concepts associated with orthotic management of neuropathic foot. Literature review and clinical case study. Relevant literature were reviewed and summarized, and a clinical case study synthesizing reviewed concepts was presented. Given the multifactorial nature of the neuropathic foot, treatments must be multifaceted and patient-specific to effectively address the underlying disease processes. While systemic issues such as peripheral arterial disease are treated by physicians, local issues such as foot deformity are managed by orthotists. Orthotic interventions commonly include custom footwear to reduce the risk of ulceration through creation of a protective environment or targeted plantar offloading. Patient and caregiver education to encourage management compliance is equally as important to ensure successful treatment. Patients with neuropathic foot benefit from an interdisciplinary care approach which engages physicians, wound care practitioners, and orthotists to treat and manage systemic and local problems. Addressing this pathology through interdisciplinary care may positively affect the patient's health status while lowering associated healthcare costs through improved treatment efficacy. The commonality of neuropathic foot and associated complications including ulceration, infection, and Charcot joint arthropathy requires that the patient care team have a fundamental understanding of these pathologies and common treatment modalities. We review orthotic treatment modalities to assist clinicians with the management of patients with neuropathic foot. © The International Society for Prosthetics and Orthotics 2014.

Effects of XIST/miR-137 axis on neuropathic pain by targeting TNFAIP1 in a rat model.

PubMed

Zhao, Ying; Li, Sen; Xia, Nin; Shi, Yan; Zhao, Chang-Ming

2018-05-01

Non-coding RNAs have been reported to participate in the pathophysiology of neuropathic pain. The objective of our study was to investigate the biological role of XIST in neuropathic pain development. In our study, we identify and validate that lncRNA XIST was markedly increased and miR-137 was significantly decreased in chronic constriction injury (CCI) rats. XIST silencing alleviated pain behaviors including both mechanical and thermal hyperalgesia in the CCI rats. XIST was predicted to interact with miR-137 by bioinformatics technology and dual-luciferase reporter assays confirmed the correlation between XIST and miR-137. miR-137 was negatively modulated by XIST and upregulation of miR-137 greatly reduced neuropathic pain development in CCI rats. Moreover, we observed that tumor necrosis factor alpha-induced protein 1 (TNFAIP1) was enhanced in CCI rats and 3'-untranslated region (UTR) of TNFAIP1 was exhibited to be a target of miR-137 by bioinformatics prediction. TNFAIP1 can act as a crucial inflammation regulator by activating NF-kB activity. Overexpression of miR-137 significantly suppressed TNFAIP1 both in vitro and in vivo. Furthermore, upregulation of XIST reversed the inhibitory role of miR-137 in neuropathic pain development by inhibiting TNFAIP1. In conclusion, our current study indicates that XIST can positively regulate neuropathic pain in rats through regulating the expression of miR-137 and TNFAIP1. Our results imply that XIST/miR-137/TNFAIP1 axis may serve as a novel therapeutic target in neuropathic pain. © 2017 Wiley Periodicals, Inc.

Prevalence and biochemical risk factors of diabetic peripheral neuropathy with or without neuropathic pain in Taiwanese adults with type 2 diabetes mellitus.

PubMed

Pai, Yen-Wei; Lin, Ching-Heng; Lee, I-Te; Chang, Ming-Hong

To investigate the prevalence and risk factors for diabetic peripheral neuropathy with or without neuropathic pain in Taiwanese. A cross-sectional, hospital-based observational study was conducted. We enrolled 2837 adults with type 2 diabetes mellitus. Diabetic peripheral neuropathy with or without pain were diagnosed using 2 validated screening tools, namely the Michigan Neuropathy Screening Instrument and Douleur Neuropathique 4 questionnaire. In our sample, 2233 participants had no neuropathy, 476 had diabetic peripheral neuropathy without pain, and 128 had diabetic peripheral neuropathy with neuropathic pain, representing an overall diabetic peripheral neuropathy prevalence of 21.3%, and the prevalence of neuropathic pain in diabetic peripheral neuropathy was 21.2%. Multivariate analysis revealed that older age (P<0.001), treatment with insulin (P=0.004), microalbuminuria (P=0.001) or overt proteinuria (P<0.001) were independently associated with diabetic peripheral neuropathy, whereas older age (P<0.001), elevated glycated haemoglobin (P=0.011), lower high-density lipoprotein cholesterol (P=0.033), and overt proteinuria (P<0.001) were independently associated with diabetic peripheral neuropathy with neuropathic pain. During clinical visits involving biochemical studies, the risk for diabetic peripheral neuropathy with neuropathic pain should be considered for people with older age, elevated glycated haemoglobin, low high-density lipoprotein cholesterol and overt proteinuria, with particular attention given to increased levels of albuminuria while concerning neuropathic pain. Copyright © 2017 Diabetes India. Published by Elsevier Ltd. All rights reserved.

Cross-cultural Adaptation and Linguistic Validation of the Korean Version of the Leeds Assessment of Neuropathic Symptoms and Signs Pain Scale

PubMed Central

Park, Cholhee; Lee, Youn-Woo; Yoon, Duck Mi; Kim, Do Wan; Nam, Da Jeong

2015-01-01

Distinction between neuropathic pain and nociceptive pain helps facilitate appropriate management of pain; however, diagnosis of neuropathic pain remains a challenge. The aim of this study was to develop a Korean version of the Leeds Assessment of Neuropathic Symptoms and Signs (LANSS) pain scale and assess its reliability and validity. The translation and cross-cultural adaptation of the original LANSS pain scale into Korean was established according to the published guidelines. The Korean version of the LANSS pain scale was applied to a total of 213 patients who were expertly diagnosed with neuropathic (n = 113) or nociceptive pain (n = 100). The Korean version of the scale had good reliability (Cronbach's α coefficient = 0.815, Guttman split-half coefficient = 0.800). The area under the receiver operating characteristic curve was 0.928 with a 95% confidence interval of 0.885-0.959 (P < 0.001), suggesting good discriminate value. With a cut-off score ≥ 12, sensitivity was 72.6%, specificity was 98.0%, and the positive and negative predictive values were 98% and 76%, respectively. The Korean version of the LANSS pain scale is a useful, reliable, and valid instrument for screening neuropathic pain from nociceptive pain. PMID:26339176

miR-155 modulates the progression of neuropathic pain through targeting SGK3

PubMed Central

Liu, Shaoxing; Zhu, Bo; Sun, Yan; Xie, Xianfeng

2015-01-01

This study aimed to illustrate the potential effects of miR-155 in neuropathic pain and its potential mechanism. Spragure-Dawley (SD) rats were used for neuropathic pain model of bilateral chronic constriction injury (bCCI) construction. Effects of miR-155 expression on pain threshold of mechanical stimuli (MWT), paw withdrawal threshold latency (PMTL) and cold threshold were analyzed. Target for miR-155 was analyzed using bioinformatics methods. Moreover, effects of miR-155 target gene expression on pain thresholds were also assessed. Compared with the controls and sham group, miR-155 was overexpressed in neuropathic pain rats (P<0.05), but miR-155 slicing could significantly decreased the pain thresholds (P<0.05). Serum and glucocorticoid regulated protein kinase 3 (SGK3) was predicted as the target gene for miR-155, and miR-155 expression was negatively correlated to SGK3 expression. Furthermore, SGK3 overexpression could significantly decreased the pain thresholds which was the same as miR-155 (P<0.05). Moreover, miR-155 slicing and SGK3 overexpression could significantly decrease the painthreshold. The data presented in this study suggested that miR-155 slicing could excellently alleviate neuropathic pain in rats through targeting SGK3 expression. miR-155 may be a potential therapeutic target for neuropathic pain treatment. PMID:26823753

Cross-cultural Adaptation and Linguistic Validation of the Korean Version of the Leeds Assessment of Neuropathic Symptoms and Signs Pain Scale.

PubMed

Park, Cholhee; Lee, Youn-Woo; Yoon, Duck Mi; Kim, Do Wan; Nam, Da Jeong; Kim, Do-Hyeong

2015-09-01

Distinction between neuropathic pain and nociceptive pain helps facilitate appropriate management of pain; however, diagnosis of neuropathic pain remains a challenge. The aim of this study was to develop a Korean version of the Leeds Assessment of Neuropathic Symptoms and Signs (LANSS) pain scale and assess its reliability and validity. The translation and cross-cultural adaptation of the original LANSS pain scale into Korean was established according to the published guidelines. The Korean version of the LANSS pain scale was applied to a total of 213 patients who were expertly diagnosed with neuropathic (n = 113) or nociceptive pain (n = 100). The Korean version of the scale had good reliability (Cronbach's α coefficient = 0.815, Guttman split-half coefficient = 0.800). The area under the receiver operating characteristic curve was 0.928 with a 95% confidence interval of 0.885-0.959 (P < 0.001), suggesting good discriminate value. With a cut-off score ≥ 12, sensitivity was 72.6%, specificity was 98.0%, and the positive and negative predictive values were 98% and 76%, respectively. The Korean version of the LANSS pain scale is a useful, reliable, and valid instrument for screening neuropathic pain from nociceptive pain.

A review of the use of ketamine in pain management.

PubMed

Tawfic, Qutaiba A

2013-01-01

Ketamine is a noncompetitive antagonist of N-methyl-d-aspartate receptor. It has been widely used in anesthesia and pain management. Ketamine has been administered via the intravenous, intramuscular, subcutaneous, oral, rectal, topical, intranasal, sublingual, epidural, and caudal routes. Ketamine improves postoperative and posttrauma pain scores and reduces opioid consumption. It has special indication for patients with opioid tolerance, acute hyperalgesia, and neuropathic pain. It also has a role in the management of chronic pain including both cancer and noncancer pain. Recreational use of ketamine is increasing as well through different routes of administration like inhalation, smoking, or intravenous injection. Long-time exposure to ketamine, especially in the abusers, may lead to serious side effects. This review is trying to define the role of ketamine in pain management.

An algorithm for assessment and treatment of postherniorrhaphy pain.

PubMed

Voorbrood, C E H; Burgmans, J P J; Van Dalen, T; Breel, J; Clevers, G J; Wille, F; Simmermacher, R K J

2015-08-01

Inguinal pain after groin hernia repair is a challenging issue. About 50 % of postherniorrhaphy pain allegedly is neuropathic, treatment of which is cumbersome given the limited efficacy of current therapeutic modalities. Possibly a clear protocol assessing the type of pain and treating it accordingly could improve its treatment. A prospective study was done to evaluate an algorithm in patients with chronic postherniorrhaphy groin pain, aiming to select those with neuropathic pain and to treat appropriately. Treatment consisted of ultrasound-guided nerve blocks as an initial treatment for neuropathic pain. If long-term pain reduction proved inadequate, peripheral nerve stimulation was offered. After our diagnostic workup consisting of anamnesis, physical examination and imaging, 68 patients out of 105 were diagnosed as having non-neuropathic pain. These patients were referred to the most appropriate consultant, treated accordingly or sometimes pain appeared to be self-limiting. Thirty-seven (35 %) patients were diagnosed as having neuropathic pain with a median NRS of 7 (range 4-9) and were referred for further treatment to our pain clinic. The majority (21 of 28 patients) suffered ileo-inguinal nerve involvement. After ultrasound-guided nerve blocks, a permanent reduction in pain was achieved in 18 patients (62 %) with a median post-treatment NRS of 1 (range 0-3). In six patients to which an additional peripheral nerve stimulator (PNS) was offered, pain reduction to a level of mild complaints with a median NRS of 2 (range 1-8) was observed. In total, 24 of the 28 patients (83 %) diagnosed with neuropathic postherniorrhaphy pain achieved significant pain reduction after algorithm-based treatment. In the present study, we implemented a diagnostic workup for patients with postherniorrhaphy inguinal pain to select those with neuropathic pain. Eighty-three percent of the patients with neuropathic groin pain obtained significant improvement of their pain scores after our protocolled treatment. The effect was achieved by nerve infiltrations and in some cases by an implanted PNS when the former was unsuccessful.

Under Pressure: Applying Practice-Based Learning and Improvement to the Treatment of Chronic Neuropathic Pain in Patients with Burns.

PubMed

Rapolti, Mihaela; Wu, Cindy; Schuth, Olga A; Hultman, Charles Scott

2017-10-01

Chronic neuropathic pain after burn injury may have multiple causes, such as direct nerve injury, nerve compression, or neuroma formation, and can significantly impair quality of life and limit functional recovery. Management includes a team-based approach that involves close collaboration between occupational and physical therapists, plastic surgeons, and experts in chronic pain, from neurology, anesthesia, psychiatry, and physiatry. Carefully selected patients with an anatomic cause of chronic neuropathic pain unequivocally benefit from surgical intervention. Self-reflection and analysis yield improvement in both efficiency and effectiveness when managing patients with burns with chronic neuropathic pain. Copyright © 2017 Elsevier Inc. All rights reserved.

Cross-Cultural Psychometric Assessment of the Leeds Assessment of Neuropathic Symptoms and Signs (LANSS) Pain Scale in the Portuguese Population.

PubMed

Barbosa, Margarida; Bennett, Michael I; Verissimo, Ramiro; Carvalho, Davide

2014-09-01

Chronic pain is a well-known phenomenon. The differential diagnosis between neuropathic and nociceptive pain syndromes is a challenge. Consequently, assessment instruments that can distinguish between these conditions in a standardized way are of the utmost importance. The Leeds Assessment of Neuropathic Symptoms and Signs (LANSS) is a screening tool developed to identify chronic neuropathic pain. The aim of this study was the Portuguese language translation, linguistic adaptation of the LANSS pain scale, its semantic validation, internal consistency, temporal stability, as well its validity and discriminative power. LANSS Portuguese version scale was applied to 165 consecutive patients attending the pain clinic: 103 fulfilled the clinical criteria for the diagnosis of pain of neuropathic origin and the remaining 62 fulfilled the criteria for nociceptive pain. The scale proved to be an internally consistent (Cronbach's alpha = 0.78) and reliable instrument with good test-retest stability (r = 0.7; P < 0.001). However, its validity and specificity with a cutoff point of ≥ 12, for differentiating patients with neuropathic pain from those with non-neuropathic pain, had 89% sensitivity, 74% specificity, positive predictive value of 85%, and negative predictive value of 81%. The Portuguese LANSS version pain scale properties lead us to the conclusion that such a cross-cultural version is a reliable and valid instrument for the differentiation of this type of pain. Its usage is recommended. © 2013 World Institute of Pain.

Neuropathic pain: an updated grading system for research and clinical practice.

PubMed

Finnerup, Nanna B; Haroutounian, Simon; Kamerman, Peter; Baron, Ralf; Bennett, David L H; Bouhassira, Didier; Cruccu, Giorgio; Freeman, Roy; Hansson, Per; Nurmikko, Turo; Raja, Srinivasa N; Rice, Andrew S C; Serra, Jordi; Smith, Blair H; Treede, Rolf-Detlef; Jensen, Troels S

2016-08-01

The redefinition of neuropathic pain as "pain arising as a direct consequence of a lesion or disease affecting the somatosensory system," which was suggested by the International Association for the Study of Pain (IASP) Special Interest Group on Neuropathic Pain (NeuPSIG) in 2008, has been widely accepted. In contrast, the proposed grading system of possible, probable, and definite neuropathic pain from 2008 has been used to a lesser extent. Here, we report a citation analysis of the original NeuPSIG grading paper of 2008, followed by an analysis of its use by an expert panel and recommendations for an improved grading system. As of February, 2015, 608 eligible articles in Scopus cited the paper, 414 of which cited the neuropathic pain definition. Of 220 clinical studies citing the paper, 56 had used the grading system. The percentage using the grading system increased from 5% in 2009 to 30% in 2014. Obstacles to a wider use of the grading system were identified, including (1) questions about the relative significance of confirmatory tests, (2) the role of screening tools, and (3) uncertainties about what is considered a neuroanatomically plausible pain distribution. Here, we present a revised grading system with an adjusted order, better reflecting clinical practice, improvements in the specifications, and a word of caution that even the "definite" level of neuropathic pain does not always indicate causality. In addition, we add a table illustrating the area of pain and sensory abnormalities in common neuropathic pain conditions and propose areas for further research.

Exploration of a Novel Persistent Reversal of Pathological Pain: Mechanisms and Mediators

DTIC Science & Technology

2015-04-01

ability of a single IT ATL313 dose to reverse neuropathic pain from traumatic peripheral neuropathy . Milestone 2 is complete. We determined that 1 pmol...cord injury; to prevent and reverse neuropathic pain from inflammatory peripheral neuropathy following either IT or peri-sciatic nerve ( peripheral ...ATL313 can reverse neuropathic pain from inflammatory peripheral neuropathy following either IT or peri-sciatic nerve ( peripheral ) injections. We also

Practice guideline summary: Treatment of restless legs syndrome in adults

PubMed Central

Winkelman, John W.; Armstrong, Melissa J.; Allen, Richard P.; Chaudhuri, K. Ray; Ondo, William; Trenkwalder, Claudia; Zee, Phyllis C.; Gronseth, Gary S.; Gloss, David; Zesiewicz, Theresa

2016-01-01

Objective: To make evidence-based recommendations regarding restless legs syndrome (RLS) management in adults. Methods: Articles were classified per the 2004 American Academy of Neurology evidence rating scheme. Recommendations were tied to evidence strength. Results and recommendations: In moderate to severe primary RLS, clinicians should consider prescribing medication to reduce RLS symptoms. Strong evidence supports pramipexole, rotigotine, cabergoline, and gabapentin enacarbil use (Level A); moderate evidence supports ropinirole, pregabalin, and IV ferric carboxymaltose use (Level B). Clinicians may consider prescribing levodopa (Level C). Few head-to-head comparisons exist to suggest agents preferentially. Cabergoline is rarely used (cardiac valvulopathy risks). Augmentation risks with dopaminergic agents should be considered. When treating periodic limb movements of sleep, clinicians should consider prescribing ropinirole (Level A) or pramipexole, rotigotine, cabergoline, or pregabalin (Level B). For subjective sleep measures, clinicians should consider prescribing cabergoline or gabapentin enacarbil (Level A), or ropinirole, pramipexole, rotigotine, or pregabalin (Level B). For patients failing other treatments for RLS symptoms, clinicians may consider prescribing prolonged-release oxycodone/naloxone where available (Level C). In patients with RLS with ferritin ≤75 μg/L, clinicians should consider prescribing ferrous sulfate with vitamin C (Level B). When nonpharmacologic approaches are desired, clinicians should consider prescribing pneumatic compression (Level B) and may consider prescribing near-infrared spectroscopy or transcranial magnetic stimulation (Level C). Clinicians may consider prescribing vibrating pads to improve subjective sleep (Level C). In patients on hemodialysis with secondary RLS, clinicians should consider prescribing vitamin C and E supplementation (Level B) and may consider prescribing ropinirole, levodopa, or exercise (Level C). PMID:27856776

Neuropathic pain screening questionnaires have limited measurement properties. A systematic review.

PubMed

Mathieson, Stephanie; Maher, Christopher G; Terwee, Caroline B; Folly de Campos, Tarcisio; Lin, Chung-Wei Christine

2015-08-01

The Douleur Neuropathique 4 (DN4), ID Pain, Leeds Assessment of Neuropathic Symptoms and Signs (LANSS), PainDETECT, and Neuropathic Pain Questionnaire have been recommended as screening questionnaires for neuropathic pain. This systematic review aimed to evaluate the measurement properties (eg, criterion validity and reliability) of these questionnaires. Online database searches were conducted and two independent reviewers screened studies and extracted data. Methodological quality of included studies and the measurement properties were assessed against established criteria. A modified Grading of Recommendations Assessment, Development and Evaluation approach was used to summarize the level of evidence. Thirty-seven studies were included. Most studies recruited participants from pain clinics. The original version of the DN4 (French) and Neuropathic Pain Questionnaire (English) had the most number of satisfactory measurement properties. The ID Pain (English) demonstrated satisfactory hypothesis testing and reliability, but all other properties tested were unsatisfactory. The LANSS (English) was unsatisfactory for all properties, except specificity. The PainDETECT (English) demonstrated satisfactory hypothesis testing and criterion validity. In general, the cross-cultural adaptations had less evidence than the original versions. Overall, the DN4 and Neuropathic Pain Questionnaire were most suitable for clinical use. These screening questionnaires should not replace a thorough clinical assessment. Crown Copyright © 2015. Published by Elsevier Inc. All rights reserved.

Superior analgesic effect of H-Dmt-D-Arg-Phe-Lys-NH2 ([Dmt1]DALDA), a multifunctional opioid peptide, compared to morphine in a rat model of neuropathic pain.

PubMed

Shimoyama, Megumi; Schiller, Peter W; Shimoyama, Naohito; Toyama, Satoshi; Szeto, Hazel H

2012-11-01

H-Dmt-D-Arg-Phe-Lys-NH(2) ([Dmt(1)]DALDA) is a synthetic tetrapeptide with extraordinary selectivity for the mu-opioid receptor and is an extremely potent analgesic. [Dmt(1) ]DALDA is unusual in the way that the greater part of its analgesic potency appears to be produced by its actions in the spinal cord. Furthermore, [Dmt(1) ]DALDA inhibits norepinephrine re-uptake and is a mitochondria-targeted antioxidant. Such characteristics may make [Dmt(1)]DALDA particularly effective against neuropathic pain. The present study was designed to compare the effects of [Dmt(1)]DALDA and morphine on thermal hyperalgesia in an experimental neuropathic pain model. Neuropathic pain was induced in rats by surgical ligation of the L5 spinal nerve, and thermal pain thresholds were assessed by latencies of paw withdrawal to radiant heat. The increase in paw withdrawal latency was greater after the administration of [Dmt(1) ]DALDA than that of morphine in neuropathic rats at doses that were equianalgesic in naïve animals. We conclude that [Dmt(1)]DALDA is more effective than morphine against thermal hyperalgesia in this experimental model of neuropathic pain. © 2012 John Wiley & Sons A/S.

Pregabalin versus placebo in targeting pro-nociceptive mechanisms to prevent chronic pain after whiplash injury in at-risk individuals - a feasibility study for a randomised controlled trial.

PubMed

Nikles, J; Keijzers, G; Mitchell, G; Schug, S; Ware, R; McLean, S A; Connelly, L; Gibson, S; Farrell, S F; Sterling, M

2018-01-17

Whiplash-associated disorders (WAD) are an enormous and costly burden to Australian society. Up to 50% of people who experience a whiplash injury will never fully recover. Whiplash is resistant to treatment and no early management approach has yet been shown to prevent chronic pain. The early presence of central sensitization is associated with poor recovery. Pregabalin's effects on central sensitization indicate the potential to prevent or modulate these processes after whiplash injury and to improve health outcomes, but this has not been investigated. This paper describes the protocol for a feasibility study for a randomised controlled trial of pregabalin plus evidence-based advice compared to placebo plus evidence-based advice for individuals with acute whiplash injury who are at risk of poor recovery. This double blind, placebo-controlled randomised feasibility study will examine the feasibility and potential effectiveness of pregabalin and evidence-based advice (intervention) compared to placebo and evidence-based advice (control) for individuals with acute whiplash injury at risk of poor recovery. Thirty participants (15 per group) aged 18-65 years with Grade II WAD, within 48 hours of injury and currently experiencing at least moderate pain (NRS: ≥ 5/10) will be recruited from Emergency Departments of public hospitals in Queensland, Australia. Pregabalin will be commenced at 75 mg bd and titrated up to 300 mg bd as tolerated for 4 weeks followed by 1 week of weaning. The feasibility of trial procedures will be tested, as well as the potential effect of the intervention on the outcomes. The primary outcome of neck pain intensity at 3 months from randomisation will be compared between the treatment groups using standard analysis of variance techniques. Feasibility and potential effectiveness data will inform an appropriately powered full trial, which if successful, will provide an effective and cost-effective intervention for a costly and treatment resistant condition. It will also have implications for the early management of other traumatic conditions beyond whiplash. Clinical Trials Primary Registry: Australian and New Zealand Clinical Trials Registry. ACTRN12617000059369 . Date of Registration: 11/01/2017. Primary Trial Sponsor: The University of Queensland, Brisbane QLD 4072 Australia.

Conditioned pain modulation: a predictor for development and treatment of neuropathic pain.

PubMed

Granovsky, Yelena

2013-09-01

Psychophysical evaluation of endogenous pain inhibition via conditioned pain modulation (CPM) represents a new generation of laboratory tests for pain assessment. In this review we discuss recent findings on CPM in neuropathic pain and refer to psychophysical, neurophysiological, and methodological aspects of its clinical implications. Typically, chronic neuropathic pain patients express less efficient CPM, to the extent that incidence of acquiring neuropathic pain (e.g. post-surgery) and its intensity can be predicted by a pre-surgery CPM assessment. Moreover, pre-treatment CPM evaluation may assist in the correct choice of serotonin-noradrenalin reuptake inhibitor analgesic agents for individual patients. Evaluation of pain modulation capabilities can serve as a step forward in individualizing pain medicine.

Effect of Aromatherapy Massage on Chemotherapy-Induced Peripheral Neuropathic Pain and Fatigue in Patients Receiving Oxaliplatin: An Open Label Quasi-Randomized Controlled Pilot Study.

PubMed

Izgu, Nur; Ozdemir, Leyla; Bugdayci Basal, Fatma

2017-12-02

Patients receiving oxaliplatin may experience peripheral neuropathic pain and fatigue. Aromatherapy massage, a nonpharmacological method, may help to control these symptoms. The aim of this open-label, parallel-group, quasi-randomized controlled pilot study was to investigate the effect of aromatherapy massage on chemotherapy-induced peripheral neuropathic pain and fatigue in patients receiving oxaliplatin. Stratified randomization was used to allocate 46 patients to 2 groups: intervention (n = 22) and control (n = 24). Between week 1 and week 6, participants in the intervention group (IG) received aromatherapy massage 3 times a week. There was no intervention in weeks 7 and 8. The control group (CG) received routine care. Neuropathic pain was identified using the Douleur Neuropathique 4 Questions; severity of painful paresthesia was assessed with the numerical rating scale; fatigue severity was identified with the Piper Fatigue Scale. At week 6, the rate of neuropathic pain was significantly lower in the IG, when compared with the CG. The severity of painful paresthesia based on numerical rating scale in the IG was significantly lower than that in the CG at weeks 2, 4, and 6. At week 8, fatigue severity in the IG was significantly lower when compared with CG (P < .05). Aromatherapy massage may be useful in the management of chemotherapy-induced peripheral neuropathic pain and fatigue. This pilot study suggests that aromatherapy massage may be useful to relieve neuropathic pain and fatigue. However, there is a need for further clinical trials to validate the results of this study.

Inhibition of CaMKIV relieves streptozotocin-induced diabetic neuropathic pain through regulation of HMGB1.

PubMed

Zhao, Xin; Shen, Le; Xu, Li; Wang, Zhiyao; Ma, Chao; Huang, Yuguang

2016-05-23

The pathogenesis of diabetic neuropathic pain is complicated and its underlying mechanisms remain unclear. Calmodulin-dependent protein kinases (CaMKs) IV (CaMKIV), one of CaMKs, regulates several transcription factors in pain mechanisms. High-mobility group box 1 (HMGB1) is a key mediator in diabetic neuropathic pain. This study aims to find the roles and mechanisms of CaMIV in diabetic neuropathic pain. Diabetic animal models were constructed by injecting with streptozotocin (STZ) intraperitoneally. They were randomly divided into seven groups (n = 6 per group): Naive, Normal Saline, STZ, STZ + Sham, STZ + DMSO and STZ + KN93 (an inhibitor of CaMKIV) (50 μg), STZ + KN93 (100 μg), which received KN93 (50 or 100 μg) intrathecally after the administration of STZ. Phospho-CaMKIV (pCaMKIV) and HMGB1 expression in rat dorsal root ganglion (DRG) and RAW264.7 cell line were measured by western blot. Distribution of pCaMKIV immune reactivity in different subpopulations of DRG neurons was measured by double-immunofluorescence staining. The pCaMKIV and HMGB1 in DRG significantly increased after STZ administration, and pCaMKIV can regulate the expression of HMGB1 based on both cellular and animal models. Pretreatment with CaMKIV inhibitor attenuated STZ-induced mechanical allodynia and thermal hyperalgesia, as well as reduced HMGB1 expression in the DRG. This study demonstrates that CaMKIV can relieve STZ-induced diabetic neuropathic pain. The mechanism of this function depended on the process: pCaMKIV localized in the nuclei of DRG neurons and regulated HMGB1 which was an important mediator of neuropathic pain. These findings reported CaMKIV may be a potential target or important node in relieving diabetic neuropathic pain.

HDAC inhibition inhibits brachial plexus avulsion induced neuropathic pain.

PubMed

Zhao, Yingbo; Wu, Tianjian

2018-05-09

Introduction Neuropathic pain induced by brachial plexus avulsion (BPA) is a pathological condition. We hypothesized that inhibition of histone deacetylase (HDAC) could suppress BPA-induced neuropathic pain through inhibition of transient reception potential (TRP) overexpression and protein kinase B (Akt) mediated mammalian target of rapamycin (mTOR) activation. Methods We generated a rat BPA model, administered HDAC inhibitor Tricostatin A (TSA) for 7 days post-surgery and assessed the effects on HDAC expression, Akt phosphorylation, neuroinflammation and mTOR activation. Results TSA treatment alleviated BPA induced mechanical hyperalgesia, suppressed Akt phosphorylation and increased HDAC. We found suppressed pro-inflammatory cytokine levels, TRP cation channel subfamily V member 1 (TRPV1) and TRP melastatin 8 (TRPM8) expression and mTOR activity in TSA treated BPA rats. Discussion Our results suggest that altered HDAC and Akt signaling are involved in BPA-induced neuropathic pain and that inhibition of HDAC could be an effective therapeutic approach in reducing neuropathic pain. This article is protected by copyright. All rights reserved. © 2018 Wiley Periodicals, Inc.

A tactile stimulus applied to the leg improves postural stability in young, old and neuropathic subjects.

PubMed

Menz, Hylton B; Lord, Stephen R; Fitzpatrick, Richard C

2006-10-02

The purpose of this study was to determine whether the application of passive tactile cues to the lower limb could improve postural stability in healthy young controls, older people and people with diabetic peripheral neuropathy. Antero-posterior sway was measured with eyes open and closed in 10 healthy young subjects (mean age 27 years, 5 male, 5 female), 10 older subjects without diabetic peripheral neuropathy (mean age 88 years, 2 male, 8 female) and 10 subjects with diabetic peripheral neuropathy (mean age 65 years, 6 male, 4 female) while a small piece of Velcro attached to a flexible mount was applied to three different sites on the leg (ankle, calf, and knee). Across all conditions, the mean sway of the neuropathic subjects was 93% greater than for the young subjects and 11% more than the older subjects. On average, subjects swayed 10% more with the eyes closed than with the eyes open. Each stimulus reduced sway, but the effect increased approximately in proportion to the height of the stimulus above the ankles (ankle 7.6%, calf 13.5%, knee 20.1% reduction compared to the no stimulus condition). This experiment demonstrates that a passive stimulus applied to the skin of the leg, which provides sensory information about body movement, significantly reduces body sway during standing. This applies to older subjects and subjects with peripheral neuropathy as well as healthy young subjects. These results have implications for novel approaches for improving stability in people with peripheral sensory loss.

Combined use of Pregabalin and Memantine in Fibromyalgia Syndrome Treatment: A Novel Analgesic and Neuroprotective Strategy?

PubMed Central

Recla, Jill M.; Sarantopoulos, Constantine D.

2009-01-01

Fibromyalgia syndrome (FMS) is a chronic widespread pain syndrome that is estimated to affect 4 to 8 million U.S. adults. The exact molecular mechanisms underlying this illness remain unclear, rendering most clinical treatment and management techniques relatively ineffective. It is now known that abnormalities in both nociceptive and central pain processing systems are necessary (but perhaps not sufficient) to condition the onset and maintenance of FMS. These same systemic abnormalities are thought to be responsible for the loss of cephalic gray matter density observed in all FMS patients groups studied to date. The current scope of FMS treatment focuses largely on analgesia and does not clearly address potential neuroprotective strategies. This article proposes a combined treatment of pregabalin and memantine to decrease the pain and rate of gray matter atrophy associated with FMS. This dual-drug therapy targets the voltage-gated calcium ion channel (VGCC) and the N-methyl D-aspartate receptor (NMDAR) (respectively), two primary components of the human nociceptive and pain processing systems. PMID:19362430

An examination of the divergent general, specific, and other criminogenic risk/needs across neuropathic and psychopathic pathways to homicide.

PubMed

Gilligan, D G; Lennings, C J

2011-08-01

The social learning theory underlying Andrews and Bonta's Psychology of Criminal Conduct model has generally been seen as guiding risk assessment, with good relevance to mentally ill as well as non-mentally ill offenders. The current study reports a novel approach to qualitative assessment of 26 murderers found not guilty by reason of insanity (NGRI), divided into two groups--neuropathic offenders characterised by frontal lobe deficits and psychosis and psychopathic murderers characterised by high scores on psychopathy and an absence of neuropathic factors. The findings of the present research support the notion that the two pathways are embedded in two diverging theoretical frameworks of psychopathology and social learning theory, with each corresponding to the neuropathic and psychopathic pathways, respectively. Models of social learning theory may have limited utility to the total mentally disordered offender population overall as they apply more specifically to offenders within special offender groups or perhaps more specifically to offenders with psychopathic characteristics. However, the significantly greater association of the other social, physical, and mental health risk/needs with the neuropathic pathway suggests that pathological models are important for understanding the neuropathic pathway in relation to homicide offence and risk of future violence in NGRI samples.

Complex regional pain syndrome (CRPS/RSD) and neuropathic pain: role of intravenous bisphosphonates as analgesics.

PubMed

Yanow, Jennifer; Pappagallo, Marco; Pillai, Letha

2008-02-25

Neuropathic pain is a sequela of dysfunction, injuries, or diseases of the peripheral and/or central nervous system pain pathways, which has historically been extremely difficult to treat. Complex regional pain syndrome (CRPS) types 1 and 2 are neuropathic pain conditions that have a long history in the medical literature but whose pathophysiology remains elusive and whose available treatment options remain few. While an exact animal model for CRPS doesn't yet exist, there are several animal models of neuropathic pain that develop behaviors of hypersensitivity, one of the hallmark signs of neuropathic pain in humans. Bisphosphonates have been used for pathologic conditions associated with abnormal bone metabolism, such as osteoporosis, Paget's disease and cancer-related bone pain for many years. More recently, results of clinical trials have indicated the potential role of bisphosphonates in the treatment of CRPS/RSD. In this paper we will review the preclinical studies regarding the use of bisphosphonates as analgesics in animal models of neuropathic pain, and also summarize the clinical trials that have been done to date. We will give an overview of bisphosphonate pharmacology and discuss several potential mechanisms by which bisphosphonates may be analgesic in CRPS/RSD and bone pain of noncancer origin.

JNK-induced MCP-1 production in spinal cord astrocytes contributes to central sensitization and neuropathic pain

PubMed Central

Gao, Yong-Jing; Zhang, Ling; Samad, Omar Abdel; Suter, Marc R.; Yasuhiko, Kawasaki; Xu, Zhen-Zhong; Park, Jong-Yeon; Lind, Anne-Li; Ma, Qiufu; Ji, Ru-Rong

2009-01-01

Our previous study showed that activation of c-jun-N-terminal kinase (JNK) in spinal astrocytes plays an important role in neuropathic pain sensitization. We further investigated how JNK regulates neuropathic pain. In cultured astrocytes, TNF-α transiently activated JNK via TNF receptor-1. Cytokine array indicated that the chemokine CCL2/MCP-1 (monocyte chemoattractant protein-1) was strongly induced by the TNF-α/JNK pathway. MCP-1 upregulation by TNF-α was dose-dependently inhibited by the JNK inhibitors SP600125 and D-JNKI-1. Spinal injection of TNF-α produced JNK-dependent pain hypersensitivity and MCP-1 upregulation in the spinal cord. Further, spinal nerve ligation (SNL) induced persistent neuropathic pain and MCP-1 upregulation in the spinal cord, and both were suppressed by D-JNKI-1. Remarkably, MCP-1 was primarily induced in spinal cord astrocytes after SNL. Spinal administration of MCP-1 neutralizing antibody attenuated neuropathic pain. Conversely, spinal application of MCP-1 induced heat hyperalgesia and phosphorylation of extracellular signal-regulated kinase (ERK) in superficial spinal cord dorsal horn neurons, indicative of central sensitization (hyperactivity of dorsal horn neurons). Patch clamp recordings in lamina II neurons of isolated spinal cord slices showed that MCP-1 not only enhanced spontaneous excitatory synaptic currents (sEPSCs) but also potentiated NMDA- and AMPA-induced currents. Finally, the MCP-1 receptor CCR2 was expressed in neurons and some non-neuronal cells in the spinal cord. Taken together, we have revealed a previously unknown mechanism of MCP-1 induction and action. MCP-1 induction in astrocytes following JNK activation contributes to central sensitization and neuropathic pain facilitation by enhancing excitatory synaptic transmission. Inhibition of the JNK/MCP-1 pathway may provide a new therapy for neuropathic pain management. PMID:19339605

Management of Neuropathic Chronic Pain with Methadone Combined with Ketamine: A Randomized, Double Blind, Active-Controlled Clinical Trial.

PubMed

Rigo, Flavia Karine; Trevisan, Gabriela; Godoy, Maria C; Rossato, Mateus Fortes; Dalmolin, Gerusa D; Silva, Mariane A; Menezes, Mirian S; Caumo, Wolnei; Ferreira, Juliano

2017-03-01

Methadone and ketamine are used in neuropathic pain management. However, the benefits of both drugs association are uncertain in the treatment of neuropathic pain. Our primary objective was test the hypothesis that oral methadone combined with oral ketamine is more effective than oral methadone or ketamine alone in reducing neuropathic pain. We conducted a randomized, double blind, active-controlled parallel-group clinical trial. Forty-two patients with neuropathic pain refractory to conventional therapy were randomly assigned to receive oral methadone (n = 14), ketamine (n = 14), or methadone plus ketamine (n = 14) over a 3-month period. During these 90 days, we observed pain scores using a visual analogical scale (VAS), allodynia, burning/shooting pain, and some side effects. All treatments were effective in reducing pain scores by at least 40%. However, a significant improvement in pain was observed only in the ketamine alone group compared with both the methadone or methadone/ketamine groups. No significant differences were observed among the treatment groups for the reduction of burning or shooting pain, while ketamine alone was more effective than methadone or methadone/ketamine for the reduction of allodynia. Formal assessment for awareness of the allocation was not performed, some co-intervention bias may have occurred, our results could be only relevant to the patient population investigated and the use of VAS as the primary outcome detect changes in pain intensity but not to assess neuropathic pain symptoms. This study indicates that ketamine was better than methadone or methadone/ketamine for treating neuropathic pain.Key words: Multimodal analgesia, refractory pain, NMDA receptor, opioid.

Dopaminergic tone does not influence pain levels during placebo interventions in patients with chronic neuropathic pain.

PubMed

Skyt, Ina; Moslemi, Kurosh; Baastrup, Cathrine; Grosen, Kasper; Benedetti, Fabrizio; Petersen, Gitte L; Price, Donald D; Hall, Kathryn T; Kaptchuk, Ted J; Svensson, Peter; Jensen, Troels S; Vase, Lene

2017-10-23

Placebo effects have been reported in patients with chronic neuropathic pain. Expected pain levels and positive emotions are involved in the observed pain relief, but the underlying neurobiology is largely unknown. Patients with neuropathic pain are highly motivated for pain relief, and as motivational factors such as expectations of reward, as well as pain processing in itself, are related to the dopaminergic system, it can be speculated that dopamine release contributes to placebo effects in neuropathic pain. Nineteen patients with neuropathic pain after thoracic surgery were tested during a placebo intervention consisting of open and hidden applications of the pain-relieving agent lidocaine (2 mL) and no treatment. The dopamine antagonist haloperidol (2 mg) and the agonist levodopa/carbidopa (100/25 mg) were administered to test the involvement of dopamine. Expected pain levels, desire for pain relief, and ongoing and evoked pain were assessed on mechanical visual analog scales (0-10). Significant placebo effects on ongoing (P ≤ 0.003) and evoked (P ≤ 0.002) pain were observed. Expectancy and desire accounted for up to 41.2% and 71.5% of the variance in ongoing and evoked pain, respectively, after the open application of lidocaine. We found no evidence for an effect of haloperidol and levodopa/carbidopa on neuropathic pain levels (P = 0.071-0.963). Dopamine seemed to influence the levels of expectancy and desire, yet there was no evidence for indirect or interaction effects on the placebo effect. This is the first study to suggest that dopamine does not contribute to placebo effects in chronic neuropathic pain.

