Gastric pentadecapeptide BPC 157 counteracts morphine-induced analgesia in mice.

PubMed

Boban Blagaic, A; Turcic, P; Blagaic, V; Dubovecak, M; Jelovac, N; Zemba, M; Radic, B; Becejac, T; Stancic Rokotov, D; Sikiric, P

2009-12-01

Previously, the gastric pentadecapeptide BPC 157, (PL 14736, Pliva) has been shown to have several beneficial effects, it exert gastroprotective, anti-inflammatory actions, stimulates would healing and has therapeutic value in inflammatory bowel disease. The present study aimed to study the effect of naloxone and BPC 157 on morphine-induced antinociceptive action in hot plate test in the mouse. It was found that naloxone and BPC 157 counteracted the morphine (16 mg/kg s.c.) - analgesia. Naloxone (10 mg/kg s.c.) immediately antagonised the analgesic action and the reaction time returned to the basic values, the development of BPC 157-induced action (10 pg/kg, 10 ng/kg, 10 microg/kg i.p.) required 30 minutes. When haloperidol, a central dopamine-antagonist (1 mg/kg i.p.), enhanced morphine-analgesia, BPC 157 counteracted this enhancement and naloxone reestablished the basic values of pain reaction. BPC 157, naloxone, and haloperidol per se failed to exert analgesic action. In summary, interaction between dopamine-opioid systems was demonstrated in analgesia, BPC 157 counteracted the haloperidol-induced enhancement of the antinociceptive action of morphine, indicating that BPC acts mainly through the central dopaminergic system.

Peripheral analgesic sites of action of anti-inflammatory drugs.

PubMed

Ferreira, S H

2002-07-01

Inflammatory signs and symptoms of redness, swelling, heat and pain are due to the effects of inflammatory mediators released during the inflammatory response. Depending on the type of injurious stimuli and the tissue involved, the array of mediators may differ but eicosanoids are involved in the genesis of inflammatory pain. They are responsible for the hypersensitisation of the nociceptors (allodynialhyperalgesia). The basic mechanism of analgesic action of nonsteroidal anti-inflammatory drugs results from the inhibition of prostaglandin synthesis (prostacyclin or PGE2), thus preventing nociceptor threshold lowering. Because there is a temporal hierarchy in the release of inflammatory mediators, there are several targets for the action of peripheral acting analgesics before and after the inhibition of prostaglandin synthesis. Blockade of the release and inhibition of inducible cyclooxygenase explain the analgesic action of glucocorticoids. Nimesulide also has an inhibitory action on the cascade of hypersensitising cytokines. Some analgesics, such as dipyrone, flurbiprofen or diclofenac, act directly upon ongoing inflammatory hypersensitisation. Those analgesics restore the nociceptor by stimulating the arginine/NO/cGMP/K(ATP) channel pathway.

Incorporation of monodisperse oligoethyleneglycol amino acids into anticonvulsant analogues of galanin and neuropeptide y provides peripherally acting analgesics.

PubMed

Zhang, Liuyin; Klein, Brian D; Metcalf, Cameron S; Smith, Misty D; McDougle, Daniel R; Lee, Hee-Kyoung; White, H Steve; Bulaj, Grzegorz

2013-02-04

Delivery of neuropeptides into the central and/or peripheral nervous systems supports development of novel neurotherapeutics for the treatment of pain, epilepsy and other neurological diseases. Our previous work showed that the combination of lipidization and cationization applied to anticonvulsant neuropeptides galanin (GAL) and neuropeptide Y (NPY) improved their penetration across the blood-brain barrier yielding potent antiepileptic lead compounds, such as Gal-B2 (NAX 5055) or NPY-B2. To dissect peripheral and central actions of anticonvulsant neuropeptides, we rationally designed, synthesized and characterized GAL and NPY analogues containing monodisperse (discrete) oligoethyleneglycol-lysine (dPEG-Lys). The dPEGylated analogues Gal-B2-dPEG(24), Gal-R2-dPEG(24) and NPY-dPEG(24) displayed analgesic activities following systemic administration, while avoiding penetration into the brain. Gal-B2-dPEG(24) was synthesized by a stepwise deprotection of orthogonal 4-methoxytrityl and allyloxycarbonyl groups, and subsequent on-resin conjugations of dPEG(24) and palmitic acids, respectively. All the dPEGylated analogues exhibited substantially decreased hydrophobicity (expressed as logD values), increased in vitro serum stabilities and pronounced analgesia in the formalin and carrageenan inflammatory pain assays following systemic administration, while lacking apparent antiseizure activities. These results suggest that discrete PEGylation of neuropeptides offers an attractive strategy for developing neurotherapeutics with restricted penetration into the central nervous system.

NKTR-181: A Novel Mu-Opioid Analgesic with Inherently Low Abuse Potential.

PubMed

Miyazaki, Takahiro; Choi, Irene Y; Rubas, Werner; Anand, Neel K; Ali, Cherie; Evans, Juli; Gursahani, Hema; Hennessy, Marlene; Kim, Grace; McWeeney, Daniel; Pfeiffer, Juergen; Quach, Phi; Gauvin, David; Riley, Timothy A; Riggs, Jennifer A; Gogas, Kathleen; Zalevsky, Jonathan; Doberstein, Stephen K

2017-10-01

The increasing availability of prescription opioid analgesics for the treatment of pain has been paralleled by an epidemic of opioid misuse, diversion, and overdose. The development of abuse-deterrent formulations (ADFs) of conventional opioids such as oxycodone and morphine represents an advance in the field and has had a positive but insufficient impact, as most opioids are still prescribed in highly abusable, non-ADF forms, and abusers can tamper with ADF medications to liberate the abusable opioid within. The abuse liability of mu-opioid agonists appears to be dependent on their rapid rate of entry into the central nervous system (CNS), whereas analgesic activity appears to be a function of CNS exposure alone, suggesting that a new opioid agonist with an inherently low rate of influx across the blood-brain barrier could mediate analgesia with low abuse liability, regardless of formulation or route of administration. NKTR-181 is a novel, long-acting, selective mu-opioid agonist with structural properties that reduce its rate of entry across the blood-brain barrier compared with traditional mu-opioid agonists. NKTR-181 demonstrated maximum analgesic activity comparable to that of oxycodone in hot-plate latency and acetic-acid writhing models. NKTR-181 was distinguishable from oxycodone by its reduced abuse potential in self-administration and progressive-ratio break point models, with behavioral effects similar to those of saline, as well as reduced CNS side effects as measured by the modified Irwin test. The in vitro and in vivo studies presented here demonstrate that NKTR-181 is the first selective mu-opioid agonist to combine analgesic efficacy and reduced abuse liability through the alteration of brain-entry kinetics. Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics.

Lack of synergistic interaction between the two mechanisms of action of tapentadol in gastrointestinal transit.

PubMed

Cowan, A; Raffa, R B; Tallarida, C S; Tallarida, R J; Christoph, T; Schröder, W; Tzschentke, T M

2014-09-01

A multi-mechanistic approach offers potential enhancement of analgesic efficacy, but therapeutic gain could be offset by an increase in adverse events. The centrally acting analgesic tapentadol [(-)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol hydrochloride] combines μ-opioid receptor (MOR) agonism and neuronal noradrenaline reuptake inhibition (NRI), both of which contribute to its analgesic effects. Previously, isobolographic analysis of occupation-effect data and a theoretically equivalent methodology determining interactions from the effect scale demonstrated pronounced synergistic interaction between the two mechanisms of action of tapentadol in two models of antinociception (low-intensity tail-flick and spinal nerve ligation). The present study investigated the nature of interaction of the two mechanisms on a surrogate measure for gastrointestinal adverse effect (inhibition of gastrointestinal transit). Dose-response curves were generated in rats for tapentadol alone or in combination with the opioid receptor antagonist, naloxone, or the α2 -adrenoceptor antagonist, yohimbine, to reveal the effect of tapentadol based upon MOR agonism, NRI, and combined mechanisms. The dose-effect curve of tapentadol was shifted to the right by both antagonists, thereby providing data to distinguish between MOR agonism and NRI. Analysis revealed a simple additive interaction between the two mechanisms on this endpoint, in contrast to the synergistic interaction previously demonstrated for antinociception. We believe this is the first published evaluation of mechanistic interaction for a surrogate measure of adverse effect of a single compound with two mechanisms of action, and the results suggest that there is a greater separation between the analgesic and gastrointestinal effects of tapentadol than expected based upon its analgesic efficacy. © 2014 European Pain Federation - EFIC®

Midazolam as an active placebo in 3 fentanyl-validated nociceptive pain models.

PubMed

Prosenz, Julian; Gustorff, Burkhard

2017-07-01

The use of inactive placebos in early translational trials of potentially analgesic compounds is discouraged because of the side-effect profiles of centrally acting analgesics. Therefore, benzodiazepines are used, although their use has not been validated in this context. Whether benzodiazepines confound the results of acute pain tests is unknown. Midazolam (0.06 mg/kg) as an active placebo was investigated in 3 nociceptive models that included contact heat, electrical pain, and pressure pain thresholds in 24 healthy volunteers. Fentanyl (1 μg/kg) served as an internal validator in this randomized, placebo (saline) controlled, 3-way cross-over trial. The primary outcome parameter (contact heat pain) was analyzed using a one-way, repeated measures analysis of variance and Tukey's post test. Midazolam did not reduce pain ([numeric rating scale], 0-100) in a statistically significant manner compared with placebo for the contact heat (mean difference -1.7, 95% confidence interval -10.6 to 7.3; P = 0.89) or electrical pain (4.3, -5.1 to 13.7; P = 0.51) test, nor did it raise the pressure pain thresholds (-28 kPa, -122; 64 kPa, P = 0.73). The width of the confidence intervals suggested that there were no clinically meaningful analgesic effects compared with the placebo. In contrast, the analgesic efficacy of fentanyl was effectively demonstrated in all 3 models (P < 0.01 vs midazolam and placebo). The findings of this study show that midazolam can be used as an active placebo in analgesic drug trials. Furthermore, the proposed models were simple to implement and very effective in detecting analgesia. The test battery can be used in translational trials for new compounds and comes with an active placebo and an optional active comparator.

Naloxegol: A Novel Therapy in the Management of Opioid-Induced Constipation.

PubMed

Jones, Rachel; Prommer, Eric; Backstedt, David

2016-11-01

Opioid-related bowel dysfunction is a common and potentially severe adverse effect from treatment with opioid analgesics. Its development is not dose related, nor do patients develop tolerance. Opioid-induced constipation (OIC) can lead to fecal impaction, bowel obstruction, and bowel perforation as well as noncompliance with opioid analgesics and poor quality of life. Routine administration of laxatives is necessary to maintain bowel function, and, in refractory cases, other modalities must be pursued. Available options are limited but include peripherally acting μ-opioid receptor antagonists (PAMORAs), including methylnaltrexone. Naloxegol is a newly developed PAMORA that is available through the oral route. At the therapeutic dose of 25 mg daily, naloxegol is effective and safe, with a limited side effect profile and is associated with preservation of centrally mediated analgesia. In this article, we discuss the pharmacokinetics, pharmacodynamics, adverse effects, clinical trials, and cost considerations of naloxegol. Finally, we discuss its potential role as a novel key treatment for OIC in palliative medicine patients. © The Author(s) 2015.

Comparative metabolism of tramadol and tapentadol: a toxicological perspective.

PubMed

Barbosa, Joana; Faria, Juliana; Queirós, Odília; Moreira, Roxana; Carvalho, Félix; Dinis-Oliveira, Ricardo Jorge

2016-11-01

Tramadol and tapentadol are centrally acting, synthetic opioid analgesics used in the treatment of moderate to severe pain. Main metabolic patterns for these drugs in humans are well characterized. Tramadol is mainly metabolized by cytochrome P450 CYP2D6 to O-desmethyltramadol (M1), its main active metabolite. M1 and tapentadol undergo mainly glucuronidation reactions. On the other hand, the pharmacokinetics of tramadol and tapentadol are dependent on multiple factors, such as the route of administration, genetic variability in pharmacokinetic components and concurrent consumption of other drugs. This review aims to comparatively discuss the metabolomics of tramadol and tapentadol, namely by presenting all their known metabolites. An exhaustive literature search was performed using textual and structural queries for tramadol and tapentadol, and associated known metabolizing enzymes and metabolites. A thorough knowledge about tramadol and tapentadol metabolomics is expected to provide additional insights to better understand the interindividual variability in their pharmacokinetics and dose-responsiveness, and contribute to the establishment of personalized therapeutic approaches, minimizing side effects and optimizing analgesic efficacy.

Monitoring risk: post marketing surveillance and signal detection.

PubMed

Dart, Richard C

2009-12-01

The primary goal of postmarketing surveillance is to provide information for risk assessment of a drug. Drugs affecting the central nervous system form a unique group of products for surveillance because they are often misused, abused, and diverted. These medications include opioid analgesics, stimulants, sedative-hypnotics, muscle relaxants, anticonvulsants and other drug classes. Their adverse events are difficult to monitor because the perpetrator often attempts to conceal the misuse, abuse and diversion of the product. A postmarketing surveillance system for prescription drugs of abuse in the U.S. should include product specific information that is accurate, immediately available, geographically specific and includes all areas of the country. Most producers of branded opioid analgesic products have created systems that measure abuse from multiple vantage points: criminal justice, treatment professionals, susceptible patient populations and acute health events. In the past, the U.S. government has not established similar requirements for the same products produced by generic manufacturers. However, the Food and Drug Administration Amendments Act of 2007 includes generic opioid analgesic products by requiring that all products containing potent opioid drugs perform rigorous surveillance and risk management. While general risk management guidance has been developed by FDA, more specific analyses and guidance are needed to improve surveillance methodology for drugs which are misused, abused, diverted.

Non-psychotropic analgesic drugs from the endocannabinoid system: "magic bullet" or "multiple-target" strategies?

PubMed

Starowicz, Katarzyna; Di Marzo, Vincenzo

2013-09-15

The exploitation of preparations of Cannabis sativa to combat pain seems to date back to time immemorial, although their psychotropic effects, which are at the bases of their recreational use and limit their therapeutic use, are at least as ancient. Indeed, it has always been different to tease apart the unwanted central effects from the therapeutic benefits of Δ⁹-tetrahydrocannabinol (THC), the main psychotropic component of cannabis. The discovery of the cannabinoid receptors and of their endogenous ligands, the endocannabinoids, which, unlike THC, play a pro-homeostatic function in a tissue- and time-selective manner, offered the opportunity to develop new analgesics from synthetic inhibitors of endocannabinoid inactivation. The advantages of this approach over direct activation of cannabinoid receptors as a therapeutic strategy against neuropathic and inflammatory pain are discussed here along with its potential complications. These latter have been such that clinical success has been achieved so far more rapidly with naturally occurring THC or endocannabinoid structural analogues acting at a plethora of cannabinoid-related and -unrelated molecular targets, than with selective inhibitors of endocannabinoid enzymatic hydrolysis, thus leading to revisit the potential usefulness of "multi-target" versus "magic bullet" compounds as new analgesics. © 2013 Elsevier B.V. All rights reserved.

Direct conversion from tramadol to tapentadol prolonged release for moderate to severe, chronic malignant tumour-related pain.

PubMed

Kress, H G; Koch, E D; Kosturski, H; Steup, A; Karcher, K; Dogan, C; Etropolski, M; Eerdekens, M

2016-10-01

A recent randomized-withdrawal, active- and placebo-controlled, double-blind phase 3 study showed that tapentadol prolonged release (PR) was effective and well tolerated for managing moderate to severe, chronic malignant tumour-related pain in patients who were opioid naive or dissatisfied with current treatment (Pain Physician, 2014, 17, 329-343). This post hoc, subgroup analysis evaluated the efficacy and tolerability of tapentadol PR in patients who previously received and were dissatisfied with tramadol for any reason and who had a pain intensity ≥5 (11-point numerical rating scale) before converting directly to tapentadol PR. In the original study, eligible patients had been randomized (2:1) and titrated to their optimal dose of tapentadol PR (100-250 mg bid) or morphine sulphate-controlled release (40-100 mg bid) over 2 weeks. The present report focuses on results during the titration period for a subgroup of patients randomized to tapentadol PR after having been on tramadol treatment prior to randomization in the study (n = 129). Results for this subgroup are compared with results for all 338 patients who received tapentadol PR during titration (overall tapentadol PR group). Responder rates (responders: completed titration, mean pain intensity <5 [0-10 scale] and ≤20 mg/day rescue medication during last 3 days) were slightly better for the tramadol/tapentadol PR subgroup (69.8% [90/129]) vs. the overall tapentadol PR group (63.9% [214/335]). Tolerability profiles were comparable for both groups. Results of this subgroup analysis indicate that patients with cancer pain could safely switch from prior treatment with the weak centrally acting analgesic tramadol directly to the strong centrally acting analgesic tapentadol PR, for an improved analgesic therapy for severe pain. WHAT DOES THIS STUDY ADD?: Results of this post hoc analysis show that patients who had received prior tramadol therapy could switch directly to tapentadol PR, with the majority (˜70%) experiencing improved efficacy. © 2016 The Authors. European Journal of Pain published by John Wiley & Sons Ltd on behalf of European Pain Federation - EFIC®.

Preventing the development of chronic pain after orthopaedic surgery with preventive multimodal analgesic techniques.

PubMed

Reuben, Scott S; Buvanendran, Asokumar

2007-06-01

The prevalences of complex regional pain syndrome, phantom limb pain, chronic donor-site pain, and persistent pain following total joint arthroplasty are alarmingly high. Central nervous system plasticity that occurs in response to tissue injury may contribute to the development of persistent postoperative pain. Many researchers have focused on methods to prevent central neuroplastic changes from occurring through the utilization of preemptive or preventive multimodal analgesic techniques. Multimodal analgesia allows a reduction in the doses of individual drugs for postoperative pain and thus a lower prevalence of opioid-related adverse events. The rationale for this strategy is the achievement of sufficient analgesia due to the additive effects of, or the synergistic effects between, different analgesics. Effective multimodal analgesic techniques include the use of nonsteroidal anti-inflammatory drugs, local anesthetics, alpha-2 agonists, ketamine, alpha(2)-delta ligands, and opioids.

The role of the central nervous system in the generation and maintenance of chronic pain in rheumatoid arthritis, osteoarthritis and fibromyalgia

PubMed Central

2011-01-01

Pain is a key component of most rheumatologic diseases. In fibromyalgia, the importance of central nervous system pain mechanisms (for example, loss of descending analgesic activity and central sensitization) is well documented. A few studies have also noted alterations in central pain processing in osteoarthritis, and some data, including the observation of widespread pain sensitivity, suggest that central pain-processing defects may alter the pain response in rheumatoid arthritis patients. When central pain is identified, different classes of analgesics (for example, serotonin-norepinephrine reuptake inhibitors, α2δ ligands) may be more effective than drugs that treat peripheral or nociceptive pain (for example, nonsteroidal anti-inflammatory drugs and opioids). PMID:21542893

Ketamine: A Review of Clinical Pharmacokinetics and Pharmacodynamics in Anesthesia and Pain Therapy.

PubMed

Peltoniemi, Marko A; Hagelberg, Nora M; Olkkola, Klaus T; Saari, Teijo I

2016-09-01

Ketamine is a phencyclidine derivative, which functions primarily as an antagonist of the N-methyl-D-aspartate receptor. It has no affinity for gamma-aminobutyric acid receptors in the central nervous system. Ketamine shows a chiral structure consisting of two optical isomers. It undergoes oxidative metabolism, mainly to norketamine by cytochrome P450 (CYP) 3A and CYP2B6 enzymes. The use of S-ketamine is increasing worldwide, since the S(+)-enantiomer has been postulated to be a four times more potent anesthetic and analgesic than the R(-)-enantiomer and approximately two times more effective than the racemic mixture of ketamine. Because of extensive first-pass metabolism, oral bioavailability is poor and ketamine is vulnerable to pharmacokinetic drug interactions. Sublingual and nasal formulations of ketamine are being developed, and especially nasal administration produces rapid maximum plasma ketamine concentrations with relatively high bioavailability. Ketamine produces hemodynamically stable anesthesia via central sympathetic stimulation without affecting respiratory function. Animal studies have shown that ketamine has neuroprotective properties, and there is no evidence of elevated intracranial pressure after ketamine dosing in humans. Low-dose perioperative ketamine may reduce opioid consumption and chronic postsurgical pain after specific surgical procedures. However, long-term analgesic effects of ketamine in chronic pain patients have not been demonstrated. Besides analgesic properties, ketamine has rapid-acting antidepressant effects, which may be useful in treating therapy-resistant depressive patients. Well-known psychotomimetic and cognitive adverse effects restrict the clinical usefulness of ketamine, even though fewer psychomimetic adverse effects have been reported with S-ketamine in comparison with the racemate. Safety issues in long-term use are yet to be resolved.

Disambiguating Pharmacodynamic Efficacy from Behavior with Neuroimaging: Implications for Analgesic Drug Development.

PubMed

Wanigasekera, Vishvarani; Mezue, Melvin; Andersson, Jesper; Kong, Yazhuo; Tracey, Irene

2016-01-01

Attrition rates of new analgesics during drug development are high; poor assay sensitivity with reliance on subjective outcome measures being a crucial factor. The authors assessed the utility of functional magnetic resonance imaging with capsaicin-induced central sensitization, a mechanism relevant in neuropathic pain, for obtaining mechanism-based objective outcome measures that can differentiate an effective analgesic (gabapentin) from an ineffective analgesic (ibuprofen) and both from placebo. The authors used a double-blind, randomized phase I study design (N = 24) with single oral doses. Only gabapentin suppressed the secondary mechanical hyperalgesia-evoked neural response in a region of the brainstem's descending pain modulatory system (right nucleus cuneiformis) and left (contralateral) posterior insular cortex and secondary somatosensory cortex. Similarly, only gabapentin suppressed the resting-state functional connectivity during central sensitization between the thalamus and secondary somatosensory cortex, which was plasma gabapentin level dependent. A power analysis showed that with 12 data sets, when using neural activity from the left posterior insula and right nucleus cuneiformis, a statistically significant difference between placebo and gabapentin was detected with probability ≥ 0.8. When using subjective pain ratings, this reduced to less than or equal to 0.6. Functional imaging with central sensitization can be used as a sensitive mechanism-based assay to guide go/no-go decisions on selecting analgesics effective in neuropathic pain in early human drug development. We also show analgesic modulation of neural activity by using resting-state functional connectivity, a less challenging paradigm that is ideally suited for patient studies because it requires no task or pain provocation.

Study of analgesic effect of earthworm extract

PubMed Central

Luo, Wei; Deng, Zhen-han; Li, Rui; Cheng, Guo; Kotian, Ronak Naveenchandra

2017-01-01

Pain represents a major clinical problem and one which has exercised generations of healthcare professionals. Earthworms are used as a traditional Chinese medicine, and have been applied pharmacologically and clinically since a long time in China. However, the analgesic effects of earthworm extract (EE) are seldom studied. Hence, we evaluated the analgesic effects of EE in mice. The obtained data showed that EE increased pain threshold and exhibited peripheral but not central analgesic effects in mice; evidenced by increased inhibition ratio in acetic acid writhing test and formalin test, whereas only slight increase in inhibition ratio in hot plate test and tail immersion test. In addition, EE decreased serum norepinephrine (NE), 5-hydroxytryptamine (5-HT), and nitric oxide (NO) synthase (NOS) concentration, similar to other analgesic drugs like morphine and aspirin. In a nutshell, the obtained data have demonstrated that EE has peripheral analgesic properties and could be used as a promising analgesic drug. PMID:29273677

Tolerance develops to the antiallodynic effects of the peripherally acting opioid loperamide hydrochloride in nerve-injured rats

PubMed Central

He, Shao-Qiu; Yang, Fei; Perez, Federico M.; Xu, Qian; Shechter, Ronen; Cheong, Yong-Kwan; Carteret, Alene F.; Dong, Xinzhong; Sweitzer, Sarah M.; Raja, Srinivasa N.; Guan, Yun

2013-01-01

Peripherally acting opioids are potentially attractive drugs for the clinical management of certain chronic pain states due to the lack of centrally mediated adverse effects. However, it remains unclear whether tolerance develops to peripheral opioid analgesic effects under neuropathic pain conditions. We subjected rats to L5 spinal nerve ligation (SNL) and examined the analgesic effects of repetitive systemic and local administration of loperamide hydrochloride, a peripherally acting opioid agonist. We found that the inhibition of mechanical hypersensitivity, an important manifestation of neuropathic pain, by systemic loperamide (1.5 mg/kg subcutaneously) decreased after repetitive drug treatment (tolerance-inducing dose: 0.75 to 6.0 mg/kg subcutaneously). Similarly, repeated intraplantar injection of loperamide (150 µg/50 µL intraplantarly) and D-Ala2-MePhe4-Glyol5 enkephalin (300 µg/50 µL), a highly selective mu-opioid receptor (MOR) agonist, also resulted in decreased inhibition of mechanical hypersensitivity. Pretreatment with naltrexone hydrochloride (5 mg/kg intraperitoneally) and MK-801 (0.2 mg/kg intraperitoneally) attenuated systemic loperamide tolerance. Western blot analysis showed that repetitive systemic administration of morphine (3 mg/kg subcutaneously), but not loperamide (3 mg/kg subcutaneously) or saline, significantly increased MOR phosphorylation in the spinal cord of SNL rats. In cultured rat dorsal root ganglion neurons, loperamide dose-dependently inhibited KCl-induced increases in [Ca2+]i. However, this drug effect significantly decreased in cells pretreated with loperamide (3 µM, 72 hours). Intriguingly, in loperamide-tolerant cells, the delta-opioid receptor antagonist naltrindole restored loperamide’s inhibition of KCl-elicited [Ca2+]i increase. Our findings indicate that animals with neuropathic pain may develop acute tolerance to the antiallodynic effects of peripherally acting opioids after repetitive systemic and local drug administration. PMID:23880055

Opioid tolerance and urine drug testing among initiates of extended-release or long-acting opioids in Food and Drug Administration's Sentinel System.

PubMed

Larochelle, Marc R; Cocoros, Noelle M; Popovic, Jennifer; Dee, Elizabeth C; Kornegay, Cynthia; Ju, Jing; Racoosin, Judith A

A risk evaluation and mitigation strategy for extended-release and long-acting (ER/LA) opioid analgesics was approved by the Food and Drug Administration in 2012. Our objective was to assess frequency of opioid tolerance and urine drug testing for individuals initiating ER/LA opioid analgesics. Retrospective cohort study. Sentinel, a distributed database with electronic healthcare data on >190 million predominantly commercially insured members. Members under age 65 initiating ER/LA opioid analgesics between January 2009 and December 2013. We examined the proportion of opioid-tolerant-only ER/LA opioid analgesic initiates meeting tolerance criteria: receipt of ≥30 mg oxycodone equivalents per day in 7 days prior to the first opioid-tolerant-only dispensing. We separately examined the proportion of new users of extended-release oxycodone (ERO) and other ER/LA opioid analgesics with a claim for a urine drug test in the 30 days prior to, and separately for the 183 days after, dispensing. We identified 79,824 ERO, 7,343 extended-release hydromorphone, and 91,778 transdermal fentanyl opi-oid-tolerant-only episodes. Tolerance criteria were met in 64 percent of ERO, 64 percent of extended-release hydromorphone and 40 percent of transdermal fentanyl episodes. We identified 210,581 incident ERO and 311,660 other ER/LA opioid analgesic episodes. Use of urine drug testing for ERO compared with other ER/LA opioid analgesics was: 4 percent vs 14 percent respectively in the 30 days prior to initiation and 9 percent vs 23 percent respectively in the 183 days following initiation. These results suggest potential areas for improving appropriate ER/LA opioid analgesic prescribing practices.

Analgesic, antibacterial and central nervous system depressant activities of Albizia procera leaves.

PubMed

Khatoon, Mst Mahfuza; Khatun, Mst Hajera; Islam, Md Ekramul; Parvin, Mst Shahnaj

2014-04-01

To ascertain analgesic, antibacterial and central nervous system (CNS) depressant activities of ethyl acetate, dichloromethane and carbon tetrachloride fractions of methanol extract of Albizia procera (A. procera) leaves. Leaves extracts of A. procera were tested for analgesic activity by acetic acid induced and formalin test method in mice. The in vitro antibacterial activity was performed by agar well diffusion method. CNS depressant activity was evaluated by hole cross and open field tests. All the extracts at 200 mg/kg exhibited significant (P<0.01) analgesic activity in acetic acid induced and formalin tests method in mice. Analgesic activity of the ethyl acetate fraction was almost same like as standard drug indomethacin in acetic acid induced method. The CNS depressant activity of the extracts at 500 mg/kg was comparable to the positive control diazepam as determined by hole cross and open field test method. The extracts exhibited moderate antimicrobial activity against all the tested microorganisms (Staphylococcus aureus, Bacillus cereus, Pseudomonas aeruginosa, Esherichia coli, Shigella soneii, Shigella boydii) at concentration of 0.8 mg/disc. The measured diameter of zone of inhibition for the extracts was within the range of 7 to 12 mm which was less than the standard kanamycin (16-24 mm). It is concluded that all the extracts possess potential analgesic and CNS depressants activity. This study also showed that different fractions of methanol extract could be potential sources of new antimicrobial agents.

Involvement of peripheral mechanism in the verapamil-induced potentiation of morphine analgesia in mice.

PubMed

Shimizu, Norifumi; Kishioka, Shiroh; Maeda, Takehiko; Fukazawa, Yohji; Dake, Yoshihiro; Yamamoto, Chizuko; Ozaki, Masanobu; Yamamoto, Hiroyuki

2004-08-01

Morphine's analgesic actions are thought to be mediated through both the central and peripheral nervous systems. L-type calcium channel blockers have been reported to potentiate the analgesic effects of morphine, but the locus of this interaction is not known. In this experiment, we examined the site of verapamil-induced potentiation of morphine analgesia in mice using the quaternary opioid receptor antagonist naloxone-methiodide (NLX-M). Subcutaneous injections of morphine increased locomotor activity and serum corticosterone level, which are mediated by the central nervous system. These central effects were not antagonized by 0.1 mg/kg of NLX-M, whereas this dose of NLX-M partially antagonized the analgesic effect of morphine. Treatment with verapamil potentiated morphine analgesia in a dose-dependent manner. The verapamil-induced potentiation of morphine analgesia was abolished by pretreatment with NLX-M (0.1 and 1 mg/kg). These findings suggest that peripheral mechanisms partially contribute to morphine analgesia and mediate the potentiation of morphine analgesia by verapamil.

Pharmacologic management of non-cancer pain among nursing home residents.

PubMed

Lapane, Kate L; Quilliam, Brian J; Chow, Wing; Kim, Myoung S

2013-01-01

Pain is common in nursing home settings. To describe scheduled analgesic use among nursing home (NH) residents experiencing non-cancer pain and evaluate factors associated with scheduled analgesic use. We identified 2508 residents living in one of 185 NHs predominantly from one for-profit chain, with pain recorded on two consecutive Minimum Data Set assessments. Pharmacy transaction files provided detailed medication information. Logistic regression models adjusted for clustering of residents in NHs identified factors related to scheduled prescription analgesics. Twenty-three percent had no scheduled analgesics prescribed. Those with scheduled analgesics were more likely to have excruciating pain (5.5% vs. 1.2%) and moderate pain documented (64.7% vs. 47.5%) than residents without scheduled analgesics. Hydrocodone (41.7%), short-acting oxycodone (16.6%), and long-acting fentanyl (9.4%) were common, and 13.8% reported any nonsteroidal anti-inflammatory agent use. Factors associated with decreased odds of scheduled analgesics included severe cognitive impairment (adjusted odds ratio [AOR] 0.56; 95% confidence interval [CI] 0.36 to 0.88), age more than 85 years (AOR 0.57; 95% CI 0.41 to 0.80), and Parkinson's disease (AOR 0.55; 95% CI 0.30 to 0.99). Factors associated with increased odds of scheduled analgesic use included history of fracture (AOR 1.79; 95% CI 1.16 to 2.76), diabetes (AOR 1.30; 95% CI 1.02 to 1.66), and higher Minimum Data Set mood scores (AOR 1.11; 95% CI 1.04 to 1.19). Some improvements in pharmacologic management of pain in NHs have been realized. Yet, presence of pain without scheduled analgesics prescribed was still common. Evidence-based procedures to assure adherence to clinical practice guidelines for pain management in this setting are warranted. Copyright © 2013 U.S. Cancer Pain Relief Committee. Published by Elsevier Inc. All rights reserved.

Access to Strong Opioid Analgesics in the Context of Legal and Regulatory Barriers in Eleven Central and Eastern European Countries.

PubMed

Vranken, Marjolein J M; Mantel-Teeuwisse, Aukje K; Schutjens, Marie-Hélène D B; Scholten, Willem K; Jünger, Saskia; Medic, Dr Rer; Leufkens, Hubert G M

2018-04-06

In 2011-2013, >95% of the global opioid analgesics consumption occurred in three regions, accounting for 15% of the world population. Despite abundant literature on barriers to access, little is known on the correlation between actual access to opioid analgesics and barriers to access, including legal and regulatory barriers. This study aimed to evaluate the correlation between access to strong opioid analgesics and barriers to access in national legislation and regulations in 11 central and eastern European countries that participated in the Access to Opioid Medication in Europe (ATOME) project. Two variables were contrasted to assess their correlation: the country level of access to strong opioid analgesics indicated by the Adequacy of Consumption Measure (ACM) and the number of potential legal and regulatory barriers identified by an external review of legislation and regulations. A linear correlation was evaluated using a squared linear correlation coefficient. Evaluation of the correlation between the ACM and the number of potential barriers produces an R 2 value of 0.023 and a correlation plot trend line gradient of -0.075, indicating no correlation between access to strong opioid analgesics and the number of potential barriers in national legislation and regulations in the countries studied. No correlation was found, which indicates that other factors besides potential legal and regulatory barriers play a critical role in withholding prescribers and patients essential pain medication in the studied countries. More research is needed toward better understanding of the complex interplay of factors that determine access to strong opioid analgesics.

Effects of intravenous propranolol on heat pain sensitivity in healthy men.

PubMed

Schweinhardt, P; Abulhasan, Y B; Koeva, V; Balderi, T; Kim, D J; Alhujairi, M; Carli, F

2013-05-01

Clinical studies have shown opioid-sparing effects of β-adrenergic antagonists perioperatively and β-blockers are being investigated for chronic musculoskeletal pain. However, the direct analgesic effects of β-blockers have rarely been examined in healthy humans. In a randomized, counter-balanced, double-blind, within-subject crossover design, we tested the effect of the lipophilic β-blocker propranolol (0.035 mg/kg body weight i.v.) on heat pain sensitivity in 39 healthy males, compared with placebo. To test for peripheral versus central effects, the peripherally acting β-blocker sotalol was also examined. Experimental stimuli were brief superficial noxious heat stimuli applied to the volar forearm. Non-painful cold stimuli were included to test for specificity. Sedation, mood and anxiety were assessed to investigate potential mechanisms underlying any analgesic effect. β-blocker effects on blood pressure were incorporated into the analysis because of a known inverse relationship between pain sensitivity and systolic blood pressure. Propranolol significantly decreased perceived intensity of heat pain stimuli but only in participants with small propranolol-induced blood pressure decreases. Even in this group, the effect was small (4%). Propranolol did not influence perceived intensity of non-noxious stimuli and had no effect on sedation, anxiety or mood. Sotalol did not influence heat pain sensitivity. Propranolol decreased pain sensitivity but its analgesic effects were small and counteracted by blood pressure decreases. The analgesic effects were not mediated by peripheral β-receptor blockade, sedation, mood or anxiety. The small effect indicates that the utility of β-blockers for clinical pain must be related to factors that do not play a significant role for experimental pain. © 2012 European Federation of International Association for the Study of Pain Chapters.

Synthesis and evaluation of aryl-naloxamide opiate analgesics targeting truncated exon 11-associated μ opioid receptor (MOR-1) splice variants.

PubMed

Majumdar, Susruta; Subrath, Joan; Le Rouzic, Valerie; Polikar, Lisa; Burgman, Maxim; Nagakura, Kuni; Ocampo, Julie; Haselton, Nathan; Pasternak, Anna R; Grinnell, Steven; Pan, Ying-Xian; Pasternak, Gavril W

2012-07-26

3-Iodobenzoylnaltrexamide 1 (IBNtxA) is a potent analgesic acting through a novel receptor target that lack many side-effects of traditional opiates composed, in part, of exon 11-associated truncated six transmembrane domain MOR-1 (6TM/E11) splice variants. To better understand the SAR of this drug target, a number of 4,5-epoxymorphinan analogues were synthesized. Results show the importance of a free 3-phenolic group, a phenyl ring at the 6 position, an iodine at the 3'or 4' position of the phenyl ring, and an N-allyl or c-propylmethyl group to maintain high 6TM/E11 affinity and activity. 3-Iodobenzoylnaloxamide 15 (IBNalA) with a N-allyl group displayed lower δ opioid receptor affinity than its naltrexamine analogue, was 10-fold more potent an analgesic than morphine, elicited no respiratory depression or physical dependence, and only limited inhibition of gastrointestinal transit. Thus, the aryl-naloxamide scaffold can generate a potent analgesic acting through the 6TM/E11 sites with advantageous side-effect profile and greater selectivity.

Designing Safer Analgesics via μ-Opioid Receptor Pathways.

PubMed

Chan, H C Stephen; McCarthy, Dillon; Li, Jianing; Palczewski, Krzysztof; Yuan, Shuguang

2017-11-01

Pain is both a major clinical and economic problem, affecting more people than diabetes, heart disease, and cancer combined. While a variety of prescribed or over-the-counter (OTC) medications are available for pain management, opioid medications, especially those acting on the μ-opioid receptor (μOR) and related pathways, have proven to be the most effective, despite some serious side effects including respiration depression, pruritus, dependence, and constipation. It is therefore imperative that both academia and industry develop novel μOR analgesics which retain their opioid analgesic properties but with fewer or no adverse effects. In this review we outline recent progress towards the discovery of safer opioid analgesics. Copyright © 2017 Elsevier Ltd. All rights reserved.

Designing Safer Analgesics via μ-Opioid Receptor Pathways

PubMed Central

Chan, H.C. Stephen; McCarthy, Dillon; Li, Jianing; Palczewski, Krzysztof; Yuan, Shuguang

2017-01-01

Pain is both a major clinical and economic problem, affecting more people than diabetes, heart disease, and cancer combined. While a variety of prescribed or over-the-counter (OTC) medications are available for pain management, opioid medications, especially those acting on the μ-opioid receptor (μOR) and related pathways, have proven to be the most effective, despite some serious side effects including respiration depression, pruritus, dependence, and constipation. It is therefore imperative that both academia and industry develop novel μOR analgesics which retain their opioid analgesic properties but with fewer or no adverse effects. In this review we outline recent progress towards the discovery of safer opioid analgesics. PMID:28935293

Analgesic, antibacterial and central nervous system depressant activities of Albizia procera leaves

PubMed Central

Khatoon, Mst. Mahfuza; Khatun, Mst. Hajera; Islam, Md. Ekramul; Parvin, Mst. Shahnaj

2014-01-01

Objective To ascertain analgesic, antibacterial and central nervous system (CNS) depressant activities of ethyl acetate, dichloromethane and carbon tetrachloride fractions of methanol extract of Albizia procera (A. procera) leaves. Methods Leaves extracts of A. procera were tested for analgesic activity by acetic acid induced and formalin test method in mice. The in vitro antibacterial activity was performed by agar well diffusion method. CNS depressant activity was evaluated by hole cross and open field tests. Results All the extracts at 200 mg/kg exhibited significant (P<0.01) analgesic activity in acetic acid induced and formalin tests method in mice. Analgesic activity of the ethyl acetate fraction was almost same like as standard drug indomethacin in acetic acid induced method. The CNS depressant activity of the extracts at 500 mg/kg was comparable to the positive control diazepam as determined by hole cross and open field test method. The extracts exhibited moderate antimicrobial activity against all the tested microorganisms (Staphylococcus aureus, Bacillus cereus, Pseudomonas aeruginosa, Esherichia coli, Shigella soneii, Shigella boydii) at concentration of 0.8 mg/disc. The measured diameter of zone of inhibition for the extracts was within the range of 7 to 12 mm which was less than the standard kanamycin (16-24 mm). Conclusions It is concluded that all the extracts possess potential analgesic and CNS depressants activity. This study also showed that different fractions of methanol extract could be potential sources of new antimicrobial agents. PMID:25182551

Differences in prescription opioid analgesic availability: comparing minority and white pharmacies across Michigan.

PubMed

Green, Carmen R; Ndao-Brumblay, S Khady; West, Brady; Washington, Tamika

2005-10-01

Little is known about physical barriers to adequate pain treatment for minorities. This investigation explored sociodemographic determinants of pain medication availability in Michigan pharmacies. A cross-sectional survey-based study with census data and data provided by Michigan community retail pharmacists was designed. Sufficient opioid analgesic supplies was defined as stocking at least one long-acting, short-acting, and combination opioid analgesic. Pharmacies located in minority (or=70% white residents) zip code areas were randomly selected by using a 2-stage sampling selection process (response rate, 80%). For the 190 pharmacies surveyed, most were located in white areas (51.6%) and had sufficient supplies (84.1%). After accounting for zip code median age and stratifying by income, pharmacies in white areas (odds ratio, 13.36 high income vs 54.42 low income) and noncorporate pharmacies (odds ratio, 24.92 high income vs 3.61 low income) were more likely to have sufficient opioid analgesic supplies (P < .005). Racial differences in the odds of having a sufficient supply were significantly higher in low income areas when compared with high income areas. Having a pharmacy located near a hospital did not change the availability for opioid analgesics. Persons living in predominantly minority areas experienced significant barriers to accessing pain medication, with greater disparities in low income areas regardless of ethnic composition. Differences were also found on the basis of pharmacy type, suggesting variability in pharmacist's decision making. Michigan pharmacies in minority zip codes were 52 times less likely to carry sufficient opioid analgesics than pharmacies in white zip codes regardless of income. Lower income areas and corporate pharmacies were less likely to carry sufficient opioid analgesics. This study illustrates barriers to pain care and has public health implications.

Adherence to Analgesics for Cancer Pain: A Comparative Study of African Americans and Whites Using an Electronic Monitoring Device.

PubMed

Meghani, Salimah H; Thompson, Aleda M L; Chittams, Jesse; Bruner, Deborah W; Riegel, Barbara

2015-09-01

Despite well-documented disparities in cancer pain outcomes among African Americans, surprisingly little research exists on adherence to analgesia for cancer pain in this group. We compared analgesic adherence for cancer-related pain over a 3-month period between African Americans and whites using the Medication Event Monitoring System (MEMS). Patients (N = 207) were recruited from outpatient medical oncology clinics of an academic medical center in Philadelphia (≥18 years of age, diagnosed with solid tumors or multiple myeloma, with cancer-related pain, and at least 1 prescription of oral around-the-clock analgesic). African Americans reported significantly greater cancer pain (P < .001), were less likely than whites to have a prescription of long-acting opioids (P < .001), and were more likely to have a negative Pain Management Index (P < .001). There were considerable differences between African Americans and whites in the overall MEMS dose adherence, ie, percentage of the total number of prescribed doses that were taken (53% vs 74%, P < .001). On subanalysis, analgesic adherence rates for African Americans ranged from 34% (for weak opioids) to 63% (for long-acting opioids). Unique predictors of analgesic adherence varied by race; income levels, analgesic side effects, and fear of distracting providers predicted analgesic adherence for African Americans but not for whites. Perspective: Despite evidence of disparities in cancer pain outcomes among African Americans, surprisingly little research exists on African Americans' adherence to analgesia for cancer pain. This prospective study uses objective measures to compare adherence to prescribed pain medications between African American and white patients with cancer pain. Copyright © 2015 American Pain Society. Published by Elsevier Inc. All rights reserved.

Opening of brain blood barrier induced by red light and central analgesic improvement of cobra neurotoxin.

PubMed

Ye, Yong; Li, Yue; Fang, Fei

2014-05-05

Cobra neurotoxin (NT) has central analgesic effects, but it is difficult to pass through brain blood barrier (BBB). A novel method of red light induction is designed to help NT across BBB, which is based on photosensitizer activation by red light to generate reactive oxygen species (ROS) to open BBB. The effects were evaluated on cell models and animals in vivo with illumination by semiconductor laser at 670nm on photosensitizer pheophorbide isolated from silkworm excrement. Brain microvascular endothelial cells and astrocytes were co-cultured to build up BBB cell model. The radioactivity of (125)I-NT was measured in cells and tissues for NT permeation. Three ways of cranial irradiation, nasal cavity and intravascular irradiation were tested with combined injection of (125)I-NT 20μg/kg and pheophorbide 100μg/kg to rats, and organs of rats were separated and determined the radioactivity. Paw pressure test in rats, hot plate and writhing test in mice were applied to appraise the analgesic effects. NT across BBB cell model increased with time of illumination, and reached stable level after 60min. So did ROS in cells. NT mainly distributed in liver and kidney of rats, significantly increased in brain after illumination, and improved analgesic effects. Excitation of pheophorbide at red light produces ROS to open BBB, help NT enter brain, and enhance its central action. This research provides a new method for drug across BBB to improve its central role. Copyright © 2014 Elsevier B.V. All rights reserved.

Characterisation of tramadol, morphine and tapentadol in an acute pain model in Beagle dogs.

PubMed

Kögel, Babette; Terlinden, Rolf; Schneider, Johannes

2014-05-01

To evaluate the analgesic potential of the centrally acting analgesics tramadol, morphine and the novel analgesic tapentadol in a pre-clinical research model of acute nociceptive pain, the tail-flick model in dogs. Prospective part-randomized pre-clinical research trial. Fifteen male Beagle dogs (HsdCpb:DOBE), aged 12-15 months. On different occasions separated by at least 1 week, dogs received intravenous (IV) administrations of tramadol (6.81, 10.0 mg kg(-1) ), tapentadol (2.15, 4.64, 6.81 mg kg(-1) ) or morphine (0.464, 0.681, 1.0 mg kg(-1) ) with subsequent measurement of tail withdrawal latencies from a thermal stimulus (for each treatment n = 5). Blood samples were collected immediately after the pharmacodynamic measurements of tramadol to determine pharmacokinetics and the active metabolite O-demethyltramadol (M1). Tapentadol and morphine induced dose-dependent antinociception with ED50-values of 4.3 mg kg(-1) and 0.71 mg kg(-1) , respectively. In contrast, tramadol did not induce antinociception at any dose tested. Measurements of the serum levels of tramadol and the M1 metabolite revealed only marginal amounts of the M1 metabolite, which explains the absence of the antinociceptive effect of tramadol in this experimental pain model in dogs. Different breeds of dogs might not or only poorly respond to treatment with tramadol due to low metabolism of the drug. Tapentadol and morphine which act directly on μ-opioid receptors without the need for metabolic activation are demonstrated to induce potent antinociception in the experimental model used and should also provide a reliable pain management in the clinical situation. The non-opioid mechanisms of tramadol do not provide antinociception in this experimental setting. This contrasts to many clinical situations described in the literature, where tramadol appears to provide useful analgesia in dogs for post-operative pain relief and in more chronically pain states. © 2014 Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesia and Analgesia.

Evidence-based recommendations for analgesic efficacy to treat pain of endodontic origin: A systematic review of randomized controlled trials.

PubMed

Aminoshariae, Anita; Kulild, James C; Donaldson, Mark; Hersh, Elliot V

2016-10-01

The purpose of this investigation was to identify evidence-based clinical trials to aid dental clinicians in establishing the efficacy for recommending or prescribing analgesics for pain of endodontic origin. The authors prepared and registered a protocol on PROSPERO and conducted electronic searches in MEDLINE, Scopus, the Cochrane Library, and ClinicalTrials.gov. In addition, the authors manually searched the bibliographies of all relevant articles, the gray literature, and textbooks for randomized controlled trials. Two authors selected the relevant articles independently. There were no disagreements between the authors. The authors analyzed 27 randomized, placebo-controlled trials. The authors divided the studies into 2 groups: preoperative and postoperative analgesic treatments. There was moderate evidence to support the use of steroids for patients with symptomatic irreversible pulpitis. Also, there was moderate evidence to support nonsteroidal anti-inflammatory drugs (NSAIDs) preoperatively or postoperatively to control pain of endodontic origin. When NSAIDs were not effective, a combination of NSAIDs with acetaminophen, tramadol, or an opioid appeared beneficial. NSAIDs should be considered as the drugs of choice to alleviate or minimize pain of endodontic origin if there are no contraindications for the patient to ingest an NSAID. In situations in which NSAIDs alone are not effective, the combination of an NSAID with acetaminophen or a centrally acting drug is recommended. Steroids appear effective in irreversible pulpitis. Copyright © 2016 American Dental Association. Published by Elsevier Inc. All rights reserved.

Minocycline encapsulated chitosan nanoparticles for central antinociceptive activity.

PubMed

Nagpal, Kalpana; Singh, S K; Mishra, D N

2015-01-01

The purpose of the study is to explore the central anti-nociceptive activity of brain targeted nanoparticles (NP) of minocycline hydrochloride (MH). The NP were formulated using the modified ionotropic gelation method (MHNP) and were coated with Tween 80 (T80) to target them to brain (cMHNP). The formulated nanoparticles have already been characterized for particle size, zeta potential, drug entrapment efficiency and in vitro drug release. The nanoparticles were then evaluated for pharmacodynamic activity using thermal methods. The pure drug and the formulation, MHNP were not able to show a statistically significant central analgesic activity. cMHNP on the other hand evidenced a significant central analgesic activity. Animal models evidenced that brain targeted nanoparticles may be utilized for effective delivery of central anti-nociceptive effect of MH. Further clinical studies are required to explore the activity for mankind. Copyright © 2014 Elsevier B.V. All rights reserved.

Analgesic and Antineuropathic Drugs Acting Through Central Cholinergic Mechanisms

PubMed Central

Bartolini, Alessandro; Cesare Mannelli, Lorenzo Di; Ghelardini, Carla

2011-01-01

The role of muscarinic and nicotinic cholinergic receptors in analgesia and neuropathic pain relief is relatively unknown. This review describes how such drugs induce analgesia or alleviate neuropathic pain by acting on the central cholinergic system. Several pharmacological strategies are discussed which increase synthesis and release of acetylcholine (ACh) from cholinergic neurons. The effects of their acute and chronic administration are described. The pharmacological strategies which facilitate the physiological functions of the cholinergic system without altering the normal modulation of cholinergic signals are highlighted. It is proposed that full agonists of muscarinic or nicotinic receptors should be avoided. Their activation is too intense and un-physiological because neuronal signals are distorted when these receptors are constantly activated. Good results can be achieved by using agents that are able to a) increase ACh synthesis, b) partially inhibit cholinesterase activity c) selectively block the autoreceptor or heteroreceptor feedback mechanisms. Activation of M1 subtype muscarinic receptors induces analgesia. Chronic stimulation of nicotinic (N1) receptors has neuronal protective effects. Recent experimental results indicate a relationship between repeated cholinergic stimulation and neurotrophic activation of the glial derived neurotrophic factor (GDNF) family. At least 9 patents covering novel chemicals for cholinergic system modulation and pain control are discussed. PMID:21585331

Effects of tiletamine on the adenosine monophosphate-activated protein kinase signaling pathway in the rat central nervous system.

PubMed

Su, Li-Xue; Shi, Xing-Xing; Yang, Peng; Chen, Hao; Li, Xin; Fan, Hong-Gang; Wang, Hong-Bin

2017-10-01

The dissociative anesthetic tiletamine, which acts on the central nervous system (CNS), is widely used in veterinary medicine and animal experiments. Recent studies indicate that adenosine 5'-monophosphate activated protein kinase (AMPK) plays a key role in the analgesic action of tiletamine. In the present study, the effects of tiletamine on the AMPK signaling pathway in rats were investigated. Sprague-Dawley rats were injected intraperitoneally with tiletamine and executed at 10, 20, 40 and 60min post injection. The cerebral cortex, hippocampus, thalamus, cerebellum and brainstem were immediately taken out to evaluate the mRNA and protein phosphorylation levels of liver kinase B1 (LKB1), AMPKα and eIF4E-binding protein 1 (4EBP1) using quantitative real-time polymerase chain reaction and western blot analysis. Tiletamine increased AMPK mRNA expression in the rat brain (P<0.01). Increased mRNA expression of AMPK was accompanied by an increase in phosphorylation of LKB1, resulting in significant decreases in the phosphorylation levels of 4EBP1 in the corresponding brain regions (P<0.01). In summary, the findings indicate that tiletamine regulates the mRNA expression and protein phosphorylation levels of LKB1, AMPK and 4EBP1 in the CNS, suggesting that the analgesic effect of the anesthetic is mediated, at least in part, by the AMPK signaling pathway. Copyright © 2017 Elsevier Ltd. All rights reserved.

Synthesis and evaluation of aryl-naloxamide opiate analgesics targeting truncated exon 11-associated mu opioid receptor (MOR-1) splice variants

PubMed Central

Majumdar, Susruta; Subrath, Joan; Le Rouzic, Valerie; Polikar, Lisa; Burgman, Maxim; Nagakura, Kuni; Ocampo, Julie; Haselton, Nathan; Pasternak, Anna R.; Grinnell, Steven; Pan, Ying-Xian; Pasternak, Gavril W.

2012-01-01

3-Iodobenzoylnaltrexamide 1 (IBNtxA) is a potent analgesic acting through a novel receptor target that lack many side-effects of traditional opiates composed, in part, of exon 11-associated truncated six transmembrane domain MOR-1 (6TM/E11) splice variants. To better understand the SAR of this drug target, a number of 4,5-epoxymorphinan analogs were synthesized. Results show the importance of a free 3-phenolic group, a phenyl ring at the 6 position, an iodine at the 3′ or 4′ position of the phenyl ring and an N-allyl or c-propylmethyl group to maintain high 6TM/E11 affinity and activity. 3-Iodobenzoylnaloxamide 15 (IBNalA) with a N-allyl group displayed lower delta opioid receptor affinity than its naltrexamine analog, was 10-fold more potent an analgesic than morphine, elicited no respiratory depression or physical dependence and only limited inhibition of gastrointestinal transit. Thus, the aryl-naloxamide scaffold can generate a potent analgesic acting through the 6TM/E11 sites with advantageous side-effect profile and greater selectivity. PMID:22734622

Cancer Pain Management Education Rectifies Patients' Misconceptions of Cancer Pain, Reduces Pain, and Improves Quality of Life.

PubMed

Koh, Su-Jin; Keam, Bhumsuk; Hyun, Min Kyung; Ju Seo, Jeong; Uk Park, Keon; Oh, Sung Yong; Ahn, Jinseok; Lee, Ja Youn; Kim, JinShil

2018-03-26

More than half of the patients have reported improper management of breakthrough cancer pain. Empirical evidence is lacking concerning the effectiveness of cancer pain education on breakthrough pain control. This study aimed to examine the effects of individual pain education on pain control, use of short-acting analgesics for breakthrough pain, quality of life outcomes, and rectification of patients' misconceptions regarding cancer pain. A quasi-experimental design was used. In total, 176 (102 inpatients and 74 outpatients) and 163 (93 inpatients and 70 outpatients) cancer patients completed questionnaires on pain intensity, quality of life, use of short-acting medication for breakthrough pain, and misconceptions about cancer pain and opioid use before and immediately and/or seven days after individual pain education. The mean age of the participants was 60.9 years (±11.2), and 56.3% were male. The most common cancers were lung cancer (17.0%), colon cancer (15.9%), and breast cancer (12.5%). The subjects' reasons for attrition were conditional deterioration, death, or voluntary withdrawal (N = 13, 7.4%). Following the education, there was a significant reduction in overall pain intensity over 24 hours (P < 0.001). The outpatients showed more use of short-acting analgesics for breakthrough pain. Sleep quality change was most significantly associated with intervention; other quality of life aspects (e.g., general feelings and life enjoyment) also improved. Pain education also significantly reduced misconceptions regarding cancer pain management. The present educational intervention was effective in encouraging short-acting analgesic use for breakthrough pain, improving quality of life outcomes, and rectifying patients' misconceptions about analgesic use.

[Use of alpha-lipoic acid and omega-3 in postpartum pain treatment].

PubMed

Costantino, D; Guaraldi, C; Costantino, M; Bounous, V E

2015-10-01

Postpartum pain is a frequent condition that negatively affects women's quality of life, interferring with everyday life. Analgesic drugs and surgery are often contraindicated in pregnancy and during breast feeding. This review of the literature aims to evaluate the rational of the association of lipoic acid and omega-3 employ in the management of postpartum pain. Lipoic acid is a cofactor essential in mitochondrial metabolism with antioxidant and anti-inflammatory activity. Lipoic acid has been shown to be effective in neuropatic pain treatment in patients with sciatica, carpal tunnel syndrome and diabetic neuropathy. Omega-3 are known for their anti-inflammatory and neurotrophic activity. The peripheral and central activity of both substances allows to act on neuroinflammation mechanisms thus reducing cronicization of pain and also determining a potential improvement of women's emotional status. The preliminary data here presented confirm the positive effect of this association on the treatment of postpartum perineal pain. The supplementation of lipoic acid in association with omega-3 seems effective and safe for the treatment of chronic postpartum pain, allowing a pathogenetic approach to neuroinflammation, thus reducing the consumption of analgesic drugs, often contraindicated during breast-feeding.

Identification and Functional Characterization of a Stable, Centrally Active Derivative of the Neurotensin (8–13) Fragment as a Potential First-in-Class Analgesic

PubMed Central

Hughes, Francis M.; Shaner, Brooke E.; May, Lisa A.; Zotian, Lyndsay; Brower, Justin O.; Woods, R. Jeremy; Cash, Michael; Morrow, Dustin; Massa, Fabienne; Mazella, Jean; Dix, Thomas A.

2010-01-01

The neurotensin hexapapetide fragment NT(8–13) is a potent analgesic when administered directly to the central nervous system, but does not cross the blood brain barrier. A total of 43 novel derivatives of NT(8–13) were evaluated with one, ABS212 (1), being most active in four rat models of pain when administered peripherally. Compound 1 binds to human neurotensin receptors 1 and 2 with IC50s of 10.6 and 54.2 nM, respectively and tolerance to the compound in a rat pain model did not develop after 12 days of daily administration. When administered peripherally, serum levels and neurotensin receptor binding potency of 1 peaked within 5 min and returned to baseline within 90–120 min, however analgesic activity remained near maximum for >240 min. This could be due to its metabolism into an active fragment; however, all 4- and 5-mer hydrolysis products were inactive. This pharmacokinetic/pharmacodynamic dichotomy is discussed. Compound 1 is a candidate for development as a first-in-class analgesic. PMID:20481538

The Effects of Psychotropic Drugs.

ERIC Educational Resources Information Center

Bonnardeaux, Jef-Louis

1984-01-01

Presents information on psychotropic drugs for individuals who are not specialists in pharmacology. Discusses: alcohol and barbituates; dependence and withdrawal; central nervous system depressors (anaesthetics, narcotic analgesics, sedatives and hypnotic drugs, tranquilizers), central nervous stimulants (amphetamines, cocaine, tobacco, caffeine),…

Exploring the Neuroimmunopharmacology of Opioids: An Integrative Review of Mechanisms of Central Immune Signaling and Their Implications for Opioid Analgesia

PubMed Central

Shavit, Yehuda; Grace, Peter M.; Rice, Kenner C.; Maier, Steven F.; Watkins, Linda R.

2011-01-01

Vastly stimulated by the discovery of opioid receptors in the early 1970s, preclinical and clinical research was directed at the study of stereoselective neuronal actions of opioids, especially those played in their crucial analgesic role. However, during the past decade, a new appreciation of the non-neuronal actions of opioids has emerged from preclinical research, with specific appreciation for the nonclassic and nonstereoselective sites of action. Opioid activity at Toll-like receptors, newly recognized innate immune pattern recognition receptors, adds substantially to this unfolding story. It is now apparent from molecular and rodent data that these newly identified signaling events significantly modify the pharmacodynamics of opioids by eliciting proinflammatory reactivity from glia, the immunocompetent cells of the central nervous system. These central immune signaling events, including the release of cytokines and chemokines and the associated disruption of glutamate homeostasis, cause elevated neuronal excitability, which subsequently decreases opioid analgesic efficacy and leads to heightened pain states. This review will examine the current preclinical literature of opioid-induced central immune signaling mediated by classic and nonclassic opioid receptors. A unification of the preclinical pharmacology, neuroscience, and immunology of opioids now provides new insights into common mechanisms of chronic pain, naive tolerance, analgesic tolerance, opioid-induced hyperalgesia, and allodynia. Novel pharmacological targets for future drug development are discussed in the hope that disease-modifying chronic pain treatments arising from the appreciation of opioid-induced central immune signaling may become practical. PMID:21752874

Comparison of the antinociceptive action of crude Fuzei, the root of Aconitum, and its processed products.

PubMed

Liou, Shorong-Shii; Liu, I-Min; Lai, Mei Chou; Cheng, Juei-Tang

2005-07-14

The antinociceptive effects of crude Fuzei, the root of Aconitum carmichaeli and of Fuzei processed by three different methods were determined in mice and rats using the light tail-flick assay. A dose-dependent and significant increase in pain threshold was found at 60 min post treatment, with doses of 20-60 mg/kg crude Fuzei. The analgesic effects of processed Fuzei (20-60 mg/kg) exhibited a dose-dependent inhibition of tail-flick, but the effects were lower than those produced by crude Fuzei in the same tests. The analgesic effect of Yan-Fuzei, the salt baking product, was the most potent of the processed products and was nearly that provided by crude Fuzei. Although the concentrations of aconitine were significantly lower in the processed Fuzei than in the crude Fuzei, a higher oral LD50 was found for all of the processed Fuzei formulations. Moreover, antinociception of crude Fuzei and its processed products was attenuated but not totally blocked by naloxone at doses sufficient to block opioid mu-receptors. Furthermore, the analgesic effect of crude Fuzei and its processed products was decreased in opioid mu-receptor knockout mice, but the effect remained unaltered in mice with opioid mu-receptors, indicating that the analgesic effect of Fuzei is centrally mediated. These results demonstrate that Fuzei processed by salt baking possesses analgesic effects within a large therapeutic range, probably via a mechanism involving central opioid receptors that mediate the antinociception.

Efficacy of Tramadol as a Sole Analgesic for Postoperative Pain in Male and Female Mice

PubMed Central

Wolfe, A Marissa; Kennedy, Lucy H; Na, Jane J; Nemzek-Hamlin, Jean A

2015-01-01

Tramadol is a centrally acting weak μ opioid agonist that has few of the adverse side effects common to other opioids. Little work has been done to establish an effective analgesic dose of tramadol specific for surgical laparotomy and visceral manipulation in mice. We used general appearance parameters to score positive indicators of pain including posture, coat condition, activity, breathing, and interactions with other mice, activity events (that is, the number of times each mouse stretched up in a 3-min period) used as an indicator of decreased pain, von Frey fibers, and plasma levels of corticosterone to determine whether tramadol at 20, 40, or 80 mg/kg prevented postoperative pain in male and female C57BL/6 mice. A ventral midline laparotomy with typhlectomy was used as a model of postoperative pain. In male mice, none of the markers differed between groups that received tramadol (regardless of dose) and the saline-treated controls. However, general appearance scores and plasma corticosterone levels were lower in female mice that received 80 mg/kg tramadol compared with saline. In summary, for severe postoperative pain after laparotomy and aseptic typhlectomy, tramadol was ineffective in male C57BL/6 mice at all doses tested. Although 80 mg/kg ameliorated postoperative pain in female C57BL/6 mice, this dose is very close to the threshold reported to cause toxic side effects, such as tremors and seizures. Therefore, we do not recommend the use of tramadol as a sole analgesic in this mouse model of postoperative pain. PMID:26224442

Efficacy of Tramadol as a Sole Analgesic for Postoperative Pain in Male and Female Mice.

PubMed

Wolfe, A Marissa; Kennedy, Lucy H; Na, Jane J; Nemzek-Hamlin, Jean A

2015-07-01

Tramadol is a centrally acting weak μ opioid agonist that has few of the adverse side effects common to other opioids. Little work has been done to establish an effective analgesic dose of tramadol specific for surgical laparotomy and visceral manipulation in mice. We used general appearance parameters to score positive indicators of pain including posture, coat condition, activity, breathing, and interactions with other mice, activity events (that is, the number of times each mouse stretched up in a 3-min period) used as an indicator of decreased pain, von Frey fibers, and plasma levels of corticosterone to determine whether tramadol at 20, 40, or 80 mg/kg prevented postoperative pain in male and female C57BL/6 mice. A ventral midline laparotomy with typhlectomy was used as a model of postoperative pain. In male mice, none of the markers differed between groups that received tramadol (regardless of dose) and the saline-treated controls. However, general appearance scores and plasma corticosterone levels were lower in female mice that received 80 mg/kg tramadol compared with saline. In summary, for severe postoperative pain after laparotomy and aseptic typhlectomy, tramadol was ineffective in male C57BL/6 mice at all doses tested. Although 80 mg/kg ameliorated postoperative pain in female C57BL/6 mice, this dose is very close to the threshold reported to cause toxic side effects, such as tremors and seizures. Therefore, we do not recommend the use of tramadol as a sole analgesic in this mouse model of postoperative pain.

Effects of ketoprofen, morphine, and kappa opioids on pain-related depression of nesting in mice.

PubMed

Negus, S Stevens; Neddenriep, Bradley; Altarifi, Ahmad A; Carroll, F Ivy; Leitl, Michael D; Miller, Laurence L

2015-06-01

Pain-related functional impairment and behavioral depression are diagnostic indicators of pain and targets for its treatment. Nesting is an innate behavior in mice that may be sensitive to pain manipulations and responsive to analgesics. The goal of this study was to develop and validate a procedure for evaluation of pain-related depression of nesting in mice. Male ICR mice were individually housed and tested in their home cages. On test days, a 5- × 5-cm Nestlet was subdivided into 6 pieces, the pieces were evenly distributed on the cage floor, and Nestlet consolidation was quantified during 100-minute sessions. Baseline nesting was stable within and between subjects, and nesting was depressed by 2 commonly used inflammatory pain stimuli (intraperitoneal injection of dilute acid; intraplantar injection of complete Freund adjuvant). Pain-related depression of nesting was alleviated by drugs from 2 classes of clinically effective analgesics (the nonsteroidal anti-inflammatory drug ketoprofen and the μ-opioid receptor agonist morphine) but not by a drug from a class that has failed to yield effective analgesics (the centrally acting kappa opioid agonist U69,593). Neither ketoprofen nor morphine alleviated depression of nesting by U69,593, which suggests that ketoprofen and morphine effects were selective for pain-related depression of nesting. In contrast to ketoprofen and morphine, the kappa opioid receptor antagonist JDTic blocked depression of nesting by U69,593 but not by acid or complete Freund adjuvant. These results support utility of this procedure to assess expression and treatment of pain-related depression in mice.

The Efficacy and Safety of the Novel Peripheral Analgesic Isovaline as an Adjuvant to Propofol for General Anesthesia and Conscious Sedation: A Proof-of-Principle Study in Mice.

PubMed

Whitehead, Ryan A; Schwarz, Stephan K W; Asiri, Yahya I; Fung, Timothy; Puil, Ernest; MacLeod, Bernard A

2015-12-01

The combination of propofol and an opioid analgesic is widely used for procedural sedation, as well as total IV anesthesia. However, opioids produce respiratory depression, a primary cause of death due to these agents. We recently reported on the antinociceptive actions of isovaline, a small nonbiogenic amino acid that does not readily cross the blood-brain barrier and acts on peripheral γ-aminobutyric acid type B receptors. Here, we explored the possibility that isovaline may be an effective and safe alternative to opioids as an adjunct to propofol for producing anesthesia. With approval from our Animal Care Committee, we conducted an in vivo study in adult female CD-1 mice using Dixon's "up-and-down" method for dose assessment. Animals received intraperitoneal saline, propofol, isovaline, fentanyl, or coadministration of propofol with isovaline or fentanyl. We assessed hypnosis by a loss of righting reflex and immobility by an absence of motor response to tail clip application. General anesthesia was defined as the presence of both hypnosis and immobility. We assessed conscious sedation as a decrease in time on a rotarod. The maximal dose without respiratory rates of <4 per minute, apnea, or death was defined as the maximal tolerated dose. Either isovaline or fentanyl coadministered with propofol at its half-maximal effective dose (ED50) for hypnosis produced general anesthesia (isovaline ED50, 96 mg/kg [95% confidence interval {CI}, 88-124 mg/kg]; fentanyl ED50, 0.12 mg/kg [95% CI, 0.08-3.5 mg/kg]). Propofol produced hypnosis (ED50, 124 mg/kg [95% CI, 84-3520 mg/kg]) but did not block responses to tail clip application. Neither isovaline nor fentanyl produced hypnosis at doses which produced immobility (isovaline ED50, 350 mg/kg [95% CI, 286-1120 mg/kg]; fentanyl ED50, 0.35 mg/kg [95% CI, 0.23-0.51 mg/kg]). Isovaline at its analgesic ED50, coadministered with a subhypnotic dose of propofol (40 mg/kg), did not exacerbate propofol-induced deficits in rotarod performance. The median maximal tolerated dose of fentanyl coadministered with the hypnotic ED50 of propofol was 11 mg/kg (95% CI, 8-18 mg/kg). Isovaline at a maximal deliverable (soluble) dose of 5000 mg/kg produced no apparent respiratory depression or other adverse effects. The novel analgesic, isovaline, coadministered with propofol, produced general anesthesia and conscious sedation in mice. The margin of safety for propofol-isovaline was considerably higher than that for propofol-fentanyl. This study's results show that propofol-based sedation and general anesthesia can be effectively and safely produced by replacing the conventional opioid component with a brain-impermeant peripherally acting γ-aminobutyric acid type B receptor agonist. The results provide proof of the principle of combining a peripheral analgesic with a centrally acting hypnotic to produce general anesthesia. This principle suggests a novel approach to clinical general anesthesia and conscious sedation.

Transmission Pathways and Mediators as the Basis for Clinical Pharmacology of Pain

PubMed Central

Kirkpatrick, Daniel R.; McEntire, Dan M.; Smith, Tyler A.; Dueck, Nicholas P.; Kerfeld, Mitchell J.; Hambsch, Zakary J.; Nelson, Taylor J.; Reisbig, Mark D.; Agrawal, Devendra K.

2016-01-01

Introduction Mediators in pain transmission are the targets of a multitude of different analgesic pharmaceuticals. This review explores the most significant mediators of pain transmission as well as the pharmaceuticals that act on them. Areas Covered The review explores many of the key mediators of pain transmission. In doing so, this review uncovers important areas for further research. It also highlights agents with potential for producing novel analgesics, probes important interactions between pain transmission pathways that could contribute to synergistic analgesia, and emphasizes transmission factors that participate in transforming acute injury into chronic pain. Expert Commentary This review examines current pain research, particularly in the context of identifying novel analgesics, highlighting interactions between analgesic transmission pathways, and discussing factors that may contribute to the development of chronic pain after an acute injury. PMID:27322358

The anti-inflammatory effect of tramadol in the temporomandibular joint of rats.

PubMed

Lamana, Simone Monaliza S; Napimoga, Marcelo H; Nascimento, Ana Paula Camatta; Freitas, Fabiana F; de Araujo, Daniele R; Quinteiro, Mariana S; Macedo, Cristina G; Fogaça, Carlos L; Clemente-Napimoga, Juliana T

2017-07-15

Tramadol is a centrally acting analgesic drug able to prevent nociceptor sensitization when administered into the temporomandibular joint (TMJ) of rats. The mechanism underlying the peripheral anti-inflammatory effect of tramadol remains unknown. This study demonstrated that intra-TMJ injection of tramadol (500µg/TMJ) was able to inhibit the nociceptive response induced by 1.5% formalin or 1.5% capsaicin, suggesting that tramadol has an antinociceptive effect, acting directly on the primary nociceptive neurons activating the nitric oxide/cyclic guanosine monophosphate signaling pathway. Tramadol also inhibited the nociceptive response induced by carrageenan (100µg/TMJ) or 5-hydroxytryptamine (225µg/TMJ) along with inhibition of inflammatory cytokines levels, leukocytes migration and plasma extravasation. In conclusion, the results demonstrate that peripheral administration of tramadol has a potential antinociceptive and anti-inflammatory effect. The antinociceptive effect is mediated by activation of the intracellular nitric oxide/cyclic guanosine monophosphate pathway, at least in part, independently from the opioid system. Copyright © 2017 Elsevier B.V. All rights reserved.

[Opioids in chronic noncancer pain-are opioids superior to nonopioid analgesics? A systematic review and meta-analysis of efficacy, tolerability and safety in randomized head-to-head comparisons of opioids versus nonopioid analgesics of at least four week's duration].

PubMed

Welsch, P; Sommer, C; Schiltenwolf, M; Häuser, W

2015-02-01

Some leading German pain medicine experts postulate that there is a type of chronic non-cancer pain (CNCP) with an opioid requirement. We tested whether opioids are superior to nonopioid analgesics in the management of CNCP in studies of at least 4 week's duration. We screened MEDLINE, Scopus and the Cochrane Central Register of Controlled Trials (CENTRAL) up until October 2013, as well as the reference sections of original studies and systematic reviews of randomised controlled trials (RCTs) of opioids in CNCP. We included double-blind RTCs comparing opioids to nonopioid analgesics of at least 4 week's duration. Relative risks differences (RD) of categorical data and standardized mean differences (SMD) of continuous variables were calculated using a random effects model. We included 10 RCTs with 3046 participants. Median study duration was 6 weeks (range 4-12 weeks). Five studies compared tramadol with nonsteroidal anti-inflammatory drugs (NSAIDs) in osteoarthritis pain and one trial compared tramadol to flupirtine in low back pain. Morphine was compared to antidepressants (two studies), an anticonvulsant (one study) and an antiarrhythmic (one study) in different neuropathic pain syndromes. There was no significant difference between opioids and nonopioid analgesics in pain reduction (SMD 0.03 [95 % confidence interval, CI - 0.18, 0.24]; p = 0.76). Nonopioid analgesics were superior to opioids in improving physical function (SMD 0.17 [95 % CI 0.02, 0.32]; p = 0.03). Patients dropped out due to adverse events more frequently with opioids than with nonopioid analgesics (RD 0.09 [95 % CI 0.06, 0.13]; p < 0.0001). There was no significant difference between opioids and nonopioid analgesics in terms of serious adverse events or dropout rates due to lack of efficacy. Nonopioid analgesics are superior to opioids in terms of improvement of physical function and tolerability in short-term (4-12 weeks) therapy of neuropathic, low back and osteoarthritis pain. Our results do not support the concept of an"opioid-requiring" CNCP. The English full-text version of this article is freely available at SpringerLink (under "Supplemental").

Nicotine-Induced Antinociception in Male and Female Sprague-Dawley Rats

DTIC Science & Technology

1999-07-21

drugs, e.g., ibuprofen , naproxen, and fenbufen. These agents provide analgesia and also may act peripherally to decrease the inflammatory cascade (Wall...although a single dose of ibuprofen (a non-steroidal analgesic) was an effective analgesic against electrically-induced experimental pain in male subjects...discomfort from illness or injUry (e.g., ibuprofen ). Although these two drugs have been used safely and effectively for many years, we still do not know

Assessment of extended-release opioid analgesics for the treatment of chronic pain.

PubMed

Gudin, Jeffrey A

2013-03-01

Approximately 3.8 million patients annually receive extended-release (ER) or long-acting opioid prescriptions in the outpatient setting, around half of which are written by primary care physicians. Compared with short-acting, immediate-release (IR) formulations, ER and oral long-acting opioid analgesics are associated with clinical advantages, such as extended periods of time during which drug plasma levels are within the therapeutic range, decreased peak-to-trough fluctuations, and prolonged analgesia over the dosing period. Additionally, ER opioids offer a more convenient, less frequent dosing regimen to chronic pain patients who are often taking several concomitant medications. The increased utilization of ER opioids has been accompanied by a rise in the misuse and abuse of these formulations. Certain pharmacokinetic parameters (e.g., longer time to maximum drug plasma concentration, lower maximum drug plasma concentration) may decrease the abuse potential of intact ER opioids by limiting the positive subjective and reinforcing effects relative to IR formulations. Putative abuse-deterrent formulations have also recently been introduced to impede physical manipulation of these formulations, or reduce the harm resulting from such behavior. Such formulations may represent an incremental advance to reduce non-oral forms of abuse. This article reviews the pharmacokinetic profiles and abuse-deterrent features of newer ER opioid analgesics for the treatment of moderate to severe chronic pain.

The recent progress in research on effects of anesthetics and analgesics on G protein-coupled receptors.

PubMed

Minami, Kouichiro; Uezono, Yasuhito

2013-04-01

The exact mechanisms of action behind anesthetics and analgesics are still unclear. Much attention was focused on ion channels in the central nervous system as targets for anesthetics and analgesics in the 1980s. During the 1990s, major advances were made in our understanding of the physiology and pharmacology of G protein coupled receptor (GPCR) signaling. Thus, several lines of studies have shown that G protein coupled receptors (GPCRs) are one of the targets for anesthetics and analgesics and especially, that some of them inhibit the functions of GPCRs, i.e,, muscarinic receptors and substance P receptors. However, these studies had been focused on only G(q) coupled receptors. There has been little work on G(s)- and G(i)-coupled receptors. In the last decade, a new assay system, using chimera G(i/o)-coupled receptor fused to Gq(i5), has been established and the effects of anesthetics and analgesics on the function of G(i)-coupled receptors is now more easily studied. This review highlights the recent progress of the studies regarding the effects of anesthetics and analgesics on GPCRs.

Are Prescription Opioids Driving the Opioid Crisis? Assumptions vs Facts.

PubMed

Rose, Mark Edmund

2018-04-01

Sharp increases in opioid prescriptions, and associated increases in overdose deaths in the 2000s, evoked widespread calls to change perceptions of opioid analgesics. Medical literature discussions of opioid analgesics began emphasizing patient and public health hazards. Repetitive exposure to this information may influence physician assumptions. While highly consequential to patients with pain whose function and quality of life may benefit from opioid analgesics, current assumptions about prescription opioid analgesics, including their role in the ongoing opioid overdose epidemic, have not been scrutinized. Information was obtained by searching PubMed, governmental agency websites, and conference proceedings. Opioid analgesic prescribing and associated overdose deaths both peaked around 2011 and are in long-term decline; the sharp overdose increase recorded in 2014 was driven by illicit fentanyl and heroin. Nonmethadone prescription opioid analgesic deaths, in the absence of co-ingested benzodiazepines, alcohol, or other central nervous system/respiratory depressants, are infrequent. Within five years of initial prescription opioid misuse, 3.6% initiate heroin use. The United States consumes 80% of the world opioid supply, but opioid access is nonexistent for 80% and severely restricted for 4.1% of the global population. Many current assumptions about opioid analgesics are ill-founded. Illicit fentanyl and heroin, not opioid prescribing, now fuel the current opioid overdose epidemic. National discussion has often neglected the potentially devastating effects of uncontrolled chronic pain. Opioid analgesic prescribing and related overdoses are in decline, at great cost to patients with pain who have benefited or may benefit from, but cannot access, opioid analgesic therapy.

Canadian veterinarians’ use of analgesics in cattle, pigs, and horses in 2004 and 2005

PubMed Central

Hewson, Caroline J.; Dohoo, Ian R.; Lemke, Kip A.; Barkema, Herman W.

2007-01-01

Anecdotal evidence suggests that many veterinarians may not use analgesics in livestock for routine surgical procedures or painful disease states. To investigate this, we conducted a national mail survey of a random sample of 1431 Canadian veterinarians (response rate, 50.1%). Questions primarily concerned veterinarians’ analgesic usage for common surgeries and medical conditions in beef and dairy cattle, pigs, and horses, and attitudes toward pain management. More than 90% of veterinarians used analgesic drugs for equine surgeries, for cesarean section in sows and cows, and for bovine claw amputation and omentopexy. However, in these and other categories, the analgesics used were often inadequate, and many veterinarians did not give analgesics to young animals. When castrated, < 0.001% of piglets received analgesia, compared with 6.9% of beef calves and 18.7% of dairy calves ≤ 6 mo of age, 19.9% of beef calves and 33.2% of dairy calves > 6 mo of age, and 95.8% of horses. Respondents largely agreed that there are no long-acting, cost-effective analgesics available for use in livestock (median rating 8/10; interquartile range 4–9), and that the long or unknown withdrawal periods of some drugs outweighed the benefits of using them (median rating 7/10; interquartile range 4–9). The results indicate an urgent need for veterinarians to manage pain in livestock better. Continuing education would help, as would an increase in the number of approved, cost-effective analgesic drugs with known withdrawal periods. PMID:17334029

Enhanced Analgesic Responses After Preferential Delivery of Morphine and Fentanyl to the Olfactory Epithelium in Rats

PubMed Central

Hoekman, John D.; Ho, Rodney J.Y.

