Negative allosteric modulation of the mGlu7 receptor reduces visceral hypersensitivity in a stress-sensitive rat strain

PubMed Central

Moloney, Rachel D.; Golubeva, Anna V.; O'Connor, Richard M.; Kalinichev, Mikhail; Dinan, Timothy G.; Cryan, John F.

2015-01-01

Glutamate, the main excitatory neurotransmitter in the central nervous system, exerts its effect through ionotropic and metabotropic receptors. Of these, group III mGlu receptors (mGlu 4, 6, 7, 8) are among the least studied due to a lack of pharmacological tools. mGlu7 receptors, the most highly conserved isoform, are abundantly distributed in the brain, especially in regions, such as the amygdala, known to be crucial for the emotional processing of painful stimuli. Visceral hypersensitivity is a poorly understood phenomenon manifesting as an increased sensitivity to visceral stimuli. Glutamate has long been associated with somatic pain processing leading us to postulate that crossover may exist between these two modalities. Moreover, stress has been shown to exacerbate visceral pain. ADX71743 is a novel, centrally penetrant, negative allosteric modulator of mGlu7 receptors. Thus, we used this tool to explore the possible involvement of this receptor in the mediation of visceral pain in a stress-sensitive model of visceral hypersensitivity, namely the Wistar Kyoto (WKY) rat. ADX71743 reduced visceral hypersensitivity in the WKY rat as exhibited by increased visceral sensitivity threshold with concomitant reductions in total number of pain behaviours. Moreover, AD71743 increased total distance and distance travelled in the inner zone of the open field. These findings show, for what is to our knowledge, the first time, that mGlu7 receptor signalling plays a role in visceral pain processing. Thus, negative modulation of the mGlu7 receptor may be a plausible target for the amelioration of stress-induced visceral pain where there is a large unmet medical need. PMID:26844237

Effect of a single session of muscle-biased therapy on pain sensitivity: a systematic review and meta-analysis of randomized controlled trials

PubMed Central

Gay, Charles W; Alappattu, Meryl J; Coronado, Rogelio A; Horn, Maggie E; Bishop, Mark D

2013-01-01

Background Muscle-biased therapies (MBT) are commonly used to treat pain, yet several reviews suggest evidence for the clinical effectiveness of these therapies is lacking. Inadequate treatment parameters have been suggested to account for inconsistent effects across studies. Pain sensitivity may serve as an intermediate physiologic endpoint helping to establish optimal MBT treatment parameters. The purpose of this review was to summarize the current literature investigating the short-term effect of a single dose of MBT on pain sensitivity in both healthy and clinical populations, with particular attention to specific MBT parameters of intensity and duration. Methods A systematic search for articles meeting our prespecified criteria was conducted using Cumulative Index to Nursing and Allied Health Literature (CINAHL) and MEDLINE from the inception of each database until July 2012, in accordance with guidelines from the Preferred Reporting Items for Systematic reviews and Meta-Analysis. Relevant characteristics from studies included type, intensity, and duration of MBT and whether short-term changes in pain sensitivity and clinical pain were noted with MBT application. Study results were pooled using a random-effects model to estimate the overall effect size of a single dose of MBT on pain sensitivity as well as the effect of MBT, dependent on comparison group and population type. Results Reports from 24 randomized controlled trials (23 articles) were included, representing 36 MBT treatment arms and 29 comparative groups, where 10 groups received active agents, 11 received sham/inert treatments, and eight received no treatment. MBT demonstrated a favorable and consistent ability to modulate pain sensitivity. Short-term modulation of pain sensitivity was associated with short-term beneficial effects on clinical pain. Intensity of MBT, but not duration, was linked with change in pain sensitivity. A meta-analysis was conducted on 17 studies that assessed the effect of MBT on pressure pain thresholds. The results suggest that MBT had a favorable effect on pressure pain thresholds when compared with no-treatment and sham/inert groups, and effects comparable with those of other active treatments. Conclusion The evidence supports the use of pain sensitivity measures by future research to help elucidate optimal therapeutic parameters for MBT as an intermediate physiologic marker. PMID:23403507

Painful purinergic receptors.

PubMed

Donnelly-Roberts, Diana; McGaraughty, Steve; Shieh, Char-Chang; Honore, Prisca; Jarvis, Michael F

2008-02-01

Multiple P2 receptor-mediated mechanisms exist by which ATP can alter nociceptive sensitivity following tissue injury. Evidence from a variety of experimental strategies, including genetic disruption studies and the development of selective antagonists, has indicated that the activation of P2X receptor subtypes, including P2X(3), P2X(2/3), P2X(4) and P2X(7), and P2Y (e.g., P2Y(2)) receptors, can modulate pain. For example, administration of a selective P2X(3) antagonist, A-317491, has been shown to effectively block both hyperalgesia and allodynia in different animal models of pathological pain. Intrathecally delivered antisense oligonucleotides targeting P2X(4) receptors decrease tactile allodynia following nerve injury. Selective antagonists for the P2X(7) receptor also reduce sensitization in animal models of inflammatory and neuropathic pain, providing evidence that purinergic glial-neural interactions are important modulators of noxious sensory neurotransmission. Furthermore, activation of P2Y(2) receptors leads to sensitization of polymodal transient receptor potential-1 receptors. Thus, ATP acting at multiple purinergic receptors, either directly on neurons (e.g., P2X(3), P2X(2/3), and P2Y receptors) or indirectly through neural-glial cell interactions (P2X(4) and P2X(7) receptors), alters nociceptive sensitivity. The development of selective antagonists for some of these P2 receptors has greatly aided investigations into the nociceptive role of ATP. This perspective highlights some of the recent advances to identify selective P2 receptor ligands, which has enhanced the investigation of ATP-related modulation of pain sensitivity.

Hippocampal GABAA Receptor and Pain Sensitivity during Estrous Cycle in the Rat

PubMed Central

Taherianfard, Mahnaz; Mosavi, Mahnaz

2011-01-01

Background: Estradiol and progesterone as well as hippocampal GABAA receptors are believed to play a role in the modulation of pain. The aim of present study was to investigate the effect of intrahippocampal injections of GABAA receptor agonist (muscimol) and GABAA receptor antagonist (picrotoxin) on pain sensitivity during estrous cycle. Methods: Pain sensitivity was evaluated in rats by formalin test during all stages of estrous cycle. Animals were divided into five groups including; 1- control (intact animal); 2- sham 1 receiving 0.75 µl artificial cerebrospinal fluids (ACSF); 3- sham 2 receiving 0.75 µl alcoholic ACSF; 4- experimental 1 receiving 250 or 500 µg/rat of muscimol in 0.75 µl vehicle, and 5- experimental 2 receiving 20 or 30 µg/rat picrotoxin in 0.75 µl vehicle. Data were analyzed by Kruskal-Wallis followed by Tucky's test for pairwise comparisons using a P value of ≤0.50 for statistical significance. Results: Muscimol significantly (P<0.05) decreased pain sensitivity in all stages of estrous cycle, and the analgesic effect was higher during proestrus and estrus stages of estrous cycle than that during metestrus and diestrus stages. Picrotoxin significantly (P<0.05) increased pain sensitivity in all stages of estrous cycle, and such a hyperalgesic effect was lower during proestrus and estrus stages of estrous cycle than that during metestrus and diestrus stages. Conclusion: The findings of the present study indicate that the role of hippocampal GABAA receptor in the control of the pain sensitivity can be modulated by variation in gonadal steroids during different stages of the estrous cycle. PMID:23115414

Involvement of α2-adrenoceptors in inhibitory and facilitatory pain modulation processes.

PubMed

Vo, L; Drummond, P D

2016-03-01

In healthy humans, high-frequency electrical stimulation (HFS) of the forearm not only produces hyperalgesia at the site of stimulation but also reduces sensitivity to pressure-pain on the ipsilateral side of the forehead. In addition, HFS augments the ipsilateral trigeminal nociceptive blink reflex and intensifies the ipsilateral component of conditioned pain modulation. The aim of this study was to determine whether α2-adrenoceptors mediate these ipsilateral nociceptive influences. The α2-adrenoceptor antagonist yohimbine was administered to 22 participants in a double-blind, placebo-controlled crossover study. In each session, thermal and mechanical sensitivity in the forearms and forehead was assessed before and after HFS. In addition, the combined effect of HFS and yohimbine on the nociceptive blink reflex and on conditioned pain modulation was explored. In this paradigm, the conditioning stimulus was cold pain in the ipsilateral or contralateral temple, and the test stimulus was electrically evoked pain in the forearm. Blood pressure and electrodermal activity increased for several hours after yohimbine administration, consistent with blockade of central α2-adrenoceptors. Yohimbine not only augmented the nociceptive blink reflex ipsilateral to HFS but also intensified the inhibitory influence of ipsilateral temple cooling on electrically evoked pain at the HFS-treated site in the forearm. Yohimbine had no consistent effect on primary or secondary hyperalgesia in the forearm or on pressure-pain in the ipsilateral forehead. These findings imply involvement of α2-adrenoceptors both in ipsilateral antinociceptive and pronociceptive pain modulation processes. However, a mechanism not involving α2-adrenoceptors appears to mediate analgesia in the ipsilateral forehead after HFS. © 2015 European Pain Federation - EFIC®

Conditioned Pain Modulation in Women with Irritable Bowel Syndrome

PubMed Central

Jarrett, Monica E.; Shulman, Robert J.; Cain, Kevin C.; Deechakawan, Wimon; Smith, Lynne T.; Richebé, Philippe; Eugenio, Margaret; Heitkemper, Margaret M.

2013-01-01

Evidence suggests that patients with irritable bowel syndrome (IBS) are more vigilant to pain-associated stimuli. The aims of this study were to compare women with IBS (n = 20) to healthy control (HC, n = 20) women on pain sensitivity, conditioned pain modulation (CPM) efficiency and salivary cortisol levels before and after the CPM test; and examine the relationship of CPM efficiency with gastrointestinal, somatic pain, and psychological distress symptoms in each group. Women, ages 20–42, gave consent, completed questionnaires and kept a symptom diary for 2 weeks. CPM efficiency was tested with a heat test stimulus and cold water condition stimulus in a laboratory between 8 and 10 a.m. on a follicular phase day. Salivary cortisol samples were collected just before and after the experimental testing. Compared to the HC group, women with IBS reported more days with gastrointestinal and somatic pain/discomfort, psychological distress, fatigue, and feeling stressed. During the CPM baseline testing women with IBS reported greater pain sensitivity compared to the HC group. In the IBS group, CPM efficiency was associated with the pain impact (PROMIS) measure, daily abdominal pain/discomfort, psychological distress, in particular anxiety. There was no group difference in salivary cortisol levels. Overall, women with IBS exhibit an increased sensitivity to thermal stimuli. Impaired CPM was present in a subset of women with IBS. PMID:24463504

Hopes for the Future of Pain Control.

PubMed

Bannister, Kirsty; Kucharczyk, Mateusz; Dickenson, Anthony H

2017-12-01

Here we aim to present an accessible review of the pharmacological targets for pain management, and succinctly discuss the newest trends in pain therapy. A key task for current pain pharmacotherapy is the identification of receptors and channels orchestrating nociception. Notwithstanding peripheral alterations in the receptors and channels following pathophysiological events, the modulatory mechanisms in the central nervous system are also fundamental to the regulation of pain perception. Bridging preclinical and clinical studies of peripheral and central components of pain modulation, we present the different types of pain and relate these to pharmacological interventions. We firstly highlight the roles of several peripheral nociceptors, such as NGF, CGRP, sodium channels, and TRP-family channels that may become novel targets for therapies. In the central nervous system, the roles of calcium channels and gabapentinoids as well as NMDA receptors in generating excitability are covered including ideas on central sensitization. We then turn to central modulatory systems and discuss opioids and monoamines. We aim to explain the importance of central sensitization and the dialogue of the spinal circuits with the brain descending modulatory controls before discussing a mechanism-based effectiveness of antidepressants in pain therapy and their potential to modulate the descending controls. Emphasizing the roles of conditioned pain modulation and its animal's equivalent, diffuse noxious inhibitory controls, we discuss these unique descending modulations as a potential tool for understanding mechanisms in patients suffering from pain. Mechanism-based therapy is the key to picking the correct treatments and recent clinical studies using sensory symptoms of patients as surrogates for underlying mechanisms can be used to subgroup patients and reveal actions of drugs that may be lost when studying heterogenous groups of patients. Key advances in the understanding of basic pain principles will impact our thinking about therapy targets. The complexity of pain syndromes will require tailored pharmacological drugs, often in combination or through drugs with more than one action, and often psychotherapy, to fully control pain.

Endogenous pain modulation in chronic orofacial pain: a systematic review and meta-analysis.

PubMed

Moana-Filho, Estephan J; Herrero Babiloni, Alberto; Theis-Mahon, Nicole R

2018-06-15

Abnormal endogenous pain modulation was suggested as a potential mechanism for chronic pain, ie, increased pain facilitation and/or impaired pain inhibition underlying symptoms manifestation. Endogenous pain modulation function can be tested using psychophysical methods such as temporal summation of pain (TSP) and conditioned pain modulation (CPM), which assess pain facilitation and inhibition, respectively. Several studies have investigated endogenous pain modulation function in patients with nonparoxysmal orofacial pain (OFP) and reported mixed results. This study aimed to provide, through a qualitative and quantitative synthesis of the available literature, overall estimates for TSP/CPM responses in patients with OFP relative to controls. MEDLINE, Embase, and the Cochrane databases were searched, and references were screened independently by 2 raters. Twenty-six studies were included for qualitative review, and 22 studies were included for meta-analysis. Traditional meta-analysis and robust variance estimation were used to synthesize overall estimates for standardized mean difference. The overall standardized estimate for TSP was 0.30 (95% confidence interval: 0.11-0.49; P = 0.002), with moderate between-study heterogeneity (Q [df = 17] = 41.8, P = 0.001; I = 70.2%). Conditioned pain modulation's estimated overall effect size was large but above the significance threshold (estimate = 1.36; 95% confidence interval: -0.09 to 2.81; P = 0.066), with very large heterogeneity (Q [df = 8] = 108.3, P < 0.001; I = 98.0%). Sensitivity analyses did not affect the overall estimate for TSP; for CPM, the overall estimate became significant if specific random-effect models were used or if the most influential study was removed. Publication bias was not present for TSP studies, whereas it substantially influenced CPM's overall estimate. These results suggest increased pain facilitation and trend for pain inhibition impairment in patients with nonparoxysmal OFP.

Triathletes Lose Their Advantageous Pain Modulation under Acute Psychosocial Stress.

PubMed

Geva, Nirit; Pruessner, Jens; Defrin, Ruth

2017-02-01

Triathletes, who constantly engage in intensely stressful sport, were recently found to exhibit greater pain tolerance and more efficient pain inhibition capabilities than nonathletes. However, pain inhibition correlated negatively with retrospective reports of mental stress during training and competition. The aim of the current study was to test pain inhibition capabilities of triathletes under acute, controlled psychological stress manipulation. Participants were 25 triathletes and ironman triathletes who underwent the measurement of pain threshold, pain intolerance, tonic suprathreshold pain, and conditioned pain modulation before and during exposure to the Montreal Imaging Stress Task (MIST). Perceived ratings of stress and anxiety, autonomic variables, and salivary cortisol levels were obtained as indices of stress. The MIST induced a significant stress reaction manifested in the subjective and objective indices. Overall, a significant reduction in pain threshold and in conditioned pain modulation efficacy was observed after the MIST, which reached the baseline levels observed previously in nonathletes. Paradoxically, the magnitude of this stress-induced hyperalgesia (SIH) correlated negatively with the magnitude of the stress response; low-stress responders exhibited greater SIH than high-stress responders. The results suggest that under acute psychological stress, triathletes not only react with SIH and a reduction in pain modulation but also lose their advantageous pain modulation over nonathletes. The stronger the stress response recorded, the weaker the SIH. It appears that triathletes are not resilient to stress, responding with an increase in the sensitivity to pain as well as a decrease in pain inhibition. The possible effects of athletes' baseline pain profile and stress reactivity on SIH are discussed.

Ecological aspects of pain in sensory modulation disorder.

PubMed

Bar-Shalita, T; Deutsch, L; Honigman, L; Weissman-Fogel, I

2015-01-01

Sensory Modulation Disorder (SMD) interferes with the daily life participation of otherwise healthy individuals and is characterized by over-, under- or seeking responsiveness to naturally occurring sensory stimuli. Previous laboratory findings indicate pain hyper-sensitivity in SMD individuals suggesting CNS alteration in pain processing and modulation. However, laboratory studies lack ecological validity, and warrant clinical completion in order to elicit a sound understanding of the phenomenon studied. Thus, this study explored the association between sensory modulation and pain in a daily life context in a general population sample. Daily life context of pain and sensations were measured in 250 adults (aged 23-40 years; 49.6% males) using 4 self-report questionnaires: Pain Sensitivity Questionnaire (PSQ) and Pain Catastrophizing Scale (PCS) to evaluate the sensory and cognitive aspects of pain; the Sensory Responsiveness Questionnaire (SRQ) to appraise SMD; and the Short Form - 36 Health Survey, version 2 (SF36) to assess health related Quality of Life (QoL). Thirty two individuals (12.8%) were found with over-responsiveness type of SMD, forming the SOR-SMD group. While no group differences (SOR-SMD vs. Non-SMD) were found, low-to-moderate total sample correlations were demonstrated between the SRQ-Aversive sub-scale and i) PSQ total (r=0.31, p<0.01) and sub-scales scores (r=0.27-0.28, p<0.01), as well as ii) PCS total and the sub-scales of Rumination and Helplessness scores (r=0.15, p<0.05). PSQ total and sub-scale scores were more highly correlated with SRQ-Aversive in the SOR-SMD group (r=0.57-0.68, p=0.03-<0.01) compared to Non-SMD group. The Physical Health - Total score (but not the Mental Health - Total) of the SF36 was lower for the SOR-SMD group (p=0.03), mainly due to the difference in the Body pain sub-scale (p=0.04). Results suggest that SOR-SMD is strongly associated with the sensory aspect of pain but weakly associated with the cognitive aspect. This indicates that SMD co-occurs with daily pain sensitivity, thus reducing QoL, but less with the cognitive-catastrophizing manifestation of pain perception. Copyright © 2015 Elsevier Ltd. All rights reserved.

Impaired conditioned pain modulation in youth with functional abdominal pain

PubMed Central

Morris, Matthew C.; Walker, Lynn S.; Bruehl, Stephen; Stone, Amanda L.; Mielock, Alyssa S.; Rao, Uma

2016-01-01

Functional abdominal pain (FAP) is associated with enhanced pain responsiveness. Although impaired conditioned pain modulation (CPM) characterizes adults with a variety of chronic pain conditions, relatively little is known about CPM in youth with FAP. The present study assessed CPM to evoked thermal pain in 140 youth (ages 10 to 17), 63 of whom had FAP and 77 of whom were healthy controls. Multilevel models demonstrated weaker CPM effects in FAP than healthy youth, as evident in slower within-person decreases in pain ratings during the conditioning phase. Weaker CPM effects were associated with greater somatic symptom severity and functional disability. Pain responses in FAP youth were heterogeneous, with 43% of youth showing an unexpected increase in pain ratings during the conditioning phase, suggesting sensitization rather than CPM-related pain inhibition. These findings highlight directions for future research on the emergence and maintenance of FAP in youth. PMID:27389918

Impaired conditioned pain modulation in youth with functional abdominal pain.

PubMed

Morris, Matthew C; Walker, Lynn S; Bruehl, Stephen; Stone, Amanda L; Mielock, Alyssa S; Rao, Uma

2016-10-01

Functional abdominal pain (FAP) is associated with enhanced pain responsiveness. Although impaired conditioned pain modulation (CPM) characterizes adults with a variety of chronic pain conditions, relatively little is known about CPM in youth with FAP. This study assessed CPM to evoked thermal pain in 140 youth (ages 10-17), 63 of whom had FAP and 77 of whom were healthy controls. Multilevel models demonstrated weaker CPM effects in youth with FAP than in healthy youth, as evident in slower within-person decreases in pain ratings during the conditioning phase. Weaker CPM effects were associated with greater somatic symptom severity and functional disability. Pain responses in youth with FAP were heterogeneous, with 43% of youth showing an unexpected increase in pain ratings during the conditioning phase, suggesting sensitization rather than CPM-related pain inhibition. These findings highlight directions for future research on the emergence and maintenance of FAP in youth.

Pain facilitation and pain inhibition during conditioned pain modulation in fibromyalgia and in healthy controls.

PubMed

Potvin, Stéphane; Marchand, Serge

2016-08-01

Although fibromyalgia (FM) is associated with a deficit in inhibitory conditioned pain modulation (CPM), the discriminative power of CPM procedures is unknown. Moreover, the high intersubject heterogeneity in CPM responses in FM raises the possibility that a sizeable subgroup of these patients may experience pain facilitation during CPM, but the phenomenon has not been explicitly studied. To address these issues, 96 patients with FM and 71 healthy controls were recruited. Thermal stimuli were used to measure pain thresholds. Pain inhibition was elicited using a tonic thermal test (Peltier thermode) administered before and after activation of CPM mechanisms using a cold pressor test. Thermal pain thresholds were lower in patients with FM than in healthy controls. Pain ratings during the cold pressor test were higher in patients with FM, relative to controls. The CPM inhibitory efficacy was lower in patients with FM than in controls. The CPM procedure had good specificity (78.9%) but low sensitivity (45.7%), whereas a composite pain index had good sensitivity (75.0%) and specificity (78.9%). Finally, the rate of patients with FM who reported pain facilitation during the CPM procedure was found to be significantly increased compared with that of controls (41.7% vs 21.2%). The good discriminative power of the composite pain index highlights the need for further validation studies using mechanistically relevant psychophysical procedures in FM. The low sensitivity of the CPM procedure, combined with the large proportion of patients with FM experiencing pain facilitation during CPM, strongly suggests that endogenous pain inhibition mechanisms are deeply impaired in patients with FM, but only in a subgroup of them.

Laterality of pain: modulation by placebo and participants' paranormal belief.

PubMed

Klemenz, Caroline; Regard, Marianne; Brugger, Peter; Emch, Oliver

2009-09-01

To investigate the effects of placebo and paranormal belief on the laterality of pain perception. The right hemisphere is dominantly involved in both the mediation of pain sensation and the belief in paranormal phenomena. We set out to assess a possible influence of long-term belief systems on placebo analgesia in response to unilateral nociceptive stimuli. Forty healthy participants (20 high and 20 low believers as indexed by the Magical Ideation Scale) underwent a placebo analgesia study measuring stimulus detection, pain threshold, and pain tolerance by electrostimulation on the right and left hand. Placebo treatment consisted of the application of a sham cream on the hands. Placebo had a positive influence on pain perception in the 3 variables. Enhanced pain sensitivity for the left side was only found for the disbelievers. Placebo treatment resulted in a double dissociation: in believers, it increased tolerance exclusively on the left side, in disbelievers on the right side. Our results confirm laterality effects in pain perception. However, only disbelievers conformed to the expected higher left-sided sensitivity. Placebo effects were dissociated between believers and disbelievers suggesting that short-term reactions to a placebo are modulated by a person's long-term belief system.

Rab7-a novel redox target that modulates inflammatory pain processing.

PubMed

Kallenborn-Gerhardt, Wiebke; Möser, Christine V; Lorenz, Jana E; Steger, Mirco; Heidler, Juliana; Scheving, Reynir; Petersen, Jonas; Kennel, Lea; Flauaus, Cathrin; Lu, Ruirui; Edinger, Aimee L; Tegeder, Irmgard; Geisslinger, Gerd; Heide, Heinrich; Wittig, Ilka; Schmidtko, Achim

2017-07-01

Chronic pain is accompanied by production of reactive oxygen species (ROS) in various cells that are important for nociceptive processing. Recent data indicate that ROS can trigger specific redox-dependent signaling processes, but the molecular targets of ROS signaling in the nociceptive system remain largely elusive. Here, we performed a proteome screen for pain-dependent redox regulation using an OxICAT approach, thereby identifying the small GTPase Rab7 as a redox-modified target during inflammatory pain in mice. Prevention of Rab7 oxidation by replacement of the redox-sensing thiols modulates its GTPase activity. Immunofluorescence studies revealed Rab7 expression to be enriched in central terminals of sensory neurons. Knockout mice lacking Rab7 in sensory neurons showed normal responses to noxious thermal and mechanical stimuli; however, their pain behavior during inflammatory pain and in response to ROS donors was reduced. The data suggest that redox-dependent changes in Rab7 activity modulate inflammatory pain sensitivity.

Adaptability to pain is associated with potency of local pain inhibition, but not conditioned pain modulation: a healthy human study.

PubMed

Zheng, Zhen; Wang, Kelun; Yao, Dongyuan; Xue, Charlie C L; Arendt-Nielsen, Lars

2014-05-01

This study investigated the relationship between pain sensitivity, adaptability, and potency of endogenous pain inhibition, including conditioned pain modulation (CPM) and local pain inhibition. Forty-one healthy volunteers (20 male, 21 female) received conditioning stimulation (CS) over 2 sessions in a random order: tonic heat pain (46 °C) on the right leg for 7 minutes and cold pressor pain (1 °C to 4 °C) on the left hand for 5 minutes. Participants rated the intensity of pain continuously using a 0 to 10 electronic visual analogue scale. The primary outcome measures were pressure pain thresholds (PPT) measured at the heterotopic and homotopic location to the CS sites before, during, and 20 minutes after CS. Two groups of participants, pain adaptive and pain nonadaptive, were identified based on their response to pain in the cold pressor test. Pain-adaptive participants showed a pain reduction between peak pain and pain at end of the test by at least 2 of 10 (n=16); whereas the pain-nonadaptive participants reported unchanged peak pain during 5-minute CS (n=25). Heterotopic PPTs during the CS did not differ between the 2 groups. However, increased homotopic PPTs measured 20 minutes after CS correlated with the amount of pain reduction during CS. These results suggest that individual sensitivity and adaptability to pain does not correlate with the potency of CPM. Adaptability to pain is associated with longer-lasting local pain inhibition. Copyright © 2014 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

Mechanistic experimental pain assessment in computer users with and without chronic musculoskeletal pain.

PubMed

Ge, Hong-You; Vangsgaard, Steffen; Omland, Øyvind; Madeleine, Pascal; Arendt-Nielsen, Lars

2014-12-06

Musculoskeletal pain from the upper extremity and shoulder region is commonly reported by computer users. However, the functional status of central pain mechanisms, i.e., central sensitization and conditioned pain modulation (CPM), has not been investigated in this population. The aim was to evaluate sensitization and CPM in computer users with and without chronic musculoskeletal pain. Pressure pain threshold (PPT) mapping in the neck-shoulder (15 points) and the elbow (12 points) was assessed together with PPT measurement at mid-point in the tibialis anterior (TA) muscle among 47 computer users with chronic pain in the upper extremity and/or neck-shoulder pain (pain group) and 17 pain-free computer users (control group). Induced pain intensities and profiles over time were recorded using a 0-10 cm electronic visual analogue scale (VAS) in response to different levels of pressure stimuli on the forearm with a new technique of dynamic pressure algometry. The efficiency of CPM was assessed using cuff-induced pain as conditioning pain stimulus and PPT at TA as test stimulus. The demographics, job seniority and number of working hours/week using a computer were similar between groups. The PPTs measured at all 15 points in the neck-shoulder region were not significantly different between groups. There were no significant differences between groups neither in PPTs nor pain intensity induced by dynamic pressure algometry. No significant difference in PPT was observed in TA between groups. During CPM, a significant increase in PPT at TA was observed in both groups (P < 0.05) without significant differences between groups. For the chronic pain group, higher clinical pain intensity, lower PPT values from the neck-shoulder and higher pain intensity evoked by the roller were all correlated with less efficient descending pain modulation (P < 0.05). This suggests that the excitability of the central pain system is normal in a large group of computer users with low pain intensity chronic upper extremity and/or neck-shoulder pain and that increased excitability of the pain system cannot explain the reported pain. However, computer users with higher pain intensity and lower PPTs were found to have decreased efficiency in descending pain modulation.

Evaluating an Innovative eLearning Pain Education Interprofessional Resource: A Pre-Post Study.

PubMed

Watt-Watson, Judy; McGillion, Michael; Lax, Leila; Oskarsson, Jon; Hunter, Judith; MacLennan, Cameron; Knickle, Kerry; Victor, J Charles

2018-06-20

The challenges of moving the pain education agenda forward are significant worldwide, and resources, including online, are needed to help educators in curriculum development. Online resources are available but with insufficient evaluation in the context of prelicensure pain education. Therefore, this pre-post study examined the impact of an innovative eLearning model: the Pain Education Interprofessional Resource (PEIR) on usability, pain knowledge, beliefs, and understanding of pain assessment skills including empathy. Participants were students (N = 96) recruited from seven prelicensure health sciences programs at the University of Toronto. They worked through three multifaceted modules, developed by an interprofessional team, that followed a patient with acute to persistent postsurgical pain up to one year. Module objectives, content, and assessment were based on International Association for the Study of Pain Pain Curricula domains and related pain core competencies. Multimedia interactive components focused on pain mechanisms and key pain care issues. Outcome measures included previously validated tools; data were analyzed in SPSS. Online exercises provided concurrent individual feedback throughout all modules. The completion rate for modules and online assessments was 100%. Overall usability scores (SD) were strong 4.27/5 (0.56). On average, pain knowledge scores increased 20% (P < 0.001). The Pain Assessment Skills Tool was sensitive to differences in student and expert pain assessment evaluation ratings and was useful as a tool to deliver formative feedback while engaged in interactive eLearning about pain assessment. PEIR is an effective eLearning program with high student ratings for educational design and usability that significantly improved pain knowledge and understanding of collaborative care.

Reduced Modulation of Pain in Older Adults After Isometric and Aerobic Exercise.

PubMed

Naugle, Kelly M; Naugle, Keith E; Riley, Joseph L

2016-06-01

Laboratory-based studies show that acute aerobic and isometric exercise reduces sensitivity to painful stimuli in young healthy individuals, indicative of a hypoalgesic response. However, little is known regarding the effect of aging on exercise-induced hypoalgesia (EIH). The purpose of this study was to examine age differences in EIH after submaximal isometric exercise and moderate and vigorous aerobic exercise. Healthy older and younger adults completed 1 training session and 4 testing sessions consisting of a submaximal isometric handgrip exercise, vigorous or moderate intensity stationary cycling, or quiet rest (control). The following measures were taken before and after exercise/quiet rest: 1) pressure pain thresholds, 2) suprathreshold pressure pain ratings, 3) pain ratings during 30 seconds of prolonged noxious heat stimulation, and 4) temporal summation of heat pain. The results revealed age differences in EIH after isometric and aerobic exercise, with younger adults experiencing greater EIH compared with older adults. The age differences in EIH varied across pain induction techniques and exercise type. These results provide evidence for abnormal pain modulation after acute exercise in older adults. This article enhances our understanding of the influence of a single bout of exercise on pain sensitivity and perception in healthy older compared with younger adults. This knowledge could help clinicians optimize exercise as a method of pain management. Copyright © 2016 American Pain Society. Published by Elsevier Inc. All rights reserved.

Operant conditioning of enhanced pain sensitivity by heat-pain titration.

PubMed

Becker, Susanne; Kleinböhl, Dieter; Klossika, Iris; Hölzl, Rupert

2008-11-15

Operant conditioning mechanisms have been demonstrated to be important in the development of chronic pain. Most experimental studies have investigated the operant modulation of verbal pain reports with extrinsic reinforcement, such as verbal reinforcement. Whether this reflects actual changes in the subjective experience of the nociceptive stimulus remained unclear. This study replicates and extends our previous demonstration that enhanced pain sensitivity to prolonged heat-pain stimulation could be learned in healthy participants through intrinsic reinforcement (contingent changes in nociceptive input) independent of verbal pain reports. In addition, we examine whether different magnitudes of reinforcement differentially enhance pain sensitivity using an operant heat-pain titration paradigm. It is based on the previously developed non-verbal behavioral discrimination task for the assessment of sensitization, which uses discriminative down- or up-regulation of stimulus temperatures in response to changes in subjective intensity. In operant heat-pain titration, this discriminative behavior and not verbal pain report was contingently reinforced or punished by acute decreases or increases in heat-pain intensity. The magnitude of reinforcement was varied between three groups: low (N1=13), medium (N2=11) and high reinforcement (N3=12). Continuous reinforcement was applied to acquire and train the operant behavior, followed by partial reinforcement to analyze the underlying learning mechanisms. Results demonstrated that sensitization to prolonged heat-pain stimulation was enhanced by operant learning within 1h. The extent of sensitization was directly dependent on the received magnitude of reinforcement. Thus, operant learning mechanisms based on intrinsic reinforcement may provide an explanation for the gradual development of sustained hypersensitivity during pain that is becoming chronic.

Sex differences in how social networks and relationship quality influence experimental pain sensitivity.

PubMed

Vigil, Jacob M; Rowell, Lauren N; Chouteau, Simone; Chavez, Alexandre; Jaramillo, Elisa; Neal, Michael; Waid, David

2013-01-01

This is the first study to examine how both structural and functional components of individuals' social networks may moderate the association between biological sex and experimental pain sensitivity. One hundred and fifty-two healthy adults (mean age = 22yrs., 53% males) were measured for cold pressor task (CPT) pain sensitivity (i.e., intensity ratings) and core aspects of social networks (e.g., proportion of friends vs. family, affection, affirmation, and aid). Results showed consistent sex differences in how social network structures and intimate relationship functioning modulated pain sensitivity. Females showed higher pain sensitivity when their social networks consisted of a higher proportion of intimate types of relationship partners (e.g., kin vs. non kin), when they had known their network partners for a longer period of time, and when they reported higher levels of logistical support from their significant other (e.g., romantic partner). Conversely, males showed distinct patterns in the opposite direction, including an association between higher levels of logistical support from one's significant other and lower CPT pain intensity. These findings show for the first time that the direction of sex differences in exogenous pain sensitivity is likely dependent on fundamental components of the individual's social environment. The utility of a social-signaling perspective of pain behaviors for examining, comparing, and interpreting individual and group differences in experimental and clinical pain reports is discussed.

Sex Differences in How Social Networks and Relationship Quality Influence Experimental Pain Sensitivity

PubMed Central

Vigil, Jacob M.; Rowell, Lauren N.; Chouteau, Simone; Chavez, Alexandre; Jaramillo, Elisa; Neal, Michael; Waid, David

2013-01-01

This is the first study to examine how both structural and functional components of individuals’ social networks may moderate the association between biological sex and experimental pain sensitivity. One hundred and fifty-two healthy adults (mean age = 22yrs., 53% males) were measured for cold pressor task (CPT) pain sensitivity (i.e., intensity ratings) and core aspects of social networks (e.g., proportion of friends vs. family, affection, affirmation, and aid). Results showed consistent sex differences in how social network structures and intimate relationship functioning modulated pain sensitivity. Females showed higher pain sensitivity when their social networks consisted of a higher proportion of intimate types of relationship partners (e.g., kin vs. non kin), when they had known their network partners for a longer period of time, and when they reported higher levels of logistical support from their significant other (e.g., romantic partner). Conversely, males showed distinct patterns in the opposite direction, including an association between higher levels of logistical support from one’s significant other and lower CPT pain intensity. These findings show for the first time that the direction of sex differences in exogenous pain sensitivity is likely dependent on fundamental components of the individual’s social environment. The utility of a social-signaling perspective of pain behaviors for examining, comparing, and interpreting individual and group differences in experimental and clinical pain reports is discussed. PMID:24223836

Preventing Chronic Pain following Acute Pain: Risk Factors, Preventive Strategies, and their Efficacy

PubMed Central

McGreevy, Kai; Bottros, Michael M.; Raja, Srinivasa N.

2011-01-01

Chronic pain is the leading cause of disability in the United States. The transition from acute to persistent pain is thought to arise from maladaptive neuroplastic mechanisms involving three intertwined processes, peripheral sensitization, central sensitization, and descending modulation. Strategies aimed at preventing persistent pain may target such processes. Models for studying preventive strategies include persistent post-surgical pain (PPP), persistent post-trauma pain (PTP) and post-herpetic neuralgia (PHN). Such entities allow a more defined acute onset of tissue injury after which study of the long-term effects is more easily examined. In this review, we examine the pathophysiology, epidemiology, risk factors, and treatment strategies for the prevention of chronic pain using these models. Both pharmacological and interventional approaches are described, as well as a discussion of preventive strategies on the horizon. PMID:22102847

Using multilevel growth curve modeling to examine emotional modulation of temporal summation of pain (TS-pain) and the nociceptive flexion reflex (TS-NFR).

PubMed

Rhudy, Jamie L; Martin, Satin L; Terry, Ellen L; Delventura, Jennifer L; Kerr, Kara L; Palit, Shreela

2012-11-01

Emotion can modulate pain and spinal nociception, and correlational data suggest that cognitive-emotional processes can facilitate wind-up-like phenomena (ie, temporal summation of pain). However, there have been no experimental studies that manipulated emotion to determine whether within-subject changes in emotion influence temporal summation of pain (TS-pain) and the nociceptive flexion reflex (TS-NFR, a physiological measure of spinal nociception). The present study presented a series of emotionally charged pictures (mutilation, neutral, erotic) during which electric stimuli at 2 Hz were delivered to the sural nerve to evoke TS-pain and TS-NFR. Participants (n=46 healthy; 32 female) were asked to rate their emotional reactions to pictures as a manipulation check. Pain outcomes were analyzed using statistically powerful multilevel growth curve models. Results indicated that emotional state was effectively manipulated. Further, emotion modulated the overall level of pain and NFR; pain and NFR were highest during mutilation and lowest during erotic pictures. Although pain and NFR both summated in response to the 2-Hz stimulation series, the magnitude of pain summation (TS-pain) and NFR summation (TS-NFR) was not modulated by picture-viewing. These results imply that, at least in healthy humans, within-subject changes in emotions do not promote central sensitization via amplification of temporal summation. However, future studies are needed to determine whether these findings generalize to clinical populations (eg, chronic pain). Copyright © 2012 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

Peripheral input and its importance for central sensitization.

PubMed

Baron, Ralf; Hans, Guy; Dickenson, Anthony H

2013-11-01

Many pain states begin with damage to tissue and/or nerves in the periphery, leading to enhanced transmitter release within the spinal cord and central sensitization. Manifestations of this central sensitization are windup and long-term potentiation. Hyperexcitable spinal neurons show reduced thresholds, greater evoked responses, increased receptive field sizes, and ongoing stimulus-independent activity; these changes probably underlie the allodynia, hyperalgesia, and spontaneous pain seen in patients. Central sensitization is maintained by continuing input from the periphery, but also modulated by descending controls, both inhibitory and facilitatory, from the midbrain and brainstem. The projections of sensitized spinal neurons to the brain, in turn, alter the processing of painful messages by higher centers. Several mechanisms contribute to central sensitization. Repetitive activation of primary afferent C fibers leads to a synaptic strengthening of nociceptive transmission. It may also induce facilitation of non-nociceptive Aβ fibers and nociceptive Aδ fibers, giving rise to dynamic mechanical allodynia and mechanical hyperalgesia. In postherpetic neuralgia and complex regional pain syndrome, for example, these symptoms are maintained and modulated by peripheral nociceptive input. Diagnosing central sensitization can be particularly difficult. In addition to the medical history, quantitative sensory testing and functional magnetic resonance imaging may be useful, but diagnostic criteria that include both subjective and objective measures of central augmentation are needed. Mounting evidence indicates that treatment strategies that desensitize the peripheral and central nervous systems are required. These should generally involve a multimodal approach, so that therapies may target the peripheral drivers of central sensitization and/or the central consequences. © 2013 American Neurological Association.

The association of greater dispositional optimism with less endogenous pain facilitation is indirectly transmitted through lower levels of pain catastrophizing.

PubMed

Goodin, Burel R; Glover, Toni L; Sotolongo, Adriana; King, Christopher D; Sibille, Kimberly T; Herbert, Matthew S; Cruz-Almeida, Yenisel; Sanden, Shelley H; Staud, Roland; Redden, David T; Bradley, Laurence A; Fillingim, Roger B

2013-02-01

Dispositional optimism has been shown to beneficially influence various experimental and clinical pain experiences. One possibility that may account for decreased pain sensitivity among individuals who report greater dispositional optimism is less use of maladaptive coping strategies such as pain catastrophizing, a negative cognitive/affective response to pain. An association between dispositional optimism and conditioned pain modulation, a measure of endogenous pain inhibition, has previously been reported. However, it remains to be determined whether dispositional optimism is also associated with temporal summation (TS), a measure of endogenous pain facilitation. The current study examined whether pain catastrophizing mediated the association between dispositional optimism and TS among 140 older, community-dwelling adults with symptomatic knee osteoarthritis. Individuals completed measures of dispositional optimism and pain catastrophizing. TS was then assessed using a tailored heat pain stimulus on the forearm. Greater dispositional optimism was significantly related to lower levels of pain catastrophizing and TS. Bootstrapped confidence intervals revealed that less pain catastrophizing was a significant mediator of the relation between greater dispositional optimism and diminished TS. These findings support the primary role of personality characteristics such as dispositional optimism in the modulation of pain outcomes by abatement of endogenous pain facilitation and less use of catastrophizing. Results from this study further support the body of evidence that attests to the beneficial effects of positive personality traits on pain sensitivity and pain processing. Further, this study identified diminished pain catastrophizing as an important mechanism explaining the inverse relation between dispositional optimism and endogenous pain facilitation. Copyright © 2013 American Pain Society. Published by Elsevier Inc. All rights reserved.

Ionotropic glutamate receptors contribute to pain transmission and chronic pain.

PubMed

Zhuo, Min

2017-01-01

Investigation of the synaptic mechanisms for sensory transmission and modulation provide us with critical information about the transmission of painful sensation as well as the basic mechanisms of chronic pain. Recent studies consistently demonstrate that glutamatergic synapses not only play an important role in sensory transmission, including pain and itch transmission, but also contribute to nociceptive sensitization at different levels of the brain. Different subtypes of glutamate receptors play selective roles in synaptic transmission and long-term potentiation (LTP), as well as synaptic modulation. Understanding the contribution of each subtype of glutamate receptors, and related downstream signaling pathways may provide a new opportunity to design better medicine for the treatment of different forms of chronic pain. This article is part of the Special Issue entitled 'Ionotropic glutamate receptors'. Copyright © 2016 Elsevier Ltd. All rights reserved.

Implantation of hyaluronic acid hydrogel prevents the pain phenotype in a rat model of intervertebral disc injury

PubMed Central

Sakai, Daisuke; Dockery, Peter

2018-01-01

Painful intervertebral disc degeneration is mediated by inflammation that modulates glycosylation and induces hyperinnervation and sensory sensitization, which result in discogenic pain. Hyaluronic acid (HA) used as a therapeutic biomaterial can reduce inflammation and pain, but the effects of HA therapy on glycosylation and pain associated with disc degeneration have not been previously determined. We describe a novel rat model of pain induced by intervertebral disc injury, with validation of the pain phenotype by morphine treatment. Using this model, we assessed the efficacy of HA hydrogel for the alleviation of pain, demonstrating that it reduced nociceptive behavior, an effect associated with down-regulation of nociception markers and inhibition of hyperinnervation. Furthermore, HA hydrogel altered glycosylation and modulated key inflammatory and regulatory signaling pathways, resulting in attenuation of inflammation and regulation of matrix components. Our results suggest that HA hydrogel is a promising clinical candidate for the treatment of back pain caused by degenerated discs. PMID:29632893

Cognitive Performance Is Related to Central Sensitization and Health-related Quality of Life in Patients with Chronic Whiplash-Associated Disorders and Fibromyalgia.

PubMed

Coppieters, Iris; Ickmans, Kelly; Cagnie, Barbara; Nijs, Jo; De Pauw, Robby; Noten, Suzie; Meeus, Mira

2015-01-01

A growing body of research has demonstrated that impaired central pain modulation or central sensitization (CS) is a crucial mechanism for the development of persistent pain in chronic whiplash-associated disorders (WAD) and fibromyalgia (FM) patients. Furthermore, there is increasing evidence for cognitive dysfunctions among these patients. In addition, chronic WAD and FM patients often report problems with health-related quality of life (QoL). Yet, there is limited research concerning the interrelations between cognitive performance, indices of CS, and health-related QoL in these patients. (1) Examining the presence of cognitive impairment, CS, and limitations on health-related QoL in patients with chronic WAD and FM compared to healthy controls. (2) Examining interrelations between performance-based cognitive functioning, CS, and self-reported health-related QoL in these 3 study groups. A case-control study was conducted. The present study took place at the University Hospital Brussels, the University of Brussels, and the University of Antwerp. Fifty-nine patients (16 chronic WAD patients, 21 FM patients, and 22 pain-free volunteers) filled out the Short Form 36 item Health Survey (SF-36), a self-reported psychosocial questionnaire, to assess health-related QoL. Next, they were subjected to various pain measurements (pressure hyperalgesia, deep-tissue hyperalgesia, temporal summation [TS], and conditioned pain modulation [CPM]). Finally, participants completed a battery of performance-based cognitive tests (Stroop task, psychomotor vigilance task [PVT], and operation span task [OSPAN]). Significant cognitive impairment, bottom-up sensitization, and decreased health-related QoL were demonstrated in patients with chronic WAD and FM compared to healthy controls (P < 0.017). CPM was comparable between the 3 groups. Cognitive performance was significantly related to central pain modulation (deep-tissue hyperalgesia, TS, CPM) as well as to self-reported health-related QoL (P < 0.05). Decreased cognitive performance was related to deficient central pain modulation in healthy controls. Further, significant correlations between decreased cognitive performance and reduced health-related QoL were revealed among all study groups. Additionally, FM patients showed correlations between cognitive impairment and increased health-related QoL. Remarkably, impaired selective attention and working memory were related to less TS, whereas impaired sustained attention was correlated with dysfunctional CPM in FM patients. Based on the current cross-sectional study no firm conclusions can be drawn on the causality of the relations. In conclusion, this paper has demonstrated significant cognitive deficits, signs of CS, and reduced health-related QoL in chronic WAD and FM patients compared to healthy individuals. Significant relations between cognitive performance and CS as well as health-related QoL were demonstrated. These results provide preliminary evidence for the clinical importance of objectively measured cognitive deficits in patients with chronic WAD and FM. Chronic pain, fibromyalgia, whiplash, central sensitization, conditioned pain modulation, temporal summation, cognition, quality of life.

Effects of Stress and Relaxation on Central Pain Modulation in Chronic Whiplash and Fibromyalgia Patients Compared to Healthy Controls.

PubMed

Coppieters, Iris; Cagnie, Barbara; Nijs, Jo; van Oosterwijck, Jessica; Danneels, Lieven; De Pauw, Robby; Meeus, Mira

2016-03-01

Compelling evidence has demonstrated that impaired central pain modulation contributes to persistent pain in patients with chronic whiplash associated disorders (WAD) and fibromyalgia (FM). However, there is limited research concerning the influence of stress and relaxation on central pain modulation in patients with chronic WAD and FM. The present study aims to investigate the effects of acute cognitive stress and relaxation on central pain modulation in chronic WAD and FM patients compared to healthy individuals. A randomized crossover design was employed. The present study took place at the University of Brussels, the University Hospital Brussels, and the University of Antwerp. Fifty-nine participants (16 chronic WAD patients, 21 FM, 22 pain-free controls) were enrolled and subjected to various pain measurements. Temporal summation (TS) of pain and conditioned pain modulation (CPM) were evaluated. Subsequently, participants were randomly allocated to either a group that received progressive relaxation therapy or a group that performed a battery of cognitive tests (= cognitive stressor). Afterwards, all pain measurements were repeated. One week later participant groups were switched. A significant difference was found between the groups in the change in TS in response to relaxation (P = 0.008) and cognitive stress (P = 0.003). TS decreased in response to relaxation and cognitive stress in chronic WAD patients and controls. In contrast, TS increased after both interventions in FM patients. CPM efficacy decreased in all 3 groups in response to relaxation (P = 0.002) and cognitive stress (P = 0.001). The obtained results only apply for a single session of muscle relaxation therapy and cognitive stress, whereby no conclusions can be made for effects on pain perception and modulation of chronic cognitive stress and long-term relaxation therapies. A single relaxation session as well as cognitive stress may have negative acute effects on pain modulation in patients with FM, while cognitive stress and relaxation did not worsen bottom-up sensitization in chronic WAD patients and healthy persons. However, endogenous pain inhibition, assessed using a CPM paradigm, worsened in chronic WAD and FM patients, as well as in healthy people following both interventions.

Variation in the dopamine D2 receptor gene plays a key role in human pain and its modulation by transcranial magnetic stimulation.

PubMed

Jääskeläinen, Satu K; Lindholm, Pauliina; Valmunen, Tanja; Pesonen, Ullamari; Taiminen, Tero; Virtanen, Arja; Lamusuo, Salla; Forssell, Heli; Hagelberg, Nora; Hietala, Jarmo; Pertovaara, Antti

2014-10-01

We tested whether variation of the dopamine D2 receptor (DRD2) gene contributes to individual differences in thermal pain sensitivity and analgesic efficacy of repetitive transcranial magnetic stimulation (rTMS) in healthy subjects (n=29) or susceptibility to neuropathic pain in patients with neurophysiologically confirmed diagnosis (n=16). Thermal sensitivity of healthy subjects was assessed before and after navigated rTMS provided to the S1/M1 cortex. All subjects were genotyped for the DRD2 gene 957C>T and catechol-O-methyltransferase (COMT) protein Val158Met polymorphisms. In healthy subjects, 957C>T influenced both innocuous and noxious thermal detection thresholds that were lowest in 957TT homozygotes (P values from .0277 to .0462). rTMS to S1 cortex had analgesic effect only in 957TT homozygote genotype (P=.0086). In patients, prevalence of 957TT homozygote genotype was higher than in a healthy Finnish population (50% vs 27%; P=.0191). Patients with 957TT genotype reported more severe pain than patients with other genotypes (P=.0351). COMT Val158Met polymorphism was not independently associated with the studied variables. Genetic regulation of DRD2 function by 957C>T polymorphism thus seems to influence thermal and pain sensitivity, its modulation by rTMS, and susceptibility to neuropathic pain. This indicates a central role for the dopamine system and DRD2 in pain and analgesia. This may have clinical implications regarding individualized selection of patients for rTMS treatment and assessment of risks for neuropathic pain. Copyright © 2014 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

DREAM regulates BDNF-dependent spinal sensitization

PubMed Central

2010-01-01

Background The transcriptional repressor DREAM (downstream regulatory element antagonist modulator) controls the expression of prodynorphin and has been involved in the modulation of endogenous responses to pain. To investigate the role of DREAM in central mechanisms of pain sensitization, we used a line of transgenic mice (L1) overexpressing a Ca2+- and cAMP-insensitive DREAM mutant in spinal cord and dorsal root ganglia. Results L1 DREAM transgenic mice showed reduced expression in the spinal cord of several genes related to pain, including prodynorphin and BDNF (brain-derived neurotrophic factor) and a state of basal hyperalgesia without change in A-type currents. Peripheral inflammation produced enhancement of spinal reflexes and increased expression of BDNF in wild type but not in DREAM transgenic mice. The enhancement of the spinal reflexes was reproduced in vitro by persistent electrical stimulation of C-fibers in wild type but not in transgenic mice. Exposure to exogenous BDNF produced a long-term enhancement of dorsal root-ventral root responses in transgenic mice. Conclusions Our results indicate that endogenous BDNF is involved in spinal sensitization following inflammation and that blockade of BDNF induction in DREAM transgenic mice underlies the failure to develop spinal sensitization. PMID:21167062

Clinical presentation and manual therapy for upper quadrant musculoskeletal conditions

PubMed Central

Isabel de-la-Llave-Rincón, Ana; Puentedura, Emilio J; Fernández-de-las-Peñas, César

2011-01-01

In recent years, increased knowledge of the pathogenesis of upper quadrant pain syndromes has translated to better management strategies. Recent studies have demonstrated evidence of peripheral and central sensitization mechanisms in different local pain syndromes of the upper quadrant such as idiopathic neck pain, lateral epicondylalgia, whiplash-associated disorders, shoulder impingement, and carpal tunnel syndrome. Therefore, a treatment-based classification approach where subjects receive matched interventions has been developed and, it has been found that these patients experience better outcomes than those receiving non-matched interventions. There is evidence suggesting that the cervical and thoracic spine is involved in upper quadrant pain. Spinal manipulation has been found to be effective for patients with elbow pain, neck pain, or cervicobrachial pain. Additionally, it is known that spinal manipulative therapy exerts neurophysiological effects that can activate pain modulation mechanisms. This paper exposes some manual therapies for upper quadrant pain syndromes, based on a nociceptive pain rationale for modulating central nervous system including trigger point therapy, dry needling, mobilization or manipulation, and cognitive pain approaches. PMID:23115473

Increased Sensitivity to Thermal Pain and Reduced Subcutaneous Lidocaine Efficacy in Redheads

PubMed Central

Liem, Edwin B.; Joiner, Teresa V.; Tsueda, Kentaro; Sessler, Daniel I.

2005-01-01

Background: Anesthetic requirement in redheads is exaggerated, suggesting that redheads may be especially sensitive to pain. We therefore tested the hypotheses that women with natural red hair are more sensitive to pain, and that redheads are resistant to topical and subcutaneous lidocaine. Methods: We evaluated pain sensitivity in red-haired (n=30) or dark-haired (n=30) women by determining the electrical current perception threshold, pain perception, and maximum pain tolerance with a Neurometer CPT/C (Neurotron, Inc., Baltimore, MD). We evaluated the analogous warm and cold temperature thresholds with the TSA-II Neurosensory Analyzer (Medoc Ltd., Minneapolis, MN). Volunteers were tested with both devices at baseline and with the Neurometer after 1-hour exposure to 4% liposomal lidocaine and after subcutaneous injection of 1% lidocaine. Data are presented as medians [interquartile ranges]. Results: Current perception, pain perception, and pain tolerance thresholds were similar in the red-haired and dark-haired women at 2000, 250, and 5 Hz. In contrast, redheads were more sensitive to cold pain perception (22.6°C [15.1, 26.1] vs. 12.6°C [0, 20], P=0.004), cold pain tolerance (6.0°C [0, 9.7] vs. 0.0°C [0.0, 2.0], P=0.001), and heat pain (46.3°C [45.7, 47.5] vs. 47.7°C [46.6, 48.7], P=0.009). Subcutaneous, lidocaine was significantly less effective in redheads, e.g., pain tolerance threshold at 2000 Hz stimulation in redheads was 11.0 mA [8.5, 16.5] vs. >20.0 mA [14.5, >20] in others, P=0.005). Conclusion: Red hair is the phenotype for mutations of the melanocortin 1 receptor. Our results indicate that redheads are more sensitive to thermal pain and are resistant to the analgesic effects of subcutaneous lidocaine. Mutations of the melanocortin 1 receptor, or a consequence thereof, thus modulate pain sensitivity. PMID:15731586

Seeing the Body Distorts Tactile Size Perception

ERIC Educational Resources Information Center

Longo, Matthew R.; Sadibolova, Renata

2013-01-01

Vision of the body modulates somatosensation, even when entirely non-informative about stimulation. For example, seeing the body increases tactile spatial acuity, but reduces acute pain. While previous results demonstrate that vision of the body modulates somatosensory sensitivity, it is unknown whether vision also affects metric properties of…

Do pain-associated contexts increase pain sensitivity? An investigation using virtual reality.

PubMed

Harvie, Daniel S; Sterling, Michele; Smith, Ashley D

2018-04-30

Pain is not a linear result of nociception, but is dependent on multisensory inputs, psychological factors, and prior experience. Since nociceptive models appear insufficient to explain chronic pain, understanding non-nociceptive contributors is imperative. Several recent models propose that cues associatively linked to painful events might acquire the capacity to augment, or even cause, pain. This experiment aimed to determine whether contexts associated with pain, could modulate mechanical pain thresholds and pain intensity. Forty-eight healthy participants underwent a contextual conditioning procedure, where three neutral virtual reality contexts were paired with either unpredictable noxious stimulation, unpredictable vibrotactile stimulation, or no stimulation. Following the conditioning procedure, mechanical pain thresholds and pain evoked by a test stimulus were examined in each context. In the test phase, the effect of expectancy was equalised across conditions by informing participants when thresholds and painful stimuli would be presented. Contrary to our hypothesis, scenes that were associated with noxious stimulation did not increase mechanical sensitivity (p=0.08), or increase pain intensity (p=0.46). However, an interaction with sex highlighted the possibility that pain-associated contexts may alter pain sensitivity in females but not males (p=0.03). Overall, our data does not support the idea that pain-associated contexts can alter pain sensitivity in healthy asymptomatic individuals. That an effect was shown in females highlights the possibility that some subgroups may be susceptible to such an effect, although the magnitude of the effect may lack real-world significance. If pain-associated cues prove to have a relevant pain augmenting effect, in some subgroups, procedures aimed at extinguishing pain-related associations may have therapeutic potential.

Tonic blood pressure modulates the relationship between baroreceptor cardiac reflex sensitivity and cognitive performance.

PubMed

Del Paso, Gustavo A Reyes; González, M Isabel; Hernández, José Antonio; Duschek, Stefan; Gutiérrez, Nicolás

2009-09-01

This study explored the effects of tonic blood pressure on the association between baroreceptor cardiac reflex sensitivity and cognitive performance. Sixty female participants completed a mental arithmetic task. Baroreceptor reflex sensitivity was assessed using sequence analysis. An interaction was found, indicating that the relationship between baroreceptor reflex sensitivity and cognitive performance is modulated by blood pressure levels. Reflex sensitivity was inversely associated to performance indices in the subgroup of participants with systolic blood pressure above the mean, whereas the association was positive in participants with systolic values below the mean. These results are in accordance with the findings in the field of pain perception and suggest that tonic blood pressure modulates the inhibitory effects of baroreceptor stimulation on high central nervous functions.

Acute psychosocial stress reduces pain modulation capabilities in healthy men.

PubMed

Geva, Nirit; Pruessner, Jens; Defrin, Ruth

2014-11-01

Anecdotes on the ability of individuals to continue to function under stressful conditions despite injuries causing excruciating pain suggest that acute stress may induce analgesia. However, studies exploring the effect of acute experimental stress on pain perception show inconsistent results, possibly due to methodological differences. Our aim was to systematically study the effect of acute stress on pain perception using static and dynamic, state-of-the-art pain measurements. Participants were 29 healthy men who underwent the measurement of heat-pain threshold, heat-pain intolerance, temporal summation of pain, and conditioned pain modulation (CPM). Testing was conducted before and during exposure to the Montreal Imaging Stress Task (MIST), inducing acute psychosocial stress. Stress levels were evaluated using perceived ratings of stress and anxiety, autonomic variables, and salivary cortisol. The MIST induced a significant stress reaction. Although pain threshold and pain intolerance were unaffected by stress, an increase in temporal summation of pain and a decrease in CPM were observed. These changes were significantly more robust among individuals with stronger reaction to stress ("high responders"), with a significant correlation between the perception of stress and the performance in the pain measurements. We conclude that acute psychosocial stress seems not to affect the sensitivity to pain, however, it significantly reduces the ability to modulate pain in a dose-response manner. Considering the diverse effects of stress in this and other studies, it appears that the type of stress and the magnitude of its appraisal determine its interactions with the pain system. Copyright © 2014 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

Social context and perceived agency affects empathy for pain: an event-related fMRI investigation.

PubMed

Akitsuki, Yuko; Decety, Jean

2009-08-15

Studying of the impact of social context on the perception of pain in others is important for understanding the role of intentionality in interpersonal sensitivity, empathy, and implicit moral reasoning. Here we used an event-related fMRI with pain and social context (i.e., the number of individuals in the stimuli) as the two factors to investigate how different social contexts and resulting perceived agency modulate the neural response to the perception of pain in others. Twenty-six healthy participants were scanned while presented with short dynamic visual stimuli depicting painful situations accidentally caused by or intentionally caused by another individual. The main effect of perception of pain was associated with signal increase in the aMCC, insula, somatosensory cortex, SMA and PAG. Importantly, perceiving the presence of another individual led to specific hemodynamic increase in regions involved in representing social interaction and emotion regulation including the temporoparietal junction, medial prefrontal cortex, inferior frontal gyrus, and orbitofrontal cortex. Furthermore, the functional connectivity pattern between the left amygdala and other brain areas was modulated by the perceived agency. Our study demonstrates that the social context in which pain occurs modulate the brain response to other's pain. This modulation may reflect successful adaptation to potential danger present in a social interaction. Our results contribute to a better understanding of the neural mechanisms underpinning implicit moral reasoning that concern actions that can harm other people.

New Strategies to Develop Novel Pain Therapies: Addressing Thermoreceptors from Different Points of View

PubMed Central

Fernández-Carvajal, Asia; Fernández-Ballester, Gregorio; Devesa, Isabel; González-Ros, José Manuel; Ferrer-Montiel, Antonio

2011-01-01

One approach to develop successful pain therapies is the modulation of dysfunctional ion channels that contribute to the detection of thermal, mechanical and chemical painful stimuli. These ion channels, known as thermoTRPs, promote the sensitization and activation of primary sensory neurons known as nociceptors. Pharmacological blockade and genetic deletion of thermoTRP have validated these channels as therapeutic targets for pain intervention. Several thermoTRP modulators have progressed towards clinical development, although most failed because of the appearance of unpredicted side effects. Thus, there is yet a need to develop novel channel modulators with improved therapeutic index. Here, we review the current state-of-the art and illustrate new pharmacological paradigms based on TRPV1 that include: (i) the identification of activity-dependent modulators of this thermoTRP channel; (ii) the design of allosteric modulators that interfere with protein-protein interaction involved in the functional coupling of stimulus sensing and gate opening; and (iii) the development of compounds that abrogate the inflammation-mediated increase of receptor expression in the neuronal surface. These new sites of action represent novel strategies to modulate pathologically active TRPV1, while minimizing an effect on the TRPV1 subpopulation involved in physiological and protective roles, thus increasing their potential therapeutic use. PMID:24288041

Lack of Gender and Age Differences in Pain Measurements Following Exercise in People with Chronic Whiplash-Associated Disorders.

PubMed

Ickmans, Kelly; Malfliet, Anneleen; De Kooning, Margot; Goudman, Lisa; Hubloue, Ives; Schmitz, Tom; Goubert, Dorien; Aguilar-Ferrandiz, Maria Encarnacion

2017-09-01

Individuals with chronic whiplash associated disorders (WAD) present persistent pain in the absence of structural pathology. In these people, altered central pain processing and central sensitization are observed. The role of personal factors, such as gender and age, on pain processing mechanisms in chronic WAD, however, is still unclear. This study investigated possible gender- and age-related differences in self-reported and experimental pain measurements in people with chronic WAD. Besides the exercise-induced response on pain measurements between gender and age subgroups was recorded. Case-control study. University Hospital, Brussels. Self-reported pain and experimental pain measurements (pressure pain thresholds [PPT], occlusion cuff pressure, temporal summation, and conditioned pain modulation) were performed in 52 individuals (26 chronic WAD patients and 26 healthy controls), before and after a submaximal cycle exercise. Lower PPTs and occlusion cuff pressures were shown in chronic WAD in comparison with healthy controls. No gender and age differences regarding PPTs, occlusion cuff pressures and conditioned pain modulation were found in chronic WAD. Within the chronic WAD group, men showed higher self-reported pain compared to women and younger adults showed enhanced generalized pain facilitation compared to older adults. In addition, chronic WAD patients are able to inhibit exercise-induced hyperalgesia, but no gender and age differences in pain response following exercise were found. This study was sufficiently powered to detect differences between the chronic WAD and control group. However, a sufficient power was not reached when patients were divided in age and gender groups. Furthermore, only mechanical stimuli were included in the experimental pain measurements. Besides, psychosocial factors were not taken into account. Some alterations of altered pain processing are present in chronic WAD patients, however not in response to exercise. No gender and age differences in pain measurements were observed in people with chronic WAD.Key words: Neck pain, whiplash associated disorders, chronic pain, personal factors, age, gender, central sensitization, exercise induced hyperalgesia, pressure pain thresholds, self reported pain.

Epigenetic modification of DRG neuronal gene expression subsequent to nerve injury: etiological contribution to complex regional pain syndromes (Part II).

PubMed

Wang, Fuzhou; Stefano, George B; Kream, Richard M

2014-07-12

Cumulating evidence indicated that nerve injury-associated cellular and molecular changes play an essential role in contributing to the development of pathological pain, and more recent findings implicated the critical role of epigenetic mechanisms in pain-related sensitization in the DRG subsequent to nerve injury. In this part of the dyad review (Part II), we reviewed and paid special attention on the etiological contribution of DGR gene expression modulated by epigenetic mechanisms of CRPS. As essential effectors to different molecular activation, we first discussed the activation of various signaling pathways that subsequently from nerve injury, and in further illustrated the fundamental and functional underpinnings of nerve injury-induced pain, in which we argued for the potential epigenetic mechanisms in response to sensitizing stimuli or injury. Therefore, understanding the specific mediating factors that influence individual epigenetic differences contributing to pain sensitivity and responsiveness to analgesics possesses crucial clinical implications.

Immediate Changes Following Manual Therapy in Resting State Functional Connectivity As Measured By Magnetic Resonance Imaging (fMRI) In Subjects With Induced Low Back Pain

PubMed Central

Gay, Charles W.; Robinson, Michael E.; George, Steven Z.; Perlstein, William M.; Bishop, Mark D.

2014-01-01

Objective The purpose of this study was to use functional magnetic resonance imaging (fMRI) to investigate the immediate changes in functional connectivity (FC) between brain regions that process and modulate the pain experience following 3 different types of manual therapies (MT) and to identify reductions in experimentally induced myalgia and changes in local and remote pressure pain sensitivity. Methods Twenty-four participants (17 females, mean age ± SD = 21.6 ± 4.2 years), who completed an exercise-injury protocol to induce low back pain, were randomized into 3 groups: chiropractic spinal manipulation (n=6), spinal mobilization (n=8) or therapeutic touch (n=10). The primary outcome was the immediate change in FC as measured on fMRI between the following brain regions: somatosensory cortex, secondary somatosensory cortex, thalamus, anterior and posterior cingulate cortices, anterior and poster insula, and periaqueductal grey. Secondary outcomes were immediate changes in pain intensity measured with a 101-point numeric rating scale, and pain sensitivity, measured with a hand-held dynamometer. Repeated measures ANOVA models and correlation analyses were conducted to examine treatment effects and the relationship between within-person changes across outcome measures. Results Changes in FC were found between several brain regions that were common to all 3 manual therapy interventions. Treatment-dependent changes in FC were also observed between several brain regions. Improvement was seen in pain intensity following all interventions (p<0.05) with no difference between groups (p>0.05). There were no observed changes in pain sensitivity, or an association between primary and secondary outcome measures. Conclusion These results suggest that manual therapies (chiropractic spinal manipulation, spinal mobilization, and therapeutic touch) have an immediate effect on the FC between brain regions involved in processing and modulating the pain experience. This suggests that neurophysiological changes following MT may be an underlying mechanism of pain relief. PMID:25284739

Swimming Training Reduces Neuroma Pain by Regulating Neurotrophins

PubMed Central

TIAN, JINGE; YU, TINGTING; XU, YONGMING; PU, SHAOFENG; LV, YINGYING; ZHANG, XIN; DU, DONGPING

2018-01-01

ABSTRACT Introduction Neuroma formation after peripheral nerve transection leads to severe neuropathic pain in amputees. Previous studies suggested that physical exercise could bring beneficial effect on alleviating neuropathic pain. However, the effect of exercise on neuroma pain still remained unclear. In addition, long-term exercise can affect the expression of neurotrophins (NT), such as nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF), which play key roles in nociceptor sensitization and nerve sprouting after nerve injury. Here, we investigated whether long-term swimming exercise could relieve neuroma pain by modulating NT expression. Methods We used a tibial neuroma transposition (TNT) rat model to mimic neuroma pain. After TNT surgery, rats performed swimming exercise for 5 wk. Neuroma pain and tactile sensitivities were detected using von Frey filaments. Immunofluorescence was applied to analyze neuroma formation. NGF and BDNF expressions in peripheral neuroma, dorsal root ganglion, and the spinal cord were measured using enzyme-linked immunosorbent assay and Western blotting. Results TNT led to neuroma formation, induced neuroma pain, and mechanical allodynia in hind paw. Five-week swimming exercise inhibited neuroma formation and relieved mechanical allodynia in the hind paw and neuroma pain in the lateral ankle. The analgesic effect lasted for at least 1 wk, even when the exercise ceased. TNT elevated the expressions of BDNF and NGF in peripheral neuroma, dorsal root ganglion, and the spinal cord to different extents. Swimming also decreased the elevation of NT expression. Conclusions Swimming exercise not only inhibits neuroma formation induced by nerve transection but also relieves pain behavior. These effects might be associated with the modulation of NT. PMID:28846565

Swimming Training Reduces Neuroma Pain by Regulating Neurotrophins.

PubMed

Tian, Jinge; Yu, Tingting; Xu, Yongming; Pu, Shaofeng; Lv, Yingying; Zhang, Xin; DU, Dongping

2018-01-01

Neuroma formation after peripheral nerve transection leads to severe neuropathic pain in amputees. Previous studies suggested that physical exercise could bring beneficial effect on alleviating neuropathic pain. However, the effect of exercise on neuroma pain still remained unclear. In addition, long-term exercise can affect the expression of neurotrophins (NT), such as nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF), which play key roles in nociceptor sensitization and nerve sprouting after nerve injury. Here, we investigated whether long-term swimming exercise could relieve neuroma pain by modulating NT expression. We used a tibial neuroma transposition (TNT) rat model to mimic neuroma pain. After TNT surgery, rats performed swimming exercise for 5 wk. Neuroma pain and tactile sensitivities were detected using von Frey filaments. Immunofluorescence was applied to analyze neuroma formation. NGF and BDNF expressions in peripheral neuroma, dorsal root ganglion, and the spinal cord were measured using enzyme-linked immunosorbent assay and Western blotting. TNT led to neuroma formation, induced neuroma pain, and mechanical allodynia in hind paw. Five-week swimming exercise inhibited neuroma formation and relieved mechanical allodynia in the hind paw and neuroma pain in the lateral ankle. The analgesic effect lasted for at least 1 wk, even when the exercise ceased. TNT elevated the expressions of BDNF and NGF in peripheral neuroma, dorsal root ganglion, and the spinal cord to different extents. Swimming also decreased the elevation of NT expression. Swimming exercise not only inhibits neuroma formation induced by nerve transection but also relieves pain behavior. These effects might be associated with the modulation of NT.

The association of greater dispositional optimism with less endogenous pain facilitation is indirectly transmitted through lower levels of pain catastrophizing

PubMed Central

Goodin, Burel R.; Glover, Toni L.; Sotolongo, Adriana; King, Christopher D.; Sibille, Kimberly T.; Herbert, Matthew S.; Cruz-Almeida, Yenisel; Sanden, Shelley H.; Staud, Roland; Redden, David T.; Bradley, Laurence A.; Fillingim, Roger B.

2012-01-01

Dispositional optimism has been shown to beneficially influence various experimental and clinical pain experiences. One possibility that may account for decreased pain sensitivity among individuals who report greater dispositional optimism is less use of maladaptive coping strategies like pain catastrophizing, a negative cognitive/affective response to pain. An association between dispositional optimism and conditioned pain modulation (CPM), a measure of endogenous pain inhibition, has previously been reported. However, it remains to be determined whether dispositional optimism is also associated with temporal summation (TS), a measure of endogenous pain facilitation. The current study examined whether pain catastrophizing mediated the association between dispositional optimism and TS among 140 older, community-dwelling adults with symptomatic knee osteoarthritis. Individuals completed measures of dispositional optimism and pain catastrophizing. TS was then assessed using a tailored heat pain stimulus on the forearm. Greater dispositional optimism was significantly related to lower levels of pain catastrophizing and TS. Bootstrapped confidence intervals revealed that less pain catastrophizing was a significant mediator of the relation between greater dispositional optimism and diminished TS. These findings support the primary role of personality characteristics such as dispositional optimism in the modulation of pain outcomes by abatement of endogenous pain facilitation and less use of catastrophizing. PMID:23218934

Increased pain sensitivity but normal function of exercise induced analgesia in hip and knee osteoarthritis--treatment effects of neuromuscular exercise and total joint replacement.

PubMed

Kosek, E; Roos, E M; Ageberg, E; Nilsdotter, A

2013-09-01

To assess exercise induced analgesia (EIA) and pain sensitivity in hip and knee osteoarthritis (OA) and to study the effects of neuromuscular exercise and surgery on these parameters. The dataset consisted of knee (n = 66) and hip (n = 47) OA patients assigned for total joint replacement at Lund University Hospital undergoing pre-operative neuromuscular exercise and 43 matched controls. Sensitivity to pressure pain was assessed by pressure algometry at 10 sites. Subjects were then instructed to perform a standardized static knee extension. Pressure pain thresholds (PPTs) were assessed at the contracting quadriceps muscle (Q) and at the resting deltoid muscle (D) before and during contraction. The relative increase in PPTs during contraction was taken as a measure of localized (Q) or generalized (D) EIA. Patients were assessed at baseline, following on average 12 weeks of neuromuscular exercise and 3 months following surgery. We found a normal function of EIA in OA patients at baseline. Previous studies have reported beneficial effects of physical exercise on pain modulation in healthy subjects. However, no treatment effects on EIA were seen in OA patients despite the increase in muscle strength following neuromuscular exercise and reduced pain following surgery. Compared to controls, OA patients had increased pain sensitivity and no beneficial effects on pain sensitivity were seen following treatment. To our knowledge, this is the first study of EIA in OA patients. Despite increased pain sensitivity, OA patients had a normal function of EIA. Copyright © 2013 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.

Effect of ketamine on endogenous pain modulation in healthy volunteers.

PubMed

Niesters, Marieke; Dahan, Albert; Swartjes, Maarten; Noppers, Ingeborg; Fillingim, Roger B; Aarts, Leon; Sarton, Elise Y

2011-03-01

Inhibitory and facilitatory descending pathways, originating at higher central nervous system sites, modulate activity of dorsal horn nociceptive neurons, and thereby influence pain perception. Dysfunction of inhibitory pain pathways or a shift in the balance between pain facilitation and pain inhibition has been associated with the development of chronic pain. The N-methyl-d-aspartate receptor antagonist ketamine has a prolonged analgesic effect in chronic pain patients. This effect is due to desensitization of sensitized N-methyl-d-aspartate receptors. Additionally, ketamine may modulate or enhance endogenous inhibitory control of pain perception. Diffuse noxious inhibitory control (DNIC) and offset analgesia (OA) are 2 mechanisms involved in descending inhibition. The present study investigates the effect of a ketamine infusion on subsequent DNIC and OA responses to determine whether ketamine has an influence on descending pain control. Ten healthy subjects (4 men/6 women) received a 1-hour placebo or S(+)-ketamine (40mg per 70kg) infusion on 2 separate occasions in random order. Upon the termination of the infusion, DNIC and OA responses were obtained. After placebo treatment, significant descending inhibition of pain responses was present for DNIC and OA. In contrast, after ketamine infusion, no DNIC was observed, but rather a significant facilitatory pain response (P<0.01); the OA response remained unchanged. These findings suggest that the balance between pain inhibition and pain facilitation was shifted by ketamine towards pain facilitation. The absence of an effect of ketamine on OA indicates differences in the mechanisms and neurotransmitter influences between OA and DNIC. Diffuse noxious inhibitory control responses following a 1-hour low-dose ketamine treatment displayed facilitation of pain in response to experimental noxious thermal stimulation. Copyright © 2010 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

Pain Processing after Social Exclusion and Its Relation to Rejection Sensitivity in Borderline Personality Disorder

PubMed Central

Bungert, Melanie; Koppe, Georgia; Niedtfeld, Inga; Vollstädt-Klein, Sabine; Schmahl, Christian

2015-01-01

Objective There is a general agreement that physical pain serves as an alarm signal for the prevention of and reaction to physical harm. It has recently been hypothesized that “social pain,” as induced by social rejection or abandonment, may rely on comparable, phylogenetically old brain structures. As plausible as this theory may sound, scientific evidence for this idea is sparse. This study therefore attempts to link both types of pain directly. We studied patients with borderline personality disorder (BPD) because BPD is characterized by opposing alterations in physical and social pain; hyposensitivity to physical pain is associated with hypersensitivity to social pain, as indicated by an enhanced rejection sensitivity. Method Twenty unmedicated female BPD patients and 20 healthy participants (HC, matched for age and education) played a virtual ball-tossing game (cyberball), with the conditions for exclusion, inclusion, and a control condition with predefined game rules. Each cyberball block was followed by a temperature stimulus (with a subjective pain intensity of 60% in half the cases). The cerebral responses were measured by functional magnetic resonance imaging. The Adult Rejection Sensitivity Questionnaire was used to assess rejection sensitivity. Results Higher temperature heat stimuli had to be applied to BPD patients relative to HCs to reach a comparable subjective experience of painfulness in both groups, which suggested a general hyposensitivity to pain in BPD patients. Social exclusion led to a subjectively reported hypersensitivity to physical pain in both groups that was accompanied by an enhanced activation in the anterior insula and the thalamus. In BPD, physical pain processing after exclusion was additionally linked to enhanced posterior insula activation. After inclusion, BPD patients showed reduced amygdala activation during pain in comparison with HC. In BPD patients, higher rejection sensitivity was associated with lower activation differences during pain processing following social exclusion and inclusion in the insula and in the amygdala. Discussion Despite the similar behavioral effects in both groups, BPD patients differed from HC in their neural processing of physical pain depending on the preceding social situation. Rejection sensitivity further modulated the impact of social exclusion on neural pain processing in BPD, but not in healthy controls. PMID:26241850

Quantitative Sensory Testing Predicts Pregabalin Efficacy in Painful Chronic Pancreatitis

PubMed Central

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

2013-01-01

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

The therapeutic potential of Na+ and Ca2+ channel blockers in pain management.

PubMed

Sabido-David, Cibele; Faravelli, Laura; Salvati, Patricia

2004-10-01

Chronic pain affects a large percentage of the population, representing a socio-economic burden. Current treatments are characterised by suboptimal efficacy and/or side effects that limit their use. Among several approaches to treating chronic pain, voltage-sensitive Ca(2+) and Na(+) channels are promising targets. This review evaluates the preclinical evidence that supports the involvement of these targets, with specific attention to those subtypes that appear more strictly correlated with pain generation and sustainment, as well as those compounds that modulate the activity of Ca(2+) and/or Na(+) channels that are currently in clinical development for chronic pain conditions.

Epigenetic modification of DRG neuronal gene expression subsequent to nerve injury: etiological contribution to complex regional pain syndromes (Part I).

PubMed

Wang, Fuzhou; Stefano, George B; Kream, Richard M

2014-06-25

DRG is of importance in relaying painful stimulation to the higher pain centers and therefore could be a crucial target for early intervention aimed at suppressing primary afferent stimulation. Complex regional pain syndrome (CRPS) is a common pain condition with an unknown etiology. Recently added new information enriches our understanding of CRPS pathophysiology. Researches on genetics, biogenic amines, neurotransmitters, and mechanisms of pain modulation, central sensitization, and autonomic functions in CRPS revealed various abnormalities indicating that multiple factors and mechanisms are involved in the pathogenesis of CRPS. Epigenetics refers to mitotically and meiotically heritable changes in gene expression that do not affect the DNA sequence. As epigenetic modifications potentially play an important role in inflammatory cytokine metabolism, neurotransmitter responsiveness, and analgesic sensitivity, they are likely key factors in the development of chronic pain. In this dyad review series, we systematically examine the nerve injury-related changes in the neurological system and their contribution to CRPS. In this part, we first reviewed and summarized the role of neural sensitization in DRG neurons in performing function in the context of pain processing. Particular emphasis is placed on the cellular and molecular changes after nerve injury as well as different models of inflammatory and neuropathic pain. These were considered as the potential molecular bases that underlie nerve injury-associated pathogenesis of CRPS.

Effects of cardiopulmonary baroreceptor activation on pain may be moderated by risk for hypertension.

PubMed

Ditto, Blaine; Lewkowski, Maxim D; Rainville, Pierre; Duncan, Gary H

2009-10-01

Cardiopulmonary baroreceptor stimulation may modulate pain, though the literature is much smaller than research showing that sinoaortic baroreceptor stimulation can buffer pain. To examine the possibility that risk for established high blood pressure may moderate the effects of cardiopulmonary baroreceptor stimulation on pain, 22 borderline hypertensive and 18 normotensive men participated in a laboratory experiment. Group differences in blood pressure were documented by 24-h ambulatory blood pressure recording. Ratings of the intensity of acute heat pain were influenced by both group membership and leg position. Passive elevation of the legs, a technique that stimulates cardiopulmonary baroreceptors, reduced ratings of heat pain though only among borderline hypertensives. Alteration of pain sensitivity may reflect the development of the hypertensive process.

Sensitization of the Nociceptive System in Complex Regional Pain Syndrome

PubMed Central

Diedrichs, Carolina; Baron, Ralf; Gierthmühlen, Janne

2016-01-01

Background Complex regional pain syndrome type I (CRPS-I) is characterized by sensory, motor and autonomic abnormalities without electrophysiological evidence of a nerve lesion. Objective Aims were to investigate how sensory, autonomic and motor function change in the course of the disease. Methods 19 CRPS-I patients (17 with acute, 2 with chronic CRPS, mean duration of disease 5.7±8.3, range 1–33 months) were examined with questionnaires (LANSS, NPS, MPI, Quick DASH, multiple choice list of descriptors for sensory, motor, autonomic symptoms), motor and autonomic tests as well as quantitative sensory testing according to the German Research Network on Neuropathic Pain at two visits (baseline and 36±10.6, range 16–53 months later). Results CRPS-I patients had an improvement of sudomotor and vasomotor function, but still a great impairment of sensory and motor function upon follow-up. Although pain and mechanical detection improved upon follow-up, thermal and mechanical pain sensitivity increased, including the contralateral side. Increase in mechanical pain sensitivity and loss of mechanical detection were associated with presence of ongoing pain. Conclusions The results demonstrate that patients with CRPS-I show a sensitization of the nociceptive system in the course of the disease, for which ongoing pain seems to be the most important trigger. They further suggest that measured loss of function in CRPS-I is due to pain-induced hypoesthesia rather than a minimal nerve lesion. In conclusion, this article gives evidence for a pronociceptive pain modulation profile developing in the course of CRPS and thus helps to assess underlying mechanisms of CRPS that contribute to the maintenance of patients’ pain and disability. PMID:27149519

Transcranial Direct Current Stimulation (tDCS) Targeting Left Dorsolateral Prefrontal Cortex Modulates Task-Induced Acute Pain in Healthy Volunteers.

PubMed

Mariano, Timothy Y; Van't Wout, Mascha; Garnaat, Sarah L; Rasmussen, Steven A; Greenberg, Benjamin D

2016-04-01

Current chronic pain treatments target nociception rather than affective "suffering" and its associated functional and psychiatric comorbidities. The left dorsolateral prefrontal cortex (DLPFC) has been implicated in affective, cognitive, and attentional aspects of pain and is a primary target of neuromodulation for affective disorders. Transcranial direct current stimulation (tDCS) can non-invasively modulate cortical activity. The present study tests whether anodal tDCS targeting the left DLPFC will increase tolerability of acute painful stimuli vs cathodal tDCS. Forty tDCS-naive healthy volunteers received anodal and cathodal stimulation targeting the left DLPFC in two randomized and counterbalanced sessions. During stimulation, each participant performed cold pressor (CP) and breath holding (BH) tasks. We measured pain intensity with the Defense and Veterans Pain Rating Scale (DVPRS) before and after each task. Mixed ANOVA revealed no main effect of stimulation polarity for mean CP threshold, tolerance, or endurance, or mean BH time (allP > 0.27). However, DVPRS rise associated with CP was significantly smaller with anodal vs cathodal tDCS (P = 0.024). We further observed a significant tDCS polarity × stimulation order interaction (P = 0.042) on CP threshold, suggesting task sensitization. Although our results do not suggest that polarity of tDCS targeting the left DLPFC differentially modulates the tolerability of CP- and BH-related pain distress in healthy volunteers, there was a significant effect on DVPRS pain ratings. This contrasts with our previous findings that tDCS targeting the left dorsal anterior cingulate cortex showed a trend toward higher mean CP tolerance with cathodal vs anodal stimulation. The present results may suggest tDCS-related effects on nociception or DLPFC-mediated attention, or preferential modulation of the affective valence of pain as captured by the DVPRS. Sham-controlled clinical studies are needed. © 2015 American Academy of Pain Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Is altered central pain processing related to disease stage in chronic pancreatitis patients with pain? An exploratory study.

PubMed

Bouwense, Stefan A W; Olesen, Søren S; Drewes, Asbjørn M; Frøkjær, Jens B; van Goor, Harry; Wilder-Smith, Oliver H G

2013-01-01

The most dominant feature in chronic pancreatitis is intense abdominal pain. Changes in spinal and/or supraspinal central nervous system pain processing due to visceral nociceptive input play an important role in this pain. How altered pain processing is related to disease stage still needs study. Sixty chronic pancreatitis patients were compared to 15 healthy controls. Two subgroups of pancreatitis patients were defined based on the M-ANNHEIM severity index of chronic pancreatitis; i.e. moderate and severe. Pain detection and tolerance thresholds for pressure and electric stimuli were measured in six selected dermatomes (C5, T4, T10, L1, L4 and T10BACK). In addition, the conditioned pain modulation response to cold pressor task was determined. These measures were compared between the healthy controls and chronic pancreatitis patients. Severe pancreatitis patients showed lower pain thresholds than moderate pancreatitis patients or healthy volunteers. Healthy controls showed a significantly larger conditioned pain modulation response compared to all chronic pancreatitis patients taken together. The present study confirms that chronic pancreatitis patients show signs of altered central processing of nociception compared to healthy controls. The study further suggests that these changes, i.e. central sensitization, may be influenced by disease stage. These findings underline the need to take altered central pain processing into account when managing the pain of chronic pancreatitis.

Relationship Between ABCB1 Polymorphisms and Cold Pain Sensitivity Among Healthy Opioid-naive Malay Males.