Physical therapy modalities and rehabilitation techniques in the management of neuropathic pain.

PubMed

Akyuz, Gulseren; Kenis, Ozge

2014-03-01

Neuropathic pain is an important problem because of its complex natural history, unclear etiology, and poor response to standard physical therapy agents. It causes severe disability unrelated to its etiology. The primary goals of the management of neuropathic pain are to detect the underlying cause, to define the differential diagnosis and eliminate risk factors, and to reduce the pain. The physician should also know the functional and psychologic conditions of the patient. Therefore, a multimodal management plan in neuropathic pain is essential. This review aimed to reflect a diverse point of view about various physical therapy modalities and rehabilitation techniques. Physical therapy modalities and rehabilitation techniques are important options and must be considered when pharmacotherapy alone is not sufficient. In addition, psychosocial support and cognitive behavioral therapy could also be taken into consideration. It has been suggested that the importance of pain rehabilitation techniques will increase in time and these will take a larger part in the management of neuropathic pain. However, it is now early to comment on these methods because of the lack of adequate publications.

Neuropathic pain: an updated grading system for research and clinical practice

PubMed Central

Finnerup, Nanna B.; Haroutounian, Simon; Kamerman, Peter; Baron, Ralf; Bennett, David L.H.; Bouhassira, Didier; Cruccu, Giorgio; Freeman, Roy; Hansson, Per; Nurmikko, Turo; Raja, Srinivasa N.; Rice, Andrew S.C.; Serra, Jordi; Smith, Blair H.; Treede, Rolf-Detlef; Jensen, Troels S.

2016-01-01

Abstract The redefinition of neuropathic pain as “pain arising as a direct consequence of a lesion or disease affecting the somatosensory system,” which was suggested by the International Association for the Study of Pain (IASP) Special Interest Group on Neuropathic Pain (NeuPSIG) in 2008, has been widely accepted. In contrast, the proposed grading system of possible, probable, and definite neuropathic pain from 2008 has been used to a lesser extent. Here, we report a citation analysis of the original NeuPSIG grading paper of 2008, followed by an analysis of its use by an expert panel and recommendations for an improved grading system. As of February, 2015, 608 eligible articles in Scopus cited the paper, 414 of which cited the neuropathic pain definition. Of 220 clinical studies citing the paper, 56 had used the grading system. The percentage using the grading system increased from 5% in 2009 to 30% in 2014. Obstacles to a wider use of the grading system were identified, including (1) questions about the relative significance of confirmatory tests, (2) the role of screening tools, and (3) uncertainties about what is considered a neuroanatomically plausible pain distribution. Here, we present a revised grading system with an adjusted order, better reflecting clinical practice, improvements in the specifications, and a word of caution that even the “definite” level of neuropathic pain does not always indicate causality. In addition, we add a table illustrating the area of pain and sensory abnormalities in common neuropathic pain conditions and propose areas for further research. PMID:27115670

Predictors of a favourable outcome in patients with fibromyalgia: results of 1-year follow-up.

PubMed

Kim, Ji-Eun; Park, Dong-Jin; Choi, Sung-Eun; Kang, Ji-Hyoun; Yim, Yi-Rang; Lee, Jeong-Won; Lee, Kyung-Eun; Wen, Lihui; Kim, Seong-Kyu; Choe, Jung-Yoon; Lee, Shin-Seok

2016-01-01

To determine the outcomes of Korean patients with fibromyalgia (FM) and to identify prognostic factors associated with improvement at 1-year follow-up. Forty-eight patients with FM were enrolled and examined every 3 months for 1 year. At the time of enrollment, we interviewed all patients using a structured questionnaire that recorded socio-demographic data, current or past FM symptoms, and current use of relevant medications. Tender point counts and scores were assessed by thumb palpation. Patients were asked to complete the Korean versions of the Fibromyalgia Impact Questionnaire (FIQ), the Brief Fatigue Inventory, the SF-36, the Beck Depression Inventory, the State-Trait Anxiety Inventory (STAI), the Self-Efficacy Scale, and the Social Support Scale. Tender points, FIQ scores, and the use of relevant medications were recorded during one year of follow-up. Of the 48 patients, 32 (66.7%) had improved FIQ scores 1 year after enrollment. Improved patients had higher baseline FIQ scores (68.4±13.9 vs. 48.4±20.8, p=0.001) and STAI-II scores (55.8±10.9 vs. 11.5±11.5, p=0.022). Patients treated with pregabalin were more likely to improve after 1 year, based on the FIQ scores (71.9% vs. 37.5%, p=0.031). On multivariate logistic regression analysis, a higher STAI-II score at the time of enrollment and pregabalin treatment during one year of follow-up were the predictors of improvement. Two-thirds of our Korean FM patients experienced some clinical improvement by 1-year follow-up. A high baseline STAI-II score and treatment with pregabalin were the important predictor of improved FM.

CXCR4 chemokine receptor signaling mediates pain in diabetic neuropathy

PubMed Central

2014-01-01

Background Painful Diabetic Neuropathy (PDN) is a debilitating syndrome present in a quarter of diabetic patients that has a substantial impact on their quality of life. Despite this significant prevalence and impact, current therapies for PDN are only partially effective. Moreover, the cellular mechanisms underlying PDN are not well understood. Neuropathic pain is caused by a variety of phenomena including sustained excitability in sensory neurons that reduces the pain threshold so that pain is produced in the absence of appropriate stimuli. Chemokine signaling has been implicated in the pathogenesis of neuropathic pain in a variety of animal models. We therefore tested the hypothesis that chemokine signaling mediates DRG neuronal hyperexcitability in association with PDN. Results We demonstrated that intraperitoneal administration of the specific CXCR4 antagonist AMD3100 reversed PDN in two animal models of type II diabetes. Furthermore DRG sensory neurons acutely isolated from diabetic mice displayed enhanced SDF-1 induced calcium responses. Moreover, we demonstrated that CXCR4 receptors are expressed by a subset of DRG sensory neurons. Finally, we observed numerous CXCR4 expressing inflammatory cells infiltrating into the DRG of diabetic mice. Conclusions These data suggest that CXCR4/SDF-1 signaling mediates enhanced calcium influx and excitability in DRG neurons responsible for PDN. Simultaneously, CXCR4/SDF-1 signaling may coordinate inflammation in diabetic DRG that could contribute to the development of pain in diabetes. Therefore, targeting CXCR4 chemokine receptors may represent a novel intervention for treating PDN. PMID:24961298

Fast Synaptic Inhibition in Spinal Sensory Processing and Pain Control

PubMed Central

Zeilhofer, Hanns Ulrich; Wildner, Hendrik; Yevenes, Gonzalo E.

2013-01-01

The two amino acids γ-amino butyric acid (GABA) and glycine mediate fast inhibitory neurotransmission in different CNS areas and serve pivotal roles in the spinal sensory processing. Under healthy conditions, they limit the excitability of spinal terminals of primary sensory nerve fibers and of intrinsic dorsal horn neurons through pre- and postsynaptic mechanisms, and thereby facilitate the spatial and temporal discrimination of sensory stimuli. Removal of fast inhibition not only reduces the fidelity of normal sensory processing but also provokes symptoms very much reminiscent of pathological and chronic pain syndromes. This review summarizes our knowledge of the molecular bases of spinal inhibitory neurotransmission and its organization in dorsal horn sensory circuits. Particular emphasis is placed on the role and mechanisms of spinal inhibitory malfunction in inflammatory and neuropathic chronic pain syndromes. PMID:22298656

Interference with work in fibromyalgia - effect of treatment with pregabalin and relation to pain response

PubMed Central

2011-01-01

Background Clinical trials in chronic pain often collect information about interference with work as answers to component questions of commonly used questionnaires but these data are not normally analysed separately. Methods We performed a meta-analysis of individual patient data from four large trials of pregabalin for fibromyalgia lasting 8-14 weeks. We analysed data on interference with work, inferred from answers to component questions of Fibromyalgia Impact Questionnaire (FIQ), Short Form 36 Health Survey, Sheehan Disability Scale, and Multidimensional Assessment of Fatigue, including "How many days in the past week did you miss work, including housework, because of fibromyalgia?" from FIQ. Analyses were performed according to randomised treatment group (pregabalin 150-600 mg daily or placebo), pain improvement (0-10 numerical pain rating scale scores at trial beginning vs. end), and end of trial pain state (100 mm visual analogue pain scale [VAS]). Results Comparing treatment group average outcomes revealed modest improvement over the duration of the trials, more so with active treatment than with placebo. For the 'work missed' question from FIQ the change for patients on placebo was from 2.2 (standard deviation [SD] 2.3) days of work lost per week at trial beginning to 1.9 (SD 2.1) days lost at trial end (p < 0.01). For patients on 600 mg pregabalin the change was from 2.1 (SD 2.2) days to 1.6 (SD 2.0) days (p < 0.001). However, the change in days of work lost was substantial in patients with a good pain response: from 2.0 (SD 2.2) days to 0.97 (SD 1.6) days (p < 0.0001) for those experiencing >/= 50% pain improvement and from 1.9 (SD 2.2) days to 0.73 (SD 1.4) days (p < 0.0001) for those achieving a low level of pain at trial end (<30 mm on the VAS). Patients achieving both >/= 50% pain improvement and a pain score <30 mm on the VAS had the largest improvement, from 2.0 (SD 2.2) days to 0.60 (SD 1.3) days (p < 0.0001). Analysing answers to the other questions yielded qualitatively similar results. Conclusions Effective pain treatment goes along with benefit regarding work. A reduction in time off work >1 day per week can be achieved in patients with good pain responses. PMID:21639874

JNK-induced MCP-1 production in spinal cord astrocytes contributes to central sensitization and neuropathic pain.

PubMed

Gao, Yong-Jing; Zhang, Ling; Samad, Omar Abdel; Suter, Marc R; Yasuhiko, Kawasaki; Xu, Zhen-Zhong; Park, Jong-Yeon; Lind, Anne-Li; Ma, Qiufu; Ji, Ru-Rong

2009-04-01

Our previous study showed that activation of c-jun-N-terminal kinase (JNK) in spinal astrocytes plays an important role in neuropathic pain sensitization. We further investigated how JNK regulates neuropathic pain. In cultured astrocytes, tumor necrosis factor alpha (TNF-alpha) transiently activated JNK via TNF receptor-1. Cytokine array indicated that the chemokine CCL2/MCP-1 (monocyte chemoattractant protein-1) was strongly induced by the TNF-alpha/JNK pathway. MCP-1 upregulation by TNF-alpha was dose dependently inhibited by the JNK inhibitors SP600125 (anthra[1,9-cd]pyrazol-6(2H)-one) and D-JNKI-1. Spinal injection of TNF-alpha produced JNK-dependent pain hypersensitivity and MCP-1 upregulation in the spinal cord. Furthermore, spinal nerve ligation (SNL) induced persistent neuropathic pain and MCP-1 upregulation in the spinal cord, and both were suppressed by D-JNKI-1. Remarkably, MCP-1 was primarily induced in spinal cord astrocytes after SNL. Spinal administration of MCP-1 neutralizing antibody attenuated neuropathic pain. Conversely, spinal application of MCP-1 induced heat hyperalgesia and phosphorylation of extracellular signal-regulated kinase in superficial spinal cord dorsal horn neurons, indicative of central sensitization (hyperactivity of dorsal horn neurons). Patch-clamp recordings in lamina II neurons of isolated spinal cord slices showed that MCP-1 not only enhanced spontaneous EPSCs but also potentiated NMDA- and AMPA-induced currents. Finally, the MCP-1 receptor CCR2 was expressed in neurons and some non-neuronal cells in the spinal cord. Together, we have revealed a previously unknown mechanism of MCP-1 induction and action. MCP-1 induction in astrocytes after JNK activation contributes to central sensitization and neuropathic pain facilitation by enhancing excitatory synaptic transmission. Inhibition of the JNK/MCP-1 pathway may provide a new therapy for neuropathic pain management.

Is there pain with neuropathic characteristics in patients with amyotrophic lateral sclerosis? A cross-sectional study.

PubMed

Moisset, Xavier; Cornut-Chauvinc, Catherine; Clavelou, Pierre; Pereira, Bruno; Dallel, Radhouane; Guy, Nathalie

2016-05-01

Amyotrophic lateral sclerosis is a progressive debilitating and lethal disorder, characterized by degeneration of motor neurons that warrant palliative care. Pain is frequent in patients with amyotrophic lateral sclerosis and significantly impacts on quality of life. To describe pain and assess the prevalence of pain with neuropathic characteristics in patients with amyotrophic lateral sclerosis. Cross-sectional survey from March 2009 to October 2013. Amyotrophic lateral sclerosis patients underwent multidisciplinary assessment and completed questionnaires measuring the severity and impact of pain and anxiety. The Douleur Neuropathique-4 questionnaire was used to look for pain with neuropathic characteristics. Of 96 clinical evaluations, 93 were usable for analysis (age at onset: 62 ± 12.5 years; disease duration: 34 ± 33 months). The overall pain prevalence was 66%, with 9% experiencing pain with neuropathic characteristics. Pain was most often located in the neck and shoulders (38% of pain patients). Neck and shoulder pain was associated with neck (p = 0.04) and proximal upper limb muscular weakness (p = 0.02), respectively. Pain was not associated with disease duration, respiratory or nutritional parameters, but with higher anxiety scores (p = 0.01). Patients with neuropathic characteristics pain did not differ significantly from patients with or without pain, except that they had higher minimal pain intensity score (p < 0.05). Neuropathic characteristics pain was frequently spontaneous (rarely evoked) and described as numbness, burning, electric shock, tingling, and pins-and-needle. Even if amyotrophic lateral sclerosis is a disease of the motor system, pain is frequent and can rarely have neuropathic characteristics. Pain must be always sought and appropriately treated to limit quality of life impairment. © The Author(s) 2015.

Adoptive transfer of M2 macrophages reduces neuropathic pain via opioid peptides.

PubMed

Pannell, Maria; Labuz, Dominika; Celik, Melih Ö; Keye, Jacqueline; Batra, Arvind; Siegmund, Britta; Machelska, Halina

2016-10-07

During the inflammation which occurs following nerve damage, macrophages are recruited to the site of injury. Phenotypic diversity is a hallmark of the macrophage lineage and includes pro-inflammatory M1 and anti-inflammatory M2 populations. Our aim in this study was to investigate the ability of polarized M0, M1, and M2 macrophages to secrete opioid peptides and to examine their relative contribution to the modulation of neuropathic pain. Mouse bone marrow-derived cells were cultured as unstimulated M0 macrophages or were stimulated into an M1 phenotype using lipopolysaccharide and interferon-γ or into an M2 phenotype using interleukin-4. The macrophage phenotypes were verified using flow cytometry for surface marker analysis and cytokine bead array for cytokine profile assessment. Opioid peptide levels were measured by radioimmunoassay and enzyme immunoassay. As a model of neuropathic pain, a chronic constriction injury (CCI) of the sciatic nerve was employed. Polarized M0, M1, and M2 macrophages (5 × 10 5 cells) were injected perineurally twice, on days 14 and 15 following CCI or sham surgery. Mechanical and heat sensitivity were measured using the von Frey and Hargreaves tests, respectively. To track the injected macrophages, we also transferred fluorescently stained polarized cells and analyzed the surface marker profile of endogenous and injected cells in the nerves ex vivo. Compared to M0 and M1 cells, M2 macrophages contained and released higher amounts of opioid peptides, including Met-enkephalin, dynorphin A (1-17), and β-endorphin. M2 cells transferred perineurally at the nerve injury site reduced mechanical, but not heat hypersensitivity following the second injection. The analgesic effect was reversed by the perineurally applied opioid receptor antagonist naloxone methiodide. M2 cells did not affect sensitivity following sham surgery. Neither M0 nor M1 cells altered mechanical and heat sensitivity in CCI or sham-operated animals. Tracing the fluorescently labeled M0, M1, and M2 cells ex vivo showed that they remained in the nerve and preserved their phenotype. Perineural transplantation of M2 macrophages resulted in opioid-mediated amelioration of neuropathy-induced mechanical hypersensitivity, while M1 macrophages did not exacerbate pain. Therefore, rather than focusing on macrophage-induced pain generation, promoting opioid-mediated M2 actions may be more relevant for pain control.

Molecular mechanisms underlying the effects of acupuncture on neuropathic pain.

PubMed

Ju, Ziyong; Cui, Huashun; Guo, Xiaohui; Yang, Huayuan; He, Jinsen; Wang, Ke

2013-09-05

Acupuncture has been used to treat neuropathic pain for a long time, but its mechanisms of action remain unknown. In this study, we observed the effects of electroacupuncture and manual acu-puncture on neuropathic pain and on ephrin-B/EphB signaling in rats models of chronic constriction injury-induced neuropathic pain. The results showed that manual acupuncture and elec-puncture significantly reduced mechanical hypersensitivity following chronic constriction injury, es-pecially electroacupuncture treatment. Real-time PCR results revealed that ephrin-B1/B3 and EphB1/B2 mRNA expression levels were significantly increased in the spinal dorsal horns of chronic constriction injury rats. Electroacupuncture and manual acupuncture suppressed the high sion of ephrin-B1 mRNA, and elevated EphB3/B4 mRNA expression. Electroacupuncture signifi-cantly enhanced the mRNA expression of ephrin-B3 and EphB3/B6 in the dorsal horns of neuro-pathic pain rats. Western blot results revealed that electroacupuncture in particular, and manual acupuncture, significantly up-regulated ephrin-B3 protein levels in rat spinal dorsal horns. The re-sults of this study suggest that acupuncture could activate ephrin-B/EphB signaling in neuropathic pain rats and improve neurological function.

A rare case of idiopathic thumb CMC joint neuropathic arthropathy complicated by blunt trauma.

PubMed

Singh, Manavdeep; Butala, R R; Khedekar, R G; Tripati, Manish

2016-01-01

Neuropathic arthropathy (Charcot joints), which most frequently affects the weight-bearing joints of the body, is commonly associated with a variety of medical and neurological conditions, and is notoriously difficult to treat due to the nature of the underlying pathology. We present a case of idiopathic neuropathic arthropathy of the thumb CMC joint of an elderly female complicated by blunt trauma to the thumb. To our knowledge, this is the first reported case in the literature of this rare association.

Long non-coding RNA CCAT1 modulates neuropathic pain progression through sponging miR-155.

PubMed

Dou, Lidong; Lin, Hongqi; Wang, Kaiwei; Zhu, Guosong; Zou, Xuli; Chang, Enqiang; Zhu, Yongfeng

2017-10-27

Neuropathic pain is caused by dysfunction or primary injury of the somatosensory nervous system. Long noncoding RNAs (lncRNAs) play important roles in the development of neuropathic pain. However, the effects of lncRNA colon cancer associated transcript-1 (CCAT1) in neuropathic pain have not been reported. The model of bilateral sciatic nerve chronic constriction injuries (bCCI) is regarded as long-lasting mechanical hypersensitivity and cold allodynia, which is the representative symptom in the human subjects suffering from the neuropathic pain. In this study, we found that CCAT1 expression was decreased in the spinal dorsal horn, dorsal root ganglion (DRG), hippocampus, and anterior cingulate cortex (ACC) of rats with bCCI. The rats of bCCI presented the cold allodynia after the 14 th day of postoperation. We furtherly showed that lncRNA CCAT1 decreased miR-155 expression and enhanced Serum and glucocorticoid regulated protein kinase 3 (SGK3) expression in the NGF-differentiated PC12 cell. We found that miR-155 expression was increased in the spinal dorsal horn, DRG, hippocampus, and ACC of rats with bCCI injuries. However, SGK3 expression was downregulated in the spinal dorsal horn, DRG, hippocampus, and ACC of rats with bCCI injuries. Moreover, lncRNA CCAT1 overexpression could alleviate the pain thresholds and inhibited expression of SGK3 could rescue this effect. In conclusion, these results suggested the crucial roles of CCAT1 and SGK3 in the neuropathic pain.

Identification of a vesicular ATP release inhibitor for the treatment of neuropathic and inflammatory pain.

PubMed

Kato, Yuri; Hiasa, Miki; Ichikawa, Reiko; Hasuzawa, Nao; Kadowaki, Atsushi; Iwatsuki, Ken; Shima, Kazuhiro; Endo, Yasuo; Kitahara, Yoshiro; Inoue, Tsuyoshi; Nomura, Masatoshi; Omote, Hiroshi; Moriyama, Yoshinori; Miyaji, Takaaki

2017-07-18

Despite the high incidence of neuropathic and inflammatory pain worldwide, effective drugs with few side effects are currently unavailable for the treatment of chronic pain. Recently, researchers have proposed that inhibitors of purinergic chemical transmission, which plays a key role in the pathological pain response, may allow for targeted treatment of pathological neuropathic and inflammatory pain. However, such therapeutic analgesic agents have yet to be developed. In the present study, we demonstrated that clodronate, a first-generation bisphosphonate with comparatively fewer side effects than traditional treatments, significantly attenuates neuropathic and inflammatory pain unrelated to bone abnormalities via inhibition of vesicular nucleotide transporter (VNUT), a key molecule for the initiation of purinergic chemical transmission. In vitro analyses indicated that clodronate inhibits VNUT at a half-maximal inhibitory concentration of 15.6 nM without affecting other vesicular neurotransmitter transporters, acting as an allosteric modulator through competition with Cl - A low concentration of clodronate impaired vesicular ATP release from neurons, microglia, and immune cells. In vivo analyses revealed that clodronate is more effective than other therapeutic agents in attenuating neuropathic and inflammatory pain, as well as the accompanying inflammation, in wild-type but not VNUT -/- mice, without affecting basal nociception. These findings indicate that clodronate may represent a unique treatment strategy for chronic neuropathic and inflammatory pain via inhibition of vesicular ATP release.

Validating a human model for anxiety using startle potentiated by cue and context: the effects of alprazolam, pregabalin, and diphenhydramine

PubMed Central

Mol, N.; Kenemans, J. L.; Prinssen, E. P.; Niklson, I.; Xia-Chen, C.; Broeyer, F.; van Gerven, J.

2009-01-01

Background Fear-potentiated startle has been suggested as a translational model for evaluating efficacy of anxiolytic compounds in humans. Several known anxiolytic compounds have been tested as well as several putative anxiolytics. Because results of these studies have been equivocal, the aim of the present study was to examine another pharmacological permutation of the human potentiated startle model by comparing two anxiolytic agents to a non-anxiolytic sedative and placebo. Methods Twenty healthy volunteers participated in a double-blind, placebo-controlled, cross-over study with four sessions in which they received single doses of the anxiolytics alprazolam (1 mg) and pregabalin (200 mg), as well as diphenhydramine (50 mg) as a non-anxiolytic sedative control and placebo. The design included a cued shock condition that presumably evokes fear and an unpredictable shock context condition presumably evoking anxiety. Results None of the treatments reliably reduced either fear- or anxiety-potentiated startle. Alprazolam and diphenhydramine reduced overall baseline startle. Alprazolam was found to only affect contextual anxiety in a statistical significant way after two subjects who failed to show a contextual anxiety effect in the placebo condition were excluded from the analysis. Pregabalin did not significantly affect any of the physiological measures. Discussion The negative findings from this study are discussed in terms of methodological differences between designs and in variability of startle both between and within study participants. Conclusion Even though fear-potentiated startle may be used to translate preclinical evidence to human populations, methodological issues still hamper the application of this model to early screening of putative anxiolytic drugs. PMID:19415242

Molecular mechanisms underlying the effects of acupuncture on neuropathic pain

PubMed Central

Ju, Ziyong; Cui, Huashun; Guo, Xiaohui; Yang, Huayuan; He, Jinsen; Wang, Ke

2013-01-01

Acupuncture has been used to treat neuropathic pain for a long time, but its mechanisms of action remain unknown. In this study, we observed the effects of electroacupuncture and manual acu-puncture on neuropathic pain and on ephrin-B/EphB signaling in rats models of chronic constriction injury-induced neuropathic pain. The results showed that manual acupuncture and elec-puncture significantly reduced mechanical hypersensitivity following chronic constriction injury, es-pecially electroacupuncture treatment. Real-time PCR results revealed that ephrin-B1/B3 and EphB1/B2 mRNA expression levels were significantly increased in the spinal dorsal horns of chronic constriction injury rats. Electroacupuncture and manual acupuncture suppressed the high sion of ephrin-B1 mRNA, and elevated EphB3/B4 mRNA expression. Electroacupuncture signifi-cantly enhanced the mRNA expression of ephrin-B3 and EphB3/B6 in the dorsal horns of neuro-pathic pain rats. Western blot results revealed that electroacupuncture in particular, and manual acupuncture, significantly up-regulated ephrin-B3 protein levels in rat spinal dorsal horns. The re-sults of this study suggest that acupuncture could activate ephrin-B/EphB signaling in neuropathic pain rats and improve neurological function. PMID:25206545

Synthesis and biological evaluation of compact, conformationally constrained bifunctional opioid agonist – neurokinin-1 antagonist peptidomimetics

PubMed Central

Guillemyn, Karel; Kleczkowska, Patrycia; Lesniak, Anna; Dyniewicz, Jolanta; Van der Poorten, Olivier; Van den Eynde, Isabelle; Keresztes, Attila; Varga, Eva; Lai, Josephine; Porreca, Frank; Chung, Nga N.; Lemieux, Carole; Mika, Joanna; Rojewska, Ewelina; Makuch, Wioletta; Van Duppen, Joost; Przewlocka, Barbara; Broeck, Jozef Vanden; Lipkowski, Andrzej W.; Schiller, Peter W.; Tourwé, Dirk; Ballet, Steven

2014-01-01

A reported mixed opioid agonist - neurokinin 1 receptor (NK1R) antagonist 4 (Dmt-D-Arg-Aba-Gly-(3’,5’-(CF3)2)NMe-benzyl) was modified to identify important features in both pharmacophores. The new dual ligands were tested in vitro and subsequently two compounds (lead structure 4 and one of the new analogues 22, Dmt-D-Arg-Aba-β-Ala-NMe-Bn) were selected for in vivo behavioral assays, which were conducted in acute (tail-flick) and neuropathic pain models (cold plate and von Frey) in rats. Compared to the parent opioid compound 33 (without NK1R pharmacophore), hybrid 22 was more active in the neuropathic pain models. Attenuation of neuropathic pain emerged from NK1R antagonism as demonstrated by the pure NK1R antagonist 6. Surprisingly, despite a lower in vitro activity at NK1R in comparison with 4, compound 22 was more active in the neuropathic pain models. Although potent analgesic effects were observed for 4 and 22, upon chronic administration, both manifested a tolerance profile similar to that of morphine and cross tolerance with morphine in a neuropathic pain model in rat. PMID:25544687

Motor cortex stimulation and neuropathic pain: how does motor cortex stimulation affect pain-signaling pathways?

PubMed

Kim, Jinhyung; Ryu, Sang Baek; Lee, Sung Eun; Shin, Jaewoo; Jung, Hyun Ho; Kim, Sung June; Kim, Kyung Hwan; Chang, Jin Woo

2016-03-01

Neuropathic pain is often severe. Motor cortex stimulation (MCS) is used for alleviating neuropathic pain, but the mechanism of action is still unclear. This study aimed to understand the mechanism of action of MCS by investigating pain-signaling pathways, with the expectation that MCS would regulate both descending and ascending pathways. Neuropathic pain was induced in Sprague-Dawley rats. Surface electrodes for MCS were implanted in the rats. Tactile allodynia was measured by behavioral testing to determine the effect of MCS. For the pathway study, immunohistochemistry was performed to investigate changes in c-fos and serotonin expression; micro-positron emission tomography (mPET) scanning was performed to investigate changes of glucose uptake; and extracellular electrophysiological recordings were performed to demonstrate brain activity. MCS was found to modulate c-fos and serotonin expression. In the mPET study, altered brain activity was observed in the striatum, thalamic area, and cerebellum. In the electrophysiological study, neuronal activity was increased by mechanical stimulation and suppressed by MCS. After elimination of artifacts, neuronal activity was demonstrated in the ventral posterolateral nucleus (VPL) during electrical stimulation. This neuronal activity was effectively suppressed by MCS. This study demonstrated that MCS effectively attenuated neuropathic pain. MCS modulated ascending and descending pain pathways. It regulated neuropathic pain by affecting the striatum, periaqueductal gray, cerebellum, and thalamic area, which are thought to regulate the descending pathway. MCS also appeared to suppress activation of the VPL, which is part of the ascending pathway.

Intravenous Ketamine Infusions for Neuropathic Pain Management: A Promising Therapy in Need of Optimization.

PubMed

Maher, Dermot P; Chen, Lucy; Mao, Jianren

2017-02-01

Intravenous ketamine infusions have been used extensively to treat often-intractable neuropathic pain conditions. Because there are many widely divergent ketamine infusion protocols described in the literature, the variation in these protocols presents a challenge for direct comparison of one protocol with another and in discerning an optimal protocol. Careful examination of the published literature suggests that ketamine infusions can be useful to treat neuropathic pain and that certain characteristics of ketamine infusions may be associated with better clinical outcomes. Increased duration of relief from neuropathic pain is associated with (1) higher total infused doses of ketamine; (2) prolonged infusion durations, although the rate of infusion does not appear to be a factor; and (3) coadministration of adjunct medications such as midazolam and/or clonidine that mitigate some of the unpleasant psychomimetic side effects. However, there are few studies designed to optimize ketamine infusion protocols by defining what an effective infusion protocol entails with regard to a respective neuropathic pain condition. Therefore, despite common clinical practice, the current state of the literature leaves the use of ketamine infusions without meaningful guidance from high-quality comparative evidence. The objectives of this topical review are to (1) analyze the available clinical evidence related to ketamine infusion protocols and (2) call for clinical studies to identify optimal ketamine infusion protocols tailored for individual neuropathic pain conditions. The Oxford Center for Evidence-Based Medicine classification for levels of evidence was used to stratify the grades of clinical recommendation for each infusion variable studied.

The application of neuropathic pain questionnaires in burning mouth syndrome patients.

PubMed

Heo, Jun-Young; Ok, Soo-Min; Ahn, Yong-Woo; Ko, Myung-Yun; Jeong, Sung-Hee

2015-01-01

To evaluate and compare the validity of the PainDETECT, DN4, and abbreviated DN4 (DN4i) neuropathic pain questionnaires for primary burning mouth syndrome (BMS), which is a burning sensation in the oral mucosa in the absence of any identifiable organic etiology. Eighty-one patients (42 with primary BMS and 39 with nociceptive pain) complaining of a burning sensation and pain in their oral mucosa were enrolled in this study. All of the patients completed the neuropathic pain questionnaires. The sensitivity, specificity, positive predictive value, negative predictive value, and the area under the receiver operating characteristic (ROC) curve were estimated. Then the relationship between pain intensity and total neuropathic pain score was investigated. Data were analyzed with the chi-square test and independent t test for subjects' baseline characteristic differences, and with Pearson correlation coefficients for the relationship of variables. The mean area under the ROC curves (AUCs) for PainDETECT, DN4, and DN4i were 0.81, 0.79, and 0.81, respectively. There was no statistically significant difference in the AUCs among the questionnaires. PainDETECT, DN4, and DN4i had a lower sensitivity and specificity for BMS compared to previous validation studies. The total scores for PainDETECT, DN4, and DN4i in the primary BMS group were significantly associated with pain intensity. Although the results of this study suggest that neuropathic pain questionnaires, such as PainDETECT and DN4, are not ideal principal screening tools for BMS patients, a substantial proportion of neuropathic symptoms in primary BMS patients were identified.

Overexpression of GDNF in the uninjured DRG exerts analgesic effects on neuropathic pain following segmental spinal nerve ligation in mice.

PubMed

Takasu, Kumiko; Sakai, Atsushi; Hanawa, Hideki; Shimada, Takashi; Suzuki, Hidenori

2011-11-01

Glial cell line-derived neurotrophic factor (GDNF), a survival-promoting factor for a subset of nociceptive small-diameter neurons, has been shown to exert analgesic effects on neuropathic pain. However, its detailed mechanisms of action are still unknown. In the present study, we investigated the site-specific analgesic effects of GDNF in the neuropathic pain state using lentiviral vector-mediated GDNF overexpression in mice with left fifth lumbar (L5) spinal nerve ligation (SNL) as a neuropathic pain model. A lentiviral vector expressing both GDNF and enhanced green fluorescent protein (EGFP) was constructed and injected into the left dorsal spinal cord, uninjured fourth lumbar (L4) dorsal root ganglion (DRG), injured L5 DRG, or plantar skin of mice. In SNL mice, injection of the GDNF-EGFP-expressing lentivirus into the dorsal spinal cord or uninjured L4 DRG partially but significantly reduced the mechanical allodynia in association with an increase in GDNF protein expression in each virus injection site, whereas injection into the injured L5 DRG or plantar skin had no effects. These results suggest that GDNF exerts its analgesic effects in the neuropathic pain state by acting on the central terminals of uninjured DRG neurons and/or on the spinal cells targeted by the uninjured DRG neurons. This article shows that GDNF exerts its analgesic effects on neuropathic pain by acting on the central terminals of uninjured DRG neurons and/or on the spinal cells targeted by these neurons. Therefore, research focusing on these GDNF-dependent neurons in the uninjured DRG would provide a new strategy for treating neuropathic pain. Copyright © 2011 American Pain Society. Published by Elsevier Inc. All rights reserved.

[Prevalence and characteristics of chronic pain with neuropathic component at Parakou in northern Benin in 2012].

PubMed

Adoukonou, T; Gnonlonfoun, D; Kpozehouen, A; Adjien, C; Tchaou, B; Tognon-Tchegnonsi, F; Adechina, H; Covi, R; Houinato, D

2014-11-01

The burden of chronic and neuropathic pain is high making it an important public health problem. The epidemiology is not well known in the general population in sub-Saharan Africa. We aimed to determine the prevalence of chronic pain with a neuropathic component at Tititou in Parakou in northeastern Benin. A cross-sectional study was conducted from 1st April to 31 May 2012 and included 2314 people in a door-to-door survey. Chronic pain was defined as pain occurring for more than three months. Neuropathic pain was assessed with the DN4 score. A neurological exam was performed by a young physician for all people with chronic pain. During the interview, sociodemographic data, past medical history, weight and height were recorded. Multivariate logistic regression was performed to analyze the main associated factors. Among the 2314 people included in this survey, 49.7% were male. The mean age was 32.3 ± 13.1 years. Nine hundred seven reported pain occurring for more than 3 months. The prevalence of chronic pain was 39.2% (CI95%: 29.3-34.7). It was more frequent in females, older people, among diabetics, people with a history of any surgery, stroke, brain trauma, and alcoholism. The prevalence of chronic pain with a neuropathic component was 6.3% (CI95%: 5.0-7.9). The main associated factors were age, matrimonial status, professional occupation, body mass index, diabetes, history of zoster, history of any surgery, brain trauma. People with neuropathic pain often reported pain with burning (87.6%), prickling (82.8%), numbness (66.9%), tingling (63.4%), and lightning pain (48.3%). The main locations were the lower limbs and low back pain. This study suggested the high frequency of chronic neuropathic pain in the general population in Parakou compared with rates reported in western countries. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

TRPA1 Contributes to Cold Hypersensitivity

PubMed Central

Camino, Donato del; Murphy, Sarah; Heiry, Melissa; Barrett, Lee B.; Earley, Taryn J.; Cook, Colby A.; Petrus, Matt J.; Zhao, Michael; D'Amours, Marc; Deering, Nate; Brenner, Gary J.; Costigan, Michael; Hayward, Neil J.; Chong, Jayhong A.; Fanger, Christopher M.; Woolf, Clifford J.; Patapoutian, Ardem; Moran, Magdalene M.

2010-01-01

TRPA1 is a non-selective cation channel expressed by nociceptors. While it is widely accepted that TRPA1 serves as a broad irritancy receptor for a variety of reactive chemicals, its role in cold sensation remains controversial. Here, we demonstrate that mild cooling markedly increases agonist-evoked rat TRPA1 currents. In the absence of an agonist, even noxious cold only increases current amplitude slightly. These results suggest that TRPA1 is a key mediator of cold hypersensitivity in pathological conditions where reactive oxygen species and pro-inflammatory activators of the channel are present, but likely plays a comparatively minor role in acute cold sensation. Supporting this, cold hypersensitivity can be induced in wild-type but not Trpa1-/- mice by subcutaneous administration of a TRPA1 agonist. Furthermore, the selective TRPA1 antagonist HC-030031 reduces cold hypersensitivity in rodent models of inflammatory and neuropathic pain. PMID:21068322

Differential expression of miRNAs in the nervous system of a rat model of bilateral sciatic nerve chronic constriction injury.

PubMed

Li, Haixia; Shen, Le; Ma, Chao; Huang, Yuguang

2013-07-01

Chronic neuropathic pain is associated with global changes in gene expression in different areas of the nociceptive pathway. MicroRNAs (miRNAs) are small (~22 nt long) non-coding RNAs, which are able to regulate hundreds of different genes post-transcriptionally. The aim of this study was to determine the miRNA expression patterns in the different regions of the pain transmission pathway using a rat model of human neuropathic pain induced by bilateral sciatic nerve chronic constriction injury (bCCI). Using microarray analysis and quantitative reverse transcriptase-PCR, we observed a significant upregulation in miR-341 expression in the dorsal root ganglion (DRG), but not in the spinal dorsal horn (SDH), hippocampus or anterior cingulate cortex (ACC), in the rats with neuropathic pain compared to rats in the naïve and sham-operated groups. By contrast, the expression of miR-203, miR-181a-1* and miR-541* was significantly reduced in the SDH of rats with neuropathic pain. Our data indicate that miR-341 is upregulated in the DRG, whereas miR-203, miR-181a-1* and miR-541* are downregulated in the SDH under neuropathic pain conditions. Thus, the differential expression of miRNAs in the nervous system may play a role in the development of chronic pain. These observations may aid in the development of novel treatment methods for neuropathic pain, which may involve miRNA gene therapy in local regions.

Long non-coding RNA CCAT1 modulates neuropathic pain progression through sponging miR-155

PubMed Central

Dou, Lidong; Lin, Hongqi; Wang, Kaiwei; Zhu, Guosong; Zou, Xuli; Chang, Enqiang; Zhu, Yongfeng

2017-01-01

Neuropathic pain is caused by dysfunction or primary injury of the somatosensory nervous system. Long noncoding RNAs (lncRNAs) play important roles in the development of neuropathic pain. However, the effects of lncRNA colon cancer associated transcript-1 (CCAT1) in neuropathic pain have not been reported. The model of bilateral sciatic nerve chronic constriction injuries (bCCI) is regarded as long-lasting mechanical hypersensitivity and cold allodynia, which is the representative symptom in the human subjects suffering from the neuropathic pain. In this study, we found that CCAT1 expression was decreased in the spinal dorsal horn, dorsal root ganglion (DRG), hippocampus, and anterior cingulate cortex (ACC) of rats with bCCI. The rats of bCCI presented the cold allodynia after the 14th day of postoperation. We furtherly showed that lncRNA CCAT1 decreased miR-155 expression and enhanced Serum and glucocorticoid regulated protein kinase 3 (SGK3) expression in the NGF-differentiated PC12 cell. We found that miR-155 expression was increased in the spinal dorsal horn, DRG, hippocampus, and ACC of rats with bCCI injuries. However, SGK3 expression was downregulated in the spinal dorsal horn, DRG, hippocampus, and ACC of rats with bCCI injuries. Moreover, lncRNA CCAT1 overexpression could alleviate the pain thresholds and inhibited expression of SGK3 could rescue this effect. In conclusion, these results suggested the crucial roles of CCAT1 and SGK3 in the neuropathic pain. PMID:29163801

A multidisciplinary cognitive behavioural programme for coping with chronic neuropathic pain following spinal cord injury: the protocol of the CONECSI trial

PubMed Central

2010-01-01

Background Most people with a spinal cord injury rate neuropathic pain as one of the most difficult problems to manage and there are no medical treatments that provide satisfactory pain relief in most people. Furthermore, psychosocial factors have been considered in the maintenance and aggravation of neuropathic spinal cord injury pain. Psychological interventions to support people with spinal cord injury to deal with neuropathic pain, however, are sparse. The primary aim of the CONECSI (COping with NEuropathiC Spinal cord Injury pain) trial is to evaluate the effects of a multidisciplinary cognitive behavioural treatment programme on pain intensity and pain-related disability, and secondary on mood, participation in activities, and life satisfaction. Methods/Design CONECSI is a multicentre randomised controlled trial. A sample of 60 persons with chronic neuropathic spinal cord injury pain will be recruited from four rehabilitation centres and randomised to an intervention group or a waiting list control group. The control group will be invited for the programme six months after the intervention group. Main inclusion criteria are: having chronic (> 6 months) neuropathic spinal cord injury pain as the worst pain complaint and rating the pain intensity in the last week as 40 or more on a 0-100 scale. The intervention consists of educational, cognitive, and behavioural elements and encompasses 11 sessions over a 3-month period. Each meeting will be supervised by a local psychologist and physical therapist. Measurements will be perfomed before starting the programme/entering the control group, and at 3, 6, 9, and 12 months. Primary outcomes are pain intensity and pain-related disability (Chronic Pain Grade questionnaire). Secondary outcomes are mood (Hospital Anxiety and Depression Scale), participation in activities (Utrecht Activities List), and life satisfaction (Life Satisfaction Questionnaire). Pain coping and pain cognitions will be assessed with three questionnaires (Coping Strategy Questionnaire, Pain Coping Inventory, and Pain Cognition List). Discussion The CONECSI trial will reveal the effects of a multidisciplinary cognitive behavioural programme for people with chronic neuropathic spinal cord injury pain. This intervention is expected to contribute to the rehabilitation treatment possibilities for this population. Trial Registration Dutch Trial Register NTR1580. PMID:20961406

The neuropathic foot.