2011-01-01

Background Centrally acting opioid analgesics such as morphine and fentanyl are effective, but their efficacy is often limited by a delayed response or side effects resulting from systemic first-pass before reaching the brain and the central nervous system (CNS). It is generally accepted that drugs applied to the nasal cavity can directly access the brain and the CNS, which could provide therapeutic advantages such as rapid onset and lower systemic exposure. The olfactory region of the nasal cavity has been implicated in facilitating this direct nose-to-CNS transfer. If the fraction of opioid administered to the olfactory region could be improved, there could be a larger fraction of drug directly delivered to the CNS, mediating greater therapeutic benefit. Methods We have developed a pressurized olfactory delivery (POD) device to consistently and non-invasively deposit a majority of drug on the olfactory region of the nasal cavity in Sprague-Dawley rats. Using the tail-flick latency test and analysis of plasma and CNS tissue drug exposure, we compared distribution and efficacy of the opioids morphine and fentanyl administered to the nasal olfactory region with the POD device or the nasal respiratory region with nose drops or systemically via intraperitoneal (IP) injection. Results Compared to nose drop, POD administration of morphine resulted in significantly higher overall therapeutic effect (AUCeffect) without a significant increase in plasma drug exposure (AUCplasma). POD delivery of morphine resulted in a nose-to-CNS direct transport percentage of 38–55%. POD delivery of fentanyl led to a faster (5 min vs. 10 min) and more intense analgesic effect compared to nasal respiratory administration. Unlike IP injection or nose drop administration, both morphine and fentanyl given by the POD device to olfactory nasal epithelium exhibited clockwise [plasma] versus effect hysteresis after nasal POD administration, consistent with direct nose-to-CNS drug transport mechanism. Conclusions Deposition of opioids to the olfactory region within the nasal cavity could have a significant impact on drug distribution and pharmacodynamic effect, and thus should be considered into account in future nasally administered opioid studies. PMID:21709146

Electroencephalography and analgesics.

PubMed

Malver, Lasse Paludan; Brokjaer, Anne; Staahl, Camilla; Graversen, Carina; Andresen, Trine; Drewes, Asbjørn Mohr

2014-01-01

To assess centrally mediated analgesic mechanisms in clinical trials with pain patients, objective standardized methods such as electroencephalography (EEG) has many advantages. The aim of this review is to provide the reader with an overview of present findings in analgesics assessed with spontaneous EEG and evoked brain potentials (EPs) in humans. Furthermore, EEG methodologies will be discussed with respect to translation from animals to humans and future perspectives in predicting analgesic efficacy. We searched PubMed with MeSH terms 'analgesics', 'electroencephalography' and 'evoked potentials' for relevant articles. Combined with a search in their reference lists 15 articles on spontaneous EEG and 55 papers on EPs were identified. Overall, opioids produced increased activity in the delta band in the spontaneous EEG, but increases in higher frequency bands were also seen. The EP amplitudes decreased in the majority of studies. Anticonvulsants used as analgesics showed inconsistent results. The N-methyl-D-aspartate receptor antagonist ketamine showed an increase in the theta band in spontaneous EEG and decreases in EP amplitudes. Tricyclic antidepressants increased the activity in the delta, theta and beta bands in the spontaneous EEG while EPs were inconsistently affected. Weak analgesics were mainly investigated with EPs and a decrease in amplitudes was generally observed. This review reveals that both spontaneous EEG and EPs are widely used as biomarkers for analgesic drug effects. Methodological differences are common and a more uniform approach will further enhance the value of such biomarkers for drug development and prediction of treatment response in individual patients. © 2013 The British Pharmacological Society.

Analgesic, anti-inflammatory, antipyretic and haematological effects of aethiopinone, an o-naphthoquinone diterpenoid from Salvia aethiopis roots and two hemisynthetic derivatives.

PubMed

Hernández-Pérez, M; Rabanal, R M; de la Torre, M C; Rodríguez, B

1995-12-01

Aethiopinone (1), an o-naphthoquinone diterpene from Salvia aethiopis L. roots and two hemisynthetic derivatives 2 and 3 have been evaluated for toxicity, anti-inflammatory, analgesic, antipyretic, and haemostatic activities. The compounds tested showed low toxicity and a pharmacological profile similar to other NSAI substances on reducing the edema induced by carrageenan and contractions induced by phenyl-p-quinone; the most active compounds were 1 and 2. In the same way and as expected with these types of substances, the bleeding time increased. In the TPA-induced ear inflammation model, the three compounds showed a moderate reduction of edema, and 1 produced a significant increase in the reaction time against thermal painful stimuli in the tail immersion test. The results demonstrated strong anti-inflammatory, peripheral and central analgesic properties for 1, as well as antiedematose topical action and peripheral analgesic properties for 2 and 3.

Genetic variation in the serotonin transporter gene (5-HTTLPR, rs25531) influences the analgesic response to the short acting opioid Remifentanil in humans

PubMed Central

Kosek, Eva; Jensen, Karin B; Lonsdorf, Tina B; Schalling, Martin; Ingvar, Martin

2009-01-01

Background There is evidence from animal studies that serotonin (5-HT) can influence the antinociceptive effects of opioids at the spinal cord level. Therefore, there could be an influence of genetic polymorphisms in the serotonin system on individual variability in response to opioid treatment of pain. The serotonin transporter (5-HTT) is a key regulator of serotonin metabolism and availability and its gene harbors several known polymorphisms that are known to affect 5-HTT expression (e.g. 5-HTTLPR, rs25531). The aim of this study was to investigate if the triallelic 5-HTTLPR influences pain sensitivity or the analgesic effect of opioids in humans. 43 healthy volunteers (12 men, 31 women, mean age 26 years) underwent heat pain stimulations before and after intravenous injection of Remifentanil; a rapid and potent opioid drug acting on μ-type receptors. Subjects rated their perceived pain on a visual analogue scale (VAS). All participants were genotyped for the 5-HTTLPR and the rs25531 polymorphism. We recruited by advertising, with no history of drug abuse, chronic pain or psychiatric disorders. Results At baseline, there was no difference in pain ratings for the different triallelic 5-HTTLPR genotype groups. However, the opiod drug had a differential analgesic effect depending on the triallelic 5-HTTLPR genotype. Remifentanil had a significantly better analgesic effect in individuals with a genotype coding for low 5-HTT expression (SA/SA and SA/LG) as compared to those with high expression(LA/LA), p < 0.02. The analgesic effect for the three different genotype groups was linear to degree of 5-HTT expression. Conclusion This is the first report showing an influence of the triallelic 5-HTTLPR on pain sensitivity or the analgesic effect of opioids in humans. Previously the 5-HTTLPR s-allele has been associated with higher risk of developing chronic pain conditions but in this study we show that the genotype coding for low 5-HTT expression is associated with a better analgesic effect of an opioid. The s-allele has been associated with downregulation of 5-HT1 receptors and we suggest that individuals with a desensitization of 5-HT1 receptors have an increased analgesic response to opioids during acute pain stimuli, but may still be at increased risk of developing chronic pain conditions. PMID:19570226

Genetic variation in the serotonin transporter gene (5-HTTLPR, rs25531) influences the analgesic response to the short acting opioid Remifentanil in humans.

PubMed

Kosek, Eva; Jensen, Karin B; Lonsdorf, Tina B; Schalling, Martin; Ingvar, Martin

2009-07-01

There is evidence from animal studies that serotonin (5-HT) can influence the antinociceptive effects of opioids at the spinal cord level. Therefore, there could be an influence of genetic polymorphisms in the serotonin system on individual variability in response to opioid treatment of pain. The serotonin transporter (5-HTT) is a key regulator of serotonin metabolism and availability and its gene harbors several known polymorphisms that are known to affect 5-HTT expression (e.g. 5-HTTLPR, rs25531). The aim of this study was to investigate if the triallelic 5-HTTLPR influences pain sensitivity or the analgesic effect of opioids in humans. 43 healthy volunteers (12 men, 31 women, mean age 26 years) underwent heat pain stimulations before and after intravenous injection of Remifentanil; a rapid and potent opioid drug acting on micro-type receptors. Subjects rated their perceived pain on a visual analogue scale (VAS). All participants were genotyped for the 5-HTTLPR and the rs25531 polymorphism. We recruited by advertising, with no history of drug abuse, chronic pain or psychiatric disorders. At baseline, there was no difference in pain ratings for the different triallelic 5-HTTLPR genotype groups. However, the opiod drug had a differential analgesic effect depending on the triallelic 5-HTTLPR genotype. Remifentanil had a significantly better analgesic effect in individuals with a genotype coding for low 5-HTT expression (SA/SA and SA/LG) as compared to those with high expression(LA/LA), p < 0.02. The analgesic effect for the three different genotype groups was linear to degree of 5-HTT expression. This is the first report showing an influence of the triallelic 5-HTTLPR on pain sensitivity or the analgesic effect of opioids in humans. Previously the 5-HTTLPR s-allele has been associated with higher risk of developing chronic pain conditions but in this study we show that the genotype coding for low 5-HTT expression is associated with a better analgesic effect of an opioid. The s-allele has been associated with downregulation of 5-HT1 receptors and we suggest that individuals with a desensitization of 5-HT1 receptors have an increased analgesic response to opioids during acute pain stimuli, but may still be at increased risk of developing chronic pain conditions.

Low power radiofrequency electromagnetic radiation for the treatment of pain due to osteoarthritis of the knee.

PubMed

Alcidi, L; Beneforti, E; Maresca, M; Santosuosso, U; Zoppi, M

2007-01-01

To investigate the analgesic effect of low power radiofrequency electromagnetic radiation (RF) in osteoarthritis (OA) of the knee. In a randomized study on 40 patients the analgesic effect of RF was compared with the effect of transcutaneous electrical nerve stimulation (TENS). RF and TENS applications were repeated every day for a period of 5 days. The therapeutic effect was evaluated by a visual analogue scale (VAS) and by Lequesne's index: tests were performed before, immediately after and 30 days after therapy. RF therapy induced a statistically significant and long lasting decrease of VAS and of Lequesne's index; TENS induced a decrease of VAS and of Lequesne's index which was not statistically significant. A therapeutic effect of RF was therefore demonstrated on pain and disability due to knee OA. This effect was better than the effect of TENS, which is a largely used analgesic technique. Such a difference of the therapeutic effect may be due to the fact that TENS acts only on superficial tissues and nerve terminals, while RF acts increasing superficial and deep tissue temperature.

The synergistic effect of treatment with triptolide and MK-801 in the rat neuropathic pain model

PubMed Central

Wang, Jian; Qiao, Yu; Yang, Ri-Sheng; Zhang, Chun-Kui; Wu, Huang-Hui; Lin, Jia-Ji; Zhang, Ting

2017-01-01

Triptolide (T10), an active component of Tripterygium wilfordii Hook F, is reported to have potent anti-inflammatory and analgesic effects. Additionally, MK-801, a noncompetitive N-methyl-D-aspartate receptor antagonist, can reduce glutamate toxicity and has a significant analgesic effect on chronic pain. In this study, we tested the possible synergistic analgesic ability by intrathecal administration of T10 and MK-801 for the treatment of neuropathic pain. Single T10 (3, 10, or 30 µg/kg), MK-801 (10, 30, or 90 µg/kg), or a combination of them were intrathecally administrated in rats with spinal nerve ligation. We found that single administration of T10 caused a slow-acting but long-term analgesic effect, while single administration of MK-801 caused a fast-acting but short-term effect. Administration of their combination showed obviously synergic analgesia and the 1:3 ratio of T10 to MK-801 reached the peak effect. Furthermore, application of T10 and/or MK-801 significantly inhibited the activation of microglia and astrocyte and phosphorylation of STAT3 and NR2B in the spinal dorsal horn induced by chronic neuropathic pain. Our data suggest that the combination of T10 and MK-801 may be a potentially novel strategy for treatment of neuropathic pain. PMID:29166839

Evaluation of analgesic and anti-inflammatory activity of a combination of tramadol-ibuprofen in experimental animals.

PubMed

Suthakaran, Chidambarann; Kayalvizhi, Muniyagounder K; Nithya, Karnam; Raja, Thozhudalangudy Ar

2017-01-01

Pain is the major concern of patients attending dental clinics, and satisfactory pain relief has always been difficult to achieve. Since the pathophysiology of pain is a complex, central and peripheral nervous system process, combined analgesic regimens with different mechanisms of action as a multimodal approach are becoming popular among the clinicians and dentists. The aim of the present study was to evaluate the analgesic and anti-inflammatory activity of ibuprofen and tramadol when used alone or in combination in animal models of pain and inflammation. The animals were divided into six groups with six animals in each group. Analgesic activity was assessed by hot plate method in rats and by acetic acid-induced writhing test in mice. Paw edema model in rats after induction with 0.1 mL of 1% carrageenan was used to assess the anti-inflammatory activity. Analysis of variance followed by Tukey's honestly significant difference post hoc test was used for statistical analysis. Combined use of tramadol and ibuprofen provided enhanced analgesic and anti-inflammatory effects in animal models of pain and inflammation.

The use of central nervous system drugs and analgesics among very old people with and without dementia.

PubMed

Lövheim, Hugo; Karlsson, Stig; Gustafson, Yngve

2008-09-01

Old people in general, and particularly those with dementia, are more sensitive to adverse drug effects than younger people. Despite this, the use of central nervous system (CNS) drugs among old people is common. The aim of the present study was to compare the use of central nervous system drugs and analgesics among people aged 85 years or older, with and without dementia. One half of all people aged 85 years old and all those aged 90, 95 and above in Umeå, Sweden and Vaasa and Mustasaari, Finland, were asked to participate in this part of the GERDA/Umeå 85+ study. Both those living in their own homes and those in institutions were included. Trained investigators performed structured interviews and assessments. Medication data were obtained from the participants and medical records. Dementia disorders were diagnosed according to DSM-IV. Dementia was diagnosed in 247/546 participants (45.2%). A higher proportion of the participants with dementia used paracetamol (50.6% compared to 21.4%, p < 0.001), antipsychotics (22.3% and 2.7%, p < 0.001), antidepressants (33.6% and 11.4%, p < 0.001) and anxiolytics (19.0% and 8.0%, p < 0.001). There were no differences in the use of opioid analgesics, anticonvulsants and hypnotics. The use of CNS drugs and analgesics was common among this population of very old people. Furthermore, the prescription of CNS drugs was more common among people with dementia. The use of antipsychotics in people with dementia should arouse particular concern, because of the high risk of severe adverse events and the limited evidence of positive effects.

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®

Diversion and Illicit Sale of Extended Release Tapentadol in the United States

PubMed Central

Surratt, Hilary L.; Le Lait, Marie-Claire; Stivers, Yami; Bebarta, Vikhyat S.; Freifeld, Clark C.; Brownstein, John S.; Burke, John J.; Kurtz, Steven P.; Dasgupta, Nabarun

2016-01-01

Objective.  Prescription opioid analgesics are commonly prescribed for moderate to severe pain. An unintended consequence of prescribing opioid analgesics is the abuse and diversion of these medications. Tapentadol ER is a recently approved centrally acting analgesic with synergistic mechanisms of action: μ-opioid receptor agonism and inhibition of norepinephrine reuptake. We assessed the amount of diversion and related cost of obtaining tapentadol IR (Nucynta®) and tapentadol ER (Nucynta ER®) as well as other Schedule II opioid medications in street transactions in the United States using the Researched Abuse, Diversion and Addiction-Related Surveillance (RADARS®) System. Methods.  The Drug Diversion Program measures the number of cases opened by 260 drug diversion investigators in 49 states. StreetRxTM uses a crowd-sourcing Website to collect the prices paid for licit or illicit drugs. Results.  The population-based rates of diversion were 0.003 (tapentadol IR), 0.001 (tapentadol ER), and 1.495 (other Schedule II opioid tablets) reports per 100,000 population. The tapentadol ER rate was lower than the other Schedule II opioid tablets (P < 0.001) and tapentadol IR (P= 0.004). Diversion rates based on drug availability were 0.03 (tapentadol IR), 0.016 (tapentadol ER), and 0.172 (other Schedule II opioid tablets) per 1,000 prescriptions dispensed. The median street price per milligram was $0.18 (tapentadol IR), $0.10 (tapentadol ER), and $1.00 (other Schedule II opioid tablets). Discussion.  Our results indicate that tapentadol ER is rarely sold illicitly in the United States. When sold illicitly, tapentadol ER costs less than other Schedule II opioid products. PMID:26814267

Acetaminophen Metabolite N-Acylphenolamine Induces Analgesia via Transient Receptor Potential Vanilloid 1 Receptors Expressed on the Primary Afferent Terminals of C-fibers in the Spinal Dorsal Horn.

PubMed

Ohashi, Nobuko; Uta, Daisuke; Sasaki, Mika; Ohashi, Masayuki; Kamiya, Yoshinori; Kohno, Tatsuro

2017-08-01

The widely used analgesic acetaminophen is metabolized to N-acylphenolamine, which induces analgesia by acting directly on transient receptor potential vanilloid 1 or cannabinoid 1 receptors in the brain. Although these receptors are also abundant in the spinal cord, no previous studies have reported analgesic effects of acetaminophen or N-acylphenolamine mediated by the spinal cord dorsal horn. We hypothesized that clinical doses of acetaminophen induce analgesia via these spinal mechanisms. We assessed our hypothesis in a rat model using behavioral measures. We also used in vivo and in vitro whole cell patch-clamp recordings of dorsal horn neurons to assess excitatory synaptic transmission. Intravenous acetaminophen decreased peripheral pinch-induced excitatory responses in the dorsal horn (53.1 ± 20.7% of control; n = 10; P < 0.01), while direct application of acetaminophen to the dorsal horn did not reduce these responses. Direct application of N-acylphenolamine decreased the amplitudes of monosynaptic excitatory postsynaptic currents evoked by C-fiber stimulation (control, 462.5 ± 197.5 pA; N-acylphenolamine, 272.5 ± 134.5 pA; n = 10; P = 0.022) but not those evoked by stimulation of Aδ-fibers. These phenomena were mediated by transient receptor potential vanilloid 1 receptors, but not cannabinoid 1 receptors. The analgesic effects of acetaminophen and N-acylphenolamine were stronger in rats experiencing an inflammatory pain model compared to naïve rats. Our results suggest that the acetaminophen metabolite N-acylphenolamine induces analgesia directly via transient receptor potential vanilloid 1 receptors expressed on central terminals of C-fibers in the spinal dorsal horn and leads to conduction block, shunt currents, and desensitization of these fibers.

Parallel Synthesis of Hexahydrodiimidazodiazepines Heterocyclic Peptidomimetics and Their in Vitro and in Vivo Activities at μ (MOR), δ (DOR), and κ (KOR) Opioid Receptors.

PubMed

Eans, Shainnel O; Ganno, Michelle L; Mizrachi, Elisa; Houghten, Richard A; Dooley, Colette T; McLaughlin, Jay P; Nefzi, Adel

2015-06-25

In the development of analgesics with mixed-opioid agonist activity, peripherally selective activity is expected to decrease side effects, minimizing respiratory depression and reinforcing properties generating significantly safer analgesic therapeutics. We synthesized diazaheterocyclics from reduced tripeptides. In vitro screening with radioligand competition binding assays demonstrated variable affinity for μ (MOR), δ (DOR), and κ (KOR) opioid receptors across the series, with the diimidazodiazepine 14 (2065-14) displaying good affinity for DOR and KOR. Central (icv), intraperitoneal (ip), or oral (po) administration of 14 produced dose-dependent, opioid-receptor mediated antinociception in the mouse, as determined from a 55 °C warm-water tail-withdrawal assay. Only trace amounts of compound 14 was found in brain up to 90 min later, suggesting poor BBB penetration and possible peripherally restricted activity. Central administration of 14 did not produce locomotor effects, acute antinociceptive tolerance, or conditioned-place preference or aversion. The data suggest these diazaheterocyclic mixed activity opioid receptor agonists may hold potential as new analgesics with fewer liabilities of use.

Daily home opioid use in adults with sickle cell disease: The PiSCES project.

PubMed

Smith, Wally R; McClish, Donna K; Dahman, Bassam A; Levenson, James L; Aisiku, Imoigele P; de A Citero, Vanessa; Bovbjerg, Viktor E; Roberts, John D; Penberthy, Lynne T; Roseff, Susan D

2015-01-01

Although opioid prescribing in sickle cell disease (SCD) can be controversial, little is published about patterns of opioid use. To report on home opioid use among adults with SCD. Cohort study. Adults with SCD (n=219) who completed daily pain diaries for up to 6 months and had at least one home pain day. Use of long-acting or short-acting opioids, other analgesics, or adjuvants; the proportion of home days, home pain days, and home crisis days with opioid use; these two outcomes according to patient characteristics. Patients used opioids on 12,311 (78 percent) of 15,778 home pain days. Eighty-five patients (38.8 percent) used long-acting opioids with or without short-acting opioids and 103 (47.0 percent) used only short-acting opioids. Twenty-one (9.6 percent) patients used only non-opioid analgesics and 10 (4.6 percent) used no analgesics. Both pain intensity and pain frequency were higher among opioid users (analysis of variance [ANOVA], p<0.0001). Opioid users used hydroxyurea more often than nonusers, even when controlling for mean pain on pain days. Among all patients, significant relationships were found between any opioid use and somatic symptom burden, SCD stress, negative coping, and physical and mental quality of life (QOL); the relationship with SCD stress and physical QOL remained when controlled for mean pain. Among opioid users, similar associations were found between frequency of opioid use and some disease-related and psychosocial variables. In this adult SCD sample, opioids were used by the majority of patients. Pain was the overwhelming characteristic associated with use, but disease-related and psychosocial variables were also associated.

Analgesics in postoperative care in hip fracture patients with dementia - reported by nurses.

PubMed

Rantala, Maija; Hartikainen, Sirpa; Kvist, Tarja; Kankkunen, Päivi

2014-11-01

To describe the analgesic use in hip fracture patients with dementia during the first two postoperative days as reported by nurses. Nurses play a pivotal role in treating postoperative pain in patients with dementia and monitoring the effects of administered analgesics. Cross-sectional descriptive questionnaire study in seven university hospitals and 10 central hospitals in Finland. The study was conducted from March until May in 2011 in Finland. For this analysis, the focus was on the sample of nurses (n = 269) who were working in orthopaedic units. Analgesics were classified according to the Anatomical Therapeutic Chemical Classification System. Nonparametric tests were applied to find out the significant differences between analgesic use and different hospitals. Paracetamol and strong opioids administered orally or parenterally seemed to be the most typical of postoperatively used types of analgesics in patients with dementia. Nonsteroidal anti-inflammatory analgesics and weak opioids were also commonly reported to be in use. There were no statistically significant differences between hospitals in typical daily doses. The majority of the nurses reported that the primary aim of postoperative pain management in hip fracture patients with dementia was 'slight pain, which does not prevent normal functioning' (72%). The pharmacological postoperative pain treatment in acute care was commonly based on the use of strong opioids and paracetamol in hip fracture patients with dementia. The reported use of transdermal opioids and codeine combination warrants further examination. Further studies are also needed to find out whether the pain is appropriately and adequately treated. Transdermal opioids and codeine combination may not be relevant analgesics for acute pain management in older adults. It is important to create a balance between sufficient pain relief and adverse effects of analgesics to allow early mobilisation and functional recovery. © 2014 John Wiley & Sons Ltd.

Evaluation of Analgesic Activity of Papaver libanoticum Extract in Mice: Involvement of Opioids Receptors

PubMed Central

El-Mallah, Ahmed; Aboul-Ela, Maha; Ellakany, Abdalla

2017-01-01

Papaver libanoticum is an endemic plant to Lebanese region (family Papaveraceae) that has not been investigated before. The present study aimed to explore the analgesic activity of dried ethanolic extract of Papaver libanoticum (PLE) using tail flick, hot plate, and acetic acid induced writhing models in mice. The involvement of opioid receptors in the analgesic mechanism was investigated using naloxone antagonism. Results demonstrated that PLE exhibited a potent dose dependent analgesic activity in all tested models for analgesia. The analgesic effect involved activation of opioid receptors in the central nervous system, where both spinal and supraspinal components might be involved. The time course for analgesia revealed maximum activity after three hours in both tail flick and hot plate methods, which was prolonged to 24 hours. Metabolites of PLE could be responsible for activation of opioid receptors. The EC50 of PLE was 79 and 50 mg/kg in tail flick and hot plate tests, respectively. The total coverage of analgesia by PLE was double that of morphine in both tests. In conclusion, PLE proved to have opioid agonistic activity with a novel feature of slow and prolonged effect. The present study could add a potential tool in the armaments of opioid drugs as a natural potent analgesic and for treatment of opioid withdrawal syndrome. PMID:28280516

Evaluation of Analgesic Activity of Papaver libanoticum Extract in Mice: Involvement of Opioids Receptors.

PubMed

Hijazi, Mohamad Ali; El-Mallah, Ahmed; Aboul-Ela, Maha; Ellakany, Abdalla

2017-01-01

Papaver libanoticum is an endemic plant to Lebanese region (family Papaveraceae) that has not been investigated before. The present study aimed to explore the analgesic activity of dried ethanolic extract of Papaver libanoticum (PLE) using tail flick, hot plate, and acetic acid induced writhing models in mice. The involvement of opioid receptors in the analgesic mechanism was investigated using naloxone antagonism. Results demonstrated that PLE exhibited a potent dose dependent analgesic activity in all tested models for analgesia. The analgesic effect involved activation of opioid receptors in the central nervous system, where both spinal and supraspinal components might be involved. The time course for analgesia revealed maximum activity after three hours in both tail flick and hot plate methods, which was prolonged to 24 hours. Metabolites of PLE could be responsible for activation of opioid receptors. The EC50 of PLE was 79 and 50 mg/kg in tail flick and hot plate tests, respectively. The total coverage of analgesia by PLE was double that of morphine in both tests. In conclusion, PLE proved to have opioid agonistic activity with a novel feature of slow and prolonged effect. The present study could add a potential tool in the armaments of opioid drugs as a natural potent analgesic and for treatment of opioid withdrawal syndrome.

Analgesic activity of Gleditsia triacanthos methanolic fruit extract and its saponin-containing fraction.

PubMed

Saleh, Dalia Osama; Kassem, Iman; Melek, Farouk Rasmy

2016-01-01

Gleditsia triacanthos L. (Leguminosae) pods are used in folk medicine for pain relief as anodyne and narcotic. The objective of this study is to evaluate analgesic activity of Gleditsia triacanthos methanolic fruit extract (MEGT) and its saponin-containing fraction (SFGT). Peripheral analgesic activity was assessed using the acetic acid-induced writhing model in mice at doses of 140, 280, and 560 mg/kg and formalin test in rats at 100, 200, and 400 mg/kg doses. Central analgesic activity was evaluated using the hotplate method in rats (100, 200, and 400 mg/kg). In the writhing test, six mice groups treated with MEGT and SFGT found ED50 values 268.2 and 161.2 mg/kg, respectively, displayed a significant decrease in writhing count compared with the group treated with standard drug indomethacin (14 mg/kg). SFGT (280 and 560 mg/kg) showed 64.94 and 70.78% protection, respectively, which are more than double % protection caused by indomethacin (31.82%). In the formalin test, MEGT and SFGT (ED50 values 287.6 and 283.4 mg/kg for phase I as well as 295.1 and 290.4 mg/kg for phase II, respectively) at 400 mg/kg showed significant % inhibition in both phase I (18.86 and 52.57%) and phase II (39.36 and 44.29%) with reference to 10 mg/kg indomethacin (56.0 and 32.29%). MEGT and SFGT caused significant delay in responses in hotplate model (ED50 values 155.4 and 200.6 mg/kg, respectively) compared with that of 10 mg/kg indomethacin at 30, 60, and 120 min. Central and peripheral analgesic activities induced by Gleditsia triacanthos fruits might account for its uses in folk medicine.

Interactions Between Dyspnea and the Brain Processing of Nociceptive Stimuli: Experimental Air Hunger Attenuates Laser-Evoked Brain Potentials in Humans.

PubMed

Dangers, Laurence; Laviolette, Louis; Similowski, Thomas; Morélot-Panzini, Capucine

2015-01-01

Dyspnea and pain share several characteristics and certain neural networks and interact with each other. Dyspnea-pain counter-irritation consists of attenuation of preexisting pain by intercurrent dyspnea and has been shown to have neurophysiological correlates in the form of inhibition of the nociceptive spinal reflex RIII and laser-evoked potentials (LEPs). Experimentally induced exertional dyspnea inhibits RIII and LEPs, while "air hunger" dyspnea does not inhibit RIII despite its documented analgesic effects. We hypothesized that air hunger may act centrally and inhibit LEPs. LEPs were obtained in 12 healthy volunteers (age: 21-29) during spontaneous breathing (FB), ventilator-controlled breathing (VC) tailored to FB, after inducing air hunger by increasing the inspired fraction of carbon dioxide -FiCO2- (VCCO2), and during ventilator-controlled breathing recovery (VCR). VCCO2 induced intense dyspnea (visual analog scale = 63% ± 6% of full scale, p < 0.001 vs. VC), predominantly of the air hunger type. VC alone reduced the amplitude of the N2-P2 component of LEPs (Δ = 24.0% ± 21.1%, p < 0.05, effect-size = 0.74) predominantly through a reduction in P2, and the amplitude of this inhibition was further reduced by inducting air hunger (Δ = 22.6% ± 17.9%, p < 0.05, effect-size = 0.53), predominantly through a reduction in N2. Somatosensory-evoked potentials (SEPs) were not affected by VC or VCCO2, suggesting that the observed effects are specific to pain transmission. We conclude that air hunger interferes with the cortical mechanisms responsible for the cortical response to painful laser skin stimulation, which provides a neurophysiological substrate to the central nature of its otherwise documented analgesic effects.

European pain management discussion forum.

PubMed

Breivik, Harald

2012-12-01

Queries from European physicians about analgesic pharmacotherapy and responses from the author are presented. Topics addressed in this issue pertain to epidural injection for painful central lumbar stenosis and epicondolysis.

Electroencephalography and analgesics

PubMed Central

Malver, Lasse Paludan; Brokjær, Anne; Staahl, Camilla; Graversen, Carina; Andresen, Trine; Drewes, Asbjørn Mohr

2014-01-01

To assess centrally mediated analgesic mechanisms in clinical trials with pain patients, objective standardized methods such as electroencephalography (EEG) has many advantages. The aim of this review is to provide the reader with an overview of present findings in analgesics assessed with spontaneous EEG and evoked brain potentials (EPs) in humans. Furthermore, EEG methodologies will be discussed with respect to translation from animals to humans and future perspectives in predicting analgesic efficacy. We searched PubMed with MeSH terms ‘analgesics’, ‘electroencephalography’ and ‘evoked potentials’ for relevant articles. Combined with a search in their reference lists 15 articles on spontaneous EEG and 55 papers on EPs were identified. Overall, opioids produced increased activity in the delta band in the spontaneous EEG, but increases in higher frequency bands were also seen. The EP amplitudes decreased in the majority of studies. Anticonvulsants used as analgesics showed inconsistent results. The N-methyl-D-aspartate receptor antagonist ketamine showed an increase in the theta band in spontaneous EEG and decreases in EP amplitudes. Tricyclic antidepressants increased the activity in the delta, theta and beta bands in the spontaneous EEG while EPs were inconsistently affected. Weak analgesics were mainly investigated with EPs and a decrease in amplitudes was generally observed. This review reveals that both spontaneous EEG and EPs are widely used as biomarkers for analgesic drug effects. Methodological differences are common and a more uniform approach will further enhance the value of such biomarkers for drug development and prediction of treatment response in individual patients. PMID:23593934

Analgesic Efficacy and Safety of Hydromorphone in Chinchillas (Chinchilla lanigera).

PubMed

Evenson, Emily A; Mans, Christoph

2018-05-01

Limited information is available regarding the efficacy of opioid analgesics in chinchillas. Here we sought to evaluate the analgesic efficacy and safety of hydromorphone in chinchillas. In a randomized, controlled, blind, complete crossover design, hydromorphone was administered at 0.5, 1, and 2 mg/kg SC to 16 chinchillas. Analgesic efficacy was determined by measuring hindlimb withdrawal latencies after a thermal noxious stimulus (Hargreaves method) at 0, 1, 2, 4, and 8 h after drug administration. Changes in daily food intake and fecal output after hydromorphone administration were recorded. At 2 mg/kg SC, but not at lower dosages, hydromorphone increased withdrawal latencies for less than 4 h. Food intake was reduced after all 3 dosages, and fecal output decreased in the 1- and 2-mg/kg groups. The decreases in these parameters were dose-dependent, with the greatest reduction measured over the first 24 h. Our current results indicate that hydromorphone at 2 mg/kg SC is an effective, short-acting analgesic drug in chinchillas that transiently reduces food intake and fecal output. Further studies are needed to evaluate the safety of hydromorphone in animals undergoing surgical procedures and general anesthesia and to determine whether lower doses provide analgesia in different nociceptive models.

[Clinical study on analgesic mechanism of bitongxiao in treating neck pain due to cervical spondylitis].

PubMed

Li, J X; Xiang, C J; Liu, X Q

2001-07-01

To study the analgesic mechanism of Bitongxiao (BTX, a Chinese herbal decoction) in treating neck pain due to cervical spondylitis (CS). BTX and Jingfukang (JFK) granule were used to treat the treated and the control group separately in 102 CS cases. Plasma leucine enkephalin (LEK), substance P (SP) and prostaglandin E2 (PGE2) before and after treatment were assayed by radioimmunoassay (RIA). Twelve patients in the treated group were clinically cured, 36 markedly effectively, 3 effectively and 1 ineffectively, while in the control group they were 5, 33, 14 and 0 cases respectively. The cured and marked effective rate in the treated group was 92.3%, while that in the control group 72.0%. After treatment the pain score (VAS) of both groups were significantly reduced, but the reduction was higher in the treated group than that in the control. Before treatment, plasma LEK in all patients was abnormally low, but after treatment, it raised obviously more in the treated group than that in the control (P < 0.05). Plasma SP of both groups were obviously elevated, and PGE2 revealed unaltered after treatment. BTX has strong, fast-acting and long-lasting analgesic effect with no side-effects, it could elevate the lowered plasma LEK level in cervical spondylitis patients and increase plasma SP level. The analgesic mechanism of BTX might be associated with its effect on LEK, SP or other endorphins, directly acting on the pain modulation system.

Ulcers in restrained rats: Study of protective substances

NASA Technical Reports Server (NTRS)

Buche, L.; Gallaire, D.

1980-01-01

The genesis of ulcers in restrained rats is discussed through an investigation of the relationship between the protective effects of nervous system effectual substances examined vis-a-vis ulcers in restrained rats and their elective or secondary pharmacologic effects. The substances used were capable of either peripheral parasympatholytic, sympatholytic, ganglioplegic, spasmolytic effects or central, hypnotic, tranquilizing, neuroleptic, analgesic effects. The regular and considerable protection observed with parasympatholytics (atropine sulfate, benzylonium bromide, dihexyverine, J.L. 1344) and a ganglioplegic (pentamethonium) is a function of their anticholinergic properties. It is of less importance with dibenamine, a sympatholytic action on the adrenergic receptors. Among the central depressive substances tested (hypnotics, tranquilizers, neuroleptics, analgesic), phenobarbital at a nonhypnotic dose, and dextromoramide at a nonanalgesic dose, show antiulcerous effects, which are found with chlorpromazine only at cataleptogenic doses.

Down-regulation of NR2B receptors partially contributes to analgesic effects of Gentiopicroside in persistent inflammatory pain.

PubMed

Chen, Lei; Liu, Jin-cheng; Zhang, Xiao-nan; Guo, Yan-yan; Xu, Zhao-hui; Cao, Wei; Sun, Xiao-li; Sun, Wen-ji; Zhao, Ming-Gao

2008-06-01

Gentiopicroside is one of the secoiridoid compound isolated from Gentiana lutea. It exhibits analgesic activities in the mice. The anterior cingulate cortex (ACC) is a forebrain structure known for its roles in pain transmission and modulation. Painful stimuli potentiate the prefrontal synaptic transmission and induce glutamate NMDA NR2B receptor expression in the ACC. But little is known about Gentiopicroside on the persistent inflammatory pain and chronic pain-induced synaptic transmission changes in the ACC. The present study was undertaken to investigate its analgesic activities and central synaptic modulation to the peripheral painful inflammation. Gentiopicroside produced significant analgesic effects against persistent inflammatory pain stimuli in mice. Systemic administration of Gentiopicroside significantly reversed NR2B over-expression during the chronic phases of persistent inflammation caused by hind-paw administration of complete Freunds adjuvant (CFA) in mice. Whole-cell patch clamp recordings revealed that Gentiopicroside significantly reduced NR2B receptors mediated postsynaptic currents in the ACC. Our findings provide strong evidence that analgesic effects of Gentiopicroside involve down-regulation of NR2B receptors in the ACC to persistent inflammatory pain.

In vivo analgesic activity, toxicity and phytochemical screening of the hydroalcoholic extract from the leaves of Psidium cattleianum Sabine.

PubMed

Alvarenga, Felipe Queiroz; Mota, Bárbara C F; Leite, Marcel N; Fonseca, Jaciara M S; Oliveira, Dario A; Royo, Vanessa de Andrade; e Silva, Márcio L A; Esperandim, Viviane; Borges, Alexandre; Laurentiz, Rosangela S

2013-10-28

Psidium cattleianum Sabine is extensively used in Brazilian traditional medicine to treat several diseases including painful disorders. Aim of the study to investigate the toxicity and the possible analgesic activities of the hydroalcoholic extract from the leaves of Psidium cattleianum Sabine (ELPCS), to support its use in folk medicine. To screen the major phytochemical constituents of this extract and evaluate their antioxidant activity. ELPCS was assessed for its antioxidant activity using the DPPH model. Its analgesic activity was examined using mouse models of acetic acid-induced writhing and hot plate paw licking models. The major phytochemical constituents of the extract were screened; their toxicity on LLC-MK2 mammalian cells was evaluated. ELPCS exhibited significant peripheral analgesic activity at doses of 60, 80, 100, 200 and 400mg/kg in mice, but it did not display central analgesic activity and not was toxic to LLC-MK2 cell (LD50>400 µg/mL). The extract exhibited free radical scavenging activity as evidenced by IC50 values (15.9 µg/mL) obtained by the DPPH method. Phytochemical screening detected flavonoids, saponins, cardiac glycosides, anthraquinones, and tannins. The results of the experimental studies proved the analgesic activity of ELPCS and supported the traditional use of this plant. © 2013 Elsevier Ireland Ltd. All rights reserved.

Pharmacist's impact on acute pain management during trauma resuscitation.

PubMed

Montgomery, Kayla; Hall, A Brad; Keriazes, Georgia

2015-01-01

The timely administration of analgesics is crucial to the comprehensive management of trauma patients. When an emergency department (ED) pharmacist participates in trauma resuscitation, the pharmacist acts as a medication resource for trauma team members and facilitates the timely administration of analgesics. This study measured the impact of a pharmacist on time to first analgesic dose administered during trauma resuscitation. All adult (>18 years) patients who presented to this level II trauma center via activation of the trauma response system between January 1, 2009, and May 31, 2013, were screened for eligibility. For inclusion, patients must have received intravenous fentanyl, morphine, or hydromorphone in the trauma bay. The time to medication administration was defined as the elapsed time from ED arrival to administration of first analgesic. There were 1328 trauma response system activations during the study period; of which 340 patients were included. The most common analgesic administered was fentanyl (62% in both groups). When a pharmacist was participating, the mean time to first analgesic administered was decreased (17 vs 21 minutes; P = .03). Among the 78% of patients with documented pain scores, the overall mean reduction in pain scores from ED arrival to ED discharge was similar between the 2 groups. There was a 2.4 point reduction with a pharmacist versus 2.7 without a pharmacist, using a 0 to 10 numeric pain rating scale. The participation of a clinical pharmacist during trauma resuscitation significantly decreased the time to first analgesic administration in trauma patients. The results of this study supplement the literature supporting the integration of clinical ED pharmacists on trauma teams.

Imidazopyridine CB2 agonists: optimization of CB2/CB1 selectivity and implications for in vivo analgesic efficacy.

PubMed

Trotter, B Wesley; Nanda, Kausik K; Burgey, Christopher S; Potteiger, Craig M; Deng, James Z; Green, Ahren I; Hartnett, John C; Kett, Nathan R; Wu, Zhicai; Henze, Darrell A; Della Penna, Kimberly; Desai, Reshma; Leitl, Michael D; Lemaire, Wei; White, Rebecca B; Yeh, Suzie; Urban, Mark O; Kane, Stefanie A; Hartman, George D; Bilodeau, Mark T

2011-04-15

A new series of imidazopyridine CB2 agonists is described. Structural optimization improved CB2/CB1 selectivity in this series and conferred physical properties that facilitated high in vivo exposure, both centrally and peripherally. Administration of a highly selective CB2 agonist in a rat model of analgesia was ineffective despite substantial CNS exposure, while administration of a moderately selective CB2/CB1 agonist exhibited significant analgesic effects. Copyright © 2011 Elsevier Ltd. All rights reserved.

Sedatives and Analgesics Given to Infants in Neonatal Intensive Care Units at the End of Life

PubMed Central

Zimmerman, Kanecia O.; Hornik, Christoph P.; Ku, Lawrence; Watt, Kevin; Laughon, Matthew M.; Bidegain, Margarita; Clark, Reese H.; Smith, P. Brian

2015-01-01

Objective To describe the administration of sedatives and analgesics at the end of life in a large cohort of infants in North American neonatal intensive care units (NICUs). Study design Data on mortality and sedative and analgesic administration were obtained from infants who died from 1997–2012 in 348 NICUs managed by the Pediatrix Medical Group. Sedatives and analgesics of interest included opioids (fentanyl, methadone, morphine), benzodiazepines (clonazepam, diazepam, lorazepam, midazolam), central alpha-2 agonists (clonidine, dexmedetomidine), ketamine, and pentobarbital. We used multivariable logistic regression to evaluate the association between administration of these drugs on the day of death and infant demographics and illness severity. Results We identified 19,726 infants who died. Of these, 6188 (31%) received a sedative or analgesic on the day of death; opioids were most frequently administered, 5366/19,726 (27%). Administration of opioids and benzodiazepines increased during the study period, from 16/283 (6%) for both in 1997 to 523/1465 (36%) and 295/1465 (20%) in 2012, respectively. Increasing gestational age, increasing postnatal age, invasive procedure within 2 days of death, more recent year of death, mechanical ventilation, inotropic support, and antibiotics on the day of death were associated with exposure to sedatives or analgesics. Conclusions Administration of sedatives and analgesics increased over time. Infants of older gestational age and those more critically ill were more likely to receive these drugs on the day of death. These findings suggest that drug administration may be driven by severity of illness. PMID:26012893

Pattern of self-medication with analgesics among Iranian University students in central Iran

PubMed Central

Sarahroodi, Shadi; Maleki-Jamshid, Ali; Sawalha, Ansam F.; Mikaili, Peyman; Safaeian, Leila

2012-01-01

Background: Self-medication is defined as the use of drugs for the treatment of self-diagnosed disorders. It is influenced by factors such as education, family, society, law, availability of drugs and exposure to advertisements. This study was performed to evaluate self-medication with analgesics and its pattern among different groups of Iranian University Students. Materials and Methods: A randomized, cross-sectional, multicenter study was conducted from December 2009 to February 2010. The target population of this study was 564 students out of 10,000 students attending four medical and non-medical science universities in Qom state. Data was analyzed using SPSS version 16, and analysis was conducted with descriptive analysis procedures. Results: 76.6% of the students had used analgesics in self-medication in the previous 3 months. The frequency of analgesic use in the study period was once in 19.2% of the participants, twice in 22.2%, three times in 16.3% and more than three times in 35.5% of the participants, although 6.8% of them were not sure when they were used. Of all the respondents, 49.8% reported headache as the problem. This was the most common problem, after which came Dysmenorrhea,headache and stomach ache. Bone and joint pains were other problems that led to the use of analgesics. The most commonly used source of information for self-medication with analgesics was advice from friends and family (54.7%), previously prescribed medications (30.1%), their medical knowledge (13.3%) and recommendation of a pharmacist (1.9%). Conclusion: Self-medication with analgesics is very high among Iranian students in Qom city. This could be an index for other parts of the Iranian community. Because the source of information about analgesics is inappropriate, we would recommend education courses about analgesics and self-medication on the radio and television for the entire population. PMID:22870417

Pattern of self-medication with analgesics among Iranian University students in central Iran.

PubMed

Sarahroodi, Shadi; Maleki-Jamshid, Ali; Sawalha, Ansam F; Mikaili, Peyman; Safaeian, Leila

2012-05-01

Self-medication is defined as the use of drugs for the treatment of self-diagnosed disorders. It is influenced by factors such as education, family, society, law, availability of drugs and exposure to advertisements. This study was performed to evaluate self-medication with analgesics and its pattern among different groups of Iranian University Students. A randomized, cross-sectional, multicenter study was conducted from December 2009 to February 2010. The target population of this study was 564 students out of 10,000 students attending four medical and non-medical science universities in Qom state. Data was analyzed using SPSS version 16, and analysis was conducted with descriptive analysis procedures. 76.6% of the students had used analgesics in self-medication in the previous 3 months. The frequency of analgesic use in the study period was once in 19.2% of the participants, twice in 22.2%, three times in 16.3% and more than three times in 35.5% of the participants, although 6.8% of them were not sure when they were used. Of all the respondents, 49.8% reported headache as the problem. This was the most common problem, after which came Dysmenorrhea,headache and stomach ache. Bone and joint pains were other problems that led to the use of analgesics. The most commonly used source of information for self-medication with analgesics was advice from friends and family (54.7%), previously prescribed medications (30.1%), their medical knowledge (13.3%) and recommendation of a pharmacist (1.9%). Self-medication with analgesics is very high among Iranian students in Qom city. This could be an index for other parts of the Iranian community. Because the source of information about analgesics is inappropriate, we would recommend education courses about analgesics and self-medication on the radio and television for the entire population.

[Analgesic effect and clinical tolerability of the combination of paracetamol 500 mg and caffeine 50 mg versus paracetamol 400 mg and dextropropoxyphene 30 mg in back pain].

PubMed

Kuntz, D; Brossel, R

1996-09-07

A double-blind randomized multicentric study was performed to test the hypothesis that the analgesic effect of paracetamol-cafeine is equivalent to that of paracetamol-dextropropoxyphen in patients suffering from pain due to osteoarthritis of the spine. Rhumatologists included 124 patients who were randomized into two groups of 62 each. Pain was measured daily during the seven-day treatment Huskisson's Analog Visual Scales; 112 were per protocol and evaluable. The two treatment groups were statistically similar for demographics, vital signs, medical and treatment history. A majority of them had pain located at the lumbar spine only; the other patients had either pain at the cervical or dorsal spine or at several sites. At the end of the week there was a major reduction in pain level: 51.2% in patients given paracetamol-cafeine and 47.0% in those given paracetamol-dextropropoxyphen. The main criteria of efficacy--the percentage of success (decrease of pain > 50%)--was similar in the two groups as well in the intention-to-treat population (p = 0.01) as the per protocol population (p = 0.028). Kinetics of pain decrease during the first day of treatment were assessed with an hourly evaluation during the six first hours and at the 12th hour. There was no difference between the two groups. There was no serious adverse event and the frequency and intensity of the adverse events were similar in the two groups. The potentializing action of cafeine on paracetamol-induced pain relief enables a degree of pain relief equivalent to that of a combination using an analgesic with a peripheral action, paracetamol, and another with a central action, dextropoxyphen. The fact that the paracetamol-cafeine combination does not have a central action avoids secondary effects induced by central analgesics (drowsiness, constipation) in patients with osteoarthritis back pain.

Low dose ketamine use in the emergency department, a new direction in pain management.

PubMed

Pourmand, A; Mazer-Amirshahi, M; Royall, C; Alhawas, R; Shesser, R

2017-06-01

There is a need for alternative non-opioid analgesics for the treatment of acute, chronic, and refractory pain in the emergency department (ED). Ketamine is a fast acting N-methyl-d-aspartate (NMDA) receptor antagonist that provides safe and effective analgesia. The use of low dose ketamine (LDK) (<1mg/kg) provides sub-dissociative levels of analgesia and has been studied as an alternative and/or adjunct to opioid analgesics. We reviewed 11 studies using LDK either alone or in combination with opioid analgesics in the ED. Ketamine was shown to be efficacious at treating a variety of painful conditions. It has a favorable adverse effect profile when given at sub-dissociative doses. Studies have also compared LDK to opioids in the ED. Although ketamine's analgesic effects were not shown to be superior, they were comparable to opioids. LDK has the benefit of causing less respiratory depression. It likely has less wide spread potential for abuse. Nursing protocols for the administration of LDK have been studied. We believe that LDK has the potential to be a safe and effective alternative and/or adjunct to opioid analgesics in the ED. Additional studies are needed to expand upon and determine the optimal use of LDK in the ED. Copyright © 2017 Elsevier Inc. All rights reserved.

Assessing the impact of the extended-release/long-acting opioid an-algesics risk evaluation and mitigation strategies on opioid prescrip-tion volume.

PubMed

Divino, Victoria; Cepeda, M Soledad; Coplan, Paul; Maziere, Jean-Yves; Yuan, Yingli; Wade, Rolin L

The Food and Drug Administration approved the extended-release/long-acting (ER/LA) opioid analgesics risk evaluation and mitigation strategies (REMS) in July 2012 to educate healthcare providers and patients about safe and appropriate opioid analgesic use. The authors evaluated the impact of the REMS on ER/LA opioid analgesic utilization, overall and stratified by patient characteristics and prescriber type associated with greater expected need for analgesia. Retrospective repeated cross-sectional study. QuintilesIMS's National Prescription Audit™ and LifeLink™ patient-level longitudinal prescription databases measured prescription volumes, projected to national estimates. Changes were assessed in ER/LA opioid analgesic prescriptions dispensed from the 2-year pre-REMS implementation (July 2010 to June 2012) to the 18-month post-REMS implementation (July 2013 to December 2014) periods (with 12-month transitional implementation period in between). Average quarterly ER/LA opioid prescription volume significantly decreased by 4.3 percent from Preimple-mentation to the Active Period (5.58 vs 5.34 million, p < 0.001). Differences in prescription volume change were observed between age, gender, and payer types. Prescription volume either significantly decreased or remained stable from Preimplementation to the Active Period among most provider specialties evaluated. The largest volume decreases were observed for dentists (-48.5 percent) and emergency medicine specialists (-25.5 percent) (both p < 0.001). The largest increases were observed for nurse practitioners (+33.7 percent) and physician assistants (+31.2 percent; both p < 0.001), whose overall prescribing of nonopioid medications also increased. A significant decrease in dispensed ER/LA opioid prescriptions was observed following REMS implementation compared to Preimplementation. The impact on volume varied by patient characteristics and prescriber specialty. The REMS program, in conjunction with other healthcare policies and initiatives, likely influenced these observations.

Evaluation of antinociceptive effect of Petiveria alliacea (Guiné) in animals.

PubMed

de Lima, T C; Morato, G S; Takahashi, R N

1991-01-01

Petiveria alliacea (Phytolaccaceae) is a bush widely distributed in South America including Brazil, where it is popularly known as "guiné", "pipi", "tipi" or "erva-de-tipi". Brazilian folk medicine attributes to the hot water infusion of its roots or leaves the following pharmacological properties: antipyretic, antispasmodic, abortifacient, antirrheumatic, diuretic, analgesic and sedative. The present study has evaluated the alleged effects of P. alliacea on central nervous system (CNS), particularly, the sedative and analgesic properties of root crude aqueous extract of this plant in mice and rats. This extract showed an antinociceptive effect in acetic acid--acetylcholine--and hypertonic saline--induced abdominal constrictions, but not in hot-plate and tail flick tests. P. alliacea did not produce any CNS depressor effect. Thus its antinociceptive action in animals can be responsible by its popular use as an analgesic.

Antipyretic and analgesic activities of Caesalpinia bonducella seed kernel extract.

PubMed

Archana, P; Tandan, S K; Chandra, S; Lal, J

2005-05-01

Ethanolic extract (70%) of Caesalpinia bonducella seed kernel has been subjected for its antipyretic and antinociceptive activities in adult albino rats or mice of either sex at 30, 100 and 300 mg/kg orally. The extract demonstrated marked antipyretic activity against Brewer's yeast-induced pyrexia in rats. The extract had significant central analgesic activity in hot plate and tail flick methods. It also exhibited marked peripheral analgesic effect in both acetic acid-induced writhing test in mice and Randall-Selitto assay in rats. It also significantly inhibited the formalin-induced hind paw licking in mice. In conclusion, the present study suggests that the ethanolic extract of Caesalpinia bonducella seed kernel possesses potent antipyretic and antinociceptive activities and thus, validates its use in the treatment of pain and pyretic disorders. Copyright (c) 2005 John Wiley & Sons, Ltd.

Synthesis and characterization of a dual kappa-delta opioid receptor agonist analgesic blocking cocaine reward behavior.

PubMed

Váradi, András; Marrone, Gina F; Eans, Shainnel O; Ganno, Michelle L; Subrath, Joan J; Le Rouzic, Valerie; Hunkele, Amanda; Pasternak, Gavril W; McLaughlin, Jay P; Majumdar, Susruta

2015-11-18

3-Iodobenzoyl naltrexamine (IBNtxA) is a potent analgesic belonging to the pharmacologically diverse 6β-amidoepoxymorphinan group of opioids. We present the synthesis and pharmacological evaluation of five analogs of IBNtxA. The scaffold of IBNtxA was modified by removing the 14-hydroxy group, incorporating a 7,8 double bond and various N-17 alkyl substituents. The structural modifications resulted in analogs with picomolar affinities for opioid receptors. The lead compound (MP1104) was found to exhibit approximately 15-fold greater antinociceptive potency (ED50 = 0.33 mg/kg) compared with morphine, mediated through the activation of kappa- and delta-opioid receptors. Despite its kappa agonism, this lead derivative did not cause place aversion or preference in mice in a place-conditioning assay, even at doses 3 times the analgesic ED50. However, pretreatment with the lead compound prevented the reward behavior associated with cocaine in a conditioned place preference assay. Together, these results suggest the promise of dual acting kappa- and delta-opioid receptor agonists as analgesics and treatments for cocaine addiction.

Truncated G protein-coupled mu opioid receptor MOR-1 splice variants are targets for highly potent opioid analgesics lacking side effects

PubMed Central

Majumdar, Susruta; Grinnell, Steven; Le Rouzic, Valerie; Burgman, Maxim; Polikar, Lisa; Ansonoff, Michael; Pintar, John; Pan, Ying-Xian; Pasternak, Gavril W.

2011-01-01

Pain remains a pervasive problem throughout medicine, transcending all specialty boundaries. Despite the extraordinary insights into pain and its mechanisms over the past few decades, few advances have been made with analgesics. Most pain remains treated by opiates, which have significant side effects that limit their utility. We now describe a potent opiate analgesic lacking the traditional side effects associated with classical opiates, including respiratory depression, significant constipation, physical dependence, and, perhaps most important, reinforcing behavior, demonstrating that it is possible to dissociate side effects from analgesia. Evidence indicates that this agent acts through a truncated, six-transmembrane variant of the G protein-coupled mu opioid receptor MOR-1. Although truncated splice variants have been reported for a number of G protein-coupled receptors, their functional relevance has been unclear. Our evidence now suggests that truncated variants can be physiologically important through heterodimerization, even when inactive alone, and can comprise new therapeutic targets, as illustrated by our unique opioid analgesics with a vastly improved pharmacological profile. PMID:22106286

Truncated G protein-coupled mu opioid receptor MOR-1 splice variants are targets for highly potent opioid analgesics lacking side effects.

PubMed

Majumdar, Susruta; Grinnell, Steven; Le Rouzic, Valerie; Burgman, Maxim; Polikar, Lisa; Ansonoff, Michael; Pintar, John; Pan, Ying-Xian; Pasternak, Gavril W

2011-12-06

Pain remains a pervasive problem throughout medicine, transcending all specialty boundaries. Despite the extraordinary insights into pain and its mechanisms over the past few decades, few advances have been made with analgesics. Most pain remains treated by opiates, which have significant side effects that limit their utility. We now describe a potent opiate analgesic lacking the traditional side effects associated with classical opiates, including respiratory depression, significant constipation, physical dependence, and, perhaps most important, reinforcing behavior, demonstrating that it is possible to dissociate side effects from analgesia. Evidence indicates that this agent acts through a truncated, six-transmembrane variant of the G protein-coupled mu opioid receptor MOR-1. Although truncated splice variants have been reported for a number of G protein-coupled receptors, their functional relevance has been unclear. Our evidence now suggests that truncated variants can be physiologically important through heterodimerization, even when inactive alone, and can comprise new therapeutic targets, as illustrated by our unique opioid analgesics with a vastly improved pharmacological profile.

Differential Consequences of Tramadol in Overdosing: Dilemma of a Polymorphic Cytochrome P450 2D6-Mediated Substrate.

PubMed

Srinivas, Nuggehally R

2015-09-01

Tramadol is a centrally acting opioid analgesic that is prone to polymorphic metabolism via cytochrome P450 (CYP) 2D6. The generation of the active metabolite, O-desmethyltramadol, which occurs through the CYP 2D6 pathway, significantly contributes to the drug's activity. However, dosage adjustments of tramadol are typically not practiced in the clinic when treating patients who are homozygous extensive metabolizers, heterozygous extensive metabolizers, or poor metabolizers. In the event of a tramadol overdose, the consequences may be influenced importantly by the genotype or phenotype status of the subject. Depending on the individual subject's CYP 2D6 status, one may see excessive miotic-related toxicity driven by the excessive availability of O-desmethyltramadol or one may manifest mydriatic-related toxicity driven by the excessive availability of tramadol. This report provides pharmacokinetic perspectives in situations of tramadol overdosing.

Repetitive transcranial magnetic stimulation of the left premotor/dorsolateral prefrontal cortex does not have analgesic effect on central poststroke pain.

PubMed

de Oliveira, Rogério Adas Ayres; de Andrade, Daniel Ciampi; Mendonça, Melina; Barros, Rafael; Luvisoto, Tatiana; Myczkowski, Martin Luiz; Marcolin, Marco Antonio; Teixeira, Manoel Jacobsen

2014-12-01

Central poststroke pain (CPSP) is caused by an encephalic vascular lesion of the somatosensory pathways and is commonly refractory to current pharmacologic treatments. Repetitive transcranial magnetic stimulation (rTMS) of the premotor cortex/dorsolateral prefrontal cortex (PMC/DLPFC) can change thermal pain threshold toward analgesia in healthy subjects and has analgesic effects in acute postoperative pain as well as in fibromyalgia patients. However, its effect on neuropathic pain and in CPSP, in particular, has not been assessed. The aim of this prospective, double-blind, placebo-controlled study was to evaluate the analgesic effect of PMC/DLPFC rTMS in CPSP patients. Patients were randomized into 2 groups, active (a-) rTMS and sham (s-) rTMS, and were treated with 10 daily sessions of rTMS over the left PMC/DLPFC (10 Hz, 1,250 pulses/d). Outcomes were assessed at baseline, during the stimulation phase, and at 1, 2, and 4 weeks after the last stimulation. The main outcome was pain intensity changes measured by the visual analog scale on the last stimulation day compared to baseline. Interim analysis was scheduled when the first half of the patients completed the study. The study was terminated because of a significant lack of efficacy of the active arm after 21 patients completed the whole treatment and follow-up phases. rTMS of the left PMC/DLPFC did not improve pain in CPSP. The aim of this double-blind, placebo-controlled study was to evaluate the analgesic effects of rTMS to the PMC/DLPFC in CPSP patients. An interim analysis showed a consistent lack of analgesic effect, and the study was terminated. rTMS of the PMC/DLPFC is not effective in relieving CPSP. Copyright © 2014 American Pain Society. Published by Elsevier Inc. All rights reserved.

Analgesic Effects of Toad Cake and Toad-cake-containing Herbal Drugs: Analgesic effects of toad cake.

PubMed

Inoue, Eiji; Shimizu, Yasuharu; Masui, Ryo; Usui, Tomomi; Sudoh, Keiichi

2014-03-01

This study was conducted to clarify the analgesic effect of toad cake and toad-cake-containing herbal drugs. We counted the writhing response of mice after the intraperitoneal administration of acetic acid as a nociceptive pain model and the withdrawal response after the plantar surface stimulation of the hind paw induced by partial sciatic nerve ligation of the mice as a neuropathic pain model to investigate the analgesic effect of toad cake and toad-cake-containing herbal drugs. A co-treatment study with serotonin biosynthesis inhibitory drug 4-chloro- DL-phenylalanine methyl ester hydrochloride (PCPA), the catecholamine biosynthesis inhibitory drug α-methyl- DL-tyrosine methyl ester hydrochloride (AMPT) or the opioid receptor antagonist naloxone hydrochloride was also conducted. Analgesic effects in a mouse model of nociceptive pain and neuropathic pain were shown by oral administration of toad cake and toad-cake-containing herbal drugs. The effects of toad cake and toad-cake-containing herbal drugs disappeared upon co-treatment with PCPA, but not with AMPT or naloxone in the nociceptive pain model; the analgesic effect of toad-cake-containing herbal drugs also disappeared upon co-treatment with PCPA in the neuropathic pain model. Toad cake and toad-cake-containing herbal drugs have potential for the treatments of nociceptive pain and of neuropathic pain, such as post-herpetic neuralgia, trigeminal neuralgia, diabetic neuralgia, and postoperative or posttraumatic pain, by activation of the central serotonin nervous system.

A Subanalgesic Dose of Morphine Eliminates Nalbuphine Anti-analgesia in Postoperative Pain

PubMed Central

Gear, Robert W.; Gordon, Newton C.; Hossaini-Zadeh, Mehran; Lee, Janice S.; Miaskowski, Christine; Paul, Steven M.; Levine, Jon D.

2008-01-01

The agonist-antagonist kappa-opioid nalbuphine administered for postoperative pain produces greater analgesia in females than in males. In fact, males administered nalbuphine (5 mg) experience pain greater than those receiving placebo, suggesting the existence of an anti-analgesic effect. These sexually dimorphic effects on postoperative pain can be eliminated by co-administration of a fixed ratio of the prototypical opioid receptor antagonist naloxone with nalbuphine, implying a role for opioid receptors in the anti-analgesic as well as analgesic effects of nalbuphine. In the present study, we further evaluated the role of opioid receptors in the sex-specific effects on pain produced by nalbuphine by co-administering a dose of morphine low enough that it does not produce analgesia. Following extraction of bony impacted third molar teeth, nalbuphine (5 mg) was administered alone or in combination with either of two low doses of morphine (2 mg or 4 mg). Both doses of morphine reversed nalbuphine-induced anti-analgesia in males, but only the lower dose (2 mg) reached statistical significance. Neither dose affected nalbuphine-induced analgesia in females, and when administered alone in either males or females, morphine (2 mg) had no analgesic effect. Though not observed in females, the effect of morphine in males argues that, like naloxone, low dose morphine may act as an anti-analgesia opioid receptor antagonist. Perspective Previously we reported that the nalbuphine produces both analgesic and anti-analgesic effects, and that the opioid antagonist naloxone can enhance nalbuphine analgesia by selectively antagonizing the anti-analgesic effect. Here we show that morphine, given in a subanalgesic dose, reverses nalbuphine-induced anti-analgesia in males, perhaps by a similar mechanism. PMID:18201935

Pharmacological evaluation of Musa seminifera Lour. fruit.

PubMed

Saha, Sanjib; Hossain, Faroque; Anisuzzman, Md; Islam, Md Khirul

2013-07-01

To study potential antioxidant, analgesic, antidiarrheal, and antibacterial activities of the ethanol extract of Musa seminifera Lour. fruit in different established in vivo and in vitro experimental models. In vitro antioxidant activity was studied in 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical-scavenging assay. Phenolic content was determined using Folin-Ciocalteu's reagent. Reducing ability was evaluated by ferric reducing power assay. Peripherally and centrally acting analgesic activity was studied in three different in vivo models, namely, acetic acid-induced writhing, hot-plate test, and tail-flick test in Swiss albino mice. In vivo antidiarrheal activity was evaluated in castor oil- and magnesium sulfate-induced diarrhea in mice. Gastrointestinal motility test was also carried out in mice. All studies in mice were undertaken at the doses of 250 and 500 mg/kg body weight. Antibacterial activity was assessed by disk diffusion assay against some Gram-positive and Gram-negative bacterial strains. Acute toxicity test was conducted to assess the safe doses of the extract. The extract showed 50% inhibitory concentration value of 12.65 μg/mL in DPPH radical-scavenging assay. Phenolic content was found to be 589.83 mg gallic acid equivalent per 100 g of dried fruits extract. Reducing power was in a concentration-dependent manner, and strongly comparable with the standard ascorbic acid. The extract demonstrated significant inhibition of writhing in acetic acid-induced writhing test at both dose levels (P<0.01). The extract also raised pain threshold in both hot-plate and tail-flick test in a dose-dependent manner, and the results were statistically significant (P<0.01). The extract significantly (P<0.01) increased latent period, and decreased defecation in both castor oil- and magnesium sulfate-induced diarrhea. The extract also decreased gastrointestinal motility in mice. In disk diffusion assay, the extract showed potential antibacterial activity against all the tested bacterial strains. The results suggest that the ethanol extract of M. seminifera fruit has potential antioxidant, analgesic, antidiarrheal, and antibacterial activities.

PHARMACOKINETICS OF TRAMADOL HYDROCHLORIDE AND ITS METABOLITE O-DESMETHYLTRAMADOL FOLLOWING A SINGLE, ORALLY ADMINISTERED DOSE IN CALIFORNIA SEA LIONS (ZALOPHUS CALIFORNIANUS).

PubMed

Boonstra, Jennifer L; Barbosa, Lorraine; Van Bonn, William G; Johnson, Shawn P; Gulland, Frances M D; Cox, Sherry K; Martin-Jimenez, Tomas

2015-09-01

Tramadol is a synthetic, centrally acting, opiate-like analgesic that is structurally related to codeine and morphine. The objective of this study was to determine the pharmacokinetics of tramadol hydrochloride and its major active metabolite O-desmethyltramadol (M1) in the California sea lion (Zalophus californianus). A single dose of tramadol was administered orally in fish at 2 mg/kg to a total of 15 wild California sea lions admitted for rehabilitation. Twenty-four total blood samples were collected post drug administration at 10, 20, 30, and 45 min and at 1, 3, 5, 6, 8, 12, and 24 hr. Blood plasma was separated and stored at -80°C until analysis with high-performance liquid chromatography was performed to determine levels of tramadol and M1, the major active metabolite. The results indicate that the plasma levels of parent tramadol are low or negligible during the first 30-45 min and then reach the predicted mean maximum plasma concentration of 358 ng/ml at 1.52 hr. The M1 metabolite was not detectable in 21 of 24 plasma samples, below the level of quantification of 5 ng/ml in one sample, and detectable at 11 and 17 ng/ml in two of the samples. This study suggests that a 2 mg/kg dose would need to be administered every 6-8 hr to maintain concentrations of tramadol above the minimum human analgesic level for mild to moderate pain. Based on dosing simulations, a dose of 4 mg/kg q8 hr or q12 hr, on average, may represent an adequate compromise, but further studies are needed using a larger sample size. Pharmacodynamic studies are warranted to determine if tramadol provides analgesic effects in this species. The potential for tramadol toxicosis at any dose also has not been determined in this species.

Perioperative pain control: a strategy for management.

PubMed

Cohen, Mitchell Jay; Schecter, William P

2005-12-01

A thorough understanding of the anatomy and neurophysiology of the pain response is necessary for the effective treatment of perioperative pain. This article describes the mechanisms that produce pain,including those related to inflammation. Other topics include the pharmacologies of nonopioid and opioid analgesics. Nonopioid analgesics can be separated into two categories: nonsteroidal anti-inflammatory drugs, such as salicylates, and acetaminophen. Opioids include morphine, fentanyl, and meperidine. The pharmacology of local anesthesia is discussed. The six major adverse reactions to local anesthetics are cardiac arrhythmias, hypertension, direct tissue toxicity, central nervous system toxicity, methemoglobinemia and allergic reactions. Methods for measuring pain are described.

Antinociceptive properties of physalins from Physalis angulata.

PubMed

Lima, Milena da Silva; Evangelista, Afrânio Ferreira; Santos, Gisele Graça Leite Dos; Ribeiro, Ivone Maria; Tomassini, Therezinha Coelho Barbosa; Pereira Soares, Milena Botelho; Villarreal, Cristiane Flora

2014-11-26

Pain is the most common reason a patient sees a physician. Nevertheless, the use of typical painkillers is not completely effective in controlling all pain syndromes; therefore further attempts have been made to develop improved analgesic drugs. The present study was undertaken to evaluate the antinociceptive properties of physalins B (1), D (2), F (3), and G (4) isolated from Physalis angulata in inflammatory and centrally mediated pain tests in mice. Systemic pretreatment with 1-4 produced dose-related antinociceptive effects on the writhing and formalin tests, traditional screening tools for the assessment of analgesic drugs. On the other hand, only 3 inhibited inflammatory parameters such as hyperalgesia, edema, and local production of TNF-α following induction with complete Freund's adjuvant. Treatment with 1, 3, and 4 produced an antinociceptive effect on the tail flick test, suggesting a centrally mediated antinociception. Reinforcing this idea, 2-4 enhanced the mice latency reaction time during the hot plate test. Mice treated with physalins did not demonstrate motor performance alterations. These results suggest that 1-4 present antinociceptive properties associated with central, but not anti-inflammatory, events and indicate a new pharmacological property of physalins.

Analgesic and antiinflammatory activity of Morinda citrifolia L. (Noni) fruit.

PubMed

Basar, Simla; Uhlenhut, Klaus; Högger, Petra; Schöne, Florian; Westendorf, Johannes

2010-01-01

M. citrifolia is a tropical plant with a long tradition of medicinal use in Polynesia and tropical parts of eastern Asia and Australia. One of its favorite uses is the treatment of painful inflammatory conditions, such as arthritis. The analgesic activity of Noni fruit puree on mice was investigated using the hot plate test. A 10% solution of freeze concentrated Noni fruit puree in the drinking water of mice reduced the pain sensitivity comparably to the central analgesic drug tramadol. This effect was only partly reversed by the application of the morphine antagonist naloxone. An alcohol extract of noni fruit puree also caused an inhibition of MMP-9 release from human monocytes after stimulation with LPS. This effect was comparable to hydrocortisone (10(-5) m). The findings suggest that preparations of noni fruits are effective in decreasing pain and joint destruction caused by arthritis. (c) 2009 John Wiley & Sons, Ltd.

Antioxidant, antinociceptive, and anti-inflammatory effects of carotenoids extracted from dried pepper (Capsicum annuum L.).

PubMed

Hernández-Ortega, Marcela; Ortiz-Moreno, Alicia; Hernández-Navarro, María Dolores; Chamorro-Cevallos, Germán; Dorantes-Alvarez, Lidia; Necoechea-Mondragón, Hugo

2012-01-01

Carotenoids extracted from dried peppers were evaluated for their antioxidant, analgesic, and anti-inflammatory activities. Peppers had a substantial carotenoid content: guajillo 3406 ± 4 μg/g, pasilla 2933 ± 1 μg/g, and ancho 1437 ± 6 μg/g of sample in dry weight basis. A complex mixture of carotenoids was discovered in each pepper extract. The TLC analysis revealed the presence of chlorophylls in the pigment extract from pasilla and ancho peppers. Guajillo pepper carotenoid extracts exhibited good antioxidant activity and had the best scavenging capacity for the DPPH(+) cation (24.2%). They also exhibited significant peripheral analgesic activity at 5, 20, and 80 mg/kg and induced central analgesia at 80 mg/kg. The results suggest that the carotenoids in dried guajillo peppers have significant analgesic and anti-inflammatory benefits and could be useful for pain and inflammation relief.

Antioxidant, Antinociceptive, and Anti-Inflammatory Effects of Carotenoids Extracted from Dried Pepper (Capsicum annuum L.)

PubMed Central

Hernández-Ortega, Marcela; Ortiz-Moreno, Alicia; Hernández-Navarro, María Dolores; Chamorro-Cevallos, Germán; Dorantes-Alvarez, Lidia; Necoechea-Mondragón, Hugo

2012-01-01

Carotenoids extracted from dried peppers were evaluated for their antioxidant, analgesic, and anti-inflammatory activities. Peppers had a substantial carotenoid content: guajillo 3406 ± 4 μg/g, pasilla 2933 ± 1 μg/g, and ancho 1437 ± 6 μg/g of sample in dry weight basis. A complex mixture of carotenoids was discovered in each pepper extract. The TLC analysis revealed the presence of chlorophylls in the pigment extract from pasilla and ancho peppers. Guajillo pepper carotenoid extracts exhibited good antioxidant activity and had the best scavenging capacity for the DPPH+ cation (24.2%). They also exhibited significant peripheral analgesic activity at 5, 20, and 80 mg/kg and induced central analgesia at 80 mg/kg. The results suggest that the carotenoids in dried guajillo peppers have significant analgesic and anti-inflammatory benefits and could be useful for pain and inflammation relief. PMID:23091348

Emerging targets and therapeutic approaches for the treatment of osteoarthritis pain.

PubMed

Rahman, Wahida; Dickenson, Anthony H

2015-06-01

Osteoarthritis is a complex and often painful disease that is inadequately controlled with current analgesics. This review discusses emerging targets and therapeutic approaches that may lead to the development of better analgesics. Aberrant excitability in peripheral and central pain pathways drives osteoarthritis pain, reversing this via modulation of nerve growth factor, voltage-gated sodium channel, voltage-gated calcium channel and transient receptor potential vanilloid one activity, and increasing inhibitory mechanisms through modulation of cannabinoid and descending modulatory systems hold promise for osteoarthritis pain therapy. Somatosensory phenotyping of chronic pain patients, as a surrogate of putative pain generating mechanisms, may predict patient response to treatment. Identification of new targets will inform and guide future research, aiding the development of more effective analgesics. Future clinical trial designs should implement sensory phenotyping of patients, as an inclusion or stratification criterion, in order to establish an individualized, mechanism-based treatment of osteoarthritis pain.

The opioid systems--panacea and nemesis.

PubMed

Terenius, Lars; Johansson, Björn

2010-05-21

This mini-review outlines the opioid systems and their roles primarily as related to reward and compulsive drug/alcohol intake. The central role is taken by the mu-opioid receptor, target for opiate analgesics and also a central target in compulsive alcohol abuse, alcoholism. The mu-opioid receptor and the cognate opioid neuropeptides from proenkephalin and proopiomelancortin are members of a superfamily of opioid systems, each with unique and still to be defined roles in the central nervous system. 2010. Published by Elsevier Inc.

Imaging drugs with and without clinical analgesic efficacy.

PubMed

Upadhyay, Jaymin; Anderson, Julie; Schwarz, Adam J; Coimbra, Alexandre; Baumgartner, Richard; Pendse, G; George, Edward; Nutile, Lauren; Wallin, Diana; Bishop, James; Neni, Saujanya; Maier, Gary; Iyengar, Smriti; Evelhoch, Jeffery L; Bleakman, David; Hargreaves, Richard; Becerra, Lino; Borsook, David

2011-12-01

The behavioral response to pain is driven by sensory and affective components, each of which is mediated by the CNS. Subjective pain ratings are used as readouts when appraising potential analgesics; however, pain ratings alone cannot enable a characterization of CNS pain circuitry during pain processing or how this circuitry is modulated pharmacologically. Having a more objective readout of potential analgesic effects may allow improved understanding and detection of pharmacological efficacy for pain. The pharmacological/functional magnetic resonance imaging (phMRI/fMRI) methodology can be used to objectively evaluate drug action on the CNS. In this context, we aimed to evaluate two drugs that had been developed as analgesics: one that is efficacious for pain (buprenorphine (BUP)) and one that failed as an analgesic in clinical trials aprepitant (APREP). Using phMRI, we observed that activation induced solely by BUP was present in regions with μ-opioid receptors, whereas APREP-induced activation was seen in regions expressing NK(1) receptors. However, significant pharmacological modulation of functional connectivity in pain-processing pathways was only observed following BUP administration. By implementing an evoked pain fMRI paradigm, these drugs could also be differentiated by comparing the respective fMRI signals in CNS circuits mediating sensory and affective components of pain. We report a correlation of functional connectivity and evoked pain fMRI measures with pain ratings as well as peak drug concentration. This investigation demonstrates how CNS-acting drugs can be compared, and how the phMRI/fMRI methodology may be used with conventional measures to better evaluate candidate analgesics in small subject cohorts.

Imaging Drugs with and without Clinical Analgesic Efficacy

PubMed Central

Upadhyay, Jaymin; Anderson, Julie; Schwarz, Adam J; Coimbra, Alexandre; Baumgartner, Richard; Pendse, G; George, Edward; Nutile, Lauren; Wallin, Diana; Bishop, James; Neni, Saujanya; Maier, Gary; Iyengar, Smriti; Evelhoch, Jeffery L; Bleakman, David; Hargreaves, Richard; Becerra, Lino; Borsook, David

2011-01-01

The behavioral response to pain is driven by sensory and affective components, each of which is mediated by the CNS. Subjective pain ratings are used as readouts when appraising potential analgesics; however, pain ratings alone cannot enable a characterization of CNS pain circuitry during pain processing or how this circuitry is modulated pharmacologically. Having a more objective readout of potential analgesic effects may allow improved understanding and detection of pharmacological efficacy for pain. The pharmacological/functional magnetic resonance imaging (phMRI/fMRI) methodology can be used to objectively evaluate drug action on the CNS. In this context, we aimed to evaluate two drugs that had been developed as analgesics: one that is efficacious for pain (buprenorphine (BUP)) and one that failed as an analgesic in clinical trials aprepitant (APREP). Using phMRI, we observed that activation induced solely by BUP was present in regions with μ-opioid receptors, whereas APREP-induced activation was seen in regions expressing NK1 receptors. However, significant pharmacological modulation of functional connectivity in pain-processing pathways was only observed following BUP administration. By implementing an evoked pain fMRI paradigm, these drugs could also be differentiated by comparing the respective fMRI signals in CNS circuits mediating sensory and affective components of pain. We report a correlation of functional connectivity and evoked pain fMRI measures with pain ratings as well as peak drug concentration. This investigation demonstrates how CNS-acting drugs can be compared, and how the phMRI/fMRI methodology may be used with conventional measures to better evaluate candidate analgesics in small subject cohorts. PMID:21849979

Preemptive, preventive, multimodal analgesia: what do they really mean?

PubMed

Rosero, Eric B; Joshi, Girish P

2014-10-01

To improve postoperative pain management, several concepts have been developed, including preemptive analgesia, preventive analgesia, and multimodal analgesia. This article will discuss the role of these concepts in improving perioperative pain management. Preemptive analgesia refers to the administration of an analgesic treatment before the surgical insult or tissue injury. Several randomized clinical trials have, however, provided equivocal evidence regarding the benefits of preincisional compared with postincisional analgesic administration. Current general consensus, therefore, indicates that use of preemptive analgesia does not translate into consistent clinical benefits after surgery. Preventive analgesia is a wider concept where the timing of analgesic administration in relation to the surgical incision is not critical. The aim of preventive analgesia is to minimize sensitization induced by noxious stimuli arising throughout the perioperative period. Multimodal analgesia consists of the administration of 2 or more drugs that act by different mechanisms for providing analgesia. These drugs may be administered via the same route or by different routes. Thus, the aim of multimodal analgesia is to improve pain relief while reducing opioid requirements and opioid-related adverse effects. Analgesic modalities currently available for postoperative pain control include opioids, local anesthetic techniques [local anesthetic infiltration, peripheral nerve blocks, and neuraxial blocks (epidural and paravertebral)], acetaminophen, nonsteroidal anti-inflammatory drugs, and cyclooxygenase-2-specific inhibitors as well as analgesic adjuncts such as steroids, ketamine, α-2 agonists, and anticonvulsants.