PubMed

Zahari, Zalina; Lee, Chee Siong; Ibrahim, Muslih Abdulkarim; Musa, Nurfadhlina; Mohd Yasin, Mohd Azhar; Lee, Yeong Yeh; Tan, Soo Choon; Mohamad, Nasir; Ismail, Rusli

2017-09-01

Endogenous and exogenous opioids are substrates of the permeability glycoprotein (P-gp) efflux transporter, which is encoded by the ABCB1 (MDR1) gene. Genetic polymorphisms of ABCB1 may contribute to interindividual differences in pain modulation and analgesic responses. We investigated the relationship between ABCB1 polymorphisms and cold pain sensitivity among healthy males. Cold pain responses, including pain threshold and pain tolerance, were measured using the cold-pressor test (CPT). DNA was extracted from whole blood and genotyped for ABCB1 polymorphisms, including c.1236C>T (rs1128503), c.2677G>T/A (rs2032582), and c.3435C>T (rs1045642), using the allelic discrimination real-time polymerase chain reaction. A total of 152 participants were recruited in this observational study. Frequencies of mutated allele for c.1236C>T, c.2677G>T/A, and c.3435C>T polymorphisms were 56.6%, 49.7%, and 43.4%, respectively. Our results revealed an association of the CGC/CGC diplotype (c.1236C>T, c.2677G>T/A, and c.3435C>T) with cold pain sensitivity. Participants with the CGC/CGC diplotype had 90% and 72% higher cold pain thresholds (87.62 seconds vs. 46.19 seconds, P = 0.010) and cold pain tolerances (97.24 seconds vs. 56.54 seconds, P = 0.021), respectively, when compared with those without the diplotype. The CGC/CGC diplotype of ABCB1 polymorphisms was associated with variability in cold pain threshold and pain tolerance in healthy males. © 2016 World Institute of Pain.

Somatosensory nociceptive characteristics differentiate subgroups in people with chronic low back pain: a cluster analysis.

PubMed

Rabey, Martin; Slater, Helen; OʼSullivan, Peter; Beales, Darren; Smith, Anne

2015-10-01

The objectives of this study were to explore the existence of subgroups in a cohort with chronic low back pain (n = 294) based on the results of multimodal sensory testing and profile subgroups on demographic, psychological, lifestyle, and general health factors. Bedside (2-point discrimination, brush, vibration and pinprick perception, temporal summation on repeated monofilament stimulation) and laboratory (mechanical detection threshold, pressure, heat and cold pain thresholds, conditioned pain modulation) sensory testing were examined at wrist and lumbar sites. Data were entered into principal component analysis, and 5 component scores were entered into latent class analysis. Three clusters, with different sensory characteristics, were derived. Cluster 1 (31.9%) was characterised by average to high temperature and pressure pain sensitivity. Cluster 2 (52.0%) was characterised by average to high pressure pain sensitivity. Cluster 3 (16.0%) was characterised by low temperature and pressure pain sensitivity. Temporal summation occurred significantly more frequently in cluster 1. Subgroups were profiled on pain intensity, disability, depression, anxiety, stress, life events, fear avoidance, catastrophizing, perception of the low back region, comorbidities, body mass index, multiple pain sites, sleep, and activity levels. Clusters 1 and 2 had a significantly greater proportion of female participants and higher depression and sleep disturbance scores than cluster 3. The proportion of participants undertaking <300 minutes per week of moderate activity was significantly greater in cluster 1 than in clusters 2 and 3. Low back pain, therefore, does not appear to be homogeneous. Pain mechanisms relating to presentations of each subgroup were postulated. Future research may investigate prognoses and interventions tailored towards these subgroups.

Neuron-Glia Crosstalk and Neuropathic Pain: Involvement in the Modulation of Motor Activity in the Orofacial Region.

PubMed

Hossain, Mohammad Zakir; Unno, Shumpei; Ando, Hiroshi; Masuda, Yuji; Kitagawa, Junichi

2017-09-26

Neuropathic orofacial pain (NOP) is a debilitating condition. Although the pathophysiology remains unclear, accumulating evidence suggests the involvement of multiple mechanisms in the development of neuropathic pain. Recently, glial cells have been shown to play a key pathogenetic role. Nerve injury leads to an immune response near the site of injury. Satellite glial cells are activated in the peripheral ganglia. Various neural and immune mediators, released at the central terminals of primary afferents, lead to the sensitization of postsynaptic neurons and the activation of glia. The activated glia, in turn, release pro-inflammatory factors, further sensitizing the neurons, and resulting in central sensitization. Recently, we observed the involvement of glia in the alteration of orofacial motor activity in NOP. Microglia and astroglia were activated in the trigeminal sensory and motor nuclei, in parallel with altered motor functions and a decreased pain threshold. A microglial blocker attenuated the reduction in pain threshold, reduced the number of activated microglia, and restored motor activity. We also found an involvement of the astroglial glutamate-glutamine shuttle in the trigeminal motor nucleus in the alteration of the jaw reflex. Neuron-glia crosstalk thus plays an important role in the development of pain and altered motor activity in NOP.

Neuron–Glia Crosstalk and Neuropathic Pain: Involvement in the Modulation of Motor Activity in the Orofacial Region

PubMed Central

Unno, Shumpei; Ando, Hiroshi; Masuda, Yuji; Kitagawa, Junichi

2017-01-01

Neuropathic orofacial pain (NOP) is a debilitating condition. Although the pathophysiology remains unclear, accumulating evidence suggests the involvement of multiple mechanisms in the development of neuropathic pain. Recently, glial cells have been shown to play a key pathogenetic role. Nerve injury leads to an immune response near the site of injury. Satellite glial cells are activated in the peripheral ganglia. Various neural and immune mediators, released at the central terminals of primary afferents, lead to the sensitization of postsynaptic neurons and the activation of glia. The activated glia, in turn, release pro-inflammatory factors, further sensitizing the neurons, and resulting in central sensitization. Recently, we observed the involvement of glia in the alteration of orofacial motor activity in NOP. Microglia and astroglia were activated in the trigeminal sensory and motor nuclei, in parallel with altered motor functions and a decreased pain threshold. A microglial blocker attenuated the reduction in pain threshold, reduced the number of activated microglia, and restored motor activity. We also found an involvement of the astroglial glutamate–glutamine shuttle in the trigeminal motor nucleus in the alteration of the jaw reflex. Neuron–glia crosstalk thus plays an important role in the development of pain and altered motor activity in NOP. PMID:28954391

Transcranial Direct Current Stimulation (tDCS) Targeting Left Dorsolateral Prefrontal Cortex Modulates Task-Induced Acute Pain in Healthy Volunteers

PubMed Central

Mariano, Timothy Y.; Wout, Mascha van't; Garnaat, Sarah L.; Rasmussen, Steven A.; Greenberg, Benjamin D.

2016-01-01

Objective Current chronic pain treatments target nociception rather than affective “suffering” and its associated functional and psychiatric comorbidities. Left dorsolateral prefrontal cortex (DLPFC) has been implicated in affective, cognitive, and attentional aspects of pain and is a primary target of neuromodulation for affective disorders. Transcranial direct current stimulation (tDCS) can noninvasively modulate cortical activity. The present study tests if anodal tDCS targeting left DLPFC will increase tolerability of acute painful stimuli versus cathodal tDCS. Methods Forty tDCS-naive healthy volunteers received anodal and cathodal stimulation targeting left DLPFC in two randomized and counterbalanced sessions. During stimulation, each participant performed cold pressor (CP) and breath holding (BH) tasks. We measured pain intensity with the Defense and Veterans Pain Rating Scale (DVPRS) before and after each task. Results Mixed ANOVA revealed no main effect of stimulation polarity for mean CP threshold, tolerance, or endurance, or mean BH time (all p > 0.27). However, DVPRS rise associated with CP was significantly smaller with anodal versus cathodal tDCS (p = 0.024). We further observed a significant tDCS polarity × stimulation order interaction (p = 0.042) on CP threshold suggesting task sensitization. Conclusions Although our results do not suggest that polarity of tDCS targeting left DLPFC differentially modulates tolerability of CP- and BH-related pain distress in healthy volunteers, there was a significant effect on DVPRS pain ratings. This contrasts with our previous findings that tDCS targeting left dorsal anterior cingulate cortex showed a trend towards higher mean CP tolerance with cathodal versus anodal stimulation. The present results may suggest tDCS-related effects on nociception or DLPFC-mediated attention, or preferential modulation of the affective valence of pain as captured by DVPRS. Sham-controlled clinical studies are needed. PMID:26814276

Joint Mobilization Enhances Mechanisms of Conditioned Pain Modulation in Individuals With Osteoarthritis of the Knee.

PubMed

Courtney, Carol A; Steffen, Alana D; Fernández-de-Las-Peñas, César; Kim, John; Chmell, Samuel J

2016-03-01

An experimental laboratory study with a repeated-measures crossover design. Treatment effects of joint mobilization may occur in part by decreasing excitability of central nociceptive pathways. Impaired conditioned pain modulation (CPM) has been found experimentally in persons with knee and hip osteoarthritis, indicating impaired inhibition of central nociceptive pathways. We hypothesized increased effectiveness of CPM following application of joint mobilization, determined via measures of deep tissue hyperalgesia. To examine the effect of joint mobilization on impaired CPM. An examination of 40 individuals with moderate/severe knee osteoarthritis identified 29 (73%) with impaired CPM. The subjects were randomized to receive 6 minutes of knee joint mobilization (intervention) or manual cutaneous input only, 1 week apart. Deep tissue hyperalgesia was examined via pressure pain thresholds bilaterally at the knee medial joint line and the hand at baseline, postintervention, and post-CPM testing. Further, vibration perception threshold was measured at the medial knee epicondyle at baseline and post-CPM testing. Joint mobilization, but not cutaneous input intervention, resulted in a global increase in pressure pain threshold, indicated by diminished hyperalgesic responses to pressure stimulus. Further, CPM was significantly enhanced following joint mobilization. Diminished baseline vibration perception threshold acuity was enhanced following joint mobilization at the knee that received intervention, but not at the contralateral knee. Resting pain was also significantly lower following the joint intervention. Conditioned pain modulation was enhanced following joint mobilization, demonstrated by a global decrease in deep tissue pressure sensitivity. Joint mobilization may act via enhancement of descending pain mechanisms in patients with painful knee osteoarthritis.

Dynamic Pain Phenotypes are Associated with Spinal Cord Stimulation-Induced Reduction in Pain: A Repeated Measures Observational Pilot Study.

PubMed

Campbell, Claudia M; Buenaver, Luis F; Raja, Srinivasa N; Kiley, Kasey B; Swedberg, Lauren J; Wacnik, Paul W; Cohen, Steven P; Erdek, Michael A; Williams, Kayode A; Christo, Paul J

2015-07-01

Spinal cord stimulation (SCS) has become a widely used treatment option for a variety of pain conditions. Substantial variability exists in the degree of benefit obtained from SCS and patient selection is a topic of expanding interest and importance. However, few studies have examined the potential benefits of dynamic quantitative sensory testing (QST) to develop objective measures of SCS outcomes or as a predictive tool to help patient selection. Psychological characteristics have been shown to play an important role in shaping individual differences in the pain experience and may aid in predicting responses to SCS. Static laboratory pain-induction measures have also been examined in their capacity for predicting SCS outcomes. The current study evaluated clinical, psychological and laboratory pain measures at baseline, during trial SCS lead placement, as well as 1 month and 3 months following permanent SCS implantation in chronic pain patients who received SCS treatment. Several QST measures were conducted, with specific focus on examination of dynamic models (central sensitization and conditioned pain modulation [CPM]) and their association with pain outcomes 3 months post SCS implantation. Results suggest few changes in QST over time. However, central sensitization and CPM at baseline were significantly associated with clinical pain at 3 months following SCS implantation, controlling for psycho/behavioral factors and pain at baseline. Specifically, enhanced central sensitization and reduced CPM were associated with less self-reported pain 3 months following SCS implantation. These findings suggest a potentially important role for dynamic pain assessment in individuals undergoing SCS, and hint at potential mechanisms through which SCS may impart its benefit. Wiley Periodicals, Inc.

Effects of music engagement on responses to painful stimulation.

PubMed

Bradshaw, David H; Chapman, C Richard; Jacobson, Robert C; Donaldson, Gary W

2012-06-01

We propose a theoretical framework for the behavioral modulation of pain based on constructivism, positing that task engagement, such as listening for errors in a musical passage, can establish a construction of reality that effectively replaces pain as a competing construction. Graded engagement produces graded reductions in pain as indicated by reduced psychophysiological arousal and subjective pain report. Fifty-three healthy volunteers having normal hearing participated in 4 music listening conditions consisting of passive listening (no task) or performing an error detection task varying in signal complexity and task difficulty. During all conditions, participants received normally painful fingertip shocks varying in intensity while stimulus-evoked potentials (SEP), pupil dilation responses (PDR), and retrospective pain reports were obtained. SEP and PDR increased with increasing stimulus intensity. Task performance decreased with increasing task difficulty. Mixed model analyses, adjusted for habituation/sensitization and repeated measures within person, revealed significant quadratic trends for SEP and pain report (Pchange<0.001) with large reductions from no task to easy task and smaller graded reductions corresponding to increasing task difficulty/complexity. PDR decreased linearly (Pchange<0.001) with graded task condition. We infer that these graded reductions in indicators of central and peripheral arousal and in reported pain correspond to graded increases in engagement in the music listening task. Engaging activities may prevent pain by creating competing constructions of reality that draw on the same processing resources as pain. Better understanding of these processes will advance the development of more effective pain modulation through improved manipulation of engagement strategies.

Neurophysiology of pruritus: interaction of itch and pain.

PubMed

Ikoma, Akihiko; Rukwied, Roman; Ständer, Sonja; Steinhoff, Martin; Miyachi, Yoshiki; Schmelz, Martin

2003-11-01

The discovery of an itch-specific neuronal pathway, which is distinct from the pain-processing pathway, has clarified the neuronal basis for the itch sensation. Albeit being distinct, there are complex interactions between pain and itch. The inhibition of itch by pain is well known and can explain the antipruritic effect of scratching. However, the opposite effect also exists and has major clinical implications: inhibition of pain processing (eg, by spinal opioids) can generate itch. Conversely, blockade of spinal opioid receptors can be used as an antipruritic therapy. Moreover, the spinal processing of pain and itch can be modulated, resulting in a hypersensitivity or hyposensitivity to pain or itch: similar to chronic painful conditions, ongoing activity of pruriceptors can induce a spinal hypersensitivity for itch in patients with chronic pruritus. Therapeutic antipruritic approaches therefore should target both local inflammation and spinal sensitization of itch processing.

Redox modulation of A-type K+ currents in pain-sensing dorsal root ganglion neurons.

PubMed

Hsieh, Chi-Pan

2008-06-06

Redox modulation of fast inactivation has been described in certain cloned A-type voltage-gated K(+) (Kv) channels in expressing systems, but the effects remain to be demonstrated in native neurons. In this study, we examined the effects of cysteine-specific redox agents on the A-type K(+) currents in acutely dissociated small diameter dorsal root ganglion (DRG) neurons from rats. The fast inactivation of most A-type currents was markedly removed or slowed by the oxidizing agents 2,2'-dithio-bis(5-nitropyridine) (DTBNP) and chloramine-T. Dithiothreitol, a reducing agent for the disulfide bond, restored the inactivation. These results demonstrated that native A-type K(+) channels, probably Kv1.4, could switch the roles between inactivating and non-inactivating K(+) channels via redox regulation in pain-sensing DRG neurons. The A-type channels may play a role in adjusting pain sensitivity in response to peripheral redox conditions.

Effect of commensals and probiotics on visceral sensitivity and pain in irritable bowel syndrome

PubMed Central

Theodorou, Vassilia; Belgnaoui, Afifa Ait; Agostini, Simona; Eutamene, Helene

2014-01-01

The last ten years’ wide progress in the gut microbiota phylogenetic and functional characterization has been made evidencing dysbiosis in several gastrointestinal diseases including inflammatory bowel diseases and irritable bowel syndrome (IBS). IBS is a functional gut disease with high prevalence and negative impact on patient’s quality of life characterized mainly by visceral pain and/or discomfort, representing a good paradigm of chronic gut hypersensitivity. The IBS features are strongly regulated by bidirectional gut-brain interactions and there is increasing evidence for the involvement of gut bacteria and/or their metabolites in these features, including visceral pain. Further, gut microbiota modulation by antibiotics or probiotics has been promising in IBS. Mechanistic data provided mainly by animal studies highlight that commensals or probiotics may exert a direct action through bacterial metabolites on sensitive nerve endings in the gut mucosa, or indirect pathways targeting the intestinal epithelial barrier, the mucosal and/or systemic immune activation, and subsequent neuronal sensitization and/or activation. PMID:25184834

The Analgesic and Anxiolytic Effect of Souvenaid, a Novel Nutraceutical, Is Mediated by Alox15 Activity in the Prefrontal Cortex.

PubMed

Shalini, Suku-Maran; Herr, Deron R; Ong, Wei-Yi

2017-10-01

Pain and anxiety have a complex relationship and pain is known to share neurobiological pathways and neurotransmitters with anxiety. Top-down modulatory pathways of pain have been shown to originate from cortical and subcortical regions, including the dorsolateral prefrontal cortex. In this study, a novel docosahexaenoic acid (DHA)-containing nutraceutical, Souvenaid, was administered to mice with infraorbital nerve ligation-induced neuropathic pain and behavioral responses recorded. Infraorbital nerve ligation resulted in increased face wash strokes of the face upon von Frey hair stimulation, indicating increased nociception. Part of this response involves general pain sensitization that is dependent on the CNS, since increased nociception was also found in the paws during the hot plate test. Mice receiving oral gavage of Souvenaid, a nutraceutical containing DHA; choline; and other cell membrane components, showed significantly reduced pain sensitization. The mechanism of Souvenaid's activity involves supraspinal antinociception, originating in the prefrontal cortex, since inhibition of the DHA-metabolizing enzyme 15-lipoxygenase (Alox15) in the prefrontal cortex attenuated the antinociceptive effect of Souvenaid. Alox15 inhibition also modulated anxiety behavior associated with pain after infraorbital nerve ligation. The effects of Souvenaid components and Alox15 on reducing central sensitization of pain may be due to strengthening of a known supraspinal antinociceptive pathway from the prefrontal cortex to the periaqueductal gray. Together, results indicate the importance of the prefrontal cortex and DHA/Alox15 in central antinociceptive pathways and suggest that Souvenaid may be a novel therapeutic for neuropathic pain.

Biopsychosocial influence on shoulder pain: risk subgroups translated across preclinical and clinical prospective cohorts

PubMed Central

George, Steven Z.; Wallace, Margaret R.; Wu, Samuel S.; Moser, Michael W.; Wright, Thomas W.; Farmer, Kevin W.; Borsa, Paul A.; Parr, Jeffrey J.; Greenfield, Warren H.; Dai, Yunfeng; Li, Hua; Fillingim, Roger B.

2016-01-01

Tailored treatment based on individual risk factors is an area with promise to improve options for pain relief. Musculoskeletal pain has a biopsychosocial nature, and multiple factors should be considered when determining risk for chronic pain. This study investigated whether subgroups comprised genetic and psychological factors predicted outcomes in preclinical and clinical models of shoulder pain. Classification and regression tree analysis was performed for an exercise-induced shoulder injury cohort (n = 190) to identify high-risk subgroups, and a surgical pain cohort (n = 150) was used for risk validation. Questionnaires for fear of pain and pain catastrophizing were administered before injury and preoperatively. DNA collected from saliva was genotyped for a priori selected genes involved with pain modulation (COMT and AVPR1A) and inflammation (IL1B and TNF/LTA). Recovery was operationalized as a brief pain inventory rating of 0/10 for current pain intensity and <2/10 for worst pain intensity. Follow-up for the preclinical cohort was in daily increments, whereas follow-up for the clinical cohort was at 3, 6, and 12 months postoperatively. Risk subgroups comprised the COMT high pain sensitivity variant and either pain catastrophizing or fear of pain were predictive of heightened shoulder pain responses in the preclinical model. Further analysis in the clinical model identified the COMT high pain sensitivity variant and pain catastrophizing subgroup as the better predictor. Future studies will determine whether these findings can be replicated in other anatomical regions and whether personalized medicine strategies can be developed for this risk subgroup. PMID:25599310

Electrical stimulation of the insular cortex as a novel target for the relief of refractory pain: An experimental approach in rodents.

PubMed

Dimov, Luiz Fabio; Toniolo, Elaine Flamia; Alonso-Matielo, Heloísa; de Andrade, Daniel Ciampi; Garcia-Larrea, Luis; Ballester, Gerson; Teixeira, Manoel Jacobsen; Dale, Camila Squarzoni

2018-07-02

Cortical electrical stimulation (CES) has shown to be an effective therapeutic alternative for neuropathic pain refractory to pharmacological treatment. The primary motor cortex(M1) was the main cortical target used in the vast majority of both invasive and non-invasive studies. Despite positive results M1-based approaches still fail to relieve pain in a significant proportion of individuals. It has been advocated that the direct stimulation of cortical areas directly implicated in the central integration of pain could increase the efficacy of analgesic brain stimulation. Here, we evaluated the behavioral effects of electrical stimulation of the insular cortex (ESI) on pain sensitivity in an experimental rat model of peripheral neuropathy, and have described the pathways involved. Animals underwent chronic constriction of the sciatic nerve in the right hind limb and had concentric electrodes implanted in the posterior dysranular insular cortex. Mechanical nociception responses were evaluated before and at the end of a 15-min session of ESI (60Hz, 210μs, 1V). ESI reversed mechanical hypersensitivity in the paw contralateral to the brain hemisphere stimulated, without inducing motor impairment in the open-field test. Pharmacological blockade of μ-opioid (MOR) or type 1-cannabinoid receptors (CB1R) abolished ESI-induced antinociceptive effects. Evaluation of CB1R and MOR spatial expression demonstrated differential modulation of CB1R and MOR in the periaqueductal gray matter (PAG) of ESI-treated rats in sub-areas involved in pain processing/modulation. These results indicate that ESI induces antinociception by functionally modulating opioid and cannabinoid systems in the PAG pain circuitry in rats with experimentally induced neuropathic pain. Copyright © 2017 Elsevier B.V. All rights reserved.

Bifidobacteria modulate cognitive processes in an anxious mouse strain.

PubMed

Savignac, H M; Tramullas, M; Kiely, B; Dinan, T G; Cryan, J F

2015-01-01

Increasing evidence suggests that a brain-gut-microbiome axis exists, which has the potential to play a major role in modulating behaviour. However, the role of this axis in cognition remains relatively unexplored. Probiotics, which are commensal bacteria offering potential health benefit, have been shown to decrease anxiety, depression and visceral pain-related behaviours. In this study, we investigate the potential of two Bifidobacteria strains to modulate cognitive processes and visceral pain sensitivity. Adult male BALB/c mice were fed daily for 11 weeks with B. longum 1714, B. breve 1205 or vehicle treatment. Starting at week 4, animals were behaviourally assessed in a battery of tests relevant to different aspects of cognition, as well as locomotor activity and visceral pain. In the object recognition test, B. longum 1714-fed mice discriminated between the two objects faster than all other groups and B. breve 1205-fed mice discriminated faster than vehicle animals. In the Barnes maze, B. longum 1714-treated mice made fewer errors than other groups, suggesting a better learning. In the fear conditioning, B. longum 1714-treated group also showed better learning and memory, yet presenting the same extinction learning profile as controls. None of the treatments affected visceral sensitivity. Altogether, these data suggest that B. longum 1714 had a positive impact on cognition and also that the effects of individual Bifidobacteria strains do not generalise across the species. Clinical validation of the effects of probiotics on cognition is now warranted. Copyright © 2015 Elsevier B.V. All rights reserved.

Endogenous Opioid Antagonism in Physiological Experimental Pain Models: A Systematic Review

PubMed Central

Werner, Mads U.; Pereira, Manuel P.; Andersen, Lars Peter H.; Dahl, Jørgen B.

2015-01-01

Opioid antagonists are pharmacological tools applied as an indirect measure to detect activation of the endogenous opioid system (EOS) in experimental pain models. The objective of this systematic review was to examine the effect of mu-opioid-receptor (MOR) antagonists in placebo-controlled, double-blind studies using ʻinhibitoryʼ or ʻsensitizingʼ, physiological test paradigms in healthy human subjects. The databases PubMed and Embase were searched according to predefined criteria. Out of a total of 2,142 records, 63 studies (1,477 subjects [male/female ratio = 1.5]) were considered relevant. Twenty-five studies utilized ʻinhibitoryʼ test paradigms (ITP) and 38 studies utilized ʻsensitizingʼ test paradigms (STP). The ITP-studies were characterized as conditioning modulation models (22 studies) and repetitive transcranial magnetic stimulation models (rTMS; 3 studies), and, the STP-studies as secondary hyperalgesia models (6 studies), ʻpainʼ models (25 studies), summation models (2 studies), nociceptive reflex models (3 studies) and miscellaneous models (2 studies). A consistent reversal of analgesia by a MOR-antagonist was demonstrated in 10 of the 25 ITP-studies, including stress-induced analgesia and rTMS. In the remaining 14 conditioning modulation studies either absence of effects or ambiguous effects by MOR-antagonists, were observed. In the STP-studies, no effect of the opioid-blockade could be demonstrated in 5 out of 6 secondary hyperalgesia studies. The direction of MOR-antagonist dependent effects upon pain ratings, threshold assessments and somatosensory evoked potentials (SSEP), did not appear consistent in 28 out of 32 ʻpainʼ model studies. In conclusion, only in 2 experimental human pain models, i.e., stress-induced analgesia and rTMS, administration of MOR-antagonist demonstrated a consistent effect, presumably mediated by an EOS-dependent mechanisms of analgesia and hyperalgesia. PMID:26029906

Neuroimmune interactions in itch: Do chronic itch, chronic pain, and chronic cough share similar mechanisms?

PubMed

Ji, Ru-Rong

2015-12-01

Itch and pain are closely related but also clearly distinct sensations. Pain is known to suppress itch, while analgesics such as morphine can provoke itch. However, in pathological and chronic conditions, pain and itch also have similarities. Dysfunction of the nervous system, as manifested by neural plastic changes in primary sensory neurons of the peripheral nervous system (peripheral sensitization) and spinal cord and brain stem neurons in the central nervous system (central sensitization) will result in chronic pain and itch. Importantly, these diseases also result from immune dysfunction, since inflammatory mediators can directly activate or sensitize nociceptive and pruriceptive neurons in the peripheral and central nervous system, leading to pain and itch hypersensitivity. In this mini-review, I discuss the roles of Toll-like receptors (TLRs), transient receptor potential ankyrin 1 (TRPA1) ion channel, and Nav1.7 sodium channel in regulating itch and inflammation, with special emphasis of neuronal TLR signaling and the interaction of TLR7 and TRPA1. Chronic pain and chronic itch are debilitating diseases and dramatically impact the life quality of patients. Targeting TLRs for the control of inflammation, neuroinflammation (inflammation restricted in the nervous system), and hyperexcitability of nociceptors and pruriceptors will lead to new therapeutics for the relief of chronic pain and chronic itch. Finally, given the shared mechanisms among chronic cough, chronic pain, and chronic itch and the demonstrated efficacy of the neuropathic pain drug gabapentin in treating chronic cough, novel therapeutics targeting TRPA1, Nav1.7, and TLRs may also help to alleviate refractory cough via modulating neuron-immune interaction. Copyright © 2015 Elsevier Ltd. All rights reserved.

The Pain System in Oesophageal Disorders: Mechanisms, Clinical Characteristics, and Treatment

PubMed Central

Lottrup, Christian; Olesen, Søren Schou; Drewes, Asbjørn Mohr

2011-01-01

Pain is common in gastroenterology. This review aims at giving an overview of pain mechanisms, clinical features, and treatment options in oesophageal disorders. The oesophagus has sensory receptors specific for different stimuli. Painful stimuli are encoded by nociceptors and communicated via afferent nerves to the central nervous system. The pain stimulus is further processed and modulated in specific pain centres in the brain, which may undergo plastic alterations. Hence, tissue inflammation and long-term exposure to pain can cause sensitisation and hypersensitivity. Oesophageal sensitivity can be evaluated ,for example, with the oesophageal multimodal probe. Treatment should target the cause of the patient's symptoms. In gastro-oesophageal reflux diseases, proton pump inhibitors are the primary treatment option, surgery being reserved for patients with severe disease resistant to drug therapy. Functional oesophageal disorders are treated with analgesics, antidepressants, and psychological therapy. Lifestyle changes are another option with less documentation. PMID:21826137

Insights into the mechanisms and the emergence of sex-differences in pain.

PubMed

Melchior, Meggane; Poisbeau, Pierrick; Gaumond, Isabelle; Marchand, Serge

2016-12-03

Recent studies describe sex and gender as critical factors conditioning the experience of pain and the strategies to respond to it. It is now clear that men and women have different physiological and behavioral responses to pain. Some pathological pain states are also highly sex-specific. This clinical observation has been often verified with animal studies which helped to decipher the mechanisms underlying the observed female hyper-reactivity and hyper-sensitivity to pain states. The role of gonadal hormones in the modulation of pain responses has been a straightforward hypothesis but, if pertinent in many cases, cannot fully account for this complex sensation, which includes an important cognitive component. Clinical and fundamental data are reviewed here with a special emphasis on possible developmental processes giving rise to sex-differences in pain processing. Copyright © 2016 IBRO. Published by Elsevier Ltd. All rights reserved.

Effects of stress and relaxation on pain perception in subjects with pain-free occlusional disharmony compared with healthy controls.

PubMed

Ruscheweyh, R; Becker, T; Born, Y; Çolak-Ekici, R; Marziniak, M; Evers, S; Gerlach, A L; Wolowski, A

2015-04-01

The significance of occlusal disharmony for the development of painful temporomandibular disorder (TMD) is controversial. The ongoing biomechanical strain caused by occlusal disharmony might lead to sensitization processes in the nociceptive system. Understanding these processes might be an important step toward understanding the possible relationship between occlusal disharmony and TMD. In this study, we therefore investigated whether subjects with occlusal disharmony (n = 22) differ from healthy controls (n = 26) in their pain perception and pain modulation by stress and relaxation. Trigeminal and extratrigeminal experimental pain perception (pinprick, heat, and pressure pain) was assessed before and after stress (mental arithmetic) and relaxation (viewing of low-arousal pictures). There were no group differences in pain perception at baseline or during the stress task. Compared with controls, the occlusal disharmony group exhibited an inadequate reduction in pain perception during relaxation, which was significant for the extratrigeminal site (P < 0.01) and reached a trend for significance at the trigeminal site (P = 0.1). These results suggest that subjects with occlusal disharmony show signs of disturbed endogenous pain inhibition during relaxation. There is evidence for the presence of sensitization of the nociceptive system in subjects with occlusal disharmony. Possibly, deficient inhibition of extratrigeminal and trigeminal pain perception by relaxation might contribute to the development of TMD or other chronic pain disorders. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Growth hormone regulates the sensitization of developing peripheral nociceptors during cutaneous inflammation.

PubMed

Liu, Xiaohua; Green, Kathryn J; Ford, Zachary K; Queme, Luis F; Lu, Peilin; Ross, Jessica L; Lee, Frank B; Shank, Aaron T; Hudgins, Renita C; Jankowski, Michael P

2017-02-01

Cutaneous inflammation alters the function of primary afferents and gene expression in the affected dorsal root ganglia (DRG). However, specific mechanisms of injury-induced peripheral afferent sensitization and behavioral hypersensitivity during development are not fully understood. Recent studies in children suggest a potential role for growth hormone (GH) in pain modulation. Growth hormone modulates homeostasis and tissue repair after injury, but how GH affects nociception in neonates is not known. To determine whether GH played a role in modulating sensory neuron function and hyperresponsiveness during skin inflammation in young mice, we examined behavioral hypersensitivity and the response properties of cutaneous afferents using an ex vivo hairy skin-saphenous nerve-DRG-spinal cord preparation. Results show that inflammation of the hairy hind paw skin initiated at either postnatal day 7 (P7) or P14 reduced GH levels specifically in the affected skin. Furthermore, pretreatment of inflamed mice with exogenous GH reversed mechanical and thermal hypersensitivity in addition to altering nociceptor function. These effects may be mediated through an upregulation of insulin-like growth factor 1 receptor (IGFr1) as GH modulated the transcriptional output of IGFr1 in DRG neurons in vitro and in vivo. Afferent-selective knockdown of IGFr1 during inflammation also prevented the observed injury-induced alterations in cutaneous afferents and behavioral hypersensitivity similar to that after GH pretreatment. These results suggest that GH can block inflammation-induced nociceptor sensitization during postnatal development leading to reduced pain-like behaviors, possibly by suppressing the upregulation of IGFr1 within DRG.

Growth hormone regulates the sensitization of developing peripheral nociceptors during cutaneous inflammation

PubMed Central

Liu, Xiaohua; Green, Kathryn J.; Ford, Zachary K.; Queme, Luis F.; Lu, Peilin; Ross, Jessica L.; Lee, Frank B.; Shank, Aaron T.; Hudgins, Renita C.; Jankowski, Michael P.

2016-01-01

Cutaneous inflammation alters the function of primary afferents and gene expression in the affected dorsal root ganglia (DRGs). However specific mechanisms of injury-induced peripheral afferent sensitization and behavioral hypersensitivity during development are not fully understood. Recent studies in children suggest a potential role for growth hormone (GH) in pain modulation. GH modulates homeostasis and tissue repair after injury, but how GH effects nociception in neonates is not known. To determine if GH played a role in modulating sensory neuron function and hyper-responsiveness during skin inflammation in young mice, we examined behavioral hypersensitivity and the response properties of cutaneous afferents using an ex vivo hairy skin-saphenous nerve-dorsal root ganglion (DRG)-spinal cord preparation. Results show that inflammation of the hairy hindpaw skin initiated at either postnatal day 7 (P7) or P14 reduced GH levels specifically in the affected skin. Furthermore, pretreatment of inflamed mice with exogenous GH reversed mechanical and thermal hypersensitivity in addition to altering nociceptor function. These effects may be mediated via an upregulation of insulin-like growth factor 1 receptor (IGFr1) as GH modulated the transcriptional output of IGFr1 in DRG neurons in vitro and in vivo. Afferent-selective knockdown of IGFr1 during inflammation also prevented the observed injury-induced alterations in cutaneous afferents and behavioral hypersensitivity similar to that following GH pretreatment. These results suggest that GH can block inflammation-induced nociceptor sensitization during postnatal development leading to reduced pain-like behaviors, possibly by suppressing the upregulation of IGFr1 within DRGs. PMID:27898492

Sexually dimorphic effects of unpredictable early life adversity on visceral pain behavior in a rodent model.

PubMed

Chaloner, Aaron; Greenwood-Van Meerveld, Beverley

2013-03-01

Visceral pain is the hallmark feature of irritable bowel syndrome (IBS), a gastrointestinal disorder, which is more commonly diagnosed in women. Female IBS patients frequently report a history of early life adversity (ELA); however, sex differences in ELA-induced visceral pain and the role of ovarian hormones have yet to be investigated. Therefore, we tested the hypothesis that ELA induces visceral hypersensitivity through a sexually dimorphic mechanism mediated via estradiol. As a model of ELA, neonatal rats were exposed to different pairings of an odor and shock to control for trauma predictability. In adulthood, visceral sensitivity was assessed via a visceromotor response to colorectal distension. Following ovariectomy and estradiol replacement in a separate group of rats, the visceral sensitivity was quantified. We found that females that received unpredictable odor-shock developed visceral hypersensitivity in adulthood. In contrast, visceral sensitivity was not significantly different following ELA in adult males. Ovariectomy reversed visceral hypersensitivity following unpredictable ELA, whereas estradiol replacement reestablished visceral hypersensitivity in the unpredictable group. This study is the first to show sex-related differences in visceral sensitivity following unpredictable ELA. Our data highlight the activational effect of estradiol as a pivotal mechanism in maintaining visceral hypersensitivity. This article directly implicates a critical role for ovarian hormones in maintaining visceral hypersensitivity following ELA, specifically identifying the activational effect of estradiol as a key modulator of visceral sensitivity. These data suggest that ELA induces persistent functional abdominal pain in female IBS patients through an estrogen-dependent mechanism. Copyright © 2013 American Pain Society. All rights reserved.

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.

Gender differences in pain: do emotions play a role?

PubMed

Rhudy, Jamie L; Williams, Amy E

2005-12-01

Research suggests that the influence of gender on the processing and experience of pain is a result of several mechanisms. One mediating variable is emotion, which may modulate pain through an interaction of valence (pleasant-unpleasant) and arousal (calm-excited). This review examines whether gender differences in the experience and processing of emotion contribute to differences in the modulation and perception of pain. An English-language search of MEDLINE and PsycINFO was conducted from 1887 to May 2005. Additional literature was obtained from reference lists of articles retained in the initial search. Emotion appears to influence pain through a valence-by-arousal interaction. Specifically, negatively valenced emotions with low to moderate arousal (eg, anxiety) enhance pain, whereas negatively valenced emotions with high arousal (eg, fear) reduce pain. In contrast, positively valenced emotions always reduce pain, as long as minimal arousal is achieved. Some evidence suggests that women are more sensitive than men to threat-related stimuli and thus experience more negative affect than men. This would generally lead to enhanced pain perception in women. It is also possible that women are more likely than men to experience negative affect with high arousal (intense fear) and thus pain inhibition. However, the relatively lower base rate of intense negative emotions is not likely to contribute much to gender differences in pain. Evidence also suggests that men may be more sensitive to positive events, particularly sexual/erotic stimuli, which may lead to more positive emotion-induced pain reduction in men, relative to women. This review suggests that gender differences in the experience of pain may arise from differences in the experience and processing of emotion that, in turn, differentially alter pain processing. Specifically, the system associated with negative affect may be more attuned to threatening stimuli in women, and the system associated with positive affect may be more attuned to pleasurable stimuli in men. However, there is a paucity of research directly addressing this issue; much of the research on this topic has failed to test a comprehensive model of emotion, failed to use adequate manipulation checks, or failed to use within-subject experimental designs that control for intra- and interindividual differences. Therefore, it is concluded that additional research is warranted.

The lateral prefrontal cortex mediates the hyperalgesic effects of negative cognitions in chronic pain patients.

PubMed

Loggia, Marco L; Berna, Chantal; Kim, Jieun; Cahalan, Christine M; Martel, Marc-Olivier; Gollub, Randy L; Wasan, Ajay D; Napadow, Vitaly; Edwards, Robert R

2015-08-01

Although high levels of negative affect and cognitions have been associated with greater pain sensitivity in chronic pain conditions, the neural mechanisms mediating the hyperalgesic effect of psychological factors in patients with pain disorders are largely unknown. In this cross-sectional study, we hypothesized that 1) catastrophizing modulates brain responses to pain anticipation and 2) anticipatory brain activity mediates the hyperalgesic effect of different levels of catastrophizing in fibromyalgia (FM) patients. Using functional magnetic resonance imaging, we scanned the brains of 31 FM patients exposed to visual cues anticipating the onset of moderately intense deep-tissue pain stimuli. Our results indicated the existence of a negative association between catastrophizing and pain-anticipatory brain activity, including in the right lateral prefrontal cortex. A bootstrapped mediation analysis revealed that pain-anticipatory activity in the lateral prefrontal cortex mediates the association between catastrophizing and pain sensitivity. These findings highlight the role of the lateral prefrontal cortex in the pathophysiology of FM-related hyperalgesia and suggest that deficits in the recruitment of pain-inhibitory brain circuitry during pain-anticipatory periods may play an important contributory role in the association between various degrees of widespread hyperalgesia in FM and levels of catastrophizing, a well-validated measure of negative cognitions and psychological distress. This article highlights the presence of alterations in pain-anticipatory brain activity in FM. These findings provide the rationale for the development of psychological or neurofeedback-based techniques aimed at modifying patients' negative affect and cognitions toward pain. Copyright © 2015 American Pain Society. Published by Elsevier Inc. All rights reserved.

Deficient pain modulatory systems in patients with mild traumatic brain and chronic post-traumatic headache: implications for its mechanism.

PubMed

Defrin, Ruth; Riabinin, Miri; Feingold, Yelena; Schreiber, Shaul; Pick, Chaim G

2015-01-01

Although the prevalence rate of chronic post-traumatic headache (CPTHA) after mild traumatic brain injury (TBI) reaches up to 95%, its mechanism is unknown, and little is known about the characteristics of the pain system in this condition. Our aim was to investigate the capabilities of two pain modulatory systems among individuals with CPTHA and study their association with CPTHA, here for the first time. Forty-six subjects participated; 16 with TBI and CPTHA, 12 with TBI without CPTHA, and 18 healthy controls. Testing included the measurement of heat-pain (HPT) and pressure-pain (PPT) thresholds in the forehead and forearm, pain adaptation to tonic noxious heat, and conditioned pain modulation (CPM).The participants completed a post-traumatic stress disorder (PTSD) questionnaire. The two TBI groups did not differ in the TBI and background characteristics. However, TBI patients with CPTHA had significantly higher HPT and lower PPT in the cranium and higher PTSD symptomatology than TBI patients without CPTHA and healthy controls. Adaptation to pain and CPM were diminished in the CPTHA group compared with the two control groups. The intensity of CPTHA correlated negatively with cranial PPT, magnitude of pain adaptation, and CPM. CPTHA intensity correlated positively with PTSD symptomatology. CPTHA appears to be characterized by cranial hyperalgesia and dysfunctional pain modulation capabilities, which are associated with CPTHA magnitude. It is concluded that damage to pain modulatory systems along with chronic cranial sensitization underlies the development of CPTHA. PTSD may reinforce CPTHA and vice versa. Clinical implications are discussed.

Deficient Pain Modulatory Systems in Patients with Mild Traumatic Brain and Chronic Post-Traumatic Headache: Implications for its Mechanism

PubMed Central

Riabinin, Miri; Feingold, Yelena; Schreiber, Shaul; Pick, Chaim G.

2015-01-01

Abstract Although the prevalence rate of chronic post-traumatic headache (CPTHA) after mild traumatic brain injury (TBI) reaches up to 95%, its mechanism is unknown, and little is known about the characteristics of the pain system in this condition. Our aim was to investigate the capabilities of two pain modulatory systems among individuals with CPTHA and study their association with CPTHA, here for the first time. Forty-six subjects participated; 16 with TBI and CPTHA, 12 with TBI without CPTHA, and 18 healthy controls. Testing included the measurement of heat-pain (HPT) and pressure-pain (PPT) thresholds in the forehead and forearm, pain adaptation to tonic noxious heat, and conditioned pain modulation (CPM).The participants completed a post-traumatic stress disorder (PTSD) questionnaire. The two TBI groups did not differ in the TBI and background characteristics. However, TBI patients with CPTHA had significantly higher HPT and lower PPT in the cranium and higher PTSD symptomatology than TBI patients without CPTHA and healthy controls. Adaptation to pain and CPM were diminished in the CPTHA group compared with the two control groups. The intensity of CPTHA correlated negatively with cranial PPT, magnitude of pain adaptation, and CPM. CPTHA intensity correlated positively with PTSD symptomatology. CPTHA appears to be characterized by cranial hyperalgesia and dysfunctional pain modulation capabilities, which are associated with CPTHA magnitude. It is concluded that damage to pain modulatory systems along with chronic cranial sensitization underlies the development of CPTHA. PTSD may reinforce CPTHA and vice versa. Clinical implications are discussed. PMID:25068510

Divergent functions of the left and right central amygdala in visceral nociception.

PubMed

Sadler, Katelyn E; McQuaid, Neal A; Cox, Abigail C; Behun, Marissa N; Trouten, Allison M; Kolber, Benedict J

2017-04-01

The left and right central amygdalae (CeA) are limbic regions involved in somatic and visceral pain processing. These 2 nuclei are asymmetrically involved in somatic pain modulation; pain-like responses on both sides of the body are preferentially driven by the right CeA, and in a reciprocal fashion, nociceptive somatic stimuli on both sides of the body predominantly alter molecular and physiological activities in the right CeA. Unknown, however, is whether this lateralization also exists in visceral pain processing and furthermore what function the left CeA has in modulating nociceptive information. Using urinary bladder distension (UBD) and excitatory optogenetics, a pronociceptive function of the right CeA was demonstrated in mice. Channelrhodopsin-2-mediated activation of the right CeA increased visceromotor responses (VMRs), while activation of the left CeA had no effect. Similarly, UBD-evoked VMRs increased after unilateral infusion of pituitary adenylate cyclase-activating polypeptide in the right CeA. To determine intrinsic left CeA involvement in bladder pain modulation, this region was optogenetically silenced during noxious UBD. Halorhodopsin (NpHR)-mediated inhibition of the left CeA increased VMRs, suggesting an ongoing antinociceptive function for this region. Finally, divergent left and right CeA functions were evaluated during abdominal mechanosensory testing. In naive animals, channelrhodopsin-2-mediated activation of the right CeA induced mechanical allodynia, and after cyclophosphamide-induced bladder sensitization, activation of the left CeA reversed referred bladder pain-like behaviors. Overall, these data provide evidence for functional brain lateralization in the absence of peripheral anatomical asymmetries.

Gene-to-gene interactions regulate endogenous pain modulation in fibromyalgia patients and healthy controls—antagonistic effects between opioid and serotonin-related genes

PubMed Central

Tour, Jeanette; Löfgren, Monika; Mannerkorpi, Kaisa; Gerdle, Björn; Larsson, Anette; Palstam, Annie; Bileviciute-Ljungar, Indre; Bjersing, Jan; Martin, Ingvar; Ernberg, Malin; Schalling, Martin; Kosek, Eva

2017-01-01

Abstract Chronic pain is associated with dysfunctional endogenous pain modulation, involving both central opioid and serotonergic (5-HT) signaling. Fibromyalgia (FM) is a chronic pain syndrome, characterized by widespread musculoskeletal pain and reduced exercise-induced hypoalgesia (EIH). In this study, we assessed the effects of 3 functional genetic polymorphisms on EIH in 130 patients with FM and 132 healthy controls. Subjects were genotyped regarding the mu-opioid receptor (OPRM1) gene (rs1799971), the serotonin transporter (5-HTT) gene (5-HTTLPR/rs25531), and the serotonin-1a receptor (5-HT1a) gene (rs6296). The patients with FM had increased pain sensitivity and reduced EIH compared with healthy controls. None of the polymorphisms had an effect on EIH on their own. We found significant gene-to-gene interactions between OPRM1 x 5-HTT and OPRM1 x 5-HT1a regarding activation of EIH, with no statistically significant difference between groups. Better EIH was found in individuals with genetically inferred strong endogenous opioid signaling (OPRM1 G) in combination with weak 5-HT tone (5-HTT low/5-HT1a G), compared with strong 5-HT tone (5-HTT high/5-HT1a CC). Based on the proposed mechanisms of these genetic variants, the findings indicate antagonistic interactions between opioid and serotonergic mechanisms during EIH. Moreover, despite different baseline pain level, similar results were detected in FM and controls, not supporting an altered interaction between opioid and 5-HT mechanisms as the basis for dysfunction of EIH in patients with FM. In summary, our results suggest that, by genetic association, the mu-opioid receptor interacts with 2 major serotonergic structures involved in 5-HT reuptake and release, to modulate EIH. PMID:28282362

Gene-to-gene interactions regulate endogenous pain modulation in fibromyalgia patients and healthy controls-antagonistic effects between opioid and serotonin-related genes.

PubMed

Tour, Jeanette; Löfgren, Monika; Mannerkorpi, Kaisa; Gerdle, Björn; Larsson, Anette; Palstam, Annie; Bileviciute-Ljungar, Indre; Bjersing, Jan; Martin, Ingvar; Ernberg, Malin; Schalling, Martin; Kosek, Eva

2017-07-01

Chronic pain is associated with dysfunctional endogenous pain modulation, involving both central opioid and serotonergic (5-HT) signaling. Fibromyalgia (FM) is a chronic pain syndrome, characterized by widespread musculoskeletal pain and reduced exercise-induced hypoalgesia (EIH). In this study, we assessed the effects of 3 functional genetic polymorphisms on EIH in 130 patients with FM and 132 healthy controls. Subjects were genotyped regarding the mu-opioid receptor (OPRM1) gene (rs1799971), the serotonin transporter (5-HTT) gene (5-HTTLPR/rs25531), and the serotonin-1a receptor (5-HT1a) gene (rs6296). The patients with FM had increased pain sensitivity and reduced EIH compared with healthy controls. None of the polymorphisms had an effect on EIH on their own. We found significant gene-to-gene interactions between OPRM1 x 5-HTT and OPRM1 x 5-HT1a regarding activation of EIH, with no statistically significant difference between groups. Better EIH was found in individuals with genetically inferred strong endogenous opioid signaling (OPRM1 G) in combination with weak 5-HT tone (5-HTT low/5-HT1a G), compared with strong 5-HT tone (5-HTT high/5-HT1a CC). Based on the proposed mechanisms of these genetic variants, the findings indicate antagonistic interactions between opioid and serotonergic mechanisms during EIH. Moreover, despite different baseline pain level, similar results were detected in FM and controls, not supporting an altered interaction between opioid and 5-HT mechanisms as the basis for dysfunction of EIH in patients with FM. In summary, our results suggest that, by genetic association, the mu-opioid receptor interacts with 2 major serotonergic structures involved in 5-HT reuptake and release, to modulate EIH.

The role of circulating sex hormones in menstrual cycle dependent modulation of pain-related brain activation

PubMed Central

Veldhuijzen, Dieuwke S.; Keaser, Michael L.; Traub, Deborah S.; Zhuo, Jiachen; Gullapalli, Rao P.; Greenspan, Joel D.

2013-01-01

Sex differences in pain sensitivity have been consistently found but the basis for these differences is incompletely understood. The present study assessed how pain-related neural processing varies across the menstrual cycle in normally cycling, healthy females, and whether menstrual cycle effects are based on fluctuating sex hormone levels. Fifteen subjects participated in four test sessions during their menstrual, mid-follicular, ovulatory, and midluteal phases. Brain activity was measured while nonpainful and painful stimuli were applied with a pressure algometer. Serum hormone levels confirmed that scans were performed at appropriate cycle phases in 14 subjects. No significant cycle phase differences were found for pain intensity or unpleasantness ratings of stimuli applied during fMRI scans. However, lower pressure pain thresholds were found for follicular compared to other phases. Pain-specific brain activation was found in several regions traditionally associated with pain processing, including the medial thalamus, anterior and mid-insula, mid-cingulate, primary and secondary somatosensory cortices, cerebellum, and frontal regions. The inferior parietal lobule, occipital gyrus, cerebellum and several frontal regions demonstrated interaction effects between stimulus level and cycle phase, indicating differential processing of pain-related responses across menstrual cycle phases. Correlational analyses indicated that cycle-related changes in pain sensitivity measures and brain activation were only partly explained by varying sex hormone levels. These results show that pain-related cerebral activation varies significantly across the menstrual cycle, even when perceived pain intensity and unpleasantness remain constant. The involved brain regions suggest that cognitive pain or more general bodily awareness systems are most susceptible to menstrual cycle effects. PMID:23528204

Has aerobic exercise effect on pain perception in persons with migraine and coexisting tension-type headache and neck pain? A randomized, controlled, clinical trial.

PubMed

Krøll, L S; Sjödahl Hammarlund, C; Gard, G; Jensen, R H; Bendtsen, L

2018-04-10

A large subset of persons with migraine suffers from coexisting tension-type headache and neck pain which may adversely affect the prognosis of migraine. Aerobic exercise has been shown to decrease migraine burden in these persons. Therefore, the aim of this study was to investigate whether the effect of aerobic exercise in persons with migraine and coexisting tension-type headache and neck pain can be explained by changes in pain perception. Seventy consecutively recruited persons with migraine and coexisting tension-type headache and neck pain were randomized into exercise group or control group. Aerobic exercise consisted of bike/cross-trainer/brisk walking for 45 min, three times/week for 3 months. Controls continued their usual daily activities. Pericranial tenderness, pain thresholds, supra-thresholds and temporal summation were assessed at baseline, after treatment and at follow-up (6 months from baseline). Fifty-two persons with migraine and coexisting tension-type headache and neck pain completed the study. Aerobic exercise did not induce consistent changes in nociceptive pathways measured by pericranial tenderness, pressure pain thresholds and sensitivity to electrical stimulation. The effect of aerobic exercise cannot be explained by measurable effects on the pain modulation system. Thus, the positive effect on migraine burden may rather be explained by positive alteration of avoidance behaviour. Aerobic exercise can be recommended as a safe and inexpensive migraine treatment strategy. This study adds further knowledge about the positive effect of aerobic exercise for persons with migraine and coexisting tension-type headache and neck pain. This effect cannot be measured by changes in pain modulation, but may rather be explained by positive alteration of avoidance behaviour. © 2018 European Pain Federation - EFIC®.

Stress-Induced Chronic Visceral Pain of Gastrointestinal Origin

PubMed Central

Greenwood-Van Meerveld, Beverley; Johnson, Anthony C.

2017-01-01

Visceral pain is generally poorly localized and characterized by hypersensitivity to a stimulus such as organ distension. In concert with chronic visceral pain, there is a high comorbidity with stress-related psychiatric disorders including anxiety and depression. The mechanisms linking visceral pain with these overlapping comorbidities remain to be elucidated. Evidence suggests that long term stress facilitates pain perception and sensitizes pain pathways, leading to a feed-forward cycle promoting chronic visceral pain disorders such as irritable bowel syndrome (IBS). Early life stress (ELS) is a risk-factor for the development of IBS, however the mechanisms responsible for the persistent effects of ELS on visceral perception in adulthood remain incompletely understood. In rodent models, stress in adult animals induced by restraint and water avoidance has been employed to investigate the mechanisms of stress-induce pain. ELS models such as maternal separation, limited nesting, or odor-shock conditioning, which attempt to model early childhood experiences such as neglect, poverty, or an abusive caregiver, can produce chronic, sexually dimorphic increases in visceral sensitivity in adulthood. Chronic visceral pain is a classic example of gene × environment interaction which results from maladaptive changes in neuronal circuitry leading to neuroplasticity and aberrant neuronal activity-induced signaling. One potential mechanism underlying the persistent effects of stress on visceral sensitivity could be epigenetic modulation of gene expression. While there are relatively few studies examining epigenetically mediated mechanisms involved in visceral nociception, stress-induced visceral pain has been linked to alterations in DNA methylation and histone acetylation patterns within the brain, leading to increased expression of pro-nociceptive neurotransmitters. This review will discuss the potential neuronal pathways and mechanisms responsible for stress-induced exacerbation of chronic visceral pain. Additionally, we will review the importance of specific experimental models of adult stress and ELS in enhancing our understanding of the basic molecular mechanisms of pain processing. PMID:29213232

Expression of A-type K channel alpha subunits Kv 4.2 and Kv 4.3 in rat spinal lamina II excitatory interneurons and colocalization with pain-modulating molecules.

PubMed

Huang, Hsin-Yi; Cheng, Jen-Kun; Shih, Yang-Hsin; Chen, Pei-Hsuan; Wang, Chin-Lin; Tsaur, Meei-Ling

2005-09-01

Voltage-gated K(+) channel alpha subunits Kv 4.2 and Kv 4.3 are the major contributors of somatodendritic A-type K(+) currents in many CNS neurons. A recent hypothesis suggests that Kv 4 subunits may be involved in pain modulation in dorsal horn neurons. However, whether Kv 4 subunits are expressed in dorsal horn neurons remains unknown. Using immunohistochemistry, we found that Kv 4.2 and Kv 4.3 immunoreactivity was concentrated in the superficial dorsal horn, mainly in lamina II. Both Kv 4.2 and Kv 4.3 appeared on many rostrocaudally orientated dendrites, whereas Kv 4.3 could be also detected from certain neuronal somata. Kv 4.3(+) neurons were a subset of excitatory inerneurons with calretinin(+)/calbindin(-)/PKCgamma(-) markers, and a fraction of them expressed micro-opioid receptors. Kv 4.3(+) neurons also expressed ERK 2 and mGluR 5, which are molecules related to the induction of central sensitization, a mechanism mediating nociceptive plasticity. Together with the expression of Kv 4.3 in VR 1(+) DRG neurons, our data suggest that Kv C4 subunits could be involved in pain modulation.

Hyaluronan modulates TRPV1 channel opening, reducing peripheral nociceptor activity and pain

PubMed Central

Caires, Rebeca; Luis, Enoch; Taberner, Francisco J.; Fernandez-Ballester, Gregorio; Ferrer-Montiel, Antonio; Balazs, Endre A.; Gomis, Ana; Belmonte, Carlos; de la Peña, Elvira

2015-01-01

Hyaluronan (HA) is present in the extracellular matrix of all body tissues, including synovial fluid in joints, in which it behaves as a filter that buffers transmission of mechanical forces to nociceptor nerve endings thereby reducing pain. Using recombinant systems, mouse-cultured dorsal root ganglia (DRG) neurons and in vivo experiments, we found that HA also modulates polymodal transient receptor potential vanilloid subtype 1 (TRPV1) channels. HA diminishes heat, pH and capsaicin (CAP) responses, thus reducing the opening probability of the channel by stabilizing its closed state. Accordingly, in DRG neurons, HA decreases TRPV1-mediated impulse firing and channel sensitization by bradykinin. Moreover, subcutaneous HA injection in mice reduces heat and capsaicin nocifensive responses, whereas the intra-articular injection of HA in rats decreases capsaicin joint nociceptor fibres discharge. Collectively, these results indicate that extracellular HA reduces the excitability of the ubiquitous TRPV1 channel, thereby lowering impulse activity in the peripheral nociceptor endings underlying pain. PMID:26311398

Drosophila Nociceptive Sensitization Requires BMP Signaling via the Canonical SMAD Pathway.

PubMed

Follansbee, Taylor L; Gjelsvik, Kayla J; Brann, Courtney L; McParland, Aidan L; Longhurst, Colin A; Galko, Michael J; Ganter, Geoffrey K

2017-08-30

Nociceptive sensitization is a common feature in chronic pain, but its basic cellular mechanisms are only partially understood. The present study used the Drosophila melanogaster model system and a candidate gene approach to identify novel components required for modulation of an injury-induced nociceptive sensitization pathway presumably downstream of Hedgehog. This study demonstrates that RNAi silencing of a member of the Bone Morphogenetic Protein (BMP) signaling pathway, Decapentaplegic (Dpp), specifically in the Class IV multidendritic nociceptive neuron, significantly attenuated ultraviolet injury-induced sensitization. Furthermore, overexpression of Dpp in Class IV neurons was sufficient to induce thermal hypersensitivity in the absence of injury. The requirement of various BMP receptors and members of the SMAD signal transduction pathway in nociceptive sensitization was also demonstrated. The effects of BMP signaling were shown to be largely specific to the sensitization pathway and not associated with changes in nociception in the absence of injury or with changes in dendritic morphology. Thus, the results demonstrate that Dpp and its pathway play a crucial and novel role in nociceptive sensitization. Because the BMP family is so strongly conserved between vertebrates and invertebrates, it seems likely that the components analyzed in this study represent potential therapeutic targets for the treatment of chronic pain in humans. SIGNIFICANCE STATEMENT This report provides a genetic analysis of primary nociceptive neuron mechanisms that promote sensitization in response to injury. Drosophila melanogaster larvae whose primary nociceptive neurons were reduced in levels of specific components of the BMP signaling pathway, were injured and then tested for nocifensive responses to a normally subnoxious stimulus. Results suggest that nociceptive neurons use the BMP2/4 ligand, along with identified receptors and intracellular transducers to transition to a sensitized state. These findings are consistent with the observation that BMP receptor hyperactivation correlates with bone abnormalities and pain sensitization in fibrodysplasia ossificans progressiva (Kitterman et al., 2012). Because nociceptive sensitization is associated with chronic pain, these findings indicate that human BMP pathway components may represent targets for novel pain-relieving drugs. Copyright © 2017 the authors 0270-6474/17/378524-10$15.00/0.

Drosophila Nociceptive Sensitization Requires BMP Signaling via the Canonical SMAD Pathway

PubMed Central

Follansbee, Taylor L.; Gjelsvik, Kayla J.; Brann, Courtney L.; McParland, Aidan L.

2017-01-01

Nociceptive sensitization is a common feature in chronic pain, but its basic cellular mechanisms are only partially understood. The present study used the Drosophila melanogaster model system and a candidate gene approach to identify novel components required for modulation of an injury-induced nociceptive sensitization pathway presumably downstream of Hedgehog. This study demonstrates that RNAi silencing of a member of the Bone Morphogenetic Protein (BMP) signaling pathway, Decapentaplegic (Dpp), specifically in the Class IV multidendritic nociceptive neuron, significantly attenuated ultraviolet injury-induced sensitization. Furthermore, overexpression of Dpp in Class IV neurons was sufficient to induce thermal hypersensitivity in the absence of injury. The requirement of various BMP receptors and members of the SMAD signal transduction pathway in nociceptive sensitization was also demonstrated. The effects of BMP signaling were shown to be largely specific to the sensitization pathway and not associated with changes in nociception in the absence of injury or with changes in dendritic morphology. Thus, the results demonstrate that Dpp and its pathway play a crucial and novel role in nociceptive sensitization. Because the BMP family is so strongly conserved between vertebrates and invertebrates, it seems likely that the components analyzed in this study represent potential therapeutic targets for the treatment of chronic pain in humans. SIGNIFICANCE STATEMENT This report provides a genetic analysis of primary nociceptive neuron mechanisms that promote sensitization in response to injury. Drosophila melanogaster larvae whose primary nociceptive neurons were reduced in levels of specific components of the BMP signaling pathway, were injured and then tested for nocifensive responses to a normally subnoxious stimulus. Results suggest that nociceptive neurons use the BMP2/4 ligand, along with identified receptors and intracellular transducers to transition to a sensitized state. These findings are consistent with the observation that BMP receptor hyperactivation correlates with bone abnormalities and pain sensitization in fibrodysplasia ossificans progressiva (Kitterman et al., 2012). Because nociceptive sensitization is associated with chronic pain, these findings indicate that human BMP pathway components may represent targets for novel pain-relieving drugs. PMID:28855331

Current pain education within undergraduate medical studies across Europe: Advancing the Provision of Pain Education and Learning (APPEAL) study.

PubMed

Briggs, Emma V; Battelli, Daniele; Gordon, David; Kopf, Andreas; Ribeiro, Sofia; Puig, Margarita M; Kress, Hans G

2015-08-10

Unrelieved pain is a substantial public health concern necessitating improvements in medical education. The Advancing the Provision of Pain Education and Learning (APPEAL) study aimed to determine current levels and methods of undergraduate pain medicine education in Europe. Using a cross-sectional design, publicly available curriculum information was sought from all medical schools in 15 representative European countries in 2012-2013. Descriptive analyses were performed on: the provision of pain teaching in dedicated pain modules, other modules or within the broader curriculum; whether pain teaching was compulsory or elective; the number of hours/credits spent teaching pain; pain topics; and teaching and assessment methods. Curriculum elements were publicly available from 242 of 249 identified schools (97%). In 55% (133/242) of schools, pain was taught only within compulsory non-pain-specific modules. The next most common approaches were for pain teaching to be provided wholly or in part via a dedicated pain module (74/242; 31%) or via a vertical or integrated approach to teaching through the broader curriculum, rather than within any specific module (17/242; 7%). The curricula of 17/242 schools (7%) showed no evidence of any pain teaching. Dedicated pain modules were most common in France (27/31 schools; 87%). Excluding France, only 22% (47/211 schools) provided a dedicated pain module and in only 9% (18/211) was this compulsory. Overall, the median number of hours spent teaching pain was 12.0 (range 4-56.0 h; IQR: 12.0) for compulsory dedicated pain modules and 9.0 (range 1.0-60.0 h; IQR: 10.5) for other compulsory (non-pain specific) modules. Pain medicine was principally taught in classrooms and assessed by conventional examinations. There was substantial international variation throughout. Documented pain teaching in many European medical schools falls far short of what might be expected given the prevalence and public health burden of pain. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

Serotonin-1A Receptor Polymorphism (rs6295) Associated with Thermal Pain Perception

PubMed Central

Lindstedt, Fredrik; Karshikoff, Bianka; Schalling, Martin; Olgart Höglund, Caroline; Ingvar, Martin; Lekander, Mats; Kosek, Eva

2012-01-01

Background Serotonin (5-HT) is highly involved in pain regulation and serotonin-1A (5-HT1A) receptors are important in determining central 5-HT tone. Accordingly, variation in the 5-HT1A receptor gene (HTR1A) may contribute to inter-individual differences in human pain sensitivity. The minor G-allele of the HTR1A single nucleotide polymorphism (SNP) rs6295 attenuates firing of serotonergic neurons and reduces postsynaptic expression of the receptor. Experiments in rodents suggest that 5-HT1A-agonism modulates pain in opposite directions at mild compared to high noxious intensities. Based upon this and several other similar observations, we hypothesized that G-carriers would exhibit a relative hypoalgesia at mild thermal stimuli but tend towards hyperalgesia at higher noxious intensities. Methods Fourty-nine healthy individuals were selectively genotyped for rs6295. Heat- and cold-pain thresholds were assessed along with VAS-ratings of a range of suprathreshold noxious heat intensities (45°C–49°C). Nociceptive-flexion reflex (NFR) thresholds were also assessed. Results Volunteers did not deviate significantly from Hardy-Weinberg equilibrium. G-carriers were less sensitive to threshold-level thermal pain. This relative hypoalgesia was abolished at suprathreshold noxious intensities where G-carriers instead increased their ratings of heat-pain significantly more than C-homozygotes. No differences with regard to NFR-thresholds emerged. Conclusion/Significance To the best of our knowledge this is the first study of human pain perception on the basis of variation in HTR1A. The results illustrate the importance of including a range of stimulus intensities in assessments of pain sensitivity. In speculation, we propose that an attenuated serotonergic tone may be related to a ‘hypo- to hyperalgesic’ response-pattern. The involved mechanisms could be of clinical interest as variation in pain regulation is known to influence the risk of developing pain pathologies. Further investigations are therefore warranted. PMID:22952650

Sex moderates the effects of positive and negative affect on clinical pain in patients with knee osteoarthritis.

PubMed

Speed, Traci J; Richards, Jessica M; Finan, Patrick H; Smith, Michael T

2017-07-01

Sex differences in clinical pain severity and response to experimental pain are commonly reported, with women generally showing greater vulnerability. Affect, including state (a single rating) and stable (average daily ratings over two weeks) positive affect and negative affect has also been found to impact pain sensitivity and severity, and research suggests that affect may modulate pain differentially as a function of sex. The current study aimed to examine sex as a moderator of the relationships between affect and pain-related outcomes among participants with knee osteoarthritis (KOA). One hundred and seventy-nine participants (59 men) with KOA completed electronic diaries assessing clinical pain, positive affect, and negative affect. A subset of participants (n=120) underwent quantitative sensory testing, from which a single index of central sensitization to pain was derived. We used multiple regression models to test for the interactive effects of sex and affect (positive versus negative and stable versus state) on pain-related outcomes. We used mixed effects models to test for the moderating effects of sex on the relationships between state affect and pain over time. Sex differences in affect and pain were identified, with men reporting significantly higher stable positive affect and lower central sensitization to pain indexed by quantitative sensory testing, as well as marginally lower KOA-specific clinical pain compared to women. Moreover, there was an interaction between stable positive affect and sex on KOA-specific clinical pain and average daily non-specific pain ratings. Post hoc analyses revealed that men showed trends towards an inverse relationship between stable positive affect and pain outcomes, while women showed no relationship between positive affect and pain. There was also a significant interaction between sex and stable negative affect and sex on KOA-specific pain such that men showed a significantly stronger positive relationship between stable negative affect and KOA-specific pain than women. Sex did not interact with state affect on pain outcomes. Findings suggest that men may be particularly sensitive to the effects of stable positive affect and negative affect on clinical pain. Future work with larger samples is needed in order to identify potential mechanisms driving the sex-specific effects of affect on pain. The current study provides novel data that suggesting that the association of positive affect, negative affect, and pain are different in men versus women with KOA. Further understanding of the difference in affective expression between men and women may lead to the development of novel therapeutic interventions and help to identify additional modifiable factors in the prevention and management of pain. Copyright © 2017 Scandinavian Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

Selective spider toxins reveal a role for Nav1.1 channel in mechanical pain

PubMed Central

Osteen, Jeremiah D.; Herzig, Volker; Gilchrist, John; Emrick, Joshua J.; Zhang, Chuchu; Wang, Xidao; Castro, Joel; Garcia-Caraballo, Sonia; Grundy, Luke; Rychkov, Grigori Y.; Weyer, Andy D.; Dekan, Zoltan; Undheim, Eivind A. B.; Alewood, Paul; Stucky, Cheryl L.; Brierley, Stuart M.; Basbaum, Allan I.; Bosmans, Frank; King, Glenn F.; Julius, David

2016-01-01

Voltage-gated sodium (Nav) channels initiate action potentials in most neurons, including primary afferent nerve fibers of the pain pathway. Local anesthetics block pain through non-specific actions at all Nav channels, but the discovery of selective modulators would facilitate the analysis of individual subtypes and their contributions to chemical, mechanical, or thermal pain. Here, we identify and characterize spider toxins that selectively activate the Nav1.1 subtype, whose role in nociception and pain has not been explored. We exploit these probes to demonstrate that Nav1.1-expressing fibers are modality-specific nociceptors: their activation elicits robust pain behaviors without neurogenic inflammation and produces profound hypersensitivity to mechanical, but not thermal, stimuli. In the gut, high-threshold mechanosensitive fibers also express Nav1.1 and show enhanced toxin sensitivity in a model of irritable bowel syndrome. Altogether, these findings establish an unexpected role for Nav1.1 in regulating the excitability of sensory nerve fibers that underlie mechanical pain. PMID:27281198

Central Sensitization-Based Classification for Temporomandibular Disorders: A Pathogenetic Hypothesis

PubMed Central

Cattaneo, Ruggero; Marci, Maria Chiara; Pietropaoli, Davide; Ortu, Eleonora

2017-01-01

Dysregulation of Autonomic Nervous System (ANS) and central pain pathways in temporomandibular disorders (TMD) is a growing evidence. Authors include some forms of TMD among central sensitization syndromes (CSS), a group of pathologies characterized by central morphofunctional alterations. Central Sensitization Inventory (CSI) is useful for clinical diagnosis. Clinical examination and CSI cannot identify the central site(s) affected in these diseases. Ultralow frequency transcutaneous electrical nerve stimulation (ULFTENS) is extensively used in TMD and in dental clinical practice, because of its effects on descending pain modulation pathways. The Diagnostic Criteria for TMD (DC/TMD) are the most accurate tool for diagnosis and classification of TMD. However, it includes CSI to investigate central aspects of TMD. Preliminary data on sensory ULFTENS show it is a reliable tool for the study of central and autonomic pathways in TMD. An alternative classification based on the presence of Central Sensitization and on individual response to sensory ULFTENS is proposed. TMD may be classified into 4 groups: (a) TMD with Central Sensitization ULFTENS Responders; (b) TMD with Central Sensitization ULFTENS Nonresponders; (c) TMD without Central Sensitization ULFTENS Responders; (d) TMD without Central Sensitization ULFTENS Nonresponders. This pathogenic classification of TMD may help to differentiate therapy and aetiology. PMID:28932132

Cerebral interactions of pain and reward and their relevance for chronic pain.

PubMed

Becker, Susanne; Gandhi, Wiebke; Schweinhardt, Petra

2012-06-29

Pain and reward are opponent, interacting processes. Such interactions are enabled by neuroanatomical and neurochemical overlaps of brain systems that process pain and reward. Cerebral processing of hedonic ('liking') and motivational ('wanting') aspects of reward can be separated: the orbitofrontal cortex and opioids play an important role for the hedonic experience, and the ventral striatum and dopamine predominantly process motivation for reward. Supported by neuroimaging studies, we present here the hypothesis that the orbitofrontal cortex and opioids are responsible for pain modulation by hedonic experience, while the ventral striatum and dopamine mediate motivational effects on pain. A rewarding stimulus that appears to be particularly important in the context of pain is pain relief. Further, reward, including pain relief, leads to operant learning, which can affect pain sensitivity. Indirect evidence points at brain mechanisms that might underlie pain relief as a reward and related operant learning but studies are scarce. Investigating the cerebral systems underlying pain-reward interactions as well as related operant learning holds the potential of better understanding mechanisms that contribute to the development and maintenance of chronic pain, as detailed in the last section of this review. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Exercise-induced Hypoalgesia in People With Knee Osteoarthritis With Normal and Abnormal Conditioned Pain Modulation.

PubMed

Fingleton, Caitríona; Smart, Keith M; Doody, Catherine M

2017-05-01

Normal efficiency of exercise-induced hypoalgesia (EIH) has been demonstrated in people with knee osteoarthritis (OA), while recent evidence suggests that EIH may be associated with features of pain sensitization such as abnormal conditioned pain modulation (CPM). The aim of this study was to investigate whether people with knee OA with abnormal CPM have dysfunctional EIH compared with those with normal CPM and pain-free controls. Forty peoples with knee OA were subdivided into groups with abnormal and normal CPM, as determined by a decrease/increase in pressure pain thresholds (PPTs) following the cold pressor test. Abnormal CPM (n=19), normal CPM (n=21), and control participants (n=20) underwent PPT testing before, during, and after aerobic and isometric exercise protocols. Between-group differences were analyzed using repeated-measures analysis of variance and within-group differences were analyzed using Wilcoxon signed-rank tests. Significant differences were demonstrated between groups for changes in PPTs postaerobic (F2,55=4.860; P=0.011) and isometric (F2,57=4.727; P=0.013) exercise, with significant decreases in PPTs demonstrated during and postexercise in the abnormal CPM group (P<0.05), and significant increases in PPTs shown during and postexercise in the normal CPM and control groups (P<0.05). Results are suggestive of dysfunctional EIH in response to aerobic and isometric exercise in knee OA patients with abnormal CPM, and normal function of EIH in knee OA patients with an efficient CPM response. Identification of people with knee OA with inefficient endogenous pain modulation may allow for a more individualized and graded approach to exercises in these individuals.

Neuropathic pain in experimental autoimmune neuritis is associated with altered electrophysiological properties of nociceptive DRG neurons.

PubMed

Taha, Omneya; Opitz, Thoralf; Mueller, Marcus; Pitsch, Julika; Becker, Albert; Evert, Bernd Oliver; Beck, Heinz; Jeub, Monika

2017-11-01

Guillain-Barré syndrome (GBS) is an acute, immune-mediated polyradiculoneuropathy characterized by rapidly progressive paresis and sensory disturbances. Moderate to severe and often intractable neuropathic pain is a common symptom of GBS, but its underlying mechanisms are unknown. Pathology of GBS is classically attributed to demyelination of large, myelinated peripheral fibers. However, there is increasing evidence that neuropathic pain in GBS is associated with impaired function of small, unmyelinated, nociceptive fibers. We therefore examined the functional properties of small DRG neurons, the somata of nociceptive fibers, in a rat model of GBS (experimental autoimmune neuritis=EAN). EAN rats developed behavioral signs of neuropathic pain. This was accompanied by a significant shortening of action potentials due to a more rapid repolarization and an increase in repetitive firing in a subgroup of capsaicin-responsive DRG neurons. Na + current measurements revealed a significant increase of the fast TTX-sensitive current and a reduction of the persistent TTX-sensitive current component. These changes of Na + currents may account for the significant decrease in AP duration leading to an overall increase in excitability and are therefore possibly directly linked to pathological pain behavior. Thus, like in other animal models of neuropathic and inflammatory pain, Na + channels seem to be crucially involved in the pathology of GBS and may constitute promising targets for pain modulating pharmaceuticals. Copyright © 2017 Elsevier Inc. All rights reserved.

Reduction of conditioned pain modulation in humans by naltrexone: an exploratory study of the effects of pain catastrophizing

PubMed Central

Goodin, Burel; Kindler, Lindsay L.; Caudle, Robert M.; Edwards, Robert R.; Gravenstein, Nikolaus; Riley, Joseph L.; Fillingim, Roger B.

2013-01-01

The current study tested the hypothesis that conditioned pain modulation is mediated by the release of endogenous opioids with a placebo-controlled (sugar pill) study of naltrexone (50 mg) in 33 healthy volunteers over two counter-balanced sessions. Pain modulation consisted of rating of heat pain (palm) during concurrent cold water immersion (foot). Compared to baseline heat pain ratings, concurrent foot immersion lowered pain intensity ratings, which suggests an inhibitory effect, was reduced with naltrexone, suggesting at least partial dependence of inhibition on endogenous opioids. An exploratory analysis revealed that individual differences in catastrophizing moderated the effects of naltrexone; endogenous opioid blockade abolished modulation in subjects lower in catastrophizing while modulation was unaffected by naltrexone among high catastrophizers. The results suggest a role of endogenous opioids in endogenous analgesia, but hint that multiple systems might contribute to conditioned pain modulation, and that these systems might be differentially activated as a function of individual differences in responses to pain. PMID:22534819

Towards a mechanism-based approach to pain management in osteoarthritis

PubMed Central

Malfait, Anne-Marie; Schnitzer, Thomas J.

2014-01-01

Pain is the defining symptom of osteoarthritis (OA), yet available treatment options, of which NSAIDs are the most common, provide inadequate pain relief and are associated with serious health risks when used long term. Chronic pain pathways are subject to complex levels of control and modulation, both in the periphery and in the central nervous system. Ongoing clinical and basic research is uncovering how these pathways operate in OA. Indeed, clinical investigation into the types of pain associated with progressive OA, the presence of central sensitization, the correlation with structural changes in the joint, and the efficacy of novel analgesics affords new insights into the pathophysiology of OA pain. Moreover, studies in disease-specific animal models enable the unravelling of the cellular and molecular pathways involved. We expect that increased understanding of the mechanisms by which chronic OA-associated pain is generated and maintained will offer opportunities for targeting and improving the safety of analgesia. In addition, using clinical and genetic approaches, it might become possible to identify subsets of patients with pain of different pathophysiology, thus enabling a tailored approach to pain management. PMID:24045707

Divergent functions of the left and right central amygdala in visceral nociception

PubMed Central

Sadler, Katelyn E.; McQuaid, Neal A.; Cox, Abigail C.; Behun, Marissa N.; Trouten, Allison M.; Kolber, Benedict J.

2017-01-01

The left and right central amygdalae (CeA) are limbic regions involved in somatic and visceral pain processing. These 2 nuclei are asymmetrically involved in somatic pain modulation; pain-like responses on both sides of the body are preferentially driven by the right CeA, and in a reciprocal fashion, nociceptive somatic stimuli on both sides of the body predominantly alter molecular and physiological activities in the right CeA. Unknown, however, is whether this lateralization also exists in visceral pain processing and furthermore what function the left CeA has in modulating nociceptive information. Using urinary bladder distension (UBD) and excitatory optogenetics, a pronociceptive function of the right CeA was demonstrated in mice. Channelrhodopsin-2–mediated activation of the right CeA increased visceromotor responses (VMRs), while activation of the left CeA had no effect. Similarly, UBD-evoked VMRs increased after unilateral infusion of pituitary adenylate cyclase–activating polypeptide in the right CeA. To determine intrinsic left CeA involvement in bladder pain modulation, this region was optogenetically silenced during noxious UBD. Halorhodopsin (NpHR)-mediated inhibition of the left CeA increased VMRs, suggesting an ongoing antinociceptive function for this region. Finally, divergent left and right CeA functions were evaluated during abdominal mechanosensory testing. In naive animals, channelrhodopsin-2–mediated activation of the right CeA induced mechanical allodynia, and after cyclophosphamide-induced bladder sensitization, activation of the left CeA reversed referred bladder pain–like behaviors. Overall, these data provide evidence for functional brain lateralization in the absence of peripheral anatomical asymmetries. PMID:28225716

Sensory Over-Responsiveness among Healthy Subjects is Associated with a Pronociceptive State.

PubMed

Weissman-Fogel, Irit; Granovsky, Yelena; Bar-Shalita, Tami

2018-04-01

Chronic pain patients show hypersensitivity to sensory nonpainful stimuli. Sensory over-responsiveness (SOR) to innocuous daily stimuli, experienced as painful, is prevalent in 10% of the healthy population. This altered sensory processing may be an expression of overfacilitation, or a less efficient pain-inhibitory process in the pain pathways. We therefore aimed to investigate specifically the pain-inhibitory system of subjects with SOR who are otherwise healthy, not studied as of yet. Thirty healthy subjects, divided into an SOR group (n = 14) and a non-SOR group (n = 16) based on responses to the Sensory Responsiveness Questionnaire, were psychophysically tested in order to evaluate (1) hyperalgesic responses; (2) adaptation/sensitization to 14 phasic heat stimuli; (3) habituation; (4) 6-minute after-sensations; and (5) conditioned pain modulation (CPM) (ie, phasic heat stimuli applied with and without hand immersion in a hot water bath). The SOR group differed from the non-SOR group in (1) a steeper escalation in NPS ratings to temperature increase (P = 0.003), indicating hyperalgesia; (2) increased sensitization (P < 0.001); (3) habituation responses (P < 0.001); (4) enhanced pain ratings during the after-sensation (P = 0.006); and (5) no group difference was found in CPM. SOR is associated with a pronociceptive state, expressed by amplification of experimental pain, yet with sufficient inhibitory processes. Our results support previous findings of enhanced facilitation of pain-transmitting pathways but also reveal preserved inhibitory mechanisms, although they were slower to react. © 2017 World Institute of Pain.

Mood influences supraspinal pain processing separately from attention.

PubMed

Villemure, Chantal; Bushnell, M Catherine

2009-01-21

Studies show that inducing a positive mood or diverting attention from pain decreases pain perception. Nevertheless, induction manipulations, such as viewing interesting movies or performing mathematical tasks, often influence both emotional and attentional states. Imaging studies have examined the neural basis of psychological pain modulation, but none has explicitly separated the effects of emotion and attention. Using odors to modulate mood and shift attention from pain, we previously showed that the perceptual consequences of changing mood differed from those of altering attention, with mood primarily altering pain unpleasantness and attention preferentially altering pain intensity. These findings suggest that brain circuits involved in pain modulation provoked by mood or attention are partially separable. Here we used functional magnetic resonance imaging to directly compare the neurocircuitry involved in mood- and attention-related pain modulation. We manipulated independently mood state and attention direction, using tasks involving heat pain and pleasant and unpleasant odors. Pleasant odors, independent of attentional focus, induced positive mood changes and decreased pain unpleasantness and pain-related activity within the anterior cingulate (ACC), medial thalamus, and primary and secondary somatosensory cortices. The effects of attentional state were less robust, with only the activity in anterior insular cortex (aIC) showing possible attentional modulation. Lateral inferior frontal cortex [LinfF; Brodmann's area (BA) 45/47] activity correlated with mood-related modulation, whereas superior posterior parietal (SPP; BA7) and entorhinal activity correlated with attention-related modulation. ACC activity covaried with LinfF and periacqueductal gray activity, whereas aIC activity covaried with SPP activity. These findings suggest that separate neuromodulatory circuits underlie emotional and attentional modulation of pain.

Hypnotizability and Placebo Analgesia in Waking and Hypnosis as Modulators of Auditory Startle Responses in Healthy Women: An ERP Study.

PubMed

De Pascalis, Vilfredo; Scacchia, Paolo

2016-01-01

We evaluated the influence of hypnotizability, pain expectation, placebo analgesia in waking and hypnosis on tonic pain relief. We also investigated how placebo analgesia affects somatic responses (eye blink) and N100 and P200 waves of event-related potentials (ERPs) elicited by auditory startle probes. Although expectation plays an important role in placebo and hypnotic analgesia, the neural mechanisms underlying these treatments are still poorly understood. We used the cold cup test (CCT) to induce tonic pain in 53 healthy women. Placebo analgesia was initially produced by manipulation, in which the intensity of pain induced by the CCT was surreptitiously reduced after the administration of a sham analgesic cream. Participants were then tested in waking and hypnosis under three treatments: (1) resting (Baseline); (2) CCT-alone (Pain); and (3) CCT plus placebo cream for pain relief (Placebo). For each painful treatment, we assessed pain and distress ratings, eye blink responses, N100 and P200 amplitudes. We used LORETA analysis of N100 and P200 waves, as elicited by auditory startle, to identify cortical regions sensitive to pain reduction through placebo and hypnotic analgesia. Higher pain expectation was associated with higher pain reductions. In highly hypnotizable participants placebo treatment produced significant reductions of pain and distress perception in both waking and hypnosis condition. P200 wave, during placebo analgesia, was larger in the frontal left hemisphere while placebo analgesia, during hypnosis, involved the activity of the left hemisphere including the occipital region. These findings demonstrate that hypnosis and placebo analgesia are different processes of top-down regulation. Pain reduction was associated with larger EMG startle amplitudes, N100 and P200 responses, and enhanced activity within the frontal, parietal, and anterior and posterior cingulate gyres. LORETA results showed that placebo analgesia modulated pain-responsive areas known to reflect the ongoing pain experience.

Hypnotizability and Placebo Analgesia in Waking and Hypnosis as Modulators of Auditory Startle Responses in Healthy Women: An ERP Study

PubMed Central

De Pascalis, Vilfredo; Scacchia, Paolo

2016-01-01

We evaluated the influence of hypnotizability, pain expectation, placebo analgesia in waking and hypnosis on tonic pain relief. We also investigated how placebo analgesia affects somatic responses (eye blink) and N100 and P200 waves of event-related potentials (ERPs) elicited by auditory startle probes. Although expectation plays an important role in placebo and hypnotic analgesia, the neural mechanisms underlying these treatments are still poorly understood. We used the cold cup test (CCT) to induce tonic pain in 53 healthy women. Placebo analgesia was initially produced by manipulation, in which the intensity of pain induced by the CCT was surreptitiously reduced after the administration of a sham analgesic cream. Participants were then tested in waking and hypnosis under three treatments: (1) resting (Baseline); (2) CCT-alone (Pain); and (3) CCT plus placebo cream for pain relief (Placebo). For each painful treatment, we assessed pain and distress ratings, eye blink responses, N100 and P200 amplitudes. We used LORETA analysis of N100 and P200 waves, as elicited by auditory startle, to identify cortical regions sensitive to pain reduction through placebo and hypnotic analgesia. Higher pain expectation was associated with higher pain reductions. In highly hypnotizable participants placebo treatment produced significant reductions of pain and distress perception in both waking and hypnosis condition. P200 wave, during placebo analgesia, was larger in the frontal left hemisphere while placebo analgesia, during hypnosis, involved the activity of the left hemisphere including the occipital region. These findings demonstrate that hypnosis and placebo analgesia are different processes of top-down regulation. Pain reduction was associated with larger EMG startle amplitudes, N100 and P200 responses, and enhanced activity within the frontal, parietal, and anterior and posterior cingulate gyres. LORETA results showed that placebo analgesia modulated pain-responsive areas known to reflect the ongoing pain experience. PMID:27486748

Cellular prion protein protects from inflammatory and neuropathic pain

PubMed Central

2011-01-01

Cellular prion protein (PrPC) inhibits N-Methyl-D-Aspartate (NMDA) receptors. Since NMDA receptors play an important role in the transmission of pain signals in the dorsal horn of spinal cord, we thus wanted to determine if PrPC null mice show a reduced threshold for various pain behaviours. We compared nociceptive thresholds between wild type and PrPC null mice in models of inflammatory and neuropathic pain, in the presence and the absence of a NMDA receptor antagonist. 2-3 months old male PrPC null mice exhibited an MK-801 sensitive decrease in the paw withdrawal threshold in response both mechanical and thermal stimuli. PrPC null mice also exhibited significantly longer licking/biting time during both the first and second phases of formalin-induced inflammation of the paw, which was again prevented by treatment of the mice with MK-801, and responded more strongly to glutamate injection into the paw. Compared to wild type animals, PrPC null mice also exhibited a significantly greater nociceptive response (licking/biting) after intrathecal injection of NMDA. Sciatic nerve ligation resulted in MK-801 sensitive neuropathic pain in wild-type mice, but did not further augment the basal increase in pain behaviour observed in the null mice, suggesting that mice lacking PrPC may already be in a state of tonic central sensitization. Altogether, our data indicate that PrPC exerts a critical role in modulating nociceptive transmission at the spinal cord level, and fit with the concept of NMDA receptor hyperfunction in the absence of PrPC. PMID:21843375

Pain perception and hypnosis: findings from recent functional neuroimaging studies.