PubMed

Jernberger, A

1993-12-01

The neuropathic foot is described with relation to cause, presentation, dysfunction and identification. The various mechanisms of neuropathic foot lesions are outlined--overload, diabetic gangrene, continuous pressure, direct injury and cutting and temperature effects. The orthotic treatment of the foot is discussed and in particular the importance of proper shoe provision and patient education and indoctrination emphasised. The use of plaster casts and fenestrations to control pressure distribution is described. Finally results of an intensive treatment programme are presented to identify the effect on outcome, as measured by delay in amputation.

Association of Transcutaneous Electrical Nerve Stimulation and Hypnosis

ClinicalTrials.gov

2017-08-02

Limbs Arthrosis; Non Arthrosic Limbs Arthralgia; Chronic Lomboradiculalgia; Chronic Back Pain; Cervical Radiculopathy; Post-herpetic Neuralgia; Post-surgical Peripheral Neuropathic Pain; Post Trauma Neuropathic Pain; Complex Regional Pain Syndrome Type I or II; Tendinopathy

Mechanical allodynia induced by nucleoside reverse transcriptase inhibitor is suppressed by p55TNFSR mediated by herpes simplex virus vector through the SDF1α/CXCR4 system in rats.

PubMed

Huang, Wan; Zheng, Wenwen; Ouyang, Handong; Yi, Hyun; Liu, Shue; Zeng, Weian; Levitt, Roy C; Candiotti, Keith A; Lubarsky, David A; Hao, Shuanglin

2014-03-01

In the human immunodeficiency virus (HIV)-associated sensory neuropathy, neuropathic pain associated with the use of nucleoside reverse transcriptase inhibitors (NRTIs) in patients with HIV/acquired immunodeficiency syndrome is clinically common. While evidence demonstrates that neuropathic pain is influenced by neuroinflammatory events that include the proinflammatory molecules, tumor necrosis factor-α (TNF-α), stromal cell-derived factor 1-α (SDF1-α), and C-X-C chemokine receptor type 4 (CXCR4), the detailed mechanisms by which NRTIs contribute to the development of neuropathic pain are not known. In this study, we investigated the role of these proinflammatory molecules in the dorsal root ganglion (DRG) and the spinal dorsal horn in NRTIs-mediated neuropathic pain state. Neuropathic pain was induced by intraperitoneal administration of 2',3'-dideoxycytidine (ddC, one of the NRTIs). Mechanical threshold was tested using von Frey filament fibers. Nonreplicating herpes simplex virus (HSV) vectors expressing p55 TNF soluble receptor (p55TNFSR) were inoculated into hindpaw of rats. The expression of TNF-α, SDF1-α, and CXCR4 in both the lumbar spinal cord and the L4/5 DRG was examined using Western blots. Intrathecal CXCR4 antagonist was administered. The present study demonstrated that (1) systemic ddC induced upregulation of TNF-α, SDF1-α, and CXCR4 in both the lumbar spinal cord and the L4/5 DRG; (2) p55TNFSR mediated by a nonreplicating HSV vector reversed mechanical allodynia induced by systemic ddC; (3) intrathecal administration of the CXCR4 antagonist AMD3100 increased mechanical threshold; and (4) HSV vector expressing p55TNFSR reversed upregulation of TNF-α, SDF1-α, and CXCR4 induced by ddC in the lumbar spinal dorsal horn and the DRG. Our studies demonstrate that TNF-α through the SDF1/CXCR4 system is involved in the NRTIs-related neuropathic pain state and that blocking the signaling of these proinflammatory molecules is able to reduce NRTIs-related neuropathic pain. These results provide a novel mechanism-based approach (gene therapy) to treating HIV-associated neuropathic pain.

Sleep Deprivation Aggravates Median Nerve Injury-Induced Neuropathic Pain and Enhances Microglial Activation by Suppressing Melatonin Secretion

PubMed Central

Huang, Chun-Ta; Chiang, Rayleigh Ping-Ying; Chen, Chih-Li; Tsai, Yi-Ju

2014-01-01

Study Objectives: Sleep deprivation is common in patients with neuropathic pain, but the effect of sleep deprivation on pathological pain remains uncertain. This study investigated whether sleep deprivation aggravates neuropathic symptoms and enhances microglial activation in the cuneate nucleus (CN) in a median nerve chronic constriction injury (CCI) model. Also, we assessed if melatonin supplements during the sleep deprived period attenuates these effects. Design: Rats were subjected to sleep deprivation for 3 days by the disc-on-water method either before or after CCI. In the melatonin treatment group, CCI rats received melatonin supplements at doses of 37.5, 75, 150, or 300 mg/kg during sleep deprivation. Melatonin was administered at 23:00 once a day. Participants: Male Sprague-Dawley rats, weighing 180-250 g (n = 190), were used. Measurements: Seven days after CCI, behavioral testing was conducted, and immunohistochemistry, immunoblotting, and enzyme-linked immunosorbent assay were used for qualitative and quantitative analyses of microglial activation and measurements of proinflammatory cytokines. Results: In rats who underwent post-CCI sleep deprivation, microglia were more profoundly activated and neuropathic pain was worse than those receiving pre-CCI sleep deprivation. During the sleep deprived period, serum melatonin levels were low over the 24-h period. Administration of melatonin to CCI rats with sleep deprivation significantly attenuated activation of microglia and development of neuropathic pain, and markedly decreased concentrations of proinflammatory cytokines. Conclusions: Sleep deprivation makes rats more vulnerable to nerve injury-induced neuropathic pain, probably because of associated lower melatonin levels. Melatonin supplements to restore a circadian variation in melatonin concentrations during the sleep deprived period could alleviate nerve injury-induced behavioral hypersensitivity. Citation: Huang CT, Chiang RP, Chen CL, Tsai YJ. Sleep deprivation aggravates median nerve injury-induced neuropathic pain and enhances microglial activation by suppressing melatonin secretion. SLEEP 2014;37(9):1513-1523. PMID:25142572

Longitudinal Perioperative Pain Assessment in Head and Neck Cancer Surgery.

PubMed

Buchakjian, Marisa R; Davis, Andrew B; Sciegienka, Sebastian J; Pagedar, Nitin A; Sperry, Steven M

2017-09-01

To evaluate perioperative pain in patients undergoing major head and neck cancer surgery and identify associations between preoperative and postoperative pain characteristics. Patients undergoing head and neck surgery with regional/free tissue transfer were enrolled. Preoperative pain and validated screens for symptoms (neuropathic pain, anxiety, depression, fibromyalgia) were assessed. Postoperatively, patients completed a pain diary for 4 weeks. Twenty-seven patients were enrolled. Seventy-eight percent had pain prior to surgery, and for 38%, the pain had neuropathic characteristics. Thirteen patients (48%) completed at least 2 weeks of the postoperative pain diary. Patients with moderate/severe preoperative pain report significantly greater pain scores postoperatively, though daily pain decreased at a similar linear rate for all patients. Patients with more severe preoperative pain consumed greater amounts of opioids postoperatively, and this correlated with daily postoperative pain scores. Patients who screened positive for neuropathic pain also reported worse postoperative pain. Longitudinal perioperative pain assessment in head and neck patients undergoing surgery suggests that patients with worse preoperative pain continue to endorse worse pain postoperatively and require more narcotics. Patients with preoperative neuropathic pain also report poor pain control postoperatively, suggesting an opportunity to identify these patients and intervene with empiric neuropathic pain treatment.

Clinical efficacy of aconitum-containing traditional Chinese medicine for diabetic peripheral neuropathic pain.

PubMed

Feng, Ling; Liu, Wen-Ke; Deng, Lan; Tian, Jia-Xing; Tong, Xiao-Lin

2014-01-01

Diabetic peripheral neuropathy is a common chronic complication of diabetes. Routine clinical management uses analgesics to relieve pain in combination with drugs for nerve repair. The drugs are often not effective for the severe pain cases, and these western medications also have side effects. We report a more effective treatment of diabetic peripheral neuropathic pain using a high dose of a traditional Chinese medicine, aconitum (including both Radix aconite preparata and Radix aconite kusnezoffii), in combination with Huangqi Guizhi Wuwu Tang (i.e., astragalus, cassia twig, white peony root, and spatholobi). In order to achieve stronger analgesic effects, we increased the clinical dosage of aconitum from 15 to 120 g. The aconitum was boiled for 6-8 hours, and licorice was also used to reduce potential toxicities of aconitum. In the four reported cases, the patients' neuropathic pain was remarkably reduced and the EMG profile was also improved with this treatment regimen. Adverse reactions were not observed during the therapy. Thus, aconitum represents a promising and safe treatment for the well-being of patients and their diabetic peripheral neuropathic pain. Future controlled clinical trials using traditional Chinese medicines containing aconitum in treating the neuropathic pain are warranted.

Sensory Symptom Profiles and Co-Morbidities in Painful Radiculopathy

PubMed Central

Gockel, Ulrich; Brosz, Mathias; Freynhagen, Rainer; Tölle, Thomas R.; Baron, Ralf

2011-01-01

Painful radiculopathies (RAD) and classical neuropathic pain syndromes (painful diabetic polyneuropathy, postherpetic neuralgia) show differences how the patients express their sensory perceptions. Furthermore, several clinical trials with neuropathic pain medications failed in painful radiculopathy. Epidemiological and clinical data of 2094 patients with painful radiculopathy were collected within a cross sectional survey (painDETECT) to describe demographic data and co-morbidities and to detect characteristic sensory abnormalities in patients with RAD and compare them with other neuropathic pain syndromes. Common co-morbidities in neuropathic pain (depression, sleep disturbance, anxiety) do not differ considerably between the three conditions. Compared to other neuropathic pain syndromes touch-evoked allodynia and thermal hyperalgesia are relatively uncommon in RAD. One distinct sensory symptom pattern (sensory profile), i.e., severe painful attacks and pressure induced pain in combination with mild spontaneous pain, mild mechanical allodynia and thermal hyperalgesia, was found to be characteristic for RAD. Despite similarities in sensory symptoms there are two important differences between RAD and other neuropathic pain disorders: (1) The paucity of mechanical allodynia and thermal hyperalgesia might be explained by the fact that the site of the nerve lesion in RAD is often located proximal to the dorsal root ganglion. (2) The distinct sensory profile found in RAD might be explained by compression-induced ectopic discharges from a dorsal root and not necessarily by nerve damage. These differences in pathogenesis might explain why medications effective in DPN and PHN failed to demonstrate efficacy in RAD. PMID:21573064

Management of neuropathic pain following spinal cord injury: now and in the future.

PubMed

Siddall, P J

2009-05-01

To provide an overview of our current understanding of the problem of neuropathic pain following spinal cord injury (SCI) and to suggest possible therapeutic options in the near future. Original research articles, reviews and book chapters on the subject of pain and SCI. Neuropathic pain following SCI has presented a challenge not only for traditional concepts of how pain occurs but also for more recent conceptualizations. We have made substantial progress in identifying the common types of pain that occur following SCI, determining the prevalence and characteristics of pain, investigating some of the pathophysiological changes in the nervous system that may contribute to the presence of neuropathic SCI pain and examining the effectiveness of some treatments. However major challenges remain. We still need to reach consensus on an SCI pain taxonomy; our understanding of mechanisms and the relative contribution of changes in the periphery, spinal cord and brain is incompletely understood; there are few studies that indicate effective treatment options, particularly for neuropathic SCI pain; and treatment of the biological and psychological contributors to pain is often fragmented. Recent studies suggest the potential usefulness of new treatment approaches such as selective pharmacological agents, application of novel neurostimulation techniques and the use of cognitive approaches to modify the pain experience. Our increasing understanding of the problem combined with the promise of these new approaches offers hope for improved management of neuropathic pain following SCI in the near future.

Swimming Training Reduces Neuroma Pain by Regulating Neurotrophins

PubMed Central

TIAN, JINGE; YU, TINGTING; XU, YONGMING; PU, SHAOFENG; LV, YINGYING; ZHANG, XIN; DU, DONGPING

2018-01-01

ABSTRACT Introduction Neuroma formation after peripheral nerve transection leads to severe neuropathic pain in amputees. Previous studies suggested that physical exercise could bring beneficial effect on alleviating neuropathic pain. However, the effect of exercise on neuroma pain still remained unclear. In addition, long-term exercise can affect the expression of neurotrophins (NT), such as nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF), which play key roles in nociceptor sensitization and nerve sprouting after nerve injury. Here, we investigated whether long-term swimming exercise could relieve neuroma pain by modulating NT expression. Methods We used a tibial neuroma transposition (TNT) rat model to mimic neuroma pain. After TNT surgery, rats performed swimming exercise for 5 wk. Neuroma pain and tactile sensitivities were detected using von Frey filaments. Immunofluorescence was applied to analyze neuroma formation. NGF and BDNF expressions in peripheral neuroma, dorsal root ganglion, and the spinal cord were measured using enzyme-linked immunosorbent assay and Western blotting. Results TNT led to neuroma formation, induced neuroma pain, and mechanical allodynia in hind paw. Five-week swimming exercise inhibited neuroma formation and relieved mechanical allodynia in the hind paw and neuroma pain in the lateral ankle. The analgesic effect lasted for at least 1 wk, even when the exercise ceased. TNT elevated the expressions of BDNF and NGF in peripheral neuroma, dorsal root ganglion, and the spinal cord to different extents. Swimming also decreased the elevation of NT expression. Conclusions Swimming exercise not only inhibits neuroma formation induced by nerve transection but also relieves pain behavior. These effects might be associated with the modulation of NT. PMID:28846565

Aging-associated sensory neuropathy alters pressure-induced vasodilation in humans.

PubMed

Fromy, Bérengère; Sigaudo-Roussel, Dominique; Gaubert-Dahan, Marie-Line; Rousseau, Pascal; Abraham, Pierre; Benzoni, Daniel; Berrut, Gilles; Saumet, Jean Louis

2010-03-01

Healthy skin is protected from pressure-induced ischemic damage because of the presence of pressure-induced vasodilation (PIV). PIV relies on small sensory nerve fibers and endothelial function. Since aging alters both nervous and vascular functions, we hypothesized that PIV is altered with aging. We compared PIV in non-neuropathic and neuropathic older subjects (60-75 years) with that of young subjects (20-35 years). Laser Doppler flowmetry was used to evaluate the cutaneous responses to local pressure application, acetylcholine, and local heating. Quantitative sensory tests were used to evaluate sensory-nerve-fiber function. The non-neuropathic older subjects had an impaired PIV (12+/-7% increase in blood flow with pressure) compared with young subjects (62+/-4%, P<0.001). In the presence of peripheral neuropathy, the older subjects were totally deprived of PIV, leading to early pressure-induced cutaneous ischemia (-31+/-10%, P<0.001). This inability of the skin to adapt to localized pressure in older subjects is related to the severity of the sensory-fiber dysfunction rather than to endothelial dysfunction, which was comparable between the non-neuropathic (141+/-19% increased blood flow with acetylcholine, P<0.05) and neuropathic older subjects (145+/-28% increase, P<0.05) compared with young subjects (234+/-25% increase).

Effects of electroacupuncture on orphanin FQ immunoreactivity and preproorphanin FQ mRNA in nucleus of raphe magnus in the neuropathic pain rats.

PubMed

Ma, Fei; Xie, Hong; Dong, Zhi-Qiang; Wang, Yan-Qing; Wu, Gen-Cheng

2004-07-15

Orphanin FQ (OFQ) is an endogenous ligand for opioid receptor-like-1 (ORL1) receptor. Previous studies have shown that both OFQ immunoreactivity and preproorphanin FQ (ppOFQ) mRNA expression could be observed in the brain regions involved in pain modulation, e.g., nucleus of raphe magnus (NRM), dorsal raphe nucleus (DRN), and ventrolateral periaqueductal gray (vlPAG). It was reported that electroacupuncture (EA) has analgesic effect on neuropathic pain, and the analgesic effect was mediated by the endogenous opioid peptides. In the present study, we investigated the effects of EA on the changes of OFQ in the neuropathic pain rats. In the sciatic nerve chronic constriction injury (CCI) model, we investigated the changes of ppOFQ mRNA and OFQ immunoreactivity in NRM after EA by in situ hybridization (ISH) and immunohistochemistry methods, respectively. Then, the ppOFQ mRNA-positive and OFQ immunoreactive cells were counted under a computerized image analysis system. The results showed that expression of ppOFQ mRNA decreased and OFQ immunoreactivity increased after EA treatment in the neuropathic pain rats. These results indicated that EA modulated OFQ synthesis and OFQ peptide level in NRM of the neuropathic pain rats. Copyright 2004 Elsevier Inc.

Presence of neuropathic pain may explain poor performances on olfactory testing in diabetes mellitus patients.

PubMed

Brady, Shauna; Lalli, Paul; Midha, Nisha; Chan, Ayechen; Garven, Alexandra; Chan, Cynthia; Toth, Cory

2013-07-01

Olfactory dysfunction in neurodegenerative conditions such as Parkinson's syndrome and Alzheimer's disease can hallmark disease onset. We hypothesized that patients with diabetes mellitus, a condition featuring peripheral and central neurodegeneration, would have decreased olfaction abilities. We examined participants with diabetic peripheral neuropathy, participants with diabetes without diabetic peripheral neuropathy, and control participants in blinded fashion using standardized Sniffin' Sticks. Diabetic peripheral neuropathy severity was quantified using the Utah Early Neuropathy Scale. Further subcategorization of diabetic peripheral neuropathy based on presence of neuropathic pain was performed with Douleur Neuropathique 4 Questionnaires. Participants with diabetes had decreased olfactory sensitivity, impaired olfactory discrimination abilities, and reduced odor identification skills when compared with controls. However, loss of olfaction ability was, at least partially, attributed to presence of neuropathic pain on subcategory assessment, although pain severity was not associated with dysfunction. Those participants with diabetes without diabetic peripheral neuropathy and those with diabetic peripheral neuropathy without neuropathic pain had similar olfactory function as controls in general. The presence of neuropathic pain, associated with limited attention and concentration, may explain at least a portion of the olfactory dysfunction witnessed in the diabetic patient population.

Low Dose Vaporized Cannabis Significantly Improves Neuropathic Pain

PubMed Central

Wilsey, Barth; Marcotte, Thomas D.; Deutsch, Reena; Gouaux, Ben; Sakai, Staci; Donaghe, Haylee

2013-01-01

We conducted a double-blind, placebo-controlled, crossover study evaluating the analgesic efficacy of vaporized cannabis in subjects, the majority of whom were experiencing neuropathic pain despite traditional treatment. Thirty-nine patients with central and peripheral neuropathic pain underwent a standardized procedure for inhaling either medium dose (3.53%), low dose (1.29%), or placebo cannabis with the primary outcome being VAS pain intensity. Psychoactive side-effects, and neuropsychological performance were also evaluated. Mixed effects regression models demonstrated an analgesic response to vaporized cannabis. There was no significant difference between the two active dose groups’ results (p>0.7). The number needed to treat (NNT) to achieve 30% pain reduction was 3.2 for placebo vs. low dose, 2.9 for placebo vs. medium dose, and 25 for medium vs. low dose. As these NNT are comparable to those of traditional neuropathic pain medications, cannabis has analgesic efficacy with the low dose being, for all intents and purposes, as effective a pain reliever as the medium dose. Psychoactive effects were minimal and well-tolerated, and neuropsychological effects were of limited duration and readily reversible within 1–2 hours. Vaporized cannabis, even at low doses, may present an effective option for patients with treatment-resistant neuropathic pain. PMID:23237736

Neuropathic Arthropathy of the Glenohumeral Joint A Review of the Literature.

PubMed

Santiesteban, Lauren; Mollon, Brent; Zuckerman, Joseph D

2018-06-01

Neuropathic arthropathy, also known as Charcot arthropathy, is a degenerative disorder most commonly characterized by rapid destruction of the joint with extensive involvement of the bone and soft tissue. The underlying pathophysiology is thought to be due to loss of nociception (pain sensation), most frequently caused by diabetes mellitus, syphilitic myelopathy, or syringomyelia. A neuropathic shoulder is rare, with historic case series forming the bulk of the literature. The purpose of this review is to better understand the pathogenesis, clinical presentation, and management of neuropathic arthropathy of the glenohumeral joint. It should be stressed that the identification and management of the underlying etiology is paramount if the disease process is to be positively impacted. Although the mainstay of orthopedic management is non-surgical, little evidence exists to support the use of any specific therapeutic intervention. Recent literature suggests surgical reconstruction may be considered in very select patients.

A Mangifera indica L. extract could be used to treat neuropathic pain and implication of mangiferin.

PubMed

Garrido-Suárez, Bárbara B; Garrido, Gabino; Delgado, Rene; Bosch, Fe; del C Rabí, María

2010-12-09

It has been accepted that neuroinflammation, oxidative stress and glial activation are involved in the central sensitization underlying neuropathic pain. Vimang is an aqueous extract of Mangifera indica L. traditionally used in Cuba for its analgesic, anti-inflammatory, antioxidant and immunomodulatory properties. Several formulations are available, and also for mangiferin, its major component. Preclinical studies demonstrated that these products prevented tumor necrosis factor α -induced IκB degradation and the binding of nuclear factor κB to DNA, which induces the transcription of genes implicated in the expression of some mediators and enzymes involved in inflammation, pain, oxidative stress and synaptic plasticity. In this paper we propose its potential utility in the neuropathic pain treatment. This hypothesis is supported in the cumulus of preclinical and clinical evidence around the extract and mangiferin, its major component, and speculates about the possible mechanism of action according to recent advances in the physiopathology of neuropathic pain.

Venous distension in the diabetic neuropathic foot (physical sign of arteriovenous shunting).

PubMed Central

Ward, J D; Boulton, A J; Simms, J M; Sandler, D A; Knight, G

1983-01-01

A new physical sign is described in the feet of a group of diabetic patients with ulcerating neuropathic problems, in which major venous distension of the veins on the dorsum of the foot and lower calf is seen. Elevation of the leg is required to an average height of 32.3 cm to cause collapse of these distended veins. It is suggested that this clinical sign indicates the presence of arteriovenous shunting in such neuropathic legs, and as such is a simple and useful measure of this abnormality. Images Figure 1. Figure 2. PMID:6672192

Chronic non-freezing cold injury results in neuropathic pain due to a sensory neuropathy

PubMed Central

Vale, Tom A; Symmonds, Mkael; Polydefkis, Michael; Byrnes, Kelly; Rice, Andrew S C; Themistocleous, Andreas C; Bennett, David L H

2017-01-01

Abstract Non-freezing cold injury develops after sustained exposure to cold temperatures, resulting in tissue cooling but not freezing. This can result in persistent sensory disturbance of the hands and feet including numbness, paraesthesia and chronic pain. Both vascular and neurological aetiologies of this pain have been suggested but remain unproven. We prospectively approached patients referred for clinical assessment of chronic pain following non-freezing cold injury between 12 February 2014 and 30 November 2016. Of 47 patients approached, 42 consented to undergo detailed neurological evaluations including: questionnaires to detail pain location and characteristics, structured neurological examination, quantitative sensory testing, nerve conduction studies and skin biopsy for intraepidermal nerve fibre assessment. Of the 42 study participants, all had experienced non-freezing cold injury while serving in the UK armed services and the majority were of African descent (76.2%) and male (95.2%). Many participants reported multiple exposures to cold. The median time between initial injury and referral was 3.72 years. Pain was principally localized to the hands and the feet, neuropathic in nature and in all study participants associated with cold hypersensitivity. Clinical examination and quantitative sensory testing were consistent with a sensory neuropathy. In all cases, large fibre nerve conduction studies were normal. The intraepidermal nerve fibre density was markedly reduced with 90.5% of participants having a count at or below the 0.05 centile of published normative controls. Using the Neuropathic Pain Special Interest Group of the International Association for the Study of Pain grading for neuropathic pain, 100% had probable and 95.2% definite neuropathic pain. Chronic non-freezing cold injury is a disabling neuropathic pain disorder due to a sensory neuropathy. Why some individuals develop an acute painful sensory neuropathy on sustained cold exposure is not yet known, but individuals of African descent appear vulnerable. Screening tools, such as the DN4 questionnaire, and treatment algorithms for neuropathic pain should now be used in the management of these patients. PMID:28969380

Prolonged Suppression of Neuropathic Pain by Sequential Delivery of Lidocaine and Thalidomide Drugs Using PEGylated Graphene Oxide.

PubMed

Song, Tieying; Gu, Kunfeng; Wang, Wenli; Wang, Hong; Yang, Yunliang; Yang, Lijun; Ma, Pengxu; Ma, Xiaojing; Zhao, Jianhui; Yan, Ruyu; Guan, Jiao; Wang, Chunping; Qi, Yan; Ya, Jian

2015-11-01

The management of patients with neuropathic pain is challenging. Monotherapy with a single pain relief drug may encounter different difficulties, such as short duration of efficacy and hence too many times of drug administration, and inadequate drug delivery. Recently, nanocarrier-based drug delivery systems have been proved to provide promising strategies for efficient drug loading, delivery, and release. In the present study, we developed poly(ethylene glycol) methyl ether functionalized graphene oxide (GO) bearing two commonly used drugs of lidocaine (LDC) and thalidomide (THD) as an agent for the treatment of neuropathic pain. The sequential drug release of LDC and THD from the developed LDC-THD-GO nanosheets exhibited a synergistic effect on neuropathic pain in vitro and in vivo, as evidenced by the increased pain threshold in mechanical allodynia and hyperalgesic response tests, and the improved inhibition of proinflammatory cytokines TNF-α, IL-1β, IL-6, and nitric oxide. We believed that the present study herein would hold promise for future development of a new generation of potent agents for neuropathic pain relief. © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association.

Coadministration of Resveratrol and Rice Oil Mitigates Nociception and Oxidative State in a Mouse Fibromyalgia-Like Model

PubMed Central

Peres Klein, Caroline; Rodrigues Cintra, Marcos; Binda, Nancy; Montijo Diniz, Danuza; Gomez, Marcus Vinicius; Souto, Andre Arigony; de Souza, Alessandra Hubner

2016-01-01

The mechanism underlying pain symptoms in fibromyalgia (FM) is not fully understood. Oxidative stress has emerged as pathophysiological event occurring during the development of the disease. The present study aimed at investigating the efficacy of resveratrol associated with rice bran oil on fibromyalgia-like mice model. Subcutaneous injection of reserpine (0.25 mg/Kg) during 3 days produced fibromyalgia-like symptoms. Resveratrol and/or rice oil or pregabalin were administered through oral route in therapeutic (single dose) and preventive (four doses) schemes. In both schemes, treatment with resveratrol associated with rice bran oil and pregabalin significantly reduced mechanical allodynia and thermal hyperalgesia in animals. The preventive scheme displayed antidepressant effect which was demonstrated by the forced swimming test as well as reduced reactive species in the cerebrospinal fluid of reserpinized animals. Taken together, our data provide evidences that the intake of resveratrol associated with rice bran oil plays antinociceptive and antidepressant actions probably through reducing reactive species and suggests the involvement of oxidative stress in this model of FM as possible underlying mechanism of pathogenesis of the disease. PMID:27069683

Oscillatory neural representations in the sensory thalamus predict neuropathic pain relief by deep brain stimulation.

PubMed

Huang, Yongzhi; Green, Alexander L; Hyam, Jonathan; Fitzgerald, James; Aziz, Tipu Z; Wang, Shouyan

2018-01-01

Understanding the function of sensory thalamic neural activity is essential for developing and improving interventions for neuropathic pain. However, there is a lack of investigation of the relationship between sensory thalamic oscillations and pain relief in patients with neuropathic pain. This study aims to identify the oscillatory neural characteristics correlated with pain relief induced by deep brain stimulation (DBS), and develop a quantitative model to predict pain relief by integrating characteristic measures of the neural oscillations. Measures of sensory thalamic local field potentials (LFPs) in thirteen patients with neuropathic pain were screened in three dimensional feature space according to the rhythm, balancing, and coupling neural behaviours, and correlated with pain relief. An integrated approach based on principal component analysis (PCA) and multiple regression analysis is proposed to integrate the multiple measures and provide a predictive model. This study reveals distinct thalamic rhythms of theta, alpha, high beta and high gamma oscillations correlating with pain relief. The balancing and coupling measures between these neural oscillations were also significantly correlated with pain relief. The study enriches the series research on the function of thalamic neural oscillations in neuropathic pain and relief, and provides a quantitative approach for predicting pain relief by DBS using thalamic neural oscillations. Copyright © 2017 Elsevier Inc. All rights reserved.

Experienced dilemmas of everyday life in chronic neuropathic pain patients--results from a critical incident study.

PubMed

Hensing, Gunnel K E; Sverker, Annette M; Leijon, Göran S

2007-06-01

Neuropathic pain is a disabling chronic condition with limited therapeutic options. Few studies have addressed patient's experience and strategies. The aim of this study was to explore dilemmas experienced in order to improve care and rehabilitation. An interview study with 39 patients suffering from neuropathic pain of different origin was performed. We used the critical incident technique to collect data. Questions on occasions when patients had been hindered by or reminded of their neuropathic pain were included, and the self-perceived consequences and management of such occasions. The interviews were transcribed verbatim and analysed qualitatively. A broad range of experiences categorised into dilemmas, disturbances, consequences and managements from most parts of everyday life was identified. The dilemmas were 'housework', 'sitting', 'physical activity', 'personal hygiene', 'sleeping difficulties', 'hypersensitivity to external stimuli', 'social relationships', 'transportation' and 'leisure time'. Disturbances were 'failures', 'inabilities' and 'restrictions'. Consequences were 'increased pain', 'psychological reactions' and 'physical symptoms'. The majority of the patients used activity-oriented strategies to manage their pain such as alternative ways of performing the task, a cognitive approach or simply ignoring the pain. This is one of the first studies presenting detailed data on everyday dilemmas, disturbances and consequences of patients with chronic neuropathic pain. Such information is important in clinical settings to improve care and rehabilitation.

Paracetamol (acetaminophen) with or without codeine or dihydrocodeine for neuropathic pain in adults.

PubMed

Wiffen, Philip J; Knaggs, Roger; Derry, Sheena; Cole, Peter; Phillips, Tudor; Moore, R Andrew

2016-12-27

Paracetamol, either alone or in combination with codeine or dihydrocodeine, is commonly used to treat chronic neuropathic pain. This review sought evidence for efficacy and harm from randomised double-blind studies. To assess the analgesic efficacy and adverse events of paracetamol with or without codeine or dihydrocodeine for chronic neuropathic pain in adults. We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, and Embase from inception to July 2016, together with reference lists of retrieved papers and reviews, and two online study registries. We included randomised, double-blind studies of two weeks' duration or longer, comparing paracetamol, alone or in combination with codeine or dihydrocodeine, with placebo or another active treatment in chronic neuropathic pain. Two review authors independently searched for studies, extracted efficacy and adverse event data, and examined issues of study quality and potential bias. We did not carry out any pooled analyses. We assessed the quality of the evidence using GRADE. No study satisfied the inclusion criteria. Effects of interventions were not assessed as there were no included studies. We have only very low quality evidence and have no reliable indication of the likely effect. There is insufficient evidence to support or refute the suggestion that paracetamol alone, or in combination with codeine or dihydrocodeine, works in any neuropathic pain condition.

Genetic studies of human neuropathic pain conditions: a review

PubMed Central

Zorina-Lichtenwalter, Katerina; Parisien, Marc; Diatchenko, Luda

2018-01-01

Abstract Numerous studies have shown associations between genetic variants and neuropathic pain disorders. Rare monogenic disorders are caused by mutations of substantial effect size in a single gene, whereas common disorders are likely to have a contribution from multiple genetic variants of mild effect size, representing different biological pathways. In this review, we survey the reported genetic contributors to neuropathic pain and submit them for validation in a 150,000-participant sample of the U.K. Biobank cohort. Successfully replicated association with a neuropathic pain construct for 2 variants in IL10 underscores the importance of neuroimmune interactions, whereas genome-wide significant association with low back pain (P = 1.3e-8) and false discovery rate 5% significant associations with hip, knee, and neck pain for variant rs7734804 upstream of the MAT2B gene provide evidence of shared contributing mechanisms to overlapping pain conditions at the molecular genetic level. PMID:29240606

Chronobiology of chronic pain: focus on diurnal rhythmicity of neuropathic pain.

PubMed

Gilron, Ian; Ghasemlou, Nader

2014-12-01

Although circadian rhythmicity has long been recognized in various nociceptive pain conditions such as arthritis, diurnal pain patterns in neuropathic conditions have only recently been described. The purpose of this article is to review emerging evidence and discuss future research to further understand this phenomenon. Secondary analyses of neuropathic pain clinical trials demonstrate that pain intensity fluctuations exhibit a distinct diurnal pattern that contrasts that of nociceptive pain conditions. Ongoing preclinical investigations support the phenomenon of circadian pain fluctuations and provide the opportunity to better describe pain chronobiology and to elucidate underlying mechanisms of circadian pain rhythmicity. The observation of clinically relevant diurnal pain variability in neuropathic conditions has important implications for future research and treatment of pain. This is an immature research field, and further investigation is needed to better characterize these patterns in more detail, investigate contributory mechanisms, and to develop therapeutic strategies that exploit this phenomenon.

Silencing of FKBP51 alleviates the mechanical pain threshold, inhibits DRG inflammatory factors and pain mediators through the NF-kappaB signaling pathway.

PubMed

Yu, Hong-Mei; Wang, Qi; Sun, Wen-Bo

2017-09-05

Neuropathic pain is chronic pain caused by lesions or diseases of the somatosensory system, currently available analgesics provide only temporal relief. The precise role of FK506 binding protein 51 (FKBP51) in neuropathic pain induced by chronic constriction injury (CCI) is not clear. The purpose of the present study was to investigate the effects and possible mechanisms of FKBP51 in neuropathic pain in the rat model of CCI. Our results showed that FKBP51 was obviously upregulated in a time-dependent manner in the dorsal root ganglion (DRG) of CCI rats. Additionally, silencing of FKBP51 remarkably attenuated mechanical allodynia and thermal hyperalgesia as reflected by paw withdrawal threshold (PWT) and paw withdrawal latency (PWL) in CCI rats. Moreover, knockdown of FKBP51 reduced the production of pro-inflammatory cytokines (TNF-α, IL-1β and IL-6), nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) expression in the DRG of CCI rats. Furthermore, we revealed that inhibition of FKBP51 greatly suppressed the activation of the NF-kappaB (NF-κB) signaling in the DRG of CCI rats. Interestingly, similar to the FKBP51 siRNA (si-FKBP51), ammonium pyrrolidinedithiocarbamate (PDTC, an inhibitor of NF-κB) also alleviated neuropathic pain and neuro-inflammation, indicating that knockdown of FKBP51 alleviated neuropathic pain development of CCI rats by inhibiting the activation of NF-κB signaling pathway. Taken together, our findings indicate that FKBP51 may serve as a novel therapeutic target for neuropathic pain. Copyright © 2017. Published by Elsevier B.V.

Mechanical hypersensitivity, sympathetic sprouting, and glial activation are attenuated by local injection of corticosteroid near the lumbar ganglion in a rat model of neuropathic pain.

PubMed

Li, Jing-Yi; Xie, Wenrui; Strong, Judith A; Guo, Qu-Lian; Zhang, Jun-Ming

2011-01-01

Inflammatory responses in the lumbar dorsal root ganglion (DRG) play a key role in pathologic pain states. Systemic administration of a common anti-inflammatory corticosteroid, triamcinolone acetonide (TA), reduces sympathetic sprouting, mechanical pain behavior, spontaneous bursting activity, and cytokine and nerve growth factor production in the DRG. We hypothesized that systemic TA effects are primarily due to local effects on the DRG. Male Sprague-Dawley rats were divided into 4 groups: SNL (tight ligation and transection of spinal nerves) and normal with and without a single dose of TA injectable suspension slowly injected onto the surface of DRG and surrounding region at the time of SNL or sham surgery. Mechanical threshold was tested on postoperative days 1, 3, 5, and 7. Immunohistochemical staining examined tyrosine hydroxylase and glial fibrillary acidic protein in DRG and CD11B antibody (OX-42) in spinal cord. Local TA treatment attenuated mechanical sensitivity, reduced sympathetic sprouting in the DRG, and decreased satellite glia activation in the DRG and microglia activation in the spinal cord after SNL. A single injection of corticosteroid in the vicinity of the axotomized DRG can mimic many effects of systemic TA, mitigating behavioral and cellular abnormalities induced by spinal nerve ligation. This provides a further rationale for the use of localized steroid injections clinically and provides further support for the idea that localized inflammation at the level of the DRG is an important component of the spinal nerve ligation model, commonly classified as neuropathic pain model.

Swimming Training Reduces Neuroma Pain by Regulating Neurotrophins.

PubMed

Tian, Jinge; Yu, Tingting; Xu, Yongming; Pu, Shaofeng; Lv, Yingying; Zhang, Xin; DU, Dongping

2018-01-01

Neuroma formation after peripheral nerve transection leads to severe neuropathic pain in amputees. Previous studies suggested that physical exercise could bring beneficial effect on alleviating neuropathic pain. However, the effect of exercise on neuroma pain still remained unclear. In addition, long-term exercise can affect the expression of neurotrophins (NT), such as nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF), which play key roles in nociceptor sensitization and nerve sprouting after nerve injury. Here, we investigated whether long-term swimming exercise could relieve neuroma pain by modulating NT expression. We used a tibial neuroma transposition (TNT) rat model to mimic neuroma pain. After TNT surgery, rats performed swimming exercise for 5 wk. Neuroma pain and tactile sensitivities were detected using von Frey filaments. Immunofluorescence was applied to analyze neuroma formation. NGF and BDNF expressions in peripheral neuroma, dorsal root ganglion, and the spinal cord were measured using enzyme-linked immunosorbent assay and Western blotting. TNT led to neuroma formation, induced neuroma pain, and mechanical allodynia in hind paw. Five-week swimming exercise inhibited neuroma formation and relieved mechanical allodynia in the hind paw and neuroma pain in the lateral ankle. The analgesic effect lasted for at least 1 wk, even when the exercise ceased. TNT elevated the expressions of BDNF and NGF in peripheral neuroma, dorsal root ganglion, and the spinal cord to different extents. Swimming also decreased the elevation of NT expression. Swimming exercise not only inhibits neuroma formation induced by nerve transection but also relieves pain behavior. These effects might be associated with the modulation of NT.

Modulating the Delicate Glial-Neuronal Interactions in Neuropathic Pain: Promises and Potential Caveats

PubMed Central

Tiwari, Vinod; Guan, Yun; Raja, Srinivasa N.