The role of tramadol in current treatment strategies for musculoskeletal pain

PubMed Central

Schug, Stephan A

2007-01-01

Non-selective and cyclooxygenase-2 (COX-2) selective non-steroidal anti-inflammatory drugs (NSAIDs) have been the mainstay of treatment for musculoskeletal pain of moderate intensity. However, in addition to gastrointestinal and renal toxicity, an increased cardiovascular risk may be a class effect for all NSAIDs. Despite these safety risks and the acknowledged ceiling effect of NSAIDs, many doctors still use them to treat moderate, mostly musculoskeletal pain. Recent guidelines for treating osteoarthritis and low back pain, issued by numerous professional medical societies, recommend NSAIDs and COX-2 inhibitors only in strictly defined circumstances, at the lowest effective dose and for the shortest possible period of time. These recent guidelines bring more focus to the usage of paracetamol and opioids. But opioids still remain under-utilized, although they are effective with minimal organ toxicity. In this setting, the atypical, centrally acting analgesic tramadol offers important benefits. Its multi-modal effect results from a dual mode of action, ie, opioid and monoaminergic mechanisms, with efficacy in both nociceptive and neuropathic pain. Moreover, fewer instances of side effects such as constipation, respiratory depression, and sedation occur than with traditional opioids, and tramadol has been prescribed for 30 years for a broad range of indications. Tramadol is now regarded as the first-line analgesic for many musculoskeletal indications. In conclusion, it is recommended to better implement the more recent guidelines focusing on pain management and consider the role of tramadol in musculoskeletal pain treatment strategies. PMID:18472996

Central sensitization: Implications for the diagnosis and treatment of pain

PubMed Central

Woolf, Clifford J

2010-01-01

Nociceptor inputs can trigger a prolonged but reversible increase in the excitability and synaptic efficacy of neurons in central nociceptive pathways, the phenomenon of central sensitization. Central sensitization manifests as pain hypersensitivity, particularly dynamic tactile allodynia, secondary punctate or pressure hyperalgesia, aftersensations, and enhanced temporal summation. It can be readily and rapidly elicited in human volunteers by diverse experimental noxious conditioning stimuli to skin, muscles or viscera, and in addition to producing pain hypersensitivity, results in secondary changes in brain activity that can be detected by electrophysiological or imaging techniques. Studies in clinical cohorts reveal changes in pain sensitivity that have been interpreted as revealing an important contribution of central sensitization to the pain phenotype in patients with fibromyalgia, osteoarthritis, musculoskeletal disorders with generalized pain hypersensitivity, headache, temporomandibular joint disorders, dental pain, neuropathic pain, visceral pain hypersensitivity disorders and postsurgical pain. The comorbidity of those pain hypersensitivity syndromes that present in the absence of inflammation or a neural lesion, their similar pattern of clinical presentation and response to centrally acting analgesics, may reflect a commonality of central sensitization to their pathophysiology. An important question that still needs to be determined is whether there are individuals with a higher inherited propensity for developing central sensitization than others, and if so, whether this conveys an increased risk both of developing conditions with pain hypersensitivity, and their chronification. Diagnostic criteria to establish the presence of central sensitization in patients will greatly assist the phenotyping of patients for choosing treatments that produce analgesia by normalizing hyperexcitable central neural activity. We have certainly come a long way since the first discovery of activity-dependent synaptic plasticity in the spinal cord and the revelation that it occurs and produces pain hypersensitivity in patients. Nevertheless, discovering the genetic and environmental contributors to and objective biomarkers of central sensitization will be highly beneficial, as will additional treatment options to prevent or reduce this prevalent and promiscuous form of pain plasticity. PMID:20961685

Use of and barriers to access to opioid analgesics: a worldwide, regional, and national study.

PubMed

Berterame, Stefano; Erthal, Juliana; Thomas, Johny; Fellner, Sarah; Vosse, Benjamin; Clare, Philip; Hao, Wei; Johnson, David T; Mohar, Alejandro; Pavadia, Jagjit; Samak, Ahmed Kamal Eldin; Sipp, Werner; Sumyai, Viroj; Suryawati, Sri; Toufiq, Jallal; Yans, Raymond; Mattick, Richard P

2016-04-16

Despite opioid analgesics being essential for pain relief, use has been inadequate in many countries. We aim to provide up-to-date worldwide, regional, and national data for changes in opioid analgesic use, and to analyse the relation of impediments to use of these medicines. We calculated defined daily doses for statistical purposes (S-DDD) per million inhabitants per day of opioid analgesics worldwide and for regions and countries from 2001 to 2013, and we used generalised estimating equation analysis to assess longitudinal change in use. We compared use data against the prevalence of some health disorders needing opioid use. We surveyed 214 countries or territories about impediments to availability of these medicines, and used regression analyses to establish the strength of associations between impediments and use. The S-DDD of opioid analgesic use more than doubled worldwide between 2001-03 and 2011-13, from 1417 S-DDD (95% CI -732 to 3565; totalling about 3.01 billion defined daily doses per annum) to 3027 S-DDD (-1162 to 7215; totalling about 7.35 billion defined daily doses per annum). Substantial increases occurred in North America (16,046 S-DDD [95% CI 4032-28,061] to 31,453 S-DDD [8121-54,785]), western and central Europe (3079 S-DDD [1274-4883] to 9320 S-DDD [3969-14,672]), and Oceania (2275 S-DDD [763-3787] to 9136 S-DDD [2508-15,765]). Countries in other regions have shown no substantial increase in use. Impediments to use included an absence of training and awareness in medical professionals, fear of dependence, restricted financial resources, issues in sourcing, cultural attitudes, fear of diversion, international trade controls, and onerous regulation. Higher number of impediments reported was significantly associated with lower use (unadjusted incidence rate ratio 0.39 [95% CI 0.29-0.52]; p<0.0001), but not when adjusted for gross domestic product and human development index (0.91 [0.73-1.14]; p=0.4271). Use of opioid analgesics has increased, but remains low in Africa, Asia, Central America, the Caribbean, South America, and eastern and southeastern Europe. Identified impediments to use urgently need to be addressed by governments and international agencies. International Narcotics Control Board, UN. Copyright © 2016 Elsevier Ltd. All rights reserved.

A review of analgesic compounds used in food animals in the United States.

PubMed

Coetzee, Johann F

2013-03-01

Extralabel drug use for pain relief in the United States is regulated under the Animal Medicinal Drug Use Clarification Act. Agents that may provide analgesia in livestock include local anesthetics, nonsteroidal antiinflammatory drugs, opioids, α2-agonists, and N-methyl-d-aspartate receptor antagonists. The challenges associated with providing pain relief in food animals and the salient pharmacokinetic and pharmacodynamic features of the analgesic compounds that could potentially be used in livestock are reviewed. The potential use of novel agents such as bicarbonate, magnesium, ethanol, and gabapentin to augment analgesia is also discussed. Copyright © 2013 Elsevier Inc. All rights reserved.

Paraspinous Lidocaine Injection for Chronic Nonspecific Low Back Pain: A Randomized Controlled Clinical Trial.

PubMed

Imamura, Marta; Imamura, Satiko Tomikawa; Targino, Rosa Alves; Morales-Quezada, León; Onoda Tomikawa, Luis C; Onoda Tomikawa, Luis G; Alfieri, Fabio M; Filippo, Thais R; da Rocha, Ivan D; Neto, Raul Bolliger; Fregni, Felipe; Battistella, Linamara Rizzo

2016-05-01

In this large, sham-controlled, randomized trial, we examined the efficacy of the combination of standard treatment and paraspinous lidocaine injection compared with standard therapy alone in subjects with chronic low back pain. There is little research-based evidence for the routine clinical use of paraspinous lidocaine injection for low back pain. A total of 378 subjects with nonspecific chronic low back pain were randomized to 3 groups: paraspinous lidocaine injection, analgesics, and exercises (group 1, LID-INJ); sham paraspinous lidocaine injection, analgesics, and exercises (group 2, SH-INJ); and analgesics and exercises (group 3, STD-TTR). A blinded rater assessed the study outcomes at 3 time points: baseline, after treatment, and after 3 months of follow-up. There were increased frequency of pain responses and better low back functional scores in the LID-INJ group compared with the SH-INJ and STD-TTR groups. These effects remained at the 3-month follow-up but differed between all 3 groups. There were significant changes in pain threshold immediately after treatment, supporting the effects of this intervention in reducing central sensitization. Paraspinous lidocaine injection therapy is not associated with a higher risk of adverse effects compared with conventional treatment and sham injection. Its effects on hyperalgesia might correlate with changes in central sensitization. NCT02387567. There are few data to support paraspinous lidocaine injection use in patients with nonspecific chronic low back pain. Our results show that this therapy when combined with standard therapy significantly increases the number of responders versus standard treatment alone. Its effects on hyperalgesia might correlate with a change in central sensitization. Copyright © 2016. Published by Elsevier Inc.

Antiinflammatory, analgesic and hypoglycemic effects of Mangifera indica Linn. (Anacardiaceae) stem-bark aqueous extract.

PubMed

Ojewole, J A O

2005-10-01

Previous studies in our laboratories and elsewhere have shown that some members of Anacardiaceae family possess antiinflammatory, analgesic and hypoglycemic effects in man and mammalian experimental animals. The present study was, therefore, undertaken to examine the antiinflammatory, analgesic and antidiabetic properties of the stem-bark aqueous extract of Mangifera indica Linn., M. indica a member of the Anacardiaceae family, in rats and mice. The stem-bark powder of M. indica was Soxhlet extracted with distilled water and used. The analgesic effect of the plant's extract was evaluated by the hot-plate and acetic acid test models of pain in mice, while the antiinflammatory and antidiabetic effects of the stem-bark extract were investigated in rats, using fresh egg albumin-induced paw edema, and streptozotocin (STZ)-induced diabetes mellitus, respectively. Morphine (MPN, 10 mg/kg i.p.), diclofenac (DIC, 100 mg/kg i.p.), and chlorpropamide (250 mg/kg p.o.) were used respectively as reference analgesic, antiinflammatory, and hypoglycemic agents for comparison. M. indica stem-bark aqueous extract (MIE, 50-800 mg/kg i.p.) produced dose-dependent and significant (p<0.05-0.001) analgesic effects against thermally and chemically induced nociceptive pain stimuli in mice. MIE (50-800 mg/kg i.p.) also significantly (p<0.05-0.001) inhibited fresh egg albumin-induced paw edema, and caused significant (p<0.05-0.001) hypoglycemic effects in rats. It is suggested that the analgesic effects of MIE (50-800 mg/kg i.p.) may be peripherally and centrally mediated. The different chemical constituents of the plant, especially the polyphenolics, flavonoids, triterpenoids, mangiferin, and other chemical compounds present in the plant may be involved in the observed antiinflammatory, analgesic, and hypoglycemic effects of the plant's extract. However, the results of this experimental animal study lend pharmacological credence to the suggested folkloric uses of the plant in the management and control of painful, arthritic and other inflammatory conditions, as well as in the management of adult-onset type 2 diabetes mellitus in some rural African communities. (c) 2005 Prous Science. All rights reserved.

Multimodal analgesia and regional anaesthesia.

PubMed

Tornero Tornero, C; Fernández Rodríguez, L E; Orduña Valls, J

Multimodal analgesia provides quality analgesia, with fewer side effects due to the use of combined analgesics or analgesic techniques. Regional anaesthesia plays a fundamental role in achieving this goal. The different techniques of regional anaesthesia that include both peripheral and central blocks in either a single dose or in continuous infusion help to modulate the nociceptive stimuli that access the central level. The emergence of the ultrasound as an effective system to perform regional anaesthesia techniques has allowed the development of new regional anaesthesia techniques that formerly could not be carried out since only neurostimulation or skin references were used. It is essential to take into account that even with effective blocking it is advisable to associate other drugs by other routes, in this way we will be able to reduce the required doses individually and attempt to achieve a synergistic, not purely additive, effect. Copyright © 2017 Sociedad Española de Anestesiología, Reanimación y Terapéutica del Dolor. Publicado por Elsevier España, S.L.U. All rights reserved.

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.

Analgesic Effects of Toad Cake and Toad-cake-containing Herbal Drugs

PubMed Central

Inoue, Eiji; Shimizu, Yasuharu; Masui, Ryo; Usui, Tomomi; Sudoh, Keiichi

2014-01-01

Objectives: This study was conducted to clarify the analgesic effect of toad cake and toad-cake-containing herbal drugs. Methods: We counted the writhing response of mice after the intraperitoneal administration of acetic acid as a nociceptive pain model and the withdrawal response after the plantar surface stimulation of the hind paw induced by partial sciatic nerve ligation of the mice as a neuropathic pain model to investigate the analgesic effect of toad cake and toad-cake-containing herbal drugs. A co-treatment study with serotonin biosynthesis inhibitory drug 4-chloro- DL-phenylalanine methyl ester hydrochloride (PCPA), the catecholamine biosynthesis inhibitory drug α-methyl- DL-tyrosine methyl ester hydrochloride (AMPT) or the opioid receptor antagonist naloxone hydrochloride was also conducted. Results: Analgesic effects in a mouse model of nociceptive pain and neuropathic pain were shown by oral administration of toad cake and toad-cake-containing herbal drugs. The effects of toad cake and toad-cake-containing herbal drugs disappeared upon co-treatment with PCPA, but not with AMPT or naloxone in the nociceptive pain model; the analgesic effect of toad-cake-containing herbal drugs also disappeared upon co-treatment with PCPA in the neuropathic pain model. Conclusion: Toad cake and toad-cake-containing herbal drugs have potential for the treatments of nociceptive pain and of neuropathic pain, such as post-herpetic neuralgia, trigeminal neuralgia, diabetic neuralgia, and postoperative or posttraumatic pain, by activation of the central serotonin nervous system. PMID:25780693

Non-prescription (OTC) oral analgesics for acute pain - an overview of Cochrane reviews.

PubMed

Moore, R Andrew; Wiffen, Philip J; Derry, Sheena; Maguire, Terry; Roy, Yvonne M; Tyrrell, Laila

2015-11-04

Non-prescription (over-the-counter, or OTC) analgesics (painkillers) are used frequently. They are available in various brands, package sizes, formulations, and dose. They can be used for a range of different types of pain, but this overview reports on how well they work for acute pain (pain of short duration, usually with rapid onset). Thirty-nine Cochrane reviews of randomised trials have examined the analgesic efficacy of individual drug interventions in acute postoperative pain. To examine published Cochrane reviews for information about the efficacy of pain medicines available without prescription using data from acute postoperative pain. We identified OTC analgesics available in the UK, Australia, Canada, and the USA by examining online pharmacy websites. We also included some analgesics (diclofenac potassium, dexketoprofen, dipyrone) of importance in parts of the world, but not currently available in these jurisdictions.We identified systematic reviews by searching the Cochrane Database of Systematic Reviews (CDSR) on The Cochrane Library through a simple search strategy. All reviews were overseen by a single review group, had a standard title, and had as their primary outcome numbers of participants with at least 50% pain relief over four to six hours compared with placebo. From individual reviews we extracted the number needed to treat for an additional beneficial outcome (NNT) for this outcome for each drug/dose combination, and also calculated the success rate to achieve at least 50% of maximum pain relief. We also examined the number of participants experiencing any adverse event, and whether the incidence was different from placebo. We found information on 21 different OTC analgesic drugs, doses, and formulations, using information from 10 Cochrane reviews, supplemented by information from one non-Cochrane review with additional information on ibuprofen formulations (high quality evidence). The lowest (best) NNT values were for combinations of ibuprofen plus paracetamol, with NNT values below 2. Analgesics with values close to 2 included fast acting formulations of ibuprofen 200 mg and 400 mg, ibuprofen 200 mg plus caffeine 100 mg, and diclofenac potassium 50 mg. Combinations of ibuprofen plus paracetamol had success rates of almost 70%, with dipyrone 500 mg, fast acting ibuprofen formulations 200 mg and 400 mg, ibuprofen 200 mg plus caffeine 100 mg, and diclofenac potassium 50 mg having success rates above 50%. Paracetamol and aspirin at various doses had NNT values of 3 or above, and success rates of 11% to 43%. We found no information on many of the commonly available low dose codeine combinations.The proportion of participants experiencing an adverse event were generally not different from placebo, except for aspirin 1000 mg and (barely) ibuprofen 200 mg plus caffeine 100 mg. For ibuprofen plus paracetamol, adverse event rates were lower than with placebo. There is a body of reliable evidence about the efficacy of some of the most commonly available drugs and doses widely available without prescription. The postoperative pain model is predominantly pain after third molar extraction, which is used as the industry model for everyday pain. The proportion of people with acute pain who get good pain relief with any of them ranges from around 70% at best to less than 20% at worst; low doses of some drugs in fast acting formulations were among the best. Adverse events were generally no different from placebo. Consumers can make an informed choice based on this knowledge, together with availability and price. Headache and migraine were not included in this overview.

Extended-release hydrocodone – gift or curse?

PubMed Central

Krashin, Daniel; Murinova, Natalia; Trescot, Andrea M

2013-01-01

Hydrocodone is a semisynthetic opioid, which has been used for decades as a short-acting analgesic combined with acetaminophen (or less commonly ibuprofen). Several long-acting, non-acetaminophen-containing hydrocodone formulations are undergoing trials in the US under the auspices of the US Food and Drug Administration, and may be available shortly. This article reviews some of the advantages (including drug familiarity and lack of acetaminophen toxicity) and potential disadvantages (including altered use patterns and high morphine equivalent dosing) of such a medication formulation. We also discuss the abuse potential of long-acting versus short-acting opioids in general and hydrocodone specifically, as well as the metabolism of hydrocodone. PMID:23358452

The analgesic effect of clonixine is not mediated by 5-HT3 subtype receptors.

PubMed

Paeile, C; Bustamante, S E; Sierralta, F; Bustamante, D; Miranda, H F

1995-10-01

1. The analgesic effect of clonixinate of L-lysine (Clx) in the nociceptive C-fiber reflex in rat and in the writhing test in mice is reported. 2. Clx was administered by three routes, i.v., i.t. and i.c.v., inducing a dose-dependent antinociception. 3. The antinociceptive effect of Clx was 40-45% with respect to the control integration values in the nociceptive C-fiber reflex method. 4. The writhing test yielded ED50 values (mg/kg) of 12.0 +/- 1.3 (i.p.), 1.8 +/- 0.2 (i.t.) and 0.9 +/- 0.1 (i.c.v.) for Clx administration. 5. Ondansetron was not able to antagonize the antinociception response of Clx in the algesiometric tests used. 6. Chlorophenilbiguanide did not produce any significative change in the analgesic effect of Clx in the nociceptive C-fiber reflex method. 7. It is suggested that the mechanism of action of the central analgesia of Clx is not mediated by 5-HT3 subtype receptors.

Investigation of the central and peripheral analgesic and anti-inflammatory activity of Draksharishta an Indian Ayurvedic formulation

PubMed Central

Kabir, Ashraf-ul; Samad, Mehdi Bin; D′Costa, Ninadh Malrina; Hannan, Juardar Mohammad

2012-01-01

Rationale: Draksharishta (DRK) is an Ayurvedic formulation approved by the “National formulary of Ayurvedic Medicine 2011”, of Bangladesh. It is widely available in the Bangladeshi market as an effective preparation to treat lumbago, sciatia and arthritic pain of joints. But there are very scientific evidences available to support their common uses. Objectives: Our present studies make an attempt toward identifying probable antinociceptive and anti-inflammatory effect and its mechanisms of DRK. Findings: DRK, at three doses, (10 mL/kg, 20 mL/kg, and 40 mL/kg) showed no involvement of the CNS in antinociceptive activity of the test drug. Both Carrageenan-induced paw edema and acetic acid writhing tests gave significant results (P < 0.05), indicating possible peripheral analgesic and anti-inflammatory action. Formalin-induced paw- licking test showed that DRK had significant effect in suppressing inflammatory pain (P < 0.05) but not neurogenic pain. Conclusions: Hence our study shows anti-inflammatory and peripheral analgesic action for DRK. PMID:24826047

Lidocaine and Pain Management in the Emergency Department: A Review Article

PubMed Central

Golzari, Samad EJ; Soleimanpour, Hassan; Mahmoodpoor, Ata; Safari, Saeid; Ala, Alireza

2014-01-01

Context: In the present review, the analgesic effects of lidocaine in acute or chronic painful conditions in the emergency department are discussed. Lidocaine, as a medium-acting local anesthetic with short onset time, is well-recognized, not only as a valuable medication for numerous neuropathic pain conditions, but also for the management of both acute and chronic pain. Evidence Acquisition: Research studies related to the different applications of lidocaine in the emergency department were collected from different databases including Cochrane library, Medline (Ovid) and PubMed. The pooled data were categorized, summarized and finally compared. Results: Our study revealed that lidocaine is broadly used in various therapeutic approaches for different types of pain, such as visceral/central pain, renal colic etc., in the emergency department. Conclusions: The antinociceptive properties of lidocaine are derived from multifaceted mechanisms, turning it into a medication that is safe to administer via different routes which makes it available for use in a variety of medical conditions. PMID:24660158

[Biperiden abuse as a partial factor in polytoxicomania].

PubMed

Schulte, R M

1988-03-01

We found 16 patients (15%) taking the anticholinergic biperiden because of its psychotropic action, occasionally, rather frequently or regularly, among a subgroup of 120 drug-dependent patients (drugs of the barbiturate and amphetamin types) out of a studied total of 194 imprisoned male addicts. These biperiden abusers suffered without exception from polytoxicomania associated with drug dependence and alcoholism. Most prominent was drug dependence on drugs of the morphine type. We could not prove a case of an isolated "primary" abuse of biperiden. Direct medical prescription was a rather secondary factor in procuring this preparation, in contrast to analgesics, tranquilisers, barbiturates and clomethiazol. Increase of biperiden abuse is due, on the one hand, to a generally noticeable tendency to polytoxicomania, and on the other hand to a change in Federal German drug prescription rules effective 1 August 1986 according to which fenetylline hydrochloride, a sympathomimetic, is now subject to medical prescription. Other centrally acting anticholinergics were unknown among this group of patients and were not abused. The results are discussed on the basis of available literature.

A Randomized Clinical Trial of Nefopam versus Ketorolac Combined With Oxycodone in Patient-Controlled Analgesia after Gynecologic Surgery.

PubMed

Hwang, Boo-Young; Kwon, Jae-Young; Lee, Do-Won; Kim, Eunsoo; Kim, Tae-Kyun; Kim, Hae-Kyu

2015-01-01

Nefopam is a centrally-acting non-opioid analgesic, which has no effect on bleeding time and platelet aggregation. There has been no study about nefopam and oxycodone combination for postoperative analgesia. In this study, we present efficacy and side effects of nefopam/oxycodone compared with ketorolac/oxycodone in patient-controlled analgesia (PCA) after gynecologic surgery. 120 patients undergoing gynecologic surgery were divided randomly into two groups: Nefopam group treated with oxycodone 1 mg and nefopam 1 mg bolus; and Ketorolac group treated with oxycodone 1 mg and ketorolac 1.5 mg bolus. After the operation, a blinded observer assessed the pain with a numeric rating scale (NRS), infused PCA dose and sedation score at 1, 4, 24, and 48 h, nausea, vomiting, headache, shivering, pruritus and delirium at 6, 24 and 48 h, and satisfaction at 48 h after the operation. Nefopam group showed less nausea than Ketorolac group within 6 h after the operation. There were no significant differences in demographic data and other complications between both groups. At 48 h after operation, satisfaction and the infused PCA volumes of Nefopam group (34.0± 19.7 ml) showed no significant differences compared to Ketorolac group (30.7± 18.4 ml, P-value= 0.46). Nefopam showed a similar efficacy and lower incidence of nausea within 6 h after the operation to that of ketorolac in PCA. Nefopam may be a useful analgesic drug for the opioid-based PCA after gynecologic surgery. Further evaluation of accurate equivalent dose of nefopam as well as pharmacokinetics of bolus administration is required.

A recovery room-based acute pain service.

PubMed

Leykin, Y; Pellis, T; Ambrosio, C; Zanette, G; Malisano, A; Rapotec, A; Casati, A

2007-04-01

Despite routine postoperative pain management improves recovery and reduces postoperative morbidity and overall costs, and the availability of a large armamentarium of analgesic techniques and drugs, a significant portion of patients do not receive adequate postoperative pain control. We describe a recovery room (RR) based acute pain service model. Guidelines on postoperative pain and therapeutic protocols were instituted in January 1999. The analgesic endpoint was a visual analogic scale (VAS) below 4 for all surgical patients for the first 48-72 h. The RR, run by one anesthesiologist and 2 nurses and one assistant, acted as a coordination centre. Discharge from the RR was subject to achieving effective analgesia. Nurses of each ward monitored VAS along with vital signs, administered rescue doses if necessary, and reported to the RR nurse when needed. RR nurses monitored the patient at least twice daily and reported to the anesthesiologist. We have distributed an anonymous questionnaire, within surgical wards, to both surgeons and nurses to evaluate their perception of pain management and of this acute pain service (APS) model. VAS was maintained significantly <4. Analgesic drug consumption increased between 1997, 2000 (first year of APS) and 2004. The auditing process confirmed the desire of all professional figures to be informed and involved in acute pain management as part of a coordinated and systematic approach to the surgical patient. A RR-based APS can effectively act as coordinating centre for acute pain treatment without adjunctive personnel.

Muscles and their role in episodic tension-type headache: implications for treatment.

PubMed

Bendtsen, L; Ashina, S; Moore, A; Steiner, T J

2016-02-01

Tension-type headache (TTH) imposes a heavy burden on the global population but remains incompletely understood and poorly managed. Here, we review current knowledge of peripheral factors involved in the mechanism of TTH and make recommendations for the treatment of episodic TTH based on these. Peripheral activation or sensitization of myofascial nociceptors is most probably involved in the development of muscle pain and the acute episode of TTH. Repetitive episodes of muscle pain may sensitize the central nervous system resulting in progression of TTH to the chronic form. Thus, muscular factors may be responsible not only for the acute headache episode but also for chronification of the disorder. Simple analgesics and non-steroidal anti-inflammatory drugs are the mainstays of management of individual headache episodes. Ibuprofen 400 mg and aspirin 1000 mg are recommended as drugs of first choice based on treatment effect, safety profile and costs. Non-pharmacological therapies include electromyographic biofeedback, physiotherapy and muscle relaxation therapy. Future studies should aim to identify the triggers of peripheral nociception and how to avoid peripheral and central sensitization. There is a need for more effective, faster acting drugs for acute TTH. Muscular factors play an important role in episodic TTH. Ibuprofen 400 mg and aspirin 1000 mg are recommended as drugs of first choice. © 2015 European Pain Federation - EFIC®

Use of prescribed opioid analgesics and co-medication with benzodiazepines in women before, during, and after pregnancy: a population-based cohort study.

PubMed

Handal, Marte; Engeland, Anders; Rønning, Marit; Skurtveit, Svetlana; Furu, Kari

2011-09-01

The aim of the study was to describe the use of prescribed opioid analgesics for noncancer pain and the degree of possible concurrent co-medication with benzodiazepines to women in Norway before, during, and after pregnancy. This was a population-based cohort study based on linkage of two nationwide registries: the Medical Birth Registry of Norway, and the Norwegian Prescription Database. Prescribed opioid analgesics and benzodiazepines issued to women 3 months prior to, during, and 3 months after pregnancies were identified. The study population consisted of 194,937 singleton pregnancies beginning in March 2004 or later and ending before January 2009. About 6% of the women were dispensed opioid analgesics before, during, or after pregnancy. Almost all these women received weak opioids (99%) with short-acting codeine in combination with paracetamol (acetaminophen) as the most frequently dispensed drug. The dispensing of codeine was reduced from 24/1,000 women before pregnancy to 10/1,000 in the last trimester, increasing to 17/1,000 during the breastfeeding period. Most women were dispensed codeine once, and treatment was of short duration (about 1 week). A small group of women (n = 271) were dispensed opioids in all trimesters. Increasing benzodiazepine use was observed as the number of opioid prescriptions increased. The use of opioid analgesics in pregnant women in Norway was dominated by treatment of short duration of the weak opioid codeine. As pregnancy proceeded, opioid use was reduced. However, the increase in opioid use during the nursing period has the potential for serious adverse effects.

Single dose oral analgesics for acute postoperative pain in adults - an overview of Cochrane reviews.

PubMed

Moore, R Andrew; Derry, Sheena; Aldington, Dominic; Wiffen, Philip J

2015-09-28

This is an updated version of the original Cochrane overview published in Issue 9, 2011. That overview considered both efficacy and adverse events, but adverse events are now dealt with in a separate overview.Thirty-nine Cochrane reviews of randomised trials have examined the analgesic efficacy of individual drug interventions in acute postoperative pain. This overview brings together the results of those individual reviews and assesses the reliability of available data. To summarise the efficacy of pharmaceutical interventions for acute pain in adults with at least moderate pain following surgery who have been given a single dose of oral analgesic. We identified systematic reviews in the Cochrane Database of Systematic Reviews in The Cochrane Library through a simple search strategy. All reviews were overseen by a single review group, had a standard title, and had as their primary outcome the number of participants with at least 50% pain relief over four to six hours compared with placebo. For individual reviews, we extracted the number needed to treat for an additional beneficial outcome (NNT) for this outcome for each drug/dose combination, and also the percentage of participants achieving at least 50% maximum pain relief, the mean of mean or median time to remedication, and the percentage of participants remedicating by six, eight, 12, or 24 hours. Where there was adequate information for pairs of drug and dose (at least 200 participants, in at least two studies), we defined the addition of four comparisons of typical size (400 participants in total) with zero effect as making the result potentially subject to publication bias and therefore unreliable. The overview included 39 separate Cochrane Reviews with 41 analyses of single dose oral analgesics tested in acute postoperative pain models, with results from about 50,000 participants in approximately 460 individual studies. The individual reviews included only high-quality trials of standardised design, methods, and efficacy outcome reporting. No statistical comparison was undertaken.Reliable results (high quality information) were obtained for 53 pairs of drug and dose in painful postsurgical conditions; these included various fixed dose combinations, and fast acting formulations of some analgesics. NNTs varied from about 1.5 to 20 for at least 50% maximum pain relief over four to six hours compared with placebo. The proportion of participants achieving this level of benefit varied from about 30% to over 70%, and the time to remedication varied from two hours (placebo) to over 20 hours. Good (low) NNTs were obtained with ibuprofen 200 mg plus paracetamol (acetaminophen) 500 mg (NNT compared with placebo 1.6; 95% confidence interval 1.5 to 1.8), ibuprofen fast acting 200 mg (2.1; 1.9 to 2.3); ibuprofen 200 mg plus caffeine 100 mg (2.1; 1.9 to 3.1), diclofenac potassium 50 mg (2.1; 1.9 to 2.5), and etoricoxib 120 mg (1.8; 1.7 to 2.0). For comparison, ibuprofen acid 400 mg had an NNT of 2.5 (2.4 to 2.6). Not all participants had good pain relief and, for many pairs of drug and dose, 50% or more did not achieve at least 50% maximum pain relief over four to six hours.Long duration of action (eight hours or greater) was found for etoricoxib 120 mg, diflunisal 500 mg, paracetamol 650 mg plus oxycodone 10 mg, naproxen 500/550 mg, celecoxib 400 mg, and ibuprofen 400 mg plus paracetamol 1000 mg.There was no evidence of analgesic effect for aceclofenac 150 mg, aspirin 500 mg, and oxycodone 5 mg (low quality evidence). No trial data were available in reviews of acemetacin, meloxicam, nabumetone, nefopam, sulindac, tenoxicam, and tiaprofenic acid. Inadequate amounts of data were available for nine drugs and doses, and data potentially susceptible to publication bias for 13 drugs and doses (very low quality evidence). There is a wealth of reliable evidence on the analgesic efficacy of single dose oral analgesics. Fast acting formulations and fixed dose combinations of analgesics can produce good and often long-lasting analgesia at relatively low doses. There is also important information on drugs for which there are no data, inadequate data, or where results are unreliable due to susceptibility to publication bias. This should inform choices by professionals and consumers.

Sustained analgesic effect of clonidine co-polymer depot in a porcine incisional pain model.

PubMed

Wilsey, Jared T; Block, Julie H

2018-01-01

Previous research suggests that the α 2 adrenergic agonist clonidine, a centrally acting analgesic and antihypertensive, may also have direct effects on peripheral pain generators. However, aqueous injections are limited by rapid systemic absorption leading to off target effects and a brief analgesic duration of action. The aim of this study was to examine the efficacy of a sustained-release clonidine depot, placed in the wound bed, in a pig incisional pain model. The depot was a 15 mm ×5 mm ×0.3 mm poly(lactide-co-caprolactone) polymer film containing 3% (w/w) clonidine HCl (MDT3). Fifty-two young adult mix Landrace pigs (9-11 kg) were divided into seven groups. All subjects received a 6 cm, full-thickness, linear incision into the left lateral flank. Group 1 served as a Sham control group (Sham, n=8). Group 2 received three placebo strips (PBO, n=8), placed end-to-end in the subcutaneous wound bed before wound closure. Group 3 received one MDT3 and two PBO (n=8), Group 4 received two MDT3 and one PBO (n=8), and Group 5 received three MDT3 (n=8). Positive control groups received peri-incisional injections of bupivacaine solution (Group 6, 30 mg/day bupivacaine, n=8) or clonidine solution (Group 7, 225 µg/day, n=4). The surgical procedure was associated with significant peri-incisional tactile allodynia. There was a dose-dependent effect of MDT3 in partially reversing the peri-incisional tactile allodynia, with maximum pain relief relative to Sham at 72 hours. Daily injections of bupivacaine (30 mg), but not clonidine (up to 225 µg), completely reversed allodynia within 48 hours. There was a statistically significant correlation between the dose of MDT3 and cumulative withdrawal threshold from 4 hours through the conclusion of the study on day 7. These data suggest that a sustained-release clonidine depot may be a viable nonopioid, nonamide anesthetic therapy for the treatment of acute postsurgical nociceptive sensitization.

Registered Nurses' Knowledge about Adverse Effects of Analgesics when Treating Postoperative Pain in Patients with Dementia.

PubMed

Rantala, Maija; Hartikainen, Sirpa; Kvist, Tarja; Kankkunen, Päivi

2015-08-01

Registered nurses (RNs) play a pivotal role in treating pain and preventing and recognizing the adverse effects (AEs) of analgesics in patients with dementia. The purpose of this study was to determine RNs' knowledge of potentially clinically relevant AEs of analgesics. A descriptive, cross-sectional study design was used. In all, 267 RNs treating orthopedic patients, including patients with dementia, in 7 university hospitals and 10 central hospitals in Finland, completed a questionnaire. Analgesics were defined according to the Anatomic Therapeutic Classification as strong opioids, weak opioids, nonsteroidal anti-inflammatory analgesics (NSAIDs), and paracetamol. Definitions of AEs were based on the literature. Logistic regression analysis was applied to analyze which variables predicted nurses' knowledge. The RNs had a clear understanding of the AEs of paracetamol and strong opioids. However, the AEs of NSAIDs, especially renal and cardiovascular AEs, were less well known. The median percentage of correct answers was 87% when asked about strong opioids, 73% for weak opioids, and 60% for NSAIDs. Younger RNs had better knowledge of opioid-related AEs (odds ratio [OR] per 1-year increase, 0.97; 95% confidence interval [CI], 0.94-1.00) and weak opioids (OR, 0.96; 95% CI, 0.93-0.99). This study provides evidence of a deficiency in RNs' knowledge, especially regarding the adverse renal and cardiovascular effects of NSAIDs. Such lack of knowledge indicates that hospitals may need to update the knowledge of older RNs, especially those who treat vulnerable patients with dementia. Copyright © 2015 American Society for Pain Management Nursing. Published by Elsevier Inc. All rights reserved.

Analgesic and Anti-Inflammatory Effects of 80% Methanol Extract of Leonotis ocymifolia (Burm.f.) Iwarsson Leaves in Rodent Models

PubMed Central

Alemu, Asnakech

2018-01-01

Background Pain and inflammation are the major health problems commonly treated with traditional remedies mainly using medicinal plants. Leonotis ocymifolia is one of such medicinal plants used in folkloric medicine of Ethiopia. However, the plant has not been scientifically evaluated. The aim of this study was to evaluate analgesic and anti-inflammatory effects of the 80% methanol leaves extract of Leonotis ocymifolia using rodent models. Method The central and peripheral analgesic effect of the extract at 100, 200, and 400 mg/kg dose levels was evaluated using hot plate and acetic acid induced writhing rodent models, whereas carrageenan induced paw edema and cotton pellet granuloma methods were used to screen anti-inflammatory effect of the extract at the same dose levels. Acute toxicity test was also done. Data were analyzed using one-way ANOVA followed by Tukey's post hoc test and p < 0.05 was considered significant. Results The extract did not produce mortality up to 2000 mg/kg. All tested doses of the extract showed significant analgesic effect with maximum latency response of 62.8% and inhibition of acetic acid induced writhing. Maximum anti-inflammatory effect was recorded at 6 h after induction, with 75.88% reduction in carrageenan induced paw edema. Moreover, all tested doses of extract significantly inhibited the formation of inflammatory exudates and granuloma formation (p < 0.001). Conclusion The study indicated that the extract was safe in mice and it has both analgesic and anti-inflammatory effect in rodent models. PMID:29675050

Effect of a centralized prescription network on inappropriate prescriptions for opioid analgesics and benzodiazepines.

PubMed

Dormuth, Colin R; Miller, Tarita A; Huang, Anjie; Mamdani, Muhammad M; Juurlink, David N

2012-11-06

Opioid analgesics and benzodiazepines are often misused in clinical practice. We determined whether implementation of a centralized prescription network offering real-time access to patient-level data on filled prescriptions (PharmaNet) reduced the number of potentially inappropriate prescriptions for opioids and benzodiazepines. We conducted a time series analysis using prescription records between Jan. 1, 1993, and Dec. 31, 1997, for residents of the province of British Columbia who were receiving social assistance or were 65 years or older. We calculated monthly percentages of filled prescriptions for an opioid or a benzodiazepine that were deemed inappropriate (those issued by a different physician and dispensed at a different pharmacy within 7 days after a filled prescription of at least 30 tablets of the same drug). Within 6 months after implementation of PharmaNet in July 1995, we observed a relative reduction in inappropriate filled prescriptions for opioids of 32.8% (95% confidence interval [CI] 31.0%-34.7%) among patients receiving social assistance; inappropriate filled prescriptions for benzodiazepines decreased by 48.6% (95% CI 43.2%-53.1%). Similar and statistically significant reductions were observed among residents 65 years or older. The implementation of a centralized prescription network was associated with a dramatic reduction in inappropriate filled prescriptions for opioids and benzodiazepines.

Effects of Adjuvant Analgesics on Cerebral Ischemia-Induced Mechanical Allodynia.

PubMed

Matsuura, Wataru; Harada, Shinichi; Tokuyama, Shogo

2016-01-01

Central post-stroke pain (CPSP), a potential sequela of stroke, is classified as neuropathic pain. Although we recently established a CPSP-like model in mice, the effects of adjuvant analgesics as therapeutic drugs for neuropathic pain in this model are unknown. Hence, the aim of the present study was to assess the usefulness of our model by evaluating the effects of adjuvant analgesics used for treating neuropathic pain in this mouse model of CPSP. Male ddY mice were subjected to 30 min of bilateral carotid artery occlusion (BCAO). The development of hind paw mechanical allodynia was measured after BCAO using the von Frey test. The mechanical allodynia was significantly increased on day 3 after BCAO compared with that during the pre-BCAO assessment. BCAO-induced mechanical allodynia was significantly decreased by intraperitoneal injections of imipramine (a tricyclic antidepressant), mexiletine (an antiarrhythmic), gabapentin (an antiepileptic), or a subcutaneous injection of morphine (an opioid receptor agonist) compared with that following vehicle treatment in BCAO-mice. By contrast, milnacipran (a serotonin and norepinephrine reuptake inhibitor), paroxetine (selective serotonin reuptake inhibitor), carbamazepine (antiepileptic), and indomethacin (nonsteroidal anti-inflammatory drug) did not affect the BCAO-induced mechanical allodynia. Our results show that BCAO in mice may be useful as an animal model of CPSP. In addition, BCAO-induced mechanical allodynia may be suppressed by some adjuvant analgesics used to treat neuropathic pain.

Rats with decreased brain cholecystokinin levels show increased responsiveness to peripheral electrical stimulation-induced analgesia.

PubMed

Zhang, L X; Li, X L; Wang, L; Han, J S

1997-01-16

Using the P77PMC strain of rat, which is genetically prone to audiogenic seizures, and also has decreased levels of cholecystokinin (CCK), we examined the analgesic response to peripheral electrical stimulation, which is, in part, opiate-mediated. A number of studies have suggested that CCK may function as an antagonist to endogenous opiate effects. Therefore, we hypothesized that the P77PMC animals would show an enhanced analgesic response based on their decreased CCK levels producing a diminished endogenous opiate antagonism. We found that the analgesic effect on tail flick latency produced by 100 Hz peripheral electrical stimulation was more potent and longer lasting in P77PMC rats than in control rats. Moreover, the potency of the stimulation-produced analgesia correlated with the vulnerability to audiogenic seizures in these rats. We were able to block the peripheral electrical stimulation-induced analgesia (PSIA) using a cholecystokinin octapeptide (CCK-8) administered parenterally. Radioimmunoassay showed that the content of CCK-8 in cerebral cortex, hippocampus and periaqueductal gray was much lower in P77PMC rat than in controls. These results suggest that low CCK-8 content in the central nervous system of the P77PMC rats may be related to the high analgesic response to peripheral electrical stimulation, and further support the notion that CCK may be endogenous opiate antagonist.

Functional and Structural Signatures of the Anterior Insula are associated with Risk-taking Tendency of Analgesic Decision-making.

PubMed

Lin, Chia-Shu; Lin, Hsiao-Han; Wu, Shih-Yun

2016-11-28

In a medical context, decision-making is associated with complicated assessment of gains, losses and uncertainty of outcomes. We here provide novel evidence about the brain mechanisms underlying decision-making of analgesic treatment. Thirty-six healthy participants were recruited and completed the Analgesic Decision-making Task (ADT), which quantified individual tendency of risk-taking (RPI), as the frequency of choosing a riskier option to relieve pain. All the participants received resting-state (rs) functional magnetic resonance imaging (MRI) and structural MRI. On rs-functional connectome, degree centrality (DC) of the bilateral anterior insula (aINS) was positively correlated with the RPI. The functional connectivity between the aINS, the nucleus accumbens and multiple brain regions, predominantly the medial frontal cortex, was positively correlated with the RPI. On structural signatures, the RPI was positively correlated with grey matter volume at the right aINS, and such an association was mediated by DC of the left aINS. Regression analyses revealed that both DC of the left aINS and participants' imagined pain relief, as the utility of pain reduction, could predict the individual RPI. The findings suggest that the functional and structural brain signature of the aINS is associated with the individual differences of risk-taking tendency in the context of analgesic decision-making.

The Role of the Tamsulosin in the Medical Expulsion Therapy for Distal Ureteral Stones

PubMed Central

Nuraj, Petrit; Hyseni, Nexhmi

2017-01-01

Background: This research aims to evaluate the role of tamsulosin in the medical expulsion therapy for distal ureteral stones, including her effects in stone expulsion time, expulsion rates, stone size, pain episodes and analgesic dosage usage. Material and methods: The 104 patients with distal ureteral calculi were examined, with the size of the stones 4-10 mm. They were randomly divided into two groups: study group (n=52), received tamsulosin 0.4 mg in morning, for 28 days, analgesic (diclofenac 75 mg), high fluid intake and Control group (n=52) received analgesic (diclofenac 75 mg), high fluid intake. Results: There is no significant difference between groups, based on sex (P=0.835) and age (P=0.987). Average size of the stones was 6.5 mm (SD ± 1.6 mm), with no significant difference (P=0.996). Stone expulsion rate is 90.4% in the study group and 71.2% from the control group, with statistical significance (P=0.023). The average time of the expulsion of stones in the study group was 9.6 days (SD ± 7.1 days), control group 13.7 days (SD ± 7.3 days), with statistical significance, (P=0.034). Average dose of analgesics in the study group was 63.7 mg (SD ± 45.2 mg), control group is 109.2 (SD ± 53.3), with statistical significance (P=0.019). Conclusion: Our study reveals that tamsulosin is efficient for the treatment of distal ureteral stones. Tamsulosin decrease the number of ureteral colic episodes, by acting as a spasmolytic, increase and hasten stone expulsion rates, reduce days of stone expulsion, decrease analgesic dose usage. PMID:28790547

A Prospective Emergency Department Quality Improvement Project to Improve the Treatment of Vaso-Occlusive Crisis in Sickle Cell Disease: Lessons Learned.

PubMed

Tanabe, Paula; Freiermuth, Caroline E; Cline, David M; Silva, Susan

2017-03-01

Guidelines recommend rapid, aggressive management of vaso-occlusive crisis (VOC) for patients with sickle cell disease (SCD). A large prospective research and quality improvement (QI) project was conducted to measure changes in clinical outcomes in two EDs-academic medical centers with emergency medicine residency programs and Level 1 trauma centers-during a 2.5-year time period (October 2011-March 2014). A QI team used a Plan-Do-Study-Act approach to modify and implement changes to opioid analgesic protocols for the emergency department (ED) treatment of VOC. Data were collected quarterly; the team reviewed the results and made modifications to improve outcomes. A structured health record review was conducted to assess clinical outcomes (10 records/quarter/site). Patient interviews were conducted to measure satisfaction with pain management. Outcomes were compared before (T1) and after (T2) implementation of an electronic health record (EHR). One hundred ninety-six ED health records (118 unique patients, mean age = 32 [standard deviation, 11], 51% male) were analyzed. Before implementation, trends in decreasing time to initial analgesic administration were noted. There was a statistically significant increase in arrival to administration of first analgesic time between T1 and T2 at Site 1 but not at Site 2. Neither site showed significant changes in time between the administration of the first and second opioid doses, total opioid dose administered, or patient satisfaction. While QI efforts initially shortened door-to-analgesic times, these gains were not sustained. The lessons learned can help other EDs improve the timely delivery of analgesics to patients with SCD. Copyright © 2016 The Joint Commission. Published by Elsevier Inc. All rights reserved.

Single-dose intra-articular bupivacaine versus morphine after arthroscopic knee surgery: a meta-analysis of randomized-controlled studies.

PubMed

Wei, Jie; Lei, Guang-hua; Gao, Shu-Guang; Zeng, Chao; Qin, Jia-bi; Kong, Fan-jing; Yang, Tu-bao

2014-07-01

This meta-analysis compared the earliest clinical effects of intra-articular bupivacaine and morphine for pain management following arthroscopic knee surgery. A comprehensive literature search was conducted using MEDLINE (1966 to 2013), the Cochrane Central Register of Controlled Trials (CENTRAL), Embase, and Google Scholar databases for identification of randomized-controlled trials that compared IA bupivacaine and morphine for postoperative pain. The relative risk, weighted mean difference (WMD), and their corresponding 95% confidence intervals (CI) were calculated using RevMan statistical software. Bupivacaine and morphine group had similar acute postoperative pain scores (WMD: 0.07; 95% CI, -0.18 to 0.32; P=0.60); number of patients requiring supplementary analgesia (relative risk: 0.74; 95% CI, 0.42 to 1.31; P=0.30) for the trials in this meta-analysis (n=13); and side effects (relative risk: 0.63; 95% CI, 0.39 to 1.02, P=0.06). Even though, the time to first analgesic request resulted in a significant difference (WMD: 66.59; 95% CI, 11.75 to 122.14, P=0.02), this result was not supported by the sensitivity analysis. On the basis of the currently available literature, this study failed to demonstrate a significant difference between single-dose intra-articular bupivacaine and morphine at the end of the arthroscopic knee surgery in terms of pain relief, need for supplementary analgesics, times interval before the first request for additional analgesic, and short-term side effects. Level II-meta-analysis of Level I and II studies.

Biphalin preferentially recruits peripheral opioid receptors to facilitate analgesia in a mouse model of cancer pain - A comparison with morphine.

PubMed

Lesniak, Anna; Bochynska-Czyz, Marta; Sacharczuk, Mariusz; Benhye, Sandor; Misicka, Aleksandra; Bujalska-Zadrozny, Magdalena; Lipkowski, Andrzej W

2016-06-30

The search for new drugs for cancer pain management has been a long-standing goal in basic and clinical research. Classical opioid drugs exert their primary antinociceptive effect upon activating opioid receptors located in the central nervous system. A substantial body of evidence points to the relevance of peripheral opioid receptors as potential targets for cancer pain treatment. Peptides showing limited blood-brain-barrier permeability promote peripheral analgesia in many pain models. In the present study we examined the peripheral and central analgesic effect of intravenously administered biphalin - a dimeric opioid peptide in a mouse skin cancer pain model, developed by an intraplantar inoculation of B16F0 melanoma cells. The effect of biphalin was compared with morphine - a golden standard in cancer pain management. Biphalin produced profound, dose-dependent and naloxone sensitive spinal analgesia. Additionally, the effect in the tumor-bearing paw was largely mediated by peripheral opioid receptors, as it was readily attenuated by the blood-brain-barrier-restricted opioid receptor antagonist - naloxone methiodide. On the contrary, morphine facilitated its analgesic effect primarily by activating spinal opioid receptors. Both drugs induced tolerance in B16F0 - implanted paws after chronic treatment, however biphalin as opposed to morphine, showed little decrease in its activity at the spinal level. Our results indicate that biphalin may be considered a future alternative drug in cancer pain treatment due to an enhanced local analgesic activity as well as lower tolerance liability compared with morphine. Copyright © 2016 Elsevier B.V. All rights reserved.

Anti-inflammatory and analgesic activities of solvent fractions of the leaves of Moringa stenopetala Bak. (Moringaceae) in mice models.

PubMed

Tamrat, Yohannes; Nedi, Teshome; Assefa, Solomon; Teklehaymanot, Tilahun; Shibeshi, Workineh

2017-09-29

Many people still experience pain and inflammation regardless of the available drugs for treatments. In addition, the available drugs have many side effects, which necessitated a quest for new drugs from several sources in which medicinal plants are the major one. This study evaluated the analgesic and anti- inflammatory activity of the solvent fractions of Moringa stenopetala in rodent models of pain and inflammation. Successive soxhlet and maceration were used as methods of extractions using solvents of increasing polarity; chloroform, methanol and water. Swiss albino mice models were used in radiant tail flick latency, acetic acid induced writhing and carrageenan induced paw edema to assess the analgesic and anti-inflammatory activities. The test groups received different doses (100 mg/kg, 200 mg/kg and 400 mg/kg) of the three fractions (chloroform, methanol and aqueous). The positive control groups received morphine (20 mg/kg) or aspirin (100 mg/kg or 150 mg/kg) based on the respective models. The negative control groups received the 10 ml/kg of vehicles (distilled water or 2% Tween 80). In all models, the chloroform fraction had protections only at a dose of 400 mg/kg. However, the methanol and aqueous fraction at all doses have shown significant central and peripheral analgesic activities with a comparable result to the standards. The aqueous and methanol fractions significantly reduced carrageenan induced inflammation in a dose dependent manner, in which the highest reduction of inflammation was observed in aqueous fraction at 400 mg/kg. This study provided evidence on the traditionally claimed uses of the plant in pain and inflammatory diseases, and Moringa stenopetala could be potential source for development of new analgesic and anti-inflammatory drugs.

Evaluation of acute toxicity, sedative and analgesic effects of Taverniera glabra methanolic extract on mice.

PubMed

Marvi, -; Iqbal, Javeid; Muhammad, Shafi; Ahmad, Mansoor

2016-11-01

Present study was conducted on crude methanolic extract of stem and root of Taverniera glabra. In Pakistan T. glabra is found in the region of Balochistan only. T. glabra has numerous therapeutic uses in traditional medicine and it is also used for the pain relief. Current study was carried out to evaluate acute toxicity, analgesic and CNS depressant activity of the plant. Acute toxicity was carried out by oral administration of the T. glabra extract from 250 to 2000mg/kg oral dose. Analgesic activity was carried out by acetic acid induced writhing test and formalin test. Central Nervous System (CNS) depressant activity was carried out by exploratory activities (open field activity, cage crossing activity, rearing test) and forced swimming test. Oral administration of the methanolic extract of T. glabra was nontoxic at the dose of 1500mg/kg in the acute toxicity test. Exploratory behavior of mice treated with the methanolic extract of T. glabra showed sedative effects (P<0.05) in open field, cage crossing, traction and rearing test, particularly at the dose of 500mg as compared with standard drug Diazepam. In forced swimming test, mobility time was significantly (P<0.05) increased at 500mg/kg oral dose, and results were significant as compared with control. Methanolic extract of T. glabra produced significant (P<0.05) analgesic effects at the dose of 500mg/kg in the acetic acid induced writhing test and the formalin test. In conclusion, results show that the crude methanolic extract of T. glabra possess sedative as well as potent analgesic effects. Present pharmacological studies are the first ever studies conducted on the methanolic extract of T. glabra.

The role of the blood-brain barrier in the development and treatment of migraine and other pain disorders.

PubMed

DosSantos, Marcos F; Holanda-Afonso, Rosenilde C; Lima, Rodrigo L; DaSilva, Alexandre F; Moura-Neto, Vivaldo

2014-01-01

The function of the blood-brain barrier (BBB) related to chronic pain has been explored for its classical role in regulating the transcellular and paracellular transport, thus controlling the flow of drugs that act at the central nervous system, such as opioid analgesics (e.g., morphine) and non-steroidal anti-inflammatory drugs. Nonetheless, recent studies have raised the possibility that changes in the BBB permeability might be associated with chronic pain. For instance, changes in the relative amounts of occludin isoforms, resulting in significant increases in the BBB permeability, have been demonstrated after inflammatory hyperalgesia. Furthermore, inflammatory pain produces structural changes in the P-glycoprotein, the major efflux transporter at the BBB. One possible explanation for these findings is the action of substances typically released at the site of peripheral injuries that could lead to changes in the brain endothelial permeability, including substance P, calcitonin gene-related peptide, and interleukin-1 beta. Interestingly, inflammatory pain also results in microglial activation, which potentiates the BBB damage. In fact, astrocytes and microglia play a critical role in maintaining the BBB integrity and the activation of those cells is considered a key mechanism underlying chronic pain. Despite the recent advances in the understanding of BBB function in pain development as well as its interference in the efficacy of analgesic drugs, there remain unknowns regarding the molecular mechanisms involved in this process. In this review, we explore the connection between the BBB as well as the blood-spinal cord barrier and blood-nerve barrier, and pain, focusing on cellular and molecular mechanisms of BBB permeabilization induced by inflammatory or neuropathic pain and migraine.

The role of the blood–brain barrier in the development and treatment of migraine and other pain disorders

PubMed Central

DosSantos, Marcos F.; Holanda-Afonso, Rosenilde C.; Lima, Rodrigo L.; DaSilva, Alexandre F.; Moura-Neto, Vivaldo

2014-01-01

The function of the blood–brain barrier (BBB) related to chronic pain has been explored for its classical role in regulating the transcellular and paracellular transport, thus controlling the flow of drugs that act at the central nervous system, such as opioid analgesics (e.g., morphine) and non-steroidal anti-inflammatory drugs. Nonetheless, recent studies have raised the possibility that changes in the BBB permeability might be associated with chronic pain. For instance, changes in the relative amounts of occludin isoforms, resulting in significant increases in the BBB permeability, have been demonstrated after inflammatory hyperalgesia. Furthermore, inflammatory pain produces structural changes in the P-glycoprotein, the major efflux transporter at the BBB. One possible explanation for these findings is the action of substances typically released at the site of peripheral injuries that could lead to changes in the brain endothelial permeability, including substance P, calcitonin gene-related peptide, and interleukin-1 beta. Interestingly, inflammatory pain also results in microglial activation, which potentiates the BBB damage. In fact, astrocytes and microglia play a critical role in maintaining the BBB integrity and the activation of those cells is considered a key mechanism underlying chronic pain. Despite the recent advances in the understanding of BBB function in pain development as well as its interference in the efficacy of analgesic drugs, there remain unknowns regarding the molecular mechanisms involved in this process. In this review, we explore the connection between the BBB as well as the blood–spinal cord barrier and blood–nerve barrier, and pain, focusing on cellular and molecular mechanisms of BBB permeabilization induced by inflammatory or neuropathic pain and migraine. PMID:25339863

Correlation versus Causation? Pharmacovigilance of the Analgesic Flupirtine Exemplifies the Need for Refined Spontaneous ADR Reporting

PubMed Central

Anderson, Nora; Borlak, Juergen

2011-01-01

Annually, adverse drug reactions result in more than 2,000,000 hospitalizations and rank among the top 10 causes of death in the United States. Consequently, there is a need to continuously monitor and to improve the safety assessment of marketed drugs. Nonetheless, pharmacovigilance practice frequently lacks causality assessment. Here, we report the case of flupirtine, a centrally acting non-opioid analgesic. We re-evaluated the plausibility and causality of 226 unselected, spontaneously reported hepatobiliary adverse drug reactions according to the adapted Bradford-Hill criteria, CIOMS score and WHO-UMC scales. Thorough re-evaluation showed that only about 20% of the reported cases were probable or likely for flupirtine treatment, suggesting an incidence of flupirtine-related liver injury of 1∶ 100,000 when estimated prescription data are considered, or 0.8 in 10,000 on the basis of all 226 reported adverse drug reactions. Neither daily or cumulative dose nor duration of treatment correlated with markers of liver injury. In the majority of cases (151/226), an average of 3 co-medications with drugs known for their liver liability was observed that may well be causative for adverse drug reactions, but were reported under a suspected flupirtine ADR. Our study highlights the need to improve the quality and standards of ADR reporting. This should be done with utmost care taking into account contributing factors such as concomitant medications including over-the-counter drugs, the medical history and current health conditions, in order to avoid unjustified flagging and drug warnings that may erroneously cause uncertainty among healthcare professionals and patients, and may eventually lead to unjustified safety signals of useful drugs with a reasonable risk to benefit ratio. PMID:22022383

The benzomorphan-based LP1 ligand is a suitable MOR/DOR agonist for chronic pain treatment.

PubMed

Pasquinucci, Lorella; Parenti, Carmela; Turnaturi, Rita; Aricò, Giuseppina; Marrazzo, Agostino; Prezzavento, Orazio; Ronsisvalle, Simone; Georgoussi, Zafiroula; Fourla, Danai-Dionysia; Scoto, Giovanna M; Ronsisvalle, Giuseppe

2012-01-02

Powerful analgesics relieve pain primarily through activating mu opioid receptor (MOR), but the long-term use of MOR agonists, such as morphine, is limited by the rapid development of tolerance. Recently, it has been observed that simultaneous stimulation of the delta opioid receptor (DOR) and MOR limits the incidence of tolerance induced by MOR agonists. 3-[(2R,6R,11R)-8-hydroxy-6,11-dimethyl-1,4,5,6-tetrahydro-2,6-methano-3-benzazocin-3(2H)-yl]-N-phenylpropanamide (LP1) is a centrally acting agent with antinociceptive activity comparable to morphine and is able to bind and activate MOR and DOR. The aim of this work was to evaluate and compare the induction of tolerance to antinociceptive effects from treatment with LP1 and morphine. Here, we evaluated the pharmacological effects of LP1 administered at a dose of 4 mg/kg subcutaneously (s.c.) twice per day for 9 days to male Sprague-Dawley rats. In addition, the LP1 mechanism of action was assessed by measurement of LP1-induced [(35)S]GTPγS binding to the MOR and DOR. Data obtained from the radiant heat tail flick test showed that LP1 maintained its antinociceptive profile until the ninth day, while tolerance to morphine (10mg/kg s.c. twice per day) was observed on day 3. Moreover, LP1 significantly enhanced [(35)S]GTPγS binding in the membranes of HEK293 cells expressing either the MOR or the DOR. LP1 is a novel analgesic agent for chronic pain treatment, and its low tolerance-inducing capability may be correlated with its ability to bind both the MOR and DOR. Copyright © 2011 Elsevier Inc. All rights reserved.

A Randomized Clinical Trial of Nefopam versus Ketorolac Combined With Oxycodone in Patient-Controlled Analgesia after Gynecologic Surgery

PubMed Central

Hwang, Boo-Young; Kwon, Jae-Young; Lee, Do-Won; Kim, Eunsoo; Kim, Tae-Kyun; Kim, Hae-Kyu

2015-01-01

Objectives: Nefopam is a centrally-acting non-opioid analgesic, which has no effect on bleeding time and platelet aggregation. There has been no study about nefopam and oxycodone combination for postoperative analgesia. In this study, we present efficacy and side effects of nefopam/oxycodone compared with ketorolac/oxycodone in patient-controlled analgesia (PCA) after gynecologic surgery. Methods: 120 patients undergoing gynecologic surgery were divided randomly into two groups: Nefopam group treated with oxycodone 1 mg and nefopam 1 mg bolus; and Ketorolac group treated with oxycodone 1 mg and ketorolac 1.5 mg bolus. After the operation, a blinded observer assessed the pain with a numeric rating scale (NRS), infused PCA dose and sedation score at 1, 4, 24, and 48 h, nausea, vomiting, headache, shivering, pruritus and delirium at 6, 24 and 48 h, and satisfaction at 48 h after the operation. Results: Nefopam group showed less nausea than Ketorolac group within 6 h after the operation. There were no significant differences in demographic data and other complications between both groups. At 48 h after operation, satisfaction and the infused PCA volumes of Nefopam group (34.0± 19.7 ml) showed no significant differences compared to Ketorolac group (30.7± 18.4 ml, P-value= 0.46). Conclusion: Nefopam showed a similar efficacy and lower incidence of nausea within 6 h after the operation to that of ketorolac in PCA. Nefopam may be a useful analgesic drug for the opioid-based PCA after gynecologic surgery. Further evaluation of accurate equivalent dose of nefopam as well as pharmacokinetics of bolus administration is required. PMID:26283884

Distinct effect of orphanin FQ in nucleus raphe magnus and nucleus reticularis gigantocellularis on the rat tail flick reflex.

PubMed

Yang, Z; Zhang, Y; Wu, G

2001-06-22

The aim of the present study is to investigate the effects of orphanin FQ (OFQ) microinjected into the nucleus raphe magnus (NRM) and the nucleus reticularis gigantocellularis (NGC) on pain modulation. The tail-flick latency (TFL) was used as a behavioral index of nociceptive responsiveness. The result showed microinjection of OFQ into the NRM significantly increased the TFL, whereas microinjection of OFQ into the NGC decreased the TFL, suggesting the analgesic effect of OFQ in the NRM and the hyperalgesic effect of OFQ in the NGC. As there are three classes of putative pain modulating neurons in the rostral ventromedial medulla (RVM), the hyperalgesic or analgesic effect of OFQ in the RVM might depend upon the different class of the neurons being acted.

Averting Opioid-induced Respiratory Depression without Affecting Analgesia.

PubMed

Dahan, Albert; van der Schrier, Rutger; Smith, Terry; Aarts, Leon; van Velzen, Monique; Niesters, Marieke

2018-05-01

The ventilatory control system is highly vulnerable to exogenous administered opioid analgesics. Particularly respiratory depression is a potentially lethal complication that may occur when opioids are overdosed or consumed in combination with other depressants such as sleep medication or alcohol. Fatalities occur in acute and chronic pain patients on opioid therapy and individuals that abuse prescription or illicit opioids for their hedonistic pleasure. One important strategy to mitigate opioid-induced respiratory depression is cotreatment with nonopioid respiratory stimulants. Effective stimulants prevent respiratory depression without affecting the analgesic opioid response. Several pharmaceutical classes of nonopioid respiratory stimulants are currently under investigation. The majority acts at sites within the brainstem respiratory network including drugs that act at α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (ampakines), 5-hydroxytryptamine receptor agonists, phospodiesterase-4 inhibitors, D1-dopamine receptor agonists, the endogenous peptide glycyl-glutamine, and thyrotropin-releasing hormone. Others act peripherally at potassium channels expressed on oxygen-sensing cells of the carotid bodies, such as doxapram and GAL021 (Galleon Pharmaceuticals Corp., USA). In this review we critically appraise the efficacy of these agents. We conclude that none of the experimental drugs are adequate for therapeutic use in opioid-induced respiratory depression and all need further study of efficacy and toxicity. All discussed drugs, however, do highlight potential mechanisms of action and possible templates for further study and development.

Duloxetine, an antidepressant with analgesic properties – a preliminary analysis

PubMed Central

Onuţu, Adela Hilda

2015-01-01

Serotonin and norepinephrine reuptake inhibitors are second-line antidepressants largely used because of their good tolerance and their reduced side effects. Two of these drugs, duloxetine and venlafaxine, are used also in chronic pain management. In this review we present recent data regarding duloxetine’s effects on the central nervous system, linked to acute pain management, and their efficiency in reducing postoperative chronic pain. The drug’s efficacy results from its modulating effect on the descending inhibitory pain pathways and the inhibition of the nociceptive input. There are already several studies in favor of the analgesic properties of duloxetine. However, further and larger randomized studies are necessary in order to clarify duloxetine efficiency in acute postoperative settings, and thereafter on persistent chronic postoperative pain. PMID:28913467

Choosing the right analgesic. A guide to selection.

PubMed

Bushnell, Timothy G; Justins, Douglas M

1993-09-01

Pain is an unpleasant sensory and emotional experience, unique to each individual patient. In the dynamic processes of nociceptive stimulation, signal transmission, central decoding and interpretation there are many potential sites for pharmacological intervention, and there are many drugs which will produce analgesia. An analgesic 'ladder' has been proposed for rational pain relief in cancer and a similar concept should be used in all forms of acute and chronic pain. Continuing research and drug development undoubtedly extends our understanding, but consistent improvement in our clinical ability to relieve pain depends more on our willingness to consider the need of each patient individually, to tailor the drug, route and mode of administration to that patient's requirements, and then to monitor on the basis of the response of the patient to the treatment.

Redoubling the ring size of an endomorphin-2 analog transforms a centrally acting mu-opioid receptor agonist into a pure peripheral analgesic.

PubMed

Piekielna, Justyna; De Marco, Rossella; Gentilucci, Luca; Cerlesi, Maria Camilla; Calo', Girolamo; Tömböly, Csaba; Artali, Roberto; Janecka, Anna

2016-05-01

The study reports the synthesis and biological evaluation of two opioid analogs, a monomer and a dimer, obtained as products of the solid-phase, side-chain to side-chain cyclization of the pentapeptide Tyr-d-Lys-Phe-Phe-AspNH2 . The binding affinities to the mu, delta, and kappa opioid receptors, as well as results obtained in a calcium mobilization functional assay are reported. Tyr-[d-Lys-Phe-Phe-Asp]2 -NH2 1 was a potent and selective full agonist of mu with sub-nanomolar affinity, while the dimer (Tyr-[d-Lys-Phe-Phe-Asp]2 -NH2 )2 2 showed a significant mixed mu/kappa affinity, acting as an agonist at the mu. Molecular docking computations were utilized to explain the ability of the dimeric cyclopeptide 2 to interact with the receptor. Interestingly, in spite of the increased ring size, the higher flexibility allowed 2 to fold and fit into the mu receptor binding pocket. Both cyclopeptides were shown to elicit strong antinociceptive activity after intraventricular injection but only cyclomonomer 1 was able to cross the blood-brain barrier. However, the cyclodimer 2 displayed a potent peripheral antinociceptive activity in a mouse model of visceral inflammatory pain. © 2016 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 106: 309-317, 2016. © 2016 Wiley Periodicals, Inc.

Paracetamol in fever in critically ill patients-an update.

PubMed

Chiumello, D; Gotti, M; Vergani, G

2017-04-01

Fever, which is arbitrary defined as an increase in body temperature above 38.3°C, can affect up to 90% of patients admitted in intensive care unit. Induction of fever is mediated by the release of pyrogenic cytokines (tumor necrosis factor α, interleukin 1, interleukin 6, and interferons). Fever is associated with increased length of stay in intensive care unit and with a worse outcome in some subgroups of patients (mainly neurocritically ill patients). Although fever can increase oxygen consumption in unstable patients, on the contrary, it can activate physiologic systems that are involved in pathogens clearance. Treatments to reduce fever include the use of antipyretics. Thus, the reduction of fever might reduce the ability to develop an efficient host response. This balance, between harms and benefits, has to be taken into account every time we decide to treat or not to treat fever in a given patient. Among the antipyretics, paracetamol is one of the most common used. Paracetamol is a synthetic, nonopioid, centrally acting analgesic, and antipyretic drug. Its antipyretic effect occurs because it inhibits cyclooxygenase-3 and the prostaglandin synthesis, within the central nervous system, resetting the hypothalamic heat-regulation center. In this clinical review, we will summarize the use of paracetamol as antipyretic in critically ill patients (sepsis, trauma, neurological, and medical). Copyright © 2016 Elsevier Inc. All rights reserved.

The effects of tramadol on hepatic ischemia/reperfusion injury in rats

PubMed Central

Mahmoud, Mona F.; Gamal, Samar; Shaheen, Mohamed A.; El-Fayoumi, Hassan M.

2016-01-01

Objectives: Tramadol is a centrally acting synthetic analgesic. It has a cardioprotective effect against myocardial ischemia-reperfusion (I/R) injury in isolated rat heart. We hypothesized that tramadol may exert a similar protective effect on hepatic I/R injury. Hence, the current investigation was designed to study the possible protective effects of tramadol on experimentally-induced hepatic I/R injury in rats. Materials and Methods: Tramadol was administered 30 min before ischemia following which the rats were subjected to 45 min of ischemia followed by 1 h of reperfusion. Results: Tramadol attenuated hepatic injury induced by I/R as evidenced by the reduction of transaminases, structural changes, and apoptotic cell death. It decreased the level of inflammatory markers such as tumor necrosis factor-alpha (TNF-α), TNF-α/interleukin-10 (IL-10) ratio, and nuclear factor-κB gene expression. It also increased the anti-inflammatory cytokine, IL-10 levels in hepatic tissues. Furthermore, it reduced oxidative stress parameters except manganese superoxide dismutase activity. Conclusion: The results suggest that tramadol has hepatoprotective effects against hepatic I/R injury via anti-inflammatory, antiapoptotic, and antioxidant effects. PMID:27298497

The effects of tramadol on hepatic ischemia/reperfusion injury in rats.

PubMed

Mahmoud, Mona F; Gamal, Samar; Shaheen, Mohamed A; El-Fayoumi, Hassan M

2016-01-01

Tramadol is a centrally acting synthetic analgesic. It has a cardioprotective effect against myocardial ischemia-reperfusion (I/R) injury in isolated rat heart. We hypothesized that tramadol may exert a similar protective effect on hepatic I/R injury. Hence, the current investigation was designed to study the possible protective effects of tramadol on experimentally-induced hepatic I/R injury in rats. Tramadol was administered 30 min before ischemia following which the rats were subjected to 45 min of ischemia followed by 1 h of reperfusion. Tramadol attenuated hepatic injury induced by I/R as evidenced by the reduction of transaminases, structural changes, and apoptotic cell death. It decreased the level of inflammatory markers such as tumor necrosis factor-alpha (TNF-α), TNF-α/interleukin-10 (IL-10) ratio, and nuclear factor-κB gene expression. It also increased the anti-inflammatory cytokine, IL-10 levels in hepatic tissues. Furthermore, it reduced oxidative stress parameters except manganese superoxide dismutase activity. The results suggest that tramadol has hepatoprotective effects against hepatic I/R injury via anti-inflammatory, antiapoptotic, and antioxidant effects.

Impact of analgesics on executive function and memory in the Alzheimer's Disease Neuroimaging Initiative Database.

PubMed

Doan, Lisa; Choi, Daniel; Kline, Richard

2017-10-01

Pain is common in older adults but may be undertreated in part due to concerns about medication toxicity. Analgesics may affect cognition. In this retrospective cohort study, we used the Alzheimer's Disease Neuroimaging Initiative (ADNI) database to examine the interaction of cognitive status and medications, especially non-steroidal anti-inflammatory drugs (NSAIDs). We hypothesized NSAID use would be associated with cognition and that this could be mediated through changes in brain structure. In this post hoc analysis of the ADNI database, subjects were selected by searching the "concurrent medications log" for analgesic medications. Subjects were included if the analgesic was listed on the medication log prior to enrollment in ADNI and throughout the study. Subjects taking analgesics, particularly NSAIDs, at each study visit were compared to control subjects taking no analgesics. Using descriptive statistics as well as univariate, multivariate and repeated measure ANOVA, we explored the relationship between NSAID use and scores for executive function and memory related cognitive activities. We further took advantage of the extensive magnetic resonance imaging (MRI) data available in ADNI to test whether cognitive change was associated with brain structure. The multitude of imaging variables was compressed into a small number of features (five eigenvectors (EV)) using principal component analysis. There were 87 NSAID users, 373 controls, and 71 taking other analgesics. NSAID use was associated with higher executive function scores for cognitively normal (NL) subjects as well as subjects with mild cognitive impairment (MCI). NSAID use was also associated with higher memory scores, but for NL females only. We analysed MRI data using principal component analysis to generate a set of five EVs. Examining NL and MCI subjects, one EV had significantly larger values in subjects taking NSAIDs versus control. This EV was one of two EVs which significantly correlated with composite executive function and memory scores as well as cognitive diagnosis. NSAID use was associated with higher executive function, and memory scores in certain subjects and larger cortical volumes in particular regions. Limitations of the study include secondary analysis of existing data and the possibility of confounding. These results suggest it is important to consider the secondary effects of medications when choosing a treatment regimen. Further prospective studies are needed to examine the role of analgesics on cognition and whether NSAIDs act through cortical dimension changes and how they are related to gender and cognitive diagnosis. Copyright © 2017 Scandinavian Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

Effect of a centralized prescription network on inappropriate prescriptions for opioid analgesics and benzodiazepines

PubMed Central

Dormuth, Colin R.; Miller, Tarita A.; Huang, Anjie; Mamdani, Muhammad M.; Juurlink, David N.

2012-01-01

Background: Opioid analgesics and benzodiazepines are often misused in clinical practice. We determined whether implementation of a centralized prescription network offering real-time access to patient-level data on filled prescriptions (PharmaNet) reduced the number of potentially inappropriate prescriptions for opioids and benzodiazepines. Methods: We conducted a time series analysis using prescription records between Jan. 1, 1993, and Dec. 31, 1997, for residents of the province of British Columbia who were receiving social assistance or were 65 years or older. We calculated monthly percentages of filled prescriptions for an opioid or a benzodiazepine that were deemed inappropriate (those issued by a different physician and dispensed at a different pharmacy within 7 days after a filled prescription of at least 30 tablets of the same drug). Results: Within 6 months after implementation of PharmaNet in July 1995, we observed a relative reduction in inappropriate filled prescriptions for opioids of 32.8% (95% confidence interval [CI] 31.0%–34.7%) among patients receiving social assistance; inappropriate filled prescriptions for benzodiazepines decreased by 48.6% (95% CI 43.2%–53.1%). Similar and statistically significant reductions were observed among residents 65 years or older. Interpretation: The implementation of a centralized prescription network was associated with a dramatic reduction in inappropriate filled prescriptions for opioids and benzodiazepines. PMID:22949563

A substance P-opioid chimeric peptide as a unique nontolerance-forming analgesic

PubMed Central

Foran, Stacy E.; Carr, Daniel B.; Lipkowski, Andrzej W.; Maszczynska, Iwona; Marchand, James E.; Misicka, Aleksandra; Beinborn, Martin; Kopin, Alan S.; Kream, Richard M.

2000-01-01

To elucidate mechanisms of acute and chronic pain, it is important to understand how spinal excitatory systems influence opioid analgesia. The tachykinin substance P (SP) represents the prototypic spinal excitatory peptide neurotransmitter/neuromodulator, acting in concert with endogenous opioid systems to regulate analgesic responses to nociceptive stimuli. We have synthesized and pharmacologically characterized a chimeric peptide containing overlapping NH2- and COOH-terminal functional domains of the endogenous opioid endomorphin-2 (EM-2) and the tachykinin SP, respectively. Repeated administration of the chimeric molecule YPFFGLM-NH2, designated ESP7, into the rat spinal cord produces opioid-dependent analgesia without loss of potency over 5 days. In contrast, repeated administration of ESP7 with concurrent SP receptor (SPR) blockade results in a progressive loss of analgesic potency, consistent with the development of tolerance. Furthermore, tolerant animals completely regain opioid sensitivity after post hoc administration of ESP7 alone, suggesting that coactivation of SPRs is essential to maintaining opioid responsiveness. Radioligand binding and signaling assays, using recombinant receptors, confirm that ESP7 can coactivate μ-opioid receptors (MOR) and SPRs in vitro. We hypothesize that coincidental activation of the MOR- and SPR-expressing systems in the spinal cord mimics an ongoing state of reciprocal excitation and inhibition, which is normally encountered in nociceptive processing. Due to the ability of ESP7 to interact with both MOR and SPRs, it represents a unique prototypic, anti-tolerance-forming analgesic with future therapeutic potential. PMID:10852965

The role of vitamin C in the treatment of pain: new insights.

PubMed

Carr, Anitra C; McCall, Cate

2017-04-14

The vitamin C deficiency disease scurvy is characterised by musculoskeletal pain and recent epidemiological evidence has indicated an association between suboptimal vitamin C status and spinal pain. Furthermore, accumulating evidence indicates that vitamin C administration can exhibit analgesic properties in some clinical conditions. The prevalence of hypovitaminosis C and vitamin C deficiency is high in various patient groups, such as surgical/trauma, infectious diseases and cancer patients. A number of recent clinical studies have shown that vitamin C administration to patients with chronic regional pain syndrome decreases their symptoms. Acute herpetic and post-herpetic neuralgia is also diminished with high dose vitamin C administration. Furthermore, cancer-related pain is decreased with high dose vitamin C, contributing to enhanced patient quality of life. A number of mechanisms have been proposed for vitamin C's analgesic properties. Herein we propose a novel analgesic mechanism for vitamin C; as a cofactor for the biosynthesis of amidated opioid peptides. It is well established that vitamin C participates in the amidation of peptides, through acting as a cofactor for peptidyl-glycine α-amidating monooxygenase, the only enzyme known to amidate the carboxy terminal residue of neuropeptides and peptide hormones. Support for our proposed mechanism comes from studies which show a decreased requirement for opioid analgesics in surgical and cancer patients administered high dose vitamin C. Overall, vitamin C appears to be a safe and effective adjunctive therapy for acute and chronic pain relief in specific patient groups.

Tolerance to Non-Opioid Analgesics is Opioid Sensitive in the Nucleus Raphe Magnus.

PubMed

Tsagareli, Merab G; Nozadze, Ivliane; Tsiklauri, Nana; Gurtskaia, Gulnaz

2011-01-01

Repeated injection of opioid analgesics can lead to a progressive loss of effect. This phenomenon is known as tolerance. Several lines of investigations have shown that systemic, intraperitoneal administration or the microinjection of non-opioid analgesics, non-steroidal anti-inflammatory drugs (NSAIDs) into the midbrain periaqueductal gray matter induces antinociception with some effects of tolerance. Our recent study has revealed that microinjection of three drugs analgin, ketorolac, and xefocam into the central nucleus of amygdala produce tolerance to them and cross-tolerance to morphine. Here we report that repeated administrations of these NSAIDs into the nucleus raphe magnus (NRM) in the following 4 days result in progressively less antinociception compare to the saline control, i.e., tolerance develops to these drugs in male rats. Special control experiments showed that post-treatment with the μ-opioid antagonist naloxone into the NRM significantly decreased antinociceptive effects of NSAIDs on the first day of testing in the tail-flick (TF) reflex and hot plate (HP) latency tests. On the second day, naloxone generally had trend effects in both TF and HP tests and impeded the development of tolerance to the antinociceptive effect of non-opioid analgesics. These findings strongly support the suggestion of endogenous opioid involvement in NSAIDs antinociception and tolerance in the descending pain-control system. Moreover, repeated injections of NSAIDs progressively lead to tolerance to them, cross-tolerance to morphine, and the risk of a withdrawal syndrome. Therefore, these results are important for human medicine too.

Analgesic effect of paeoniflorin in rats with neonatal maternal separation-induced visceral hyperalgesia is mediated through adenosine A(1) receptor by inhibiting the extracellular signal-regulated protein kinase (ERK) pathway.

PubMed

Zhang, Xiao-Jun; Chen, Hong-Li; Li, Zhi; Zhang, Hong-Qi; Xu, Hong-Xi; Sung, Joseph J Y; Bian, Zhao-Xiang

2009-11-01

Paeoniflorin (PF), a chief active ingredient in the root of Paeonia lactiflora Pall (family Ranunculaceae), is effective in relieving colorectal distention (CRD)-induced visceral pain in rats with visceral hyperalgesia induced by neonatal maternal separation (NMS). This study aimed at exploring the underlying mechanisms of PF's analgesic effect on CRD-evoked nociceptive signaling in the central nervous system (CNS) and investigating whether the adenosine A(1) receptor is involved in PF's anti-nociception. CRD-induced visceral pain as well as phosphorylated-extracellular signal-regulated protein kinase (p-ERK) and phospho-cAMP response element-binding protein (p-CREB) expression in the CNS structures of NMS rats were suppressed by NMDA receptor antagonist dizocilpine (MK-801) and ERK phosphorylation inhibitor U0126. PF could similarly inhibit CRD-evoked p-ERK and c-Fos expression in laminae I-II of the lumbosacral dorsal horn and anterior cingulate cortex (ACC). PF could also reverse the CRD-evoked increased glutamate concentration by CRD as shown by dynamic microdialysis monitoring in ACC, whereas, DPCPX, an antagonist of adenosine A(1) receptor, significantly blocked the analgesic effect of PF and PF's inhibition on CRD-induced p-ERK and p-CREB expression. These results suggest that PF's analgesic effect is possibly mediated by adenosine A(1) receptor by inhibiting CRD-evoked glutamate release and the NMDA receptor dependent ERK signaling.