PubMed

Del Casale, Antonio; Ferracuti, Stefano; Rapinesi, Chiara; Serata, Daniele; Caltagirone, Saverio Simone; Savoja, Valeria; Piacentino, Daria; Callovini, Gemma; Manfredi, Giovanni; Sani, Gabriele; Kotzalidis, Georgios D; Girardi, Paolo

2015-01-01

Hypnosis modulates pain perception and tolerance by affecting cortical and subcortical activity in brain regions involved in these processes. By reviewing functional neuroimaging studies focusing on pain perception under hypnosis, the authors aimed to identify brain activation-deactivation patterns occurring in hypnosis-modulated pain conditions. Different changes in brain functionality occurred throughout all components of the pain network and other brain areas. The anterior cingulate cortex appears to be central in modulating pain circuitry activity under hypnosis. Most studies also showed that the neural functions of the prefrontal, insular, and somatosensory cortices are consistently modified during hypnosis-modulated pain conditions. Functional neuroimaging studies support the clinical use of hypnosis in the management of pain conditions.

The Role of the Brain's Endocannabinoid System in Pain and Its Modulation by Stress.

PubMed

Corcoran, Louise; Roche, Michelle; Finn, David P

2015-01-01

Stress has a complex, bidirectional modulatory influence on pain. Stress may either reduce (stress-induced analgesia) or exacerbate (stress-induced hyperalgesia) pain depending on the nature, duration, and intensity of the stressor. The endogenous cannabinoid (endocannabinoid) system is present throughout the neuroanatomical pathways that mediate and modulate responses to painful stimuli. The specific role of the endocannabinoid system in the brain in pain and the modulation of pain by stress is reviewed herein. We first provide a brief overview of the endocannabinoid system, followed by a review of the evidence that the brain's endocannabinoid system modulates pain. We provide a comprehensive evaluation of the role of the endocannabinoid system supraspinally, and particularly in the rostral ventromedial medulla, periaqueductal gray, amygdala, and prefrontal cortex, in pain, stress-induced analgesia, and stress-induced hyperalgesia. Increased understanding of endocannabinoid-mediated regulation of pain and its modulation by stress will inform the development of novel therapeutic approaches for pain and its comorbidity with stress-related disorders. © 2015 Elsevier Inc. All rights reserved.

Opposite Effects of Stress on Pain Modulation Depend on the Magnitude of Individual Stress Response.

PubMed

Geva, Nirit; Defrin, Ruth

2018-04-01

The effect of acute stress on pain threshold and intolerance threshold are reported as producing either hypoalgesia or hyperalgesia. Yet, the contribution of individual stress reactivity in this respect has not been established. The aim was to test 2 pain modulation paradigms under acute stress manipulation, to our knowledge, for the first time, to study whether stress differentially affects pain modulation, and whether the effect is related to individual stress response. Participants were 31 healthy subjects. Conditioned pain modulation (CPM) and pain adaptation were measured before and after inducing an acute stress response using the Montreal Imaging Stress Task. Subjects' stress response was evaluated according to salivary cortisol, autonomic function, and perceived stress and anxiety. The Montreal Imaging Stress Task induced a validated stress response. On a group level, stress induced reduction in CPM magnitude and increase in pain adaptation compared with baseline. These responses correlated with stress reactivity. When the group was subdivided according to stress reactivity, only high stress responders exhibited reduced CPM whereas only low stress responders exhibited increased pain adaptation. The results suggest that acute stress may induce opposite effects on pain modulation, depending on individual stress reactivity magnitude, with an advantage to low stress responders. This study evaluated the effect of acute stress on pain modulation. Pain modulation under stress is affected by individual stress responsiveness; decreased CPM occurs in high stress responders whereas increased pain adaptation occurs in low stress responders. Identification of high stress responders may promote better pain management. Copyright © 2017 The American Pain Society. Published by Elsevier Inc. All rights reserved.

Temperament as a modulating factor of pain sensitivity in combat sport athletes.

PubMed

Leźnicka, Katarzyna; Starkowska, Anna; Tomczak, Maciej; Cięszczyk, Paweł; Białecka, Monika; Ligocka, Maria; Żmijewski, Piotr; Pawlak, Maciej

2017-10-15

The aim of this study was to characterise the temperament of combat athletes in comparison to that of individuals who do not practise any sports with regard to pain sensitivity measured with the cold pressor test (CPT) and pressure pain threshold (PPT). The study involved 284 healthy men, aged 18 to 43years. The first group consisted of 198 combat athletes, including boxing (n=19), mixed martial arts (MMA) (n=97) and karate (n=82), aged from 18 to 43years. The control group consisted of 86 subjects between the ages of 18 and 26years, academic students not practising any sport professionally. Pain threshold and pain tolerance were evaluated using the CPT and a pressure algometer. Temperament was measured with the Formal Characteristics of Behaviour - Temperament Inventory (FCB-TI). The contact athletes showed much higher tolerance to pain than the control group using both tools: CPT (p=0.007) and PPT (p<0.001). In athletes, but not in controls, relationships were noted between BMI and endurance (r=0.20; p=0.004), BMI and activity (r=-0.283; p<0.001), BMI and pain threshold (r=0.15; p<0.05), and BMI and pain tolerance (r=0.30; p<0.001), when measured by the algometer - this necessitating adjustment for further analysis. The athletes and students in the study groups differed significantly with regard to intensity of four temperamental traits, but after BMI adjustments only group differences in Preservation, Sensory sensitivity and Emotional reactivity remained significant'. These differences indicate individual differences in perception and reaction to external stimuli. Significantly higher pain tolerance (CPT and PPT) in the athletes studied was related to specific psychological features. The obtained results of temperamental characteristics may indicate higher resilience of the nervous system in combat athletes in comparison to non-athletes. Copyright © 2017 Elsevier Inc. All rights reserved.

Effect of sympathetic activity on capsaicin-evoked pain, hyperalgesia, and vasodilatation.

PubMed

Baron, R; Wasner, G; Borgstedt, R; Hastedt, E; Schulte, H; Binder, A; Kopper, F; Rowbotham, M; Levine, J D; Fields, H L

1999-03-23

Painful nerve and tissue injuries can be exacerbated by activity in sympathetic neurons. The mechanisms of sympathetically maintained pain (SMP) are unclear. To determine the effect of cutaneous sympathetic activity on pain induced by primary afferent C-nociceptor sensitization with capsaicin in humans. In healthy volunteers capsaicin was applied topically (n = 12) or injected into the forearm skin (n = 10) to induce spontaneous pain, dynamic and punctate mechanical hyperalgesia, and antidromic (axon reflex) vasodilatation (flare). Intensity of pain and hyperalgesia, axon reflex vasodilatation (laser Doppler), and flare size and area of hyperalgesia (planimetry) were assessed. The local skin temperature at the application and measurement sites was kept constant at 35 degrees C. In each individual the analyses were performed during the presence of high and low sympathetic skin activity induced by whole-body cooling and warming with a thermal suit. By this method sympathetic vasoconstrictor activity is modulated in the widest range that can be achieved physiologically. The degree of vasoconstrictor discharge was monitored by measuring skin blood flow (laser Doppler) and temperature (infrared thermometry) at the index finger. The intensity and spatial distribution of capsaicin-evoked spontaneous pain and dynamic and punctate mechanical hyperalgesia were identical during the presence of high and low sympathetic discharge. Antidromic vasodilatation and flare size were significantly diminished when sympathetic vasoconstrictor neurons were excited. Cutaneous sympathetic vasoconstrictor activity does not influence spontaneous pain and mechanical hyperalgesia after capsaicin-induced C-nociceptor sensitization. When using physiologic stimulation of sympathetic activity, the capsaicin model is not useful for elucidating mechanisms of SMP. In neuropathic pain states with SMP, different mechanisms may be present.

Quantitative sensory testing response patterns to capsaicin- and ultraviolet-B–induced local skin hypersensitization in healthy subjects: a machine-learned analysis

PubMed Central

Lötsch, Jörn; Geisslinger, Gerd; Heinemann, Sarah; Lerch, Florian; Oertel, Bruno G.; Ultsch, Alfred

2018-01-01

Abstract The comprehensive assessment of pain-related human phenotypes requires combinations of nociceptive measures that produce complex high-dimensional data, posing challenges to bioinformatic analysis. In this study, we assessed established experimental models of heat hyperalgesia of the skin, consisting of local ultraviolet-B (UV-B) irradiation or capsaicin application, in 82 healthy subjects using a variety of noxious stimuli. We extended the original heat stimulation by applying cold and mechanical stimuli and assessing the hypersensitization effects with a clinically established quantitative sensory testing (QST) battery (German Research Network on Neuropathic Pain). This study provided a 246 × 10-sized data matrix (82 subjects assessed at baseline, following UV-B application, and following capsaicin application) with respect to 10 QST parameters, which we analyzed using machine-learning techniques. We observed statistically significant effects of the hypersensitization treatments in 9 different QST parameters. Supervised machine-learned analysis implemented as random forests followed by ABC analysis pointed to heat pain thresholds as the most relevantly affected QST parameter. However, decision tree analysis indicated that UV-B additionally modulated sensitivity to cold. Unsupervised machine-learning techniques, implemented as emergent self-organizing maps, hinted at subgroups responding to topical application of capsaicin. The distinction among subgroups was based on sensitivity to pressure pain, which could be attributed to sex differences, with women being more sensitive than men. Thus, while UV-B and capsaicin share a major component of heat pain sensitization, they differ in their effects on QST parameter patterns in healthy subjects, suggesting a lack of redundancy between these models. PMID:28700537

[Current concepts in pathophysiology of CRPS I].

PubMed

Nickel, F T; Maihöfner, C

2010-02-01

Knowledge about the pathophysiology underlying the complex regional pain syndrome (CRPS) has increased over the last years. Classically, CRPS has been considered to be mainly driven by sympathetic dysfunction with sympathetically maintained pain being its major pathogenetic mechanism. Currently, the disease is understood as result of a complex interplay between altered somatosensory, motor, autonomic and inflammatory systems. Peripheral and central sensitization is a common feature in CRPS as in other neuropathic pain syndromes. One important mechanism is the sensitization of spinal dorsal horn cells via activation of postsynaptic NMDA-receptors by chronic C-fiber input. Differential activity of endogenous pain modulating systems may play a pivotal role in the development of CRPS, too. Neuronal plasticity of the somatosensory cortex accounts for central sensory signs. Also the motor system is subject to central adaptive changes in patients with CRPS. Calcitonin-gene related peptide (CGRP) and substance P mediate neurogenic inflammation. Additionally other proinflammatory cytokines involved in the inflammatory response in CRPS have been identified. In terms of the sympathetic nervous system, recent evidence rather points to a sensitization of adrenergic receptors than to increased efferent sympathetic activity. Particularly the expression of alpha (1)-adrenoceptors on nociceptive C-fibers may play a major role. These pathophysiological ideas do not exclude each other. In fact they complement one another. The variety of the involved systems may explain the versatile clinical picture of CRPS. Georg Thieme Verlag KG Stuttgart, New York.

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

Neurotrophins and Migraine.

PubMed

Martins, L B; Teixeira, A L; Domingues, R B

2017-01-01

Neurotrophins (NTs) have been implicated in generation and modulation of nociceptive pathways. Change in NTs levels is associated with painful conditions and neurological diseases such as migraine. Currently, it is generally recognized that migraine headaches result from the activation and sensitization of trigeminal sensory afferent fibers leading to neuropeptides release such as calcitonin gene-related peptide (CGRP) and substance P (SP). This triggers an inflammatory cascade causing a neurogenic inflammation. The agents responsible for trigeminal activation and release of neuropeptides are still unclear. It is known that the transient receptor potential vanilloid receptor-1 (TRPV1) is an important mediator of CGRP and SP release. TRPV1 is closely associated with tyrosine receptors kinases (Trk), which are NTs receptors. NTs can act on TRPV1 increasing its sensitivity to painful stimuli, therefore predisposing to hyperalgesia. Upregulation of ion channels and pain receptors in dorsal root ganglion neurons may be alternative mechanisms by which NTs contribute to pain development. Only a few studies have been performed to investigate the role of NTs in migraine. These studies have reported changes in NTs levels in migraine patients either during the migraine attack or in free-headache periods. © 2017 Elsevier Inc. All rights reserved.

The Potential Utility of the Patient Health Questionnaire as a Screener for Psychiatric Comorbidity in a Chronic Disabling Occupational Musculoskeletal Disorder Population.

PubMed

Asih, Sali; Mayer, Tom G; Bradford, E McKenna; Neblett, Randy; Williams, Mark J; Hartzell, Meredith M; Gatchel, Robert J

2016-02-01

The patient health questionnaire (PHQ) is designed for screening psychopathology in primary care settings. However, little is known about its clinical utility in other chronic pain populations, which usually have high psychiatric comorbidities. A consecutive cohort of 546 patients with chronic disabling occupational musculoskeletal disorder (CDOMD) was administered and compared upon psychosocial assessments, including the PHQ and a structured clinical interview for DSM-IV (SCID). Four PHQ modules were assessed: major depressive disorder (MDD), generalized anxiety disorder (GAD), panic disorder (PD), and alcohol use disorders (AUD) [including both alcohol abuse and dependence]. Based on the SCID diagnosis, sensitivity and specificity were determined. The specificity of the PHQ ranged from moderate to high for all 4 PHQ modules (MDD, 0.79; GAD, 0.67; PD, 0.89; AUD, 0.97). However, the sensitivity was relatively low: MDD (0.58); GAD (0.61); PD (0.49); and AUD (0.24). The PHQ was also associated with psychosocial variables. Patients whose PHQ showed MDD, GAD, or PD reported significantly more depressive symptoms and perceived disability than patients who did not (Ps < 0.001). Patients with MDD or GAD reported significantly higher pain than those without (Ps < 0.001). The strong specificity of the PHQ appears to be its primary strength for this cohort. Due to its high specificity, the PHQ could be employed as an additional screening tool to help rule out potential psychiatric comorbidity in patients with CDOMD. The low sensitivity of the PHQ in this population, however, remains a weakness of the PHQ. © 2015 World Institute of Pain.

Racial Bias in Neural Response for Pain Is Modulated by Minimal Group

PubMed Central

Shen, Fengtao; Hu, Yang; Fan, Mingxia; Wang, Huimin; Wang, Zhaoxin

2018-01-01

Whether empathic racial bias could be modulated is a subject of intense interest. The present study was carried out to explore whether empathic racial bias for pain is modulated by minimal group. Chinese/Western faces with neutral expressions receiving painful (needle penetration) or non-painful (Q-tip touch) stimulation were presented. Participants were asked to rate the pain intensity felt by Chinese/Western models of ingroup/outgroup members. Their implicit racial bias were also measured. Two lines of evidence indicated that the anterior cingulate cortex (ACC) was modulated by racial bias: (1) Chinese models elicited stronger activity than Western did in the ACC, and (2) activity in the ACC was modulated by implicit racial bias. Whereas the right anterior insula (rAI) were modulated by ingroup bias, in which ingroup member elicited stronger activity than outgroup member did. Furthermore, activity in the ACC was modulated by activity of rAI (i.e., ingroup bias) in the pain condition, while activity in the rAI was modulated by activity of ACC (i.e., racial bias) in the nopain condition. Our results provide evidence that there are different neural correlates for racial bias and ingroup bias, and neural racial bias for pain can be modulated by minimal group. PMID:29379429

Racial Bias in Neural Response for Pain Is Modulated by Minimal Group.

PubMed

Shen, Fengtao; Hu, Yang; Fan, Mingxia; Wang, Huimin; Wang, Zhaoxin

2017-01-01

Whether empathic racial bias could be modulated is a subject of intense interest. The present study was carried out to explore whether empathic racial bias for pain is modulated by minimal group. Chinese/Western faces with neutral expressions receiving painful (needle penetration) or non-painful (Q-tip touch) stimulation were presented. Participants were asked to rate the pain intensity felt by Chinese/Western models of ingroup/outgroup members. Their implicit racial bias were also measured. Two lines of evidence indicated that the anterior cingulate cortex (ACC) was modulated by racial bias: (1) Chinese models elicited stronger activity than Western did in the ACC, and (2) activity in the ACC was modulated by implicit racial bias. Whereas the right anterior insula (rAI) were modulated by ingroup bias, in which ingroup member elicited stronger activity than outgroup member did. Furthermore, activity in the ACC was modulated by activity of rAI (i.e., ingroup bias) in the pain condition, while activity in the rAI was modulated by activity of ACC (i.e., racial bias) in the nopain condition. Our results provide evidence that there are different neural correlates for racial bias and ingroup bias, and neural racial bias for pain can be modulated by minimal group.

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

PubMed

Granovsky, Yelena

2013-09-01

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

Teaching Pain Management in Interprofessional Medical Education: A Review of Three Portal of Geriatric Online Education Modules.

PubMed

Madaus, Stacy M; Lim, Lionel S

2016-10-01

Chronic pain is an international healthcare crisis that affects an estimated 1.5 billion individuals worldwide, but pain management is not emphasized in the medical school curriculum, and thus supplemental education is essential. The Portal of Geriatric Online Education (POGOe) is a free repository of teaching modules for use by geriatric educators and learners. This article highlights three teaching modules available on this site: It's My Old Back Again: An Approach to Diagnosing and Managing Back Pain in the Older Adult (POGOe ID: 21670), Computer Based Learning Workbook, Third Edition module on Pain Management (POGOe ID: 21036), and Aging Q3 Curriculum on Pain Management of Older Adult Patients (POGOe ID: 21187). These modules were chosen based on their ability to address the major topics that the International Association for the Study of Pain proposes should be included in medical school curricula: mulitdimensional nature of pain, pain assessment and measurement, management of pain, and clinical conditions resulting in pain in older adults. They were also selected for their ability to be adapted for interprofessional education and how well they integrate basic science and clinical principles. © 2016, Copyright the Authors Journal compilation © 2016, The American Geriatrics Society.

Visceral Pain: The Neurophysiological Mechanism

PubMed Central

Sengupta, Jyoti N.

2011-01-01

The mechanism of visceral pain is still less understood compared with that of somatic pain. This is primarily due to the diverse nature of visceral pain compounded by multiple factors such as sexual dimorphism, psychological stress, genetic trait, and the nature of predisposed disease. Due to multiple contributing factors there is an enormous challenge to develop animal models that ideally mimic the exact disease condition. In spite of that, it is well recognized that visceral hypersensitivity can occur due to (1) sensitization of primary sensory afferents innervating the viscera, (2) hyperexcitability of spinal ascending neurons (central sensitization) receiving synaptic input from the viscera, and (3) dysregulation of descending pathways that modulate spinal nociceptive transmission. Depending on the type of stimulus condition, different neural pathways are involved in chronic pain. In early-life psychological stress such as maternal separation, chronic pain occurs later in life due to dysregulation of the hypothalamic–pituitary–adrenal axis and significant increase in corticotrophin releasing factor (CRF) secretion. In contrast, in early-life inflammatory conditions such as colitis and cystitis, there is dysregulation of the descending opioidergic system that results excessive pain perception (i.e., visceral hyperalgesia). Functional bowel disorders and chronic pelvic pain represent unexplained pain that is not associated with identifiable organic diseases. Often pain overlaps between two organs and approximately 35% of patients with chronic pelvic pain showed significant improvement when treated for functional bowel disorders. Animal studies have documented that two main components such as (1) dichotomy of primary afferent fibers innervating two pelvic organs and (2) common convergence of two afferent fibers onto a spinal dorsal horn are contributing factors for organ-to-organ pain overlap. With reports emerging about the varieties of peptide molecules involved in the pathological conditions of visceral pain, it is expected that better therapy will be achieved relatively soon to manage chronic visceral pain. PMID:19655104

Pain Sensitivity Subgroups in Individuals With Spine Pain: Potential Relevance to Short-Term Clinical Outcome

PubMed Central

Bialosky, Joel E.; Robinson, Michael E.

2014-01-01

Background Cluster analysis can be used to identify individuals similar in profile based on response to multiple pain sensitivity measures. There are limited investigations into how empirically derived pain sensitivity subgroups influence clinical outcomes for individuals with spine pain. Objective The purposes of this study were: (1) to investigate empirically derived subgroups based on pressure and thermal pain sensitivity in individuals with spine pain and (2) to examine subgroup influence on 2-week clinical pain intensity and disability outcomes. Design A secondary analysis of data from 2 randomized trials was conducted. Methods Baseline and 2-week outcome data from 157 participants with low back pain (n=110) and neck pain (n=47) were examined. Participants completed demographic, psychological, and clinical information and were assessed using pain sensitivity protocols, including pressure (suprathreshold pressure pain) and thermal pain sensitivity (thermal heat threshold and tolerance, suprathreshold heat pain, temporal summation). A hierarchical agglomerative cluster analysis was used to create subgroups based on pain sensitivity responses. Differences in data for baseline variables, clinical pain intensity, and disability were examined. Results Three pain sensitivity cluster groups were derived: low pain sensitivity, high thermal static sensitivity, and high pressure and thermal dynamic sensitivity. There were differences in the proportion of individuals meeting a 30% change in pain intensity, where fewer individuals within the high pressure and thermal dynamic sensitivity group (adjusted odds ratio=0.3; 95% confidence interval=0.1, 0.8) achieved successful outcomes. Limitations Only 2-week outcomes are reported. Conclusions Distinct pain sensitivity cluster groups for individuals with spine pain were identified, with the high pressure and thermal dynamic sensitivity group showing worse clinical outcome for pain intensity. Future studies should aim to confirm these findings. PMID:24764070

Calcium channel modulation as a target in chronic pain control

PubMed Central

Montagut‐Bordas, Carlota; Dickenson, Anthony H

2017-01-01

Neuropathic pain remains poorly treated for large numbers of patients, and little progress has been made in developing novel classes of analgesics. To redress this issue, ziconotide (Prialt™) was developed and approved as a first‐in‐class synthetic version of ω‐conotoxin MVIIA, a peptide blocker of Cav2.2 channels. Unfortunately, the impracticalities of intrathecal delivery, low therapeutic index and severe neurological side effects associated with ziconotide have restricted its use to exceptional circumstances. Ziconotide exhibits no state or use‐dependent block of Cav2.2 channels; activation state‐dependent blockers were hypothesized to circumvent the side effects of state‐independent blockers by selectively targeting high‐frequency firing of nociceptive neurones in chronic pain states, thus alleviating aberrant pain but not affecting normal sensory transduction. Unfortunately, numerous drugs, including state‐dependent calcium channel blockers, have displayed efficacy in preclinical models but have subsequently been disappointing in clinical trials. In recent years, it has become more widely acknowledged that trans‐aetiological sensory profiles exist amongst chronic pain patients and may indicate similar underlying mechanisms and drug sensitivities. Heterogeneity amongst patients, a reliance on stimulus‐evoked endpoints in preclinical studies and a failure to utilize translatable endpoints, all are likely to have contributed to negative clinical trial results. We provide an overview of how electrophysiological and operant‐based assays provide insight into sensory and affective aspects of pain in animal models and how these may relate to chronic pain patients in order to improve the bench‐to‐bedside translation of calcium channel modulators. Linked Articles This article is part of a themed section on Recent Advances in Targeting Ion Channels to Treat Chronic Pain. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.12/issuetoc PMID:28320042

Nitroxyl inhibits overt pain-like behavior in mice: role of cGMP/PKG/ATP-sensitive potassium channel signaling pathway

PubMed Central

Staurengo-Ferrari, Larissa; Zarpelon, Ana C.; Longhi-Balbinot, Daniela T.; Marchesi, Mario; Cunha, Thiago M.; Alves-Filho, José C.; Cunha, Fernando Q.; Ferreira, Sergio H.; Casagrande, Rubia; Miranda, Katrina M.; Verri, Waldiceu A.

2014-01-01

Background Several lines of evidence have indicated that nitric oxide (NO) plays complex and diverse roles in modulation of pain/analgesia. However, the roles of charged and uncharged congeners of NO are less well understood. In the present study, the antinociceptive effect of the nitroxyl (HNO) donor, Angeli’s salt (Na2N2O3; AS) was investigated in models of overt pain-like behavior. Moreover, whether the antinociceptive effect of nitroxyl was dependent on the activation of cGMP (cyclic guanosine monophosphate)/PKG (protein kinase G)/ATP-sensitive potassium channels was addressed. Methods The antinociceptive effect of AS was evaluated on phenyl-p-benzoquinone (PBQ)- and acetic acid-induced writhings and via the formalin test. In addition, pharmacological treatments targeting guanylate cyclase (ODQ), PKG (KT5923) and ATP-sensitive potassium channel (glybenclamide) were used. Results PBQ and acetic acid induced significant writhing responses over 20 min. The nociceptive response in these models were significantly reduced in a dose-dependent manner by subcutaneous pre-treatment with AS. Furthermore, AS also inhibited both phases of the formalin test. Subsequently, the inhibitory effect of AS in writhing and flinching responses were prevented by ODQ, KT5823 and glybenclamide, although these inhibitors alone did not alter the writhing score. Furthermore, pretreatment with L-cysteine, an HNO scavenger, confirmed that the antinociceptive effect of AS depends on HNO. Conclusion The present study demonstrates the efficacy of a nitroxyl donor and its analgesic mechanisms in overt pain-like behavior by activating the cGMP/PKG/ATP-sensitive potassium channel (K+) signaling pathway. PMID:24948073

The stress regulator FKBP51: a novel and promising druggable target for the treatment of persistent pain states across sexes.

PubMed

Maiarù, Maria; Morgan, Oakley B; Mao, Tianqi; Breitsamer, Michaela; Bamber, Harry; Pöhlmann, Max; Schmidt, Mathias V; Winter, Gerhard; Hausch, Felix; Géranton, Sandrine M

2018-03-12

It is well established that FKBP51 regulates the stress system by modulating the sensitivity of the glucocorticoid receptor to stress hormones. Recently, we have demonstrated that FKBP51 also drives long-term inflammatory pain states in male mice by modulating glucocorticoid signalling at spinal cord level. Here, we explored the potential of FKBP51 as a new pharmacological target for the treatment of persistent pain across the sexes. First, we demonstrated that FKBP51 regulates long-term pain states of different aetiologies independently of sex. Deletion of FKBP51 reduced the mechanical hypersensitivity seen in joint inflammatory and neuropathic pain states in female and male mice. Furthermore, FKBP51 deletion also reduced the hypersensitivity seen in a translational model of chemotherapy-induced pain. Interestingly, these 3 pain states were associated with changes in glucocorticoid signalling, as indicated by the increased expression, at spinal cord level, of the glucocorticoid receptor isoform associated with glucocorticoid resistance, GRβ, and increased levels of plasma corticosterone. These pain states were also accompanied by an upregulation of interleukin-6 in the spinal cord. Crucially, we were able to pharmacologically reduce the severity of the mechanical hypersensitivity seen in these 3 models of persistent pain with the unique FKBP51 ligand SAFit2. When SAFit2 was combined with a state-of-the-art vesicular phospholipid gel formulation for slow release, a single injection of SAFit2 offered pain relief for at least 7 days. We therefore propose the pharmacological blockade of FKBP51 as a new approach for the treatment of persistent pain across sexes, likely in humans as well as rodents.This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Personalized Pain Medicine: The Clinical Value of Psychophysical Assessment of Pain Modulation Profile

PubMed Central

Granovsky, Yelena; Yarnitsky, David

2013-01-01

Experimental pain stimuli can be used to simulate patients’ pain experience. We review recent developments in psychophysical pain testing, focusing on the application of the dynamic tests—conditioned pain modulation (CPM) and temporal summation (TS). Typically, patients with clinical pain of various types express either less efficient CPM or enhanced TS, or both. These tests can be used in prediction of incidence of acquiring pain and of its intensity, as well as in assisting the correct choice of analgesic agents for individual patients. This can help to shorten the commonly occurring long and frustrating process of adjusting analgesic agents to the individual patients. We propose that evaluating pain modulation can serve as a step forward in individualizing pain medicine. PMID:24228167

Personalized pain medicine: the clinical value of psychophysical assessment of pain modulation profile.

PubMed

Granovsky, Yelena; Yarnitsky, David

2013-01-01

Experimental pain stimuli can be used to simulate patients' pain experience. We review recent developments in psychophysical pain testing, focusing on the application of the dynamic tests-conditioned pain modulation (CPM) and temporal summation (TS). Typically, patients with clinical pain of various types express either less efficient CPM or enhanced TS, or both. These tests can be used in prediction of incidence of acquiring pain and of its intensity, as well as in assisting the correct choice of analgesic agents for individual patients. This can help to shorten the commonly occurring long and frustrating process of adjusting analgesic agents to the individual patients. We propose that evaluating pain modulation can serve as a step forward in individualizing pain medicine.

The role of endogenous molecules in modulating pain through transient receptor potential vanilloid 1 (TRPV1)

PubMed Central

Morales-Lázaro, Sara L; Simon, Sidney A; Rosenbaum, Tamara

2013-01-01

Pain is a physiological response to a noxious stimulus that decreases the quality of life of those sufferring from it. Research aimed at finding new therapeutic targets for the treatment of several maladies, including pain, has led to the discovery of numerous molecular regulators of ion channels in primary afferent nociceptive neurons. Among these receptors is TRPV1 (transient receptor potential vanilloid 1), a member of the TRP family of ion channels. TRPV1 is a calcium-permeable channel, which is activated or modulated by diverse exogenous noxious stimuli such as high temperatures, changes in pH, and irritant and pungent compounds, and by selected molecules released during tissue damage and inflammatory processes. During the last decade the number of endogenous regulators of TRPV1's activity has increased to include lipids that can negatively regulate TRPV1, as is the case for cholesterol and PIP2 (phosphatidylinositol 4,5-biphosphate) while, in contrast, other lipids produced in response to tissue injury and ischaemic processes are known to positively regulate TRPV1. Among the latter, lysophosphatidic acid activates TRPV1 while amines such as N-acyl-ethanolamines and N-acyl-dopamines can sensitize or directly activate TRPV1. It has also been found that nucleotides such as ATP act as mediators of chemically induced nociception and pain and gases, such as hydrogen sulphide and nitric oxide, lead to TRPV1 activation. Finally, the products of lipoxygenases and omega-3 fatty acids among other molecules, such as divalent cations, have also been shown to endogenously regulate TRPV1 activity. Here we provide a comprehensive review of endogenous small molecules that regulate the function of TRPV1. Acting through mechanisms that lead to sensitization and desensitization of TRPV1, these molecules regulate pathways involved in pain and nociception. Understanding how these compounds modify TRPV1 activity will allow us to comprehend how some pathologies are associated with its deregulation. PMID:23613529

The role of endogenous molecules in modulating pain through transient receptor potential vanilloid 1 (TRPV1).

PubMed

Morales-Lázaro, Sara L; Simon, Sidney A; Rosenbaum, Tamara

2013-07-01

Pain is a physiological response to a noxious stimulus that decreases the quality of life of those sufferring from it. Research aimed at finding new therapeutic targets for the treatment of several maladies, including pain, has led to the discovery of numerous molecular regulators of ion channels in primary afferent nociceptive neurons. Among these receptors is TRPV1 (transient receptor potential vanilloid 1), a member of the TRP family of ion channels. TRPV1 is a calcium-permeable channel, which is activated or modulated by diverse exogenous noxious stimuli such as high temperatures, changes in pH, and irritant and pungent compounds, and by selected molecules released during tissue damage and inflammatory processes. During the last decade the number of endogenous regulators of TRPV1's activity has increased to include lipids that can negatively regulate TRPV1, as is the case for cholesterol and PIP2 (phosphatidylinositol 4,5-biphosphate) while, in contrast, other lipids produced in response to tissue injury and ischaemic processes are known to positively regulate TRPV1. Among the latter, lysophosphatidic acid activates TRPV1 while amines such as N-acyl-ethanolamines and N-acyl-dopamines can sensitize or directly activate TRPV1. It has also been found that nucleotides such as ATP act as mediators of chemically induced nociception and pain and gases, such as hydrogen sulphide and nitric oxide, lead to TRPV1 activation. Finally, the products of lipoxygenases and omega-3 fatty acids among other molecules, such as divalent cations, have also been shown to endogenously regulate TRPV1 activity. Here we provide a comprehensive review of endogenous small molecules that regulate the function of TRPV1. Acting through mechanisms that lead to sensitization and desensitization of TRPV1, these molecules regulate pathways involved in pain and nociception. Understanding how these compounds modify TRPV1 activity will allow us to comprehend how some pathologies are associated with its deregulation.

αCGRP is essential for algesic exocytotic mobilization of TRPV1 channels in peptidergic nociceptors

PubMed Central

Devesa, Isabel; Ferrándiz-Huertas, Clotilde; Mathivanan, Sakthikumar; Wolf, Christoph; Luján, Rafael; Changeux, Jean-Pierre; Ferrer-Montiel, Antonio

2014-01-01

Proalgesic sensitization of peripheral nociceptors in painful syndromes is a complex molecular process poorly understood that involves mobilization of thermosensory receptors to the neuronal surface. However, whether recruitment of vesicular thermoTRP channels is a general mechanism underlying sensitization of all nociceptor types or is subtype-specific remains controversial. We report that sensitization-induced Ca2+-dependent exocytotic insertion of transient receptor potential vanilloid 1 (TRPV1) receptors to the neuronal plasma membrane is a mechanism specifically used by peptidergic nociceptors to potentiate their excitability. Notably, we found that TRPV1 is present in large dense-core vesicles (LDCVs) that were mobilized to the neuronal surface in response to a sensitizing insult. Deletion or silencing of calcitonin-gene–related peptide alpha (αCGRP) gene expression drastically reduced proalgesic TRPV1 potentiation in peptidergic nociceptors by abrogating its Ca2+-dependent exocytotic recruitment. These findings uncover a context-dependent molecular mechanism of TRPV1 algesic sensitization and a previously unrecognized role of αCGRP in LDCV mobilization in peptidergic nociceptors. Furthermore, these results imply that concurrent secretion of neuropeptides and channels in peptidergic C-type nociceptors facilitates a rapid modulation of pain signaling. PMID:25489075

Brain imaging of pain sensitization in patients with knee osteoarthritis.

PubMed

Pujol, Jesus; Martínez-Vilavella, Gerard; Llorente-Onaindia, Jone; Harrison, Ben J; López-Solà, Marina; López-Ruiz, Marina; Blanco-Hinojo, Laura; Benito, Pere; Deus, Joan; Monfort, Jordi

2017-09-01

A relevant aspect in osteoarthritic pain is neural sensitization. This phenomenon involves augmented responsiveness to painful stimulation and may entail a clinically worse prognosis. We used functional magnetic resonance imaging (fMRI) to study pain sensitization in patients with knee osteoarthritis. Sixty patients were recruited and pain sensitization was clinically defined on the basis of regional spreading of pain (spreading sensitization) and increased pain response to repeated stimulation (temporal summation). Functional magnetic resonance imaging testing involved assessing brain responses to both pressure and heat stimulation. Thirty-three patients (55%) showed regional pain spreading (simple sensitization) and 19 patients (32%) showed both regional spreading and temporal summation. Sensitized patients were more commonly women. Direct painful pressure stimulation of the joint (articular interline) robustly activated all of the neural elements typically involved in pain perception, but did not differentiate sensitized and nonsensitized patients. Painful pressure stimulation on the anterior tibial surface (sensitized site) evoked greater activation in sensitized patients in regions typically involved in pain and also beyond these regions, extending to the auditory, visual, and ventral sensorimotor cortices. Painful heat stimulation of the volar forearm did not discriminate the sensitization phenomenon. Results confirm the high prevalence of pain sensitization secondary to knee osteoarthritis. Relevantly, the sensitization phenomenon was associated with neural changes extending beyond strict pain-processing regions with enhancement of activity in general sensory, nonnociceptive brain areas. This effect is in contrast to the changes previously identified in primary pain sensitization in fibromyalgia patients presenting with a weakening of the general sensory integration.

Efficient conditioned pain modulation despite pain persistence in painful diabetic neuropathy.

PubMed

Granovsky, Yelena; Nahman-Averbuch, Hadas; Khamaisi, Mogher; Granot, Michal

2017-05-01

Alleviation of pain, by either medical or surgical therapy, is accompanied by transition from less efficient, or pro-nociceptive, to efficient conditioned pain modulation (CPM). Spontaneous decrease or resolution of pain with disease progression is reported for some patients with painful diabetic neuropathy (PDN). To explore whether CPM changes similarly in parallel to spontaneous resolution of pain in PDN patients. In this cross-sectional study, thirty-three patients with PDN underwent psychophysical assessment of pain modulation on the forearm, remote from the clinical pain. Pain duration was not correlated with neuropathic pain intensity, yet, it correlated with CPM efficiency; patients with longer pain duration had same pain level, but more efficient CPM than those with short-pain duration (ρ = -0.417; P = 0.025, Spearman correlation). Patients with pain more than 2 years (median split) expressed efficient CPM that was not different from that of healthy controls. These patients also had lower temporal summation of pain than the short-pain duration patients group ( P < 0.05). The 2 patient groups did not differ in clinical pain characteristics or use of analgesics. Pro-nociception, expressed by less efficient CPM and high temporal summation that usually accompanies clinical painful conditions, seems to "normalize" with chronicity of the pain syndrome. This is despite continuing pain, suggesting that pro-nociceptivity in pain syndromes is multifactorial. Because the pain modulation profile affects success of therapy, this suggests that different drugs might express different efficacy pending on duration of the pain in patients with PDN.

Current Concepts of Bruxism.

PubMed

Manfredini, Daniele; Serra-Negra, Junia; Carboncini, Fabio; Lobbezoo, Frank

Bruxism is a common phenomenon, and emerging evidence suggests that biologic, psychologic, and exogenous factors have greater involvement than morphologic factors in its etiology. Diagnosis should adopt the grading system of possible, probable, and definite. In children, it could be a warning sign of certain psychologic disorders. The proposed mechanism for the bruxism-pain relationship at the individual level is that stress sensitivity and anxious personality traits may be responsible for bruxism activities that may lead to temporomandibular pain, which in turn is modulated by psychosocial factors. A multiple-P (plates, pep talk, psychology, pills) approach involving reversible treatments is recommended, and adult prosthodontic management should be based on a common-sense cautionary approach.

Pronociceptive pain modulation in patients with painful chemotherapy-induced polyneuropathy.

PubMed

Nahman-Averbuch, Hadas; Yarnitsky, David; Granovsky, Yelena; Sprecher, Elliot; Steiner, Mariana; Tzuk-Shina, Tzahala; Pud, Dorit

2011-08-01

Several chemotherapy agents induce polyneuropathy that is painful for some patients, but not for others. We assumed that these differences might be attributable to varying patterns of pain modulation. The aim of the present study was to evaluate pain modulation in such patients. Twenty-seven patients with chemotherapy-induced polyneuropathy were tested for detection thresholds (cold, warm, and mechanical) in both the forearm and foot, as well as for heat pain threshold, mechanical temporal summation (TS), and conditioned pain modulation (CPM; also known as the diffuse noxious inhibitory control-like effect), which were tested in the upper limbs. Positive correlations were found between clinical pain levels and both TS (r=0.52, P=0.005) and CPM (r=0.40, P=0.050) for all patients. In addition, higher TS was associated with less efficient CPM (r=0.56, P=0.004). The group of patients with painful polyneuropathy (n=12) showed a significantly higher warm detection threshold in the foot (P=0.03), higher TS (P<0.01), and less efficient CPM (P=0.03) in comparison to the group with nonpainful polyneuropathy. The painfulness of polyneuropathy is associated with a "pronociceptive" modulation pattern, which may be primary to the development of pain. The higher warm sensory thresholds in the painful polyneuropathy group suggest that the severity of polyneuropathy may be another factor in determining its painfulness. Copyright © 2011 U.S. Cancer Pain Relief Committee. Published by Elsevier Inc. All rights reserved.

Systematic mechanism-orientated approach to chronic pancreatitis pain.

PubMed

Bouwense, Stefan A W; de Vries, Marjan; Schreuder, Luuk T W; Olesen, Søren S; Frøkjær, Jens B; Drewes, Asbjørn M; van Goor, Harry; Wilder-Smith, Oliver H G

2015-01-07

Pain in chronic pancreatitis (CP) shows similarities with other visceral pain syndromes (i.e., inflammatory bowel disease and esophagitis), which should thus be managed in a similar fashion. Typical causes of CP pain include increased intrapancreatic pressure, pancreatic inflammation and pancreatic/extrapancreatic complications. Unfortunately, CP pain continues to be a major clinical challenge. It is recognized that ongoing pain may induce altered central pain processing, e.g., central sensitization or pro-nociceptive pain modulation. When this is present conventional pain treatment targeting the nociceptive focus, e.g., opioid analgesia or surgical/endoscopic intervention, often fails even if technically successful. If central nervous system pain processing is altered, specific treatment targeting these changes should be instituted (e.g., gabapentinoids, ketamine or tricyclic antidepressants). Suitable tools are now available to make altered central processing visible, including quantitative sensory testing, electroencephalograpy and (functional) magnetic resonance imaging. These techniques are potentially clinically useful diagnostic tools to analyze central pain processing and thus define optimum management approaches for pain in CP and other visceral pain syndromes. The present review proposes a systematic mechanism-orientated approach to pain management in CP based on a holistic view of the mechanisms involved. Future research should address the circumstances under which central nervous system pain processing changes in CP, and how this is influenced by ongoing nociceptive input and therapies. Thus we hope to predict which patients are at risk for developing chronic pain or not responding to therapy, leading to improved treatment of chronic pain in CP and other visceral pain disorders.

Clinical presentation and manual therapy for lower quadrant musculoskeletal conditions.

PubMed

Courtney, Carol A; Clark, Jeffrey D; Duncombe, Alison M; O'Hearn, Michael A

2011-11-01

Chronic lower quadrant injuries constitute a significant percentage of the musculoskeletal cases seen by clinicians. While impairments may vary, pain is often the factor that compels the patient to seek medical attention. Traumatic injury from sport is one cause of progressive chronic joint pain, particularly in the lower quarter. Recent studies have demonstrated the presence of peripheral and central sensitization mechanisms in different lower quadrant pain syndromes, such as lumbar spine related leg pain, osteoarthritis of the knee, and following acute injuries such as lateral ankle sprain and anterior cruciate ligament rupture. Proper management of lower quarter conditions should include assessment of balance and gait as increasing pain and chronicity may lead to altered gait patterns and falls. In addition, quantitative sensory testing may provide insight into pain mechanisms which affect management and prognosis of musculoskeletal conditions. Studies have demonstrated analgesic effects and modulation of spinal excitability with use of manual therapy techniques, with clinical outcomes of improved gait and functional ability. This paper will discuss the evidence which supports the use of manual therapy for lower quarter musculoskeletal dysfunction.

Pain hypervigilance is associated with greater clinical pain severity and enhanced experimental pain sensitivity among adults with symptomatic knee osteoarthritis

PubMed Central

Herbert, Matthew S.; Goodin, Burel R.; Pero, Samuel T.; Schmidt, Jessica K.; Sotolongo, Adriana; Bulls, Hailey W.; Glover, Toni L.; King, Christopher D.; Sibille, Kimberly T.; Cruz-Almeida, Yenisel; Staud, Roland; Fessler, Barri J.; Bradley, Laurence A.; Fillingim, Roger B.

2014-01-01

Background Pain hypervigilance is an important aspect of the fear-avoidance model of pain that may help explain individual differences in pain sensitivity among persons with knee osteoarthritis (OA). Purpose The purpose of this study was to examine the contribution of pain hypervigilance to clinical pain severity and experimental pain sensitivity in persons with symptomatic knee OA. Methods We analyzed cross-sectional data from 168 adults with symptomatic knee OA. Quantitative sensory testing was used to measure sensitivity to heat pain, pressure pain, and cold pain, as well as temporal summation of heat pain, a marker of central sensitization. Results Pain hypervigilance was associated with greater clinical pain severity, as well as greater pressure pain. Pain hypervigilance was also a significant predictor of temporal summation of heat pain. Conclusions Pain hypervigilance may be an important contributor to pain reports and experimental pain sensitivity among persons with knee OA. PMID:24352850

Emotional modulation of pain: is it the sensation or what we recall?

PubMed

Godinho, Fabio; Magnin, Michel; Frot, Maud; Perchet, Caroline; Garcia-Larrea, Luis

2006-11-01

Emotions modulate pain perception, although the mechanisms underlying this phenomenon remain unclear. In this study, we show that intensity reports significantly increased when painful stimuli were concomitant to images showing human pain, whereas pictures with identical emotional values but without somatic content failed to modulate pain. Early somatosensory responses (<200 ms) remained unmodified by emotions. Conversely, late responses showed a significant enhancement associated with increased pain ratings, localized to the right prefrontal, right temporo-occipital junction, and right temporal pole. In contrast to selective attention, which enhances pain ratings by increasing sensory gain, emotions triggered by seeing other people's pain did not alter processing in SI-SII (primary and second somatosensory areas), but may have biased the transfer to, and the representation of pain in short-term memory buffers (prefrontal), as well as the affective assignment to this representation (temporal pole). Memory encoding and recall, rather than sensory processing, appear to be modulated by empathy with others' physical suffering.

Brain network alterations in the inflammatory soup animal model of migraine.

PubMed

Becerra, Lino; Bishop, James; Barmettler, Gabi; Kainz, Vanessa; Burstein, Rami; Borsook, David

2017-04-01

Advances in our understanding of the human pain experience have shifted much of the focus of pain research from the periphery to the brain. Current hypotheses suggest that the progression of migraine depends on abnormal functioning of neurons in multiple brain regions. Accordingly, we sought to capture functional brain changes induced by the application of an inflammatory cocktail known as inflammatory soup (IS), to the dura mater across multiple brain networks. Specifically, we aimed to determine whether IS alters additional neural networks indirectly related to the primary nociceptive pathways via the spinal cord to the thalamus and cortex. IS comprises an acidic combination of bradykinin, serotonin, histamine and prostaglandin PGE2 and was introduced to basic pain research as a tool to activate and sensitize peripheral nociceptors when studying pathological pain conditions associated with allodynia and hyperalgesia. Using this model of intracranial pain, we found that dural application of IS in awake, fully conscious, rats enhanced thalamic, hypothalamic, hippocampal and somatosensory cortex responses to mechanical stimulation of the face (compared to sham synthetic interstitial fluid administration). Furthermore, resting state MRI data revealed altered functional connectivity in a number of networks previously identified in clinical chronic pain populations. These included the default mode, sensorimotor, interoceptive (Salience) and autonomic networks. The findings suggest that activation and sensitization of meningeal nociceptors by IS can enhance the extent to which the brain processes nociceptive signaling, define new level of modulation of affective and cognitive responses to pain; set new tone for hypothalamic regulation of autonomic outflow to the cranium; and change cerebellar functions. Copyright © 2017. Published by Elsevier B.V.

Brain network alterations in the inflammatory soup animal model of migraine

PubMed Central

Becerra, Lino; Bishop, James; Barmettler, Gabi; Kainz, Vanessa; Burstein, Rami; Borsook, David

2017-01-01

Advances in our understanding of the human pain experience have shifted much of the focus of pain research from the periphery to the brain. Current hypotheses suggest that the progression of migraine depends on abnormal functioning of neurons in multiple brain regions. Accordingly, we sought to capture functional brain changes induced by the application of an inflammatory cocktail known as inflammatory soup (IS), to the dura mater across multiple brain networks. Specifically, we aimed to determine whether IS alters additional neural networks indirectly related to the primary nociceptive pathways via the spinal cord to the thalamus and cortex. IS comprises an acidic combination of bradykinin, serotonin, histamine and prostaglandin PGE2 and was introduced to basic pain research as a tool to activate and sensitize peripheral nociceptors when studying pathological pain conditions associated with allodynia and hyperalgesia. Using this model of intracranial pain, we found that dural application of IS in awake, fully conscious, rats enhanced thalamic, hypothalamic, hippocampal and somatosensory cortex responses to mechanical stimulation of the face (compared to sham synthetic interstitial fluid administration). Furthermore, resting state MRI data revealed altered functional connectivity in a number of networks previously identified in clinical chronic pain populations. These included the default mode, sensorimotor, interoceptive (Salience) and autonomic networks. The findings suggest that activation and sensitization of meningeal nociceptors by IS can enhance the extent to which the brain processes nociceptive signaling, define new level of modulation of affective and cognitive responses to pain; set new tone for hypothalamic regulation of autonomic outflow to the cranium; and change cerebellar functions. PMID:28167076

Conditioned pain modulation predicts duloxetine efficacy in painful diabetic neuropathy.

PubMed

Yarnitsky, David; Granot, Michal; Nahman-Averbuch, Hadas; Khamaisi, Mogher; Granovsky, Yelena

2012-06-01

This study aims to individualize the selection of drugs for neuropathic pain by examining the potential coupling of a given drug's mechanism of action with the patient's pain modulation pattern. The latter is assessed by the conditioned pain modulation (CPM) and temporal summation (TS) protocols. We hypothesized that patients with a malfunctioning pain modulation pattern, such as less efficient CPM, would benefit more from drugs augmenting descending inhibitory pain control than would patients with a normal modulation pattern of efficient CPM. Thirty patients with painful diabetic neuropathy received 1 week of placebo, 1 week of 30 mg/d duloxetine, and 4 weeks of 60 mg/d duloxetine. Pain modulation was assessed psychophysically, both before and at the end of treatment. Patient assessment of drug efficacy, assessed weekly, was the study's primary outcome. Baseline CPM was found to be correlated with duloxetine efficacy (r=0.628, P<.001, efficient CPM is marked negative), such that less efficient CPM predicted efficacious use of duloxetine. Regression analysis (R(2)=0.673; P=.012) showed that drug efficacy was predicted only by CPM (P=.001) and not by pretreatment pain levels, neuropathy severity, depression level, or patient assessment of improvement by placebo. Furthermore, beyond its predictive value, the treatment-induced improvement in CPM was correlated with drug efficacy (r=-0.411, P=.033). However, this improvement occurred only in patients with less efficient CPM (16.8±16.0 to -1.1±15.5, P<.050). No predictive role was found for TS. In conclusion, the coupling of CPM and duloxetine efficacy highlights the importance of pain pathophysiology in the clinical decision-making process. This evaluative approach promotes personalized pain therapy. Copyright © 2012 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

Machine-learned analysis of the association of next-generation sequencing-based human TRPV1 and TRPA1 genotypes with the sensitivity to heat stimuli and topically applied capsaicin.

PubMed

Kringel, Dario; Geisslinger, Gerd; Resch, Eduard; Oertel, Bruno G; Thrun, Michael C; Heinemann, Sarah; Lötsch, Jörn

2018-03-27

Heat pain and its modulation by capsaicin varies among subjects in experimental and clinical settings. A plausible cause is a genetic component, of which TRPV1 ion channels, by their response to both heat and capsaicin, are primary candidates. However, TRPA1 channels can heterodimerize with TRPV1 channels and carry genetic variants reported to modulate heat pain sensitivity. To address the role of these candidate genes in capsaicin-induced hypersensitization to heat, pain thresholds acquired before and after topical application of capsaicin and TRPA1/TRPV1 exomic sequences derived by next-generation sequencing were assessed in n = 75 healthy volunteers and the genetic information comprised 278 loci. Gaussian mixture modeling indicated 2 phenotype groups with high or low capsaicin-induced hypersensitization to heat. Unsupervised machine learning implemented as swarm-based clustering hinted at differences in the genetic pattern between these phenotype groups. Several methods of supervised machine learning implemented as random forests, adaptive boosting, k-nearest neighbors, naive Bayes, support vector machines, and for comparison, binary logistic regression predicted the phenotype group association consistently better when based on the observed genotypes than when using a random permutation of the exomic sequences. Of note, TRPA1 variants were more important for correct phenotype group association than TRPV1 variants. This indicates a role of the TRPA1 and TRPV1 next-generation sequencing-based genetic pattern in the modulation of the individual response to heat-related pain phenotypes. When considering earlier evidence that topical capsaicin can induce neuropathy-like quantitative sensory testing patterns in healthy subjects, implications for future analgesic treatments with transient receptor potential inhibitors arise.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.

Pain modulatory phenotypes differentiate subgroups with different clinical and experimental pain sensitivity.

PubMed

Vaegter, Henrik B; Graven-Nielsen, Thomas

2016-07-01

Pain biomarkers are warranted for individualized pain management. Based on different pain modulatory phenotypes, the objectives of this study were to explore the existence of subgroups within patients with nonmalignant chronic pain and to investigate differences in clinical pain and pain hypersensitivity between subgroups. Cuff algometry was performed on lower legs in 400 patients with chronic pain to assess pressure pain threshold, pressure pain tolerance, temporal summation of pain (TSP: increase in pain scores to 10 repeated stimulations), and conditioned pain modulation (CPM: increase in cuff pressure pain threshold during cuff pain conditioning on the contralateral leg). Heat detection and heat pain thresholds at clinical painful and nonpainful body areas were assessed. Based on TSP and CPM, 4 distinct groups were formed: group 1 (n = 85) had impaired CPM and facilitated TSP; group 2 (n = 148) had impaired CPM and normal TSP; group 3 (n = 45) had normal CPM and facilitated TSP; and group 4 (n = 122) had normal CPM and normal TSP. Group 1 showed more pain regions than the other 3 groups (P < 0.001), indicating that impaired CPM and facilitated TSP play an important role in widespread pain. Groups 1 and 2 compared with group 4 had lower heat pain threshold at nonpainful areas and lower cuff pressure pain tolerance (P < 0.02), indicating that CPM plays a role for widespread hyperalgesia. Moreover, group 1 demonstrated higher clinical pain scores than group 4 (P < 0.05). Although not different between subgroups, patients were profiled on demographics, disability, pain catastrophizing, and fear of movement. Future research should investigate interventions tailored towards these subgroups.

Inventory of Personal Factors Influencing Conditioned Pain Modulation in Healthy People: A Systematic Literature Review.

PubMed

Hermans, Linda; Van Oosterwijck, Jessica; Goubert, Dorien; Goudman, Lisa; Crombez, Geert; Calders, Patrick; Meeus, Mira

2016-07-01

Conditioned pain modulation (CPM) is believed to play an important role in the development and exacerbation of chronic pain, because dysfunction of CPM is associated with a shift in balance between pain facilitation and pain inhibition. In many patients with central sensitization, CPM is less efficacious. Besides that, efficacy of CPM is highly variable in healthy people. Consequently, it seems that several individual variables may influence CPM. A systematic review examining personal factors influencing CPM was conducted. This systematic review follows the PRISMA guidelines. "Pubmed" and "Web of Science" were searched using different synonyms of CPM. Full-text clinical reports addressing the influence of personal factors on CPM in healthy adults were included. Checklists for RCTs and case-control studies provided by the Dutch Institute for Healthcare Improvement (CBO) and the Dutch Cochrane Centre were utilized to assess methodological quality. Levels of evidence and strength of conclusion were assigned using the CBO guidelines. Forty-six articles were identified that reported the influence of personal factors on CPM. Quality assessment revealed 10 studies with a methodological quality less than 50% wherefore they were excluded (21.8%), resulting in a general total methodological quality score of 72.5%. Overall younger adult age, male gender, ovulatory phase, positive expectations, attention to the conditioning stimulus, and carrier of the 5-HTTLPR long allele result in better CPM. It is advised for future studies to take these factors into account. Further research regarding the influence of oral contraceptives, catastrophizing, information about conditioning stimulation, distraction, physical activity, and genetics on CPM magnitude is required. © 2015 World Institute of Pain.

A novel paradigm to evaluate conditioned pain modulation in fibromyalgia.

PubMed

Schoen, Cynthia J; Ablin, Jacob N; Ichesco, Eric; Bhavsar, Rupal J; Kochlefl, Laura; Harris, Richard E; Clauw, Daniel J; Gracely, Richard H; Harte, Steven E

2016-01-01

Application of noxious stimulation to one body area reduces pain sensitivity in a remote body area through activation of an endogenous pain-inhibitory network, a behavioral phenomenon referred to as conditioned pain modulation (CPM). The efficiency of CPM is predictive of a variety of health outcomes, while impaired CPM has been associated with various chronic pain conditions. Current methods used to assess CPM vary widely, and interest in CPM method development remains strong. Here, we evaluated a novel method for assessing CPM in healthy controls and fibromyalgia (FM) patients using thumb pressure as both a test and conditioning stimulus. Sixteen female FM patients and 14 matched healthy controls underwent CPM testing with thumbnail pressure as the test stimulus, and either cold water or noxious pressure as the conditioning stimulus. CPM magnitude was evaluated as the difference in pain rating of the test stimulus applied before and during the conditioning stimulus. In healthy controls, application of either pressure or cold water conditioning stimulation induced CPM as evidenced by a significant reduction in test stimulus pain rating during conditioning ( P =0.007 and P =0.021, respectively). In contrast, in FM patients, neither conditioning stimulus induced a significant CPM effect ( P >0.274). There was a significant difference in CPM magnitude for FM patients compared to healthy controls with noxious pressure conditioning stimulation ( P =0.023); however, no significant difference in CPM was found between groups using cold water as a conditioning stimulus ( P =0.269). The current study demonstrates that thumbnail pressure can be used as both a test and conditioning stimulus in the assessment of CPM. This study further confirms previous findings of attenuated CPM in FM patients compared with healthy controls.

A novel paradigm to evaluate conditioned pain modulation in fibromyalgia

PubMed Central

Schoen, Cynthia J; Ablin, Jacob N; Ichesco, Eric; Bhavsar, Rupal J; Kochlefl, Laura; Harris, Richard E; Clauw, Daniel J; Gracely, Richard H; Harte, Steven E

2016-01-01

Introduction Application of noxious stimulation to one body area reduces pain sensitivity in a remote body area through activation of an endogenous pain-inhibitory network, a behavioral phenomenon referred to as conditioned pain modulation (CPM). The efficiency of CPM is predictive of a variety of health outcomes, while impaired CPM has been associated with various chronic pain conditions. Current methods used to assess CPM vary widely, and interest in CPM method development remains strong. Here, we evaluated a novel method for assessing CPM in healthy controls and fibromyalgia (FM) patients using thumb pressure as both a test and conditioning stimulus. Methods Sixteen female FM patients and 14 matched healthy controls underwent CPM testing with thumbnail pressure as the test stimulus, and either cold water or noxious pressure as the conditioning stimulus. CPM magnitude was evaluated as the difference in pain rating of the test stimulus applied before and during the conditioning stimulus. Results In healthy controls, application of either pressure or cold water conditioning stimulation induced CPM as evidenced by a significant reduction in test stimulus pain rating during conditioning (P=0.007 and P=0.021, respectively). In contrast, in FM patients, neither conditioning stimulus induced a significant CPM effect (P>0.274). There was a significant difference in CPM magnitude for FM patients compared to healthy controls with noxious pressure conditioning stimulation (P=0.023); however, no significant difference in CPM was found between groups using cold water as a conditioning stimulus (P=0.269). Conclusion The current study demonstrates that thumbnail pressure can be used as both a test and conditioning stimulus in the assessment of CPM. This study further confirms previous findings of attenuated CPM in FM patients compared with healthy controls. PMID:27713648

Efficient conditioned pain modulation despite pain persistence in painful diabetic neuropathy

PubMed Central

Granovsky, Yelena; Nahman-Averbuch, Hadas; Khamaisi, Mogher; Granot, Michal

2017-01-01

Abstract Introduction: Alleviation of pain, by either medical or surgical therapy, is accompanied by transition from less efficient, or pro-nociceptive, to efficient conditioned pain modulation (CPM). Spontaneous decrease or resolution of pain with disease progression is reported for some patients with painful diabetic neuropathy (PDN). Objectives: To explore whether CPM changes similarly in parallel to spontaneous resolution of pain in PDN patients. Methods: In this cross-sectional study, thirty-three patients with PDN underwent psychophysical assessment of pain modulation on the forearm, remote from the clinical pain. Results: Pain duration was not correlated with neuropathic pain intensity, yet, it correlated with CPM efficiency; patients with longer pain duration had same pain level, but more efficient CPM than those with short-pain duration (ρ = −0.417; P = 0.025, Spearman correlation). Patients with pain more than 2 years (median split) expressed efficient CPM that was not different from that of healthy controls. These patients also had lower temporal summation of pain than the short-pain duration patients group (P < 0.05). The 2 patient groups did not differ in clinical pain characteristics or use of analgesics. Conclusion: Pro-nociception, expressed by less efficient CPM and high temporal summation that usually accompanies clinical painful conditions, seems to “normalize” with chronicity of the pain syndrome. This is despite continuing pain, suggesting that pro-nociceptivity in pain syndromes is multifactorial. Because the pain modulation profile affects success of therapy, this suggests that different drugs might express different efficacy pending on duration of the pain in patients with PDN. PMID:29392208

Attention to pain! A neurocognitive perspective on attentional modulation of pain in neuroimaging studies.

PubMed

Torta, D M; Legrain, V; Mouraux, A; Valentini, E

2017-04-01

Several studies have used neuroimaging techniques to investigate brain correlates of the attentional modulation of pain. Although these studies have advanced the knowledge in the field, important confounding factors such as imprecise theoretical definitions of attention, incomplete operationalization of the construct under exam, and limitations of techniques relying on measuring regional changes in cerebral blood flow have hampered the potential relevance of the conclusions. Here, we first provide an overview of the major theories of attention and of attention in the study of pain to bridge theory and experimental results. We conclude that load and motivational/affective theories are particularly relevant to study the attentional modulation of pain and should be carefully integrated in functional neuroimaging studies. Then, we summarize previous findings and discuss the possible neural correlates of the attentional modulation of pain. We discuss whether classical functional neuroimaging techniques are suitable to measure the effect of a fluctuating process like attention, and in which circumstances functional neuroimaging can be reliably used to measure the attentional modulation of pain. Finally, we argue that the analysis of brain networks and spontaneous oscillations may be a crucial future development in the study of attentional modulation of pain, and why the interplay between attention and pain, as examined so far, may rely on neural mechanisms shared with other sensory modalities. Copyright © 2017 Elsevier Ltd. All rights reserved.

Unimpaired endogenous pain inhibition in the early phase of complex regional pain syndrome.

PubMed

Kumowski, N; Hegelmaier, T; Kolbenschlag, J; Maier, C; Mainka, T; Vollert, J; Enax-Krumova, E

2017-05-01

The complex regional pain syndrome (CRPS) is characterized by distal generalisation of pain beyond the initial trauma. This might be the result of impaired endogenous pain inhibition. We compared Conditioned Pain Modulation (CPM) between patients with CRPS (n = 24; pain: 4.5 ± 2.2, NRS 0-10; disease duration <1 year), neuralgia (n = 17; pain: 5.5 ± 1.1) and healthy subjects (n = 23) and its correlation with loss and gain of function as assessed by Quantitative Sensory Testing (QST). CPM was assessed with heat as test stimulus (TS) and cold water as conditioning stimulus (CS). The early CPM-effect was calculated as difference between heat pain during and before conditioning, the late CPM-effect, 5 minutes after and before conditioning, respectively. Heat pain decreased comparably after CS in all groups, resulting in a significant CPM-effect (healthy: -12.5 ± 12.4, NRS 0-100; CRPS: -14.7 ± 15.7; neuralgia: -7.9 ± 9.8; p < 0.001). When compared to healthy subjects, heat pain declined significantly steeper in CRPS patients (healthy: -2.0 ± 5.5, NRS 0-100/10 s; CRPS: -6.3 ± 8.1; p < 0.05). Only CRPS patients demonstrated a late CPM effect (-6.0 ± 9.0, p < 0.005). Neither spontaneous pain nor any QST parameter correlated with CPM, with the exception of a decreased cold pain threshold, which correlated with an enhanced CPM in CRPS patients only (r = -0.456, p < 0.05). An impairment of endogenous pain inhibition does not explain the extent of pain in the early stage of CRPS or in neuralgia. The unexpectedly high CPM in CRPS patients might result from activation of the intact descending pathways in response to central sensitization, as cold hyperalgesia correlated with the CPM-effect. Conditioned pain modulation (CPM) is not impaired in the early phase of complex regional pain syndrome (CRPS) and neuralgia. Only in CRPS higher CPM was associated with lower cold pain thresholds. © 2017 European Pain Federation - EFIC®.

Warm hands, cold heart: progressive whole-body cooling increases warm thermosensitivity of human hands and feet in a dose-dependent fashion.

PubMed

Filingeri, Davide; Morris, Nathan B; Jay, Ollie

2017-01-01

What is the central question of this study? Investigations on inhibitory/facilitatory modulation of vision, touch and pain show that conditioning stimuli outside the receptive field of testing stimuli modulate the central processing of visual, touch and painful stimuli. We asked whether contextual modulation also exists in human temperature integration. What is the main finding and its importance? Progressive decreases in whole-body mean skin temperature (the conditioning stimulus) significantly increased local thermosensitivity to skin warming but not cooling (the testing stimuli) in a dose-dependent fashion. In resembling the central mechanisms underlying endogenous analgesia, our findings point to the existence of an endogenous thermosensory system in humans that could modulate local skin thermal sensitivity to facilitate thermal behaviour. Although inhibitory/facilitatory central modulation of vision and pain has been investigated, contextual modulation of skin temperature integration has not been explored. Hence, we tested whether progressive decreases in whole-body mean skin temperature (T sk ; a large conditioning stimulus) alter the magnitude estimation of local warming and cooling stimuli applied to hairy and glabrous skin. On four separate occasions, eight men (27 ± 5 years old) underwent a 30 min whole-body cooling protocol (water-perfused suit; temperature, 5°C), during which a quantitative thermosensory test, consisting of reporting the perceived magnitude of warming and cooling stimuli (±8°C from 30°C baseline) applied to the hand (palm/dorsum) and foot (sole/dorsum), was performed before cooling and every 10 min thereafter. The cooling protocol resulted in large progressive reductions in T sk [10 min, -3.36°C (95% confidence interval -2.62 to -4.10); 20 min, -5.21°C (-4.47 to -5.95); and 30 min, -6.32°C (-5.58 to -7.05); P < 0.001], with minimal changes (∼0.08°C) in rectal temperature. While thermosensitivity to local skin cooling remained unchanged (P = 0.831), sensitivity to skin warming increased significantly at each level of T sk for all skin regions [10 min, +4.9% (-1.1 to +11.0); 20 min, +6.1% (+0.1-12.2); and 30 min, +7.9% (+1.9-13.9); P = 0.009]. Linear regression indicated a 1.2% °C -1 increase in warm thermosensitivity with whole-body skin cooling. Overall, large decreases in T sk significantly facilitated warm but not cold sensory processing of local thermal stimuli, in a dose-dependent fashion. In highlighting a novel feature of human temperature integration, these findings point to the existence of an endogenous thermosensory system that could modulate local skin thermal sensitivity in relationship to whole-body thermal states. © 2016 The Authors. Experimental Physiology © 2016 The Physiological Society.

Neural and psychosocial mechanisms of pain sensitivity in fibromyalgia.

PubMed

English, Brian

2014-06-01

Fibromyalgia is a chronic musculoskeletal pain disorder that affects an estimated 5 million adults in the U.S. The hallmark is burning, searing, tingling, shooting, stabbing, deep aching, or sharp pain. Fibromyalgia is generally considered to be a "central sensitivity syndrome" where central sensitization is regarded as the cause of pain in its own right. Nonetheless, the case continues to be made that all central and spatially distributed peripheral components of fibromyalgia pain would fade if the peripheral generators could be silenced. Although neural mechanisms are clearly important in pain sensitivity, cognitive and social mechanisms also need to be considered. The aim of this review is to examine four mechanisms responsible for heightened pain sensitivity in fibromyalgia: peripheral sensitization, central sensitization, cognitive-emotional sensitization, and interpersonal sensitization. The purpose of framing the review in terms of pain sensitivity in fibromyalgia is to highlight that different mechanisms of sensitization are appropriately regarded as intervening variables when it comes to understanding individual differences in the experience of pain. The paper concludes by considering the implications of the findings of the review for explanations of fibromyalgia pain by nurses working in multidisciplinary teams. The trend appears to be able to explain the cause of fibromyalgia pain in terms of sensitization per se. The recommended alternative is to explain fibromyalgia pain in terms of changes in pain sensitivity and the role of underlying neural and psychosocial mechanisms. Copyright © 2014 American Society for Pain Management Nursing. Published by Elsevier Inc. All rights reserved.

Examining the relationship between endogenous pain modulation capacity and endurance exercise performance.

PubMed

Flood, Andrew; Waddington, Gordon; Cathcart, Stuart

2017-01-01

The aim of the current study was to examine the relationship between pain modulatory capacity and endurance exercise performance. Twenty-seven recreationally active males between 18 and 35 years of age participated in the study. Pain modulation was assessed by examining the inhibitory effect of a noxious conditioning stimulus (cuff occlusion) on the perceived intensity of a second noxious stimulus (pressure pain threshold). Participants completed two, maximal voluntary contractions followed by a submaximal endurance time task. Both performance tasks involved an isometric contraction of the non-dominant leg. The main analysis uncovered a correlation between pain modulatory capacity and performance on the endurance time task (r = -.425, p = .027), such that those with elevated pain modulation produced longer endurance times. These findings are the first to demonstrate the relationship between pain modulation responses and endurance exercise performance.

Role of Principal Ionotropic and Metabotropic Receptors in Visceral Pain

PubMed Central

Kannampalli, Pradeep; Sengupta, Jyoti N

2015-01-01

Visceral pain is the most common form of pain caused by varied diseases and a major reason for patients to seek medical consultation. It also leads to a significant economic burden due to workdays lost and reduced productivity. Further, long-term use of non-specific medications is also associated with side effects affecting the quality of life. Despite years of extensive research and the availability of several therapeutic options, management of patients with chronic visceral pain is often inadequate, resulting in frustration for both patients and physicians. This is, most likely, because the mechanisms associated with chronic visceral pain are different from those of acute pain. Accumulating evidence from years of research implicates several receptors and ion channels in the induction and maintenance of central and peripheral sensitization during chronic pain states. Understanding the specific role of these receptors will facilitate to capitalize on their unique properties to augment the therapeutic efficacy while at the same time minimizing unwanted side effects. The aim of this review is to provide a concise review of the recent literature that reports on the role of principal ionotropic receptors and metabotropic receptors in the modulation visceral pain. We also include an overview of the possibility of these receptors as potential new targets for the treatment of chronic visceral pain conditions. PMID:25843070

The Effect of Motivation on Movement: A Study of Bradykinesia in Parkinson’s Disease

PubMed Central

Shiner, Tamara; Seymour, Ben; Symmonds, Mkael; Dayan, Peter; Bhatia, Kailash P.; Dolan, Raymond J.

2012-01-01

Background Bradykinesia is a cardinal feature of Parkinson’s disease (PD). Despite its disabling impact, the precise cause of this symptom remains elusive. Recent thinking suggests that bradykinesia may be more than simply a manifestation of motor slowness, and may in part reflect a specific deficit in the operation of motivational vigour in the striatum. In this paper we test the hypothesis that movement time in PD can be modulated by the specific nature of the motivational salience of possible action-outcomes. Methodology/Principal Findings We developed a novel movement time paradigm involving winnable rewards and avoidable painful electrical stimuli. The faster the subjects performed an action the more likely they were to win money (in appetitive blocks) or to avoid a painful shock (in aversive blocks). We compared PD patients when OFF dopaminergic medication with controls. Our key finding is that PD patients OFF dopaminergic medication move faster to avoid aversive outcomes (painful electric shocks) than to reap rewarding outcomes (winning money) and, unlike controls, do not speed up in the current trial having failed to win money in the previous one. We also demonstrate that sensitivity to distracting stimuli is valence specific. Conclusions/Significance We suggest this pattern of results can be explained in terms of low dopamine levels in the Parkinsonian state leading to an insensitivity to appetitive outcomes, and thus an inability to modulate movement speed in the face of rewards. By comparison, sensitivity to aversive stimuli is relatively spared. Our findings point to a rarely described property of bradykinesia in PD, namely its selective regulation by everyday outcomes. PMID:23077557

The effect of motivation on movement: a study of bradykinesia in Parkinson's disease.

PubMed

Shiner, Tamara; Seymour, Ben; Symmonds, Mkael; Dayan, Peter; Bhatia, Kailash P; Dolan, Raymond J

2012-01-01

Bradykinesia is a cardinal feature of Parkinson's disease (PD). Despite its disabling impact, the precise cause of this symptom remains elusive. Recent thinking suggests that bradykinesia may be more than simply a manifestation of motor slowness, and may in part reflect a specific deficit in the operation of motivational vigour in the striatum. In this paper we test the hypothesis that movement time in PD can be modulated by the specific nature of the motivational salience of possible action-outcomes. We developed a novel movement time paradigm involving winnable rewards and avoidable painful electrical stimuli. The faster the subjects performed an action the more likely they were to win money (in appetitive blocks) or to avoid a painful shock (in aversive blocks). We compared PD patients when OFF dopaminergic medication with controls. Our key finding is that PD patients OFF dopaminergic medication move faster to avoid aversive outcomes (painful electric shocks) than to reap rewarding outcomes (winning money) and, unlike controls, do not speed up in the current trial having failed to win money in the previous one. We also demonstrate that sensitivity to distracting stimuli is valence specific. We suggest this pattern of results can be explained in terms of low dopamine levels in the Parkinsonian state leading to an insensitivity to appetitive outcomes, and thus an inability to modulate movement speed in the face of rewards. By comparison, sensitivity to aversive stimuli is relatively spared. Our findings point to a rarely described property of bradykinesia in PD, namely its selective regulation by everyday outcomes.

Quantitative sensory testing response patterns to capsaicin- and ultraviolet-B-induced local skin hypersensitization in healthy subjects: a machine-learned analysis.

PubMed

Lötsch, Jörn; Geisslinger, Gerd; Heinemann, Sarah; Lerch, Florian; Oertel, Bruno G; Ultsch, Alfred

2017-08-16

The comprehensive assessment of pain-related human phenotypes requires combinations of nociceptive measures that produce complex high-dimensional data, posing challenges to bioinformatic analysis. In this study, we assessed established experimental models of heat hyperalgesia of the skin, consisting of local ultraviolet-B (UV-B) irradiation or capsaicin application, in 82 healthy subjects using a variety of noxious stimuli. We extended the original heat stimulation by applying cold and mechanical stimuli and assessing the hypersensitization effects with a clinically established quantitative sensory testing (QST) battery (German Research Network on Neuropathic Pain). This study provided a 246 × 10-sized data matrix (82 subjects assessed at baseline, following UV-B application, and following capsaicin application) with respect to 10 QST parameters, which we analyzed using machine-learning techniques. We observed statistically significant effects of the hypersensitization treatments in 9 different QST parameters. Supervised machine-learned analysis implemented as random forests followed by ABC analysis pointed to heat pain thresholds as the most relevantly affected QST parameter. However, decision tree analysis indicated that UV-B additionally modulated sensitivity to cold. Unsupervised machine-learning techniques, implemented as emergent self-organizing maps, hinted at subgroups responding to topical application of capsaicin. The distinction among subgroups was based on sensitivity to pressure pain, which could be attributed to sex differences, with women being more sensitive than men. Thus, while UV-B and capsaicin share a major component of heat pain sensitization, they differ in their effects on QST parameter patterns in healthy subjects, suggesting a lack of redundancy between these models.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.

Sex differences in brain response to anticipated and experienced visceral pain in healthy subjects.

PubMed

Kano, Michiko; Farmer, Adam D; Aziz, Qasim; Giampietro, Vincent P; Brammer, Michael J; Williams, Steven C R; Fukudo, Shin; Coen, Steven J

2013-04-15

Women demonstrate higher pain sensitivity and prevalence of chronic visceral pain conditions such as functional gastrointestinal disorders than men. The role of sex differences in the brain processing of visceral pain is still unclear. In 16 male and 16 female healthy subjects we compared personality, anxiety levels, skin conductance response (SCR), and brain processing using functional MRI during anticipation and pain induced by esophageal distension at pain toleration level. There was no significant difference in personality scores, anxiety levels, SCR, and subjective ratings of pain between sexes. In group analysis, both men and women demonstrated a similar pattern of brain activation and deactivation during anticipation and pain consistent with previous reports. However, during anticipation women showed significantly greater activation in the cuneus, precuneus, and supplementary motor area (SMA) and stronger deactivation in the right amygdala and left parahippocampal gyrus, whereas men demonstrated greater activation in the cerebellum. During pain, women demonstrated greater activation in the midcingulate cortex, anterior insula, premotor cortex, and cerebellum and stronger deactivation in the caudate, whereas men showed increased activity in the SMA. The pattern of brain activity suggests that, during anticipation, women may demonstrate stronger limbic inhibition, which is considered to be a cognitive modulation strategy for impending painful stimulation. During pain, women significantly activate brain areas associated with the affective and motivation components of pain. These responses may underlie the sex differences that exist in pain conditions, whereby women may attribute more emotional importance to painful stimuli compared with men.

Dysfunctional pain modulation in somatoform pain disorder patients.

PubMed

Klug, Stefanie; Stefanie, Klug; Anderer, Peter; Peter, Anderer; Saletu-Zyhlarz, Gerda; Gerda, Saletu-Zyhlarz; Freidl, Marion; Marion, Freidl; Saletu, Bernd; Bernd, Saletu; Prause, Wolfgang; Wolfgang, Prause; Aigner, Martin; Martin, Aigner

2011-06-01

To date, pain perception is thought to be a creative process of modulation carried out by an interplay of pro- and anti-nociceptive mechanisms. Recent research demonstrates that pain experience constitutes the result of top-down processes represented in cortical descending pain modulation. Cortical, mainly medial and frontal areas, as well as subcortical structures such as the brain stem, medulla and thalamus seem to be key players in pain modulation. An imbalance of pro- and anti-nociceptive mechanisms are assumed to cause chronic pain disorders, which are associated with spontaneous pain perception without physiologic scaffolding or exaggerated cortical activation in response to pain exposure. In contrast to recent investigations, the aim of the present study was to elucidate cortical activation of somatoform pain disorder patients during baseline condition. Scalp EEG, quantitative Fourier-spectral analyses and LORETA were employed to compare patient group (N = 15) to age- and sex-matched controls (N = 15) at rest. SI, SII, ACC, SMA, PFC, PPC, insular, amygdale and hippocampus displayed significant spectral power reductions within the beta band range (12-30 Hz). These results suggest decreased cortical baseline arousal in somatoform pain disorder patients. We finally conclude that obtained results may point to an altered baseline activity, maybe characteristic for chronic somatoform pain disorder.

Gender-related differences in irritable bowel syndrome: Potential mechanisms of sex hormones

PubMed Central

Meleine, Mathieu; Matricon, Julien

2014-01-01

According to epidemiological studies, twice as many women as men are affected by irritable bowel syndrome (IBS) in western countries, suggesting a role for sex hormones in IBS pathophysiology. Despite growing evidence about the implications of sex hormones in IBS symptom modulation, data on mechanisms by which they influence disease development are sparse. This review aims to determine the state of knowledge about the role of sex hormones in sensorimotor dysfunctions and to address the possible interplay of sex hormones with common risk factors associated with IBS. The scientific bibliography was searched using the following keywords: irritable bowel syndrome, sex, gender, ovarian hormone, estradiol, progesterone, testosterone, symptoms, pain, sensitivity, motility, permeability, stress, immune system, brain activity, spinal, supraspinal, imaging. Ovarian hormones variations along the menstrual cycle affect sensorimotor gastrointestinal function in both healthy and IBS populations. They can modulate pain processing by interacting with neuromodulator systems and the emotional system responsible for visceral pain perception. These hormones can also modulate the susceptibility to stress, which is a pivotal factor in IBS occurrence and symptom severity. For instance, estrogen-dependent hyper-responsiveness to stress can promote immune activation or impairments of gut barrier function. In conclusion, whereas it is important to keep in mind that ovarian hormones cannot be considered as a causal factor of IBS, they arguably modulate IBS onset and symptomatology. However, our understanding of the underlying mechanisms remains limited and studies assessing the link between IBS symptoms and ovarian hormone levels are needed to improve our knowledge of the disease evolution with regard to gender. Further studies assessing the role of male hormones are also needed to understand fully the role of sex hormones in IBS. Finally, investigation of brain-gut interactions is critical to decipher how stress, ovarian hormones, and female brain processing of pain can translate into gut dysfunctions. PMID:24944465

Gender-related differences in irritable bowel syndrome: potential mechanisms of sex hormones.

PubMed

Meleine, Mathieu; Matricon, Julien

2014-06-14

According to epidemiological studies, twice as many women as men are affected by irritable bowel syndrome (IBS) in western countries, suggesting a role for sex hormones in IBS pathophysiology. Despite growing evidence about the implications of sex hormones in IBS symptom modulation, data on mechanisms by which they influence disease development are sparse. This review aims to determine the state of knowledge about the role of sex hormones in sensorimotor dysfunctions and to address the possible interplay of sex hormones with common risk factors associated with IBS. The scientific bibliography was searched using the following keywords: irritable bowel syndrome, sex, gender, ovarian hormone, estradiol, progesterone, testosterone, symptoms, pain, sensitivity, motility, permeability, stress, immune system, brain activity, spinal, supraspinal, imaging. Ovarian hormones variations along the menstrual cycle affect sensorimotor gastrointestinal function in both healthy and IBS populations. They can modulate pain processing by interacting with neuromodulator systems and the emotional system responsible for visceral pain perception. These hormones can also modulate the susceptibility to stress, which is a pivotal factor in IBS occurrence and symptom severity. For instance, estrogen-dependent hyper-responsiveness to stress can promote immune activation or impairments of gut barrier function. In conclusion, whereas it is important to keep in mind that ovarian hormones cannot be considered as a causal factor of IBS, they arguably modulate IBS onset and symptomatology. However, our understanding of the underlying mechanisms remains limited and studies assessing the link between IBS symptoms and ovarian hormone levels are needed to improve our knowledge of the disease evolution with regard to gender. Further studies assessing the role of male hormones are also needed to understand fully the role of sex hormones in IBS. Finally, investigation of brain-gut interactions is critical to decipher how stress, ovarian hormones, and female brain processing of pain can translate into gut dysfunctions.

Systematic mechanism-orientated approach to chronic pancreatitis pain

PubMed Central

Bouwense, Stefan AW; de Vries, Marjan; Schreuder, Luuk TW; Olesen, Søren S; Frøkjær, Jens B; Drewes, Asbjørn M; van Goor, Harry; Wilder-Smith, Oliver HG

2015-01-01

Pain in chronic pancreatitis (CP) shows similarities with other visceral pain syndromes (i.e., inflammatory bowel disease and esophagitis), which should thus be managed in a similar fashion. Typical causes of CP pain include increased intrapancreatic pressure, pancreatic inflammation and pancreatic/extrapancreatic complications. Unfortunately, CP pain continues to be a major clinical challenge. It is recognized that ongoing pain may induce altered central pain processing, e.g., central sensitization or pro-nociceptive pain modulation. When this is present conventional pain treatment targeting the nociceptive focus, e.g., opioid analgesia or surgical/endoscopic intervention, often fails even if technically successful. If central nervous system pain processing is altered, specific treatment targeting these changes should be instituted (e.g., gabapentinoids, ketamine or tricyclic antidepressants). Suitable tools are now available to make altered central processing visible, including quantitative sensory testing, electroencephalograpy and (functional) magnetic resonance imaging. These techniques are potentially clinically useful diagnostic tools to analyze central pain processing and thus define optimum management approaches for pain in CP and other visceral pain syndromes. The present review proposes a systematic mechanism-orientated approach to pain management in CP based on a holistic view of the mechanisms involved. Future research should address the circumstances under which central nervous system pain processing changes in CP, and how this is influenced by ongoing nociceptive input and therapies. Thus we hope to predict which patients are at risk for developing chronic pain or not responding to therapy, leading to improved treatment of chronic pain in CP and other visceral pain disorders. PMID:25574079

The body fades away: investigating the effects of transparency of an embodied virtual body on pain threshold and body ownership.

PubMed

Martini, Matteo; Kilteni, Konstantina; Maselli, Antonella; Sanchez-Vives, Maria V

2015-09-29

The feeling of "ownership" over an external dummy/virtual body (or body part) has been proven to have both physiological and behavioural consequences. For instance, the vision of an "embodied" dummy or virtual body can modulate pain perception. However, the impact of partial or total invisibility of the body on physiology and behaviour has been hardly explored since it presents obvious difficulties in the real world. In this study we explored how body transparency affects both body ownership and pain threshold. By means of virtual reality, we presented healthy participants with a virtual co-located body with four different levels of transparency, while participants were tested for pain threshold by increasing ramps of heat stimulation. We found that the strength of the body ownership illusion decreases when the body gets more transparent. Nevertheless, in the conditions where the body was semi-transparent, higher levels of ownership over a see-through body resulted in an increased pain sensitivity. Virtual body ownership can be used for the development of pain management interventions. However, we demonstrate that providing invisibility of the body does not increase pain threshold. Therefore, body transparency is not a good strategy to decrease pain in clinical contexts, yet this remains to be tested.

The body fades away: investigating the effects of transparency of an embodied virtual body on pain threshold and body ownership

PubMed Central

Martini, Matteo; Kilteni, Konstantina; Maselli, Antonella; Sanchez-Vives, Maria V.

2015-01-01

The feeling of “ownership” over an external dummy/virtual body (or body part) has been proven to have both physiological and behavioural consequences. For instance, the vision of an “embodied” dummy or virtual body can modulate pain perception. However, the impact of partial or total invisibility of the body on physiology and behaviour has been hardly explored since it presents obvious difficulties in the real world. In this study we explored how body transparency affects both body ownership and pain threshold. By means of virtual reality, we presented healthy participants with a virtual co-located body with four different levels of transparency, while participants were tested for pain threshold by increasing ramps of heat stimulation. We found that the strength of the body ownership illusion decreases when the body gets more transparent. Nevertheless, in the conditions where the body was semi-transparent, higher levels of ownership over a see-through body resulted in an increased pain sensitivity. Virtual body ownership can be used for the development of pain management interventions. However, we demonstrate that providing invisibility of the body does not increase pain threshold. Therefore, body transparency is not a good strategy to decrease pain in clinical contexts, yet this remains to be tested. PMID:26415748

Effect of intrathecal baclofen on evoked pain perception: an evoked potentials and quantitative thermal testing study.