2014-01-01

During neuropathic pain, glial cells (mainly astrocytes and microglia) become activated and initiate a series of signaling cascades that modulate pain processing at both spinal and supraspinal levels. It has been generally accepted that glial cell activation contributes to neuropathic pain because glia release proinflammatory cytokines, chemokines, and factors such as calcitonin gene-related peptide, substance P, and glutamate, which are known to facilitate pain signaling. However, recent research has shown that activation of glia also leads to some beneficial outcomes. Glia release anti-inflammatory factors that protect against neurotoxicity and restore normal pain. Accordingly, use of glial inhibitors might compromise the protective functions of glia in addition to suppressing their detrimental effects. With a better understanding of how different conditions affect glial cell activation, we may be able to promote the protective function of glia and pave the way for future development of novel, safe, and effective treatments of neuropathic pain. PMID:24820245

Cancer Pain Management and Bone Metastases: An Update for the Clinician

PubMed Central

Schneider, Guido; Voltz, Raymond; Gaertner, Jan

2012-01-01

Breast cancer patients with bone metastases often suffer from cancer pain. In general, cancer pain treatment is far from being optimal for many patients. To date, morphine remains the gold standard as first-line therapy, but other pure μ agonists such as hydromorphone, fentanyl, or oxycodone can be considered. Transdermal opioids are an important option if the oral route is impossible. Due to its complex pharmacology, methadone should be restricted to patients with difficult pain syndromes. The availability of a fixed combination of oxycodone and naloxone is a promising development for the reduction of opioid induced constipation. Especially bone metastases often result in breakthrough pain episodes. Thus, the provision of an on-demand opioid (e.g., immediate-release morphine or rapid-onset fentanyl) in addition to the baseline (regular) opioid therapy (e.g., sustained-release morphine tablets) is mandatory. Recently, rapid onset fentanyls (buccal or nasal) have been strongly recommended for breakthrough cancer pain due to their fast onset and their shorter duration of action. If available, metamizole is an alternative non-steroid-anti-inflammatory-drug. The indication for bisphosphonates should always be checked early in the disease. In advanced cancer stages, glucocorticoids are an important treatment option. If bone metastases lead to neuropathic pain, coanalgetics (e.g., pregabalin) should be initiated. In localized bone pain, radiotherapy is the gold standard for pain reduction in addition to pharmacologic pain management. In diffuse bone pain radionuclids (such as samarium) can be beneficial. Invasive measures (e.g., neuroaxial blockage) are rarely necessary but are an important option if patients with cancer pain syndromes are refractory to pharmacologic management and radiotherapy as described above. Clinical guidelines agree that cancer pain management in incurable cancer is best provided as part of a multiprofessional palliative care approach and all other domains of suffering (psychosocial, spiritual, and existential) need to be carefully addressed («total pain»). PMID:22740797

Development and validation of Arabic version of the Neuropathic Pain Questionnaire-Short Form.

PubMed

Terkawi, Abdullah Sulieman; Backonja, Miroslav Misha; Abolkhair, Abdullah; Almaharbi, Sameeh; Joy, Jaya; Foula, Farida; Alswiti, Mousa; Terkawi, Yazzed Sulieman; Al-Zhahrani, Tariq; Alghamdi, Faris Saeed; Tsang, Siny

2017-05-01

The Neuropathic Pain Questionnaire-Short Form (NPQ-SF) is the shortest diagnostic tool for the assessment of neuropathic pain, designed with the goal to differentiate between neuropathic and nonneuropathic pain. The aim of this study was to translate, culturally adapt, and validate the NPQ-SF questionnaire in Arabic. A systematic translation process was used to translate the original English NPQ-SF into Arabic. After the pilot study, the Arabic version was validated among patients with chronic pain in two tertiary care centers. Reliability of the translated version was examined using internal consistency, test-retest reliability, and intraclass correlation coefficient (ICC). We examined the validity of the Arabic NPQ-SF via construct validity, concurrent validity (associations with the numeric pain scale, Brief Pain Inventory, and Self-completed Leeds Assessment of Neuropathic Symptoms and Signs [S-LANSS]), face validity, and diagnostic validity. To investigate the responsiveness, the translated NPQ-SF questionnaire was administered twice among the same group of patients. A total of 142 subjects (68 men, 74 women) were included in the study. Cronbach's α were 0.45 (95% CI: 0.29, 0.61) and 0.48 (95% CI: 0.33, 0.63), and the ICC was 0.78 (95% CI: 0.72, 0.85). The NPQ-SF was moderately to strongly associated with the S-LANSS questionnaire. Results showed our Arabic NPQ-SF to have good diagnostic accuracy, with area under the curve of 0.76 (95% CI: 0.67, 0.84). Results from the receiver operating characteristic analysis identified a cut-off score of ≥0.52 as the best score to distinguish between patients with or without neuropathic pain, which was higher than the recommended cut-off score (≥0) in the original study. With both sensitivity and specificity of 71%. Most patients found the NPQ-SF questionnaire to be clear and easy to understand. Our translated version of NPQ-SF is reliable and valid for use, thus providing physicians a new tool with which to evaluate and diagnose neuropathic pain among Arabic-speaking patients.

Intervertebral Foramen Injection of Ozone Relieves Mechanical Allodynia and Enhances Analgesic Effect of Gabapentin in Animal Model of Neuropathic Pain.

PubMed

Luo, Wen-Jun; Yang, Fan; Yang, Fei; Sun, Wei; Zheng, Wei; Wang, Xiao-Liang; Wu, Fang-Fang; Wang, Jiang-Lin; Wang, Jia-Shuang; Guan, Su-Min; Chen, Jun

2017-07-01

In a 5-year follow-up study in a hospital in southern China, it was shown that intervertebral foramen (IVF) injection of ozone at the involved segmental levels could significantly alleviate paroxysmal spontaneous pain and mechanical allodynia in patients with chronic, intractable postherpetic neuralgia (PHN) and improve the quality of life. However, so far no proof-of-concept studies in animals have been available. This study was designed to investigate whether IVF ozone has an analgesic effect on animal models of neuropathic and inflammatory pain. Experimental trial in rats. Institute for Biomedical Sciences of Pain. By IVF injection, a volume of 50 µl containing 30 µg/mL ozone-oxygen mixture or 50 µl air was carried out on male Sprague-Dawley rats of naïve, inflammatory pain states produced by injections of either bee venom or complete Freud's adjuvant, and neuropathic pain state produced by spared nerve injury, respectively. The effects of IVF ozone on pain-related behaviors were evaluated for 2 weeks or one month. Then combined use of gabapentin (100 mg/1 kg body weight) with IVF ozone was evaluated in rats with neuropathic pain by intraperitoneal administration 5 days after the ozone treatment. Finally, the analgesic effects of another 4 drugs, AMD3100 (a CXCR4 antagonist), A-803467 (a selective Nav1.8 blocker), rapamycin (the mTOR inhibitor), and MGCD0103 (a selective histone deacetylase inhibitor) were evaluated for long term through IVF injection, respectively. (1) IVF injection of ozone at L4-5 was only effective in suppression of mechanical allodynia in rats with neuropathic pain but not with inflammatory pain; (2) the analgesic effects of IVF ozone lasted much longer (> 14 days) than other selective molecular target drugs (< 48 hours) inhibiting or antagonizing at Nav1.8 (A-803467), CXCR4 (AMD3100), mTOR (rapamycin), and histone deacetylase (MGCD0103); (3) combined use of systemic gabapentin and IVF ozone produced a synergistic analgesic effect in rats with neuropathic pain. Evaluation of the possible analgesic effects of the intraplantar injection of ozone was not performed. In the present study, we provided a line of evidence for the first time that IVF injection of ozone selectively relieved neuropathic pain but not inflammatory pain, and enhanced the analgesic effect of gabapentin. Chronic pain, neuropathic pain, inflammatory pain, ozone therapy, interventional therapy, gabapentin, spared nerve injury, bee venom, complete Freud's adjuvant.

Neuropathic Pain Following Poly-L-Lactic Acid (Sculptra) Injection.

PubMed

Vrcek, Ivan; El-Sawy, Tarek; Chou, Eva; Allen, Theresa; Nakra, Tanuj

Injectable fillers have become a prevalent means of facial rejuvenation and volume expansion. While typically well tolerated, serious complications have been reported. The authors present a case in which an otherwise healthy female with a history of multiple filler injections including poly-L-lactic acid, developed 3 weeks of neuropathic pain in the left temporal fossa following injection. To the best of the authors knowledge, neuropathic pain has not been reported as a complication following poly-L-lactic acid injection. The patient was treated with an injection of steroid and long-acting anesthetic with resolution of symptoms.

Characterizing and understanding body weight patterns in patients treated with pregabalin.

PubMed

Cabrera, Javier; Emir, Birol; Dills, Diana; Murphy, T Kevin; Whalen, Ed; Clair, Andrew

2012-06-01

We examined patterns of weight change among patients treated with pregabalin for up to 1 year. Patients with ≥1 pre-treatment weight measurement, ≥2 measurements in Period 1 (day 2-56), and ≥2 during Period 2 (day 57-356) were identified from pooled data of 106 studies including 43,525 patients. Seven patterns were developed and used for exploratory 'change point' analyses (day on-treatment when weight-change trend changed from initial trajectory) and to assess patterns of weight change by baseline weight/body mass index (BMI). A total of 3187 patients (from 41 studies) were eligible. 98.9% of patients were described by three of the seven patterns. The majority of patients (2607/3187 [81.8%]) remained within ±7% of baseline weight ('Pattern 4'). Fewer patients (463/3187 [14.5%]) were 'delayed weight gainers' (exceeded 7% weight gain in Period 2 but not Period 1 ['Pattern 6']), fewer still (82/3187 [2.6%]) were 'early weight gainers' (exceeded ≥7% baseline weight in Period 1 and remained above 7% or continued to gain weight in Period 2 ['Pattern 7']). Overall weight gainers (Patterns 6, 7) experienced 1-year weight gain (median [% change]) of +6.20 kg [+9.12%] and 5.46 kg [+13.9%] vs. 2.22 kg [+2.10%] for non-weight gainers (Pattern 4). Average baseline weight/BMI was lower for weight gainers (Patterns 6, 7) versus other patterns. Early weight gainers (Pattern 7) had change point day at day 40 versus day 54 for Pattern 4 and day 69 for Pattern 6. Use of concomitant medications and influence of comorbid conditions on weight should be considered as inherent variables when interpreting the study. The majority of patients treated with pregabalin (150-600 mg/day) for 1 year maintained weight within ±7% baseline weight. One in six patients gained ≥7% weight from baseline, and generally exceeded 7%, 2-12 months after treatment onset.

Peripheral neuropathic pain: a mechanism-related organizing principle based on sensory profiles

PubMed Central

Baron, Ralf; Maier, Christoph; Attal, Nadine; Binder, Andreas; Bouhassira, Didier; Cruccu, Giorgio; Finnerup, Nanna B.; Haanpää, Maija; Hansson, Per; Hüllemann, Philipp; Jensen, Troels S.; Freynhagen, Rainer; Kennedy, Jeffrey D.; Magerl, Walter; Mainka, Tina; Reimer, Maren; Rice, Andrew S.C.; Segerdahl, Märta; Serra, Jordi; Sindrup, Sören; Sommer, Claudia; Tölle, Thomas; Vollert, Jan; Treede, Rolf-Detlef

2016-01-01

Abstract Patients with neuropathic pain are heterogeneous in etiology, pathophysiology, and clinical appearance. They exhibit a variety of pain-related sensory symptoms and signs (sensory profile). Different sensory profiles might indicate different classes of neurobiological mechanisms, and hence subgroups with different sensory profiles might respond differently to treatment. The aim of the investigation was to identify subgroups in a large sample of patients with neuropathic pain using hypothesis-free statistical methods on the database of 3 large multinational research networks (German Research Network on Neuropathic Pain (DFNS), IMI-Europain, and Neuropain). Standardized quantitative sensory testing was used in 902 (test cohort) and 233 (validation cohort) patients with peripheral neuropathic pain of different etiologies. For subgrouping, we performed a cluster analysis using 13 quantitative sensory testing parameters. Three distinct subgroups with characteristic sensory profiles were identified and replicated. Cluster 1 (sensory loss, 42%) showed a loss of small and large fiber function in combination with paradoxical heat sensations. Cluster 2 (thermal hyperalgesia, 33%) was characterized by preserved sensory functions in combination with heat and cold hyperalgesia and mild dynamic mechanical allodynia. Cluster 3 (mechanical hyperalgesia, 24%) was characterized by a loss of small fiber function in combination with pinprick hyperalgesia and dynamic mechanical allodynia. All clusters occurred across etiologies but frequencies differed. We present a new approach of subgrouping patients with peripheral neuropathic pain of different etiologies according to intrinsic sensory profiles. These 3 profiles may be related to pathophysiological mechanisms and may be useful in clinical trial design to enrich the study population for treatment responders. PMID:27893485

Peripheral neuropathic pain: a mechanism-related organizing principle based on sensory profiles.

PubMed

Baron, Ralf; Maier, Christoph; Attal, Nadine; Binder, Andreas; Bouhassira, Didier; Cruccu, Giorgio; Finnerup, Nanna B; Haanpää, Maija; Hansson, Per; Hüllemann, Philipp; Jensen, Troels S; Freynhagen, Rainer; Kennedy, Jeffrey D; Magerl, Walter; Mainka, Tina; Reimer, Maren; Rice, Andrew S C; Segerdahl, Märta; Serra, Jordi; Sindrup, Sören; Sommer, Claudia; Tölle, Thomas; Vollert, Jan; Treede, Rolf-Detlef

2017-02-01

Patients with neuropathic pain are heterogeneous in etiology, pathophysiology, and clinical appearance. They exhibit a variety of pain-related sensory symptoms and signs (sensory profile). Different sensory profiles might indicate different classes of neurobiological mechanisms, and hence subgroups with different sensory profiles might respond differently to treatment. The aim of the investigation was to identify subgroups in a large sample of patients with neuropathic pain using hypothesis-free statistical methods on the database of 3 large multinational research networks (German Research Network on Neuropathic Pain (DFNS), IMI-Europain, and Neuropain). Standardized quantitative sensory testing was used in 902 (test cohort) and 233 (validation cohort) patients with peripheral neuropathic pain of different etiologies. For subgrouping, we performed a cluster analysis using 13 quantitative sensory testing parameters. Three distinct subgroups with characteristic sensory profiles were identified and replicated. Cluster 1 (sensory loss, 42%) showed a loss of small and large fiber function in combination with paradoxical heat sensations. Cluster 2 (thermal hyperalgesia, 33%) was characterized by preserved sensory functions in combination with heat and cold hyperalgesia and mild dynamic mechanical allodynia. Cluster 3 (mechanical hyperalgesia, 24%) was characterized by a loss of small fiber function in combination with pinprick hyperalgesia and dynamic mechanical allodynia. All clusters occurred across etiologies but frequencies differed. We present a new approach of subgrouping patients with peripheral neuropathic pain of different etiologies according to intrinsic sensory profiles. These 3 profiles may be related to pathophysiological mechanisms and may be useful in clinical trial design to enrich the study population for treatment responders.

Hyperbaric oxygen attenuates neuropathic pain and reverses inflammatory signaling likely via the Kindlin-1/Wnt-10a signaling pathway in the chronic pain injury model in rats.

PubMed

Zhao, Baisong; Pan, Yongying; Xu, Haiping; Song, Xingrong

2017-12-01

Hyperbaric oxygen (HBO) therapy is proven to attenuate neuropathic pain in rodents. The goal of the present study was to determine the potential involvement of the Kindlin-1/Wnt-10a signaling pathway during astrocyte activation and inflammation in a rodent model of neuropathic pain. Rats were assigned into sham operation, chronic constriction injury (CCI), and CCI + HBO treatment groups. Neuropathic pain developed in rats following CCI of the sciatic nerve. Rats in the CCI + HBO group received HBO treatment for five consecutive days beginning on postoperative day 1. The mechanical withdrawal threshold (MWT) and the thermal withdrawal latency (TWL) tests were performed to determine mechanical and heat hypersensitivity of animals, respectively. Kindlin-1, Wnt-10a and β-catenin protein expression was examined by immunohistochemistry and Western blot analysis. Expression of tumor necrosis factor (TNF)-α was also determined by ELISA. Our findings demonstrated that HBO treatment significantly suppressed mechanical and thermal hypersensitivity in the CCI neuropathic pain model in rats. HBO therapy significantly reversed the up-regulation of Kindlin-1 in dorsal root ganglia (DRG), spinal cord, and hippocampus of CCI rats. CCI-induced astrocyte activation and increased levels of TNF-α were efficiently reversed by HBO (P < 0.05 vs. CCI). HBO also reversed Wnt-10a up-regulation induced by CCI in the DRG, spinal cord, and hippocampus (P < 0.05 vs. CCI). Our findings demonstrate that HBO attenuated CCI-induced rat neuropathic pain and inflammatory responses, possibly through regulation of the Kindlin-1/Wnt-10a signaling pathway.

Continuous neurophatic orofacial pain: A retrospective study of 23 cases.

PubMed

Sotorra-Figuerola, Dídac; Sánchez-Torres, Alba; Valmaseda-Castellón, Eduard; Gay-Escoda, Cosme

2016-04-01

To determine the clinical characteristics of Continuous Neuropathic Orofacial Pain in patients that suffer Persistent Idiopathic Facial Pain (PIFP), Painful Post-Traumatic Trigeminal Neuropathy (PPTTN) or Burning Mouth Syndrome (BMS) and to describe their treatment. A retrospective observational study was made, reviewing the clinical history of the patients diagnosed with Continuous Neuropathic Orofacial Pain between 2004 and 2011 at the Orofacial Pain Unit of the Master of Oral Surgery and Implantology of the University of Barcelona and at the Orofacial Pain Unit of the Teknon Medical Center of Barcelona. The average age of the patients with Continuous Neuropathic Orofacial Pain was 54.5, with a clear female predominance (86.9%, n=20). Of all patients, 60.9% (n=14) were suffering a PIFP, 21.7% (n=5) had a BMS and 17.4% (n=4) were presenting a PPTTN. The pain quality described by the patients with Continuous Neuropathic Orofacial Pain was oppressive (43.47%, n=10), widely represented by patients with PIFP, and burning (39.13%, n=9) being the only quality that described patients with BMS. The treatment carried out with the patients was only pharmacologic. The most used drugs for the treatment of PIFP and PPTTN were clonazepam (50%, n=9) and amitriptyline (44.44%, n=8). However, a 55.5% (n=10) of the patients with PIFP or PPTTN required the association of two or more drugs for a correct pain control. All the patients with BMS responded satisfactorily to clonazepam. Continuous Neuropathic Orofacial Pain is a little known condition among the general population, physicians and dentists. This favors a late diagnosis and inaccurate treatments which entail unnecessary suffering. It is important to inform both the general population and health professionals concerning this painful condition. Continuous neuropathic orofacial pain, persistent idiopathic facial pain, painful post-traumatic trigeminal neuropathy, burning mouth syndrome, atypical odontalgia.

Low doses of dextromethorphan have a beneficial effect in the treatment of neuropathic pain.

PubMed

Morel, Véronique; Pickering, Gisèle; Etienne, Monique; Dupuis, Amandine; Privat, Anne-Marie; Chalus, Maryse; Eschalier, Alain; Daulhac, Laurence

2014-12-01

N-methyl-D-aspartate receptor (NMDAR) antagonists may be given in persistent neuropathic pain, but adverse events especially with ketamine may limit their clinical use. Less central and cognitive adverse events are described with dextromethorphan and memantine. These molecules have been explored in many preclinical and clinical studies, but data are conflicting as regards neuropathic pain alleviation. Dextromethorphan and memantine have been administered to animals after spinal nerve ligation (SNL) to evaluate their antinociceptive/cognitive effects and associated molecular events, including the phosphorylation of several tyrosine (pTyr(1336), pTyr(1472)) residues in the NR2B NMDAR subunit. Spinal nerve ligation and sham animals received dextromethorphan (10 mg/kg, i.p.), memantine (20 mg/kg, i.p.) or saline (1 mL/kg, i.p.). These drugs were administered once symptoms of allodynia and hyperalgesia had developed. Tests were carried out before and after surgery. Tactile allodynia, mechanical hyperalgesia and spatial memory were, respectively, evaluated by von Frey, Randall & Selitto and Y-maze tests and molecular events by Western blot analysis. Spinal nerve-ligated animals displayed nociception and impaired spatial memory. Dextromethorphan, but not memantine, reversed neuropathic pain (NP) symptoms, restored spatial memory integrity and decreased the expression of pTyr(1336)NR2B. Following postoperative administration of dextromethorphan, this study has demonstrated for the first time a concordance between behaviour, cognitive function and molecular events via pTyr(1336)NR2B for neuropathic pain alleviation. Confirmation of these findings in patients would constitute a major step forward in the treatment of neuropathic pain and in the improvement of cognitive function and quality of life. © 2014 Société Française de Pharmacologie et de Thérapeutique.

Suppression of Pax2 attenuates allodynia and hyperalgesia through ET-1-ETAR-NFAT5 signaling in a rat model of neuropathic pain.

PubMed

Tai, Lydia Wai; Pan, Zhiqiang; Sun, Liting; Li, Haobo; Gu, Pan; Wong, Stanley Sau Ching; Chung, Sookja K; Cheung, Chi Wai

2018-05-27

Endothelin-1 (ET-1) and its receptors (ETAR/ETBR) emerge to be a key signaling axis in neuropathic pain processing and are recognized as new therapeutic targets. Yet, little is known on the functional regulation of ET-1 axis during neuropathic pain. Bioinformatics analysis indicated that paired box gene 2 (Pax2) or nuclear factor of activated T-cells 5 (NFAT5), two transcription factors involved in the modulation of neurotransmission, may regulate ET-1. Therefore, we hypothesized that ET-1 axis may be regulated by Pax2 or NFAT5 in the development of neuropathic pain. After partial sciatic nerve ligation (pSNL), rats displayed allodynia and hyperalgesia, which was associated with increased mRNA and protein expressions of spinal Pax2, NFAT5, and mRNA levels of ET-1 and ETAR, but not ETBR. Knockdown of Pax2 or NFAT5 with siRNA, or inhibition of ETAR with BQ-123 attenuated pSNL-induced pain-like behaviors. At molecular level, Pax2 siRNA, but not NFAT5 siRNA, downregulated ET-1 and ETAR, while ETAR inhibitor reduced NFAT5, indicating Pax2 in the upstream of ET-1 axis with NFAT5 in the downstream. Further, suppression of Pax2 (inhibiting ET-1) or impairment of ET-1 signaling (inhibition of ETAR and/or decrease of NFAT5) deactivated mitogen-activated protein kinases (MAPK) and nuclear factor-kappa B (NF-κB) signaling pathways, supporting the significance of functional regulation of ET-1 axis in neuropathic pain signaling. These findings demonstrate that Pax2 targeting ET-1-ETAR-NFAT5 is a novel regulatory mechanism underlying neuropathic pain. Copyright © 2018 IBRO. Published by Elsevier Ltd. All rights reserved.

Bifunctional peptide-based opioid agonist/nociceptin antagonist ligand for dual treatment of nociceptive and neuropathic pain

PubMed Central

Lagard, Camille; Chevillard, Lucie; Guillemyn, Karel; Risède, Patricia; Laplanche, Jean-Louis; Spetea, Mariana; Ballet, Steven; Mégarbane, Bruno

2016-01-01

Abstract Drugs able to treat both nociceptive and neuropathic pain effectively without major side effects are lacking. We developed a bifunctional peptide-based hybrid (KGNOP1) that structurally combines a mu-opioid receptor agonist (KGOP1) with antinociceptive activity and a weak nociceptin receptor antagonist (KGNOP3) with anti-neuropathic pain activity. We investigated KGNOP1-related behavioral effects after intravenous administration in rats by assessing thermal nociception, cold hyperalgesia in a model of neuropathic pain induced by chronic constriction injury of the sciatic nerve, and plethysmography parameters including inspiratory time (TI) and minute ventilation (VM) in comparison to the well-known opioid analgesics, tramadol and morphine. Time-course and dose-dependent effects were investigated for all behavioral parameters to determine the effective doses 50% (ED50). Pain-related effects on cold hyperalgesia were markedly increased by KGNOP1 as compared to KGNOP3 and tramadol (ED50: 0.0004, 0.32, and 12.1 μmol/kg, respectively), whereas effects on thermal nociception were significantly higher with KGNOP1 as compared to morphine (ED50: 0.41 and 14.7 μmol/kg, respectively). KGNOP1 and KGOP1 produced a larger increase in TI and deleterious decrease in VM in comparison to morphine and tramadol (ED50(TI): 0.63, 0.52, 12.2, and 50.9 μmol/kg; ED50(VM): 0.57, 0.66, 10.6, and 50.0 μmol/kg, respectively). Interestingly, the calculated ratios of anti-neuropathic pain/antinociceptive to respiratory effects revealed that KGNOP1 was safer than tramadol (ED50 ratio: 5.44 × 10−3 vs 0.24) and morphine (ED50 ratio: 0.72 vs 1.39). We conclude that KGNOP1 is able to treat both experimental neuropathic and nociceptive pain, more efficiently and safely than tramadol and morphine, respectively, and thus should be a candidate for future clinical developments. PMID:28135212

Increased expression of CaV3.2 T-type calcium channels in damaged DRG neurons contributes to neuropathic pain in rats with spared nerve injury.

PubMed

Kang, Xue-Jing; Chi, Ye-Nan; Chen, Wen; Liu, Feng-Yu; Cui, Shuang; Liao, Fei-Fei; Cai, Jie; Wan, You

2018-01-01

Ion channels are very important in the peripheral sensitization in neuropathic pain. Our present study aims to investigate the possible contribution of Ca V 3.2 T-type calcium channels in damaged dorsal root ganglion neurons in neuropathic pain. We established a neuropathic pain model of rats with spared nerve injury. In these model rats, it was easy to distinguish damaged dorsal root ganglion neurons (of tibial nerve and common peroneal nerve) from intact dorsal root ganglion neurons (of sural nerves). Our results showed that Ca V 3.2 protein expression increased in medium-sized neurons from the damaged dorsal root ganglions but not in the intact ones. With whole cell patch clamp recording technique, it was found that after-depolarizing amplitudes of the damaged medium-sized dorsal root ganglion neurons increased significantly at membrane potentials of -85 mV and -95 mV. These results indicate a functional up-regulation of Ca V 3.2 T-type calcium channels in the damaged medium-sized neurons after spared nerve injury. Behaviorally, blockade of Ca V 3.2 with antisense oligodeoxynucleotides could significantly reverse mechanical allodynia. These results suggest that Ca V 3.2 T-type calcium channels in damaged medium-sized dorsal root ganglion neurons might contribute to neuropathic pain after peripheral nerve injury.

Intrathecal Infusion of Hydrogen-Rich Normal Saline Attenuates Neuropathic Pain via Inhibition of Activation of Spinal Astrocytes and Microglia in Rats

PubMed Central

Sun, Xuejun; Xiang, Zhenghua; Yang, Liqun; Huang, Shengdong; Lu, Zhijie; Sun, Yuming; Yu, Wei-Feng

2014-01-01

Background Reactive oxygen and nitrogen species are key molecules that mediate neuropathic pain. Although hydrogen is an established antioxidant, its effect on chronic pain has not been characterized. This study was to investigate the efficacy and mechanisms of hydrogen-rich normal saline induced analgesia. Methodology/Principal findings In a rat model of neuropathic pain induced by L5 spinal nerve ligation (L5 SNL), intrathecal injection of hydrogen-rich normal saline relieved L5 SNL-induced mechanical allodynia and thermal hyperalgesia. Importantly, repeated administration of hydrogen-rich normal saline did not lead to tolerance. Preemptive treatment with hydrogen-rich normal saline prevented development of neuropathic pain behavior. Immunofluorochrome analysis revealed that hydrogen-rich normal saline treatment significantly attenuated L5 SNL-induced increase of 8-hydroxyguanosine immunoreactive cells in the ipsilateral spinal dorsal horn. Western blot analysis of SDS/PAGE-fractionated tyrosine-nitrated proteins showed that L5 SNL led to increased expression of tyrosine-nitrated Mn-containing superoxide dismutase (MnSOD) in the spinal cord, and hydrogen-rich normal saline administration reversed the tyrosine-nitrated MnSOD overexpression. We also showed that the analgesic effect of hydrogen-rich normal saline was associated with decreased activation of astrocytes and microglia, attenuated expression of interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) in the spinal cord. Conclusion/Significance Intrathecal injection of hydrogen-rich normal saline produced analgesic effect in neuropathic rat. Hydrogen-rich normal saline-induced analgesia in neuropathic rats is mediated by reducing the activation of spinal astrocytes and microglia, which is induced by overproduction of hydroxyl and peroxynitrite. PMID:24857932

RNA editing enzyme ADAR2 is a mediator of neuropathic pain after peripheral nerve injury.

PubMed

Uchida, Hitoshi; Matsumura, Shinji; Okada, Shunpei; Suzuki, Tsutomu; Minami, Toshiaki; Ito, Seiji

2017-05-01

Transcriptional and post-translational regulations are important in peripheral nerve injury-induced neuropathic pain, but little is known about the role of post-transcriptional modification. Our objective was to determine the possible effect of adenosine deaminase acting on RNA (ADAR) enzymes, which catalyze post-transcriptional RNA editing, in tactile allodynia, a hallmark of neuropathic pain. Seven days after L5 spinal nerve transection (SNT) in adult mice, we found an increase in ADAR2 expression and a decrease in ADAR3 expression in the injured, but not in the uninjured, dorsal root ganglions (DRGs). These changes were accompanied by elevated levels of editing at the D site of the serotonin (5-hydroxytryptamine) 2C receptor (5-HT 2C R), at the I/V site of coatomer protein complex subunit α (COPA), and at the R/G site of AMPA receptor subunit GluA2 in the injured DRG. Compared to Adar2 +/+ /Gria2 R/R littermate controls, Adar2 -/- /Gria2 R/R mice completely lacked the increased editing of 5-HT 2C R, COPA, and GluA2 transcripts in the injured DRG and showed attenuated tactile allodynia after SNT. Furthermore, the antidepressant fluoxetine inhibited neuropathic allodynia after injury and reduced the COPA I/V site editing in the injured DRG. These findings suggest that ADAR2 is a mediator of injury-induced tactile allodynia and thus a potential therapeutic target for the treatment of neuropathic pain.-Uchida, H., Matsumura, S., Okada, S., Suzuki, T., Minami, T., Ito, S. RNA editing enzyme ADAR2 is a mediator of neuropathic pain after peripheral nerve injury. © FASEB.

Low-dose vaporized cannabis significantly improves neuropathic pain.

PubMed

Wilsey, Barth; Marcotte, Thomas; Deutsch, Reena; Gouaux, Ben; Sakai, Staci; Donaghe, Haylee

2013-02-01

We conducted a double-blind, placebo-controlled, crossover study evaluating the analgesic efficacy of vaporized cannabis in subjects, the majority of whom were experiencing neuropathic pain despite traditional treatment. Thirty-nine patients with central and peripheral neuropathic pain underwent a standardized procedure for inhaling medium-dose (3.53%), low-dose (1.29%), or placebo cannabis with the primary outcome being visual analog scale pain intensity. Psychoactive side effects and neuropsychological performance were also evaluated. Mixed-effects regression models demonstrated an analgesic response to vaporized cannabis. There was no significant difference between the 2 active dose groups' results (P > .7). The number needed to treat (NNT) to achieve 30% pain reduction was 3.2 for placebo versus low-dose, 2.9 for placebo versus medium-dose, and 25 for medium- versus low-dose. As these NNTs are comparable to those of traditional neuropathic pain medications, cannabis has analgesic efficacy with the low dose being as effective a pain reliever as the medium dose. Psychoactive effects were minimal and well tolerated, and neuropsychological effects were of limited duration and readily reversible within 1 to 2 hours. Vaporized cannabis, even at low doses, may present an effective option for patients with treatment-resistant neuropathic pain. The analgesia obtained from a low dose of delta-9-tetrahydrocannabinol (1.29%) in patients, most of whom were experiencing neuropathic pain despite conventional treatments, is a clinically significant outcome. In general, the effect sizes on cognitive testing were consistent with this minimal dose. As a result, one might not anticipate a significant impact on daily functioning. Published by Elsevier Inc.

Diagnostic accuracy of an identification tool for localized neuropathic pain based on the IASP criteria.

PubMed

Mayoral, Víctor; Pérez-Hernández, Concepción; Muro, Inmaculada; Leal, Ana; Villoria, Jesús; Esquivias, Ana

2018-04-27

Based on the clear neuroanatomical delineation of many neuropathic pain (NP) symptoms, a simple tool for performing a short structured clinical encounter based on the IASP diagnostic criteria was developed to identify NP. This study evaluated its accuracy and usefulness. A case-control study was performed in 19 pain clinics within Spain. A pain clinician used the experimental screening tool (the index test, IT) to assign the descriptions of non-neuropathic (nNP), non-localized neuropathic (nLNP), and localized neuropathic (LNP) to the patients' pain conditions. The reference standard was a formal clinical diagnosis provided by another pain clinician. The accuracy of the IT was compared with that of the Douleur Neuropathique en 4 questions (DN4) and the Leeds Assessment of Neuropathic Signs and Symptoms (LANSS). Six-hundred and sixty-six patients were analyzed. There was a good agreement between the IT and the reference standard (kappa =0.722). The IT was accurate in distinguishing between LNP and nLNP (83.2% sensitivity, 88.2% specificity), between LNP and the other pain categories (nLNP + nNP) (80.0% sensitivity, 90.7% specificity), and between NP and nNP (95.5% sensitivity, 89.1% specificity). The accuracy in distinguishing between NP and nNP was comparable with that of the DN4 and the LANSS. The IT took a median of 10 min to complete. A novel instrument based on an operationalization of the IASP criteria can not only discern between LNP and nLNP, but also provide a high level of diagnostic certainty about the presence of NP after a short clinical encounter.

Platelet-Rich Plasma Injection in Burn Scar Areas Alleviates Neuropathic Scar Pain

PubMed Central

Huang, Shu-Hung; Wu, Sheng-Hua; Lee, Su-Shin; Lin, Yun-Nan; Chai, Chee-Yin; Lai, Chung-Sheng; Wang, Hui-Min David

2018-01-01

Objective: No effective treatments have yet been developed for burn-induced neuropathic pain. Platelet-rich plasma (PRP) has been reported to ameliorate various types of inflammation pain. However, the effect of PRP on burn-induced neuropathic pain is unclear. Methods: Burn-induced neuropathic pain Sprague-Dawley rat model was confirmed using a mechanical response test 4 weeks after the burn injuries were sustained, following which PRP was injected in the scar area. The rats were divided into four groups (n = 6) as following: Group A, Sham; Group B, Sham + PRP; Group C, Burn; and Group D, Burn + PRP. Four weeks after the PRP injection, the animals were subjected to behavior tests and then sacrificed; specimens were collected for inflammation tests, Masson's trichrome stain and chromosome 10 (PTEN) in the injured skin; and PTEN, phosphorylated mammalian target of rapamycin (p-mTOR), p38, nuclear factor κB (NFκB), chemokine (CC motif) ligand 2 (CCL2), and CCL2 cognate receptor (CCR2) in spinal cord dorsal horns through immunohistochemistry and immunofluorescence staining. Results: PRP significantly alleviated allodynia in burn-induced neuropathic pain 4 weeks after treatment, and PTEN expression in the skin and spinal cord were significantly increased in group D compared with the group C. p-PTEN, p-mTOR, and CCL2 expression in neuron cells; p-p38 and p-NFκB expression in microglia; and p-JNK and p-NFκB activation in spinal astrocytes decreased significantly in the group D compared with the group C. Conclusions: PRP is effective in treating burn-induced neuropathic pain and may be used in clinical practice. PMID:29483815

Prevalence of neuropathic features of back pain in clinical populations: implications for the diagnostic triage paradigm.

PubMed

Hush, Julia M; Marcuzzi, Anna

2012-07-01

SUMMARY Contemporary clinical assessment of back pain is based on the diagnostic triage paradigm. The most common diagnostic classification is nonspecific back pain, considered to be of nociceptive etiology. A small proportion are diagnosed with radicular pain, of neuropathic origin. In this study we review the body of literature on the prevalence of neuropathic features of back pain, revealing that the point prevalence is 17% in primary care, 34% in mixed clinical settings and 53% in tertiary care. There is evidence that neuropathic features of back pain are not restricted to typical clinical radicular pain phenotypes and may be under-recognized, particularly in primary care. The consequence of this is that in the clinic, diagnostic triage may erroneously classify patients with nonspecific back pain or radicular pain. A promising alternative is the development of mechanism-based pain phenotyping in patients with back pain. Timely identification of contributory pain mechanisms may enable greater opportunity to select appropriate therapeutic targets and improve patient outcomes.

Intermittent fasting alleviates the neuropathic phenotype in a mouse model of Charcot-Marie-Tooth disease

PubMed Central

Madorsky, Irina; Opalach, Katherine; Waber, Amanda; Verrier, Jonathan D.; Solmo, Chelsea; Foster, Thomas; Dunn, William A; Notterpek, Lucia

2009-01-01

Charcot-Marie-Tooth type 1A (CMT1A) neuropathies linked to the misexpression of peripheral myelin protein 22 (PMP22) are progressive demyelinating disorders of the peripheral nervous system. In this study we asked whether dietary restriction by intermittent fasting (IF) could alleviate the neuropathic phenotype in the Trembler J (TrJ) mouse model of CMT1A. Our results show that neuropathic mice kept on a five month long IF regimen had improved locomotor performance compared to ad libitum (AL) fed littermates. The functional benefits of this dietary intervention are associated with an increased expression of myelin proteins combined with a thicker myelin sheath, less redundant basal lamina, and a reduction in aberrant Schwann cell proliferation. These morphological improvements are accompanied by a decrease in PMP22 protein aggregates, and enhanced expression of cytosolic chaperones and constituents of the autophagy-lysosomal pathway. These results indicate that dietary restriction is beneficial for peripheral nerve function in TrJ neuropathic mice, as it promotes the maintenance of locomotor performance. PMID:19320048

Impact of chronobiology on neuropathic pain treatment.

PubMed

Gilron, Ian

2016-01-01

Inflammatory pain exhibits circadian rhythmicity. Recently, a distinct diurnal pattern has been described for peripheral neuropathic conditions. This diurnal variation has several implications: advancing understanding of chronobiology may facilitate identification of new and improved treatments; developing pain-contingent strategies that maximize treatment at times of the day associated with highest pain intensity may provide optimal pain relief as well as minimize treatment-related adverse effects (e.g., daytime cognitive dysfunction); and consideration of the impact of chronobiology on pain measurement may lead to improvements in analgesic study design that will maximize assay sensitivity of clinical trials. Recent and ongoing chronobiology studies are thus expected to advance knowledge and treatment of neuropathic pain.

How to diagnose neuropathic pain? The contribution from clinical examination, pain questionnaires and diagnostic tests.

PubMed

La Cesa, S; Tamburin, S; Tugnoli, V; Sandrini, G; Paolucci, S; Lacerenza, M; Marchettini, P; Cruccu, G; Truini, A

2015-12-01

Patients with peripheral and central nervous system diseases may suffer from different types of pain, namely nociceptive, neuropathic and mixed pain. Although in some cases, the distinction between these types of pain is clinically evident, yet in some patients an accurate differential diagnosis requires dedicated clinical examination, screening questionnaires and diagnostic techniques some of which are available only in specialized pain centres. This review briefly addresses the currently agreed definitions of the different types of pain and shows how clinical examination, pain questionnaires and diagnostic tests can help the clinicians in identifying neuropathic pain.

Alleviation of chronic neuropathic pain by environmental enrichment in mice well after the establishment of chronic pain.

PubMed

Vachon, Pascal; Millecamps, Magali; Low, Lucie; Thompsosn, Scott J; Pailleux, Floriane; Beaudry, Francis; Bushnell, Catherine M; Stone, Laura S

2013-06-07

In animal models, the impact of social and environmental manipulations on chronic pain have been investigated in short term studies where enrichment was implemented prior to or concurrently with the injury. The focus of this study was to evaluate the impact of environmental enrichment or impoverishment in mice three months after induction of chronic neuropathic pain. Thirty-four CD-1 seven to eight week-old male mice were used. Mice underwent surgery on the left leg under isoflurane anesthesia to induce the spared nerve injury model of neuropathic pain or sham condition. Mice were then randomly assigned to one of four groups: nerve injury with enriched environment (n = 9), nerve injury with impoverished environment (n = 8), sham surgery with enriched environment (n = 9), or sham surgery with impoverished environment (n = 8). The effects of environmental manipulations on mechanical (von Frey filaments) heat (hot plate) and cold (acetone test) cutaneous hypersensitivities, motor impairment (Rotarod), spontaneous exploratory behavior (open field test), anxiety-like behavior (elevated plus maze) and depression-like phenotype (tail suspension test) were assessed in neuropathic and control mice 1 and 2 months post-environmental change. Finally, the effect of the environment on spinal expression of the pro-nociceptive neuropeptides substance P and CGRP form the lumbar spinal cord collected at the end of the study was evaluated by tandem liquid chromatography mass spectrometry. Environmental enrichment attenuated nerve injury-induced hypersensitivity to mechanical and cold stimuli. In contrast, an impoverished environment exacerbated mechanical hypersensitivity. No antidepressant effects of enrichment were observed in animals with chronic neuropathic pain. Finally, environmental enrichment resulted lower SP and CGRP concentrations in neuropathic animals compared to impoverishment. These effects were all observed in animals that had been neuropathic for several months prior to intervention. These results suggest that environmental factors could play an important role in the rehabilitation of chronic pain patients well after the establishment of chronic pain. Enrichment is a potentially inexpensive, safe and easily implemented non-pharmacological intervention for the treatment of chronic pain.