Methyl-N-methylanthranilate, a pungent compound from Citrus reticulata Blanco leaves.

PubMed

Correa, Edwin; Quiñones, Winston; Echeverri, Fernando

2016-01-01

More analgesic compounds are needed in medicine against pain since the available drugs displayed secondary effects. Natural products are a source of molecules to develop new analgesics, using the information of plants, applied against pain, with effects such as pungency, tingling, and needle, due to their possible role in the central nervous system (NCS). Citrus reticulata Blanco (Rutaceae) leaves are usually bitten to flavor the mouth and possess this type effect in lips and tongues; due to this fact the structure of the bioctive compound could be the source of other types of analgesics. The objective of this study is to determine the causal agent of the pungent effect in mandarin essential oil. Mandarin essential oil was obtained and then purified by column chromatography. Each fraction was tested and pungency was detected only in the first fraction which was pure. The compound responsible for the pungency in the essential oils of leaves from Citrus reticulata (mandarin) was purified and the structure was assigned as methyl-N-methylanthranilate, on the basis of NMR 1D and 2D and MS. This substance corresponds to another type of molecule involving an antinociceptive effect. Terpenes are compounds found in essential oils. The compound responsible for the pungency of mandarin and other citrus leaves was isolated, and surprisingly it was identified as a methyl-N-methylanthranilate. This kind of molecules with this activity could be used to discover new analgesics in human therapy against pain.

Intrathecal resiniferatoxin in a dog model: Efficacy in bone cancer pain

PubMed Central

Brown, Dorothy Cimino; Agnello, Kimberly; Iadarola, Michael J.

2015-01-01

Resiniferatoxin (RTX) is the most potent amongst all known endogenous and synthetic agonists for the transient receptor potential vanilloid 1 (TRPV1) receptor, which is a calcium permeable non-selective cation channel, expressed on the peripheral and central terminals of small diameter sensory neurons. [11,32] Prolonged calcium influx induced by RTX causes cytotoxicity and death of only those sensory neurons that express the TRPV1 ion channel leading to selective targeting and permanent deletion of the TRPV1-expressing C-fiber neuronal cell bodies in the dorsal root ganglia. [10,17] The goal of this project was to provide pre-clinical efficacy data, that intrathecal RTX could provide effective pain relief and improve function in dogs with bone cancer without significant long-term side effects. In a single blind, controlled study, 72 companion dogs with bone cancer pain were randomized to standard of care analgesic therapy alone (control, n=36) or 1.2 mcg/kg intrathecal RTX in addition to standard of care analgesic therapy (treated, n=36). Significantly more dogs in the control group (78%) required unblinding and adjustment in analgesic protocol or euthanasia within 6 weeks of randomization, than dogs that were treated with RTX (50%; p<0.03); and overall, dogs in the control group required unblinding significantly sooner than dogs that had been treated with RTX (p<0.02). The analgesic effect was documented in these dogs without any evidence of development of deafferentation pain syndrome that can be seen with neurolytic therapies. PMID:25659068

[Ziconotide: an innovative alternative for intense chronic neuropathic pain].

PubMed

Valía-Vera, J C; Villanueva, V L; Asensio-Samper, J M; López-Alarcón, M D; de Andrés, J A

Intense chronic pain is a very important health problem, as it has a high prevalence (5-10%), a multifactorial aetiology and its management is very often a very complex affair. Treatment of severe cases sometimes requires interventional approaches, such as continuous intrathecal infusion of opioids. We report the case of a 38-year-old female with intense neuropathic pain in the lower back and the lower limbs secondary to three operations on the L5-S1 lumbar segment. After implementing several different pharmacological regimes involving both oral and implanted systems (spinal cord stimulation and subarachnoid infusion pump with different pharmacological combinations) with no clinical improvement, intrathecal infusion with ziconotide was included in the protocol. Ziconotide is the first specific neuronal blocker that acts on the calcium channel by blocking the N-type voltage-dependent calcium channels. It is a new non-opioid analgesic with approved indication in the treatment of intense chronic pain, in patients who require intrathecal analgesics and are refractory to other analgesic treatments. Therefore, we shall have to consider this drug as a therapeutic alternative in patients do not experience sufficient relief with the pharmacological agents and means currently available to treat them.

Nonnarcotic analgesics and tricyclic antidepressants for the treatment of chronic nonmalignant pain.

PubMed

Richlin, D M

1991-05-01

Chronic nonmalignant pain is often characterized by multiple treatment failures, a pattern of maladaptive behavior, and depression. Often there is a history of inappropriate and excessive use of medications for pain. Prior and ongoing use of narcotics and sedatives acts to compound and aggravate the chronic pain syndrome. A first step in treatment is controlled withdrawal of these agents. Nonnarcotic analgesics, NSAIDs, and tricyclic antidepressants are commonly employed in patients with chronic pain. Effective use of these agents requires understanding of their pharmacokinetic and pharmacodynamic properties. Use of a fixed-time schedule is necessary to achieve an effective, sustained therapeutic response. Careful patient education and monitoring for side effects and toxicity are necessary, particularly in the elderly and patients with coexisting medical disorders. Incidence of side effects and toxicity may be reduced by choice of drug and modification of dosing regimen. Nonnarcotic analgesics, TCAs, and NSAIDs are seldom effective by themselves in resolving the pain and distress of patients with chronic nonmalignant pain. This is particularly true when maladaptive behavior coexists. A comprehensive multimodal pain management program encompassing additional pain-relieving strategies and behavior-modifying techniques should be considered and utilized in conjunction with medication.

Local Infiltration Analgesia for Postoperative Pain Control following Total Hip Arthroplasty: A Systematic Review

PubMed Central

McCarthy, Denise; Iohom, Gabriella

2012-01-01

Local infiltration analgesia (LIA) is an analgesic technique that has gained popularity since it was first brought to widespread attention by Kerr and Kohan in 2008. The technique involves the infiltration of a large volume dilute solution of a long-acting local anesthetic agent, often with adjuvants (e.g., epinephrine, ketorolac, an opioid), throughout the wound at the time of surgery. The analgesic effect duration can then be prolonged by the placement of a catheter to the surgical site for postoperative administration of further local anesthetic. The technique has been adopted for use for postoperative analgesia following a range of surgical procedures (orthopedic, general, gynecological, and breast surgeries). The primary objective of this paper was to determine, based on the current evidence, if LIA is superior when compared to no intervention, placebo, and alternative analgesic methods in patients following total hip arthroplasty, in terms of certain outcome measures. The outcomes considered were postoperative analgesia scores, joint function/rehabilitation, and length of hospital stay. Secondary objectives were to review available evidence and current knowledge regarding the pharmacokinetics of local anesthetic and adjuvant drugs when administered in this way and the occurrence of adverse events. PMID:22829813

Postoperative pain management in the postanesthesia care unit: an update

PubMed Central

Luo, Jie; Min, Su

2017-01-01

Acute postoperative pain remains a major problem, resulting in multiple undesirable outcomes if inadequately controlled. Most surgical patients spend their immediate postoperative period in the postanesthesia care unit (PACU), where pain management, being unsatisfactory and requiring improvements, affects further recovery. Recent studies on postoperative pain management in the PACU were reviewed for the advances in assessments and treatments. More objective assessments of pain being independent of patients’ participation may be potentially appropriate in the PACU, including photoplethysmography-derived parameters, analgesia nociception index, skin conductance, and pupillometry, although further studies are needed to confirm their utilities. Multimodal analgesia with different analgesics and techniques has been widely used. With theoretical basis of preventing central sensitization, preventive analgesia is increasingly common. New opioids are being developed with minimization of adverse effects of traditional opioids. More intravenous nonopioid analgesics and adjuncts (such as dexmedetomidine and dexamethasone) are introduced for their opioid-sparing effects. Current evidence suggests that regional analgesic techniques are effective in the reduction of pain and stay in the PACU. Being available alternatives to epidural analgesia, perineural techniques and infiltrative techniques including wound infiltration, transversus abdominis plane block, local infiltration analgesia, and intraperitoneal administration have played a more important role for their effectiveness and safety. PMID:29180895

Stress and visceral pain: from animal models to clinical therapies

PubMed Central

Larauche, Muriel; Mulak, Agata; Taché, Yvette

2011-01-01

Epidemiological studies have implicated stress (psychosocial and physical) as a trigger of first onset or exacerbation of irritable bowel syndrome (IBS) symptoms of which visceral pain is an integrant landmark. A number of experimental acute or chronic exteroceptive or interoceptive stressors induce visceral hyperalgesia in rodents although recent evidence also points to stress-related visceral analgesia as established in the somatic pain field. Underlying mechanisms of stress-related visceral hypersensitivity may involve a combination of sensitization of primary afferents, central sensitization in response to input from the viscera and dysregulation of descending pathways that modulate spinal nociceptive transmission or analgesic response. Biochemical coding of stress involves the recruitment of corticotropin releasing factor (CRF) signaling pathways. Experimental studies established that activation of brain and peripheral CRF receptor subtype 1 plays a primary role in the development of stress-related delayed visceral hyperalgesia while subtype 2 activation induces analgesic response. In line with stress pathways playing a role in IBS, non-pharmacologic and pharmacologic treatment modalities aimed at reducing stress perception using a broad range of evidence-based mind-body interventions and centrally-targeted medications to reduce anxiety impact on brain patterns activated by visceral stimuli and dampen visceral pain. PMID:21575632

Cannabinoids in the management of difficult to treat pain.

PubMed

Russo, Ethan B

2008-02-01

This article reviews recent research on cannabinoid analgesia via the endocannabinoid system and non-receptor mechanisms, as well as randomized clinical trials employing cannabinoids in pain treatment. Tetrahydrocannabinol (THC, Marinol((R))) and nabilone (Cesamet((R))) are currently approved in the United States and other countries, but not for pain indications. Other synthetic cannabinoids, such as ajulemic acid, are in development. Crude herbal cannabis remains illegal in most jurisdictions but is also under investigation. Sativex((R)), a cannabis derived oromucosal spray containing equal proportions of THC (partial CB(1) receptor agonist ) and cannabidiol (CBD, a non-euphoriant, anti-inflammatory analgesic with CB(1) receptor antagonist and endocannabinoid modulating effects) was approved in Canada in 2005 for treatment of central neuropathic pain in multiple sclerosis, and in 2007 for intractable cancer pain. Numerous randomized clinical trials have demonstrated safety and efficacy for Sativex in central and peripheral neuropathic pain, rheumatoid arthritis and cancer pain. An Investigational New Drug application to conduct advanced clinical trials for cancer pain was approved by the US FDA in January 2006. Cannabinoid analgesics have generally been well tolerated in clinical trials with acceptable adverse event profiles. Their adjunctive addition to the pharmacological armamentarium for treatment of pain shows great promise.

Pharmacological interactions of anti-inflammatory-analgesics in odontology.

PubMed

Gómez-Moreno, Gerardo; Guardia, Javier; Cutando, Antonio; Calvo-Guirado, José Luis

2009-02-01

In this second article we describe the more interesting pharmacological interactions in dental practice based on the prescription of analgesic narcotics, paracetamol and non-selective non-steroid anti-inflammatory drugs (NSAI) (which inhibit cyclooxigenase 1 -COX 1- and cyclooxigenase 2 -COX 2-) and selective NSAIs (COX 2 inhibitors). The importance of preventing the appearance of these pharmacological interactions is because these are medicaments prescribed daily in odontology for moderate pain treatment and inflammation in the oral cavity. Paracetamol can interact with warfarin and therefore care should be taken with chronic alcoholic patients. All NSAIs reduce renal blood flow and consequently are capable of reducing the efficacy of medicaments used for treating arterial hypertension, which act via a renal mechanism. Especial attention should be taken considering the risk of interaction between the antagonists of AT1 receptors of angiostensin II (ARAII) and the NSAIs.

The analgesic effect of trans-resveratrol is regulated by calcium channels in the hippocampus of mice.

PubMed

Wang, Weijie; Yu, Yingcong; Li, Jing; Wang, Lin; Li, Zhi; Zhang, Chong; Zhen, Linlin; Ding, Lianshu; Wang, Gang; Sun, Xiaoyang; Xu, Ying

2017-08-01

Resveratrol has been widely studied in terms of it's potential to slow the progression of many diseases. But little is known about the mechanism of action in neuropathic pain. Neuropathic pain is the main type of chronic pain associated with tissue injury. Calcium channels and calcium/caffeine-sensitive pools are associated with analgesic pathway involving neuropathic pain. Our previous study suggested that the antinociceptive effect of resveratrol was involved in Ca 2+ /calmodulin-dependent signaling in the spinal cord of mice. The aim of this study was to explore the involvement of Ca 2+ in analgesic effects of trans-resveratrol in neuropathic pain and signal pathway in hippocampus. Hot plate test was used to assess antinociceptive response when mice were treated with trans-resveratrol alone or in combination with Mk 801, nimodipine, CaCl 2 , ryanodine or EGTA. The effects of trans-resveratrol and the combination on Ca 2+ /calmodulin-dependent protein kinase II (CaMKII) and BDNF (brain-derived neurotrophic factor) expression in hippocampus were also investigated. The results showed that trans-resveratrol increased paw withdraw latency in the hot plate test. The effect of resveratrol was enhanced by Mk 801 and nimodipine. Central administration of Ca 2+ , however, abolished the antinociceptive effects of resveratrol. In contrast, centrally administered EGTA or ryanodine improved trans-resveratrol induced antinociception. There was a significant increase in p-CaMKII and BDNF expression in the hippocampus when resveratrol were combined with Mk 801, nimodipine, ryanodine and EGTA. Administration of CaCl 2 blocked changes in p-CaMKII and BDNF levels in the hippocampus. These findings suggest that trans-resveratrol exerts the effects of antinociception through regulation of calcium channels and calcium/caffeine-sensitive pools.

Efficacy, Tolerability, and Dose-Dependent Effects of Opioid Analgesics for Low Back Pain: A Systematic Review and Meta-analysis.

PubMed

Abdel Shaheed, Christina; Maher, Chris G; Williams, Kylie A; Day, Richard; McLachlan, Andrew J

2016-07-01

Opioid analgesics are commonly used for low back pain, however, to our knowledge there has been no systematic evaluation of the effect of opioid dose and use of enrichment study design on estimates of treatment effect. To evaluate efficacy and tolerability of opioids in the management of back pain; and investigate the effect of opioid dose and use of an enrichment study design on treatment effect. Medline, EMBASE, CENTRAL, CINAHL, and PsycINFO (inception to September 2015) with citation tracking from eligible randomized clinical trials (RCTs). Placebo-controlled RCTs in any language. Two authors independently extracted data and assessed risk of bias. Data were pooled using a random effects model with strength of evidence assessed using the grading of recommendations assessment, development, and evaluation (GRADE). The primary outcome measure was pain. Pain and disability outcomes were converted to a common 0 to 100 scale, with effects greater than 20 points considered clinically important. Of 20 included RCTs of opioid analgesics (with a total of 7925 participants), 13 trials (3419 participants) evaluated short-term effects on chronic low back pain, and no placebo-controlled trials enrolled patients with acute low back pain. In half of these 13 trials, at least 50% of participants withdrew owing to adverse events or lack of efficacy. There was moderate-quality evidence that opioid analgesics reduce pain in the short term; mean difference (MD), -10.1 (95% CI, -12.8 to -7.4). Meta-regression revealed a 12.0 point greater pain relief for every 1 log unit increase in morphine equivalent dose (P = .046). Clinically important pain relief was not observed within the dose range evaluated (40.0-240.0-mg morphine equivalents per day). There was no significant effect of enrichment study design. For people with chronic low back pain who tolerate the medicine, opioid analgesics provide modest short-term pain relief but the effect is not likely to be clinically important within guideline recommended doses. Evidence on long-term efficacy is lacking. The efficacy of opioid analgesics in acute low back pain is unknown.

Molecular Signatures of Chronic Pain Subtypes

DTIC Science & Technology

2015-03-01

injury, omega-3 fatty acid supplementation may act as a safe and novel preventive analgesic therapy . We have recently completed enrollment of one...chemical or physical structure of DNA [15]. Structural and chemical changes in DNA may be influenced by experience (acute pain and perioperative inflam...DNMT inhibitors appear to be another promising epigenetically active therapy to prevent chronic pain after surgery [39]. There appears to be a

Combined analgesics in (headache) pain therapy: shotgun approach or precise multi-target therapeutics?

PubMed

Straube, Andreas; Aicher, Bernhard; Fiebich, Bernd L; Haag, Gunther

2011-03-31

Pain in general and headache in particular are characterized by a change in activity in brain areas involved in pain processing. The therapeutic challenge is to identify drugs with molecular targets that restore the healthy state, resulting in meaningful pain relief or even freedom from pain. Different aspects of pain perception, i.e. sensory and affective components, also explain why there is not just one single target structure for therapeutic approaches to pain. A network of brain areas ("pain matrix") are involved in pain perception and pain control. This diversification of the pain system explains why a wide range of molecularly different substances can be used in the treatment of different pain states and why in recent years more and more studies have described a superior efficacy of a precise multi-target combination therapy compared to therapy with monotherapeutics. In this article, we discuss the available literature on the effects of several fixed-dose combinations in the treatment of headaches and discuss the evidence in support of the role of combination therapy in the pharmacotherapy of pain, particularly of headaches. The scientific rationale behind multi-target combinations is the therapeutic benefit that could not be achieved by the individual constituents and that the single substances of the combinations act together additively or even multiplicatively and cooperate to achieve a completeness of the desired therapeutic effect.As an example the fixed-dose combination of acetylsalicylic acid (ASA), paracetamol (acetaminophen) and caffeine is reviewed in detail. The major advantage of using such a fixed combination is that the active ingredients act on different but distinct molecular targets and thus are able to act on more signalling cascades involved in pain than most single analgesics without adding more side effects to the therapy. Multitarget therapeutics like combined analgesics broaden the array of therapeutic options, enable the completeness of the therapeutic effect, and allow doctors (and, in self-medication with OTC medications, the patients themselves) to customize treatment to the patient's specific needs. There is substantial clinical evidence that such a multi-component therapy is more effective than mono-component therapies.

[Legal issues of physician-assisted euthanasia. Part II--Help in the dying process, direct and indirect active euthanasia].

PubMed

Laux, Johannes; Röbel, Andreas; Parzeller, Markus

2013-01-01

In Germany, physician-assisted euthanasia involves numerous risks for the attending physician under criminal and professional law. In the absence of clear legal provisions, four different categories of euthanasia have been developed in legal practice and the relevant literature: help in the dying process, direct active euthanasia, indirect active euthanasia and passive euthanasia. The so-called "help during the dying process" by administering medically indicated analgesic drugs without a life-shortening effect is exempt from punishment if it corresponds to the will of the patient. If the physician omits to give such analgesic drugs although the patient demands them, this is deemed a punishable act of bodily injury. The same applies if the physician administers analgesics against the will of the patient. Medically indicated pain treatment which has a potential or certain life-shortening effect (indirect active euthanasia) is permitted under certain conditions: if there are no alternative and equally suitable treatment options without the risk of shortening the patient's life, if the patient has given his consent to the treatment and if the physician does not act with the intention to kill. The deliberate killing of a dying or terminally ill patient for the purpose of ending his suffering (direct active euthanasia) is prohibited. This includes both deliberately killing a patient against or without his will (by so-called "angels of death") and the killing of a patient who expressly and earnestly demands such an act from his physician (killing on request/on demand). Physician-assisted suicide is generally not liable to punishment in Germany. Nevertheless, the action may be subject to punishment if the physician omits to rescue the life of an unconscious suicide victim. "Palliative sedation" is regarded as a special case. It may become necessary if certain symptoms in the terminal stage of a fatal disease unbearable for the patient cannot be controlled by any other means. The legal assessment of "palliative sedation" depends on the circumstances of the individual case, in particular the "informed consent" of the patient and the physician's intention.

Combined analgesics in (headache) pain therapy: shotgun approach or precise multi-target therapeutics?

PubMed Central

2011-01-01

Background Pain in general and headache in particular are characterized by a change in activity in brain areas involved in pain processing. The therapeutic challenge is to identify drugs with molecular targets that restore the healthy state, resulting in meaningful pain relief or even freedom from pain. Different aspects of pain perception, i.e. sensory and affective components, also explain why there is not just one single target structure for therapeutic approaches to pain. A network of brain areas ("pain matrix") are involved in pain perception and pain control. This diversification of the pain system explains why a wide range of molecularly different substances can be used in the treatment of different pain states and why in recent years more and more studies have described a superior efficacy of a precise multi-target combination therapy compared to therapy with monotherapeutics. Discussion In this article, we discuss the available literature on the effects of several fixed-dose combinations in the treatment of headaches and discuss the evidence in support of the role of combination therapy in the pharmacotherapy of pain, particularly of headaches. The scientific rationale behind multi-target combinations is the therapeutic benefit that could not be achieved by the individual constituents and that the single substances of the combinations act together additively or even multiplicatively and cooperate to achieve a completeness of the desired therapeutic effect. As an example the fixesd-dose combination of acetylsalicylic acid (ASA), paracetamol (acetaminophen) and caffeine is reviewed in detail. The major advantage of using such a fixed combination is that the active ingredients act on different but distinct molecular targets and thus are able to act on more signalling cascades involved in pain than most single analgesics without adding more side effects to the therapy. Summary Multitarget therapeutics like combined analgesics broaden the array of therapeutic options, enable the completeness of the therapeutic effect, and allow doctors (and, in self-medication with OTC medications, the patients themselves) to customize treatment to the patient's specific needs. There is substantial clinical evidence that such a multi-component therapy is more effective than mono-component therapies. PMID:21453539

Making the decision to stop pain: Probability and magnitude effects of expected pain relief on the choice of analgesics.

PubMed

Lin, C

2013-04-01

Pain is a major ailment that motivates individuals to look for treatment. Despite its enormous clinical relevance, very little is known about the factors that influence our preference of an analgesic (or pain-relieving treatment). The current study investigated the influence of the information regarding the probability and the magnitude of the expected analgesic effect on preference of analgesic options. Twenty-four healthy volunteers were instructed to imagine pain across different scenarios and choose between two hypothetical analgesics that differed in their probabilities to successfully relieve pain and the magnitude of their expected analgesic effects. The conservative analgesic was more reliable but less potent than the radical analgesic, whereas the radical analgesic was less reliable but more potent than the conservative analgesic. Consistent with the predictions of prospect theory, a larger proportion of the participants chose the radical analgesic when the overall probability of both analgesics decreased, and when the potency of the radical analgesic was expected to be stronger relative to the conservative analgesic. At the individual level, individuals' relative imagined pain relief (radical analgesic/conservative analgesic) predicted their preference for the radical analgesic. Our findings revealed that preference of analgesic options is mediated by the overall probability of analgesic effect and the relative potency of analgesics. The expected relief one imagines to obtain from analgesics would guide preference. The findings highlight the importance for clinicians to understand how patients subjectively frame the probability and magnitude factors related to decision making in medical context. © 2012 European Federation of International Association for the Study of Pain Chapters.

Ginger (Zingiber officinale) as an Analgesic and Ergogenic Aid in Sport: A Systemic Review.

PubMed

Wilson, Patrick B

2015-10-01

Ginger is a popular spice used to treat a variety of maladies, including pain. Nonsteroidal anti-inflammatory drugs (NSAIDs) are frequently used by athletes to manage and prevent pain; unfortunately, NSAIDs contribute to substantial adverse effects, including gastrointestinal (GI) dysfunction, exercise-induced bronchoconstriction, hyponatremia, impairment of connective tissue remodeling, endurance competition withdrawal, and cardiovascular disease. Ginger, however, may act as a promoter of GI integrity and as a bronchodilator. Given these potentially positive effects of ginger, a systematic review of randomized trials was performed to assess the evidence for ginger as an analgesic and ergogenic aid for exercise training and sport. Among 7 studies examining ginger as an analgesic, the evidence indicates that roughly 2 g·d(-1) of ginger may modestly reduce muscle pain stemming from eccentric resistance exercise and prolonged running, particularly if taken for a minimum of 5 days. Among 9 studies examining ginger as an ergogenic aid, no discernable effects on body composition, metabolic rate, oxygen consumption, isometric force generation, or perceived exertion were observed. Limited data suggest that ginger may accelerate recovery of maximal strength after eccentric resistance exercise and reduce the inflammatory response to cardiorespiratory exercise. Major limitations to the research include the use of untrained individuals, insufficient reporting on adverse events, and no direct comparisons with NSAID ingestion. While ginger taken over 1-2 weeks may reduce pain from eccentric resistance exercise and prolonged running, more research is needed to evaluate its safety and efficacy as an analgesic for a wide range of athletic endeavors.

Anti-nociceptive efficacy of carprofen, levomethadone and buprenorphine for pain relief in cats following major orthopaedic surgery.

PubMed

Möllenhoff, A; Nolte, I; Kramer, S

2005-05-01

A placebo-controlled, randomized blind study was conducted in cats (n = 60) after fracture repair to compare the analgesic effects as well as the side-effects of carprofen, buprenorphine and levomethadone during a 5-day treatment. Cats with severe shock symptoms or increases in blood urea nitrogen (BUN) and creatinine were excluded from the study. The cats were randomly assigned to four groups (n= 15). In group 1, carprofen was administered upon extubation at an initial dose of 4 mg/kg body weight, followed by one-third of that dose three times daily on days 2 to 5. In group 2, buprenorphine was administered in a single dose of 0.01 mg/kg body weight upon extubation and subsequently every 8 h. Levomethadone (group 3) was applied according to the same scheme at a dosage of 0.3 mg/kg body weight each time. The placebo (group 4) was given at the same time intervals as the opioids. Examinations were carried out prior to anaesthesia, between 30 min and 8 h after extubation, and on the following 4 days, 1 h after administration of the analgesics or the placebo as well as 1 h before the next administration. Pain and sedation evaluation was carried out with a visual analogue system (VAS) and with the aid of a numerical estimation scale (NRS). Pain was also scored by measuring mechanical nociceptive threshold of traumatized tissue. Plasma glucose and cortisol concentration, heart rate, respiration rate, blood pressure and body temperature were measured. Furthermore, a complete blood count and clinical chemistry including BUN, creatinine, alanine aminotransferase (ALT), glutamate dehydrogenase (GLDH), arterial blood pressure (AP), total protein and electrolytes of the cats were checked on the day of admission as well as on the last day of this study (day 5). Defaecation and urination as well as wound healing were monitored. On the basis of the mechanical nociceptive threshold of the traumatized tissue, concentrations of plasma glucose and cortisol and pain assessment using NRS and VAS, carprofen was found to have better anti-nociceptive efficacy when compared with the two opioid analgesics, while the analgesic effect of levomethadone was similar to that of buprenorphine. However, the carprofen group also showed comparably high median NRS and VAS pain scores in addition to occasional broad deviations from the group mean on the first post-operative treatment day. Sedative effects were detected for buprenorphine and levomethadone; in addition, symptoms of central excitation were noted with levomethadone. There was no indication of any clinically relevant respiratory depressive or cardiovascular effects, nor of any undesired renal, gastrointestinal or hepatic effects of the analgesics applied. However, the somewhat insensitive examination methods did not permit sufficient evaluation of side-effects, particularly on the gastrointestinal tract and the kidneys. It was found that carprofen and buprenorphine were well-tolerated analgesics for a 5-day administration in the cat, whereas levomethadone caused central excitation in some cases in the dosage scheme used here. However, it was apparent that none of the tested analgesics induced sufficient analgesia in the post-operative phase. For this reason, suitable methods must be found to improve analgesia, particularly in the immediate post-operative phase.

Remifentanil for the insertion and removal of long-term central venous access during monitored anesthesia care.

PubMed

Burlacu, Crina L; McKeating, Kevin; McShane, Alan J

2011-06-01

To determine the analgesic efficacy of three different rates of remifentanil infusion in patients undergoing insertion or removal of long-term central venous access devices during monitored anesthesia care and local anesthetic field infiltration. Double-blinded, randomized, controlled study. Operating theatre of an University hospital. 44 unpremedicated, ASA physical status 1 and 2 patients, aged 18-65 years, undergoing insertion or removal of a Port-a-Cath or Hickman catheter. Patients sedated with a propofol target-controlled infusion were randomly allocated to three groups: Group R25 (n = 14), Group R50 (n = 15), and Group R75 (n = 15), to receive remifentanil 0.025, 0.05, and 0.075 μg/kg/min, respectively. Rescue remifentanil 0.5 μg/kg was administered for pain scores > 3. The remifentanil infusion rate was maintained constant unless respiratory and/or cardiovascular unwanted events occurred, whereupon the rate was adjusted in 0.01 μg/kg/min decrements as necessary. Pain scores (primary outcome), sedation, and movement scores (secondary outcomes) were assessed during local anesthetic infiltration of the anterior chest wall and 5 other procedural steps. All infusion rates had equal analgesic efficacy, as shown by comparable pain scores, number of rescue boluses, and number of patients requiring rescue analgesia. Excessive sedation was associated with the highest remifentanil rate such that Group R75 patients were significantly more sedated than Groups R25 or R50 at selective procedural steps (P < 0.05). More Group R75 patients (6/15) required remifentanil rate reduction than did patients from Group R50 (1/15) or Group R25 (0/14), P < 0.01, most commonly because of respiratory depression. For the insertion or removal of long-term central venous access devices, all three remifentanil infusion rates proved to be equally analgesic-efficient. However, the excessive sedation and tendency to respiratory and cardiovascular events associated with the highest remifentanil infusion rate renders such a rate less desirable for this purpose. Copyright © 2011 Elsevier Inc. All rights reserved.

Ziconotide--a novel neuron-specific calcium channel blocker for the intrathecal treatment of severe chronic pain--a short review.

PubMed

Klotz, U

2006-10-01

Worldwide a large number of patients suffer from severe chronic pain even after treatment with opioids following the 3-step analgesic ladder developed by the WHO. Intraspinal agents, including morphine, have been tried as a fourth step. However, approximately 20% of cases remain refractory. Ziconotide, an intrathecal analgesic with orphan drug status, is a novel alternative for the management of chronic intractable pain. Ziconotide is a synthetic peptide based on the toxin of the fish-hunting marine snail, Conus magus. It is the first therapeutic agent in a new pharmacological class of "topically" active analgesics that selectively target neuron-specific (N-type), voltage-gated calcium channels. Ziconotide produces potent analgesia by interruption of Ca-dependent primary afferent transmission of pain signals in the spinal cord. Ziconotide was significantly more effective than placebo in the treatment of chronic malignant (p < 0.001) and non-malignant pain (p < 0.001). In several clinical studies morphine dosages could be substituted by ziconotide. The drug has a lag-time for the onset and offset of analgesia and adverse effects. Initial doses should therefore be low (2.4 microg/day) and titrated slowly (increasing up to a maximum of 21.6 microg/day in increases of 2.4 microg/day no more than twice weekly). The gradual increase in dose helps to reduce the incidence and severity of adverse events which affect primarily the central nervous system (e.g. dizziness, nausea, confusion). Ziconotide maintains its analgesic efficacy over months and does not cause tolerance, dependence or respiratory depression. Following intrathecal infusion ziconotide is distributed within the cerebral spinal fluid (CSF) where its clearance (0.38 ml/min) corresponds to the rate of turnover of the CSF. Negligible amounts of ziconotide are present in the systemic circulation where it is rapidly degraded by proteolysis. In conclusion, ziconotide is a new and valuable alternative analgesic for the acute and long-term treatment of severe pain, especially in patients refractory to opioids.

The analgesic effect of orexin-A in a murine model of chemotherapy-induced neuropathic pain.

PubMed

Toyama, Satoshi; Shimoyama, Naohito; Shimoyama, Megumi

2017-02-01

Orexins are neuropeptides that are localized to neurons in the lateral and dorsal hypothalamus but its receptors are distributed to many different regions of the central nervous system. Orexins are implicated in a variety of physiological functions including sleep regulation, energy homeostats, and stress reactions. Furthermore, orexins administered exogenously have been shown to have analgesic effects in animal models. A type of intractable pain in patients is pain due to chemotherapy-induced peripheral neuropathy (CIPN). Several chemotherapeutic agents used for the treatment of malignant diseases induce dose-limiting neuropathic pain that compromises patients' quality of life. Here, we examined the analgesic effect of orexin-A in a murine model of CIPN, and compared it with the effect of duloxetine, the only drug recommended for the treatment of CIPN pain in patients. CIPN was induced in male BALB/c mice by repeated intraperitoneal injection of oxaliplatin, a platinum chemotherapeutic agent used for the treatment of advanced colorectal cancer. Neuropathic mechanical allodynia was assessed by the von Frey test, and the effect on acute thermal pain was assessed by the tail flick test. Intracerebroventricularly administered orexin-A dose-dependently attenuated oxaliplatin-induced mechanical allodynia and increased tail flick latencies. Oxaliplatin-induced mechanical allodynia was completely reversed by orexin-A at a low dose that did not increase tail flick latency. Duloxetine only partially reversed mechanical allodynia and had no effect on tail flick latency. The analgesic effect of orexin-A on oxaliplatin-induced mechanical allodynia was completely antagonized by prior intraperitoneal injection of SB-408124 (orexin type-1 receptor antagonist), but not by prior intraperitoneal injection of TCS-OX2-29 (orexin type-2 receptor antagonist). Our findings suggest that orexin-A is more potent than duloxetine in relieving pain CIPN pain and its analgesic effect is mediated by orexin type-1 receptors. Orexin type-1 receptor agonists may have potential therapeutic roles in the treatment of CIPN pain in patients. Copyright © 2016 Elsevier Ltd. All rights reserved.

Multimodal analgesia in moderate-to-severe pain: a role for a new fixed combination of dexketoprofen and tramadol.

PubMed

Varrassi, Giustino; Hanna, Magdi; Macheras, Giorgos; Montero, Antonio; Montes Perez, Antonio; Meissner, Winfried; Perrot, Serge; Scarpignato, Carmelo

2017-06-01

Untreated and under-treated pain represent one of the most pervasive health problems, which is worsening as the population ages and accrues risk for pain. Multiple treatment options are available, most of which have one mechanism of action, and cannot be prescribed at unlimited doses due to the ceiling of efficacy and/or safety concerns. Another limitation of single-agent analgesia is that, in general, pain is due to multiple causes. Combining drugs from different classes, with different and complementary mechanism(s) of action, provides a better opportunity for effective analgesia at reduced doses of individual agents. Therefore, there is a potential reduction of adverse events, often dose-related. Analgesic combinations are recommended by several organizations and are used in clinical practice. Provided the two agents are combined in a fixed-dose ratio, the resulting medication may offer advantages over extemporaneous combinations. Dexketoprofen/tramadol (25 mg/75 mg) is a new oral fixed-dose combination offering a comprehensive multimodal approach to moderate-to-severe acute pain that encompasses central analgesic action, peripheral analgesic effect and anti-inflammatory activity, together with a good tolerability profile. The analgesic efficacy of dexketoprofen/tramadol combination is complemented by a favorable pharmacokinetic and pharmacodynamic profile, characterized by rapid onset and long duration of action. This has been well documented in both somatic- and visceral-pain human models. This review discusses the available clinical evidence and the future possible applications of dexketoprofen/tramadol fixed-dose combination that may play an important role in the management of moderate-to-severe acute pain.

Comparison of analgesic interventions for traumatic rib fractures: a systematic review and meta-analysis.

PubMed

Peek, Jesse; Smeeing, Diederik P J; Hietbrink, Falco; Houwert, Roderick M; Marsman, Marije; de Jong, Mirjam B

2018-02-06

Many studies report on outcomes of analgesic therapy for (suspected) traumatic rib fractures. However, the literature is inconclusive and diverse regarding the management of pain and its effect on pain relief and associated complications. This systematic review and meta-analysis summarizes and compares reduction of pain for the different treatment modalities and as secondary outcome mortality during hospitalization, length of mechanical ventilation, length of hospital stay, length of intensive care unit stay (ICU) and complications such as respiratory, cardiovascular, and/or analgesia-related complications, for four different types of analgesic therapy: epidural analgesia, intravenous analgesia, paravertebral blocks and intercostal blocks. PubMed, EMBASE and CENTRAL databases were searched to identify comparative studies investigating epidural, intravenous, paravertebral and intercostal interventions for traumatic rib fractures, without restriction for study type. The search strategy included keywords and MeSH or Emtree terms relating blunt chest trauma (including rib fractures), analgesic interventions, pain management and complications. A total of 19 papers met our inclusion criteria and were finally included in this systematic review. Significant differences were found in favor of epidural analgesia for the reduction of pain. No significant differences were observed between epidural analgesia, intravenous analgesia, paravertebral blocks and intercostal blocks, for the secondary outcomes. Results of this study show that epidural analgesia provides better pain relief than the other modalities. No differences were observed for secondary endpoints like length of ICU stay, length of mechanical ventilation or pulmonary complications. However, the quality of the available evidence is low, and therefore, preclude strong recommendations.

Analgesic Effect of Maternal Human Milk Odor on Premature Neonates: A Randomized Controlled Trial.

PubMed

Baudesson de Chanville, Audrey; Brevaut-Malaty, Véronique; Garbi, Aurélie; Tosello, Barthelemy; Baumstarck, Karine; Gire, Catherine

2017-05-01

Two studies have demonstrated an analgesic effect of maternal milk odor in preterm neonates, without specifying the method of olfactory stimulation. Research aim: This study aimed to assess the analgesic effect of maternal milk odor in preterm neonates by using a standardized method of olfactory stimulation. This trial was prospective, randomized, controlled, double blinded, and centrally administered. The inclusion criteria for breastfed infants included being born between 30 and 36 weeks + 6 days gestational age and being less than 10 days postnatal age. There were two groups: (a) A maternal milk odor group underwent a venipuncture with a diffuser emitting their own mother's milk odor and (2) a control group underwent a venipuncture with an odorless diffuser. The primary outcome was the Premature Infant Pain Profile (PIPP) score, with secondary outcomes being the French scale of neonatal pain-Douleur Aiguë du Nouveau-né (DAN) scale-and crying duration. All neonates were given a dummy. Our study included 16 neonates in the maternal milk odor group and 17 in the control group. Neonates exposed to their own mother's milk odor had a significantly lower median PIPP score during venipuncture compared with the control group (6.3 [interquartile range (IQR) = 5-10] versus 12.0 [IQR = 7-13], p = .03). There was no significant difference between the DAN scores in the two groups ( p = .06). Maternal milk odor significantly reduced crying duration after venipuncture (0 [IQR = 0-0] versus 0 [IQR = 0-18], p = .04). Maternal milk odor has an analgesic effect on preterm neonates.

Effects of Gentiana lutea ssp. symphyandra on the central nervous system in mice.

PubMed

Oztürk, Nilgün; Başer, K Hüsnü Can; Aydin, Süleyman; Oztürk, Yusuf; Caliş, Ihsan

2002-11-01

A methanolic extact of Gentiana lutea ssp. symphyandra roots has been investigated for its possible effects on the central nervous system of mice. At doses of 250 and 500 mg/kg (i.p.), the methanol extract of Gentiana roots caused a significant increase in the swimming endurance test and exhibited slight analgesic activity, but no lethality in mice suggesting some activity on the central nervous system. However, there was no indication of sedation or muscular fatigue at the doses employed. HPLC analysis showed that three secoiridoid compounds, gentiopicroside, swertiamarine and sweroside were present and may have been responsible for the CNS effects of the methanol extract of Gentiana lutea ssp. symphyandra roots. Copyright 2002 John Wiley & Sons, Ltd.

Novel Oral Therapies for Opioid-induced Bowel Dysfunction in Patients with Chronic Noncancer Pain.

PubMed

Holder, Renee M; Rhee, Diane

2016-03-01

Opioid analgesics are frequently prescribed and play an important role in chronic pain management. Opioid-induced bowel dysfunction, which includes constipation, hardened stool, incomplete evacuation, gas, and nausea and vomiting, is the most common adverse event associated with opioid use. Mu-opioid receptors are specifically responsible for opioid-induced bowel dysfunction, resulting in reduced peristaltic and secretory actions. Agents that reverse these actions in the bowel without reversing pain control in the central nervous system may be preferred over traditional laxatives. The efficacy and safety of these agents in chronic noncancer pain were assessed from publications identified through Ovid and PubMed database searches. Trials that evaluated the safety and efficacy of oral agents for opioid-induced constipation or opioid-induced bowel dysfunction, excluding laxatives, were reviewed. Lubiprostone and naloxegol are approved in the United States by the Food and Drug Administration for use in opioid-induced constipation. Axelopran (TD-1211) and sustained-release naloxone have undergone phase 2 and phase 1 studies, respectively, for the same indication. Naloxegol and axelopran are peripherally acting μ-opioid receptor antagonists. Naloxone essentially functions as a peripherally acting μ-opioid receptor antagonist when administered orally in a sustained-release formulation. Lubiprostone is a locally acting chloride channel (CIC-2) activator that increases secretions and peristalsis. All agents increase spontaneous bowel movements and reduce other bowel symptoms compared with placebo in patients with noncancer pain who are chronic opioid users. The most common adverse events were gastrointestinal in nature, and none of the drugs were associated with severe adverse or cardiovascular events. Investigations comparing these agents to regimens using standard laxative and combination therapy and trials in special populations and patients with active cancer are needed to further define their role in therapy. © 2016 Pharmacotherapy Publications, Inc.

Prescription of opioid and nonopioid analgesics for dental care in emergency departments: Findings from the National Hospital Ambulatory Medical Care Survey.

PubMed

Okunseri, Christopher; Okunseri, Elaye; Xiang, Qun; Thorpe, Joshua M; Szabo, Aniko

2014-01-01

The aim of this study was to examine trends and associated factors in the prescription of opioid analgesics, nonopioid analgesics, opioid and nonopioid analgesic combinations, and no analgesics by emergency physicians for nontraumatic dental condition (NTDC)-related visits. Our secondary aim was to investigate whether race/ethnicity is a possible predictor of receiving a prescription for either type of medication for NTDC visits in emergency departments (EDs) after adjustment for potential covariates. We analyzed data from the National Hospital Ambulatory Medical Care Survey for 1997-2000 and 2003-2007, and used multinomial multivariate logistic regression to estimate the probability of receiving a prescription for opioid analgesics, nonopioid analgesics, or a combination of both, compared with receiving no analgesics for NTDC-related visits. During 1997-2000 and 2003-2007, prescription of opioid analgesics and combinations of opioid and nonopioid analgesics increased, and that of no analgesics decreased over time. The prescription rates for opioid analgesics, nonopioid analgesics, opioid and nonopioid analgesic combinations, and no analgesics for NTDC-related visits in EDs were 43 percent, 20 percent, 12 percent, and 25 percent, respectively. Majority of patients categorized as having severe pain received prescriptions for opioids for NTDC-related visits in EDs. After adjusting for covariates, patients with self-reported dental reasons for visit and severe pain had a significantly higher probability of receiving prescriptions for opioid analgesics and opioid and nonopioid analgesic combinations. Prescription of opioid analgesics increased over time. ED physicians were more likely to prescribe opioid analgesics and opioid and nonopioid analgesic combinations for NTDC-related visits with reported severe pain. © 2014 American Association of Public Health Dentistry.

Prescription of Opioid and Non-opioid Analgesics for Dental Care in Emergency Departments: Findings from the National Hospital Ambulatory Medical Care Survey

PubMed Central

Okunseri, Christopher; Okunseri, Elaye; Xiang, Qun; Thorpe, Joshua M.; Szabo, Aniko

2014-01-01

Objective The aim of this study was to examine trends and associated factors in the prescription of opioid analgesics, non-opioid analgesics, opioid and non-opioid analgesic combinations and no analgesics by emergency physicians for nontraumatic dental condition (NTDC)-related visits. Our secondary aim was to investigate whether race/ethnicity is a possible predictor of receiving a prescription for either type of medication for NTDC visits in emergency departments (EDs) after adjustment for potential covariates. Methods We analyzed data from the National Hospital Ambulatory Medical Care Survey for 1997–2000 and 2003–2007, and used multinomial multivariate logistic regression to estimate the probability of receiving a prescription for opioid analgesics, non-opioid analgesics, or a combination of both compared to receiving no analgesics for NTDC-related visits. Results During 1997–2000 and 2003–2007, prescription of opioid analgesics and combinations of opioid and non-opioid analgesics increased and that of no analgesics decreased over time. The prescription rates for opioid analgesics, non-opioid analgesics, opioid and non-opioid analgesic combinations and no analgesics for NTDC-related visits in EDs were 43%, 20%, 12% and 25% respectively. Majority of patients categorized as having severe pain received prescriptions for opioids for NTDC-related visits in EDs. After adjusting for covariates, patients with self-reported dental reasons for visit and severe pain had a significantly higher probability of receiving prescriptions for opioid analgesics and opioid and non-opioid analgesic combinations. Conclusion Prescription of opioid analgesics increased over time. ED physicians were more likely to prescribe opioid analgesics and opioid and non-opioid analgesic combinations for NTDC-related visits with reported severe pain. PMID:24863407

75 FR 71726 - Central Utah Project Completion Act

Federal Register 2010, 2011, 2012, 2013, 2014

2010-11-24

... DEPARTMENT OF THE INTERIOR Central Utah Project Completion Act AGENCY: Department of the Interior..., Orem, Utah 84058-7303. Department of the Interior, Central Utah Project Completion Act Office, 302 East....cupcao.gov . FOR FURTHER INFORMATION: Contact Mr. Lee Baxter, Central Utah Project Completion Act Office...

Comparison of analgesic effect of direct breastfeeding, oral 25% dextrose solution and placebo during 1st DPT vaccination in healthy term infants: a randomized, placebo controlled trial.

PubMed

Goswami, Gaurav; Upadhyay, Amit; Gupta, Navratan Kumar; Chaudhry, Rajesh; Chawla, Deepak; Sreenivas, V

2013-07-01

To compare analgesic effect of direct breast feeding, 25% dextrose solution and placebo as we give 1st intramuscular whole cell DPT injection to 6week - 3month old infants. Randomized, placebo controlled trial. Immunization clinic of Department of Pediatrics, LLRM Medical College. Infants coming for their 1st DPT vaccination were randomized in to three groups of 40 each. The primary outcome variable was the duration of cry after vaccination. Secondary outcome variables were Modified Facial Coding Score (MFCS) and latency of onset of cry. 120 babies were equally enrolled in breast feed group, 25% dextrose fed group and distilled water fed group. Median (interquartile range) of duration of cry was significantly lower in breast fed (33.5 (17-54) seconds) and 25% dextrose fed babies (47.5 (31-67.5) seconds) as compared to babies given distilled water (80.5 (33.5-119.5) seconds) (P<0.001). MFCS at 1 min and 3 min was significantly lower in direct breast fed and dextrose fed babies. Direct breastfeeding and 25% dextrose act as analgesic in young infants undergoing DPT vaccination in young infants less than 3 month of age.

Spinal Ceramide and Neuronal Apoptosis in Morphine Antinociceptive Tolerance

PubMed Central

Bryant, Leesa; Doyle, Tim; Chen, Zhoumo; Cuzzocrea, Salvatore; Masini, Emanuela; Vinci, M. Cristina; Esposito, Emanuela; Mazzon, Emanuela; Petrusca, Daniela Nicoleta; Petrache, Irina; Salvemini, Daniela

2009-01-01

Opiates, like morphine, are the most effective analgesics for treating acute and chronic severe pain, but their use is limited by the development of analgesic tolerance and hypersensitivity to innocuous and noxious stimuli. Because opioids are a mainstay of pain management, restoring their efficacy has great clinical importance. We have recently demonstrated that spinal ceramide, a sphingolipid signaling molecule plays a central role in the development of morphine antinociceptive tolerance. We now report that ceramide up-regulation in dorsal horn tissues in response to chronic morphine administration is associated with significant neuronal apoptosis. Inhibition of ceramide biosynthesis attenuated both the increase in neuronal apoptosis and the development of antinociceptive tolerance. These findings indicate that spinal ceramide upregulation is a key pro-apoptotic event that occurs upstream of the development of morphine antinociceptive tolerance and support the rationale for development of inhibitors of ceramide biosynthesis as adjuncts to opiates for the management of chronic pain. PMID:19631718

Drug Management of Visceral Pain: Concepts from Basic Research

PubMed Central

Davis, Mellar P.

2012-01-01

Visceral pain is experienced by 40% of the population, and 28% of cancer patients suffer from pain arising from intra- abdominal metastasis or from treatment. Neuroanatomy of visceral nociception and neurotransmitters, receptors, and ion channels that modulate visceral pain are qualitatively or quantitatively different from those that modulate somatic and neuropathic pain. Visceral pain should be recognized as distinct pain phenotype. TRPV1, Na 1.8, and ASIC3 ion channels and peripheral kappa opioid receptors are important mediators of visceral pain. Mu agonists, gabapentinoids, and GABAB agonists reduce pain by binding to central receptors and channels. Combinations of analgesics and adjuvants in animal models have supra-additive antinociception and should be considered in clinical trials. This paper will discuss the neuroanatomy, receptors, ion channels, and neurotransmitters important to visceral pain and provide a basic science rationale for analgesic trials and management. PMID:22619712

Efficacy of Periarticular Injection With a Long-Acting Local Analgesic in Joint Arthroplasty.

PubMed

Barrington, John W

2015-10-01

Attention to patient satisfaction is critical in today's health care environment-satisfaction surveys inform the development of hospital performance standards and can influence an institution's rankings and reimbursement. The effectiveness of postoperative pain management can affect clinical outcomes and also influence the patient's perception of the overall surgical experience. Ample clinical- trial data now exist that demonstrate the benefits of periarticular injections as part of a multimodal regimen in patients undergoing joint arthroplasty. One option that surgeons now use widely is bupivacaine liposome injectable suspension (EXPAREL®, Pacira Pharmaceuticals, Inc), a long-acting local analgesic that the orthopedic surgeon can administer intraoperatively. The US Food and Drug Administration has approved liposomal bupivacaine for injection into the surgical site to produce postsurgical analgesia. The safety and efficacy of liposomal bupivacaine has been demonstrated in clinical studies in multiple types of surgical procedure, including double-blind, randomized, controlled clinical trials that involved over 1300 patients. In a case-control study comparing clinical and economic parameters before and after the introduction of liposomal bupivacaine as a component of the multimodal perioperative pain regimen for total joint arthroplasty, liposomal bupivacaine provided improved overall pain scores, an increase in patients reporting a pain score of 0, increased patient satisfaction, decreased length of stay, and a decrease in overall costs.

Peripheral μ-opioid receptor mediated inhibition of calcium signaling and action potential-evoked calcium fluorescent transients in primary afferent CGRP nociceptive terminals.

PubMed

Baillie, Landon D; Schmidhammer, Helmut; Mulligan, Sean J

2015-06-01

While μ-opioid receptor (MOR) agonists remain the most powerful analgesics for the treatment of severe pain, serious adverse side effects that are secondary to their central nervous system actions pose substantial barriers to therapeutic use. Preclinical and clinical evidence suggest that peripheral MORs play an important role in opioid analgesia, particularly under inflammatory conditions. However, the mechanisms of peripheral MOR signaling in primary afferent pain fibres remain to be established. We have recently introduced a novel ex vivo optical imaging approach that, for the first time, allows the study of physiological functioning within individual peripheral nociceptive fibre free nerve endings in mice. In the present study, we found that MOR activation in selectively identified, primary afferent CGRP nociceptive terminals caused inhibition of N-type Ca(2+) channel signaling and suppression of action potential-evoked Ca(2+) fluorescent transients mediated by 'big conductance' Ca(2+)-activated K(+) channels (BKCa). In the live animal, we showed that the peripherally acting MOR agonist HS-731 produced analgesia and that BKCa channels were the major effectors of the peripheral MOR signaling. We have identified two key molecular transducers of MOR activation that mediate significant inhibition of nociceptive signaling in primary afferent terminals. Understanding the mechanisms of peripheral MOR signaling may promote the development of pathway selective μ-opioid drugs that offer improved therapeutic profiles for achieving potent analgesia while avoiding serious adverse central side effects. Copyright © 2015 Elsevier Ltd. All rights reserved.

Analgesic effects of treatments for non-specific low back pain: a meta-analysis of placebo-controlled randomized trials.

PubMed

Machado, L A C; Kamper, S J; Herbert, R D; Maher, C G; McAuley, J H

2009-05-01

Estimates of treatment effects reported in placebo-controlled randomized trials are less subject to bias than those estimates provided by other study designs. The objective of this meta-analysis was to estimate the analgesic effects of treatments for non-specific low back pain reported in placebo-controlled randomized trials. Medline, Embase, Cinahl, PsychInfo and Cochrane Central Register of Controlled Trials databases were searched for eligible trials from earliest records to November 2006. Continuous pain outcomes were converted to a common 0-100 scale and pooled using a random effects model. A total of 76 trials reporting on 34 treatments were included. Fifty percent of the investigated treatments had statistically significant effects, but for most the effects were small or moderate: 47% had point estimates of effects of <10 points on the 100-point scale, 38% had point estimates from 10 to 20 points and 15% had point estimates of >20 points. Treatments reported to have large effects (>20 points) had been investigated only in a single trial. This meta-analysis revealed that the analgesic effects of many treatments for non-specific low back pain are small and that they do not differ in populations with acute or chronic symptoms.

Delta-opioid receptors as targets for migraine therapy.

PubMed

Charles, Andrew; Pradhan, Amynah A

2016-06-01

The purpose of this review is to contrast the properties of the δ-opioid receptor with those of the μ-opioid receptor, which is the primary target of most currently available opioid analgesics. We also discuss preclinical evidence that indicates the potential efficacy of δ-opioid receptor agonists as migraine therapy. The use of currently available opioid analgesics is highly problematic for patients with migraine. Delta-opioid receptors have key differences from μ receptors; these differences make the δ receptor an attractive therapeutic target for migraine. Delta-opioid receptors are expressed in both the peripheral and central nervous system in anatomical regions and cell types that are believed to play a role in migraine. Delta-receptor agonists have also shown promising effects in multiple migraine models, including nitroglycerin evoked hyperalgesia and conditioned place aversion, and cortical spreading depression. Evidence from animal models indicates that activation of δ receptors is less likely to cause tolerance and dependence, and less likely to cause hyperalgesia. In addition, δ receptors may have antidepressant and anxiolytic properties that are distinct from those of μ receptors. In human studies investigating other conditions, δ-receptor agonists have been generally safe and well tolerated. Delta-opioid receptor agonists have promising potential as acute and/or preventive migraine therapies, without the problems associated with currently used opioid analgesics.

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.

The Analgesic Effects of Different Extracts of Aerial Parts of Coriandrum Sativum in Mice

PubMed Central

Fatemeh Kazempor, Seyedeh; Vafadar langehbiz, Shabnam; Hosseini, Mahmoud; Naser Shafei, Mohammad; Ghorbani, Ahmad; Pourganji, Masoomeh

2015-01-01

Regarding the effects of Coriandrum sativum (C. sativum) on central nervous system, in the present study analgesic properties of different extracts of C. sativum aerial partswere investigated. The mice were treated by saline, morphine, three doses (20, 100 and 500 mg/kg) of aqueous, ethanolic, choloroformic extracts of C. sativum and one dose (100 mg/kg) of aqueous, two doses of ethanolic (100 and 500 mg/kg) and one dose of choloroformic (20 mg/kg) extracts of C. sativum pretreated by naloxone. Recording of the hot plate test was performed 10 min before injection of the drugs as a base and it was consequently repeated every 10 minutes after the extracts injection. The maximal percent effect (MPE) in the groups treated by three doses of aqueous, ethanolic and chloroformic extracts were significantly higher than saline group which were comparable to the effect of morphine. The effects of most effective doses of extracts were reversed by naloxone. The results of present study showed analgesic effect of aqueous, ethanolic and chloroformic extracts of C. sativum extract. These effects of the extracts may be mediated by opioid system. However, more investigations are needed to elucidate the exact responsible mechanism(s) and the effective compound(s).

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

JPRS Report, Science & Technology, Central Eurasia: Life Sciences.

DTIC Science & Technology

1992-06-02

pharmaceutical situation in our country? where millions of women and men of young age are becoming infertile . We need comprehensive programs to [Hayes...Ritmodan, the periph- eral vasodilatory drug Trental, the nonsteroid anti- inflammatory anti- rheumatic analgesic Surgam, and the [Advertisement] antibiotic...also in sore need of antibiotics and asthma With slightly more than 100 beds, the hospital does not drugs because children on Kola suffer from diseases

JPRS Report, Science & Technology, USSR: Life Sciences.

DTIC Science & Technology

1990-10-24

genesis was used to produce two mutant rhodopsins with amino acid substitutions in the C-terminal domain. The substitution of Cys-316->Ser does not...proteins, and also as a system for large scale synthesis of protein for practical use with a continuous supply of energy sources and amino acids into the...better than traditional neuroleptic analgesic in analysis of central peripheral hemodynamics, oxygen-transport, gas composition, and acid -base

Electroacupuncture in conscious free-moving mice reduces pain by ameliorating peripheral and central nociceptive mechanisms

PubMed Central

Wang, Ying; Lei, Jianxun; Gupta, Mihir; Peng, Fei; Lam, Sarah; Jha, Ritu; Raduenz, Ellis; Beitz, Al J.; Gupta, Kalpna

2016-01-01

Integrative approaches such as electroacupuncture, devoid of drug effects are gaining prominence for treating pain. Understanding the mechanisms of electroacupuncture induced analgesia would benefit chronic pain conditions such as sickle cell disease (SCD), for which patients may require opioid analgesics throughout life. Mouse models are instructive in developing a mechanistic understanding of pain, but the anesthesia/restraint required to administer electroacupuncture may alter the underlying mechanisms. To overcome these limitations, we developed a method to perform electroacupuncture in conscious, freely moving, unrestrained mice. Using this technique we demonstrate a significant analgesic effect in transgenic mouse models of SCD and cancer as well as complete Freund’s adjuvant-induced pain. We demonstrate a comprehensive antinociceptive effect on mechanical, cold and deep tissue hyperalagesia in both genders. Interestingly, individual mice showed a variable response to electroacupuncture, categorized into high-, moderate-, and non-responders. Mechanistically, electroacupuncture significantly ameliorated inflammatory and nociceptive mediators both peripherally and centrally in sickle mice correlative to the antinociceptive response. Application of sub-optimal doses of morphine in electroacupuncture-treated moderate-responders produced equivalent antinociception as obtained in high-responders. Electroacupuncture in conscious freely moving mice offers an effective approach to develop a mechanism-based understanding of analgesia devoid of the influence of anesthetics or restraints. PMID:27687125

Electroacupuncture in conscious free-moving mice reduces pain by ameliorating peripheral and central nociceptive mechanisms.

PubMed

Wang, Ying; Lei, Jianxun; Gupta, Mihir; Peng, Fei; Lam, Sarah; Jha, Ritu; Raduenz, Ellis; Beitz, Al J; Gupta, Kalpna

2016-09-30

Integrative approaches such as electroacupuncture, devoid of drug effects are gaining prominence for treating pain. Understanding the mechanisms of electroacupuncture induced analgesia would benefit chronic pain conditions such as sickle cell disease (SCD), for which patients may require opioid analgesics throughout life. Mouse models are instructive in developing a mechanistic understanding of pain, but the anesthesia/restraint required to administer electroacupuncture may alter the underlying mechanisms. To overcome these limitations, we developed a method to perform electroacupuncture in conscious, freely moving, unrestrained mice. Using this technique we demonstrate a significant analgesic effect in transgenic mouse models of SCD and cancer as well as complete Freund's adjuvant-induced pain. We demonstrate a comprehensive antinociceptive effect on mechanical, cold and deep tissue hyperalagesia in both genders. Interestingly, individual mice showed a variable response to electroacupuncture, categorized into high-, moderate-, and non-responders. Mechanistically, electroacupuncture significantly ameliorated inflammatory and nociceptive mediators both peripherally and centrally in sickle mice correlative to the antinociceptive response. Application of sub-optimal doses of morphine in electroacupuncture-treated moderate-responders produced equivalent antinociception as obtained in high-responders. Electroacupuncture in conscious freely moving mice offers an effective approach to develop a mechanism-based understanding of analgesia devoid of the influence of anesthetics or restraints.

Ethnopharmacological investigation of the aerial part of Phragmites karka (Poaceae).

PubMed

Sultan, Ramiz Ahmed; Kabir, Mohammad Shah Hafez; Uddin, Mir Muhammad Nasir; Uddin, Mohi; Mahmud, Zobaer Al; Raihan, Sheikh Zahir; Qais, Nazmul

2017-05-01

In this ethnopharmacological study, methanolic extract of the aerial plant parts of Phragmites karka (Family: Poaceae) and its petroleum ether and carbon tetrachloride fractions were investigated for bioactivities in Swiss-albino mice, namely, analgesic, central nervous system (CNS) depressant, hypoglycemic, and antidiarrheal activity. The cold methanolic extract of the aerial plant parts of Phragmites karka (MEPK) was first prepared, and it was then further fractionated as petroleum ether (PEFMEPK) and carbon tetrachloride (CTFMEPK) fractions. Analgesic activity was performed employing acidic acid-induced writhing test, central analgesic effect by radiant heat tail-flick method. CNS depressant activity was evaluated by phenobarbitone-induced sleeping time test. Hypoglycemic activity was tested by glucose tolerance test (GTT). Antidiarrheal activity was evaluated by castor oil-induced diarrhea method. For all in vivo tests, doses of 200 and 400 mg/kg body weight were used. In the mice model, the MEPK, PEFMEPK, and CTFMEPK fractions showed significant peripheral analgesic activity at a dose of 400 mg/kg body weight with percentage of inhibition of acetic acid-induced writhing 77.67 (p<0.001), 33.50 (p<0.001), and 40.29 (p<0.001), respectively, compared to the standard dichlofenac (60.68%, p<0.001) group. The hypoglycemic properties of MEPK, PEFMEPK, and CTFMEPK extracts were evaluated in normoglycemic mice where the reduction of blood glucose level after 30 min of glucose load were 69.85%, 78.91%, and 72.73%, respectively, and for standard glibenclamide, the reduction was 72.85%. All results were significant (p<0.05). In the case of the CNS depressant activity by phenobarbitone-induced sleeping time test, the crude ME significantly reduced sleep latency by 57.14% and increased the duration of sleep by 63.29% compared to the control, which were comparable to that of standard diazepam (65.71% and 77.62%, respectively). Among all the extract and fractions, methanolic extract showed the maximum antidiarrheal effect. The methanolic extract at 200 mg/kg dose induced a significant decrease in the total number of defecation in 4 h (69.05% of inhibition, p<0.001) and at 400 mg/kg dose showed 76.19% of inhibition (p<0.001). In light of the available literature, these findings represent the first experimental investigation of biological activities of P. karka in the perspective of their traditional use.

A disposition kinetic study of Tramadol in bile duct ligated rats in perfused rat liver model.

PubMed

Esmaeili, Zohre; Mohammadi, Saeid; Nezami, Alireza; Rouini, Mohammad Reza; Ardakani, Yalda Hosseinzadeh; Lavasani, Hoda; Ghazi-Khansari, Mahmoud

2017-07-01

Tramadol hydrochloride is a centrally acting synthetic opioid analgesic drug and is used to treat chronic pain. In this study, the effects of Bile Duct Ligation (BDL) on the pharmacokinetics of tramadol in a liver recirculating perfusion system of male rats were used. Twenty-four Wistar male rats were randomly divided into four groups: control, sham and two weeks BDL and four weeks BDL. Serum levels of liver enzymes were measured before perfusion and the pharmacokinetics of tramadol was evaluated by using liver recirculating perfusion system. Tramadol and metabolites concentrations were determined by HPLC-FL. The sharp increase in liver enzymes level in both BDL groups was observed and significant changes were also observed in liver weight and volume. Tramadol metabolites concentration significantly decreased compared with the control and sham group (P<0.05). The decrease in the hepatic metabolism of tramadol and increase in the half-life of the elimination of tramadol in rats with BDL suggests that personalized treatment and the therapeutic drug monitoring (TDM) data examination are necessary for patients with bile duct diseases and the dose of tramadol should be accordingly adjusted. Copyright © 2017 Elsevier Masson SAS. 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®.

Supra-additive effects of tramadol and acetaminophen in a human pain model.

PubMed

Filitz, Jörg; Ihmsen, Harald; Günther, Werner; Tröster, Andreas; Schwilden, Helmut; Schüttler, Jürgen; Koppert, Wolfgang

2008-06-01

The combination of analgesic drugs with different pharmacological properties may show better efficacy with less side effects. Aim of this study was to examine the analgesic and antihyperalgesic properties of the weak opioid tramadol and the non-opioid acetaminophen, alone as well as in combination, in an experimental pain model in humans. After approval of the local Ethics Committee, 17 healthy volunteers were enrolled in this double-blind and placebo-controlled study in a cross-over design. Transcutaneous electrical stimulation at high current densities (29.6+/-16.2 mA) induced spontaneous acute pain (NRS=6 of 10) and distinct areas of hyperalgesia for painful mechanical stimuli (pinprick-hyperalgesia). Pain intensities as well as the extent of the areas of hyperalgesia were assessed before, during and 150 min after a 15 min lasting intravenous infusion of acetaminophen (650 mg), tramadol (75 mg), a combination of both (325 mg acetaminophen and 37.5mg tramadol), or saline 0.9%. Tramadol led to a maximum pain reduction of 11.7+/-4.2% with negligible antihyperalgesic properties. In contrast, acetaminophen led to a similar pain reduction (9.8+/-4.4%), but a sustained antihyperalgesic effect (34.5+/-14.0% reduction of hyperalgesic area). The combination of both analgesics at half doses led to a supra-additive pain reduction of 15.2+/-5.7% and an enhanced antihyperalgesic effect (41.1+/-14.3% reduction of hyperalgesic areas) as compared to single administration of acetaminophen. Our study provides first results on interactions of tramadol and acetaminophen on experimental pain and hyperalgesia in humans. Pharmacodynamic modeling combined with the isobolographic technique showed supra-additive effects of the combination of acetaminophen and tramadol concerning both, analgesia and antihyperalgesia. The results might act as a rationale for combining both analgesics.

Analgesic and anti-inflammatory effects of UP1304, a botanical composite containing standardized extracts of Curcuma longa and Morus alba.

PubMed

Yimam, Mesfin; Lee, Young-Chul; Moore, Breanna; Jiao, Ping; Hong, Mei; Nam, Jeong-Bum; Kim, Mi-Ran; Hyun, Eu-Jin; Chu, Min; Brownell, Lidia; Jia, Qi

2016-01-01

Though the initial etiologies of arthritis are multifactorial, clinically, patients share the prime complaints of the disease, pain. Here the authors assessed the analgesic and anti-inflammatory effects of UP1304, a composite that contains a standardized blend of extracts from the rhizome of Curcuma longa and the root bark of Morus alba, on rats with carrageenan-induced paw edema. A plant library was screened for bradykinin receptor antagonists. In vivo, the anti-inflammatory and analgesic effects of the standardized composite, UP1304, were evaluated in rats with carrageenan-induced paw edema using oral dose ranges of 100-400 mg/kg. Ibuprofen, at a dose of 200 mg/kg, was used as a reference compound. In vitro, cyclooxygenase (COX) and lipoxygenase (LOX) inhibition assays were performed to evaluate the degree of inflammation. Statistically significant improvements in pain resistance and paw edema suppression were observed in animals treated with UP1304, when compared to vehicle-treated rats. Results from the highest dose of UP1304 (400 mg/kg) were similar to those achieved by ibuprofen treatment at 200 mg/kg. In vitro, UP1304 showed dose-dependent inhibition of the enzymatic activities of COX and LOX. A half-maximal inhibitory concentration of 9.6 μg/mL for bradykinin B1 inhibition was calculated for the organic extract of C. longa. Curcumin showed Ki values of 2.73 and 58 μg/mL for bradykinin receptors B1 and B2, respectively. Data presented here suggest that UP1304, analgesic and anti-inflammatory agent of botanical origin, acted as a bradykinin receptor B1 and B2 antagonist, and inhibited COX and LOX enzyme activities. This compound should be considered for the management of symptoms associated with arthritis.

CYP2D6 genetic polymorphisms and their relevance for poisoning due to amfetamines, opioid analgesics and antidepressants.

PubMed

Haufroid, Vincent; Hantson, Philippe

2015-07-01

Cytochrome P450 2D6 (CYP2D6) is a member of the cytochrome P450 (CYP) superfamily involved in the biotransformation of drugs and substances of abuse encountered in clinical toxicology. Among the CYP superfamily, the CYP2D6 gene is considered as the most polymorphic as more than 105 different alleles have been identified so far. CYP2D6 genetic polymorphisms have the potential to affect the toxicity of their substrates. This review will focus specifically on CYP2D6 genetic polymorphisms and their relevance for poisoning due to amfetamines, opioid analgesics and antidepressants in humans. PubMed (up to August 2013) was searched with the following selection criteria: 'CYP2D6 AND (toxicology OR poisoning OR intoxication OR overdose)'. Of the 454 citations retrieved, only 46 papers dealt with the impact of CYP2D6 polymorphisms on poisoning due to amfetamines, opioid analgesics and antidepressants. amfetamines. While some in vitro studies suggest that CYP2D6-mediated metabolites of 3,4-methylenedioxymethamfetamine (MDMA) are substantially more cytotoxic compared with unchanged MDMA, it is not yet confirmed in human cases of MDMA intoxication that extensive/ultra-rapid CYP2D6 metabolisers could be at higher risk. This would also apply to methamfetamine exposure and the related cardiac and central nervous system toxicity. Opioid analgesics. CYP2D6 ultra-rapid metabolisers are more likely to experience the adverse effects of codeine and tramadol. Opioid analgesics that do not rely on CYP2D6 for therapeutic activity, such as morphine and hydromorphone, may therefore be a better alternative to codeine and tramadol, with the limitation that these drugs have their own set of adverse reactions. Antidepressants. CYP2D6 poor metabolisers are generally more prone to adverse effects. Among them, the four drugs with the highest level of evidence are amitriptyline, nortriptyline, venlafaxine and fluoxetine. Further data are needed, however, for doxepin and paroxetine, while citalopram adverse effects seem definitely less influenced by CYP2D6 genetic polymorphisms. Either poor or extensive/ultra-rapid CYP2D6 metabolisers may be exposed to toxic effects of amfetamines, opioid analgesics and antidepressants. In these three categories, the level of evidence is substance dependent, with differences within the same pharmacological class.

Neural hyperactivity in the amygdala induced by chronic treatment of rats with analgesics may elucidate the mechanisms underlying psychiatric comorbidities associated with medication-overuse headache.

PubMed

Wanasuntronwong, Aree; Jansri, Ukkrit; Srikiatkhachorn, Anan

2017-01-03

Patients with medication-overuse headache suffer not only from chronic headache, but often from psychiatric comorbidities, such as anxiety and depression. The mechanisms underlying these comorbidities are unclear, but the amygdala is likely to be involved in their pathogenesis. To investigate the mechanisms underlying the comorbidities we used elevated plus maze and open field tests to assess anxiety-like behavior in rats chronically treated with analgesics. We measured the electrical properties of neurons in the amygdala, and examined the cortical spreading depression (CSD)-evoked expression of Fos in the trigeminal nucleus caudalis (TNC) and amygdala of rats chronically treated with analgesics. CSD, an analog of aura, evokes Fos expression in the TNC of rodents suggesting trigeminal nociception, considered to be a model of migraine. Increased anxiety-like behavior was seen both in elevated plus maze and open field tests in a model of medication overuse produced in male rats by chronic treatment with aspirin or acetaminophen. The time spent in the open arms of the maze by aspirin- or acetaminophen-treated rats (53 ± 36.1 and 37 ± 29.5 s, respectively) was significantly shorter than that spent by saline-treated vehicle control rats (138 ± 22.6 s, P < 0.001). Chronic treatment with the analgesics increased the excitability of neurons in the central nucleus of the amygdala as indicated by their more negative threshold for action potential generation (-54.6 ± 5.01 mV for aspirin-treated, -55.2 ± 0.97 mV for acetaminophen-treated, and -31.50 ± 5.34 mV for saline-treated rats, P < 0.001). Chronic treatment with analgesics increased the CSD-evoked expression of Fos in the TNC and amygdala [18 ± 10.2 Fos-immunoreactive (IR) neurons per slide in the amygdala of rats treated with aspirin, 11 ± 5.4 IR neurons per slide in rats treated with acetaminophen, and 4 ± 3.7 IR neurons per slide in saline-treated control rats, P < 0.001]. Chronic treatment with analgesics can increase the excitability of neurons in the amygdala, which could underlie the anxiety seen in patients with medication-overuse headache.

Factors influencing use of analgesics among construction workers in the Ga-Eastmunicipality of the Greater Accra region, Ghana.

PubMed

Badzi, Caroline D; Ackumey, Mercy M

2017-12-01

Analgesics also known as painkillers are widely used for pain relief. There are severe health implications associated with excessive use of analgesics. This paper examines factors influencing the use of analgesics among construction workers in the Ga-East Municipality (GEM) of the Greater Accra region of Ghana. This is a cross-sectional study involving 206 construction workers randomly sampled from 7 construction sites in the GEM. A structured questionnaire was used to elicit responses on knowledge of analgesics, types of analgesics used and factors influencing the use of analgesics. Chi-square test analysis was used to examine factors influencing analgesic use. The majority of workers were aged between 15 to 44 years (89.8%) and 51.9 percent of respondents had completed Junior high school. Many respondents (68.0%) used Brand 1 a locally manufactured analgesic with paracetamol, aspirin and caffeine as the active ingredients and 31.6 percent of respondents had no knowledge of possible side effects of continuous use of analgesics. Chi square analysis showed that age was significantly associated with use of analgesics (p<0.01). Knowledge of the types of analgesics, dosage and side effects did not influence use (p>0.05). Television and radio advertisements influenced use of analgesics (p<0.01). Knowledge on analgesic use and knowledge of probable serious side effects was inadequate. Pharmacists and chemists involvement in education of clients of the side effects of analgesics is highly recommended to minimise misuse. The Food and Drugs Authority should regulate the proliferation of advertisements for analgesics in the media. None declared.

Pharmacological activities of the organic extracts and fatty acid composition of the petroleum ether extract from Haplophyllum tuberculatum leaves.

PubMed

Hamdi, Assia; Majouli, Kaouther; Abdelhamid, Amal; Marzouk, Belsem; Belghith, Hèla; Chraief, Imed; Bouraoui, Abderrahman; Marzouk, Zohra; Heyden, Yvan Vander

2018-04-24

Haplophyllum tuberculatum is used in traditional medicine to treat many disorders including inflammation and pain. The aim of this study is to investigate the organic extracts from H. tuberculatum leaves against inflammation, gastric ulcer and pain. Acute toxicity was studied in vivo to determine the toxic doses of the organic extracts. Anti-inflammatory activity was also evaluated in vivo using carrageenan-induced paw edema in Wistar rats. Gastroprotective activity was tested using the HCl/ethanol-induced gastric ulcer test in rats. Peripheral and central analgesic activities were assessed using the acetic acid-induced writhing test and the hot-plate method, respectively. The chemical composition of the fatty acids in the petroleum ether (PE) extract was determined with GC-MS. At 25, 50 and 100mg/kg PE extract was the most active against inflammation. Percentages inhibition 5h after carrageenan-injection were 51.12; 86.71% and 96.92%, respectively. The same extract at 100mg/kg showed good analgesic activities using the acetic acid-induced writhing test and the hot-plate method. The chloroform, ethyl acetate (EtOAc) and butanolic (n-BuOH) extracts exhibited strong anti-inflammatory, gastroprotective and analgesic activities at 100mg/kg. The GC-FID analysis revealed that the PE extract was rich in γ-linolenic acid (45.50%) followed by palmitic acid (18.48%), linoleic acid (10.73%), erucic acid (4.72), stearic acid (3.96%) and oleic acid (2.57%). The results of the present study support the traditional use of the leaves of H. tuberculatum and may possibly serve as prospective material for further development of safe new phytochemical anti-inflammatory, gastroprotective and/or analgesic agents. Copyright © 2018 Elsevier B.V. All rights reserved.

In vivo anti-inflammatory and anti-nociceptive activities of Cheilanthes farinosa.

PubMed

Yonathan, Mariamawit; Asres, Kaleab; Assefa, Ashenafi; Bucar, Franz

2006-12-06

In Ethiopia inflammatory skin diseases are among the most common health problems treated with traditional remedies which mainly comprise medicinal plants. In the present work, the anti-inflammatory and anti-nociceptive activities of Cheilanthes farinosa (Forsk.) Kaulf (Adianthaceae), a fern used in many parts of Ethiopia to treat inflammatory skin disorders, were studied using in vivo models of inflammation and pain. The results of the study showed that the fronds Cheilanthes farinosa possess strong anti-inflammatory and anti-nociceptive properties. It was further demonstrated that the active ingredients of the fern reside mainly in the methanol fraction from which three compounds viz. the flavonol glycoside rutin, and the natural cinnamic acids, caffeic acid and its quinic acid derivative chlorogenic acid have been isolated. The methanol extract was also shown to potentiate the anti-inflammatory activity of acetyl salicylic acid. At the tested concentrations, the methanol extract displayed a better anti-nociceptive activity than that of ASA in both the early and late phases of formalin induced nociception in mice. However, the activity of the extract was more pronounced in the late phase, which is commonly associated with inflammatory pain. Evaluation of the pharmacological properties of the compounds isolated from the active fractions pointed out that chlorogenic acid possesses strong anti-inflammatory and anti-nociceptive activities while caffeic acid and rutin were inactive. Moreover, on molar basis chlorogenic acid was proved to be superior in its anti-inflammatory action to acetyl salicylic acid. It was therefore concluded that chlorogenic acid contributes, in full or in part, to the anti-inflammatory and anti-nociceptive activities of Cheilanthes farinosa. Both the methanolic extract and pure chlorogenic acid failed to display anti-nociceptive activity when tested by the tail-flick test indicating that the plant is not a centrally acting analgesic but instead exerts its analgesic activity by way of its antinflammtory action.

Nefopam, a Non-sedative Benzoxazocine Analgesic, Selectively Reduces the Shivering Threshold

PubMed Central

Alfonsi, Pascal; Adam, Frederic; Passard, Andrea; Guignard, Bruno; Sessler, Daniel I.; Chauvin, Marcel

2005-01-01

Background The analgesic nefopam does not compromise ventilation, is minimally sedating, and is effective as a treatment for postoperative shivering. We evaluated the effects of nefopam on the major thermoregulatory responses in humans: sweating, vasoconstriction, and shivering. Methods Nine volunteers were studied on three randomly assigned days: 1) control (Saline), 2) nefopam at a target plasma concentration of 35 ng/ml (Small Dose), and 3) nefopam at a target concentration of 70 ng/ml (Large Dose, ≈20 mg total). Each day, skin and core temperatures were increased to provoke sweating and then reduced to elicit peripheral vasoconstriction and shivering. We determined the thresholds (triggering core temperature at a designated skin temperature of 34°C) by mathematically compensating for changes in skin temperature using the established linear cutaneous contributions to control of each response. Results Nefopam did not significantly modify the slopes for sweating (0.0 ± 4.9°C·μg−1·ml; r2 = 0.73 ± 0.32) or vasoconstriction (−3.6 ± 5.0°C·μg−1·ml; r2=−0.47± 0.41). In contrast, nefopam significantly reduced the slope of shivering (−16.8 ± 9.3°C·μg−1·ml; r2 = 0.92 ± 0.06). Large-Dose nefopam thus reduced the shivering threshold by 0.9 ± 0.4°C (P<0.001) without any discernable effect on the sweating or vasoconstriction thresholds. Conclusions Most drugs with thermoregulatory actions — including anesthetics, sedatives, and opioids — synchronously reduce the vasoconstriction and shivering thresholds. Nefopam however reduced only the shivering threshold. This pattern has not previously been reported for a centrally acting drug. That pharmacologic modulation of vasoconstriction and shivering can be separated is of clinical and physiologic interest. PMID:14695722

Effects of Systemic Magnesium on Post-operative Analgesia: Is the Current Evidence Strong Enough?