PubMed

Kumru, H; Kofler, M; Flores, M C; Portell, E; Robles, V; Leon, N; Vidal, J

2013-08-01

Somatic antinociceptive effects of baclofen have been demonstrated in animal models. We hypothesized that if enhanced thermal or pain sensitivity is produced by loss of gamma-aminobutyric acid (GABA)-ergic tone in the central nervous system, spinal administration of GABA agonists might be predicted to be effective in thermal and/or pain perception changes and pain-related evoked potentials in candidates for intrathecal baclofen (ITB) treatment. Eleven patients with severe spinal cord injury (SCI) who suffered from severe spasticity were evaluated during a 50-μg ITB bolus test. Warm and heat pain thresholds, evoked heat pain perception, and contact heat-evoked potentials (CHEPs) were determined above SCI level from the right and left sides. Nine age- and gender-matched healthy volunteers undergoing repeat testing without any placebo injection served as control group. In patients, heat pain perception threshold increased, and evoked pain perception and amplitude of CHEPs decreased significantly after ITB bolus application in comparison with baseline (p < 0.005), with no change in warm perception threshold. In controls, no significant changes were observed in repeat testing over time. Our findings indicate that ITB modulates heat pain perception threshold, evoked heat pain perception and heat pain-related evoked potentials without inducing warm perception threshold changes in SCI patients. This phenomenon should be taken into account in the clinical evaluation and management of pain in patients receiving baclofen. © 2012 European Federation of International Association for the Study of Pain Chapters.

The Missing “P” in Psychiatric Training: Why is it Important to Teach Pain to Psychiatrists?

PubMed Central

Elman, Igor; Zubieta, Jon-Kar; Borsook, David

2011-01-01

Context Pain problems are exceedingly prevalent among psychiatric patients. Moreover, clinical impressions and neurobiological research suggest that physical and psychological aspects of pain are closely related entities. Nonetheless, remarkably few pain-related themes are presently included in psychiatric residency training. Objective Our objective is twofold: (1) to provide clinical and scientific rationale for psychiatric training enrichment with basic tenets of pain medicine and (2) to raise the awareness and sensitivity of clinicians, scientists and educators alike to the important yet unmet clinical and public health need. Results Three lines of translational research evidence, extracted from the comprehensive literature review, are presented in support of the objective. First, the neuroanatomical and functional overlap between pain and emotion/reward/motivation brain circuits suggests integration and mutual modulation of these systems. Second, psychiatric disorders are commonly associated with alterations in pain processing, whereas chronic pain may impair emotional and neurocognitive functioning. Third, pain may serve as a functional probe for unraveling pathophysiological mechanisms inherent in psychiatric morbidity given its stressful nature for the organism. Conclusions Pain training in psychiatry will not only contribute to deeper and more sophisticated insights into pain syndromes but also into psychiatric morbidity at large regardless of patients’ pain status. Furthermore, it will ease artificial boundaries separating psychiatric and medical formulations of brain disorders, thus fostering cross-fertilizing interactions between specialists in various disciplines entrusted with the care of pain patients. PMID:21199962

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

PubMed

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

2013-08-15

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

Anxiety sensitivity, fear of pain and pain-related disability in children and adolescents with chronic pain

PubMed Central

Martin, Andrea L; McGrath, Patricia A; Brown, Stephen C; Katz, Joel

2007-01-01

BACKGROUND: Converging lines of evidence suggest that anxiety sensitivity and fear of pain may be important vulnerability factors in the development of avoidance behaviours and disability in adults with chronic pain. However, these factors have not been evaluated in children with chronic pain. OBJECTIVES: To examine the relationships among anxiety sensitivity, fear of pain and pain-related disability in children and adolescents with chronic pain. METHODS: An interview and five questionnaires (Childhood Anxiety Sensitivity Index, Pain Anxiety Symptoms Scale, Functional Disability Inventory, Multidimensional Anxiety Scale for Children, and Reynolds Child or Adolescent Depression Scale) were administered to 21 children and adolescents eight to 17 years of age (mean ± SD 14.24±2.21 years) who continued to experience pain an average of three years after discharge from a specialized pain clinic for children. RESULTS: Anxiety sensitivity accounted for 38.6% of the variance in fear of pain (F[1,20]=11.30; P=0.003) and fear of pain accounted for 39.9% of the variance in pain-related disability (F[1,20]=11.95; P=0.003), but anxiety sensitivity was not significantly related to pain disability (R2=0.09; P>0.05). CONCLUSIONS: These findings indicate that children with high levels of anxiety sensitivity had a higher fear of pain, which, in turn, was linked to increased pain disability. The results of this study suggest that anxiety sensitivity and fear of pain may play important and distinct roles in the processes that maintain chronic pain and pain-related disability in children. PMID:18080045

Conditioned pain modulation in patients with nonspecific chronic back pain with chronic local pain, chronic widespread pain, and fibromyalgia.

PubMed

Gerhardt, Andreas; Eich, Wolfgang; Treede, Rolf-Detlef; Tesarz, Jonas

2017-03-01

Findings considering conditioned pain modulation (CPM) in chronic back pain (CBP) are contradictory. This might be because many patients with CBP report pain in further areas of the body, and altered CPM might influence spatial extent of pain rather than CBP per se. Therefore, we compared CPM in patients with CBP with different pain extent. Patients with fibromyalgia syndrome (FMS), for whom CPM impairment is reported most consistently, were measured for comparison. Based on clinical evaluation and pain drawings, patients were categorized into chronic local back pain (CLP; n = 53), chronic widespread back pain (CWP; n = 32), and FMS (n = 92). Conditioned pain modulation was measured by the difference in pressure pain threshold (test stimuli) at the lower back before and after tonic heat pain (conditioning stimulus). We also measured psychosocial variables. Pressure pain threshold was significantly increased in CLP patients after tonic heat pain (P < 0.001) indicating induction of CPM. Conditioned pain modulation in CLP was significantly higher than that in CWP and FMS (P < 0.001), but CPM in CWP and FMS did not differ. Interestingly, a higher number of painful areas (0-10) were associated with lower CPM (r = 0.346, P = 0.001) in CBP but not in FMS (r = -0.013, P = 0.903). Anxiety and depression were more pronounced in FMS than in CLP or CWP (P values <0.01). Our findings suggest that CPM dysfunction is associated with CWP and not with FMS as suggested previously. FMS seems to differ from CWP without FMS by higher psychosocial burden. Moreover, patients with CBP should be stratified into CLP and CWP, and centrally acting treatments targeting endogenous pain inhibition seem to be more indicated the higher the pain extent.

The cerebral signature for pain perception and its modulation.

PubMed

Tracey, Irene; Mantyh, Patrick W

2007-08-02

Our understanding of the neural correlates of pain perception in humans has increased significantly since the advent of neuroimaging. Relating neural activity changes to the varied pain experiences has led to an increased awareness of how factors (e.g., cognition, emotion, context, injury) can separately influence pain perception. Tying this body of knowledge in humans to work in animal models of pain provides an opportunity to determine common features that reliably contribute to pain perception and its modulation. One key system that underpins the ability to change pain intensity is the brainstem's descending modulatory network with its pro- and antinociceptive components. We discuss not only the latest data describing the cerebral signature of pain and its modulation in humans, but also suggest that the brainstem plays a pivotal role in gating the degree of nociceptive transmission so that the resultant pain experienced is appropriate for the particular situation of the individual.

Descending pain modulation in irritable bowel syndrome (IBS): a systematic review and meta-analysis.

PubMed

Chakiath, Rosemary J; Siddall, Philip J; Kellow, John E; Hush, Julia M; Jones, Mike P; Marcuzzi, Anna; Wrigley, Paul J

2015-12-10

Irritable bowel syndrome (IBS) is a common functional gastrointestinal disorder. While abdominal pain is a dominant symptom of IBS, many sufferers also report widespread hypersensitivity and present with other chronic pain conditions. The presence of widespread hypersensitivity and extra-intestinal pain conditions suggests central nervous dysfunction. While central nervous system dysfunction may involve the spinal cord (central sensitisation) and brain, this review will focus on one brain mechanism, descending pain modulation. We will conduct a comprehensive search for the articles indexed in the databases Ovid MEDLINE, Ovid Embase, Ovid PsycINFO and Cochrane Central Register of Controlled Trial (CENTRAL) from their inception to August 2015, that report on any aspect of descending pain modulation in irritable bowel syndrome. Two independent reviewers will screen studies for eligibility, assess risk of bias and extract relevant data. Results will be tabulated and, if possible, a meta-analysis will be carried out. The systematic review outlined in this protocol aims to summarise current knowledge regarding descending pain modulation in IBS. PROSPERO CRD42015024284.

Zinc activates damage-sensing TRPA1 ion channels.

PubMed

Hu, Hongzhen; Bandell, Michael; Petrus, Matt J; Zhu, Michael X; Patapoutian, Ardem

2009-03-01

Zinc is an essential biological trace element. It is required for the structure or function of over 300 proteins, and it is increasingly recognized for its role in cell signaling. However, high concentrations of zinc have cytotoxic effects, and overexposure to zinc can cause pain and inflammation through unknown mechanisms. Here we show that zinc excites nociceptive somatosensory neurons and causes nociception in mice through TRPA1, a cation channel previously shown to mediate the pungency of wasabi and cinnamon through cysteine modification. Zinc activates TRPA1 through a unique mechanism that requires zinc influx through TRPA1 channels and subsequent activation via specific intracellular cysteine and histidine residues. TRPA1 is highly sensitive to intracellular zinc, as low nanomolar concentrations activate TRPA1 and modulate its sensitivity. These findings identify TRPA1 as an important target for the sensory effects of zinc and support an emerging role for zinc as a signaling molecule that can modulate sensory transmission.

Visceral pain hypersensitivity in functional gastrointestinal disorders.

PubMed

Farmer, A D; Aziz, Q

2009-01-01

Functional gastrointestinal disorders (FGIDs) are a highly prevalent group of heterogeneous disorders whose diagnostic criteria are symptom based in the absence of a demonstrable structural or biochemical abnormality. Chronic abdominal pain or discomfort is a defining characteristic of these disorders and a proportion of patients may display heightened pain sensitivity to experimental visceral stimulation, termed visceral pain hypersensitivity (VPH). We examined the most recent literature in order to concisely review the evidence for some of the most important recent advances in the putative mechanisms concerned in the pathophysiology of VPH. VPH may occur due to anomalies at any level of the visceral nociceptive neuraxis. Important peripheral and central mechanisms of sensitization that have been postulated include a wide range of ion channels, neurotransmitter receptors and trophic factors. Data from functional brain imaging studies have also provided evidence for aberrant central pain processing in cortical and subcortical regions. In addition, descending modulation of visceral nociceptive pathways by the autonomic nervous system, hypothalamo-pituitary-adrenal axis and psychological factors have all been implicated in the generation of VPH. Particular areas of controversy have included the development of efficacious treatment of VPH. Therapies have been slow to emerge, mainly due to concerns regarding safety. The burgeoning field of genome wide association studies may provide further evidence for the pleiotropic genetic basis of VPH development. Tangible progress will only be made in the treatment of VPH when we begin to individually characterize patients with FGIDs based on their clinical phenotype, genetics and visceral nociceptive physiology.

A comprehensive review of opioid-induced hyperalgesia.

PubMed

Lee, Marion; Silverman, Sanford M; Hansen, Hans; Patel, Vikram B; Manchikanti, Laxmaiah

2011-01-01

Opioid-induced hyperalgesia (OIH) is defined as a state of nociceptive sensitization caused by exposure to opioids. The condition is characterized by a paradoxical response whereby a patient receiving opioids for the treatment of pain could actually become more sensitive to certain painful stimuli. The type of pain experienced might be the same as the underlying pain or might be different from the original underlying pain. OIH appears to be a distinct, definable, and characteristic phenomenon that could explain loss of opioid efficacy in some patients. Findings of the clinical prevalence of OIH are not available. However, several observational, cross-sectional, and prospective controlled trials have examined the expression and potential clinical significance of OIH in humans. Most studies have been conducted using several distinct cohorts and methodologies utilizing former opioid addicts on methadone maintenance therapy, perioperative exposure to opioids in patients undergoing surgery, and healthy human volunteers after acute opioid exposure using human experimental pain testing. The precise molecular mechanism of OIH, while not yet understood, varies substantially in the basic science literature, as well as clinical medicine. It is generally thought to result from neuroplastic changes in the peripheral and central nervous system (CNS) that lead to sensitization of pronociceptive pathways. While there are many proposed mechanisms for OIH, 5 mechanisms involving the central glutaminergic system, spinal dynorphins, descending facilitation, genetic mechanisms, and decreased reuptake and enhanced nociceptive response have been described as the important mechanisms. Of these, the central glutaminergic system is considered the most common possibility. Another is the hypothesis that N-methyl-D-aspartate (NMDA) receptors in OIH include activation, inhibition of the glutamate transporter system, facilitation of calcium regulated intracellular protein kinase C, and cross talk of neural mechanisms of pain and tolerance. Clinicians should suspect OIH when opioid treatment's effect seems to wane in the absence of disease progression, particularly if found in the context of unexplained pain reports or diffuse allodynia unassociated with the original pain, and increased levels of pain with increasing dosages. The treatment involves reducing the opioid dosage, tapering them off, or supplementation with NMDA receptor modulators. This comprehensive review addresses terminology and definition, prevalence, the evidence for mechanism and physiology with analysis of various factors leading to OIH, and effective strategies for preventing, reversing, or managing OIH.

Validating the M. D. Anderson Symptom Inventory (MDASI) for use in patients with ovarian cancer

PubMed Central

Sailors, Mary H.; Bodurka, Diane C.; Gning, Ibrahima; Ramondetta, Lois M.; Williams, Loretta A.; Mendoza, Tito R.; Agarwal, Sonika; Sun, Charlotte C.; Cleeland, Charles S.

2013-01-01

Objective The M. D. Anderson Symptom Inventory (MDASI) captures the severity of common cancer symptoms from the patients’ perspective. We describe the validity and sensitivity of a module of the MDASI to be used with patients having ovarian cancer (MDASI-OC). Methods Ovarian cancer–specific module items were developed from 14 qualitative patient interviews. 128 patients with invasive epithelial ovarian, peritoneal, or fallopian-tube cancer treated at MD Anderson Cancer Center were recruited. Patients completed the MDASI-OC, socio-demographic questionnaires, the Functional Assessment of Cancer Therapy-Ovary (FACT-O), and a global quality-of-life (QOL) item. Reliability was assessed using Cronbach α and sensitivity using known group was assessed. Construct validity was tested using exploratory factor analysis. Results The sample was primarily white (85.2%), had a mean age of 57.5 years (±12.7 years), and had previously been treated with chemotherapy (75.0%) and/or surgery (93.8%). Approximately 30% of patients reported disturbed sleep, fatigue, or numbness/tingling of at least moderate severity (≥5 on a 0–10 scale). On the ovarian-cancer-specific symptoms, approximately 20% reported back pain, feeling bloated, or constipation of at least moderate severity. Factor analysis revealed six underlying constructs (pain/sleep; cognitive; disease-related and numbness; treatment-related; affective; gastrointestinal-specific). MDASI-OC symptom and interference items had Cronbach α values of 0.90 and 0.89, respectively. The MDASI-OC was sensitive to symptom severity by performance status (p=0.009), QOL (p=0.002), and FACT-O scores (p<0.001). Conclusions The 27-item MDASI-OC meets common criteria for validation and reliability and is sensitive to expected changes in symptoms related to differences in disease and treatment status. PMID:23685012

Rational Basis for the Use of Bergamot Essential Oil in Complementary Medicine to Treat Chronic Pain.

PubMed

Rombolà, L; Amantea, D; Russo, R; Adornetto, A; Berliocchi, L; Tridico, L; Corasaniti, M T; Sakurada, S; Sakurada, T; Bagetta, G; Morrone, L A

2016-01-01

In complementary medicine, aromatherapy uses essential oils to improve agitation and aggression observed in dementia, mood, depression, anxiety and chronic pain. Preclinical research studies have reported that the essential oil obtained from bergamot (BEO) fruit (Citrus bergamia, Risso) modifies normal and pathological synaptic plasticity implicated, for instance, in nociceptive and neuropathic pain. Interestingly, recent results indicated that BEO modulates sensitive perception of pain in different models of nociceptive, inflammatory and neuropathic pain modulating endogenous systems. Thus, local administration of BEO inhibited the nociceptive behavioral effect induced by intraplantar injection of capsaicin or formalin in mice. Similar effects were observed with linalool and linalyl acetate, major volatile components of the phytocomplex, Pharmacological studies showed that the latter effects are reversed by local or systemic pretreatment with the opioid antagonist naloxone hydrochloride alike with naloxone methiodide, high affinity peripheral μ-opioid receptor antagonist. These results and the synergistic effect observed following systemic or intrathecal injection of an inactive dose of morphine with BEO or linalool indicated an activation of peripheral opioid system. Recently, in neuropathic pain models systemic or local administration of BEO or linalool induced antiallodynic effects. In particular, in partial sciatic nerve ligation (PSNL) model, intraplantar injection of the phytocomplex or linalool in the ipsilateral hindpaw, but not in the contralateral, reduced PSNL-induced extracellularsignal- regulated kinase (ERK) activation and mechanical allodynia. In neuropathic pain high doses of morphine are needed to reduce pain. Interestingly, combination of inactive doses of BEO or linalool with a low dose of morphine induced antiallodynic effects in mice. Peripheral cannabinoid and opioid systems appear to be involved in the antinociception produced by intraplantar injection of β -caryophyllene, present in different essential oils including BEO. The data gathered so far indicate that the essential oil of bergamot is endowed with antinociceptive and antiallodynic effects and contribute to form the rational basis for rigorous testing of its efficacy in complementary medicine.

Calcium channel modulation as a target in chronic pain control.

PubMed

Patel, Ryan; Montagut-Bordas, Carlota; Dickenson, Anthony H

2018-06-01

Neuropathic pain remains poorly treated for large numbers of patients, and little progress has been made in developing novel classes of analgesics. To redress this issue, ziconotide (Prialt™) was developed and approved as a first-in-class synthetic version of ω-conotoxin MVIIA, a peptide blocker of Ca v 2.2 channels. Unfortunately, the impracticalities of intrathecal delivery, low therapeutic index and severe neurological side effects associated with ziconotide have restricted its use to exceptional circumstances. Ziconotide exhibits no state or use-dependent block of Ca v 2.2 channels; activation state-dependent blockers were hypothesized to circumvent the side effects of state-independent blockers by selectively targeting high-frequency firing of nociceptive neurones in chronic pain states, thus alleviating aberrant pain but not affecting normal sensory transduction. Unfortunately, numerous drugs, including state-dependent calcium channel blockers, have displayed efficacy in preclinical models but have subsequently been disappointing in clinical trials. In recent years, it has become more widely acknowledged that trans-aetiological sensory profiles exist amongst chronic pain patients and may indicate similar underlying mechanisms and drug sensitivities. Heterogeneity amongst patients, a reliance on stimulus-evoked endpoints in preclinical studies and a failure to utilize translatable endpoints, all are likely to have contributed to negative clinical trial results. We provide an overview of how electrophysiological and operant-based assays provide insight into sensory and affective aspects of pain in animal models and how these may relate to chronic pain patients in order to improve the bench-to-bedside translation of calcium channel modulators. This article is part of a themed section on Recent Advances in Targeting Ion Channels to Treat Chronic Pain. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.12/issuetoc. © 2017 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.

Theta-frequency phase-locking of single anterior cingulate cortex neurons and synchronization with the medial thalamus are modulated by visceral noxious stimulation in rats.

PubMed

Wang, J; Cao, B; Yu, T R; Jelfs, B; Yan, J; Chan, R H M; Li, Y

2015-07-09

The rodent anterior cingulate cortex (ACC) is critical for visceral pain and pain-related aversive response in chronic visceral hypersensitive (VH) state. Long-term potentiation (LTP), induced by theta burst stimulation (TBS) in the medial thalamus (MT)-ACC pathway, is blocked in VH rats. However, the neuronal intrinsic firing characteristics and the MT-ACC connectivity have not been investigated in visceral pain. Using repetitive distension of the colon and rectum (rCRD) as a sensitization paradigm, we have identified that the spontaneous firing rates of ACC neurons and the CRD-stimulated neuronal firings were increased after repetitive visceral noxious stimulation. This correlates with increases in visceral pain responses (visceromotor responses, VMRs). Two multichannel arrays of electrodes were implanted in the MT and ACC. Recordings were performed in free-moving rats before and after repeated CRD treatment. Power spectral density analysis showed that the local field potential (LFP) recorded in the ACC displayed increases in theta band power (4-10 Hz) that were modulated by rCRD. Neural spike activity in the ACC becomes synchronized with ongoing theta oscillations of LFP. Furthermore, cross correlation analysis showed augmented synchronization of thalamo-ACC theta band LFPs, which was consistent with an increase of neuronal communication between the two regions. In conclusion, these results reveal theta oscillations and theta-frequency phase-locking as prominent features of neural activity in the ACC and a candidate neural mechanism underlying acute visceral pain. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

Pain Sensitivity Risk Factors for Chronic TMD: Descriptive Data and Empirically Identified Domains from the OPPERA Case Control Study

PubMed Central

Greenspan, Joel D.; Slade, Gary D.; Bair, Eric; Dubner, Ronald; Fillingim, Roger B.; Ohrbach, Richard; Knott, Charlie; Mulkey, Flora; Rothwell, Rebecca; Maixner, William

2011-01-01

Many studies report that people with temporomandibular disorders (TMD) are more sensitive to experimental pain stimuli than TMD-free controls. Such differences in sensitivity are observed in remote body sites as well as in the orofacial region, suggesting a generalized upregulation of nociceptive processing in TMD cases. This large case-control study of 185 adults with TMD and 1,633 TMD-free controls measured sensitivity to painful pressure, mechanical cutaneous, and heat stimuli, using multiple testing protocols. Based on an unprecedented 36 experimental pain measures, 28 showed statistically significantly greater pain sensitivity in TMD cases than controls. The largest effects were seen for pressure pain thresholds at multiple body sites and cutaneous mechanical pain threshold. The other mechanical cutaneous pain measures and many of the heat pain measures showed significant differences, but with lesser effect sizes. Principal component analysis (PCA) of the pain measures derived from 1,633 controls identified five components labeled: (1) heat pain ratings, (2) heat pain aftersensations and tolerance, (3) mechanical cutaneous pain sensitivity, (4) pressure pain thresholds, and (5) heat pain temporal summation. These results demonstrate that, compared to TMD-free controls, chronic TMD cases are more sensitive to many experimental noxious stimuli at extra-cranial body sites, and provides for the first time the ability to directly compare the case-control effect sizes of a wide range of pain sensitivity measures. PMID:22074753

Are measures of pain sensitivity associated with pain and disability at 12-month follow up in chronic neck pain?

PubMed

Moloney, Niamh; Beales, Darren; Azoory, Roxanne; Hübscher, Markus; Waller, Robert; Gibbons, Rebekah; Rebbeck, Trudy

2018-06-14

Pain sensitivity and psychosocial issues are prognostic of poor outcome in acute neck disorders. However, knowledge of associations between pain sensitivity and ongoing pain and disability in chronic neck pain are lacking. We aimed to investigate associations of pain sensitivity with pain and disability at the 12-month follow-up in people with chronic neck pain. The predictor variables were: clinical and quantitative sensory testing (cold, pressure); neural tissue sensitivity; neuropathic symptoms; comorbidities; sleep; psychological distress; pain catastrophizing; pain intensity (for the model explaining disability at 12 months only); and disability (for the model explaining pain at 12 months only). Data were analysed using uni- and multivariate regression models to assess associations with pain and disability at the 12-month follow-up (n = 64 at baseline, n = 51 at follow-up). Univariable associations between all predictor variables and pain and disability were evident (r > 0.3; p < 0.05), except for cold and pressure pain thresholds and cold sensitivity. For disability at the 12-month follow-up, 24.0% of the variance was explained by psychological distress and comorbidities. For pain at 12 months, 39.8% of the variance was explained primarily by baseline disability. Neither clinical nor quantitative measures of pain sensitivity were meaningfully associated with long-term patient-reported outcomes in people with chronic neck pain, limiting their clinical application in evaluating prognosis. Copyright © 2018 John Wiley & Sons, Ltd.

The therapeutic potential of renin angiotensin aldosterone system (RAAS) in chronic pain: from preclinical studies to clinical trials.

PubMed

Bessaguet, Flavien; Magy, Laurent; Desmoulière, Alexis; Demiot, Claire

2016-01-01

The prevalence rate of chronic pain is 15% to 25% in adults while the therapeutic arsenal is still insufficient, especially in relieving neuropathic pain. Peripheral pain transmission is conducted by the small Aδ and C sensory nerve fibres. They express elements from the renin-angiotensin-aldosterone system (RAAS), a well-known blood pressure regulator. Recently, studies have demonstrated the role of angiotensin II, its derivatives and aldosterone in the modulation of pain perception, by interacting with receptors expressed by sensory nerve fibres or through the central nervous system. Here, we assess the effects of RAAS modulators in the conduction of pain with molecular, preclinical and clinical approaches, in normal or pathological conditions. Currently, some clinical studies have been carried out on the pain-relieving effect of RAAS modulators and suggest their potential in the management of chronic, inflammatory or neuropathic pain.

Characterization of Macrophage/Microglial Activation and Effect of Photobiomodulation in the Spared Nerve Injury Model of Neuropathic Pain.

PubMed

Kobiela Ketz, Ann; Byrnes, Kimberly R; Grunberg, Neil E; Kasper, Christine E; Osborne, Lisa; Pryor, Brian; Tosini, Nicholas L; Wu, Xingjia; Anders, Juanita J

2017-05-01

Neuropathic pain is common and debilitating with limited effective treatments. Macrophage/microglial activation along ascending somatosensory pathways following peripheral nerve injury facilitates neuropathic pain. However, polarization of macrophages/microglia in neuropathic pain is not well understood. Photobiomodulation treatment has been used to decrease neuropathic pain, has anti-inflammatory effects in spinal injury and wound healing models, and modulates microglial polarization in vitro. Our aim was to characterize macrophage/microglia response after peripheral nerve injury and modulate the response with photobiomodulation. Adult male Sprague-Dawley rats were randomly assigned to sham (N = 13), spared nerve injury (N = 13), or injury + photobiomodulation treatment groups (N = 7). Mechanical hypersensitivity was assessed with electronic von Frey. Photobiomodulation (980 nm) was applied to affected hind paw (output power 1 W, 20 s, 41cm above skin, power density 43.25 mW/cm 2 , dose 20 J), dorsal root ganglia (output power 4.5W, 19s, in skin contact, power density 43.25 mW/cm 2 , dose 85.5 J), and spinal cord regions (output power 1.5 W, 19s, in skin contact, power density 43.25 mW/cm 2 , dose 28.5 J) every other day from day 7-30 post-operatively. Immunohistochemistry characterized macrophage/microglial activation. Injured groups demonstrated mechanical hypersensitivity 1-30 days post-operatively. Photobiomodulation-treated animals began to recover after two treatments; at day 26, mechanical sensitivity reached baseline. Peripheral nerve injury caused region-specific macrophages/microglia activation along spinothalamic and dorsal-column medial lemniscus pathways. A pro-inflammatory microglial marker was expressed in the spinal cord of injured rats compared to photobiomodulation-treated and sham group. Photobiomodulation-treated dorsal root ganglion macrophages expressed anti-inflammatory markers. Photobiomodulation effectively reduced mechanical hypersensitivity, potentially through modulating macrophage/microglial activation to an anti-inflammatory phenotype. 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.

Fear-avoidance beliefs and temporal summation of evoked thermal pain influence self-report of disability in patients with chronic low back pain.

PubMed

George, Steven Z; Wittmer, Virgil T; Fillingim, Roger B; Robinson, Michael E

2006-03-01

Quantitative sensory testing has demonstrated a promising link between experimentally determined pain sensitivity and clinical pain. However, previous studies of quantitative sensory testing have not routinely considered the important influence of psychological factors on clinical pain. This study investigated whether measures of thermal pain sensitivity (temporal summation, first pulse response, and tolerance) contributed to clinical pain reports for patients with chronic low back pain, after controlling for depression or fear-avoidance beliefs about work. Consecutive patients (n=27) with chronic low back pain were recruited from an interdisciplinary pain rehabilitation program in Jacksonville, FL. Patients completed validated self-report questionnaires for depression, fear-avoidance beliefs, clinical pain intensity, and clinical pain related disability. Patients also underwent quantitative sensory testing from previously described protocols to determine thermal pain sensitivity (temporal summation, first pulse response, and tolerance). Hierarchical regression models investigated the contribution of depression and thermal pain sensitivity to clinical pain intensity, and fear-avoidance beliefs and thermal pain sensitivity to clinical pain related disability. None of the measures of thermal pain sensitivity contributed to clinical pain intensity after controlling for depression. Temporal summation of evoked thermal pain significantly contributed to clinical pain disability after controlling for fear-avoidance beliefs about work. Measures of thermal pain sensitivity did not contribute to pain intensity, after controlling for depression. Fear-avoidance beliefs about work and temporal summation of evoked thermal pain significantly influenced pain related disability. These factors should be considered as potential outcome predictors for patients with work-related low back pain. This study supported the neuromatrix theory of pain for patients with CLBP, as cognitive-evaluative factor contributed to pain perception, and cognitive-evaluative and sensory-discriminative factors uniquely contributed to an action program in response to chronic pain. Future research will determine if a predictive model consisting of fear-avoidance beliefs and temporal summation of evoked thermal pain has predictive validity for determining clinical outcome in rehabilitation or vocational settings.

Cross-modal and modality-specific expectancy effects between pain and disgust

PubMed Central

Sharvit, Gil; Vuilleumier, Patrik; Delplanque, Sylvain; Corradi-Dell’ Acqua, Corrado

2015-01-01

Pain sensitivity increases when a noxious stimulus is preceded by cues predicting higher intensity. However, it is unclear whether the modulation of nociception by expectancy is sensory-specific (“modality based”) or reflects the aversive-affective consequence of the upcoming event (“unpleasantness”), potentially common with other negative events. Here we compared expectancy effects for pain and disgust by using different, but equally unpleasant, nociceptive (thermal) and olfactory stimulations. Indeed both pain and disgust are aversive, associated with threat to the organism, and processed in partly overlapping brain networks. Participants saw cues predicting the unpleasantness (high/low) and the modality (pain/disgust) of upcoming thermal or olfactory stimulations, and rated the associated unpleasantness after stimuli delivery. Results showed that identical thermal stimuli were perceived as more unpleasant when preceded by cues threatening about high (as opposed to low) pain. A similar expectancy effect was found for olfactory disgust. Critically, cross-modal expectancy effects were observed on inconsistent trials when thermal stimuli were preceded by high-disgust cues or olfactory stimuli preceded by high-pain cues. However, these effects were stronger in consistent than inconsistent conditions. Taken together, our results suggest that expectation of an unpleasant event elicits representations of both its modality-specific properties and its aversive consequences. PMID:26631975

Patient evaluation and general treatment planning.

PubMed

Fechtel, Scot Gerald

2006-05-01

Treating pain patients is difficult. The usual problems encountered in providing coherent and effective treatment for any chronic medical illness are compounded in painful conditions by time, society's choices, and the cultural role of the patient. Effective treatment of these patients depends on the persistence of the clinician. We must persist in requiring a complete history to understand the patient and his or her problem. We must persist in performing a thorough physical examination to uncover sufficient under-standing of the patient's physiology. We must persist in developing a comprehensive treatment plan to cover all of the intervening concerns. We must persist in following the patient in the clinic to make sure that the plan is completed and that complications that arise are dealt with efficiently. This can lead to considerable satisfaction and frustration. There remain many unanswered questions in the evaluation of pain patients and of pain itself. How accurate is physical examination in providing information about a given patient that is relevant to treating pain? Can physical examination reliably elicit a nociceptive focus for a specific individual's chronic pain experience? Is all long-term pain a smorgasbord of nociceptive, central sensitization, and neuromodulatory mechanisms? Can acute pain be more consistently aborted to minimize the development of chronic pain? Over the next few years, as our expanding knowledge of neuropharmacology, neurophysiology, and pain modulation in the CNS combines with better understanding of pain psychology and sociology, we clinicians will expect to have happier and more productive patients.

Sustained deep-tissue pain alters functional brain connectivity.

PubMed

Kim, Jieun; Loggia, Marco L; Edwards, Robert R; Wasan, Ajay D; Gollub, Randy L; Napadow, Vitaly

2013-08-01

Recent functional brain connectivity studies have contributed to our understanding of the neurocircuitry supporting pain perception. However, evoked-pain connectivity studies have employed cutaneous and/or brief stimuli, which induce sensations that differ appreciably from the clinical pain experience. Sustained myofascial pain evoked by pressure cuff affords an excellent opportunity to evaluate functional connectivity change to more clinically relevant sustained deep-tissue pain. Connectivity in specific networks known to be modulated by evoked pain (sensorimotor, salience, dorsal attention, frontoparietal control, and default mode networks: SMN, SLN, DAN, FCN, and DMN) was evaluated with functional-connectivity magnetic resonance imaging, both at rest and during a sustained (6-minute) pain state in healthy adults. We found that pain was stable, with no significant changes of subjects' pain ratings over the stimulation period. Sustained pain reduced connectivity between the SMN and the contralateral leg primary sensorimotor (S1/M1) representation. Such SMN-S1/M1 connectivity decreases were also accompanied by and correlated with increased SLN-S1/M1 connectivity, suggesting recruitment of activated S1/M1 from SMN to SLN. Sustained pain also increased DAN connectivity to pain processing regions such as mid-cingulate cortex, posterior insula, and putamen. Moreover, greater connectivity during pain between contralateral S1/M1 and posterior insula, thalamus, putamen, and amygdala was associated with lower cuff pressures needed to reach the targeted pain sensation. These results demonstrate that sustained pain disrupts resting S1/M1 connectivity by shifting it to a network known to process stimulus salience. Furthermore, increased connectivity between S1/M1 and both sensory and affective processing areas may be an important contribution to interindividual differences in pain sensitivity. Copyright © 2013 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

Pain sensitivity profiles in patients with advanced knee osteoarthritis

PubMed Central

Frey-Law, Laura A.; Bohr, Nicole L.; Sluka, Kathleen A.; Herr, Keela; Clark, Charles R.; Noiseux, Nicolas O.; Callaghan, John J; Zimmerman, M Bridget; Rakel, Barbara A.

2016-01-01

The development of patient profiles to subgroup individuals on a variety of variables has gained attention as a potential means to better inform clinical decision-making. Patterns of pain sensitivity response specific to quantitative sensory testing (QST) modality have been demonstrated in healthy subjects. It has not been determined if these patterns persist in a knee osteoarthritis population. In a sample of 218 participants, 19 QST measures along with pain, psychological factors, self-reported function, and quality of life were assessed prior to total knee arthroplasty. Component analysis was used to identify commonalities across the 19 QST assessments to produce standardized pain sensitivity factors. Cluster analysis then grouped individuals that exhibited similar patterns of standardized pain sensitivity component scores. The QST resulted in four pain sensitivity components: heat, punctate, temporal summation, and pressure. Cluster analysis resulted in five pain sensitivity profiles: a “low pressure pain” group, an “average pain” group, and three “high pain” sensitivity groups who were sensitive to different modalities (punctate, heat, and temporal summation). Pain and function differed between pain sensitivity profiles, along with sex distribution; however no differences in OA grade, medication use, or psychological traits were found. Residualizing QST data by age and sex resulted in similar components and pain sensitivity profiles. Further, these profiles are surprisingly similar to those reported in healthy populations suggesting that individual differences in pain sensitivity are a robust finding even in an older population with significant disease. PMID:27152688

Love as a Modulator of Pain

PubMed Central

Tamam, Sofina; Ahmad, Asma Hayati

2017-01-01

Pain is modulated by various factors, the most notable of which is emotions. Since love is an emotion, it can also modulate pain. The answer to the question of whether it enhances or reduces pain needs to be determined. A review was conducted of animal and human studies in which this enigmatic emotion and its interaction with pain was explored. Recent advances in neuroimaging have revealed similarities in brain activation relating to love and pain. At the simplest level, this interaction can be explained by the overlapping network structure in brain functional connectivity, although the explanation is considerably more complex. The effect of love can either result in increased or decreased pain perception. An explanation of the interaction between pain and love relates to the functional connectivity of the brain and to the psychological construct of the individual, as well as to his or her ability to engage resources relating to emotion regulation. In turn, this determines how a person relates to love and reacts to pain. PMID:28814928

Sex, Gender, and Pain: A Review of Recent Clinical and Experimental Findings

PubMed Central

Fillingim, Roger B.; King, Christopher D.; Ribeiro-Dasilva, Margarete C.; Rahim-Williams, Bridgett; Riley, Joseph L.

2009-01-01

Sex-related influences on pain and analgesia have become a topic of tremendous scientific and clinical interest, especially in the last 10 to 15 years. Members of our research group published reviews of this literature more than a decade ago, and the intervening time period has witnessed robust growth in research regarding sex, gender, and pain. Therefore, it seems timely to revisit this literature. Abundant evidence from recent epidemiologic studies clearly demonstrates that women are at substantially greater risk for many clinical pain conditions, and there is some suggestion that postoperative and procedural pain may be more severe among women than men. Consistent with our previous reviews, current human findings regarding sex differences in experimental pain indicate greater pain sensitivity among females compared with males for most pain modalities, including more recently implemented clinically relevant pain models such as temporal summation of pain and intramuscular injection of algesic substances. The evidence regarding sex differences in laboratory measures of endogenous pain modulation is mixed, as are findings from studies using functional brain imaging to ascertain sex differences in pain-related cerebral activation. Also inconsistent are findings regarding sex differences in responses to pharmacologic and non-pharmacologic pain treatments. The article concludes with a discussion of potential biopsychosocial mechanisms that may underlie sex differences in pain, and considerations for future research are discussed. Perspective This article reviews the recent literature regarding sex, gender, and pain. The growing body of evidence that has accumulated in the past 10 to 15 years continues to indicate substantial sex differences in clinical and experimental pain responses, and some evidence suggests that pain treatment responses may differ for women versus men. PMID:19411059

Sustained deep-tissue pain alters functional brain connectivity

PubMed Central

Kim, Jieun; Loggia, Marco L.; Edwards, Robert; Wasan, Ajay D.; Gollub, Randy L.; Napadow, Vitaly

2013-01-01

Recent functional brain connectivity studies have contributed to our understanding of the neurocircuitry supporting pain perception. However, evoked-pain connectivity studies have employed cutaneous and/or brief stimuli, which induce sensations that differ appreciably from the clinical pain experience. Sustained myofascial pain evoked by pressure cuff affords an excellent opportunity to evaluate functional connectivity change to more clinically-relevant sustained deep-tissue pain. Connectivity in specific networks known to be modulated by evoked pain (sensorimotor, salience, dorsal attention, fronto-parietal control and default mode networks; SMN, SLN, DAN, FCN and DMN) was evaluated with functional-connectivity MRI, both at rest and during a sustained (6-minute) pain state in healthy adults. We found that pain was stable with no significant changes of subjects’ pain ratings over the stimulation period. Sustained pain reduced connectivity between the SMN and the contralateral leg primary sensorimotor (S1/M1) representation. Such SMN-S1/M1 connectivity decreases were also accompanied by and correlated with increased SLN-S1/M1 connectivity, suggesting recruitment of activated S1/M1 from SMN to SLN. Sustained pain also increased DAN connectivity to pain processing regions such as mid-cingulate cortex, posterior insula and putamen. Moreover, greater connectivity during pain between contralateral S1/M1 and posterior insula, thalamus, putamen, and amygdala, was associated with lower cuff pressures needed to reach the targeted pain sensation. These results demonstrate that sustained pain disrupts resting S1/M1 connectivity by shifting it to a network known to process stimulus salience. Furthermore, increased connectivity between S1/M1 and both sensory and affective processing areas may be an important contribution to inter-individual differences in pain sensitivity. PMID:23718988

Drama-induced affect and pain sensitivity.

PubMed

Zillmann, D; de Wied, M; King-Jablonski, C; Jenzowsky, S

1996-01-01

This study was conducted to examine the pain-ameliorating and pain-sensitizing effects of exposure to emotionally engaging drama. Specifically, the consequences for pain sensitivity of exposure to dramatic expositions differing in both excitatory and hedonic qualities were determined. Hedonically negative, neutral, and positive affective states were induced in male respondents by exposure to excerpts from cinematic drama. Pain sensitivity was assessed by the cuff-pressure procedure before and after exposure and by the cold pressor test after exposure only. When compared against the control condition, pain sensitivity diminished under conditions of hedonically positive affect. An inverse effect was suggested for hedonically negative conditions, but proved tentative and statistically unreliable. The findings are consistent with earlier demonstrations of mood effects on pain sensitivity. Unlike inconclusive earlier findings concerning the magnitude of directional effects, however, they suggest an asymmetry that emphasizes the pain-ameliorating effect of positive affects while lending little, if any, support to the proposal of a pain-sensitizing effect of negative affects. The investigation did not accomplish the intended creation of conditions necessary to test the proposal that heightened sympathetic activity diminishes pain sensitivity. The utility of a rigorous determination of this hypothesized relationship is emphasized, and procedures for a viable test of the proposal are suggested.

Pain thresholds, supra-threshold pain and lidocaine sensitivity in patients with erythromelalgia, including the I848Tmutation in NaV 1.7.

PubMed

Helås, T; Sagafos, D; Kleggetveit, I P; Quiding, H; Jönsson, B; Segerdahl, M; Zhang, Z; Salter, H; Schmelz, M; Jørum, E

2017-09-01

Nociceptive thresholds and supra-threshold pain ratings as well as their reduction upon local injection with lidocaine were compared between healthy subjects and patients with erythromelalgia (EM). Lidocaine (0.25, 0.50, 1.0 or 10 mg/mL) or placebo (saline) was injected intradermally in non-painful areas of the lower arm, in a randomized, double-blind manner, to test the effect on dynamic and static mechanical sensitivity, mechanical pain sensitivity, thermal thresholds and supra-threshold heat pain sensitivity. Heat pain thresholds and pain ratings to supra-threshold heat stimulation did not differ between EM-patients (n = 27) and controls (n = 25), neither did the dose-response curves for lidocaine. Only the subgroup of EM-patients with mutations in sodium channel subunits Na V 1.7, 1.8 or 1.9 (n = 8) had increased lidocaine sensitivity for supra-threshold heat stimuli, contrasting lower sensitivity to strong mechanical stimuli. This pattern was particularly clear in the two patients carrying the Na V 1.7 I848T mutations in whom lidocaine's hyperalgesic effect on mechanical pain sensitivity contrasted more effective heat analgesia. Heat pain thresholds are not sensitized in EM patients, even in those with gain-of-function mutations in Na V 1.7. Differential lidocaine sensitivity was overt only for noxious stimuli in the supra-threshold range suggesting that sensitized supra-threshold encoding is important for the clinical pain phenotype in EM in addition to lower activation threshold. Intracutaneous lidocaine dose-dependently blocked nociceptive sensations, but we did not identify EM patients with particular high lidocaine sensitivity that could have provided valuable therapeutic guidance. Acute pain thresholds and supra-threshold heat pain in controls and patients with erythromelalgia do not differ and have the same lidocaine sensitivity. Acute heat pain thresholds even in EM patients with the Na V 1.7 I848T mutation are normal and only nociceptor sensitivity to intradermal lidocaine is changed. Only in EM patients with mutations in Na V 1.7, 1.8 or 1.9 supra-threshold heat and mechanical pain shows differential lidocaine sensitivity as compared to controls. © 2017 European Pain Federation - EFIC®.

Stress-Related Alterations of Visceral Sensation: Animal Models for Irritable Bowel Syndrome Study

PubMed Central

Mulak, Agata; Taché, Yvette

2011-01-01

Stressors of different psychological, physical or immune origin play a critical role in the pathophysiology of irritable bowel syndrome participating in symptoms onset, clinical presentation as well as treatment outcome. Experimental stress models applying a variety of acute and chronic exteroceptive or interoceptive stressors have been developed to target different periods throughout the lifespan of animals to assess the vulnerability, the trigger and perpetuating factors determining stress influence on visceral sensitivity and interactions within the brain-gut axis. Recent evidence points towards adequate construct and face validity of experimental models developed with respect to animals' age, sex, strain differences and specific methodological aspects such as non-invasive monitoring of visceromotor response to colorectal distension as being essential in successful identification and evaluation of novel therapeutic targets aimed at reducing stress-related alterations in visceral sensitivity. Underlying mechanisms of stress-induced modulation of visceral pain involve a combination of peripheral, spinal and supraspinal sensitization based on the nature of the stressors and dysregulation of descending pathways that modulate nociceptive transmission or stress-related analgesic response. PMID:21860814

Pain sensitivity and tactile spatial acuity are altered in healthy musicians as in chronic pain patients

PubMed Central

Zamorano, Anna M.; Riquelme, Inmaculada; Kleber, Boris; Altenmüller, Eckart; Hatem, Samar M.; Montoya, Pedro

2015-01-01

Extensive training of repetitive and highly skilled movements, as it occurs in professional classical musicians, may lead to changes in tactile sensitivity and corresponding cortical reorganization of somatosensory cortices. It is also known that professional musicians frequently experience musculoskeletal pain and pain-related symptoms during their careers. The present study aimed at understanding the complex interaction between chronic pain and music training with respect to somatosensory processing. For this purpose, tactile thresholds (mechanical detection, grating orientation, two-point discrimination) and subjective ratings to thermal and pressure pain stimuli were assessed in 17 professional musicians with chronic pain, 30 pain-free musicians, 20 non-musicians with chronic pain, and 18 pain-free non-musicians. We found that pain-free musicians displayed greater touch sensitivity (i.e., lower mechanical detection thresholds), lower tactile spatial acuity (i.e., higher grating orientation thresholds) and increased pain sensitivity to pressure and heat compared to pain-free non-musicians. Moreover, we also found that musicians and non-musicians with chronic pain presented lower tactile spatial acuity and increased pain sensitivity to pressure and heat compared to pain-free non-musicians. The significant increment of pain sensitivity together with decreased spatial discrimination in pain-free musicians and the similarity of results found in chronic pain patients, suggests that the extensive training of repetitive and highly skilled movements in classical musicians could be considered as a risk factor for developing chronic pain, probably due to use-dependent plastic changes elicited in somatosensory pathways. PMID:25610384

Modification of COMT-dependent pain sensitivity by psychological stress and sex.

PubMed

Meloto, Carolina B; Bortsov, Andrey V; Bair, Eric; Helgeson, Erika; Ostrom, Cara; Smith, Shad B; Dubner, Ronald; Slade, Gary D; Fillingim, Roger B; Greenspan, Joel D; Ohrbach, Richard; Maixner, William; McLean, Samuel A; Diatchenko, Luda

2016-04-01

Catecholamine-O-methyltransferase (COMT) is a polymorphic gene whose variants affect enzymatic activity and pain sensitivity via adrenergic pathways. Although COMT represents one of the most studied genes in human pain genetics, findings regarding its association with pain phenotypes are not always replicated. Here, we investigated if interactions among functional COMT haplotypes, stress, and sex can modify the effect of COMT genetic variants on pain sensitivity. We tested these interactions in a cross-sectional study, including 2 cohorts, one of 2972 subjects tested for thermal pain sensitivity (Orofacial Pain: Prospective Evaluation and Risk Assessment) and one of 948 subjects with clinical acute pain after motor vehicle collision (post-motor vehicle collision). In both cohorts, the COMT high-pain sensitivity (HPS) haplotype showed robust interaction with stress and number of copies of the HPS haplotype was positively associated with pain sensitivity in nonstressed individuals, but not in stressed individuals. In the post-motor vehicle collision cohort, there was additional modification by sex: the HPS-stress interaction was apparent in males, but not in females. In summary, our findings indicate that stress and sex should be evaluated in association studies aiming to investigate the effect of COMT genetic variants on pain sensitivity.

Pleasure and pain: the effect of (almost) having an orgasm on genital and nongenital sensitivity.

PubMed

Paterson, Laurel Q P; Amsel, Rhonda; Binik, Yitzchak M

2013-06-01

The effect of sexual arousal and orgasm on genital sensitivity has received little research attention, and no study has assessed sensation pleasurableness as well as painfulness. To clarify the relationship between sexual arousal, orgasm, and sensitivity in a healthy female sample. Twenty-six women privately masturbated to orgasm and almost to orgasm at two separate sessions, during which standardized pressure stimulation was applied to the glans clitoris, vulvar vestibule, and volar forearm at three testing times: (i) baseline; (ii) immediately following masturbation; and (iii) following a subsequent 15-minute rest period. Touch thresholds (tactile detection sensitivity), sensation pleasurableness ratings (pleasurable sensitivity), and pain thresholds (pain sensitivity). Pleasurableness ratings were higher on the glans clitoris than the vulvar vestibule, and at most testing times on the vulvar vestibule than the volar forearm; and at baseline and immediately after masturbation than 15 minutes later, mainly on the genital locations only. Pain thresholds were lower on the genital locations than the volar forearm, and immediately and 15 minutes after masturbation than at baseline. After orgasm, genital pleasurableness ratings and vulvar vestibular pain thresholds were lower than after masturbation almost to orgasm. Post-masturbation pleasurableness ratings were positively correlated with pain thresholds but only on the glans clitoris. Hormonal contraception users had lower pleasurableness ratings and pain thresholds on all locations than nonusers. There were no significant effects for touch thresholds. Masturbation appears to maintain pleasurable genital sensitivity but increase pain sensitivity, with lower genital pleasurable sensitivity and higher vulvar vestibular pain sensitivity when orgasm occurs. Findings suggest that enhancing stimulation pleasurableness, psychological sexual arousal and lubrication mitigate normative increases in pain sensitivity during sexual activity, and underscore the importance of measuring both pleasure and pain in sensation research. © 2013 International Society for Sexual Medicine.

A pain in the bud? Implications of cross-modal sensitivity for pain experience.

PubMed

Perkins, Monica; de Bruyne, Marien; Giummarra, Melita J

2016-11-01

There is growing evidence that enhanced sensitivity to painful clinical procedures and chronic pain are related to greater sensitivity to other sensory inputs, such as bitter taste. We examined cross-modal sensitivities in two studies. Study 1 assessed associations between bitter taste sensitivity, pain tolerance, and fear of pain in 48 healthy young adults. Participants were classified as non-tasters, tasters and super-tasters using a bitter taste test (6-n-propythiouracil; PROP). The latter group had significantly higher fear of pain (Fear of Pain Questionnaire) than tasters (p=.036, effect size r = .48). There was only a trend for an association between bitter taste intensity ratings and intensity of pain at the point of pain tolerance in a cold pressor test (p=.04). In Study 2, 40 healthy young adults completed the Adolescent/Adult Sensory Profile before rating intensity and unpleasantness of innocuous (33 °C), moderate (41 °C), and high intensity (44 °C) thermal pain stimulations. The sensory-sensitivity subscale was positively correlated with both intensity and unpleasantness ratings. Canonical correlation showed that only sensitivity to audition and touch (not taste/smell) were associated with intensity of moderate and high (not innocuous) thermal stimuli. Together these findings suggest that there are cross-modal associations predominantly between sensitivity to exteroceptive inputs (i.e., taste, touch, sound) and the affective dimensions of pain, including noxious heat and intolerable cold pain, in healthy adults. These cross-modal sensitivities may arise due to greater psychological aversion to salient sensations, or from shared neural circuitry for processing disparate sensory modalities.

Hormones in pain modulation and their clinical implications for pain control: a critical review.

PubMed

Chen, Xueyin; Zhang, Jinyuan; Wang, Xiangrui

2016-07-01

Recently, more and more studies have found that pain generation, transmission and modulation are under hormonal regulation. Indeed, hormonal dysregulation is a common component of chronic pain syndromes. Studies have attempted to determine whether the relationship between the pain and its perception and hormones is a causative relationship and how these processes interrelate. This review summarizes and analyzes the current experimental data and provides an overview of the studies addressing these questions. The relationship between pain perception and endocrine effects suggests that hormones can be used as important biomarkers of chronic pain syndromes and/or be developed into therapeutic agents in the fight against pain.

Differences in Clinical Pain and Experimental Pain Sensitivity Between Asian Americans and Whites With Knee Osteoarthritis.

PubMed

Ahn, Hyochol; Weaver, Michael; Lyon, Debra E; Kim, Junglyun; Choi, Eunyoung; Staud, Roland; Fillingim, Roger B

2017-02-01

Ethnicity has been associated with clinical and experimental pain responses. Whereas ethnic disparities in pain in other minority groups compared with whites are well described, pain in Asian Americans remains poorly understood. The purpose of this study was to characterize differences in clinical pain intensity and experimental pain sensitivity among older Asian American and non-Hispanic white (NHW) participants with knee osteoarthritis (OA). Data were collected from 50 Asian Americans ages 45 to 85 (28 Korean, 9 Chinese, 7 Japanese, 5 Filipino, and 1 Indian) and compared with 50 age-matched and sex-matched NHW individuals with symptomatic knee OA pain. The Western Ontario and McMaster Universities Osteoarthritis Index and Graded Chronic Pain Scale were used to assess the intensity of clinical knee pain. In addition, quantitative sensory testing was used to measure experimental sensitivity to heat-induced and mechanically induced pain. Asian American participants had significantly higher levels of clinical pain intensity than NHW participants with knee OA. In addition, Asian American participants had significantly higher experimental pain sensitivity than NHW participants with knee OA. These findings add to the growing literature regarding ethnic and racial differences in clinical pain intensity and experimental pain sensitivity. Asian Americans in particular may be at risk for clinical pain and heightened experimental pain sensitivity. Further investigation is needed to identify the mechanisms underlying ethnic group differences in pain between Asian Americans and NHWs, and to ensure that ethnic group disparities in pain are ameliorated.

Perceived Pain Extent is Not Associated With Widespread Pressure Pain Sensitivity, Clinical Features, Related Disability, Anxiety, or Depression in Women With Episodic Migraine.

PubMed

Fernández-de-Las-Peñas, Cesar; Falla, Deborah; Palacios-Ceña, María; Fuensalida-Novo, Stella; Arias-Buría, Jose L; Schneebeli, Alessandro; Arend-Nielsen, Lars; Barbero, Marco

2018-03-01

People with migraine present with varying pain extent and an expanded distribution of perceived pain may reflect central sensitization. The relationship between pain extent and clinical features, psychological outcomes, related disability, and pressure pain sensitivity in migraine has been poorly investigated. Our aim was to investigate whether the perceived pain extent, assessed from pain drawings, relates to measures of pressure pain sensitivity, clinical, psychological outcomes, and related disability in women with episodic migraine. A total of 72 women with episodic migraine completed pain drawings, which were subsequently digitized allowing pain extent to be calculated utilising novel software. Pressure pain thresholds were assessed bilaterally over the temporalis muscle (trigeminal area), the cervical spine (extratrigeminal area), and tibialis anterior muscle (distant pain-free area). Clinical features of migraine, migraine-related disability (migraine disability assessment questionnaire [MIDAS]), and anxiety and depression (Hospital Anxiety-Depression Scale [HADS]) were also assessed. Spearman ρ correlation coefficients were computed to reveal correlations between pain extent and the remaining outcomes. No significant associations were observed between pain extent and pressure pain thresholds in trigeminal, extratrigeminal or distant pain-free areas, migraine pain features, or psychological variables including anxiety or depression, and migraine-related disability. Pain extent within the trigeminocervical area was not associated with any of the measured clinical outcomes and not related to the degree of pressure pain sensitization in women with episodic migraine. Further research is needed to determine if the presence of expanded pain areas outside of the trigeminal area can play a relevant role in the sensitization processes in migraine.

Recommendations on practice of conditioned pain modulation (CPM) testing.

PubMed

Yarnitsky, D; Bouhassira, D; Drewes, A M; Fillingim, R B; Granot, M; Hansson, P; Landau, R; Marchand, S; Matre, D; Nilsen, K B; Stubhaug, A; Treede, R D; Wilder-Smith, O H G

2015-07-01

Protocols for testing conditioned pain modulation (CPM) vary between different labs/clinics. In order to promote research and clinical application of this tool, we summarize the recommendations of interested researchers consensus meeting regarding the practice of CPM and report of its results. © 2014 European Pain Federation - EFIC®

Resting blood pressure differentially predicts time course in a tonic pain experiment.

PubMed

Horing, Bjoern; McCubbin, James A; Moore, Dewayne; Muth, Eric R

2016-10-01

Resting blood pressure (BP) shows a negative relationship with pain sensitivity (BP-related hypoalgesia). In chronic pain conditions, this relationship is inverted. The precise mechanisms responsible for the inversion are unknown. Using a tonic pain protocol, we report findings closely resembling this inversion in healthy participants. Resting BP and state measures of anxiety and mood were assessed from 33 participants (21 female). Participants then immersed their dominant hand in painfully hot water (47 °C) for five trials of 1-min duration, with 30-s intertrial intervals. Throughout the trials, participants continually registered their pain. After a 35-min intermission, the trial sequence was repeated. A disassociation of the negative relationship of resting systolic BP (as per Trial 1) was found using hierarchical linear modeling (p < .001, R(2)  = .07). The disassociation unfolds over each consecutive trial, with an increasingly positive relationship. In Sequence 2, the initially negative relationship is almost completely absent. Furthermore, the association of BP and pain was found to be moderated by anxiety, such that only persons with low anxiety exhibited BP hypoalgesia. Our findings expand the existing literature by incorporating anxiety as a moderator of BP hypoalgesia. Furthermore, the protocol emulates the changing relationship between BP and pain observed in chronic pain patients. The protocol has potential as a model for chronic pain; however, future research should determine if similar physiological systems are involved. The finding holds potential diagnostic or prognostic relevance for certain clinical pain conditions, especially those involving dysfunction of the descending modulation of pain. © 2016 Society for Psychophysiological Research.

An investigation into the effects of frequency-modulated transcutaneous electrical nerve stimulation (TENS) on experimentally-induced pressure pain in healthy human participants.

PubMed

Chen, Chih-Chung; Johnson, Mark I

2009-10-01

Frequency-modulated transcutaneous electrical nerve stimulation (TENS) delivers currents that fluctuate between preset boundaries over a fixed period of time. This study compared the effects of constant-frequency TENS and frequency-modulated TENS on blunt pressure pain in healthy human volunteers. Thirty-six participants received constant-frequency TENS (80 pps), frequency-modulated TENS (20 to 100 pps), and placebo (no current) TENS at a strong nonpainful intensity in a randomized cross-over manner. Pain threshold was taken from the forearm using pressure algometry. There were no statistical differences between constant-frequency TENS and frequency-modulated TENS after 20 minutes (OR = 1.54; CI, 0.29, 8.23, P = 1.0). Both constant-frequency TENS and frequency-modulated TENS were superior to placebo TENS (OR = 59.5, P < .001 and OR = 38.5, P < .001, respectively). Frequency-modulated TENS does not influence hypoalgesia to any greater extent than constant-frequency TENS when currents generate a strong nonpainful paraesthesia at the site of pain. The finding that frequency-modulated TENS and constant-frequency TENS were superior to placebo TENS provides further evidence that a strong yet nonpainful TENS intensity is a prerequisite for hypoalgesia. This study provides evidence that TENS, delivered at a strong nonpainful intensity, increases pain threshold to pressure algometry in healthy participants over and above that seen with placebo (no current) TENS. Frequency-modulated TENS does not increase hypoalgesia to any appreciable extent to that seen with constant-frequency TENS.

Reticular Formation and Pain: The Past and the Future

PubMed Central

Martins, Isabel; Tavares, Isaura

2017-01-01

The involvement of the reticular formation (RF) in the transmission and modulation of nociceptive information has been extensively studied. The brainstem RF contains several areas which are targeted by spinal cord afferents conveying nociceptive input. The arrival of nociceptive input to the RF may trigger alert reactions which generate a protective/defense reaction to pain. RF neurons located at the medulla oblongata and targeted by ascending nociceptive information are also involved in the control of vital functions that can be affected by pain, namely cardiovascular control. The RF contains centers that belong to the pain modulatory system, namely areas involved in bidirectional balance (decrease or enhancement) of pain responses. It is currently accepted that the imbalance of pain modulation towards pain facilitation accounts for chronic pain. The medullary RF has the peculiarity of harboring areas involved in bidirectional pain control namely by the existence of specific neuronal populations involved in antinociceptive or pronociceptive behavioral responses, namely at the rostroventromedial medulla (RVM) and the caudal ventrolateral medulla (VLM). Furthermore the dorsal reticular nucleus (also known as subnucleus reticularis dorsalis; DRt) may enhance nociceptive responses, through a reverberative circuit established with spinal lamina I neurons and inhibit wide-dynamic range (WDR) neurons of the deep dorsal horn. The components of the triad RVM-VLM-DRt are reciprocally connected and represent a key gateway for top-down pain modulation. The RVM-VLM-DRt triad also represents the neurobiological substrate for the emotional and cognitive modulation of pain, through pathways that involve the periaqueductal gray (PAG)-RVM connection. Collectively, we propose that the RVM-VLM-DRt triad represents a key component of the “dynamic pain connectome” with special features to provide integrated and rapid responses in situations which are life-threatening and involve pain. The new available techniques in neurobiological studies both in animal and human studies are producing new and fascinating data which allow to understand the complex role of the RF in pain modulation and its integration with several body functions and also how the RF accounts for chronic pain. PMID:28725185

Reticular Formation and Pain: The Past and the Future.

PubMed

Martins, Isabel; Tavares, Isaura

2017-01-01

The involvement of the reticular formation (RF) in the transmission and modulation of nociceptive information has been extensively studied. The brainstem RF contains several areas which are targeted by spinal cord afferents conveying nociceptive input. The arrival of nociceptive input to the RF may trigger alert reactions which generate a protective/defense reaction to pain. RF neurons located at the medulla oblongata and targeted by ascending nociceptive information are also involved in the control of vital functions that can be affected by pain, namely cardiovascular control. The RF contains centers that belong to the pain modulatory system, namely areas involved in bidirectional balance (decrease or enhancement) of pain responses. It is currently accepted that the imbalance of pain modulation towards pain facilitation accounts for chronic pain. The medullary RF has the peculiarity of harboring areas involved in bidirectional pain control namely by the existence of specific neuronal populations involved in antinociceptive or pronociceptive behavioral responses, namely at the rostroventromedial medulla (RVM) and the caudal ventrolateral medulla (VLM). Furthermore the dorsal reticular nucleus (also known as subnucleus reticularis dorsalis; DRt) may enhance nociceptive responses, through a reverberative circuit established with spinal lamina I neurons and inhibit wide-dynamic range (WDR) neurons of the deep dorsal horn. The components of the triad RVM-VLM-DRt are reciprocally connected and represent a key gateway for top-down pain modulation. The RVM-VLM-DRt triad also represents the neurobiological substrate for the emotional and cognitive modulation of pain, through pathways that involve the periaqueductal gray (PAG)-RVM connection. Collectively, we propose that the RVM-VLM-DRt triad represents a key component of the "dynamic pain connectome" with special features to provide integrated and rapid responses in situations which are life-threatening and involve pain. The new available techniques in neurobiological studies both in animal and human studies are producing new and fascinating data which allow to understand the complex role of the RF in pain modulation and its integration with several body functions and also how the RF accounts for chronic pain.

Ion channel blockers for the treatment of neuropathic pain.

PubMed

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

2010-05-01

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

The interfaces between vitamin D, sleep and pain.

PubMed

de Oliveira, Daniela Leite; Hirotsu, Camila; Tufik, Sergio; Andersen, Monica Levy

2017-07-01

The role of vitamin D in osteomineral metabolism is well known. Several studies have suggested its action on different biological mechanisms, such as nociceptive sensitivity and sleep-wake cycle modulation. Sleep is an important biological process regulated by different regions of the central nervous system, mainly the hypothalamus, in combination with several neurotransmitters. Pain, which can be classified as nociceptive, neuropathic and psychological, is regulated by both the central and peripheral nervous systems. In the peripheral nervous system, the immune system participates in the inflammatory process that contributes to hyperalgesia. Sleep deprivation is an important condition related to hyperalgesia, and recently it has also been associated with vitamin D. Poor sleep efficiency and sleep disorders have been shown to have an important role in hyperalgesia, and be associated with different vitamin D values. Vitamin D has been inversely correlated with painful manifestations, such as fibromyalgia and rheumatic diseases. Studies have demonstrated a possible action of vitamin D in the regulatory mechanisms of both sleep and pain. The supplementation of vitamin D associated with good sleep hygiene may have a therapeutic role, not only in sleep disorders but also in the prevention and treatment of chronic pain conditions. © 2017 Society for Endocrinology.

Does experimental pain affect auditory processing of speech-relevant signals? A study in healthy young adults.

PubMed

Sapir, Shimon; Pud, Dorit

2008-01-01

To assess the effect of tonic pain stimulation on auditory processing of speech-relevant acoustic signals in healthy pain-free volunteers. Sixty university students, randomly assigned to either a thermal pain stimulation (46 degrees C/6 min) group (PS) or no pain stimulation group (NPS), performed a rate change detection task (RCDT) involving sinusoidally frequency-modulated vowel-like signals. Task difficulty was manipulated by changing the rate of the modulated signals (henceforth rate). Perceived pain intensity was evaluated using a visual analog scale (VAS) (0-100). Mean pain rating was approximately 33 in the PS group and approximately 3 in the NPS group. Pain stimulation was associated with poorer performance on the RCDT, but this trend was not statistically significant. Performance worsened with increasing rate of signal modulation in both groups (p < 0.0001), with no pain by rate interaction. The present findings indicate a trend whereby mild or moderate pain appears to affect auditory processing of speech-relevant acoustic signals. This trend, however, was not statistically significant. It is possible that more intense pain would yield more pronounced (deleterious) effects on auditory processing, but this needs to be verified empirically.

Sex differences in the relationships between parasympathetic activity and pain modulation.

PubMed

Nahman-Averbuch, Hadas; Dayan, Lior; Sprecher, Elliot; Hochberg, Uri; Brill, Silviu; Yarnitsky, David; Jacob, Giris

2016-02-01

Higher parasympathetic activity is related to lower pain perception in healthy subjects and pain patients. We aimed to examine whether this relationship depends on sex, in healthy subjects. Parasympathetic activity was assessed using time- and frequency-domain heart rate variability indices and deep breathing ratio. Pain perception parameters, consisting of heat pain thresholds and pain ratings of supra-thresholds stimuli, as well as pain modulation parameters of mechanical temporal summation, pain adaptation, offset analgesia and conditioned pain modulation (CPM) response were examined. Forty healthy subjects were examined (20 men). Women demonstrated higher parasympathetic activity compared to men (high frequency power of 0.55±0.2 and 0.40±0.2, respectively, p=0.02) and less pain reduction in the offset analgesia paradigm (-35.4±29.1 and -55.0±31.2, respectively, p=0.046). Separate slopes models analyses revealed sex differences such that a significant negative correlation was observed between higher rMSSD (the root mean square of successive differences) and higher pain adaptation in men (r=-0.649, p=0.003) but not in women (r=0.382, p=0.106). Similarly, a significant negative correlation was found between higher rMSSD and higher efficiency of the CPM response in men (r=-0.510, p=0.026) but not in women (r=0.406, p=0.085). Sex hormones levels, psychological factors or baseline autonomic activity can be possible explanations for these sex differences. Future autonomic interventions destined to change pain modulation should consider sex as an important intervening factor. Copyright © 2015 Elsevier Inc. All rights reserved.

Ethanolic extract of Aconiti Brachypodi Radix attenuates nociceptive pain probably via inhibition of voltage-dependent Na⁺ channel.

PubMed

Ren, Wei; Yuan, Lin; Li, Jun; Huang, Xian-Ju; Chen, Su; Zou, Da-Jiang; Liu, Xiangming; Yang, Xin-Zhou

2012-01-01

Aconiti Brachypodi Radix, belonging to the genus of Aconitum (Family Ranunculaceae), are used clinically as anti-rheumatic, anti-inflammatory and anti-nociceptive in traditional medicine of China. However, its mechanism and influence on nociceptive threshold are unknown and need further investigation. The analgesic effects of ethanolic extract of Aconiti Brachypodi Radix (EABR) were thus studied in vivo and in vitro. Three pain models in mice were used to assess the effect of EABR on nociceptive threshold. In vitro study was conducted to clarify the modulation of the extract on the tetrodotoxin-sensitive (TTX-S) sodium currents in rat's dorsal root ganglion (DRG) neurons using whole-cell patch clamp technique. The results showed that EABR (5-20 mg/kg, i.g.) could produce dose-dependent analgesic effect on hot-plate tests as well as writhing response induced by acetic acid. In addition, administration of 2.5-10 mg/kg EABR (i.g.) caused significant decrease in pain responses in the first and second phases of formalin test without altering the PGE₂ production in the hind paw of the mice. Moreover, EABR (10 µg/ml -1 mg/ml) could suppress TTX-S voltage-gated sodium currents in a dose-dependent way, indicating the underlying electrophysiological mechanism of the analgesic effect of the folk plant medicine. Collectively, our results indicated that EABR has analgesic property in three pain models and useful influence on TTX-S sodium currents in DRG neurons, suggesting that the interference with pain messages caused by the modulation of EABR on TTX-S sodium currents in DRG neurones may explain some of its analgesic effect.

Negative Illness Perceptions are Associated with a Pro-nociceptive Modulation Profile and Augmented Pelvic Pain.

PubMed

Grinberg, Keren; Granot, Michal; Lowenstein, Lior; Abramov, Liora; Weissman-Fogel, Irit

2018-05-25

A patient's personal interpretations of a health threat or "illness perceptions" (IPs) are associated with their clinical outcomes. This study explored whether IPs are associated with pain severity and ability to modulate pain in women with chronic pelvic pain syndrome (CPPS), as well as the predictive value of IPs on Myofascial Physical Therapy (MPT) success. Illness Perceptions Questionnaire - Revised (IPQ-R), mechanical and heat pain thresholds, mechanical temporal summation (mTS), and conditioned pain modulation (CPM) were evaluated in CPPS patients (n=39) before, and 3 months after MPT. CPPS severity was obtained by the Brief Pain Inventory (BPI). Stronger perceptions of illness chronicity were correlated with less efficient CPM (r=0.488, P=0.002) and increased mechanical pain intensity (r=0.405, P=0.02). Lower perceptions of control over illness were associated with enhanced mTS (r=0.399, P=0.01). Higher BPI scores were correlated with emotional representations ("negative emotional representations") and severe consequences due to CPPS. Regression analyses revealed that negative IPs predict less efficient MPT. Cognitive representations play a unique role in CPPS expression and MPT outcomes. The interplay between negative IPs and a pro-nociceptive modulation profile, mediated by enhanced facilitatory and reduced inhibitory processes, may be involved in the manifestation of CPPS.

Differences in Clinical Pain and Experimental Pain Sensitivity between Asian Americans and Whites with Knee Osteoarthritis

PubMed Central

Ahn, Hyochol; Weaver, Michael; Lyon, Debra; Kim, Junglyun; Choi, Eunyoung; Staud, Roland; Fillingim, Roger B.

2016-01-01

Objective Ethnicity has been associated with clinical and experimental pain responses. While ethnic disparities in pain in other minority groups compared to whites are well described, pain in Asian Americans remains poorly understood. The purpose of this study was to characterize differences in clinical pain intensity and experimental pain sensitivity among older Asian American and non-Hispanic White (NHW) participants with knee osteoarthritis (OA). Methods Data were collected from 50 Asian Americans ages 45-85 (28 Korean, 9 Chinese, 7 Japanese, 5 Filipino, and 1 Indian) and compared to 50 age- and gender-matched NHW individuals with symptomatic knee OA pain. The Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and Graded Chronic Pain Scale (GCPS) were used to assess the intensity of clinical knee pain. In addition, quantitative sensory testing was used to measure experimental sensitivity to heat- and mechanically-induced pain. Results Asian American participants had significantly higher levels of clinical pain intensity than NHW participants with knee OA. In addition, Asian American participants had significantly higher experimental pain sensitivity than NHW participants with knee OA. Discussion These findings add to the growing literature regarding ethnic and racial differences in clinical pain intensity and experimental pain sensitivity. Asian Americans in particular may be at risk for clinical pain and heightened experimental pain sensitivity. Further investigation is needed to identify the mechanisms underlying ethnic group differences in pain between Asian Americans and non-Hispanic Whites, and to ensure that ethnic group disparities in pain are ameliorated. PMID:28060784

Chronic Stress, Cortisol Dysfunction, and Pain: A Psychoneuroendocrine Rationale for Stress Management in Pain Rehabilitation

PubMed Central

Bishop, Mark D.

2014-01-01

Pain is a primary symptom driving patients to seek physical therapy, and its attenuation commonly defines a successful outcome. A large body of evidence is dedicated to elucidating the relationship between chronic stress and pain; however, stress is rarely addressed in pain rehabilitation. A physiologic stress response may be evoked by fear or perceived threat to safety, status, or well-being and elicits the secretion of sympathetic catecholamines (epinephrine and norepinepherine) and neuroendocrine hormones (cortisol) to promote survival and motivate success. Cortisol is a potent anti-inflammatory that functions to mobilize glucose reserves for energy and modulate inflammation. Cortisol also may facilitate the consolidation of fear-based memories for future survival and avoidance of danger. Although short-term stress may be adaptive, maladaptive responses (eg, magnification, rumination, helplessness) to pain or non–pain-related stressors may intensify cortisol secretion and condition a sensitized physiologic stress response that is readily recruited. Ultimately, a prolonged or exaggerated stress response may perpetuate cortisol dysfunction, widespread inflammation, and pain. Stress may be unavoidable in life, and challenges are inherent to success; however, humans have the capability to modify what they perceive as stressful and how they respond to it. Exaggerated psychological responses (eg, catastrophizing) following maladaptive cognitive appraisals of potential stressors as threatening may exacerbate cortisol secretion and facilitate the consolidation of fear-based memories of pain or non–pain-related stressors; however, coping, cognitive reappraisal, or confrontation of stressors may minimize cortisol secretion and prevent chronic, recurrent pain. Given the parallel mechanisms underlying the physiologic effects of a maladaptive response to pain and non–pain-related stressors, physical therapists should consider screening for non–pain-related stress to facilitate treatment, prevent chronic disability, and improve quality of life. PMID:25035267

Chronic stress, cortisol dysfunction, and pain: a psychoneuroendocrine rationale for stress management in pain rehabilitation.

PubMed

Hannibal, Kara E; Bishop, Mark D

2014-12-01

Pain is a primary symptom driving patients to seek physical therapy, and its attenuation commonly defines a successful outcome. A large body of evidence is dedicated to elucidating the relationship between chronic stress and pain; however, stress is rarely addressed in pain rehabilitation. A physiologic stress response may be evoked by fear or perceived threat to safety, status, or well-being and elicits the secretion of sympathetic catecholamines (epinephrine and norepinepherine) and neuroendocrine hormones (cortisol) to promote survival and motivate success. Cortisol is a potent anti-inflammatory that functions to mobilize glucose reserves for energy and modulate inflammation. Cortisol also may facilitate the consolidation of fear-based memories for future survival and avoidance of danger. Although short-term stress may be adaptive, maladaptive responses (eg, magnification, rumination, helplessness) to pain or non-pain-related stressors may intensify cortisol secretion and condition a sensitized physiologic stress response that is readily recruited. Ultimately, a prolonged or exaggerated stress response may perpetuate cortisol dysfunction, widespread inflammation, and pain. Stress may be unavoidable in life, and challenges are inherent to success; however, humans have the capability to modify what they perceive as stressful and how they respond to it. Exaggerated psychological responses (eg, catastrophizing) following maladaptive cognitive appraisals of potential stressors as threatening may exacerbate cortisol secretion and facilitate the consolidation of fear-based memories of pain or non-pain-related stressors; however, coping, cognitive reappraisal, or confrontation of stressors may minimize cortisol secretion and prevent chronic, recurrent pain. Given the parallel mechanisms underlying the physiologic effects of a maladaptive response to pain and non-pain-related stressors, physical therapists should consider screening for non-pain-related stress to facilitate treatment, prevent chronic disability, and improve quality of life. © 2014 American Physical Therapy Association.

Basic science of pain.

PubMed

DeLeo, Joyce A

2006-04-01

The origin of the theory that the transmission of pain is through a single channel from the skin to the brain can be traced to the philosopher and scientist René Descartes. This simplified scheme of the reflex was the beginning of the development of the modern doctrine of reflexes. Unfortunately, Descartes' reflex theory directed both the study and treatment of pain for more than 330 years. It is still described in physiology and neuroscience textbooks as fact rather than theory. The gate control theory proposed by Melzack and Wall in 1965 rejuvenated the field of pain study and led to further investigation into the phenomena of spinal sensitization and central nervous system plasticity, which are the potential pathophysiologic correlates of chronic pain. The processing of pain takes place in an integrated matrix throughout the neuroaxis and occurs on at least three levels-at peripheral, spinal, and supraspinal sites. Basic strategies of pain control monopolize on this concept of integration by attenuation or blockade of pain through intervention at the periphery, by activation of inhibitory processes that gate pain at the spinal cord and brain, and by interference with the perception of pain. This article discusses each level of pain modulation and reviews the mechanisms of action of opioids and potential new analgesics. A brief description of animal models frames a discussion about recent advances regarding the role of glial cells and central nervous system neuroimmune activation and innate immunity in the etiology of chronic pain states. Future investigation into the discovery and development of novel, nonopioid drug therapy may provide needed options for the millions of patients who suffer from chronic pain syndromes, including syndromes in which the pain originates from peripheral nerve, nerve root, spinal cord, bone, muscle, and disc.

Pain in context: Cues predicting a reward decrease fear of movement related pain and avoidance behavior.

PubMed

Claes, Nathalie; Vlaeyen, Johan W S; Crombez, Geert

2016-09-01

Previous research shows that goal-directed behavior might be modulated by cues that predict (dis)similar outcomes. However, the literature investigating this modulation with pain outcomes is scarce. Therefore, this experiment investigated whether environmental cues predicting pain or reward modulate defensive pain responding. Forty-eight healthy participants completed a joystick movement task with two different movement orientations. Performing one movement was associated with a painful stimulus, whereas performance of another movement was associated with reward, i.e. lottery tickets. In a subsequent task, participants learned to associate three different cues withpain, reward, or neither of the two. Next, these cues were integrated in the movement task. This study demonstrates that in general, aversive cues enhance and appetitive cues reduce pain-related fear. Furthermore, we found that incongruence between the outcomes predicted by the movement and the cue results in more oscillatory behavior, i.e., participants were more willing to perform a painful movement when a cue predicting reward was simultaneously presented, and vice versa. Similarly, when given a choice, participants preferred to perform the reward movement, unless there was an incongruence between the outcomes predicted by the movements and cues. Taken together, these results provide experimental evidence that environmental cues are capable of modulating pain-related fear and avoidance behavior. Copyright © 2016 Elsevier Ltd. All rights reserved.

Somatoform Pain: A developmental theory and translational research review

PubMed Central

Landa, Alla; Peterson, Bradley S.; Fallon, Brian A.

2013-01-01

Somatoform pain is a highly prevalent, debilitating condition and a tremendous public health problem. Effective treatments for somatoform pain are urgently needed. The etiology of this condition is, however, still unknown. On the basis of a review of recent basic and clinical research, we propose one potential mechanisms of symptom formation in somatoform pain and a developmental theory of its pathogenesis. The emerging evidence from animal and human studies in developmental neurobiology, cognitive-affective neuroscience, psychoneuroimmunology, genetics, epigenetics, and clinical and treatment studies of somatoform pain all point to the existence of a shared physical and social pain neural system. Research findings also show that non-optimal early experiences interact with genetic predispositions to influence the development of this shared system and ability to regulate it in an effective way. Interpersonal affect regulation between infant and caregiver is crucial for the optimal development of these brain circuits. The aberrant development of this shared neural system during infancy, childhood and adolescence, therefore, may ultimately lead to an increased sensitivity to physical and social pain and to problems with their regulation in adulthood. The authors critically review translational research findings that support this theory and discuss its clinical and research implications. Specifically, the proposed theory and reviewed research suggest that psychotherapeutic and/or pharmacologic interventions that foster the development of affect regulation capacities in an interpersonal context will also serve to more effectively modulate aberrantly activated neural pain circuits and thus be of particular benefit in the treatment of somatoform pain. PMID:22929064

Characteristics of dorsal root ganglia neurons sensitive to Substance P.

PubMed

Moraes, Eder Ricardo; Kushmerick, Christopher; Naves, Ligia Araujo

2014-11-27

Substance P modulates ion channels and the excitability of sensory neurons in pain pathways. Within the heterogeneous population of Dorsal Root Ganglia (DRG) primary sensory neurons, the properties of cells that are sensitive to Substance P are poorly characterized. To define this population better, dissociated rat DRG neurons were tested for their responsiveness to capsaicin, ATP and acid. Responses to ATP were classified according to the kinetics of current activation and desensitization. The same cells were then tested for modulation of action potential firing by Substance P. Acid and capsaicin currents were more frequently encountered in the largest diameter neurons. P2X3-like ATP currents were concentrated in small diameter neurons. Substance P modulated the excitability in 20 of 72 cells tested (28%). Of the Substance P sensitive cells, 10 exhibited an increase in excitability and 10 exhibited a decrease in excitability. There was no significant correlation between sensitivity to capsaicin and to Substance P. Excitatory effects of Substance P were strongly associated with cells that had large diameters, fired APs with large overshoots and slowly decaying after hyperpolarizations, and expressed acid currents at pH 7. No neurons that were excited by Substance P presented P2X3-like currents. In contrast, neurons that exhibited inhibitory effects of Substance P fired action potentials with rapidly decaying after hyperpolarizations. We conclude that excitatory effects of Substance P are restricted to a specific neuronal subpopulation with limited expression of putative nociceptive markers.

Can brief measures effectively screen for pain and somatic malingering? Examination of the Modified Somatic Perception Questionnaire and Pain Disability Index.

PubMed

Crighton, Adam H; Wygant, Dustin B; Applegate, Kathryn C; Umlauf, Robert L; Granacher, Robert P

2014-09-01

Recent rise in fraudulent disability claims in the United States has resulted in psychologists being increasingly called upon to use psychological tests to determine whether disability claims based on psychological or somatic/pain complaints are legitimate. To examine two brief measures, Modified Somatic Perception Questionnaire (MSPQ) and the Pain Disability Index (PDI), and their ability to screen for malingering in relation to the Bianchini et al. criteria for malingered pain-related disability published in The Spine Journal (2005). Examined brief self-report measures between litigating and nonlitigating pain samples. We compared 144 disability litigants, predominantly presenting a history of musculoskeletal injuries with psychiatric overlay, with 167 nonlitigating pain patients who were predominantly in treatment for chronic back pain issues and other musculoskeletal conditions. Modified Somatic Perception Questionnaire, Pain Disability Index, Minnesota Multiphasic Personality Inventory-2 Restructured Form, Test of Memory Malingering, Letter Memory Test, Victoria Symptom Validity Test, Structured Interview of Reported Symptoms-second edition, Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders somatoform disorders module. We examined a sample of 144 individuals undergoing compensation-seeking evaluations in relation to 167 nonlitigating pain patients. Group differences on both the MSPQ and PDI were calculated, as well as sensitivities, specificities, and positive and negative predictive powers for both measures at selected cutoffs. The results suggest that both the MSPQ and PDI are useful to screen for pain malingering in forensic evaluations, especially the MSPQ, which performed the best in differentiating between the groups. Copyright © 2014 Elsevier Inc. All rights reserved.

Stress antagonizes morphine-induced analgesia in rats

NASA Technical Reports Server (NTRS)

Vernikos, J.; Shannon, L.; Heybach, J. P.

1981-01-01

Exposure to restraint stress resulted in antagonism of the analgesic effect of administered morphine in adult male rats. This antagonism of morphine-induced analgesia by restraint stress was not affected by adrenalectomy one day prior to testing, suggesting that stress-induced secretion of corticosteroids is not critical to this antagonism. In addition, parenteral administration of exogenous adrenocorticotropin (ACTH) mimicked the effect of stress in antagonizing morphine's analgesic efficacy. The hypothesis that ACTH is an endogenous opiate antagonist involved in modulating pain sensitivity is supported.

No effects of hydrocortisone and dexamethasone on pain sensitivity in healthy individuals.

PubMed

Wingenfeld, K; Wolf, S; Kunz, M; Krieg, J-C; Lautenbacher, S

2015-07-01

There is some evidence that stress-induced cortisol increase leads to a decrease in pain, while lowering cortisol levels enhances pain sensitivity, but no study has yet investigated both pharmacological enhancement and reduction of cortisol levels in the same individuals. Firstly, we tested in 16 healthy individuals whether the treatment with hydrocortisone and dexamethasone, respectively, results in altered pain thresholds. Secondly, we aimed to test whether hormone effects are different across the pain range by using ratings for pain stimuli with varying intensity; and thirdly, we tested whether cortisol levels influence the discrimination ability for painful stimuli. Despite substantial effects of dexamethasone and hydrocortisone administration on cortisol levels, no effect of these drugs was seen in terms of pain sensitivity (pain threshold, pain rating, pain discrimination ability), although comprehensively examined. However, in the placebo condition, a significant negative correlation between cortisol and pain thresholds was seen. Similarly, there were also strong negative associations between cortisol levels in the placebo condition and pain thresholds after drug treatment (especially after hydrocortisone). These findings suggest that short-term variations of cortisol do not influence pain sensitivity whereas, in general, high levels of cortisol are associated with increased pain sensitivity, at least for weak to moderate stimuli. © 2014 European Pain Federation - EFIC®

Nonpainful wide-area compression inhibits experimental pain.

PubMed

Honigman, Liat; Bar-Bachar, Ofrit; Yarnitsky, David; Sprecher, Elliot; Granovsky, Yelena

2016-09-01

Compression therapy, a well-recognized treatment for lymphoedema and venous disorders, pressurizes limbs and generates massive non-noxious afferent sensory barrages. The aim of this study was to study whether such afferent activity has an analgesic effect when applied on the lower limbs, hypothesizing that larger compression areas will induce stronger analgesic effects, and whether this effect correlates with conditioned pain modulation (CPM). Thirty young healthy subjects received painful heat and pressure stimuli (47°C for 30 seconds, forearm; 300 kPa for 15 seconds, wrist) before and during 3 compression protocols of either SMALL (up to ankles), MEDIUM (up to knees), or LARGE (up to hips) compression areas. Conditioned pain modulation (heat pain conditioned by noxious cold water) was tested before and after each compression protocol. The LARGE protocol induced more analgesia for heat than the SMALL protocol (P < 0.001). The analgesic effect interacted with gender (P = 0.015). The LARGE protocol was more efficient for females, whereas the MEDIUM protocol was more efficient for males. Pressure pain was reduced by all protocols (P < 0.001) with no differences between protocols and no gender effect. Conditioned pain modulation was more efficient than the compression-induced analgesia. For the LARGE protocol, precompression CPM efficiency positively correlated with compression-induced analgesia. Large body area compression exerts an area-dependent analgesic effect on experimental pain stimuli. The observed correlation with pain inhibition in response to robust non-noxious sensory stimulation may suggest that compression therapy shares similar mechanisms with inhibitory pain modulation assessed through CPM.