Effects of exogenous galanin on neuropathic pain state and change of galanin and its receptors in DRG and SDH after sciatic nerve-pinch injury in rat.

PubMed

Xu, Xiaofeng; Yang, Xiangdong; Zhang, Ping; Chen, Xiuying; Liu, Huaxiang; Li, Zhenzhong

2012-01-01

A large number of neuroanatomical, neurophysiologic, and neurochemical mechanisms are thought to contribute to the development and maintenance of neuropathic pain. However, mechanisms responsible for neuropathic pain have not been completely delineated. It has been demonstrated that neuropeptide galanin (Gal) is upregulated after injury in the dorsal root ganglion (DRG) and spinal dorsal horn (SDH) where it plays a predominantly antinociceptive role. In the present study, sciatic nerve-pinch injury rat model was used to determine the effects of exogenous Gal on the expression of the Gal and its receptors (GalR1, GalR2) in DRG and SDH, the alterations of pain behavior, nerve conduction velocity (NCV) and morphology of sciatic nerve. The results showed that exogenous Gal had antinociceptive effects in this nerve-pinch injury induced neuropathic pain animal model. It is very interesting that Gal, GalR1 and GalR2 change their expression greatly in DRG and SDH after nerve injury and intrathecal injection of exougenous Gal. Morphological investigation displays a serious damage after nerve-pinch injury and an amendatory regeneration after exogenous Gal treatment. These findings imply that Gal, via activation of GalR1 and/or GalR2, may have neuroprotective effects in reducing neuropathic pain behaviors and improving nerve regeneration after nerve injury.

Wen-Luo-Tong Prevents Glial Activation and Nociceptive Sensitization in a Rat Model of Oxaliplatin-Induced Neuropathic Pain.

PubMed

Deng, Bo; Jia, Liqun; Pan, Lin; Song, Aiping; Wang, Yuanyuan; Tan, Huangying; Xiang, Qing; Yu, Lili; Ke, Dandan

2016-01-01

One of the main dose-limiting complications of the chemotherapeutic agent oxaliplatin (OXL) is painful neuropathy. Glial activation and nociceptive sensitization may be responsible for the mechanism of neuropathic pain. The Traditional Chinese Medicine (TCM) Wen-luo-tong (WLT) has been widely used in China to treat chemotherapy induced neuropathic pain. However, there is no study on the effects of WLT on spinal glial activation induced by OXL. In this study, a rat model of OXL-induced chronic neuropathic pain was established and WLT was administrated. Pain behavioral tests and morphometric examination of dorsal root ganglia (DRG) were conducted. Glial fibrillary acidic protein (GFAP) immunostaining was performed, glial activation was evaluated, and the excitatory neurotransmitter substance P (SP) and glial-derived proinflammatory cytokine tumor necrosis factor-α (TNF-α) were analyzed. WLT treatment alleviated OXL-induced mechanical allodynia and mechanical hyperalgesia. Changes in the somatic, nuclear, and nucleolar areas of neurons in DRG were prevented. In the spinal dorsal horn, hypertrophy and activation of GFAP-positive astrocytes were averted, and the level of GFAP mRNA decreased significantly. Additionally, TNF-α mRNA and protein levels decreased. Collectively, these results indicate that WLT reversed both glial activation in the spinal dorsal horn and nociceptive sensitization during OXL-induced chronic neuropathic pain in rats.

Glycinergic dysfunction in a subpopulation of dorsal horn interneurons in a rat model of neuropathic pain

PubMed Central

Imlach, Wendy L.; Bhola, Rebecca F.; Mohammadi, Sarasa A.; Christie, Macdonald J.

2016-01-01

The development of neuropathic pain involves persistent changes in signalling within pain pathways. Reduced inhibitory signalling in the spinal cord following nerve-injury has been used to explain sensory signs of neuropathic pain but specific circuits that lose inhibitory input have not been identified. This study shows a specific population of spinal cord interneurons, radial neurons, lose glycinergic inhibitory input in a rat partial sciatic nerve ligation (PNL) model of neuropathic pain. Radial neurons are excitatory neurons located in lamina II of the dorsal horn, and are readily identified by their morphology. The amplitude of electrically-evoked glycinergic inhibitory post-synaptic currents (eIPSCs) was greatly reduced in radial neurons following nerve-injury associated with increased paired-pulse ratio. There was also a reduction in frequency of spontaneous IPSCs (sIPSCs) and miniature IPSCs (mIPSC) in radial neurons without significantly affecting mIPSC amplitude. A subtype selective receptor antagonist and western blots established reversion to expression of the immature glycine receptor subunit GlyRα2 in radial neurons after PNL, consistent with slowed decay times of IPSCs. This study has important implications as it identifies a glycinergic synaptic connection in a specific population of dorsal horn neurons where loss of inhibitory signalling may contribute to signs of neuropathic pain. PMID:27841371

Spinal sigma-1 receptors activate NADPH oxidase 2 leading to the induction of pain hypersensitivity in mice and mechanical allodynia in neuropathic rats.

PubMed

Choi, Sheu-Ran; Roh, Dae-Hyun; Yoon, Seo-Yeon; Kang, Suk-Yun; Moon, Ji-Young; Kwon, Soon-Gu; Choi, Hoon-Seong; Han, Ho-Jae; Beitz, Alvin J; Oh, Seog-Bae; Lee, Jang-Hern

2013-08-01

We have recently demonstrated that spinal sigma-1 receptors (Sig-1Rs) mediate pain hypersensitivity in mice and neuropathic pain in rats. In this study, we examine the role of NADPH oxidase 2 (Nox2)-induced reactive oxygen species (ROS) on Sig-1R-induced pain hypersensitivity and the induction of chronic neuropathic pain. Neuropathic pain was produced by chronic constriction injury (CCI) of the right sciatic nerve in rats. Mechanical allodynia and thermal hyperalgesia were evaluated in mice and CCI-rats. Western blotting and dihydroethidium (DHE) staining were performed to assess the changes in Nox2 activation and ROS production in spinal cord, respectively. Direct activation of spinal Sig-1Rs with the Sig-1R agonist, PRE084 induced mechanical allodynia and thermal hyperalgesia, which were dose-dependently attenuated by pretreatment with the ROS scavenger, NAC or the Nox inhibitor, apocynin. PRE084 also induced an increase in Nox2 activation and ROS production, which were attenuated by pretreatment with the Sig-1R antagonist, BD1047 or apocynin. CCI-induced nerve injury produced an increase in Nox2 activation and ROS production in the spinal cord, all of which were attenuated by intrathecal administration with BD1047 during the induction phase of neuropathic pain. Furthermore, administration with BD1047 or apocynin reversed CCI-induced mechanical allodynia during the induction phase, but not the maintenance phase. These findings demonstrate that spinal Sig-1Rs modulate Nox2 activation and ROS production in the spinal cord, and ultimately contribute to the Sig-1R-induced pain hypersensitivity and the peripheral nerve injury-induced induction of chronic neuropathic pain. Copyright © 2013 Elsevier Ltd. All rights reserved.

Initial accuracy assessment of the modified S-LANSS for the detection of neuropathic orofacial pain conditions.

PubMed

Herrero Babiloni, Alberto; Nixdorf, Donald R; Law, Alan S; Moana-Filho, Estephan J; Shueb, Sarah S; Nguyen, Ruby H; Durham, Justin

2017-01-01

To evaluate the accuracy of a questionnaire modified for the identification of intraoral pain with neuropathic characteristics in a clinical orofacial pain sample population. 136 participants with at least one of four orofacial pain diagnoses (temporomandibular disorders [TMD, n = 41], acute dental pain [ADP, n = 41], trigeminal neuralgia [TN, n = 19], persistent dentoalveolar pain disorder [PDAP, n = 14]) and a group of pain-free controls (n = 21) completed the modified S-LANSS, a previously adapted version of the original questionnaire devised to detected patients suffering from intraoral pain with neuropathic characteristics. Psychometric properties (sensitivity, specificity, positive predictive value [PPV], negative predictive value [NPV]) were calculated in two analyses with two different thresholds: (1) Detection of pain with neuropathic characteristics: PDAP + TN were considered positive, and TMD + ADP + controls were considered negative per gold standard (expert opinion). (2) Detection of PDAP: PDAP was considered positive and TMD + ADP were considered negative per gold standard. For both analyses, target values for adequate sensitivity and specificity were defined as ≥ 80%. For detection of orofacial pain with neuropathic characteristics (PDAP + TN), the modified S-LANSS presented with the most optimistic threshold sensitivity of 52% (95% confidence interval [CI], 34-69), specificity of 70% (95% CI, 60-79), PPV of 35% (95% CI, 22-51), and NPV of 82% (95% CI, 72-89). For detection of PDAP only, with the most optimistic threshold sensitivity was 64% (95% CI, 35-87), specificity 63% (95% CI, 52-74), PPV 23% (95% CI, 11-39) and NPV 91% (95% CI, 81-97). Based on a priori defined criteria, the modified S-LANSS did not show adequate accuracy to detect intraoral pain with neuropathic characteristics in a clinical orofacial pain sample.

High Rates of Undiagnosed Psychological Distress Exist in a Referral Population for Spinal Cord Stimulation in the Management of Chronic Pain.

PubMed

Shamji, Mohammed F; Rodriguez, Jessica; Shcharinsky, Alina; Paul, Darcia

2016-06-01

Neuropathic pain affects various dimensions of patient health including physical, psychological, and socioeconomic. The spectrum of psychological dysfunction that accompanies this pain phenotype is unknown, as well as differences based on the etiology of the pain among patients referred for spinal cord stimulation (SCS). We prospectively assessed SCS referral patients with neuropathic pain for features of psychological distress, either mood or anxiety. Demographic data included age, gender, diagnosis, marital status, and educational level. Screening tools were applied for neuropathic pain (Douleur Neuropathic Quatre and Leeds Assessment of Neuropathic Symptoms and Signs) and psychological distress (Beck Depression Inventory [BDI] and Beck Anxiety Inventory [BAI]). Descriptive statistics defined disease prevalence, compared by gender and diagnosis. Logistic regression correlated pain intensity with severity of psychopathology. Among 150 patients with suitable neuropathic pain diagnoses and no treatable structural pathology, 57% were women, median age was 54 years, and 35% and 42% admitted to routine smoking and alcohol use, respectively. The most common diagnoses were complex regional pain syndrome (46%) and failed back surgery syndrome (38%). Depression symptoms were screened positive by BDI in 63% of patients, and anxiety symptoms were screened positive by BAI in 23% of patients. Pain intensity correlated with BDI scores (p < 0.02) but not BAI scores (p = 0.43). The high frequency of depressive and anxiety symptoms screened by the Beck scores in this cohort is an order of magnitude higher than seen in the general population. That many of these cases are undiagnosed should motivate clinicians from primary care providers, comprehensive pain specialists, and surgeons to screen SCS patients for such psychopathology. This represents an opportunity to enhance overall pain management as well as success with invasive neuromodulation strategies. © 2015 International Neuromodulation Society.

Icariin, a flavonoid with anti-cancer effects, alleviated paclitaxel-induced neuropathic pain in a SIRT1-dependent manner.

PubMed

Gui, Yulong; Zhang, Jie; Chen, Liang; Duan, Shunyuan; Tang, Jing; Xu, Wei; Li, Aiyuan

2018-01-01

Background One of the most common side effects of paclitaxel was dosage-dependently painful neuropathy. Various reports indicated that spinal neuroinflammation was involved in paclitaxel-induced neuropathic pain. This study investigated the effect of icariin on paclitaxel-induced neuroinflammation and peripheral neuropathy in rats. Methods Two parts were included in this study. In part one, the effect of icariin on paclitaxel-induced neuropathic pain was investigated. Mechanical thresholds were measured as primary outcomes. Production of proinflammatory factors (tumor necrosis factor-α, interleukin-1 β, and interleukin-6), activation of nuclear factor-κB (NF-κB(p65)) signal, and activation of astrocytes were detected as secondary outcomes. Spinal Sirtuin 1 (SIRT1) expression, H4 acetylation, and NAD + content were measured to investigate the effect of icariin on spinal SIRT1 signal pathway. In part two, the role of SIRT1 signal on icariin-induced effect in rats was investigated, and EX527, a SIRT1 inhibitor, was employed. Results The results showed paclitaxel treatment induced significant decrease in mechanical thresholds. Paclitaxel treatment also induced NF-κB(p65) activation and upregulation of proinflammatory factors (TNF-α, IL-1β, and IL-6). Paclitaxel also induced astrocyte activation in the spinal cord. However, 100 mg/kg icariin treatment significantly alleviated paclitaxel-induced mechanical allodynia and spinal neuroinflammation. Furthermore, icariin treatment dosage-dependently reversed paclitaxel-induced SIRT1 downregulation and H4 acetylation. EX527, a selective SIRT1 inhibitor, completely reversed icariin-induced anti-neuroinflammation and anti-allodynia effects in paclitaxel-induced neuropathic pain rats. Conclusions This meant that spinal SIRT1 activation was involved in icariin-induced effects in paclitaxel-induced neuropathic pain rats. Icariin could be a potential agent for the treatment of paclitaxel-induced neuropathic pain.

Sleep deprivation aggravates median nerve injury-induced neuropathic pain and enhances microglial activation by suppressing melatonin secretion.

PubMed

Huang, Chun-Ta; Chiang, Rayleigh Ping-Ying; Chen, Chih-Li; Tsai, Yi-Ju

2014-09-01

Sleep deprivation is common in patients with neuropathic pain, but the effect of sleep deprivation on pathological pain remains uncertain. This study investigated whether sleep deprivation aggravates neuropathic symptoms and enhances microglial activation in the cuneate nucleus (CN) in a median nerve chronic constriction injury (CCI) model. Also, we assessed if melatonin supplements during the sleep deprived period attenuates these effects. Rats were subjected to sleep deprivation for 3 days by the disc-on-water method either before or after CCI. In the melatonin treatment group, CCI rats received melatonin supplements at doses of 37.5, 75, 150, or 300 mg/kg during sleep deprivation. Melatonin was administered at 23:00 once a day. Male Sprague-Dawley rats, weighing 180-250 g (n = 190), were used. Seven days after CCI, behavioral testing was conducted, and immunohistochemistry, immunoblotting, and enzyme-linked immunosorbent assay were used for qualitative and quantitative analyses of microglial activation and measurements of proinflammatory cytokines. In rats who underwent post-CCI sleep deprivation, microglia were more profoundly activated and neuropathic pain was worse than those receiving pre-CCI sleep deprivation. During the sleep deprived period, serum melatonin levels were low over the 24-h period. Administration of melatonin to CCI rats with sleep deprivation significantly attenuated activation of microglia and development of neuropathic pain, and markedly decreased concentrations of proinflammatory cytokines. Sleep deprivation makes rats more vulnerable to nerve injury-induced neuropathic pain, probably because of associated lower melatonin levels. Melatonin supplements to restore a circadian variation in melatonin concentrations during the sleep deprived period could alleviate nerve injury-induced behavioral hypersensitivity. © 2014 Associated Professional Sleep Societies, LLC.

Neuropathic Pain and Lung Delivery of Nanoparticulate Drugs: An Emerging Novel Therapeutic Strategy.

PubMed

Islam, Nazrul; Abbas, Muzaffar; Rahman, Shafiqur

2017-01-01

Neuropathic pain is a chronic neurological disorder affecting millions of people around the world. The currently available pharmacologic agents for the treatment of neuropathic pain have limited efficacy and are associated with dose related unwanted adverse effects. Due to the limited access of drug molecules across blood-brain barrier, a small percentage of drug that is administered systematically, reaches the central nervous system in active form. These therapeutic agents also require daily treatment regimen that is inconvenient and potentially impact patient compliance. Application of nanoparticulate drugs for enhanced delivery system has been explored extensively in the last decades. Pulmonary delivery of nanomedicines for the management of various diseases has become an emerging treatment strategy that ensures the targeted delivery of drugs both for systemic and local effects with low dose and limited adverse effects. To the best of our knowledge, there are no inhaled drug products available on market for the treatment of neuropathic pain. The advantages of delivering therapeutics into deep lungs include non-invasive drug delivery, higher bioavailability with low dose, lower systemic toxicity, and potentially greater blood-brain barrier penetration. This review discusses and highlights the important issues on the application of emerging nanoparticulate lung delivery of drugs for the effective treatment of neuropathic pain. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Role of MicroRNA-143 in Nerve Injury-Induced Upregulation of Dnmt3a Expression in Primary Sensory Neurons

PubMed Central

Xu, Bo; Cao, Jing; Zhang, Jun; Jia, Shushan; Wu, Shaogen; Mo, Kai; Wei, Guihua; Liang, Lingli; Miao, Xuerong; Bekker, Alex; Tao, Yuan-Xiang

2017-01-01

Peripheral nerve injury increased the expression of the DNA methyltransferase 3A (Dnmt3a) mRNA and its encoding Dnmt3a protein in injured dorsal root ganglia (DRG). This increase is considered as an endogenous instigator in neuropathic pain genesis through epigenetic silencing of pain-associated genes (such as Oprm1) in injured DRG. However, how DRG DNMT3a is increased following peripheral nerve injury is still elusive. We reported here that peripheral nerve injury caused by the fifth spinal nerve ligation (SNL) downregulated microRNA (miR)-143 expression in injured DRG. This downregulation was required for SNL-induced DRG Dnmt3a increase as rescuing miR-143 downregulation through microinjection of miR-143 mimics into injured DRG blocked the SNL-induced increase in Dnmt3a and restored the SNL-induced decreases in Oprm1 mRNA and its encoding mu opioid receptor (MOR) in injured DRG, impaired spinal cord central sensitization and neuropathic pain, and improved morphine analgesic effects following SNL. Mimicking SNL-induced DRG miR-143 downregulation through DRG microinjection of miR143 inhibitors in naive rats increased the expression of Dnmt3a and reduced the expression of Oprm1 mRNA and MOR in injected DRG and produced neuropathic pain-like symptoms. These findings suggest that miR-143 is a negative regulator in Dnmt3a expression in the DRG under neuropathic pain conditions and may be a potential target for therapeutic management of neuropathic pain. PMID:29170626

Effect of artemisinin on neuropathic pain mediated by P2X4 receptor in dorsal root ganglia.

PubMed

Ying, Mofeng; Liu, Hui; Zhang, Tengling; Jiang, Chenxu; Gong, Yingxin; Wu, Bing; Zou, Lifang; Yi, Zhihua; Rao, Shenqiang; Li, Guilin; Zhang, Chunping; Jia, Tianyu; Zhao, Shanhong; Yuan, Huilong; Shi, Liran; Li, Lin; Liang, Shangdong; Liu, Shuangmei

2017-09-01

Neuropathic pain is a type of chronic pain caused by nervous system damage and dysfunction. The pathogenesis of chronic pain is complicated, and there are no effective therapies for neuropathic pain. Studies show that the P2X 4 receptor expressed in the satellite glial cells (SGCs) of dorsal root ganglia (DRG) is related to neuropathic pain. Artemisinin is a monomeric component extracted from traditional Chinese medicine and has a variety of important pharmacological effects and potential applications. This study observed the effect of artemisinin on neuropathic pain and delineated its possible mechanism. The chronic constriction injury (CCI) rat model was used in this study. The results demonstrated that artemisinin relieved pain behaviors in the CCI rats, inhibited the expression of P2X 4 receptor in the DRG, and decreased the ATP-activated currents in HEK293 cells transfected with P2X 4 plasmid. Dual-labeling immunofluorescence showed that the coexpression of P2X 4 receptor and glial fibrillary acidic protein (GFAP) in the DRG of CCI rats was increased compared to control rats. After CCI rats were treated with artemisinin, the coexpression of P2X 4 receptor and GFAP in the DRG was significantly decreased compared to the CCI group. This finding suggested that artemisinin could inhibit the nociceptive transmission mediated by P2X 4 receptor in the DRG SGCs and thus relieve pain behaviors in the CCI rats. Copyright © 2017 Elsevier Ltd. All rights reserved.

Chemokines in neuron-glial cell interaction and pathogenesis of neuropathic pain.

PubMed

Zhang, Zhi-Jun; Jiang, Bao-Chun; Gao, Yong-Jing

2017-09-01

Neuropathic pain resulting from damage or dysfunction of the nervous system is a highly debilitating chronic pain state and is often resistant to currently available treatments. It has become clear that neuroinflammation, mainly mediated by proinflammatory cytokines and chemokines, plays an important role in the establishment and maintenance of neuropathic pain. Chemokines were originally identified as regulators of peripheral immune cell trafficking and were also expressed in neurons and glial cells in the central nervous system. In recent years, accumulating studies have revealed the expression, distribution and function of chemokines in the spinal cord under chronic pain conditions. In this review, we provide evidence showing that several chemokines are upregulated after peripheral nerve injury and contribute to the pathogenesis of neuropathic pain via different forms of neuron-glia interaction in the spinal cord. First, chemokine CX3CL1 is expressed in primary afferents and spinal neurons and induces microglial activation via its microglial receptor CX3CR1 (neuron-to-microglia signaling). Second, CCL2 and CXCL1 are expressed in spinal astrocytes and act on CCR2 and CXCR2 in spinal neurons to increase excitatory synaptic transmission (astrocyte-to-neuron signaling). Third, we recently identified that CXCL13 is highly upregulated in spinal neurons after spinal nerve ligation and induces spinal astrocyte activation via receptor CXCR5 (neuron-to-astrocyte signaling). Strategies that target chemokine-mediated neuron-glia interactions may lead to novel therapies for the treatment of neuropathic pain.

Intrathecal bone marrow stromal cells inhibit neuropathic pain via TGF-β secretion

PubMed Central

Chen, Gang; Park, Chul-Kyu; Xie, Rou-Gang; Ji, Ru-Rong

2015-01-01

Neuropathic pain remains a pressing clinical problem. Here, we demonstrate that a local, intrathecal (i.t.) injection of bone marrow stromal cells (BMSCs) following lumbar puncture alleviates early- and late-phase neuropathic pain symptoms, such as allodynia and hyperalgesia, for several weeks in murine chronic constriction injury (CCI) and spared nerve injury models. Moreover, i.t. BMSCs reduced CCI-induced spontaneous pain and axonal injury of dorsal root ganglion (DRG) neurons and inhibited CCI-evoked neuroinflammation in DRGs and spinal cord tissues. BMSCs secreted TGF-β1 into the cerebrospinal fluid, and neutralization of TGF-β1, but not IL-10, reversed the analgesic effect of BMSCs. Conversely, i.t. administration of TGF-β1 potently inhibited neuropathic pain. TGF-β1 acted as a powerful neuromodulator and rapidly (within minutes) suppressed CCI-evoked spinal synaptic plasticity and DRG neuronal hyperexcitability via TGF-β receptor 1–mediated noncanonical signaling. Finally, nerve injury upregulated CXCL12 in lumbar L4–L6 DRGs, and this upregulation caused migration of i.t.-injected BMSCs to DRGs through the CXCL12 receptor CXCR4, which was expressed on BMSCs. BMSCs that migrated from the injection site survived at the border of DRGs for more than 2 months. Our findings support a paracrine mechanism by which i.t. BMSCs target CXCL12-producing DRGs to elicit neuroprotection and sustained neuropathic pain relief via TGF-β1 secretion. PMID:26168219

Magnesium attenuates chronic hypersensitivity and spinal cord NMDA receptor phosphorylation in a rat model of diabetic neuropathic pain

PubMed Central

Rondón, L J; Privat, A M; Daulhac, L; Davin, N; Mazur, A; Fialip, J; Eschalier, A; Courteix, C

2010-01-01

Neuropathic pain is a common diabetic complication affecting 8–16% of diabetic patients. It is characterized by aberrant symptoms of spontaneous and stimulus-evoked pain including hyperalgesia and allodynia. Magnesium (Mg) deficiency has been proposed as a factor in the pathogenesis of diabetes-related complications, including neuropathy. In the central nervous system, Mg is also a voltage-dependant blocker of the N-methyl-d-aspartate receptor channels involved in abnormal processing of sensory information. We hypothesized that Mg deficiency might contribute to the development of neuropathic pain and the worsening of clinical and biological signs of diabetes and consequently, that Mg administration could prevent or improve its complications. We examined the effects of oral Mg supplementation (296 mg l−1 in drinking water for 3 weeks) on the development of neuropathic pain and on biological and clinical parameters of diabetes in streptozocin (STZ)-induced diabetic rats. STZ administration induced typical symptoms of type 1 diabetes. The diabetic rats also displayed mechanical hypersensitivity and tactile and thermal allodynia. The level of phosphorylated NMDA receptor NR1 subunit (pNR1) was higher in the spinal dorsal horn of diabetic hyperalgesic/allodynic rats. Magnesium supplementation failed to reduce hyperglycaemia, polyphagia and hypermagnesiuria, or to restore intracellular Mg levels and body growth, but increased insulinaemia and reduced polydipsia. Moreover, it abolished thermal and tactile allodynia, delayed the development of mechanical hypersensitivity, and prevented the increase in spinal cord dorsal horn pNR1. Thus, neuropathic pain symptoms can be attenuated by targeting the Mg-mediated blockade of NMDA receptors, offering new therapeutic opportunities for the management of chronic neuropathic pain. PMID:20837644

Chemokine CXCL13 mediates orofacial neuropathic pain via CXCR5/ERK pathway in the trigeminal ganglion of mice.

PubMed

Zhang, Qian; Cao, De-Li; Zhang, Zhi-Jun; Jiang, Bao-Chun; Gao, Yong-Jing

2016-07-11

Trigeminal nerve damage-induced neuropathic pain is a severely debilitating chronic orofacial pain syndrome. Spinal chemokine CXCL13 and its receptor CXCR5 were recently demonstrated to play a pivotal role in the pathogenesis of spinal nerve ligation-induced neuropathic pain. Whether and how CXCL13/CXCR5 in the trigeminal ganglion (TG) mediates orofacial pain are unknown. The partial infraorbital nerve ligation (pIONL) was used to induce trigeminal neuropathic pain in mice. The expression of ATF3, CXCL13, CXCR5, and phosphorylated extracellular signal-regulated kinase (pERK) in the TG was detected by immunofluorescence staining and western blot. The effect of shRNA targeting on CXCL13 or CXCR5 on pain hypersensitivity was checked by behavioral testing. pIONL induced persistent mechanical allodynia and increased the expression of ATF3, CXCL13, and CXCR5 in the TG. Inhibition of CXCL13 or CXCR5 by shRNA lentivirus attenuated pIONL-induced mechanical allodynia. Additionally, pIONL-induced neuropathic pain and the activation of ERK in the TG were reduced in Cxcr5 (-/-) mice. Furthermore, MEK inhibitor (PD98059) attenuated mechanical allodynia and reduced TNF-α and IL-1β upregulation induced by pIONL. TNF-α inhibitor (Etanercept) and IL-1β inhibitor (Diacerein) attenuated pIONL-induced orofacial pain. Finally, intra-TG injection of CXCL13 induced mechanical allodynia, increased the activation of ERK and the production of TNF-α and IL-1β in the TG of WT mice, but not in Cxcr5 (-/-) mice. Pretreatment with PD98059, Etanercept, or Diacerein partially blocked CXCL13-induced mechanical allodynia, and PD98059 also reduced CXCL13-induced TNF-α and IL-1β upregulation. CXCL13 and CXCR5 contribute to orofacial pain via ERK-mediated proinflammatory cytokines production. Targeting CXCL13/CXCR5/ERK/TNF-α and IL-1β pathway in the trigeminal ganglion may offer effective treatment for orofacial neuropathic pain.

Bifunctional peptide-based opioid agonist/nociceptin antagonist ligand for dual treatment of nociceptive and neuropathic pain.

PubMed

Lagard, Camille; Chevillard, Lucie; Guillemyn, Karel; Risède, Patricia; Laplanche, Jean-Louis; Spetea, Mariana; Ballet, Steven; Mégarbane, Bruno

2017-03-01

Drugs able to treat both nociceptive and neuropathic pain effectively without major side effects are lacking. We developed a bifunctional peptide-based hybrid (KGNOP1) that structurally combines a mu-opioid receptor agonist (KGOP1) with antinociceptive activity and a weak nociceptin receptor antagonist (KGNOP3) with anti-neuropathic pain activity. We investigated KGNOP1-related behavioral effects after intravenous administration in rats by assessing thermal nociception, cold hyperalgesia in a model of neuropathic pain induced by chronic constriction injury of the sciatic nerve, and plethysmography parameters including inspiratory time (TI) and minute ventilation (VM) in comparison to the well-known opioid analgesics, tramadol and morphine. Time-course and dose-dependent effects were investigated for all behavioral parameters to determine the effective doses 50% (ED50). Pain-related effects on cold hyperalgesia were markedly increased by KGNOP1 as compared to KGNOP3 and tramadol (ED50: 0.0004, 0.32, and 12.1 μmol/kg, respectively), whereas effects on thermal nociception were significantly higher with KGNOP1 as compared to morphine (ED50: 0.41 and 14.7 μmol/kg, respectively). KGNOP1 and KGOP1 produced a larger increase in TI and deleterious decrease in VM in comparison to morphine and tramadol (ED50(TI): 0.63, 0.52, 12.2, and 50.9 μmol/kg; ED50(VM): 0.57, 0.66, 10.6, and 50.0 μmol/kg, respectively). Interestingly, the calculated ratios of anti-neuropathic pain/antinociceptive to respiratory effects revealed that KGNOP1 was safer than tramadol (ED50 ratio: 5.44 × 10 vs 0.24) and morphine (ED50 ratio: 0.72 vs 1.39). We conclude that KGNOP1 is able to treat both experimental neuropathic and nociceptive pain, more efficiently and safely than tramadol and morphine, respectively, and thus should be a candidate for future clinical developments.

Spinal CPEB-mtROS-CBP signaling pathway contributes to perineural HIV gp120 with ddC-related neuropathic pain in rats.

PubMed

Iida, Takafumi; Yi, Hyun; Liu, Shue; Huang, Wan; Kanda, Hirotsugu; Lubarsky, David A; Hao, Shuanglin

2016-07-01

Human immunodeficiency virus (HIV) patients treated with nucleoside reverse transcriptase inhibitors (NRTIs), have been known to develop neuropathic pain. While there has been a major shift away from some neurotoxic NRTIs in current antiretroviral therapy, a large number of HIV patients alive today have previously received them, and many have developed painful peripheral neuropathy. The exact mechanisms by which HIV with NRTIs contribute to the development of neuropathic pain are not known. Previous studies suggest that cytoplasmic polyadenylation element-binding protein (CPEB), reactive oxygen species (ROS), and cAMP-response element-binding protein (CREB)-binding protein (CBP), are involved in the neuroimmunological diseases including inflammatory/neuropathic pain. In this study, we investigated the role of CPEB, mitochondrial ROS (mtROS), or CBP in neuropathic pain induced by HIV envelope protein gp120 combined with antiretroviral drug. The application of recombinant gp120 into the sciatic nerve plus systemic ddC (one of NRTIs) induced mechanical allodynia. Knockdown of CPEB or CBP using intrathecal antisense oligodeoxynucleotide (AS-ODN) reduced mechanical allodynia. Intrathecal mitochondrial superoxide scavenger mito-tempol (Mito-T) increased mechanical withdrawal threshold. Knockdown of CPEB using intrathecal AS-ODN, reduced the up-regulated mitochondrial superoxide in the spinal dorsal horn in rats with gp120 combined with ddC. Intrathecal Mito-T lowered the increased expression of CBP in the spinal dorsal horn. Immunostaining studies showed that neuronal CPEB positive cells were co-localized with MitoSox positive profiles, and that MitoSox positive profiles were co-localized with neuronal CBP. Our studies suggest that neuronal CPEB-mtROS-CBP pathway in the spinal dorsal horn, plays an important role in the gp120/ddC-induced neuropathic pain in rats. Copyright © 2016. Published by Elsevier Inc.

Differential effects of subcutaneous electrical stimulation (SQS) and transcutaneous electrical nerve stimulation (TENS) in rodent models of chronic neuropathic or inflammatory pain.

PubMed

Vera-Portocarrero, Louis P; Cordero, Toni; Billstrom, Tina; Swearingen, Kim; Wacnik, Paul W; Johanek, Lisa M

2013-01-01

Electrical stimulation has been used for many years for the treatment of pain. Present-day research demonstrates that stimulation targets and parameters impact the induction of specific pain-modulating mechanisms. New targets are increasingly being investigated clinically, but the scientific rationale for a particular target is often not well established. This present study compares the behavioral effects of targeting peripheral axons by electrode placement in the subcutaneous space vs. electrode placement on the surface of the skin in a rodent model. Rodent models of inflammatory and neuropathic pain were used to investigate subcutaneous electrical stimulation (SQS) vs. transcutaneous electrical nerve stimulation (TENS). Electrical parameters and relative location of the leads were held constant under each condition. SQS had cumulative antihypersensitivity effects in both inflammatory and neuropathic pain rodent models, with significant inhibition of mechanical hypersensitivity observed on days 3-4 of treatment. In contrast, reduction of thermal hyperalgesia in the inflammatory model was observed during the first four days of treatment with SQS, and reduction of cold allodynia in the neuropathic pain model was seen only on the first day with SQS. TENS was effective in the inflammation model, and in agreement with previous studies, tolerance developed to the antihypersensitivity effects of TENS. With the exception of a reversal of cold hypersensitivity on day 1 of testing, TENS did not reveal significant analgesic effects in the neuropathic pain rodent model. The results presented show that TENS and SQS have different effects that could point to unique biologic mechanisms underlying the analgesic effect of each therapy. Furthermore, this study is the first to demonstrate in an animal model that SQS attenuates neuropathic and inflammatory-induced pain behaviors. © 2013 Medtronic, Inc.

Distinct TrkA and Ret modulated negative and positive neuropathic behaviors in a mouse model of resiniferatoxin-induced small fiber neuropathy.

PubMed

Hsieh, Yu-Lin; Kan, Hung-Wei; Chiang, Hao; Lee, Yi-Chen; Hsieh, Sung-Tsang

2018-02-01

Neurotrophic factors and their corresponding receptors play key roles in the maintenance of different phenotypic dorsal root ganglion (DRG) neurons, the axons of which degenerate in small fiber neuropathy, leading to various neuropathic manifestations. Mechanisms underlying positive and negative symptoms of small fiber neuropathy have not been systematically explored. This study investigated the molecular basis of these seemingly paradoxical neuropathic behaviors according to the profiles of TrkA and Ret with immunohistochemical and pharmacological interventions in a mouse model of resiniferatoxin (RTX)-induced small fiber neuropathy. Mice with RTX neuropathy exhibited thermal hypoalgesia and mechanical allodynia, reduced skin innervation, and altered DRG expression profiles with decreased TrkA(+) neurons and increased Ret(+) neurons. RTX neuropathy induced the expression of activating transcription factor 3 (ATF3), and ATF3(+) neurons were colocalized with Ret but not with TrkA (P<0.001). As a neuroprotectant, 4-Methylcatechol (4MC) promoted skin reinnervation partially with correlated reversal of the neuropathic behaviors and altered neurochemical expression. Gambogic amide, a selective TrkA agonist, normalized thermal hypoalgesia, and GW441756, a TrkA kinase inhibitor, induced thermal hypoalgesia, which was already reversed by 4MC. Mechanical allodynia was reversed by a Ret kinase inhibitor, AST487, which induced thermal hyperalgesia in naïve mice. The activation of Ret signaling by XIB4035 induced mechanical allodynia and thermal hypoalgesia in RTX neuropathy mice in which the neuropathic behaviors were previously normalized by 4MC. Distinct neurotrophic factor receptors, TrkA and Ret, accounted for negative and positive neuropathic behaviors in RTX-induced small fiber neuropathy, respectively: TrkA for thermal hypoalgesia and Ret for mechanical allodynia and thermal hypoalgesia. Copyright © 2017 Elsevier Inc. All rights reserved.

Inhaled Cannabis for Chronic Neuropathic Pain: A Meta-analysis of Individual Patient Data.

PubMed

Andreae, Michael H; Carter, George M; Shaparin, Naum; Suslov, Kathryn; Ellis, Ronald J; Ware, Mark A; Abrams, Donald I; Prasad, Hannah; Wilsey, Barth; Indyk, Debbie; Johnson, Matthew; Sacks, Henry S

2015-12-01

Chronic neuropathic pain, the most frequent condition affecting the peripheral nervous system, remains underdiagnosed and difficult to treat. Inhaled cannabis may alleviate chronic neuropathic pain. Our objective was to synthesize the evidence on the use of inhaled cannabis for chronic neuropathic pain. We performed a systematic review and a meta-analysis of individual patient data. We registered our protocol with PROSPERO CRD42011001182. We searched in Cochrane Central, PubMed, EMBASE, and AMED. We considered all randomized controlled trials investigating chronic painful neuropathy and comparing inhaled cannabis with placebo. We pooled treatment effects following a hierarchical random-effects Bayesian responder model for the population-averaged subject-specific effect. Our evidence synthesis of individual patient data from 178 participants with 405 observed responses in 5 randomized controlled trials following patients for days to weeks provides evidence that inhaled cannabis results in short-term reductions in chronic neuropathic pain for 1 in every 5 to 6 patients treated (number needed to treat = 5.6 with a Bayesian 95% credible interval ranging between 3.4 and 14). Our inferences were insensitive to model assumptions, priors, and parameter choices. We caution that the small number of studies and participants, the short follow-up, shortcomings in allocation concealment, and considerable attrition limit the conclusions that can be drawn from the review. The Bayes factor is 332, corresponding to a posterior probability of effect of 99.7%. This novel Bayesian meta-analysis of individual patient data from 5 randomized trials suggests that inhaled cannabis may provide short-term relief for 1 in 5 to 6 patients with neuropathic pain. Pragmatic trials are needed to evaluate the long-term benefits and risks of this treatment. Copyright © 2015 American Pain Society. Published by Elsevier Inc. All rights reserved.

Effects of natural and synthetic isothiocyanate-based H2S-releasers against chemotherapy-induced neuropathic pain: Role of Kv7 potassium channels.

PubMed

Di Cesare Mannelli, Lorenzo; Lucarini, Elena; Micheli, Laura; Mosca, Ilaria; Ambrosino, Paolo; Soldovieri, Maria Virginia; Martelli, Alma; Testai, Lara; Taglialatela, Maurizio; Calderone, Vincenzo; Ghelardini, Carla

2017-07-15

Hydrogen sulfide (H 2 S) is a crucial signaling molecule involved in several physiological and pathological processes. Nonetheless, the role of this gasotransmitter in the pathogenesis and treatment of neuropathic pain is controversial. The aim of the present study was to investigate the pain relieving profile of a series of slow releasing H 2 S donors (the natural allyl-isothiocyanate and the synthetics phenyl- and carboxyphenyl-isothiocyanate) in animal models of neuropathic pain induced by paclitaxel or oxaliplatin, anticancer drugs characterized by a dose-limiting neurotoxicity. The potential contribution of Kv7 potassium channels modulation was also studied. Mice were treated with paclitaxel (2.0 mg kg -1 ) i.p. on days 1, 3, 5 and 7; oxaliplatin (2.4 mg kg -1 ) was administered i.p. on days 1-2, 5-9, 12-14. Behavioral tests were performed on day 15. In both models, single subcutaneous administrations of H 2 S donors (1.33, 4.43, 13.31 μmol kg -1 ) reduced the hypersensitivity to cold non-noxious stimuli (allodynia-related measurement). The prototypical H 2 S donor NaHS was also effective. Activity was maintained after i.c.v. administrations. On the contrary, the S-lacking molecule allyl-isocyanate did not increase pain threshold; the H 2 S-binding molecule hemoglobin abolished the pain-relieving effects of isothiocyanates and NaHS. The anti-neuropathic properties of H 2 S donors were reverted by the Kv7 potassium channel blocker XE991. Currents carried by Kv7.2 homomers and Kv7.2/Kv7.3 heteromers expressed in CHO cells were potentiated by H 2 S donors. Sistemically- or centrally-administered isothiocyanates reduced chemotherapy-induced neuropathic pain by releasing H 2 S. Activation of Kv7 channels largely mediate the anti-neuropathic effect. Copyright © 2017 Elsevier Ltd. All rights reserved.