PubMed

Guo, Bao-Lin; Lin, Yan; Hu, Wei; Zhen, Chen-Xi; Bao-Cheng, Zhao; Wu, Huang-Hui; Kaye, Alan David; Duan, Jian-Hong; Qu, Yan

2015-01-01

Clinical studies have been previously carried out on the efficacy of systemic magnesium to minimize postoperative pain, however, with controversial results. A quantitative meta-analysis was performed to evaluate the analgesic efficacy and safety of systemic magnesium on post-operative pain. Comprehensive systematic review of all relevant, publsished randomized controlled trials. A search was conducted of published literature in MEDLINE, PsycINFO, Scopus, EMBASE, and the Cochrane Central Register of Controlled Trials (CENTRAL) databases from inception to Sep-Oct 2014. Randomized controlled trials (RCTs) that compared magnesium with placebo were identified. Effects were summarized using standardized mean differences (SMDs), weighed mean differences (WMD), or odds ratio (OR) with suitable effect model. Twenty-seven RCTs involving 1,504 patients were included. In total, peri-operative magnesium significantly reduced the pain score at rest (SMD, -1.43, 95% CI, -2.74 to -0.12, < 0.01). Magnesium significantly reduced analgesic consumption (SMD, -1.72, 95% CI, -3.21 to -0.23) in patients undergoing urogenital, orthopaedic, and cardiovascular surgeries, but was inconclusive for patients receiving gastrointestinal surgeries. The obvious analgesia of systemic magnesium was observed on reducing the pain score during movement at 24 hours after operation (SMD, -0.05, 95% CI, -0.43 to 0.32). Moreover, magnesium administration showed a beneficial effect with regard to intra-operative hemodynamics and reduced extubation time in the cardiovascular surgery patients (WMD, -29.34 min, 95% CI, -35.74 to -22.94, P < 0.01). Focused only on the quality of analgesia on postoperative pain with regards to surgery type. Our study suggests that systemic magnesium during general anesthesia significantly decreases post-operative pain scores without increasing adverse events. It should be noted that since there are 18 ongoing RCTs without published data, it is still premature to draw conclusions on the long-term analgesic effects of magnesium as well as potential gender or age difference.

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ER/LA Opioid Analgesics REMS: Overview of Ongoing Assessments of Its Progress and Its Impact on Health Outcomes.

PubMed

Cepeda, M Soledad; Coplan, Paul M; Kopper, Nathan W; Maziere, Jean-Yves; Wedin, Gregory P; Wallace, Laura E

2017-01-01

Opioid abuse is a serious public health concern. In response, the Food and Drug Administration (FDA) determined that a risk evaluation and mitigation strategy (REMS) for extended-release and long-acting (ER/LA) opioids was necessary to ensure that the benefits of these analgesics continue to outweigh the risks. Key components of the REMS are training for prescribers through accredited continuing education (CE), and providing patient educational materials. The impact of this REMS has been assessed using diverse metrics including evaluation of prescriber and patient understanding of the risks associated with opioids; patient receipt and comprehension of the medication guide and patient counseling document; patient satisfaction with access to opioids; drug utilization and changes in prescribing patterns; and surveillance of ER/LA opioid misuse, abuse, overdose, addiction, and death. The results of these assessments indicate that the increasing rates of opioid abuse, addiction, overdose, and death observed prior to implementation of the REMS have since leveled off or started to decline. However, these benefits cannot be attributed solely to the ER/LA opioid analgesics REMS since many other initiatives to prevent abuse occurred contemporaneously. These improvements occurred while preserving patient access to opioids as a large majority of patients surveyed expressed satisfaction with their access to opioids. © 2016 American Academy of Pain Medicine.

ER/LA Opioid Analgesics REMS: Overview of Ongoing Assessments of Its Progress and Its Impact on Health Outcomes

PubMed Central

Cepeda, M. Soledad; Kopper, Nathan W.; Maziere, Jean-Yves; Wedin, Gregory P.; Wallace, Laura E.

2017-01-01

Objective. Opioid abuse is a serious public health concern. In response, the Food and Drug Administration (FDA) determined that a risk evaluation and mitigation strategy (REMS) for extended-release and long-acting (ER/LA) opioids was necessary to ensure that the benefits of these analgesics continue to outweigh the risks. Key components of the REMS are training for prescribers through accredited continuing education (CE), and providing patient educational materials. Methods. The impact of this REMS has been assessed using diverse metrics including evaluation of prescriber and patient understanding of the risks associated with opioids; patient receipt and comprehension of the medication guide and patient counseling document; patient satisfaction with access to opioids; drug utilization and changes in prescribing patterns; and surveillance of ER/LA opioid misuse, abuse, overdose, addiction, and death. Results and Conclusions. The results of these assessments indicate that the increasing rates of opioid abuse, addiction, overdose, and death observed prior to implementation of the REMS have since leveled off or started to decline. However, these benefits cannot be attributed solely to the ER/LA opioid analgesics REMS since many other initiatives to prevent abuse occurred contemporaneously. These improvements occurred while preserving patient access to opioids as a large majority of patients surveyed expressed satisfaction with their access to opioids. PMID:27373304

Hedgehog signaling regulates nociceptive sensitization.

PubMed

Babcock, Daniel T; Shi, Shanping; Jo, Juyeon; Shaw, Michael; Gutstein, Howard B; Galko, Michael J

2011-09-27

Nociceptive sensitization is a tissue damage response whereby sensory neurons near damaged tissue enhance their responsiveness to external stimuli. This sensitization manifests as allodynia (aversive withdrawal to previously nonnoxious stimuli) and/or hyperalgesia (exaggerated responsiveness to noxious stimuli). Although some factors mediating nociceptive sensitization are known, inadequacies of current analgesic drugs have prompted a search for additional targets. Here we use a Drosophila model of thermal nociceptive sensitization to show that Hedgehog (Hh) signaling is required for both thermal allodynia and hyperalgesia following ultraviolet irradiation (UV)-induced tissue damage. Sensitization does not appear to result from developmental changes in the differentiation or arborization of nociceptive sensory neurons. Genetic analysis shows that Hh signaling acts in parallel to tumor necrosis factor (TNF) signaling to mediate allodynia and that distinct transient receptor potential (TRP) channels mediate allodynia and hyperalgesia downstream of these pathways. We also demonstrate a role for Hh in analgesic signaling in mammals. Intrathecal or peripheral administration of cyclopamine (CP), a specific inhibitor of Sonic Hedgehog signaling, blocked the development of analgesic tolerance to morphine (MS) or morphine antinociception in standard assays of inflammatory pain in rats and synergistically augmented and sustained morphine analgesia in assays of neuropathic pain. We demonstrate a novel physiological role for Hh signaling, which has not previously been implicated in nociception. Our results also identify new potential therapeutic targets for pain treatment. Copyright © 2011 Elsevier Ltd. All rights reserved.

Characteristics of methadone maintenance treatment patients prescribed opioid analgesics.

PubMed

Glenn, Matthew C; Sohler, Nancy L; Starrels, Joanna L; Maradiaga, Jeronimo; Jost, John J; Arnsten, Julia H; Cunningham, Chinazo O

2016-01-01

Opioid analgesic use and disorders have dramatically increased among the general American population and those receiving methadone maintenance treatment (MMT). Most research among MMT patients focuses on opioid analgesics misuse or disorders; few studies focus on MMT patients prescribed opioid analgesics. We describe demographic, clinical, and substance use characteristics of MMT patients prescribed opioid analgesics and compare them with MMT patients not prescribed opioid analgesics. We conducted a cross-sectional secondary data analysis using screening interviews from a parent study. From 2012 to 2015, we recruited adults from 3 MMT Bronx clinics. Questionnaire data included patterns of opioid analgesic use, substance use, comorbid illnesses, and demographic characteristics. Our main dependent variable was patients' report of currently taking prescribed opioid analgesics. To compare characteristics between MMT patients prescribed and not prescribed opioid analgesics, we conducted chi-square tests, t tests, and Mann-Whitney U tests. Of 611 MMT patients, most reported chronic pain (62.0%), hepatitis C virus (HCV) infection (52.1%), and current use of illicit substances (64.2%). Of the 29.8% who reported currently taking prescribed opioid analgesics, most misused their opioid analgesics (57.5%). Patients prescribed (versus not prescribed) opioid analgesics were more likely to report human immunodeficiency virus (HIV) infection (adjusted odds ratio [aOR] = 1.6, 95% confidence interval [CI]: 1.1-2.3) and chronic pain (aOR = 7.6, 95% CI: 4.6-12.6). Among MMT patients primarily in 3 Bronx clinics, nearly one third reported taking prescribed opioid analgesics. Compared with patients not prescribed opioid analgesics, those prescribed opioid analgesics were more likely to report chronic pain and HIV infection. However, between these patients, there was no difference in illicit substance use. These findings highlight the complexity of addressing chronic pain in MMT patients.

Characteristics of methadone maintenance treatment patients prescribed opioid analgesics

PubMed Central

Glenn, Matthew C.; Sohler, Nancy L.; Starrels, Joanna L.; Maradiaga, Jeronimo; Jost, John J.; Arnsten, Julia H.; Cunningham, Chinazo O.

2016-01-01

Background Opioid analgesic use and disorders have dramatically increased among the general American population and those receiving methadone maintenance treatment (MMT). Most research among MMT patients focuses on opioid analgesics misuse or disorders; few studies focus on MMT patients prescribed opioid analgesics. We describe demographic, clinical, and substance use characteristics of MMT patients prescribed opioid analgesics and compare them to MMT patients not prescribed opioid analgesics. Methods We conducted a cross-sectional secondary data analysis using screening interviews from a parent study. From 2012–2015, we recruited adults from 3 MMT Bronx clinics. Questionnaire data included: patterns of opioid analgesic use, substance use, comorbid illnesses, and demographic characteristics. Our main dependent variable was patients’ report of currently taking prescribed opioid analgesics. To compare characteristics between MMT patients prescribed and not prescribed opioid analgesics, we conducted chi-squared tests, t-tests, and Mann-Whitney U tests. Results Of 611 MMT patients, most reported chronic pain (62.0%), HCV infection (52.1%), and currently using illicit substances (64.2%). Of the 29.8% who reported currently taking prescribed opioid analgesics, most misused their opioid analgesics (57.5%). Patients prescribed (versus not prescribed) opioid analgesics were more likely to report HIV infection (aOR=1.6, 95% CI: 1.1–2.3) and chronic pain (aOR=7.6, 95% CI: 4.6–12.6). Conclusion Among MMT patients primarily in three Bronx clinics, nearly one-third reported taking prescribed opioid analgesics. Compared to patients not prescribed opioid analgesics, those prescribed opioid analgesics were more likely to report chronic pain and HIV infection. However, between these patients, there was no difference in illicit substance use. These findings highlight the complexity of addressing chronic pain in MMT patients. PMID:26731299

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The anti-nociceptive potential of tilmicosin against chemical-induced but not thermal-induced pain in mice

PubMed Central

El-Mahmoudy, A; Gheith, I

2015-01-01

The aim of the present study was to assess the analgesic activity of the macrolide antibiotic tilmicosin at dose levels of 20 and 40 mg/kg of body weight, subcutaneously, against chemical- and thermal-induced acute pains, using acetic acid-induced writhing, formalin-induced pain, hot-plate, and tail-flick models in mice. Tilmicosin showed a dose-dependent significant decrease in the number of writhes in the acetic acid-induced writhing test and significant decrease in hind paw-licking time in the late phase of the formalin test. However, it did not cause any significant changes in the reaction times to heat stimuli in the hot-plate and tail-flick models. In chemically-induced pains, both dose levels of tilmicosin showed significant effects compared to those of the corresponding standard peripheral analgesic, acetylsalicylic acid (200 mg/kg of body weight, subcutaneously) being 26.37 ± 2.88 and 43.64 ± 3.85% vs. 73.35 ± 1.44% in acetic acid test; and 19.23 ± 3.85 and 44.90 ± 1.80% vs. 73.63 ± 2.39% in the late phase of formalin test, respectively. These results may indicate that tilmicosin possesses a significant peripheral but not central analgesic potential that may be beneficial in symptomatic relief of pain when it is used in therapy, in addition to its well-established antibacterial effect. PMID:26519523

Multisteric TRPV1 nocisensor: a target for analgesics.

PubMed

Szolcsányi, János; Sándor, Zoltán

2012-12-01

Cloning of the transient receptor potential vanilloid type 1 (TRPV1), the heat-gated cation channel/capsaicin receptor expressed by sensory neurons, has opened the door for development of new types of analgesics that selectively act on nociceptors. Here we summarize mutagenetic evidence for selective loss of responsiveness to vanilloids, protons, and heat stimuli to provide clues for avoiding on-target side effects of hyperthermia and burn risk. It is suggested that the complex chemoceptive thermosensor function of TRPV1 (which is modulated by depolarizing stimuli) can be attributed to multisteric gating functions. In this way, it forms the prototype of a new class of ion channels different from the canonical voltage-gated and ligand-gated ones. Several endogenous lipid ligands activate and inhibit TRPV1 and its gating initiates sensory transducer and mediator-releasing functions. Second generation TRPV1 antagonists that do not induce hyperthermia are under development, and a dermal capsaicin patch is already on the market for long-term treatment of neuropathic pain. Copyright © 2012 Elsevier Ltd. All rights reserved.

Putative kappa opioid heteromers as targets for developing analgesics free of adverse effects.

PubMed

Le Naour, Morgan; Lunzer, Mary M; Powers, Michael D; Kalyuzhny, Alexander E; Benneyworth, Michael A; Thomas, Mark J; Portoghese, Philip S

2014-08-14

It is now generally recognized that upon activation by an agonist, β-arrestin associates with G protein-coupled receptors and acts as a scaffold in creating a diverse signaling network that could lead to adverse effects. As an approach to reducing side effects associated with κ opioid agonists, a series of β-naltrexamides 3-10 was synthesized in an effort to selectively target putative κ opioid heteromers without recruiting β-arrestin upon activation. The most potent derivative 3 (INTA) strongly activated KOR-DOR and KOR-MOR heteromers in HEK293 cells. In vivo studies revealed 3 to produce potent antinociception, which, when taken together with antagonism data, was consistent with the activation of both heteromers. 3 was devoid of tolerance, dependence, and showed no aversive effect in the conditioned place preference assay. As immunofluorescence studies indicated no recruitment of β-arrestin2 to membranes in coexpressed KOR-DOR cells, this study suggests that targeting of specific putative heteromers has the potential to identify leads for analgesics devoid of adverse effects.

The bifunctional μ opioid agonist/antioxidant [Dmt(1)]DALDA is a superior analgesic in an animal model of complex regional pain syndrome-type i.

PubMed

Schiller, Peter W; Nguyen, Thi M-D; Saray, Amy; Poon, Annie Wing Hoi; Laferrière, André; Coderre, Terence J

2015-11-18

Reactive oxygen species (ROS) play an important role in the development of complex regional pain syndrome-Type I (CRPS-I), as also demonstrated with the chronic post ischemia pain (CPIP) animal model of CRPS-I. We show that morphine and the antioxidant N-acetylcysteine (NAC) act synergistically to reduce mechanical allodynia in CPIP rats. The tetrapeptide amide [Dmt(1)]DALDA (H-Dmt-d-Arg-Phe-Lys-NH2) is a potent and selective μ opioid receptor (MOR) agonist with favorable pharmacokinetic properties and with antioxidant activity due to its N-terminal Dmt (2',6'-dimethyltyrosine) residue. In the CPIP model, [Dmt(1)]DALDA was 15-fold more potent than morphine in reversing mechanical allodynia and 4.5-fold more potent as analgesic in the heat algesia test. The results indicate that bifunctional compounds with MOR agonist/antioxidant activity have therapeutic potential for the treatment of CRPS-I.

Pharmacokinetics of ketamine and its metabolite norketamine administered at a sub-anesthetic dose together with xylazine to calves prior to castration.

PubMed

Gehring, R; Coetzee, J F; Tarus-Sang, J; Apley, M D

2009-04-01

The objective of this study was to evaluate the plasma pharmacokinetics of ketamine and its active metabolite norketamine administered intravenously at a dose of 0.1 mg/kg together with xylazine (0.05 mg/kg) to control the pain associated with castration in calves. A two-compartment model with an additional metabolite compartment linked to the central compartment was used to simultaneously describe the time-concentration profiles of both ketamine and its major metabolite norketamine. Parameter values estimated from the time-concentration profiles observed in this study were volume of the central compartment (V(c) = 132.82 +/- 68.23 mL/kg), distribution clearance (CL(D) = 15.49 +/- 2.56 mL/min/kg), volume of the peripheral compartment (V(T) = 257.05 +/- 41.65 mL/kg), ketamine clearance by the formation of the norketamine metabolite (CL(2M) = 8.56 +/- 7.37 mL/kg/min) and ketamine clearance by other routes (CL(o) = 16.41 +/- 3.42 mL/kg/min). Previously published data from rats suggest that the metabolite norketamine contributes to the analgesic effect of ketamine, with a potency that is one-third of the parent drug. An understanding of the time-concentration relationships and the disposition of the parent drug and its metabolite is therefore important for a better understanding of the analgesic potential of ketamine in cattle.

High Affinity Binding of Epibatidine to Serotonin Type 3 Receptors*

PubMed Central

Drisdel, Renaldo C.; Sharp, Douglas; Henderson, Tricia; Hales, Tim G.; Green, William N.

2008-01-01

Epibatidine and mecamylamine are ligands used widely in the study of nicotinic acetylcholine receptors (nAChRs) in the central and peripheral nervous systems. In the present study, we find that nicotine blocks only 75% of 125I-epibatidine binding to rat brain membranes, whereas ligands specific for serotonin type 3 receptors (5-HT3Rs) block the remaining 25%. 125I-Epibatidine binds with a high affinity to native 5-HT3Rs of N1E-115 cells and to receptors composed of only 5-HT3A subunits expressed in HEK cells. In these cells, serotonin, the 5-HT3R-specific antagonist MDL72222, and the 5-HT3R agonist chlorophenylbiguanide readily competed with 125I-epibatidine binding to 5-HT3Rs. Nicotine was a poor competitor for 125I-epibatidine binding to 5-HT3Rs. However, the noncompetitive nAChR antagonist mecamylamine acted as a potent competitive inhibitor of 125I-epibatidine binding to 5-HT3Rs. Epibatidine inhibited serotonin-induced currents mediated by endogenous 5-HT3Rs in neuroblastoma cell lines and 5-HT3ARs expressed in HEK cells in a competitive manner. Our results demonstrate that 5-HT3Rs are previously uncharacterized high affinity epibatidine binding sites in the brain and indicate that epibatidine and mecamylamine act as 5-HT3R antagonists. Previous studies that depended on epibatidine and mecamylamine as nAChR-specific ligands, in particular studies of analgesic properties of epibatidine, may need to be reinterpreted with respect to the potential role of 5-HT3Rs. PMID:17702741

Antinociceptive potency of a fluorinated cyclopeptide Dmt-c[D-Lys-Phe-p-CF3-Phe-Asp]NH2.

PubMed

Piekielna-Ciesielska, Justyna; Mollica, Adriano; Pieretti, Stefano; Fichna, Jakub; Szymaszkiewicz, Agata; Zielińska, Marta; Kordek, Radzisław; Janecka, Anna

2018-12-01

Opioid peptides and opiate drugs such as morphine, mediate their analgesic effects, but also undesired side effects, mostly through activation of the mu opioid receptor. However, delta- and kappa-opioid receptors can also contribute to the analgesic effects of opioids. Recent findings showed that simultaneous activation of multiple opioid receptors may result in additional analgesia with fewer side effects. Here, we evaluated the pharmacological profile of our formerly developed mixed mu/kappa-opioid receptor ligands, Dmt-c[D-Lys-Phe-Phe-Asp]NH 2 (C-36) and Dmt-c[D-Lys-Phe-p-CF 3 -Phe-Asp]NH 2 (F-81). The ability of these peptides to cross the blood-brain barrier was tested in the parallel artificial membrane permeability (PAMPA) assay. On the basis of the hot-plate test in mice after central and peripheral administration, analog F-81 was selected for the anti-nociceptive and anti-inflammatory activity assessment after peripheral administration.

Potential therapeutic agents derived from the cannabinoid nucleus.

PubMed

Pars, H G; Howes, J F

1977-01-01

Drugs derived from Cannabis sativa (Cannabinceae) were used until the 1940's for their stimulant and depressant effects for treating somatic and psychiatric illnesses. Renewed interest in marihuana research began in the 1970's and again pointed to the therapeutic potential of cannabinoids. Safer and more useful therapeutic agents may be generated from cannabinoids similarly to morphine, lysergic acid diethylamide, and cocaine which have structurally related analgesics, oxytoxics, and local anesthetics respectively. It has been shown that the C-ring in cannabinoids can be substituted with a variety of nitrogen and sulfur-containing rings without loss of CNS (central nervous system) activity. Cannabinoids have been shown to inhibit prostaglandin synthesis, intensify pressor effects of endogenous amines like norepinephrine, and enhance the stimulant effects of amphetamine. Cannabinoids' therapeutic potential lies in the areas of analgesics and anticonvulsants, and for use as a sedative-hypnotic, an antiglaucoma agent, an antiasthmatic agent, an antidiarrheal agent, and possibly as an anticancer and immunosuppressant agent.

Microwave-assisted extraction and pharmacological evaluation of polysaccharides from Posidonia oceanica.

PubMed

Ben Salem, Yosra; Abdelhamid, Amal; Mkadmini Hammi, Khaoula; Le Cerf, Didier; Bouraoui, Abderrahman; Majdoub, Hatem

2017-10-01

Microwave-assisted extraction was employed for the isolation of polysaccharides from Posidonia oceanica (PPO). The extracting parameters were optimized adopting response surface methodology. The highest polysaccharide yield (2.55 ± 0.09%), which is in concordance with the predicted value (2.76%), was obtained under the following conditions: extraction time 60 s, liquid-solid ratio of 50:1 (mL/g) and power of 800 W. This polysaccharide, with molecular weight of 524 KDa, characterized by gas chromatography-mass spectrometry showed that PPO was mainly composed of galactose, glucose, and arabinose with molar percentages 25.38, 24.37, and 21.64%, respectively. The pharmacological evaluation of PPO using animal models at the dose of 100 mg/kg indicated a significant anti-inflammatory activity with a percentage of inhibition of edema of 54.65% and a significant antinociceptive activity with 78.91% inhibition of writhing for peripheral analgesic activity and an increase in the hot plate reaction time for central analgesic activity.

Single dose oral ibuprofen plus caffeine for acute postoperative pain in adults.

PubMed

Derry, Sheena; Wiffen, Philip J; Moore, R Andrew

2015-07-14

There is good evidence that combining two different analgesics in fixed doses in a single tablet can provide better pain relief in acute pain and headache than either drug alone, and that the drug-specific benefits are essentially additive. This appears to be broadly true in postoperative pain and migraine headache across a range of different drug combinations, and when tested in the same and different trials. Adding caffeine to analgesics also increases the number of people obtaining good pain relief. Combinations of ibuprofen and caffeine are available without prescription in some parts of the world. To assess the analgesic efficacy and adverse effects of a single oral dose of ibuprofen plus caffeine for moderate to severe postoperative pain, using methods that permit comparison with other analgesics evaluated in standardised trials using almost identical methods and outcomes. We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, the Oxford Pain Relief Database, two clinical trial registries, and the reference lists of articles. The date of the most recent search was 1 February 2015. Randomised, double-blind, placebo- or active-controlled clinical trials of single dose oral ibuprofen plus caffeine for acute postoperative pain in adults. Two review authors independently considered trials for inclusion in the review, assessed risk of bias, and extracted data. We used the area under the pain relief versus time curve to derive the proportion of participants with at least 50% pain relief over six hours prescribed either ibuprofen plus caffeine or placebo. We calculated the risk ratio (RR) and number needed to treat to benefit (NNT). We used information on the use of rescue medication to calculate the proportion of participants requiring rescue medication and the weighted mean of the median time to use. We also collected information on adverse effects. We identified five randomised, double-blind studies with 1501 participants, but only four had been published and had relevant outcome data. These four studies were of high quality, although two of the studies were small.Both ibuprofen 200 mg + caffeine 100 mg and ibuprofen 100 mg + caffeine 100 mg produced significantly more participants than placebo who achieved at least 50% of maximum pain relief over six hours, and both doses significantly reduced remedication rates (moderate quality evidence). For at least 50% of maximum pain relief, the NNT was 2.1 (95% confidence interval 1.8 to 2.5) for ibuprofen 200 mg + caffeine 100 mg (four studies, 334 participants) and 2.4 (1.9 to 3.1) for ibuprofen 100 mg + caffeine 100 mg (two studies, 200 participants) (moderate quality evidence). These values were close to those predicted by published models for combination analgesics in acute pain, and were supported by low (good) NNT values for prevention of remedication.Adverse event rates were low, and no sensible analysis was possible. For ibuprofen 200 mg + caffeine 100 mg particularly, the low NNT value is among the lowest (best) values for analgesics in this pain model. The combination is not commonly available, but can be probably be achieved by taking a single 200 mg ibuprofen tablet with a cup of modestly strong coffee or caffeine tablets. In principle, this can deliver good analgesia at lower doses of ibuprofen.

Development of a capillary electrophoresis method for the determination of the chiral purity of dextromethorphan by a dual selector system using quality by design methodology.

PubMed

Krait, Sulaiman; Heuermann, Matthias; Scriba, Gerhard K E

2018-03-01

Dextromethorphan is a centrally acting antitussive drug, while its enantiomer levomethorphan is an illicit drug with opioid analgesic effects. As capillary electrophoresis has been proven as an ideal technique for enantiomer analysis, the present study was conducted in order to develop a capillary electrophoresis-based limit test for levomethorphan. The analytical target profile was defined as a method that should be able to determine levomethorphan with acceptable precision and accuracy at the 0.1 % level. From initial scouting experiments, a dual selector system consisting of sulfated β-cyclodextrin and methyl-α-cyclodextrin was identified. The critical process parameters were evaluated in a fractional factorial resolution IV design followed by a central composite face-centered design and Monte Carlo simulations for defining the design space of the method. The selected working conditions consisted of a 30/40.2 cm, 50 μm id fused-silica capillary, 30 mM sodium phosphate buffer, pH 6.5, 16 mg/mL sulfated β-cyclodextrin, and 14 mg/mL methyl-α-cyclodextrin at 20°C and 20 kV. The method was validated according to ICH guideline Q2(R1) and applied to the analysis of a capsule formulation. Furthermore, the apparent binding constants between the enantiomers and the cyclodextrins as well as complex mobilities were determined to understand the migration behavior of the analytes. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

The plasticity of descending controls in pain: translational probing.

PubMed

Bannister, Kirsty; Dickenson, A H

2017-07-01

Descending controls, comprising pathways that originate in midbrain and brainstem regions and project onto the spinal cord, have long been recognised as key links in the multiple neural networks that interact to produce the overall pain experience. There is clear evidence from preclinical and clinical studies that both peripheral and central sensitisation play important roles in determining the level of pain perceived. Much emphasis has been put on spinal cord mechanisms in central excitability, but it is now becoming clear that spinal hyperexcitability can be regulated by descending pathways from the brain that originate from predominantly noradrenergic and serotonergic systems. One pain can inhibit another. In this respect diffuse noxious inhibitory controls (DNIC) are a unique form of endogenous descending inhibitory pathway since they can be easily evoked and quantified in animals and man. The spinal pharmacology of pathways that subserve DNIC are complicated; in the normal situation these descending controls produce a final inhibitory effect through the actions of noradrenaline at spinal α 2 -adrenoceptors, although serotonin, acting on facilitatory spinal 5-HT 3 receptors, influences the final expression of DNIC also. These descending pathways are altered in neuropathy and the effects of excess serotonin may now become inhibitory through activation of spinal 5-HT 7 receptors. Conditioned pain modulation (CPM) is the human counterpart of DNIC and requires a descending control also. Back and forward translational studies between DNIC and CPM, gauged between bench and bedside, are key for the development of analgesic therapies that exploit descending noradrenergic and serotonergic control pathways. © 2017 The Authors. The Journal of Physiology © 2017 The Physiological Society.

Central nervous system medications and falls risk in men aged 60-75 years: the Study on Male Osteoporosis and Aging (SOMA).

PubMed

Masud, Tahir; Frost, Morten; Ryg, Jesper; Matzen, Lars; Ibsen, Marlene; Abrahamsen, Bo; Brixen, Kim

2013-01-01

drugs acting on the central nervous system (CNS) increase falls risk. Most data on CNS drugs and falls are in women/mixed-sex populations. This study assessed the relationship between CNS drugs and falls in men aged 60-75 years. a questionnaire was sent to randomly selected Danish men aged 60-75 years. Cross-sectional data on CNS drugs and falls in the previous year were available for 4,696 men. Logistic regression investigated the relationship between falls and CNS drugs. the median age was 66.3 (IQR = 63.1-70.0) years; 21.7% were fallers. The following were associated with fallers (OR; 95% CI): opiates (2.4; 1.5-3.7), other analgesics (1.7; 1.4-2.1), antiepileptics (2.8; 1.5-5.1), antidepressants (2.8; 1.9-4.1) and anxiolytics/hypnotics (1.5; 0.9-2.6). Effects of opiates interacted strongly and significantly with age, with a marked association with falls in the older half of the subjects only. No significant associations were found between antipsychotics and fallers. Selective serotonin reuptake inhibitors and tricyclics were significantly associated with fallers (3.1; 2.0-5.0 and 2.2; 1.0-4.7, respectively). several CNS drug classes are associated with an approximately 2-3-fold increase risk of falls in men aged 60-75 years randomly selected from the population. Further longitudinal data are now required to confirm and further investigate the role of CNS drugs in falls causation in men.

Mediating Effect of Family Caregivers' Hesitancy to Use Analgesics on Homecare Cancer Patients' Analgesic Adherence.

PubMed

Lee, Bih-O; Liu, Yi; Wang, Yi-Hsien; Hsu, Hsin-Tien; Chen, Chien-Liang; Chou, Pi-Ling; Hsu, Wen-Chung

2015-12-01

Family caregivers play an increasingly critical role in cancer patients' symptom management as the number of cancer patients receiving home care grows. However, there is a lack of research measuring the impact of the family caregivers' hesitancy to use analgesics on analgesic adherence and the resulting influence on patient pain intensity. To examine whether family caregivers' hesitancy to use analgesics is a mediator that influences patient adherence and investigate how analgesic regimen adherence affects pain intensity. This study used a cross-sectional and descriptive design. One hundred seventy-six patient-family caregiver dyads (N = 352) were recruited from one local hospital in southern Taiwan. Instruments included the Short Version of the Barriers Questionnaire-Taiwan, the Morisky Medication Adherence Measure-Taiwan, the Brief Pain Inventory-Chinese, and demographic and illness questionnaires. A one-way analysis of variance and post hoc comparisons were performed to assess the influence of analgesic regimen adherence on pain intensity. Sobel tests were used to examine mediating effects. Family caregivers' hesitancy to use analgesics was a significant mediator between patient barriers to use analgesics and patient analgesic regimen adherence (P < 0.0001). Patients with low and moderate adherence levels reported significantly higher levels of pain severity (F = 3.83, P < 0.05). This study showed that family caregivers' hesitancy to use analgesics was a significant mediator associated with their hesitancy to use analgesics and the patients' analgesic adherence. It is important for health care providers to consider family caregivers' hesitancy to use analgesics when attempting to improve adherence to pain management regimens in clinical practice. Copyright © 2015 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved.

Long term use of analgesics and risk of osteoarthritis progressions and knee replacement: propensity score matched cohort analysis of data from the Osteoarthritis Initiative.

PubMed

Hafezi-Nejad, N; Guermazi, A; Roemer, F W; Eng, J; Zikria, B; Demehri, S

2016-04-01

To determine the association between the long-term use of analgesics and progression of osteoarthritis (OA) as evidenced by up to 3-years follow-up worsening of radiographic Kellgren-Lawrence (KL) grade and incidence of knee replacement (KR). Using nearest neighbor matching of the propensity scores with caliper in the Osteoarthritis Initiative (OAI) cohort, 173 index (Analgesic +) and 173 referent (Analgesic -) subjects were included. Analgesic + and - subjects had analgesics in all and none of their visits, respectively. Analgesic + and - subjects were balanced in their demographics, baseline, first, second and third year body mass index (BMI), Western Ontario and McMaster (WOMAC) total score, Physical and Mental health summary scales (SF-12), Physical Activity Scale for the Elderly (PASE) and Charleston Comorbidity Scale. Analgesic + and - subjects were also matched for baseline radiographic KL grade. Interval increase in the KL grade and incidence of KR were defined as the outcome. Included subjects had average 6.5 years of follow-up. By the third year, 44 subjects had an interval increase in the KL grade; 29 in Analgesic + and 15 among Analgesic - subjects (P = 0.024). By the eighth-year, 41 subjects had their first KR; 29 in Analgesic + and 12 among Analgesic - subjects (P = 0.005). Hazard Ratio (HR) of OA progression and KR for Analgesic + subjects was 1.91 (1.02-3.57) and 2.57 (1.31-5.04), respectively. Long-term use of analgesics may be associated with radiographic progression of knee OA and increased risk of future KR. Copyright © 2015 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.

Consumption of analgesics before a marathon and the incidence of cardiovascular, gastrointestinal and renal problems: a cohort study.

PubMed

Küster, Michael; Renner, Bertold; Oppel, Pascal; Niederweis, Ursula; Brune, Kay

2013-01-01

To prevent pain inhibiting their performance, many athletes ingest over-the-counter (OTC) analgesics before competing. We aimed at defining the use of analgesics and the relation between OTC analgesic use/dose and adverse events (AEs) during and after the race, a relation that has not been investigated to date. Prospective (non-interventional) cohort study, using an online questionnaire. The Bonn marathon 2010. 3913 of 7048 participants in the Bonn marathon 2010 returned their questionnaires. Intensity of analgesic consumption before sports; incidence of AEs in the cohort of analgesic users as compared to non-users. There was no significant difference between the premature race withdrawal rate in the analgesics cohort and the cohort who did not take analgesics ('controls'). However, race withdrawal because of gastrointestinal AEs was significantly more frequent in the analgesics cohort than in the control. Conversely, withdrawal because of muscle cramps was rare, but it was significantly more frequent in controls. The analgesics cohort had an almost 5 times higher incidence of AEs (overall risk difference of 13%). This incidence increased significantly with increasing analgesic dose. Nine respondents reported temporary hospital admittance: three for temporary kidney failure (post-ibuprofen ingestion), four with bleeds (post-aspirin ingestion) and two cardiac infarctions (post-aspirin ingestion). None of the control reported hospital admittance. The use of analgesics before participating in endurance sports may cause many potentially serious, unwanted AEs that increase with increasing analgesic dose. Analgesic use before endurance sports appears to pose an unrecognised medical problem as yet. If verifiable in other endurance sports, it requires the attention of physicians and regulatory authorities.

Adverse selection? A multi-dimensional profile of people dispensed opioid analgesics for persistent non-cancer pain.

PubMed

Rogers, Kris D; Kemp, Anna; McLachlan, Andrew J; Blyth, Fiona

2013-01-01

This study investigates utilisation patterns for prescription opioid analgesics in the Australian community and how these are associated with a framework of individual-level factors related to healthcare use. Self-reported demographic and health information from participants in the 45 and Up Study cohort were linked to pharmaceutical claims from 2006-2009. Participants comprised 19,816 people with ≥1 opioid analgesic dispensing in the 12-months after recruitment to the cohort and 79,882 people not dispensed opioid analgesics. All participants were aged ≥45 years, were social security pharmaceutical beneficiaries, with no history of cancer. People dispensed opioid analgesics were classified as having acute (dispensing period <90 days), episodic (≥90 days and <3 'authority' prescriptions for increased quantity supply) or long-term treatment (≥90 days and ≥3 authority prescriptions). Of participants dispensed opioid analgesic 52% received acute treatment, 25% episodic treatment and 23% long-term treatment. People dispensed opioid analgesics long-term had an average of 14.9 opioid analgesic prescriptions/year from 2.0 doctors compared with 1.5 prescriptions from 1.1 doctors for people receiving acute treatment. People dispensed opioid analgesics reported more need-related factors such as poorer physical functioning and higher psychological distress. Long-term users were more likely to have access-related factors such as low-income and living outside major cities. After simultaneous adjustment, association with predisposing health factors and access diminished, but indicators of need such as osteoarthritis treatment, paracetamol use, and poor physical function were the strongest predictors for all opioid analgesic users. People dispensed opioid analgesics were in poorer health, reported higher levels of distress and poorer functioning than people not receiving opioid analgesics. Varying dispensing profiles were evident among people dispensed opioid analgesics for persistent pain, with those receiving episodic and long-term treatment dispensed the strongest opioid analgesics. The findings highlight the broad range of factors associated with longer term opioid analgesics use.

Perioperative Opioid Analgesics and Hip Arthroscopy: Trends, Risk Factors for Prolonged Use, and Complications.

PubMed

Anciano Granadillo, Victor; Cancienne, Jourdan M; Gwathmey, F Winston; Werner, Brian C

2018-05-02

The purpose of this article is to (1) examine trends in preoperative and prolonged postoperative opioid analgesic use in patient undergoing hip arthroscopy, (2) characterize risk factors for prolonged opioid analgesic use following hip arthroscopy, and (3) explore preoperative and prolonged postoperative opioid analgesic use as independent risk factors for complications following hip arthroscopy. A private insurance database was queried for patients undergoing hip arthroscopy from 2007 to 2015 with a minimum of 6 months of follow-up. Independent risk factors for prolonged opioid analgesic use were determined. Preoperative and prolonged opioid analgesic use as risk factors for complications were examined. There was a significantly decreasing trend in preoperative (P = .002) and prolonged postoperative (P = .009) opioid analgesic use. The most significant risk factor for prolonged postoperative opioid analgesic use was preoperative use (odds ratio [OR], 3.61; P < .0001). Other preoperative prescriptions, including muscle relaxants (OR, 1.5; P < .0001) and anxiolytics (OR, 2.0; P < .0001), were also significant risk factors. Preoperative opioid analgesic use was a significant risk factor for postoperative complications, including emergency room visits (OR, 2.1; P < .0001) and conversion to total hip arthroplasty (THA) (OR, 1.6; P < .0001). Prolonged postoperative opioid analgesic use was associated with a higher risk of revision hip arthroscopy (OR, 1.4; P = .0004) and conversion to THA (OR, 1.8; P < .0001). More than a quarter of patients undergoing hip arthroscopy continue to receive opioid analgesic prescriptions more than 3 months postoperatively. The most significant risk factor for prolonged opioid analgesic use is preoperative opioid analgesic use. Additionally, anxiolytics, substance use or abuse, morbid obesity, and back pain were among the more notable risk factors for prolonged postoperative opioid analgesic use. Preoperative and prolonged postoperative opioid analgesic use was associated with a higher likelihood of several adverse effects/complications. Level III, retrospective comparative study. Copyright © 2018 Arthroscopy Association of North America. Published by Elsevier Inc. All rights reserved.

Risk perception about medication sharing among patients: a focus group qualitative study on borrowing and lending of prescription analgesics.

PubMed

Markotic, Filipa; Vrdoljak, Davorka; Puljiz, Marijana; Puljak, Livia

2017-01-01

One form of self-medication is sharing of medications, defined as borrowing or lending medications in situations where the receiver of these drugs is not the individual to whom the medications were allocated. To explore experiences and opinions of patients about sharing prescription analgesics, reasons for sharing prescription analgesics, the way in which patients choose to share those medications, their awareness of risk regarding sharing prescription analgesics, and how they estimated the potential risk. This qualitative study was conducted by focus group discussions with 40 participants led by a moderator trained in focus group methodology using a semi-structured moderator guide. Adults aged ≥18 years who had received a prescription for an analgesic at least once in a lifetime were included. Six separate focus groups were conducted to discuss participants' perception of risks associated with sharing of prescription analgesics among patients. Additionally, participants filled out two questionnaires on demographic data, their own behavior regarding sharing analgesics, and their attitudes about risks associated with sharing prescription analgesics. In a questionnaire, 55% of the participants indicated that they personally shared prescription analgesics, while subsequently in the focus group discussions, 76% confessed to such behavior. Participants recognized certain risks related to sharing of prescription analgesics, mentioned a number of reasons for engaging in such behavior, and indicated certain positive aspects of such behavior. Forty-five percent of the participants indicated that sharing prescription analgesics is riskier than sharing nonprescription analgesics. There is a prevalent attitude among participants that sharing prescription analgesics is a positive behavior, where potential benefits outweigh risks.

National Collegiate Athletic Association Division I Athletes’ Use of Nonprescription Medication

PubMed Central

Wolf, Douglas A.; Miller, Thomas W.; Pescatello, Linda S.; Barnes, Christopher

2011-01-01

Background: Athletes are known to use over-the-counter pain medication. However, the frequency of such use among National Collegiate Athletic Association (NCAA) Division I-A football athletes is unknown. Hypothesis: NCAA Division I-A football athletes who use nonprescription analgesics for pain misuse these medications. Study Design: Cross-sectional study. Methods: The football players (N, 144) who met the criteria and agreed to participate were from 8 NCAA Division I-A schools. The participants were administered the Over the Counter Drug Screen for Athletes, which measures attitudes toward the use of a spectrum of substances. Results: Among football athletes surveyed who took nonprescription analgesics for football-related pain, 37% reported taking more than the recommended dose. This was slightly higher than the 28% of players who stated they have not taken nonprescription analgesics for football-related pain. Thirty-four percent of all athletes reported using more than the recommended dose of nonprescription analgesics. Athletes who purchased their own nonprescription analgesics communicated poorly regarding nonprescription analgesics use. Those lacking knowledge about nonprescription analgesics and those using nonprescription analgesics in anticipation of pain or to avoid missing a practice or game were most likely to misuse nonprescription analgesics. Conclusion: NCAA Division I-A football athletes who use nonprescription analgesics for athletic competition do not misuse nonprescription analgesics. PMID:23015987

Prescribing of opioid analgesics and related mortality before and after the introduction of long-acting oxycodone

PubMed Central

Dhalla, Irfan A.; Mamdani, Muhammad M.; Sivilotti, Marco L.A.; Kopp, Alex; Qureshi, Omar; Juurlink, David N.

2009-01-01

Introduction Opioid-related mortality appears to be increasing in Canada. We examined the true extent of the problem and the impact of the introduction of long-acting oxycodone. Methods We examined trends in the prescribing of opioid analgesics in the province of Ontario from 1991 to 2007. We reviewed all deaths related to opioid use between 1991 and 2004. We linked 3271 of these deaths to administrative data to examine the patients’ use of health care services before death. Using time-series analysis, we determined whether the addition of long-acting oxycodone to the provincial drug formulary in January 2000 was associated with an increase in opioid-related mortality. Results From 1991 to 2007, annual prescriptions for opioids increased from 458 to 591 per 1000 individuals. Opioid-related deaths doubled, from 13.7 per million in 1991 to 27.2 per million in 2004. Prescriptions of oxycodone increased by 850% between 1991 and 2007. The addition of long-acting oxycodone to the drug formulary was associated with a 5-fold increase in oxycodone-related mortality (p < 0.01) and a 41% increase in overall opioid-related mortality (p = 0.02). The manner of death was deemed unintentional by the coroner in 54.2% and undetermined in 21.9% of cases. Use of health care services in the month before death was common: for example, of the 3066 patients for whom data on physician visits were available, 66.4% had visited a physician in the month before death; of the 1095 patients for whom individual-level prescribing data were available, 56.1% had filled a prescription for an opioid in the month before death. Interpretation Opioid-related deaths in Ontario have increased markedly since 1991. A significant portion of the increase was associated with the addition of long-acting oxycodone to the provincial drug formulary. Most of the deaths were deemed unintentional. The frequency of visits to a physician and prescriptions for opioids in the month before death suggests a missed opportunity for prevention. PMID:19969578

Local infiltrative anesthesia for transaxillary subpectoral breast implants.

PubMed

Mottura, A A

1995-01-01

Breast augmentations using a transaxillary subpectoral approach are usually performed under general anesthesia. This article describes a technique that uses local infiltrative anesthesia in breast augmentation, adenomastectomies with immediate breast reconstruction, and when placing breast expansors. Large anesthetic solutions with vasoconstrictor and long-acting effects are prepared. The axila, the subpectoral space, and a surrounding area of 3 cm outside the demarcation limits are infiltrated. Minimal bleeding, long-lasting effects, and a considerable postoperative analgesic effect are some of the advantages of this procedure.

[Competitive study of the effects of naloxone and of almitrine on fentanyl analgesia in the anesthetized dog: effects on the muzzle opening reflex and blood gases].

PubMed

Dauthier, C; Gaudy, J H; Willer, J C

1980-01-01

The search for a technique making it possible to dissociate the analgesia and ventilatory depression of central analgesics led to a comparison of the effects of naloxone, a specific morphinomimetic antagonist, with almitrine, a ventilatory stimulant with a peripheral action, on muzzle opening reflex and blood gases. Five male dogs (Beagles, aged one year), anaesthetised with Alfetesine were treated separately with the two drugs used alone and after fentanyl analgesia (injection of fractionnated doses up to the threshold of apnoea). The association of the two drugs was also tested in tyhe dog after analgesia. The parameters studied were muzzle opening reflex, as an indication of analgesia, and blood gases, and were observed for 45 minutes, including 15 minutes control. 1 - The intravenous injection of 1,2 mg of naloxone had the effect of increasing the surface area of muscle potentials with a maximum of 7 per cent (p 0.001) at the 15 th minute. By contrast, no significant change in blood gases was seen. In the same dogs given fentanyl analgesia, naloxone not only reversed respiratory depression but had a stimulatory effect on MOR reaching 7 per cent (p 0.001) at the 30 th minute. 2 - The effects of 1 mg.kg-1 of almitrine were characterised by a fall in MOR for a period equal to that of the study and a minimum of 7.8 per cent (p 0.001) at the 20 th minute. At the same time, marked ventilatory stimulation was seen. PO2 rose by 22.7 per cent (p 0.02) at the 5 th minute. PCO2 fell during the 30 minutes studied with a minimum of 39.6 per cent (p 0.01) at the 20 th minute. Almitrine did not antagonise the depression of MOR caused by fentanyl but reversed the respiratory depression of the analgesic, increasing PO2 by 26 per cent (p 0.01) and decreasing PCO2 by 25.7 per cent (p 0.01). 3 - The combination of both drugs cancelled out the abolition of the reflex by fentanyl then facilitated it up to 24.7 per cent (p 0.001) in comparison with the animal not receiving any analgesic. By contrast, the ventilatory action of almitrine was not potentialised by naloxone. In view of these data, and in the absence of any emergency, the choice of naloxone as an antagonist of ventilatory depression of central analgesics should not be preferential in order to avoid the rebound effect.

Factors influencing the postoperative use of analgesics in dogs and cats by Canadian veterinarians.

PubMed

Dohoo, S E; Dohoo, I R

1996-09-01

Four hundred and seventeen Canadian veterinarians were surveyed to determine their postoperative use of analgesics in dogs and cats following 6 categories of surgeries, and their opinion toward pain perception and perceived complications associated with the postoperative use of potent opioid analgesics. Three hundred and seventeen (76%) returned the questionnaire. An analgesic user was defined as a veterinarian who administers analgesics to at least 50% of dogs or 50% of cats following abdominal surgery, excluding ovariohysterectomy. The veterinarians responding exhibited a bimodal distribution of analgesic use, with 49.5% being defined as analgesic users. These veterinarians tended to use analgesics in 100% of animals following abdominal surgery. Veterinarians defined as analgesic nonusers rarely used postoperative analgesics following any abdominal surgery. Pain perception was defined as the average of pain rankings (on a scale of 1 to 10) following abdominal surgery, or the value for dogs or cats if the veterinarian worked with only 1 of the 2 species. Maximum concern about the risks associated with the postoperative use of potent opioid agonists was defined as the highest ranking assigned to any of the 7 risks evaluated in either dogs or cats. Logistic regression analysis identified the pain perception score and the maximum concern regarding the use of potent opioid agonists in the postoperative period as the 2 factors that distinguished analgesic users from analgesic nonusers. This model correctly classified 68% of veterinarians as analgesic users or nonusers. Linear regression analysis identified gender and the presence of an animal health technologist in the practice as the 2 factors that influenced pain perception by veterinarians. Linear regression analysis identified working with an animal health technologist, graduation within the past 10 years, and attendance at continuing education as factors that influenced maximum concern about the postoperative use of opioid agonists.

Factors associated with a continuous regular analgesic use - a population-based study of more than 45,000 Danish women and men 18-45 years of age.

PubMed

Hargreave, Marie; Andersen, Tina Veje; Nielsen, Ann; Munk, Christian; Liaw, Kai-Li; Kjaer, Susanne K

2010-01-01

Widespread use of and serious adverse effects associated with use of analgesics accentuates the need to consider factors related to analgesic use. The objective of this study was to describe continuous regular analgesics use and examine factors associated with a continuous regular analgesic use. The study was based on data from two surveys and included a random sample of women and men aged 18-45 years from the general Danish population. Information on analgesics use, self-rated health, demographic and lifestyle factors was collected using a self-administered questionnaire. A total of 28,000 women and 33 000 men were invited to participate and 22,199 women (response-rate 81.4%) and 23,080 men (response-rate 71.0%), respectively, were included in the study. Data were analyzed using multivariate logistic regression. We found that 27% of the women and 18% of the men reported a regular monthly use of at least seven analgesic tablets during the last year (continuous regular analgesics use). Besides poor self-rated health we found in both sexes that increasing age, poor self-rated fitness, and smoking were related to a continuous regular analgesics use. Nulliparity, low level of education, overweight/obesity, binge drinking, and abstinence were associated with a continuous regular analgesics use for women, while underweight and marital/cohabiting status were associated with a continuous regular analgesics use only for men. Regular monthly analgesic use during the last year was generally prevalent. Besides self-rated health, several socio-demographic and lifestyle factors were associated with a continuous regular analgesic use, although with some gender differences.

Post natal use of analgesics: comparisons between conventional postnatal wards and a maternity hotel.

PubMed

Nordeng, Hedvig; Eskild, Anne; Nesheim, Britt-Ingjerd

2010-04-01

To investigate factors related to analgesic use after delivery, and especially whether rates of analgesic use were different in a midwife-managed maternity hotel as compared to conventional postnatal wards. One maternity hotel and two conventional postnatal wards at Ullevål University Hospital in Oslo, Norway. Data were obtained from hospital records for 804 women with vaginal deliveries. Postnatal analgesic use. Overall, approximately half the women used analgesics after vaginal delivery in both conventional postnatal wards and maternity hotel. The factors that were significantly associated with use of analgesics postnatally in multivariate analysis were multiparity, having a non-Western ethnicity, smoking in pregnancy, younger age, instrumental delivery, analgesic use during labour, maternal complications post partum, and duration of postnatal stay 4 days or more. The use of analgesics is determined by socio-demographic and obstetric factors rather than the organisation of the ward.

Perioperative analgesic use by Ontario veterinarians, 2012

PubMed Central

Reimann, Jessica; Dewey, Cate; Bateman, Shane W.; Kerr, Carolyn; Johnson, Ron

2017-01-01

The objectives of this study were to describe the routine use of analgesics by Ontario veterinarians for common surgeries in dogs and cats, and to compare routine use of analgesics between species and surgeries, using Chi-square analyses. In total, 239 veterinarians responded to the questionnaires; a response rate of 13.1%. Fifty-two percent to 79% of veterinarians used meloxicam for both species and all surgeries. Approximately 9% of veterinarians did not use analgesics for dog ovariohysterectomy and castration, while 16% to 22% did not use analgesics for these surgeries in cats. Veterinarians used and dispensed analgesics to dogs more often than to cats (P < 0.05). Many (60% or more) veterinarians administered analgesics pre-emptively to both dogs and cats for all surgeries. Continuing education for veterinarians needs to focus on understanding of pre-emptive analgesia, preventive analgesia, and the importance of dispensing analgesic drugs after surgery for all surgeries. PMID:28216684

Adverse Selection? A Multi-Dimensional Profile of People Dispensed Opioid Analgesics for Persistent Non-Cancer Pain

PubMed Central

Rogers, Kris D.; Kemp, Anna; McLachlan, Andrew J.; Blyth, Fiona

2013-01-01

Objectives This study investigates utilisation patterns for prescription opioid analgesics in the Australian community and how these are associated with a framework of individual-level factors related to healthcare use. Methods Self-reported demographic and health information from participants in the 45 and Up Study cohort were linked to pharmaceutical claims from 2006–2009. Participants comprised 19,816 people with ≥1 opioid analgesic dispensing in the 12-months after recruitment to the cohort and 79,882 people not dispensed opioid analgesics. All participants were aged ≥45 years, were social security pharmaceutical beneficiaries, with no history of cancer. People dispensed opioid analgesics were classified as having acute (dispensing period <90 days), episodic (≥90 days and <3 ‘authority’ prescriptions for increased quantity supply) or long-term treatment (≥90 days and ≥3 authority prescriptions). Results Of participants dispensed opioid analgesic 52% received acute treatment, 25% episodic treatment and 23% long-term treatment. People dispensed opioid analgesics long-term had an average of 14.9 opioid analgesic prescriptions/year from 2.0 doctors compared with 1.5 prescriptions from 1.1 doctors for people receiving acute treatment. People dispensed opioid analgesics reported more need-related factors such as poorer physical functioning and higher psychological distress. Long-term users were more likely to have access-related factors such as low-income and living outside major cities. After simultaneous adjustment, association with predisposing health factors and access diminished, but indicators of need such as osteoarthritis treatment, paracetamol use, and poor physical function were the strongest predictors for all opioid analgesic users. Conclusions People dispensed opioid analgesics were in poorer health, reported higher levels of distress and poorer functioning than people not receiving opioid analgesics. Varying dispensing profiles were evident among people dispensed opioid analgesics for persistent pain, with those receiving episodic and long-term treatment dispensed the strongest opioid analgesics. The findings highlight the broad range of factors associated with longer term opioid analgesics use. PMID:24312456

76 FR 58840 - Central Valley Project Improvement Act; Refuge Water Management Plans

Federal Register 2010, 2011, 2012, 2013, 2014

2011-09-22

... DEPARTMENT OF THE INTERIOR Bureau of Reclamation Central Valley Project Improvement Act; Refuge Water Management Plans AGENCY: Bureau of Reclamation, Interior. ACTION: Notice of availability. SUMMARY: To meet the requirements of the Central Valley Project Improvement Act of 1992 (CVPIA) and subsequent...

75 FR 56079 - Privacy Act of 1974; System of Records

Federal Register 2010, 2011, 2012, 2013, 2014

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Analgesics use in competitive triathletes: its relationship to doping and on predicting its usage.

PubMed

Dietz, Pavel; Dalaker, Robert; Letzel, Stephan; Ulrich, Rolf; Simon, Perikles

2016-10-01

The two major objectives of this study were (i) to assess variables that predict the use of analgesics in competitive athletes and (ii) to test whether the use of analgesics is associated with the use of doping. A questionnaire primarily addressing the use of analgesics and doping was distributed among 2,997 triathletes. Binary logistic regression analysis was performed to predict the use of analgesics. Moreover, the randomised response technique (RRT) was used to estimate the prevalence of doping in order to assess whether users of analgesics have a higher potential risk for doping than non-users. Statistical power analyses were performed to determine sample size. The bootstrap method was used to assess the statistical significance of the prevalence difference for doping between users and non-users of analgesics. Four variables from a pool of 16 variables were identified that predict the use of analgesics. These were: "version of questionnaire (English)", "gender (female)", "behaviour in case of pain (continue training)", and "hours of training per week (>12 h/week)". The 12-month prevalence estimate for the use of doping substances (overall estimate 13.0%) was significantly higher in athletes that used analgesics (20.4%) than in those athletes who did not use analgesics (12.4%). The results of this study revealed that athletes who use analgesics prior to competition may be especially prone to using doping substances. The predictors of analgesic use found in the study may be of importance to prepare education material and prevention models against the misuse of drugs in athletes.

A unique role of RGS9-2 in the striatum as a positive or negative regulator of opiate analgesia.

PubMed

Psifogeorgou, Kassi; Psigfogeorgou, Kassi; Terzi, Dimitra; Papachatzaki, Maria Martha; Varidaki, Artemis; Ferguson, Deveroux; Gold, Stephen J; Zachariou, Venetia

2011-04-13

The signaling molecule RGS9-2 is a potent modulator of G-protein-coupled receptor function in striatum. Our earlier work revealed a critical role for RGS9-2 in the actions of the μ-opioid receptor (MOR) agonist morphine. In this study, we demonstrate that RGS9-2 may act as a positive or negative modulator of MOR-mediated behavioral responses in mice depending on the agonist administered. Paralleling these findings we use coimmunoprecipitation assays to show that the signaling complexes formed between RGS9-2 and Gα subunits in striatum are determined by the MOR agonist, and we identify RGS9-2 containing complexes associated with analgesic tolerance. In striatum, MOR activation promotes the formation of complexes between RGS9-2 and several Gα subunits, but morphine uniquely promotes an association between RGS9-2 and Gαi3. In contrast, RGS9-2/Gαq complexes assemble after acute application of several MOR agonists but not after morphine application. Repeated morphine administration leads to the formation of distinct complexes, which contain RGS9-2, Gβ5, and Gαq. Finally, we use simple pharmacological manipulations to disrupt RGS9-2 complexes formed during repeated MOR activation to delay the development of analgesic tolerance to morphine. Our data provide a better understanding of the brain-region-specific signaling events associated with opiate analgesia and tolerance and point to pharmacological approaches that can be readily tested for improving chronic analgesic responsiveness.

Activation of alpha2 adrenergic receptors suppresses fear conditioning: expression of c-Fos and phosphorylated CREB in mouse amygdala.

PubMed

Davies, M Frances; Tsui, Janet; Flannery, Judy A; Li, Xiangqi; DeLorey, Timothy M; Hoffman, Brian B

2004-02-01

alpha(2) adrenergic agonists such as dexmedetomidine generally suppress noradrenergic transmission and have sedative, analgesic, and antihypertensive properties. Considering the importance of the neurotransmitter norepinephrine in forming memories for fearful events, we have investigated the acute and chronic effects of dexmedetomidine on discrete cue and contextual fear conditioning in mice. When administered before training, dexmedetomidine (10-20 microg/kg, i.p.) selectively suppressed discrete cue fear conditioning without affecting contextual memory. This behavioral change was associated with a decrease in memory retrieval-induced expression of c-Fos and P-CREB in the lateral, basolateral, and central nuclei of the amygdala. Dexmedetomidine's action on discrete cue memory did not occur in alpha(2A) adrenoceptor knockout (KO) mice. When dexmedetomidine was administered after training, it suppressed contextual memory, an effect that did not occur in alpha(2A) adrenoceptor KO mice. We conclude that dexmedetomidine, acting at alpha(2A) adrenoceptors, must be present during the encoding process to decrease discrete cue fear memory; however, its ability to suppress contextual memory is likely the result of blocking the consolidation process. The ability of alpha(2) agonists to suppress fear memory may be a valuable property clinically in order to suppress the formation of memories during stressful situations.

Tramadol, an Opioid Receptor Agonist: An Inhibitor of Growth, Morphogenesis, and Biofilm Formation in the Human Pathogen, Candida albicans.

PubMed

Kathwate, Gunderao Hanumantrao; Karuppayil, S Mohan

2016-12-01

Tramadol is a synthetic, centrally acting low-affinity agonist of μ-opioid receptors in humans. It is used as an analgesic and is shown to have local anesthetic action. In this study, we have tried to explore its anti-Candida potential. Minimum inhibitory concentration (MIC50) and minimum fungicidal concentration (MFC) values were established. MIC50 ranged from 2 to 4 mg/mL, whereas MFC was recorded at 8 mg/mL. Also, the effect of tramadol on germ tube formation, adhesion, and biofilms in Candida albicans was studied. Tramadol impaired in vitro growth of C. albicans. A time-dependent killing assay showed that it kills C. albicans within 24 h of exposure. Tramadol has strong activity against Candida virulence factors such as yeast-to-hyphal form switching and adhesion. C. albicans biofilms, which are notoriously resistant to many antifungals, were sensitive to tramadol. At 8 mg/mL of tramadol, 82% of early stage biofilms and 52.88% of matured biofilms were inhibited. Although our results show that the antifungal effect of tramadol requires concentrations that can be achieved only locally, they may provide potential candidates for development of novel antifungal drugs.

Efficacy of an alpha1 blocker in expulsive therapy of lower ureteral stones.

PubMed

Wang, Chung-Jing; Huang, Shi-Wei; Chang, Chien-Hsing

2008-01-01

To evaluate the clinical role of an alpha(1a-1d)-specific blocker in the medical expulsive therapy of symptomatic lower ureteral stones. This prospective study was carried out from May 2005 to December 2006 and involved 95 patients. All patients, who had symptomatic lower ureteral stones <10 mm diameter, were enrolled in this prospective study, and were randomly divided into three groups using the statistical software programs Plus 1.0 and Plus 2.10. Group 1 (32 patients) received tamsulosin (0.4 mg daily), group 2 (32 patients) received terazosin (2 mg daily), group 3 (31 patients) acted as controls. All patients were diagnosed with x-rays of the kidneys, ureters, and bladder, urinary ultrasonography, and intravenous urography. All patients received the same analgesic regimen and sublingual buprenorphine on demand. The number of colic episodes, lower urinary tract symptoms, analgesic dosages, and the number of days required for spontaneous passage of the stones were all recorded in a diary. Expulsion was observed in 26 of 32 patients in group 1 (81%), 25 of 32 in group 2 (78%), and 17 of 31 in group 3 (55%). The average expulsion time for groups 1, 2, and 3 were 6.3, 6.3, and 10.1 days, respectively. Mean analgesic dosage per patient in groups 1, 2, and 3 were 231, 256, and 347 mg, respectively. A statistically significant difference was observed between groups 1 and 2 with respect to group 3 for all three of these parameters. Adverse effects were also seen in 5 of 32 patients in group 2 (16%), a statistically significant difference with regard to groups 1 and 3. Medical treatment with alpha(1a-1d)-blocker proved to be safe and effective as demonstrated by the increased stone expulsion rate and reduced expulsion time, as well as the need for analgesics.

76 FR 18581 - Correction; Central Valley Project Improvement Act, Standard Criteria for Agricultural and Urban...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-04-04

... DEPARTMENT OF THE INTERIOR Bureau of Reclamation Correction; Central Valley Project Improvement Act, Standard Criteria for Agricultural and Urban Water Management Plans AGENCY: Bureau of Reclamation... notice in the Federal Register at 76 FR 16818 on the Central Valley Project Improvement Act Standard...

77 FR 56628 - Privacy Act of 1974; System of Records

Federal Register 2010, 2011, 2012, 2013, 2014

2012-09-13

... to the National Security Agency/Central Security Service, Freedom of Information Act/Privacy Act...; System of Records AGENCY: National Security Agency/Central Security Service, DoD. ACTION: Notice to add a system of records. SUMMARY: The National Security Agency/Central Security Service proposes to add a new...

Kinetics of acetaminophen degradation by Fenton oxidation in a fluidized-bed reactor.

PubMed

de Luna, Mark Daniel G; Briones, Rowena M; Su, Chia-Chi; Lu, Ming-Chun

2013-01-01

Acetaminophen (ACT), an analgesic and antipyretic substance, is one of the most commonly detected pharmaceutical compound in surface waters and wastewaters. In this study, fluidized-bed Fenton (FB-Fenton) was used to decompose ACT into its final degradation products. The 1.45-L cylindrical glass reactor had inlet, outlet and recirculating sections. SiO(2) carrier particles were supported by glass beads with 2-4 mm in diameter. ACT concentration was determined by high performance liquid chromatography (HPLC). During the first 40 min of reaction, a fast initial ACT removal was observed and the "two-stage" ACT degradation conformed to a pseudo reaction kinetics. The effects of ferrous ion dosage and [Fe(2+)]/[H(2)O(2)] (FH ratio) were integrated into the derived pseudo second-order kinetic model. A reaction pathway was proposed based on the intermediates detected through SPME/GC-MS. The aromatic intermediates identified were hydroquinone, benzaldehydes and benzoic acids while the non-aromatic substances include alcohols, ketones, aldehydes and carboxylic acids. Rapid initial ACT degradation rate can be accomplished by high initial ferrous ion concentration and/or low FH ratio. Copyright © 2012 Elsevier Ltd. All rights reserved.

The anti-nociceptive potential of tilmicosin against chemical-induced but not thermal-induced pain in mice.

PubMed

El-Mahmoudy, A; Gheith, I

2016-03-01

The aim of the present study was to assess the analgesic activity of the macrolide antibiotic tilmicosin at dose levels of 20 and 40 mg/kg of body weight, subcutaneously, against chemical- and thermal-induced acute pains, using acetic acid-induced writhing, formalin-induced pain, hot-plate, and tail-flick models in mice. Tilmicosin showed a dose-dependent significant decrease in the number of writhes in the acetic acid-induced writhing test and significant decrease in hind paw-licking time in the late phase of the formalin test. However, it did not cause any significant changes in the reaction times to heat stimuli in the hot-plate and tail-flick models. In chemically-induced pains, both dose levels of tilmicosin showed significant effects compared to those of the corresponding standard peripheral analgesic, acetylsalicylic acid (200 mg/kg of body weight, subcutaneously) being 26.37±2.88 and 43.64±3.85% vs. 73.35±1.44% in acetic acid test; and 19.23±3.85 and 44.90±1.80% vs. 73.63±2.39% in the late phase of formalin test, respectively. These results may indicate that tilmicosin possesses a significant peripheral but not central analgesic potential that may be beneficial in symptomatic relief of pain when it is used in therapy, in addition to its well-established antibacterial effect. © The Author(s) 2015.

Potent analgesic effects of anticonvulsants on peripheral thermal nociception in rats

PubMed Central

Todorovic, Slobodan M; Rastogi, A J; Jevtovic-Todorovic, Vesna

2003-01-01

Anticonvulsant agents are commonly used to treat neuropathic pain conditions because of their effects on voltage- and ligand-gated channels in central pain pathways. However, their interaction with ion channels in peripheral pain pathways is poorly understood. Therefore, we studied the potential analgesic effects of commonly used anticonvulsant agents in peripheral nociception. We injected anticonvulsants intradermally into peripheral receptive fields of sensory neurons in the hindpaws of adult rats, and studied pain perception using the model of acute thermal nociception. Commonly used anticonvulsants such as voltage-gated Na+ channel blockers, phenytoin and carbamazepine, and voltage-gated Ca2+ channel blockers, gabapentin and ethosuximide, induced dose-dependent analgesia in the injected paw, with ED50 values of 0.30, 0.32 and 8, 410 μg per 100 μl, respectively. Thermal nociceptive responses were not affected in the contralateral, noninjected paws, indicating a lack of systemic effects with doses of anticonvulsants that elicited local analgesia. Hill slope coefficients for the tested anticonvulsants indicate that the dose–response curve was less steep for gabapentin than for phenytoin, carbamazepine and ethosuximide. Our data strongly suggest that cellular targets like voltage-gated Na+ and Ca2+ channels, similar to those that mediate the effects of anticonvulsant agents in the CNS, may exist in the peripheral nerve endings of rat sensory neurons. Thus, peripherally applied anticonvulsants that block voltage-gated Na+ and Ca2+ channels may be useful analgesics. PMID:12970103

Analgesic efficacy of cerebral and peripheral electrical stimulation in chronic nonspecific low back pain: a randomized, double-blind, factorial clinical trial.

PubMed

Hazime, Fuad Ahmad; de Freitas, Diego Galace; Monteiro, Renan Lima; Maretto, Rafaela Lasso; Carvalho, Nilza Aparecida de Almeida; Hasue, Renata Hydee; João, Silvia Maria Amado

2015-01-31

Chronic non-specific low back pain is a major socioeconomic public health issue worldwide and, despite the volume of research in the area, it is still a difficult-to-treat condition. The conservative analgesic therapy usually comprises a variety of pharmacological and non-pharmacological strategies, such as transcutaneous electrical nerve stimulation. The neuromatrix pain model and the new findings on the process of chronicity of pain point to a higher effectiveness of treatments that address central rather than peripheral structures. The transcranial direct current stimulation is a noninvasive technique of neuromodulation that has made recent advances in the treatment of chronic pain. The simultaneous combination of these two electrostimulation techniques (cerebral and peripheral) can provide an analgesic effect superior to isolated interventions. However, all the evidence on the analgesic efficacy of these techniques, alone or combined, is still fragmented. This is a protocol for a randomized clinical trial to investigate whether cerebral electrical stimulation combined with peripheral electrical stimulation is more effective in relieving pain than the isolated application of electrical stimulations in patients with chronic nonspecific low back pain. Ninety-two patients will be randomized into four groups to receive transcranial direct current stimulation (real/sham) + transcutaneous electrical nerve stimulation (real/sham) for 12 sessions over a period of four weeks. The primary clinical outcome (pain intensity) and the secondary ones (sensory and affective aspects of pain, physical functioning and global perceived effect) will be recorded before treatment, after four weeks, in Month 3 and in Month 6 after randomization. Confounding factors such as anxiety and depression, the patient's satisfaction with treatment and adverse effects will also be listed. Data will be collected by an examiner unaware of (blind to) the treatment allocation. The results of this study may assist in clinical decision-making about the combined use of cerebral and peripheral electrical stimulation for pain relief in patients with chronic low back pain. NCT01896453.

Metamizole-Associated Adverse Events: A Systematic Review and Meta-Analysis

PubMed Central

Fässler, Margrit; Blozik, Eva; Linde, Klaus; Jüni, Peter; Reichenbach, Stephan; Scherer, Martin

2015-01-01

Background Metamizole is used to treat pain in many parts of the world. Information on the safety profile of metamizole is scarce; no conclusive summary of the literature exists. Objective To determine whether metamizole is clinically safe compared to placebo and other analgesics. Methods We searched CENTRAL, MEDLINE, EMBASE, CINAHL, and several clinical trial registries. We screened the reference lists of included trials and previous systematic reviews. We included randomized controlled trials that compared the effects of metamizole, administered to adults in any form and for any indication, to other analgesics or to placebo. Two authors extracted data regarding trial design and size, indications for pain medication, patient characteristics, treatment regimens, and methodological characteristics. Adverse events (AEs), serious adverse events (SAEs), and dropouts were assessed. We conducted separate meta-analyses for each metamizole comparator, using standard inverse-variance random effects meta-analysis to pool the estimates across trials, reported as risk ratios (RRs). We calculated the DerSimonian and Laird variance estimate T2 to measure heterogeneity between trials. The pre-specified primary end point was any AE during the trial period. Results Of the 696 potentially eligible trials, 79 trials including almost 4000 patients with short-term metamizole use of less than two weeks met our inclusion criteria. Fewer AEs were reported for metamizole compared to opioids, RR = 0.79 (confidence interval 0.79 to 0.96). We found no differences between metamizole and placebo, paracetamol and NSAIDs. Only a few SAEs were reported, with no difference between metamizole and other analgesics. No agranulocytosis or deaths were reported. Our results were limited by the mediocre overall quality of the reports. Conclusion For short-term use in the hospital setting, metamizole seems to be a safe choice when compared to other widely used analgesics. High-quality, adequately sized trials assessing the intermediate- and long-term safety of metamizole are needed. PMID:25875821

Gene transfer of a naked plasmid (pUDK-HGF) encoding human hepatocyte growth factor attenuates skin/muscle incision and retraction-induced chronic post-surgical pain in rats.

PubMed

Hu, C; Lu, Y; Chen, X; Wu, Z; Zhang, Q

2018-05-01

Chronic post-surgical pain (CPSP) remains a major clinical problem and is often refractory to current treatments. New analgesic medications and strategies for pain relief are needed. Hepatocyte growth factor (HGF) is known to be a multi-functional growth factor and regulates various biological activities. We investigated the analgesic effect and underlying mechanism of plasmid pUDK-HGF encoding human HGF gene on CPSP induced by skin/muscle incision and retraction (SMIR) in rats. The possible changes of inflammatory factors, glial cell activation and pain sensitivity after pUDK-HGF administration were investigated by ELISA, western blot and Von Frey tests, respectively. In behavioural assays, we found that a single intramuscular or intrathecal injection of pUDK-HGF significantly attenuated mechanical hypersensitivity to von Frey stimulation of plantar ipsilateral hind paw after SMIR. Intramuscular injection of pUDK-HGF promoted blood flow and proliferation of satellite cells and inhibited inflammatory cells recruitment, collagen accumulation and expression of pronociceptive factors. Intrathecal injection of pUDK-HGF inhibited activation of spinal glial cells and production of inflammatory mediators induced by SMIR. pUDK-HGF has a strong analgesic potency and efficacy in CPSP induced by SMIR in rats. This study highlights a new strategy for the treatment of CPSP. The CPSP occurs following various surgical procedures and remains a major clinical problem due to the lack of study on the mechanisms of CPSP. Our findings provide the first evidence that pUDK-HGF attenuates SMIR-induced pain behaviuors through peripheral or central mechanisms. The peripheral analgesic effect of pUDK-HGF is associated with promoting tissue repair and inhibiting inflammatory response; furthermore, pUDK-HGF inhibits activation of spinal glial cells and overexpression of inflammatory mediators in spinal cord. Therefore, naked pUDK-HGF may be a potential therapeutic strategy for treatment of CPSP in clinic. © 2018 European Pain Federation - EFIC®.

Risk Evaluation and Mitigation Strategies (REMS) for extended-release and long-acting opioid analgesics: considerations for palliative care practice.

PubMed

Gudin, Jeffrey

2012-06-01

Prescription opioid analgesics are an essential treatment option for patients with moderate to severe pain. Over the last decade the increased medical use of these agents has contributed to a public health epidemic of abuse, addiction, and overdose-related deaths. These medications remain mainstays in both primary care and pain management practices. As palliative services are incorporated at earlier stages of the disease process and the number of individuals with chronic illness increases, palliative care specialists may encounter an increasing number of patients with opioid abuse and addiction problems. Extended-release (ER) and long-acting (LA) opioid formulations are administered to patients with moderate to severe chronic pain requiring around-the-clock analgesia. Given the large quantity of active ingredient contained within some dosage strengths, this medication class is associated with serious risks when taken improperly. In response to growing reports of abuse and overdose deaths, the US Food and Drug Administration (FDA) announced the need for a risk mitigation strategy for the entire class of medication. The class-wide Risk Evaluation and Mitigation Strategy (REMS) for ER/LA opioids will emphasize prescriber training and patient education to ensure that the therapeutic benefits outweigh the risks of addiction, unintentional overdose, and death. As primary care, pain management, and palliative care clinicians often encounter patients who require ER/LA opioids, an understanding of the suggested requirements and potential impact of this regulation is essential.

Prescribing pattern of analgesics in orthopedic in-patient department at tertiary care hospital in Guwahati, Assam, Northeast India

PubMed Central

Choudhury, Dwijen Kumar; Bezbaruah, Babul Kumar

2016-01-01

Objectives: The aim of this study is to evaluate the prescribing pattern of analgesics and analyze the rational use of analgesic in orthopedic in-patient department of tertiary care teaching hospital, Guwahati, Assam. Subjects and Methods: An observational and cross-sectional study was carried out for 1 month from April to May 2014. Collected data included age, sex, diagnosis and line of management during the study. The generic name and the average cost of treatment per patient were evaluated using Indian Drug Review, 2014. The prescribed drugs were assessed with respective National Model List of Essential Medicines (NLEM), 2011 and the rationality of prescriptions was determined using the World Health Organization indicators of drug utilization. The patients’ details were recorded in a predeigned data collection form and results were analyzed by descriptive statistics. Results: Out of 200 patients, 123 were male and 77 were female. The average number of analgesic per prescription was 1.46. In this study, 55.5% of patients had received single analgesic. Diclofenac was the most commonly prescribed analgesic (43.49%). During hospitalization, majority of the patients have received parenteral preparation. Gastroprotective agents and antimicrobials were frequently prescribed along with analgesics. Out of 292 analgesics prescribed, 183 (62.67%) were from the NLEM, India. Furthermore, 176 (57.19%) analgesics were prescribed by generic name. The average cost of treatment per patient was 2151.72 INR. Utilization of analgesic in terms of defined daily dose/100 bed-days was 104.01. Conclusion: The percentages of analgesics prescribing from NLEM and the use of analgesic by generic name were found satisfactory. Regular educational interventions to improve prescribing practices among physicians at different levels may further promote rational prescribing. PMID:27756947

Per-capita consumption of analgesics: a nine-country survey over 20 years.

PubMed

Diener, H-C; Schneider, R; Aicher, B

2008-08-01

There are no reliable data at present on use of analgesics in various countries. We compared per-capita consumption in nine different countries during the period 1986-2005. The per-capita consumption was calculated on the basis of the sales figures of distributors to pharmacies and direct purchases by pharmaceutical companies in a sample of 1,000 pharmacies. The countries studied were: Australia, Austria, Belgium, Canada, France, Germany, Sweden, Switzerland, and the USA. In international comparison Austria, Switzerland, and Germany showed the lowest per-capita consumption of analgesics (approx. 40-50 Standard Units (SU) per capita per year), while in Sweden and France consumption was three times as high. The correlation analysis over the various countries and time points confirmed a significant correlation between use of single analgesics and overall use of analgesics. In Germany, where an allegedly particularly high and constantly rising analgesic use has been discussed controversially (Meiner, Pharm Ind 49:1247-1251, 1987), per-capita consumption of analgesics from 1980 to 2005 remained practically unchanged at approx. 50 SU per capita per year. The prevalence of conditions inducing analgesic use shows appropriate analgesics use on an overall population level.

Physicochemical and Pharmacological Characterization of Permanently Charged Opioids.

PubMed

Mazak, Karoly; Noszal, Bela; Hosztafi, Sandor

2017-01-01

The main aim of synthesizing permanently charged opioids is to ensure that they do not enter the central nervous system. Such drugs can provide analgesic activity with reduced sedation and other side effects on the central nervous system. We undertook a search of bibliographic databases for peer-reviewed research literature and also summarized our published results in this field. The present review focuses on the characterization of permanently charged opioids by various physicochemical methods, and in vitro as well as in vivo tests. The basicity and lipophilicity of opioid alkaloids are discussed at the microscopic, speciesspecific level. Glucuronide conjugates of opioids are also reviewed. Whereas the primary metabolite morphine-3-glucuronide does not bind to opioid receptors with high affinity, morphine-6-glucuronide is a potent analgesic, at least, partly due to its unexpectedly high lipophilicity. We discuss the quaternary ammonium opioid derivatives of a permanent positive charge, detailing their antinociceptive activity and effects on gastrointestinal motility in various in vivo animal tests and in vitro studies. Compounds with antagonistic activity are also reviewed. The last part of our study concentrates on sulfate conjugates of morphine derivatives that display unique pharmacological properties because they carry a negative charge at any pH value in the human body. In conclusion, the findings of this review confirm the importance of permanently charged opioids in the investigated fields of pharmacology. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Design and Synthesis of Mannich bases as Benzimidazole Derivatives as Analgesic Agents.

PubMed

Datar, Prasanna A; Limaye, Saleel A

2015-01-01

Mannich bases were selected for 2D QSAR study to derive meaningful relationship between the structural features and analgesic activity. Using the knowledge of important features a novel series was designed to obtain improved analgesic activity. A series of novel Mannich bases 1-(N-substituted amino)methyl]-2-substituted benzimidazole derivatives were synthesized and were screened for analgesic activity. Some of these compounds showed promising analgesic activity when compared with the standard drug diclofenac sodium.

Bottlenecks in the development of topical analgesics: molecule, formulation, dose-finding, and phase III design.

PubMed

Keppel Hesselink, Jan M; Kopsky, David J; Stahl, Stephen M

2017-01-01

Topical analgesics can be defined as topical formulations containing analgesics or co-analgesics. Since 2000, interest in such formulations has been on the rise. There are, however, four critical issues in the research and development phases of topical analgesics: 1) The selection of the active pharmaceutical ingredient. Analgesics and co-analgesics differ greatly in their mechanism of action, and it is required to find the most optimal fit between such mechanisms of action and the pathogenesis of the targeted (neuropathic) pain. 2) Issues concerning the optimized formulation. For relevant clinical efficacy, specific characteristics for the selected vehicle (eg, cream base or gel base) are required, depending on the physicochemical characteristics of the active pharmaceutical ingredient(s) to be delivered. 3) Well-designed phase II dose-finding studies are required, and, unfortunately, such trials are missing. In fact, we will demonstrate that underdosing is one of the major hurdles to detect meaningful and statistically relevant clinical effects of topical analgesics. 4) Selection of clinical end points and innovatively designed phase III trials. End point selection can make or break a trial. For instance, to include numbness together with tingling as a composite end point for neuropathic pain seems stretching the therapeutic impact of an analgesic too far. Given the fast onset of action of topical analgesics (usually within 30 minutes), enrichment designs might enhance the chances for success, as the placebo response might decrease. Topical analgesics may become promising inroads for the treatment of neuropathic pain, once sufficient attention is given to these four key aspects.

Comparison of tissue distribution, phrenic nerve involvement, and epidural spread in standard- vs low-volume ultrasound-guided interscalene plexus block using contrast magnetic resonance imaging: a randomized, controlled trial.