A common pronociceptive pain modulation profile typifying subgroups of chronic pelvic pain syndromes is interrelated with enhanced clinical pain.

PubMed

Grinberg, Keren; Granot, Michal; Lowenstein, Lior; Abramov, Liora; Weissman-Fogel, Irit

2017-06-01

Provoked vestibulodynia (PVD) and painful bladder syndrome (PBS), subgroups of chronic pelvic pain syndromes (CPPS), are considered to share common biophysiological peripheral mechanisms. In addition, indications of a pronociceptive pain profile coexisting with psychological vulnerability suggest common dysfunctional pain processing and pain modulation in these 2 subgroups of CPPS. We therefore aimed at comparing the pain profile and psychological traits of patients with PVD and PBS to see whether the pain profile contributes to intersubject variability of clinical pain symptoms. Patients with PVD (n = 18) and PBS (n = 21) were compared with healthy controls (n = 20) in their responses to (1) pain psychophysical tests applied to both referred (suprapubis) and remote (hand) body areas and (2) pain-related psychological factors (pain catastrophizing, depression, anxiety, and somatization). We found a similar pronociceptive pain profile in the 2 subgroups of CPPS-enhanced facilitation (ie, hyperalgesia in the referred body area [P < 0.001]) and inefficient inhibition (ie, reduced conditioned pain modulation [P < 0.001] that were associated with both enhanced pain ratings evoked during trigger point examination [P < 0.037]) and higher Brief Pain Inventory ratings (P = 0.002). The latter was also correlated with pain catastrophizing (r = 0.504, P = 0.001) and depression symptoms (r = 0.361, P = 0.024). The findings suggest common mechanisms underlying a dysfunctional nociceptive system in both PVD and PBS. The intersubject variability in the level of dysfunction and its association with disease severity recommends a personalized pain treatment that may alleviate daily pain and dysfunction in patients with CPPS.

Motor Cortex Excitability and BDNF Levels in Chronic Musculoskeletal Pain According to Structural Pathology

PubMed Central

Caumo, Wolnei; Deitos, Alícia; Carvalho, Sandra; Leite, Jorge; Carvalho, Fabiana; Dussán-Sarria, Jairo Alberto; Lopes Tarragó, Maria da Graça; Souza, Andressa; Torres, Iraci Lucena da Silva; Fregni, Felipe

2016-01-01

The central sensitization syndrome (CSS) encompasses disorders with overlapping symptoms in a structural pathology spectrum ranging from persistent nociception [e.g., osteoarthritis (OA)] to an absence of tissue injuries such as the one presented in fibromyalgia (FM) and myofascial pain syndrome (MPS). First, we hypothesized that these syndromes present differences in their cortical excitability parameters assessed by transcranial magnetic stimulation (TMS), namely motor evoked potential (MEP), cortical silent period (CSP), short intracortical inhibition (SICI) and short intracortical facilitation (SICF). Second, considering that the presence of tissue injury could be detected by serum neurotrophins, we hypothesized that the spectrum of structural pathology (i.e., from persistent nociception like in OA, to the absence of tissue injury like in FM and MPS), could be detected by differential efficiency of their descending pain inhibitory system, as assessed by the conditioned pain modulation (CPM) paradigm. Third, we explored whether brain-derived neurotrophic factor (BDNF) had an influence on the relationship between motor cortex excitability and structural pathology. This cross-sectional study pooled baseline data from three randomized clinical trials. We included females (n = 114), aged 19–65 years old with disability by chronic pain syndromes (CPS): FM (n = 19), MPS (n = 54), OA (n = 27) and healthy subjects (n = 14). We assessed the serum BDNF, the motor cortex excitability by parameters the TMS measures and the change on numerical pain scale [NPS (0–10)] during CPM-task. The adjusted mean (SD) on the SICI observed in the absence of tissue injury was 56.36% lower than with persistent nociceptive input [0.31(0.18) vs. 0.55 (0.32)], respectively. The BDNF was inversely correlated with the SICI and with the change on NPS (0–10)during CPM-task. These findings suggest greater disinhibition in the motor cortex and the descending pain inhibitory system in FM and MPS than in OA and healthy subjects. Likewise, the inter-hemispheric disinhibition as well as the dysfunction in the descending pain modulatory system is higher in chronic pain without tissue injury compared to a structural lesion. In addition, they suggest that a greater level of serum BDNF may be involved in the processes that mediate the disinhibition of motor cortex excitability, as well as the function of descending inhibitory pain modulation system, independently of the physiopathology mechanism of musculoskeletal pain syndromes. PMID:27471458

Task modulations of racial bias in neural responses to others' suffering.

PubMed

Sheng, Feng; Liu, Qiang; Li, Hong; Fang, Fang; Han, Shihui

2014-03-01

Recent event related brain potential research observed a greater frontal activity to pain expressions of racial in-group than out-group members and such racial bias in neural responses to others' suffering was modulated by task demands that emphasize race identity or painful feeling. However, as pain expressions activate multiple brain regions in the pain matrix, it remains unclear which part of the neural circuit in response to others' suffering undergoes modulations by task demands. We scanned Chinese adults, using functional MRI, while they categorized Asian and Caucasian faces with pain or neutral expressions in terms of race or identified painful feelings of each individual face. We found that pain vs. neutral expressions of Asian but not Caucasian faces activated the anterior cingulate (ACC) and anterior insular (AI) activity during race judgments. However, pain compared to race judgments increased ACC and AI activity to pain expressions of Caucasian but not Asian faces. Moreover, race judgments induced increased activity in the dorsal medial prefrontal cortex whereas pain judgments increased activity in the bilateral temporoparietal junction. The results suggest that task demands emphasizing an individual's painful feeling increase ACC/AI activities to pain expressions of racial out-group members and reduce the racial bias in empathic neural responses. © 2013.

Reduced Pain Sensation and Reduced BOLD Signal in Parietofrontal Networks during Religious Prayer

PubMed Central

Elmholdt, Else-Marie; Skewes, Joshua; Dietz, Martin; Møller, Arne; Jensen, Martin S.; Roepstorff, Andreas; Wiech, Katja; Jensen, Troels S.

2017-01-01

Previous studies suggest that religious prayer can alter the experience of pain via expectation mechanisms. While brain processes related to other types of top-down modulation of pain have been studied extensively, no research has been conducted on the potential effects of active religious coping. Here, we aimed at investigating the neural mechanisms during pain modulation by prayer and their dependency on the opioidergic system. Twenty-eight devout Protestants performed religious prayer and a secular contrast prayer during painful electrical stimulation in two fMRI sessions. Naloxone or saline was administered prior to scanning. Results show that pain intensity was reduced by 11% and pain unpleasantness by 26% during religious prayer compared to secular prayer. Expectancy predicted large amounts (70–89%) of the variance in pain intensity. Neuroimaging results revealed reduced neural activity during religious prayer in a large parietofrontal network relative to the secular condition. Naloxone had no significant effect on ratings or neural activity. Our results thus indicate that, under these conditions, pain modulation by prayer is not opioid-dependent. Further studies should employ an optimized design to explore whether reduced engagement of the frontoparietal system could indicate that prayer may attenuate pain through a reduction in processing of pain stimulus saliency and prefrontal control rather than through known descending pain inhibitory systems. PMID:28701940

Reduced Pain Sensation and Reduced BOLD Signal in Parietofrontal Networks during Religious Prayer.

PubMed

Elmholdt, Else-Marie; Skewes, Joshua; Dietz, Martin; Møller, Arne; Jensen, Martin S; Roepstorff, Andreas; Wiech, Katja; Jensen, Troels S

2017-01-01

Previous studies suggest that religious prayer can alter the experience of pain via expectation mechanisms. While brain processes related to other types of top-down modulation of pain have been studied extensively, no research has been conducted on the potential effects of active religious coping. Here, we aimed at investigating the neural mechanisms during pain modulation by prayer and their dependency on the opioidergic system. Twenty-eight devout Protestants performed religious prayer and a secular contrast prayer during painful electrical stimulation in two fMRI sessions. Naloxone or saline was administered prior to scanning. Results show that pain intensity was reduced by 11% and pain unpleasantness by 26% during religious prayer compared to secular prayer. Expectancy predicted large amounts (70-89%) of the variance in pain intensity. Neuroimaging results revealed reduced neural activity during religious prayer in a large parietofrontal network relative to the secular condition. Naloxone had no significant effect on ratings or neural activity. Our results thus indicate that, under these conditions, pain modulation by prayer is not opioid-dependent. Further studies should employ an optimized design to explore whether reduced engagement of the frontoparietal system could indicate that prayer may attenuate pain through a reduction in processing of pain stimulus saliency and prefrontal control rather than through known descending pain inhibitory systems.

Nociceptive transmission and modulation via P2X receptors in central pain syndrome.

PubMed

Kuan, Yung-Hui; Shyu, Bai-Chuang

2016-05-26

Painful sensations are some of the most frequent complaints of patients who are admitted to local medical clinics. Persistent pain varies according to its causes, often resulting from local tissue damage or inflammation. Central somatosensory pathway lesions that are not adequately relieved can consequently cause central pain syndrome or central neuropathic pain. Research on the molecular mechanisms that underlie this pathogenesis is important for treating such pain. To date, evidence suggests the involvement of ion channels, including adenosine triphosphate (ATP)-gated cation channel P2X receptors, in central nervous system pain transmission and persistent modulation upon and following the occurrence of neuropathic pain. Several P2X receptor subtypes, including P2X2, P2X3, P2X4, and P2X7, have been shown to play diverse roles in the pathogenesis of central pain including the mediation of fast transmission in the peripheral nervous system and modulation of neuronal activity in the central nervous system. This review article highlights the role of the P2X family of ATP receptors in the pathogenesis of central neuropathic pain and pain transmission. We discuss basic research that may be translated to clinical application, suggesting that P2X receptors may be treatment targets for central pain syndrome.

Part-time, e-learning interprofessional pain management education for the primary and community care setting.

PubMed

Jenkins, M Sue; Bean, W Geinor; Luke, Karl

2014-02-01

Chronic pain is a long-term condition, which has a major impact on patients, carers and the health service. Despite the Chief Medical Officer setting chronic pain and its management as a national priority in 2008, the utilisation of health services by patients with long-term conditions is increasing, people with pain-related problems are not seen early enough and pain-related attendances to accident and emergency departments is increasing. Early assessment with appropriate evidence-based intervention and early recognition of when to refer to specialist and specialised services is key to addressing the growing numbers suffering with chronic pain. Pain education is recommended in many guidelines, as part of the process to address pain in these issues. Cardiff University validated an e-learning, master's level pain management module for healthcare professionals working in primary and community care. The learning outcomes revolve around robust early assessment and management of chronic pain in primary and community care and the knowledge when to refer on. The module focuses on the biopsychosocial aspects of pain and its management, using a blog as an online case study assessment for learners to demonstrate their knowledge, understanding and application to practice. The module has resulted in learners developing evidence-based recommendations, for pain management in clinical practice.

The Key Role of Pain Catastrophizing in the Disability of Patients with Acute Back Pain.

PubMed

Ramírez-Maestre, C; Esteve, R; Ruiz-Párraga, G; Gómez-Pérez, L; López-Martínez, A E

2017-04-01

This study investigated the role of anxiety sensitivity, resilience, pain catastrophizing, depression, pain fear-avoidance beliefs, and pain intensity in patients with acute back pain-related disability. Two hundred and thirty-two patients with acute back pain completed questionnaires on anxiety sensitivity, resilience, pain catastrophizing, fear-avoidance beliefs, depression, pain intensity, and disability. A structural equation modelling analysis revealed that anxiety sensitivity was associated with pain catastrophizing, and resilience was associated with lower levels of depression. Pain catastrophizing was positively associated with fear-avoidance beliefs and pain intensity. Depression was associated with fear-avoidance beliefs, but was not associated with pain intensity. Finally, catastrophizing, fear-avoidance beliefs, and pain intensity were positively and significantly associated with acute back pain-related disability. Although fear-avoidance beliefs and pain intensity were associated with disability, the results showed that pain catastrophizing was a central variable in the pain experience and had significant direct associations with disability when pain was acute. Anxiety sensitivity appeared to be an important antecedent of catastrophizing, whereas the influence of resilience on the acute back pain experience was limited to its relationship with depression.

Altered Pain Sensitivity in Elderly Women with Chronic Neck Pain

PubMed Central

Uthaikhup, Sureeporn; Prasert, Romchat; Paungmali, Aatit; Boontha, Kritsana

2015-01-01

Background Age-related changes occur in both the peripheral and central nervous system, yet little is known about the influence of chronic pain on pain sensitivity in older persons. The aim of this study was to investigate pain sensitivity in elders with chronic neck pain compared to healthy elders. Methods Thirty elderly women with chronic neck pain and 30 controls were recruited. Measures of pain sensitivity included pressure pain thresholds, heat/cold pain thresholds and suprathreshold heat pain responses. The pain measures were assessed over the cervical spine and at a remote site, the tibialis anterior muscle. Results Elders with chronic neck pain had lower pressure pain threshold over the articular pillar of C5-C6 and decreased cold pain thresholds over the cervical spine and tibialis anterior muscle when compared with controls (p < 0.05). There were no between group differences in heat pain thresholds and suprathreshold heat pain responses (p > 0.05). Conclusion The presence of pain hypersensitivity in elderly women with chronic neck pain appears to be dependent on types of painful stimuli. This may reflect changes in the peripheral and central nervous system with age. PMID:26039149

Pain Sensitization Associated with Non-Response Following Physiotherapy in People with Knee Osteoarthritis.

PubMed

O'Leary, Helen; Smart, Keith M; Moloney, Niamh A; Blake, Catherine; Doody, Catherine M

2018-05-22

In knee osteoarthritis (OA) pain sensitization has been linked to a more severe symptomatology, but the prognostic implications of pain sensitivity in people undergoing conservative treatment such as physiotherapy are not established. This study aimed to prospectively investigate the association between features of pain sensitization and clinical outcome (non-response) following guideline-based physiotherapy in people with knee OA. Participants (n=156) with moderate/severe knee OA were recruited from secondary care. All participants completed self-administered questionnaires and underwent quantitative sensory testing (QST) at baseline, thereby establishing subjective and objective measures of pain sensitization. Participants (n=134) were later classified following a physiotherapy intervention, using treatment responder criteria (responder/non-responder). QST data was reduced to a core set of latent variables using principal component analysis. A hierarchical logistic regression model was constructed to investigate if features related to pain sensitization predicted non-response after controlling for other known predictors of poor outcome in knee OA. Higher temporal summation (TS) (OR 2.00, 95% CI 1.23 to 3.27) and lower pressure pain thresholds (PPT) (OR 0.48, 95% CI 0.29 to 0.81) emerged as robust predictors of non-response following physiotherapy, along with a higher comorbidity score. The model demonstrated high sensitivity (87.8%) but modest specificity (52.3%). The independent relationship between pain sensitization and non-response may indicate an underlying explanatory association between neuroplastic changes in nociceptive processing and the maintenance of on-going pain and disability in knee OA pain. These preliminary results suggest interventions targeting pain sensitization may warrant future investigation in this population.

Heart rate variability and pain: associations of two interrelated homeostatic processes.

PubMed

Appelhans, Bradley M; Luecken, Linda J

2008-02-01

Between-person variability in pain sensitivity remains poorly understood. Given a conceptualization of pain as a homeostatic emotion, we hypothesized inverse associations between measures of resting heart rate variability (HRV), an index of autonomic regulation of heart rate that has been linked to emotionality, and sensitivity to subsequently administered thermal pain. Resting electrocardiography was collected, and frequency-domain measures of HRV were derived through spectral analysis. Fifty-nine right-handed participants provided ratings of pain intensity and unpleasantness following exposure to 4 degrees C thermal pain stimulation, and indicated their thresholds for barely noticeable and moderate pain during three exposures to decreasing temperature. Greater low-frequency HRV was associated with lower ratings of 4 degrees C pain unpleasantness and higher thresholds for barely noticeable and moderate pain. High-frequency HRV was unrelated to measures of pain sensitivity. Findings suggest pain sensitivity is influenced by characteristics of a central homeostatic system also involved in emotion.

Cerebral responses and role of the prefrontal cortex in conditioned pain modulation: an fMRI study in healthy subjects

PubMed Central

Bogdanov, Volodymyr B.; Viganò, Alessandro; Noirhomme, Quentin; Bogdanova, Olena V.; Guy, Nathalie; Laureys, Steven; Renshaw, Perry F.; Dallel, Radhouane; Phillips, Christophe; Schoenen, Jean

2017-01-01

The mechanisms underlying conditioned pain modulation (CPM) are multifaceted. We searched for a link between individual differences in prefrontal cortex activity during multi-trial heterotopic noxious cold conditioning and modulation of the cerebral response to phasic heat pain. In 24 healthy female subjects, we conditioned laser heat stimuli to the left hand by applying alternatively ice-cold or lukewarm compresses to the right foot. We compared pain ratings with cerebral fMRI BOLD responses. We also analyzed the relation between CPM and BOLD changes produced by the heterotopic cold conditioning itself, as well as the impact of anxiety and habituation of cold-pain ratings. Specific cerebral activation was identified in precuneus and left posterior insula/SII, respectively, during early and sustained phases of cold application. During cold conditioning, laser pain decreased (n = 7), increased (n = 10) or stayed unchanged (n = 7). At the individual level, the psychophysical effect was directly proportional to the cold-induced modulation of the laser-induced BOLD response in left posterior insula/SII. The latter correlated with the BOLD response recorded 80 s earlier during the initial 10-s phase of cold application in anterior cingulate, orbitofrontal and lateral prefrontal cortices. High anxiety and habituation of cold pain were associated with greater laser heat-induced pain during heterotopic cold stimulation. The habituation was also linked to the early cold-induced orbitofrontal responses. We conclude that individual differences in conditioned pain modulation are related to different levels of prefrontal cortical activation by the early part of the conditioning stimulus, possibly due to different levels in trait anxiety. PMID:25461267

Quantitative sensory testing and pain-evoked cytokine reactivity: comparison of patients with sickle cell disease to healthy matched controls.

PubMed

Campbell, Claudia M; Carroll, C Patrick; Kiley, Kasey; Han, Dingfen; Haywood, Carlton; Lanzkron, Sophie; Swedberg, Lauren; Edwards, Robert R; Page, Gayle G; Haythornthwaite, Jennifer A

2016-04-01

Sickle cell disease (SCD) is an inherited blood disorder associated with significant morbidity, which includes severe episodic pain, and, often, chronic pain. Compared to healthy individuals, patients with SCD report enhanced sensitivity to thermal detection and pain thresholds and have altered inflammatory profiles, yet no studies to date have examined biomarker reactivity after laboratory-induced pain. We sought to examine this relationship in patients with SCD compared to healthy control participants. We completed quantitative sensory testing in 83 patients with SCD and sequential blood sampling in 27 of them, whom we matched (sex, age, race, body mass index, and education) to 27 healthy controls. Surprisingly, few quantitative sensory testing differences emerged between groups. Heat pain tolerance, pressure pain threshold at the trapezius, thumb, and quadriceps, and thermal temporal summation at 45°C differed between groups in the expected direction, whereas conditioned pain modulation and pain ratings to hot water hand immersion were counterintuitive, possibly because of tailoring the water temperature to a perceptual level; patients with SCD received milder temperatures. In the matched subsample, group differences and group-by-time interactions were observed in biomarkers including tumor necrosis factor alpha, interleukin-1ß, interleukin-4, and neuropeptide Y. These findings highlight the utility of laboratory pain testing methods for understanding individual differences in inflammatory cytokines. Our findings suggest amplified pain-evoked proinflammatory cytokine reactivity among patients with SCD relative to carefully matched controls. Future research is warranted to evaluate the impact of enhanced pain-related cytokine response and whether it is predictive of clinical characteristics and the frequency/severity of pain crises in patients with SCD.

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

Perinatal maternal stress and serotonin signaling: effects on pain sensitivity in offspring.

PubMed

Knaepen, Liesbeth; Pawluski, Jodi L; Patijn, Jacob; van Kleef, Maarten; Tibboel, Dick; Joosten, Elbert A

2014-07-01

It has been estimated that 20% of pregnant women are facing perinatal stress and depression. Perinatal maternal stress has been shown to increase pain sensitivity in offspring. For the treatment of their depressive symptoms, pregnant women are frequently prescribed selective serotonin reuptake inhibitors (SSRIs). Since the descending pain inhibitory circuit matures perinatally, perinatal SSRI exposure has been shown to affect pain sensitivity in offspring. In the present review, we summarize experimental and clinical evidence for the effect of perinatal maternal stress and SSRI exposure on pain sensitivity in offspring. Both experimental and clinical studies show the effect of perinatal maternal stress on regulation of the hypothalamic-pituitary-adrenal (HPA) system and the serotonin pain inhibitory system. Alterations in these two systems likely underlie long-term alterations in the development of pain sensitivity. This review sheds light on the effect of perinatal maternal stress and treatment with SSRIs on offspring pain sensitivity, in relation to the developing HPA system and 5-HT signaling. © 2013 Wiley Periodicals, Inc.

Nipple pain associated with breastfeeding: incorporating current neurophysiology into clinical reasoning.

PubMed

Amir, Lisa H; Jones, Lester E; Buck, Miranda L

2015-03-01

New mothers frequently experience breastfeeding problems, in particular nipple pain. This is often attributed to compression, skin damage, infection or dermatitis. To outline an integrated approach to breastfeeding pain assessment that seeks to enhance current practice. Our clinical reasoning model resolves the complexity of pain into three categories: local stimulation, external influences and central modulation. Tissue pathology, damage or inflammation leads to local stimulation of nociceptors. External influences such as creams and breast pumps, as well as factors related to the mother, the infant and the maternal-infant interaction, may exacerbate the pain. Central nervous system modulation includes the enhancement of nociceptive transmission at the spinal cord and modification of the descending inhibitory influences. A broad range of factors can modulate pain through central mechanisms including maternal illness, exhaustion, lack of support, anxiety, depression or history of abuse. General practitioners (GPs) can use this model to explain nipple pain in complex settings, thus increasing management options for women.

Pain sensitivity and temperament in extremely low-birth-weight premature toddlers and preterm and full-term controls.

PubMed

Grunau, R V; Whitfield, M F; Petrie, J H

1994-09-01

High-technology medical care of extremely low-birth-weight (ELBW) infants (< 1001 g) involves repeated medical interventions which are potentially painful and may later affect reaction to pain. At 18 months corrected age (CCA), we examined parent ratings of pain sensitivity and how pain sensitivity ratings related to child temperament and parenting style in 2 groups of ELBW children (49 with a birth weight of 480-800 g and 75 with a birth weight of 801-1000 g) and 2 control groups (42 heavier preterm (1500-2499 g) and 29 full-birth-weight (FBW) children (> 2500 g). Both groups of ELBW toddlers were rated by parents as significantly lower in pain sensitivity compared with both control groups. The relationships between child temperament and pain sensitivity rating varied systematically across the groups. Temperament was strongly related to rated pain sensitivity in the FBW group, moderately related in the heavier preterm and ELBW 801-1000 g groups, and not related in the lowest birth-weight group (< 801 g). Parental style did not mediate ratings of pain sensitivity. The results suggest that parents perceive differences in pain behavior of ELBW toddlers compared with heavier preterm and FBW toddlers, especially for those less than 801 g. Longitudinal research into the development of pain behavior for infants who experience lengthy hospitalization is warranted.

Co-morbid pain and opioid addiction: Long term effect of opioid maintenance on acute pain

PubMed Central

Wachholtz, Amy; Gonzalez, Gerardo

2014-01-01

Introduction Medication assisted treatment for opioid dependence alters the pain experience. This study will evaluate changes pain sensitivity and tolerance with opioid treatments; and duration of this effect after treatment cessation. Method 120 individuals with chronic pain were recruited in 4 groups (n=30): 1-methadone for opioid addiction; 2-buprenorphine for opioid addiction; 3-history of opioid maintenance treatment for opioid addiction but with prolonged abstinence (M=121 weeks; SD=23.3); and 4-opioid naïve controls. Participants completed a psychological assessment and a cold water task including, time to first pain (sensitivity) and time to stopping the pain task (tolerance). Data analysis used survival analyses. Results A Kaplan-Meier-Cox survival analysis showed group differences for both pain sensitivity (Log rank=15.50; p<.001) and tolerance (Log rank=20.11; p<.001). Current or historical use of opioid maintenance resulted in differing pain sensitivity compared to opioid naïve (p’s<.01). However, tolerance to pain was better among those with a history of opioid maintenance compared to active methadone patients (p<.05), with the highest tolerance found among opioid naïve control group participants (p’s<.001). Correlations within the prolonged abstinent group indicated pain tolerance was significantly improved as length of opioid abstinence increased (R=.37; p<.05); but duration of abstinence did not alter sensitivity (ns). Conclusion Among individuals with a history of prolonged opioid maintenance, there appears to be long-term differences in pain sensitivity that do not resolve with discontinuation of opioid maintenance. Although pain sensitivity does not change, pain tolerance does improve after opioid maintenance cessation. Implications for treating co-morbid opioid addiction and pain (acute and chronic) are discussed. PMID:25456326

Co-morbid pain and opioid addiction: long term effect of opioid maintenance on acute pain.

PubMed

Wachholtz, Amy; Gonzalez, Gerardo

2014-12-01

Medication assisted treatment for opioid dependence alters the pain experience. This study will evaluate changes pain sensitivity and tolerance with opioid treatments; and duration of this effect after treatment cessation. 120 Individuals with chronic pain were recruited in 4 groups (N = 30): 1-methadone for opioid addiction; 2-buprenorphine for opioid addiction; 3-history of opioid maintenance treatment for opioid addiction but with prolonged abstinence (M = 121 weeks; SD = 23.3); and 4-opioid naïve controls. Participants completed a psychological assessment and a cold water task including, time to first pain (sensitivity) and time to stopping the pain task (tolerance). Data analysis used survival analyses. A Kaplan-Meier-Cox survival analysis showed group differences for both pain sensitivity (log rank = 15.50; p < .001) and tolerance (log rank = 20.11; p < .001). Current or historical use of opioid maintenance resulted in differing pain sensitivity compared to opioid naïve (p's < .01). However, tolerance to pain was better among those with a history of opioid maintenance compared to active methadone patients (p < .05), with the highest tolerance found among opioid naïve control group participants (p's < .001). Correlations within the prolonged abstinent group indicated pain tolerance was significantly improved as length of opioid abstinence increased (R = .37; p < .05); but duration of abstinence did not alter sensitivity (ns). Among individuals with a history of prolonged opioid maintenance, there appears to be long-term differences in pain sensitivity that do not resolve with discontinuation of opioid maintenance. Although pain sensitivity does not change, pain tolerance does improve after opioid maintenance cessation. Implications for treating co-morbid opioid addiction and pain (acute and chronic) are discussed. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Cluster subgroups based on overall pressure pain sensitivity and psychosocial factors in chronic musculoskeletal pain: Differences in clinical outcomes.

PubMed

Almeida, Suzana C; George, Steven Z; Leite, Raquel D V; Oliveira, Anamaria S; Chaves, Thais C

2018-05-17

We aimed to empirically derive psychosocial and pain sensitivity subgroups using cluster analysis within a sample of individuals with chronic musculoskeletal pain (CMP) and to investigate derived subgroups for differences in pain and disability outcomes. Eighty female participants with CMP answered psychosocial and disability scales and were assessed for pressure pain sensitivity. A cluster analysis was used to derive subgroups, and analysis of variance (ANOVA) was used to investigate differences between subgroups. Psychosocial factors (kinesiophobia, pain catastrophizing, anxiety, and depression) and overall pressure pain threshold (PPT) were entered into the cluster analysis. Three subgroups were empirically derived: cluster 1 (high pain sensitivity and high psychosocial distress; n = 12) characterized by low overall PPT and high psychosocial scores; cluster 2 (high pain sensitivity and intermediate psychosocial distress; n = 39) characterized by low overall PPT and intermediate psychosocial scores; and cluster 3 (low pain sensitivity and low psychosocial distress; n = 29) characterized by high overall PPT and low psychosocial scores compared to the other subgroups. Cluster 1 showed higher values for mean pain intensity (F (2,77)  = 10.58, p < 0.001) compared with cluster 3, and cluster 1 showed higher values for disability (F (2,77)  = 3.81, p = 0.03) compared with both clusters 2 and 3. Only cluster 1 was distinct from cluster 3 according to both pain and disability outcomes. Pain catastrophizing, depression, and anxiety were the psychosocial variables that best differentiated the subgroups. Overall, these results call attention to the importance of considering pain sensitivity and psychosocial variables to obtain a more comprehensive characterization of CMP patients' subtypes.

Recognition of central sensitization in patients with musculoskeletal pain: Application of pain neurophysiology in manual therapy practice.

PubMed

Nijs, Jo; Van Houdenhove, Boudewijn; Oostendorp, Rob A B

2010-04-01

Central sensitization plays an important role in the pathophysiology of numerous musculoskeletal pain disorders, yet it remains unclear how manual therapists can recognize this condition. Therefore, mechanism based clinical guidelines for the recognition of central sensitization in patients with musculoskeletal pain are provided. By using our current understanding of central sensitization during the clinical assessment of patients with musculoskeletal pain, manual therapists can apply the science of nociceptive and pain processing neurophysiology to the practice of manual therapy. The diagnosis/assessment of central sensitization in individual patients with musculoskeletal pain is not straightforward, however manual therapists can use information obtained from the medical diagnosis, combined with the medical history of the patient, as well as the clinical examination and the analysis of the treatment response in order to recognize central sensitization. The clinical examination used to recognize central sensitization entails the distinction between primary and secondary hyperalgesia. Copyright 2009 Elsevier Ltd. All rights reserved.

Lumbopelvic Core Stabilization Exercise and Pain Modulation Among Individuals with Chronic Nonspecific Low Back Pain.

PubMed

Paungmali, Aatit; Joseph, Leonard H; Sitilertpisan, Patraporn; Pirunsan, Ubon; Uthaikhup, Sureeporn

2017-11-01

Lumbopelvic stabilization training (LPST) may provide therapeutic benefits on pain modulation in chronic nonspecific low back pain conditions. This study aimed to examine the effects of LPST on pain threshold and pain intensity in comparison with the passive automated cycling intervention and control intervention among patients with chronic nonspecific low back pain. A within-subject, repeated-measures, crossover randomized controlled design was conducted among 25 participants (7 males and 18 females) with chronic nonspecific low back pain. All the participants received 3 different types of experimental interventions, which included LPST, the passive automated cycling intervention, and the control intervention randomly, with 48 hours between the sessions. The pressure pain threshold (PPT), hot-cold pain threshold, and pain intensity were estimated before and after the interventions. Repeated-measures analysis of variance showed that LPST provided therapeutic effects as it improved the PPT beyond the placebo and control interventions (P < 0.01). The pain intensity under the LPST condition was significantly better than that under the passive automated cycling intervention and controlled intervention (P < 0.001). Heat pain threshold under the LPST condition also showed a significant trend of improvement beyond the control (P < 0.05), but no significant effects on cold pain threshold were evident. Lumbopelvic stabilization training may provide therapeutic effects by inducing pain modulation through an improvement in the pain threshold and reduction in pain intensity. LPST may be considered as part of the management programs for treatment of chronic low back pain. © 2017 World Institute of Pain.

Racial and ethnic differences in experimental pain sensitivity: systematic review and meta-analysis.

PubMed

Kim, Hee Jun; Yang, Gee Su; Greenspan, Joel D; Downton, Katherine D; Griffith, Kathleen A; Renn, Cynthia L; Johantgen, Meg; Dorsey, Susan G

2017-02-01

Our objective was to describe the racial and ethnic differences in experimental pain sensitivity. Four databases (PubMed, EMBASE, the Cochrane Central Register of Controlled Trials, and PsycINFO) were searched for studies examining racial/ethnic differences in experimental pain sensitivity. Thermal-heat, cold-pressor, pressure, ischemic, mechanical cutaneous, electrical, and chemical experimental pain modalities were assessed. Risk of bias was assessed using the Agency for Healthcare Research and Quality guideline. Meta-analysis was used to calculate standardized mean differences (SMDs) by pain sensitivity measures. Studies comparing African Americans (AAs) and non-Hispanic whites (NHWs) were included for meta-analyses because of high heterogeneity in other racial/ethnic group comparisons. Statistical heterogeneity was assessed by subgroup analyses by sex, sample size, sample characteristics, and pain modalities. A total of 41 studies met the review criteria. Overall, AAs, Asians, and Hispanics had higher pain sensitivity compared with NHWs, particularly lower pain tolerance, higher pain ratings, and greater temporal summation of pain. Meta-analyses revealed that AAs had lower pain tolerance (SMD: -0.90, 95% confidence intervals [CIs]: -1.10 to -0.70) and higher pain ratings (SMD: 0.50, 95% CI: 0.30-0.69) but no significant differences in pain threshold (SMD: -0.06, 95% CI: -0.23 to 0.10) compared with NHWs. Estimates did not vary by pain modalities, nor by other demographic factors; however, SMDs were significantly different based on the sample size. Racial/ethnic differences in experimental pain sensitivity were more pronounced with suprathreshold than with threshold stimuli, which is important in clinical pain treatment. Additional studies examining mechanisms to explain such differences in pain tolerance and pain ratings are needed.

Disrupted functional connectivity of the periaqueductal gray in chronic low back pain

PubMed Central

Yu, Rongjun; Gollub, Randy L.; Spaeth, Rosa; Napadow, Vitaly; Wasan, Ajay; Kong, Jian

2014-01-01

Chronic low back pain is a common neurological disorder. The periaqueductal gray (PAG) plays a key role in the descending modulation of pain. In this study, we investigated brain resting state PAG functional connectivity (FC) differences between patients with chronic low back pain (cLBP) in low pain or high pain condition and matched healthy controls (HCs). PAG seed based functional connectivity (FC) analysis of the functional MR imaging data was performed to investigate the difference among the connectivity maps in the cLBP in the low or high pain condition and HC groups as well as within the cLBP at differing endogenous back pain intensities. Results showed that FC between the PAG and the ventral medial prefrontal cortex (vmPFC)/rostral anterior cingulate cortex (rACC) increased in cLBP patients compared to matched controls. In addition, we also found significant negative correlations between pain ratings and PAG–vmPFC/rACC FC in cLBP patients after pain-inducing maneuver. The duration of cLBP was negatively correlated with PAG–insula and PAG–amygdala FC before pain-inducing maneuver in the patient group. These findings are in line with the impairments of the descending pain modulation reported in patients with cLBP. Our results provide evidence showing that cLBP patients have abnormal FC in PAG centered pain modulation network during rest. PMID:25379421

Evoked potentials after painful cutaneous electrical stimulation depict pain relief during a conditioned pain modulation.

PubMed

Höffken, Oliver; Özgül, Özüm S; Enax-Krumova, Elena K; Tegenthoff, Martin; Maier, Christoph

2017-08-29

Conditioned pain modulation (CPM) evaluates the pain modulating effect of a noxious conditioning stimulus (CS) on another noxious test stimulus (TS), mostly based solely on subjective pain ratings. We used painful cutaneous electrical stimulation (PCES) to induce TS in a novel CPM-model. Additionally, to evaluate a more objective parameter, we recorded the corresponding changes of cortical evoked potentials (PCES-EP). We examined the CPM-effect in 17 healthy subjects in a randomized controlled cross-over design during immersion of the non-dominant hand into 10 °C or 24 °C cold water (CS). Using three custom-built concentric surface electrodes, electrical stimuli were applied on the dominant hand, inducing pain of 40-60 on NRS 0-100 (TS). At baseline, during and after CS we assessed the electrically induced pain intensity and electrically evoked potentials recorded over the central electrode (Cz). Only in the 10 °C-condition, both pain (52.6 ± 4.4 (baseline) vs. 30.3 ± 12.5 (during CS)) and amplitudes of PCES-EP (42.1 ± 13.4 μV (baseline) vs. 28.7 ± 10.5 μV (during CS)) attenuated during CS and recovered there after (all p < 0.001). In the 10 °C-condition changes of subjective pain ratings during electrical stimulation and amplitudes of PCES-EP correlated significantly with each other (r = 0.5) and with CS pain intensity (r = 0.5). PCES-EPs are a quantitative measure of pain relief, as changes in the electrophysiological response are paralleled by a consistent decrease in subjective pain ratings. This novel CPM paradigm is a feasible method, which could help to evaluate the function of the endogenous pain modulation processes. German Clinical Trials Register DRKS-ID: DRKS00012779 , retrospectively registered on 24 July 2017.

Low Dose MDCT with Tube Current Modulation: Role in Detection of Urolithiasis and Patient Effective Dose Reduction

PubMed Central

Kakkar, Chandan; Sripathi, Smiti; Parakh, Anushri; Shrivastav, Rajendra

2016-01-01

Introduction Urolithiasis is one of the major, recurring problem in young individuals and CT being the commonest diagnostic modality used. In order to reduce the radiation dose to the patient who are young and as stone formation is a recurring process; one of the simplest way would be, low dose CT along with tube current modulation. Aim Aim of this study was to compare the sensitivity and specificity of low dose (70mAs) with standard dose (250mAs) protocol in detecting urolithiasis and to define the tube current and mean effective patient dose by these protocols. Materials and Methods A prospective study was conducted in 200 patients over a period of 2 years with acute flank pain presentation. CT was performed in 100 cases with standard dose and another 100 with low dose protocol using tube current modulation. Sensitivity and specificity for calculus detection, percentage reduction of dose and tube current with low dose protocol was calculated. Results Urolithiasis was detected in 138 patients, 67 were examined by high dose and 71 were by low dose protocol. Sensitivity and Specificity of low dose protocol was 97.1% and 96.4% with similar results found in high BMI patients. Tube current modulation resulted in reduction of effective tube current by 12.17%. The mean effective patient dose for standard dose was 10.33 mSv whereas 2.92 mSv for low dose with 51.13–53.8% reduction in low dose protocol. Conclusion The study has reinforced that low-dose CT with tube current modulation is appropriate for diagnosis of urolithiasis with significant reduction in tube current and patient effective dose. PMID:27437322

Low Dose MDCT with Tube Current Modulation: Role in Detection of Urolithiasis and Patient Effective Dose Reduction.

PubMed

Koteshwar, Prakashini; Kakkar, Chandan; Sripathi, Smiti; Parakh, Anushri; Shrivastav, Rajendra

2016-05-01

Urolithiasis is one of the major, recurring problem in young individuals and CT being the commonest diagnostic modality used. In order to reduce the radiation dose to the patient who are young and as stone formation is a recurring process; one of the simplest way would be, low dose CT along with tube current modulation. Aim of this study was to compare the sensitivity and specificity of low dose (70mAs) with standard dose (250mAs) protocol in detecting urolithiasis and to define the tube current and mean effective patient dose by these protocols. A prospective study was conducted in 200 patients over a period of 2 years with acute flank pain presentation. CT was performed in 100 cases with standard dose and another 100 with low dose protocol using tube current modulation. Sensitivity and specificity for calculus detection, percentage reduction of dose and tube current with low dose protocol was calculated. Urolithiasis was detected in 138 patients, 67 were examined by high dose and 71 were by low dose protocol. Sensitivity and Specificity of low dose protocol was 97.1% and 96.4% with similar results found in high BMI patients. Tube current modulation resulted in reduction of effective tube current by 12.17%. The mean effective patient dose for standard dose was 10.33 mSv whereas 2.92 mSv for low dose with 51.13-53.8% reduction in low dose protocol. The study has reinforced that low-dose CT with tube current modulation is appropriate for diagnosis of urolithiasis with significant reduction in tube current and patient effective dose.

Relationship between cold pressor pain-sensitivity and sleep quality in opioid-dependent males on methadone treatment

PubMed Central

Lee, Chee Siong; Tan, Soo Choon; Mohamad, Nasir; Lee, Yeong Yeh; Ismail, Rusli

2015-01-01

Aim. Poor sleep quality due to pain has been reported among opioid-dependent male patients on methadone maintenance therapy (MMT) but objective pain data are lacking. This study aimed to investigate the rate of pain-sensitivity using cold pressor test (CPT) and the relationship between pain-sensitivity and sleep quality in this population. Methods. A total of 168 male participants were included into the study. Objective pain-tolerance was evaluated at 0 h and at 24 h after the first CPT. Malay version of the Pittsburgh Sleep Quality Index (PSQI) and the subjective opiate withdrawal scale (SOWS) questionnaires were administered to evaluate the quality of sleep and withdrawal symptoms, respectively. Results. The mean age of study participants was 37.22 (SD 6.20) years old. Mean daily methadone dose was 76.64 (SD 37.63) mg/day, mean global PSQI score was 5.47 (SD 2.74) and mean averaged SOWS score was 5.43 (SD 6.91). The averaged pain-tolerance time ranged from 7 to 300 s with a mean time of 32.16 (SE 2.72) s, slightly below the cut-off score of 37.53 s. More specifically, 78.6% (n = 132) of participants were identified as pain-sensitive (averaged pain-tolerance time ≤37.53 s), and 36 (21.4%) participants were pain-tolerant (averaged pain-tolerance time >37.53 s). The pain-sensitive group reported poorer sleep quality with mean (SD) PSQI of 5.78 (2.80) compared with the pain-tolerant group with mean (SD) PSQI of 4.31 (2.18) (p = 0.005). With analysis of covariance, pain-sensitive group was found to have higher global PSQI scores (adjusted mean 5.76, 95% CI 5.29; 6.22) than pain-tolerant participants (adjusted mean 4.42, 95% CI 3.52; 5.32) (p = 0.010). Conclusions. Majority of opioid-dependent male patients on methadone treatment are pain-sensitive with CPT. Poor sleep quality is associated with cold pressor pain-sensitivity. Pain and sleep complaints in this male population should not be overlooked. PMID:25870765

Pharmacologic Modulation of Hand Pain in Osteoarthritis: A Double-Blind Placebo-Controlled Functional Magnetic Resonance Imaging Study Using Naproxen

PubMed Central

Sanders, Duncan; Krause, Kristina; O'Muircheartaigh, Jonathan; Thacker, Michael A; Huggins, John P; Vennart, William; Massat, Nathalie J; Choy, Ernest; Williams, Steven C R; Howard, Matthew A

2015-01-01

Objective In an attempt to shed light on management of chronic pain conditions, there has long been a desire to complement behavioral measures of pain perception with measures of underlying brain mechanisms. Using functional magnetic resonance imaging (fMRI), we undertook this study to investigate changes in brain activity following the administration of naproxen or placebo in patients with pain related to osteoarthritis (OA) of the carpometacarpal (CMC) joint. Methods A placebo-controlled, double-blind, 2-period crossover study was performed in 19 individuals with painful OA of the CMC joint of the right hand. Following placebo or naproxen treatment periods, a functionally relevant task was performed, and behavioral measures of the pain experience were collected in identical fMRI examinations. Voxelwise and a priori region of interest analyses were performed to detect between-period differences in brain activity. Results Significant reductions in brain activity following treatment with naproxen, compared to placebo, were observed in brain regions commonly associated with pain perception, including the bilateral primary somatosensory cortex, thalamus, and amygdala. Significant relationships between changes in perceived pain intensity and changes in brain activity were also observed in brain regions previously associated with pain intensity. Conclusion This study demonstrates the sensitivity of fMRI to detect the mechanisms underlying treatments of known efficacy. The data illustrate the enticing potential of fMRI as an adjunct to self-report for detecting early signals of efficacy of novel therapies, both pharmacologic and nonpharmacologic, in small numbers of individuals with persistent pain. PMID:25533872

Postoperative pain management techniques in hip and knee arthroplasty.

PubMed

Parvizi, Javad; Porat, Manny; Gandhi, Kishor; Viscusi, Eugene R; Rothman, Richard H

2009-01-01

Adequate control of postoperative pain following hip and knee arthroplasty can be a challenging task fraught with potential complications. Postoperative pain is perceived by the patient via a complex network and a multitude of molecular messengers in both the peripheral and central nervous systems. This allows the physician to modulate pain via an array of medications that act on different sites within the body. Using both contemporary and traditional pain modulators, the delivery and timing of these medications can affect postoperative pain and, ultimately, rehabilitation of the arthroplasty patient. Current techniques for controlling pain use both multimodal and preemptive analgesia to improve the outcome of the surgery while minimizing the potential adverse effects of the medications given.

Pain catastrophizing mediates the relationship between self-reported strenuous exercise involvement and pain ratings: moderating role of anxiety sensitivity.

PubMed

Goodin, Burel R; McGuire, Lynanne M; Stapleton, Laura M; Quinn, Noel B; Fabian, Lacy A; Haythornthwaite, Jennifer A; Edwards, Robert R

2009-11-01

To investigate the cross-sectional associations among self-reported weekly strenuous exercise bouts, anxiety sensitivity, and their interaction with pain catastrophizing and pain responses to the cold pressor task (CPT) in healthy, ethnically diverse young adults (n = 79). Exercise involvement has been shown to have hypoalgesic effects and cognitive factors may partially explain this effect. Particularly, alterations in pain catastrophizing have been found to mediate the positive pain outcomes of multidisciplinary treatments incorporating exercise. Further, recent evidence suggests that exercise involvement and anxiety sensitivity may act together, as interacting factors, to exert an effect on catastrophizing and pain outcomes; however, further research is needed to clarify the nature of this interaction. Before the CPT, participants were asked to complete the Godin Leisure-Time Exercise Questionnaire, the Beck Depression Inventory, and the Anxiety Sensitivity Index. After the CPT, participants completed a modified version of the Pain Catastrophizing Scale and the Short Form-McGill Pain Questionnaire. At a high level of anxiety sensitivity, controlling for depressive symptoms, CPT immersion time, and sex differences, a bias-corrected (BC), bootstrapped confidence interval revealed that pain catastrophizing significantly mediated the relationship between self-reported weekly strenuous exercise bouts and pain response (95% BC Confidence Interval = -9.558, -0.800 with 1000 resamples). At intermediate and low levels of anxiety sensitivity, no significant mediation effects were found. These findings support that, for pain catastrophizing to mediate the strenuous exercise-pain response relation, individuals must possess a high level of anxiety sensitivity.

The effect of chemically induced colitis, psychological stress and their combination on visceral pain in female Wistar rats.

PubMed

Deiteren, Annemie; Vermeulen, Wim; Moreels, Tom G; Pelckmans, Paul A; De Man, Joris G; De Winter, Benedicte Y

2014-09-01

Visceral sensitivity is of pathophysiological importance in abdominal pain disorders and can be modulated by inflammation and stress. However, it is unclear whether inflammation and stress alter visceral perception independently of each other or in conjunction through neuroendocrine interactions. Therefore, we compared the short- and long-term effects of experimental colitis and water avoidance stress (WAS), alone or in combination, on visceral sensitivity in female Wistar rats. Colitis was induced by trinitrobenzene sulfonic acid (TNBS) and colonoscopically confirmed. During WAS, rats were placed on a platform surrounded by water for 1 h. Visceral sensitivity was assessed by quantifying the visceromotor responses (VMRs) to colorectal distension. Activation of the hypothalamic-pituitary-adrenal axis was determined by measuring serum corticosterone in a separate protocol. TNBS instillation resulted in overt colitis, associated with significant visceral hypersensitivity during the acute inflammatory phase (3 days post-TNBS; n = 8/group); after colitis had subsided (28 days post-TNBS), hypersensitivity was resolved (n = 4-8/group). Single WAS was associated with increased VMRs of a magnitude comparable to acute TNBS-induced hypersensitivity (n = 8/group). However, after repetitive WAS no significant hypersensitivity was present (n = 8/group). No additive effect of colitis and stress was seen on visceral pain perception (n = 6-8/group). Corticosterone levels were only increased in acute TNBS-colitis, acute WAS and their combination. To conclude, both colitis and stress successfully induced short-term visceral hypersensitivity and activated the hypothalamic-pituitary-adrenal axis, but long-term effects were absent. In addition, our current findings do not support an additive effect of colitis and stress on visceral sensitivity in female Wistar rats.

Expectancy Effects on Conditioned Pain Modulation Are Not Influenced by Naloxone or Morphine.

PubMed

France, Christopher R; Burns, John W; Gupta, Rajnish K; Buvanendran, Asokumar; Chont, Melissa; Schuster, Erik; Orlowska, Daria; Bruehl, Stephen

2016-08-01

Recent studies suggest that participant expectations influence pain ratings during conditioned pain modulation testing. The present study extends this work by examining expectancy effects among individuals with and without chronic back pain after administration of placebo, naloxone, or morphine. This study aims to identify the influence of individual differences in expectancy on changes in heat pain ratings obtained before, during, and after a forearm ischemic pain stimulus. Participants with chronic low back pain (n = 88) and healthy controls (n = 100) rated heat pain experience (i.e., "test stimulus") before, during, and after exposure to ischemic pain (i.e., "conditioning stimulus"). Prior to testing, participants indicated whether they anticipated that their heat pain would increase, decrease, or remain unchanged during ischemic pain. Analysis of the effects of expectancy (pain increase, decrease, or no change), drug (placebo, naloxone, or morphine), and group (back pain, healthy) on changes in heat pain revealed a significant main effect of expectancy (p = 0.001), but no other significant main effects or interactions. Follow-up analyses revealed that individuals who expected lower pain during ischemia reported significantly larger decreases in heat pain as compared with those who expected either no change (p = 0.004) or increased pain (p = 0.001). The present findings confirm that expectancy is an important contributor to conditioned pain modulation effects, and therefore significant caution is needed when interpreting findings that do not account for this individual difference. Opioid mechanisms do not appear to be involved in these expectancy effects.

Self-perceived weather sensitivity and joint pain in older people with osteoarthritis in six European countries: results from the European Project on OSteoArthritis (EPOSA)

PubMed Central

2014-01-01

Background People with osteoarthritis (OA) frequently report that their joint pain is influenced by weather conditions. This study aimed to examine whether there are differences in perceived joint pain between older people with OA who reported to be weather-sensitive versus those who did not in six European countries with different climates and to identify characteristics of older persons with OA that are most predictive of perceived weather sensitivity. Methods Baseline data from the European Project on OSteoArthritis (EPOSA) were used. ACR classification criteria were used to determine OA. Participants with OA were asked about their perception of weather as influencing their pain. Using a two-week follow-up pain calendar, average self-reported joint pain was assessed (range: 0 (no pain)-10 (greatest pain intensity)). Linear regression analyses, logistic regression analyses and an independent t-test were used. Analyses were adjusted for several confounders. Results The majority of participants with OA (67.2%) perceived the weather as affecting their pain. Weather-sensitive participants reported more pain than non-weather-sensitive participants (M = 4.1, SD = 2.4 versus M = 3.1, SD = 2.4; p < 0.001). After adjusting for several confounding factors, the association between self-perceived weather sensitivity and joint pain remained present (B = 0.37, p = 0.03). Logistic regression analyses revealed that women and more anxious people were more likely to report weather sensitivity. Older people with OA from Southern Europe were more likely to indicate themselves as weather-sensitive persons than those from Northern Europe. Conclusions Weather (in)stability may have a greater impact on joint structures and pain perception in people from Southern Europe. The results emphasize the importance of considering weather sensitivity in daily life of older people with OA and may help to identify weather-sensitive older people with OA. PMID:24597710

Self-perceived weather sensitivity and joint pain in older people with osteoarthritis in six European countries: results from the European Project on OSteoArthritis (EPOSA).

PubMed

Timmermans, Erik J; van der Pas, Suzan; Schaap, Laura A; Sánchez-Martínez, Mercedes; Zambon, Sabina; Peter, Richard; Pedersen, Nancy L; Dennison, Elaine M; Denkinger, Michael; Castell, Maria Victoria; Siviero, Paola; Herbolsheimer, Florian; Edwards, Mark H; Otero, Angel; Deeg, Dorly J H

2014-03-05

People with osteoarthritis (OA) frequently report that their joint pain is influenced by weather conditions. This study aimed to examine whether there are differences in perceived joint pain between older people with OA who reported to be weather-sensitive versus those who did not in six European countries with different climates and to identify characteristics of older persons with OA that are most predictive of perceived weather sensitivity. Baseline data from the European Project on OSteoArthritis (EPOSA) were used. ACR classification criteria were used to determine OA. Participants with OA were asked about their perception of weather as influencing their pain. Using a two-week follow-up pain calendar, average self-reported joint pain was assessed (range: 0 (no pain)-10 (greatest pain intensity)). Linear regression analyses, logistic regression analyses and an independent t-test were used. Analyses were adjusted for several confounders. The majority of participants with OA (67.2%) perceived the weather as affecting their pain. Weather-sensitive participants reported more pain than non-weather-sensitive participants (M = 4.1, SD = 2.4 versus M = 3.1, SD = 2.4; p < 0.001). After adjusting for several confounding factors, the association between self-perceived weather sensitivity and joint pain remained present (B = 0.37, p = 0.03). Logistic regression analyses revealed that women and more anxious people were more likely to report weather sensitivity. Older people with OA from Southern Europe were more likely to indicate themselves as weather-sensitive persons than those from Northern Europe. Weather (in)stability may have a greater impact on joint structures and pain perception in people from Southern Europe. The results emphasize the importance of considering weather sensitivity in daily life of older people with OA and may help to identify weather-sensitive older people with OA.

Pathophysiology and principles of management of the many faces of the acute vaso-occlusive crisis in patients with sickle cell disease.

PubMed

Ballas, Samir K

2015-08-01

Effective management of sickle cell pain entails a thorough understanding of its pathophysiology and the pharmacogenomics of the opioids used to manage it. In recent years, there has been significant progress along these two lines. At the pathophysiologic level, there is evidence that the severity and frequency of painful stimuli modulate their transmission at the level of the dorsal horn of the spinal cord. This modulation is achieved via two channels: the α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and NMDA receptors. Initially, the AMPA channel controls the transmission of stimuli of mild-moderate severity. Once the AMPA channel reaches its limit of membrane depolarization, the NMDA channel is activated and facilitates the transmission of painful stimuli in a progressive fashion leading to central sensitization and glial activation. At the level of pharmacogenomics, the metabolism of each opioid is patient-specific. Glucuronidation is unique for the metabolism of morphine, hydromorphone, and oxymorphone. The metabolism of all other opioids requires specific Cytochrome P450 (CYP) isoenzymes. The activity of each isoenzyme and the activity of the metabolites of each opioid vary among patients depending on their genetic makeup and coexistent environmental factors such as the use of other medications that may enhance or inhibit the CYP isoenzyme activity. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Association of Chronic Pelvic Pain and Endometriosis With Signs of Sensitization and Myofascial Pain

PubMed Central

Stratton, Pamela; Khachikyan, Izabella; Sinaii, Ninet; Ortiz, Robin; Shah, Jay

2014-01-01

Objective To evaluate sensitization, myofascial trigger points, and quality of life in women with chronic pelvic pain with and without endometriosis. Methods A cross-sectional prospective study of women aged 18 to 50 with pain suggestive of endometriosis and healthy, pain-free volunteers without history of endometriosis. Patients underwent a physiatric neuro-musculoskeletal assessment of clinical signs of sensitization and myofascial trigger points in the abdominopelvic region. Pain symptoms, psychosocial, and quality-of-life measures were also assessed. All pain participants underwent laparoscopic excision of suspicious lesions to confirm endometriosis diagnosis by histologic evaluation. Results Patients included 18 with current, biopsy-proven endometriosis, 11 with pain only, and 20 healthy volunteers. The prevalence of sensitization as measured by regional allodynia and hyperalgesia was similar in both pain groups (83% and 82%) but much lower among healthy volunteers (15%, p<0.001). Nearly all women with pain had myofascial trigger points (94% and 91%). Adjusting for study group, those with high anxiety (OR=1.05, 95% CI:1.004–1.099; p=0.031) and depression (OR=1.06, 95% CI:1.005–1.113; p=0.032) scores were more likely to have sensitization. Pain patients with any history of endometriosis had the highest proportion of sensitization compared to the others (87% v 67% v 15%; p<0.001). Adjusting for any history of endometriosis, those with myofascial trigger points were most likely sensitized (OR=9.41, 95% CI:1.77–50.08, p=0.009). Conclusions Sensitization and myofascial trigger points were common in women with pain regardless of whether they had endometriosis at surgery. Those with any history of endometriosis were most likely to have sensitization. Traditional methods of classifying endometriosis-associated pain based on disease, duration, and anatomy are inadequate and should be replaced by a mechanism-based evaluation, as our study illustrates. PMID:25730237

Does catastrophic thinking enhance oesophageal pain sensitivity? An experimental investigation.

PubMed

Martel, M O; Olesen, A E; Jørgensen, D; Nielsen, L M; Brock, C; Edwards, R R; Drewes, A M

2016-09-01

Gastro-oesophageal reflux disease (GORD) is a major health problem that is frequently accompanied by debilitating oesophageal pain symptoms. The first objective of the study was to examine the association between catastrophizing and oesophageal pain sensitivity. The second objective was to examine whether catastrophizing was associated with the magnitude of acid-induced oesophageal sensitization. Twenty-five healthy volunteers (median age: 24.0 years; range: 22-31) were recruited and were asked to complete the Pain Catastrophizing Scale (PCS). During two subsequent study visits, mechanical, thermal, and electrical pain sensitivity in the oesophagus was assessed before and after inducing oesophageal sensitization using a 30-min intraluminal oesophageal acid perfusion procedure. Analyses were conducted based on data averaged across the two study visits. At baseline, catastrophizing was significantly associated with mechanical (r = -0.42, p < 0.05) and electrical (r = -0.60, p < 0.01) pain thresholds. After acid perfusion, catastrophizing was also significantly associated with mechanical (r = -0.58, p < 0.01) and electrical (r = -0.50, p < 0.05) pain thresholds. Catastrophizing was not significantly associated with thermal pain thresholds. Subsequent analyses revealed that catastrophizing was not significantly associated with the magnitude of acid-induced oesophageal sensitization. Taken together, findings from the present study suggest that catastrophic thinking exerts an influence on oesophageal pain sensitivity, but not necessarily on the magnitude of acid-induced oesophageal sensitization. WHAT DOES THIS STUDY ADD?: Catastrophizing is associated with heightened pain sensitivity in the oesophagus. This was substantiated by assessing responses to noxious stimulation of the oesophagus using an experimental paradigm mimicking features and symptoms experienced by patients with gastro-oesophageal reflux disease (GORD). © 2016 European Pain Federation - EFIC®

Effects of Transcranial Direct Current Stimulation (tDCS) on Pain Distress Tolerance: A Preliminary Study.

PubMed

Mariano, Timothy Y; van't Wout, Mascha; Jacobson, Benjamin L; Garnaat, Sarah L; Kirschner, Jason L; Rasmussen, Steven A; Greenberg, Benjamin D

2015-08-01

Pain remains a critical medical challenge. Current treatments target nociception without addressing affective symptoms. Medically intractable pain is sometimes treated with cingulotomy or deep brain stimulation to increase tolerance of pain-related distress. Transcranial direct current stimulation (tDCS) may noninvasively modulate cortical areas related to sensation and pain representations. The present study aimed to test the hypothesis that cathodal ("inhibitory") stimulation targeting left dorsal anterior cingulate cortex (dACC) would increase tolerance to distress from acute painful stimuli vs anodal stimulation. Forty healthy volunteers received both anodal and cathodal stimulation. During stimulation, we measured pain distress tolerance with three tasks: pressure algometer, cold pressor, and breath holding. We measured pain intensity with a visual-analog scale before and after each task. Mixed ANOVA revealed that mean cold pressor tolerance tended to be higher with cathodal vs anodal stimulation (P = 0.055) for participants self-completing the task. Pressure algometer (P = 0.81) and breath holding tolerance (P = 0.19) did not significantly differ. The pressure algometer exhibited a statistically significant order effect irrespective of stimulation polarity (all P < 0.008). Pain intensity ratings increased acutely after cold pressor and pressure algometer tasks (both P < 0.01), but not after breath holding (P = 0.099). Cold pressor pain ratings tended to rise less after cathodal vs anodal tDCS (P = 0.072). Although our primary results were nonsignificant, there is a preliminary suggestion that cathodal tDCS targeting left dACC may increase pain distress tolerance to cold pressor. Pressure algometer results are consistent with task-related sensitization. Future studies are needed to refine this novel approach for pain neuromodulation. Wiley Periodicals, Inc.

Nonpainful wide-area compression inhibits experimental pain

PubMed Central

Honigman, Liat; Bar-Bachar, Ofrit; Yarnitsky, David; Sprecher, Elliot; Granovsky, Yelena

2016-01-01

Abstract Compression therapy, a well-recognized treatment for lymphoedema and venous disorders, pressurizes limbs and generates massive non-noxious afferent sensory barrages. The aim of this study was to study whether such afferent activity has an analgesic effect when applied on the lower limbs, hypothesizing that larger compression areas will induce stronger analgesic effects, and whether this effect correlates with conditioned pain modulation (CPM). Thirty young healthy subjects received painful heat and pressure stimuli (47°C for 30 seconds, forearm; 300 kPa for 15 seconds, wrist) before and during 3 compression protocols of either SMALL (up to ankles), MEDIUM (up to knees), or LARGE (up to hips) compression areas. Conditioned pain modulation (heat pain conditioned by noxious cold water) was tested before and after each compression protocol. The LARGE protocol induced more analgesia for heat than the SMALL protocol (P < 0.001). The analgesic effect interacted with gender (P = 0.015). The LARGE protocol was more efficient for females, whereas the MEDIUM protocol was more efficient for males. Pressure pain was reduced by all protocols (P < 0.001) with no differences between protocols and no gender effect. Conditioned pain modulation was more efficient than the compression-induced analgesia. For the LARGE protocol, precompression CPM efficiency positively correlated with compression-induced analgesia. Large body area compression exerts an area-dependent analgesic effect on experimental pain stimuli. The observed correlation with pain inhibition in response to robust non-noxious sensory stimulation may suggest that compression therapy shares similar mechanisms with inhibitory pain modulation assessed through CPM. PMID:27152691

Pain sensitivity is inversely related to regional grey matter density in the brain.

PubMed

Emerson, Nichole M; Zeidan, Fadel; Lobanov, Oleg V; Hadsel, Morten S; Martucci, Katherine T; Quevedo, Alexandre S; Starr, Christopher J; Nahman-Averbuch, Hadas; Weissman-Fogel, Irit; Granovsky, Yelena; Yarnitsky, David; Coghill, Robert C

2014-03-01

Pain is a highly personal experience that varies substantially among individuals. In search of an anatomical correlate of pain sensitivity, we used voxel-based morphometry to investigate the relationship between grey matter density across the whole brain and interindividual differences in pain sensitivity in 116 healthy volunteers (62 women, 54 men). Structural magnetic resonance imaging (MRI) and psychophysical data from 10 previous functional MRI studies were used. Age, sex, unpleasantness ratings, scanner sequence, and sensory testing location were added to the model as covariates. Regression analysis of grey matter density across the whole brain and thermal pain intensity ratings at 49°C revealed a significant inverse relationship between pain sensitivity and grey matter density in bilateral regions of the posterior cingulate cortex, precuneus, intraparietal sulcus, and inferior parietal lobule. Unilateral regions of the left primary somatosensory cortex also exhibited this inverse relationship. No regions showed a positive relationship to pain sensitivity. These structural variations occurred in areas associated with the default mode network, attentional direction and shifting, as well as somatosensory processing. These findings underscore the potential importance of processes related to default mode thought and attention in shaping individual differences in pain sensitivity and indicate that pain sensitivity can potentially be predicted on the basis of brain structure. Copyright © 2013 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

Pain Sensitivity is Inversely Related to Regional Grey Matter Density in the Brain

PubMed Central

Emerson, Nichole M.; Zeidan, Fadel; Lobanov, Oleg V.; Hadsel, Morten S.; Martucci, Katherine T.; Quevedo, Alexandre S.; Starr, Christopher J.; Nahman-Averbuch, Hadas; Weissman-Fogel, Irit; Granovsky, Yelena; Yarnitsky, David; Coghill, Robert C.

2014-01-01

Pain is a highly personal experience that varies substantially among individuals. In search of an anatomical correlate of pain sensitivity we used voxel-based morphometry (VBM) to investigate the relationship between grey matter density across the whole brain and inter-individual differences in pain sensitivity in 116 healthy volunteers (62 females, 54 males). Structural MRI and psychophysical data from 10 previous fMRI studies were used. Age, sex, unpleasantness ratings, scanner sequence, and sensory testing location were added to the model as covariates. Regression analysis of grey matter density across the whole brain and thermal pain intensity ratings at 49°C revealed a significant inverse relationship between pain sensitivity and grey matter density in bilateral regions of the posterior cingulate cortex, precuneus, intraparietal sulcus, and inferior parietal lobule. Unilateral regions of the left primary somatosensory cortex also exhibited this inverse relationship. No regions exhibited a positive relationship to pain sensitivity. These structural variations occurred in areas associated with the default mode network, attentional direction and shifting, as well as somatosensory processing. These findings underscore the potential importance of processes related to default mode thought and attention in shaping individual differences in pain sensitivity and indicate that pain sensitivity can potentially be predicted on the basis of brain structure. PMID:24333778

Childhood Adversity and Pain Sensitization.

PubMed

You, Dokyoung Sophia; Meagher, Mary W

Childhood adversity is a vulnerability factor for chronic pain. However, the underlying pain mechanisms influenced by childhood adversity remain unknown. The aim of the current study was to evaluate the impact of childhood adversity on dynamic pain sensitivity in young adults. After screening for childhood adverse events and health status, healthy individuals reporting low (below median; n = 75) or high levels of adversity (the top 5%; n = 51) were invited for pain testing. Both groups underwent heat pain threshold and temporal summation of second pain (TSSP) testing after reporting depressive symptoms. TSSP refers to a progressive increase in pain intensity with repetition of identical noxious stimuli and is attributed to central sensitization. Changes in pain ratings over time (slope) were computed for TSSP sensitization and decay of subsequent aftersensations. The high-adversity group showed greater TSSP sensitization (meanslope, 0.75; SDpositive slope, 1.78), and a trend toward a slower decay (meanslope, -11.9; SD, 3.4), whereas the low-adversity group showed minimal sensitization (meanslope, 0.07; SDnear-zero slope, 1.77), F(1,123) = 5.84, p = .017 and faster decay (meanslope, -13.1; SD, 3.4), F(1,123) = 3.79, p = .054. This group difference remained significant even after adjusting for adult depressive symptoms (p = .033). No group difference was found in heat pain threshold (p = .85). Lastly, the high-adversity group showed blunted cardiac and skin conductance responses. These findings suggest that enhancement of central sensitization may provide a mechanism underlying the pain hypersensitivity and chronicity linked to childhood adversity.

Acute and chronic craniofacial pain: brainstem mechanisms of nociceptive transmission and neuroplasticity, and their clinical correlates.

PubMed

Sessle, B J

2000-01-01

This paper reviews the recent advances in knowledge of brainstem mechanisms related to craniofacial pain. It also draws attention to their clinical implications, and concludes with a brief overview and suggestions for future research directions. It first describes the general organizational features of the trigeminal brainstem sensory nuclear complex (VBSNC), including its input and output properties and intrinsic characteristics that are commensurate with its strategic role as the major brainstem relay of many types of somatosensory information derived from the face and mouth. The VBSNC plays a crucial role in craniofacial nociceptive transmission, as evidenced by clinical, behavioral, morphological, and electrophysiological data that have been especially derived from studies of the relay of cutaneous nociceptive afferent inputs through the subnucleus caudalis of the VBSNC. The recent literature, however, indicates that some fundamental differences exist in the processing of cutaneous vs. other craniofacial nociceptive inputs to the VBSNC, and that rostral components of the VBSNC may also play important roles in some of these processes. Modulatory mechanisms are also highlighted, including the neurochemical substrate by which nociceptive transmission in the VBSNC can be modulated. In addition, the long-term consequences of peripheral injury and inflammation and, in particular, the neuroplastic changes that can be induced in the VBSNC are emphasized in view of the likely role that central sensitization, as well as peripheral sensitization, can play in acute and chronic pain. The recent findings also provide new insights into craniofacial pain behavior and are particularly relevant to many approaches currently in use for the management of pain and to the development of new diagnostic and therapeutic procedures aimed at manipulating peripheral inputs and central processes underlying nociceptive transmission and its control within the VBSNC.

Experimental Psychological Stress on Quantitative Sensory Testing Response in Patients with Temporomandibular Disorders.

PubMed

Araújo Oliveira Ferreira, Dyna Mara; Costa, Yuri Martins; de Quevedo, Henrique Müller; Bonjardim, Leonardo Rigoldi; Rodrigues Conti, Paulo César

2018-05-15

To assess the modulatory effects of experimental psychological stress on the somatosensory evaluation of myofascial temporomandibular disorder (TMD) patients. A total of 20 women with myofascial TMD and 20 age-matched healthy women were assessed by means of a standardized battery of quantitative sensory testing. Cold detection threshold (CDT), warm detection threshold (WDT), cold pain threshold (CPT), heat pain threshold (HPT), mechanical pain threshold (MPT), wind-up ratio (WUR), and pressure pain threshold (PPT) were performed on the facial skin overlying the masseter muscle. The variables were measured in three sessions: before (baseline) and immediately after the Paced Auditory Serial Addition Task (PASAT) (stress) and then after a washout period of 20 to 30 minutes (poststress). Mixed analysis of variance (ANOVA) was applied to the data, and the significance level was set at P = .050. A significant main effect of the experimental session on all thermal tests was found (ANOVA: F > 4.10, P < .017), where detection tests presented an increase in thresholds in the poststress session compared to baseline (CDT, P = .012; WDT, P = .040) and pain thresholds were reduced in the stress (CPT, P < .001; HPT, P = .001) and poststress sessions (CPT, P = .005; HPT, P = .006) compared to baseline. In addition, a significant main effect of the study group on all mechanical tests (MPT, WUR, and PPT) was found (ANOVA: F > 4.65, P < .037), where TMD patients were more sensitive than healthy volunteers. Acute mental stress conditioning can modulate thermal sensitivity of the skin overlying the masseter in myofascial TMD patients and healthy volunteers. Therefore, psychological stress should be considered in order to perform an unbiased somatosensory assessment of TMD patients.

Sensory focusing versus distraction and pain: moderating effects of anxiety sensitivity in males and females.

PubMed

Thompson, Trevor; Keogh, Edmund; French, Christopher C

2011-08-01

Although previous research has examined whether the relative effects of distraction and sensory focusing on pain are dependent upon anxiety sensitivity, such research has concentrated primarily on females. Given the increasing emergence of sex differences in pain processing, the current study aimed to examine whether any influence of anxiety sensitivity on coping effectiveness differs for males and females. The sample consisted of 76 healthy adults (41 males and 35 females), all of whom received distraction and sensory-focusing instructions and underwent noxious thermal testing (cold and heat). Results showed that anxiety sensitivity was positively associated with the emotional qualities of cold pain, and that males exhibited significantly greater heat pain tolerance than females. In addition, within males, a significant coping × anxiety sensitivity effect was found for cold tolerance, with distraction superior to sensory focusing only when anxiety sensitivity was high. In females, however, distraction was a superior strategy irrespective of anxiety sensitivity. This study highlights the importance of considering anxiety sensitivity and sex when examining the relative effectiveness of attentional pain coping strategies. This finding may be potentially beneficial to clinicians considering pain management interventions that include a cognitive or attentional component. Copyright © 2011 American Pain Society. Published by Elsevier Inc. All rights reserved.

E-learning module on chronic low back pain in older adults: evidence of effect on medical student objective structured clinical examination performance.

PubMed

Weiner, Debra K; Morone, Natalia E; Spallek, Heiko; Karp, Jordan F; Schneider, Michael; Washburn, Carol; Dziabiak, Michael P; Hennon, John G; Elnicki, D Michael

2014-06-01

The Institute of Medicine has highlighted the urgent need to close undergraduate and graduate educational gaps in treating pain. Chronic low back pain (CLBP) is one of the most common pain conditions, and older adults are particularly vulnerable to potential morbidities associated with misinformed treatment. An e-learning case-based interactive module was developed at the University of Pittsburgh Center of Excellence in Pain Education, one of 12 National Institutes of Health-designated centers, to teach students important principles for evaluating and managing CLBP in older adults. A team of six experts in education, information technology, pain management, and geriatrics developed the module. Teaching focused on common errors, interactivity, and expert modeling and feedback. The module mimicked a patient encounter using a standardized patient (the older adult with CLBP) and a pain expert (the patient provider). Twenty-eight medical students were not exposed to the module (Group 1) and 27 were exposed (Group 2). Their clinical skills in evaluating CLBP were assessed using an objective structured clinical examination (OSCE). Mean scores were 62.0 ± 8.6 for Group 1 and 79.5 ± 10.4 for Group 2 (P < .001). Using an OSCE pass-fail cutoff score of 60%, 17 of 28 Group 1 students (60.7%) and 26 of 27 Group 2 students (96.3%) passed. The CLBP OSCE was one of 10 OSCE stations in which students were tested at the end of a Combined Ambulatory Medicine and Pediatrics Clerkship. There were no between-group differences in performance on eight of the other nine OSCE stations. This module significantly improved medical student clinical skills in evaluating CLBP. Additional research is needed to ascertain the effect of e-learning modules on more-advanced learners and on improving the care of older adults with CLBP. © 2014, Copyright the Authors Journal compilation © 2014, The American Geriatrics Society.

E-Learning Module on Chronic Low Back Pain in Older Adults: Evidence of Effect on Medical Student Objective Structured Clinical Examination Performance

PubMed Central

Weiner, Debra K.; Morone, Natalia E.; Spallek, Heiko; Karp, Jordan F.; Schneider, Michael; Washburn, Carol; Dziabiak, Michael P.; Hennon, John G.; Elnicki, D. Michael

2015-01-01

The Institute of Medicine has highlighted the urgent need to close undergraduate and graduate educational gaps in treating pain. Chronic low back pain (CLBP) is one of the most common pain conditions, and older adults are particularly vulnerable to potential morbidities associated with misinformed treatment. An e-learning case-based interactive module was developed at the University of Pittsburgh Center of Excellence in Pain Education, one of 12 National Institutes of Health–designated centers, to teach students important principles for evaluating and managing CLBP in older adults. A team of six experts in education, information technology, pain management, and geriatrics developed the module. Teaching focused on common errors, interactivity, and expert modeling and feedback. The module mimicked a patient encounter using a standardized patient (the older adult with CLBP) and a pain expert (the patient provider). Twenty-eight medical students were not exposed to the module (Group 1) and 27 were exposed (Group 2). Their clinical skills in evaluating CLBP were assessed using an objective structured clinical examination (OSCE). Mean scores were 62.0 ± 8.6 for Group 1 and 79.5 ± 10.4 for Group 2 (P < .001). Using an OSCE pass–fail cutoff score of 60%, 17 of 28 Group 1 students (60.7%) and 26 of 27 Group 2 students (96.3%) passed. The CLBP OSCE was one of 10 OSCE stations in which students were tested at the end of a Combined Ambulatory Medicine and Pediatrics Clerkship. There were no between-group differences in performance on eight of the other nine OSCE stations. This module significantly improved medical student clinical skills in evaluating CLBP. Additional research is needed to ascertain the effect of e-learning modules on more-advanced learners and on improving the care of older adults with CLBP. PMID:24833496

Increased excitability of spinal pain reflexes and altered frequency-dependent modulation in the dopamine D3-receptor knockout mouse.

PubMed

Keeler, Benjamin E; Baran, Christine A; Brewer, Kori L; Clemens, Stefan

2012-12-01

Frequency-dependent modulation and dopamine (DA) receptors strongly modulate neural circuits in the spinal cord. Of the five known DA receptor subtypes, the D3 receptor has the highest affinity to DA, and D3-mediated actions are mainly inhibitory. Using an animal model of spinal sensorimotor dysfunction, the D3 receptor knockout mouse (D3KO), we investigated the physiological consequences of D3 receptor dysfunction on pain-associated signaling pathways in the spinal cord, the initial integration site for the processing of pain signaling. In the D3KO spinal cord, inhibitory actions of DA on the proprioceptive monosynaptic stretch reflex are converted from depression to facilitation, but its effects on longer-latency and pain-associated reflex responses and the effects of FM have not been studied. Using behavioral approaches in vivo, we found that D3KO animals exhibit reduced paw withdrawal latencies to thermal pain stimulation (Hargreaves' test) over wild type (WT) controls. Electrophysiological and pharmacological approaches in the isolated spinal cord in vitro showed that constant current stimulation of dorsal roots at a pain-associated frequency was associated with a significant reduction in the frequency-dependent modulation of longer-latency reflex (LLRs) responses but not monosynaptic stretch reflexes (MSRs) in D3KO. Application of the D1 and D2 receptor agonists and the voltage-gated calcium-channel ligand, pregabalin, but not DA, was able to restore the frequency-dependent modulation of the LLR in D3KO to WT levels. Thus we demonstrate that nociception-associated LLRs and proprioceptive MSRs are differentially modulated by frequency, dopaminergics and the Ca(2+) channel ligand, pregabalin. Our data suggest a role for the DA D3 receptor in pain modulation and identify the D3KO as a possible model for increased nociception. Copyright © 2012 Elsevier Inc. All rights reserved.

Cold Pressor Pain Sensitivity in Twins Discordant for Chronic Fatigue Syndrome

PubMed Central

Ullrich, Phil; Afari, Niloofar; Jacobsen, Clemma; Goldberg, Jack; Buchwald, Dedra

2010-01-01

Objective Individuals with chronic fatigue syndrome (CFS) experience many pain symptoms. The present study examined whether pain and fatigue ratings and pain threshold and tolerance levels for cold pain differed between twins with CFS and their cotwins without CFS. Design Cotwin control design to assess cold pain sensitivity, pain, and fatigue in monozygotic twins discordant for CFS. Patients and Setting Fifteen twin pairs discordant for CFS recruited from the volunteer Chronic Fatigue Twin Registry at the University of Washington. Results Although cold pain threshold and tolerance levels were slightly lower in twins with CFS than their cotwins without CFS, these differences failed to reach statistical significance. Subjective ratings of pain and fatigue at multiple time points during the experimental protocol among twins with CFS were significantly higher than ratings of pain (p = 0.003) and fatigue (p < 0.001) by their cotwins without CFS. Conclusions These results, while preliminary, highlight the perceptual and cognitive components to the pain experience in CFS. Future studies should focus on examining the heritability of pain sensitivity and the underlying mechanisms involved in the perception of pain sensitivity in CFS. PMID:17371408

Ethnicity is associated with alterations in oxytocin relationships to pain sensitivity in women

PubMed Central

Grewen, Karen M.; Light, Kathleen C.; Mechlin, Beth; Girdler, Susan S.

2015-01-01

It is well established that African Americans (AA) experience greater pain associated with a variety of clinical conditions, and greater pain sensitivity to experimental pain tasks relative to non-Hispanic Whites (W). Notably, African Americans do not show the same relationships involving endogenous pain regulatory mechanisms and pain sensitivity documented in Caucasians, including positive associations between blood pressure, norepinephrine, cortisol and greater pain tolerance. Objectives The purpose of this study was to examine the relationship between plasma oxytocin (OT) and pain sensitivity and to explore the relation of OT to other factors known to influence pain perception. Design OT concentration and sensitivity to ischemic, cold pressor, and thermal pain tasks were assessed in African American (n=25) and non-Hispanic White (n=23) pre-menopausal women. Results African American women demonstrated significantly lower pain tolerance across tasks compared with Whites (F1,46 =6.31, p=0.0156) and also exhibited lower plasma OT levels (AA: 3.90, W: 7.05 pg/mL; p=0.0014). Greater OT levels were correlated with greater tolerance to ischemic pain (r=0.36, p=0.013) and accounted for a marginally significant portion of the ethnic difference in ischemic pain tolerance (B=+0.29, p=0.06). Greater OT was also correlated with greater tolerance of cold pressor pain (r=0.31, p=0.03); however, this association was no longer seen after the variance due to ethnicity was accounted for. Conclusion These data suggest that reduced oxytocinergic function may be one of multiple biological factors contributing to the greater sensitivity to experimental ischemic pain, and to the greater burden of some types of clinical pain experienced by African Americans compared with Whites. PMID:18568974

Subjective Sleep Quality Deteriorates Prior to Development of Painful Temporomandibular Disorder

PubMed Central

Sanders, Anne E.; Akinkugbe, Aderonke A.; Bair, Eric; Fillingim, Roger B.; Greenspan, Joel D.; Ohrbach, Richard; Dubner, Ronald; Maixner, William; Slade, Gary D.

2016-01-01

There is good evidence that poor sleep quality increases risk of painful temporomandibular disorder (TMD). However little is known about the course of sleep quality in the months preceding TMD onset, and whether the relationship is mediated by heightened sensitivity to pain. The Pittsburgh Sleep Quality Index was administered at enrollment into the OPPERA prospective cohort study. Thereafter the Sleep Quality Numeric Rating Scale was administered every three months to 2,453 participants. Sensitivity to experimental pressure pain and pinprick pain stimuli was measured at baseline and repeated during follow-up of incident TMD cases (n=220) and matched TMD-free controls (n=193). Subjective sleep quality deteriorated progressively, but only in those who subsequently developed TMD. A Cox proportional hazards model showed that risk of TMD was greater among participants whose sleep quality worsened during follow-up (adjusted hazard ratio=1.73, 95% confidence limits: 1.29, 2.32). This association was independent of baseline measures of sleep quality, psychological stress, somatic awareness, comorbid conditions, non-pain facial symptoms and demographics. Poor baseline sleep quality was not significantly associated with baseline pain sensitivity or with subsequent change in pain sensitivity. Furthermore the relationship between sleep quality and TMD incidence was not mediated via baseline pain sensitivity nor change in pain sensitivity. PMID:26902644

Endogenous Pain Modulation Induced by Extrinsic and Intrinsic Psychological Threat in Healthy Individuals.

PubMed

Gibson, William; Moss, Penny; Cheng, Tak Ho; Garnier, Alexandre; Wright, Anthony; Wand, Benedict M

2018-03-01

Many factors interact to influence threat perception and the subsequent experience of pain. This study investigated the effect of observing pain (extrinsic threat) and intrinsic threat of pain to oneself on pressure pain threshold (PPT). Forty socially connected pairs of healthy volunteers were threat-primed and randomly allocated to experimental or control roles. An experimental pain modulation paradigm was applied, with non-nociceptive threat cues used as conditioning stimuli. In substudy 1, the extrinsic threat to the experimental participant was observation of the control partner in pain. The control participant underwent hand immersion in noxious and non-noxious water baths in randomized order. Change in the observing participant's PPT from baseline to mid- and postimmersion was calculated. A significant interaction was found for PPT between conditions and test time (F 2,78  = 24.9, P < .005). PPT increased by 23.6% ± 19.3% between baseline and during hand immersion (F 1,39  = 43.7, P < .005). Substudy 2 investigated threat of imminent pain to self. After a 15-minute break, the experimental participant's PPT was retested ("baseline 2"). Threat was primed by suggestion of whole arm immersion in an icier, larger water bath. PPT was tested immediately before anticipated arm immersion, after which the experiment ended. A significant increase in PPT between "baseline 2" and "pre-immersion" was seen (t = -7.6, P = .005), a pain modulatory effect of 25.8 ± 20.7%. Extrinsic and intrinsic threat of pain, in the absence of any afferent input therefore influences pain modulation. This may need to be considered in studies that use noxious afferent input with populations who show dysfunctional pain modulation. The effect on endogenous analgesia of observing another's pain and of threat of pain to oneself was investigated. Extrinsic as well as intrinsic threat cues, in the absence of any afferent input, increased pain thresholds, suggesting that mere threat of pain may initiate analgesic effects in traditional noxious experimental paradigms. Copyright © 2017 The American Pain Society. Published by Elsevier Inc. All rights reserved.

Decreased low back pain intensity and differential gene expression following Calmare®: results from a double-blinded randomized sham-controlled study.

PubMed

Starkweather, Angela R; Coyne, Patrick; Lyon, Debra E; Elswick, R K; An, Kyungeh; Sturgill, Jamie

2015-02-01

In this double-blinded, randomized controlled trial we evaluated the effects of Calmare®, a non-invasive neurocutaneous electrical pain intervention, on lower back pain intensity as measured by the "worst" pain score and on pain interference using the Brief Pain Inventory-Short Form, on measures of pain sensitivity assessed by quantitative sensory testing, and on mRNA expression of pain sensitivity genes. Thirty participants were randomized to receive up to 10 sessions of Calmare® treatment (n = 15) or a sham treatment (n = 15) using the same device at a non-therapeutic threshold. At 3 weeks after conclusion of treatment, compared with the sham group, the Calmare® group reported a significant decrease in the "worst" pain and interference scores. There were also significant differences in pain sensitivity and differential mRNA expression of 17 pain genes, suggesting that Calmare® can be effective in reducing pain intensity and interference in individuals with persistent low back pain by altering the mechanisms of enhanced pain sensitivity. Further study of long-term pain outcomes, particularly functional status, analgesic use and health care utilization, is warranted. © 2015 Wiley Periodicals, Inc.

An imaging genetics approach to understanding social influence

PubMed Central

Falk, Emily B.; Way, Baldwin M.; Jasinska, Agnes J.

2012-01-01

Normative social influences shape nearly every aspect of our lives, yet the biological processes mediating the impact of these social influences on behavior remain incompletely understood. In this Hypothesis, we outline a theoretical framework and an integrative research approach to the study of social influences on the brain and genetic moderators of such effects. First, we review neuroimaging evidence linking social influence and conformity to the brain's reward system. We next review neuroimaging evidence linking social punishment (exclusion) to brain systems involved in the experience of pain, as well as evidence linking exclusion to conformity. We suggest that genetic variants that increase sensitivity to social cues may predispose individuals to be more sensitive to either social rewards or punishments (or potentially both), which in turn increases conformity and susceptibility to normative social influences more broadly. To this end, we review evidence for genetic moderators of neurochemical responses in the brain, and suggest ways in which genes and pharmacology may modulate sensitivity to social influences. We conclude by proposing an integrative imaging genetics approach to the study of brain mediators and genetic modulators of a variety of social influences on human attitudes, beliefs, and actions. PMID:22701416

Modulation of thermal pain-related brain activity with virtual reality: evidence from fMRI.

PubMed

Hoffman, Hunter G; Richards, Todd L; Coda, Barbara; Bills, Aric R; Blough, David; Richards, Anne L; Sharar, Sam R

2004-06-07

This study investigated the neural correlates of virtual reality analgesia. Virtual reality significantly reduced subjective pain ratings (i.e. analgesia). Using fMRI, pain-related brain activity was measured for each participant during conditions of no virtual reality and during virtual reality (order randomized). As predicted, virtual reality significantly reduced pain-related brain activity in all five regions of interest; the anterior cingulate cortex, primary and secondary somatosensory cortex, insula, and thalamus (p<0.002, corrected). Results showed direct modulation of human brain pain responses by virtual reality distraction. Copyright 2004 Lippincott Williams and Wilkins

Blood pressure and pain sensitivity in children and adolescents.