Neuropathic pain in post-burn hypertrophic scars: a psychophysical and neurophysiological study.

PubMed

Isoardo, Gianluca; Stella, Maurizio; Cocito, Dario; Risso, Daniela; Migliaretti, Giuseppe; Cauda, Franco; Palmitessa, Angela; Faccani, Giuliano; Ciaramitaro, Palma

2012-06-01

Pain complicates hypertrophic post-burn pathologic scars (PPS) METHODS: To investigate the possible neuropathic origin of pain, 13 patients with painful PPS involving at least 1 hand underwent clinical examination, including the Douleur Neuropathique en 4 questions (DN4) questionnaire; median, ulnar, and radial nerve conduction studies (NCS); cold- (CDT) and heat-induced pain threshold evaluation by quantitative sensory testing; and cutaneous silent period (CSP) testing of the abductor pollicis brevis. Controls included 9 patients with non-painful PPS, 52 healthy subjects, and 28 patients with carpal tunnel syndrome (CTS). All patients with painful PPS had possible neuropathic pain (DN4 score ≥4). NCS signs of CTS were similarly present in PPS subjects with or without pain. Hands with painful PPS had lower CDT and CSP duration, more frequent cold- and heat-pain hypesthesia, and more thermal allodynia than controls. In PPS, possible neuropathic pain is associated with psychophysical and neurophysiological abnormalities suggestive of small-fiber damage. Copyright © 2011 Wiley Periodicals, Inc.

Peroxisome proliferator-activated receptor agonists modulate neuropathic pain: a link to chemokines?

PubMed Central

Freitag, Caroline M.; Miller, Richard J.

2014-01-01

Chronic pain presents a widespread and intractable medical problem. While numerous pharmaceuticals are used to treat chronic pain, drugs that are safe for extended use and highly effective at treating the most severe pain do not yet exist. Chronic pain resulting from nervous system injury (neuropathic pain) is common in conditions ranging from multiple sclerosis to HIV-1 infection to type II diabetes. Inflammation caused by neuropathy is believed to contribute to the generation and maintenance of neuropathic pain. Chemokines are key inflammatory mediators, several of which (MCP-1, RANTES, MIP-1α, fractalkine, SDF-1 among others) have been linked to chronic, neuropathic pain in both human conditions and animal models. The important roles chemokines play in inflammation and pain make them an attractive therapeutic target. Peroxisome proliferator-activated receptors (PPARs) are a family of nuclear receptors known for their roles in metabolism. Recent research has revealed that PPARs also play a role in inflammatory gene repression. PPAR agonists have wide-ranging effects including inhibition of chemokine expression and pain behavior reduction in animal models. Experimental evidence suggests a connection between the pain ameliorating effects of PPAR agonists and suppression of inflammatory gene expression, including chemokines. In early clinical research, one PPARα agonist, palmitoylethanolamide (PEA), shows promise in relieving chronic pain. If this link can be better established, PPAR agonists may represent a new drug therapy for neuropathic pain. PMID:25191225

Neuropathic pain in experimental autoimmune neuritis is associated with altered electrophysiological properties of nociceptive DRG neurons.

PubMed

Taha, Omneya; Opitz, Thoralf; Mueller, Marcus; Pitsch, Julika; Becker, Albert; Evert, Bernd Oliver; Beck, Heinz; Jeub, Monika

2017-11-01

Guillain-Barré syndrome (GBS) is an acute, immune-mediated polyradiculoneuropathy characterized by rapidly progressive paresis and sensory disturbances. Moderate to severe and often intractable neuropathic pain is a common symptom of GBS, but its underlying mechanisms are unknown. Pathology of GBS is classically attributed to demyelination of large, myelinated peripheral fibers. However, there is increasing evidence that neuropathic pain in GBS is associated with impaired function of small, unmyelinated, nociceptive fibers. We therefore examined the functional properties of small DRG neurons, the somata of nociceptive fibers, in a rat model of GBS (experimental autoimmune neuritis=EAN). EAN rats developed behavioral signs of neuropathic pain. This was accompanied by a significant shortening of action potentials due to a more rapid repolarization and an increase in repetitive firing in a subgroup of capsaicin-responsive DRG neurons. Na + current measurements revealed a significant increase of the fast TTX-sensitive current and a reduction of the persistent TTX-sensitive current component. These changes of Na + currents may account for the significant decrease in AP duration leading to an overall increase in excitability and are therefore possibly directly linked to pathological pain behavior. Thus, like in other animal models of neuropathic and inflammatory pain, Na + channels seem to be crucially involved in the pathology of GBS and may constitute promising targets for pain modulating pharmaceuticals. Copyright © 2017 Elsevier Inc. All rights reserved.

Electroconvulsive stimulation (ECS) increases the expression of neuropeptide Y (NPY) in rat brains in a model of neuropathic pain: a quantitative real-time polymerase chain reaction (RT-PCR) study.

PubMed

Okabe, Tadashi; Sato, Chiyo; Matsumoto, Keisuke; Ozawa, Hitoshi; Sakamoto, Atsuhiro

2009-11-01

Electroconvulsive shock therapy (ECT) has been widely used as an effective and established treatment for refractory depression and schizophrenia. Some reports have shown that ECT is also effective for treating refractory neuropathic pain. In a rat model of neuropathic pain produced by chronic constrictive injury (CCI) of the sciatic nerve, thermal hyperalgesia, and mechanical allodynia were observed from day 2 after surgery. An electroconvulsive shock (ECS) was administered to rodents once daily for 6 days on days 7-12 after CCI operation using a pulse generator. Thermal and mechanical stimulation tests were performed to assess pain thresholds. Real-time polymerase chain reaction was used to measure the gene expression levels for 5HT(1A)R, 5HT(2A)R, neuropeptide Y (NPY), and GABAA(alpha1)R in the brain. After ECS, the latency to withdrawal from thermal stimulation was significantly increased; however, pain withdrawal thresholds in response to mechanical stimulation were not significantly changed. Expression ratios of NPY were significantly greater after ECS. Symptoms of neuropathic pain improved and expression of NPY in the brain was increased in CCI model rats after ECS, suggesting that changes in the expression of NPY in the brain may be related to the mechanism of action of ECT in treating neuropathic pain.

Sensory neuropathic symptoms in idiopathic Parkinson's disease: prevalence and impact on quality of life.

PubMed

Adewusi, Joy K; Hadjivassiliou, Marios; Vinagre-Aragón, Ana; O'Connor, Karen Ruth; Khan, Aijaz; Grünewald, Richard Adam; Zis, Panagiotis

2018-05-23

Neuropathic symptoms are commonly reported in Parkinson's disease (PD), but robust data on the epidemiology of such symptoms are lacking. The present study sought to investigate the prevalence and determinants of peripheral sensory neuropathic symptoms (PSNS) in idiopathic PD (IPD) and ascertain the effects of such symptoms on the patients' quality of life (QoL). Patients with IPD and age-matched and gender-matched controls were screened for neuropathic symptoms using the Michigan Neuropathy Screening Instrument. The impact of neuropathic symptoms on QoL was investigated using the 36-Item Short Form Survey. Fifty-two patients and 52 age-matched and gender-matched controls were recruited. PSNS were reported more frequently in patients with IPD than in the control subjects (57.7 versus 28.8%, p = 0.003). No significant relationships were found between PD-related clinical characteristics (i.e. disease severity and duration, duration of exposure to levodopa) and the presence of PSNS. Significant correlations were found between the number of PSNS and physical functioning (Spearman's Rho - 0.351), even after adjusting for age, gender and Hoehn and Yahr score. Our results support the notion of a greater prevalence of PSNS in IPD patients as compared to the general population, which, at least in part, may be secondary to large and/or small fibre peripheral neuropathy. This warrants further investigation in larger studies that include detailed neurophysiological assessments.

Minocycline Does Not Decrease Intensity of Neuropathic Pain Intensity, But Does Improve Its Affective Dimension.

PubMed

Sumitani, Masahiko; Ueda, Hiroshi; Hozumi, Jun; Inoue, Reo; Kogure, Takamichi; Yamada, Yoshitsugu; Kogure, Takamichi

2016-01-01

Recent understanding of the neuron-glia communication shed light on an important role of microglia to develop neuropathic pain The analgesic effect of minocycline on neuropathic pain is promising but it remains unclear in clinical settings. This study included 20 patients with neuropathic pain of varied etiologies. We administered 100 mg/day of minocycline for 1 week and then 200 mg/day for 3 weeks, as an open-label adjunct to conventional analgesics. An 11-point numerical rating scale. (NRS) and the short-form McGill Pain Questionnaire (SF-MPQ) were used to evaluate pain severity. The data were collected at baseline and after 4 weeks of therapy and analyzed using the Wilcoxon signed-rank test. All except two of the patients tolerated the full dose of minocycline. There was no significant improvement in the scoring of NRS (5.6 ± 1.2 at baseline vs. 5.3 ± 1.9 at 4 weeks; P =.60). The total score of the SF-MPQ decreased significantly (17.2 ± 7.4 vs. 13.9 ± 9.6; P =.02), particularly in the affective subscale (4.4 ± 2.7 vs. 3.3 ± 3.6; P =.007) but not so in the sensory subscale (12.8 ± 5.2 vs. 10.6 ± 6.2; P =.06). We conclude that minocycline failed to decrease pain intensity but succeeded in reducing the affective dimension associated with neuropathic pain.

Reduction in voltage-gated K+ channel activity in primary sensory neurons in painful diabetic neuropathy: role of brain-derived neurotrophic factor.

PubMed

Cao, Xue-Hong; Byun, Hee-Sun; Chen, Shao-Rui; Cai, You-Qing; Pan, Hui-Lin

2010-09-01

Abnormal hyperexcitability of primary sensory neurons plays an important role in neuropathic pain. Voltage-gated potassium (Kv) channels regulate neuronal excitability by affecting the resting membrane potential and influencing the repolarization and frequency of the action potential. In this study, we determined changes in Kv channels in dorsal root ganglion (DRG) neurons in a rat model of diabetic neuropathic pain. The densities of total Kv, A-type (IA) and sustained delayed (IK) currents were markedly reduced in medium- and large-, but not in small-, diameter DRG neurons in diabetic rats. Quantitative RT-PCR analysis revealed that the mRNA levels of IA subunits, including Kv1.4, Kv3.4, Kv4.2, and Kv4.3, in the DRG were reduced approximately 50% in diabetic rats compared with those in control rats. However, there were no significant differences in the mRNA levels of IK subunits (Kv1.1, Kv1.2, Kv2.1, and Kv2.2) in the DRG between the two groups. Incubation with brain-derived neurotrophic factor (BDNF) caused a large reduction in Kv currents, especially IA currents, in medium and large DRG neurons from control rats. Furthermore, the reductions in Kv currents and mRNA levels of IA subunits in diabetic rats were normalized by pre-treatment with anti-BDNF antibody or K252a, a TrkB tyrosine kinase inhibitor. In addition, the number of medium and large DRG neurons with BDNF immunoreactivity was greater in diabetic than control rats. Collectively, our findings suggest that diabetes primarily reduces Kv channel activity in medium and large DRG neurons. Increased BDNF activity in these neurons likely contributes to the reduction in Kv channel function through TrkB receptor stimulation in painful diabetic neuropathy.

Plasma cytokine profiles in HIV-1 infected patients developing neuropathic symptoms shortly after commencing antiretroviral therapy: a case-control study.

PubMed

Van der Watt, Johan J; Wilkinson, Katalin A; Wilkinson, Robert J; Heckmann, Jeannine M

2014-02-10

In patients infected with human immunodeficiency virus 1 (HIV-1) neuropathic symptoms may develop within weeks of starting combination antiretroviral therapy (cART). This timing coincides with the occurrence of immune reconstitution inflammatory syndrome. Our objective was to investigate the longitudinal association of plasma cytokine and soluble receptor concentrations with incident neuropathic symptoms within 12 weeks of starting programme-based cART in a nested case-control study. One hundred and twenty adults without neuropathic symptoms and about to initiate cART were followed longitudinally for 24 weeks after cART initiation. Subjects were examined for peripheral neuropathy at baseline (pre-cART) and 2-, 4-, 12- and 24 weeks thereafter. Individuals developing neuropathic symptoms within 12 weeks of starting cART were matched in a nested case-control design with those remaining symptom-free for at least 24 weeks. Plasma was collected at each visit. Cytokines and soluble receptors were quantified using multiplex immunometric assays. Incident neuropathic symptoms occurred in 32 (27%) individuals within 12 weeks of starting cART for the first time. Cytokine concentrations increased at 2 weeks, irrespective of symptom-status, returning to baseline concentrations at 12 weeks. Compared to the control group, the symptomatic group had higher baseline levels of interleukin-1 receptor (IL-1R)-antagonist. The symptomatic group also showed greater increases in soluble interleukin-2 receptor-alpha and tumour necrosis factor (TNF) receptor-II levels at week 2 and soluble interleukin-6 receptor levels at week 12. Ratios of pro-inflammatory- vs anti-inflammatory cytokines were higher for TNF-alpha/IL-4 (p = 0.022) and interferon-gamma/IL-10 (p = 0.044) in those developing symptoms. After 24 weeks of cART, the symptomatic group showed higher CD4+ counts (p = 0.002). The initiation of cART in previously treatment naïve individuals was associated with a cytokine 'burst' between 2- and 4 weeks compared with pre-cART levels. Individuals developing neuropathic symptoms within 12 weeks of starting cART showed evidence of altered cytokine concentrations even prior to initiating cART, most notably higher circulating IL-1R-antagonist levels, and altered ratios of "pain-associated" cytokine and soluble receptors shortly after cART initiation.

Effect of dipyrone and thalidomide alone and in combination on STZ-induced diabetic neuropathic pain.

PubMed

Chauhan, Neha; Taliyan, Rajeev; Sharma, Pyare Lal

2012-05-01

Diabetic neuropathy is recognized as one of the most common complications of chronic diabetes, but its pathophysiological mechanism is complex and yet to be completely explored. Monotherapy with conventional analgesics fails to provide adequate pain relief in peripheral diabetic neuropathy. There are a number of evidence suggesting that tumor necrosis factor (TNF-α) plays an important role in the pathogenesis of peripheral diabetic neuropathy. TNF-α up-regulation activates nuclear factor κB, which further up-regulates cyclooxygenase (COX)-2 leading to altered prostaglandin profile. Inhibition of TNF-α and COX-2 provides beneficial effect on diabetic neuropathy by decreasing the oxidative stress level and by preventing neuronal hypersensitivity due to an increased prostaglandin level. The present study was designed to assess the effect of dipyrone and thalidomide on streptozotocin (STZ)-induced neuropathic pain behavior in rats. STZ 50 mg/kg, i.p. was administered to induce experimental diabetes in the rats. Three weeks following STZ, dipyrone (300 and 600 mg/kg, i.p.) and thalidomide (25 and 50 mg/kg, i.p.) alone and subeffective dose combination of dipyrone and thalidomide (300 and 25 mg/kg(-1), i.p.) administered daily for 2 weeks significantly attenuated thermal hyperalgesia, mechanical allodynia, and formalin-induced phase-2 flinching response. Moreover, the subeffective dose combination of dipyrone and thalidomide and preemptive treatment with thalidomide (50 mg/kg) reduces oxidative stress in diabetic rats. In conclusion, the combination of subeffective dose of dipyrone and thalidomide prevented the development and maintenance of experimental diabetic neuropathy. The combination of thalidomide (TNF-α inhibitor) and dipyrone (COX inhibitor) may be used as a potential therapeutic agent for the treatment of diabetic neuropathy.

Fisetin exerts antihyperalgesic effect in a mouse model of neuropathic pain: engagement of spinal serotonergic system

PubMed Central

Zhao, Xin; Wang, Chuang; Cui, Wu-Geng; Ma, Qing; Zhou, Wen-Hua

2015-01-01

Fisetin, a natural flavonoid, has been shown in our previous studies to exert antidepressant-like effect. As antidepressant drugs are clinically used to treat chronic neuropathic pain, this work aimed to investigate the potential antinociceptive efficacies of fisetin against neuropathic pain and explore mechanism(s). We subjected mice to chronic constriction injury (CCI) by loosely ligating the sciatic nerves, and Hargreaves test or von Frey test was used to assess thermal hyperalgesia or mechanical allodynia, respectively. Chronic fisetin treatment (5, 15 or 45 mg/kg, p.o.) ameliorated thermal hyperalgesia (but not mechanical allodynia) in CCI mice, concomitant with escalated levels of spinal monoamines and suppressed monoamine oxidase (MAO)-A activity. The antihyperalgesic action of fisetin was abolished by chemical depletion of spinal serotonin (5-HT) but potentiated by co-treatment with 5-HTP, a precursor of 5-HT. Moreover, intraperitoneal (i.p.) or intrathecal (i.t.) co-treatment with 5-HT7 receptor antagonist SB-258719 completely abrogated fisetin's antihyperalgesia. These findings confirm that chronic fisetin treatment exerts antinociceptive effect on thermal hyperalgesia in neuropathic mice, with spinal serotonergic system (coupled with 5-HT7) being critically involved. Of special benefit, fisetin attenuated co-morbidly behavioral symptoms of depression and anxiety (evaluated in forced swim test, novelty suppressed feeding test and light-dark test) evoked by neuropathic pain. PMID:25761874

Evaluation of aqueous and ethanolic extracts of saffron, Crocus sativus L., and its constituents, safranal and crocin in allodynia and hyperalgesia induced by chronic constriction injury model of neuropathic pain in rats.

PubMed

Amin, Bahareh; Hosseinzadeh, Hossein

2012-07-01

The current study was designed to evaluate therapeutic potential of systemically administered ethanolic and aqueous extracts of saffron as well as its bioactive ingredients, safranal and crocin, in chronic constriction injury (CCI)-induced neuropathic pain in rats. The von Frey filaments, acetone drop, and radiant heat test were performed to assess the degree of mechanical allodynia, thermal allodynia and thermal hyperalgesia respectively, at different time intervals, i.e., one day before surgery and 3, 5, 7 and 10 days post surgery. The ambulatory behavior was evaluated using the open field test. A 7-day treatment with the ethanolic and aqueous extracts (50,100 and 200 mg/kg, i.p.) and safranal (0.025, 0.05 and 0.1 mg/kg, i.p.), attenuated the behavioral symptoms of neuropathic pain in a dose dependent manner. Crocin even at the high dose (50 mg/kg) failed to produce any protective role. However, gabapentine (100 mg/kg) as a reference drug significantly alleviated all behavioral manifestations of neuropathic pain compared to control group. In conclusion, the results of this study suggest that ethanolic and aqueous extracts of saffron as well as safranal could be useful in treatment of different kinds of neuropathic pains and as an adjuvant to conventional medicines. Copyright © 2012 Elsevier B.V. All rights reserved.

The effects of music therapy on pain in patients with neuropathic pain.

PubMed

Korhan, Esra Akın; Uyar, Meltem; Eyigör, Can; Hakverdioğlu Yönt, Gülendam; Çelik, Serkan; Khorshıd, Leyla

2014-03-01

The aim of this study was to investigate the effect of relaxing music on pain intensity in patients with neuropathic pain. A quasi-experimental study, repeated measures design was used. Thirty patients, aged 18-70 years, with neuropathic pain and hospitalized in an Algology clinic were identified as a convenience sample. Participants received 60 minutes of music therapy. Classical Turkish music was played to patients using a media player (MP3) and headphones. Participants had pain scores taken immediately before the intervention and at the 30th and 60th minutes of the intervention. Data were collected over a 6-month period in 2012. The patients' mean pain intensity scores were reduced by music, and that decrease was progressive over the 30th and 60th minutes of the intervention, indicating a cumulative dose effect. The results of this study implied that the inclusion of music therapy in the routine care of patients with neuropathic pain could provide nurses with an effective practice for reducing patients' pain intensity. Copyright © 2014 American Society for Pain Management Nursing. Published by Elsevier Inc. All rights reserved.

Simultaneous determination of gabapentin, pregabalin, vigabatrin, and topiramate in plasma by HPLC with fluorescence detection.

PubMed

Martinc, Boštjan; Roškar, Robert; Grabnar, Iztok; Vovk, Tomaž

2014-07-01

Therapeutic drug monitoring (TDM) of antiepileptic drugs (AEDs) has been recognized as a useful tool in management of epilepsy. We developed a simple analytical method for simultaneous determination of four second generation AEDs, including gabapentin (GBP), pregabalin (PGB), vigabatrin (VGB), and topiramate (TOP). Analytes were extracted from human plasma using universal solid phase extraction, derivatized with 4-chloro-7-nitrobenzofurazan (NBD-Cl) and analyzed by HPLC with fluorescence detection. Using mass spectrometry we confirmed that NBD-Cl reacts with sulfamate group of TOP similarly as with amine group of the other three analytes. The method is linear (r(2)>0.998) across investigated analytical ranges (0.375-30.0μg/mL for GBP, PGB, and VGB; 0.50-20.0μg/mL for TOP). Intraday and interday precision do not exceed 9.40%. The accuracy is from 95.6% to 106%. The recovery is higher than 80.6%, and the lower limit of quantification is at least 0.5μg/mL. The method is selective and robust. For TOP determination the method was compared to a previously published method and the results obtained by the two methods were in good agreement. The developed method is suitable for routine TDM. Copyright © 2014 Elsevier B.V. All rights reserved.

[Randomized comparative trial of a collagen/oxidized regenerated cellulose dressing in the treatment of neuropathic diabetic foot ulcers].

PubMed

Lázaro-Martínez, José Luis; García-Morales, Esther; Beneit-Montesinos, Juan V; Martínez-de-Jesús, Fermín R; Aragón-Sánchez, Francisco Javier

2007-07-01

Diabetic foot is a complication of diabetes mellitus that manifests with the development of ulcers that frequently precede amputation. Several studies have verified that the environment of the diabetic neuropathic foot ulcer contains a high concentration of metalloproteinases. The aim of the present study was to evaluate the efficacy of a protease-modulating dressing in the treatment of neuropathic diabetic foot ulcers. A randomized controlled trial was conducted in 40 patients with a 6-week or longer history of neuropathic diabetic foot ulcer. The patients were randomized to two groups: group 1 (n = 20) received treatment with the protease-modulating dressing while the control group (group 2; n = 20) received the treatment specified in the standardized protocol for good wound care. The patients were then followed-up for 6 weeks. After 6 weeks, healing was achieved in 12 patients (63% of n = 19) in group 1 under treatment with the protease-modulating dressing versus three patients (15% of n = 19) in the control group (p < 0.03). The mean time to healing was 23.3 +/- 9.9 days in group 1 and 40.6 +/- 1.15 days in group 2 (p < 0.01). The results confirm the hypothesis that the use of protease-modulating dressings in patients with neuropathic diabetic foot ulcers leads to better tissue regeneration than good wound care.

Antinociception induced by rosuvastatin in murine neuropathic pain.

PubMed

Miranda, Hugo F; Sierralta, Fernando; Aranda, Nicolas; Poblete, Paula; Castillo, Rodrigo L; Noriega, Viviana; Prieto, Juan Carlos

2018-06-01

Neuropathic pain, and subsequent hypernociception, can be induced in mice by paclitaxel (PTX) administration and partial sciatic nerve ligation (PSNL). Its pharmacotherapy has been a clinical challenge, due to a lack of effective treatment. In two models of mouse neuropathic pain (PTX and PSNL) the antinociception induced by rosuvastatin and the participation of proinflammatory biomarkers, interleukin (IL)- 1β, TBARS and glutathione were evaluated. A dose-response curve for rosuvastatin ip was obtained on cold plate, hot plate and Von Frey assays. Changes on spinal cord levels of IL-1β, glutathione and lipid peroxidation were measured at 7 and 14days in PTX and PSNL murine models. PTX or PSNL were able to induce in mice peripheral neuropathy with hypernociception, either to 7 and 14days. Rosuvastatin induced a dose dependent antinociception in hot plate, cold plate and Von Frey assays. The increased levels of IL-1β or TBARS induced by pretreatment with PTX or PSNL were reduced by rosuvastatin. The reduction of spinal cord glutathione, by PTX or PSNL, expressed as the ratio GSH/GSSG, were increased significantly in animals pretreated with rosuvastatin. The anti-inflammatory properties of statins could underlie their beneficial effects on neuropathic pain by reduction of proinflammatory biomarkers and activation of glia. The findings of this study suggest a potential usefulness of rosuvastatin in the treatment of neuropathic pain. Copyright © 2018 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier B.V. All rights reserved.

DRG Voltage-Gated Sodium Channel 1.7 Is Upregulated in Paclitaxel-Induced Neuropathy in Rats and in Humans with Neuropathic Pain.

PubMed

Li, Yan; North, Robert Y; Rhines, Laurence D; Tatsui, Claudio Esteves; Rao, Ganesh; Edwards, Denaya D; Cassidy, Ryan M; Harrison, Daniel S; Johansson, Caj A; Zhang, Hongmei; Dougherty, Patrick M

2018-01-31

Chemotherapy-induced peripheral neuropathy (CIPN) is a common adverse effect experienced by cancer patients receiving treatment with paclitaxel. The voltage-gated sodium channel 1.7 (Na v 1.7) plays an important role in multiple preclinical models of neuropathic pain and in inherited human pain phenotypes, and its gene expression is increased in dorsal root ganglia (DRGs) of paclitaxel-treated rats. Hence, the potential of change in the expression and function of Na v 1.7 protein in DRGs from male rats with paclitaxel-related CIPN and from male and female humans with cancer-related neuropathic pain was tested here. Double immunofluorescence in CIPN rats showed that Na v 1.7 was upregulated in small DRG neuron somata, especially those also expressing calcitonin gene-related peptide (CGRP), and in central processes of these cells in the superficial spinal dorsal horn. Whole-cell patch-clamp recordings in rat DRG neurons revealed that paclitaxel induced an enhancement of ProTx II (a selective Na v 1.7 channel blocker)-sensitive sodium currents. Bath-applied ProTx II suppressed spontaneous action potentials in DRG neurons occurring in rats with CIPN, while intrathecal injection of ProTx II significantly attenuated behavioral signs of CIPN. Complementarily, DRG neurons isolated from segments where patients had a history of neuropathic pain also showed electrophysiological and immunofluorescence results indicating an increased expression of Na v 1.7 associated with spontaneous activity. Na v 1.7 was also colocalized in human cells expressing transient receptor potential vanilloid 1 and CGRP. Furthermore, ProTx II decreased firing frequency in human DRGs with spontaneous action potentials. This study suggests that Na v 1.7 may provide a potential new target for the treatment of neuropathic pain, including chemotherapy (paclitaxel)-induced neuropathic pain. SIGNIFICANCE STATEMENT This work demonstrates that the expression and function of the voltage-gated sodium channel Na v 1.7 are increased in a preclinical model of chemotherapy-induced peripheral neuropathy (CIPN), the most common treatment-limiting side effect of all the most common anticancer therapies. This is key as gain-of-function mutations in human Na v 1.7 recapitulate both the distribution and pain percept as shown by CIPN patients. This work also shows that Na v 1.7 is increased in human DRG neurons only in dermatomes where patients are experiencing acquired neuropathic pain symptoms. This work therefore has major translational impact, indicating an important novel therapeutic avenue for neuropathic pain as a class. Copyright © 2018 the authors 0270-6474/18/381124-13$15.00/0.

Antidepressants Are Effective in Decreasing Neuropathic Pain After SCI: A Meta-Analysis.

PubMed

Mehta, Swati; Guy, Stacey; Lam, Tracey; Teasell, Robert; Loh, Eldon

2015-01-01

To systematically review and assess the effectiveness and safety of antidepressants for neuropathic pain among individuals with spinal cord injury (SCI). A systematic search was conducted using multiple databases for relevant articles published from 1980 to April 2014. Randomized controlled trials (RCTs) involving antidepressant treatment of neuropathic pain with ≥ 3 individuals and ≥ 50% of study population with SCI were included. Two independent reviewers selected studies based on inclusion criteria and then extracted data. Pooled analysis using Cohen's d to calculate standardized mean difference, standard error, and 95% confidence interval for primary (pain) and other secondary outcomes was conducted. Four RCTs met inclusion criteria. Of these, 2 studies assessed amitriptyline, 1 trazadone, and 1 duloxetine among individuals with neuropathic SCI pain. A small effect was seen in the effectiveness of antidepressants in decreasing pain among individuals with SCI (standardized mean difference = 0.34 ± 0.15; 95% CI, 0.05-0.62; P = .02). A number needed to treat of 3.4 for 30% or more pain relief was found by pooling 2 studies. Of these, significantly higher risk of experiencing constipation (risk ratio [RR] = 1.74; 95% CI, 1.09-2.78; P = .02) and dry mouth (RR = 1.39; 95% CI, 1.04-1.85; P = .02) was found amongst individuals receiving antidepressant treatment compared to those in the control group. The current meta-analysis demonstrates that antidepressants are effective in reducing neuropathic SCI pain. However, this should be interpreted with caution due to the limited number of studies. Further evaluation of long-term therapeutic options may be required.

Aromatherapy Massage for Neuropathic Pain and Quality of Life in Diabetic Patients.

PubMed

Gok Metin, Zehra; Arikan Donmez, Ayse; Izgu, Nur; Ozdemir, Leyla; Arslan, Ismail Emre

2017-07-01

This study aimed to examine the effects of aromatherapy massage on neuropathic pain severity and quality of life (QoL) in patients suffering from painful diabetic neuropathy. This open-label randomized controlled clinical study was conducted in a university hospital endocrine outpatient clinic in Turkey. The study sample consisted of 46 patients, randomly allocated to an intervention group (n = 21) and a control group (n = 25). The intervention group received aromatherapy massage three times per week for a period of 4 weeks. The control group received only routine care. Data were collected from patients using the Douleur Neuropathique questionnaire, the visual analog scale, and the Neuropathic Pain Impact on Quality of Life questionnaire. Neuropathic pain scores significantly decreased in the intervention group compared with the control group in the fourth week of the study. Similarly, QoL scores significantly improved in the intervention group in the fourth week of the study. Aromatherapy massage is a simple and effective nonpharmacological nursing intervention that can be used to manage neuropathic pain and improve QoL in patients with painful neuropathy. Aromatherapy massage is a well-tolerated, feasible, and safe nonpharmacological method that can be readily integrated into clinical settings by nursing staff. The essential oils rosemary, geranium, lavender, eucalyptus, and chamomile can be safely used by nurses in the clinical setting, if applicable. However, training and experience of nurses in aromatherapy massage is critical to achieving positive results. © 2017 Sigma Theta Tau International.

Topical Ketamine 10% for Neuropathic Pain in Spinal Cord Injury Patients: An Open-Label Trial.

PubMed

Rabi, Joseph; Minori, Joshua; Abad, Hasan; Lee, Ray; Gittler, Michelle

2016-01-01

Topical ketamine, an N-methyl-D-aspartate antagonist, has been shown to be effective in certain neuropathic pain syndromes. The objective of this study was to determine the efficacy of topical ketamine in spinal cord injury patients with neuropathic pain. An open label trial enrolled five subjects at an outpatient rehabilitation hospital with traumatic spinal cord injuries who had neuropathic pain at or below the level of injury. Subjects applied topical ketamine 10% three times a day for a two-week duration. Subjects recorded their numerical pain score-ranging from 0 to 10, with 0 representing "no pain, 5 representing "moderate pain," and 10 being described as "worst possible pain"-in a journal at the time of application of topical ketamine and one hour after application. Using a numerical pain scale allows for something as subjective as pain to be given an objective quantification. Subjects also recorded any occurrence of adverse events and level of satisfaction. All five subjects had a decrease in their numerical pain scale by the end of two weeks, ranging from 14% to 63%. The duration ranged from one hour in one subject to the next application in other subjects. There were no adverse effects. Overall, four out of the five subjects stated they were satisfied. Topical ketamine 10% is an effective neuropathic pain medicine in patients with spinal cord injuries; however, further studies need to be done with a placebo and larger sample size. Copyright© by International Journal of Pharmaceutical Compounding, Inc.

Preemptive application of QX-314 attenuates trigeminal neuropathic mechanical allodynia in rats.

PubMed

Yoon, Jeong-Ho; Son, Jo-Young; Kim, Min-Ji; Kang, Song-Hee; Ju, Jin-Sook; Bae, Yong-Chul; Ahn, Dong-Kuk

2018-05-01

The aim of the present study was to examine the effects of preemptive analgesia on the development of trigeminal neuropathic pain. For this purpose, mechanical allodynia was evaluated in male Sprague-Dawley rats using chronic constriction injury of the infraorbital nerve (CCI-ION) and perineural application of 2% QX-314 to the infraorbital nerve. CCI-ION produced severe mechanical allodynia, which was maintained until postoperative day (POD) 30. An immediate single application of 2% QX-314 to the infraorbital nerve following CCI-ION significantly reduced neuropathic mechanical allodynia. Immediate double application of QX-314 produced a greater attenuation of mechanical allodynia than a single application of QX-314. Immediate double application of 2% QX-314 reduced the CCI-ION-induced upregulation of GFAP and p-p38 expression in the trigeminal ganglion. The upregulated p-p38 expression was co-localized with NeuN, a neuronal cell marker. We also investigated the role of voltage-gated sodium channels (Navs) in the antinociception produced by preemptive application of QX-314 through analysis of the changes in Nav expression in the trigeminal ganglion following CCI-ION. Preemptive application of QX-314 significantly reduced the upregulation of Nav1.3, 1.7, and 1.9 produced by CCI-ION. These results suggest that long-lasting blockade of the transmission of pain signaling inhibits the development of neuropathic pain through the regulation of Nav isoform expression in the trigeminal ganglion. Importantly, these results provide a potential preemptive therapeutic strategy for the treatment of neuropathic pain after nerve injury.

EMA401: an old antagonist of the AT2R for a new indication in neuropathic pain.

PubMed

Keppel Hesselink, Jan M; Schatman, Michael E

2017-01-01

EMA401 is an old molecule, synthesized by Parke-Davis in the last century and characterized at that time as an AT2R antagonist. Professor Maree Smith and her group from the University of Queensland (Australia) patented the drug and many related derivatives and other compounds with high affinity for the AT2R for the indication neuropathic pain in 2004, an example of drug repositioning. After some years of university work, the Australian biotech company Spinifex Pharmaceuticals took over further research and development and characterized the S-enantiomer, code name EMA401, and related compounds in a variety of animal models for neuropathic and cancer pain. EMA401 was selected as the lead compound, based on high selectivity for the AT2R and good oral bioavailability (33%). EMA401, however, was only administered once in a chronic neuropathic pain model, and no data have been published in other pain models, or during steady state, although such data were available for the racemate EMA400 and some related compounds (EMA200, EMA400). A pilot phase IIa study demonstrated the efficacy and safety of the drug taken twice daily as two capsules of 50 mg (400 mg/day). In 2015, Novartis took over the clinical development. Two phase IIb studies designed by Spinifex Pharmaceuticals were put on hold, probably because Novartis wanted to improve the clinical design or collect additional preclinical data. Further data are eagerly awaited, especially since EMA401 is first-in-class in neuropathic pain.

Most Relevant Neuropathic Pain Treatment and Chronic Low Back Pain Management Guidelines: A Change Pain Latin America Advisory Panel Consensus.

PubMed

Amescua-Garcia, Cesar; Colimon, Frantz; Guerrero, Carlos; Jreige Iskandar, Aziza; Berenguel Cook, Maria; Bonilla, Patricia; Campos Kraychete, Durval; Delgado Barrera, William; Alberto Flores Cantisani, Jose; Hernandez-Castro, John Jairo; Lara-Solares, Argelia; Perez Hernandez, Concepcion; Rico, Maria Antonieta; Del Rocio Guillen Nunez, Maria; Sempertegui Gallegos, Manuel; Garcia, Joao Batista Santos

2018-03-01

Chronic pain conditions profoundly affect the daily living of a significant number of people and are a major economic and social burden, particularly in developing countries. The Change Pain Latin America (CPLA) advisory panel aimed to identify the most appropriate guidelines for the treatment of neuropathic pain (NP) and chronic low back pain (CLBP) for use across Latin America. Published systematic reviews or practice guidelines were identified by a systematic search of PubMed, the Guidelines Clearinghouse, and Google. Articles were screened by an independent reviewer, and potential candidate guidelines were selected for more in-depth review. A shortlist of suitable guidelines was selected and critically evaluated by the CPLA advisory panel. Searches identified 674 and 604 guideline articles for NP and CLBP, respectively. Of these, 14 guidelines were shortlisted for consensus consideration, with the following final selections made: "Recommendations for the pharmacological management of neuropathic pain from the Neuropathic Pain Special Interest Group in 2015-pharmacotherapy for neuropathic pain in adults: A systematic review and meta-analysis."Diagnosis and treatment of low back pain: A joint clinical practice guideline from the American College of Physicians and the American Pain Society" (2007). The selected guidelines were endorsed by all members of the CPLA advisory board as the best fit for use across Latin America. In addition, regional considerations were discussed and recorded. We have included this expert local insight and advice to enhance the implementation of each guideline across all Latin American countries.

Electroacupuncture Reduces the Effects of Acute Noxious Stimulation on the Electrical Activity of Pain-Related Neurons in the Hippocampus of Control and Neuropathic Pain Rats

PubMed Central

Wang, Jun-Ying; Chen, Renbo; Feng, Xiu-Mei; Yan, Yaxia; Lippe, Irmgard Th.

2016-01-01

To study the effects of acupuncture analgesia on the hippocampus, we observed the effects of electroacupuncture (EA) and mitogen-activated protein kinase (MEK) inhibitor on pain-excited neurons (PENs) and pain-inhibited neurons (PINs) in the hippocampal area CA1 of sham or chronic constrictive injury (CCI) rats. The animals were randomly divided into a control, a CCI, and a U0126 (MEK1/2 inhibitor) group. In all experiments, we briefly (10-second duration) stimulated the sciatic nerve electrically and recorded the firing rates of PENs and PINs. The results showed that in both sham and CCI rats brief sciatic nerve stimulation significantly increased the electrical activity of PENs and markedly decreased the electrical activity of PINs. These effects were significantly greater in CCI rats compared to sham rats. EA treatment reduced the effects of the noxious stimulus on PENs and PINs in both sham and CCI rats. The effects of EA treatment could be inhibited by U0126 in sham-operated rats. The results suggest that EA reduces effects of acute sciatic nerve stimulation on PENs and PINs in the CA1 region of the hippocampus of both sham and CCI rats and that the ERK (extracellular regulated kinase) signaling pathway is involved in the modulation of EA analgesia. PMID:27833763

Diagnostic and Therapeutic Advances: Distal Symmetric Polyneuropathy

PubMed Central

Callaghan, Brian C.; Price, Raymond S.; Feldman, Eva L.

2016-01-01

Importance Peripheral neuropathy is a highly prevalent and morbid condition affecting 2–7% of the population. Patients frequently suffer from pain and are at risk of falls, ulcerations, and amputations. We aimed to review recent diagnostic and therapeutic advances in peripheral neuropathy in distal symmetric polyneuropathy, the most common subtype of peripheral neuropathy. Observations and Advances Current evidence supports limited routine laboratory testing in patients with distal symmetric polyneuropathy. Patients without a known cause should have a complete blood count, comprehensive metabolic panel, B12, serum protein electrophoresis with immunofixation, fasting glucose, and a glucose tolerance test. The presence of atypical features such as asymmetry, non-length-dependence, motor predominance, acute or subacute onset, and/or prominent autonomic involvement should prompt a consultation with a neurologist or neuromuscular specialist. Electrodiagnostic tests and magnetic resonance imaging of the neuroaxis are the main drivers of the cost of the diagnostic evaluation, but evidence supporting their use is lacking. Strong evidence supports the use of tricyclic antidepressants, serotonin and norepinephrine reuptake inhibitors, and voltage-gated calcium channel ligands in the treatment of neuropathic pain. More intensive glucose control substantially reduces the incidence of distal symmetric polyneuropathy in patients with type 1 diabetes, but does not in type 2 diabetes. Conclusions and Relevance The opportunity exists to improve guideline concordant testing in distal symmetric polyneuropathy patients. Moreover, the role of electrodiagnostic tests needs to be further defined, and interventions to reduce magnetic resonance imaging use in this population are needed. Even though several efficacious medications exist for neuropathic pain treatment, pain is still under-recognized and undertreated. New disease modifying medications are needed to prevent and treat peripheral neuropathy, particularly in type 2 diabetes. PMID:26599185

The refined biomimetic NeuroDigm GEL™ model of neuropathic pain in a mature rat

PubMed Central

Hannaman, Mary R.; Fitts, Douglas A.; Doss, Rose M.; Weinstein, David E.; Bryant, Joseph L.