PubMed

Stundner, O; Meissnitzer, M; Brummett, C M; Moser, S; Forstner, R; Koköfer, A; Danninger, T; Gerner, P; Kirchmair, L; Fritsch, G

2016-03-01

Ultrasound guidance allows for the use of much lower volumes of local anaesthetics for nerve blocks, which may be associated with less aberrant spread and fewer complications. This randomized, controlled study used contrast magnetic resonance imaging to view the differential-volume local anaesthetic distribution, and compared analgesic efficacy and respiratory impairment. Thirty patients undergoing shoulder surgery were randomized to receive ultrasound-guided interscalene block by a single, blinded operator with injection of ropivacaine 0.75% (either 20 or 5 ml) plus the contrast dye gadopentetate dimeglumine, followed by magnetic resonance imaging. The primary outcome was epidural spread. Secondary outcomes were central non-epidural spread, contralateral epidural spread, spread to the phrenic nerve, spirometry, ultrasound investigation of the diaphragm, block duration, pain scores during the first 24 h, time to first analgesic consumption, and total analgesic consumption. All blocks provided fast onset and adequate intra- and postoperative analgesia, with no significant differences in pain scores at any time point. Epidural spread occurred in two subjects of each group (13.3%); however, spread to the intervertebral foramen and phrenic nerve and extensive i.m. local anaesthetic deposition were significantly more frequent in the 20 ml group. Diaphragmatic paralysis occurred twice as frequently (n=8 vs 4), and changes from baseline peak respiratory flow rate were larger [Δ=-2.66 (1.99 sd) vs -1.69 (2.0 sd) l min(-1)] in the 20 ml group. This study demonstrates that interscalene block is associated with epidural spread irrespective of injection volume; however, less central (foraminal) and aberrant spread after low-volume injection may be associated with a more favourable risk profile. This study was registered with the European Medicines Agency (Eudra-CT number 2013-004219-36) and with the US National Institutes' of Health registry and results base, clinicaltrials.gov (identifier NCT02175069). © The Author 2016. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Multimodal pediatric pain management (part 2).

PubMed

Friedrichsdorf, Stefan J

2017-05-01

Dr Stefan Friedrichsdorf speaks to Commissioning Editor Jade Parker: Stefan Friedrichsdorf, MD, is medical director of the Department of Pain Medicine, Palliative Care and Integrative Medicine at Children's Hospitals and Clinics of Minnesota in Minneapolis/St Paul, MN, USA, home to one of the largest and most comprehensive programs of its kind in the country. The pain and palliative care program is devoted to control acute, chronic/complex and procedural pain for inpatients and outpatients in close collaboration with all pediatric subspecialties at Children's Minnesota. The team also provides holistic, interdisciplinary care for children and teens with life limiting or terminal diseases and their families. Integrative medicine provides and teaches integrative, nonpharmacological therapies (such as massage, acupuncture/acupressure, biofeedback, aromatherapy and self-hypnosis) to provide care that promotes optimal health and supports the highest level of functioning in all individual children's activities. In this second part of the interview they discuss multimodal (opioid-sparing) analgesia for hospitalized children in pain and how analgesics and adjuvant medications, interventions, rehabilitation, psychological and integrative therapies act synergistically for more effective pediatric pain control with fewer side effects than a single analgesic or modality.

Some patients don't need analgesics after surgery.

PubMed Central

McQuay, H J; Bullingham, R E; Moore, R A; Evans, P J; Lloyd, J W

1982-01-01

Postoperative analgesic requirements of 410 patients undergoing elective orthopaedic limb surgery were studied. Premedication and anaesthetic were standardized with no narcotic. Twenty-three patients required no analgesic at all during their hospital stay. The importance of acknowledging the existence of this group of patients is discussed. The distribution of time to first analgesic requirement for the other patients was obtained. The importance of knowing the distribution for particular operative procedures and the effect of analgesic interventions such as premedication is discussed. PMID:7120254

Role of Dentists in Prescribing Opioid Analgesics and Antibiotics: An Overview.

PubMed

Dana, Ralph; Azarpazhooh, Amir; Laghapour, Nima; Suda, Katie J; Okunseri, Christopher

2018-04-01

Opioid analgesics and antibiotics prescribed by dentists is a useful and cost-effective measure when prescribed appropriately. Common dental conditions are best managed by extracting the offending tooth, restoring the tooth with an appropriate filling material, performing root canal therapy, and/or fabricating a prosthesis for the edentulous space. Unnecessary prescription of opioid analgesics and antibiotics to treat dental pain and bacterial infection is a growing public health concern. This article highlights the state of the literature on opioid analgesic and antibiotic prescribing practices in dentistry, the impact of opioid analgesic overdose, and prevention strategies to reduce opioid analgesics and antibiotic overprescription. Copyright © 2017 Elsevier Inc. All rights reserved.

Efficacy of Common Analgesics for Postsurgical Pain in Rats

PubMed Central

Waite, Megan E; Tomkovich, Ashleigh; Quinn, Tammie L; Schumann, Alan P; Dewberry, L Savannah; Totsch, Stacie K; Sorge, Robert E

2015-01-01

Each year, millions of rats undergo surgery for research purposes and receive analgesics to alleviate pain. We sought to evaluate the efficacy of common analgesics in tests of hot-plate nociception and postsurgical pain by using the Rat Grimace Scale. Rats received a single dose of one of several drug–dose combinations and were tested by using the hot-plate test (acute pain) or after laparotomy (with either prophylactic or intraoperative analgesic). The efficacy of analgesics for hot-plate pain was generally not predictive of efficacy for surgical pain. Carprofen and ketoprofen were rarely effective in any of the conditions tested. With the exception of the opioid buprenorphine, several of the drugs we tested required higher-than-recommended doses to alleviate pain. Taken together, our data suggest that current analgesic use frequently is insufficient, and many rats may experience significant postsurgical pain even when analgesics are used in commonly recommended doses. PMID:26224443

Purification and function of two analgesic and anti-inflammatory peptides from coelomic fluid of the earthworm, Eisenia foetida.

PubMed

Li, Chunlong; Chen, Mengrou; Li, Xiaojie; Yang, Meifeng; Wang, Ying; Yang, Xinwang

2017-03-01

The potential application of anti-inflammatory and analgesic compounds in medication and therapeutic care have become of increasing interest. We purified and characterized two novel analgesic and anti-inflammatory peptides, VQ-5 and AQ-5, from the coelomic fluid of the earthworm (Eisenia foetida). Their primary structures were determined as VSSVQ and AMADQ, respectively. Both peptides, especially AQ-5, exhibited analgesic activity in mouse models of persistent neuropathic pain and inflammation. AQ-5 also inhibited tumor necrosis factor alpha and cyclooxygenase-2 production. The mitogen-activated protein kinase signaling pathway, which is involved in analgesic and anti-inflammatory functions, was inhibited by AQ-5. Thus, the analgesic and anti-inflammatory effects of these peptides, especially AQ-5, demonstrated their potential as candidates for the development of novel analgesic medicines. Copyright © 2017 Elsevier Inc. All rights reserved.

Reduced suppression of CO2-induced ventilatory stimulation by endomorphins relative to morphine.

PubMed

Czapla, Marc A; Zadina, James E

2005-10-19

Opioids are among the most effective analgesics, but a major limitation for their therapeutic usefulness is their induction of respiratory depression. Endomorphin-1 (EM1), in contrast to several other mu opioids, exhibits a threshold for respiratory depression that is well above its threshold for analgesia. Its effect on sensitivity to CO(2), however, remains unknown. Minute ventilation (V(E)) in 2, 4, and 6% CO(2) was measured before and after systemic administration of EM1, endomorphin-2 (EM2), DAMGO, and morphine in the conscious rat. EM1 and EM2 attenuated the hypercapnic ventilatory response (HCVR) only in high doses, while DAMGO and morphine diminished the HCVR in much lower doses. The ventilatory effects of high doses of all 4 agonists were blocked by the mu-opioid antagonist naloxone (0.4 mg/kg i.v.), but not by the peripherally restricted mu-opioid antagonist, methyl-naloxone (0.4 mg/kg i.v.). It was concluded that the endomorphins attenuated the HCVR only in large doses, well beyond the analgesic threshold, and did so through a centrally mediated mu-opioid mechanism.

A Randomized, Placebo-Controlled, Crossover Trial of Cannabis Cigarettes in Neuropathic Pain

PubMed Central

Wilsey, Barth; Marcotte, Thomas; Tsodikov, Alexander; Millman, Jeanna; Bentley, Heather; Gouaux, Ben; Fishman, Scott

2016-01-01

The Food and Drug Administration (FDA), Substance Abuse and Mental Health Services Administration (SAMHSA), and the National Institute for Drug Abuse (NIDA) report that no sound scientific studies support the medicinal use of cannabis. Despite this lack of scientific validation, many patients routinely use “medical marijuana,” and in many cases this use is for pain related to nerve injury. We conducted a double-blinded, placebo-controlled, crossover study evaluating the analgesic efficacy of smoking cannabis for neuropathic pain. Thirty-eight patients with central and peripheral neuropathic pain underwent a standardized procedure for smoking either high-dose (7%), low-dose (3.5%), or placebo cannabis. In addition to the primary outcome of pain intensity, secondary outcome measures included evoked pain using heat-pain threshold, sensitivity to light touch, psychoactive side effects, and neuropsychological performance. A mixed linear model demonstrated an analgesic response to smoking cannabis. No effect on evoked pain was seen. Psychoactive effects were minimal and well-tolerated, with some acute cognitive effects, particularly with memory, at higher doses. PMID:18403272

Ibuprofen alters human testicular physiology to produce a state of compensated hypogonadism.

PubMed

Kristensen, David Møbjerg; Desdoits-Lethimonier, Christèle; Mackey, Abigail L; Dalgaard, Marlene Danner; De Masi, Federico; Munkbøl, Cecilie Hurup; Styrishave, Bjarne; Antignac, Jean-Philippe; Le Bizec, Bruno; Platel, Christian; Hay-Schmidt, Anders; Jensen, Tina Kold; Lesné, Laurianne; Mazaud-Guittot, Séverine; Kristiansen, Karsten; Brunak, Søren; Kjaer, Michael; Juul, Anders; Jégou, Bernard

2018-01-23

Concern has been raised over increased male reproductive disorders in the Western world, and the disruption of male endocrinology has been suggested to play a central role. Several studies have shown that mild analgesics exposure during fetal life is associated with antiandrogenic effects and congenital malformations, but the effects on the adult man remain largely unknown. Through a clinical trial with young men exposed to ibuprofen, we show that the analgesic resulted in the clinical condition named "compensated hypogonadism," a condition prevalent among elderly men and associated with reproductive and physical disorders. In the men, luteinizing hormone (LH) and ibuprofen plasma levels were positively correlated, and the testosterone/LH ratio decreased. Using adult testis explants exposed or not exposed to ibuprofen, we demonstrate that the endocrine capabilities from testicular Leydig and Sertoli cells, including testosterone production, were suppressed through transcriptional repression. This effect was also observed in a human steroidogenic cell line. Our data demonstrate that ibuprofen alters the endocrine system via selective transcriptional repression in the human testes, thereby inducing compensated hypogonadism. Copyright © 2018 the Author(s). Published by PNAS.

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.

A critical evaluation of validity and utility of translational imaging in pain and analgesia: Utilizing functional imaging to enhance the process.

PubMed

Upadhyay, Jaymin; Geber, Christian; Hargreaves, Richard; Birklein, Frank; Borsook, David

2018-01-01

Assessing clinical pain and metrics related to function or quality of life predominantly relies on patient reported subjective measures. These outcome measures are generally not applicable to the preclinical setting where early signs pointing to analgesic value of a therapy are sought, thus introducing difficulties in animal to human translation in pain research. Evaluating brain function in patients and respective animal model(s) has the potential to characterize mechanisms associated with pain or pain-related phenotypes and thereby provide a means of laboratory to clinic translation. This review summarizes the progress made towards understanding of brain function in clinical and preclinical pain states elucidated using an imaging approach as well as the current level of validity of translational pain imaging. We hypothesize that neuroimaging can describe the central representation of pain or pain phenotypes and yields a basis for the development and selection of clinically relevant animal assays. This approach may increase the probability of finding meaningful new analgesics that can help satisfy the significant unmet medical needs of patients. Copyright © 2017 Elsevier Ltd. All rights reserved.

Pharmacodynamic and pharmacokinetic effects of the intravenous CB1 receptor agonist Org 26828 in healthy male volunteers.

PubMed

Zuurman, Lineke; Passier, Paul C C M; de Kam, Marieke L; Kleijn, Huub J; Cohen, Adam F; van Gerven, Joop M A

2010-11-01

An ideal drug for outpatient treatments under conscious sedation would have both sedative and analgesic properties. CB1/CB2 agonists are expected to have sedative, amnestic, analgesic and anti-emetic properties. The main objective of this first study in humans was to assess the sedative properties of intravenous Org 26828. In addition, pharmacokinetics, amnestic properties, postural stability, and behavioural and cardiovascular effects were studied. Midazolam intravenous 0.1 mg/kg and placebo were used as controls. The pharmacokinetic parameters (Cmax and AUC0-inf) of the main metabolite Org 26761 were proportional to dose. No effects were observed after doses up to 0.3 μg/kg of Org 26828. Dose-related effects were observed at higher doses. Although subjects reported subjective sedation after administration of Org 26828 at 3 and 6 μg/kg, the observed sedation was considerably less than after midazolam. Doses higher than the maximum tolerated dose of 1 μg/kg of Org 26828 caused unpleasant central nervous system effects (anxiety, paranoia, hallucinations). Therefore, Org 26828 is not suitable for providing sedation for outpatient surgical procedures.

14-Methoxymetopon, a highly potent mu opioid agonist, biphasically affects ethanol intake in Sardinian alcohol-preferring rats.

PubMed

Sabino, Valentina; Cottone, Pietro; Steardo, Luca; Schmidhammer, Helmut; Zorrilla, Eric P

2007-07-01

Increased opioidergic activity is thought to increase the propensity to consume ethanol. However, the dose monotonicity and receptor subtype for this effect remain uncertain. 14-methoxymetopon is a centrally acting, selective micro opioid receptor agonist with greater systemic antinociceptive potency than morphine and a putatively improved therapeutic index. To determine whether 14-methoxymetopon influenced voluntary ethanol intake in Sardinian alcohol-preferring (sP) rats. Male sP rats with continuous 2-bottle choice access to ethanol (10% v/v) or water were subjects. The effects of systemic 14-methoxymetopon administration (2, 5, 12.25, 30 micro/kg, s.c.) on 4-h ethanol intake were determined. The ability of naltrexone (50 micro/kg, s.c.), an opioid antagonist, to block actions of 14-methoxymetopon (12.25, 30 micro/kg, s.c.) was examined as were the effects of 14-methoxymetopon (12.25 micro/kg, s.c.) on self-administered blood alcohol levels (BALs) and clearance of a passive ethanol bolus (1 g/kg). Finally, the effects of central 14-methoxymetopon administration (0.0003-100 ng, i.c.v.) on 4-h ethanol intake were evaluated. Systemic 14-methoxymetopon very potently and dose-dependently suppressed ethanol and food intake for 30 min, followed by a greater, longer-lasting, and behaviorally specific increase in ethanol intake. The increased ethanol intake led to threefold higher BALs, was naltrexone-reversible, and not due to altered ethanol clearance. Intracerebroventricular 14-methoxymetopon administration rapidly altered ethanol intake per an inverted U-shaped dose-response function, increasing it at a 10 pg dose, while suppressing it at a 10,000-fold higher dose. The novel mu analgesic increases ethanol intake, a potential therapeutic liability, and results suggest a non-monotonic influence of brain mu opioid receptor stimulation on ethanol intake.

Central and peripheral anti-hyperalgesic effects of diosmin in a neuropathic pain model in rats.

PubMed

Carballo-Villalobos, Azucena Ibeth; González-Trujano, María Eva; Pellicer, Francisco; Alvarado-Vásquez, Noé; López-Muñoz, Francisco Javier

2018-01-01

Flavonoids are natural compounds showing anti-hyperalgesic activity in models of pain. Diosmin is a compound poorly studied in the treatment of neuropathic pain. This study evaluates the anti-hyperalgesic actions of diosmin and possible mechanisms of action involved by using a neuropathic pain model in rats. Experimental neuropathic pain was induced by chronic constriction injury (CCI) in male Wistar rats, then aesthesiometric index and plantar tests were assessed to evaluate mechanical and thermal hyperalgesia, respectively, in order to explore the analgesic effects of acute and sub-chronic treatment with diosmin. The GABA A , 5-HT 1A , D 2 -like and opioid receptors participation, as well as levels of TNF-α, IL-1β and IL-6, were evaluated in the spinal cord and sciatic nerve tissues after acute and subchronic diosmin administration. In addition, the presence of diosmin on cerebral samples was determined by UHPLC-MS analysis. Acute and sub-chronic treatment with diosmin significantly diminished the mechanical and thermal hyperalgesia induced by CCI in rats. This anti-hyperalgesic effects of diosmin were modified in the presence of naloxone (1mg/kg, i.p.) and haloperidol (0.1mg/kg, i.p.), but not by GABA A and 5-HT 1A receptor antagonists. The anti-hyperalgesic effects of diosmin were also linked with reduced levels of TNF-α, IL-1β and IL-6. The presence of diosmin in the cerebral samples was confirmed by chromatographic analysis. In conclusion, our results provide evidence that diosmin produces significant anti-hyperalgesic effects acting at central level by an opioid and D 2 dopaminergic receptors participation, and at peripheral level by reducing proinflammatory cytokines. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

What do we (not) know about how paracetamol (acetaminophen) works?

PubMed

Toussaint, K; Yang, X C; Zielinski, M A; Reigle, K L; Sacavage, S D; Nagar, S; Raffa, R B

2010-12-01

Although paracetamol (acetaminophen), N-(4-Hydroxyphenyl)acetamide, is one of the world's most widely used analgesics, the mechanism by which it produces its analgesic effect is largely unknown. This lack is relevant because: (i) optimal pain treatment matches the analgesic mechanism to the (patho)physiology of the pain and (ii) modern drug discovery relies on an appropriate screening assay. To review the clinical profile and preclinical studies of paracetamol as means of gaining insight into its mechanism of analgesic action. A literature search was conducted of clinical and preclinical literature and the information obtained was organized and reviewed from the perspective of its contribution to an understanding of the mechanism of analgesic action of paracetamol. Paracetamol's broad spectrum of analgesic and other pharmacological actions is presented, along with its multiple postulated mechanism(s) of action. No one mechanism has been definitively shown to account for its analgesic activity. Further research is needed to uncover the mechanism of analgesic action of paracetamol. The lack of this knowledge affects optimal clinical use and impedes drug discovery efforts. © 2010 The Authors. JCPT © 2010 Blackwell Publishing Ltd.

Analysis of factors related to the use of opioid analgesics in regional cancer centers in Japan.

PubMed

Sugiura, Munetoshi; Miyashita, Mitsunori; Sato, Kazuki; Tsuneto, Satoru; Matoba, Motohiro; Sano, Motohiko; Shima, Yasuo

2010-07-01

The use of opioid analgesics and nonopioid medicines for the treatment of various symptoms in regional cancer centers is considered to be an index of the effectiveness of the structural plan for palliative care in such institutions. The present study aimed to establish an accurate representation of the actual use of opioid analgesics for palliative care in regional cancer centers. In November 2007, a questionnaire regarding the use of medications for palliative care was conducted in 288 regional cancer centers in Japan. Valid responses were received from 264 institutions (response rate, 91.4%). All regional cancer centers reported using both opioid analgesics and nonopioid medicines. However, regarding opioid analgesics, the use of each standard strength ranged from 7% to 100%. The total amount of opioid analgesics used was 1739.6 +/- 1216.5 g (mean +/- SD). Factors found to be significantly related to the total amount of opioid analgesics used in an institution were the number of opioid analgesic medicines in use (p = 0.008), the number of inpatients with cancer (p < 0.001), the number of deaths among patients with cancer (p < 0.001), and the number of beds (p < 0.001). Increase in the amount of opioid analgesics might improve the quality of palliative care at regional cancer centers.

Analgesic Activity of Some 1,2,4-Triazole Heterocycles Clubbed with Pyrazole, Tetrazole, Isoxazole and Pyrimidine

PubMed Central

Gajanan Khanage, Shantaram; Raju, Appala; Baban Mohite, Popat; Bhanudas Pandhare, Ramdas

2013-01-01

Purpose: In the present study in vivo analgesic activity of some previously synthesized 1,2,4-triazole derivatives containing pyrazole, tetrazole, isoxazole and pyrimidine ring have been evaluated. Methods: Acetic acid induced writhing method and Hot plate method has been described to study analgesic activity of some 1,2,4-triazole derivatives containing pyrazole, tetrazole, isoxazole and pyrimidine as a pharmacological active lead. Results: Thirty six different derivatives containing 1,2,4-triazole ring were subjected to study their in vivo analgesic activity. Chloro, nitro and methoxy, hydroxy and bromo substituted derivatives showed excellent analgesic activity and dimethylamino, furan and phenyl substituted derivatives showed moderate analgesic activity in both of the methods. Compounds IIIa, IIId, IIIf, IIIi, IIIj, IVa, IVb, IVd, IVf, IVh, IVj IV3a and IIj were found to be superior analgesic agents after screening by Acetic acid induced writhing method. Compounds IIIb, IIId, IIIf, IIIh, IIIj, IVa, IVb, IVd, IVf, IVh, IVi, IV3c, IV3e and IIj were showed analgesic potential after screening of Hot plate method. Conclusion: All tested compounds containing 1,2,4-triazole were found to be promising analgesic agents, for this activity pyrazole, tetrazole, isoxazole and pyrimidine leads might be supported. PMID:24312806

Drug-poisoning Deaths Involving Opioid Analgesics: United States, 1999-2011.

PubMed

Chen, Li Hui; Hedegaard, Holly; Warner, Margaret

2014-09-01

Data from the National Vital Statistics System, Mortality File. The age-adjusted rate for opioid-analgesic poisoning deaths nearly quadrupled from 1.4 per 100,000 in 1999 to 5.4 per 100,000 in 2011. Although the opioid-analgesic poisoning death rates increased each year from 1999 through 2011, the rate of increase has slowed since 2006. Natural and semisynthetic opioid analgesics, such as hydrocodone, morphine, and oxycodone, were involved in 11,693 drug-poisoning deaths in 2011, up from 2,749 deaths in 1999. Benzodiazepines were involved in 31% of the opioid-analgesic poisoning deaths in 2011, up from 13% of the opioid-analgesic poisoning deaths in 1999. During the past decade, adults aged 55-64 and non-Hispanic white persons experienced the greatest increase in the rates of opioid-analgesic poisoning deaths. Poisoning is the leading cause of injury death in the United States (1). Drugs-both illicit and pharmaceutical-are the major cause of poisoning deaths, accounting for 90% of poisoning deaths in 2011. Misuse or abuse of prescription drugs, including opioid-analgesic pain relievers, is responsible for much of the recent increase in drug-poisoning deaths (2). This report highlights trends in drug-poisoning deaths involving opioid analgesics (referred to as opioid-analgesic poisoning deaths) and updates previous Data Briefs on this topic. All material appearing in this report is in the public domain and may be reproduced or copied without permission; citation as to source, however, is appreciated.

Impact of Internet Pharmacy Regulation on Opioid Analgesic Availability*

PubMed Central

Boyer, Edward W.; Wines, James D.

2008-01-01

Objective: Access to prescription opioid analgesics has made Internet pharmacies the object of increased regulatory scrutiny, but the effectiveness of regulatory changes in curtailing availability of opioid analgesics from online sources has been not assessed. As part of an ongoing investigation into the relationship between the Internet and substance abuse, we examined the availability of prescription opioid analgesics from online pharmacies. Method: From a pharmacy watch Web site, we constructed a data set of postings entered every 3 months beginning November 1, 2005, that were related to the purchase of prescription opioid analgesics. Trained examiners assessed whether the final post described accessibility of pain medications that was increasing or decreasing. Results: We identified 45 threads related to the availability of opioid analgesics from Internet pharmacies. Of the 41 (91%) threads describing the declining availability of opioid analgesic agents from Internet pharmacies, 34 (82%) received posts on November 1, 2007. Despite the subjective nature of the research question, there was high interobserver agreement between coders (κ = .845) that availability of opioid analgesics from online pharmacies had decreased. This finding was supported by a dramatic rise in the number of pageviews (an accepted measure of Web site visitor interest in a page's content) of Web pages describing decreased availability of opioid analgesics. Conclusions: These data suggest striking decreases in the availability of prescription opioid analgesic pharmaceuticals. This self-reported change in drug availability may be related to increased regulation of and law enforcement operations directed against Internet pharmacies. PMID:18781245

Impact of Internet pharmacy regulation on opioid analgesic availability.

PubMed

Boyer, Edward W; Wines, James D

2008-09-01

Access to prescription opioid analgesics has made Internet pharmacies the object of increased regulatory scrutiny, but the effectiveness of regulatory changes in curtailing availability of opioid analgesics from online sources has been not assessed. As part of an ongoing investigation into the relationship between the Internet and substance abuse, we examined the availability of prescription opioid analgesics from online pharmacies. From a pharmacy watch Web site, we constructed a data set of postings entered every 3 months beginning November 1, 2005, that were related to the purchase of prescription opioid analgesics. Trained examiners assessed whether the final post described accessibility of pain medications that was increasing or decreasing. We identified 45 threads related to the availability of opioid analgesics from Internet pharmacies. Of the 41 (91%) threads describing the declining availability of opioid analgesic agents from Internet pharmacies, 34 (82%) received posts on November 1, 2007. Despite the subjective nature of the research question, there was high interobserver agreement between coders (kappa= .845) that availability of opioid analgesics from online pharmacies had decreased. This finding was supported by a dramatic rise in the number of pageviews (an accepted measure of Web site visitor interest in a page's content) of Web pages describing decreased availability of opioid analgesics. These data suggest striking decreases in the availability of prescription opioid analgesic pharmaceuticals. This self-reported change in drug availability may be related to increased regulation of and law enforcement operations directed against Internet pharmacies.

The pharmacological effects of Salvia species on the central nervous system.

PubMed

Imanshahidi, Mohsen; Hosseinzadeh, Hossein

2006-06-01

Salvia is an important genus consisting of about 900 species in the family Lamiaceae. Some species of Salvia have been cultivated world wide for use in folk medicine and for culinary purposes. The dried root of Salvia miltiorrhiza, for example, has been used extensively for the treatment of coronary and cerebrovascular disease, sleep disorders, hepatitis, hepatocirrhosis, chronic renal failure, dysmenorrhea, amenorrhea, carbuncles and ulcers. S. officinalis, S. leriifolia, S. haematodes, S. triloba and S. divinorum are other species with important pharmacological effects. In this review, the pharmacological effects of Salvia species on the central nervous system will be reviewed. These include sedative and hypnotic, hallucinogenic, skeletal muscle relaxant, analgesic, memory enhancing, anticonvulsant, neuroprotective and antiparkinsonian activity, as well as the inhibition of ethanol and morphine withdrawal syndrome.

25 CFR 273.27 - Central Office review and decision.

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Fatty Acid Amide Hydrolase-Dependent Generation of Antinociceptive Drug Metabolites Acting on TRPV1 in the Brain

PubMed Central

Blomgren, Anders; Simonsen, Charlotte; Daulhac, Laurence; Libert, Frédéric; Chapuy, Eric; Etienne, Monique; Högestätt, Edward D.; Zygmunt, Peter M.; Eschalier, Alain

2013-01-01

The discovery that paracetamol is metabolized to the potent TRPV1 activator N-(4-hydroxyphenyl)-5Z,8Z,11Z,14Z-eicosatetraenamide (AM404) and that this metabolite contributes to paracetamol’s antinociceptive effect in rodents via activation of TRPV1 in the central nervous system (CNS) has provided a potential strategy for developing novel analgesics. Here we validated this strategy by examining the metabolism and antinociceptive activity of the de-acetylated paracetamol metabolite 4-aminophenol and 4-hydroxy-3-methoxybenzylamine (HMBA), both of which may undergo a fatty acid amide hydrolase (FAAH)-dependent biotransformation to potent TRPV1 activators in the brain. Systemic administration of 4-aminophenol and HMBA led to a dose-dependent formation of AM404 plus N-(4-hydroxyphenyl)-9Z-octadecenamide (HPODA) and arvanil plus olvanil in the mouse brain, respectively. The order of potency of these lipid metabolites as TRPV1 activators was arvanil = olvanil>>AM404> HPODA. Both 4-aminophenol and HMBA displayed antinociceptive activity in various rodent pain tests. The formation of AM404, arvanil and olvanil, but not HPODA, and the antinociceptive effects of 4-aminophenol and HMBA were substantially reduced or disappeared in FAAH null mice. The activity of 4-aminophenol in the mouse formalin, von Frey and tail immersion tests was also lost in TRPV1 null mice. Intracerebroventricular injection of the TRPV1 blocker capsazepine eliminated the antinociceptive effects of 4-aminophenol and HMBA in the mouse formalin test. In the rat, pharmacological inhibition of FAAH, TRPV1, cannabinoid CB1 receptors and spinal 5-HT3 or 5-HT1A receptors, and chemical deletion of bulbospinal serotonergic pathways prevented the antinociceptive action of 4-aminophenol. Thus, the pharmacological profile of 4-aminophenol was identical to that previously reported for paracetamol, supporting our suggestion that this drug metabolite contributes to paracetamol’s analgesic activity via activation of bulbospinal pathways. Our findings demonstrate that it is possible to construct novel antinociceptive drugs based on fatty acid conjugation as a metabolic pathway for the generation of TRPV1 modulators in the CNS. PMID:23940628

75 FR 67697 - Privacy Act of 1974; Systems of Records

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Analgesic effects of carprofen and liposome-encapsulated butorphanol tartrate in Hispaniolan parrots (Amazona ventralis) with experimentally induced arthritis.

PubMed

Paul-Murphy, Joanne R; Sladky, Kurt K; Krugner-Higby, Lisa A; Stading, Ben R; Klauer, Julia M; Keuler, Nicholas S; Brown, Carolyn S; Heath, Timothy D

2009-10-01

To evaluate the microcrystalline sodium urate (MSU) method for inducing arthritis in parrots and to compare the analgesic efficacy of long-acting liposome-encapsulated butorphanol (LEBT), carprofen, or a combination of both. 20 Hispaniolan parrots. MSU was injected into a tibiotarsal-tarsometatarsal (intertarsal) joint to induce arthritis (time 0). Four treatments were compared (LEBT [15 mg/kg, SC] administered once at time 0; injections of carprofen [3 mg/kg, IM, q 12 h] starting at time 0; administration of LEBT plus carprofen; and a control treatment of saline [0.9% NaCl] solution). Weight load testing and behavioral scoring were conducted at 0, 2, 6, 26, and 30 hours. Injection of MSU into the intertarsal joint induced arthritis, which resolved within 30 hours. Treatment with LEBT or LEBT plus carprofen resulted in significantly greater weight-bearing load on the limb with induced arthritis, compared with the control treatment. Treatment with carprofen alone caused a slight but nonsignificant improvement in weight-bearing load on the arthritic limb, compared with the control treatment. Behaviors associated with motor activity and weight bearing differed between the control and analgesic treatments. Butorphanol was an effective treatment for pain associated with arthritis, but carprofen administered every 12 hours was insufficient. Injection of MSU to induce arthritis in a single joint was a good method for evaluating tonic pain in parrots, and measurement of the weight-bearing load was accurate for assessment of arthritic pain; however, behavioral changes associated with pain were subtle.

Analgesic effect of Minocycline in rat model of inflammation-induced visceral pain

PubMed Central

Kannampalli, Pradeep; Pochiraju, Soumya; Bruckert, Mitchell; Shaker, Reza; Banerjee, Banani; Sengupta, Jyoti N.

2014-01-01

The present study investigates the analgesic effect of minocycline, a semi-synthetic tetracycline antibiotic, in a rat model of inflammation-induced visceral pain. Inflammation was induced in male rats by intracolonic administration of tri-nitrobenzenesulphonic acid (TNBS). Visceral hyperalgesia was assessed by comparing the viscero-motor response (VMR) to graded colorectal distension (CRD) prior and post 7 days after TNBS treatment. Electrophysiology recordings from CRD-sensitive pelvic nerve afferents (PNA) and lumbo-sacral (LS) spinal neurons were performed in naïve and inflamed rats. Colonic inflammation produced visceral hyperalgesia characterized by increase in the VMRs to CRD accompanied with simultaneous activation of microglia in the spinal cord and satellite glial cells (SGCs) in the dorsal root ganglions (DRGs). Selectively inhibiting the glial activation following inflammation by araC (Arabinofuranosyl Cytidine) prevented the development of visceral hyperalgesia. Intrathecal minocycline significantly attenuated the VMR to CRD in inflamed rats, whereas systemic minocycline produced a delayed effect. In electrophysiology experiments, minocycline significantly attenuated the mechanotransduction of CRD-sensitive PNAs and the responses of CRD-sensitive LS spinal neurons in TNBS-treated rats. While the spinal effect of minocycline was observed within 5 min of administration, systemic injection of the drug produced a delayed effect (60 min) in inflamed rats. Interestingly, minocycline did not exhibit analgesic effect in naïve, non-inflamed rats. The results demonstrate that intrathecal injection of minocycline can effectively attenuate inflammation-induced visceral hyperalgesia. Minocycline might as well act on neuronal targets in the spinal cord of inflamed rats, in addition to the widely reported glial inhibitory action to produce analgesia. PMID:24485889

Plants and the central nervous system.

PubMed

Carlini, E A

2003-06-01

This review article draws the attention to the many species of plants possessing activity on the central nervous system (CNS). In fact, they cover the whole spectrum of central activity such as psychoanaleptic, psycholeptic and psychodysleptic effects, and several of these plants are currently used in therapeutics to treat human ailments. Among the psychoanaleptic (stimulant) plants, those utilized by human beings to reduce body weight [Ephedra spp. (Ma Huang), Paullinia spp. (guaraná), Catha edulis Forssk. (khat)] and plants used to improve general health conditions (plant adaptogens) were scrutinized. Many species of hallucinogenic (psychodysleptic) plants are used by humans throughout the world to achieve states of mind distortions; among those, a few have been used for therapeutic purposes, such as Cannabis sativa L., Tabernanthe iboga Baill. and the mixture of Psychotria viridis Ruiz and Pav. and Banisteriopsis caapi (Spruce ex Griseb.) C.V. Morton. Plants showing central psycholeptic activities, such as analgesic or anxiolytic actions (Passiflora incarnata L., Valeriana spp. and Piper methysticum G. Forst.), were also analysed.Finally, the use of crude or semipurified extracts of such plants instead of the active substances seemingly responsible for their therapeutic effect is discussed.

Use of analgesics in young adults as a predictor of health care utilization and pain prevalence: Israel defense forces experience.

PubMed

Dorfman, Karina; Komargodski, Olga; Magnezi, Racheli; Lifshitz, Stanislav; Tzur, Dorit; Yavnai, Nirit; Ifergane, Gal

2017-06-01

Pain evaluation in large community studies is difficult. Analgesics can be a useful tool in estimating pain-related conditions in which analgesic use is highly regulated. In this study, we evaluated analgesics consumption patterns of regular Israel Defense Force soldiers. We have performed a historical cohort study of 665,137 young adults during active duty in 2002 to 2012. Analgesics were prescribed to 518,242 (78%) soldiers, mostly for musculoskeletal pain (69.3%), abdominal pain (12.7%), and headache (12.1%). Acute (1-14 days), subacute (15-90), and chronic (>90 days) analgesic use episodes were experienced by 396,987 (59.7%), 74,591 (11.2%), and 46,664 (7%) of the population. In a multivariate model, predictors for chronic analgesics use were as follows: low intelligence, service in a combat supporting unit, previous pain diagnosis, male sex, Israeli nativity, low socioeconomic status, and high body mass index. Low intelligence had the highest odds ratio for chronic analgesic consumption (2.1) compared with other predictors. Chronic analgesic use was associated with a significant increase in health care utilization cost per year (911$ per soldier vs 199$ for nonusers), increased sick leave days per year (7.09 vs 0.67 for nonusers), and higher dropout rate from combat units (25% vs 9.2% for nonusers). Chronic use of analgesics is common among young adults, and it is an important predictor for unsuccessful military service and high health care utilization costs. Further studies in other setups are indicated.

Risks, Management, and Monitoring of Combination Opioid, Benzodiazepines, and/or Alcohol Use

PubMed Central

Gudin, Jeffrey A.; Mogali, Shanthi; Jones, Jermaine D.; Comer, Sandra D.

2014-01-01

The concurrent use of opioids, benzodiazepines (BZDs), and/or alcohol poses a formidable challenge for clinicians who manage chronic pain. While the escalating use of opioid analgesics for the treatment of chronic pain and the concomitant rise in opioid-related abuse and misuse are widely recognized trends, the contribution of combination use of BZDs, alcohol, and/or other sedative agents to opioid-related morbidity and mortality is underappreciated, even when these agents are used appropriately. Patients with chronic pain who use opioid analgesics along with BZDs and/or alcohol are at higher risk for fatal/nonfatal overdose and have more aberrant behaviors. Few practice guidelines for BZD treatment are readily available, especially when they are combined clinically with opioid analgesics and other central nervous system–depressant agents. However, coadministration of these agents produces a defined increase in rates of adverse events, overdose, and death, warranting close monitoring and consideration when treating patients with pain. To improve patient outcomes, ongoing screening for aberrant behavior, monitoring of treatment compliance, documentation of medical necessity, and the adjustment of treatment to clinical changes are essential. In this article, we review the prevalence and pharmacologic consequences of BZDs and/or alcohol use among patients with pain on chronic opioid therapy, as well as the importance of urine drug testing, an indispensable tool for therapeutic drug monitoring, which helps to ensure the continued safety of patients. Regardless of risk or known aberrant drug-related behaviors, patients on chronic opioid therapy should periodically undergo urine drug testing to confirm adherence to the treatment plan. PMID:23933900

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.

TRPV1 in Brain Is Involved in Acetaminophen-Induced Antinociception

PubMed Central

Eschalier, Alain; Zygmunt, Peter M.; Högestätt, Edward D.

2010-01-01

Background Acetaminophen, the major active metabolite of acetanilide in man, has become one of the most popular over-the-counter analgesic and antipyretic agents, consumed by millions of people daily. However, its mechanism of action is still a matter of debate. We have previously shown that acetaminophen is further metabolized to N-(4-hydroxyphenyl)-5Z,8Z,11Z,14Z -eicosatetraenamide (AM404) by fatty acid amide hydrolase (FAAH) in the rat and mouse brain and that this metabolite is a potent activator of transient receptor potential vanilloid 1 (TRPV1) in vitro. Pharmacological activation of TRPV1 in the midbrain periaqueductal gray elicits antinociception in rats. It is therefore possible that activation of TRPV1 in the brain contributes to the analgesic effect of acetaminophen. Methodology/Principal Findings Here we show that the antinociceptive effect of acetaminophen at an oral dose lacking hypolocomotor activity is absent in FAAH and TRPV1 knockout mice in the formalin, tail immersion and von Frey tests. This dose of acetaminophen did not affect the global brain contents of prostaglandin E2 (PGE2) and endocannabinoids. Intracerebroventricular injection of AM404 produced a TRPV1-mediated antinociceptive effect in the mouse formalin test. Pharmacological inhibition of TRPV1 in the brain by intracerebroventricular capsazepine injection abolished the antinociceptive effect of oral acetaminophen in the same test. Conclusions This study shows that TRPV1 in brain is involved in the antinociceptive action of acetaminophen and provides a strategy for developing central nervous system active oral analgesics based on the coexpression of FAAH and TRPV1 in the brain. PMID:20862299

Efficacy of buprenorphine added to 2% lignocaine plus adrenaline 1:80,000 in providing postoperative analgesia after lower third molar surgery.

PubMed

Chhabra, N; Sharma, P; Chhabra, S; Gupta, N

2016-12-01

A number of trials have examined the peripheral analgesic effect of opioids, known to have an anti-nociceptive effect at the central and/or spinal cord level. This study aimed to evaluate the efficacy of buprenorphine added to 2% lignocaine with adrenaline 1:80,000 in providing postoperative analgesia after lower third molar surgery. Sixty patients were randomized to three groups: group A received lignocaine 2% with adrenaline 1:80,000 for inferior alveolar nerve block (IANB), along with intramuscular (IM) injection of 1ml saline; group B received buprenorphine mixed with lignocaine 2% with adrenaline 1:80,000 for IANB (0.01mg buprenorphine/ml lignocaine with adrenaline), along with 1ml saline IM; group C received lignocaine 2% with adrenaline 1:80,000 for IANB, along with 0.03mg buprenorphine IM. Mean postoperative pain scores (visual analogue scale; when the patient first felt pain) were 6.0 for group A, 1.0 for group B, and 4.4 for group C. The mean duration of postoperative analgesia was 3.5h in groups A and C and 12h in group B. The mean number of postoperative analgesics consumed was 5.8 in groups A and C and 3.9 in group B. The addition of buprenorphine (0.03mg) to 2% lignocaine with adrenaline 1:80,000 significantly reduced the severity of postoperative pain and prolonged the duration of analgesia, thereby decreasing the need for postoperative analgesics. Copyright © 2016 International Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.

Use of medications and resources for treatment of nausea, vomiting, or constipation in hospitalized patients treated with analgesics.

PubMed

Suh, Dong-Churl; Kim, Myoung S; Chow, Wing; Jang, Eun-Jin

2011-01-01

Hospitalized patients often experience adverse events of the gastrointestinal tract due to analgesic treatment. The objectives of this study were to estimate use of medications for treatment of nausea, vomiting, or constipation (NVC medications) after initiation of analgesic treatment, and to compare differences in length of stay and treatment costs between patients who received NVC medications and those who did not. This retrospective cohort study used the Premier Perspective data from January 1, 2005 to December 31, 2007 and stratified inpatients into 4 groups based on the first analgesic agent they were given. Patients were observed for 14 days after the first analgesic use until a regimen change, first use of NVC medication, or hospital discharge, whichever occurred first. Data were analyzed using a Cox proportional hazards model and a generalized linear model. This study found that 239,183 (55.1%) of 434,304 patients received NVC medications after analgesic administration. Compared with oral nonopioid analgesics, the risk of using NVC medication was 4.8 times higher for injectable opioid analgesics after controlling for confounders. Patients who received NVC medications were hospitalized 0.26 days longer (P < 0.0001) at an additional cost of $756 per patient compared with patients who did not receive NVC medications (P < 0.0001). Use of an analgesic with improved gastrointestinal tolerability may potentially reduce use of NVC medications and hospital resources.

An evaluation of analgesic regimens for abdominal surgery in mice.

PubMed

Hayes, K E; Raucci, J A; Gades, N M; Toth, L A

2000-11-01

This study was designed to evaluate the efficacy of several analgesic regimens for use after intraperitoneal implantation of telemetry transmitters in mice. The lengths of time required for postoperative recovery of food and water intake, locomotor activity, and core temperature of mice that did not receive postsurgical analgesic medication were compared to those of mice that were given either an analgesic in the drinking water or buprenorphine injections. Many measured variables were not substantially altered by analgesic medications. However, ibuprofen-treated mice demonstrated significantly greater locomotor activity on days 2 through 5 after surgery and a more rapid return to stable postsurgical levels of activity and water intake as compared to those in untreated mice. These changes are consistent with potential analgesic efficacy of the ibuprofen treatment regimen. Buprenorphine injections elicited hyperactivity, hyperthermia, and reduced food and water intake during both the immediate postsurgical recovery period and after apparent recuperation from surgery, as compared to effects observed in saline-treated mice. Evaluating the effect of analgesic regimens on postsurgical changes in physiologic and behavioral variables can be useful in assessing the efficacy of analgesic treatments, but some changes may indicate pharmacologic effects that do not reflect pain relief.

Intravenous subhypnotic propofol in central pain: a double-blind, placebo-controlled, crossover study.

PubMed

Canavero, S; Bonicalzi, V

2004-01-01

To validate IV subhypnotic propofol, a gamma-aminobutyric acid A (GABA-A) agonist, as a diagnostic test for central pain. The efficacy of systemic propofol (0.2 mg/kg IV bolus) was evaluated in a double-blind, placebo-controlled and crossover fashion on both spontaneous ongoing pain and allodynia in 44 patients with chronic central pain of both brain and cord origin. Propofol was significantly superior to the placebo (Intralipid, Kabi Pharmacia) in reducing the intensity of spontaneous ongoing pain for up to 1 hour after the injection: 24 of 44 patients (55%) receiving propofol showed a significant reduction in spontaneous pain, whereas only 6 patients showed this after the placebo. Propofol also significantly reduced the intensity of both mechanical and cold allodynia. In a few cases, only the evoked components were abolished but not the spontaneous pain. In general, the side effects were minimal and consisted mainly of transitory burning upon injection of both propofol and placebo and slight lightheadedness in a few cases. Systemic propofol induces analgesic effects on all studied components of central pain and highlights the key role of GABA modulation in central pain.

Safety of lornoxicam in the treatment of postoperative pain: a post-marketing study of analgesic regimens containing lornoxicam compared with standard analgesic treatment in 3752 day-case surgery patients.

PubMed

Rawal, Narinder; Krøner, Karsten; Simin-Geertsen, Marija; Hejl, Charlotte; Likar, Rudolf

2010-01-01

Post-marketing surveillance studies can provide supplemental data on the safety of medications in the general population. This study aimed to evaluate the safety of analgesic regimens including the NSAID lornoxicam in the short-term treatment of postoperative pain in a clinically relevant population. Randomized, open-label, multicentre, multinational, observational cohort study of 4 days' duration. In-hospital postoperative setting, with discharge to home treatment within 24 hours of surgery. Adults aged > or =18 years expected to be in need of analgesic treatment after day-case surgery. Analgesic regimens containing lornoxicam were compared with a standard analgesic treatment, which was defined as the treatment that the patient would normally receive at the centre. Following day-case surgery, patients were provided with appropriate analgesic medication, and adverse events (AEs; defined as all recorded events with symptoms) were recorded by the investigator during the in-hospital stay and by the patient for the next 3 days using entries recorded morning and evening in a patient diary. Statistical analyses tested for between-treatment differences in AEs, adverse drug reactions (ADRs; defined as events probably, possibly or unlikely to be related to treatment) and gastrointestinal AEs (GI-AEs). A total of 4152 patients were randomized to treatment. Since 400 patients did not take any analgesic, the safety population consisted of 1838 patients for lornoxicam and 1914 patients for standard analgesic treatment. Demographic and disease characteristics were similar between the two treatment groups, as were the type of surgery and the anaesthesia used in surgery. In the safety population, 16.9% of patients received no analgesic in hospital, and when analgesics were provided they were often administered in combination. Similarly, approximately 17% of patients did not take any analgesics at home. AEs were reported in 27.1% and 29.4% of patients in the lornoxicam and standard analgesic treatment groups, respectively, and ADRs constituted the majority of these events. No significant differences were demonstrated with regard to the incidence of AEs between the two groups. Most events were of mild or moderate intensity. Consistent with what may be expected for an NSAID, most AEs with lornoxicam were related to the GI system. GI-AEs were reported in 19.5% and 21.3% of patients in the lornoxicam and standard analgesic treatment groups, respectively, and most of these were considered ADRs. Most patients were satisfied with their pain treatment both in hospital and at home. Lornoxicam-containing regimens are as well tolerated as other analgesic regimens over 4 days in the treatment of postoperative pain.

Changes in misuse and abuse of prescription opioids following implementation of Extended-Release and Long-Acting Opioid Analgesic Risk Evaluation and Mitigation Strategy.

PubMed

Bucher Bartelson, Becki; Le Lait, M Claire; Green, Jody L; Cepeda, M Soledad; Coplan, Paul M; Maziere, Jean-Yves; Wedin, Gregory P; Dart, Richard C

2017-09-01

An unintended consequence of extended-release (ER) and long-acting (LA) prescription opioids is that these formulations can be more attractive to abusers than immediate-release (IR) formulations. The US Food and Drug Administration recognized these risks and approved the ER/LA Opioid Analgesic Risk Evaluation and Mitigation Strategy (ER/LA REMS), which has a goal of reducing opioid misuse and abuse and their associated consequences. The primary objective of this analysis is to determine whether ER/LA REMS implementation was associated with decreased reports of misuse and abuse. Data from the Researched Abuse, Diversion and Addiction-Related Surveillance (RADARS(R)) System Poison Center Program were utilized. Poison center cases are assigned a reason for exposure, a medical outcome, and a level of health care received. Rates adjusted for population and drug utilization were analyzed over time. RADARS System Poison Center Program data indicate a notable decrease in ER/LA opioid rates of intentional abuse and misuse as well as major medical outcomes or hospitalizations following implementation of the ER/LA REMS. While similar decreases were observed for the IR prescription opioid group, the decreasing rate for the ER/LA opioids exceeded the decreasing rates for the IR prescription opioids and was distinctly different than that for the prescription stimulants, indicating that the ER/LA REMS program may have had an additional effect on decreases in opioid abuse and intentional misuse beyond secular trends. Copyright © 2017 John Wiley & Sons, Ltd.

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12 CFR 725.1 - Scope.

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... ADMINISTRATION CENTRAL LIQUIDITY FACILITY § 725.1 Scope. This part contains the regulations implementing the National Credit Union Central Liquidity Facility Act, subchapter III of the Federal Credit Union Act. The National Credit Union Administration Central Liquidity Facility is a mixed-ownership Government corporation...

Mechanisms of topical analgesics in relieving pain in an animal model of muscular inflammation.

PubMed

Duan, Wan-Ru; Lu, Jie; Xie, Yi-Kuan

2013-09-01

To investigate the possible mechanisms of topical analgesics in relieving pain in an animal model of muscular inflammation. Adult Sprague-Dawley rats of both sexes were injected with complete Freund's adjuvant to induce inflammation in the anterior tibialis muscle of left hindlimb. One of two types of topical analgesics: Xiaotong Tiegao (XTT), a Tibetan herb compound, or Capzasin (CAP), a cream containing 0.1% capsaicin, was applied to the skin over the inflamed anterior tibialis muscle. The following experiments were performed: pain behavioral tests, evaluation of plasma extravasation in the affected limb, and electrophysiological recordings of afferent nerve fibers. The behavioral experiments demonstrated that applications of either type of topical analgesic to the skin over the inflamed muscle significantly reduced muscular inflammatory pain, as indicated by the increased weight bearing capacity on the affected hindlimb (with latencies of 10 minutes for XTT and 1-2 hours for CAP). Meanwhile, both analgesics caused plasma extravasation in the affected skin. Electrophysiological recordings from the afferent fibers in the related cutaneous nerve indicated that topical analgesics selectively activated C-fibers, but not A-fibers innervating the same region of receptive field. The latency and duration of C-fiber activation was similar to those of the reduction of muscular inflammatory pain. On the contrary, topical analgesics substantially decreased C-fiber afferent spontaneous firing in the nerve innervating the inflamed muscle. Moreover, denervation of the affected skin blocked the analgesic effects of both topical analgesics in muscular inflammatory pain. This study suggests that topical analgesics may reduce the nociceptive input from inflamed muscles via a reflex mechanism by activating the cutaneous nociceptive afferents. Wiley Periodicals, Inc.

Effect of spinal monoaminergic neuronal system dysfunction on pain threshold in rats, and the analgesic effect of serotonin and norepinephrine reuptake inhibitors.

PubMed

Tamano, Ryuta; Ishida, Mitsuhiro; Asaki, Toshiyuki; Hasegawa, Minoru; Shinohara, Shunji

2016-02-26

Dysfunction in the central serotonin (5-HT) and norepinephrine (NE) systems cause depression and pain. Descending spinal pain modulatory pathways are important in the analgesic mechanisms of antidepressants, particularly serotonin and norepinephrine reuptake inhibitors (SNRIs). While many non-clinical studies have demonstrated the roles of central monoaminergic systems in pain, there is little evidence to illuminate the direct contribution of spinal descending pain modulatory systems independently of depressive-like behavior. To examine the effects of dysfunction of spinal monoaminergic systems on pain sensitivity, we established a rat chronic pain model by administering lumbar-intrathecal reserpine to minimize its influence on brain. Lumbar-intrathecal reserpine evoked persistent mechanical hypersensitivity and corresponding reductions in spinal 5-HT and NE concentrations (from 767.2 to 241.6ng/g and from 455.9 to 41.7ng/g, respectively after reserpine 30nmol). Lumbar-intrathecal reserpine did not deplete brain monoamines or bring about depressive-like behavior in the forced swim test. Spinal monoamines depletion-induced pain sensitivity was ameliorated by lumbar-intrathecal administration of the SNRIs (duloxetine and milnacipran) in dose-dependent manners. These suggest that increased pain sensitivity could be induced by dysfunction solely of the descending pain modulatory system, regardless of depressive-like behavior, and lumbar-intrathecal administration of SNRIs could ameliorate the pain sensitivity which might be mediated by affecting the descending pain modulatory system in the spinal cord, not via their antidepressant effects. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Time trends in 20 years of medication use in older adults: Findings from three elderly cohorts in Stockholm, Sweden.

PubMed

Craftman, Åsa Gransjön; Johnell, Kristina; Fastbom, Johan; Westerbotn, Margareta; von Strauss, Eva

2016-01-01

New drugs and expanded drug indications are constantly being introduced. Welfare states strive to provide equity in drug treatment for all of its citizens and todaýs healthcare systems spend financial resources on drugs for the elderly in a higher rate than for any other age group. Drug utilization in elderly persons has an impact in health and wellbeing in older people. It was to describe the changes in medication use including people aged 78 years and over regardless of residence and other characteristics over 20 years. The study population consisted of 4304 participants in three population-based cross-sectional surveys conducted in the Kungsholmen area of central Stockholm, Sweden. The participant's current drug utilization was reviewed by physicians following standardized protocols. Data were statistical analyzed. Logistic regression models was used to estimate odds ratios and 95% confidence intervals for use of analgesics and psychotropic drugs in the cohorts of 2001 and 2007, controlling for age, gender, education and cognition. Results shows that the prevalence of medication use and polypharmacy in older adults has increased dramatically the late 1980s to the 2000s in central Stockholm, Sweden. In particular, the use of analgesics increased significantly, while some drug groups decreased, i.e., antipsychotics. Women used more medication than men in all three cohorts. Older adults living in service buildings used the largest amount of drugs in 1987, whereas those living in institutions were the most frequent users in 2001 and 2007. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Personalized Medicine and Opioid Analgesic Prescribing for Chronic Pain: Opportunities and Challenges

PubMed Central

Bruehl, Stephen; Apkarian, A. Vania; Ballantyne, Jane C.; Berger, Ann; Borsook, David; Chen, Wen G.; Farrar, John T.; Haythornthwaite, Jennifer A.; Horn, Susan D.; Iadarola, Michael J.; Inturrisi, Charles E.; Lao, Lixing; Mackey, Sean; Mao, Jianren; Sawczuk, Andrea; Uhl, George R.; Witter, James; Woolf, Clifford J.; Zubieta, Jon-Kar; Lin, Yu

2013-01-01

Use of opioid analgesics for pain management has increased dramatically over the past decade, with corresponding increases in negative sequelae including overdose and death. There is currently no well-validated objective means of accurately identifying patients likely to experience good analgesia with low side effects and abuse risk prior to initiating opioid therapy. This paper discusses the concept of data-based personalized prescribing of opioid analgesics as a means to achieve this goal. Strengths, weaknesses, and potential synergism of traditional randomized placebo-controlled trial (RCT) and practice-based evidence (PBE) methodologies as means to acquire the clinical data necessary to develop validated personalized analgesic prescribing algorithms are overviewed. Several predictive factors that might be incorporated into such algorithms are briefly discussed, including genetic factors, differences in brain structure and function, differences in neurotransmitter pathways, and patient phenotypic variables such as negative affect, sex, and pain sensitivity. Currently available research is insufficient to inform development of quantitative analgesic prescribing algorithms. However, responder subtype analyses made practical by the large numbers of chronic pain patients in proposed collaborative PBE pain registries, in conjunction with follow-up validation RCTs, may eventually permit development of clinically useful analgesic prescribing algorithms. Perspective Current research is insufficient to base opioid analgesic prescribing on patient characteristics. Collaborative PBE studies in large, diverse pain patient samples in conjunction with follow-up RCTs may permit development of quantitative analgesic prescribing algorithms which could optimize opioid analgesic effectiveness, and mitigate risks of opioid-related abuse and mortality. PMID:23374939

[Use and potential risks of over-the-counter analgesics].

PubMed

Freytag, A; Quinzler, R; Freitag, M; Bickel, H; Fuchs, A; Hansen, H; Hoefels, S; König, H-H; Mergenthal, K; Riedel-Heller, S G; Schön, G; Weyerer, S; Wegscheider, K; Scherer, M; van den Bussche, H; Haefeli, W E; Gensichen, J

2014-04-01

We investigated the use of prescription and non-prescription (over-the-counter, OTC) analgesics and the associated risks in elderly patients with multiple morbidities. Pain medication use was evaluated from the baseline data (2008/2009) of the MultiCare cohort enrolling elderly patients with multiple morbidities who were treated by primary care physicians (trial registration: ISRCTN89818205). We considered opioids (N02A), other analgesics, and antipyretics (N02B) as well as nonsteroidal anti-inflammatory drugs (NSAIDs; M01A). OTC use, duplicate prescription, dosages, and interactions were examined for acetylsalicylic acid, diclofenac, (dex)ibuprofen, naproxen, and acetaminophen. Of 3,189 patients with multiple morbidities aged 65-85 years, 1,170 patients reported to have taken at least one prescription or non-prescription analgesic within the last 3 months (36.7 %). Of these, 289 patients (24.7 % of 1,170) took at least one OTC analgesic. Duplicate prescription was observed in 86 cases; 15 of these cases took the analgesics regularly. In two cases, the maximum daily dose of diclofenac was exceeded due to duplicate prescription. In 235 cases, patients concurrently took a drug with a potentially clinically relevant interaction. In 43 cases (18.3 % of 235) an OTC analgesic, usually ibuprofen, was involved. About one third of the elderly patients took analgesics regularly or as needed. Despite the relatively high use of OTC analgesics, the proportions of duplicate prescription, medication overdoses, and adverse interactions due to OTC products was low.

Do caffeine-containing analgesics promote dependence? A review and evaluation.

PubMed

Feinstein, A R; Heinemann, L A; Dalessio, D; Fox, J M; Goldstein, J; Haag, G; Ladewig, D; O'Brien, C P

2000-11-01

Debates about the suspected association between kidney disease and use of analgesics have led to concern about whether caffeine could stimulate an undesirable overuse of phenacetin-free combined analgesics. A committee was asked to critically review the pertinent literature and to suggest guides for clinical practice and for consideration of international regulatory authorities. A group of international scientists, jointly selected by the regulatory authorities of Germany, Switzerland, and Austria and the pharmaceutical industry. All invited experts evaluated relevant literature and reports and added further information and comments. Caffeine has a synergistic effectiveness with analgesics. Although caffeine has a dependence potential, the potential is low. Experimental data regarding dependence potential for caffeine alone may not correspond to the conditions in patients with pain. Withdrawal is not likely to cause stimulation or sustainment of analgesic intake. For drug-induced headache, no single or combined analgesic was consistently identified as causative, and no evidence exists for a special role of caffeine. Strong dependence behavior was observed only in patients using phenacetin-containing preparations, coformulated with antipyretics/analgesics and caffeine. This finding may have led to the impression that caffeine stimulates overuse of analgesics. Although more experimental and long-term data would be desirable to show possible mechanisms of dependence and to offer unequivocal proof of safety, the committee concluded that the available evidence does not support the claim that analgesics coformulated with caffeine, in the absence of phenacetin, stimulate or sustain overuse.

76 FR 54251 - Central Valley Project Improvement Act, Water Management Plans

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32 CFR 1910.1 - General.

Code of Federal Regulations, 2010 CFR

2010-07-01

... Other Regulations Relating to National Defense CENTRAL INTELLIGENCE AGENCY DEBARMENT AND SUSPENSION PROCEDURES § 1910.1 General. The Central Intelligence Agency (CIA), in accordance with its authorities under the Central Intelligence Agency Act of 1949, as amended, and the National Security Act of 1947, as...

32 CFR 1910.1 - General.

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2011-07-01

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32 CFR 1910.1 - General.

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32 CFR 1910.1 - General.

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2013-07-01

... Other Regulations Relating to National Defense CENTRAL INTELLIGENCE AGENCY DEBARMENT AND SUSPENSION PROCEDURES § 1910.1 General. The Central Intelligence Agency (CIA), in accordance with its authorities under the Central Intelligence Agency Act of 1949, as amended, and the National Security Act of 1947, as...

Rational use of analgesic combinations.

PubMed

Phero, James C; Becker, Daniel

2002-10-01

Careful selection of an effective analgesic regimen based on the amount and type of pain the patient is expected to have can prevent the stress and anxiety associated with breakthrough pain. When analgesics fail, it is not unusual for patients to go to desperate lengths to seek relief. The clinician can and should develop a variety of effective, safe analgesic regimens based on estimates of anticipated pain intensity that apply sound pharmacologic principles.

Analgesic Activity of Tramadol and Buprenorphine after Voluntary Ingestion by Rats (Rattus norvegicus)

PubMed Central

Taylor, Bryan F; Ramirez, Harvey E; Battles, August H; Andrutis, Karl A; Neubert, John K

2016-01-01

Effective pain management for rats and mice is crucial due to the continuing increase in the use of these species in biomedical research. Here we used a recently validated operant orofacial pain assay to determine dose–response curves for buprenorphine and tramadol when mixed in nut paste and administered to male and female rats. Statistically significant analgesic doses of tramadol in nut paste included doses of 20, 30, and 40 mg/kg for female rats but only 40 mg/kg for male rats. For male rats receiving buprenorphine mixed in nut paste, a significant analgesic response was observed at 0.5 and 0.6 mg/kg. None of the doses tested produced a significant analgesic response in female rats. Our results indicate that at the doses tested, tramadol and buprenorphine produced an analgesic response in male rats. In female rats, tramadol shows a higher analgesic effect than buprenorphine. The analgesic effects observed 60 min after administration of the statistically significant oral doses of both drugs were similar to the analgesic effects of 0.03 mg/kg subcutaneous buprenorphine 30 min after administration. The method of voluntary ingestion could be effective, is easy to use, and would minimize stress to the rats during the immediate postoperative period. PMID:26817983

Opioid Receptors: Toward Separation of Analgesic from Undesirable Effects

PubMed Central

Law, P.Y.; Reggio, Patricia H.; Loh, H.H.

2013-01-01

The use of opioid analgesics for pain has always been hampered by their many side effects; in particular, the addictive liability associated with chronic use. Recently, attempts to develop analgesic agents with reduced side effects have targeted either the putative opioid receptor splice variants or the receptor heterooligomers. This review discusses the potential for receptor splice variant- and the hetero-oligomer-based discovery of new opioid analgesics. We also examine an alternative approach of using receptor mutants for pain management. Finally, we discuss the role of the biased agonism observed and the recently reported opioid receptor crystal structures in guiding the future development of opioid analgesics PMID:23598157

Endomorphin derivatives with improved pharmacological properties.

PubMed

Varamini, Pegah; Blanchfield, Joanne T; Toth, Istvan

2013-01-01

Centrally acting opioids, such as morphine, are the most frequently used analgesic agents for the treatment of severe pain. However, their usefulness is limited by the production of a range of adverse effects such as constipation, respiratory depression, tolerance and physical dependence. In addition, opioids generally exhibit poor efficacy against neuropathic pain. Endomorphin-1 and -2, two endogenous opioid peptides, have been shown to produce potent antinociception in rodent models of acute and neuropathic pain with less undesirable side effects than opioid alkaloids. However, native endomorphins are poorly suited to clinical applications without modifications. Like all small peptides, endomorphins suffer from poor metabolic stability and a relative inability to penetrate the gastro-intestinal mucosa and blood-brain-barrier. Since the discovery of endomorphins in 1997, a huge number of endomorphin analogs have been designed and synthesized with the aim of developing compounds with improved barrier penetration and resistance to enzymatic degradation. In this review we describe various strategies that have been adopted so far to conquer the major drawbacks associated with endomorphins. They include chemical modifications to produce locally or globally-restricted peptide analogs in addition to application of peptidase inhibitors, which is of minor importance compared to the former strategy. Diverse approaches that resulted in the design and synthesis of pharmacologically active endomorphin analogs with less adverse effects are also discussed giving an insight into the development of opioid peptides with an improved side effect profile.

[Management of opioid maintenance treatments when analgesic treatments are required].

PubMed

Laprevote, Vincent; Geoffroy, Pierre A; Rolland, Benjamin; Leheup, Benoît F; Di Patrizio, Paolo; Cottencin, Olivier; Schwan, Raymund

2013-01-01

Opioid maintenance treatments (OMT) reduce illicit opiate use and its associated risks. They are often prescribed on a long-term basis. Physiological changes induced by long-term OMT may cause hyperalgesia and cross-tolerance to opioid agonists, which suggests that the dosage of analgesic treatment should be modified in cases of acute pain, especially when an opioid-based analgesia is required. When treatment with analgesics is necessary, OMT must be maintained, except in exceptional cases. If a split-dosing schedule is temporarily employed during OMT, the daily dosage should not be increased for analgesic purposes. Analgesic treatment must be managed differently in case of treatment with buprenorphine or methadone. With buprenorphine, non-opioid analgesics should be introduced first, if possible. If this strategy is inefficient or contraindicated, a temporary or definitive switch to methadone should be considered. In the case of methadone-based OMT, opioid analgesics should be added directly and the dosage should be adapted according to the level of pain reported by the patient. Copyright © 2013 Elsevier Masson SAS. All rights reserved.

32 CFR 1906.102 - Application.

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2012-07-01

... Defense Other Regulations Relating to National Defense CENTRAL INTELLIGENCE AGENCY ENFORCEMENT OF NONDISCRIMINATION ON THE BASIS OF HANDICAP IN PROGRAMS OR ACTIVITIES CONDUCTED BY THE CENTRAL INTELLIGENCE AGENCY... National Security Act of 1947 (50 U.S.C. 402 et seq.), as amended; the Central Intelligence Agency Act of...

32 CFR 1906.102 - Application.

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19 CFR 10.581 - Scope.

Code of Federal Regulations, 2013 CFR

2013-04-01

... CONDITIONALLY FREE, SUBJECT TO A REDUCED RATE, ETC. Dominican Republic-Central America-United States Free Trade... provisions applicable to imported and exported goods under the Dominican Republic—Central America—United...—Central America—United States Free Trade Agreement Implementation Act (the Act; Pub. L. 109-53, 119 Stat...

19 CFR 10.581 - Scope.

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2014-04-01

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19 CFR 10.581 - Scope.

Code of Federal Regulations, 2012 CFR

2012-04-01

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Central nervous system activity of the ethanol leaf extract of Sida acuta in rats.

PubMed

Ibironke, G F; Umukoro, A S; Ajonijebu, D C

2014-03-01

The study investigated the pharmacological effects of ethanol extract of Sida acuta leaves on central nervous system activities in mice. Adult male mice (18 - 25g) were used for the study. The extract was administered orally in male mice and evaluated in the following tests: forced swimming, tail suspension, formalin-induced paw licking, acetic acid--induced mouse writhing and apomorphine-induced stereotypy. The results revealed a reduction in the frequency of abdominal constrictions induced by acetic acid, decreased licking times in both phases of the formalin test, reduction in immobility times in forced swimming and tail suspension tests. However, the extract produced no effect on apomorphine-induced stereotyped behaviour. These results suggest that the ethanol extract of Sida acuta contains psychoactive substances with analgesic and antidepressant-like properties which may be beneficial in the management of pain.

The association between adolescent and parental use of non-prescription analgesics for headache and other somatic pain - A cross-sectional study.

PubMed

Hasseleid, Synva Nesheim; Clench-Aas, Jocelyne; Raanaas, Ruth Kjærsti; Lundqvist, Christofer

2017-07-01

Over the last years, concern has been expressed about adolescents' possible liberal attitude towards - and use of - non-prescription analgesics. A high consumption of analgesics is unfortunate as it may lead to various harmful effects and worsening of headache. In order to address this challenge, it is necessary to achieve a more extensive knowledge about adolescent consumption. The main aim of this study was to examine the association between adolescent and parental use of non-prescription analgesics, taking into account headache as well as other somatic pain. The effects of parental prescription analgesics use was a secondary aim. The study is based on data from two cross-sectional health studies conducted in 2005 and 2012 in Norway, including 646 adolescents and an accompanying parent. By using sample weights, the final weighted sample used in the analysis was 1326. Data was collected through postal questionnaires to parents and adolescents as well as parental telephone interviews. Questionnaires included questions on different pain locations and the pain for each location was graded according to how troubling the pain was. Medication data on prescription and non-prescription analgesics was from telephone interviews and was quantified based on the pattern over the past 4 weeks. Multivariate logistic regression models and complex samples analyses were used. 20% of adolescents were reported as using non-prescription analgesics during the previous 4 weeks. Girls were more often reported to use non-prescription analgesics than boys. Headache and all other somatic pain locations except back pain were reported more frequently among girls while boys more frequently reported back pain. There was a clear association between the use of non-prescription analgesics and headache with 34% of adolescents with headache using non-prescription analgesics versus 19% of adolescents with other somatic pain and 14% of adolescents not reporting pain. Among adolescents reporting headache, 9% were reported to use non-prescription analgesics daily or almost daily versus 3% and 2% among those reporting other somatic pain and reporting no pain respectively. In addition, parental use of non-prescription analgesics was a strong independent predictor of adolescent use (adjusted OR 1.69 for boys, 1.54 for girls). This relationship increased when the adolescents were less bothered by headache themselves. Headache is the dominant medication-driving pain for non-prescription analgesics among adolescents but parental medication use of non-prescription analgesics also strongly influences adolescent use. There is a need for health services to improve information to parents and adolescents about risks associated with use of analgesics and also to work on prophylactic strategies focusing on adolescents. Parents should be made aware that their medicine use strongly influences that of their children. Copyright © 2017 Scandinavian Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

Analgesic activity of Nelsonia canescens (Lam.) Spreng.root in albino rats

PubMed Central

Mohaddesi, Behzad; Dwivedi, Ravindra; Ashok, B. K.; Aghera, Hetal; Acharya, Rabinarayan; Shukla, V. J.

2013-01-01

Present study was undertaken to evaluate analgesic activity of root of Nelsonia canescens (Lam.) Spreng, a folklore medicinal plant used as the one of the source plant of Rasna. Study was carried out at two dose levels (270 mg/kg and 540 mg/kg) in albino rats. Analgesic activity was evaluated in formalin induced paw licking, and tail flick methods whereas indomethacin and pentazocine were used as standard analgesic drugs, respectively. At both the dose levels, test drug non-significantly decreased paw licking response at both time intervals. In tail flick model, the administration of the test drug increased pain threshold response in a dose dependent manner. In therapeutically equivalent dose level, analgesic activity was observed only after 180 min while in TED ×2 treated group analgesia was observed at 30 min and lasted even up to 240 min. The results suggested that N.canescens root possess moderate analgesic activity. PMID:24250136

32 CFR 1901.62 - General exemptions.

Code of Federal Regulations, 2011 CFR

2011-07-01

... National Defense Other Regulations Relating to National Defense CENTRAL INTELLIGENCE AGENCY PUBLIC RIGHTS... in section (j) of the Privacy Act, the Director of Central Intelligence has determined to exempt from... Privacy Act, the Director of Central Intelligence has determined to exempt from sections (c)(3) and (e)(3...

32 CFR 1901.62 - General exemptions.

Code of Federal Regulations, 2013 CFR

2013-07-01

... National Defense Other Regulations Relating to National Defense CENTRAL INTELLIGENCE AGENCY PUBLIC RIGHTS... in section (j) of the Privacy Act, the Director of Central Intelligence has determined to exempt from... Privacy Act, the Director of Central Intelligence has determined to exempt from sections (c)(3) and (e)(3...

Meperidine utilization and compliance with Agency for Health Care Policy and Research guidelines in a tertiary care hospital.

PubMed

Pellegrini, J E; Paice, J; Faut-Callahan, M

1999-11-01

The Agency for Health Care Policy and Research (AHCPR) established guidelines for the use of meperidine (demerol), a common inpatient analgesic. These guidelines define standards of care for acute and chronic cancer pain management and address many of the problems with meperidine and its metabolite, normeperidine. The purpose of this study was to determine whether meperidine was prescribed in compliance with AHCPR guidelines, whether patients exhibited any adverse reactions to meperidine, and to determine the analgesic efficacy of meperidine. Three hundred inpatient charts were reviewed and identified meperidine as the primary analgesic in 157 nonobstetric inpatients. Age, sex, weight, dosing interval, route of administration, duration of meperidine use, serum chemistry values, primary diagnosis, associated medical conditions, and medications concurrently being taken with meperidine were the parameters analyzed. An interview was conducted to ascertain medical and drug history, chronicity of pain syndromes, analgesic drug history, and analgesic efficacy. A visual analog scale for pain (range = 0 to 10) and an analgesic satisfaction survey (range = 1 to 5) were used. Of 157 patients, 124 (79.8%) were in conflict with AHCPR guidelines. The most frequent conflict was found to be suboptimal dosing regimen and treatment of chronic pain. Often concurrent analgesics were given with the meperidine to achieve adequate analgesia. Higher analgesic satisfaction scores were noted when meperidine was given with concurrent analgesics. Meperidine also was administered to patients in renal failure or with medications contraindicated with meperidine use. No significant adverse effects were noted with meperidine use in this sample population other than an increased incidence of confusion in the elderly population.

Clinical Analysis of Analgesics and Steroids Use for Extraction of Teeth in Patients with Intellectual Disability Under General Anesthesia.

PubMed

Maeda, Shigeru; Honda, Yuka; Tanimura, Hiroshi; Tomoyasu, Yumiko; Higuchi, Hitoshi; Murata, Naomichi; Egusa, Masahiko; Miyawaki, Takuya

2017-01-01

The extraction of lower wisdom teeth is often performed under general anesthesia in patients with intellectual disabilities. However, the choice of analgesics has not yet been investigated. To analyze the use of analgesics during general anesthesia for extraction including lower wisdom teeth in patients with intellectual disabilities. This research is a retrospective observational study. The study population was composed of all patients presenting for extraction of lower wisdom teeth under ambulatory general anesthesia in the clinic of Special Needs Dentistry in Okayama University Hospital from April 2011 to March 2016. The distribution of the combination of analgesics and the relationship between the use of analgesics and the type of extraction were investigated. One hundred and twelve cases were enrolled in this study. Intravenous injections of flurbiprofen, acetaminophen and betamethasone were used in 96 (85.7%), 12 (10.7%) and 26 cases (23.2%), respectively. Flurbiprofen is a non-steroid anti-inflammatory drugs (NSAIDs). Acetaminophen is an old analgesic, but an injection of acetaminophen is new, which was released in 2013 in Japan. And betamethasone is not an analgesic, but a steroid. Betamethasone was used in combination with other analgesics, and was used at a higher dose in a case in which four wisdom teeth were extracted. Flurbiprofen was the main analgesic used for extraction of wisdom teeth under general anesthesia in patients with intellectual disabilities. Betamethasone was used to support flurbiprofen or acetaminophen for extractions of multiple wisdom teeth, with the aim of controlling swelling rather than relieving pain.

Cannabis Use is Associated with Lower Odds of Prescription Opioid Analgesic Use Among HIV-Infected Individuals with Chronic Pain.

PubMed

Sohler, Nancy L; Starrels, Joanna L; Khalid, Laila; Bachhuber, Marcus A; Arnsten, Julia H; Nahvi, Shadi; Jost, John; Cunningham, Chinazo O

2018-01-17

Chronic pain is common in the United States and prescribed opioid analgesics use for noncancer pain has increased dramatically in the past two decades, possibly accounting for the current opioid addiction epidemic. Co-morbid drug use in those prescribed opioid analgesics is common, but there are few data on polysubstance use patterns. We explored patterns of use of cigarette, alcohol, and illicit drugs in HIV-infected people with chronic pain who were prescribed opioid analgesics. We conducted a secondary data analysis of screening interviews conducted as part of a parent randomized trial of financial incentives to improve HIV outcomes among drug users. In a convenience sample of people with HIV and chronic pain, we collected self-report data on demographic characteristics; pain; patterns of opioid analgesic use (both prescribed and illicit); cigarette, alcohol, and illicit drug use (including cannabis, heroin, and cocaine) within the past 30 days; and current treatment for drug use and HIV. Almost half of the sample of people with HIV and chronic pain reported current prescribed opioid analgesic use (N = 372, 47.1%). Illicit drug use was common (N = 505, 63.9%), and cannabis was the most commonly used illicit substance (N = 311, 39.4%). In multivariate analyses, only cannabis use was significantly associated with lower odds of prescribed opioid analgesic use (adjusted odds ratio = 0.57; 95% confidence interval: 0.38-0.87). Conclusions/Importance: Our data suggest that new medical cannabis legislation might reduce the need for opioid analgesics for pain management, which could help to address adverse events associated with opioid analgesic use.

Clinical pharmacology of analgesics assessed with human experimental pain models: bridging basic and clinical research

PubMed Central

Oertel, Bruno Georg; Lötsch, Jörn

2013-01-01

The medical impact of pain is such that much effort is being applied to develop novel analgesic drugs directed towards new targets and to investigate the analgesic efficacy of known drugs. Ongoing research requires cost-saving tools to translate basic science knowledge into clinically effective analgesic compounds. In this review we have re-examined the prediction of clinical analgesia by human experimental pain models as a basis for model selection in phase I studies. The overall prediction of analgesic efficacy or failure of a drug correlated well between experimental and clinical settings. However, correct model selection requires more detailed information about which model predicts a particular clinical pain condition. We hypothesized that if an analgesic drug was effective in an experimental pain model and also a specific clinical pain condition, then that model might be predictive for that particular condition and should be selected for development as an analgesic for that condition. The validity of the prediction increases with an increase in the numbers of analgesic drug classes for which this agreement was shown. From available evidence, only five clinical pain conditions were correctly predicted by seven different pain models for at least three different drugs. Most of these models combine a sensitization method. The analysis also identified several models with low impact with respect to their clinical translation. Thus, the presently identified agreements and non-agreements between analgesic effects on experimental and on clinical pain may serve as a solid basis to identify complex sets of human pain models that bridge basic science with clinical pain research. PMID:23082949

Periosteal infusion of bupivacaine/morphine post sternal fracture: a new analgesic technique.

PubMed

Duncan, Michael A; McNicholas, Walter; O'Keeffe, Declan; O'Reilly, Maeve

2002-01-01

Sternal fracture pain is severe and is difficult to alleviate due to the forces acting on the chest wall during respiration. We describe a continuous infusion regional analgesic technique for pain due to sternal fracture. A 47-year-old woman presented with a spontaneous sternal fracture, precluding effective coughing. Diclofenac and increasing doses of opioids did not give adequate pain relief and led to opioid toxicity. Two brief periods of analgesia were achieved with deep subcutaneous infiltration of bupivacaine. An epidural catheter was positioned periosteally, and an infusion of bupivacaine was commenced at 5 mL/h, achieving long-lasting analgesia. The bupivacaine concentration was reduced in a stepwise fashion from 0.5% to 0.25% and was changed to levobupivacaine after 3 days. Adding morphine (5 mg/60 mL levobupivicaine) permitted a reduction in infusion rate. The catheter was removed after 14 days because a local infection developed that resolved uneventfully with antibiotic therapy. Continuous infusion of local anesthetic and opioid to a sternal fracture site using a periosteally positioned catheter led to successful analgesia and hence improved respiratory function. Clinicians should consider placing a periosteal catheter when pain associated with sternal fracture cannot be adequately controlled with conventional methods.

β-Arrestins: Regulatory Role and Therapeutic Potential in Opioid and Cannabinoid Receptor-Mediated Analgesia

PubMed Central

Bohn, Laura M.

2016-01-01

Pain is a complex disorder with neurochemical and psychological components contributing to the severity, the persistence, and the difficulty in adequately treating the condition. Opioid and cannabinoids are two classes of analgesics that have been used to treat pain for centuries and are arguably the oldest of “pharmacological” interventions used by man. Unfortunately, they also produce several adverse side effects that can complicate pain management. Opioids and cannabinoids act at G protein-coupled receptors (GPCRs), and much of their effects are mediated by the mu-opioid receptor (MOR) and cannabinoid CB1 receptor (CB1R), respectively. These receptors couple to intracellular second messengers and regulatory proteins to impart their biological effects. In this chapter, we review the role of the intracellular regulatory proteins, β-arrestins, in modulating MOR and CB1R and how they influence the analgesic and side-effect profiles of opioid and cannabinoid drugs in vivo. This review of the literature suggests that the development of opioid and cannabinoid agonists that bias MOR and CB1R toward G protein signaling cascades and away from β-arrestin interactions may provide a novel mechanism by which to produce analgesia with less severe adverse effects. PMID:24292843

US Food and Drug Administration's Risk Evaluation and Mitigation Strategy for extended-release and long-acting opioids: pros and cons, and a European perspective.