PubMed

Drouin, Sammantha; McGrath, Jennifer J

2013-06-01

Elevated blood pressure is associated with diminished pain sensitivity. While this finding is well established in adults, it is less clear when the relation between blood pressure and pain sensitivity emerges across the life course. Evidence suggests this phenomenon may exist during childhood. Children (N = 309; 56% boys) aged 10-15 years and their parents participated. Blood pressure readings were taken during a resting baseline. Maximum pain intensity was rated using a visual analogue scale (rated 0-10) in response to a finger prick pain induction. Parent-measured resting blood pressure was inversely associated with boys' pain ratings only. Cross-sectionally, lower pain ratings were related to higher SBP, univariately. Longitudinally, pain ratings predicted higher DBP, even after controlling for covariates. Determining when and how the relation between blood pressure and pain sensitivity emerges may elucidate the pathophysiology of hypertension. Copyright © 2013 Society for Psychophysiological Research.

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

Pressure and cold pain threshold reference values in a large, young adult, pain-free population.

PubMed

Waller, Robert; Smith, Anne Julia; O'Sullivan, Peter Bruce; Slater, Helen; Sterling, Michele; McVeigh, Joanne Alexandra; Straker, Leon Melville

2016-10-01

Currently there is a lack of large population studies that have investigated pain sensitivity distributions in healthy pain free people. The aims of this study were: (1) to provide sex-specific reference values of pressure and cold pain thresholds in young pain-free adults; (2) to examine the association of potential correlates of pain sensitivity with pain threshold values. This study investigated sex specific pressure and cold pain threshold estimates for young pain free adults aged 21-24 years. A cross-sectional design was utilised using participants (n=617) from the Western Australian Pregnancy Cohort (Raine) Study at the 22-year follow-up. The association of site, sex, height, weight, smoking, health related quality of life, psychological measures and activity with pain threshold values was examined. Pressure pain threshold (lumbar spine, tibialis anterior, neck and dorsal wrist) and cold pain threshold (dorsal wrist) were assessed using standardised quantitative sensory testing protocols. Reference values for pressure pain threshold (four body sites) stratified by sex and site, and cold pain threshold (dorsal wrist) stratified by sex are provided. Statistically significant, independent correlates of increased pressure pain sensitivity measures were site (neck, dorsal wrist), sex (female), higher waist-hip ratio and poorer mental health. Statistically significant, independent correlates of increased cold pain sensitivity measures were, sex (female), poorer mental health and smoking. These data provide the most comprehensive and robust sex specific reference values for pressure pain threshold specific to four body sites and cold pain threshold at the dorsal wrist for young adults aged 21-24 years. Establishing normative values in this young age group is important given that the transition from adolescence to adulthood is a critical temporal period during which trajectories for persistent pain can be established. These data will provide an important research resource to enable more accurate profiling and interpretation of pain sensitivity in clinical pain disorders in young adults. The robust and comprehensive data can assist interpretation of future clinical pain studies and provide further insight into the complex associations of pain sensitivity that can be used in future research. Crown Copyright © 2016. Published by Elsevier B.V. All rights reserved.

Pain sensitivity mediates the relationship between stress and headache intensity in chronic tension-type headache.

PubMed

Cathcart, Stuart; Bhullar, Navjot; Immink, Maarten; Della Vedova, Chris; Hayball, John

2012-01-01

A central model for chronic tension-type headache (CTH) posits that stress contributes to headache, in part, by aggravating existing hyperalgesia in CTH sufferers. The prediction from this model that pain sensitivity mediates the relationship between stress and headache activity has not yet been examined. To determine whether pain sensitivity mediates the relationship between stress and prospective headache activity in CTH sufferers. Self-reported stress, pain sensitivity and prospective headache activity were measured in 53 CTH sufferers recruited from the general population. Pain sensitivity was modelled as a mediator between stress and headache activity, and tested using a nonparametric bootstrap analysis. Pain sensitivity significantly mediated the relationship between stress and headache intensity. The results of the present study support the central model for CTH, which posits that stress contributes to headache, in part, by aggravating existing hyperalgesia in CTH sufferers. Implications for the mechanisms and treatment of CTH are discussed.

Modulation of pain by estrogens.

PubMed

Craft, Rebecca M

2007-11-01

It has become increasingly apparent that women suffer a disproportionate amount of pain during their lifetime compared to men. Over the past 15 years, a growing number of studies have suggested a variety of causes for this sex difference, from cellular to psychosocial levels of analysis. From a biological perspective, sexual differentiation of pain appears to occur similarly to sexual differentiation of other phenomena: it results in large part from organizational and activational effects of gonadal steroid hormones. The focus of this review is the activational effects of a single group of ovarian hormones, the estrogens, on pain in humans and animals. The effects of estrogens (estradiol being the most commonly examined) on experimentally induced acute pain vs. clinical pain are summarized. For clinical pain, the review is limited to a few syndromes for which there is considerable evidence for estrogenic involvement: migraine, temporomandibular disorder (TMD) and arthritis. Because estrogens can modulate the function of the nervous, immune, skeletal, and cardiovascular systems, estrogenic modulation of pain is an exceedingly complex, multi-faceted phenomenon, with estrogens producing both pro- and antinociceptive effects that depend on the extent to which each of these systems of the body is involved in a particular type of pain. Forging a more complete understanding of the myriad ways that estrogens can ameliorate vs. facilitate pain will enable us to better prevent and treat pain in both women and men.

Optogenetic exploration and modulation of pain processing.

PubMed

Xie, Yu-Feng; Wang, Jing; Bonin, Robert P

2018-08-01

Intractable pain is the single most common cause of disability, affecting more than 20% of the population world-wide. There is accordingly a global effort to decipher how changes in nociceptive processing in the peripheral and central nervous systems contribute to the onset and maintenance of chronic pain. The past several years have brought rapid progress in the adaptation of optogenetic approaches to study and manipulate the activity of sensory afferents and spinal cord neurons in freely behaving animals, and to investigate cortical processing and modulation of pain responses. This review discusses methodological advances that underlie this recent progress, and discusses practical considerations for the optogenetic modulation of nociceptive sensory processing. Crown Copyright © 2018. Published by Elsevier Inc. All rights reserved.

Evaluation of a Postoperative Pain-Like State on Motivated Behavior in Rats: Effects of Plantar Incision on Progressive-Ratio Food-Maintained Responding.

PubMed

Warner, Emily; Krivitsky, Rebecca; Cone, Katherine; Atherton, Phillip; Pitre, Travis; Lanpher, Janell; Giuvelis, Denise; Bergquist, Ivy; King, Tamara; Bilsky, Edward J; Stevenson, Glenn W

2015-12-01

There has been recent interest in characterizing the effects of pain-like states on motivated behaviors in order to quantify how pain modulates goal-directed behavior and the persistence of that behavior. The current set of experiments assessed the effects of an incisional postoperative pain manipulation on food-maintained responding under a progressive-ratio (PR) operant schedule. Independent variables included injury state (plantar incision or anesthesia control) and reinforcer type (grain pellet or sugar pellet); dependent variables were tactile sensory thresholds and response breakpoint. Once responding stabilized on the PR schedule, separate groups of rats received a single ventral hind paw incision or anesthesia (control condition). Incision significantly reduced breakpoints in rats responding for grain, but not sugar. In rats responding for sugar, tactile hypersensitivity recovered within 24 hr, indicating a faster recovery of incision-induced tactile hypersensitivity compared to rats responding for grain, which demonstrated recovery at PD2. The NSAID analgesic, diclofenac (5.6 mg/kg) completely restored incision-depressed PR operant responding and tactile sensitivity at 3 hr following incision. The PR schedule differentiated between sucrose and grain, suggesting that relative reinforcing efficacy may be an important determinant in detecting pain-induced changes in motivated behavior. © 2015 Wiley Periodicals, Inc.

Evaluation of a post-operative pain-like state on motivated behavior in rats: Effects of plantar incision on progressive-ratio food-maintained responding

PubMed Central

Warner, Emily; Krivitsky, Rebecca; Cone, Katherine; Atherton, Phillip; Pitre, Travis; Lanpher, Janell; Giuvelis, Denise; Bergquist, Ivy; King, Tamara; Bilsky, Edward J.; Stevenson, Glenn W.

2015-01-01

There has been recent interest in characterizing the effects of pain-like states on motivated behaviors in order to quantify how pain modulates goal-directed behavior and the persistence of that behavior. The current set of experiments assessed the effects of an incisional post-operative pain manipulation on food-maintained responding under a progressive-ratio (PR) operant schedule. Independent variables included injury state (plantar incision or anesthesia control) and reinforcer type (grain pellet or sugar pellet); dependent variables were tactile sensory thresholds and response breakpoint. Once responding stabilized on the PR schedule, separate groups of rats received a single ventral hind paw incision or anesthesia (control condition). Incision significantly reduced breakpoints in rats responding for grain, but not sugar. In rats responding for sugar, tactile hypersensitivity recovered within 24 hrs, indicating a faster recovery of incision-induced tactile hypersensitivity compared to rats responding for grain, which demonstrated recovery at PD2. The NSAID analgesic, diclofenac (5.6 mg/kg) completely restored incision-depressed PR operant responding and tactile sensitivity at 3 hr following incision. The PR schedule differentiated between sucrose and grain, suggesting that relative reinforcing efficacy may be an important determinant in detecting pain-induced changes in motivated behavior. PMID:26494422

Interactions among sex, ethnicity, religion, and gender role expectations of pain.

PubMed

Defrin, Ruth; Eli, Ilana; Pud, Dorit

2011-06-01

Sex, gender, ethnicity, and religion are powerful factors that may affect pain experience. Recently, gender role expectations of pain (GREP) were suggested to account for some of the differences in pain perception between men and women. However, the interaction between GREP and ethnicity and religion was not examined. This interaction was studied with regard to pain sensitivity, pain endurance, and willingness to report pain. Our objective was to study the interaction among GREP, sex, and ethno-religious belonging. Participants (548 healthy men and women) of 3 different ethno-religious groups (341 Jews, 105 Muslim-Arabs, 102 Christian-Arabs) completed the GREP questionnaire; pain sensitivity, pain endurance, and willingness to report pain were analyzed. Men of all 3 ethno-religious groups perceived themselves and other men as less sensitive and less willing to report pain than typical women. Women of all 3 ethno-religious groups perceived themselves and other women as more sensitive and more willing to report pain than men. Ethno-religious differences were observed in the attitudes towards typical men and women, with Christian men and women exhibiting stronger stereotypical views regarding pain sensitivity and pain endurance. Individual's perceptions of pain regarding one's self compared with the same or opposite sex were similar regardless of ethno-religious belonging and were related to sex. However, attitudes on pain of typical men and women seemed to be influenced by ethno-religious belonging. This differential effect of ethno-religion on GREP with relation to sex suggests that these factors should be considered when pain perception is evaluated. Copyright © 2011 Elsevier HS Journals, Inc. All rights reserved.

Dissociable influences of opiates and expectations on pain

PubMed Central

Atlas, Lauren Y.; Whittington, Robert A.; Lindquist, Martin A.; Wielgosz, Joe; Sonty, Nomita; Wager, Tor D.

2012-01-01

Placebo treatments and opiate drugs are thought to have common effects on the opioid system and pain-related brain processes. This has created excitement about the potential for expectations to modulate drug effects themselves. If drug effects differ as a function of belief, this would challenge the assumptions underlying the standard clinical trial. We conducted two studies to directly examine the relationship between expectations and opioid analgesia. We administered the opioid agonist remifentanil to human subjects during experimental thermal pain and manipulated participants’ knowledge of drug delivery using an open-hidden design. This allowed us to test drug effects, expectancy (knowledge) effects, and their interactions on pain reports and pain-related responses in the brain. Remifentanil and expectancy both reduced pain, but drug effects on pain reports and fMRI activity did not interact with expectancy. Regions associated with pain processing showed drug-induced modulation during both Open and Hidden conditions, with no differences in drug effects as a function of expectation. Instead, expectancy modulated activity in frontal cortex, with a separable time course from drug effects. These findings reveal that opiates and placebo treatments both influence clinically relevant outcomes and operate without mutual interference. PMID:22674280

Somatosensory profiles in subgroups of patients with myogenic temporomandibular disorders and Fibromyalgia Syndrome.

PubMed

Pfau, Doreen B; Rolke, Roman; Nickel, Ralf; Treede, Rolf-Detlef; Daublaender, Monika

2009-12-15

Some patients with myofascial pain from temporomandibular disorders (TMD) report pain in extra-trigeminal body regions. Our aim was to distinguish TMD as regional musculoskeletal pain syndrome (n=23) from a widespread pain syndrome (FMS; n=18) based on patients' tender point scores, pain drawings and quantitative sensory testing (QST) profiles. Referenced to 18 age- and gender-matched healthy subjects significant group differences for cold, pressure and pinprick pain thresholds, suprathreshold pinprick sensitivity and mechanical detection thresholds were found. Pain sensitivity in TMD patients ranged between those of FMS patients and healthy controls. The group of TMD patients was inhomogeneous with respect to their tender point count with an insensitive group (n=12) resembling healthy controls and a sensitive TMD group (n=9) resembling FMS patients. Nevertheless sensitive TMD patients did not fulfil diagnostic criteria for FMS in regard to widespread pain as shown by their pain drawings. TMD subgroups did not differ with respect to psychological parameters. The sensitive subgroup was more sensitive compared to healthy controls and to insensitive TMD patients in regard to their QST profile over all test areas as well as to their tenderness over orofacial muscles and trigeminal foramina. However, sensitive TMD patients had a short pain duration arguing against a transition from TMD to FMS over time. Data rather suggest an overlap in pathophysiology with FMS, e.g. a disturbance of central pain processing, in this subgroup of TMD patients. Those patients could be identified on the basis of their tender point count as an easy practicable screening tool.

International field testing of the reliability and validity of the EORTC QLQ-BM22 module to assess health-related quality of life in patients with bone metastases.

PubMed

Chow, Edward; Nguyen, Janet; Zhang, Liying; Tseng, Ling-Ming; Hou, Ming-Feng; Fairchild, Alysa; Vassiliou, Vassilios; Jesus-Garcia, Reynaldo; Alm El-Din, Mohamed A; Kumar, Aswin; Forges, Fabien; Chie, Wei-Chu; Bottomley, Andrew

2012-03-01

The objective of this international field study was to test the reliability, validity, and responsiveness of the European Organization for Research and Treatment of Cancer (EORTC) QLQ-BM22 module to assess health-related quality of life (HRQOL) in patients with bone metastases. Patients undergoing a variety of bone metastases-specific treatments were accrued. The QLQ-BM22 was administered with the QLQ-C30 at baseline and at 1 follow-up time point internationally. A debriefing questionnaire was administered to determine patient acceptability and understanding. Large-scale field testing of the QLQ-BM22 in addition to the QLQ-C30 took place in 7 countries: Brazil, Canada, Cyprus, Egypt, France, India, and Taiwan. A total of 400 patients participated. Multitrait scaling analyses confirmed 4 scales in the 22-item module. The scales were able to discriminate between clinically distinct patient groups, such as between those with a poor and those with a better performance status. The QLQ-BM22 was well received in all 7 countries, and the majority of patients did not recommend any significant changes from the module in its current form. The final QLQ-BM22 module contains 22 items and 4 scales assessing Painful Sites, Painful Characteristics, Functional Interference, and Psychosocial Aspects. Results confirmed the validity, reliability, cross-cultural applicability, and sensitivity of the 22-item EORTC QLQ-BM22. It is therefore recommended that the QLQ-BM22 be used in addition to the QLQ-C30 in clinical trials to assess HRQOL in patients with bone metastases. Copyright © 2011 American Cancer Society.

γ-Aminobutyric acid (GABA) oral rinse reduces capsaicin-induced burning mouth pain sensation: An experimental quantitative sensory testing study in healthy subjects.

PubMed

Zhang, Y; Wang, K; Arendt-Nielsen, L; Cairns, B E

2018-02-01

In burning mouth patients, analgesia after oral administration of clonazepam may result from modulation of peripheral γ-aminobutyric acid (GABA) receptors. The effect of oral administration of test solutions (water, 0.5 mol/L or 0.05 mol/L GABA, 1% lidocaine) was investigated for the amelioration of pain and sensitivity induced by application of capsaicin (1%, 2 min) to the tongue of thirty healthy male and female subjects in this four-session, randomized, placebo-controlled, double-blinded, cross-over study. Intra-oral quantitative sensory testing was used to assess cold (CDT), warm (WDT) and mechanical (MDT) detection thresholds as well as mechanical (MPT) and heat (HPT) pain thresholds. Capsaicin-induced pain intensity was continuously rated on a 0-10 electronic visual analogue scale (VAS). The area under the VAS curve (VASAUC) after rinsing was calculated for each solution. Capsaicin application on the tongue evoked burning pain with a peak of 4.8/10, and significantly increased CDT and MDT while significantly decreasing WDT, HPT, and MPT. The VASAUC was significantly smaller after oral rinse with 0.05 mol/L GABA, 0.5 mol/L GABA, and 1% lidocaine than after oral rinse with water. Rinse with 0.5 mol/L or 0.05 mol/L GABA were similarly effective in decreasing VASAUC. Rinsing with either 1% lidocaine, 0.5 mol/L or 0.05 mol/L GABA also significantly attenuated the effects of capsaicin on WDT and HPT in a treatment independent manner. There were no sex-related differences in these effects of GABA. Capsaicin-induced burning tongue pain and decreases in WDT and HPT can be ameliorated by rinsing the mouth with lidocaine and GABA solutions. Rinsing the mouth with an oral GABA containing solution ameliorated burning pain and increased heat sensitivity produced by application of capsaicin to the tongue. This finding suggests that GABA can act as a local analgesic agent in the oral cavity. © 2017 European Pain Federation - EFIC®.

Cell cycle inhibition limits development and maintenance of neuropathic pain following spinal cord injury

PubMed Central

Wu, Junfang; Zhao, Zaorui; Zhu, Xiya; Renn, Cynthia L.; Dorsey, Susan G.; Faden, Alan I.

2016-01-01

Chronic pain after spinal cord injury (SCI) may present as hyperalgesia, allodynia, and/or spontaneous pain and is often resistant to conventional pain medications. Identifying more effective interventions to manage SCI-Pain requires improved understanding of the pathophysiological mechanisms involved. Cell cycle activation (CCA) has been implicated as a key pathophysiological event following SCI. We have shown that early central or systemic administration of a cell cycle inhibitor reduces CCA, prevents glial changes, and limits SCI-induced hyperesthesia. Here we compared the effects of early versus late treatment with the pan-cyclin dependent kinase inhibitor flavopiridol on allodynia as well as spontaneous pain. Adult C57BL/6 male mice subjected to moderate SCI were treated with intraperitoneal injections of flavopiridol (1 mg/kg), daily for 7 days beginning either 3 h or 5 weeks after injury. Mechanical/thermal allodynia was evaluated, as well as spontaneous pain using the mouse grimace scale (MGS). We show that sensitivity to mechanical and thermal stimulation, and locomotor dysfunction were significantly reduced by early flavopiridol treatment compared to vehicle treated controls. SCI caused robust and extended increases of MGS up to 3 weeks after trauma. Early administration of flavopiridol significantly shortened duration of MGS changes. Late flavopiridol intervention significantly limited hyperesthesia at 7 days after treatment, associated with reduced glial changes, but without effect on locomotion. Thus, our data suggest that cell cycle modulation may provide an effective therapeutic strategy to reduce hyperesthesia after SCI, with a prolonged therapeutic window. PMID:26797506

Intergroup relationships do not reduce racial bias in empathic neural responses to pain.

PubMed

Contreras-Huerta, Luis Sebastian; Hielscher, Emily; Sherwell, Chase S; Rens, Natalie; Cunnington, Ross

2014-11-01

Perceiving the pain of others activates similar neural structures to those involved in the direct experience of pain, including sensory and affective-motivational areas. Empathic responses can be modulated by race, such that stronger neural activation is elicited by the perception of pain in people of the same race compared with another race. In the present study, we aimed to identify when racial bias occurs in the time course of neural empathic responses to pain. We also investigated whether group affiliation could modulate the race effect. Using the minimal group paradigm, we assigned participants to one of two mixed-race teams. We examined event-related potentials from participants when viewing members of their own and the other team receiving painful or non-painful touch. We identified a significant racial bias in early ERP components at N1 over frontal electrodes, where Painful stimuli elicited a greater negative shift relative to Non-Painful stimuli in response to own race faces only. A long latency empathic response was also found at P3, where there was significant differentiation between Painful and Non-Painful stimuli regardless of Race or Group. There was no evidence that empathy-related brain activity was modulated by minimal group manipulation. These results support a model of empathy for pain that consists of early, automatic bias towards own-race empathic responses and a later top-down cognitive evaluation that does not differentiate between races and may ultimately lead to unbiased behaviour. Copyright © 2014 Elsevier Ltd. All rights reserved.

Gender expression, sexual orientation and pain sensitivity in women.

PubMed

Vigil, Jacob M; Rowell, Lauren N; Lutz, Charlotte

2014-01-01

Despite a growing body of literature investigating sex differences with regard to pain, surprisingly little research has been conducted on the influence of various aspects of self-identity, including gender expression and sexual orientation, on pain sensitivity within each sex, particularly among women. In men, dispositional femininity is linked to greater clinical pain and trait masculinity is associated with higher pain thresholds. To examine whether gender expression and sexual orientation are associated with within-sex differences in ischemic pain sensitivity in healthy young women. A convenience sample of 172 females (mean age 21.4 years; range 18 to 30 years of age; 56.0% white, 89% heterosexual) performed an ischemic pain task in counterbalanced order. Desired levels of dispositional femininity for a preferred romantic partner and self-described levels of personal dispositional femininity were measured. Compared with heterosexual women, lesbian and bisexual women reported lower pain intensity ratings early in the discomfort task. Irrespective of sexual orientation, attraction to more feminine romantic partners and dispositional masculinity were correlated with lower pain intensity, and with higher pain thresholds and tolerance levels. These preliminary findings suggest that within-sex differences in sexual orientation and other aspects of identity, irrespective of biological sex, may be important to consider when examining experimental pain performance and clinical pain experiences. Larger investigations of the psychophysiological relationships among sexual orientation, gender expression and pain sensitivity are warranted. These findings may have implications for differences in clinical pain sensitivity of lesbian and bisexual women compared with heterosexual women.

Effects of neonatal pain, stress and their interrelation on pain sensitivity in later life in male rats.

PubMed

Butkevich, Irina P; Mikhailenko, Viktor A; Vershinina, Elena A; Aloisi, Anna Maria

2016-08-31

Neonatal pain and stress induce long-term changes in pain sensitivity. Therefore their interrelation is a topical subject of clinical and basic research. The present study investigated the effects of inflammatory peripheral pain and stress of maternal deprivation (MD)-isolation in 1-2- and 7-8-day-old Wistar rats (P1,2 and P7,8 respectively, ages comparable to preterm and full-term human babies) on basal pain and pain sensitivity in conditions of inflammatory pain (formalin test) during adolescence. The neonatal impacts were: pain (formalin injection, FOR in the paw), stress (a short 60-min MD), or pain+stress combination (FOR+MD), and appropriate controls. We found that stress of short-term maternal deprivation-isolation and inflammatory pain on P1,2 and P7,8 significantly increased the vulnerability of the nociceptive system to inflammatory pain. Maternal deprivation-isolation on P1,2 as compared with a similar impact on P7,8 had a greater effect on pain sensitivity of the adolescent rats, but the influence of early pain was independent of the injury age. Only adolescent rats with an early combination of pain and maternal deprivation-isolation showed hypoalgesia in the hot plate (HP) test. However licking duration (reflecting pain sensitivity) in these rats did not exceed licking duration in animals exposed only to maternal deprivation-isolation or pain. This study adds new data to the growing body of work demonstrating that early noxious impacts have long-term consequences for the functional activity of the nociceptive system. Our new findings may help to understand the impact of pain and maternal separation in the neonatal intensive care unit.

Central sensitization in chronic low back pain: A narrative review.

PubMed

Sanzarello, Ilaria; Merlini, Luciano; Rosa, Michele Attilio; Perrone, Mariada; Frugiuele, Jacopo; Borghi, Raffaele; Faldini, Cesare

2016-11-21

Low back pain is one of the four most common disorders in all regions, and the greatest contributor to disability worldwide, adding 10.7% of total years lost due to this health state. The etiology of chronic low back pain is, in most of the cases (up to 85%), unknown or nonspecific, while the specific causes (specific spinal pathology and neuropathic/radicular disorders) are uncommon. Central sensitization has been recently recognized as a potential pathophysiological mechanism underlying a group of chronic pain conditions, and may be a contributory factor for a sub-group of patients with chronic low back pain. The purposes of this narrative review are twofold. First, to describe central sensitization and its symptoms and signs in patients with chronic pain disorders in order to allow its recognition in patients with nonspecific low back pain. Second, to provide general treatment principles of chronic low back pain with particular emphasis on pharmacotherapy targeting central sensitization.

Salivary Cortisol and Cold Pain Sensitivity in Female Twins

PubMed Central

Godfrey, Kathryn M; Strachan, Eric; Dansie, Elizabeth; Crofford, Leslie J; Buchwald, Dedra; Goldberg, Jack; Poeschla, Brian; Succop, Annemarie; Noonan, Carolyn; Afari, Niloofar

2013-01-01

Background There is a dearth of knowledge about the link between cortisol and pain sensitivity. Purpose We examined the association of salivary cortisol with indices of cold pain sensitivity in 198 female twins and explored the role of familial confounding. Methods Three-day saliva samples were collected for cortisol levels and a cold pressor test was used to collect pain ratings and time to threshold and tolerance. Linear regression modeling with generalized estimating equations examined the overall and within-pair associations. Results Lower diurnal variation of cortisol was associated with higher pain ratings at threshold (p = 0.02) and tolerance (p < 0.01). The relationship of diurnal variation with pain ratings at threshold and tolerance was minimally influenced by familial factors (i.e., genetics and common environment). Conclusions Understanding the genetic and non-genetic mechanisms underlying the link between HPA axis dysregulation and pain sensitivity may help to prevent chronic pain development and maintenance. PMID:23955075

Learned control over spinal nociception in patients with chronic back pain.

PubMed

Krafft, S; Göhmann, H-D; Sommer, J; Straube, A; Ruscheweyh, R

2017-10-01

Descending pain inhibition suppresses spinal nociception, reducing nociceptive input to the brain. It is modulated by cognitive and emotional processes. In subjects with chronic pain, it is impaired, possibly contributing to pain persistence. A previously developed feedback method trains subjects to activate their descending inhibition. Participants are trained to use cognitive-emotional strategies to reduce their spinal nociception, as quantified by the nociceptive flexor reflex (RIII reflex), under visual feedback about their RIII reflex size. The aim of the present study was to test whether also subjects with chronic back pain can achieve a modulation of their descending pain inhibition under RIII feedback. In total, 33 subjects with chronic back pain received either true (n = 18) or sham RIII feedback (n = 15), 15 healthy control subjects received true RIII feedback. All three groups achieved significant RIII suppression, largest in controls (to 76 ± 26% of baseline), intermediate in chronic back pain subjects receiving true feedback (to 82 ± 13%) and smallest in chronic back pain subjects receiving sham feedback (to 89 ± 14%, all p < 0.05). However, only chronic pain subjects receiving true feedback significantly improved their descending inhibition over the feedback training, quantified by the conditioned pain modulation effect (test pain reduction of baseline before training: to 98 ± 26%, after: to 80 ± 21%, p < 0.01). Our results show that subjects with chronic back pain can achieve a reduction of their spinal nociception and improve their descending pain inhibition under RIII feedback training. Subjects with chronic back pain can learn to control their spinal nociception, quantified by the RIII reflex, when they receive feedback about the RIII reflex. © 2017 European Pain Federation - EFIC®.

A Brief Mindfulness Meditation Training Increases Pain Threshold and Accelerates Modulation of Response to Tonic Pain in an Experimental Study.

PubMed

Reiner, Keren; Granot, Michal; Soffer, Eliran; Lipsitz, Joshua Dan

2016-04-01

Research shows that mindfulness meditation (MM) affects pain perception; however, studies have yet to measure patterns of change over time. We examined effects of MM on perception of experimental heat pain using multiple psychophysical indices, including pattern of change in response to tonic painful stimuli. We also tested the potential moderating role of baseline mindfulness. Forty participants were randomly assigned to a brief MM training or control group. We assessed: a) heat pain threshold (HPT), b) temperature which induces pain at a fixed, target intensity level, and c) response pattern over time to tonic heat pain. Compared to control group, the MM group showed increased HPT and more rapid attenuation of pain intensity for tonic pain stimuli. Moderation analyses indicated that baseline mindfulness moderated effects of MM on HPT. A brief MM intervention appears to affect perception of experimental pain both by increasing pain threshold and accelerating modulation of response. Findings may help elucidate mechanisms of MM for chronic pain. © 2015 American Academy of Pain Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Hypnotic analgesia reduces brain responses to pain seen in others.

PubMed

Braboszcz, Claire; Brandao-Farinelli, Edith; Vuilleumier, Patrik

2017-08-29

Brain responses to pain experienced by oneself or seen in other people show consistent overlap in the pain processing network, particularly anterior insula, supporting the view that pain empathy partly relies on neural processes engaged by self-nociception. However, it remains unresolved whether changes in one's own pain sensation may affect empathic responding to others' pain. Here we show that inducing analgesia through hypnosis leads to decreased responses to both self and vicarious experience of pain. Activations in the right anterior insula and amygdala were markedly reduced when participants received painful thermal stimuli following hypnotic analgesia on their own hand, but also when they viewed pictures of others' hand in pain. Functional connectivity analysis indicated that this hypnotic modulation of pain responses was associated with differential recruitment of right prefrontal regions implicated in selective attention and inhibitory control. Our results provide novel support to the view that self-nociception is involved during empathy for pain, and demonstrate the possibility to use hypnotic procedures to modulate higher-level emotional and social processes.

A preclinical physiological assay to test modulation of knee joint pain in the spinal cord: effects of oxycodone and naproxen.

PubMed

Miranda, Jason A; Stanley, Phil; Gore, Katrina; Turner, Jamie; Dias, Rebecca; Rees, Huw

2014-01-01

Sensory processing in the spinal cord during disease states can reveal mechanisms for novel treatments, yet very little is known about pain processing at this level in the most commonly used animal models of articular pain. Here we report a test of the prediction that two clinically effective compounds, naproxen (an NSAID) and oxycodone (an opiate), are efficacious in reducing the response of spinal dorsal horn neurons to noxious knee joint rotation in the monosodium iodoacetate (MIA) sensitized rat. The overall objective for these experiments was to develop a high quality in vivo electrophysiology assay to confidently test novel compounds for efficacy against pain. Given the recent calls for improved preclinical experimental quality we also developed and implemented an Assay Capability Tool to determine the quality of our assay and ensure the quality of our results. Spinal dorsal horn neurons receiving input from the hind limb knee joint were recorded in anesthetized rats 14 days after they were sensitized with 1 mg of MIA. Intravenous administered oxycodone and naproxen were each tested separately for their effects on phasic, tonic, ongoing and afterdischarge action potential counts in response to innocuous and noxious knee joint rotation. Oxycodone reduced tonic spike counts more than the other measures, doing so by up to 85%. Tonic counts were therefore designated the primary endpoint when testing naproxen which reduced counts by up to 81%. Both reductions occurred at doses consistent with clinically effective doses for osteoarthritis. These results demonstrate that clinically effective doses of standard treatments for osteoarthritis reduce pain processing measured at the level of the spinal cord for two different mechanisms. The Assay Capability Tool helped to guide experimental design leading to a high quality and robust preclinical assay to use in discovering novel treatments for pain.

A Preclinical Physiological Assay to Test Modulation of Knee Joint Pain in the Spinal Cord: Effects of Oxycodone and Naproxen

PubMed Central

Miranda, Jason A.; Stanley, Phil; Gore, Katrina; Turner, Jamie; Dias, Rebecca; Rees, Huw

2014-01-01

Sensory processing in the spinal cord during disease states can reveal mechanisms for novel treatments, yet very little is known about pain processing at this level in the most commonly used animal models of articular pain. Here we report a test of the prediction that two clinically effective compounds, naproxen (an NSAID) and oxycodone (an opiate), are efficacious in reducing the response of spinal dorsal horn neurons to noxious knee joint rotation in the monosodium iodoacetate (MIA) sensitized rat. The overall objective for these experiments was to develop a high quality in vivo electrophysiology assay to confidently test novel compounds for efficacy against pain. Given the recent calls for improved preclinical experimental quality we also developed and implemented an Assay Capability Tool to determine the quality of our assay and ensure the quality of our results. Spinal dorsal horn neurons receiving input from the hind limb knee joint were recorded in anesthetized rats 14 days after they were sensitized with 1 mg of MIA. Intravenous administered oxycodone and naproxen were each tested separately for their effects on phasic, tonic, ongoing and afterdischarge action potential counts in response to innocuous and noxious knee joint rotation. Oxycodone reduced tonic spike counts more than the other measures, doing so by up to 85%. Tonic counts were therefore designated the primary endpoint when testing naproxen which reduced counts by up to 81%. Both reductions occurred at doses consistent with clinically effective doses for osteoarthritis. These results demonstrate that clinically effective doses of standard treatments for osteoarthritis reduce pain processing measured at the level of the spinal cord for two different mechanisms. The Assay Capability Tool helped to guide experimental design leading to a high quality and robust preclinical assay to use in discovering novel treatments for pain. PMID:25157947

Slow Temporal Summation of Pain for Assessment of Central Pain Sensitivity and Clinical Pain of Fibromyalgia Patients

PubMed Central

Staud, Roland; Weyl, Elizabeth E.; Riley, Joseph L.; Fillingim, Roger B.

2014-01-01

Background In healthy individuals slow temporal summation of pain or wind-up (WU) can be evoked by repetitive heat-pulses at frequencies of ≥.33 Hz. Previous WU studies have used various stimulus frequencies and intensities to characterize central sensitization of human subjects including fibromyalgia (FM) patients. However, many trials demonstrated considerable WU-variability including zero WU or even wind-down (WD) at stimulus intensities sufficient for activating C-nociceptors. Additionally, few WU-protocols have controlled for contributions of individual pain sensitivity to WU-magnitude, which is critical for WU-comparisons. We hypothesized that integration of 3 different WU-trains into a single WU-response function (WU-RF) would not only control for individuals’ pain sensitivity but also better characterize their central pain responding including WU and WD. Methods 33 normal controls (NC) and 38 FM patients participated in a study of heat-WU. We systematically varied stimulus intensities of.4 Hz heat-pulse trains applied to the hands. Pain summation was calculated as difference scores of 1st and 5th heat-pulse ratings. WU-difference (WU-Δ) scores related to 3 heat-pulse trains (44°C, 46°C, 48°C) were integrated into WU-response functions whose slopes were used to assess group differences in central pain sensitivity. WU-aftersensations (WU-AS) at 15 s and 30 s were used to predict clinical FM pain intensity. Results WU-Δ scores linearly accelerated with increasing stimulus intensity (p<.001) in both groups of subjects (FM>NC) from WD to WU. Slope of WU-RF, which is representative of central pain sensitivity, was significantly steeper in FM patients than NC (p<.003). WU-AS predicted clinical FM pain intensity (Pearson’s r = .4; p<.04). Conclusions Compared to single WU series, WU-RFs integrate individuals’ pain sensitivity as well as WU and WD. Slope of WU-RFs was significantly different between FM patients and NC. Therefore WU-RF may be useful for assessing central sensitization of chronic pain patients in research and clinical practice. PMID:24558475

FMRI connectivity analysis of acupuncture effects on an amygdala-associated brain network

PubMed Central

Qin, Wei; Tian, Jie; Bai, Lijun; Pan, Xiaohong; Yang, Lin; Chen, Peng; Dai, Jianping; Ai, Lin; Zhao, Baixiao; Gong, Qiyong; Wang, Wei; von Deneen, Karen M; Liu, Yijun

2008-01-01

Background Recently, increasing evidence has indicated that the primary acupuncture effects are mediated by the central nervous system. However, specific brain networks underpinning these effects remain unclear. Results In the present study using fMRI, we employed a within-condition interregional covariance analysis method to investigate functional connectivity of brain networks involved in acupuncture. The fMRI experiment was performed before, during and after acupuncture manipulations on healthy volunteers at an acupuncture point, which was previously implicated in a neural pathway for pain modulation. We first identified significant fMRI signal changes during acupuncture stimulation in the left amygdala, which was subsequently selected as a functional reference for connectivity analyses. Our results have demonstrated that there is a brain network associated with the amygdala during a resting condition. This network encompasses the brain structures that are implicated in both pain sensation and pain modulation. We also found that such a pain-related network could be modulated by both verum acupuncture and sham acupuncture. Furthermore, compared with a sham acupuncture, the verum acupuncture induced a higher level of correlations among the amygdala-associated network. Conclusion Our findings indicate that acupuncture may change this amygdala-specific brain network into a functional state that underlies pain perception and pain modulation. PMID:19014532

Spinal Manipulative Therapy Has an Immediate Effect on Thermal Pain Sensitivity in People With Low Back Pain: A Randomized Controlled Trial

PubMed Central

Bishop, Mark D.; Robinson, Michael E.; Zeppieri, Giorgio; George, Steven Z.

2009-01-01

Background Current evidence suggests that spinal manipulative therapy (SMT) is effective in the treatment of people with low back pain (LBP); however, the corresponding mechanisms are unknown. Hypoalgesia is associated with SMT and is suggestive of specific mechanisms. Objective The primary purpose of this study was to assess the immediate effects of SMT on thermal pain perception in people with LBP. A secondary purpose was to determine whether the resulting hypoalgesia was a local effect and whether psychological influences were associated with changes in pain perception. Design This study was a randomized controlled trial. Setting A sample of convenience was recruited from community and outpatient clinics. Participants Thirty-six people (10 men, 26 women) currently experiencing LBP participated in the study. The average age of the participants was 32.39 (SD=12.63) years, and the average duration of LBP was 221.79 (SD=365.37) weeks. Intervention and Measurements Baseline demographic and psychological measurements were obtained, followed by quantitative sensory testing to assess temporal summation and Aδ fiber–mediated pain perception. Next, participants were randomly assigned to ride a stationary bicycle, perform low back extension exercises, or receive SMT. Finally, the same quantitative sensory testing protocol was reassessed to determine the immediate effects of each intervention on thermal pain sensitivity. Results Hypoalgesia to Aδ fiber–mediated pain perception was not observed. Group-dependent hypoalgesia of temporal summation specific to the lumbar innervated region was observed. Pair-wise comparisons indicated significant hypoalgesia in participants who received SMT, but not in those who rode a stationary bicycle or performed low back extension exercises. Psychological factors did not significantly correlate with changes in temporal summation in participants who received SMT. Limitations Only immediate effects of SMT were measured, so the authors are unable to comment on whether the inhibition of temporal summation is a lasting effect. Furthermore, the authors are unable to comment on the relationship between their findings and changes in clinical pain. Conclusions Inhibition of Aδ fiber–mediated pain perception was similar for all groups. However, inhibition of temporal summation was observed only in participants receiving SMT, suggesting a modulation of dorsal horn excitability that was observed primarily in the lumbar innervated area. PMID:19797305

Music modulation of pain perception and pain-related activity in the brain, brain stem, and spinal cord: a functional magnetic resonance imaging study.

PubMed

Dobek, Christine E; Beynon, Michaela E; Bosma, Rachael L; Stroman, Patrick W

2014-10-01

The oldest known method for relieving pain is music, and yet, to date, the underlying neural mechanisms have not been studied. Here, we investigate these neural mechanisms by applying a well-defined painful stimulus while participants listened to their favorite music or to no music. Neural responses in the brain, brain stem, and spinal cord were mapped with functional magnetic resonance imaging spanning the cortex, brain stem, and spinal cord. Subjective pain ratings were observed to be significantly lower when pain was administered with music than without music. The pain stimulus without music elicited neural activity in brain regions that are consistent with previous studies. Brain regions associated with pleasurable music listening included limbic, frontal, and auditory regions, when comparing music to non-music pain conditions. In addition, regions demonstrated activity indicative of descending pain modulation when contrasting the 2 conditions. These regions include the dorsolateral prefrontal cortex, periaqueductal gray matter, rostral ventromedial medulla, and dorsal gray matter of the spinal cord. This is the first imaging study to characterize the neural response of pain and how pain is mitigated by music, and it provides new insights into the neural mechanism of music-induced analgesia within the central nervous system. This article presents the first investigation of neural processes underlying music analgesia in human participants. Music modulates pain responses in the brain, brain stem, and spinal cord, and neural activity changes are consistent with engagement of the descending analgesia system. Copyright © 2014 American Pain Society. Published by Elsevier Inc. All rights reserved.

Preoperative Pain Neuroscience Education Combined With Knee Joint Mobilization for Knee Osteoarthritis: A Randomized Controlled Trial.

PubMed

Lluch, Enrique; Dueñas, Lirios; Falla, Deborah; Baert, Isabel; Meeus, Mira; Sánchez-Frutos, José; Nijs, Jo

2018-01-01

This study aimed to first compare the effects of a preoperative treatment combining pain neuroscience education (PNE) with knee joint mobilization versus biomedical education with knee joint mobilization on central sensitization (CS) in patients with knee osteoarthritis, both before and after surgery. Second, we wanted to compare the effects of both interventions on knee pain, disability, and psychosocial variables. Forty-four patients with knee osteoarthritis were allocated to receive 4 sessions of either PNE combined with knee joint mobilization or biomedical education with knee joint mobilization before surgery. All participants completed self-administered questionnaires and quantitative sensory testing was performed at baseline, after treatment and at a 1 month follow-up (all before surgery), and at 3 months after surgery. Significant and clinically relevant differences before and after surgery were found after treatments for both knee pain and disability, and some measures of CS (ie, widespread hyperalgesia, CS inventory), with no significant between-group differences. Other indicators of CS (ie, conditioned pain modulation, temporal summation) did not change over time following either treatment, and in some occasions the observed changes were not in the expected direction. Patients receiving PNE with knee joint mobilization achieved greater improvements in psychosocial variables (pain catastrophizing, kinesiophobia) both before and after surgery. Preoperative PNE combined with knee joint mobilization did not produce any additional benefits over time for knee pain and disability, and CS measures compared with biomedical education with knee joint mobilization. Superior effects in the PNE with knee joint mobilization group were only observed for psychosocial variables related to pain catastrophizing and kinesiophobia.

An experimental study of pain upon stimulation of the nasal and sinus cavities.

PubMed

Clerico, Dean M

2014-01-01

To map different areas of pain sensitivity and to determine the existence and/or pattern of referred pain from upon stimulating the sinonasal cavity. Experimental human study. Mechanical and electrical stimulations to various anatomical structures and areas of the nasal and sinus cavities were conducted on nine volunteers. Intensity, location and character of pain were recorded in all subjects. The postero-superior (cephalic) aspect of the nasal cavity, primarily the anterior face of the sphenoid sinus and the superior turbinate, were the most sensitive sites, and the antero-inferior (caudal) region was the least sensitive. Referred pain to the head and face was reported by several subjects. Topographical differences in pain sensitivity exist in the sinonasal cavity. The phenomenon of referred pain from the nasal cavity was demonstrated. Copyright © 2014 Elsevier Inc. All rights reserved.

Pain sensitivity mediates the relationship between stress and headache intensity in chronic tension-type headache

PubMed Central

Cathcart, Stuart; Bhullar, Navjot; Immink, Maarten; Della Vedova, Chris; Hayball, John

2012-01-01

BACKGROUND: A central model for chronic tension-type headache (CTH) posits that stress contributes to headache, in part, by aggravating existing hyperalgesia in CTH sufferers. The prediction from this model that pain sensitivity mediates the relationship between stress and headache activity has not yet been examined. OBJECTIVE: To determine whether pain sensitivity mediates the relationship between stress and prospective headache activity in CTH sufferers. METHOD: Self-reported stress, pain sensitivity and prospective headache activity were measured in 53 CTH sufferers recruited from the general population. Pain sensitivity was modelled as a mediator between stress and headache activity, and tested using a nonparametric bootstrap analysis. RESULTS: Pain sensitivity significantly mediated the relationship between stress and headache intensity. CONCLUSIONS: The results of the present study support the central model for CTH, which posits that stress contributes to headache, in part, by aggravating existing hyperalgesia in CTH sufferers. Implications for the mechanisms and treatment of CTH are discussed. PMID:23248808

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.

Mindfulness meditation-related pain relief: Evidence for unique brain mechanisms in the regulation of pain

PubMed Central

Zeidan, F.; Grant, J.A.; Brown, C.A.; McHaffie, J.G.; Coghill, R.C.

2013-01-01

The cognitive modulation of pain is influenced by a number of factors ranging from attention, beliefs, conditioning, expectations, mood, and the regulation of emotional responses to noxious sensory events. Recently, mindfulness meditation has been found attenuate pain through some of these mechanisms including enhanced cognitive and emotional control, as well as altering the contextual evaluation of sensory events. This review discusses the brain mechanisms involved in mindfulness meditation-related pain relief across different meditative techniques, expertise and training levels, experimental procedures, and neuroimaging methodologies. Converging lines of neuroimaging evidence reveal that mindfulness meditation-related pain relief is associated with unique appraisal cognitive processes depending on expertise level and meditation tradition. Moreover, it is postulated that mindfulness meditation-related pain relief may share a common final pathway with other cognitive techniques in the modulation of pain. PMID:22487846

Gender expression, sexual orientation and pain sensitivity in women

PubMed Central

Vigil, Jacob M; Rowell, Lauren N; Lutz, Charlotte

2014-01-01

BACKGROUND: Despite a growing body of literature investigating sex differences with regard to pain, surprisingly little research has been conducted on the influence of various aspects of self-identity, including gender expression and sexual orientation, on pain sensitivity within each sex, particularly among women. In men, dispositional femininity is linked to greater clinical pain and trait masculinity is associated with higher pain thresholds. OBJECTIVES: To examine whether gender expression and sexual orientation are associated with within-sex differences in ischemic pain sensitivity in healthy young women. METHODS: A convenience sample of 172 females (mean age 21.4 years; range 18 to 30 years of age; 56.0% white, 89% heterosexual) performed an ischemic pain task in counterbalanced order. Desired levels of dispositional femininity for a preferred romantic partner and self-described levels of personal dispositional femininity were measured. RESULTS: Compared with heterosexual women, lesbian and bisexual women reported lower pain intensity ratings early in the discomfort task. Irrespective of sexual orientation, attraction to more feminine romantic partners and dispositional masculinity were correlated with lower pain intensity, and with higher pain thresholds and tolerance levels. DISCUSSION: These preliminary findings suggest that within-sex differences in sexual orientation and other aspects of identity, irrespective of biological sex, may be important to consider when examining experimental pain performance and clinical pain experiences. CONCLUSION: Larger investigations of the psychophysiological relationships among sexual orientation, gender expression and pain sensitivity are warranted. These findings may have implications for differences in clinical pain sensitivity of lesbian and bisexual women compared with heterosexual women. PMID:24575419

Neuropeptide Y in the rostral ventromedial medulla reverses inflammatory and nerve injury hyperalgesia in rats via non-selective excitation of local neurons

PubMed Central

Cleary, Daniel R.; Roeder, Zachary; Elkhatib, Rania; Heinricher, Mary M.

2014-01-01

Chronic pain reflects not only sensitization of the ascending nociceptive pathways, but also changes in descending modulation. The rostral ventromedial medulla (RVM) is a key structure in a well-studied descending pathway, and contains two classes of modulatory neurons, the ON-cells and the OFF-cells. Disinhibition of OFF-cells depresses nociception; increased ON-cell activity facilitates nociception. Multiple lines of evidence show that sensitization of ON-cells contributes to chronic pain, and reversing or blocking this sensitization is of interest as a treatment of persistent pain. Neuropeptide Y (NPY) acting via the Y1 receptor has been shown to attenuate hypersensitivity in nerve-injured animals without affecting normal nociception when microinjected into the RVM, but the neural basis for this effect was unknown. We hypothesized that behavioral anti-hyperalgesia was due to selective inhibition of ON-cells by NPY at the Y1 receptor. To explore the possibility of Y1 selectivity on ON-cells, we stained for the NPY-Y1 receptor in the RVM, and found it broadly expressed on both serotonergic and non-serotonergic neurons. In subsequent behavioral experiments, NPY microinjected into the RVM in lightly anesthetized animals reversed signs of mechanical hyperalgesia following either nerve injury or chronic hindpaw inflammation. Unexpectedly, rather than decreasing ON-cell activity, NPY increased spontaneous activity of both ON- and OFF-cells without altering noxious-evoked changes in firing. Based on these results, we conclude that the anti-hyperalgesic effects of NPY in the RVM are not explained by selective inhibition of ON-cells, but rather by increased spontaneous activity of OFF-cells. Although ON-cells undoubtedly facilitate nociception and contribute to hypersensitivity, the present results highlight the importance of parallel OFF-cell mediated descending inhibition in limiting the expression of chronic pain. PMID:24792711

Predictors and Moderators of Post-traumatic Stress Disorder: An Investigation of Anxiety Sensitivity and Resilience in Individuals with Chronic Pain.

PubMed

Lies, July; Lau, Shi Ting; Jones, Lester E; Jensen, Mark P; Tan, Gabriel

2017-03-01

Anxiety sensitivity has been proposed as a psychological vulnerability factor for post-traumatic stress disorder (PTSD). Studies have also supported the protective role of resilience for overcoming the negative effects of trauma exposure. Given the linkages between anxiety sensitivity, resilience, trauma exposure and post-traumatic stress, this study explored the potential moderating roles of anxiety sensitivity and resilience on the association between trauma history and PTSD symptoms in a sample of individuals with chronic pain. A total of 100 patients with chronic pain were recruited from a large public hospital. Patients who had pain lasting for more than 3 months and a pain intensity rating of at least 4/10 were included. The study participants were administered measures of PTSD symptoms (PTSD Checklist - Civilian Version), resilience (Brief Resilient Coping Scale) and anxiety sensitivity (Anxiety Sensitivity Index). An analysis of outcome measures indicated that anxiety sensitivity and resilience were independently associated with PTSD symptoms, where βs were 0.57 and -0.23, respectively. The relationship between trauma and PTSD symptom severity was also moderated by anxiety sensitivity. Trauma history was associated with higher PTSD symptom severity only in those with high anxiety sensitivity. However, contrary to the hypotheses, resilience did not serve as a moderator. There are potential benefits of PTSD interventions that increase resilience and decrease anxiety sensitivity in individuals with chronic pain, especially for those who have experienced a traumatic event. Given that the presence of PTSD symptomatology in chronic pain populations negatively impact patient well-being, it would be important for clinicians to assess, monitor and treat PTSD in individuals with chronic pain.

Social hierarchy modulates neural responses of empathy for pain

PubMed Central

Feng, Chunliang; Li, Zhihao; Feng, Xue; Wang, Lili; Tian, Tengxiang

2016-01-01

Recent evidence indicates that empathic responses to others’ pain are modulated by various situational and individual factors. However, few studies have examined how empathy and underlying brain functions are modulated by social hierarchies, which permeate human society with an enormous impact on social behavior and cognition. In this study, social hierarchies were established based on incidental skill in a perceptual task in which all participants were mediumly ranked. Afterwards, participants were scanned with functional magnetic resonance imaging while watching inferior-status or superior-status targets receiving painful or non-painful stimulation. The results revealed that painful stimulation applied to inferior-status targets induced higher activations in the anterior insula (AI) and anterior medial cingulate cortex (aMCC), whereas these empathic brain activations were significantly attenuated in response to superior-status targets’ pain. Further, this neural empathic bias to inferior-status targets was accompanied by stronger functional couplings of AI with brain regions important in emotional processing (i.e. thalamus) and cognitive control (i.e. middle frontal gyrus). Our findings indicate that emotional sharing with others’ pain is shaped by relative positions in a social hierarchy such that underlying empathic neural responses are biased toward inferior-status compared with superior-status individuals. PMID:26516169

Persistent post-surgical pain and experimental pain sensitivity in the Tromsø study: comorbid pain matters.

PubMed

Johansen, Aslak; Schirmer, Henrik; Stubhaug, Audun; Nielsen, Christopher S

2014-02-01

In a large survey incorporating medical examination (N=12,981), information on chronic pain and surgery was collected, and sensitivity to different pain modalities was tested. Tolerance to the cold pressor test was analysed with survival statistics for 10,486 individuals, perceived cold pressor pain intensity was calculated for 10,367 individuals, heat pain threshold was assessed for 4,054 individuals, and pressure pain sensitivity for 4,689 individuals. Persistent post-surgical pain, defined by self-report, was associated with lower cold pressor tolerance (sex-adjusted hazard ratio=1.34, 95% confidence interval=1.08-1.66), but not when adjusting for other chronic pain. Other experimental pain modalities did not differentiate between individuals with or without post-surgical pain. Of the individuals with chronic pain (N=3352), 6.2% indicated surgery as a cause, although only 0.5% indicated surgery as the only cause. The associations found between persistent post-surgical pain and cold pressor tolerance is largely explained by the co-existence of chronic pain from other causes. We conclude that most cases of persistent post-surgical pain are coexistent with other chronic pain, and that, in an unselected post-surgical population, persistent post-surgical pain is not significantly associated with pain sensitivity when controlling for comorbid pain from other causes. A low prevalence of self-reported persistent pain from surgery attenuates statistically significant associations. We hypothesize that general chronic pain is associated with central changes in pain processing as expressed by reduced tolerance for the cold pressor test. Copyright © 2013 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

Endogenous inhibition of pain and spinal nociception in women with premenstrual dysphoric disorder

PubMed Central

Palit, Shreela; Bartley, Emily J; Kuhn, Bethany L; Kerr, Kara L; DelVentura, Jennifer L; Terry, Ellen L; Rhudy, Jamie L

2016-01-01

Purpose Premenstrual dysphoric disorder (PMDD) is characterized by severe affective and physical symptoms, such as increased pain, during the late-luteal phase of the menstrual cycle. The mechanisms underlying hyperalgesia in women with PMDD have yet to be identified, and supraspinal pain modulation has yet to be examined in this population. The present study assessed endogenous pain inhibitory processing by examining conditioned pain modulation (CPM, a painful conditioning stimulus inhibiting pain evoked by a test stimulus at a distal body site) of pain and the nociceptive flexion reflex (NFR, a spinally-mediated withdrawal reflex) during the mid-follicular, ovulatory, and late-luteal phases of the menstrual cycle. Methods Participants were regularly-cycling women (14 without PMDD; 14 with PMDD). CPM was assessed by delivering electrocutaneous test stimuli to the sural nerve before, during, and after a painful conditioning ischemia task. Participants rated their pain to electrocutaneous stimuli, and NFR magnitudes were measured. A linear mixed model analysis was used to assess the influence of group and menstrual phase on CPM. Results Compared with controls, women with PMDD experienced greater pain during the late-luteal phase and enhanced spinal nociception during the ovulation phase, both of which were independent of CPM. Both groups showed CPM inhibition of pain that did not differ by menstrual phase. Only women with PMDD evidenced CPM inhibition of NFR. Conclusion Endogenous modulation of pain and spinal nociception is not disrupted in women with PMDD. Additionally, greater NFR magnitudes during ovulation in PMDD may be due to tonically-engaged descending mechanisms that facilitate spinal nociception, leading to enhanced pain during the premenstrual phase. PMID:26929663

Combined glutamate and glutamine levels in pain-processing brain regions are associated with individual pain sensitivity.

PubMed

Zunhammer, Matthias; Schweizer, Lauren M; Witte, Vanessa; Harris, Richard E; Bingel, Ulrike; Schmidt-Wilcke, Tobias

2016-10-01

The relationship between glutamate and γ-aminobutyric acid (GABA) levels in the living human brain and pain sensitivity is unknown. Combined glutamine/glutamate (Glx), as well as GABA levels can be measured in vivo with single-voxel proton magnetic resonance spectroscopy. In this cross-sectional study, we aimed at determining whether Glx and/or GABA levels in pain-related brain regions are associated with individual differences in pain sensitivity. Experimental heat, cold, and mechanical pain thresholds were obtained from 39 healthy, drug-free individuals (25 men) according to the quantitative sensory testing protocol and summarized into 1 composite measure of pain sensitivity. The Glx levels were measured using point-resolved spectroscopy at 3 T, within a network of pain-associated brain regions comprising the insula, the anterior cingulate cortex, the mid-cingulate cortex, the dorsolateral prefrontal cortex, and the thalamus. GABA levels were measured using GABA-edited spectroscopy (Mescher-Garwood point-resolved spectroscopy) within the insula, the anterior cingulate cortex, and the mid-cingulate cortex. Glx and/or GABA levels correlated positively across all brain regions. Gender, weekly alcohol consumption, and depressive symptoms were significantly associated with Glx and/or GABA levels. A linear regression analysis including all these factors indicated that Glx levels pooled across pain-related brain regions were positively associated with pain sensitivity, whereas no appreciable relationship with GABA was found. In sum, we show that the levels of the excitatory neurotransmitter glutamate and its precursor glutamine across pain-related brain regions are positively correlated with individual pain sensitivity. Future studies will have to determine whether our findings also apply to clinical populations.

Identification of clusters of individuals relevant to temporomandibular disorders and other chronic pain conditions: the OPPERA study

PubMed Central

Bair, Eric; Gaynor, Sheila; Slade, Gary D.; Ohrbach, Richard; Fillingim, Roger B.; Greenspan, Joel D.; Dubner, Ronald; Smith, Shad B.; Diatchenko, Luda; Maixner, William

2016-01-01

The classification of most chronic pain disorders gives emphasis to anatomical location of the pain to distinguish one disorder from the other (eg, back pain vs temporomandibular disorder [TMD]) or to define subtypes (eg, TMD myalgia vs arthralgia). However, anatomical criteria overlook etiology, potentially hampering treatment decisions. This study identified clusters of individuals using a comprehensive array of biopsychosocial measures. Data were collected from a case–control study of 1031 chronic TMD cases and 3247 TMD-free controls. Three subgroups were identified using supervised cluster analysis (referred to as the adaptive, pain-sensitive, and global symptoms clusters). Compared with the adaptive cluster, participants in the pain-sensitive cluster showed heightened sensitivity to experimental pain, and participants in the global symptoms cluster showed both greater pain sensitivity and greater psychological distress. Cluster membership was strongly associated with chronic TMD: 91.5% of TMD cases belonged to the pain-sensitive and global symptoms clusters, whereas 41.2% of controls belonged to the adaptive cluster. Temporomandibular disorder cases in the pain-sensitive and global symptoms clusters also showed greater pain intensity, jaw functional limitation, and more comorbid pain conditions. Similar results were obtained when the same methodology was applied to a smaller case–control study consisting of 199 chronic TMD cases and 201 TMD-free controls. During a median 3-year follow-up period of TMD-free individuals, participants in the global symptoms cluster had greater risk of developing first-onset TMD (hazard ratio = 2.8) compared with participants in the other 2 clusters. Cross-cohort predictive modeling was used to demonstrate the reliability of the clusters. PMID:26928952

Examining the Sensitivity and Specificity of 2 Screening Instruments: Odontogenic or Temporomandibular Disorder Pain?

PubMed

Fonseca Alonso, Barbara; Nixdorf, Donald R; Shueb, Sarah S; John, Mike T; Law, Alan S; Durham, Justin

2017-01-01

Two groups of patients with orofacial pains that are clinically important to distinguish from each other are patients with odontogenic pain and temporomandibular disorder (TMD) pain. The aim of this study was to determine the sensitivity and specificity of 2 screening instruments in distinguishing between patients with these types of pain. A convenience sample of patients seeking care at an endodontic clinic and an orofacial pain clinic were recruited. The 14-item dental pain questionnaire (DePaQ) was used to screen for odontogenic pain and the 6-item TMD screener was used to screen for TMD pain. Sensitivity and specificity calculations with 95% confidence intervals (CIs) were performed for both instruments, and thresholds/acceptability/performance was assessed using published guidelines. Thirty-four patients with odontogenic pain and 37 patients with TMD pain were included in this study. The sensitivity of the DePaQ was 0.85 (95% CI, 0.69-0.95), and specificity was 0.11 (95% CI, 0.03-0.25). The sensitivity of the TMD screener was 0.92 (95% CI, 0.78-0.98), and specificity was 0.59 (95% CI, 0.41-0.75). The point estimates, a single value used to estimate the population parameter, for both the DePaQ and TMD screener were "acceptable" in identifying patients who had the pain condition in question (ie, sensitivity), whereas the point estimate for appropriately identifying patients who did not have the pain condition when they did not have it (ie, specificity) was "nonacceptable" for both. The DePaQ and the TMD screener lack diagnostic accuracy for differentiating TMD from odontogenic tooth pain without adjunctive (clinical) investigation(s) or examination. However, the TMD screener has high sensitivity for identifying true positives (ie, TMD pain) and would therefore be useful as a screening instrument when one can definitively exclude odontogenic etiology for pain on clinical and radiographic grounds, for instance in endodontic practices. In this study, the negative predictive value was also high in the TMD screener, and, therefore, we can trust a negative result (ie, when the TMD screener is negative, we can be fairly certain the pain diagnosis is not TMD and rule out TMD). Crown Copyright © 2016. Published by Elsevier Inc. All rights reserved.

Assessment of deep dynamic mechanical sensitivity in individuals with tension-type headache: The dynamic pressure algometry.

PubMed

Palacios-Ceña, M; Wang, K; Castaldo, M; Guerrero-Peral, Á; Caminero, A B; Fernández-de-Las-Peñas, C; Arendt-Nielsen, L

2017-09-01

To explore the validity of dynamic pressure algometry for evaluating deep dynamic mechanical sensitivity by assessing its association with headache features and widespread pressure sensitivity in tension-type headache (TTH). One hundred and eighty-eight subjects with TTH (70% women) participated. Deep dynamic sensitivity was assessed with a dynamic pressure algometry set (Aalborg University, Denmark © ) consisting of 11 different rollers including fixed levels from 500 g to 5300 g. Each roller was moved at a speed of 0.5 cm/s over a 60-mm horizontal line covering the temporalis muscle. Dynamic pain threshold (DPT-level of the first painful roller) was determined and pain intensity during DPT was rated on a numerical pain rate scale (NPRS, 0-10). Headache clinical features were collected on a headache diary. As gold standard, static pressure pain thresholds (PPT) were assessed over temporalis, C5/C6 joint, second metacarpal, and tibialis anterior muscle. Side-to-side consistency between DPT (r = 0.843, p < 0.001) and pain evoked (r = 0.712; p < 0.001) by dynamic algometer was observed. DPT was moderately associated with widespread PPTs (0.526 > r > 0.656, all p < 0.001). Furthermore, pain during DPT was negatively associated with widespread PPTs (-0.370 < r < -0.162, all p < 0.05). Dynamic pressure algometry was a valid tool for assessing deep dynamic mechanical sensitivity in TTH. DPT was associated with widespread pressure sensitivity independently of the frequency of headaches supporting that deep dynamic pressure sensitivity within the trigeminal area is consistent with widespread pressure sensitivity. Assessing deep static and dynamic somatic tissue pain sensitivity may provide new opportunities for differentiated diagnostics and possibly a new tool for assessing treatment effects. The current study found that dynamic pressure algometry in the temporalis muscle was associated with widespread pressure pain sensitivity in individuals with tension-type headache. The association was independent of the frequency of headaches. Assessing deep static and dynamic somatic tissue pain sensitivity may provide new opportunities for differentiated diagnostics and possibly a tool for assessing treatment effects. © 2017 European Pain Federation - EFIC®.

Treatment of central sensitization in patients with 'unexplained' chronic pain: what options do we have?

PubMed

Nijs, Jo; Meeus, Mira; Van Oosterwijck, Jessica; Roussel, Nathalie; De Kooning, Margot; Ickmans, Kelly; Matic, Milica

2011-05-01

Central sensitization accounts for chronic 'unexplained' pain in a wide variety of disorders, including chronic whiplash-associated disorders, temporomandibular disorders, chronic low back pain, osteoarthritis, fibromyalgia, chronic fatigue syndrome and chronic tension-type headache among others. Given the increasing evidence supporting the clinical significance of central sensitization in those with unexplained chronic pain, the awareness is growing that central sensitization should be a treatment target in these patients. This article provides an overview of the treatment options available for desensitizing the CNS in patients with chronic pain due to central sensitization. It focuses on those strategies that specifically target pathophysiological mechanisms known to be involved in central sensitization. In addition, pharmacological options, rehabilitation and neurotechnology options are discussed. Acetaminophen, serotonin-reuptake inhibitor drugs, selective and balanced serototin and norepinephrine-reuptake inhibitor drugs, the serotonin precursor tryptophan, opioids, N-methyl-d-aspartate (NMDA)-receptor antagonists, calcium-channel alpha(2)delta (a2δ) ligands, transcranial magnetic stimulation, transcutaneous electric nerve stimulation (TENS), manual therapy and stress management each target central pain processing mechanisms in animals that - theoretically - desensitize the CNS in humans. To provide a comprehensive treatment for 'unexplained' chronic pain disorders characterized by central sensitization, it is advocated to combine the best evidence available with treatment modalities known to target central sensitization. © 2011 Informa UK, Ltd

Cognitive modulation of pain and predictive coding. Comment on “Facing the experience of pain: A neuropsychological perspective” by Fabbro and Crescentini

NASA Astrophysics Data System (ADS)

Pagnoni, Giuseppe; Porro, Carlo A.

2014-09-01

Pain is a phenomenologically complex experience whose sensory and psychological dimensions are deeply intertwined. In their perspective article, Fabbro and Crescentini [1] review the physiological and neural mechanisms underlying nociception and its cognitive modulation within the broader concept of suffering, which includes psychological pain [2] in its culturally mediated and existentially nuanced forms. The tight link between affective and cognitive processes, on the one hand, and pain, on the other, is illustrated by examining in turn the placebo effect, empathy for other people's afflictions, clinical depression, and the role that mindfulness-based practices may play in alleviating suffering.

Myofascial trigger points: spontaneous electrical activity and its consequences for pain induction and propagation

PubMed Central

2011-01-01

Active myofascial trigger points are one of the major peripheral pain generators for regional and generalized musculoskeletal pain conditions. Myofascial trigger points are also the targets for acupuncture and/or dry needling therapies. Recent evidence in the understanding of the pathophysiology of myofascial trigger points supports The Integrated Hypothesis for the trigger point formation; however unanswered questions remain. Current evidence shows that spontaneous electrical activity at myofascial trigger point originates from the extrafusal motor endplate. The spontaneous electrical activity represents focal muscle fiber contraction and/or muscle cramp potentials depending on trigger point sensitivity. Local pain and tenderness at myofascial trigger points are largely due to nociceptor sensitization with a lesser contribution from non-nociceptor sensitization. Nociceptor and non-nociceptor sensitization at myofascial trigger points may be part of the process of muscle ischemia associated with sustained focal muscle contraction and/or muscle cramps. Referred pain is dependent on the sensitivity of myofascial trigger points. Active myofascial trigger points may play an important role in the transition from localized pain to generalized pain conditions via the enhanced central sensitization, decreased descending inhibition and dysfunctional motor control strategy. PMID:21439050

Morning Versus Evening Bright Light Treatment at Home to Improve Function and Pain Sensitivity for Women with Fibromyalgia: A Pilot Study.

PubMed

Burgess, Helen J; Park, Margaret; Ong, Jason C; Shakoor, Najia; Williams, David A; Burns, John

2017-01-01

To test the feasibility, acceptability, and effects of a home-based morning versus evening bright light treatment on function and pain sensitivity in women with fibromyalgia. A single blind randomized study with two treatment arms: 6 days of a 1 hour morning light treatment or 6 days of a 1 hour evening light treatment. Function, pain sensitivity, and circadian timing were assessed before and after treatment. Participants slept at home, except for two nights in Sleep Center. Ten women meeting the American College of Rheumatology's diagnostic criteria for fibromyalgia, including normal blood test results. Self-reported function was assessed with the Fibromyalgia Impact Questionnaire (FIQ). Pain sensitivity was assessed using a heat stimulus that gave measures of threshold and tolerance. Circadian timing was assessed with the dim light melatonin onset. Both morning and evening light treatments led to improvements in function and pain sensitivity. However, only the morning light treatment led to a clinically meaningful improvement in function (>14% reduction from baseline FIQ) and morning light significantly increased pain threshold more than evening light ( P  < 0.05). Phase advances in circadian timing were associated with an increase in pain tolerance (r = 0.67, P  < 0.05). Bright light treatment appears to be a feasible and acceptable adjunctive treatment to women with fibromyalgia. Those who undergo morning light treatment may show improvements in function and pain sensitivity. Advances in circadian timing may be one mechanism by which morning light improves pain sensitivity. Findings can inform the design of a randomized controlled trial. © 2016 American Academy of Pain Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com

Inflammation-induced pain sensitization in men and women: does sex matter in experimental endotoxemia?

PubMed Central

Wegner, Alexander; Elsenbruch, Sigrid; Rebernik, Laura; Roderigo, Till; Engelbrecht, Elisa; Jäger, Marcus; Engler, Harald; Schedlowski, Manfred; Benson, Sven

2015-01-01

Abstract A role of the innate immune system is increasingly recognized as a mechanism contributing to pain sensitization. Experimental administration of the bacterial endotoxin lipopolysaccharide (LPS) constitutes a model to study inflammation-induced pain sensitization, but all existing human evidence comes from male participants. We assessed visceral and musculoskeletal pain sensitivity after low-dose LPS administration in healthy men and women to test the hypothesis that women show greater LPS-induced hyperalgesia compared with men. In this randomized, double-blind, placebo-controlled crossover study, healthy men (n = 20) and healthy women using oral contraceptives (n = 20) received an intravenous injection of 0.4 ng/kg body weight LPS or placebo. Pain sensitivity was assessed with established visceral and musculoskeletal pain models (ie, rectal pain thresholds; pressure pain thresholds for different muscle groups), together with a heartbeat perception (interoceptive accuracy) task. Plasma cytokines (tumor necrosis factor-α and interleukin-6) were measured along with state anxiety at baseline and up to 6-hour postinjection. Lipopolysaccharide application led to significant increases in plasma cytokines and state anxiety and decreased interoceptive awareness in men and women (P < 0.001, condition effects), with more pronounced LPS-induced cytokine increases in women (P < 0.05, interaction effects). Although both rectal and pressure pain thresholds were significantly decreased in the LPS condition (all P < 0.05, condition effect), no sex differences in endotoxin-induced sensitization were observed. In summary, LPS-induced systemic immune activation leads to visceral and musculoskeletal hyperalgesia, irrespective of biological sex. These findings support the broad applicability of experimental endotoxin administration as a translational preclinical model of inflammation-induced pain sensitization in both sexes. PMID:26058036

SLOWLY REPEATED EVOKED PAIN (SREP) AS A MARKER OF CENTRAL SENSITIZATION IN FIBROMYALGIA: DIAGNOSTIC ACCURACY AND RELIABILITY IN COMPARISON WITH TEMPORAL SUMMATION OF PAIN.

PubMed

de la Coba, Pablo; Bruehl, Stephen; Gálvez-Sánchez, Carmen María; Reyes Del Paso, Gustavo A

2018-05-01

This study examined the diagnostic accuracy and test-retest reliability of a novel dynamic evoked pain protocol (slowly repeated evoked pain; SREP) compared to temporal summation of pain (TSP), a standard index of central sensitization. Thirty-five fibromyalgia (FM) and 30 rheumatoid arthritis (RA) patients completed, in pseudorandomized order, a standard mechanical TSP protocol (10 stimuli of 1s duration at the thenar eminence using a 300g monofilament with 1s interstimulus interval) and the SREP protocol (9 suprathreshold pressure stimuli of 5s duration applied to the fingernail with a 30s interstimulus interval). In order to evaluate reliability for both protocols, they were repeated in a second session 4-7 days later. Evidence for significant pain sensitization over trials (increasing pain intensity ratings) was observed for SREP in FM (p<.001) but not in RA (p=.35), whereas significant sensitization was observed in both diagnostic groups for the TSP protocol (p's<.008). Compared to TSP, SREP demonstrated higher overall diagnostic accuracy (87.7% vs. 64.6%), greater sensitivity (0.89 vs. 0.57), and greater specificity (0.87 vs. 0.73) in discriminating between FM and RA patients. Test-retest reliability of SREP sensitization was good in FM (ICCs: 0.80), and moderate in RA (ICC: 0.68). SREP seems to be a dynamic evoked pain index tapping into pain sensitization that allows for greater diagnostic accuracy in identifying FM patients compared to a standard TSP protocol. Further research is needed to study mechanisms underlying SREP and the potential utility of adding SREP to standard pain evaluation protocols.

Adoptive transfer of M2 macrophages reduces neuropathic pain via opioid peptides.

PubMed

Pannell, Maria; Labuz, Dominika; Celik, Melih Ö; Keye, Jacqueline; Batra, Arvind; Siegmund, Britta; Machelska, Halina

2016-10-07

During the inflammation which occurs following nerve damage, macrophages are recruited to the site of injury. Phenotypic diversity is a hallmark of the macrophage lineage and includes pro-inflammatory M1 and anti-inflammatory M2 populations. Our aim in this study was to investigate the ability of polarized M0, M1, and M2 macrophages to secrete opioid peptides and to examine their relative contribution to the modulation of neuropathic pain. Mouse bone marrow-derived cells were cultured as unstimulated M0 macrophages or were stimulated into an M1 phenotype using lipopolysaccharide and interferon-γ or into an M2 phenotype using interleukin-4. The macrophage phenotypes were verified using flow cytometry for surface marker analysis and cytokine bead array for cytokine profile assessment. Opioid peptide levels were measured by radioimmunoassay and enzyme immunoassay. As a model of neuropathic pain, a chronic constriction injury (CCI) of the sciatic nerve was employed. Polarized M0, M1, and M2 macrophages (5 × 10 5 cells) were injected perineurally twice, on days 14 and 15 following CCI or sham surgery. Mechanical and heat sensitivity were measured using the von Frey and Hargreaves tests, respectively. To track the injected macrophages, we also transferred fluorescently stained polarized cells and analyzed the surface marker profile of endogenous and injected cells in the nerves ex vivo. Compared to M0 and M1 cells, M2 macrophages contained and released higher amounts of opioid peptides, including Met-enkephalin, dynorphin A (1-17), and β-endorphin. M2 cells transferred perineurally at the nerve injury site reduced mechanical, but not heat hypersensitivity following the second injection. The analgesic effect was reversed by the perineurally applied opioid receptor antagonist naloxone methiodide. M2 cells did not affect sensitivity following sham surgery. Neither M0 nor M1 cells altered mechanical and heat sensitivity in CCI or sham-operated animals. Tracing the fluorescently labeled M0, M1, and M2 cells ex vivo showed that they remained in the nerve and preserved their phenotype. Perineural transplantation of M2 macrophages resulted in opioid-mediated amelioration of neuropathy-induced mechanical hypersensitivity, while M1 macrophages did not exacerbate pain. Therefore, rather than focusing on macrophage-induced pain generation, promoting opioid-mediated M2 actions may be more relevant for pain control.

Sex differences in sensorimotor mu rhythms during selective attentional processing.

PubMed

Popovich, C; Dockstader, C; Cheyne, D; Tannock, R

2010-12-01

We used magnetoencephalography to investigate the effect of directed attention on sensorimotor mu (8-12 Hz) response (mu reactivity) to non-painful electrical stimulation of the median nerve in healthy adults. Mu desynchronization in the 10-12 Hz bandwidth is typically observed during higher-order cognitive functions including selective attentional processing of sensorimotor information (Pfurtscheller, Neuper, & Krauz, 2000). We found attention-related sex differences in mu reactivity, with females showing (i) prolonged mu desynchrony when attending to somatosensory stimuli, (ii) attentional modulation of the mu response based on whether attention was directed towards or away from somatosensory stimuli, which was absent in males, and (iii) a trend for greater neuronal excitability of the primary somatosensory region suggesting greater physiological responsiveness to sensory stimulation overall. Our findings suggest sex differences in attentional control strategies when processing somatosensory stimuli, whose salience may be greater for females. These sex differences in attention to somatosensory stimuli may help elucidate the well-documented sex biases in pain processing wherein females typically report greater sensitivity to experimental and clinical pain. Copyright © 2010 Elsevier Ltd. All rights reserved.

Low-threshold mechanoreceptors play a frequency-dependent dual role in subjective ratings of mechanical allodynia.

PubMed

Löken, Line S; Duff, Eugene P; Tracey, Irene

2017-12-01

In the setting of injury, myelinated primary afferent fibers that normally signal light touch are thought to switch modality and instead signal pain. In the absence of injury, touch is perceived as more intense when firing rates of Aβ afferents increase. However, it is not known if varying the firing rates of Aβ afferents have any consequence to the perception of dynamic mechanical allodynia (DMA). We hypothesized that, in the setting of injury, the unpleasantness of DMA would be intensified as the firing rates of Aβ afferents increase. Using a stimulus-response protocol established in normal skin, where an increase in brush velocity results in an increase of Aβ afferent firing rates, we tested if brush velocity modulated the unpleasantness of capsaicin-induced DMA. We analyzed how changes in estimated low-threshold mechanoreceptor firing activity influenced perception and brain activity (functional MRI) of DMA. Brushing on normal skin was perceived as pleasant, but brushing on sensitized skin produced both painful and pleasant sensations. Surprisingly, there was an inverse relationship between Aβ firing rates and unpleasantness such that brush stimuli that produced low firing rates were most painful and those that elicited high firing rates were rated as pleasant. Concurrently to this, we found increased cortical activity in response to low Aβ firing rates in regions previously implicated in pain processing during brushing of sensitized skin, but not normal skin. We suggest that Aβ signals do not merely switch modality to signal pain during injury. Instead, they exert a high- and low-frequency-dependent dual role in the injured state, with respectively both pleasant and unpleasant consequences. NEW & NOTEWORTHY We suggest that Aβ signals do not simply switch modality to signal pain during injury but play a frequency-dependent and dual role in the injured state with both pleasant and unpleasant consequences. These results provide a framework to resolve the apparent paradox of how touch can inhibit pain, as proposed by the Gate Control Theory and the existence of dynamic mechanical allodynia.

Spinal Manipulative Therapy Specific Changes In Pain Sensitivity In Individuals With Low Back Pain (NCT01168999)

PubMed Central

Bialosky, Joel E; George, Steven Z; Horn, Maggie E; Price, Donald D; Staud, Roland; Robinson, Michael E

2013-01-01

Spinal Manipulative Therapy (SMT) is effective for some individuals experiencing low back pain (LBP); however, the mechanisms are not established regarding the role of placebo. SMT is associated with changes in pain sensitivity suggesting related altered central nervous system response or processing of afferent nociceptive input. Placebo is also associated with changes in pain sensitivity and the efficacy of SMT for changes in pain sensitivity beyond placebo has not been adequately considered. We randomly assigned 110 participants with LBP to receive SMT, placebo SMT, placebo SMT with the instructional set, “The manual therapy technique you will receive has been shown to significantly reduce low back pain in some people”, or no intervention. Participants receiving the SMT and placebo SMT received their assigned intervention 6 times over two weeks. Pain sensitivity was assessed prior to and immediately following the assigned intervention during the first session. Clinical outcomes were assessed at baseline and following two weeks of participation in the study. Immediate attenuation of suprathreshold heat response was greatest following SMT (p= 0.05, partial η2= 0.07). Group dependent differences were not observed for changes in pain intensity and disability at two week. Participant satisfaction was greatest following the enhanced placebo SMT. PMID:24361109

Reward Circuitry Plasticity in Pain Perception and Modulation

PubMed Central

DosSantos, Marcos F.; Moura, Brenda de Souza; DaSilva, Alexandre F.

2017-01-01

Although pain is a widely known phenomenon and an important clinical symptom that occurs in numerous diseases, its mechanisms are still barely understood. Owing to the scarce information concerning its pathophysiology, particularly what is involved in the transition from an acute state to a chronic condition, pain treatment is frequently unsatisfactory, therefore contributing to the amplification of the chronic pain burden. In fact, pain is an extremely complex experience that demands the recruitment of an intricate set of central nervous system components. This includes cortical and subcortical areas involved in interpretation of the general characteristics of noxious stimuli. It also comprises neural circuits that process the motivational-affective dimension of pain. Hence, the reward circuitry represents a vital element for pain experience and modulation. This review article focuses on the interpretation of the extensive data available connecting the major components of the reward circuitry to pain suffering, including the nucleus accumbens, ventral tegmental area, and the medial prefrontal cortex; with especial attention dedicated to the evaluation of neuroplastic changes affecting these structures found in chronic pain syndromes, such as migraine, trigeminal neuropathic pain, chronic back pain, and fibromyalgia. PMID:29209204

What we know about primary dysmenorrhea today: a critical review.

PubMed

Iacovides, Stella; Avidon, Ingrid; Baker, Fiona C

2015-01-01

Primary dysmenorrhea, or painful menstruation in the absence of pelvic pathology, is a common, and often debilitating, gynecological condition that affects between 45 and 95% of menstruating women. Despite the high prevalence, dysmenorrhea is often poorly treated, and even disregarded, by health professionals, pain researchers, and the women themselves, who may accept it as a normal part of the menstrual cycle. This review reports on current knowledge, particularly with regards to the impact and consequences of recurrent menstrual pain on pain sensitivity, mood, quality of life and sleep in women with primary dysmenorrhea. Comprehensive literature searches on primary dysmenorrhea were performed using the electronic databases PubMed, Google Scholar and the Cochrane Library. Full-text manuscripts published between the years 1944 and 2015 were reviewed for relevancy and reference lists were cross-checked for additional relevant studies. In combination with the word 'dysmenorrhea' one or more of the following search terms were used to obtain articles published in peer-reviewed journals only: pain, risk factors, etiology, experimental pain, clinical pain, adenomyosis, chronic pain, women, menstrual cycle, hyperalgesia, pain threshold, pain tolerance, pain sensitivity, pain reactivity, pain perception, central sensitization, quality of life, sleep, treatment, non-steroidal anti-inflammatory drugs. Women with dysmenorrhea, compared with women without dysmenorrhea, have greater sensitivity to experimental pain both within and outside areas of referred menstrual pain. Importantly, the enhanced pain sensitivity is evident even in phases of the menstrual cycle when women are not experiencing menstrual pain, illustrating that long-term differences in pain perception extend outside of the painful menstruation phase. This enhanced pain sensitivity may increase susceptibility to other chronic pain conditions in later life; dysmenorrhea is a risk factor for fibromyalgia. Further, dysmenorrheic pain has an immediate negative impact on quality of life, for up to a few days every month. Women with primary dysmenorrhea have a significantly reduced quality of life, poorer mood and poorer sleep quality during menstruation compared with their pain-free follicular phase, and compared with the menstruation phase of pain-free control women. The prescribed first-line therapy for menstrual pain remains non-steroidal anti-inflammatory drugs, which are effective in relieving daytime and night-time pain. Further study is needed to determine whether effectively blocking dysmenorrheic pain ameliorates risk for the development of chronic pain disorders and to explore whether it is possible to prevent the development-and not just treat-severe dysmenorrheic pain in adolescent girls. In conclusion, we demonstrate the extensive multi-factorial impact of dysmenorrhea and we encourage and direct researchers to necessary future studies. © The Author 2015. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

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

PubMed

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

2017-12-29

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

Psychophysiology of arterial baroreceptors and the etiology of hypertension.

PubMed

Rau, H; Elbert, T

2001-01-01

Arterial baroreceptors are sensitive to blood pressure dependent blood vessel dilation. They play a key role in the short term regulation of blood pressure. Their impact on psychological and psychophysiological aspects is of increasing interest. The review focuses on experimental techniques for the controlled baroreceptor manipulation. Results from the application of these techniques show that baroreceptor activation influences the cardiovascular system as well as central nervous functioning: Behavioral and electrophysiological measures of arousal, low level reflexes and pain responses are modulated through baroreceptor manipulation. The observation of an overall dampening ('barbiturate like') effect of baroreceptor activity led Dworkin et al. formulate the theory of learned hypertension: Subjects might experience blood pressure dependent baroreceptor activation as stress and pain relieving. High blood pressure periods become negatively reinforced. Phasic high blood pressure might develop as a coping strategy. Data from a longitudinal human study supporting this theory are reported.

An imaging informatics-based system utilizing DICOM objects for treating pain in spinal cord injury patients utilizing proton beam radiotherapy

NASA Astrophysics Data System (ADS)

Verma, Sneha K.; Liu, Brent J.; Chun, Sophia; Gridley, Daila S.

2014-03-01

Many US combat personnel have sustained nervous tissue trauma during service, which often causes Neuropathic pain as a side effect and is difficult to manage. However in select patients, synapse lesioning can provide significant pain control. Our goal is to determine the effectiveness of using Proton Beam radiotherapy for treating spinal cord injury (SCI) related neuropathic pain as an alternative to invasive surgical lesioning. The project is a joint collaboration of USC, Spinal Cord Institute VA Healthcare System, Long Beach, and Loma Linda University. This is first system of its kind that supports integration and standardization of imaging informatics data in DICOM format; clinical evaluation forms outcomes data and treatment planning data from the Treatment planning station (TPS) utilized to administer the proton therapy in DICOM-RT format. It also supports evaluation of SCI subjects for recruitment into the clinical study, which includes the development, and integration of digital forms and tools for automatic evaluation and classification of SCI pain. Last year, we presented the concept for the patient recruitment module based on the principle of Bayesian decision theory. This year we are presenting the fully developed patient recruitment module and its integration to other modules. In addition, the DICOM module for integrating DICOM and DICOM-RT-ION data is also developed and integrated. This allows researchers to upload animal/patient study data into the system. The patient recruitment module has been tested using 25 retrospective patient data and DICOM data module is tested using 5 sets of animal data.

Ethnicity Interacts with the OPRM1 Gene in Experimental Pain Sensitivity

PubMed Central

Hastie, Barbara A.; Riley, Joseph L.; Kaplan, Lee; Herrera, Dyanne G.; Campbell, Claudia M.; Virtusio, Kathrina; Mogil, Jeffrey S.; Wallace, Margaret R.; Fillingim, Roger B.