2017-01-01

Background: Many humans suffering with chronic neuropathic pain have no objective evidence of an etiological lesion or disease. Frequently their persistent pain occurs after the healing of a soft tissue injury. Based on clinical observations over time, our hypothesis was that after an injury in mammals the process of tissue repair could cause chronic neural pain. Our objectives were to create the delayed onset of neuropathic pain in rats with minimal nerve trauma using a physiologic hydrogel, and characterize the rats’ responses to known analgesics and a targeted biologic. Methods: In mature male Sprague Dawley rats (age 9.5 months) a percutaneous implant of tissue-derived hydrogel was placed in the musculofascial tunnel of the distal tibial nerve. Subcutaneous morphine (3 mg/kg), celecoxib (10 mg/kg), gabapentin (25 mg/kg) and duloxetine (10 mg/kg) were each screened in the model three times each over 5 months after pain behaviors developed. Sham and control groups were used in all screenings. A pilot study followed in which recombinant human erythropoietin (200 units) was injected by the GEL™ neural procedure site. Results: The GEL group gradually developed mechanical hypersensitivity lasting months. Morphine, initially effective, had less analgesia over time. Celecoxib produced no analgesia, while gabapentin and duloxetine at low doses demonstrated profound analgesia at all times tested. The injected erythropoietin markedly decreased bilateral pain behavior that had been present for over 4 months, p ≤ 0.001. Histology of the GEL group tibial nerve revealed a site of focal neural remodeling, with neural regeneration, as found in nerve biopsies of patients with neuropathic pain. Conclusion: The refined NeuroDigm GEL™ model induces a neural response resulting in robust neuropathic pain behavior. The analgesic responses in this model reflect known responses of humans with neuropathic pain. The targeted recombinant human erythropoietin at the ectopic neural lesion appears to alleviate the persistent pain behavior in the GEL™ model rodents. PMID:28620451

Increased miR-132-3p expression is associated with chronic neuropathic pain

PubMed Central

Leinders, M.; Üçeyler, N.; Pritchard, R.A.; Sommer, C.; Sorkin, L.S.

2016-01-01

Alterations in the neuro-immune balance play a major role in the pathophysiology of chronic neuropathic pain. MicroRNAs (miRNA) can regulate both immune and neuronal processes and may function as master switches in chronic pain development and maintenance. We set out to analyze the role of miR-132-3p, first in patients with peripheral neuropathies and second in an animal model of neuropathic pain. We initially determined miR-132-3p expression by measuring its levels in white blood cells (WBC) of 30 patients and 30 healthy controls and next in sural nerve biopsies of 81 patients with painful or painless inflammatory or non-inflammatory neuropathies based on clinical diagnosis. We found a 2.6 fold increase in miR-132-3p expression in WBC of neuropathy patients compared to healthy controls (p<0.001). MiR-132-3p expression was also slightly up-regulated in sural nerve biopsies from neuropathy patients suffering from neuropathic pain compared to those without pain (1.2 fold; p<0.001). These promising findings were investigated further in an animal model of neuropathic pain, the spared nerve injury model (SNI). For this purpose miR-132-3p expression levels were measured in dorsal root ganglia and spinal cord of rats. Subsequently, miR-132-3p expression was pharmacologically modulated with miRNA antagonists or mimetics, and evoked pain and pain aversion were assessed. Spinal miR-132-3p levels were highest 10 days after SNI, a time when persistent allodynia was established (p<0.05). Spinal administration of miR-132-3p antagonists via intrathecal (i.t.) catheters dose dependently reversed mechanical allodyina (p<0.001) and eliminated pain behavior in the place escape avoidance paradigm (p<0.001). Intrathecal administration of miR-132-3p mimetic dose-dependently induced pain behavior in naïve rats (p<0.001). Taken together these results indicate a pro-nociceptive effect of miR-132-3p in chronic neuropathic pain. PMID:27349406

Emg Signal Analysis of Healthy and Neuropathic Individuals

NASA Astrophysics Data System (ADS)

Gupta, Ashutosh; Sayed, Tabassum; Garg, Ridhi; Shreyam, Richa

2017-08-01

Electromyography is a method to evaluate levels of muscle activity. When a muscle contracts, an action potential is generated and this circulates along the muscular fibers. In electromyography, electrodes are connected to the skin and the electrical activity of muscles is measured and graph is plotted. The surface EMG signals picked up during the muscular activity are interfaced with a system. The EMG signals from individual suffering from Neuropathy and healthy individual, so obtained, are processed and analyzed using signal processing techniques. This project includes the investigation and interpretation of EMG signals of healthy and Neuropathic individuals using MATLAB. The prospective use of this study is in developing the prosthetic device for the people with Neuropathic disability.

Application of the capsaicin 8% cutaneous patch in neuropathic pain of the head and face: A case series.

PubMed

Gaul, Charly; Resch, Sonja

2015-05-01

Treatment of neuropathic or neuralgic head and facial pain due to dental, traumatic or surgical nerve lesions or post-herpetic neuropathy is often challenging. We are reporting on four patients with neuropathic pain syndromes successfully treated with a capsaicin 8% patch in the affected area of the head or face. Treatment with the capsaicin 8% patch seems to be effective and safe for application to the facial and head region. The capsaicin 8% patch might be an additional treatment option if first-line treatment with anticonvulsants or antidepressants was ineffective or limited by side effects. © International Headache Society 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.

Agreement Between the Douleur Neuropathique in 4 Questions and Leeds Assessment of Neuropathic Symptoms and Signs Questionnaires to Classify Neuropathic Pain Among Patients with Leprosy.

PubMed

Santana, Jamilly C V; Santos, Victor S; Gurgel, Ricardo Q; Santana, Julianne C V; Reis, Francisco P; Cuevas, Luis E; Feitosa, Vera L C

2016-10-05

Neuropathic pain (NP) often occurs during the course of leprosy, and screening tools to differentiate NP from non-NP are often used. However, their performance varies in different settings. The most frequently used scales are the Douleur Neuropathique in 4 questions (DN4) and the Leeds assessment of neuropathic symptoms and signs (LANSS) questionnaires. Thus, we conducted a study to evaluate the agreement between DN4 and LANSS questionnaires to classify NP in 195 leprosy patients attending two reference centers in Sergipe, Brazil. The DN4 and LANSS classified 166 and 110 patients, respectively, as having NP. One hundred and seven (54.8%) were classified as NP by both questionnaires; 59 (30.2%) solely by the DN4 questionnaire and three (1.5%) solely by the LANSS. The agreement of the questionnaires was 66.2% (weak agreement, Kappa = 0.30). Although both questionnaires identified a high proportion of NP, the development of more robust instruments is necessary to ensure the accuracy of diagnosis of leprosy patients classified as having NP. © The American Society of Tropical Medicine and Hygiene.

Bi-modal radiofrequency treatment for coexisting neuralgia and neuropathy in adjacent divisions of the trigeminal nerve.

PubMed

Bhatjiwale, M; Bhatjiwale, M; Naik, L D; Chopade, P

2018-05-29

Trigeminal neuralgia and deafferentation neuropathic pain, or trigeminal neuropathy, are different symptomatologies, rarely reported to present together. The case of a 65-year-old gentleman suffering from trigeminal neuralgia of the maxillary and mandibular division is reported. He first underwent an infraorbital neurectomy that was complicated by deafferentation neuropathic pain, whilst his mandibular neuralgia continued. He was treated successfully for both the neuropathic and neuralgic symptoms in the same session using ultra-extended euthermic pulsed radiofrequency treatment for the maxillary division (V2) and radiofrequency thermocoagulation for the mandibular division (V3). This report is novel in describing the use of dual modalities in the same session for two distinct coexisting clinical entities in two different divisions of the same cranial nerve. The use of ultra-extended pulsed radiofrequency treatment for neuropathic pain in this case is also unique. Nearly 2years after the procedure, the patient continues to have complete pain relief. Copyright © 2018 International Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.

[Anxiety and depression in patients with chronic pain: neuropathic and nociceptive].

PubMed

Morales-Vigil, Tania; Alfaro-Ramírez del Castillo, Olga Isabel; Sánchez-Román, Sofía; Guevara-López, Uriah; Vázquez-Pineda, Fernando

2008-01-01

To describe and compare anxiety and depression symptoms between two group patients with neuropathic and nociceptive pain those arrive for first time to a clinic of pain. Non-experimental, exploratory and descriptive design. Seventy-eight patients that arrive the first time to a clinic of pain were evaluated; those patients were divided in two groups: neuropathic pain with 44 patients and nociceptive pain with 34 patients. To evaluate anxiety and depression we use the Anxiety and Depression Scale (HAD), this scale is adapted and validated in Mexico. From the 78 patients in the study, the 76.9% were female and 23.1% were male. The age average was (56.9 +/- 16.8 year-old for neuropathic pain and 63.1 +/- 17.2 year-old for nociceptive pain). The reliability of the scale HAD was evaluated by the Chronbach's alpha analysis with an r = 0.826. There was no significance difference in anxiety and depression between types of pain, but after analyzing all of the patients we found that anxiety was more frequent than depression p < 0.0001. Independently of the algological diagnosis, patients presented almost the same affective symptoms.

Continuous subcutaneous infusion of ketorolac in cancer neuropathic pain unresponsive to opioid and adjuvant drugs. A case report.

PubMed

Ripamonti, C; Ticozzi, C; Zecca, E; Rodriguez, C H; De Conno, F

1996-01-01

Ketorolac is a new non-steroidal anti-inflammatory drug (NSAID) having a potent nonopioid analgesic activity. Administered by continuous subcutaneous infusion (CSI), its analgesic efficacy has been documented in the treatment of somatic and visceral cancer pain whilst it has been shown to be ineffective in the treatment of neuropathic pain. Here is a description of a cancer patient with neuropathic pain unresponsive to anticonvulsant or antidepressant drugs administered in association or not with oral opioids but who was successfully treated with ketorolac alone via CSI. Furthermore, the analgesia lasted over 75 days of treatment without any significant renal and gastric side effects.

A longitudinal investigation into the functional and physical durability of insoles used for the preventive management of neuropathic diabetic feet.

PubMed

Paton, Joanne S; Stenhouse, Elizabeth; Bruce, Graham; Jones, Ray

2014-01-01

Insoles are commonly used to assist in the prevention of diabetic neuropathic foot ulceration. Insole replacement is often triggered only when foot lesions deteriorate, an indicator that functional performance is comprised and patients are exposed to unnecessary ulcer risk. We investigated the durability of insoles used for ulcer prevention in neuropathic diabetic feet over 12 months. Sixty neuropathic individuals with diabetes were provided with insoles and footwear. Insole durability over 12 months was evaluated using an in-shoe pressure measurement device and through repeated measurement of material depth at the first metatarsal head and the heel seat. Analysis of variance was performed to assess change across time (at issue, 6 months, and 12 months). Analyses were conducted using all available data (n = 43) and compliant data (n = 18). No significant difference was found in the reduction of mean peak pressure tested across time (P < .05). For both sites, significant differences in insole depth were identified between issue and 6 months and between issue and 12 months but not between 6 and 12 months (P < .05). Most insole compression occurred during the initial 6 months. Visual material compression does not seem to be a reliable indicator of insole usefulness. Frequency of insole replacement is best informed by a functional review of effect determined using an in-shoe pressure measurement system. These results suggest that insoles for diabetic neuropathic patients can be effective in maintaining peak pressure reduction for 12 months regardless of wear frequency.

Effects of dextromethorphan and oxycodone on treatment of neuropathic pain in mice.

PubMed

Yang, Pao-Pao; Yeh, Geng-Chang; Huang, Eagle Yi-Kung; Law, Ping-Yee; Loh, Horace H; Tao, Pao-Luh

2015-09-22

Neuropathic pain is a very troublesome and difficult pain to treat. Although opioids are the best analgesics for cancer and surgical pain in clinic, only oxycodone among opioids shows better efficacy to alleviate neuropathic pain. However, many side effects associated with the use of oxycodone render the continued use of it in neuropathic pain treatment undesirable. Hence, we explored whether dextromethorphan (DM, a known N-methyl-D-aspartate receptor antagonist with neuroprotective properties) could potentiate the anti-allodynic effect of oxycodone and underlying mechanisms regarding to glial cells (astrocytes and microglia) activation and proinflammatory cytokines release in a spinal nerve injury (SNL) mice model. Oxycodone produced a dose-dependent anti-allodynic effect. Co-administration of DM at a dose of 10 mg/kg (i.p.) (DM10) which had no anti-allodynic effect by itself enhanced the acute oxycodone (1 mg/kg, s.c.) effect. When the chronic anti-allodynic effects were examined, co-administration of DM10 also significantly enhanced the oxycodone effect at 3 mg/kg. Furthermore, oxycodone decreased SNL-induced activation of glial cells (astrocytes and microglia) and plasma levels of proinflammatory cytokines (IL-6, IL-1β and TNF-α). Co-administration of DM10 potentiated these effects of oxycodone. The combined use of DM with oxycodone may have therapeutic potential for decreasing the effective dose of oxycodone on the treatment of neuropathic pain. Attenuation of the glial activation and proinflammatory cytokines in the spinal cord may be important mechanisms for these effects of DM.

An evaluation of the antinociceptive effects of Phα1β, a neurotoxin from the spider Phoneutria nigriventer, and ω-conotoxin MVIIA, a cone snail Conus magus toxin, in rat model of inflammatory and neuropathic pain.

PubMed

de Souza, Alessandra Hubner; Castro, Célio J; Rigo, Flavia Karine; de Oliveira, Sara Marchesan; Gomez, Renato Santiago; Diniz, Danuza Montijo; Borges, Marcia Helena; Cordeiro, Marta Nascimento; Silva, Marco Aurélio Romano; Ferreira, Juliano; Gomez, Marcus Vinicius

2013-01-01

Voltage-sensitive calcium channels (VSCCs) underlie cell excitability and are involved in the mechanisms that generate and maintain neuropathic and inflammatory pain. We evaluated in rats the effects of two VSCC blockers, ω-conotoxin MVIIA and Phα1β, in models of inflammatory and neuropathic pain induced with complete Freund's adjuvant (CFA) and chronic constrictive injury (CCI), respectively. We also evaluated the effects of the toxins on capsaicin-induced Ca(2+) influx in dorsal root ganglion (DRG) neurons obtained from rats exposed to both models of pain. A single intrathecal injection of Phα1β reversibly inhibits CFA and CCI-induced mechanical hyperalgesia longer than a single injection of ω-conotoxin MVIIA. Phα1β and MVIIA also inhibited capsaicin-induced Ca(2+) influx in DRG neurons. The inhibitory effect of Phα1β on capsaicin-induced calcium transients in DRG neurons was greater in the CFA model of pain, while the inhibitory effect of ω-conotoxin MVIIA was greater in the CCI model. The management of chronic inflammatory and neuropathic pain is still a major challenge for clinicians. Phα1β, a reversible inhibitor of VSCCs with a preference for N-type Ca(2+) channels, has potential as a novel therapeutic agent for inflammatory and neuropathic pain. Clinical studies are necessary to establish the role of Phα1β in the treatment of chronic pain.

Neuropathic orofacial pain: Facts and fiction.

PubMed

Baad-Hansen, Lene; Benoliel, Rafael

2017-06-01

Definition and taxonomy This review deals with neuropathic pain of traumatic origin affecting the trigeminal nerve, i.e. painful post-traumatic trigeminal neuropathy (PTTN). Symptomatology The clinical characteristics of PTTN vary considerably, partly due to the type and extent of injury. Symptoms involve combinations of spontaneous and evoked pain and of positive and negative somatosensory signs. These patients are at risk of going through unnecessary dental/surgical procedures in the attempt to eradicate the cause of the pain, due to the fact that most dentists only rarely encounter PTTN. Epidemiology Overall, approximately 3% of patients with trigeminal nerve injuries develop PTTN. Patients are most often female above the age of 45 years, and both physical and psychological comorbidities are common. Pathophysiology PTTN shares many pathophysiological mechanisms with other peripheral neuropathic pain conditions. Diagnostic considerations PTTN may be confused with one of the regional neuralgias or other orofacial pain conditions. For intraoral PTTN, early stages are often misdiagnosed as odontogenic pain. Pain management Management of PTTN generally follows recommendations for peripheral neuropathic pain. Expert opinion International consensus on classification and taxonomy is urgently needed in order to advance the field related to this condition.

Recent clinical advances in diabetic polyneuropathy.

PubMed

Horowitz, Steven H

2006-10-01

Recent dramatic increases in the incidence and prevalence of diabetes make an understanding of chronic symmetric sensorimotor diabetic polyneuropathy, the most common and problematic of chronic diabetic complications, essential for a wide range of medical practitioners. The demonstration of neuropathic dysfunction in patients with prediabetes or impaired glucose tolerance emphasizes the susceptibility of peripheral nerve fibers, especially small A delta fibers and C fibers, to relatively mild, short-duration hyperglycemia. New testing can reveal peripheral nerve dysfunction prior to clinical neuropathic symptoms and signs. In the absence of effective medications to halt or reverse nerve damage or promote nerve regeneration, early diagnosis of diabetic polyneuropathy, followed by tight glycemic control with diet and exercise, offers the best opportunity to prevent progressive symptoms of sensory loss, pain, autonomic dysfunction, ulcerations, and amputations. Some patients with impaired glucose tolerance have a reversal of neuropathic features with tight glycemic control. Nonpharmacologic therapies for neuropathic pain in diabetic polyneuropathy appear promising. Tight glycemic control, especially early in diabetes, is the best approach to minimizing the prevalence and severity of diabetic polyneuropathy and makes research into the deleterious effects of even mild hyperglycemia imperative.

Dimerization with Cannabinoid Receptors Allosterically Modulates Delta Opioid Receptor Activity during Neuropathic Pain

PubMed Central

Stockton, Steven D.; Miller, Lydia K.; Devi, Lakshmi A.

2012-01-01

The diversity of receptor signaling is increased by receptor heteromerization leading to dynamic regulation of receptor function. While a number of studies have demonstrated that family A G-protein-coupled receptors are capable of forming heteromers in vitro, the role of these heteromers in normal physiology and disease has been poorly explored. In this study, direct interactions between CB1 cannabinoid and delta opioid receptors in the brain were examined. Additionally, regulation of heteromer levels and signaling in a rodent model of neuropathic pain was explored. First we examined changes in the expression, function and interaction of these receptors in the cerebral cortex of rats with a peripheral nerve lesion that resulted in neuropathic pain. We found that, following the peripheral nerve lesion, the expression of both cannabinoid type 1 receptor (CB1R) and the delta opioid receptor (DOR) are increased in select brain regions. Concomitantly, an increase in CB1R activity and decrease in DOR activity was observed. We hypothesize that this decrease in DOR activity could be due to heteromeric interactions between these two receptors. Using a CB1R-DOR heteromer-specific antibody, we found increased levels of CB1R-DOR heteromer protein in the cortex of neuropathic animals. We subsequently examined the functionality of these heteromers by testing whether low, non-signaling doses of CB1R ligands influenced DOR signaling in the cortex. We found that, in cortical membranes from animals that experienced neuropathic pain, non-signaling doses of CB1R ligands significantly enhanced DOR activity. Moreover, this activity is selectively blocked by a heteromer-specific antibody. Together, these results demonstrate an important role for CB1R-DOR heteromers in altered cortical function of DOR during neuropathic pain. Moreover, they suggest the possibility that a novel heteromer-directed therapeutic strategy for enhancing DOR activity, could potentially be employed to reduce anxiety associated with chronic pain. PMID:23272051

Rapamycin ameliorates neuropathic pain by activating autophagy and inhibiting interleukin-1β in the rat spinal cord.

PubMed

Feng, Tao; Yin, Qin; Weng, Ze-lin; Zhang, Jian-cheng; Wang, Kun-feng; Yuan, Shi-ying; Cheng, Wei

2014-12-01

Autophagy acts as an important homoeostatic mechanism by degradation of cytosolic constituents and plays roles in many physiological processes. Recent studies demonstrated that autophagy can also regulate the production and secretion of the proinflammatory cytokine interleukin-1β (IL-1β), which plays a critical role in the development and maintenance of neuropathic pain. In the present study, the paw withdrawal threshold (PWT) and paw withdrawal latency (PWL) were significantly decreased after spinal nerve ligation (SNL), and the changes were accompanied by inhibited autophagy in the spinal microglia and increased mRNA and protein levels of IL-1β in the ipsilateral spinal cord. We then investigated the antinociceptive effect of rapamycin, a widely used autopahgy inducer, on SNL-induced neuropathic pain in rats and found that treatment with intrathecal rapamycin significantly attenuated the mechanical allodynia and thermal hyperalgesia. Moreover, rapamycin significantly enhanced autophagy in the spinal microglia, whereas it reduced the mRNA and protein levels of IL-1β in the ipsilateral spinal cord. Our results showed that rapamycin could ameliorate neuropathic pain by activating autophagy and inhibiting IL-1β in the spinal cord.

Translational neuropathic pain research: A clinical perspective.

PubMed

Bouhassira, D; Attal, N

2016-12-03

Neuropathic pain encompasses a broad range of conditions associated with a lesion or disease of the peripheral or central somatosensory system and its prevalence in the general population may be as high as 7-8%. The interest in the pathophysiology of neuropathic pain has increased over the last two decades with an exponential increase in the number of experimental studies. However, despite the hopes raised by scientific discoveries, there has been no rational development of a truly new class of drugs. This situation revealing the limitations of certain experimental models, also results of limitations in clinical research. One of the reasons for the therapeutic difficulties in these patients is probably due to the fact that treatments are used in a uniform fashion whatever the clinical picture, while these syndromes are in fact highly heterogeneous. Clinical advances have recently been made in this field, following the validation of new specific clinical tools and the standardization of quantitative sensory testing paradigms facilitating improvements in the clinical characterization of these syndromes. It has been clearly demonstrated that neuropathic pain is a consistent clinical entity, but it is multidimensional in terms of its clinical expression, with different sensory profiles, potentially reflecting specific pathophysiological mechanisms. This new conceptualization of neuropathic pain should improve the characterization of the responder profiles in clinical trials and provide valuable information for the development of new and more clinically sound translational approaches in experimental models in animals. Copyright © 2016. Published by Elsevier Ltd.

Safety and Utility of Quantitative Sensory Testing among Adults with Sickle Cell Disease: Indicators of Neuropathic Pain?

PubMed Central

Ezenwa, Miriam O.; Molokie, Robert E.; Wang, Zaijie Jim; Yao, Yingwei; Suarez, Marie L.; Pullum, Cherese; Schlaeger, Judith M.; Fillingim, Roger B.; Wilkie, Diana J.

2014-01-01

Objectives Pain is the hallmark symptom of sickle cell disease (SCD), yet the types of pain that these patients experience, and the underlying mechanisms, have not been well characterized. The study purpose was to determine the safety and utility of a mechanical and thermal quantitative sensory testing (QST) protocol and the feasibility of utilizing neuropathic pain questionnaires among adults with SCD. Methods A convenience sample (N=25, 18 women, mean age 38.5 ± 12.5 [20–58 years]) completed self-report pain and quality-of-life tools. Subjects also underwent testing with the TSA-II NeuroSensory Analyzer and calibrated von Frey microfilaments. Results We found that the QST protocol was safe and did not stimulate a SCD pain crisis. There was evidence of central sensitization (n=15), peripheral sensitization (n=1), a mix of central and peripheral sensitization (n=8), or no sensitization (n=1). The neuropathic pain self-report tools were feasible with evidence of construct validity; 40% of the subjects reported S-LANSS scores that were indicative of neuropathic pain and had evidence of central, peripheral or mixed sensitization. Discussion The QST protocol can be safely conducted in adults with SCD and provides evidence of central or peripheral sensitization, which is consistent with a neuropathic component to SCD pain. These findings are novel, warrant a larger confirmatory study, and indicate the need for normative QST data from African American adults and older adults. PMID:25581383

EMA401: an old antagonist of the AT2R for a new indication in neuropathic pain

PubMed Central

Keppel Hesselink, Jan M; Schatman, Michael E

2017-01-01

EMA401 is an old molecule, synthesized by Parke-Davis in the last century and characterized at that time as an AT2R antagonist. Professor Maree Smith and her group from the University of Queensland (Australia) patented the drug and many related derivatives and other compounds with high affinity for the AT2R for the indication neuropathic pain in 2004, an example of drug repositioning. After some years of university work, the Australian biotech company Spinifex Pharmaceuticals took over further research and development and characterized the S-enantiomer, code name EMA401, and related compounds in a variety of animal models for neuropathic and cancer pain. EMA401 was selected as the lead compound, based on high selectivity for the AT2R and good oral bioavailability (33%). EMA401, however, was only administered once in a chronic neuropathic pain model, and no data have been published in other pain models, or during steady state, although such data were available for the racemate EMA400 and some related compounds (EMA200, EMA400). A pilot phase IIa study demonstrated the efficacy and safety of the drug taken twice daily as two capsules of 50 mg (400 mg/day). In 2015, Novartis took over the clinical development. Two phase IIb studies designed by Spinifex Pharmaceuticals were put on hold, probably because Novartis wanted to improve the clinical design or collect additional preclinical data. Further data are eagerly awaited, especially since EMA401 is first-in-class in neuropathic pain. PMID:28255254

Assessment of the clinical relevance of quantitative sensory testing with Von Frey monofilaments in patients with allodynia and neuropathic pain. A pilot study.

PubMed

Keizer, D; van Wijhe, M; Post, W J; Uges, D R A; Wierda, J M K H

2007-08-01

Allodynia is a common and disabling symptom in many patients with neuropathic pain. Whereas quantification of pain mostly depends on subjective pain reports, allodynia can also be measured objectively with quantitative sensory testing. In this pilot study, we investigated the clinical relevance of quantitative sensory testing with Von Frey monofilaments in patients with allodynia as a consequence of a neuropathic pain syndrome, by means of correlating subjective pain scores with pain thresholds obtained with quantitative sensory testing. During a 4-week trial, we administered a cannabis extract to 17 patients with allodynia. We quantified the severity of the allodynia with Von Frey monofilaments before, during and after the patients finished the trial. We also asked the patients to rate their pain on a numeric rating scale at these three moments. We found that most of the effect of the cannabis occurred in the last 2 weeks of the trial. In this phase, we observed that the pain thresholds, as measured with Von Frey monofilaments, were inversely correlated with a decrease of the perceived pain intensity. These preliminary findings indicate clinical relevance of quantitative sensory testing with Von Frey monofilaments in the quantification of allodynia in patients with neuropathic pain, although confirmation of our data is still required in further studies to position this method of quantitative sensory testing as a valuable tool, for example, in the evaluation of therapeutic interventions for neuropathic pain.

Neuropathic pain and use of PainDETECT in patients with fibromyalgia: a cohort study.

PubMed

Gauffin, Jarno; Hankama, Tiina; Kautiainen, Hannu; Hannonen, Pekka; Haanpää, Maija

2013-02-14

Fibromyalgia has a plethorae of symptoms, which can be confusing and even misleading. Accurate evaluation is necessary when patients with fibromyalgia are treated. Different types of instruments are available for the clinicians to supplement evaluation. Our objective was to study the applicability of the PainDETECT instrument to screen neuropathic pain in patients with fibromyalgia. 158 patients with primary fibromyalgia underwent a neurological examination including bedside sensory testing. They also fulfilled four questionnaires: PainDETECT, Beck depression inventory IA (BDI IA), Fibromyalgia Impact Questionnaire (FIQ) and a self-made questionnaire regarding present pain and pain relieving methods of the patients. The results of the clinical evaluation and questionnaires were then compared. Clinically verified neuropathic pain was diagnosed in 53/158 [34% (95% Cl: 26 to 41)] patients. The ROC curve achieved a maximum Youden´s index at score of 17 when sensitivity was 0.79 (95% Cl: 0.66 to 0.89) and specificity 0.53 (95% Cl: 0.43 to 0.63). The PainDETECT total score (OR: 1.14 95% Cl: 1.06 to 1.22), FM as the worst current pain (OR: 0.31; 95% 0.16 to 0.62), body mass index (BMI) (OR: 1.05; 95% Cl: 1.00 to 1.11) and the intensity of current pain (OR: 1.20; 95% Cl: 1.01 to 1.41) were significantly associated with the presence of neuropathic pain in univariate analyses. This study highlights the importance of thorough clinical examination. The Neuropathic pain screening tool PainDETECT is not as useful in patients with fibromyalgia as in patients with uncompromised central pain control.

Topical combinations aimed at treating microvascular dysfunction reduce allodynia in rat models of CRPS-I and neuropathic pain.

PubMed

Ragavendran, J Vaigunda; Laferrière, André; Xiao, Wen Hua; Bennett, Gary J; Padi, Satyanarayana S V; Zhang, Ji; Coderre, Terence J

2013-01-01

Growing evidence indicates that various chronic pain syndromes exhibit tissue abnormalities caused by microvasculature dysfunction in the blood vessels of skin, muscle, or nerve. We tested whether topical combinations aimed at improving microvascular function would relieve allodynia in animal models of complex regional pain syndrome type I (CRPS-I) and neuropathic pain. We hypothesized that topical administration of either α(2)-adrenergic (α(2)A) receptor agonists or nitric oxide (NO) donors combined with either phosphodiesterase (PDE) or phosphatidic acid (PA) inhibitors would effectively reduce allodynia in these animal models of chronic pain. Single topical agents produced significant dose-dependent antiallodynic effects in rats with chronic postischemia pain, and the antiallodynic dose-response curves of PDE and PA inhibitors were shifted 2.5- to 10-fold leftward when combined with nonanalgesic doses of α(2)A receptor agonists or NO donors. Topical combinations also produced significant antiallodynic effects in rats with sciatic nerve injury, painful diabetic neuropathy, and chemotherapy-induced painful neuropathy. These effects were shown to be produced by a local action, lasted up to 6 hours after acute treatment, and did not produce tolerance over 15 days of chronic daily dosing. The present results support the hypothesis that allodynia in animal models of CRPS-I and neuropathic pain is effectively relieved by topical combinations of α(2)A or NO donors with PDE or PA inhibitors. This suggests that topical treatments aimed at improving microvascular function may reduce allodynia in patients with CRPS-I and neuropathic pain. This article presents the synergistic antiallodynic effects of combinations of α(2)A or NO donors with PDE or PA inhibitors in animal models of CRPS-I and neuropathic pain. The data suggest that effective clinical treatment of chronic neuropathic pain may be achieved by therapies that alleviate microvascular dysfunction in affected areas. Copyright © 2013 American Pain Society. Published by Elsevier Inc. All rights reserved.

Stimulation of spinal dorsal horn β2-adrenergic receptor ameliorates neuropathic mechanical hypersensitivity through a reduction of phosphorylation of microglial p38 MAP kinase and astrocytic c-jun N-terminal kinase.

PubMed

Zhang, Fang Fang; Morioka, Norimitsu; Abe, Hiromi; Fujii, Shiori; Miyauchi, Kazuki; Nakamura, Yoki; Hisaoka-Nakashima, Kazue; Nakata, Yoshihiro

2016-12-01

The noradrenaline-adrenergic system has a crucial role in controlling nociceptive transduction at the spinal level. While α-adrenergic receptors are known to regulate nociceptive neurotransmitter release at the spinal presynaptic level, it is not entirely clear whether β-adrenergic receptors are involved in controlling pain transduction at the spinal level as well. The current study elucidated a role of β-adrenergic receptors in neuropathic pain in mice following a partial sciatic nerve ligation (PSNL). In addition, the cellular and intracellular signaling cascade induced by β-adrenergic receptors in neuropathic mice was elaborated. Intrathecal injection of isoproterenol (1 nmol), a nonselective β-adrenergic receptor agonist, briefly ameliorated hind paw mechanical hypersensitivity of PSNL mice. Isoproterenol's antinociceptive effect was mediated through β2-adrenergic receptors since pretreatment with ICI118551, a selective β2-adrenergic receptor antagonist, but not with CGP20712A, a selective β1-adrenergic receptor antagonist, significantly attenuated isoproterenol's effect. Furthermore, intrathecal treatment with a selective β2-adrenergic receptor agonist, terbutaline, but not a selective β1-adrenergic receptor agonist, dobutamine, also significantly ameliorated neuropathic pain. Fourteen days after PSNL, increased phosphorylation of both p38 Mitogen-activated protein kinase (MAPK) in microglia and c-jun N-terminal kinase (JNK) in astrocytes of ipsilateral spinal dorsal horn were observed. Phosphorylation of both microglial p38 MAPK and astrocytic JNK were downregulated by stimulation of the β2-adrenergic receptor. Together, these results suggest that spinal β2-adrenergic receptor have an inhibitory role in neuropathic nociceptive transduction at the spinal level through a downregulation of glial activity, perhaps through modulation of MAP kinases phosphorylation. Thus, targeting of β2-adrenergic receptors could be an effective therapeutic strategy in treating neuropathic pain. Copyright © 2016 Elsevier Ltd. All rights reserved.

Coregulation of endoplasmic reticulum stress and oxidative stress in neuropathic pain and disinhibition of the spinal nociceptive circuitry.

PubMed

Ge, Yanhu; Jiao, Yingfu; Li, Peiying; Xiang, Zhenghua; Li, Zhi; Wang, Long; Li, Wenqian; Gao, Hao; Shao, Jiayun; Wen, Daxiang; Yu, Weifeng

2018-05-01

The accumulation of unfolded or misfolded proteins in the endoplasmic reticulum (ER) lumen leads to ER stress, which is related to cellular reactive oxygen species production. Neuropathic pain may result from spinal dorsal horn (SDH) ER stress. In this study, we examined the cause-effect relationship between ER stress and neuropathic pain using the spinal nerve ligation (SNL) rat model. We showed that ER stress was mutually promotive with oxidative stress during the process. We also tested the hypothesis that spinal sensitization arose from reduced activities of GABA-ergic interneurons and that spinal sensitization was mediated by SDH ER stress. Other important findings in this study including the following: (1) nociceptive behavior was alleviated in SNL rat as long as tauroursodeoxycholic acid injections were repeated to inhibit ER stress; (2) inducing SDH ER stress in healthy rat resulted in mechanical hyperalgesia; (3) blocking protein disulfide isomerase pharmacologically reduced ER stress and nociceptive behavior in SNL rat; (4) cells in the dorsal horn with elevated ER stress were mainly neurons; and (5) whole-cell recordings made in slide preparations revealed significant inhibition of GABA-ergic interneuron activity in the dorsal horn with ER stress vs in the healthy dorsal horn. Taken together, results of the current study demonstrate that coregulation of ER stress and oxidative stress played an important role in neuropathic pain process. Inhibiting SDH ER stress could be a potential novel strategy to manage neuropathic pain.

Neuropathic pain promotes adaptive changes in gene expression in brain networks involved in stress and depression.

PubMed

Descalzi, Giannina; Mitsi, Vasiliki; Purushothaman, Immanuel; Gaspari, Sevasti; Avrampou, Kleopatra; Loh, Yong-Hwee Eddie; Shen, Li; Zachariou, Venetia

2017-03-21

Neuropathic pain is a complex chronic condition characterized by various sensory, cognitive, and affective symptoms. A large percentage of patients with neuropathic pain are also afflicted with depression and anxiety disorders, a pattern that is also seen in animal models. Furthermore, clinical and preclinical studies indicate that chronic pain corresponds with adaptations in several brain networks involved in mood, motivation, and reward. Chronic stress is also a major risk factor for depression. We investigated whether chronic pain and stress affect similar molecular mechanisms and whether chronic pain can affect gene expression patterns that are involved in depression. Using two mouse models of neuropathic pain and depression [spared nerve injury (SNI) and chronic unpredictable stress (CUS)], we performed next-generation RNA sequencing and pathway analysis to monitor changes in gene expression in the nucleus accumbens (NAc), the medial prefrontal cortex (mPFC), and the periaqueductal gray (PAG). In addition to finding unique transcriptome profiles across these regions, we identified a substantial number of signaling pathway-associated genes with similar changes in expression in both SNI and CUS mice. Many of these genes have been implicated in depression, anxiety, and chronic pain in patients. Our study provides a resource of the changes in gene expression induced by long-term neuropathic pain in three distinct brain regions and reveals molecular connections between pain and chronic stress. Copyright © 2017, American Association for the Advancement of Science.

Actions of the dual FAAH/MAGL inhibitor JZL195 in a murine neuropathic pain model

PubMed Central

Adamson Barnes, Nicholas S.; Mitchell, Vanessa A.; Kazantzis, Nicholas P.

2015-01-01

Background and Purpose While cannabinoids have been proposed as a potential treatment for neuropathic pain, they have limitations. Cannabinoid receptor agonists have good efficacy in animal models of neuropathic pain; they have a poor therapeutic window. Conversely, selective fatty acid amide hydrolase (FAAH) inhibitors that enhance the endocannabinoid system have a better therapeutic window, but lesser efficacy. We examined whether JZL195, a dual inhibitor of FAAH and monacylglycerol lipase (MAGL), could overcome these limitations. Experimental Approach C57BL/6 mice underwent the chronic constriction injury (CCI) model of neuropathic pain. Mechanical and cold allodynia, plus cannabinoid side effects, were assessed in response to systemic drug application. Key Results JZL195 and the cannabinoid receptor agonist WIN55212 produced dose‐dependent reductions in CCI‐induced mechanical and cold allodynia, plus side effects including motor incoordination, catalepsy and sedation. JZL195 reduced allodynia with an ED50 at least four times less than that at which it produced side effects. By contrast, WIN55212 reduced allodynia and produce side effects with similar ED50s. The maximal anti‐allodynic effect of JZL195 was greater than that produced by selective FAAH, or MAGL inhibitors. The JZL195‐induced anti‐allodynia was maintained during repeated treatment. Conclusions and Implications These findings suggest that JZL195 has greater anti‐allodynic efficacy than selective FAAH, or MAGL inhibitors, plus a greater therapeutic window than a cannabinoid receptor agonist. Thus, dual FAAH/MAGL inhibition may have greater potential in alleviating neuropathic pain, compared with selective FAAH and MAGL inhibitors, or cannabinoid receptor agonists. PMID:26398331

Evaluation of the fibromyalgia impact questionnaire at baseline as a predictor for time to pain improvement in two clinical trials of pregabalin.

PubMed

Bushmakin, A G; Cappelleri, J C; Chandran, A B; Zlateva, G

2013-01-01

The Fibromyalgia Impact Questionnaire (FIQ) is a patient-reported outcome that evaluates the impact of fibromyalgia (FM) on daily life. This study evaluated the relationships between the functional status of FM patients, measured with the FIQ at baseline, and median time to a clinically relevant pain reduction. Data were derived from two randomised, placebo-controlled trials that evaluated pregabalin 300, 450 and 600 mg/day for the treatment of FM. The Kaplan-Meier (nonparametric) method was applied to estimate median times to 'transient' and 'stable' events. The transient event was defined as a ≥ 27.9% improvement on an 11-point daily pain diary scale (0 = no pain, 10 = worst possible pain), and the stable event was defined as the mean of the daily improvements ≥ 27.9% relative to baseline over the subsequent study duration starting on the day of the transient event. A parametric model using time-to-event analysis was developed for evaluating the relationship between baseline FIQ score and the median time to these events. Median time was longer among patients treated with placebo relative to pregabalin for the transient events (11-12 days vs. 5-7 days) and stable events (86 days vs. 13-29 days). A significant association was observed between baseline FIQ scores and median time to transient and stable events (p < 0.001). Median times to events were similar between the studies. For transient pain reduction events, median times ranged from 3.0 to 4.5 days for baseline FIQ scores of 10, and 9.1-9.6 days for FIQ scores of 100; for stable pain reduction events, the median time ranged from 11.0 to 13.0 days and from 27.0 to 28.5 days for baseline FIQ scores of 10 and 100 respectively. Time to a clinically relevant reduction in pain was significantly associated with FM severity at baseline as measured by the FIQ. Such an analysis can inform patient and physician expectations in clinical practice. © 2012 Blackwell Publishing Ltd.

Guideline for the management of wounds in patients with lower-extremity neuropathic disease: an executive summary.