PubMed

Mercadante, Sebastiano; Craig, David; Giarratano, Antonello

2012-12-24

Prescriptions for opioid analgesics to manage moderate-to-severe chronic non-cancer pain have increased markedly over the last decade. An unintentional consequence of greater prescription opioid utilization has been the parallel increase in misuse, abuse and overdose, which are serious risks associated with all opioid analgesics. In response to disturbing rises in prescription opioid abuse, the US Food and Drug Administration (FDA) has proposed the implementation of aggressive Risk Evaluation and Mitigation Strategies (REMS). While REMS could dramatically change the development, release, marketing and prescription of extended-release opioids, questions remain on how these programmes may influence prescribing practices, patient safety and ultimately patient access to these agents. The extent of the availability and misuse of prescription opioids in Europe is difficult to assess from the data currently available, due in large part to the considerable differences in prescribing patterns and regulations between countries. Balancing the availability of prescription opioids for those patients who have pain, while discouraging illicit use, is a complex challenge and requires effective efforts on many levels, particularly in Europe where policies are quite different between countries.

High use of over-the-counter analgesic; possible warnings of reduced quality of life in adolescents - a qualitative study.

PubMed

Skarstein, Siv; Lagerløv, Per; Kvarme, Lisbeth Gravdal; Helseth, Sølvi

2016-01-01

Use of over-the-counter analgesics among adolescents has increased markedly. High consumption of over-the-counter analgesics among adolescents is associated with frequent pain, lower self-esteem, reduced sleep, lower educational ambition, binge drinking, higher caffeine consumption, and part-time employment. Knowledge about life experiences of adolescents who frequently use over-the-counter analgesics may be useful to prevent health problems. The purpose of the study was to increase knowledge about adolescents who suffer from frequent pain and have a high consumption of over-the-counter analgesics. A qualitative study, employing one-on-one, in-depth interviews using a thematic interview guide. Data were collected in Norway in 2013-2014. Three boys and sixteen girls; aged 14-16 years, who continuously consumed over-the-counter analgesics were recruited from ten high schools in urban and suburban districts. Candidate participants were excluded if they were medically diagnosed with an acute or chronic illness, requiring extended use of over-the-counter analgesics within the last year. The interviews were taped, transcribed and analysed as text according to Kvale's three contexts of interpretation: self-understanding, common sense and theory. All participants disclosed unresolved physical and psychosocial distress characterized as pain. Frequent pain from various body parts made everyday life challenging. Methods of pain self-appraisal and over-the-counter analgesics use often mimicked maternal patterns. Participants reported being raised under unpredictable circumstances that contributed to long lasting family conflicts and peer-group problems. Participants wanted to feel appreciated and to be socially and academically successful. However, pain reduced their ability to manage everyday life, hampered experienced possibilities for success, and made social settings difficult. Childhood experiences influence how adolescents experience pain and use over-the-counter analgesics. Coping with difficult situations or attempting to mask symptoms with over-the-counter analgesics can perpetuate and amplify underlying problems. High consumption of over-the-counter analgesics and frequent pain may be warning signs of adolescents with possible health threatening conditions and reduced quality of life. These adolescent might be in need of support from school nurses and General Practitioners. This study identifies new perspectives that may lead to novel approaches to identify, guide, and support adolescents with frequent pain and high consumption of over-the-counter analgesics.

Targeted nanoparticles that mimic immune cells in pain control inducing analgesic and anti-inflammatory actions: a potential novel treatment of acute and chronic pain condition.

PubMed

Hua, Susan; Cabot, Peter J

2013-01-01

The peripheral immune-derived opioid analgesic pathway has been well established as a novel target in the clinical pain management of a number of painful pathologies, including acute inflammatory pain, neuropathic pain, and rheumatoid arthritis. Our objective was to engineer targeted nanoparticles that mimic immune cells in peripheral pain control to deliver opioids, in particular loperamide HCl, specifically to peripheral opioid receptors to induce analgesic and anti-inflammatory actions for use in painful inflammatory conditions. This peripheral analgesic system is devoid of central opioid mediated side effects (e.g., respiratory depression, sedation, dependence, tolerance). A randomized, double blind, controlled animal trial. Thirty-six adult male Wistar rats (200 - 250 g) were randomly divided into 6 groups: loperamide HCl-encapsulated anti-ICAM-1 immunoliposomes, naloxone methiodide + loperamide HCl-encapsulated anti-ICAM-1 immunoliposomes, loperamide HCl-encapsulated liposomes, empty anti-ICAM-1 immunoliposomes, empty liposomes, and loperamide solution. Animals received an intraplantar injection of 150 μL Complete Freund's Adjuvant (CFA) into the right hindpaw and experiments were performed 5 days post-CFA injection, which corresponded to the peak inflammatory response. All formulations were administered intravenously via tail vein injection. The dose administered was 200 μL, which equated to 0.8 mg of loperamide HCl for the loperamide HCl treatment groups (sub-therapeutic dose). Naloxone methiodide (1 mg/kg) was administered via intraplantar injection, 15 minutes prior to loperamide-encapsulated anti-ICAM-1 immunoliposomes. An investigator blinded to the treatment administered assessed the time course of the antinociceptive and anti-inflammatory effects using a paw pressure analgesiometer and plethysmometer, respectively. Biodistribution studies were performed 5 days post-CFA injection with anti-ICAM-1 immunoliposomes and control liposomes via tail vein injection using liquid scintillation counting (LSC). Administration of liposomes loaded with loperamide HCl, and conjugated with antibody to intercellular adhesion molecule-1 (anti-ICAM-1), exerted analgesic and anti-inflammatory effects exclusively in peripheral painful inflamed tissue. These targeted nanoparticles produced highly significant analgesic and anti-inflammatory effects over the 48 hour time course studied following intravenous administration in rats with Complete Freund's Adjuvant-induced inflammation of the paw. All control groups showed no significant antinociceptive or anti-inflammatory effects. Our biodistribution study demonstrated specific localization of the targeted nanoparticles to peripheral inflammatory tissue and no significant uptake into the brain. In vivo studies were performed in the well-established rodent model of acute inflammatory pain. We are currently studying this approach in chronic pain models known to have clinical activation of the peripheral immune-derived opioid response. The study presents a novel approach of opioid delivery specifically to injured tissues for pain control. The study also highlights a novel anti-inflammatory role for peripheral opioid targeting, which is of clinical relevance. The potential also exists for the modification of these targeted nanoparticles with other therapeutic compounds for use in other painful conditions.

Prehospital and En Route Analgesic Use in the Combat Setting: A Prospectively Designed, Multicenter, Observational Study

DTIC Science & Technology

2015-03-01

combat medic has access to both opioid and nonopioid analgesics.3 Morphine and fentanyl are effective opioid analgesics and are commonly used...transmucosal (TM) fentanyl8,9 or parenteral ketamine. YM fentanyl has been shown to be a safe, effective, and easy method of administer- ing analgesics in a...a subsequent different drug, or the same drug via an alternative route). Ketamine was most frequently administered, followed by fentanyl , mor- phine

Preventability of adverse effects of analgesics: analysis of spontaneous reports.

PubMed

Cazacu, Irina; Miremont-Salamé, Ghada; Mogosan, Cristina; Fourrier-Réglat, Annie; Loghin, Felicia; Haramburu, Françoise

2015-05-01

The aims of this study were to determine the patterns of analgesic adverse drug reactions (ADRs) and to assess their preventability and contributing factors. This is a retrospective, descriptive study conducted on ADRs of analgesics and other drugs indicated as analgesics, spontaneously reported to the Bordeaux pharmacovigilance center from January 2011 to June 2012. The 141 cases selected for the analysis included 16 cases of medication errors (11.3%) and 15 addiction cases (10.6%). In total, 214 ADRs were registered, for which 173 analgesic medicines were suspected. The most frequent ADRs reported were nervous system disorders (26.6%), psychiatric disorders (15.0%), and skin and subcutaneous tissue disorders (12.1%). Tramadol alone or in combination (17.3%), followed by morphine (15%), fentanyl (9.8%), and paracetamol (8.7%) were the most frequently involved analgesics. More than half of the cases (54.6%) were serious and led to hospitalization or prolonged hospitalization. Preventability was determined for 134 cases (95%): 51.5% were considered as preventable, 26.1% not preventable, and 22.4% not assessable. The main contributing factors for the preventable cases included negligence of recommendations for analgesic use and failure to consider patients' risk factors when prescribing. A significant number of analgesic ADRs could be prevented, and being aware of their contributing factors promotes efficient analgesia with minimum risks to the patients.

Clinical and demographic covariates of chronic opioid and non-opioid analgesic use in rural-dwelling older adults: the MoVIES project.

PubMed

Karp, Jordan F; Lee, Ching-Wen; McGovern, Jonathan; Stoehr, Gary; Chang, Chung-Chou H; Ganguli, Mary

2013-11-01

To describe covariates and patterns of late-life analgesic use in the rural, population-based MoVIES cohort from 1989 to 2002. Secondary analysis of epidemiologic survey of elderly people conducted over six biennial assessment waves. Potential covariates of analgesic use included age, gender, depression, sleep, arthritis, smoking, alcohol, and general health status. Of the original cohort of 1,681, this sample comprised 1,109 individuals with complete data on all assessments. Using trajectory analysis, participants were characterized as chronic or non-chronic users of opioid and non-opioid analgesics. Multivariable regression was used to model predictors of chronic analgesic use. The cohort was followed for mean (SD) 7.3 (2.7) years. Chronic use of opioid analgesics was reported by 7.2%, while non-opioid use was reported by 46.1%. In the multivariable model, predictors of chronic use of both opioid and non-opioid analgesics included female sex, taking ≥2 prescription medications, and "arthritis" diagnoses. Chronic opioid use was also associated with age 75-84 years; chronic non-opioid use was also associated with sleep continuity disturbance. These epidemiological data confirm clinical observations and generate hypotheses for further testing. Future studies should investigate whether addressing sleep problems might lead to decreased use of non-opioid analgesics and possibly enhanced pain management.

Caffeine as an opioid analgesic adjuvant in fibromyalgia

PubMed Central

Scott, J Ryan; Hassett, Afton L; Brummett, Chad M; Harris, Richard E; Clauw, Daniel J; Harte, Steven E

2017-01-01

Background Caffeine’s properties as an analgesic adjuvant with nonsteroidal anti-inflammatory drugs/acetaminophen are well documented. However, little clinical research has explored caffeine’s effects on opioid analgesia. This study assessed the effects of caffeine consumption on pain and other symptoms in opioid-using and nonusing chronic pain patients meeting the survey criteria for fibromyalgia. Materials and methods Patients presenting to a university-based pain clinic completed validated self-report questionnaires assessing symptoms. Patients (N=962) meeting the fibromyalgia survey criteria were stratified by opioid use and further split into groups based on caffeine amount consumed per day (no caffeine, or low, moderate, high caffeine). Analysis of covariance with Dunnett’s post hoc testing compared pain and symptom severity between the no caffeine group and the caffeine consuming groups. Results In opioid users, caffeine consumption had modest but significant effects on pain, catastrophizing, and physical function. Lower levels of pain interference were associated with low and moderate caffeine use compared to no caffeine intake. Lower pain catastrophizing and higher physical function were observed in all caffeine dose groups, relative to the no caffeine group. Lower pain severity and depression were observed only in the moderate caffeine group. In opioid nonusers, low caffeine intake was associated with higher physical function; however, no other significant effects were observed. Conclusion Caffeine consumption was associated with decreased pain and symptom severity in opioid users, but not in opioid nonusers, indicating caffeine may act as an opioid adjuvant in fibromyalgia-like chronic pain patients. These data suggest that caffeine consumption concomitant with opioid analgesics could provide therapeutic benefits not seen with opioids or caffeine alone. PMID:28814895

NOP Receptor Mediates Anti-analgesia Induced by Agonist-Antagonist Opioids

PubMed Central

Gear, Robert W.; Bogen, Oliver; Ferrari, Luiz F.; Green, Paul G.; Levine, Jon D.

2014-01-01

Clinical studies have shown that agonist-antagonist opioid analgesics that produce their analgesic effect via action on the kappa-opioid receptor, produce a delayed-onset anti-analgesia in men but not women, an effect blocked by co-administration of a low dose of naloxone. We now report the same time-dependent anti-analgesia and its underlying mechanism in an animal model. Using the Randall-Selitto paw-withdrawal assay in male rats, we found that nalbuphine, pentazocine, and butorphanol each produced analgesia during the first hour followed by anti-analgesia starting at ~90 minutes after administration in males but not females, closely mimicking its clinical effects. As observed in humans, co-administration of nalbuphine with naloxone in a dose ratio of 12.5:1 blocked anti-analgesia but not analgesia. Administration of the highly selective kappa-opioid receptor agonist U69,593 produced analgesia without subsequent anti-analgesia, and confirmed by the failure of the selective kappa antagonist nor-binaltorphimine to block nalbuphine-induced anti-analgesia, indicating that anti-analgesia is not mediated by kappa-opioid receptors. We therefore tested the role of other receptors in nalbuphine anti-analgesia. Nociceptin/orphanin FQ (NOP) and sigma-1 and sigma-2 receptors were chosen on the basis of their known anti-analgesic effects and receptor binding studies. The selective NOP receptor antagonists, JTC801, and J113397, but not the sigma receptor antagonist, BD 1047, antagonized nalbuphine anti-analgesia. Furthermore, the NOP receptor agonist NNC 63-0532 produced anti-analgesia with the same delay in onset observed with the three agonist-antagonists, but without producing preceding analgesia and this anti-analgesia was also blocked by naloxone. These results strongly support the suggestion that clinically used agonist-antagonists act at the NOP receptor to produce anti-analgesia. PMID:24188792

Ligand requirements for involvement of PKCε in synergistic analgesic interactions between spinal μ and δ opioid receptors.

PubMed

Schuster, D J; Metcalf, M D; Kitto, K F; Messing, R O; Fairbanks, C A; Wilcox, G L

2015-01-01

We recently found that PKCε was required for spinal analgesic synergy between two GPCRs, δ opioid receptors and α2 A adrenoceptors, co-located in the same cellular subpopulation. We sought to determine if co-delivery of μ and δ opioid receptor agonists would similarly result in synergy requiring PKCε. Combinations of μ and δ opioid receptor agonists were co-administered intrathecally by direct lumbar puncture to PKCε-wild-type (PKCε-WT) and -knockout (PKCε-KO) mice. Antinociception was assessed using the hot-water tail-flick assay. Drug interactions were evaluated by isobolographic analysis. All agonists produced comparable antinociception in both PKCε-WT and PKCε-KO mice. Of 19 agonist combinations that produced analgesic synergy, only 3 required PKCε for a synergistic interaction. In these three combinations, one of the agonists was morphine, although not all combinations involving morphine required PKCε. Morphine + deltorphin II and morphine + deltorphin I required PKCε for synergy, whereas a similar combination, morphine + deltorphin, did not. Additionally, morphine + oxymorphindole required PKCε for synergy, whereas a similar combination, morphine + oxycodindole, did not. We discovered biased agonism for a specific signalling pathway at the level of spinally co-delivered opioid agonists. As the bias is only revealed by an appropriate ligand combination and cannot be accounted for by a single drug, it is likely that the receptors these agonists act on are interacting with each other. Our results support the existence of μ and δ opioid receptor heteromers at the spinal level in vivo. This article is part of a themed section on Opioids: New Pathways to Functional Selectivity. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue-2. © 2014 The British Pharmacological Society.

The effect of local anesthetic infiltration around nephrostomy tract on postoperative pain control after percutaneous nephrolithotomy.

PubMed

Tüzel, Emre; Kızıltepe, Günes; Akdoğan, Bülent

2014-08-01

The objective of the study was to investigate the effect of a long acting local anesthetic infiltration around nephrostomy tract on pain control after percutaneous nephrolithotomy. Forty-six patients with kidney stones of >2 cm undergoing single access subcostal percutaneous nephrolithotomy (PCNL) were enrolled in the study. Patients were randomized to levobupivacaine (Group I) and saline (Group II) infiltration groups. Group I patients (n = 23) had 75 mg/30 cc levobupivacaine infiltration around the access site after placement of nephrostomy catheter. Group II patients had 30 cc saline infiltration. Postoperatively the patients were given narcotics on demand. Pain scores were collected using a visual analog scale (VAS) at 2, 4, 6, 8, 12 and 24 h postoperatively. The VAS scores, time to analgesic demand, ambulation, and duration of nephrostomy tube were compared between two groups. The mean age was 44 and 45 years in group I and II patients. There were no significant differences between the two groups with regard to demographics, surgery or stone characteristics. Comparison of pain scores at all postoperative time points was not statistically significant between the two groups. Time to first analgesic demand and total narcotic analgesic dose per patient were 1.2 ± 1.05 and 4.04 ± 1.57 h; and 96 and 112 mg for group I and II patients (p = 0.009 and p = 0.41, respectively). Ambulation time and duration of nephrostomy tube were also similar. Infiltration of nephrostomy tract site with levobupivacaine does not have a superior effect compared to saline on postoperative pain control in patients undergoing PCNL.To prolong analgesia, the effect of intermittent tract injections or continuous infusion of local anesthetics for the postoperative maintenance of the local anesthetic effect seems worth to investigate in future studies.

SCOPE of Pain: An Evaluation of an Opioid Risk Evaluation and Mitigation Strategy Continuing Education Program

PubMed Central

Zisblatt, Lara; Ng, Pamela; Hayes, Sean M.; Peloquin, Sophie; Hardesty, Ilana; White, Julie L.

2016-01-01

Objective. Due to the high prevalence of prescription opioid misuse, the US Food and Drug Administration (FDA) mandated a Risk Evaluation and Mitigation Strategy (REMS) requiring manufacturers of extended-release/long-acting (ER/LA) opioid analgesics to fund continuing education based on a FDA Blueprint. This article describes the Safe and Competent Opioid Prescribing Education (SCOPE of Pain) program, an ER/LA opioid analgesic REMS program, and its impact on clinician knowledge, confidence, attitudes, and self-reported clinical practice. Method. Participants of the 3-h SCOPE of Pain training completed pre-, immediate post- and 2-month post-assessments. Subjects. The primary target group (n = 2,850), and a subset (n = 476) who completed a 2-month post-assessment, consisted of clinicians licensed to prescribe ER/LA opioid analgesics, who care for patients with chronic pain and who completed the 3-h training between February 28, 2013 and June 13, 2014. Results. Immediately post-program, there was a significant increase in correct responses to knowledge questions (60% to 84%, P ≤ 0.02) and 87% of participants planned to make practice changes. At 2-months post-program, there continued to be a significant increase in correct responses to knowledge questions (60% to 69%, P ≤ 0.03) and 67% reported increased confidence in applying safe opioid prescribing care and 86% reported implementing practice changes. There was also an improvement in alignment of desired attitudes toward safe opioid prescribing. Conclusions. The SCOPE of Pain program improved knowledge, attitudes, confidence, and self-reported clinical practice in safe opioid prescribing. This national REMS program holds potential to improve the safe use of opioids for the treatment of chronic pain. PMID:26304703

Lion's Mane Medicinal Mushroom, Hericium erinaceus (Agaricomycetes), Modulates Purinoceptor-Coupled Calcium Signaling and Murine Nociceptive Behavior.

PubMed

Liu, Pei-Shan; Chueh, Sheau-Huei; Chen, Chin-Chu; Lee, Li-Ya; Shiu, Li-Yen

2017-01-01

Hericium erinaceus is well known for the neurotrophic effect it confers by promoting nerve growth factor biosynthesis. We discovered a novel bioactivity of H. erinaceus in its ability to suppress adenosine triphosphate (ATP)-induced calcium signaling in neuronal PC12 cells. ATP, known primarily as a neurotransmitter, also acts on purinoceptors (P2 purinergic receptor [P2R]) to generate the cellular calcium signaling and secretion that mediate P2R physiological manifestations, including pain. Chronic pain reduces quality of life. However, constant analgesic administration can cause liver and kidney injury, as well as loss of the analgesic effect because of desensitization. In this study we investigated the analgesic potential of H. erinaceus through measurements of ATP-induced Ca2+ signaling in cell lines and observation of pain behaviors in mice. In P2R-coupled Ca2+ signaling measurements, extracts of H. erinaceus mycelia (HEEs) blocked ATP-induced Ca2+ signaling in both rat PC12 cells and human HOS cells. HEEs completely blocked ATP-induced Ca2+ signaling in human HOS cells, suggesting that this effect of HEEs is exerted through the P2R subtypes present in HOS cells, which include the P2X4, P2X7, P2Y2, and P2Y4 subtypes. In observations of animal behavior during pain, HEEs significantly reduced heat-induced pain, including postponing both the tail-flick response to heat stimulation and the paw-lifting response to a hot plate. This study demonstrates novel characteristics of H. erinaceus in reducing nociceptive behavior and blocking the functional activity of P2R. Further studies are required to verify this linkage and its molecular mechanisms.

Increases in the use of prescription opioid analgesics and the lack of improvement in disability metrics among users.

PubMed

Sites, Brian D; Beach, Michael L; Davis, Matthew A

2014-01-01

In the United States, use of oral opioid analgesics has been associated with increasing rates of addiction, abuse, and diversion. However, little is known about the recent national use of non-illicit prescription opioid analgesics (those prescribed in a physician-patient relationship), the primary source of these drugs for the general US population. Our primary objective was to examine trends in the use of prescription opioid analgesics in the United States and to identify defining characteristics of patient users of prescribed opioids from 2000 to 2010. We used the nationally representative Medical Expenditure Panel Survey to examine trends in prescription oral opioid analgesic use from 2000 to 2010. We used survey design methods to make national estimates of adults (18 years and older) who reported receiving an opioid analgesic prescription (referred to as opioid users) and used logistic regression to examine predictors of opioid analgesic use. Our primary outcome measures were national estimates of total users of prescription opioid analgesics and total number of prescriptions. Our secondary outcome was that of observing changes in the disability and health of the users. The estimated total number of opioid analgesic prescriptions in the United States increased by 104%, from 43.8 million in 2000 to 89.2 million in 2010. In 2000, an estimated 7.4% (95% confidence interval, 6.9-7.9) of adult Americans were prescription opioid users compared with 11.8% (95% confidence interval, 11.2-12.4) in 2010. On the basis of estimates adjusted for changes in the general population, each year was associated with a 6% increase in the likelihood of receiving an opioid prescription from 2000 to 2010. Despite the apparent increase in use, there were no demonstrable improvements in the age- or sex-adjusted disability and health status measures of opioid users. The use of prescription opioid analgesics among adult Americans has increased in recent years, and this increase does not seem to be associated with improvements in disability and health status among users. On a public health level, these data suggest that there may be an opportunity to reduce the prescribing of opioid analgesics without worsening of population health metrics.

Nursing knowledge and beliefs regarding patient-controlled oral analgesia (PCOA).

PubMed

Sawhney, Monakshi; Maeda, Eri

2013-12-01

Patient-controlled oral analgesia (PCOA) allows patients to self-administer oral opioids for pain management. Advantages of PCOA include improved pain control with lower doses of opioids, decreased length of stay, increased patient satisfaction, and better functional outcomes than conventional nurse-administered oral analgesia. Sucessful PCOA programs are well described in the literature. However, nurses have concerns about allowing patients to self-administer opioids. The purpose of this study was to identify nurses' knowledge and beliefs regarding PCOA. Nurses who work at the Holland Orthopaedic and Arthritic Centre were asked to complete a survey exploring their beliefs regarding PCOA. The nurses were asked to complete the same survey twice: before an education program in February 2010, and 3 months after implementation of PCOA in June 2010. In February 2010, 74 nurses and in June 2010, 32 nurses participated in the survey. Some nurses (18%) had previous experience with PCOA. At both the pre-education and the postimplementation times, nurses thought that the PCOA program reduced wait times for analgesics and improved patient satisfaction with pain management. Before program implementation, negative beliefs included that patients on the PCOA program would lose their analgesics, would give their analgesics to visitors or other patients, and were at risk for having their analgesics stolen and that the nurse was liable if the patient's analgesics were lost or stolen. After program implementation, no nurse believed that patients would lose their analgesics or give their analgesics to visitors or other patients or that they were liable for lost or stolen analgesics. However, nurses continued to think that patients were at risk for having their analgesics stolen. We found that nurses were concerned that analgesics could be lost, misused, or stolen and that they would be liable for lost analgesics. These findings were consistent with literature discussing patients' outcomes regarding PCOA. However, after education and experience these concerns decreased or resolved. It is important to address these concerns before PCOA program implementation. Copyright © 2013 American Society for Pain Management Nursing. Published by Elsevier Inc. All rights reserved.

Pattern of Self Prescribed Analgesic Use in a Rural Area of Delhi: Exploring the Potential Role of Internet.

PubMed

Kochhar, Anjali; Gupta, Tanya

2017-07-01

Analgesics are the most common self prescribed drugs. Although considered to be relatively safe, side effects are often seen when these drugs are used for prolonged period, in high doses or used where contraindicated. Majority of the consumers are not aware of the side effects. These days ample amount of information is available on web, it is important to explore its role in educating the population regarding the safe use of self prescribed analgesics. To explore pattern of analgesic use, to identify population at risk of developing side effects related to analgesic use, awareness of side effects and potential role of internet to bring awareness about safe use of self prescribed analgesic drugs in a rural area of Delhi. A cross-sectional survey based study was done on 500 adults in the age group of 18-65 years of Madanpur Khadar area of South Delhi, India. Data collection was done by conducting visits to pharmacy shops from the people who were buying drugs without prescription and taking face to face interviews using a semi-structured questionnaire. Statistical analysis was performed using descriptive tests with Microsoft office excel 2007. Results of our study showed that among all the self prescribed analgesics paracetamol (57%) was used most frequently followed by aspirin and other NSAIDs. It was found that 9.6% of the consumers were having associated co-morbid illness, 11.4% were simultaneously taking other drugs and 15.2% were alcoholics. Majority (65.4%) of the buyers were not aware about any kind of side effects of the analgesics. Internet friendly consumers were found to be 44%. Ability to use internet and education level were found to be directly related (r=0.802). The pattern of analgesic consumption in the rural population of Delhi shows that a large number of consumers may be at risk of developing side effects of self prescribed analgesics. The awareness about the side effects is limited. A significant number of consumers are internet friendly. Hence, we recommend use of website/mobile apps as potential source of information in educating the population regarding the use of self prescribed analgesics.

NSAI activity study of 4-phenyl-2-thioxo-benzo[4,5]thieno[2,3-d]pyrimidine derivatives.

PubMed

Darias, V; Abdallah, S S; Tello, M L; Delgado, L D; Vega, S

1994-12-01

A series of 4-phenyl-2-thioxo-benzo[4,5]thieno[2,3-d]pyrimidine derivatives endowed with anti-inflammatory and related pharmacological properties were submitted to a more extensive study to know their exact pharmacological profile and their possible side effects. The studied compounds possess a remarkable analgesic activity, devoid of central effects. They also show an interesting anti-inflammatory profile evidenced by their effectiveness in different experimental models of inflammation. In addition, these compounds exhibit none or very little activity on CNS, scarce toxicity and low gastrointestinal aggressivity.

Physicochemical and biological evaluation of a cinnamamide derivative R,S-(2E)-1-(3-hydroxypiperidin-1-yl)-3-phenylprop-2-en-1-one (KM-608) for nervous system disorders.

PubMed

Gunia-Krzyżak, Agnieszka; Żesławska, Ewa; Bareyre, Florence M; Nitek, Wojciech; Waszkielewicz, Anna M; Marona, Henryk

2017-08-01

A cinnamamide scaffold has been successfully incorporated in several compounds possessing desirable pharmacological activities in central and peripheral nervous system such as anticonvulsant, antidepressant, neuroprotective, analgesic, anti-inflammatory, muscle relaxant, and sedative/hypnotic properties. R,S-(2E)-1-(3-hydroxypiperidin-1-yl)-3-phenylprop-2-en-1-one (KM-608), a cinnamamide derivative, was synthesized, its chemical structure was confirmed by means of spectroscopy and crystallography, and additionally, thermal analysis showed that it exists in one crystalline form. The compound was evaluated in vivo in rodents as anticonvulsant, antiepileptogenic, analgesic, and neuroprotective agent. The beneficial properties of the compound were found in animal models of seizures evoked electrically (maximal electroshock test, 6-Hz) and chemically (subcutaneous pentylenetetrazole seizure test) as well as in three animal models of epileptogenesis: corneal-kindled mice, hippocampal-kindled rats, and lamotrigine-resistant amygdala-kindled rats. Quantitative pharmacological parameters calculated for the tested compound were comparable to those of currently used antiepileptic drugs. In vivo pharmacological profile of KM-608 corresponds with the activity of valproic acid. © 2017 John Wiley & Sons A/S.

Will peripherally restricted kappa-opioid receptor agonists (pKORAs) relieve pain with less opioid adverse effects and abuse potential?

PubMed

Albert-Vartanian, A; Boyd, M R; Hall, A L; Morgado, S J; Nguyen, E; Nguyen, V P H; Patel, S P; Russo, L J; Shao, A J; Raffa, R B

2016-08-01

Optimal utilization of opioid analgesics is significantly limited by the central nervous system adverse effects and misuse/abuse potential of currently available drugs. It has been postulated that opioid-associated adverse effects and abuse potential would be greatly reduced if opioids could be excluded from reaching the brain. We review the basic science and clinical evidence of one such approach - peripherally restricted kappa-opioid receptor (KOR) agonists (pKORAs). Published and unpublished literature, websites and other sources were searched for basic science and clinical information related to the potential benefits and development of peripherally restricted kappa-opioid receptor agonists. Each source was summarized, reviewed and assessed. The historical development of pKORAs can be traced from the design of increasingly KOR-selective agonists, elucidation of the pharmacologic attributes of such compounds and strategies to restrict passage across the blood-brain barrier. Novel compounds are under development and have progressed to clinical trials. The results from recent clinical trials suggest that peripherally restricted opioids can be successfully designed and that they can retain analgesic efficacy with a more favourable adverse effect profile. © 2016 John Wiley & Sons Ltd.

Physico-chemical characterization and pharmacological activities of sulfated polysaccharide from sea urchin, Paracentrotus lividus.

PubMed

Salem, Yosra Ben; Amri, Safa; Hammi, Khaoula Mkadmini; Abdelhamid, Amal; Cerf, Didier Le; Bouraoui, Abderrahman; Majdoub, Hatem

2017-04-01

Sulfated polysaccharide (SP) from the eggs of sea urchin Paracentrotus lividus, extracted by papain digestion, was characterized by size exclusion chromatography coupling on-line with light scattering and viscosity detectors (SEC/MALS/VD/DRI), gas chromatography coupled to mass spectrometer (GC-MS), and Fourier transform infrared spectroscopy (FTIR) analysis. The native molecular mass of the extracted polysaccharide is high (≥22 000 KDa) and it is composed mainly of arabinose, accompanied by other monosaccharides (mostly galactose, glucose and fucose), significant amounts of uronic acids (18.4%) and relatively high proportions of sulfate (22.4%). The pharmacological evaluation of SP showed a significant in vivo anti-inflammatory activity (p<0.001), 3h after injection, the edema inhibition was 75.8% at the dose of 100mg/Kg; a significant peripheral analgesic activity (p<0.001), with 64.9% of writhing inhibition, and a significant increase in the hot plate reaction time in mice indicating central analgesic activity. In addition, an interesting gastroprotective effect was observed with this polysaccharide; the gastric ulcer inhibition was 69.7%, at the dose of 100mg/Kg. Copyright © 2017 Elsevier B.V. All rights reserved.

Adverse drug reactions of non-opioid and opioid analgesics reported to Croatian national authority from 2007 to 2014.

PubMed

Sunara, Petra; Krnic, Darko; Puljak, Livia

2017-11-01

Adverse drug reactions (ADRs) are commonly observed in the health services because of system weaknesses and individual errors. Analgesics are widely used and it can be expected that with the increased use one can expect increased number of ADRs of analgesics. The aim of this study was to analyze ADRs of non-opioid and opioid analgesics reported to the Croatian Agency for Medicinal Products and Medical Devices (HALMED) from 2007 to 2014. HALMED provided data on generic drug name, year of the ADR report, type of report, institution, reporting person, patient's age, sex and ADR type. In the analyzed period 796 ADRs of analgesics were reported, of which 367 (46%) were serious ADRs. Number of ADR reports was continuously increasing during the analyzed period. There were 20 analgesics that had ≥5 reports, making 597 (75%) of all ADR reports for analgesics. The most common adverse reaction reports of those 20 analgesics referred to individual drugs (n=16; 80%). Most of the ADR reports were filed by physicians (n=257; 43%), followed by pharmacists (n=252; 42%). Most side effects (n=572; 96%) were reported spontaneously through appropriate forms by patients or health professionals. ADRs were most commonly reported in women (n=352; 59%) and most of them have occurred in adults (n=354; 59%). The most common ADRs of opioid and non-opioid analgesics have been reported on the skin and mucous membranes. Most serious ADRs were result of action of opioid analgesics. Number of ADR reports in Croatia is continuously increasing and a considerable number of them refers to serious ADRs. To keep better track of medications and ADRs it is necessary to educate and encourage health professionals and patients in reporting side effects. Copyright © 2017 by Academy of Sciences and Arts of Bosnia and Herzegovina.

Patterns and predictors of analgesic use in pregnancy: a longitudinal drug utilization study with special focus on women with migraine.

PubMed

Harris, Gerd-Marie Eskerud; Wood, Mollie; Eberhard-Gran, Malin; Lundqvist, Christofer; Nordeng, Hedvig

2017-07-14

Few studies have investigated the drug utilization patterns and factors predicting drug use in pregnant women with migraine. This longitudinal drug utilization study aimed to describe patterns of analgesic use in a sample of Norwegian pregnant women according to their migraine history, and to identify predictors for analgesic use among these women. Pregnant women giving birth at Akershus University Hospital between 2008 and 2010 were recruited at ultrasound examination in gestational week 17. Data were collected by questionnaires in gestational weeks 17 and 32, and at 8 weeks postpartum, and linked to birth records. Women were grouped into four categories according to migraine history: no migraine history, previous migraine history, recent migraine history (within 1 year prior to pregnancy) and migraine in pregnancy. Patterns of use of analgesics were analyzed descriptively. Multivariable logistic regression was used to identify factors predicting analgesic use. Out of 1981 women, 5.0% reported having migraine in pregnancy, 13.2% had a recent history of migraine, 11.5% had a previous history of migraine, and 68.8% reported no history of migraine. Analgesic use declined during pregnancy. Many women switched from triptans and non-steroidal anti-inflammatory drugs to paracetamol, which constituted most of the analgesic use. Factors associated with analgesic use included recent migraine history (OR 1.6, 95% CI 1.2-2.2), more severe headache intensity (OR 1.3, 95% CI 1.3-1.4), smoking (OR 1.9, 95% CI 1.1-3.3) and multiparity (OR 1.4, 95% CI 1.1-1.7). Women with migraine stop or switch medications during pregnancy. Analgesic use in pregnancy is affected by migraine characteristics and intensity, and also by socio-demographic factors. Clinicians should bear this in mind when giving advice on adequate management of migraine in pregnancy and safe analgesic use.

The Efficacy and Clinical Safety of Various Analgesic Combinations for Post-Operative Pain after Third Molar Surgery: A Systematic Review and Meta-Analysis

PubMed Central

Au, Alvin Ho Yeung; Choi, Siu Wai; Cheung, Chi Wai; Leung, Yiu Yan

2015-01-01

Objectives To run a systematic review and meta-analysis of randomized clinical trials aiming to answer the clinical question “which analgesic combination and dosage is potentially the most effective and safe for acute post-operative pain control after third molar surgery?”. Materials and Methods A systematic search of computer databases and journals was performed. The search and the evaluations of articles were performed by 2 independent reviewers in 3 rounds. Randomized clinical trials related to analgesic combinations for acute post-operative pain control after lower third molar surgery that matched the selection criteria were evaluated to enter in the final review. Results Fourteen studies with 3521 subjects, with 10 groups (17 dosages) of analgesic combinations were included in the final review. The analgesic efficacy were presented by the objective pain measurements including sum of pain intensity at 6 hours (SPID6) and total pain relief at 6 hours (TOTPAR6). The SPID6 scores and TOTPAR6 scores of the reported analgesic combinations were ranged from 1.46 to 6.44 and 3.24 – 10.3, respectively. Ibuprofen 400mg with oxycodone HCL 5mg had superior efficacy (SPID6: 6.44, TOTPAR6: 9.31). Nausea was the most common adverse effect, with prevalence ranging from 0-55%. Ibuprofen 200mg with caffeine 100mg or 200mg had a reasonable analgesic effect with fewer side effects. Conclusion This systematic review and meta-analysis may help clinicians in their choices of prescribing an analgesic combination for acute post-operative pain control after lower third molar surgery. It was found in this systematic review Ibuprofen 400mg combined with oxycodone HCL 5mg has superior analgesic efficacy when compared to the other analgesic combinations included in this study. PMID:26053953

Anti-nociceptive effect of methanol extract of leaves of Senna singueana in mice.

PubMed

Hishe, Hailemichael Zeru; Ambech, Tamrat Abate; Hiben, Mebrahtom Gebrelibanos; Fanta, Biruk Sintayehu

2018-05-10

Senna singueana (Del.) Lock (Fabaceae) is a shrub or tree found in Ethiopia and other African countries. It has been traditionally used for different conditions including treatment of pain conditions in humans and animals. Although various reports are available in the literature claiming different activities of the plant, scientific studies supporting analgesic potential of S. singueana are lacking and the present study aimed to investigate the antinociceptive effect of methanol extract of leaves of S. singueana in mice. Anti-nociceptive activity of S. singueana (200 mg/kg and 400 mg/kg, p.o) was investigated using acetic acid-induced writhing, formalin-induced paw licking, and hot plate tests. Acute oral toxicity was determined using a slightly modified guideline (423) of the Organization for Economic Cooperation and Development. S. singueana extract increased the percentage of inhibition of writhing response and licking response (neurogenic and inflammatory phase) in acetic acid-induced writhing and formalin-induced paw licking tests, respectively. It also significantly (p ≤ 0.05) increased the percentage of mean maximal effect (%MPE) compared to control group in the hot-plate test. In all models, the combination of S. singueana with either diclofenac or morphine produced statistically significant increase (p ≤ 0.05) in the percentage of inhibition of writhing, paw licking, and %MPE compared to single treatment groups. It was also found that the 400 mg/kg extract produced higher antinociceptive effects (p ≤ 0.05) compared to the 200 mg/kg. S. singueana leaves may have analgesic effect that is mediated through both peripheral and central mechanisms and could be used as adjuvant treatment to the modern analgesics. Copyright © 2018 Elsevier B.V. All rights reserved.

Perioperative pharmacokinetics of ibuprofen enantiomers after rectal administration.

PubMed

Kyllönen, Matti; Olkkola, Klaus T; Seppälä, Timo; Ryhänen, Pauli

2005-07-01

Ibuprofen is a nonsteroidal anti-inflammatory drug which has both peripheral and central analgesic effects. Ibuprofen has been shown to be an effective antipyretic and postoperative analgesic drug both in adults and children with few side effects. Pharmacokinetics of rectal ibuprofen has not been studied, although suppositories are frequently used for perioperative pain control in children. There were four study groups: full-term infants aged 1-7 weeks (n = 9), infants aged 8-25 weeks (n = 8), and infants aged 26-52 weeks (n = 7). Adult patients were 20-40 years old (n = 7). Ibuprofen suppository 20 mg.kg(-1) was administered after induction of anesthesia. Blood samples were collected from 20 min to 10 h after dosing and pharmacokinetic analysis of ibuprofen enantiomers were done. Both ibuprofen enantiomers were detectable in blood in 20 min. Total ibuprofen plasma concentrations >10 mg.l(-1) were seen from 40 min to 8 h. Values for T(max) of ibuprofen enantiomers and total ibuprofen were higher in the adult group than any of the infant groups (P < 0.05). In addition, values for physiological (standardized) t(1/2) of (R)-(-)- and (S)-(+)-ibuprofen were higher in infants aged 1-7 weeks than the adults (P < 0.05). None of the other pharmacokinetic variables, C(max), AUC, chronological t(1/2) or AUC ratio differed between the groups. A single dose of ibuprofen suppository 20 mg.kg(-1) after induction of anesthesia guarantees analgesic plasma concentrations during the early postoperative period. Except for the delayed absorption of ibuprofen in adults and higher physiological t(1/2) in infants aged 1-7 weeks, no major pharmacokinetic differences were observed between study groups.

Three-phase Bone Scintigraphy Can Predict the Analgesic Efficacy of Ketamine Therapy in CRPS.

PubMed

Sorel, Marc; Beatrix, Jacques-Christian; Locko, Blanche; Armessen, Catherine; Domec, Anne-Marie; Lecompte, Otilia; Boucheneb, Sofiane; Harache, Benoit; Robert, Jacques; Lefaucheur, Jean-Pascal

2018-03-13

The efficacy of ketamine in relieving complex regional pain syndrome (CRPS) lacks predictive factors. The value of three-phase bone scintigraphy (TPBS) was assessed or this purpose. TPBS was performed in 105 patients with unilateral, focal CRPS of type 1 before 5 days of ketamine infusions. Tracer uptake was measured in the region of interest concerned by CRPS and the contralateral homologous region. For the three scintigraphic phases (vascular, tissular, and bone phases), an asymmetry ratio of fixation was calculated between the affected and the unaffected sides (VPr, TPr, and BPr). Ketamine efficacy was assessed on pain intensity scores. Ketamine-induced pain relief did not correlate with VPr, TPr, and BPr, but with the ratios of these ratios: BPr/TPr (r=0.32, P=0.009), BPr/VPr (r=0.34, P=0.005), and TPr/VPr (r=0.23, P=0.02). The optimum cut-off value for predicting the response to ketamine therapy was >1.125 for BPr/TPr, >1.075 for BPr/VPr, and >0.935 for TPr/VPr. The combination of increased values of BPr/TPr, BPr/VPr, and TPr/VPr was extremely significantly associated with ketamine therapy outcome. The relative hyperfixation of the radioactive tracer in the limb region concerned by CRPS in phases 2 and 3 versus phase 1 of TPBS correlated positively to the analgesic efficacy of ketamine. This study shows for the first time the potential predictive value of TPBS regarding ketamine therapy outcome. In addition, these results suggest that the analgesic action of ketamine is not restricted to "central" mechanisms, but may also involve "peripheral" mechanisms related to tissue inflammation and bone remodeling.

Intervention of electroacupuncture on spinal p38 MAPK/ATF-2/VR-1 pathway in treating inflammatory pain induced by CFA in rats.

PubMed

Fang, Jian-Qiao; Du, Jun-Ying; Liang, Yi; Fang, Jun-Fan

2013-03-22

Previous studies have demonstrated that p38 MAPK signal transduction pathway plays an important role in the development and maintenance of inflammatory pain. Electroacupuncture (EA) can suppress the inflammatory pain. However, the relationship between EA effect and p38 MAPK signal transduction pathway in inflammatory pain remains poorly understood. It is our hypothesis that p38 MAPK/ATF-2/VR-1 and/or p38 MAPK/ATF-2/COX-2 signal transduction pathway should be activated by inflammatory pain in CFA-injected model. Meanwhile, EA may inhibit the activation of p38 MAPK signal transduction pathway. The present study aims to investigate that anti-inflammatory and analgesic effect of EA and its intervention on the p38 MAPK signal transduction pathway in a rat model of inflammatory pain. EA had a pronounced anti-inflammatory and analgesic effect on CFA-induced chronic inflammatory pain in rats. EA could quickly raise CFA-rat's paw withdrawal thresholds (PWTs) and maintain good and long analgesic effect, while it subdued the ankle swelling of CFA rats only at postinjection day 14. EA could down-regulate the protein expressions of p-p38 MAPK and p-ATF-2, reduced the numbers of p-p38 MAPK-IR cells and p-ATF-2-IR cells in spinal dorsal horn in CFA rats, inhibited the expressions of both protein and mRNA of VR-1, but had no effect on the COX-2 mRNA expression. The present study indicates that inhibiting the activation of spinal p38 MAPK/ATF-2/VR-1 pathway may be one of the main mechanisms via central signal transduction pathway in the process of anti-inflammatory pain by EA in CFA rats.

Analgesic Effects of Duloxetine on Formalin-Induced Hyperalgesia and Its Underlying Mechanisms in the CeA

PubMed Central

Zhang, Lie; Yin, Jun-Bin; Hu, Wei; Zhao, Wen-Jun; Fan, Qing-Rong; Qiu, Zhi-Chun; He, Ming-Jie; Ding, Tan; Sun, Yan; Kaye, Alan D.; Wang, En-Ren

2018-01-01

In rodents, the amygdala has been proposed to serve as a key center for the nociceptive perception. Previous studies have shown that extracellular signal-regulated kinase (ERK) signaling cascade in the central nucleus of amygdala (CeA) played a functional role in inflammation-induced peripheral hypersensitivity. Duloxetine (DUL), a serotonin and noradrenaline reuptake inhibitor, produced analgesia on formalin-induced spontaneous pain behaviors. However, it is still unclear whether single DUL pretreatment influences formalin-induced hypersensitivity and what is the underlying mechanism. In the current study, we revealed that systemic pretreatment with DUL not only dose-dependently suppressed the spontaneous pain behaviors, but also relieved mechanical and thermal hypersensitivity induced by formalin hindpaw injection. Consistent with the analgesic effects of DUL on the pain behaviors, the expressions of Fos and pERK that were used to check the neuronal activities in the spinal cord and CeA were also dose-dependently reduced following DUL pretreatment. Meanwhile, no emotional aversive behaviors were observed at 24 h after formalin injection. The concentration of 5-HT in the CeA was correlated with the dose of DUL in a positive manner at 24 h after formalin injection. Direct injecting 5-HT into the CeA suppressed both the spontaneous pain behaviors and hyperalgesia induced by formalin injection. However, DUL did not have protective effects on the formalin-induced edema of hindpaw. In sum, the activation of CeA neurons may account for the transition from acute pain to long-term hyperalgesia after formalin injection. DUL may produce potent analgesic effects on the hyperalgesia and decrease the expressions of p-ERK through increasing the concentration of serotonin in the CeA. PMID:29692727

Analgesic Effects of Duloxetine on Formalin-Induced Hyperalgesia and Its Underlying Mechanisms in the CeA.

PubMed

Zhang, Lie; Yin, Jun-Bin; Hu, Wei; Zhao, Wen-Jun; Fan, Qing-Rong; Qiu, Zhi-Chun; He, Ming-Jie; Ding, Tan; Sun, Yan; Kaye, Alan D; Wang, En-Ren

2018-01-01

In rodents, the amygdala has been proposed to serve as a key center for the nociceptive perception. Previous studies have shown that extracellular signal-regulated kinase (ERK) signaling cascade in the central nucleus of amygdala (CeA) played a functional role in inflammation-induced peripheral hypersensitivity. Duloxetine (DUL), a serotonin and noradrenaline reuptake inhibitor, produced analgesia on formalin-induced spontaneous pain behaviors. However, it is still unclear whether single DUL pretreatment influences formalin-induced hypersensitivity and what is the underlying mechanism. In the current study, we revealed that systemic pretreatment with DUL not only dose-dependently suppressed the spontaneous pain behaviors, but also relieved mechanical and thermal hypersensitivity induced by formalin hindpaw injection. Consistent with the analgesic effects of DUL on the pain behaviors, the expressions of Fos and pERK that were used to check the neuronal activities in the spinal cord and CeA were also dose-dependently reduced following DUL pretreatment. Meanwhile, no emotional aversive behaviors were observed at 24 h after formalin injection. The concentration of 5-HT in the CeA was correlated with the dose of DUL in a positive manner at 24 h after formalin injection. Direct injecting 5-HT into the CeA suppressed both the spontaneous pain behaviors and hyperalgesia induced by formalin injection. However, DUL did not have protective effects on the formalin-induced edema of hindpaw. In sum, the activation of CeA neurons may account for the transition from acute pain to long-term hyperalgesia after formalin injection. DUL may produce potent analgesic effects on the hyperalgesia and decrease the expressions of p-ERK through increasing the concentration of serotonin in the CeA.

Intervention of electroacupuncture on spinal p38 MAPK/ATF-2/VR-1 pathway in treating inflammatory pain induced by CFA in rats

PubMed Central

2013-01-01

Background Previous studies have demonstrated that p38 MAPK signal transduction pathway plays an important role in the development and maintenance of inflammatory pain. Electroacupuncture (EA) can suppress the inflammatory pain. However, the relationship between EA effect and p38 MAPK signal transduction pathway in inflammatory pain remains poorly understood. It is our hypothesis that p38 MAPK/ATF-2/VR-1 and/or p38 MAPK/ATF-2/COX-2 signal transduction pathway should be activated by inflammatory pain in CFA-injected model. Meanwhile, EA may inhibit the activation of p38 MAPK signal transduction pathway. The present study aims to investigate that anti-inflammatory and analgesic effect of EA and its intervention on the p38 MAPK signal transduction pathway in a rat model of inflammatory pain. Results EA had a pronounced anti-inflammatory and analgesic effect on CFA-induced chronic inflammatory pain in rats. EA could quickly raise CFA-rat’s paw withdrawal thresholds (PWTs) and maintain good and long analgesic effect, while it subdued the ankle swelling of CFA rats only at postinjection day 14. EA could down-regulate the protein expressions of p-p38 MAPK and p-ATF-2, reduced the numbers of p-p38 MAPK-IR cells and p-ATF-2-IR cells in spinal dorsal horn in CFA rats, inhibited the expressions of both protein and mRNA of VR-1, but had no effect on the COX-2 mRNA expression. Conclusions The present study indicates that inhibiting the activation of spinal p38 MAPK/ATF-2/VR-1 pathway may be one of the main mechanisms via central signal transduction pathway in the process of anti-inflammatory pain by EA in CFA rats. PMID:23517865

Analgesic and anticonvulsant effects of extracts from the leaves of Kalanchoe crenata (Andrews) Haworth (Crassulaceae).

PubMed

Nguelefack, T B; Nana, P; Atsamo, A D; Dimo, T; Watcho, P; Dongmo, A B; Tapondjou, L A; Njamen, D; Wansi, S L; Kamanyi, A

2006-06-15

Kalanchoe crenata Andr. (Crassulaceae) is a fleshy herbaceous plant used in the African traditional medicine as remedies against otitis, headache, inflammations, convulsions and general debility. In the present work, the analgesic effects of methylene chloride/methanol (1:1) (CH(2)Cl(2)/CH(3)OH) extract and its hexane, methylene chloride (CH(2)Cl(2)), ethyl acetate, n-butanol fractions and aqueous residue have been evaluated using acetic acid, formalin and pressure test. The anticonvulsant effects of the CH(2)Cl(2)/CH(3)OH extract were also investigated on seizures induced by pentylenetetrazol (PTZ 70 mg/kg), strychnine sulphate (STN 2.5 mg/kg) and thiosemicarbazide (TSC 50 mg/kg). CH(2)Cl(2)/CH(3)OH extract and its fractions, administered orally at the doses of 150 and 300 mg/kg, exhibited protective effect of at least 30% on the pain induced by acetic acid. The CH(2)Cl(2) fraction at 300 mg/kg showed a maximal effect of 78.49%. The CH(2)Cl(2)/CH(3)OH extract and its CH(2)Cl(2) fraction at the doses of 150 and 300 mg/kg significantly reduced the first phase of pain induced by formalin while the second phase was completely inhibited. The CH(2)Cl(2) fraction produced more than 45% reduction in the sensitivity to pain induced by pressure. The CH(2)Cl(2)/CH(3)OH extract of Kalanchoe crenata significantly increased the latency period in seizures induced by PTZ and significantly reduced the duration of seizures induced by the three convulsant agents. The extract protected 20% of animals against death in seizures induced by TSC and STN. These results suggest a peripheral and central analgesic activities as well as an anticonvulsant effect of the leaves of Kalanchoe crenata.

Endomorphin-2 analogs with C-terminal esterification produce potent systemic antinociception with reduced tolerance and gastrointestinal side effects.

PubMed

Wang, Chang-Lin; Qiu, Ting-Ting; Yang, Dai-Jun; Yuan, Bi-Yu; Han, Feng-Tong; Li, Li; Gu, Ning

2017-04-01

C-terminal esterification of opioid peptides may change their opioid activities due to the modified physicochemical properties. In the present study, the pharmacological activities of C-terminal esterified endomorphin-2 (EM-2) analogs 1-3 were characterized by in vitro metabolic stability and octanol/buffer distribution assays. Also, the antinociceptive profiles in the radiant heat paw withdrawal test and related side effects of these analogs were determined. Our results showed that all three analogs significantly increased the metabolic stability and lipophilicity. Moreover, analogs 1-3 displayed potent antinociceptive activities after intracerebroventricular (i.c.v.) administration. Analogs 1 and 3 exhibited about 2-fold higher antinociception than EM-2, and differential opioid mechanisms were involved. In addition, EM-2 at 50 μmol/kg failed to produce any significant antinociceptive activity after subcutaneous (s.c.) administration, whereas equimolar dose of analogs 1-3 produced significant analgesic effects. Analog 3 showed the highest antinociceptive activity after systemic administration, which was consistent with its in vitro stability and lipophilicity. We further evaluated the antinociceptive tolerance of analogs 1-3. In acute tolerance test, analogs 1-3 shifted the dose-response curves rightward by only 1.4-3.2 fold as determined by tolerance ratio, whereas EM-2 by 5.6-fold, demonstrating reduced antinociceptive tolerance. Also, analogs 1 and 2 decreased chronic antinociceptive tolerance by central and peripheral administration of drugs. In particular, analogs 3 displayed insignificant chronic antinociceptive tolerance. Furthermore, analogs 1-3 were less prone to induce gastrointestinal side effects at analgesic doses. The present investigation gave the evidence that C-terminal esterified modifications of EM-2 will facilitate the development of novel opioid analgesics with reduced side effects. Copyright © 2016 Elsevier Ltd. All rights reserved.

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

[Caffeine as adjuvant analgeticum for treating acute pain].

PubMed

Nikolajsen, Lone; Haroutiunian, Simon

2013-10-14

Based on 19 studies (7,238 participants) a Cochrane review concludes that the addition of caffeine to an analgesic drug provides superior analgesia compared with the analgesic drug alone. The benefit is small, with a number needed to treat of approx. 16. The use of analgesics containing caffeine is associated with an increased risk of the development of physical dependence, overuse headache, and withdrawal symptoms upon abrupt discontinuation. Combination analgesics with caffeine should only be used temporarily and exclusively for the treatment of acute pain conditions.

Prevalence of Analgesic Prescriptions among Patients with Cancer in Japan: An Analysis of Health Insurance Claims Data

PubMed Central

Higashi, Takahiro; Yoshimoto, Tetsusuke; Matoba, Motohiro

2012-01-01

Objectives: To promote effective management of cancer pain as a nationwide health policy, it is necessary to monitor the performance of health care providers in managing pain in their patients. To plan a system that monitors the performance of pain management, the exact methods of measurement, including the range of target patients, and estimate the resources must be defined. Performance in pain management can be evaluated either in all patients with cancer or restricted to patients with cancer who are already taking analgesics. Restricting the target patient group to patients on analgesics may be more efficient but the extent of that efficiency remains uncertain. Methods: Using insurance claims from eight employer-sponsored insurance companies, we analyzed data from patients (N = 2858) who had received anti-cancer treatment (ie, surgery, chemotherapy, and radiation therapy) for the five major cancers in Japan (ie, breast, colorectal, liver, lung, and stomach cancers). Results: Overall, 22.9% of patients received some kind of analgesic prescription in the course of a month. Lung cancer patients were more likely to be prescribed analgesic prescriptions (any analgesics 34.8%; opioids 18.2%) than patients with the other four cancers. The observed percentage of patients who received analgesic prescriptions over the study period (ie, January 2005 to November 2009) decreased. Conclusion: If we limit the target patient group to patients with cancer already on analgesics, we can reduce the number of persons to be contacted by about three-fourths, compared to assessing pain in all patients with cancer. Although we do not wish to ignore the problem of undetected pain among patients with cancer, beginning our systematic evaluation with patients with cancer already on analgesics may be a realistic option. PMID:23121757

Inequality in analgesic prescription in Spain. A gender development issue.

PubMed

Chilet-Rosell, Elisa; Ruiz-Cantero, M Teresa; Sáez, José Fernández; Alvarez-Dardet, Carlos

2013-01-01

It is well known that sex differences in analgesic prescription are not merely the logical result of greater prevalence of pain in women, since this therapeutic variability is related to factors such as educational level or social class. This study aims to analyse the relationship between analgesic prescription and gender development in different regions of Spain. Cross-sectional study of sex-differences in analgesic prescription according to the gender development of the regions studied. Analgesic prescription, pain and demographic variables were obtained from the Spanish Health Interview Survey in 2006. Gender development was measured with the Gender Development Index (GDI). A logistic regression analysis was conducted to compare analgesic prescription by sex in regions with a GDI above or below the Spanish average. Once adjusted by pain, age and social class, women were more likely to be prescribed analgesics than men, odds ratio (OR) = 1.74 (1.59-1.91), as residents in regions with a lower GDI compared with those in region with a higher GDI: ORWomen = 1.26 (1.12-1.42), ORMen = 1.30 (1.13-1.50). Women experiencing pain in regions with a lower GDI were more likely than men to be treated by a general practitioner rather than by a specialist, OR = 1.32 (1.04-1.67), irrespective of age and social class. Gender bias may be one of the pathways by which inequalities in analgesic treatment adversely affect women's health. Moreover, research into the adequacy of analgesic treatment and the possible medicalisation of women should consider contextual factors, such as gender development. Copyright © 2011 SESPAS. Published by Elsevier Espana. All rights reserved.

Adherence to Analgesics in Oncology Outpatients: Focus on Taking Analgesics on Time.

PubMed

Oldenmenger, Wendy H; Sillevis Smitt, Peter A E; de Raaf, Pleun J; van der Rijt, Carin C D

2017-06-01

Inadequate adherence to prescribed analgesics may be one of the reasons why patients with cancer experience unrelieved pain. Adherence is directly influenced by patients' barriers about pain management. Patient pain education programs (PEPs) have been developed to reduce patients' barriers and increase patients' adherence to their analgesics. The purpose of this article was to evaluate patients' adherence in patients receiving a pain consult and patient pain education in comparison with patients receiving standard pain treatment (standard care [SC]), to better explore the difficulties in medication adherence in cancer-related pain and the effects of PEP. In 54 adult outpatients with cancer-related pain, patients' adherence to the prescribed around-the-clock analgesics was measured with a Medication Event Monitoring System, in the following time intervals: weeks 1 and 2, weeks 3 and 4, and weeks 7 and 8 after randomization. Adherence was differentiated into taking adherence, taking the correct dose, and taking analgesics at the right time intervals. Taking adherence increased in the intervention group compared to baseline (from 91% to 93%) and decreased in the SC group (from 85% to 78%; P < 0.05). At the end of the study, more patients in the intervention group took their analgesics at the right intervals (78%) than did patients in the SC group (64%, P < 0.05). During the study, patients were more adherent to opioids than to World Health Organization step 1 analgesics. The combined intervention can increase adherence. The true problem in pain management is that patients do not take their prescribed analgesics at the right time intervals. With the detailed adherence information from this study, it is possible to further tailor patient education to the individual patient. © 2016 World Institute of Pain.

Vocal local versus pharmacological treatments for pain management in tubal ligation procedures in rural Kenya: a non-inferiority trial.

PubMed

Keogh, Sarah C; Fry, Kenzo; Mbugua, Edwin; Ayallo, Mark; Quinn, Heidi; Otieno, George; Ngo, Thoai D

2014-02-04

Vocal local (VL) is a non-pharmacological pain management technique for gynecological procedures. In Africa, it is usually used in combination with pharmacological analgesics. However, analgesics are associated with side-effects, and can be costly and subject to frequent stock-outs, particularly in remote rural settings. We compared the effectiveness of VL + local anesthesia + analgesics (the standard approach), versus VL + local anesthesia without analgesics, on pain and satisfaction levels for women undergoing tubal ligations in rural Kenya. We conducted a site-randomised non-inferiority trial of 884 women receiving TLs from 40 Marie Stopes mobile outreach sites in Kisii and Machakos Districts. Twenty sites provided VL + local anesthesia + analgesics (control), while 20 offered VL + local anesthesia without additional analgesics (intervention). Pain was measured using a validated 11-point Numeric Rating Scale; satisfaction was measured using 11-point scales. A total of 461 women underwent tubal ligations with VL + local anesthesia, while 423 received tubal ligations with VL + local anesthesia + analgesics. The majority were aged ≥30 years (78%), and had >3 children (99%). In a multivariate analysis, pain during the procedure was not significantly different between the two groups. The pain score after the procedure was significantly lower in the intervention group versus the control group (by 0.40 points; p = 0.041). Satisfaction scores were equally high in both groups; 96% would recommend the procedure to a friend. VL + local anesthesia is as effective as VL + local anesthesia + analgesics for pain management during tubal ligation in rural Kenya. Avoiding analgesics is associated with numerous benefits including cost savings and fewer issues related to the maintenance, procurement and monitoring of restricted opioid drugs, particularly in remote low-resource settings where these systems are weak. Pan-African Clinical Trials Registry PACTR201304000495942.

Analgesic properties of Capraria biflora leaves aqueous extract.

PubMed

Acosta, S L; Muro, L V; Sacerio, A L; Peña, A R; Okwei, S N

2003-12-01

The analgesic properties of dried leaves of Capraria biflora were investigated. The aqueous extract (50-200 mg kg(-1)) produced moderate inhibition of acetic acid-induced writhing in mice. At the same doses, a better analgesic effect was observed on the hot plate test.

Role of preemptive tapentadol in reduction of postoperative analgesic requirements after laparoscopic cholecystectomy

PubMed Central

Yadav, Ghanshyam; Jain, Gaurav; Samprathi, Abhishek; Baghel, Annavi; Singh, Dinesh Kumar

2016-01-01

Background and Aims: Poorly managed acute postoperative pain may result in prolonged morbidity. Various pharmacotherapies have targeted this, but research on an ideal preemptive analgesic continues, taking into account drug-related side effects. Considering the better tolerability profile of tapentadol, we assessed its role as a preemptive analgesic in the reduction of postoperative analgesic requirements, after laparoscopic cholecystectomy. Material and Methods: In a prospective-double-blinded fashion, sixty patients posted for above surgery, were randomized to receive tablet tapentadol 75 mg (Group A) or starch tablets (Group B) orally, an hour before induction of general anesthesia. Perioperative analgesic requirement, time to first analgesia, pain, and sedation score were compared for first 24 h during the postoperative period and analyzed by one-way analysis of variance test. A P < 0.05 was considered significant. Results: Sixty patients were analyzed. The perioperative analgesic requirement was significantly lower in Group A. Verbal numerical score was significantly lower in Group A at the time point, immediately after shifting the patient to the postanesthesia care unit. Ramsay sedation scores were similar between the groups. No major side effects were observed except for nausea and vomiting in 26 cases (10 in Group A, 16 in Group B). Conclusion: Single preemptive oral dose of tapentadol (75 mg) is effective in reducing perioperative analgesic requirements and acute postoperative pain, without added side effects. It could be an appropriate preemptive analgesic, subjected to future trials concentrating upon its dose-response effects. PMID:28096581

Can quantitative sensory testing predict responses to analgesic treatment?

PubMed

Grosen, K; Fischer, I W D; Olesen, A E; Drewes, A M

2013-10-01

The role of quantitative sensory testing (QST) in prediction of analgesic effect in humans is scarcely investigated. This updated review assesses the effectiveness in predicting analgesic effects in healthy volunteers, surgical patients and patients with chronic pain. A systematic review of English written, peer-reviewed articles was conducted using PubMed and Embase (1980-2013). Additional studies were identified by chain searching. Search terms included 'quantitative sensory testing', 'sensory testing' and 'analgesics'. Studies on the relationship between QST and response to analgesic treatment in human adults were included. Appraisal of the methodological quality of the included studies was based on evaluative criteria for prognostic studies. Fourteen studies (including 720 individuals) met the inclusion criteria. Significant correlations were observed between responses to analgesics and several QST parameters including (1) heat pain threshold in experimental human pain, (2) electrical and heat pain thresholds, pressure pain tolerance and suprathreshold heat pain in surgical patients, and (3) electrical and heat pain threshold and conditioned pain modulation in patients with chronic pain. Heterogeneity among studies was observed especially with regard to application of QST and type and use of analgesics. Although promising, the current evidence is not sufficiently robust to recommend the use of any specific QST parameter in predicting analgesic response. Future studies should focus on a range of different experimental pain modalities rather than a single static pain stimulation paradigm. © 2013 European Federation of International Association for the Study of Pain Chapters.

Temporal Trends in Analgesic Use in Long-Term Care Facilities: A Systematic Review of International Prescribing.

PubMed

La Frenais, Francesca L; Bedder, Rachel; Vickerstaff, Victoria; Stone, Patrick; Sampson, Elizabeth L

2018-02-01

To explore global changes in the prescription of analgesic drugs over time in the international long-term care (LTC) population. Systematic review. We included original research articles in English, published and unpublished, that included number of participants, country and year(s) of data collection, and prescription of analgesics (analgesics not otherwise specified, opioids, acetaminophen; scheduled only, or scheduled plus as needed (PRN)). LTC residents. We searched PubMed, EMBASE, CINAHL, International Pharmaceutical Abstracts, PsycINFO, Cochrane, Web of Science, Google Scholar, using keywords for LTC facilities and analgesic medication; hand-searched references of eligible papers; correspondence. Studies were quality rated using an adapted Newcastle-Ottawa scale. Pearson correlation coefficients were generated between percentage of residents prescribed an analgesic and year of data collection. If available, we investigated changes in acetaminophen and opioid prescriptions. Forty studies met inclusion criteria. A moderate correlation (0.59) suggested that scheduled prescription rates for analgesics have increased over time. Similar findings were reflected in scheduled prescriptions for acetaminophen and opioids. No increase was seen when analyzing scheduled plus PRN analgesics. Use of opioids (scheduled plus PRN) appears to have increased over time. Worldwide, use of opioids and acetaminophen has increased in LTC residents. Research is needed to explore whether this reflects appropriate pain management for LTC residents and if PRN medication is used effectively. © 2017 The Authors. Journal of the American Geriatrics Society published by Wiley Periodicals, Inc. on behalf of The American Geriatrics Society.

Analgesic Prodrugs for Combating their Side-Effects: Rational Approach.

PubMed

Ruchita; Sucheta; Nanda, Sanju; Pathak, Dharampal

2017-01-01

Analgesics are the drugs which bring insensibility to pain without loosing consciousness. Treatment strategy is generally based on the type of pain. Most of the analgesics are associated with serious side effects, such as NSAIDS can cause severe GI disturbance and opioids can cause addiction. There are various ways to reduce their side effects The analgesic prodrug approach is one of the several strategies used to attain the required pharmacological response with a considerable decrease in side effects. The aim of this paper is to introduce in depth the rational behind the use of the analgesic prodrug approach from past to present. Data is collected from online as well as from extensive literature survey which have appeared on this subject during the last decades. This review will map the origins and development of the most important of the analgesic prodrugs to date. This review indicates that, designing analgesic prodrugs represent successful strategy to gain the required pharmacological activity with a considerable decrease in side effects. However thorough knowledge of diverse biological phenomena is needed which enables scientists to invent and design superior, nontoxic and better-targeted prodrugs. The newly synthesized chemical entity or prodrugs may or may not have intrinsic pharmacological activity and also synthesizing novel molecules consume a lot of time and money than developing prodrugs of existing clinically used analgesic drugs which is surely an attractive and promising area of research now a days. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Polyglycerol-opioid conjugate produces analgesia devoid of side effects.

PubMed

González-Rodríguez, Sara; Quadir, Mohiuddin A; Gupta, Shilpi; Walker, Karolina A; Zhang, Xuejiao; Spahn, Viola; Labuz, Dominika; Rodriguez-Gaztelumendi, Antonio; Schmelz, Martin; Joseph, Jan; Parr, Maria K; Machelska, Halina; Haag, Rainer; Stein, Christoph

2017-07-04

Novel painkillers are urgently needed. The activation of opioid receptors in peripheral inflamed tissue can reduce pain without central adverse effects such as sedation, apnoea, or addiction. Here, we use an unprecedented strategy and report the synthesis and analgesic efficacy of the standard opioid morphine covalently attached to hyperbranched polyglycerol (PG-M) by a cleavable linker. With its high-molecular weight and hydrophilicity, this conjugate is designed to selectively release morphine in injured tissue and to prevent blood-brain barrier permeation. In contrast to conventional morphine, intravenous PG-M exclusively activated peripheral opioid receptors to produce analgesia in inflamed rat paws without major side effects such as sedation or constipation. Concentrations of morphine in the brain, blood, paw tissue, and in vitro confirmed the selective release of morphine in the inflamed milieu. Thus, PG-M may serve as prototype of a peripherally restricted opioid formulation designed to forego central and intestinal side effects.

New Molecular Targets for Antiepileptic Drugs: α2δ, SV2A, and Kv7/KCNQ/M Potassium Channels

PubMed Central

Rogawski, Michael A.; Bazil, Carl W.

2008-01-01

Many currently prescribed antiepileptic drugs (AEDs) act via voltage-gated sodium channels, through effects on γ-aminobutyric acid–mediated inhibition, or via voltage-gated calcium channels. Some newer AEDs do not act via these traditional mechanisms. The molecular targets for several of these nontraditional AEDs have been defined using cellular electrophysiology and molecular approaches. Here, we describe three of these targets: α2δ, auxiliary subunits of voltage-gated calcium channels through which the gabapentinoids gabapentin and pregabalin exert their anticonvulsant and analgesic actions; SV2A, a ubiquitous synaptic vesicle glycoprotein that may prepare vesicles for fusion and serves as the target for levetiracetam and its analog brivaracetam (which is currently in late-stage clinical development); and Kv7/KCNQ/M potassium channels that mediate the M-current, which acts a brake on repetitive firing and burst generation and serves as the target for the investigational AEDs retigabine and ICA-105665. Functionally, all of the new targets modulate neurotransmitter output at synapses, focusing attention on presynaptic terminals as critical sites of action for AEDs. PMID:18590620

New molecular targets for antiepileptic drugs: alpha(2)delta, SV2A, and K(v)7/KCNQ/M potassium channels.

PubMed

Rogawski, Michael A; Bazil, Carl W

2008-07-01

Many currently prescribed antiepileptic drugs (AEDs) act via voltage-gated sodium channels, through effects on gamma-aminobutyric acid-mediated inhibition, or via voltage-gated calcium channels. Some newer AEDs do not act via these traditional mechanisms. The molecular targets for several of these nontraditional AEDs have been defined using cellular electrophysiology and molecular approaches. Here, we describe three of these targets: alpha(2)delta, auxiliary subunits of voltage-gated calcium channels through which the gabapentinoids gabapentin and pregabalin exert their anticonvulsant and analgesic actions; SV2A, a ubiquitous synaptic vesicle glycoprotein that may prepare vesicles for fusion and serves as the target for levetiracetam and its analog brivaracetam (which is currently in late-stage clinical development); and K(v)7/KCNQ/M potassium channels that mediate the M-current, which acts a brake on repetitive firing and burst generation and serves as the target for the investigational AEDs retigabine and ICA-105665. Functionally, all of the new targets modulate neurotransmitter output at synapses, focusing attention on presynaptic terminals as critical sites of action for AEDs.

Intimate partner violence and prescription of potentially addictive drugs: prospective cohort study of women in the Oslo Health Study.

PubMed

Stene, Lise Eilin; Dyb, Grete; Tverdal, Aage; Jacobsen, Geir Wenberg; Schei, Berit

2012-01-01

To investigate the prescription of potentially addictive drugs, including analgesics and central nervous system depressants, to women who had experienced intimate partner violence (IPV). Prospective population-based cohort study. Information about IPV from the Oslo Health Study 2000/2001 was linked with prescription data from the Norwegian Prescription Database from 1 January 2004 through 31 December 2009. The study included 6081 women aged 30-60 years. Prescription rate ratios (RRs) for potentially addictive drugs derived from negative binomial models, adjusted for age, education, paid employment, marital status, chronic musculoskeletal pain, mental distress and sleep problems. Altogether 819 (13.5%) of 6081 women reported ever experiencing IPV: 454 (7.5%) comprised physical and/or sexual IPV and 365 (6.0%) psychological IPV alone. Prescription rates for potentially addictive drugs were clearly higher among women who had experienced IPV: crude RRs were 3.57 (95% CI 2.89 to 4.40) for physical/sexual IPV and 2.13 (95% CI 1.69 to 2.69) for psychological IPV alone. After full adjustment RRs were 1.83 (1.50 to 2.22) for physical/sexual IPV, and 1.97 (1.59 to 2.45) for psychological IPV alone. Prescription rates were increased both for potentially addictive analgesics and central nervous system depressants. Furthermore, women who reported IPV were more likely to receive potentially addictive drugs from multiple physicians. Women who had experienced IPV, including psychological violence alone, more often received prescriptions for potentially addictive drugs. Researchers and clinicians should address the possible adverse health and psychosocial impact of such prescription and focus on developing evidence-based healthcare for women who have experienced IPV.

Drugs for relief of pain in patients with sciatica: systematic review and meta-analysis

PubMed Central

Maher, Chris G; Ferreira, Manuela L; Ferreira, Paulo H; Hancock, Mark; Oliveira, Vinicius C; McLachlan, Andrew J; Koes, Bart

2012-01-01

Objective To investigate the efficacy and tolerability of analgesic and adjuvant pain drugs typically administered in primary care for the management of patients with sciatica. Design Systematic review. Data source International Pharmaceutical Abstracts, PsycINFO, Medline, Embase, Cochrane Central Register of Clinical Trials (CENTRAL), CINAHL, and LILACS. Study selection Randomised controlled trials assessing the efficacy and tolerability of drugs versus placebo or other treatment for sciatica. Data extraction Two independent reviewers extracted data and assessed methodological quality using the PEDro scale. Pain and disability outcomes were converted to a common 0 to 100 scale. Data were pooled with a random effects model, and the GRADE approach was used in summary conclusions. Results Twenty three published reports met the inclusion criteria. The evidence to judge the efficacy of non-steroidal anti-inflammatory drugs (NSAIDs), corticosteroids, antidepressants, anticonvulsants, muscle relaxants, and opioid analgesics ranged from moderate to low quality. Most of the pooled estimates did not favour the active treatment over placebo. The pooled results of two trials of corticosteroids (mean difference in overall and leg pain −12.2, 95% confidence interval −20.9 to −3.4) and a single trial of the anticonvulsant gabapentin for chronic sciatica (mean difference in overall pain relief −26.6, −38.3 to −14.9) showed some benefits but only in the short term. The median rate of adverse events was 17% (interquartile range 10-30%) for the active drugs and 11% (3-23%) for placebo. Trial limitations included failure to use validated outcome measures, lack of long term follow-up, and small sample size. Conclusions As the existing evidence from clinical trials is of low quality, the efficacy and tolerability of drugs commonly prescribed for the management of sciatica in primary care is unclear. PMID:22331277

The effects of analgesics on central processing of tonic pain: A cross-over placebo controlled study.

PubMed

Lelic, Dina; Hansen, Tine M; Mark, Esben B; Olesen, Anne E; Drewes, Asbjørn M

2017-09-01

Opioids and antidepressants that inhibit serotonin and norepinephrine reuptake (SNRI) are recognized as analgesics to treat moderate to severe pain, but the central mechanisms underlying their analgesia remain unclear. This study investigated how brain activity at rest and exposed to tonic pain is modified by oxycodone (opioid) and venlafaxine (SNRI). Twenty healthy males were included in this randomized, cross-over, double-blinded study. 61-channel electroencephalogram (EEG) was recorded before and after five days of treatment with placebo, oxycodone (10 mg extended release b.i.d) or venlafaxine (37.5 mg extended release b.i.d) at rest and during tonic pain (hand immersed in 2 °C water for 80 s). Subjective pain and unpleasantness scores of tonic pain were recorded. Spectral analysis and sLORETA source localization were done in delta (1-4 Hz), theta (4-8 Hz), alpha (8-12 Hz), beta1 (12-18 Hz) and beta2 (18-32 Hz) frequency bands. Oxycodone decreased pain and unpleasantness scores (P < 0.05), whereas venlafaxine decreased the pain scores (P < 0.05). None of the treatments changed the spectral indices or brain sources underlying resting EEG. Venlafaxine decreased spectral indices in alpha band of the EEG to tonic pain, whereas oxycodone decreased the spectral indices and brain source activity in delta and theta frequency bands (all P < 0.05). The brain source activity predominantly decreased in the insula and inferior frontal gyrus. The decrease of activity within insula and inferior frontal gyrus is likely involved in pain inhibition due to oxycodone treatment, whereas the decrease in alpha activity is likely involved in pain inhibition due to venlafaxine treatment. Copyright © 2017 Elsevier Ltd. All rights reserved.

Self-reported sleep duration associated with distraction analgesia, hyperemia, and secondary hyperalgesia in the heat-capsaicin nociceptive model.

PubMed

Campbell, Claudia M; Bounds, Sara C; Simango, Mpepera B; Witmer, Kenneth R; Campbell, James N; Edwards, Robert R; Haythornthwaite, Jennifer A; Smith, Michael T

2011-07-01

Although sleep deprivation is known to heighten pain sensitivity, the mechanisms by which sleep modifies nociception are largely unknown. Few studies of sleep-pain interactions have utilized quantitative sensory testing models that implicate specific underlying physiologic mechanisms. One possibility, which is beginning to receive attention, is that differences in sleep may alter the analgesic effects of distraction. We utilized the heat-capsaicin nociceptive model to examine whether self-reported habitual sleep duration is associated with distraction analgesia, the degree of secondary hyperalgesia and skin flare, markers implicating both central and peripheral processes that heighten pain. Twenty-eight healthy participants completed three experimental sessions in a randomized within subjects design. In the pain only condition, pain was induced for approximately 70-min via application of heat and capsaicin to the dorsum of the non-dominant hand. Verbal pain ratings were obtained at regular intervals. In the distraction condition, identical procedures were followed, but during heat-capsaicin pain, subjects played a series of video games. The third session involved assessing performance on the video games (no capsaicin). Participants indicated their normal self-reported habitual sleep duration over the past month. Individuals who slept less than 6.5 h/night in the month prior to the study experienced significantly less behavioral analgesia, increased skin flare and augmented secondary hyperalgesia. These findings suggest that reduced sleep time is associated with diminished analgesic benefits from distraction and/or individuals obtaining less sleep have a reduced ability to disengage from pain-related sensations. The secondary hyperalgesia finding may implicate central involvement, whereas enhanced skin flare response suggests that sleep duration may also impact peripheral inflammatory mechanisms. Copyright © 2010 European Federation of International Association for the Study of Pain Chapters. Published by Elsevier Ltd. All rights reserved.

21 CFR 348.10 - Analgesic, anesthetic, and antipruritic active ingredients.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 21 Food and Drugs 5 2013-04-01 2013-04-01 false Analgesic, anesthetic, and antipruritic active ingredients. 348.10 Section 348.10 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN... Active Ingredients § 348.10 Analgesic, anesthetic, and antipruritic active ingredients. The active...

21 CFR 346.16 - Analgesic, anesthetic, and antipruritic active ingredients.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 21 Food and Drugs 5 2012-04-01 2012-04-01 false Analgesic, anesthetic, and antipruritic active... SERVICES (CONTINUED) DRUGS FOR HUMAN USE ANORECTAL DRUG PRODUCTS FOR OVER-THE-COUNTER HUMAN USE Active Ingredients § 346.16 Analgesic, anesthetic, and antipruritic active ingredients. The active ingredient of the...

21 CFR 348.10 - Analgesic, anesthetic, and antipruritic active ingredients.

Code of Federal Regulations, 2012 CFR

2012-04-01

... 21 Food and Drugs 5 2012-04-01 2012-04-01 false Analgesic, anesthetic, and antipruritic active ingredients. 348.10 Section 348.10 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN... Active Ingredients § 348.10 Analgesic, anesthetic, and antipruritic active ingredients. The active...

21 CFR 346.16 - Analgesic, anesthetic, and antipruritic active ingredients.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 5 2014-04-01 2014-04-01 false Analgesic, anesthetic, and antipruritic active... SERVICES (CONTINUED) DRUGS FOR HUMAN USE ANORECTAL DRUG PRODUCTS FOR OVER-THE-COUNTER HUMAN USE Active Ingredients § 346.16 Analgesic, anesthetic, and antipruritic active ingredients. The active ingredient of the...