2013-01-01

Robust inter-individual variation in pain sensitivity has been observed and recent evidence suggests that some of the variability may be genetically-mediated. Our previous data revealed significantly higher pressure pain thresholds among individuals possessing the minor G allele of the A118G SNP of the mu-opioid receptor gene (OPRM1) compared to those with two consensus alleles. Moreover, ethnic differences in pain sensitivity have been widely reported. Yet, little is known about the potential interactive associations of ethnicity and genotype with pain perception. This study aimed to identify ethnic differences in OPRM1 allelic associations with experimental pain responses. Two-hundred and forty-seven healthy young adults from three ethnic groups (81 African Americans; 79 non-white Hispanics; and 87 non-Hispanic whites) underwent multiple experimental pain modalities (thermal, pressure, ischemic, cold pressor). Few African Americans (7.4%) expressed the rare allele of OPRM1 compared to non-Hispanic-whites and Hispanics (28.7% vs. 27.8%, respectively). Across the entire sample, OPRM1 genotype did not significantly affect pain sensitivity. However, analysis in each ethnic group separately revealed significant genotype effects for most pain modalities among non-Hispanic-whites (ps<0.05) but not Hispanics or African Americans. The G allele was associated with decreased pain sensitivity among whites only; a trend in the opposite direction emerged in Hispanics. The reasons for this dichotomy are unclear but may involve ethnic differences in haplotypic structure or A118G may be a tag-SNP linked to other functional polymorphisms. These findings demonstrate an ethnic-dependent association of OPRM1 genotype with pain sensitivity. Additional research is warranted to uncover the mechanisms influencing these relationships. PMID:22717102

Depression and Pain in Asian and White Americans With Knee Osteoarthritis.

PubMed

Ahn, Hyochol; Weaver, Michael; Lyon, Debra; Choi, Eunyoung; Fillingim, Roger B

2017-10-01

Few studies have examined the underlying psychosocial mechanisms of pain in Asian Americans. Using the biopsychosocial model, we sought to determine whether variations in depression contribute to racial group differences in symptomatic knee osteoarthritis pain between Asian Americans and non-Hispanic white Americans. The sample consisted of 100 participants, including 50 Asian Americans (28 Korean Americans, 9 Chinese Americans, 7 Japanese Americans, 5 Filipino Americans, and 1 Indian American) and 50 age- and sex-matched non-Hispanic white Americans with symptomatic knee osteoarthritis pain. The Centers for Epidemiologic Studies Depression Scale was used to assess symptoms of depression, and the Western Ontario and McMaster Universities Osteoarthritis Index and the Graded Chronic Pain Scale were used to measure clinical pain. In addition, quantitative sensory testing was used to measure experimental sensitivity to heat- and mechanically-induced pain. The results indicated that higher levels of depression in Asian Americans may contribute to greater clinical pain and experimental pain sensitivity. These findings add to the growing literature regarding ethnic and racial differences in pain and its associated psychological conditions, and additional research is warranted to strengthen these findings. This article shows the contribution of depression to clinical pain and experimental pain sensitivity in Asian Americans with knee osteoarthritis. Our results suggest that Asian Americans have higher levels of depressive symptoms and that depression plays a relevant role in greater clinical pain and experimental pain sensitivity in Asian Americans. Copyright © 2017 American Pain Society. Published by Elsevier Inc. All rights reserved.

Night-shift work is associated with increased pain perception.

PubMed

Matre, Dagfinn; Knardahl, Stein; Nilsen, Kristian Bernhard

2017-05-01

Objectives The aim of the present study was to determine whether shift workers exhibit increased perception of experimentally induced pain after working night shifts. Methods The study was a paired cross-over design with two sleep conditions, after at least two nights of habitual sleep and after two consecutive night shifts at work. Fifty-three nurses in rotating shift work participated. The sensitivity to electrically induced pain, heat pain, cold pain, pressure pain and pain inhibition was determined experimentally in each sleep condition. Sleepiness and vigilance were also assessed. Results Night-shift work (NSW) increased the sensitivity to electrically induced pain and heat pain (P≤0.001). Relative to habitual sleep, electrically induced pain increased by 22.3% and heat pain increased by 26.5%. The sensitivity to cold and pressure pain did not change, changes relative to habitual sleep was <5% (P>0.5). Pain inhibition was 66.9% stronger after NSW versus after habitual sleep (P<0.001). Sleepiness (measured with the Karolinska Sleepiness Scale) increased from 4.1 after habitual sleep to 6.9 after NSW (P<0.001). Vigilance decreased after NSW, measured as a 0.03-second decrease in reaction time (P<0.005). Conclusions Changes in pain sensitivity after NSW is measurable with clinically relevant effect sizes and may be an important marker for studies comparing the physiological effects of different shift work schedules. Explanations for the differential effect on different pain modalities should be a focus for future studies.

Safety and Utility of Quantitative Sensory Testing among Adults with Sickle Cell Disease: Indicators of Neuropathic Pain?

PubMed Central

Ezenwa, Miriam O.; Molokie, Robert E.; Wang, Zaijie Jim; Yao, Yingwei; Suarez, Marie L.; Pullum, Cherese; Schlaeger, Judith M.; Fillingim, Roger B.; Wilkie, Diana J.

2014-01-01

Objectives Pain is the hallmark symptom of sickle cell disease (SCD), yet the types of pain that these patients experience, and the underlying mechanisms, have not been well characterized. The study purpose was to determine the safety and utility of a mechanical and thermal quantitative sensory testing (QST) protocol and the feasibility of utilizing neuropathic pain questionnaires among adults with SCD. Methods A convenience sample (N=25, 18 women, mean age 38.5 ± 12.5 [20–58 years]) completed self-report pain and quality-of-life tools. Subjects also underwent testing with the TSA-II NeuroSensory Analyzer and calibrated von Frey microfilaments. Results We found that the QST protocol was safe and did not stimulate a SCD pain crisis. There was evidence of central sensitization (n=15), peripheral sensitization (n=1), a mix of central and peripheral sensitization (n=8), or no sensitization (n=1). The neuropathic pain self-report tools were feasible with evidence of construct validity; 40% of the subjects reported S-LANSS scores that were indicative of neuropathic pain and had evidence of central, peripheral or mixed sensitization. Discussion The QST protocol can be safely conducted in adults with SCD and provides evidence of central or peripheral sensitization, which is consistent with a neuropathic component to SCD pain. These findings are novel, warrant a larger confirmatory study, and indicate the need for normative QST data from African American adults and older adults. PMID:25581383

Sensory neuronal sensitisation occurs through HMGB-1/ RAGE and TRPV1 in high glucose conditions.

PubMed

Bestall, S M; Hulse, R P; Blackley, Z; Swift, M; Ved, N; Paton, K; Beazley-Long, N; Bates, D O; Donaldson, L F

2018-06-21

Many potential causes for painful diabetic neuropathy have been proposed including actions of cytokines and growth factors. High mobility group protein B1 (HMGB1) is a RAGE agonist, increased in diabetes, that contributes to pain by modulating peripheral inflammatory responses. HMGB1 enhances nociceptive behaviour in naïve animals through an unknown mechanism. We tested the hypothesis that HMGB1 causes pain through direct neuronal activation of RAGE and alteration of nociceptive neuronal responsiveness.HMGB1 and RAGE expression were increased in skin and primary sensory (DRG) neurons of diabetic rats at times when pain behaviour was enhanced. Agonist-evoked TRPV1-mediated calcium responses increased in cultured DRG neurons from diabetic rats and in neurons from naïve rats exposed to high glucose concentrations. HMGB1-mediated increases in TRPV1-evoked calcium responses in DRG neurons were RAGE and PKC-dependent, and this was blocked by co-administration of the growth factor splice variant, VEGF-A 165 b. Pain behaviour and DRG RAGE expression increases were blocked by VEGF-A 165 b treatment of diabetic rats in vivo HMGB-1-RAGE activation sensitizes DRG neurons in vitro VEGF-A 165 b blocks HMGB-1/RAGE DRG activation, which may contribute to its analgesic properties in vivo . © 2018. Published by The Company of Biologists Ltd.

Interaction between intra-oral cinnamaldehyde and nicotine assessed by psychophysical and physiological responses.

PubMed

Jensen, Tanja K; Andersen, Michelle V; Nielsen, Kent A; Arendt-Nielsen, Lars; Boudreau, Shellie A

2016-08-01

Cinnamaldehyde and nicotine activate the transient receptor potential subtype A1 (TRPA1) channel, which may cause burning sensations. This study investigated whether cinnamaldehyde modulates nicotine-induced psychophysical and physiological responses in oral tissues. Healthy non-smokers (n = 22) received, in a randomized, double-blind, crossover design, three different gums containing 4 mg of nicotine, 20 mg of cinnamaldehyde, or a combination thereof. Assessments of orofacial temperature and blood flow, blood pressure, heart rate, taste experience, and intra-oral pain/irritation area and intensity were performed before, during, and after a 10-min chewing regime. Cinnamaldehyde increased the temperature of the tongue and blood flow of the lip, and was associated with pain/irritation, especially in the mouth. Nicotine increased the temperature of the tongue and blood flow of the cheek, and produced pain/irritation in the mouth and throat. The combination of cinnamaldehyde and nicotine did not overtly change the psychophysical or physiological responses. Interestingly, half of the subjects responded to cinnamaldehyde as an irritant, and these cinnamaldehyde responders reported greater nicotine-induced pain/irritation areas in the throat. Whether sensitivity to cinnamaldehyde can predict the response to nicotine-induced oral irritation remains to be determined. A better understanding of the sensory properties of nicotine in the oral mucosa has important therapeutic implications because pain and irritation represent compliance issues for nicotine replacement products. © 2016 Eur J Oral Sci.

Modulating the Delicate Glial-Neuronal Interactions in Neuropathic Pain: Promises and Potential Caveats

PubMed Central

Tiwari, Vinod; Guan, Yun; Raja, Srinivasa N.

2014-01-01

During neuropathic pain, glial cells (mainly astrocytes and microglia) become activated and initiate a series of signaling cascades that modulate pain processing at both spinal and supraspinal levels. It has been generally accepted that glial cell activation contributes to neuropathic pain because glia release proinflammatory cytokines, chemokines, and factors such as calcitonin gene-related peptide, substance P, and glutamate, which are known to facilitate pain signaling. However, recent research has shown that activation of glia also leads to some beneficial outcomes. Glia release anti-inflammatory factors that protect against neurotoxicity and restore normal pain. Accordingly, use of glial inhibitors might compromise the protective functions of glia in addition to suppressing their detrimental effects. With a better understanding of how different conditions affect glial cell activation, we may be able to promote the protective function of glia and pave the way for future development of novel, safe, and effective treatments of neuropathic pain. PMID:24820245

Mindful Yoga Pilot Study Shows Modulation of Abnormal Pain Processing in Fibromyalgia Patients.

PubMed

Carson, James W; Carson, Kimberly M; Jones, Kim D; Lancaster, Lindsay; Mist, Scott D

2016-01-01

Published findings from a randomized controlled trial have shown that Mindful Yoga training improves symptoms, functional deficits, and coping abilities in individuals with fibromyalgia and that these benefits are replicable and can be maintained 3 months post-treatment. The aim of this study was to collect pilot data in female fibromyalgia patients (n = 7) to determine if initial evidence indicates that Mindful Yoga also modulates the abnormal pain processing that characterizes fibromyalgia. Pre- and post-treatment data were obtained on quantitative sensory tests and measures of symptoms, functional deficits, and coping abilities. Separation test analyses indicated significant improvements in heat pain tolerance, pressure pain threshold, and heat pain after-sensations at post-treatment. Fibromyalgia symptoms and functional deficits also improved significantly, including physical tests of strength and balance, and pain coping strategies. These findings indicate that further investigation is warranted into the effect of Mindful Yoga on neurobiological pain processing.

Future directions for the management of pain in osteoarthritis

PubMed Central

Sofat, Nidhi; Kuttapitiya, Anasuya

2014-01-01

Osteoarthritis (OA) is the predominant form of arthritis worldwide, resulting in a high degree of functional impairment and reduced quality of life owing to chronic pain. To date, there are no treatments that are known to modify disease progression of OA in the long term. Current treatments are largely based on the modulation of pain, including NSAIDs, opiates and, more recently, centrally acting pharmacotherapies to avert pain. This review will focus on the rationale for new avenues in pain modulation, including inhibition with anti-NGF antibodies and centrally acting analgesics. The authors also consider the potential for structure modification in cartilage/bone using growth factors and stem cell therapies. The possible mismatch between structural change and pain perception will also be discussed, introducing recent techniques that may assist in improved patient phenotyping of pain subsets in OA. Such developments could help further stratify subgroups and treatments for people with OA in future. PMID:25018771

Future directions for the management of pain in osteoarthritis.

PubMed

Sofat, Nidhi; Kuttapitiya, Anasuya

2014-04-01

Osteoarthritis (OA) is the predominant form of arthritis worldwide, resulting in a high degree of functional impairment and reduced quality of life owing to chronic pain. To date, there are no treatments that are known to modify disease progression of OA in the long term. Current treatments are largely based on the modulation of pain, including NSAIDs, opiates and, more recently, centrally acting pharmacotherapies to avert pain. This review will focus on the rationale for new avenues in pain modulation, including inhibition with anti-NGF antibodies and centrally acting analgesics. The authors also consider the potential for structure modification in cartilage/bone using growth factors and stem cell therapies. The possible mismatch between structural change and pain perception will also be discussed, introducing recent techniques that may assist in improved patient phenotyping of pain subsets in OA. Such developments could help further stratify subgroups and treatments for people with OA in future.

The effect of hydromorphone therapy on psychophysical measurements of the descending inhibitory pain systems in patients with chronic radicular pain.

PubMed

Suzan, Erica; Treister, Roi; Pud, Dorit; Haddad, May; Eisenberg, Elon

2015-01-01

Conditioned pain modulation (CPM) and offset analgesia (OA) are considered to represent paradigms of descending inhibitory pain modulation in humans. This study tested the effects of hydromorphone therapy on descending inhibitory pain modulation, as measured by changes from baseline in the magnitudes of CPM and OA. Prospective evaluation. Institute of Pain Medicine, Rambam Health Care Campus. Patients with chronic radicular pain. Thirty patients received 4 weeks of oral hydromorphone treatment at an individually titrated dose (mean ± standard deviation dose of 11.6 ± 4.8 mg/day). CPM and OA were assessed before and after hydromorphone treatment. CPM was assessed by subtracting the response to a painful phasic heat stimulus administered simultaneously with a conditioning cold pain stimulus, from the response to the same heat stimulus administered alone. The OA paradigm consisted of a three-temperature stimuli train (T1 = 49°C [5 seconds], T2 = 50°C [5 seconds], and T3 = 49°C [20 seconds]). The magnitude of OA was quantified by subtracting minimal pain scores obtained during T3 from the maximal pain scores obtained during T2. CPM scores changed from a baseline of 17.7 ± 20.6 to 21 ± 20.4 following treatment, and OA scores changed from 7.8 ± 20.5 to 9.7 ± 14.6. Wilcoxon signed rank test indicated that these changes were not significant (CPM: P = 0.22; OA: P = 0.44). McNemar test revealed that the percentage of patients who exhibited a change in the direction of CPM or OA in response to hydromorphone treatment was not significant (CPM: P = 0.37; OA: P = 0.48). These results suggest that the descending inhibitory pain modulation, as manifested in humans by CPM and OA, is unlikely to be mediated by hydromorphone therapy. Wiley Periodicals, Inc.

Joint nociceptor nerve activity and pain in an animal model of acute gout and its modulation by intra-articular hyaluronan

PubMed Central

Marcotti, Aida; Miralles, Ana; Dominguez, Eduardo; Pascual, Eliseo; Gomis, Ana; Belmonte, Carlos; de la Peña, Elvira

2018-01-01

Abstract The mechanisms whereby deposition of monosodium urate (MSU) crystals in gout activates nociceptors to induce joint pain are incompletely understood. We tried to reproduce the signs of painful gouty arthritis, injecting into the knee joint of rats suspensions containing amorphous or triclinic, needle MSU crystals. The magnitude of MSU-induced inflammation and pain behavior signs were correlated with the changes in firing frequency of spontaneous and movement-evoked nerve impulse activity recorded in single knee joint nociceptor saphenous nerve fibers. Joint swelling, mechanical and cold allodynia, and hyperalgesia appeared 3 hours after joint injection of MSU crystals. In parallel, spontaneous and movement-evoked joint nociceptor impulse activity raised significantly. Solutions containing amorphous or needle-shaped MSU crystals had similar inflammatory and electrophysiological effects. Intra-articular injection of hyaluronan (HA, Synvisc), a high-MW glycosaminoglycan present in the synovial fluid with analgesic effects in osteoarthritis, significantly reduced MSU-induced behavioral signs of pain and decreased the enhanced joint nociceptor activity. Our results support the interpretation that pain and nociceptor activation are not triggered by direct mechanical stimulation of nociceptors by MSU crystals, but are primarily caused by the release of excitatory mediators by inflammatory cells activated by MSU crystals. Intra-articular HA decreased behavioral and electrophysiological signs of pain, possibly through its viscoelastic filtering effect on the mechanical forces acting over sensitized joint sensory endings and probably also by a direct interaction of HA molecules with the transducing channels expressed in joint nociceptor terminals. PMID:29319609

Analgesic effect of clobazam in chronic low-back pain but not in experimentally induced pain.

PubMed

Schliessbach, J; Vuilleumier, P H; Siegenthaler, A; Bütikofer, L; Limacher, A; Juni, P; Zeilhofer, H U; Arendt-Nielsen, L; Curatolo, M

2017-09-01

Chronic pain is frequently associated with hypersensitivity of the nervous system, and drugs that increase central inhibition are therefore a potentially effective treatment. Benzodiazepines are potent modulators of GABAergic neurotransmission and are known to exert antihyperalgesic effects in rodents, but translation into patients are lacking. This study investigates the effect of the benzodiazepine clobazam in chronic low-back pain in humans. The aim of this study is to explore the effect of GABA modulation on chronic low-back pain and on quantitative sensory tests. In this double-blind cross-over study, 49 patients with chronic low-back pain received a single oral dose of clobazam 20 mg or active placebo tolterodine 1 mg. Pain intensity on the 0-10 numeric rating scale and quantitative sensory tests were assessed during 2 h after drug intake. Pain intensity in the supine position was significantly reduced by clobazam compared to active placebo (60 min: 2.9 vs. 3.5, p = 0.008; 90 min: 2.7 vs. 3.3, p = 0.024; 120 min: 2.4 vs. 3.1, p = 0.005). Pain intensity in the sitting position was not significantly different between groups. No effects on quantitative sensory tests were observed. This study suggests that clobazam has an analgesic effect in patients with chronic low-back pain. Muscle relaxation or sedation may have contributed to the effect. Development of substances devoid of these side effects would offer the potential to further investigate the antihyperalgesic action of GABAergic compounds. Modulation of GABAergic pain-inhibitory pathways may be a potential future therapeutic target. © 2017 European Pain Federation - EFIC®.

The Cannabinoid System and Pain

PubMed Central

Woodhams, Stephen G.; Chapman, Victoria; Finn, David P.; Hohmann, Andrea G.; Neugebauer, Volker

2018-01-01

Chronic pain states are highly prevalent and yet poorly controlled by currently available analgesics, representing an enormous clinical, societal, and economic burden. Existing pain medications have significant limitations and adverse effects including tolerance, dependence, gastrointestinal dysfunction, cognitive impairment, and a narrow therapeutic window, making the search for novel analgesics ever more important. In this article, we review the role of an important endogenous pain control system, the endocannabinoid (EC) system, in the sensory, emotional, and cognitive aspects of pain. Herein, we briefly cover the discovery of the EC system and its role in pain processing pathways, before concentrating on three areas of current major interest in EC pain research; 1. Pharmacological enhancement of endocannabinoid activity (via blockade of EC metabolism or allosteric modulation of CB1 receptors); 2. The EC System and stress-induced modulation of pain; and 3. The EC system & medial prefrontal cortex (mPFC) dysfunction in pain states. Whilst we focus predominantly on the preclinical data, we also include extensive discussion of recent clinical failures of endocannabinoid-related therapies, the future potential of these approaches, and important directions for future research on the EC system and pain. PMID:28625720

Decreased Pain Perception by Unconscious Emotional Pictures

PubMed Central

Peláez, Irene; Martínez-Iñigo, David; Barjola, Paloma; Cardoso, Susana; Mercado, Francisco

2016-01-01

Pain perception arises from a complex interaction between a nociceptive stimulus and different emotional and cognitive factors, which appear to be mediated by both automatic and controlled systems. Previous evidence has shown that whereas conscious processing of unpleasant stimuli enhances pain perception, emotional influences on pain under unaware conditions are much less known. The aim of the present study was to investigate the modulation of pain perception by unconscious emotional pictures through an emotional masking paradigm. Two kinds of both somatosensory (painful and non-painful) and emotional stimulation (negative and neutral pictures) were employed. Fifty pain-free participants were asked to rate the perception of pain they were feeling in response to laser-induced somatosensory stimuli as faster as they can. Data from pain intensity and reaction times were measured. Statistical analyses revealed a significant effect for the interaction between pain and emotional stimulation, but surprisingly this relationship was opposite to expected. In particular, lower pain intensity scores and longer reaction times were found in response to negative images being strengthened this effect for painful stimulation. Present findings suggest a clear pain perception modulation by unconscious emotional contexts. Attentional capture mechanisms triggered by unaware negative stimulation could explain this phenomenon leading to a withdrawal of processing resources from pain. PMID:27818642

Decreased Pain Perception by Unconscious Emotional Pictures.

PubMed

Peláez, Irene; Martínez-Iñigo, David; Barjola, Paloma; Cardoso, Susana; Mercado, Francisco

2016-01-01

Pain perception arises from a complex interaction between a nociceptive stimulus and different emotional and cognitive factors, which appear to be mediated by both automatic and controlled systems. Previous evidence has shown that whereas conscious processing of unpleasant stimuli enhances pain perception, emotional influences on pain under unaware conditions are much less known. The aim of the present study was to investigate the modulation of pain perception by unconscious emotional pictures through an emotional masking paradigm. Two kinds of both somatosensory (painful and non-painful) and emotional stimulation (negative and neutral pictures) were employed. Fifty pain-free participants were asked to rate the perception of pain they were feeling in response to laser-induced somatosensory stimuli as faster as they can. Data from pain intensity and reaction times were measured. Statistical analyses revealed a significant effect for the interaction between pain and emotional stimulation, but surprisingly this relationship was opposite to expected. In particular, lower pain intensity scores and longer reaction times were found in response to negative images being strengthened this effect for painful stimulation. Present findings suggest a clear pain perception modulation by unconscious emotional contexts. Attentional capture mechanisms triggered by unaware negative stimulation could explain this phenomenon leading to a withdrawal of processing resources from pain.

Social hierarchy modulates neural responses of empathy for pain.

PubMed

Feng, Chunliang; Li, Zhihao; Feng, Xue; Wang, Lili; Tian, Tengxiang; Luo, Yue-Jia

2016-03-01

Recent evidence indicates that empathic responses to others' pain are modulated by various situational and individual factors. However, few studies have examined how empathy and underlying brain functions are modulated by social hierarchies, which permeate human society with an enormous impact on social behavior and cognition. In this study, social hierarchies were established based on incidental skill in a perceptual task in which all participants were mediumly ranked. Afterwards, participants were scanned with functional magnetic resonance imaging while watching inferior-status or superior-status targets receiving painful or non-painful stimulation. The results revealed that painful stimulation applied to inferior-status targets induced higher activations in the anterior insula (AI) and anterior medial cingulate cortex (aMCC), whereas these empathic brain activations were significantly attenuated in response to superior-status targets' pain. Further, this neural empathic bias to inferior-status targets was accompanied by stronger functional couplings of AI with brain regions important in emotional processing (i.e. thalamus) and cognitive control (i.e. middle frontal gyrus). Our findings indicate that emotional sharing with others' pain is shaped by relative positions in a social hierarchy such that underlying empathic neural responses are biased toward inferior-status compared with superior-status individuals. © The Author (2015). Published by Oxford University Press. For Permissions, please email: journals.permissions@oup.com.

Stability of conditioned pain modulation in two musculoskeletal pain models: investigating the influence of shoulder pain intensity and gender

PubMed Central

2013-01-01

Background Several chronic pain populations have demonstrated decreased conditioned pain modulation (CPM). However there is still a need to investigate the stability of CPM paradigms before the measure can be recommended for implementation. The purpose of the present study was to assess whether shoulder pain intensity and gender influence CPM stability within and between sessions. Methods This study examined two different musculoskeletal pain models, clinical shoulder pain and an experimental model of shoulder pain induced with eccentric exercise in healthy participants. Patients in the clinical cohort (N = 134) were tested before surgery and reassessed 3 months post-surgery. The healthy cohort (N = 190) was examined before inducing pain at the shoulder, and 48 and 96 hours later. Results Our results provide evidence that 1) stability of inhibition is not related to changes in pain intensity, and 2) there are sex differences for CPM stability within and between days. Conclusions Fluctuation of pain intensity did not significantly influence CPM stability. Overall, the more stable situations for CPM were females from the clinical cohort and males from the healthy cohort. PMID:23758907

Adults with patellofemoral pain do not exhibit manifestations of peripheral and central sensitization when compared to healthy pain-free age and sex matched controls – An assessor blinded cross-sectional study

PubMed Central

Rathleff, Camilla Rams; Stephenson, Aoife; Mellor, Rebecca; Matthews, Mark; Crossley, Kay; Vicenzino, Bill

2017-01-01

Patellofemoral Pain (PFP) is highly prevalent among adults and adolescents. Localized mechanical hyperalgesia around the knee and tibialis anterior have been observed in people with PFP, but limited knowledge of potential manifestations of central sensitisation exists. The aims of this study were to study conditioned pain modulation (CPM) and wide-spread hyperalgesia in adults with PFP. This assessor-blinded cross-sectional study design compared CPM and mechanical pressure pain thresholds (PPT) between 33 adults (23 females) diagnosed with PFP and 32 age and sex matched pain-free controls. The investigator taking the PPT measurements was blinded to which participants had PFP. PPTs were reliably measured using a Somedic hand-held pressure algometer at three sites: 1) The centre of the patella, 2) the tibialis anterior muscle and 3) a remote site on the lateral epicondyle. For the assessment of CPM, experimental pain was induced to the contralateral hand by immersion into a cold water bath (conditioning stimulus), and assessment of PPTs (the test stimulus) was performed before and immediately after the conditioning stimulation. On average, the CPM paradigm induced a significant increase in PPTs across the three sites (6.3–13.5%, P<0.05), however there was no difference in CPM between young adults with PFP compared to the control group, (F(1,189) = 0.39, P = 0.89). There was no difference in mechanical PPTs between the two groups (F(1,189) = 0.03, P = 0.86). Contrary to our a-priori hypothesis, we found no difference in CPM or PPT between young adults with PFP and age and sex matched pain-free controls. PMID:29220355

Internal validity of inter-digital web pinching as a model for perceptual diffuse noxious inhibitory controls-induced hypoalgesia in healthy humans.

PubMed

Streff, Anouk; Michaux, Gilles; Anton, Fernand

2011-01-01

Hot and ice-water immersions are commonly used for heterotopic noxious counter-stimulation (HNCS) in investigations on endogenous pain modulation. However, coincident sympathetic thermoregulatory activity does not allow to differentiate between perceptual hypoalgesia related to baroreflex sensitivity (BRS) or diffuse noxious inhibitory controls (DNIC). The present study analysed the internal validity of another supposedly less confounded tonic pain model (inter-digital web pinching; IWP) regarding its potential as DNIC trigger. We performed a randomized controlled study in 24 healthy gender-matched drug-free volunteers aged 21-54 (median 25) years. The study protocol comprised the assessment of mechanical and thermal perceptual wind-up before and after an IWP (15N) or hot water immersion trial (HIT; 47.5°C) of 2 min duration. Wind-up was induced either by 10 repetitive (1Hz) contact heat (max. 49°C; 5×5 mm thermode) or ballistic impact stimuli (0.5g at 9 m/s) on the phalanges of the non-dominant hand. Cardiovascular activity, pain experience and corrugator muscle activity were continuously monitored. Although both HNCS forms produced a similar pain experience (45% of scale), a more pronounced cardiovascular activity was observable for the HIT (P<0.01). This indicates a higher baroreceptor activity and stronger contamination of painful water immersion by BRS-related hypoalgesia. Regardless of pain modality, wind-up was significantly reduced by HNCS, although this was stronger for painful water immersion than for noxious pinching (P<0.01). The HNCS types allow a differentiation between BRS-related and DNIC-like hypoalgesia. IWP proved its validity for DNIC induction, being practically non-confounded by BRS. Copyright © 2010 European Federation of International Association for the Study of Pain Chapters. Published by Elsevier Ltd. All rights reserved.

One night of total sleep deprivation promotes a state of generalized hyperalgesia: a surrogate pain model to study the relationship of insomnia and pain.

PubMed

Schuh-Hofer, Sigrid; Wodarski, Rachel; Pfau, Doreen B; Caspani, Ombretta; Magerl, Walter; Kennedy, Jeffrey D; Treede, Rolf-Detlef

2013-09-01

Sleep disturbances are highly prevalent in chronic pain patients. Understanding their relationship has become an important research topic since poor sleep and pain are assumed to closely interact. To date, human experimental studies exploring the impact of sleep disruption/deprivation on pain perception have yielded conflicting results. This inconsistency may be due to the large heterogeneity of study populations and study protocols previously used. In addition, none of the previous studies investigated the entire spectrum of nociceptive modalities. To address these shortcomings, a standardized comprehensive quantitative sensory protocol was used in order to compare the somatosensory profile of 14 healthy subjects (6 female, 8 male, 23.5 ± 4.1 year; mean ± SD) after a night of total sleep deprivation (TSD) and a night of habitual sleep in a cross-over design. One night of TSD significantly increased the level of sleepiness (P<0.001) and resulted in higher scores of the State Anxiety Inventory (P<0.01). In addition to previously reported hyperalgesia to heat (P<0.05) and blunt pressure (P<0.05), study participants developed hyperalgesia to cold (P<0.01) and increased mechanical pain sensitivity to pinprick stimuli (P<0.05) but no changes in temporal summation. Paradoxical heat sensations or dynamic mechanical allodynia were absent. TSD selectively modulated nociception, since detection thresholds of non-nociceptive modalities remained unchanged. Our findings show that a single night of TSD is able to induce generalized hyperalgesia and to increase State Anxiety scores. In the future, TSD may serve as a translational pain model to elucidate the pathomechanisms underlying the hyperalgesic effect of sleep disturbances. Copyright © 2013 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

Influence of prior information on pain involves biased perceptual decision-making.

PubMed

Wiech, Katja; Vandekerckhove, Joachim; Zaman, Jonas; Tuerlinckx, Francis; Vlaeyen, Johan W S; Tracey, Irene

2014-08-04

Prior information about features of a stimulus is a strong modulator of perception. For instance, the prospect of more intense pain leads to an increased perception of pain, whereas the expectation of analgesia reduces pain, as shown in placebo analgesia and expectancy modulations during drug administration. This influence is commonly assumed to be rooted in altered sensory processing and expectancy-related modulations in the spinal cord, are often taken as evidence for this notion. Contemporary models of perception, however, suggest that prior information can also modulate perception by biasing perceptual decision-making - the inferential process underlying perception in which prior information is used to interpret sensory information. In this type of bias, the information is already present in the system before the stimulus is observed. Computational models can distinguish between changes in sensory processing and altered decision-making as they result in different response times for incorrect choices in a perceptual decision-making task (Figure S1A,B). Using a drift-diffusion model, we investigated the influence of both processes in two independent experiments. The results of both experiments strongly suggest that these changes in pain perception are predominantly based on altered perceptual decision-making. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.

Autoerythrocyte sensitization syndrome presenting with general neurodermatitis

PubMed Central

Oh, In Young; Ko, Eun Jung

2013-01-01

Autoerythrocyte sensitization syndrome (AES) was first described by Gardner and Diamond in 1955, when four women with painful bruising were depicted. Patients with AES typically present with the development of recurrent, spontaneous, painful ecchymosis, frequently preceded by a prodrome of pain or itching of the skin. The patients are sensitive to their own red blood cells injected intradermally, and underlying coagulopathies are thought to be absent. We introduce a 70-year-old woman presenting with recurrent episodes of painful bruising on the trunk and extremities. PMID:23956968

Pain perception in people with Down syndrome: a synthesis of clinical and experimental research

PubMed Central

McGuire, Brian E.; Defrin, Ruth

2015-01-01

People with an intellectual disability experience both acute and chronic pain with at least the same frequency as the general population. However, considerably less is known about the pain perception of people with Down syndrome. In this review paper, we evaluated the available clinical and experimental evidence. Some experimental studies of acute pain have indicated that pain threshold was higher than normal but only when using a reaction time method to measure pain sensitivity. However, when reaction time is not part of the calculation of the pain threshold, pain sensitivity in people with Down syndrome is in fact lower than normal (more sensitive to pain). Clinical studies of chronic pain have shown that people with an intellectual disability experience chronic pain and within that population, people with Down syndrome also experience chronic pain, but the precise prevalence of chronic pain in Down syndrome has yet to be established. Taken together, the literature suggests that people with Down syndrome experience pain, both acute and chronic, with at least the same frequency as the rest of the population. Furthermore, the evidence suggests that although acute pain expression appears to be delayed, once pain is registered, there appears to be a magnified pain response. We conclude by proposing an agenda for future research in this area. PMID:26283936

Waning of "conditioned pain modulation": a novel expression of subtle pronociception in migraine.

PubMed

Nahman-Averbuch, Hadas; Granovsky, Yelena; Coghill, Robert C; Yarnitsky, David; Sprecher, Elliot; Weissman-Fogel, Irit

2013-01-01

To assess the decay of the conditioned pain modulation (CPM) response along repeated applications as a possible expression of subtle pronociception in migraine. One of the most explored mechanisms underlying the pain modulation system is "diffuse noxious inhibitory controls," which is measured psychophysically in the lab by the CPM paradigm. There are contradicting reports on CPM response in migraine, questioning whether migraineurs express pronociceptive pain modulation. Migraineurs (n = 26) and healthy controls (n = 35), all females, underwent 3 stimulation series, consisting of repeated (1) "test-stimulus" (Ts) alone that was given first followed by (2) parallel CPM application (CPM-parallel), and (3) sequential CPM application (CPM-sequential), in which the Ts is delivered during or following the conditioning-stimulus, respectively. In all series, the Ts repeated 4 times (0-3). In the CPM series, repetition "0" consisted of the Ts-alone that was followed by 3 repetitions of the Ts with a conditioning-stimulus application. Although there was no difference between migraineurs and controls for the first CPM response in each series, we found waning of CPM-parallel efficiency along the series for migraineurs (P = .005 for third vs first CPM), but not for controls. Further, greater CPM waning in the CPM-sequential series was correlated with less reported extent of pain reduction by episodic medication (r = 0.493, P = .028). Migraineurs have subtle deficits in endogenous pain modulation which requires a more challenging test protocol than the commonly used single CPM. Waning of CPM response seems to reveal this pronociceptive state. The clinical relevance of the CPM waning effect is highlighted by its association with clinical parameters of migraine. © 2013 American Headache Society.

Potential Genetic Risk Factors for Chronic TMD: Genetic Associations from the OPPERA Case Control Study

PubMed Central

Smith, Shad B.; Maixner, Dylan; Greenspan, Joel; Dubner, Ron; Fillingim, Roger; Ohrbach, Richard; Knott, Charles; Slade, Gary; Bair, Eric; Gibson, Dustin G.; Zaykin, Dmitri V.; Weir, Bruce; Maixner, William; Diatchenko, Luda

2011-01-01

Genetic factors play a role in the etiology of persistent pain conditions, putatively by modulating underlying processes such as nociceptive sensitivity, psychological well-being, inflammation, and autonomic response. However, to date, only a few genes have been associated with temporomandibular disorders (TMD). This study evaluated 358 genes involved in pain processes, comparing allelic frequencies between 166 cases with chronic TMD and 1442 controls enrolled in the OPPERA (Orofacial Pain: Prospective Evaluation and Risk Assessment) study cooperative agreement. To enhance statistical power, 182 TMD cases and 170 controls from a similar study were included in the analysis. Genotyping was performed using the Pain Research Panel, an Affymetrix gene chip representing 3295 single nucleotide polymorphisms, including ancestry-informative markers that were used to adjust for population stratification. Adjusted associations between genetic markers and TMD case status were evaluated using logistic regression. The OPPERA findings provided evidence supporting previously-reported associations between TMD and two genes: HTR2A and COMT. Other genes were revealed as potential new genetic risk factors for TMD, including NR3C1, CAMK4, CHRM2, IFRD1, and GRK5. While these findings need to be replicated in independent cohorts, the genes potentially represent important markers of risk for TMD and they identify potential targets for therapeutic intervention. PMID:22074755

Perceived trustworthiness shapes neural empathic responses toward others' pain.

PubMed

Sessa, Paola; Meconi, Federica

2015-12-01

As might be expected, neural empathic responses toward someone in pain are shaped by the affective/social relationship between the observer and the suffering person. Brain activity associated with empathy is sensitive to previous knowledge on the other's social conduct, such that, for instance, an unfair person in pain elicits in the observer reduced activations of empathy-related brain regions compared to a fair person. We conjectured that even in the absence of information on the personality and social behavior of an individual, empathy might be modulated by the 'first impression' based on other's physical facial features, such that the other is perceived as trustworthy or untrustworthy. By means of event-related potentials technique, we monitored in two experiments the neural empathic responses associated with the pain of trustworthy and untrustworthy faces, either computerized and parametrically manipulated (Experiment 1) and real faces (Experiment 2) in a cue-based paradigm. We observed P3 empathic reactions towards individuals looking trustworthy whereas the reactions towards individuals looking untrustworthy were negligible, if not null. An additional experiment (Experiment 3) was conducted in order to substantiate our conclusions by demonstrating that the experimental paradigm we designed did very likely activate an empathic response. Copyright © 2015 Elsevier Ltd. All rights reserved.

Multiple sites and actions of gabapentin-induced relief of ongoing experimental neuropathic pain.

PubMed

Bannister, Kirsty; Qu, Chaoling; Navratilova, Edita; Oyarzo, Janice; Xie, Jennifer Yanhua; King, Tamara; Dickenson, Anthony H; Porreca, Frank

2017-12-01

Gabapentin (GBP) is a first-line therapy for neuropathic pain, but its mechanisms and sites of action remain uncertain. We investigated GBP-induced modulation of neuropathic pain following spinal nerve ligation (SNL) in rats. Intravenous or intrathecal GBP reversed evoked mechanical hypersensitivity and produced conditioned place preference (CPP) and dopamine (DA) release in the nucleus accumbens (NAc) selectively in SNL rats. Spinal GBP also significantly inhibited dorsal horn wide-dynamic-range neuronal responses to a range of evoked stimuli in SNL rats. By contrast, GBP microinjected bilaterally into the rostral anterior cingulate cortex (rACC), produced CPP, and elicited NAc DA release selectively in SNL rats but did not reverse tactile allodynia and had marginal effects on wide-dynamic-range neuronal activity. Moreover, blockade of endogenous opioid signaling in the rACC prevented intravenous GBP-induced CPP and NAc DA release but failed to block its inhibition of tactile allodynia. Gabapentin, therefore, can potentially act to produce its pain relieving effects by (a) inhibition of injury-induced spinal neuronal excitability, evoked hypersensitivity, and ongoing pain and (b) selective supraspinal modulation of affective qualities of pain, without alteration of reflexive behaviors. Consistent with previous findings of pain relief from nonopioid analgesics, GBP requires engagement of rACC endogenous opioid circuits and downstream activation of mesolimbic reward circuits reflected in learned pain-motivated behaviors. These findings support the partial separation of sensory and affective dimensions of pain in this experimental model and suggest that modulation of affective-motivational qualities of pain may be the preferential mechanism of GBP's analgesic effects in patients.

Multiple sites and actions of gabapentin-induced relief of ongoing experimental neuropathic pain

PubMed Central

Bannister, Kirsty; Qu, Chaoling; Navratilova, Edita; Oyarzo, Janice; Xie, Jennifer Yanhua; King, Tamara; Dickenson, Anthony H.; Porreca, Frank

2017-01-01

Gabapentin is a first-line therapy for neuropathic pain but its mechanisms and sites of action remain uncertain. We investigated gabapentin-induced modulation of neuropathic pain following spinal nerve ligation (SNL) in rats. Intravenous or intrathecal gabapentin reversed evoked mechanical hypersensitivity, produced conditioned place preference (CPP) and dopamine release in the nucleus accumbens (NAc) selectively in SNL rats. Spinal gabapentin also significantly inhibited dorsal horn wide dynamic range (WDR) neuronal responses to a range of evoked stimuli in SNL rats. In contrast, gabapentin microinjected bilaterally into the rostral anterior cingulate cortex (rACC), produced CPP and elicited NAc dopamine release selectively in SNL rats but did not reverse tactile allodynia and had marginal effects on WDR neuronal activity. Moreover, blockade of endogenous opioid signaling in the rACC prevented intravenous gabapentin-induced CPP and NAc dopamine release but failed to block its inhibition of tactile allodynia. Gabapentin therefore can potentially act to produce its pain relieving effects by (a) inhibition of injury-induced spinal neuronal excitability, evoked hypersensitivity and ongoing pain and (b) selective supraspinal modulation of affective qualities of pain, without alteration of reflexive behaviors. Consistent with previous findings of pain relief from non-opioid analgesics, gabapentin requires engagement of rACC endogenous opioid circuits and downstream activation of mesolimbic reward circuits reflected in learned pain motivated behaviors. These findings support the partial separation of sensory and affective dimensions of pain in this experimental model and suggest that modulation of affective-motivational qualities of pain may be the preferential mechanism of gabapentin’s analgesic effects in patients. PMID:28832395

Nociceptor Sensitization Depends on Age and Pain Chronicity123

PubMed Central

Dodge, Amanda K.

2016-01-01

Abstract Peripheral inflammation causes mechanical pain behavior and increased action potential firing. However, most studies examine inflammatory pain at acute, rather than chronic time points, despite the greater burden of chronic pain on patient populations, especially aged individuals. Furthermore, there is disagreement in the field about whether primary afferents contribute to chronic pain. Therefore, we sought to evaluate the contribution of nociceptor activity to the generation of pain behaviors during the acute and chronic phases of inflammation in both young and aged mice. We found that both young (2 months old) and aged (>18 months old) mice exhibited prominent pain behaviors during both acute (2 day) and chronic (8 week) inflammation. However, young mice exhibited greater behavioral sensitization to mechanical stimuli than their aged counterparts. Teased fiber recordings in young animals revealed a twofold mechanical sensitization in C fibers during acute inflammation, but an unexpected twofold reduction in firing during chronic inflammation. Responsiveness to capsaicin and mechanical responsiveness of A-mechanonociceptor (AM) fibers were also reduced chronically. Importantly, this lack of sensitization in afferent firing during chronic inflammation occurred even as these inflamed mice exhibited continued behavioral sensitization. Interestingly, C fibers from inflamed aged animals showed no change in mechanical firing compared with controls during either the acute or chronic inflammatory phases, despite strong behavioral sensitization to mechanical stimuli at these time points. These results reveal the following two important findings: (1) nociceptor sensitization to mechanical stimulation depends on age and the chronicity of injury; and (2) maintenance of chronic inflammatory pain does not rely on enhanced peripheral drive. PMID:26866058

A cross-sectional study of pain sensitivity, disease-activity assessment, mental health, and fibromyalgia status in rheumatoid arthritis.

PubMed

Joharatnam, Nalinie; McWilliams, Daniel F; Wilson, Deborah; Wheeler, Maggie; Pande, Ira; Walsh, David A

2015-01-20

Pain remains the most important problem for people with rheumatoid arthritis (RA). Active inflammatory disease contributes to pain, but pain due to non-inflammatory mechanisms can confound the assessment of disease activity. We hypothesize that augmented pain processing, fibromyalgic features, poorer mental health, and patient-reported 28-joint disease activity score (DAS28) components are associated in RA. In total, 50 people with stable, long-standing RA recruited from a rheumatology outpatient clinic were assessed for pain-pressure thresholds (PPTs) at three separate sites (knee, tibia, and sternum), DAS28, fibromyalgia, and mental health status. Multivariable analysis was performed to assess the association between PPT and DAS28 components, DAS28-P (the proportion of DAS28 derived from the patient-reported components of visual analogue score and tender joint count), or fibromyalgia status. More-sensitive PPTs at sites over or distant from joints were each associated with greater reported pain, higher patient-reported DAS28 components, and poorer mental health. A high proportion of participants (48%) satisfied classification criteria for fibromyalgia, and fibromyalgia classification or characteristics were each associated with more sensitive PPTs, higher patient-reported DAS28 components, and poorer mental health. Widespread sensitivity to pressure-induced pain, a high prevalence of fibromyalgic features, higher patient-reported DAS28 components, and poorer mental health are all linked in established RA. The increased sensitivity at nonjoint sites (sternum and anterior tibia), as well as over joints, indicates that central mechanisms may contribute to pain sensitivity in RA. The contribution of patient-reported components to high DAS28 should inform decisions on disease-modifying or pain-management approaches in the treatment of RA when inflammation may be well controlled.

Sphingosine kinase 2-deficiency mediated changes in spinal pain processing.

PubMed

Canlas, Jastrow; Holt, Phillip; Carroll, Alexander; Rix, Shane; Ryan, Paul; Davies, Lorena; Matusica, Dusan; Pitson, Stuart M; Jessup, Claire F; Gibbins, Ian L; Haberberger, Rainer V

2015-01-01

Chronic pain is one of the most burdensome health issues facing the planet (as costly as diabetes and cancer combined), and in desperate need for new diagnostic targets leading to better therapies. The bioactive lipid sphingosine 1-phosphate (S1P) and its receptors have recently been shown to modulate nociceptive signaling at the level of peripheral nociceptors and central neurons. However, the exact role of S1P generating enzymes, in particular sphingosine kinase 2 (Sphk2), in nociception remains unknown. We found that both sphingosine kinases, Sphk1 and Sphk2, were expressed in spinal cord (SC) with higher levels of Sphk2 mRNA compared to Sphk1. All three Sphk2 mRNA-isoforms were present with the Sphk2.1 mRNA showing the highest relative expression. Mice deficient in Sphk2 (Sphk2(-/-)) showed in contrast to mice deficient in Sphk1 (Sphk1(-/-)) substantially lower spinal S1P levels compared to wild-type C57BL/6 mice. In the formalin model of acute peripheral inflammatory pain, Sphk2(-/-) mice showed facilitation of nociceptive transmission during the late response, whereas responses to early acute pain, and the number of c-Fos immunoreactive dorsal horn neurons were not different between Sphk2(-/-) and wild-type mice. Chronic peripheral inflammation (CPI) caused a bilateral increase in mechanical sensitivity in Sphk2(-/-) mice. Additionally, CPI increased the relative mRNA expression of P2X4 receptor, brain-derived neurotrophic factor and inducible nitric oxide synthase in the ipsilateral SC of wild-type but not Sphk2(-/-) mice. Similarly, Sphk2(-/-) mice showed in contrast to wild-type no CPI-dependent increase in areas of the dorsal horn immunoreactive for the microglia marker Iba-1 and the astrocyte marker Glial fibrillary acidic protein (GFAP). Our results suggest that the tightly regulated cell signaling enzyme Sphk2 may be a key component for facilitation of nociceptive circuits in the CNS leading to central sensitization and pain memory formation.

Quantitative sensory testing somatosensory profiles in patients with cervical radiculopathy are distinct from those in patients with nonspecific neck-arm pain.

PubMed

Tampin, Brigitte; Slater, Helen; Hall, Toby; Lee, Gabriel; Briffa, Noelle Kathryn

2012-12-01

The aim of this study was to establish the somatosensory profiles of patients with cervical radiculopathy and patients with nonspecific neck-arm pain associated with heightened nerve mechanosensitivity (NSNAP). Sensory profiles were compared to healthy control (HC) subjects and a positive control group comprising patients with fibromyalgia (FM). Quantitative sensory testing (QST) of thermal and mechanical detection and pain thresholds, pain sensitivity and responsiveness to repetitive noxious mechanical stimulation was performed in the maximal pain area, the corresponding dermatome and foot of 23 patients with painful C6 or C7 cervical radiculopathy, 8 patients with NSNAP in a C6/7 dermatomal pain distribution, 31 HC and 22 patients with FM. For both neck-arm pain groups, all QST parameters were within the 95% confidence interval of HC data. Patients with cervical radiculopathy were characterised by localised loss of function (thermal, mechanical, vibration detection P<.009) in the maximal pain area and dermatome (thermal detection, vibration detection, pressure pain sensitivity P<.04), consistent with peripheral neuronal damage. Both neck-arm pain groups demonstrated increased cold sensitivity in their maximal pain area (P<.03) and the foot (P<.009), and this was also the dominant sensory characteristic in patients with NSNAP. Both neck-arm pain groups differed from patients with FM, the latter characterised by a widespread gain of function in most nociceptive parameters (thermal, pressure, mechanical pain sensitivity P<.027). Despite commonalities in pain characteristics between the 2 neck-arm pain groups, distinct sensory profiles were demonstrated for each group. Copyright © 2012 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

A SCN10A SNP biases human pain sensitivity

PubMed Central

Duan, Guangyou; Han, Chongyang; Wang, Qingli; Guo, Shanna; Zhang, Yuhao; Ying, Ying; Huang, Penghao; Zhang, Li; Macala, Lawrence; Shah, Palak; Zhang, Mi; Li, Ningbo; Dib-Hajj, Sulayman D; Zhang, Xianwei

2016-01-01

Background: Nav1.8 sodium channels, encoded by SCN10A, are preferentially expressed in nociceptive neurons and play an important role in human pain. Although rare gain-of-function variants in SCN10A have been identified in individuals with painful peripheral neuropathies, whether more common variants in SCN10A can have an effect at the channel level and at the dorsal root ganglion, neuronal level leading to a pain disorder or an altered normal pain threshold has not been determined. Results: Candidate single nucleotide polymorphism association approach together with experimental pain testing in human subjects was used to explore possible common SCN10A missense variants that might affect human pain sensitivity. We demonstrated an association between rs6795970 (G > A; p.Ala1073Val) and higher thresholds for mechanical pain in a discovery cohort (496 subjects) and confirmed it in a larger replication cohort (1005 female subjects). Functional assessments showed that although the minor allele shifts channel activation by −4.3 mV, a proexcitatory attribute, it accelerates inactivation, an antiexcitatory attribute, with the net effect being reduced repetitive firing of dorsal root ganglion neurons, consistent with lower mechanical pain sensitivity. Conclusions: At the association and mechanistic levels, the SCN10A single nucleotide polymorphism rs6795970 biases human pain sensitivity. PMID:27590072

Streamlining the Evaluation of Low Back Pain in Children

PubMed Central

Auerbach, Joshua D.; Ahn, Jaimo; Zgonis, Miltiadis H.; Reddy, Sudheer C.; Ecker, Malcolm L.

2008-01-01

The workup of low back pain in children often results in overimaging so as not to miss organic back pain. The primary goal of this study was to identify which combination of imaging modalities provides the most sensitive and specific screening protocol for children with low back pain. Medical records from 100 consecutive patients between 2 and 18 years of age presenting with low back pain, without night pain or constitutional symptoms, were evaluated. A hyperextension test combined with a radiograph showed a negative predictive value of 0.81 and sensitivity of 0.90. The addition of a bone scan was highly effective in achieving good negative predictive value and sensitivity. Bone scans had perfect negative predictive value and sensitivity when symptom duration was less than 6 weeks. We identified a set of factors that is highly predictive for distinguishing organic back pain from mechanical back pain. Painless hyperextension combined with negative anteroposterior, lateral, and oblique lumbar radiographs and magnetic resonance images predicts mechanical back pain. For patients with nonneurologic back pain of less than 6 weeks duration, bone scan is the most useful screening test because it is accurate, accessible, inexpensive, and unlikely to require sedation. Level of Evidence: Level III, diagnostic study. See the Guidelines for Authors for a complete description of levels of evidence. PMID:18553213

Partner Loss in Monogamous Rodents: Modulation of Pain and Emotional Behavior in Male Prairie Voles.

PubMed

Osako, Yoji; Nobuhara, Reiko; Arai, Young-Chang P; Tanaka, Kenjiro; Young, Larry J; Nishihara, Makoto; Mitsui, Shinichi; Yuri, Kazunari

2018-01-01

Pain is modulated by psychosocial factors, and social stress-induced hyperalgesia is a common clinical symptom in pain disorders. To provide a new animal model for studying social modulation of pain, we examined pain behaviors in monogamous prairie voles experiencing partner loss. After cohabitation with novel females, males (n = 79) were divided into two groups on the basis of preference test scores. Half of the males of each group were separated from their partner (loss group), whereas the other half remained paired (paired group). Thus, males from both groups experienced social isolation. Open field tests, plantar tests, and formalin tests were then conducted on males to assess anxiety and pain-related behaviors. Loss males showing partner preferences (n = 20) displayed a significant increase in anxiety-related behavior in the open-field test (central area/total distance: 13.65% [1.58%] for paired versus 6.45% [0.87%] for loss; p < .001), a low threshold of thermal stimulus in the plantar test (withdrawal latencies: 9.69 [0.98] seconds for paired versus 6.15 [0.75] seconds for loss; p = .037), and exacerbated pain behaviors in the formalin test (total number of lifts: 40.33 [4.46] for paired versus 54.42 [1.91] for loss; p = .042) as compared with paired males (n = 20). Thermal thresholds in the plantar test significantly correlated with anxiety-related behavior in the open-field test (r = 0.64). No such differences were observed in the males that did not display partner preferences (r = 0.15). Results indicate that social bonds and their disruption, but not social housing without bonding followed by isolation, modulate pain and emotion in male prairie voles. The prairie vole is a useful model for exploring the neural mechanisms by which social relationships contribute to pain and nociceptive processing in humans.

Effect of pinching-evoked pain on jaw-stretch reflexes and exteroceptive suppression periods in healthy subjects.

PubMed

Biasiotta, A; Peddireddy, A; Wang, K; Romaniello, A; Frati, A; Svensson, P; Arendt-Nielsen, L

2007-10-01

To investigate the influence of conditioning cutaneous nociceptive inputs by a new "pinch" model on the jaw-stretch reflex and the exteroceptive suppression periods (ES1 and ES2) in jaw muscles. The jaw-stretch reflex was evoked with the use of a custom-made muscle stretcher and electrical stimuli were used to evoke an early and late exteroceptive suppression period (ES1 and ES2) in the jaw-closing muscles. Electromyographic (EMG) activity was recorded bilaterally from the masseter and temporalis muscles. These brainstem reflexes were recorded in 19 healthy men (28.8+/-1.1 years) during three different conditions: one painful clip applied to the earlobe; one painful clip applied to the nostril, and four painful clips applied simultaneously to the earlobe, nostril, eyebrow, and lower lip. Pain intensity induced by the application of the clips was scored continuously by the subjects on a 100mm visual analogue scale (VAS). The highest VAS pain scores were evoked by placement of four clips (79+/-0.5mm). There was no significant modulation of the jaw-stretch reflex (ANOVAs: P=0.929), the ES1 (P=0.298) or ES2 (P=0.082) in any of the three painful conditions. Intense and tonic cutaneous pain could be elicited by this new "pinch" pain model; however, there was no significant modulation on either excitatory or inhibitory brainstem reflex responses. The novel observation that high-intensity pinch stimuli applied to the craniofacial region fail to modulate two different brainstem reflexes is in contrast to other experimental pain studies documented facilitation of the jaw-stretch reflexes or inhibition of exteroceptive suppression periods. The clinical implication of the present findings is that only some craniofacial pain conditions could be expected to show perturbation of the brainstem reflex responses.

Deep brain stimulation of the ventral striatal area for poststroke pain syndrome: a magnetoencephalography study.

PubMed

Gopalakrishnan, Raghavan; Burgess, Richard C; Malone, Donald A; Lempka, Scott F; Gale, John T; Floden, Darlene P; Baker, Kenneth B; Machado, Andre G

2018-06-01

Poststroke pain syndrome (PSPS) is an often intractable disorder characterized by hemiparesis associated with unrelenting chronic pain. Although traditional analgesics have largely failed, integrative approaches targeting affective-cognitive spheres have started to show promise. Recently, we demonstrated that deep brain stimulation (DBS) of the ventral striatal area significantly improved the affective sphere of pain in patients with PSPS. In the present study, we examined whether electrophysiological correlates of pain anticipation were modulated by DBS that could serve as signatures of treatment effects. We recorded event-related fields (ERFs) of pain anticipation using magnetoencephalography (MEG) in 10 patients with PSPS preoperatively and postoperatively in DBS OFF and ON states. Simple visual cues evoked anticipation as patients awaited a painful (PS) or nonpainful stimulus (NPS) to the nonaffected or affected extremity. Preoperatively, ERFs showed no difference between PS and NPS anticipation to the affected extremity, possibly due to loss of salience in a network saturated by pain experience. DBS significantly modulated the early N1, consistent with improvements in affective networks involving restoration of salience and discrimination capacity. Additionally, DBS suppressed the posterior P2 (aberrant anticipatory anxiety) while enhancing the anterior N1 (cognitive and emotional regulation) in responders. DBS-induced changes in ERFs could potentially serve as signatures for clinical outcomes. NEW & NOTEWORTHY We examined the electrophysiological correlates of pain affect in poststroke pain patients who underwent deep brain stimulation (DBS) targeting the ventral striatal area under a randomized, controlled trial. DBS significantly modulated early event-related components, particularly N1 and P2, measured with magnetoencephalography during a pain anticipatory task, compared with baseline and the DBS-OFF condition, pointing to possible mechanisms of action. DBS-induced changes in event-related fields could potentially serve as biomarkers for clinical outcomes.

Masticatory and cervical muscle tenderness and pain sensitivity in a remote area in subjects with a temporomandibular disorder and neck disability.

PubMed

Silveira, Anelise; Armijo-Olivo, Susan; Gadotti, Inae C; Magee, David

2014-01-01

To compare the masticatory and cervical muscle tenderness and pain sensitivity in the hand (remote region) between patients with temporomandibular disorders (TMD) and healthy controls. Twenty female subjects were diagnosed with chronic TMD, and 20 were considered healthy. Subjects completed the Neck Disability Index and Limitations of Daily Functions in a TMD questionnaire. Tenderness of the masticatory and cervical muscles and pain sensitivity in the hand were measured using an algometer. Three-way mixed analysis of variance (ANOVA) evaluated differences in muscle tenderness between groups. One-way ANOVA compared pain sensitivity in the hand between groups. Effect sizes were assessed using Cohen guidelines. Significantly increased masticatory and cervical muscle tenderness and pain sensitivity in the hand were found in subjects with TMD when compared with healthy subjects. Moderate to high effect sizes showed the clinical relevance of the findings. The results of this study have highlighted the importance of assessing TMD patients not only in the craniofacial region but also in the neck and other parts of the body. Future studies should focus on testing the effectiveness of treatments addressing the neck and the pain sensitivity in the hand in patients with TMD.

Effectiveness of low-level laser therapy on pain intensity, pressure pain threshold, and SF-MPQ indexes of women with myofascial pain.

PubMed

Magri, Laís Valencise; Carvalho, Vinícius Almeida; Rodrigues, Flávia Cássia Cabral; Bataglion, César; Leite-Panissi, Christie Ramos Andrade

2017-02-01

Women with temporomandibular disorders (TMD) frequently report pain areas in body regions. This process is associated with central sensitization phenomena, present in chronic pain. The low-level laser therapy (LLLT) has been reported as a therapeutic option for the painful TMD treatment. The aim of this study was to analyze the effect of LLLT on pain intensity (visual analogue scale, VAS), pain sensitivity in orofacial and corporal points (pressure pain threshold, PPT), and on Short Form-McGill Pain Questionnaire (SF-MPQ) indexes of women with myofascial pain (subtype of muscle TMD). Ninety-one women (18-60 years) were included in the study, among which 61 were diagnosed with myofascial pain (Research Diagnostic Criteria for Temporomandibular Disorder-Ia and Ib) and were divided into laser (n = 31) and placebo group (n = 30), and 30 were controls. The LLLT was applied at pre-established points, twice a week, eight sessions (780 nm; masseter and anterior temporal = 5 J/cm 2 , 20 mW, 10 s; TMJ area = 7.5 J/cm 2 , 30 mW, 10 s). Pain intensity, pain sensitivity, and the SF-MPQ indexes were measured at the baseline, during laser sessions, and 30 days after treatment. For intra-group comparisons, the Friedman test was performed, and for inter-group, the Mann-Whitney test. Increased pain sensitivity was found in women with myofascial pain when compared to controls (p < 0.05). There was a reduction in pain intensity for both groups after LLLT. The LLLT did not change the PPT for any group (p > 0.05). Active laser and placebo reduced the indexes of sensory, total pain, and VAS, maintaining the results after 30 days; there was a reduction in the affective pain rating index for both groups, with no maintenance after 30 days for placebo, and the present pain intensity decreased in the laser group and did not change in the placebo after LLLT. In conclusion, the LLLT active or placebo are effective in reducing the overall subjective perception of myofascial pain (VAS and SF-MPQ indexes); however, they have no effectiveness in reducing the pain sensitivity in orofacial and corporal points (PPT increase).

Up-regulation of neural indicators of empathic concern in an offender population.

PubMed

Arbuckle, Nathan L; Shane, Matthew S

2017-08-01

Empathic concern has traditionally been conceived of as a spontaneous reaction to others experiencing pain or distress. As such, the potential role of more deliberate control over empathic responses has frequently been overlooked. The present fMRI study evaluated the role of such deliberate control in empathic concern by examining the extent to which a sample of offenders recruited through probation/parole could voluntarily modulate their neural activity to another person in pain. Offenders were asked to either passively view pictures of other people in painful or non-painful situations, or to actively modulate their level of concern for the person in pain. During passive viewing of painful versus non-painful pictures, offenders showed minimal neural activity in regions previously linked to empathy for pain (e.g., dorsal anterior cingulate cortex and bilateral insula). However, when instructed to try to increase their concern for the person in pain, offenders demonstrated significant increases within these regions. These findings are consistent with recent theories of empathy as motivational in nature, and suggest that limitations in empathic concern may include a motivational component.

Cellular, molecular, and epigenetic mechanisms in non-associative conditioning: implications for pain and memory.

PubMed

Rahn, Elizabeth J; Guzman-Karlsson, Mikael C; David Sweatt, J

2013-10-01

Sensitization is a form of non-associative conditioning in which amplification of behavioral responses can occur following presentation of an aversive or noxious stimulus. Understanding the cellular and molecular underpinnings of sensitization has been an overarching theme spanning the field of learning and memory as well as that of pain research. In this review we examine how sensitization, both in the context of learning as well as pain processing, shares evolutionarily conserved behavioral, cellular/synaptic, and epigenetic mechanisms across phyla. First, we characterize the behavioral phenomenon of sensitization both in invertebrates and vertebrates. Particular emphasis is placed on long-term sensitization (LTS) of withdrawal reflexes in Aplysia following aversive stimulation or injury, although additional invertebrate models are also covered. In the context of vertebrates, sensitization of mammalian hyperarousal in a model of post-traumatic stress disorder (PTSD), as well as mammalian models of inflammatory and neuropathic pain is characterized. Second, we investigate the cellular and synaptic mechanisms underlying these behaviors. We focus our discussion on serotonin-mediated long-term facilitation (LTF) and axotomy-mediated long-term hyperexcitability (LTH) in reduced Aplysia systems, as well as mammalian spinal plasticity mechanisms of central sensitization. Third, we explore recent evidence implicating epigenetic mechanisms in learning- and pain-related sensitization. This review illustrates the fundamental and functional overlay of the learning and memory field with the pain field which argues for homologous persistent plasticity mechanisms in response to sensitizing stimuli or injury across phyla. Copyright © 2013 Elsevier Inc. All rights reserved.

Vitamin D, Race, and Experimental Pain Sensitivity in Older Adults with Knee Osteoarthritis

PubMed Central

Glover, T.L.; Goodin, B.R.; Horgas, A.L.; Kindler, L.L.; King, C.D.; Sibille, K.T.; Peloquin, C.A.; Riley, J.L.; Staud, R.; Bradley, L.A.; Fillingim, R.B.

2012-01-01

Objective Low levels of serum circulating 25-hydroxyvitamin D have been correlated with many health conditions, including chronic pain. Recent clinical practice guidelines define vitamin D levels < 20 ng/mL as deficient and values of 21–29 ng/mL as insufficient. Vitamin D insufficiency, including the most severe levels of deficiency, is more prevalent in black Americans. Ethnic and race group differences have been reported in both clinical and experimental pain, with black Americans reporting increased pain. The purpose of this study was to examine whether variation in vitamin D levels contribute to race differences in knee osteoarthritic pain. Methods The sample consisted of 94 participants (75% female), including 45 blacks and 49 whites with symptomatic knee osteoarthritis. Average age was 55.8 years (range 45–71 years). Participants completed a questionnaire on knee osteoarthritic symptoms and underwent quantitative sensory testing, including measures of heat and mechanical pain sensitivity. Results Blacks had significantly lower levels of vitamin D compared to whites, demonstrated greater clinical pain, and showed greater sensitivity to mechanical and heat pain. Low levels of vitamin D predicted increased experimental pain sensitivity, but did not predict self-reported clinical pain. Group differences in vitamin D significantly predicted group differences in heat pain and pressure pain thresholds on the index knee and ipsilateral forearm. Conclusion These data demonstrate race differences in experimental pain are mediated by differences in vitamin D level. Vitamin D deficiency may be a risk factor for increased knee osteoarthritic pain in black Americans. PMID:23135697

Multiple Levels of Suffering: Discrimination in Health-Care Settings is Associated With Enhanced Laboratory Pain Sensitivity in Sickle Cell Disease.

PubMed

Mathur, Vani A; Kiley, Kasey B; Haywood, Carlton; Bediako, Shawn M; Lanzkron, Sophie; Carroll, C Patrick; Buenaver, Luis F; Pejsa, Megan; Edwards, Robert R; Haythornthwaite, Jennifer A; Campbell, Claudia M

2016-12-01

People living with sickle cell disease (SCD) experience severe episodic and chronic pain and frequently report poor interpersonal treatment within health-care settings. In this particularly relevant context, we examined the relationship between perceived discrimination and both clinical and laboratory pain. Seventy-one individuals with SCD provided self-reports of experiences with discrimination in health-care settings and clinical pain severity, and completed a psychophysical pain testing battery in the laboratory. Discrimination in health-care settings was correlated with greater clinical pain severity and enhanced sensitivity to multiple laboratory-induced pain measures, as well as stress, depression, and sleep. After controlling for relevant covariates, discrimination remained a significant predictor of mechanical temporal summation (a marker of central pain facilitation), but not clinical pain severity or suprathreshold heat pain response. Furthermore, a significant interaction between experience with discrimination and clinical pain severity was associated with mechanical temporal summation; increased experience with discrimination was associated with an increased correlation between clinical pain severity and temporal summation of pain. Perceived discrimination within health-care settings was associated with pain facilitation. These findings suggest that discrimination may be related to increased central sensitization among SCD patients, and more broadly that health-care social environments may interact with pain pathophysiology.

Mindfulness Meditation and Cognitive Behavioral Therapy Intervention Reduces Pain Severity and Sensitivity in Opioid-Treated Chronic Low Back Pain: Pilot Findings from a Randomized Controlled Trial.

PubMed

Zgierska, Aleksandra E; Burzinski, Cindy A; Cox, Jennifer; Kloke, John; Stegner, Aaron; Cook, Dane B; Singles, Janice; Mirgain, Shilagh; Coe, Christopher L; Bačkonja, Miroslav

2016-10-01

To assess benefits of mindfulness meditation and cognitive behavioral therapy (CBT)-based intervention for opioid-treated chronic low back pain (CLBP). 26-week parallel-arm pilot randomized controlled trial (Intervention and Usual Care versus Usual Care alone). Outpatient. Adults with CLBP, prescribed ≥30 mg/day of morphine-equivalent dose (MED) for at least 3 months. The intervention comprised eight weekly group sessions (meditation and CLBP-specific CBT components) and 30 minutes/day, 6 days/week of at-home practice. Outcome measures were collected at baseline, 8, and 26 weeks: primary-pain severity (Brief Pain Inventory) and function/disability (Oswestry Disability Index); secondary-pain acceptance, opioid dose, pain sensitivity to thermal stimuli, and serum pain-sensitive biomarkers (Interferon-γ; Tumor Necrosis Factor-α; Interleukins 1ß and 6; C-reactive Protein). Thirty-five (21 experimental, 14 control) participants were enrolled and completed the study. They were 51.8 ± 9.7 years old, 80% female, with severe CLBP-related disability (66.7 ± 11.4), moderate pain severity (5.8 ± 1.4), and taking 148.3 ± 129.2 mg/day of MED. Results of the intention-to-treat analysis showed that, compared with controls, the meditation-CBT group reduced pain severity ratings during the study (P = 0.045), with between-group difference in score change reaching 1 point at 26 weeks (95% Confidence Interval: 0.2,1.9; Cohen's d = 0.86), and decreased pain sensitivity to thermal stimuli (P < 0.05), without adverse events. Exploratory analyses suggested a relationship between the extent of meditation practice and the magnitude of intervention benefits. Meditation-CBT intervention reduced pain severity and sensitivity to experimental thermal pain stimuli in patients with opioid-treated CLBP. © 2016 American Academy of Pain Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Women experience greater heat pain adaptation and habituation than men.

PubMed

Hashmi, Javeria A; Davis, Karen D

2009-10-01

It is not clear how males and females cope with pain over time and how sensory and emotional qualities fluctuate from moment to moment, although studies of pain at discrete time points suggest that women are more pain sensitive than men. Therefore, we developed a new broader-based pain model that incorporates a temporally continuous assessment of multiple pain dimensions across sensory and affective dimensions, and normalized peak pain intensity to unmask sex differences that may otherwise be confounded by inter-individual variability in pain sensitivity. We obtained continuous ratings of pain, burning, sharp, stinging, cutting, and annoyance evoked by repeated prolonged noxious heat stimuli in 32 subjects. Strikingly, females reported more pain than males at the outset of the first exposure to pain, but then experienced less pain and annoyance than males as a painful stimulus was sustained and with repeated stimulation. Patterns of pain and annoyance attenuation in women resembled the attenuation of sharp, stinging and cutting sensations, whereas patterns of pain and annoyance in men resembled burning sensations. Taken together, these data demonstrate a prominent sex difference in the time course of pain. Notably only females demonstrate adaptation and habituation that allow them to experience less pain over time. These findings suggest a sexual dichotomy in mechanisms underlying pain intensity and annoyance that could involve specific quality-linked mechanisms. Importantly, temporal processing of pain differs between males and females when adjusted for sex differences in pain sensitivity. Our findings provide insight into sex differences in tonic and possibly chronic pains.

Disease-Related Microstructural Differences in the Brain in Women With Provoked Vestibulodynia.

PubMed

Gupta, Arpana; Woodworth, Davis C; Ellingson, Benjamin M; Rapkin, Andrea J; Naliboff, Bruce; Kilpatrick, Lisa A; Stains, Jean; Masghati, Salome; Tillisch, Kirsten; Mayer, Emeran A; Labus, Jennifer S

2018-05-01

Provoked vestibulodynia (PVD) is a chronic pelvic pain disorder affecting 16% of the female population. Neuroimaging studies have highlighted central abnormalities in PVD, similar to other chronic pelvic pain disorders, including brain regions involved in sensory processing and modulation of pain. The aim of the study was to determine alterations in the subvoxel, microstructural organization within tissues in PVD compared with healthy control participants (HCs) and a disease control group (irritable bowel syndrome [IBS]). Diffusion tensor imaging magnetic resonance imaging was conducted in 87 age-matched premenopausal women (29 PVD, 29 HCs, 29 IBS). Statistical parameter mapping of fractional anisotropy (FA) and mean diffusivity (MD) maps were used to identify microstructural difference in the brain specific to PVD or shared with IBS. PVD alterations in microstructural organization of the brain were predominantly observed in fibers associated with sensorimotor integration and pain processing that relay information between the thalamus, basal ganglia, sensorimotor, and insular cortex. PVD, compared with HCs, showed extensive increases in the FA of somatosensory and basal ganglia regions. In contrast, PVD and IBS subjects did not show any FA-related group differences. PVD subjects showed greater MD in the basal ganglia compared with HCs (higher MD in the internal capsule and pallidum) and IBS (higher MD in the putamen and pallidum). Increases in MD were associated with increased vaginal muscle tenderness and vulvar pain. The current findings highlight possible shared mechanisms between 2 different pelvic pain disorders, but also highlight the widespread alterations observed specifically in PVD compared with HCs. Alterations in microstructure in PVD were observed in fibers associated with sensorimotor integration and pain processing, which were also associated with increased vaginal muscle tenderness and vulvar pain. These alterations may be contributing to increased pain sensitivity and tenderness, highlighting the need for new therapies targeting the central nervous system. Copyright © 2018 The American Pain Society. Published by Elsevier Inc. All rights reserved.

Group III metabotropic glutamate receptors inhibit hyperalgesia in animal models of inflammation and neuropathic pain.

PubMed

Goudet, Cyril; Chapuy, Eric; Alloui, Abdelkrim; Acher, Francine; Pin, Jean-Philippe; Eschalier, Alain

2008-07-01

Glutamate plays a key role in modulation of nociceptive processing. This excitatory amino acid exerts its action through two distinct types of receptors, ionotropic and metabotropic glutamate receptors (mGluRs). Eight mGluRs have been identified and divided in three groups based on their sequence similarity, pharmacology and G-protein coupling. While the role of group I and II mGluRs is now well established, little is known about the part played by group III mGluRs in pain. In this work, we studied comparatively the involvement of spinal group III mGluR in modulation of acute, inflammatory and neuropathic pain. While intrathecal injection of ACPT-I, a selective group III mGluR agonist, failed to induce any change in vocalization thresholds of healthy animals submitted to mechanical or thermal stimuli, it dose-dependently inhibited the nociceptive behavior of rats submitted to the formalin test and the mechanical hyperalgesia associated with different animal models of inflammatory (carrageenan-treated and monoarthritic rats) or neuropathic pain (mononeuropathic and vincristine-treated rats). Similar effects were also observed following intrathecal injection of PHCCC, a positive allosteric modulator of mGlu4. Antihyperalgesia induced by ACPT-I was blocked either by LY341495, a nonselective antagonist of mGluR, by MAP4, a selective group III antagonist. This study provide new evidences supporting the role of spinal group III mGluRs in the modulation of pain perception in different pathological pain states of various etiologies but not in normal conditions. It more particularly highlights the specific involvement of mGlu4 in this process and may be a useful therapeutic approach to chronic pain treatment.

Improved Learning Outcomes After Flipping a Therapeutics Module: Results of a Controlled Trial.

PubMed

Lockman, Kashelle; Haines, Stuart T; McPherson, Mary Lynn

2017-12-01

To evaluate the impact on learning outcomes of flipping a pain management module in a doctor of pharmacy curriculum. In a required first-professional-year pharmacology and therapeutics course at the University of Maryland School of Pharmacy, the pain therapeutics content of the pain management module was flipped. This redesign transformed the module from a largely lecture-based, instructor-centered model to a learner-centered model that included a variety of preclass activities and in-class active learning exercises. In spring 2015, the module was taught using the traditional model; in spring 2016, it was taught using the flipped model. The same end-of-module objective structured clinical exam (OSCE) and multiple-choice exam were administered in 2015 to the traditional cohort (TC; n = 156) and in 2016 to the flipped cohort (FC; n = 162). Cohort performance was compared. Learning outcomes improved significantly in the FC: The mean OSCE score improved by 12.33/100 points (P < .0001; 95% CI 10.28-14.38; effect size 1.33), and performance on the multiple-choice exam's therapeutics content improved by 5.07 percentage points (P < .0001; 95% CI 2.56-7.59; effect size 0.45). Student performance on exam items assessing higher cognitive levels significantly improved under the flipped model. Grade distribution on both exams shifted, with significantly more FC students earning an A or B and significantly fewer earning a D or F compared with TC students. Student performance on knowledge- and skill-based assessments improved significantly after flipping the therapeutics content of a pain management module.

Chronic Opioid Therapy and Central Sensitization in Sickle Cell Disease

PubMed Central

Carroll, C. Patrick; Lanzkron, Sophie; Haywood, Carlton; Kiley, Kasey; Pejsa, Megan; Moscou-Jackson, Gyasi; Haythornthwaite, Jennifer A.; Campbell, Claudia M.

2016-01-01

Chronic opioid therapy (COT) for chronic non-cancer pain is frequently debated, and its effectiveness is unproven in sickle cell disease (SCD). The authors conducted a descriptive study among 83 adult SCD patients and compared severity of disease and pain symptoms among those who were prescribed COT (n=29) with those who were not using COT. All patients completed baseline laboratory pain assessment and questionnaires between January 2010 and June 2014. Thereafter, participants recorded daily pain, crises, function, and healthcare utilization for 90 days using electronic diaries. Analyses were conducted shortly after the final diary data collection period. Patients on COT did not differ on age, sex, or measures of disease severity. However, patients on COT exhibited greater levels of clinical pain (particularly non-crisis), central sensitization, depression, and increased diary measures of pain severity, function, and healthcare utilization on crisis and non-crisis diary days, as well as a greater proportion of days in crisis. Including depressive symptoms in multivariate models did not change the associations between COT and pain, interference, central sensitization, or utilization. Additionally, participants not on COT displayed the expected positive relationship between central sensitization and clinical pain, whereas those on COT demonstrated no such relationship, despite having both higher central sensitization and higher clinical pain. Overall, the results point out a high symptom burden in SCD patients on COT, including those on high-dose COT, and suggest that nociceptive processing in SCD patients on COT differs from those who are not. PMID:27320469

The changing balance of brainstem–spinal cord modulation of pain processing over the first weeks of rat postnatal life

PubMed Central

Hathway, G J; Koch, S; Low, L; Fitzgerald, M

2009-01-01

Brainstem–spinal cord connections play an essential role in adult pain processing, and the modulation of spinal pain network excitability by brainstem nuclei is known to contribute to hyperalgesia and chronic pain. Less well understood is the role of descending brainstem pathways in young animals when pain networks are more excitable and exposure to injury and stress can lead to permanent modulation of pain processing. Here we show that up to postnatal day 21 (P21) in the rat, the rostroventral medulla of the brainstem (RVM) exclusively facilitates spinal pain transmission but that after this age (P28 to adult), the influence of the RVM shifts to biphasic facilitation and inhibition. Graded electrical microstimulation of the RVM at different postnatal ages revealed a robust shift in the balance of descending control of both spinal nociceptive flexion reflex EMG activity and individual dorsal horn neuron firing properties, from excitation to inhibition, beginning after P21. The shift in polarity of descending control was also observed following excitotoxic lesions of the RVM in adult and P21 rats. In adults, RVM lesions decreased behavioural mechanical sensory reflex thresholds, whereas the same lesion in P21 rats increased thresholds. These data demonstrate, for the first time, the changing postnatal influence of the RVM in spinal nociception and highlight the central role of descending brainstem control in the maturation of pain processing. PMID:19403624

Sleep fragmentation exacerbates mechanical hypersensitivity and alters subsequent sleep-wake behavior in a mouse model of musculoskeletal sensitization.

PubMed

Sutton, Blair C; Opp, Mark R

2014-03-01

Sleep deprivation, or sleep disruption, enhances pain in human subjects. Chronic musculoskeletal pain is prevalent in our society, and constitutes a tremendous public health burden. Although preclinical models of neuropathic and inflammatory pain demonstrate effects on sleep, few studies focus on musculoskeletal pain. We reported elsewhere in this issue of SLEEP that musculoskeletal sensitization alters sleep of mice. In this study we hypothesize that sleep fragmentation during the development of musculoskeletal sensitization will exacerbate subsequent pain responses and alter sleep-wake behavior of mice. This is a preclinical study using C57BL/6J mice to determine the effect on behavioral outcomes of sleep fragmentation combined with musculoskeletal sensitization. Musculoskeletal sensitization, a model of chronic muscle pain, was induced using two unilateral injections of acidified saline (pH 4.0) into the gastrocnemius muscle, spaced 5 days apart. Musculoskeletal sensitization manifests as mechanical hypersensitivity determined by von Frey filament testing at the hindpaws. Sleep fragmentation took place during the consecutive 12-h light periods of the 5 days between intramuscular injections. Electroencephalogram (EEG) and body temperature were recorded from some mice at baseline and for 3 weeks after musculoskeletal sensitization. Mechanical hypersensitivity was determined at preinjection baseline and on days 1, 3, 7, 14, and 21 after sensitization. Two additional experiments were conducted to determine the independent effects of sleep fragmentation or musculoskeletal sensitization on mechanical hypersensitivity. Five days of sleep fragmentation alone did not induce mechanical hypersensitivity, whereas sleep fragmentation combined with musculoskeletal sensitization resulted in prolonged and exacerbated mechanical hypersensitivity. Sleep fragmentation combined with musculoskeletal sensitization had an effect on subsequent sleep of mice as demonstrated by increased numbers of sleep-wake state transitions during the light and dark periods; changes in nonrapid eye movement (NREM) sleep, rapid eye movement sleep, and wakefulness; and altered delta power during NREM sleep. These effects persisted for at least 3 weeks postsensitization. Our data demonstrate that sleep fragmentation combined with musculoskeletal sensitization exacerbates the physiological and behavioral responses of mice to musculoskeletal sensitization, including mechanical hypersensitivity and sleep-wake behavior. These data contribute to increasing literature demonstrating bidirectional relationships between sleep and pain. The prevalence and incidence of insufficient sleep and pathologies characterized by chronic musculoskeletal pain are increasing in the United States. These demographic data underscore the need for research focused on insufficient sleep and chronic pain so that the quality of life for the millions of individuals with these conditions may be improved.

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.

Current methodological approaches in conditioned pain modulation assessment in pediatrics

PubMed Central

Hwang, Philippe S; Ma, My-Linh; Spiegelberg, Nora; Ferland, Catherine E

2017-01-01

Conditioned pain modulation (CPM) paradigms have been used in various studies with healthy and non-healthy adult populations in an attempt to elucidate the mechanisms of pain processing. However, only a few studies so far have applied CPM in pediatric populations. Studies finding associations with chronic pain conditions suggest that deficiencies in underlying descending pain pathways may play an important role in the development and persistence of pain early in life. Twelve studies were identified using a PubMed search which examine solely pediatric populations, and these are reviewed with regard to demographics studied, methodological approaches, and conclusions reached. This review aimed to provide both clinicians and researchers with a brief overview of the current state of research regarding the use of CPM in children and adolescents, both healthy and clinical patients. The implications of CPM in experimental and clinical settings and its potential to aid in refining considerations to individualize treatment of pediatric pain syndromes will be discussed. PMID:29263694

Randomized Trial of Hypnosis as a Pain and Symptom Management Strategy in Adults with Sickle Cell Disease

PubMed Central

Wallen, Gwenyth R; Middleton, Kimberly R; Ames, Nancy; Brooks, Alyssa T; Handel, Daniel

2014-01-01

Sickle cell disease (SCD) is the most common genetic disease in African-Americans, characterized by recurrent painful vaso-occlusive crises. Medical therapies for controlling or preventing crises are limited because of efficacy and/or toxicity. This is a randomized, controlled, single-crossover protocol of hypnosis for managing pain in SCD patients. Participants receive hypnosis from a trained hypnosis therapist followed by six weeks of self-hypnosis using digital media. Those in the control arm receive SCD education followed by a six-week waiting period before crossing over to the hypnosis arm of the study. Outcome measures include assessments of pain (frequency, intensity and quality), anxiety, coping strategies, sleep, depression, and health care utilization. To date, there are no published randomized, controlled trials evaluating the efficacy of hypnosis on SCD pain modulation in adults. Self-hypnosis for pain management may be helpful in modulating chronic pain, improving sleep quality, and decreasing use of narcotics in patients with SCD. TRIAL REGISTRATION ClinicalTrials.gov: NCT00393250 PMID:25520557

HYPNOTIZABILITY AND PAIN MODULATION: A Body-Mind Perspective.

PubMed

Varanini, Maurizio; Balocchi, Rita; Carli, Giancarlo; Paoletti, Giulia; Santarcangelo, Enrica L

2018-01-01

The study investigated whether the cardiac activity and cognitive-emotional traits sustained by the behavioral inhibition/activation system (BIS/BAS) may contribute to hypnotizability-related pain modulation. Nociceptive stimulation (cold-pressor test) was administered to healthy participants with high (highs) and low (lows) hypnotizability in the presence and absence of suggestions for analgesia. Results showed that heart rate increased abruptly at the beginning of nociceptive stimulation in all participants. Then, only in highs heart rate decreased for the entire duration of hand immersion. During stimulation with suggestions of analgesia, pain threshold negatively correlated with heart rate. BIS/BAS activity partially accounted for the observed hypnotizability-related differences in the relation between cardiac interoception and pain experience.

Experimental teeth clenching in man.

PubMed

Christensen, L V

1989-01-01

The thesis develops an electromyographic (EMG) method to quantify maximum voluntary teeth clenching (MVC), studies the onset and endurance of jaw muscle fatigue and pain from MVC, and explores the prevention of the discomforts through pharmacological and physical means. MVC, or maximum voluntary static work efforts by the elevator muscles of the mandible, was quantified by continuous (integral) functions of variations in both time and recruitment/rate coding of motor units in the masseter muscle. Fatigue was felt in the masseter muscle after about 30 seconds of MVC; differential calculus suggested that the appearance and disappearance of fatigue was associated with primarily recruitment and decruitment of masseteric motor units, respectively. About 60 seconds of MVC elicited a mild pain in the masseter and temporalis muscles; about 120 seconds of MVC induced a moderate pain and complete exhaustion of the isometrically contracting muscles. Although pain releasing maximum static work efforts are stable variables they cannot predict the pain magnitude of brief and prolonged MVC, probably because of modulations (recruitment/decruitment/rate coding) of masseteric motor units. It is suggested that the modulations begin with the onset of fatigue, are practically complete with the onset of pain, and are absent or negligible with an experience of exhaustion. A single oral dose of 1000 mg of ibuprofen did not affect the onset, endurance, and magnitude of pain from MVC. By contrast, 30 minutes of cooling (ice) of the masseter muscle effectively prevented the onset of pain; it also increased the masseteric EMG, credibly because of modulations of myoelectrical signals and, possibly, increased MVC efforts in the absence of pain.

Cerebral somatic pain modulation during autogenic training in fMRI.

PubMed

Naglatzki, R P; Schlamann, M; Gasser, T; Ladd, M E; Sure, U; Forsting, M; Gizewski, E R

2012-10-01

Functional magnetic resonance imaging (fMRI) studies are increasingly employed in different conscious states. Autogenic training (AT) is a common clinically used relaxation method. The purpose of this study was to investigate the cerebral modulation of pain activity patterns due to AT and to correlate the effects to the degree of experience with AT and strength of stimuli. Thirteen volunteers familiar with AT were studied with fMRI during painful electrical stimulation in a block design alternating between resting state and electrical stimulation, both without AT and while employing the same paradigm when utilizing their AT abilities. The subjective rating of painful stimulation and success in modulation during AT was assessed. During painful electrical stimulation without AT, fMRI revealed activation of midcingulate, right secondary sensory, right supplementary motor, and insular cortices, the right thalamus and left caudate nucleus. In contrast, utilizing AT only activation of left insular and supplementary motor cortices was revealed. The paired t-test revealed pain-related activation in the midcingulate, posterior cingulate and left anterior insular cortices for the condition without AT, and activation in the left ventrolateral prefrontal cortex under AT. Activation of the posterior cingulate cortex and thalamus correlated with the amplitude of electrical stimulation. This study revealed an effect on cerebral pain processing while performing AT. This might represent the cerebral correlate of different painful stimulus processing by subjects who are trained in performing relaxation techniques. However, due to the absence of a control group, further studies are needed to confirm this theory. © 2012 European Federation of International Association for the Study of Pain Chapters.