PubMed

Crawford, Penny Ellen; Fields-Varnado, Myra

2013-01-01

This article summarizes the WOCN Evidence-Based Clinical Practice Guideline for Management of Wounds in Patients with Lower Extremity Neuropathic Disease. It is intended for use by physicians, nurses, therapists, and other health care professionals who work with adults who have or are at risk for, lower-extremity neuropathic disease (LEND), and includes updated scientific literature available from January 2003 through February 2012. The full guideline contains definitions of lower extremity neuropathic disorders and disease, prevalence of the problem, relevance and significance of the disorders, as well as comprehensive information about etiology, the nervous system, pathogenesis, and the overall management goals for patients at risk for developing neuropathic foot ulcers. A detailed assessment section describes how to conduct a full clinical history and physical examination. The guideline also provides two approaches to interventions. The first focuses on prevention strategies to reduce the risk of developing LEND wounds or recurrence, including life-long foot offloading, routine dermal temperature surveillance, use of adjunctive therapies, medication management, and implementing lower extremity amputation prevention measures and patient self-care education. The second approach summarized LEND wound management strategies including wound cleansing, debridement, infection management, maintenance of intact peri-wound skin, nutrition considerations, pain and paresthesia management, edema management, offloading and management of gait and foot deformity, medication management, surgical options, adjunctive therapies, patient education, and health care provider follow-up. A comprehensive reference list, glossary of terms, and several appendices regarding an algorithm to determine wound etiology, pharmacology, Lower Extremity Amputation (LEAP) Program, diabetes foot screening and other information is available at the end of the guideline.

Surgical animal models of neuropathic pain: Pros and Cons.

PubMed

Challa, Siva Reddy

2015-03-01

One of the biggest challenges for discovering more efficacious drugs for the control of neuropathic pain has been the diversity of chronic pain states in humans. It is now acceptable that different mechanisms contribute to normal physiologic pain, pain arising from tissue damage and pain arising from injury to the nervous system. To study pain transmission, spot novel pain targets and characterize the potential analgesic profile of new chemical entities, numerous experimental animal pain models have been developed that attempt to simulate the many human pain conditions. Among the neuropathic pain models, surgical models have paramount importance in the induction of pain states. Many surgical animal models exist, like the chronic constriction injury (CCI) to the sciatic nerve, partial sciatic nerve ligation (pSNL), spinal nerve ligation (SNL), spared nerve injury (SNI), brachial plexus avulsion (BPA), sciatic nerve transaction (SNT) and sciatic nerve trisection. Most of these models induce responses similar to those found in causalgia, a syndrome of sustained burning pain often seen in the distal extremity after partial peripheral nerve injury in humans. Researchers most commonly use these surgical models in both rats and mice during drug discovery to screen new chemical entities for efficacy in the area of neuropathic pain. However, there is scant literature that provides a comparative discussion of all these surgical models. Each surgical model has its own benefits and limitations. It is very difficult for a researcher to choose a suitable surgical animal model to suit their experimental set-up. Therefore, particular attention has been given in this review to comparatively provide the pros and cons of each model of surgically induced neuropathic pain.

Multivariate machine learning distinguishes cross-network dynamic functional connectivity patterns in state and trait neuropathic pain.

PubMed

Cheng, J C; Rogachov, A; Hemington, K S; Kucyi, A; Bosma, R L; Lindquist, M A; Inman, R D; Davis, K D

2018-04-26

Communication within the brain is dynamic. Chronic pain can also be dynamic, with varying intensities experienced over time. Little is known of how brain dynamics are disrupted in chronic pain, or relates to patients' pain assessed at various time-scales (e.g., short-term state versus long-term trait). Patients experience pain "traits" indicative of their general condition, but also pain "states" that vary day to day. Here, we used network-based multivariate machine learning to determine how patterns in dynamic and static brain communication are related to different characteristics and timescales of chronic pain. Our models were based on resting state dynamic and static functional connectivity (dFC, sFC) in patients with chronic neuropathic pain (NP) or non-NP. The most prominent networks in the models were the default mode, salience, and executive control networks. We also found that cross-network measures of dFC rather than sFC were better associated with patients' pain, but only in those with NP features. These associations were also more highly and widely associated with measures of trait rather than state pain. Furthermore, greater dynamic connectivity with executive control networks was associated with milder neuropathic pain, but greater dynamic connectivity with limbic networks was associated greater neuropathic pain. Compared with healthy individuals, the dFC features most highly related to trait neuropathic pain were also more abnormal in patients with greater pain. Our findings indicate that dFC reflects patients' overall pain condition (i.e., trait pain), not just their current state, and is impacted by complexities in pain features beyond intensity.

Antinociceptive effects of fisetin against diabetic neuropathic pain in mice: Engagement of antioxidant mechanisms and spinal GABAA receptors.

PubMed

Zhao, Xin; Li, Xin-Lin; Liu, Xin; Wang, Chuang; Zhou, Dong-Sheng; Ma, Qing; Zhou, Wen-Hua; Hu, Zhen-Yu

2015-12-01

Peripheral painful neuropathy is one of the most common complications in diabetes and necessitates improved treatment. Fisetin, a naturally occurring flavonoid, has been reported to exert antidepressant-like effect in previous studies. As antidepressant drugs are employed clinically to treat neuropathic pain, this work aimed to investigate whether fisetin possess beneficial effect on diabetic neuropathic pain and explore the mechanism(s). We subjected mice to diabetes by a single intraperitoneal (i.p.) injection of streptozotocin (200mg/kg), and von Frey test or Hargreaves test was used to assess mechanical allodynia or thermal hyperalgesia, respectively. Chronic treatment of diabetic mice with fisetin not only ameliorated the established symptoms of thermal hyperalgesia and mechanical allodynia, but also arrested the development of neuropathic pain when given at low doses. Although chronic fisetin administration did not impact on the symptom of hyperglycemia in diabetic mice, it reduced exacerbated oxidative stress in tissues of spinal cord, dorsal root ganglion (DRG) and sciatic verve. Furthermore, the analgesic actions of fisetin were abolished by repetitive co-treatment with the reactive oxygen species (ROS) donor tert-butyl hydroperoxide (t-BOOH), but potentiated by the ROS scavenger phenyl-N-tert-butylnitrone (PBN). Finally, acute blockade of spinal GABAA receptors by bicuculline totally counteracted such fisetin analgesia. These findings indicate that chronic fisetin treatment can delay or correct neuropathic hyperalgesia and allodynia in mice with type 1 diabetes. Mechanistically, the present fisetin analgesia may be associated with its antioxidant activity, and spinal GABAA receptors are likely rendered as downstream targets. Copyright © 2015 Elsevier Ltd. All rights reserved.

Targeting the minor pocket of C5aR for the rational design of an oral allosteric inhibitor for inflammatory and neuropathic pain relief.

PubMed

Moriconi, Alessio; Cunha, Thiago M; Souza, Guilherme R; Lopes, Alexandre H; Cunha, Fernando Q; Carneiro, Victor L; Pinto, Larissa G; Brandolini, Laura; Aramini, Andrea; Bizzarri, Cinzia; Bianchini, Gianluca; Beccari, Andrea R; Fanton, Marco; Bruno, Agostino; Costantino, Gabriele; Bertini, Riccardo; Galliera, Emanuela; Locati, Massimo; Ferreira, Sérgio H; Teixeira, Mauro M; Allegretti, Marcello

2014-11-25

Chronic pain resulting from inflammatory and neuropathic disorders causes considerable economic and social burden. Pharmacological therapies currently available for certain types of pain are only partially effective and may cause severe adverse side effects. The C5a anaphylatoxin acting on its cognate G protein-coupled receptor (GPCR), C5aR, is a potent pronociceptive mediator in several models of inflammatory and neuropathic pain. Although there has long been interest in the identification of C5aR inhibitors, their development has been complicated, as for many peptidomimetic drugs, mostly by poor drug-like properties. Herein, we report the de novo design of a potent and selective C5aR noncompetitive allosteric inhibitor, DF2593A, guided by the hypothesis that an allosteric site, the "minor pocket," previously characterized in CXC chemokine receptors-1 and -2, is functionally conserved in the GPCR class. In vitro, DF2593A potently inhibited C5a-induced migration of human and rodent neutrophils. In vivo, oral administration of DF2593A effectively reduced mechanical hyperalgesia in several models of acute and chronic inflammatory and neuropathic pain, without any apparent side effects. Mechanical hyperalgesia after spared nerve injury was also reduced in C5aR(-/-) mice compared with WT mice. Furthermore, treatment of C5aR(-/-) mice with DF2593A did not produce any further antinociceptive effect compared with C5aR(-/-) mice treated with vehicle. The successful medicinal chemistry strategy confirms that a conserved minor pocket is amenable for the rational design of selective inhibitors and the pharmacological results support that the allosteric blockade of the C5aR represents a highly promising therapeutic approach to control chronic inflammatory and neuropathic pain.

Neurophysiological role of sildenafil citrate (Viagra) on seminal parameters in diabetic males with and without neuropathy.

PubMed

Ali, Syed Tabrez; Rakkah, Nabeeh I

2007-01-01

Sildenafil citrate is a specific inhibitor of phosphodiesterase (PDE) type-5 and represents a powerful therapy for male erectile and fertility dysfunctions of different etiologies. Present study demonstrates whether sildenafil administration modifies seminal parameters in diabetic neuropathic patients. In this investigation 50 insulin dependent (IDDM) and 50 non insulin dependent (NIDDM) diabetic male patients with and without an objective evidence of neuropathy and 50 age matched non diabetic male controls were selected. Every male had age between 20 to 65 years with duration of diabetes distributed over 1 to 20 years. Treatment with 100 mg of oral sildenafil citrate on seminal parameters was evaluated by semen analysis in these patients. In both IDDM and NIDDM diabetic neuropathic patients, chronic sildenafil treatment exhibited a significant decrease in total sperm output and sperm concentration (p<0.001). On the other hand, sperm motility and semen volume were found to be increased by about 40% and 48% respectively in these patients, where as sperm morphology and quality of sperm motility remained unaffected. However both types of non neuropathic diabetics showed a non significant difference in all the above mentioned parameters when compared with the untreated groups and their respective control subjects. A comparison between IDDM and NIDDM neuropathic and non neuropathic diabetic groups further indicated a non significant difference in all the parameters of semen analysis. These findings suggest a chronic neuro physiological effect of sildenafil treatment on male fertility profile exclusively in diabetic neuropathic condition with an improvement in testicular function which was probably arrested due to some kind of testicular hyperplasia resulted by testicular necrosis and promoted spermatogenesis. Sildenafil seems to be associated with an improvement in the entire smooth musculature of reproductive tract and testicular morphology which was altered due to neuropathy like a reduction in excess accumulation of interstitial collagen and calcification in the smooth muscles of seminiferous tubules which made them rigid leading to atonia of bladder and urethra which resulted in partial or retrograde ejaculation associated with a decreased sperm motility. Sildenafil treatment returned back the spermatogenesis to normal with a positive influence on sperm motility and ejaculate volume in these neuropathic patients irrespective of the type of diabetes.

The inhibition of nitric oxide-activated poly(ADP-ribose) synthetase attenuates transsynaptic alteration of spinal cord dorsal horn neurons and neuropathic pain in the rat.

PubMed

Mao, J; Price, D D; Zhu, J; Lu, J; Mayer, D J

1997-09-01

Transsynaptic alteration of spinal cord dorsal horn neurons characterized by hyperchromatosis of cytoplasm and nucleoplasm (so-called 'dark' neurons) occurs in a rat model of neuropathic pain induced by chronic constriction injury (CCI) of the common sciatic nerve. The incidence of dark neurons in CCI rats has been proposed to be mediated by glutamate-induced neurotoxicity. In the present study, we examined whether the inhibition of the nitric oxide (NO)-activated poly(ADP-ribose) synthetase (PARS), a nuclear enzyme critical to glutamate-induced neurotoxicity, would both reduce the incidence of dark neurons and attenuate behavioral manifestations of neuropathic pain in CCI rats. Dark neurons were observed bilaterally (with ipsilateral predominance) within the spinal cord dorsal horn, particularly in laminae I-II, of rats 8 days after unilateral sciatic nerve ligation as compared to sham operated rats. The number of dark neurons in the dorsal horn was dose-dependently reduced in CCI rats receiving once daily intrathecal (i.t.) treatment with the PARS inhibitor benzamide (200 or 400 nmol, but not 100 nmol benzamide or saline) for 7 days. Consistent with the histological improvement, thermal hyperalgesia, mechanical hyperalgesia, and low threshold mechano-allodynia also were reliably reduced in CCI rats treated with either 200 or 400 nmol benzamide. Neither dark neurons nor neuropathic pain behaviors were reliably affected by i.t. administration of either 800 nmol novobiocin (a mono(ADP-ribose) synthetase) or 800 nmol benzoic acid (the backbone structure of benzamide), indicating a selective effect of benzamide. Intrathecal treatment with an NO synthase inhibitor NG-nitro-L-arginine methyl ester (40 nmol, but not its inactive D-isomer) utilizing the same benzamide treatment regimen resulted in similar reductions of both dark neurons and neuropathic pain behaviors in CCI rats. These results provide, for the first time, in vivo evidence indicating that benzamide is neuroprotective and that the PARS-mediated transsynaptic alteration of spinal cord dorsal horn neurons contributes to behavioral manifestations of neuropathic pain in CCI rats. These observations may have general implications beyond treatment of neuropathic pain in that PARS-mediated neuronal alterations may play a significant role in glutamate-mediated neurotoxicity under many other circumstances.

Chemotherapy-related neuropathic symptom management: a randomized trial of an automated symptom-monitoring system paired with nurse practitioner follow-up.

PubMed

Kolb, Noah Allan; Smith, Albert Gordon; Singleton, John Robinson; Beck, Susan L; Howard, Diantha; Dittus, Kim; Karafiath, Summer; Mooney, Kathi

2018-05-01

The purpose of this study was to evaluate a new care model to reduce chemotherapy-induced neuropathic symptoms. Neuropathic symptom usual care was prospectively compared to an automated symptom-monitoring and coaching system, SymptomCare@Home (SCH), which included nurse practitioner follow-up triggered by moderate to severe symptoms. Patients beginning chemotherapy were randomized to usual care (UC) or to the SCH intervention. This sub-analysis included only taxane/platin therapies. Participants called the automated telephone symptom-monitoring system daily to report numbness and tingling. The monitoring system recorded patient-reported neuropathic symptom severity, distress, and activity interference on a 0-10 scale. UC participants were instructed to call their oncologist for symptom management. SCH participants with symptom severity of ≥ 4 received automated self-care strategies, and a nurse practitioner (NP) provided guideline-based care. There were 252 participants, 78.6% of which were female. Mean age was 55.1 years. Mean follow-up was 90.2 ± 39.9 days (81.1 ± 40.3 calls). SCH participants had fewer days of moderate (1.8 ± 4.0 vs. 8.6 ± 17.3, p < 0.001) and severe chemotherapy-induced peripheral neuropathy symptoms (0.3 ± 1.0 vs. 1.1 ± 5.2, p = 0.006). SCH participants had fewer days with moderate and severe symptom-related distress (1.4 ± 3.7 vs. 6.9 ± 15.0, p < 0.001; 0.2 ± 0.9 vs. 1.5 ± 6.1, p = 0.001) and trended towards less activity interference (3.3 ± 1.9 vs. 3.8 ± 2.1, p = 0.08). Other neuropathic symptoms were addressed in 5.8-15.4% of SCH follow-up calls. The SCH system effectively identified neuropathic symptoms and their severity and, paired with NP follow-up, reduced symptom prevalence, severity, and distress compared to usual care.

Treatment of painful radiculopathies with capsaicin 8% cutaneous patch.

PubMed

Baron, R; Treede, R D; Birklein, F; Cegla, T; Freynhagen, R; Heskamp, M L; Kern, K U; Maier, C; Rolke, R; Seddigh, S; Sommer, C; Ständer, S; Maihöfner, C

2017-08-01

The treatment of neuropathic pain due to low-back (lumbosacral) radiculopathies, a common source of neuropathic pain, is challenging and often requires a multimodal therapeutic approach. The capsaicin 8% patch is the first topical analgesic licensed for peripheral neuropathic pain. To evaluate this treatment, a subset of patients with painful radiculopathy (lumbar and cervical, including ventral and dorsal rami) enrolled into the multicenter, non-interventional QUEPP study (Qutenza 2 - safety and effectiveness in peripheral neuropathic pain) was analyzed. Of the 1044 study participants, 50 were diagnosed with painful radiculopathy as only peripheral neuropathic pain syndrome and were eligible for evaluation. Patients received a single treatment (visit 1) with follow-up visits 2-5 at weeks 1-2, 4, 8 and 12. Parameters assessed at all visits included pain intensity, neuropathy symptoms and side effects. Quality of life (SF-12) and painDETECT 1 questionnaires were completed at baseline and final visit. Data was analyzed by patch application site and duration of pain. Topical treatment led to a significant decrease of pain intensity between weeks 1/2 and week 12 versus baseline at the application sites representing dermatomes of ventral (N = 26) and dorsal rami (N = 13) of spinal nerves. A significant decline (p ≤ .001) of numeric pain rating scale scores was observed between weeks 1/2 following patch application and the end of observation (week 12) in the overall radiculopathy group (N = 50), and the groups with either 3 months to 2 years (N = 14) or >2 years (N = 23) duration of pain. Pain relief of at least 30% was observed in 50.0%, 71.4% and 39.1% of patients in the respective groups. Four patients experienced in total seven adverse drug reactions (application site pain or pruritus). Effective neuropathic pain relief was observed after patch application within the innervation territories of both dorsal and ventral branches of the spinal nerve. Further controlled randomized trials are indicated.

Early metabolic responses to lithium/pilocarpine-induced status epilepticus in rat brain.

PubMed

Imran, Imran; Hillert, Markus H; Klein, Jochen

2015-12-01

The lithium-pilocarpine model of status epilepticus is a well-known animal model of temporal lobe epilepsy. We combined this model with in vivo microdialysis to investigate energy metabolites and acute cellular membrane damage during seizure development. Rats were implanted with dialysis probes and pretreated with lithium chloride (127 mg/kg i.p.). Twenty-four hours later, they received pilocarpine (30 mg/kg s.c.) which initiated seizures within 30 min. In the dialysate from rat hippocampus, we observed a transient increase in glucose and a prominent, five-fold increase in lactate during seizures. Lactate release was because of neuronal activation as it was strongly reduced by infusion of tetrodotoxin, administration of atropine or when seizures were terminated by diazepam or ketamine. In ex vivo assays, mitochondrial function as measured by respirometry was not affected by 90 min of seizures. Extracellular levels of choline, however, increased two-fold and glycerol levels 10-fold, which indicate cellular phospholipid breakdown during seizures. Within 60 min of pilocarpine administration, hydroxylation of salicylate increased two-fold and formation of isoprostanes 20-fold, revealing significant oxidative stress in hippocampal tissue. Increases in lactate, glycerol and isoprostanes were abrogated, and increases in choline were completely prevented, when hippocampal probes were perfused with calcium-free solution. Similarly, administration of pregabalin (100 mg/kg i.p.), a calcium channel ligand, 15 min prior to pilocarpine strongly attenuated parameters of membrane damage and oxidative stress. We conclude that seizure development in a rat model of status epilepticus is accompanied by increases in extracellular lactate, choline and glycerol, and by oxidative stress, while mitochondrial function remains intact for at least 90 min. Membrane damage depends on calcium influx and can be prevented by treatment with pregabalin. Status epilepticus (SE) was induced in rats by lithium-pilocarpine ('Pilo') administration, and extracellular metabolites were measured by microdialysis. Seizures caused several-fold increases in lactate levels which were attenuated by diazepam ('Diaz'), ketamine, atropine and tetrodotoxin (TTX). Indicators of oxidative stress and membrane damage were also increased during seizures. Omission of calcium and pregabalin, a calcium channel blocker, reduced cellular damage induced by SE. © 2015 International Society for Neurochemistry.

The pivotal role of offloading in the management of neuropathic foot ulceration.

PubMed

Wu, Stephanie C; Crews, Ryan T; Armstrong, David G

2005-12-01

Lower extremity amputations among persons with diabetes are generally preceded by neuropathic foot ulcerations. Healing of diabetic ulcerations in a timely manner is of central importance in any plan for amputation prevention. With sufficient vascular supply, appropriate débridement, and infection control, the primary mode of healing a diabetic neuropathic foot ulcer is pressure dispersion. The total contact cast has been deemed by many to be the gold standard in offloading; however, modification of a standard removable cast walker to ensure patient compliance may be as efficacious in healing diabetic foot ulcers as the total contact cast. Combining an effective, easy to use offloading device that ensures patient compliance with advanced wound healing modalities may form a formidable team in healing ulcers and potentially averting lower limb amputations.

Ambroxol for the treatment of fibromyalgia: science or fiction?

PubMed Central

Kern, Kai-Uwe; Schwickert, Myriam

2017-01-01

Fibromyalgia appears to present in subgroups with regard to biological pain induction, with primarily inflammatory, neuropathic/neurodegenerative, sympathetic, oxidative, nitrosative, or muscular factors and/or central sensitization. Recent research has also discussed glial activation or interrupted dopaminergic neurotransmission, as well as increased skin mast cells and mitochondrial dysfunction. Therapy is difficult, and the treatment options used so far mostly just have the potential to address only one of these aspects. As ambroxol addresses all of them in a single substance and furthermore also reduces visceral hypersensitivity, in fibromyalgia existing as irritable bowel syndrome or chronic bladder pain, it should be systematically investigated for this purpose. Encouraged by first clinical observations of two working groups using topical or oral ambroxol for fibromyalgia treatments, the present paper outlines the scientific argument for this approach by looking at each of the aforementioned aspects of this complex disease and summarizes putative modes of action of ambroxol. Nevertheless, at this point the evidence basis for ambroxol is not strong enough for clinical recommendation. PMID:28860846

The Effect of Exercise on Neuropathic Symptoms, Nerve Function, and Cutaneous Innervation in People with Diabetic Peripheral Neuropathy

PubMed Central

Kluding, Patricia M.; Pasnoor, Mamatha; Singh, Rupali; Jernigan, Stephen; Farmer, Kevin; Rucker, Jason; Sharma, Neena; Wright, Douglas E.

2012-01-01

Although exercise can significantly reduce the prevalence and severity of diabetic complications, no studies have evaluated the impact of exercise on nerve function in people with diagnosed diabetic peripheral neuropathy (DPN). The purpose of this pilot study was to examine feasibility and effectiveness of a supervised, moderately intense aerobic and resistance exercise program in people with DPN. We hypothesize that the exercise intervention can improve neuropathic symptoms, nerve function, and cutaneous innervation. Methods A pre-test post-test design was to assess change in outcome measures following participation in a 10-week aerobic and strengthening exercise program. Seventeen subjects with diagnosed DPN (8 males/9 females; age 58.4±5.98; duration of diabetes 12.4±12.2 years) completed the study. Outcome measures included pain measures (visual analog scale), Michigan Neuropathy Screening Instrument (MNSI) questionnaire of neuropathic symptoms, nerve function measures, and intraepidermal nerve fiber (IENF) density and branching in distal and proximal lower extremity skin biopsies. Results Significant reductions in pain (−18.1±35.5 mm on a 100 mm scale, p=0.05), neuropathic symptoms (−1.24±1.8 on MNSI, p=0.01), and increased intraepidermal nerve fiber branching (+0.11±0.15 branch nodes/fiber, p=−.008) from a proximal skin biopsy were noted following the intervention. Conclusions This is the first study to describe improvements in neuropathic and cutaneous nerve fiber branching following supervised exercise in people with diabetic peripheral neuropathy. These findings are particularly promising given the short duration of the intervention, but need to be validated by comparison with a control group in future studies. PMID:22717465

Can gradual dose titration of ketamine for management of neuropathic pain prevent psychotomimetic effects in patients with advanced cancer?

PubMed

Okamoto, Yoshiaki; Tsuneto, Satoru; Tanimukai, Hitoshi; Matsuda, Yoichi; Ohno, Yumiko; Tsugane, Mamiko; Uejima, Etsuko

2013-08-01

Ketamine is often used to manage neuropathic pain in patients with cancer. However, it occasionally causes psychotomimetic effects such as vivid dreams, nightmares, illusions, hallucinations, and altered body image. To examine whether gradual dose titration of ketamine for management of neuropathic pain prevents psychotomimetic effects in patients with advanced cancer. This was a retrospective chart review. We administered ketamine when neuropathic pain in patients with advanced cancer became refractory to opioids and oral adjuvant analgesics. The starting dose of ketamine was 10 mg/d by continuous intravenous infusion. The dose was gradually increased by 10 mg/d every 4 to 6 hours to 50 mg/d or until the pain was relieved. It was subsequently increased by 25 mg/d every 12 to 24 hours until the pain was relieved. For this study, we enrolled 46 patients with advanced cancer. The mean age was 52.2 ± 16.9 years. The mean dose at onset of action and maximum dose of ketamine were 56 ± 58 and 272 ± 214 mg/d, respectively. The mean pain intensity (numerical rating scale) decreased significantly from 7.3 ± 2.0 to 3.5 ± 2.2 after the administration of ketamine (P < .01). The effectiveness was 69.5%. No psychotomimetic effect of less than 300 mg/d was observed during the introduction phase even though psychotropic drugs were not prescribed. Mild sedation was observed in 3 patients (7%) as the only adverse effect during the introduction phase. Gradual dose titration of ketamine for management of neuropathic pain can prevent psychotomimetic effects in patients with advanced cancer.

MiR-203 involves in neuropathic pain development and represses Rap1a expression in nerve growth factor differentiated neuronal PC12 cells.

PubMed

Li, Haixia; Huang, Yuguang; Ma, Chao; Yu, Xuerong; Zhang, Zhiyong; Shen, Le

2015-01-01

Although microRNAs (miRNAs) have been shown to play a role in numerous biological processes, their function in neuropathic pain is not clear. The rat bilateral sciatic nerve chronic constriction injury (bCCI) is an established model of neuropathic pain, so we examined miRNA expression and function in the spinal dorsal horn in bCCI rats. Microarray and real-time polymerase chain reaction were used to examine the expression of miRNA in nerve system of bCCI rats, and the targets of miRNA were predicted by bioinformatic approaches. The function of specific miRNA was estimated through the methods of gene engineering. This study revealed substantially (∼10-fold) decreased miR-203 expression in the spinal dorsal horns but not the dorsal root ganglions, hippocampus, or anterior cingulate cortexes of bCCI rats. Rap1a protein expression was upregulated in bCCI rat spinal dorsal horns. We further verified that miR-203 directly targeted the 3'-untranslated region of the rap1a gene, thereby decreasing rap1a protein expression in neuron-like cells. Rap1a has diverse neuronal functions and their perturbation is responsible for several mental disorders. For example, Rap1a/MEK/ERK is involved in peripheral sensitization. These data suggest a potential role for miR-203 in regulating neuropathic pain development, and Rap1a is a validated target gene in vitro. Results from our study and others indicate the possibility that Rap1a may be involved in pain. We hope that these results can provide support for future research into miR-203 in gene therapy for neuropathic pain.

Role of dorsal root ganglion K2P1.1 in peripheral nerve injury-induced neuropathic pain

PubMed Central

Mao, Qingxiang; Yuan, Jingjing; Xiong, Ming; Wu, Shaogen; Chen, Liyong; Bekker, Alex; Yang, Tiande

2017-01-01

Peripheral nerve injury-caused hyperexcitability and abnormal ectopic discharges in the primary sensory neurons of dorsal root ganglion (DRG) play a key role in neuropathic pain development and maintenance. The two-pore domain background potassium (K2P) channels have been identified as key determinants of the resting membrane potential and neuronal excitability. However, whether K2P channels contribute to neuropathic pain is still elusive. We reported here that K2P1.1, the first identified mammalian K2P channel, was highly expressed in mouse DRG and distributed in small-, medium-, and large-sized DRG neurons. Unilateral lumbar (L) 4 spinal nerve ligation led to a significant and time-dependent reduction of K2P1.1 mRNA and protein in the ipsilateral L4 DRG, but not in the contralateral L4 or ipsilateral L3 DRG. Rescuing this reduction through microinjection of adeno-associated virus-DJ expressing full-length K2P1.1 mRNA into the ipsilateral L4 DRG blocked spinal nerve ligation-induced mechanical, thermal, and cold pain hypersensitivities during the development and maintenance periods. This DRG viral microinjection did not affect acute pain and locomotor function. Our findings suggest that K2P1.1 participates in neuropathic pain development and maintenance and may be a potential target in the management of this disorder. PMID:28326939

Changes in VGLUT1 and VGLUT2 expression in rat dorsal root ganglia and spinal cord following spared nerve injury.

PubMed

Wang, Hong-Sheng; Yu, Gang; Wang, Zhi-Tong; Yi, Shou-Pu; Su, Rui-Bin; Gong, Ze-Hui

2016-10-01

Disturbance of glutamate homeostasis is a well-characterized mechanism of neuropathic pain. Vesicular glutamate transporters (VGLUTs) determine glutamate accumulation in synaptic vesicles and their roles in neuropathic pain have been suggested by gene-knockout studies. Here, we investigated the spatio-temporal changes in VGLUT expression during the development of neuropathic pain in wild-type rats. Spared nerve injury (SNI) induced mechanical allodynia from postoperative day 1 to at least day 14. Expression of VGLUT1 and VGLUT2 in dorsal root ganglia and spinal cord was examined by western blot analyses on different postoperative days. We observed that VGLUT2 were selectively upregulated in crude vesicle fractions from the ipsilateral lumbar enlargement on postoperative days 7 and 14, while VGLUT1 was transiently downregulated in ipsilateral DRG (day 4) and contralateral lumbar enlargement (day 1). Upregulation of VGLUT2 was not accompanied by alterations in vesicular expression of synaptotagmin or glyceraldehyde-3-phosphate dehydrogenase (GAPDH). Thus, VGLUTs expression, especially VGLUT2, is regulated following peripheral nerve injury. Temporal regulation of VGLUT2 expression in spinal cord may represent a novel presynaptic mechanism contributing to injury-induced glutamate imbalance and associated neuropathic pain. Copyright © 2016 Elsevier Ltd. All rights reserved.

Lacrimal neuralgia: so far, a missing cranial neuralgia.

PubMed

Pareja, Juan A; Cuadrado, María-Luz

2013-10-01

The lacrimal nerve supplies the lacrimal gland, the lateral upper eyelid, and a small cutaneous area adjacent to the external CANTHUS . First division trigeminal neuralgia, supraorbital/supratrochlear neuralgia, and infraorbital neuralgia have been acknowledged as neuralgic causes of pain in the forehead and periorbit. However, the lacrimal nerve has never been identified as a source of facial pain. Here we report two cases of lacrimal neuralgia. A 66-year-old woman had continuous pain in the lateral aspect of her left superior eyelid and an adjacent area of the temple since age 64. A 33-year-old woman suffered from continuous pain in a small area next to the lateral CANTHUS of her left eye since age 25. In both patients the superoexternal edge of the orbit was tender. In addition, sensory dysfunction could be demonstrated within the painful area. Anaesthetic blockades of the lacrimal nerve with lidocaine 2% resulted in complete but short-lasting relief. Pregabalin provided a complete response in the first patient. The second patient was refractory to various oral and topical drugs and different radiofrequency procedures, but she eventually obtained partial relief with pregabalin. Lacrimal neuralgia should be considered among the neuralgic causes of orbital and periorbital pain.

Chronic constriction injury-induced microRNA-146a-5p alleviates neuropathic pain through suppression of IRAK1/TRAF6 signaling pathway.

PubMed

Wang, Zhiyao; Liu, Fan; Wei, Min; Qiu, Yue; Ma, Chao; Shen, Le; Huang, Yuguang

2018-06-09

microRNA-146a-5p (miRNA-146a-5p) is a key molecule in the negative regulation pathway of TLRs and IL-1 receptor (TIR) signaling. Our recent study demonstrated that MyD88-dependent signaling pathway of TIR in the dorsal root ganglion (DRG) and spinal dorsal horn (SDH) plays a role in peripheral nerve injury-induced neuropathic pain. However, it was not clear whether and how miRNA-146a-5p regulates the TIR pathway of DRG and SDH in the development of neuropathic pain. The sciatic nerve chronic constriction injury (CCI) model of rat was used to induce chronic neuropathic pain. The levels and cellular distribution of miRNA-146a-5p were detected with quantitative real-time PCR (qPCR) and fluorescent in situ hybridization (FISH). The RNA level, protein level, and cellular distribution of IRAK1 and TRAF6 that is targeted by miRNA-146a-5p were detected with qPCR, western blot, and immunofluorescent. The pain-related behavioral effect of miRNA-146a-5p was accessed after intrathecal administration. Mechanical stimuli and radiant heat were used to evaluate mechanical allodynia and thermal hyperalgesia. We found that the level of miRNA-146a-5p significantly increased in L4-L6 DRGs and SDH after CCI surgery; meanwhile, the protein level of IRAK1 and TRAF6 in DRGs was significantly increased after CCI. Intrathecal injection of miR146a-5p agomir or miRNA-146a-5p antagomir regulates miRNA-146a-5p level of L4-L6 DRGs and SDH. We found that intrathecal injection of miR146a-5p agomir can alleviate mechanical and thermal hyperalgesia in CCI rats and reverse the upregulation of IRAK1 and TRAF6 of L4-L6 DRGs and SDH induced by CCI. We furthermore found that intrathecal injection of miRNA-146a-5p antagomir can exacerbate the mechanical and thermal pain-related behavior of CCI rats and meanwhile increase IRAK1 and TRAF6 of L4-L6 DRGs and SDH expression even further. miRNA-146a-5p of DRG and SDH can modulate the development of CCI-induced neuropathic pain through inhibition of IRAK1 and TRAF6 in the TIR signaling pathway. Hence, miRNA-146a-5p may serve as a potential therapeutic target for neuropathic pain.

The Psychopharmacology Algorithm Project at the Harvard South Shore Program: An Algorithm for Generalized Anxiety Disorder.

PubMed

Abejuela, Harmony Raylen; Osser, David N

2016-01-01

This revision of previous algorithms for the pharmacotherapy of generalized anxiety disorder was developed by the Psychopharmacology Algorithm Project at the Harvard South Shore Program. Algorithms from 1999 and 2010 and associated references were reevaluated. Newer studies and reviews published from 2008-14 were obtained from PubMed and analyzed with a focus on their potential to justify changes in the recommendations. Exceptions to the main algorithm for special patient populations, such as women of childbearing potential, pregnant women, the elderly, and those with common medical and psychiatric comorbidities, were considered. Selective serotonin reuptake inhibitors (SSRIs) are still the basic first-line medication. Early alternatives include duloxetine, buspirone, hydroxyzine, pregabalin, or bupropion, in that order. If response is inadequate, then the second recommendation is to try a different SSRI. Additional alternatives now include benzodiazepines, venlafaxine, kava, and agomelatine. If the response to the second SSRI is unsatisfactory, then the recommendation is to try a serotonin-norepinephrine reuptake inhibitor (SNRI). Other alternatives to SSRIs and SNRIs for treatment-resistant or treatment-intolerant patients include tricyclic antidepressants, second-generation antipsychotics, and valproate. This revision of the GAD algorithm responds to issues raised by new treatments under development (such as pregabalin) and organizes the evidence systematically for practical clinical application.

The effect of exercise on neuropathic symptoms, nerve function, and cutaneous innervation in people with diabetic peripheral neuropathy.

PubMed

Kluding, Patricia M; Pasnoor, Mamatha; Singh, Rupali; Jernigan, Stephen; Farmer, Kevin; Rucker, Jason; Sharma, Neena K; Wright, Douglas E

2012-01-01

Although exercise can significantly reduce the prevalence and severity of diabetic complications, no studies have evaluated the impact of exercise on nerve function in people with diagnosed diabetic peripheral neuropathy (DPN). The purpose of this pilot study was to examine feasibility and effectiveness of a supervised, moderately intense aerobic and resistance exercise program in people with DPN. We hypothesized that the exercise intervention can improve neuropathic symptoms, nerve function, and cutaneous innervation. A pre-test post-test design was used to assess change in outcome measures following participation in a 10-week aerobic and strengthening exercise program. Seventeen subjects with diagnosed DPN (8 males/9 females; age 58.4±5.98; duration of diabetes 12.4±12.2 years) completed the study. Outcome measures included pain measures (visual analog scale), Michigan Neuropathy Screening Instrument (MNSI) questionnaire of neuropathic symptoms, nerve function measures, and intraepidermal nerve fiber (IENF) density and branching in distal and proximal lower extremity skin biopsies. Significant reductions in pain (-18.1±35.5 mm on a 100 mm scale, P=.05), neuropathic symptoms (-1.24±1.8 on MNSI, P=.01), and increased intraepidermal nerve fiber branching (+0.11±0.15 branch nodes/fiber, P=.008) from a proximal skin biopsy were noted following the intervention. This is the first study to describe improvements in neuropathic and cutaneous nerve fiber branching following supervised exercise in people with diabetic peripheral neuropathy. These findings are particularly promising given the short duration of the intervention, but need to be validated by comparison with a control group in future studies. Copyright © 2012 Elsevier Inc. All rights reserved.

P2Y12 shRNA treatment decreases SGC activation to relieve diabetic neuropathic pain in type 2 diabetes mellitus rats.

PubMed

Wang, Shouyu; Wang, Zilin; Li, Lin; Zou, Lifang; Gong, Yingxin; Jia, Tianyu; Zhao, Shanhong; Yuan, Huilong; Shi, Liran; Liu, Shuangmei; Wu, Bing; Yi, Zhihua; Liu, Hui; Gao, Yun; Li, Guilin; Deussing, Jan M; Li, Man; Zhang, Chunping; Liang, Shangdong

2018-06-26

Diabetic neuropathic pain is a common complication of type 2 diabetes mellitus (DM). Activation of satellite glial cells (SGCs) in the dorsal root ganglia (DRG) plays a crucial role in neuropathic pain through the release of proinflammatory cytokines. The P2Y12 receptor is expressed in SGCs of the DRG. In this study, our aim was to investigate the role of the P2Y12 receptor on the pathological changes in diabetic neuropathic pain. The present study showed that diabetic neuropathic pain increased mechanical and thermal hyperalgesia in type 2 DM model rats. The results showed that the expression levels of P2Y12 messenger RNA (mRNA) and protein in DRG SGCs were increased in DM model rats compared with control rats. Glial fibrillary acidic protein (GFAP) and interleukin-1β (IL-1β) expression levels in the DRG were increased in DM rats. Upregulation of GFAP is a marker of SGC activation. Targeting the P2Y12 receptor by short hairpin RNA (shRNA) decreased the upregulated expression of P2Y12 mRNA and protein, coexpression of P2Y12 and GFAP, the expression of GFAP, IL-1β, and tumor necrosis factor-receptor 1 in the DRG of DM rats, and relieved mechanical and thermal hyperalgesia in DM rats. After treatment with the P2Y12 receptor shRNA, the enhancing integrated OPTICAL density (IOD) ratios of p-P38 MAPK to P38 mitogen activated protein kinase (MAPK) in the DM rats treated with P2Y12 shRNA were significantly lower than that in the untreated DM rats. Therefore, P2Y12 shRNA treatment decreased SGC activation to relieve mechanical and thermal hyperalgesia in DM rats. © 2018 Wiley Periodicals, Inc.

Botulinum toxin decreases hyperalgesia and inhibits P2X3 receptor over-expression in sensory neurons induced by ventral root transection in rats.

PubMed

Xiao, Lizu; Cheng, Jianguo; Dai, Juanli; Zhang, Deren

2011-09-01

We aim to determine the effects of Botulinum toxin type A (BTX-A) on neuropathic pain behavior and the expression of P2X(3) receptor in dorsal root ganglion (DRG) in rats with neuropathic pain induced by L5 ventral root transection (L5 VRT). Neuropathic pain was induced by L5 VRT in male Sprague-Dawley rats. Either saline or BTX-A was administered to the plantar surface. Behavioral tests were conducted preoperatively and at predefined postoperative days. The expression of P2X(3) receptors in DRG neurons was detected by immunoreactivity at postoperative days 3, 7, 14, and 21. The number of positive P2X(3) neurons in the ipsilateral L5 DRG increased significantly after L5 VRT (P<0.001). This increase persisted for at least 3 weeks after the operation. No significant changes in P2X(3) expression were detected in the contralateral L5, or in the L4 DRGs bilaterally. Subcutaneous administration of BTX-A, performed on the left hindpaw at days 4, 8, or 16 post VRT surgery, significantly reduced mechanical allodynia bilaterally and inhibited P2X(3) over-expression induced by L5 VRT. L5 VRT led to over-expression of P2X(3) receptors in the L5 DRG and bilateral mechanical allodynia in rats. Subcutaneous injection of BTX-A significantly reversed the neuropathic pain behavior and the over-expression of P2X(3) receptor in nociceptive neurons. These data not only show over-expression of purinergic receptors in the VRT model of neuropathic pain but also reveal a novel mechanism of botulinum toxin action on nociceptive neurons. Wiley Periodicals, Inc.