21 CFR 348.10 - Analgesic, anesthetic, and antipruritic active ingredients.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 5 2014-04-01 2014-04-01 false Analgesic, anesthetic, and antipruritic active ingredients. 348.10 Section 348.10 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN... Active Ingredients § 348.10 Analgesic, anesthetic, and antipruritic active ingredients. The active...

21 CFR 346.16 - Analgesic, anesthetic, and antipruritic active ingredients.

Code of Federal Regulations, 2013 CFR

2013-04-01

... 21 Food and Drugs 5 2013-04-01 2013-04-01 false Analgesic, anesthetic, and antipruritic active... SERVICES (CONTINUED) DRUGS FOR HUMAN USE ANORECTAL DRUG PRODUCTS FOR OVER-THE-COUNTER HUMAN USE Active Ingredients § 346.16 Analgesic, anesthetic, and antipruritic active ingredients. The active ingredient of the...

Use and abuse of opioid analgesics in chronic pain.

PubMed Central

Goldman, B.

1993-01-01

Primary care physicians are frequently required to treat patients with chronic debilitating pain. Opioid analgesics can successfully manage chronic pain. To prescribe opioid analgesics effectively, physicians must identify appropriate patients. Several methods can be used to identify and distinguish appropriate patients, addicted patients, and for-profit drug seekers. PMID:8097128

78 FR 29142 - Anesthetic and Analgesic Drug Products Advisory Committee; Notice of Meeting

Federal Register 2010, 2011, 2012, 2013, 2014

2013-05-17

... DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration [Docket No. FDA-2013-N-0001] Anesthetic and Analgesic Drug Products Advisory Committee; Notice of Meeting AGENCY: Food and Drug...: Anesthetic and Analgesic Drug Products Advisory Committee. General Function of the Committee: To provide...

21 CFR 348.10 - Analgesic, anesthetic, and antipruritic active ingredients.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 5 2011-04-01 2011-04-01 false Analgesic, anesthetic, and antipruritic active ingredients. 348.10 Section 348.10 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN... Active Ingredients § 348.10 Analgesic, anesthetic, and antipruritic active ingredients. The active...

21 CFR 348.10 - Analgesic, anesthetic, and antipruritic active ingredients.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 5 2010-04-01 2010-04-01 false Analgesic, anesthetic, and antipruritic active ingredients. 348.10 Section 348.10 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN... Active Ingredients § 348.10 Analgesic, anesthetic, and antipruritic active ingredients. The active...

77 FR 67380 - Anesthetic and Analgesic Drug Products Advisory Committee; Notice of Meeting

Federal Register 2010, 2011, 2012, 2013, 2014

2012-11-09

... DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration [Docket No. FDA-2012-N-0001] Anesthetic and Analgesic Drug Products Advisory Committee; Notice of Meeting AGENCY: Food and Drug...: Anesthetic and Analgesic Drug Products Advisory Committee. General Function of the Committee: To provide...

76 FR 78283 - Anesthetic and Analgesic Drug Products Advisory Committee; Notice of Meeting

Federal Register 2010, 2011, 2012, 2013, 2014

2011-12-16

... DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration [Docket No. FDA-2011-N-0002] Anesthetic and Analgesic Drug Products Advisory Committee; Notice of Meeting AGENCY: Food and Drug...: Anesthetic and Analgesic Drug Products Advisory Committee. General Function of the Committee: To provide...

78 FR 37551 - Request for Nominations for Voting and/or Nonvoting Consumer Representatives on Public Advisory...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-06-21

..., Center for Drug Anesthetic and Analgesic Evaluation and Research, Food and Drug Drugs. Administration... vacancies Approximate date needed Anesthetic and Analgesic Drugs-- 1--Voting Immediately. Knowledgeable in.... Anesthetic and Analgesic Drug Products The committee reviews and evaluates available data concerning the...

77 FR 39710 - Draft Guidance for Industry on Organ-Specific Warnings: Internal Analgesic, Antipyretic, and...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-07-05

...] Draft Guidance for Industry on Organ-Specific Warnings: Internal Analgesic, Antipyretic, and... Warnings: Internal Analgesic, Antipyretic, and Antirheumatic Drug Products for Over-the-Counter Human Use... enforcement discretion with regard to the liver warning required in the labeling. DATES: Although you can...

Analgesic-Like Activity of Essential Oil Constituents: An Update

PubMed Central

de Cássia da Silveira e Sá, Rita; Lima, Tamires Cardoso; da Nóbrega, Flávio Rogério; de Brito, Anna Emmanuela Medeiros

2017-01-01

The constituents of essential oils are widely found in foods and aromatic plants giving characteristic odor and flavor. However, pharmacological studies evidence its therapeutic potential for the treatment of several diseases and promising use as compounds with analgesic-like action. Considering that pain affects a significant part of the world population and the need for the development of new analgesics, this review reports on the current studies of essential oils’ chemical constituents with analgesic-like activity, including a description of their mechanisms of action and chemical aspects. PMID:29232831

''As-Needed'' Range Orders for Opioid Analgesics in the Management of Pain: A Consensus Statement of the American Society for Pain Management Nursing and the American Pain Society.

PubMed

Drew, Debra J; Gordon, Debra B; Morgan, Bonnie; Manworren, Renee C B

2018-06-01

Effective pain management requires careful titration of analgesics and evaluation of individual patient's responses to treatment using valid and reliable pain and pain relief assessment tools, and evidence-based patient monitoring for adverse treatment effects. A registered nurse, competent in pain assessment and analgesic administration, can safely interpret and implement properly written ''as-needed'' or ''PRN'' range orders for analgesic medications. The American Society for Pain Management Nursing (ASPMN) and the American Pain Society (APS) support safe medication practices and the appropriate use of PRN range orders for opioid analgesics in the management of pain. Copyright © 2018 American Society for Pain Management Nursing. Published by Elsevier Inc. All rights reserved.

Benzodiazepines: a major component in unintentional prescription drug overdoses with opioid analgesics.

PubMed

Jann, Michael; Kennedy, William Klugh; Lopez, Gaylord

2014-02-01

The misuse and abuse of prescription medications in the United States continues to increase despite interventions by health care professionals, regulatory, and law enforcement agencies. Opioid analgesics are the leading class of prescription drugs that have caused unintentional overdose deaths. Benzodiazepines when taken alone are relatively safe agents in overdose. However, a 5-fold increase in deaths attributed to benzodiazepines occurred from 1999 to 2009. Emergency department visits related to opioid analgesics increased by 111% followed by benzodiazepines 89%. During 2003 to 2009, the 2 prescriptions drugs with the highest increase in death rates were oxycodone 264.6% and alprazolam 233.8%. Therefore, benzodiazepines have a significant impact on prescription drug unintentional overdoses second only to the opioid analgesics. The combination prescribing of benzodiazepines and opioid analgesics commonly takes place. The pharmacokinetic drug interactions between benzodiazepines and opioid analgesics are complex. The pharmacodynamic actions of these agents differ as their combined effects produce significant respiratory depression. Physician and pharmacy shopping by patients occurs, and prescription drug-monitoring programs can provide important information on benzodiazepine and opioid analgesic prescribing patterns and patient usage. Health care professionals need to inform patients and work closely with regulatory agencies and legislatures to stem the increasing fatalities from prescription drug unintentional overdoses.

Post-marketing withdrawal of analgesic medications because of adverse drug reactions: a systematic review.

PubMed

Onakpoya, Igho J; Heneghan, Carl J; Aronson, Jeffrey K

2018-01-01

Many analgesics have been withdrawn from the market because of adverse drug reactions. Controversy still surrounds the use of some approved analgesics for pain management. However, the trends and reasons for withdrawal of analgesics when harms are attributed to their use have not been systematically assessed. Areas covered: We conducted searches in PubMed; Embase; Google Scholar; clinicaltrials.gov; WHO databases of withdrawn products; websites of the European Medicines Agency, the US Food and Drug Administration, the UK Medicines and Healthcare products Regulatory Agency; Meyler's Side Effects of Drugs; Stephens' Detection of New Adverse Drug Reactions; the Pharmaceutical Manufacturing Encyclopedia; and the Merck Index. We included licensed analgesics that were withdrawn after marketing because of adverse reactions between 1950 and March 2017. We excluded herbal products, non-human medicines, and non-prescription medicines. We used the Oxford Centre for Evidence Based Medicine criteria to document the levels of evidence, and chi-squared tests to compare withdrawal patterns across geographical regions. Expert opinion: Pharmacovigilance systems in low-resource settings should be strengthened. Greater co-ordination across regulatory authorities in assessing and interpreting the benefit-harm balance of new analgesics should be encouraged. Future reporting of harms in clinical trials of analgesics should follow standardized guidelines.

[The Analgesic Sparing Effect of Ketamine for Postoperative Pain Management after Pediatric Surgery on the Body Surface].

PubMed

Urabe, Tomoaki; Nakanuno, Ryuichi; Hayase, Kazuma; Sasada, Shogo; Iwamitsu, Reimi; Senami, Masaki

2016-04-01

It is reported that ketamine, a N-methyl-D-aspertate (NMDA) receptor antagonist, can provide analgesic effect improving postoperative pain management and decrease the supplementary analgesic requirement. We investigated the analgesic sparing effect of ketamine for postoperative pain in children undergoing surgery of body surface. Fifty eight patients (0-9 yrs) who had surgery of body surface were divided into two groups (ketamine : n = 27, Group K or control : n = 31, Group N). Postoperative analgesia extracted from charts was retrospectively evaluated by the times patients used analgesics until discharge after the operations. Chi-square and Mann-Whitney U tests were used for statistical analysis. Results : The ketamine group received an intrave- nous bolus of ketamine (1 mg - kg-1) before surgical skin incision. However, there were no significant differ- ences of usage (Group K vs Group N : 4/27 vs 7/31, P=0.45) and frequency of supplementary analgesic us- ages (P=0.85) among groups. In addition, there were also no significant demographic differences between the two groups. Conclusions : Our investigation suggests that the intravenous bolus of ketamine (1 mg - kg-1) before surgical skin incision does not decrease the supple- mentary analgesic requirements on postoperative pain management in pediatric surgery of the body surface.

Screening of analgesic activity of Tunisian Urtica dioica and analysis of its major bioactive compounds by GCMS.

PubMed

Dhouibi, Raouia; Moalla, Dorsaf; Ksouda, Kamilia; Ben Salem, Maryem; Hammami, Serria; Sahnoun, Zouheir; Zeghal, Khaled Mounir; Affes, Hanen

2017-11-20

The present study was aimed to evaluate the analgesic properties of Urtica dioica (UD) and to profile phytochemicals by gas chromatography-mass spectrometry (GC-MS). The ethanolic extracts were prepared by maceration method and extraction using rotary evaporator. The analgesic activity was analysed by hot plate method, formalin test, acetic acid-induced writhing test and the tail-flick test with different doses of the ethanolic extract. In all tests, the leaf's ethanolic extract exhibited significant analgesic activity (p < .001) at a dose of 400 mg/kg. Even with a low dose, we noticed an analgesic activity with many tests. The GC-MS analysis of the ethanol extract of leaf revealed many compounds; 2-methyltetradecane dodecane, 2,6,11-trimethyl-; 2,6,11-trimethyldodecane, and trimethylhexane which are pharmaceutically the most important. These findings justify that UD can be a valuable natural analgesic source which seemed to provide potential phototherapeutics against various ailments. The analysis of ethanolic extract of UD by GCMS revealed the presence of several compounds including polyphenols, flavonoids, triterpenes which can explain the analgesic effect of UD and its mechanism of action. Hence, UD could be another therapeutic alternative for relieving pain and for minimising the use of drugs that have long-term secondary effects.

Increases in the Use of Prescription Opioid Analgesics and the Lack of Improvement in Disability Metrics Among Users

PubMed Central

Sites, Brian D.; Beach, Michael L.; Davis, Matthew

2014-01-01

Background and Objectives In the United States, use of oral opioid analgesics has been associated with increasing rates of addiction, abuse, and diversion. However, little is known about recent national use of non-illicit prescription opioid analgesics (those prescribed in a doctor-patient relationship), the primary source of these drugs for the general US population. Our primary objective was to examine trends in the use of prescription opioid analgesics in the United States and to identify defining characteristics of patient users of prescribed opioids from 2000 to 2010. Methods We used the nationally representative Medical Expenditure Panel Survey to examine trends in prescription oral opioid analgesic use from 2000 to 2010. We used survey design methods to make national estimates of adults (18 years and older) who reported receiving an opioid analgesic prescription (referred to as opioid users) and used logistic regression to examine predictors of opioid analgesic use. Our primary outcome measures were national estimates of total users of prescription opioid analgesics and total number of prescriptions. Our secondary outcome was that of observing changes in the disability and health of the users. Results The estimated total number of opioid analgesic prescriptions in the United States increased by 104%, from 43.8 million in 2000 to 89.2 million in 2010. In 2000, an estimated 7.4% (95% CI, 6.9–7.9) of adult Americans were prescription opioid users compared with 11.8% (95% CI, 11.2–12.4) in 2010. Based on estimates adjusted for changes in the general population, each year was associated with a 6% increase in the likelihood of receiving an opioid prescription from 2000 to 2010. Despite the apparent increase in use, there were no demonstrable improvements in the age- or sex-adjusted disability and health status measures of opioid users. Conclusions The use of prescription opioid analgesics among adult Americans has increased in recent years, and this increase does not appear to be associated with improvements in disability and health status among users. On a public health level, these data suggest that there may be an opportunity to reduce the prescribing of opioid analgesics without worsening of population health metrics. PMID:24310049

77 FR 59241 - Notice of Effective Date of Modifications to Certain Textile and Apparel Rules of Origin of the...

Federal Register 2010, 2011, 2012, 2013, 2014

2012-09-26

... Rules of Origin of the Dominican Republic-Central America- United States Free Trade Agreement AGENCY... Certain Textile and Apparel Rules of Origin of the Dominican Republic-Central America- United States Free...- Central America-United States Free Trade Agreement Implementation Act (the ``CAFTA-DR Act'') approved the...

Disruption of communication between peripheral and central trigeminovascular neurons mediates the antimigraine action of 5HT1B/1D receptor agonists

PubMed Central

Levy, Dan; Jakubowski, Moshe; Burstein, Rami

2004-01-01

Triptans are 5HT1B/1D receptor agonists commonly prescribed for migraine headache. Although originally designed to constrict dilated intracranial blood vessels, the mechanism and site of action by which triptans abort the migraine pain remain unknown. We showed recently that sensitization of peripheral and central trigeminovascular neurons plays an important role in the pathophysiology of migraine pain. Here we examined whether the drug sumatriptan can prevent and/or suppress peripheral and central sensitization by using single-unit recording in our animal model of intracranial pain. We found that sumatriptan effectively prevented the induction of sensitization (i.e., increased spontaneous firing; increased neuronal sensitivity to intracranial mechanical stimuli) in central trigeminovascular neurons (recorded in the dorsal horn), but not in peripheral trigeminovascular neurons (recorded in the trigeminal ganglion). After sensitization was established in both types of neuron, sumatriptan effectively normalized intracranial mechanical sensitivity of central neurons, but failed to reverse such hypersensitivity in peripheral neurons. In both the peripheral and central neurons, the drug failed to attenuate the increased spontaneous activity established during sensitization. These results suggest that neither peripheral nor central trigeminovascular neurons are directly inhibited by sumatriptan. Rather, triptan action appears to be exerted through presynaptic 5HT1B/1D receptors in the dorsal horn to block synaptic transmission between axon terminals of the peripheral trigeminovascular neurons and cell bodies of their central counterparts. We therefore suggest that the analgesic action of triptan can be attained specifically in the absence, but not in the presence, of central sensitization. PMID:15016917

Disruption of communication between peripheral and central trigeminovascular neurons mediates the antimigraine action of 5HT 1B/1D receptor agonists.

PubMed

Levy, Dan; Jakubowski, Moshe; Burstein, Rami

2004-03-23

Triptans are 5HT(1B/1D) receptor agonists commonly prescribed for migraine headache. Although originally designed to constrict dilated intracranial blood vessels, the mechanism and site of action by which triptans abort the migraine pain remain unknown. We showed recently that sensitization of peripheral and central trigeminovascular neurons plays an important role in the pathophysiology of migraine pain. Here we examined whether the drug sumatriptan can prevent and/or suppress peripheral and central sensitization by using single-unit recording in our animal model of intracranial pain. We found that sumatriptan effectively prevented the induction of sensitization (i.e., increased spontaneous firing; increased neuronal sensitivity to intracranial mechanical stimuli) in central trigeminovascular neurons (recorded in the dorsal horn), but not in peripheral trigeminovascular neurons (recorded in the trigeminal ganglion). After sensitization was established in both types of neuron, sumatriptan effectively normalized intracranial mechanical sensitivity of central neurons, but failed to reverse such hypersensitivity in peripheral neurons. In both the peripheral and central neurons, the drug failed to attenuate the increased spontaneous activity established during sensitization. These results suggest that neither peripheral nor central trigeminovascular neurons are directly inhibited by sumatriptan. Rather, triptan action appears to be exerted through presynaptic 5HT(1B/1D) receptors in the dorsal horn to block synaptic transmission between axon terminals of the peripheral trigeminovascular neurons and cell bodies of their central counterparts. We therefore suggest that the analgesic action of triptan can be attained specifically in the absence, but not in the presence, of central sensitization.

Cohort Study of the Impact of High-Dose Opioid Analgesics on Overdose Mortality.

PubMed

Dasgupta, Nabarun; Funk, Michele Jonsson; Proescholdbell, Scott; Hirsch, Annie; Ribisl, Kurt M; Marshall, Steve

2016-01-01

Previous studies examining opioid dose and overdose risk provide limited granularity by milligram strength and instead rely on thresholds. We quantify dose-dependent overdose mortality over a large spectrum of clinically common doses. We also examine the contributions of benzodiazepines and extended release opioid formulations to mortality. Prospective observational cohort with one year follow-up. One year in one state (NC) using a controlled substances prescription monitoring program, with name-linked mortality data. Residential population of North Carolina (n = 9,560,234), with 2,182,374 opioid analgesic patients. Exposure was dispensed prescriptions of solid oral and transdermal opioid analgesics; person-years calculated using intent-to-treat principles. Outcome was overdose deaths involving opioid analgesics in a primary or additive role. Poisson models were created, implemented using generalized estimating equations. Opioid analgesics were dispensed to 22.8% of residents. Among licensed clinicians, 89.6% prescribed opioid analgesics, and 40.0% prescribed ER formulations. There were 629 overdose deaths, half of which had an opioid analgesic prescription active on the day of death. Of 2,182,374 patients prescribed opioids, 478 overdose deaths were reported (0.022% per year). Mortality rates increased gradually across the range of average daily milligrams of morphine equivalents. 80.0% of opioid analgesic patients also received benzodiazepines. Rates of overdose death among those co-dispensed benzodiazepines and opioid analgesics were ten times higher (7.0 per 10,000 person-years, 95 percent CI: 6.3, 7.8) than opioid analgesics alone (0.7 per 10,000 person years, 95 percent CI: 0.6, 0.9). Dose-dependent opioid overdose risk among patients increased gradually and did not show evidence of a distinct risk threshold. There is urgent need for guidance about combined classes of medicines to facilitate a better balance between pain relief and overdose risk. Published by Oxford University Press on behalf of the American Academy of Pain Medicine. 2016. This work is written by US Government employees and is in the public domain in the US.

Reducing the default dispense quantity for new opioid analgesic prescriptions: study protocol for a cluster randomised controlled trial.

PubMed

Bachhuber, Marcus A; Nash, Denis; Southern, William N; Heo, Moonseong; Berger, Matthew; Schepis, Mark; Cunningham, Chinazo O

2018-04-20

As opioid analgesic consumption has grown, so have opioid use disorder and opioid-related overdoses. Reducing the quantity of opioid analgesics prescribed for acute non-cancer pain can potentially reduce risks to the individual receiving the prescription and to others who might unintentionally or intentionally consume any leftover tablets. Reducing the default dispense quantity for new opioid analgesic prescriptions in the electronic health record (EHR) is a promising intervention to reduce prescribing. This study is a prospective cluster randomised controlled trial with two parallel arms. Primary care sites (n=32) and emergency departments (n=4) will be randomised in matched pairs to either a modification of the EHR so that new opioid analgesic prescriptions default to a dispense quantity of 10 tablets (intervention) or to no EHR change (control). The dispense quantity will remain fully modifiable by providers in both arms. From 6 months preintervention to 18 months postintervention, patient-level data will be analysed (ie, the patient is the unit of inference). Patient eligibility criteria are: (A) received a new opioid analgesic prescription, defined as no other opioid analgesic prescription in the prior 6 months; (B) age ≥18 years; and (C) no cancer diagnosis within 1 year prior to the new opioid analgesic prescription. The primary outcome will be the quantity of opioid analgesics prescribed in the initial prescription. Secondary outcomes will include opioid analgesic reorders and health service utilisation within 30 days after the initial prescription. Outcomes will be compared between study arms using a difference-in-differences analysis. This study has been approved by the Montefiore Medical Center/Albert Einstein College of Medicine Institutional Review Board with a waiver of informed consent (2016-6036) and is registered on ClinicalTrials.gov (NCT03003832, 6 December 2016). Findings will be disseminated through publication, conferences and meetings with health system leaders. NCT03003832; Pre-results. © 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.

Evolving Role of Local Anesthetics in Managing Postsurgical Analgesia.

PubMed

Golembiewski, Julie; Dasta, Joseph

2015-06-01

Opioid analgesics, the cornerstone of effective postsurgical pain management, may be associated with risk of opioid-related adverse drug events (ADEs) that may complicate the postsurgical experience. Perioperative multimodal analgesic regimens have the potential to improve postsurgical pain control and may permit use of lower analgesic doses and reduce the incidence of opioid-related ADEs. Utility of traditional local anesthetic formulations to provide analgesia over the entire postsurgical period is limited by their short duration of action. Liposome bupivacaine, a liposomal formulation of bupivacaine indicated for single-dose administration into the surgical site to produce postsurgical analgesia, was evaluated in multiple surgical models as part of multimodal analgesic regimens and was found in clinical trials to provide postsurgical analgesia for up to 72 hours. Here, we provide an overview of the available multimodal analgesic options and recent recommendations for optimal postsurgical pain management. A review of the literature was conducted, and results from recent clinical trials are included. The use of a multimodal analgesic regimen, including liposome bupivacaine, can extend the time to first postsurgical opioid use, may reduce postsurgical opioid consumption, and reduce hospital length of stay and costs compared with an opioid-only analgesic regimen. Use of multimodal analgesic regimens is a practical way to achieve good postsurgical analgesia while minimizing reliance on opioids and associated adverse events. Taken as a whole, evidence from the clinical studies of liposome bupivacaine suggests this local anesthetic formulation may be a useful component of multimodal analgesic regimens for managing postsurgical pain in select patients, with the potential to reduce opioid use and opioid-related ADEs in the postsurgical setting. As with bupivacaine, appropriate use of liposome bupivacaine to optimize clinical effects, economic implications, and patient tolerability will depend on appropriate patient selection, practitioner training, and institutional protocols. As a component of a multimodal analgesic regimen, liposome bupivacaine represents a new approach to extending the duration of postsurgical analgesia. Further studies across a range of surgical settings should help clarify the most appropriate roles for this prolonged-release formulation of bupivacaine. Copyright © 2015 Elsevier HS Journals, Inc. All rights reserved.

Relative Efficacy of Ultrasound-guided Ilioinguinal-iliohypogastric Nerve Block versus Transverse Abdominis Plane Block for Postoperative Analgesia following Lower Segment Cesarean Section: A Prospective, Randomized Observer-blinded Trial.

PubMed

Kiran, L Vamsee; Sivashanmugam, T; Kumar, V R Hemanth; Krishnaveni, N; Parthasarathy, S

2017-01-01

Quality of postoperative analgesia after cesarean section makes difference to mother in child bonding, early ambulation, and discharge. Ilioinguinal iliohypogastric (ILIH) and transverse abdominis plane (TAP) block had been tried to reduce the opioid analgesics, but the relative efficacy is unknown. Hence, this study was designed to compare the efficacy of these two regional analgesic techniques in sparing postoperative rescue analgesic requirement following lower segment cesarean section (LSCS). Sixty patients who underwent LSCS were randomly allocated into two groups to receive either US-guided TAP block or ILIH nerve block using sealed envelope technique at the end of the surgery. In the postoperative ward, whenever patient complained of pain, pain nurse in-charge administered the rescue analgesics as per the study protocol. A blinded observer visited the patient at 0, 2, 4, 6, 8, 10, 12, and 24 h postoperative intervals and recorded the quality of pain relief and the amount of rescue analgesic consumed. All patients in both the study groups required one dose of rescue analgesics in the form of injection diclofenac sodium 50 mg intravenously but subsequently 57% of patients did not require any further analgesics till 24 h in the TAP block group whereas in ILIH group, only 13% did not require further analgesics ( P = 0.00), correspondingly the cumulative tramadol dose was significantly higher at all the time interval in the ILIH group when compared to the TAP group. Quality of postoperative analgesia provided by TAP block was superior to ILIH block following LSCS.

Analgesia (mis)usage on a dental emergency service: a patient survey.

PubMed

Hommez, Geert; Ongena, B; Cauwels, R G E C; De Paepe, P; Christiaens, V; Jacquet, W

2018-04-01

Analgesics are one of the most frequently used medicines. Self-medication and misuse have been described in the literature. The purpose of this study was to document analgesic (mis)use in a population seeking emergency dental treatment. Patients consulting a dental emergency service were randomly asked to complete a questionnaire on analgesic use, knowledge and information on the analgesics and on their pain history. A photobook was used as an aid to identify products used. Descriptive statistics were combined with chi-square and Mann-Whitney U testing. Ninety-eight patients were included. Acetaminophen (69.4%) and ibuprofen (65.3%) were the most frequently used products. Nearly half of the subjects (43.9%) combined at least two analgesics. Although 42.9% of subjects were aware of the maximum daily dose, 62.2% of the subjects exceeded this limit, specifically 76.6% of subjects using ibuprofen and 32.4% of subjects using acetaminophen overdosing. Females overdosed significantly more than males. Ingestion on medical advice did not affect the overdose rates significantly. No significant relation was found between the absence of knowledge on the maximum daily dose and actual overdosing. No higher pain reduction was found in patients overdosing analgesics. The average number of days patients experienced pain before consulting the emergency unit was 12. A significant relation was found between the lag time and overdosing. A large portion of the patients overdosed analgesics. Even prior medical advice did not reduce significantly overdose rates. Dentists treating emergency cases clearly need to be aware of the high risk and high rates of overdosing analgesics in their patients.

The evidence of neuraxial administration of analgesics for cancer-related pain: a systematic review.

PubMed

Kurita, G P; Benthien, K S; Nordly, M; Mercadante, S; Klepstad, P; Sjøgren, P

2015-10-01

The present systematic review analysed the existing evidence of analgesic efficacy and side effects of opioids without and with adjuvant analgesics delivered by neuraxial route (epidural and subarachnoid) in adult patients with cancer. Search strategy was elaborated with words related to cancer, pain, neuraxial route, analgesic and side effects. The search was performed in PubMed, EMBASE, and Cochrane for the period until February 2014. Studies were analysed according to methods, results, quality of evidence, and strength of recommendation. The number of abstracts retrieved was 2147, and 84 articles were selected for full reading. The final selection comprised nine articles regarding randomised controlled trials (RCTs) divided in four groups: neuraxial combinations of opioid and adjuvant analgesic compared with neuraxial administration of opioid alone (n = 4); single neuraxial drug in bolus compared with continuous administration (n = 2); single neuraxial drug compared with neuraxial placebo (n = 1); and neuraxial opioid combined with or without adjuvant analgesic compared with other comprehensive medical management than neuraxial analgesics (n = 2). The RCTs presented clinical and methodological diversity that precluded a meta-analysis. They also presented several limitations, which reduced study internal validity. However, they demonstrated better pain control for all interventions analysed. Side effects were described, but there were few significant differences in favour of the tested interventions. Heterogeneous characteristics and several methodological limitations of the studies resulted in evidence of low quality and a weak recommendation for neuraxial administration of opioids with or without adjuvant analgesics in adult patients with cancer. © 2015 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.

21 CFR 341.85 - Labeling of permitted combinations of active ingredients.

Code of Federal Regulations, 2012 CFR

2012-04-01

... “pain reliever” or “analgesic (pain reliever).” If the product is also labeled to relieve fever, then the analgesic-antipyretic component is identified as a “pain reliever-fever reducer” or “analgesic (pain reliever)-antipyretic (fever reducer).” (2) [Reserved] (b) Indications. The labeling of the...

21 CFR 341.85 - Labeling of permitted combinations of active ingredients.

Code of Federal Regulations, 2013 CFR

2013-04-01

... “pain reliever” or “analgesic (pain reliever).” If the product is also labeled to relieve fever, then the analgesic-antipyretic component is identified as a “pain reliever-fever reducer” or “analgesic (pain reliever)-antipyretic (fever reducer).” (2) [Reserved] (b) Indications. The labeling of the...

21 CFR 341.85 - Labeling of permitted combinations of active ingredients.

Code of Federal Regulations, 2014 CFR

2014-04-01

... “pain reliever” or “analgesic (pain reliever).” If the product is also labeled to relieve fever, then the analgesic-antipyretic component is identified as a “pain reliever-fever reducer” or “analgesic (pain reliever)-antipyretic (fever reducer).” (2) [Reserved] (b) Indications. The labeling of the...

21 CFR 346.16 - Analgesic, anesthetic, and antipruritic active ingredients.

Code of Federal Regulations, 2011 CFR

2011-04-01

... 21 Food and Drugs 5 2011-04-01 2011-04-01 false Analgesic, anesthetic, and antipruritic active ingredients. 346.16 Section 346.16 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN... Ingredients § 346.16 Analgesic, anesthetic, and antipruritic active ingredients. The active ingredient of the...

21 CFR 346.16 - Analgesic, anesthetic, and antipruritic active ingredients.

Code of Federal Regulations, 2010 CFR

2010-04-01

... 21 Food and Drugs 5 2010-04-01 2010-04-01 false Analgesic, anesthetic, and antipruritic active ingredients. 346.16 Section 346.16 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN... Ingredients § 346.16 Analgesic, anesthetic, and antipruritic active ingredients. The active ingredient of the...

Synthetic substances with morphine-like effect

PubMed Central

Braenden, Olav J.; Eddy, Nathan B.; Halbach, H.

1955-01-01

For morphine-, morphinan-, pethidine-, methadone-, and dithienyl-butenylamine groups of analgesic compounds a systematic survey is given of how analgesic activity is quantitatively affected by alteration of the chemical constitution. Features common to the structural formulae of substances with morphine-like analgesic effect are pointed out. ImagesFIG. 1FIG. 1(Contd.) PMID:13284565

S-adenosyl methionine (SAM) attenuates the development of tolerance to analgesic activity of morphine in rats.

PubMed

Katyal, Jatinder; Kumar, Hemant; Joshi, Dinesh; Gupta, Yogendra Kumar

2017-04-03

Development of tolerance to analgesic effect, on chronic administration of morphine, limits its clinical usefulness in pain management. S-adenosyl methionine (SAM) used for arthritis and approved as a supplement in many countries including United States was evaluated for reducing morphine tolerance. Male 'Wistar' rats were used. The analgesic activity was determined using tail flick analgesiometer (Columbus Instruments, USA). Rats given morphine (7mg/kg), intraperitoneally (i.p.), once daily for 5days developed tolerance to analgesic effect. To evaluate the effect of SAM on morphine tolerance, SAM 800mg/kg was administered orally (p.o.), 45min prior to each dose of morphine. The analgesic activity of SAM and opioidergic component in its activity was also evaluated. Co-administration of morphine and SAM reversed morphine tolerance. SAM exhibited analgesic effect after repeated administration which was reversed by naloxone administration. Since safety of SAM on chronic use is documented it can be a good option in morphine tolerance. Role in drug addiction and withdrawal should also be evaluated. Copyright © 2017 Elsevier B.V. All rights reserved.

Guaifenesin enhances the analgesic potency of paracetamol in mice.

PubMed

Dolezal, T; Krsiak, M

2002-12-01

Guaifenesin is used as an expectorant and it has been reported to possess muscle relaxant and sedative activity. Guaifenesin has been used as a component of composite OTC analgesics containing paracetamol for many years. The aim of our study was to ascertain effects of guaifenesin on paracetamol analgesic activity and locomotor performance. Antinociceptive efficacy was tested in mice using an acetic acid (0.7%) writhing test. Locomotor performance was tested in rota-rod test and activity cage. All drugs were given orally and tested in mice. In combination with a subeffective dose of guaifenesin (200 mg/kg), the ED(50) for paracetamol in the writhing test was significantly lower (82.2 mg/kg) than that of paracetamol administered alone (233.7 mg/kg). Guaifenesin alone did not show an analgesic effect. Guaifenesin did not produce statistically significant locomotor impairment in the rota-rod test at doses enhancing analgesic activity of paracetamol, although there was a trend for decreased locomotor activity in activity cage. The present results indicate that guaifenesin may enhance analgesic activity of paracetamol.

Options for treating postherpetic neuralgia in the medically complicated patient

PubMed Central

Bruckenthal, Patricia; Barkin, Robert L

2013-01-01

Patients with postherpetic neuralgia (PHN) are often of advanced age or immunocompromised and likely to have ≥1 comorbid medical condition for which they receive ≥1 medication (polypharmacy). Comorbidities affecting renal or hepatic function can alter pharmacokinetics, thereby impacting the efficacy or tolerability of PHN analgesic therapies. Cardiovascular, cerebrovascular, or psychiatric comorbidities may increase patient vulnerability to potential adverse events associated with some PHN analgesic therapies. Because PHN is a localized condition, localized therapy with a topical analgesic (lidocaine patch 5% and capsaicin 8% patch or cream) may provide adequate efficacy while mitigating the risk of systemic adverse events compared with oral analgesics (eg, tricyclic antidepressants, anticonvulsants, opioids). However, combined therapy with a topical and an oral analgesic or with >1 oral analgesic may be needed for optimal pain management in some patients. This review summarizes how comorbidities and concomitant medications should be taken into account when selecting among available pharmacotherapies for PHN and provides recommendations for the selection of therapies that will provide analgesia while minimizing the risk of adverse events. PMID:23990726

Opioid analgesics and P-glycoprotein efflux transporters: a potential systems-level contribution to analgesic tolerance.

PubMed

Mercer, Susan L; Coop, Andrew

2011-01-01

Chronic clinical pain remains poorly treated. Despite attempts to develop novel analgesic agents, opioids remain the standard analgesics of choice in the clinical management of chronic and severe pain. However, mu opioid analgesics have undesired side effects including, but not limited to, respiratory depression, physical dependence and tolerance. A growing body of evidence suggests that P-glycoprotein (P-gp), an efflux transporter, may contribute a systems-level approach to the development of opioid tolerance. Herein, we describe current in vitro and in vivo methodology available to analyze interactions between opioids and P-gp and critically analyze P-gp data associated with six commonly used mu opioids to include morphine, methadone, loperamide, meperidine, oxycodone, and fentanyl. Recent studies focused on the development of opioids lacking P-gp substrate activity are explored, concentrating on structure-activity relationships to develop an optimal opioid analgesic lacking this systems-level contribution to tolerance development. Continued work in this area will potentially allow for delineation of the mechanism responsible for opioid-related P-gp up-regulation and provide further support for evidence based medicine supporting clinical opioid rotation.

3D-Pharmacophore Identification for κ-Opioid Agonists Using Ligand-Based Drug-Design Techniques

NASA Astrophysics Data System (ADS)

Yamaotsu, Noriyuki; Hirono, Shuichi

A selective κ-opioid receptor (KOR) agonist might act as a powerful analgesic without the side effects of μ-opioid receptor-selective drugs such as morphine. The eight classes of known KOR agonists have different chemical structures, making it difficult to construct a pharmacophore model that takes them all into account. Here, we summarize previous efforts to identify the pharmacophore for κ-opioid agonists and propose a new three-dimensional pharmacophore model that encompasses the κ-activities of all classes. This utilizes conformational sampling of agonists by high-temperature molecular dynamics and pharmacophore extraction through a series of molecular superpositions.

Prescribing methadone for pain management in end-of-life care.

PubMed

Manfredonia, John F

2005-03-01

Methadone hydrochloride is an effective, inexpensive, and relatively safe opioid to use in the treatment of patients with chronic pain. It is especially effective in management of pain during the final stages of life, as it is the only long-acting analgesic available in liquid form. However, because methadone has a long half-life, individual wide variations, and potential for accumulation and overdosage, physicians must judiciously and conscientiously prescribe it. Also, they should closely monitor patients during the titration phase and educate them with regard to basic pharmacologic properties and potential side effects. A plan to start at low doses and proceed slowly is applicable to methadone.

Methoxyflurane and Nitrous Oxide as Obstetric Analgesics. II.—A Comparison by Self-administered Intermittent Inhalation

PubMed Central

Jones, Peter L.; Rosen, M.; Mushin, W. W.; Jones, E. V.

1969-01-01

Methoxyflurane (0·35%) in air and nitrous oxide/oxygen (50%/50%) self-administered intermittently in the usual way have been compared as analgesics for labour. There were 25 patients in each group. Objective assessment by an anaesthetist showed that methoxyflurane is the more effective analgesic, and this was supported by the opinion of the multiparae. Nausea and vomiting were significantly less with methoxyflurane. Fifty per cent. nitrous oxide in oxygen given intermittently does not appear to be the best analgesic concentration. Nevertheless, since a considerable variation in sensitivity exists, it would probably be unwise to consider the introduction of higher concentrations for use by unsupervised midwives. This trial confirms the predictions made by us using a method for screening inhalational analgesics, in which methoxyflurane and nitrous oxide were given continuously. PMID:4895339

Methoxyflurane and nitrous oxide as obstetric analgesics. II. A comparison by self-administered intermittent inhalation.

PubMed

Jones, P L; Rosen, M; Mushin, W W; Jones, E V

1969-08-02

Methoxyflurane (0.35%) in air and nitrous oxide/oxygen (50%/50%) self-administered intermittently in the usual way have been compared as analgesics for labour. There were 25 patients in each group. Objective assessment by an anaesthetist showed that methoxyflurane is the more effective analgesic, and this was supported by the opinion of the multiparae. Nausea and vomiting were significantly less with methoxyflurane. Fifty per cent. nitrous oxide in oxygen given intermittently does not appear to be the best analgesic concentration. Nevertheless, since a considerable variation in sensitivity exists, it would probably be unwise to consider the introduction of higher concentrations for use by unsupervised midwives.This trial confirms the predictions made by us using a method for screening inhalational analgesics, in which methoxyflurane and nitrous oxide were given continuously.

77 FR 4025 - Privacy Act of 1974; System of Records

Federal Register 2010, 2011, 2012, 2013, 2014

2012-01-26

...; System of Records AGENCY: U.S. Central Command, DoD. ACTION: Notice to Amend a System of Records. SUMMARY: The U.S. Central Command is amending a system of records notice in its existing inventory of record... INFORMATION: The U.S. Central Command systems of records notices subject to the Privacy Act of 1974 (5 U.S.C...

Usage of paracetamol-containing combination analgesics remains high in primary care

PubMed Central

Usher, Cara; Teeling, Mary; Bennett, Kathleen; McGowan, Bernie; Feely, John

2005-01-01

Aims Paracetamol-containing combination analgesics are widely prescribed but the use of paracetamol/dextropropoxyphene (co-proxamol) is particularly controversial. We aim to examine the prescribing patterns of the paracetamol-containing analgesics in Ireland. Methods A national primary care prescribing database was used to investigate patterns of usage. Twenty-six thousand three hundred and eighteen patients who were new to therapy with paracetamol and paracetamol-containing analgesics between January and June 2002 were identified as follows: no previous analgesic medication in the 6 months prior to enrolment into the study, and followed up for at least 12 months from the time of enrolment. Duration of therapy and the number of prescriptions received post enrolment were analyzed according to age. Odds ratios for receiving long-term (>1 month) compared with short-term (1 month) prescriptions for co-proxamol, paracetamol only or a paracetamol combination-type analgesic were calculated for women vs. men, and in those aged over 65 vs. those aged under 65 years. Results Co-proxamol was the most commonly prescribed analgesic, accounting for 42% of all prescriptions dispensed during 2003. Long-term use of paracetamol-containing analgesic preparations was uncommon, with 56.7% receiving only 1 month's prescription during the study period. However, women (OR = 1.18, 95% CI 1.07, 1.28, P < 0.0001) and those over 65 years (OR = 1.71, 95% CI 1.57, 1.86, P < 0.0001) were more likely to receive a follow-up prescription for co-proxamol, but also for paracetamol (women, OR = 1.28, 95% CI 1.16, 1.39; over 65 year olds, OR = 2.67, 95%CI 2.44, 2.93) and the paracetamol combinations (women, OR = 1.33, 95% CI 1.20, 1.47; over 65 year olds, OR = 1.69, 95% CI 1.53, 1.87). Conclusions Co-proxamol was the most commonly prescribed paracetamol-containing analgesic preparation in Ireland. The results may indicate inappropriate use in primary care. PMID:16305590

Levetiracetam interacts synergistically with nonsteroidal analgesics and caffeine to produce antihyperalgesia in rats.

PubMed

Tomić, Maja A; Micov, Ana M; Stepanović-Petrović, Radica M

2013-11-01

Levetiracetam is a novel anticonvulsant with antihyperalgesic efficacy in inflammatory pain. Nonsteroidal analgesics and caffeine, as analgesic adjuvant, are widely used against inflammatory pain. This study characterized the manner in which levetiracetam interacts with analgesics (ibuprofen, celecoxib, and paracetamol) and caffeine to suppress hyperalgesia in a model of localized inflammation. Rat paw inflammation was induced by intraplantar carrageenan (.1 mL, 1%). Hyperalgesia and antihyperalgesic effects of levetiracetam (orally), analgesics (orally), and caffeine (intraperitoneally) alone and 2-drug combinations of levetiracetam with analgesics or caffeine were examined by a modified paw pressure test. The type of interaction between components was determined by isobolographic analysis or by analysis of the log dose-response curves for drug combination and drugs alone. Levetiracetam (10-200 mg/kg), ibuprofen (12.5-100 mg/kg), celecoxib (3.75-30 mg/kg), paracetamol (50-200 mg/kg), caffeine (15-100 mg/kg), and 2-drug combinations of levetiracetam with analgesics/caffeine produced a significant, dose-dependent reduction of inflammatory hyperalgesia. Isobolographic analysis revealed that levetiracetam exerts a synergistic interaction with analgesics, with approximately 7-, 9-, and 11-fold reduction of doses of both drugs in combination of levetiracetam with paracetamol, celecoxib, and ibuprofen, respectively. Analysis of the log dose-response curves for levetiracetam (1-50 mg/kg) in the presence of caffeine (10 mg/kg) and levetiracetam applied alone also revealed a synergistic interaction. Levetiracetam's ED50 in the presence of caffeine was reduced approximately 11-fold. The presented data suggest that 2-drug combinations of levetiracetam and nonsteroidal analgesics or caffeine could be useful in treatment of inflammatory pain. The efficacy and the adverse effects of those mixtures should be explored further in clinical settings. Copyright © 2013 American Pain Society. Published by Elsevier Inc. All rights reserved.

Effects of analgesics on olfactory function and the perception of intranasal trigeminal stimuli.

PubMed

Mizera, L; Gossrau, G; Hummel, T; Haehner, A

2017-01-01

There is some evidence suggesting that analgesics have an impact on human chemosensory function, especially opioids and cannabinoids are known to interfere with olfactory function. However, largely unknown is the effect of a long-term use of analgesics on the intranasal trigeminal system so far. Here, we investigated olfactory function and the perception of intranasal trigeminal stimuli in pain patients with long-term use of analgesics compared to age-matched healthy controls. For this purpose, a psychophysical approach was chosen to measure these sensory functions in 100 chronic pain patients and 95 controls. Olfactory testing was performed using the 'Sniffin' Sticks' test kit, which involves tests for odour threshold, odour discrimination and odour identification. Further, participants were asked to rate the intensity of trigeminal stimuli by using a visual analogue scale. We observed that the chronic use of pain medication was associated with significantly reduced perception of intranasal trigeminal stimuli and olfactory function compared to age-matched controls without intake of analgesics. Results indicate that non-opioid and opioid drugs, or a combination of both did not differ in their effects on chemosensory function. Further, after eliminating the effect of a co-existing depression and the use of co-analgesics, the negative influence of analgesics on olfactory function and trigeminal perception was still evident. The observed effect might be mediated due to interaction with opioid receptors in trigeminal ganglia and nuclei or due to trigeminal/olfactory interaction. As a practical consequence, patients should be made aware of a possible impairment of their olfactory and trigeminal function under long-term analgesic treatment. WHAT DOES THIS STUDY ADD?: We observed that the chronic use of pain medication was associated with significantly reduced olfactory function and perception of intranasal trigeminal stimuli compared to age-matched controls without intake of analgesics. Non-opioid and opioid drugs did not differ in their effects on chemosensory function. © 2016 European Pain Federation - EFIC®.

Preoperative analgesics for additional pain relief in children and adolescents having dental treatment.

PubMed

Ashley, Paul F; Parekh, Susan; Moles, David R; Anand, Prabhleen; MacDonald, Laura C I

2016-08-08

Fear of dental pain is a major barrier to treatment for children who need dental care. The use of preoperative analgesics has the potential to reduce postoperative discomfort and intraoperative pain. We reviewed the available evidence to determine whether further research is warranted and to inform the development of prescribing guidelines. This is an update of a Cochrane review published in 2012. To assess the effects of preoperative analgesics for intraoperative or postoperative pain relief (or both) in children and adolescents undergoing dental treatment without general anaesthesia or sedation. We searched the following electronic databases: Cochrane Oral Health's Trials Register (to 5 January 2016), the Cochrane Central Register of Controlled Trials (CENTRAL) (the Cochrane Library 2015, Issue 12), MEDLINE via OVID (1946 to 5 January 2016), EMBASE via OVID (1980 to 5 January 2016), LILACS via BIREME (1982 to 5 January 2016) and the ISI Web of Science (1945 to 5 January 2016). We searched ClinicalTrials.gov and the World Health Organization (WHO) International Clinical Trials Registry Platform for ongoing trials to 5 January 2016. There were no restrictions regarding language or date of publication in the searches of the electronic databases. We handsearched several specialist journals dating from 2000 to 2011.We checked the reference lists of all eligible trials for additional studies. We contacted specialists in the field for any unpublished data. Randomised controlled clinical trials of analgesics given before dental treatment versus placebo or no analgesics in children and adolescents up to 17 years of age. We excluded children and adolescents having dental treatment under sedation (including nitrous oxide/oxygen) or general anaesthesia. Two review authors assessed titles and abstracts of the articles obtained from the searches for eligibility, undertook data extraction and assessed the risk of bias in the included studies. We assessed the quality of the evidence using GRADE criteria. We included five trials in the review, with 190 participants in total. We did not identify any new studies for inclusion from the updated search in January 2016.Three trials were related to dental treatment, i.e. restorative and extraction treatments; two trials related to orthodontic treatment. We did not judge any of the included trials to be at low risk of bias.Three of the included trials compared paracetamol with placebo, only two of which provided data for analysis (presence or absence of parent-reported postoperative pain behaviour). Meta-analysis of the two trials gave arisk ratio (RR) for postoperative pain of 0.81 (95% confidence interval (CI) 0.53 to 1.22; two trials, 100 participants; P = 0.31), which showed no evidence of a benefit in taking paracetamol preoperatively (52% reporting pain in the placebo group versus 42% in the paracetamol group). One of these trials was at unclear risk of bias, and the other was at high risk. The quality of the evidence is low. One study did not have any adverse events; the other two trials did not mention adverse events.Four of the included trials compared ibuprofen with placebo. Three of these trials provided useable data. One trial reported no statistical difference in postoperative pain experienced by the ibuprofen group and the control group for children undergoing dental treatment. We pooled the data from the other two trials, which included participants who were having orthodontic separator replacement without a general anaesthetic, to determine the effect of preoperative ibuprofen on the severity of postoperative pain. There was a statistically significant mean difference in severity of postoperative pain of -13.44 (95% CI -23.01 to -3.88; two trials, 85 participants; P = 0.006) on a visual analogue scale (0 to 100), which indicated a probable benefit for preoperative ibuprofen before this orthodontic procedure. However, both trials were at high risk of bias. The quality of the evidence is low. Only one of the trials reported adverse events (one participant from the ibuprofen group and one from the placebo group reporting a lip or cheek biting injury). From the available evidence, we cannot determine whether or not preoperative analgesics are of benefit in paediatric dentistry for procedures under local anaesthetic. There is probably a benefit in using preoperative analgesics prior to orthodontic separator placement. The quality of the evidence is low. Further randomised clinical trials should be completed with appropriate sample sizes and well defined outcome measures.

32 CFR 1901.22 - Action and determination(s) by originator(s) or any interested party.

Code of Federal Regulations, 2013 CFR

2013-07-01

... Defense CENTRAL INTELLIGENCE AGENCY PUBLIC RIGHTS UNDER THE PRIVACY ACT OF 1974 Action on Privacy Act... be construed to allow access to systems of records exempted by the Director of Central Intelligence...

32 CFR 1901.22 - Action and determination(s) by originator(s) or any interested party.

Code of Federal Regulations, 2011 CFR

2011-07-01

... Defense CENTRAL INTELLIGENCE AGENCY PUBLIC RIGHTS UNDER THE PRIVACY ACT OF 1974 Action on Privacy Act... be construed to allow access to systems of records exempted by the Director of Central Intelligence...

Use of opioid analgesics or sleeping medication and survival of cancer patients.

PubMed

Chang, Wen-Pei; Lin, Chia-Chin

2015-06-01

Pain and sleep disturbance have been shown to have a profound influence on the outcomes of cancer treatment. This study sought to determine whether administering opioid analgesics or sleeping medication to cancer patients during their first admission to a hospital is associated with poor prognoses. We conducted a population-based retrospective cohort study by analyzing data obtained from the National Health Insurance Research Database in Taiwan. The study population comprised cancer patients whose first admission to a hospital for initial cancer treatment was in 2004. We collected data on 2302 cancer patients. To analyze the effect of opioid analgesic and sleeping medication usage on cancer patient survival, we compared the 3-year survival rates among 4 groups of patients (no use, sleeping medications-only, opioid analgesics-only, both used). The 3-year Kaplan-Meier plots for these 4 groups show that the difference was statistically significant (log rank 48.244, p < 0.001). The longevity of cancer patients was the greatest among the no-use group, followed by the sleeping medications-only group, then the opioid analgesics-only group, and finally, the group in which both sleeping medications and opioid analgesics were used. The use of opioid analgesics or sleeping medication was shown to be negatively correlated with the survival rate of cancer patients. Copyright © 2014 Elsevier Ltd. All rights reserved.

A systematic review and meta-analysis of the ability of analgesic drugs to reduce metastasis in experimental cancer models

PubMed Central

Hooijmans, Carlijn R.; Geessink, Florentine J.; Ritskes-Hoitinga, Merel; Scheffer, Gert-Jan

2015-01-01

Abstract Analgesics are commonly used to manage pain in cancer patients. It has been suggested that there might be a relation between analgesics and the outgrowth of metastases. Opioids might increase and non-steroidal anti-inflammatory drugs decrease the risk of metastasis. Robust analysis of all preclinical evidence, however, has so far been lacking. Therefore, we conducted a systematic review and meta-analysis on the effect of treatment with analgesics on metastasis in experimental animal models. One hundred forty-seven studies met the inclusion criteria. Study characteristics, outcome data on the number, and incidence of metastases were extracted, and methodological quality was assessed. In the meta-analysis, we included 215 (±4000 animals) and 137 (±3000 animals) comparisons between analgesic vs control treatment, respectively, on the number and incidence of metastases. Overall, treatment with analgesics significantly decreases the number and risk of metastasis. This effect appears mainly to be the consequence of the efficacy of NSAIDs. Other factors that modify the efficacy are species, type of NSAIDs administered, timing, and duration of treatment. There is no evidence indicating that treatment with any analgesics increases the occurrence of metastases. Our findings appear robust for the various animal models and designs included in this review, which increases our confidence in the result and translatability to the clinical situation. PMID:26181303

The availability of prescription-only analgesics purchased from the internet in the UK.

PubMed

Raine, Connie; Webb, David J; Maxwell, Simon R J

2009-02-01

Increasing numbers of people are accessing medicines from the internet. This online market is poorly regulated and represents a potential threat to the health of patients and members of the public. Prescription-only analgesics, including controlled opioids, are readily available to the UK public through internet pharmacies that are easily identified by popular search engines. The majority of websites do not require the customer to possess a valid prescription for the drug. Less than half provide an online health screen to assess suitability for supply. The majority have no registered geographical location. Analgesic medicines are usually purchased at prices significantly above British National Formulary prices and are often supplied in large quantities. These findings are of particular relevance to pain-management specialists who are trying to improve the rational use of analgesic drugs. To explore the availability to the UK population of prescription-only analgesics from the internet. Websites were identified by using several keywords in the most popular internet search engines. From 2000 websites, details of 96 were entered into a database. Forty-six (48%) websites sold prescription analgesics, including seven opioids, two non-opioids and 18 nonsteroidal anti-inflammatory drugs. Thirty-five (76%) of these did not require the customer to possess a valid prescription. Prescription-only analgesics, including controlled opioids, are readily available from internet websites, often without a valid prescription.

Pain in children--are we accomplishing the optimal pain treatment?

PubMed

Lundeberg, Stefan

2015-01-01

Morphine, paracetamol and local anesthetics have for a long time been the foremost used analgesics in the pediatric patient by tradition but not always enough effective and associated with side effects. The purpose with this article is to propose alternative approaches in pain management, not always supported up by substantial scientific work but from a combination of science and clinical experience in the field. The scientific literature has been reviewed in parts regarding different aspects of pain assessment and analgesics used for treatment of diverse pain conditions with focus on procedural and acute pain. Clinical experience has been added to form the suggested improvements in accomplishing an improved pain management in pediatric patients. The aim with pain management in children should be a tailored analgesic medication with an individual acceptable pain level and optimal degree of mobilization with as little side effects as possible. Simple techniques of pain control are as effective as and complex techniques in pediatrics but the technique used is not of the highest importance in achieving a good pain management. Increased interest and improved education of the doctors prescribing analgesics is important in accomplishing a better pain management. The optimal treatment with analgesics is depending on the analysis of pain origin and analgesics used should be adjusted thereafter. A multimodal treatment regime is advocated for optimal analgesic effect. © 2014 John Wiley & Sons Ltd.

Comparison of Electroacupuncture and Morphine-Mediated Analgesic Patterns in a Plantar Incision-Induced Pain Model

PubMed Central

Tsai, Shih-Ying; Chen, Kuen-Bao; Hsu, Sheng-Feng; Chen, Julia Yi-Ru

2014-01-01

Electroacupuncture (EA) is a complementary therapy to improve morphine analgesia for postoperative pain, but underlying mechanism is not well-known. Herein, we investigated EA-induced analgesic effect in a plantar incision (PI) model in male Sprague-Dawley rats. PI was performed at the left hind paw. EA of 4 Hz and high intensity or sham needling was conducted at right ST36 prior to PI and repeated for another 2 days. Behavioral responses to mechanical and thermal stimuli, spinal phospho-ERK, and Fos expression were all analyzed. In additional groups, naloxone and morphine were administered to elucidate involvement of opioid receptors and for comparison with EA. EA pretreatment significantly reduced post-PI tactile allodynia for over 1 day; repeated treatments maintained analgesic effect. Intraperitoneal naloxone could reverse EA analgesia. Low-dose subcutaneous morphine (1 mg/kg) had stronger inhibitory effect on PI-induced allodynia than EA for 1 h. However, analgesic tolerance appeared after repeated morphine injections. Both EA and morphine could equally inhibit PI-induced p-ERK and Fos inductions. We conclude that though EA and morphine attenuate postincision pain through opioid receptor activations, daily EA treatments result in analgesic accumulation whereas daily morphine injections develop analgesic tolerance. Discrepant pathways and mechanisms underlying two analgesic means may account for the results. PMID:25530786

Nature and Nurture of Human Pain

PubMed Central

2013-01-01

Humans are very different when it comes to pain. Some get painful piercings and tattoos; others can not stand even a flu shot. Interindividual variability is one of the main characteristics of human pain on every level including the processing of nociceptive impulses at the periphery, modification of pain signal in the central nervous system, perception of pain, and response to analgesic strategies. As for many other complex behaviors, the sources of this variability come from both nurture (environment) and nature (genes). Here, I will discuss how these factors contribute to human pain separately and via interplay and how epigenetic mechanisms add to the complexity of their effects. PMID:24278778

21 CFR 358.760 - Labeling of permitted combinations of active ingredients for the control of dandruff.

Code of Federal Regulations, 2013 CFR

2013-04-01

... control of dandruff and external analgesic active ingredients in § 358.720(b). The label states “dandruff...) Combinations of control of dandruff and external analgesic active ingredients in § 358.720(b). The labeling.... (1) Combinations of control of dandruff and external analgesic active ingredients in § 358.720(b...

21 CFR 358.760 - Labeling of permitted combinations of active ingredients for the control of dandruff.

Code of Federal Regulations, 2014 CFR

2014-04-01

... control of dandruff and external analgesic active ingredients in § 358.720(b). The label states “dandruff...) Combinations of control of dandruff and external analgesic active ingredients in § 358.720(b). The labeling.... (1) Combinations of control of dandruff and external analgesic active ingredients in § 358.720(b...

21 CFR 358.760 - Labeling of permitted combinations of active ingredients for the control of dandruff.

Code of Federal Regulations, 2012 CFR

2012-04-01

... control of dandruff and external analgesic active ingredients in § 358.720(b). The label states “dandruff...) Combinations of control of dandruff and external analgesic active ingredients in § 358.720(b). The labeling.... (1) Combinations of control of dandruff and external analgesic active ingredients in § 358.720(b...

Comparison Between the Use of Ropivacaine Alone and Ropivacaine With Sufentanil in Epidural Labor Analgesia

PubMed Central

Wang, Xian; Xu, Shiqin; Qin, Xiang; Li, Xiaohong; Feng, Shan-Wu; Liu, Yusheng; Wang, Wei; Guo, Xirong; Shen, Rong; Shen, Xiaofeng; Wang, Fuzhou

2015-01-01

Abstract To compare the analgesic efficacy and safety of the sole local anesthetic ropivacaine with the combination of both local anesthetic ropivacaine and opioidergic analgesic sufentanil given epidurally on the labor pain control. After institutional review board approval and patient consent, a total of 500 nulliparas requesting epidural labor analgesia were enrolled and 481 eventually were randomized into 2 groups: a sole local anesthetic group (ropivacaine 0.125%) and a combination of local anesthetic and opioidergic analgesic group (0.125% ropivacaine + 0.3 μg/mL sufentanil). After the test dose, a 10-mL epidural analgesic solution was given in a single bolus, followed by intermittent bolus injection of 10 to 15 mL of the solution. The primary outcome was the analgesic efficacy measured using Numerical Rating Scale (NRS) of pain. Other maternal and infant variables were evaluated as secondary outcomes. A total of 346 participants completed the study. The median NRS pain score during the 1st stage of labor was significantly lower in the combination group 2.2 (interquartile range [IQR]: 1.8–2.7) comparing to the sole local analgesic group 2.4 (IQR: 2.0–2.8) (P < 0.0001). No significant difference was observed in NRS pain score prior epidural analgesia and during the 2nd stage of labor. Patients in both groups rated same satisfaction of analgesia. Patients in the sole local analgesic group experienced fewer side effects than those in the combination group (37.7% vs 47.2%, P = 0.082). The individual analgesia-related cost in the sole local analgesic group was less ($5.7 ± 2.06) than that in the combination group ($9.76 ± 3.54) (P < 0.0001). The incidence of 1-minute Apgar ≤ 7 was lower in the sole local analgesic group 2 (1.2%) than the combination group 10 (5.5%) (P = 0.038). No difference was found between other secondary outcomes. The sole local anesthetic ropivacaine produces a comparable labor analgesic effect as the combination of both local anesthetic ropivacaine and opioidergic analgesic sufentanil at different stages of labor (ΔNRS = 0.2) but the former has less side effects, lower cost, and less incidence of lower 1-minute Apgar scoring. These results imply the necessity of a systematic reevaluation of epidural labor analgesia with sole local anesthetics against combination regimens of local anesthetics and other opioids. PMID:26512604

Comparison Between the Use of Ropivacaine Alone and Ropivacaine With Sufentanil in Epidural Labor Analgesia.

PubMed

Wang, Xian; Xu, Shiqin; Qin, Xiang; Li, Xiaohong; Feng, Shan-Wu; Liu, Yusheng; Wang, Wei; Guo, Xirong; Shen, Rong; Shen, Xiaofeng; Wang, Fuzhou

2015-10-01

To compare the analgesic efficacy and safety of the sole local anesthetic ropivacaine with the combination of both local anesthetic ropivacaine and opioidergic analgesic sufentanil given epidurally on the labor pain control.After institutional review board approval and patient consent, a total of 500 nulliparas requesting epidural labor analgesia were enrolled and 481 eventually were randomized into 2 groups: a sole local anesthetic group (ropivacaine 0.125%) and a combination of local anesthetic and opioidergic analgesic group (0.125% ropivacaine + 0.3 μg/mL sufentanil). After the test dose, a 10-mL epidural analgesic solution was given in a single bolus, followed by intermittent bolus injection of 10 to 15 mL of the solution. The primary outcome was the analgesic efficacy measured using Numerical Rating Scale (NRS) of pain. Other maternal and infant variables were evaluated as secondary outcomes.A total of 346 participants completed the study. The median NRS pain score during the 1st stage of labor was significantly lower in the combination group 2.2 (interquartile range [IQR]: 1.8-2.7) comparing to the sole local analgesic group 2.4 (IQR: 2.0-2.8) (P < 0.0001). No significant difference was observed in NRS pain score prior epidural analgesia and during the 2nd stage of labor. Patients in both groups rated same satisfaction of analgesia. Patients in the sole local analgesic group experienced fewer side effects than those in the combination group (37.7% vs 47.2%, P = 0.082). The individual analgesia-related cost in the sole local analgesic group was less ($5.7 ± 2.06) than that in the combination group ($9.76 ± 3.54) (P < 0.0001). The incidence of 1-minute Apgar ≤ 7 was lower in the sole local analgesic group 2 (1.2%) than the combination group 10 (5.5%) (P = 0.038). No difference was found between other secondary outcomes.The sole local anesthetic ropivacaine produces a comparable labor analgesic effect as the combination of both local anesthetic ropivacaine and opioidergic analgesic sufentanil at different stages of labor (ΔNRS = 0.2) but the former has less side effects, lower cost, and less incidence of lower 1-minute Apgar scoring. These results imply the necessity of a systematic reevaluation of epidural labor analgesia with sole local anesthetics against combination regimens of local anesthetics and other opioids.

Prescription of opioid analgesics for nontraumatic dental conditions in emergency departments.

PubMed

Okunseri, Christopher; Dionne, Raymond A; Gordon, Sharon M; Okunseri, Elaye; Szabo, Aniko

2015-11-01

Opioid analgesics prescribed for nontraumatic dental conditions (NTDCs) by emergency physicians continue to receive attention because of the associated potential for misuse, abuse and addiction. This study examined rates of prescription of opioid analgesics and types of opioid analgesics prescribed for NTDC visits in U.S. emergency departments. Data from the National Hospital Ambulatory Medical Care Survey from 2007 to 2010 were analyzed. Descriptive statistics and logistic regression analysis were performed and adjusted for the survey design. NTDCs made up 1.7% of all ED visits from 2007 to 2010. The prescription of opioid analgesics was 50.3% for NTDC and 14.8% for non-NTDC visits. The overall rate of opioid analgesics prescribed for NTDCs remained fairly stable from 2007 through 2010. Prescription of opioids was highest among patients aged 19-33 years (56.8%), self-paying (57.1%), and non-Hispanic Whites (53.2%). The probability of being prescribed hydrocodone was highest among uninsured patients (68.7%) and for oxycodone, it was highest among private insurance patients (33.6%). Compared to 34-52 year olds, children 0-4 years were significantly more likely to be prescribed codeine and less likely to be prescribed oxycodone. Compared to non-Hispanic Whites, non-Hispanic Blacks had significantly higher odds of been prescribed codeine and somewhat lower odds of been prescribed oxycodone, but it was not statistically significant. There was no significant change in the rates of opioid analgesics prescribed over time for NTDC visits to EDs. Age, payer type and race/ethnicity were significant predictors for the prescription of different opioid analgesics by emergency physicians for NTDC visits. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

New Opioid Analgesic Approvals and Outpatient Utilization of Opioid Analgesics in the United States, 1997 through 2015.

PubMed

Chai, Grace; Xu, Jing; Osterhout, James; Liberatore, Mark A; Miller, Kathleen L; Wolff, Carolyn; Cruz, Marisa; Lurie, Peter; Dal Pan, Gerald

2018-05-01

The opioid epidemic, driven in part by increased prescribing, is a public health emergency. This study examines dispensed prescription patterns and approvals of new opioid analgesic products to investigate whether the introduction of these new drugs increases prescribing. Prescribing patterns based on dispensed prescription claims from the U.S. retail setting were assessed with new brand and generic opioid analgesic products approved in the United States from 1997 through 2015. From 1997 through 2015, the U.S. Food and Drug Administration (Silver Spring, Maryland) approved 263 opioid analgesic products, including 33 brand products. Dispensed prescriptions initially increased 80% from 145 million prescriptions in 1997 to a peak of 260 million prescriptions in 2012 before decreasing by 12% to 228 million prescriptions in 2015. Morphine milligram equivalents dispensed per prescription increased from 486 in 1997 to a peak of 950 in 2010, before decreasing to 905 in 2015. In 2015, generic products accounted for 96% (218/228 million prescriptions) of all opioid analgesic prescriptions dispensed. The remaining prescriptions were dispensed for brand products, of which nearly half were dispensed for one brand product (OxyContin, Purdue, USA). There has been a dramatic increase in prescriptions dispensed for opioid analgesics since 1997 and an increasing number of opioid analgesic approvals; however, the number of prescriptions dispensed has declined since 2012 despite an increasing number of approvals. Examination of dispensed prescriptions shows a shifting and complex market where multiple factors likely influence prescribing; the approval of new products alone may not be sufficient to be a primary driver of increased prescribing. An online visual overview is available for this article at http://links.lww.com/ALN/B705.

Differential Effectiveness of Clinically-Relevant Analgesics in a Rat Model of Chemotherapy-Induced Mucositis.

PubMed

Whittaker, Alexandra L; Lymn, Kerry A; Wallace, Georgia L; Howarth, Gordon S

2016-01-01

Chemotherapy-induced intestinal mucositis is characterized by pain and a pro-inflammatory tissue response. Rat models are frequently used in mucositis disease investigations yet little is known about the presence of pain in these animals, the ability of analgesics to ameliorate the condition, or the effect that analgesic administration may have on study outcomes. This study investigated different classes of analgesics with the aim of determining their analgesic effects and impact on research outcomes of interest in a rat model of mucositis. Female DA rats were allocated to 8 groups to include saline and chemotherapy controls (n = 8). Analgesics included opioid derivatives (buprenorphine; 0.05mg/kg and tramadol 12.5mg/kg) and NSAID (carprofen; 15mg/kg) in combination with either saline or 5-Fluorouracil (5-FU; 150mg/kg). Research outcome measures included daily clinical parameters, pain score and gut histology. Myeloperoxidase assay was performed to determine gut inflammation. At the dosages employed, all agents had an analgesic effect based on behavioural pain scores. Jejunal myeloperoxidase activity was significantly reduced by buprenorphine and tramadol in comparison to 5-FU control animals (53%, p = 0.0004 and 58%, p = 0.0001). Carprofen had no ameliorating effect on myeloperoxidase levels. None of the agents reduced the histological damage caused by 5-FU administration although tramadol tended to increase villus length even when administered to healthy animals. These data provide evidence that carprofen offers potential as an analgesic in this animal model due to its pain-relieving efficacy and minimal effect on measured parameters. This study also supports further investigation into the mechanism and utility of opioid agents in the treatment of chemotherapy-induced mucositis.

Pharmacogenetics of new analgesics

PubMed Central

Lötsch, Jörn; Geisslinger, Gerd

2011-01-01

Patient phenotypes in pharmacological pain treatment varies between individuals, which could be partly assigned to their genotypes regarding the targets of classical analgesics (OPRM1, PTGS2) or associated signalling pathways (KCNJ6). Translational and genetic research have identified new targets, for which new analgesics are being developed. This addresses voltage-gated sodium, calcium and potassium channels, for which SCN9A, CACNA1B, KCNQ2 and KCNQ3, respectively, are primary gene candidates because they code for the subunits of the respective channels targeted by analgesics currently in clinical development. Mutations in voltage gated transient receptor potential (TRPV) channels are known from genetic pain research and may modulate the effects of analgesics under development targeting TRPV1 or TRPV3. To this add ligand-gated ion channels including nicotinic acetylcholine receptors, ionotropic glutamate-gated receptors and ATP-gated purinergic P2X receptors with most important subunits coded by CHRNA4, GRIN2B and P2RX7. Among G protein coupled receptors, δ-opioid receptors (coded by OPRD1), cannabinoid receptors (CNR1 and CNR2), metabotropic glutamate receptors (mGluR5 coded by GRM5), bradykinin B1 (BDKRB1) and 5-HT1A (HTR1A) receptors are targeted by new analgesic substances. Finally, nerve growth factor (NGFB), its tyrosine kinase receptor (NTRK1) and the fatty acid amide hydrolase (FAAH) have become targets of interest. For most of these genes, functional variants have been associated with neuro-psychiatric disorders and not yet with analgesia. However, research on the genetic modulation of pain has already identified variants in these genes, relative to pain, which may facilitate the pharmacogenetic assessments of new analgesics. The increased number of candidate pharmacogenetic modulators of analgesic actions may open opportunities for the broader clinical implementation of genotyping information. PMID:20942817

Randomized controlled trial to compare oral analgesic requirements and patient satisfaction in using oral non-steroidal anti-inflammatory drugs versus benzydamine hydrochloride oral rinses after mandibular third molar extraction: a pilot study.

PubMed

Goswami, Devalina; Jain, Gaurav; Mohod, Mangesh; Baidya, Dalim Kumar; Bhutia, Ongkila; Roychoudhury, Ajoy

2018-02-01

Third molar extraction is associated with considerable pain and discomfort, which is mostly managed with oral analgesic medication. We assessed the analgesic effect of benzydamine hydrochloride, a topical analgesic oral rinse, for controlling postoperative pain following third molar extraction. A randomized controlled trial was conducted in 40 patients divided into two groups, for extraction of fully erupted third molar. Groups A received benzydamine hydrochloride mouthwash and group B received normal saline gargle with oral ibuprofen and paracetamol. Oral ibuprofen and paracetamol was the rescue analgesic drug in group A. Patients were evaluated on the 3 rd and 7 th post-operative days (POD) for pain using the visual analogue score (VAS), trismus, total number of analgesics consumed, and satisfaction level of patients. The VAS in groups A and B on POD3 and POD7 was 4.55 ± 2.54 and 3.95 ± 1.8, and 1.2 ± 1.64 and 0.95 ± 1.14, respectively and was statistically insignificant. The number of analgesics consumed in groups A and B on POD3 (5.25 ± 2.22 and 6.05 ± 2.43) was not statistically different from that consumed on POD7 (9.15 ± 5.93 and 10.65 ± 6.46). The p values for trismus on POD3 and POD7 were 0.609 and 0.490, respectively and those for patient satisfaction level on POD3 and POD7 were 0.283 and 0.217, respectively. Benzydamine hydrochloride oral rinses do not significantly reduce intake of oral analgesics and are inadequate for pain relief following mandibular third molar extraction.

Analgesic use and the risk of kidney cancer: a meta-analysis of epidemiologic studies.

PubMed

Choueiri, Toni K; Je, Youjin; Cho, Eunyoung

2014-01-15

Analgesics are the most commonly used over-the-counter drugs worldwide with certain analgesics having cancer prevention effect. The evidence for an increased risk of developing kidney cancer with analgesic use is mixed. Using a meta-analysis design of available observational epidemiologic studies, we investigated the association between analgesic use and kidney cancer risk. We searched the MEDLINE and EMBASE databases to identify eligible case-control or cohort studies published in English until June 2012 for three categories of analgesics: acetaminophen, aspirin or other non-steroidal anti-inflammatory drugs (NSAIDs). Study-specific effect estimates were pooled to compute an overall relative risk (RR) and its 95% confidence interval (CI) using a random-effects model for each category of the analgesics. We identified 20 studies (14 with acetaminophen, 13 with aspirin and five with other NSAIDs) that were performed in six countries, including 8,420 cases of kidney cancer. Use of acetaminophen and non-aspirin NSAIDs were associated with an increased risk of kidney cancer (pooled RR: 1.28; 95% CI: 1.15-1.44 and 1.25; 95% CI: 1.06-1.46, respectively). For aspirin use, we found no overall increased risk (pooled RR: 1.10; 95% CI: 0.95-1.28), except for non-US studies (five studies, pooled RR: 1.17; 95% CI: 1.04-1.33). Similar increases in risks were seen with higher analgesic intake. In this largest meta-analysis to date, we found that acetaminophen and non-aspirin NSAIDs are associated with a significant risk of developing kidney cancer. Further work is needed to elucidate biologic mechanisms behind these findings. © 2013 UICC.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Adams, J.U.; Andrews, J.S.; Hiller, J.M.

This study was essentially an in vivo protection experiment designed to test further the hypothesis that stress induces release of endogenous opiods which then act at opioid receptors. Rats that were either subjected to restraint stress for 1 yr or unstressed were injected ICV with either saline or 2.5 ..mu..g of ..beta..-funaltrexamine (..beta..-FNA), an irreversible opioid antagonist that alkylates the mu-opioid receptor. Twenty-four hours later, subjects were tested unstressed for morphine analgesia or were sacrificed and opioid binding in brain was determined. (/sup 3/H)D-Ala/sup 2/NMePhe/sup 4/-Gly/sup 5/(ol)enkephalin (DAGO) served as a specific ligand for mu-opioid receptors, and (/sup 3/H)-bremazocine asmore » a general ligand for all opioid receptors. Rats injected with saline while stressed were significantly less sensitive to the analgesic action of morphine 24 hr later than were their unstressed counterparts. ..beta..-FNA pretreatment attenuated morphine analgesia in an insurmountable manner. Animals pretreated with ..beta..-FNA while stressed were significantly more sensitive to the analgesic effect of morphine than were animals that received ..beta..-FNA while unstressed. ..beta..-FNA caused small and similar decreases in (/sup 3/H)-DAGO binding in brain of both stressed and unstressed animals. 35 references, 2 figures, 2 tables.« less

Comparison of abuse, suspected suicidal intent, and fatalities related to the 7-day buprenorphine transdermal patch versus other opioid analgesics in the National Poison Data System.

PubMed

Coplan, Paul M; Sessler, Nelson E; Harikrishnan, Venkatesh; Singh, Richa; Perkel, Charles

2017-01-01

Prescription opioid related abuse, suicide and death are significant public health problems. This study compares rates of poison center calls categorized as intentional abuse, suspected suicidal intent or fatality for the 7-day buprenorphine transdermal system/patch (BTDS) with other extended-release and long-acting (ER/LA) opioids indicated for chronic pain. Retrospective 24-month cohort study using National Poison Data System data from July 2012 through June 2014. BTDS was introduced in the United States in January 2011. Numbers and rates of calls of intentional abuse, suspected suicidal intent and fatalities were evaluated for BTDS, ER morphine, ER oxycodone, fentanyl patch, ER oxymorphone and methadone tablets/capsules, using prescription adjustment to account for community availability. Rate ratios (RR) and 95% confidence intervals (CI) were calculated. Absolute numbers and prescription-adjusted rates of intentional abuse and suspected suicidal intent with BTDS were significantly lower (p < .0001) than for all other ER/LA opioid analgesics examined. No fatalities associated with BTDS exposure were reported. This post-marketing evaluation of BTDS indicates infrequent poison center calls for intentional abuse and suspected suicidal intent events, suggesting lower rates of these risks with BTDS compared to other ER/LA opioids.

Pharmacokinetics of 2 Formulations of Transdermal Fentanyl in Cynomolgus Macaques (Macaca fascicularis)

PubMed Central

Carlson, Amy M; Kelly, Richard; Fetterer, David P; Rico, Pedro J; Bailey, Emily J

2016-01-01

Fentanyl is a μ-opioid agonist that often is used as the analgesic component for balanced anesthesia in both human and veterinary patients. Minimal information has been published regarding appropriate dosing, and the pharmacokinetics of fentanyl are unknown in NHP. The pharmacokinetic properties of 2 transdermal fentanyl delivery methods, a solution (2.6 and 1.95 mg/kg) and a patch (25 µg/h), were determined when applied topically to the dorsal scapular area of cynomolgus macaques (Macaca fascicularis). Serum fentanyl concentrations were analyzed by using liquid chromatography–mass spectrometry. Compared with the patch, the transdermal fentanyl solution generated higher drug concentrations over longer time. Adverse reactions occurred in the macaques that received the transdermal fentanyl solution at 2.6 mg/kg. Both preparations showed significant interanimal variability in the maximal serum drug levels, time to achieve maximal fentanyl levels, elimination half-life, and AUC values. Both the maximal concentration and the time at which this concentration occurred were increased in macaques compared with most other species after application of the transdermal fentanyl patch and compared with dogs after application of the transdermal fentanyl solution. The pharmacokinetic properties of transdermal fentanyl in macaques are markedly different from those in other veterinary species and preclude its use as a long-acting analgesic drug in NHP. PMID:27423151

Gender differences in drug use and expenditures in a privately insured population of older adults.

PubMed

Correa-de-Araujo, Rosaly; Miller, G Edward; Banthin, Jessica S; Trinh, Yen

2005-01-01

We examine gender differences in use and expenditures for prescription drugs among Medicare and privately insured older adults aged 65 and over, using data on a nationally representative sample of prescription drug purchases collected for the Medical Expenditure Panel Survey Household Component. Overall, women spent about $1,178 for drugs, about 17% more than the $1,009 in average expenditures by men. Older women constituted 50.7% of the population and had average annual aggregate expenditures for prescribed medicines of $6.93 billion compared to $5.77 billion for men. Women were more likely than men to use drugs from a number of therapeutic classes-analgesics, hormones and psychotherapeutic agents-and therapeutic subclasses-thyroid drugs, COX-2 inhibitors and anti-depressants. Women also had higher average prescriptions per user for a number of therapeutic classes-hormones, psychotherapeutic agents and analgesics-and therapeutic subclasses-anti-diabetic drugs and beta blockers. Prescribed medications are, arguably, the most important healthcare technology in preventing illness, disability, and death in older adults. It is critical that older women and men have proper access to prescribed medicines. Given the financial vulnerability of this priority population, particularly women, the expanded drug coverage available under the Medicare Modernization Act is of particular relevance in meeting this goal.

Melanocortin-1 receptor gene variants affect pain and µ-opioid analgesia in mice and humans

PubMed Central

Mogil, J; Ritchie, J; Smith, S; Strasburg, K; Kaplan, L; Wallace, M; Romberg, R; Bijl, H; Sarton, E; Fillingim, R; Dahan, A

2005-01-01

Background: A recent genetic study in mice and humans revealed the modulatory effect of MC1R (melanocortin-1 receptor) gene variants on κ-opioid receptor mediated analgesia. It is unclear whether this gene affects basal pain sensitivity or the efficacy of analgesics acting at the more clinically relevant µ-opioid receptor. Objective: To characterise sensitivity to pain and µ-opioid analgesia in mice and humans with non-functional melanocortin-1 receptors. Methods: Comparisons of spontaneous mutant C57BL/6-Mc1re/e mice to C57BL/6 wildtype mice, followed by a gene dosage study of pain and morphine-6-glucuronide (M6G) analgesia in humans with MC1R variants. Results: C57BL/6-Mc1re/e mutant mice and human redheads—both with non-functional MC1Rs—display reduced sensitivity to noxious stimuli and increased analgesic responsiveness to the µ-opioid selective morphine metabolite, M6G. In both species the differential analgesia is likely due to pharmacodynamic factors, as plasma levels of M6G are similar across genotype. Conclusions: Genotype at MC1R similarly affects pain sensitivity and M6G analgesia in mice and humans. These findings confirm the utility of cross species translational strategies in pharmacogenetics. PMID:15994880