Overcoming pain thresholds with multilevel models-an example using quantitative sensory testing (QST) data.

PubMed

Hirschfeld, Gerrit; Blankenburg, Markus R; Süß, Moritz; Zernikow, Boris

2015-01-01

The assessment of somatosensory function is a cornerstone of research and clinical practice in neurology. Recent initiatives have developed novel protocols for quantitative sensory testing (QST). Application of these methods led to intriguing findings, such as the presence lower pain-thresholds in healthy children compared to healthy adolescents. In this article, we (re-) introduce the basic concepts of signal detection theory (SDT) as a method to investigate such differences in somatosensory function in detail. SDT describes participants' responses according to two parameters, sensitivity and response-bias. Sensitivity refers to individuals' ability to discriminate between painful and non-painful stimulations. Response-bias refers to individuals' criterion for giving a "painful" response. We describe how multilevel models can be used to estimate these parameters and to overcome central critiques of these methods. To provide an example we apply these methods to data from the mechanical pain sensitivity test of the QST protocol. The results show that adolescents are more sensitive to mechanical pain and contradict the idea that younger children simply use more lenient criteria to report pain. Overall, we hope that the wider use of multilevel modeling to describe somatosensory functioning may advance neurology research and practice.

Central sensitization: a biopsychosocial explanation for chronic widespread pain in patients with fibromyalgia and chronic fatigue syndrome

PubMed Central

Meeus, Mira

2006-01-01

In addition to the debilitating fatigue, the majority of patients with chronic fatigue syndrome (CFS) experience chronic widespread pain. These pain complaints show the greatest overlap between CFS and fibromyalgia (FM). Although the literature provides evidence for central sensitization as cause for the musculoskeletal pain in FM, in CFS this evidence is currently lacking, despite the observed similarities in both diseases. The knowledge concerning the physiological mechanism of central sensitization, the pathophysiology and the pain processing in FM, and the knowledge on the pathophysiology of CFS lead to the hypothesis that central sensitization is also responsible for the sustaining pain complaints in CFS. This hypothesis is based on the hyperalgesia and allodynia reported in CFS, on the elevated concentrations of nitric oxide presented in the blood of CFS patients, on the typical personality styles seen in CFS and on the brain abnormalities shown on brain images. To examine the present hypothesis more research is required. Further investigations could use similar protocols to those already used in studies on pain in FM like, for example, studies on temporal summation, spatial summation, the role of psychosocial aspects in chronic pain, etc. PMID:17115100

Pacinian Signals Determine the Direction and Magnitude of the Effect of Vibration on Pain.

PubMed

Hollins, Mark; Corsi, Christopher; Sloan, Page

2017-08-01

Although the ability of vibration to reduce pain has been extensively documented, an occasional participant reports that vibration increases pain. For pain patients, such reports may reflect pathophysiology, but this is unlikely in studies of experimental pain in healthy participants. In the present series of experiments on 27 pain-free individuals, we manipulated both the frequency (12, 50, and 80 Hz) and amplitude of vibration to more fully characterize vibratory pain modulation. The noxious stimulus was pressure applied to a finger, and vibration was delivered to the fleshy palmar pad at the base of the same finger. Subjects continuously reported pain on a Visual Analog Scale. Intermittent vibration was used to minimize peripheral vibratory adaptation. Pain records at 12 and 50 Hz were similar; pooling them revealed significant hypoalgesia at the highest amplitude. At 80 Hz, in contrast, the middle amplitude produced hypoalgesia, but a significant shift toward hyperalgesia occurred at the highest amplitude. The strong correlation ( r = .81) between the Pacinian-weighted power of a vibration and the absolute value of the pain modulation it produces indicates that the Pacinian system plays a key role in vibratory hypoalgesia or hyperalgesia.

Social contexts modulate neural responses in the processing of others' pain: An event-related potential study.

PubMed

Cui, Fang; Zhu, Xiangru; Luo, Yuejia

2017-08-01

Two hypotheses have been proposed regarding the response that is triggered by observing others' pain: the "empathizing hypothesis" and the "threat value of pain hypothesis." The former suggests that observing others' pain triggers an empathic response. The latter suggests that it activates the threat-detection system. In the present study, participants were instructed to observe pictures that showed an anonymous hand or foot in a painful or non-painful situation in a threatening or friendly social context. Event-related potentials were recorded when the participants passively observed these pictures in different contexts. We observed an interaction between context and picture in the early automatic N1 component, in which the painful pictures elicited a larger amplitude than the non-painful pictures only in the threatening context and not in the friendly context. We also observed an interaction between context and picture in the late P3 component, in which the painful pictures elicited a larger amplitude than the non-painful pictures only in the friendly context and not in the threatening context. These results indicate that specific social contexts can modulate the neural responses to observing others' pain. The "empathic hypothesis" and "threat value of pain hypothesis" are not mutually exclusive and do not contradict each other but rather work in different temporal stages.

The Sensitivity to Change and Responsiveness of the Adult Responses to Children’s Symptoms in Children and Adolescents With Chronic Pain

PubMed Central

Alberts, Nicole; Langer, Shelby L.; Levy, Rona L.; Walker, Lynn S.; Palermo, Tonya M.

2016-01-01

Abstract Objective  To examine the sensitivity to change and responsiveness of the Adult Responses to Children’s Symptoms (ARCS) among parents of youth with chronic pain.  Methods  Participants included 330 youth (89 children aged 7–11 years, 241 children aged 12–17 years) and their parents who participated in randomized controlled trials of family-based cognitive-behavioral therapy for chronic pain. Child pain and disability, parental emotional functioning, and parental responses to child pain were assessed at baseline and posttreatment.  Results  The Protect and Monitor scales of the ARCS were sensitive to change following intervention for both developmental groups, with clinically meaningful reductions in these behaviors, thereby demonstrating responsiveness. Among the adolescent sample, greater change on some ARCS scales was associated with better parental emotional functioning and lower child pain at posttreatment.  Conclusions  Findings support the sensitivity to change and responsiveness of the Protect and Monitor scales among parents of youth with chronic pain. PMID:26493601

Association between UGT2B7 gene polymorphisms and fentanyl sensitivity in patients undergoing painful orthognathic surgery

PubMed Central

Muraoka, Wataru; Nishizawa, Daisuke; Fukuda, Kenichi; Kasai, Shinya; Hasegawa, Junko; Wajima, Koichi; Nakagawa, Taneaki

2016-01-01

Background Fentanyl is often used instead of morphine for the treatment of pain because it has fewer side effects. The metabolism of morphine by glucuronidation is known to be influenced by polymorphisms of the UGT2B7 gene. Some metabolic products of fentanyl are reportedly metabolized by glucuronate conjugation. The genes that are involved in the metabolic pathway of fentanyl may also influence fentanyl sensitivity. We analyzed associations between fentanyl sensitivity and polymorphisms of the UGT2B7 gene to clarify the hereditary determinants of individual differences in fentanyl sensitivity. Results This study examined whether single-nucleotide polymorphisms (SNPs) of the UGT2B7 gene affect cold pain sensitivity and the analgesic effects of fentanyl, evaluated by a standardized pain test and fentanyl requirements in healthy Japanese subjects who underwent uniform surgical procedures. The rs7439366 SNP of UGT2B7 is reportedly associated with the metabolism and analgesic effects of morphine. We found that this SNP is also associated with the analgesic effects of fentanyl in the cold pressor-induced pain test. It suggested that the C allele of the rs7439366 SNP may enhance analgesic efficacy. Two SNPs of UGT2B7, rs4587017 and rs1002849, were also found to be novel SNPs that may influence the analgesic effects of fentanyl in the cold pressor-induced pain test. Conclusions Fentanyl sensitivity for cold pressor-induced pain was associated with the rs7439366, rs4587017, and rs1002849 SNPs of the UGT2B7 gene. Our findings may provide valuable information for achieving satisfactory pain control and open to new avenues for personalized pain treatment. PMID:28256933

Decreased alertness due to sleep loss increases pain sensitivity in mice

PubMed Central

Alexandre, Chloe; Latremoliere, Alban; Ferreira, Ashley; Miracca, Giulia; Yamamoto, Mihoko; Scammell, Thomas E; Woolf, Clifford J

2018-01-01

Extended daytime and nighttime activities are major contributors to the growing sleep deficiency epidemic1,2, as is the high prevalence of sleep disorders like insomnia. The consequences of chronic insufficient sleep for health remain uncertain3. Sleep quality and duration predict presence of pain the next day in healthy subjects4–7, suggesting that sleep disturbances alone may worsen pain, and experimental sleep deprivation in humans supports this claim8,9. We demonstrate that sleep loss, but not sleep fragmentation, in healthy mice increases sensitivity to noxious stimuli (referred to as ‘pain’) without general sensory hyper-responsiveness. Moderate daily repeated sleep loss leads to a progressive accumulation of sleep debt and also to exaggerated pain responses, both of which are rescued after restoration of normal sleep. Caffeine and modafinil, two wake-promoting agents that have no analgesic activity in rested mice, immediately normalize pain sensitivity in sleep-deprived animals, without affecting sleep debt. The reversibility of mild sleep-loss-induced pain by wake-promoting agents reveals an unsuspected role for alertness in setting pain sensitivity. Clinically, insufficient or poor-quality sleep may worsen pain and this enhanced pain may be reduced not by analgesics, whose effectiveness is reduced, but by increasing alertness or providing better sleep. PMID:28481358

Association between pain, central sensitization and anxiety in postherpetic neuralgia.

PubMed

Schlereth, T; Heiland, A; Breimhorst, M; Féchir, M; Kern, U; Magerl, W; Birklein, F

2015-02-01

In postherpetic neuralgia (PHN), dorsal root ganglia neurons are damaged. According to the proposed models, PHN pain might be associated with nociceptive deafferentation, and peripheral (heat hyperalgesia) or central sensitization (allodynia). In 36 PHN patients, afferent nerve fibre function was characterized using quantitative sensory testing and histamine-induced flare analysis. Psychological factors were evaluated with the Hospital Anxiety and Depression Scale (HADS), disease-related quality of life (QoL) with SF-36 and pain with the McGill questionnaire [pain rating index (PRI)]. The patients were also divided into subgroups according to the presence or absence of brush-evoked allodynia as a sign of central sensitization. For all patients, warm, cold and mechanical detection was impaired (p < 0.001 each) and the size of the histamine flare was diminished on the affected side (p < 0.05); pain thresholds with the exception of brush-evoked allodynia (p < 0.05) were unaltered. Correlation analysis revealed allodynia, anxiety, depression, QoL and age as relevant factors associated with pain severity (PRI). Allodynia was present in 23 patients (64%). In these patients, heat pain perception was preserved; the histamine flare was larger; the pinprick pain was increased as were McGill PRI sensory subscore, actual pain rating and almost significantly pain (McGill PRI) over the last 4 weeks. PHN is associated with damage of afferent fibres. Central sensitization (i.e., allodynia) might contribute to PHN pain. There was a striking association between anxiety, depression and age, and the magnitude of PHN pain. © 2014 European Pain Federation - EFIC®

Effects of vicarious pain on self-pain perception: investigating the role of awareness

PubMed Central

Terrighena, Esslin L; Lu, Ge; Yuen, Wai Ping; Lee, Tatia MC; Keuper, Kati

2017-01-01

The observation of pain in others may enhance or reduce self-pain, yet the boundary conditions and factors that determine the direction of such effects are poorly understood. The current study set out to show that visual stimulus awareness plays a crucial role in determining whether vicarious pain primarily activates behavioral defense systems that enhance pain sensitivity and stimulate withdrawal or appetitive systems that attenuate pain sensitivity and stimulate approach. We employed a mixed factorial design with the between-subject factors exposure time (subliminal vs optimal) and vicarious pain (pain vs no pain images), and the within-subject factor session (baseline vs trial) to investigate how visual awareness of vicarious pain images affects subsequent self-pain in the cold-pressor test. Self-pain tolerance, intensity and unpleasantness were evaluated in a sample of 77 healthy participants. Results revealed significant interactions of exposure time and vicarious pain in all three dependent measures. In the presence of visual awareness (optimal condition), vicarious pain compared to no-pain elicited overall enhanced self-pain sensitivity, indexed by reduced pain tolerance and enhanced ratings of pain intensity and unpleasantness. Conversely, in the absence of visual awareness (subliminal condition), vicarious pain evoked decreased self-pain intensity and unpleasantness while pain tolerance remained unaffected. These findings suggest that the activation of defense mechanisms by vicarious pain depends on relatively elaborate cognitive processes, while – strikingly – the appetitive system is activated in highly automatic manner independent from stimulus awareness. Such mechanisms may have evolved to facilitate empathic, protective approach responses toward suffering individuals, ensuring survival of the protective social group. PMID:28831270

Mindfulness Meditation and Cognitive Behavioral Therapy Intervention Reduces Pain Severity and Sensitivity in Opioid-Treated Chronic Low Back Pain: Pilot Findings from a Randomized Controlled Trial

PubMed Central

Burzinski, Cindy A.; Cox, Jennifer; Kloke, John; Stegner, Aaron; Cook, Dane B.; Singles, Janice; Mirgain, Shilagh; Coe, Christopher L.; Bačkonja, Miroslav

2016-01-01

Objective. To assess benefits of mindfulness meditation and cognitive behavioral therapy (CBT)-based intervention for opioid-treated chronic low back pain (CLBP). Design. 26-week parallel-arm pilot randomized controlled trial (Intervention and Usual Care versus Usual Care alone). Setting. Outpatient. Subjects. Adults with CLBP, prescribed ≥30 mg/day of morphine-equivalent dose (MED) for at least 3 months. Methods. The intervention comprised eight weekly group sessions (meditation and CLBP-specific CBT components) and 30 minutes/day, 6 days/week of at-home practice. Outcome measures were collected at baseline, 8, and 26 weeks: primary-pain severity (Brief Pain Inventory) and function/disability (Oswestry Disability Index); secondary-pain acceptance, opioid dose, pain sensitivity to thermal stimuli, and serum pain-sensitive biomarkers (Interferon-γ; Tumor Necrosis Factor-α; Interleukins 1ß and 6; C-reactive Protein). Results. Thirty-five (21 experimental, 14 control) participants were enrolled and completed the study. They were 51.8 ± 9.7 years old, 80% female, with severe CLBP-related disability (66.7 ± 11.4), moderate pain severity (5.8 ± 1.4), and taking 148.3 ± 129.2 mg/day of MED. Results of the intention-to-treat analysis showed that, compared with controls, the meditation-CBT group reduced pain severity ratings during the study (P = 0.045), with between-group difference in score change reaching 1 point at 26 weeks (95% Confidence Interval: 0.2,1.9; Cohen’s d = 0.86), and decreased pain sensitivity to thermal stimuli (P < 0.05), without adverse events. Exploratory analyses suggested a relationship between the extent of meditation practice and the magnitude of intervention benefits. Conclusions. Meditation-CBT intervention reduced pain severity and sensitivity to experimental thermal pain stimuli in patients with opioid-treated CLBP. PMID:26968850

Moral transgressions corrupt neural representations of value.

PubMed

Crockett, Molly J; Siegel, Jenifer Z; Kurth-Nelson, Zeb; Dayan, Peter; Dolan, Raymond J

2017-06-01

Moral systems universally prohibit harming others for personal gain. However, we know little about how such principles guide moral behavior. Using a task that assesses the financial cost participants ascribe to harming others versus themselves, we probed the relationship between moral behavior and neural representations of profit and pain. Most participants displayed moral preferences, placing a higher cost on harming others than themselves. Moral preferences correlated with neural responses to profit, where participants with stronger moral preferences had lower dorsal striatal responses to profit gained from harming others. Lateral prefrontal cortex encoded profit gained from harming others, but not self, and tracked the blameworthiness of harmful choices. Moral decisions also modulated functional connectivity between lateral prefrontal cortex and the profit-sensitive region of dorsal striatum. The findings suggest moral behavior in our task is linked to a neural devaluation of reward realized by a prefrontal modulation of striatal value representations.

Allosteric Modulation of Ca2+ flux in Ligand-gated Cation Channel (P2X4) by Actions on Lateral Portals*

PubMed Central

Samways, Damien S. K.; Khakh, Baljit S.; Egan, Terrance M.

2012-01-01

Human P2X receptors are a family of seven ATP-gated ion channels that transport Na+, K+, and Ca2+ across cell surface membranes. The P2X4 receptor is unique among family members in its sensitivity to the macrocyclic lactone, ivermectin, which allosterically modulates both ion conduction and channel gating. In this paper we show that removing the fixed negative charge of a single acidic amino acid (Glu51) in the lateral entrance to the transmembrane pore markedly attenuates the effect of ivermectin on Ca2+ current and channel gating. Ca2+ entry through P2X4 receptors is known to trigger downstream signaling pathways in microglia. Our experiments show that the lateral portals could present a novel target for drugs in the treatment of microglia-associated disease including neuropathic pain. PMID:22219189

Moral transgressions corrupt neural representations of value

PubMed Central

Crockett, Molly J.; Siegel, Jenifer Z.; Kurth-Nelson, Zeb; Dayan, Peter; Dolan, Raymond J.

2017-01-01

Moral systems universally prohibit harming others for personal gain. However, we know little about how such principles guide moral behavior. Using a task that assesses the financial cost participants ascribe to harming others versus themselves, we probed the relationship between moral behavior and neural representations of profit and pain. Most participants displayed moral preferences, placing a higher cost on harming others than themselves. Moral preferences correlated with neural responses to profit, where participants with stronger moral preferences had lower dorsal striatal (DS) responses to profit gained from harming others. Lateral prefrontal cortex (LPFC) encoded profits gained from harming others, but not self, and tracked the blameworthiness of harmful choices. Moral decisions also modulated functional connectivity between LPFC and the profit-sensitive region of DS. The findings suggest moral behavior in our task is linked to a neural devaluation of reward realized by a prefrontal modulation of striatal value representations. PMID:28459442

Neuropathy-induced spinal GAP-43 expression is not a main player in the onset of mechanical pain hypersensitivity.

PubMed

Jaken, Robby J; van Gorp, Sebastiaan; Joosten, Elbert A; Losen, Mario; Martínez-Martínez, Pilar; De Baets, Marc; Marcus, Marco A; Deumens, Ronald

2011-12-01

Structural plasticity within the spinal nociceptive network may be fundamental to the chronic nature of neuropathic pain. In the present study, the spatiotemporal expression of growth-associated protein-43 (GAP-43), a protein which has been traditionally implicated in nerve fiber growth and sprouting, was investigated in relation to mechanical pain hypersensitivity. An L5 spinal nerve transection model was validated by the presence of mechanical pain hypersensitivity and an increase in the early neuronal activation marker cFos within the superficial spinal dorsal horn upon innocuous hindpaw stimulation. Spinal GAP-43 was found to be upregulated in the superficial L5 dorsal horn from 5 up to 10 days after injury. GAP-43 was co-localized with calcitonin-gene related peptide (CGRP), but not vesicular glutamate transporter-1 (VGLUT-1), IB4, or protein kinase-γ (PKC-γ), suggesting the regulation of GAP-43 in peptidergic nociceptive afferents. These GAP-43/CGRP fibers may be indicative of sprouting peptidergic fibers. Fiber sprouting largely depends on growth factors, which are typically associated with neuro-inflammatory processes. The putative role of neuropathy-induced GAP-43 expression in the development of mechanical pain hypersensitivity was investigated using the immune modulator propentofylline. Propentofylline treatment strongly attenuated the development of mechanical pain hypersensitivity and glial responses to nerve injury as measured by microglial and astroglial markers, but did not affect neuropathy-induced levels of spinal GAP-43 or GAP-43 regulation in CGRP fibers. We conclude that nerve injury induces structural plasticity in fibers expressing CGRP, which is regarded as a main player in central sensitization. Our data do not, however, support a major role of these structural changes in the onset of mechanical pain hypersensitivity.

Anxiety and depressive symptoms and anxiety sensitivity in youngsters with noncardiac chest pain and benign heart murmurs.

PubMed

Lipsitz, Joshua D; Masia-Warner, Carrie; Apfel, Howard; Marans, Zvi; Hellstern, Beth; Forand, Nicholas; Levenbraun, Yosef; Fyer, Abby J

2004-12-01

Chest pain in children and adolescents is rarely associated with cardiac disease. We sought to examine psychological symptoms in youngsters with medically unexplained chest pain. We hypothesized that children and adolescents with medically unexplained chest pain would have high rates of anxiety and depressive symptoms. We assessed 65 youngsters with noncardiac chest pain (NCCP) and 45 comparison youngsters with benign heart murmurs using self-report measures of anxiety and depressive symptoms and anxiety sensitivity. Compared with the asymptomatic benign-murmur group, youngsters with NCCP had higher levels of some anxiety symptoms and anxiety sensitivity. Differences on depressive symptoms were not significant. Though preliminary, results suggest that youngsters with chest pain may experience increased levels of some psychological symptoms. Future studies of noncardiac chest pain in youngsters should include larger samples and comprehensive diagnostic assessments as well as long-term follow-up evaluations.

Pain Adaptability in Individuals With Chronic Musculoskeletal Pain Is Not Associated With Conditioned Pain Modulation.

PubMed

Wan, Dawn Wong Lit; Arendt-Nielsen, Lars; Wang, Kelun; Xue, Charlie Changli; Wang, Yanyi; Zheng, Zhen

2018-03-27

Healthy humans can be divided into the pain adaptive (PA) and the pain nonadaptive (PNA) groups; PA showed a greater decrease in pain rating to a cold pressor test (CPT) than PNA. This study examined if the dichotomy of pain adaptability existed in individuals with chronic musculoskeletal pain. CPTs at 2°C and 7°C were used to assess the status of pain adaptability in participants with either chronic nonspecific low back pain or knee osteoarthritis. The participants' potency of conditioned pain modulation (CPM) and local inhibition were measured. The strengths of pain adaptability at both CPTs were highly correlated. PA and PNA did not differ in their demographic characteristics, pain thresholds from thermal and pressure stimuli, or potency of local inhibition or CPM. PA reached their maximum pain faster than PNA (t 41 = -2.76, P < .01), and had a gradual reduction of pain unpleasantness over 7 days whereas PNA did not (F 6,246  = 3.01, P = .01). The dichotomy of pain adaptability exists in musculoskeletal pain patients. Consistent with the healthy human study, the strength of pain adaptability and potency of CPM are not related. Pain adaptability could be another form of endogenous pain inhibition of which clinical implication is yet to be understood. The dichotomy of pain adaptability was identified in healthy humans. The current study confirms that this dichotomy also exists in individuals with chronic musculoskeletal pain, and could be reliably assessed with CPTs at 2°C and 7°C. Similar to the healthy human study, pain adaptability is not associated with CPM, and may reflect the temporal aspect of pain inhibition. Copyright © 2018 The American Pain Society. Published by Elsevier Inc. All rights reserved.

Effects of Posteroanterior Thoracic Mobilization on Heart Rate Variability and Pain in Women with Fibromyalgia

PubMed Central

Reis, Michel Silva; Durigan, João Luiz Quagliotti; Arena, Ross; Rossi, Bruno Rafael Orsini; Mendes, Renata Gonçalves; Borghi-Silva, Audrey

2014-01-01

Fibromyalgia (FM) has been associated with cardiac autonomic abnormalities and pain. Heart rate variability (HRV) is reduced in FM with autonomic tone dominated by sympathetic activity. The purpose of this study was to evaluate the effects of one session of a posteroanterior glide technique on both autonomic modulation and pain in woman with FM. This was a controlled trial with immediate followup; twenty premenopausal women were allocated into 2 groups: (i) women diagnosed with FM (n = 10) and (ii) healthy women (n = 10). Both groups received one session of Maitland mobilization grade III posteroanterior central pressure glide, at 2 Hz for 60 s at each vertebral segment. Autonomic modulation was assessed by HRV and pain by a numeric pain scale before and after the intervention. For HRV analyses, heart rate and RR intervals were recorded for 10 minutes. FM subjects demonstrated reduced HRV compared to controls. Although the mobilization technique did not significantly reduce pain, it was able to improve HRV quantified by an increase in rMSSD and SD1 indices, reflecting an improved autonomic profile through increased vagal activity. In conclusion, women with FM presented with impaired cardiac autonomic modulation. One session of Maitland spine mobilization was able to acutely improve HRV. PMID:24991436

Captured by the pain: pain steady-state evoked potentials are not modulated by selective spatial attention.

PubMed

Blöchl, Maria; Franz, Marcel; Miltner, Wolfgang H R; Weiss, Thomas

2015-04-07

Attention has been shown to affect the neural processing of pain. However, the exact mechanisms underlying this modulation remain unknown. Here, we used a new method called pain steady-state evoked potentials (PSSEPs) to investigate whether selective spatial attention affects EEG responses to tonic painful stimuli. In general, steady-state evoked potentials reflect changes in the EEG spectrum at a certain frequency that correspond to the frequency of a train of applied stimuli. In this study, high intensity transcutaneous electrical stimulation was delivered to both hands simultaneously with 31 Hz and 37 Hz, respectively. Subject׳s attention was directed to one of the two trains of stimulation in order to detect a small gap that was occasionally interspersed into the stimulus trains. Thereby, they had to ignore the stimulation applied to the other hand. Results show that PSSEPs were induced at 31 Hz and 37 Hz at frontal and central electrodes. PSSEPs occurred contralaterally to the respective hand stimulated with that frequency. Surprisingly, the magnitude of PSSEPs was not modulated by spatial attention towards one of the two stimuli. Our results indicate that attention can hardly be shifted between two simultaneously applied tonic painful stimulations. Copyright © 2015 Elsevier B.V. All rights reserved.

Reduced laser-evoked potential habituation detects abnormal central pain processing in painful radiculopathy patients.

PubMed

Hüllemann, P; von der Brelie, C; Manthey, G; Düsterhöft, J; Helmers, A K; Synowitz, M; Baron, R

2017-05-01

Repetitive painful laser stimuli lead to physiological laser-evoked potential (LEP) habituation, measurable by a decrement of the N2/P2 amplitude. The time course of LEP-habituation is reduced in the capsaicin model for peripheral and central sensitization and in patients with migraine and fibromyalgia. In the present investigation, we aimed to assess the time course of LEP-habituation in a neuropathic pain syndrome, i.e. painful radiculopathy. At the side of radiating pain, four blocks of 25 painful laser stimuli each were applied to the ventral thigh at the L3 dermatome in 27 patients with painful radiculopathy. Inclusion criteria were (1) at least one neurological finding of radiculopathy, (2) low back pain with radiation into the foot and (3) a positive one-sided compression of the L5 and/or S1 root in the MRI. The time course of LEP-habituation was compared to 20 healthy height and age matched controls. Signs of peripheral (heat hyperalgesia) and central sensitization (dynamic mechanical allodynia and hyperalgesia) at the affected L5 or S1 dermatome were assessed with quantitative sensory testing. Painful radiculopathy patients showed decreased LEP-habituation compared to controls. Patients with signs of central sensitization showed a more prominent LEP-habituation decrease within the radiculopathy patient group. Laser-evoked potential habituation is reduced in painful radiculopathy patients, which indicates an abnormal central pain processing. Central sensitization seems to be a major contributor to abnormal LEP habituation. The LEP habituation paradigm might be useful as a clinical tool to assess central pain processing alterations in nociceptive and neuropathic pain conditions. Abnormal central pain processing in neuropathic pain conditions may be revealed with the laser-evoked potential habituation paradigm. In painful radiculopathy patients, LEP-habituation is reduced compared to healthy controls. © 2017 European Pain Federation - EFIC®.

Women with dysmenorrhoea are hypersensitive to experimentally induced forearm ischaemia during painful menstruation and during the pain-free follicular phase.

PubMed

Iacovides, S; Avidon, I; Baker, F C

2015-07-01

Monthly primary dysmenorrhoeic pain is associated with increased sensitivity to painful stimuli, particularly in deep tissue. We investigated whether women with dysmenorrhoea, compared with controls, have increased sensitivity to experimentally induced deep-tissue muscle ischaemia in a body area distant from that of referred menstrual pain. The sub-maximal effort tourniquet test was used to induce forearm ischaemia in 11 women with severe dysmenorrhoea and in nine control women both during menstruation and in the follicular phase of the menstrual cycle. Von Frey hair assessments confirmed the presence of experimental ischaemia. Women rated the intensity of menstrual and ischaemic pain on a 100-mm visual analogue scale. Women with dysmenorrhoea [mean (SD): 68 (20) mm] reported significantly greater menstrual pain compared with controls [mean (SD): 2 (6) mm; p = 0.0001] during the menstruation phase. They also rated their forearm ischaemic pain as significantly greater than the controls during the menstruation [dysmenorrhoeics vs. controls mean (SD): 58 (19) mm vs. 31 (21) mm, p < 0.01] and follicular [dysmenorrhoeics vs. controls mean (SD): 60 (18) mm vs. 40 (14) mm, p < 0.01] phases of the menstrual cycle. These data show that compared with controls, women who experience severe recurrent dysmenorrhoea have deep-tissue hyperalgesia to ischaemic pain in muscles outside of the referred area of menstrual pain both during the painful menstruation phase and pain-free follicular phase. These findings suggest the presence of long-lasting changes in muscle pain sensitivity in women with dysmenorrhoea. Our findings that dysmenorrhoeic women are hyperalgesic to a clinically relevant, deep-muscle ischaemic pain in areas outside of referred menstrual pain confirm other studies showing long-lasting changes in pain sensitivity outside of the painful period during menstruation. © 2014 European Pain Federation - EFIC®

Sub-paresthesia spinal cord stimulation reverses thermal hyperalgesia and modulates low frequency EEG in a rat model of neuropathic pain.

PubMed

Koyama, Suguru; Xia, Jimmy; Leblanc, Brian W; Gu, Jianwen Wendy; Saab, Carl Y

2018-05-08

Paresthesia, a common feature of epidural spinal cord stimulation (SCS) for pain management, presents a challenge to the double-blind study design. Although sub-paresthesia SCS has been shown to be effective in alleviating pain, empirical criteria for sub-paresthesia SCS have not been established and its basic mechanisms of action at supraspinal levels are unknown. We tested our hypothesis that sub-paresthesia SCS attenuates behavioral signs of neuropathic pain in a rat model, and modulates pain-related theta (4-8 Hz) power of the electroencephalogram (EEG), a previously validated correlate of spontaneous pain in rodent models. Results show that sub-paresthesia SCS attenuates thermal hyperalgesia and power amplitude in the 3-4 Hz range, consistent with clinical data showing significant yet modest analgesic effects of sub-paresthesia SCS in humans. Therefore, we present evidence for anti-nociceptive effects of sub-paresthesia SCS in a rat model of neuropathic pain and further validate EEG theta power as a reliable 'biosignature' of spontaneous pain.

A Multidisciplinary Self-Directed Learning Module Improves Knowledge of a Quality Improvement Instrument: The HEART Pathway.

PubMed

Hartman, Nicholas D; Harper, Erin N; Leppert, Lauren M; Browning, Brittany M; Askew, Kim; Manthey, David E; Mahler, Simon A

We created and tested an educational intervention to support implementation of an institution wide QI project (the HEART Pathway) designed to improve care for patients with acute chest pain. Although online learning modules have been shown effective in imparting knowledge regarding QI projects, it is unknown whether these modules are effective across specialties and healthcare professions. Participants, including nurses, advanced practice clinicians, house staff and attending physicians (N = 486), were enrolled into an online, self-directed learning course exploring the key concepts of the HEART Pathway. The module was completed by 97% of enrollees (469/486) and 90% passed on the first attempt (422/469). Out of 469 learners, 323 completed the pretest, learning module and posttest in the correct order. Mean test scores across learners improved significantly from 74% to 89% from the pretest to the posttest. Following the intervention, the HEART Pathway was used for 88% of patients presenting to our institution with acute chest pain. Our data demonstrate that this online, self-directed learning module can improve knowledge of the HEART Pathway across specialties-paving the way for more efficient and informed care for acute chest pain patients.

Chronic post-traumatic headache: clinical findings and possible mechanisms

PubMed Central

Defrin, Ruth

2014-01-01

Chronic post-traumatic headache (CPTHA), the most frequent complaint after traumatic brain injury (TBI), dramatically affects quality of life and function. Despite its high prevalence and persistence, the mechanism of CPTHA is poorly understood. This literature review aimed to analyze the results of studies assessing the characteristics and sensory profile of CPTHA in order to shed light on its possible underlying mechanisms. The search for English language articles published between 1960 and 2013 was conducted in MEDLINE, CINAHL, and PubMed. Studies assessing clinical features of headache after TBI as well as studies conducting quantitative somatosensory testing (QST) in individuals with CPTHA and in individuals suffering from other types of pain were included. Studies on animal models of pain following damage to peripheral tissues and to the peripheral and central nervous system were also included. The clinical features of CPTHA resembled those of primary headache, especially tension-type and migraine headache. Positive and negative signs were prevalent among individuals with CPTHA, in both the head and in other body regions, suggesting the presence of local (cranial) mechanical hypersensitivity, together with generalized thermal hypoesthesia and hypoalgesia. Evidence of dysfunctional pain modulation was also observed. Chronic post-traumatic headache can result from damage to intra- and pericranial tissues that caused chronic sensitization of these tissues. Alternatively, although not mutually exclusive, CPTHA might possibly be a form of central pain due to damage to brain structures involved in pain processing. These, other possibilities, as well as risk factors for CPTHA are discussed at length. PMID:24976746

Relationships between psychological state, abuse, somatization and visceral pain sensitivity in irritable bowel syndrome

PubMed Central

Grinsvall, Cecilia; Törnblom, Hans; Tack, Jan; Van Oudenhove, Lukas; Simrén, Magnus

2018-01-01

Background and objective Psychological states may interfere with visceral sensitivity. Here we investigate associations between psychosocial factors and visceral sensitivity in irritable bowel syndrome (IBS). Methods Two IBS patient cohorts (Cohort 1: n = 231, Rome II; Cohort 2: n = 141, Rome III) underwent rectal barostat testing, and completed questionnaires for anxiety, depression, somatization, and abuse. The associations between questionnaire measures and visceral sensitivity parameters were analyzed in three-step general linear models (step1: demographic and abuse variables; step 2: anxiety and depression; step 3: somatization). Results Cohort 1. Pain threshold was positively associated with age and female gender, and negatively with adult sexual abuse and somatization. Pain referral area was negatively associated with age and positively with somatization and GI-specific anxiety, the latter effect mediated by somatization. Cohort 2. Pain threshold was positively associated with age and male gender, and negatively with adult sexual abuse. Pain intensity ratings were positively associated with somatization, female gender and depression, the latter effect mediated by somatization. Conclusion Somatization is associated with most visceral sensitivity parameters, and mediates the effect of some psychological factors on visceral sensitivity. It may reflect a psychobiological sensitization process driving symptom generation in IBS. In addition, abuse history was found to independently affect some visceral sensitivity parameters. PMID:29511560

Dissociable Neural Mechanisms Underlying the Modulation of Pain and Anxiety? An fMRI Pilot Study

PubMed Central

Moseley, Graham Lorimer; Berna, Chantal; Ploner, Markus; Tracey, Irene

2014-01-01

The down-regulation of pain through beliefs is commonly discussed as a form of emotion regulation. In line with this interpretation, the analgesic effect has been shown to co-occur with reduced anxiety and increased activity in the ventrolateral prefrontal cortex (VLPFC), which is a key region of emotion regulation. This link between pain and anxiety modulation raises the question whether the two effects are rooted in the same neural mechanism. In this pilot fMRI study, we compared the neural basis of the analgesic and anxiolytic effect of two types of threat modulation: a “behavioral control” paradigm, which involves the ability to terminate a noxious stimulus, and a “safety signaling” paradigm, which involves visual cues that signal the threat (or absence of threat) that a subsequent noxious stimulus might be of unusually high intensity. Analgesia was paralleled by VLPFC activity during behavioral control. Safety signaling engaged elements of the descending pain control system, including the rostral anterior cingulate cortex that showed increased functional connectivity with the periaqueductal gray and VLPFC. Anxiety reduction, in contrast, scaled with dorsolateral prefrontal cortex activation during behavioral control but had no distinct neural signature during safety signaling. Our pilot data therefore suggest that analgesic and anxiolytic effects are instantiated in distinguishable neural mechanisms and differ between distinct stress- and pain-modulatory approaches, supporting the recent notion of multiple pathways subserving top-down modulation of the pain experience. Additional studies in larger cohorts are needed to follow up on these preliminary findings. PMID:25502237

Small-fiber neuropathy and pain sensitization in survivors of pediatric acute lymphoblastic leukemia.

PubMed

Lieber, S; Blankenburg, M; Apel, K; Hirschfeld, G; Hernáiz Driever, P; Reindl, T

2018-05-01

Chemotherapy-induced Peripheral Neuropathy (CIPN) of large-fibers affects up to 20% of survivors of pediatric acute lymphoblastic leukemia (ALL). We aimed to describe small-fiber toxicity and pain sensitization in this group. In a cross-sectional, bicentric study we assessed 46 survivors of pediatric ALL (Mean age: 5.7 ± 3.5 years at diagnosis, median 2.5 years after therapy; males: 28). ≥6 years of age, ≥3 months after last administration of Vincristine, and cumulative dose of Vincristine 12 mg/m 2 . We used a reduced version of the Pediatric-modified Total Neuropathy Score (Ped-mTNS) as bedside test and Quantitative Sensory Testing (QST) for assessment of small- and large-fiber neuropathy as well as pain sensitization. We employed Nerve Conduction Studies (NCS) as the most accurate tool for detecting large-fiber neuropathy. Fifteen survivors (33%) had abnormal rPed-mTNS values (≥4 points) and 5 survivors (11%) reported pain. In QST, the survivor group showed significant (p < 0.001) inferior large-fiber function and pain sensitization when compared to healthy matched peers. We identified deficits of vibration in 33 (72%) and tactile hypoesthesia in 29 (63%), hyperalgesia to blunt pressure in 19 (41%), increased mechanical pain sensitivity in 12 (26%) and allodynia in 16 (35%) of 46 survivors. Only 7 survivors (15%) had pathologic NCS. QST is a sensitive tool that revealed signs of large-fiber neuropathy in two thirds, small-fiber neuropathy and pain sensitization in one third of survivors. Prospective studies using QST in pediatric oncology may help to elucidate the pathophysiology of small-fiber neuropathy and pain sensitization as well as their relevance for quality of survival. Copyright © 2018 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.

Triggering Descending Pain Inhibition by Observing Ourselves or a Loved-One in Pain.

PubMed

Gougeon, Véronique; Gaumond, Isabelle; Goffaux, Philippe; Potvin, Stéphane; Marchand, Serge

2016-03-01

Recent studies demonstrate that empathy-evoked brain responses include the activation of brainstem structures responsible for triggering descending pain inhibition. Unfortunately, direct evidence linking empathy for pain and descending inhibitory controls (conditioned pain modulation) is lacking. This study, therefore, aimed to determine if the observation of ourselves or a loved-one in pain could activate descending pain inhibition without exposure to a noxious stimulation; which is otherwise required. Descending pain inhibition was triggered by immersing the right arm of participants (15 heterosexual couples; mean age±SE: 28.89±2.14) in a bath of cold water. The effects of empathy on descending pain inhibition were observed by immersing the right arm of participants in a bath of lukewarm water while having them watch a video of either themselves or their spouse during a previous nociceptive immersion. Immersion of the arm in a bath of lukewarm water without empathic (video) observation was also included as a control condition. A strong inhibitory response activated by the mere observation of the video of themselves or their spouse in pain without a nociceptive conditioning stimulus. Associative statistics also showed that strong pain catastrophizing responses while watching the video resulted in stronger pain inhibition. Moreover, high levels of empathy were associated with stronger pain inhibition, but only for women. This study showed that observing someone in pain triggers descending pain inhibition. Results also demonstrate how empathy and gender are affecting pain modulation mechanisms.

Membrane stiffening by STOML3 facilitates mechanosensation in sensory neurons

PubMed Central

Qi, Yanmei; Andolfi, Laura; Frattini, Flavia; Mayer, Florian; Lazzarino, Marco; Hu, Jing

2015-01-01

Sensing force is crucial to maintain the viability of all living cells. Despite its fundamental importance, how force is sensed at the molecular level remains largely unknown. Here we show that stomatin-like protein-3 (STOML3) controls membrane mechanics by binding cholesterol and thus facilitates force transfer and tunes the sensitivity of mechano-gated channels, including Piezo channels. STOML3 is detected in cholesterol-rich lipid rafts. In mouse sensory neurons, depletion of cholesterol and deficiency of STOML3 similarly and interdependently attenuate mechanosensitivity while modulating membrane mechanics. In heterologous systems, intact STOML3 is required to maintain membrane mechanics to sensitize Piezo1 and Piezo2 channels. In C57BL/6N, but not STOML3−/− mice, tactile allodynia is attenuated by cholesterol depletion, suggesting that membrane stiffening by STOML3 is essential for mechanical sensitivity. Targeting the STOML3–cholesterol association might offer an alternative strategy for control of chronic pain. PMID:26443885

Predictors of the transition from acute to persistent musculoskeletal pain in children and adolescents: a prospective study

PubMed Central

Holley, Amy Lewandowski; Wilson, Anna C.; Palermo, Tonya M.

2016-01-01

Strategies directed at the prevention of disabling pain have been suggested as a public health priority, making early identification of youth at risk for poor outcomes critical. At present limited information is available to predict which youth presenting with acute pain are at risk for persistence. The aims of this prospective longitudinal study were to identify biopsychosocial factors in the acute period that predict the transition to persistent pain in youth with new-onset musculoskeletal (MSK) pain complaints. Participants were 88 children and adolescents (age 10–17 years) presenting to the emergency department (n=47) or orthopedic clinic (n=41) for evaluation of a new MSK pain complaint (< 1 month duration). Youth presented for two study visits (T1 = <1 month post pain onset; T2 = 4 month follow-up) during which they completed questionnaires (assessing pain characteristics, psychological factors, sleep quality) and participated in a lab task assessing conditioned pain modulation (CPM). Regression analyses tested T1 predictors of longitudinal pain outcomes (pain persistence, pain-related disability, quality of life). Results revealed approximately 35% of youth had persistent pain at 4-month follow-up, with persistent pain predicted by poorer CPM and female sex. Higher depressive symptoms at T1 were associated with higher pain-related disability and poorer quality of life at T2. Findings highlight the roles of depressive symptoms and pain modulation in longitudinally predicting pain persistence in treatment-seeking youth with acute MSK pain, and suggest potential mechanisms in the transition from acute to chronic MSK pain in children and adolescents. PMID:28151835

Threatening social context facilitates pain-related fear learning.

PubMed

Karos, Kai; Meulders, Ann; Vlaeyen, Johan W S

2015-03-01

This study investigated the effects of a threatening and a safe social context on learning pain-related fear, a key factor in the development and maintenance of chronic pain. We measured self-reported pain intensity, pain expectancy, pain-related fear (verbal ratings and eyeblink startle responses), and behavioral measures of avoidance (movement-onset latency and duration) using an established differential voluntary movement fear conditioning paradigm. Participants (N = 42) performed different movements with a joystick: during fear acquisition, movement in one direction (CS+) was followed by a painful stimulus (pain-US) whereas movement in another direction (CS-) was not. For participants in the threat group, an angry face was continuously presented in the background during the task, whereas in the safe group, a happy face was presented. During the extinction phase the pain-US was omitted. As compared to the safe social context, a threatening social context led to increased contextual fear and facilitated differentiation between CS+ and CS- movements regarding self-reported pain expectancy, fear of pain, eyeblink startle responses, and movement-onset latency. In contrast, self-reported pain intensity was not affected by social context. These data support the modulation of pain-related fear by social context. A threatening social context leads to stronger acquisition of (pain-related) fear and simultaneous contextual fear but does not affect pain intensity ratings. This knowledge may aid in the prevention of chronic pain and anxiety disorders and shows that social context might modulate pain-related fear without immediately affecting pain intensity itself. Copyright © 2015 American Pain Society. Published by Elsevier Inc. All rights reserved.

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.

Lubiprostone does not Influence Visceral Pain Thresholds in Patients with Irritable Bowel Syndrome

PubMed Central

Whitehead, William E.; Palsson, Olafur S.; Gangarosa, Lisa; Turner, Marsha; Tucker, Jane

2011-01-01

Background In clinical trials, lubiprostone reduced the severity of abdominal pain. Aims The primary aim was to determine whether lubiprostone raises the threshold for abdominal pain induced by intraluminal balloon distention. A secondary aim was to determine whether changes in pain sensitivity influence clinical pain independently of changes in transit time. Methods Sixty-two patients with irritable bowel syndrome with constipation (IBS-C) participated in an 8-week crossover study. All subjects completed a 14-day baseline ending with a barostat test of pain and urge sensory thresholds. Half, randomly selected, then received 48 ug/day of lubiprostone for 14 days ending with a pain sensitivity test and a Sitzmark test of transit time. This was followed by a 14-day washout and then a crossover to 14 days of placebo with tests of pain sensitivity and transit time. The other half of the subjects received placebo before lubiprostone. All kept symptom diaries. Results Stools were significantly softer when taking lubiprostone compared to placebo (Bristol Stool scores 4.20 vs. 3.44, p<0.001). However, thresholds for pain (17.36 vs. 17.83 mmHg, lubiprostone vs. placebo) and urgency to defecate (14.14 vs. 14.53 mmHg) were not affected by lubiprostone. Transit time was not significantly different between lubiprostone and placebo (51.27 vs. 51.81 hours), and neither pain sensitivity nor transit time was a significant predictor of clinical pain. Conclusions Lubiprostone has no effect on visceral sensory thresholds. The reductions in clinical pain that occur while taking lubiprostone appear to be secondary to changes in stool consistency. PMID:21914041

Somatic syndromes and chronic pain in women with overactive bladder

PubMed Central

Reynolds, W. Stuart; Mock, Stephen; Zhang, Xuechao; Kaufman, Melissa; Wein, Alan; Bruehl, Stephen; Dmochowski, Roger

2016-01-01

Aims Mechanisms underlying pain perception and afferent hypersensitivity, such as central sensitization, may impact overactive bladder (OAB) symptoms. However, little is known about associations between OAB symptom severity, pain experience, and presence of comorbid chronic pain syndromes. This study examined relationships between OAB symptoms, somatic symptoms, and specific chronic pain conditions in which central sensitization is believed to play a primary role, in a community-based sample of adult women with OAB Methods We recruited adult women with OAB to complete questionnaires assessing urinary symptoms, pain and somatic symptoms, and preexisting diagnoses of central sensitivity syndromes. We analyzed the effects of overall bodily pain intensity, general somatic symptoms, and diagnoses of central sensitivity syndromes on OAB symptom bother and health-related quality of life. Results Of the 116 women in this study, over half (54%) stated their urge to urinate was associated with pain, pressure, or discomfort. Participants reported a wide range of OAB symptoms and health-related quality of life. There was a significant, positive correlation between OAB symptoms and somatic symptoms as well as overall pain intensity. Only 7% of women met diagnostic criteria for fibromyalgia; yet these women demonstrated significantly increased OAB symptom burden and decreased OAB quality of life compared to those without fibromyalgia. Conclusion Women with more severe OAB symptoms reported increased general somatic symptom burden and increased overall body pain intensity, especially women with fibromyalgia. These findings suggest that attributes of pain and co-morbidity with chronic pain conditions may impact the experience of OAB symptoms for many women. PMID:27367486

Substance P-induced skin inflammation is not modulated by a single dose of sitagliptin in human volunteers.

PubMed

Grouzmann, Eric; Bigliardi, Paul; Appenzeller, Monique; Pannatier, André; Buclin, Thierry

2011-03-01

Substance P (SP), an undecapeptide belonging to the tachykinin family, is released during the activation of sensory nerves, and causes vasodilation, edema and pain through activation of tissular Neurokinin 1 receptors. SP proinflammatory effects are terminated by angiotensin converting enzyme (ACE) and neutral endopeptidase (NEP), while the aminopeptidase dipeptidylpeptidase IV (DPPIV) can also play a role. The aim of this randomized, crossover, double-blind study was to assess the cutaneous vasoreactivity (flare and wheal reaction, burning pain sensation) to intradermal injection of ascending doses of SP in six volunteers receiving a single therapeutic dose of the DPPIV inhibitor sitagliptin or a matching placebo. Cutaneous SP challenges produced the expected, dose-dependent flare and wheal response, while eliciting mild to moderate local pain sensation with little dose dependency. However, no differences were shown in the responses observed under sitagliptin compared with placebo, while the study would have been sufficiently powered to detect a clinically relevant increase in sensitivity to SP. The results of this pilot study are in line with proteolytic cleavage of SP by ACE and NEP compensating the blockade of DPPIV to prevent an augmentation of its proinflammatory action.

Sleep Fragmentation Exacerbates Mechanical Hypersensitivity and Alters Subsequent Sleep-Wake Behavior in a Mouse Model of Musculoskeletal Sensitization

PubMed Central

Sutton, Blair C.; Opp, Mark R.

2014-01-01

Study Objectives: Sleep deprivation, or sleep disruption, enhances pain in human subjects. Chronic musculoskeletal pain is prevalent in our society, and constitutes a tremendous public health burden. Although preclinical models of neuropathic and inflammatory pain demonstrate effects on sleep, few studies focus on musculoskeletal pain. We reported elsewhere in this issue of SLEEP that musculoskeletal sensitization alters sleep of mice. In this study we hypothesize that sleep fragmentation during the development of musculoskeletal sensitization will exacerbate subsequent pain responses and alter sleep-wake behavior of mice. Design: This is a preclinical study using C57BL/6J mice to determine the effect on behavioral outcomes of sleep fragmentation combined with musculoskeletal sensitization. Methods: Musculoskeletal sensitization, a model of chronic muscle pain, was induced using two unilateral injections of acidified saline (pH 4.0) into the gastrocnemius muscle, spaced 5 days apart. Musculoskeletal sensitization manifests as mechanical hypersensitivity determined by von Frey filament testing at the hindpaws. Sleep fragmentation took place during the consecutive 12-h light periods of the 5 days between intramuscular injections. Electroencephalogram (EEG) and body temperature were recorded from some mice at baseline and for 3 weeks after musculoskeletal sensitization. Mechanical hypersensitivity was determined at preinjection baseline and on days 1, 3, 7, 14, and 21 after sensitization. Two additional experiments were conducted to determine the independent effects of sleep fragmentation or musculoskeletal sensitization on mechanical hypersensitivity. Results: Five days of sleep fragmentation alone did not induce mechanical hypersensitivity, whereas sleep fragmentation combined with musculoskeletal sensitization resulted in prolonged and exacerbated mechanical hypersensitivity. Sleep fragmentation combined with musculoskeletal sensitization had an effect on subsequent sleep of mice as demonstrated by increased numbers of sleep-wake state transitions during the light and dark periods; changes in nonrapid eye movement (NREM) sleep, rapid eye movement sleep, and wakefulness; and altered delta power during NREM sleep. These effects persisted for at least 3 weeks postsensitization. Conclusions: Our data demonstrate that sleep fragmentation combined with musculoskeletal sensitization exacerbates the physiological and behavioral responses of mice to musculoskeletal sensitization, including mechanical hypersensitivity and sleep-wake behavior. These data contribute to increasing literature demonstrating bidirectional relationships between sleep and pain. The prevalence and incidence of insufficient sleep and pathologies characterized by chronic musculoskeletal pain are increasing in the United States. These demographic data underscore the need for research focused on insufficient sleep and chronic pain so that the quality of life for the millions of individuals with these conditions may be improved. Citation: Sutton BC; Opp MR. Sleep fragmentation exacerbates mechanical hypersensitivity and alters subsequent sleep-wake behavior in a mouse model of musculoskeletal sensitization. SLEEP 2014;37(3):515-524. PMID:24587574

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

Role of the primary motor cortex in the maintenance and treatment of pain in fibromyalgia.

PubMed

Castillo Saavedra, Laura; Mendonca, Mariana; Fregni, Felipe

2014-09-01

Fibromyalgia is a highly prevalent, debilitating disease, characterized by chronic widespread pain. The mechanisms underlying pain are not completely understood, but it is believed to be associated with important neuroplastic changes in pain-related neural circuits. Although the involvement of the pain matrix in fibromyalgia is well established, another area that has been found to play a role in the maintenance and treatment of chronic pain is the primary motor cortex (M1). Maladaptive plasticity of M1 is a common finding in patients with chronic pain and many studies in animal models and in human subjects have shown that modulation of the activity of this cortical area induces significant analgesic effects. Furthermore, studies in other chronic pain syndromes have found alterations in baseline characteristics of M1, including an increase in cortical excitability and an abnormally enhanced response to incoming sensory stimuli. Given these findings, we hypothesize that M1 is a major modulator of pain in fibromyalgia and therefore its baseline activity reflects this strong feedback between M1 and pain-related neural areas. However, the feedback loop between M1 and the pain matrix is not enough to decrease pain in fibromyalgia per se, thus increasing its modulatory effect by engaging this network through different behavioral and modulatory techniques is a potentially beneficial treatment for pain in fibromyalgia. Copyright © 2014 Elsevier Ltd. All rights reserved.

Effect of systemic monosodium glutamate (MSG) on headache and pericranial muscle sensitivity.

PubMed

Baad-Hansen, L; Cairns, Be; Ernberg, M; Svensson, P

2010-01-01

We conducted a double-blinded, placebo-controlled, crossover study to investigate the occurrence of adverse effects such as headache as well as pain and mechanical sensitivity in pericranial muscles after oral administration of monosodium glutamate (MSG). In three sessions, 14 healthy men drank sugar-free soda that contained either MSG (75 or 150 mg/kg) or NaCl (24 mg/kg, placebo). Plasma glutamate level, pain, pressure pain thresholds and tolerance levels, blood pressure (BP), heart rate and reported adverse effects were assessed for 2 h. No muscle pain or robust changes in mechanical sensitivity were detected, but there was a significant increase in reports of headache and subjectively reported pericranial muscle tenderness after MSG. Systolic BP was elevated in the high MSG session compared with low MSG and placebo. These findings add new information to the concept of MSG headache and craniofacial pain sensitivity.

ACTH-like peptides increase pain sensitivity and antagonize opiate analgesia

NASA Technical Reports Server (NTRS)

Heybach, J. P.; Vernikos, J.

1981-01-01

The role of the pituitary and of ACTH in pain sensitivity was investigated in the rat. Pain sensitivity was assessed by measuring paw-lick and jump latencies in response to being placed on a grid at 55 C. Hypophysectomy reduced pain sensitivity, and this effect was reversed by the intracerebroventricular (ICV) injection of the opiate antagonist naloxone. Similarly, the analgesia produced by a dose of morphine was antagonized by the administration of ACTH or alpha-MSH. The peripheral injection of ACTH or alpha-MSH in normal rats did not increase pain sensitivity. However, ACTH administered ICV increased pain sensivity within 10 min. The results indicate that the pituitary is the source of an endogenous opiate antagonist and hyperalgesic factor and that this factor is ACTH or an ACTH-like peptide. This activity resides in the N-terminal portion of the ACTH molecule since ACTH sub 4-10 is not active in this respect, nor does this activity require a free N-terminal serine since alpha-MSH appears to be almost as potent as the ACTH sub 1-24 peptide. It is concluded that ACTH-like peptides of pituitary origin act as endogenous hyperalgesic and opiate antagonistic factors.

Quantitative sensory testing in the German Research Network on Neuropathic Pain (DFNS): reference data for the trunk and application in patients with chronic postherpetic neuralgia.

PubMed

Pfau, Doreen B; Krumova, Elena K; Treede, Rolf-Detlef; Baron, Ralf; Toelle, Thomas; Birklein, Frank; Eich, Wolfgang; Geber, Christian; Gerhardt, Andreas; Weiss, Thomas; Magerl, Walter; Maier, Christoph

2014-05-01

Age- and gender-matched reference values are essential for the clinical use of quantitative sensory testing (QST). To extend the standard test sites for QST-according to the German Research Network on Neuropathic Pain-to the trunk, we collected QST profiles on the back in 162 healthy subjects. Sensory profiles for standard test sites were within normal interlaboratory differences. QST revealed lower sensitivity on the upper back than the hand, and higher sensitivity on the lower back than the foot, but no systematic differences between these trunk sites. Age effects were significant for most parameters. Females exhibited lower pressure pain thresholds (PPT) than males, which was the only significant gender difference. Values outside the 95% confidence interval of healthy subjects (considered abnormal) required temperature changes of >3.3-8.2 °C for thermal detection. For cold pain thresholds, confidence intervals extended mostly beyond safety cutoffs, hence only relative reference data (left-right differences, hand-trunk differences) were sufficiently sensitive. For mechanical detection and pain thresholds, left-right differences were 1.5-2.3 times more sensitive than absolute reference data. The most sensitive parameter was PPT, where already side-to-side differences >35% were abnormal. Compared to trunk reference data, patients with postherpetic neuralgia exhibited thermal and tactile deficits and dynamic mechanical allodynia, mostly without reduced mechanical pain thresholds. This pattern deviates from other types of neuropathic pain. QST reference data for the trunk will also be useful for patients with postthoracotomy pain or chronic back pain. Copyright © 2014 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

Effect of deafferentation from spinal anesthesia on pain sensitivity and resting-state functional brain connectivity in healthy male volunteers.

PubMed

Niesters, Marieke; Sitsen, Elske; Oudejans, Linda; Vuyk, Jaap; Aarts, Leon P H J; Rombouts, Serge A R B; de Rover, Mischa; Khalili-Mahani, Najmeh; Dahan, Albert

2014-08-01

Patients may perceive paradoxical heat sensation during spinal anesthesia. This could be due to deafferentation-related functional changes at cortical, subcortical, or spinal levels. In the current study, the effect of spinal deafferentation on sensory (pain) sensitivity was studied and linked to whole-brain functional connectivity as assessed by resting-state functional magnetic resonance imaging (RS-fMRI) imaging. Deafferentation was induced by sham or spinal anesthesia (15 mg bupivacaine injected at L3-4) in 12 male volunteers. RS-fMRI brain connectivity was determined in relation to eight predefined and seven thalamic resting-state networks (RSNs) and measured before, and 1 and 2 h after spinal/sham injection. To measure the effect of deafferentation on pain sensitivity, responses to heat pain were measured at 15-min intervals on nondeafferented skin and correlated to RS-fMRI connectivity data. Spinal anesthesia altered functional brain connectivity within brain regions involved in the sensory discriminative (i.e., pain intensity related) and affective dimensions of pain perception in relation to somatosensory and thalamic RSNs. A significant enhancement of pain sensitivity on nondeafferented skin was observed after spinal anesthesia compared to sham (area-under-the-curve [mean (SEM)]: 190.4 [33.8] versus 13.7 [7.2]; p<0.001), which significantly correlated to functional connectivity changes observed within the thalamus in relation to the thalamo-prefrontal network, and in the anterior cingulate cortex and insula in relation to the thalamo-parietal network. Enhanced pain sensitivity from spinal deafferentation correlated with functional connectivity changes within brain regions involved in affective and sensory pain processing and areas involved in descending control of pain.

Pain Sensitivity and Recovery From Mild Chronic Sleep Loss

PubMed Central

Roehrs, Timothy A.; Harris, Erica; Randall, Surilla; Roth, Thomas

2012-01-01

Study Objectives: To determine whether an extended bedtime in sleepy and otherwise healthy volunteers would increase alertness and thereby also reduce pain sensitivity. Setting: Outpatient with sleep laboratory assessments. Participants and Interventions: Healthy volunteers (n = 18), defined as having an average daily sleep latency on the Multiple Sleep Latency Test (MSLT) < 8 min, were randomized to 4 nights of extended bedtime (10 hr) (EXT) or 4 nights of their diary-reported habitual bedtimes (HAB). On day 1 and day 4 they received a standard MSLT (10:00, 12:00, 14:00, and 16:00 hr) and finger withdrawal latency pain testing to a radiant heat stimulus (10:30 and 14:30 hr). Results: During the four experimental nights the EXT group slept 1.8 hr per night more than the HAB group and average daily sleep latency on the MSLT increased in the EXT group, but not the HAB group. Similarly, finger withdrawal latency was increased (pain sensitivity was reduced) in the EXT group but not the HAB group. The nightly increase in sleep time during the four experimental nights was correlated with the improvement in MSLT, which in turn was correlated with reduced pain sensitivity. Conclusions: These are the first data to show that an extended bedtime in mildly sleepy healthy adults, which resulted in increased sleep time and reduced sleepiness, reduces pain sensitivity. Citation: Roehrs TA; Harris E; Randall S; Roth T. Pain sensitivity and recovery from mild chronic sleep loss. SLEEP 2012;35(12):1667-1672. PMID:23204609

Chronic Opioid Therapy and Central Sensitization in Sickle Cell Disease.

PubMed

Carroll, C Patrick; Lanzkron, Sophie; Haywood, Carlton; Kiley, Kasey; Pejsa, Megan; Moscou-Jackson, Gyasi; Haythornthwaite, Jennifer A; Campbell, Claudia M

2016-07-01

Chronic opioid therapy (COT) for chronic non-cancer pain is frequently debated, and its effectiveness is unproven in sickle cell disease (SCD). The authors conducted a descriptive study among 83 adult SCD patients and compared the severity of disease and pain symptoms among those who were prescribed COT (n=29) with those who were not using COT. All patients completed baseline laboratory pain assessment and questionnaires between January 2010 and June 2014. Thereafter, participants recorded daily pain, crises, function, and healthcare utilization for 90 days using electronic diaries. Analyses were conducted shortly after the final diary data collection period. Patients on COT did not differ on age, sex, or measures of disease severity. However, patients on COT exhibited greater levels of clinical pain (particularly non-crisis); central sensitization; and depression and increased diary measures of pain severity, function, and healthcare utilization on crisis and non-crisis diary days, as well as a greater proportion of days in crisis. Including depressive symptoms in multivariate models did not change the associations between COT and pain, interference, central sensitization, or utilization. Additionally, participants not on COT displayed the expected positive relationship between central sensitization and clinical pain, whereas those on COT demonstrated no such relationship, despite having both higher central sensitization and higher clinical pain. Overall, the results point out a high symptom burden in SCD patients on COT, including those on high-dose COT, and suggest that nociceptive processing in SCD patients on COT differs from those who are not. Copyright © 2016 American Journal of Preventive Medicine. Published by Elsevier Inc. All rights reserved.

Pain-related anxiety influences pain perception differently in men and women: a quantitative sensory test across thermal pain modalities.

PubMed

Thibodeau, Michel A; Welch, Patrick G; Katz, Joel; Asmundson, Gordon J G

2013-03-01

The sexes differ with respect to perception of experimental pain. Anxiety influences pain perception more in men than in women; however, there lacks research exploring which anxiety constructs influence pain perception differentially between men and women. Furthermore, research examining whether depression is associated with pain perception differently between the sexes remains scant. The present investigation was designed to examine how trait anxiety, pain-related anxiety constructs (ie, fear of pain, pain-related anxiety, anxiety sensitivity), and depression are associated with pain perception between the sexes. A total of 95 nonclinical participants (55% women) completed measures assessing the constructs of interest and participated in quantitative sensory testing using heat and cold stimuli administered by a Medoc Pathway Pain and Sensory Evaluation System. The findings suggest that pain-related anxiety constructs, but not trait anxiety, are associated with pain perception. Furthermore, these constructs are associated with pain intensity ratings in men and pain tolerance levels in women. This contrasts with previous research suggesting that anxiety influences pain perception mostly or uniquely in men. Depression was not systematically associated with pain perception in either sex. Systematic relationships were not identified that allow conclusions regarding how fear of pain, pain-related anxiety, and anxiety sensitivity may contribute to pain perception differentially in men and women; however, anxiety sensitivity was associated with increased pain tolerance, a novel finding needing further examination. The results provide directions for future research and clinical endeavors and support that fear and anxiety are important features associated with hyperalgesia in both men and women. Copyright © 2012 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

Investigation of central pain processing in shoulder pain: converging results from two musculoskeletal pain models

PubMed Central

Valencia, Carolina; Kindler, Lindsay L.; Fillingim, Roger B.; George, Steven Z.

2011-01-01

Recent reports suggest deficits in conditioned pain modulation (CPM) and enhanced suprathreshold heat pain response (SHPR) potentially play a role in the development of chronic pain. The purpose of this study was to investigate whether central pain processing was altered in 2 musculoskeletal shoulder pain models. The goals of this study were to determine whether central pain processing: 1) differs between healthy subjects and patients with clinical shoulder pain, 2) changes with induction of exercise induced muscle pain (EIMP), and 3) changes 3 months after shoulder surgery. Fifty eight patients with clinical shoulder pain and 56 age and sex matched healthy subjects were included in these analyses. The healthy cohort was examined before inducing EIMP, and 48 and 96 hours later. The clinical cohort was examined before shoulder surgery and 3 months later. CPM did not differ between the cohorts, however; SHPR was elevated for patients with shoulder pain compared to healthy controls. Induction of acute shoulder pain with EIMP resulted in increased shoulder pain intensity but did not change CPM or SHPR. Three months following shoulder surgery clinical pain intensity decreased but CPM was unchanged from pre-operative assessment. In contrast SHPR was decreased and showed values comparable with healthy controls at 3 months. Therefore, the present study suggests that: 1) clinical shoulder pain is associated with measurable changes in central pain processing, 2) exercise-induced shoulder pain did not affect measures of central pain processing, and 3) elevated SHPR was normalized with shoulder surgery. Collectively our findings support neuroplastic changes in pain modulation were associated with decreases in clinical pain intensity only, and could be detected more readily with thermal stimuli. PMID:22208804

Physical activity behavior predicts endogenous pain modulation in older adults.

PubMed

Naugle, Kelly M; Ohlman, Thomas; Naugle, Keith E; Riley, Zachary A; Keith, NiCole R

2017-03-01

Older adults compared with younger adults are characterized by greater endogenous pain facilitation and a reduced capacity to endogenously inhibit pain, potentially placing them at a greater risk for chronic pain. Previous research suggests that higher levels of self-reported physical activity are associated with more effective pain inhibition and less pain facilitation on quantitative sensory tests in healthy adults. However, no studies have directly tested the relationship between physical activity behavior and pain modulatory function in older adults. This study examined whether objective measures of physical activity behavior cross-sectionally predicted pain inhibitory function on the conditioned pain modulation (CPM) test and pain facilitation on the temporal summation (TS) test in healthy older adults. Fifty-one older adults wore an accelerometer on the hip for 7 days and completed the CPM and TS tests. Measures of sedentary time, light physical activity (LPA), and moderate to vigorous physical activity (MVPA) were obtained from the accelerometer. Hierarchical linear regressions were conducted to determine the relationship of TS and CPM with levels of physical activity, while controlling for demographic, psychological, and test variables. The results indicated that sedentary time and LPA significantly predicted pain inhibitory function on the CPM test, with less sedentary time and greater LPA per day associated with greater pain inhibitory capacity. Additionally, MVPA predicted pain facilitation on the TS test, with greater MVPA associated with less TS of pain. These results suggest that different types of physical activity behavior may differentially impact pain inhibitory and facilitatory processes in older adults.

Comparison of the Analgesic Effects of Dronabinol and Smoked Marijuana in Daily Marijuana Smokers

PubMed Central

Cooper, Ziva D; Comer, Sandra D; Haney, Margaret

2013-01-01

Recent studies have demonstrated the therapeutic potential of cannabinoids to treat pain, yet none have compared the analgesic effectiveness of smoked marijuana to orally administered Δ9-tetrahydrocannabinol (THC; dronabinol). This randomized, placebo-controlled, double-dummy, double-blind study compared the magnitude and duration of analgesic effects of smoked marijuana and dronabinol under well-controlled conditions using a validated experimental model of pain. Healthy male (N=15) and female (N=15) daily marijuana smokers participated in this outpatient study comparing the analgesic, subjective, and physiological effects of marijuana (0.00, 1.98, or 3.56% THC) to dronabinol (0, 10, or 20 mg). Pain response was assessed using the cold-pressor test (CPT): participants immersed their left hand in cold water (4 °C), and the time to report pain (pain sensitivity) and withdraw the hand from the water (pain tolerance) were recorded. Subjective pain and drug effect ratings were also measured as well as cardiovascular effects. Compared with placebo, marijuana and dronabinol decreased pain sensitivity (3.56% 20 mg), increased pain tolerance (1.98% 20 mg), and decreased subjective ratings of pain intensity (1.98, 3.56% 20 mg). The magnitude of peak change in pain sensitivity and tolerance did not differ between marijuana and dronabinol, although dronabinol produced analgesia that was of a longer duration. Marijuana (1.98, 3.56%) and dronabinol (20 mg) also increased abuse-related subjective ratings relative to placebo; these ratings were greater with marijuana. These data indicate that under controlled conditions, marijuana and dronabinol decreased pain, with dronabinol producing longer-lasting decreases in pain sensitivity and lower ratings of abuse-related subjective effects than marijuana. PMID:23609132

Sucrose and naltrexone prevent increased pain sensitivity and impaired long-term memory induced by repetitive neonatal noxious stimulation: Role of BDNF and β-endorphin.

PubMed

Nuseir, Khawla Q; Alzoubi, Karem H; Alhusban, Ahmed; Bawaane, Areej; Al-Azzani, Mohammed; Khabour, Omar F

2017-10-01

Pain in neonates is associated with short and long-term adverse outcomes. Data demonstrated that long-term consequences of untreated pain are linked to the plasticity of the neonate's brain. Sucrose is effective and safe for reducing painful procedures from single events. However, the mechanism of sucrose-induced analgesia is not fully understood. The role of the opioid system in this analgesia using the opioid receptor antagonist Naltrexone was investigated, plus the long-term effects on learning and memory formation during adulthood. Pain was induced in rat pups via needle pricks of the paws. Sucrose solution and/or naltrexone were administered before the pricks. All treatments started on day one of birth and continued for two weeks. At the end of 8weeks, behavioral studies were conducted to test spatial learning and memory using radial arm water maze (RAWM), and pain threshold via foot-withdrawal response to a hot plate. The hippocampus was dissected; levels of brain derived neurotrophic factor (BDNF) and endorphins were assessed using ELISA. Acute repetitive neonatal pain increased pain sensitivity later in life, while naltrexone with sucrose decreased pain sensitivity. Naltrexone and/or sucrose prevented neonatal pain induced impairment of long-term memory, while neonatal pain decreased levels of BDNF in the hippocampus; this decrease was averted by sucrose and naltrexone. Sucrose with naltrexone significantly increased β-endorphin levels in noxiously stimulated rats. In conclusion, naltrexone and sucrose can reverse increased pain sensitivity and impaired long-term memory induced by acute repetitive neonatal pain probably by normalizing BDNF expression and increasing β-endorphin levels. Copyright © 2017 Elsevier Inc. All rights reserved.

Comparison of the analgesic effects of dronabinol and smoked marijuana in daily marijuana smokers.

PubMed

Cooper, Ziva D; Comer, Sandra D; Haney, Margaret

2013-09-01

Recent studies have demonstrated the therapeutic potential of cannabinoids to treat pain, yet none have compared the analgesic effectiveness of smoked marijuana to orally administered Δ(9)-tetrahydrocannabinol (THC; dronabinol). This randomized, placebo-controlled, double-dummy, double-blind study compared the magnitude and duration of analgesic effects of smoked marijuana and dronabinol under well-controlled conditions using a validated experimental model of pain. Healthy male (N=15) and female (N=15) daily marijuana smokers participated in this outpatient study comparing the analgesic, subjective, and physiological effects of marijuana (0.00, 1.98, or 3.56% THC) to dronabinol (0, 10, or 20 mg). Pain response was assessed using the cold-pressor test (CPT): participants immersed their left hand in cold water (4 °C), and the time to report pain (pain sensitivity) and withdraw the hand from the water (pain tolerance) were recorded. Subjective pain and drug effect ratings were also measured as well as cardiovascular effects. Compared with placebo, marijuana and dronabinol decreased pain sensitivity (3.56%; 20 mg), increased pain tolerance (1.98%; 20 mg), and decreased subjective ratings of pain intensity (1.98, 3.56%; 20 mg). The magnitude of peak change in pain sensitivity and tolerance did not differ between marijuana and dronabinol, although dronabinol produced analgesia that was of a longer duration. Marijuana (1.98, 3.56%) and dronabinol (20 mg) also increased abuse-related subjective ratings relative to placebo; these ratings were greater with marijuana. These data indicate that under controlled conditions, marijuana and dronabinol decreased pain, with dronabinol producing longer-lasting decreases in pain sensitivity and lower ratings of abuse-related subjective effects than marijuana.

Rostral Ventral Medulla Cholinergic Mechanism in Pain-Induced Analgesia

PubMed Central

Gear, Robert W.; Levine, Jon D.

2009-01-01

The ascending nociceptive control (ANC), a novel spinostriatal pain modulation pathway, mediates a form of pain-induced analgesia referred to as noxious stimulus-induced antinociception (NSIA). ANC includes specific spinal cord mechanisms as well as circuitry in nucleus accumbens, a major component of the ventral striatum. Here, using the trigeminal jaw-opening reflex (JOR) in the rat as a nociceptive assay, we show that microinjection of the nicotinic acetylcholine receptor (nAChR) antagonist mecamylamine into the rostral ventral medulla (RVM) blocks NSIA, implicating RVM as a potentially important link between ANC and the PAG – RVM – spinal descending pain modulation system. A circuit connecting nucleus accumbens to the RVM is proposed as a novel striato-RVM pathway. PMID:19699268

Melatonin analgesia is associated with improvement of the descending endogenous pain-modulating system in fibromyalgia: a phase II, randomized, double-dummy, controlled trial

PubMed Central

2014-01-01

Background Central disinhibition is a mechanism involved in the physiopathology of fibromyalgia. Melatonin can improve sleep quality, pain and pain threshold. We hypothesized that treatment with melatonin alone or in combination with amitriptyline would be superior to amitriptyline alone in modifying the endogenous pain-modulating system (PMS) as quantified by conditional pain modulation (CPM), and this change in CPM could be associated with serum brain-derived neurotrophic factor (BDNF). We also tested whether melatonin improves the clinical symptoms of pain, pain threshold and sleep quality. Methods Sixty-three females, aged 18 to 65, were randomized to receive bedtime amitriptyline (25 mg) (n = 21), melatonin (10 mg) (n = 21) or melatonin (10 mg) + amitriptyline (25 mg) (n = 21) for a period of six weeks. The descending PMS was assessed with the CPM-TASK. It was assessed the pain score on the Visual Analog Scale (VAS 0-100 mm), the score on Fibromyalgia Impact Questionnaire (FIQ), heat pain threshold (HPT), sleep quality and BDNF serum. Delta values (post- minus pre-treatment) were used to compare the treatment effect. The outcomes variables were collected before, one and six weeks after initiating treatment. Results Melatonin alone or in combination with amitriptyline reduced significantly pain on the VAS compared with amitriptyline alone (P < 0.01). The delta values on the VAS scores were-12.85 (19.93),-17.37 (18.69) and-20.93 (12.23) in the amitriptyline, melatonin and melatonin+amitriptyline groups, respectively. Melatonin alone and in combination increased the inhibitory PMS as assessed by the Numerical Pain Scale [NPS(0-10)] reduction during the CPM-TASK:-2.4 (2.04) melatonin + amitriptyline,-2.65 (1.68) melatonin, and-1.04 (2.06) amitriptyline, (P < 0.05). Melatonin + amitriptyline treated displayed better results than melatonin and amitriptyline alone in terms of FIQ and PPT improvement (P < 0.05, fort both). Conclusion Melatonin increased the inhibitory endogenous pain-modulating system as assessed by the reduction on NPS(0-10) during the CPM-TASK. Melatonin alone or associated with amitriptyline was better than amitriptyline alone in improving pain on the VAS, whereas its association with amitriptyline produced only marginal additional clinical effects on FIQ and PPT. Trial registration Current controlled trail is registered at clinical trials.gov upon under number NCT02041455. Registered January 16, 2014. PMID:25052847

An E-learning Module on Chronic Low Back Pain in Older Adults: Effect on Medical Resident Attitudes, Confidence, Knowledge, and Clinical Skills.

PubMed

Jacobs, Zachary G; Elnicki, D Michael; Perera, Subashan; Weiner, Debra K

2018-01-05

To determine 1) the feasibility of implementing an e-learning module on chronic low back pain (CLBP) in an older adult into an existing internal medicine residency curriculum and 2) the impact of this module on resident attitudes, confidence, knowledge, and clinical skills relating to CLBP. Participants were assigned to complete either the online module (N = 73) or the Yale Office-based curriculum on CLBP (N = 70). Attitudes, confidence, and knowledge were evaluated pre- and postintervention via survey. A retrospective blinded chart review of resident clinic encounters was conducted, wherein diagnosis codes and physical exam documentation were rated as basic or advanced. There was no improvement in overall knowledge scores in either group (60% average on both metrics). There were tendencies for greater improvements in the intervention group compared with controls for confidence in managing fibromyalgia (2.4 to 2.9 vs 2.5 to 2.5, P = 0.06) and leg length discrepancy (1.8 to 2.5 vs 1.5 to 1.9, P = 0.05). Those exposed to the online module also showed an increase in the percentage of physical exam documentation rated as advanced following the intervention (13% to 32%, P = 0.006), whereas the control group showed no change (14% to 12%, P = 0.68). An online module on CLBP in the older adult was a feasible addition to an existing curriculum for internal medicine residents. The module positively and substantively impacted resident clinical behaviors, as evidenced by enhanced sophistication in physical exam documentation; it also was associated with improved confidence in certain aspects of chronic pain management. © 2018 American Academy of Pain Medicine. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com

An increased response to experimental muscle pain is related to psychological status in women with chronic non-traumatic neck-shoulder pain

PubMed Central

2011-01-01

Background Neck-shoulder pain conditions, e.g., chronic trapezius myalgia, have been associated with sensory disturbances such as increased sensitivity to experimentally induced pain. This study investigated pain sensitivity in terms of bilateral pressure pain thresholds over the trapezius and tibialis anterior muscles and pain responses after a unilateral hypertonic saline infusion into the right legs tibialis anterior muscle and related those parameters to intensity and area size of the clinical pain and to psychological factors (sleeping problems, depression, anxiety, catastrophizing and fear-avoidance). Methods Nineteen women with chronic non-traumatic neck-shoulder pain but without simultaneous anatomically widespread clinical pain (NSP) and 30 age-matched pain-free female control subjects (CON) participated in the study. Results NSP had lower pressure pain thresholds over the trapezius and over the tibialis anterior muscles and experienced hypertonic saline-evoked pain in the tibialis anterior muscle to be significantly more intense and locally more widespread than CON. More intense symptoms of anxiety and depression together with a higher disability level were associated with increased pain responses to experimental pain induction and a larger area size of the clinical neck-shoulder pain at its worst. Conclusion These results indicate that central mechanisms e.g., central sensitization and altered descending control, are involved in chronic neck-shoulder pain since sensory hypersensitivity was found in areas distant to the site of clinical pain. Psychological status was found to interact with the perception, intensity, duration and distribution of induced pain (hypertonic saline) together with the spreading of clinical pain. The duration and intensity of pain correlated negatively with pressure pain thresholds. PMID:21992460

MUMPS Based Integration of Disparate Computer-Assisted Medical Diagnosis Modules

DTIC Science & Technology

1989-12-12

modules use a Bayesian approach, while the Opthalmology module uses a Rule Based approach. In the current effort, MUMPS is used to develop an...Abdominal and Chest Pain modules use a Bayesian approach, while the Opthalmology module uses a Rule Based approach. In the current effort, MUMPS is used

Temporal changes in cortical activation during distraction from pain: a comparative LORETA study with conditioned pain modulation.

PubMed

Moont, Ruth; Crispel, Yonatan; Lev, Rina; Pud, Dorit; Yarnitsky, David

2012-01-30

Methods to cognitively distract subjects from pain and experimental paradigms to induce conditioned pain modulation (CPM; formerly termed diffuse noxious inhibitory controls or DNIC) have each highlighted activity changes in closely overlapping cortical areas. This is the first study, to our knowledge, to compare cortical activation changes during these 2 manipulations in the same experimental set-up. Our study sample included thirty healthy young right handed males capable of expressing CPM. We investigated brief consecutive time windows using 32-channel EEG-based sLORETA, to determine dynamic changes in localized cortical potentials evoked by phasic noxious heat stimuli to the left volar forearm. This was performed under visual cognitive distraction tasks and conditioning hot-water pain to the right hand (CPM), both individually and simultaneously. Previously we have shown that for CPM, there is increased activity in frontal cortical regions followed by reduced activation of the somatosensory areas, suggesting a pain inhibitory role for these frontal regions. We now observed that distraction caused a different extent of cortical activation; greater early activation of frontal areas (DLPFC, OFC and caudal ACC at 250-350 ms post-stimulus), yet lesser reduction in the somatosensory cortices, ACC, PCC and SMA after 350 ms post-stimulus, compared to CPM. Both CPM and distraction reduced subjective pain scores to a similar extent. Combining CPM and distraction further reduced pain ratings compared to CPM and distraction alone, supporting the dissimilarity of the mechanisms of pain modulation under these 2 manipulations. The results are discussed in terms of the differential functional roles of the prefrontal cortex. Copyright © 2011 Elsevier B.V. All rights reserved.

The role of trigeminal nucleus caudalis orexin 1 receptors in orofacial pain transmission and in orofacial pain-induced learning and memory impairment in rats.

PubMed

Kooshki, Razieh; Abbasnejad, Mehdi; Esmaeili-Mahani, Saeed; Raoof, Maryam

2016-04-01

It is widely accepted that the spinal trigeminal nuclear complex, especially the subnucleus caudalis (Vc), receives input from orofacial structures. The neuropeptides orexin-A and -B are expressed in multiple neuronal systems. Orexin signaling has been implicated in pain-modulating system as well as learning and memory processes. Orexin 1 receptor (OX1R) has been reported in trigeminal nucleus caudalis. However, its roles in trigeminal pain modulation have not been elucidated so far. This study was designed to investigate the role of Vc OX1R in the modulation of orofacial pain as well as pain-induced learning and memory deficits. Orofacial pain was induced by subcutaneous injection of capsaicin in the right upper lip of the rats. OX1R agonist (orexin-A) and antagonist (SB-334867-A) were microinjected into Vc prior capsaicin administration. After recording nociceptive times, learning and memory was investigated using Morris water maze (MWM) test. The results indicated that, orexin-A (150 pM/rat) significantly reduced the nociceptive times, while SB334867-A (80 nM/rat) exaggerated nociceptive behavior in response to capsaicin injection. In MWM test, capsaicin-treated rats showed a significant learning and memory impairment. Moreover, SB-334867-A (80 nM/rat) significantly exaggerated learning and memory impairment in capsaicin-treated rats. However, administration of orexin-A (100 pM/rat) prevented learning and memory deficits. Taken together, these results indicate that Vc OX1R was at least in part involved in orofacial pain transmission and orexin-A has also a beneficial inhibitory effect on orofacial pain-induced deficits in abilities of spatial learning and memory. Copyright © 2016 Elsevier Inc. All rights reserved.

Brief Counseling for Veterans with Musculoskeletal Disorder, Risky Substance Use, and Service Connection Claims.

PubMed

Rosen, Marc I; Becker, William C; Black, Anne C; Martino, Steve; Edens, Ellen L; Kerns, Robert D

2018-05-22

High proportions of post-9/11 veterans have musculoskeletal disorders (MSDs), but engaging them in care early in their course of illness has been challenging. The service connection application is an ideal point of contact for referring veterans to early interventions for their conditions. Among MSD claimants who reported risky substance use, we pilot-tested a counseling intervention targeting pain and risky substance use called Screening Brief Intervention and Referral to Treatment-Pain Module (SBIRT-PM). Veterans were randomly assigned in a 2:1:1 ratio to SBIRT-PM, Pain Module counseling only, or treatment as usual (TAU). Participants assigned to either counseling arm were offered a single meeting with a study therapist with two follow-up telephone calls as needed. Participants completed outcome assessments at four and 12 weeks after randomization. Of 257 veterans evaluated, 101 reported risky substance use and were randomized. Counseling was attended by 75% of veterans offered it and was well received. VA pain-related services were used by 51% of participants in either of the pain-focused conditions but only by 27% in TAU (P < 0.04). Starting with average pain severity ratings of 5.1/10 at baseline, only minimal changes in mean pain severity were noted regardless of condition. Self-reported risky substance use was significantly lower over time in the SBIRT-PM condition relative to the two other conditions (P < 0.02). At week 12, proportions of veterans reporting risky substance use were 0.39, 0.69, and 0.71 for the SBIRT-PM, Pain Module counseling, and TAU conditions, respectively. SBIRT-PM shows promise as a way to engage veterans in pain treatment and reduce substance use.

Socio-Cultural Factors and Experience of Chronic Low Back Pain: a Spanish and Brazilian Patients’ Perspective. A Qualitative Study

PubMed Central

2016-01-01

Background Low back pain (LBP) could be influenced by socio-cultural factors. Pain narratives are important to understand the influence of environment on patients with chronic LBP. There are few studies that have explored the experience of patients with chronic LBP in different socio-cultural environments. The aim of this study was to describe the experience of patients with chronic LBP in Spain and Brazil. Methods A qualitative phenomenology approach was implemented. Chronic LBP patients from the University Hospital of Salamanca (Spain), and/or Federal University of São Carlos (Brazil) were included, using purposeful sampling. Data were collected from 22 Spanish and 26 Brazilian patients during in-depth interviews and using researchers’ field notes and patients' personal diaries and letters. A thematic analysis was performed and the guidelines for reporting qualitative research were applied. Results Forty-eight patients with a mean age of 50.7 years (SD: ± 13.1 years) were included in the study. The themes identified included: a) ways of perceiving and expressing pain—the participants focused constantly on their pain and anything outside it was considered secondary; b) the socio-familial environment as a modulator of pain—most participants stated that no one was able to understand the pain they were experiencing; c) religion as a modulator of pain—all Brazilian patients stated that religious belief affected the experience of pain; and d) socio-economic and educational status as a modulator of pain—the study reported that economic factors influenced the experience of pain. Conclusions The influences of LBP can be determined based on the how a patient defines pain. Religion can be considered as a possible mechanism for patients to manage pain and as a form of solace. PMID:27434594

Overexpressed TRPV3 ion channels in skin keratinocytes modulate pain sensitivity via prostaglandin E2

PubMed Central

Huang, Susan M.; Lee, Hyosang; Chung, Man-Kyo; Park, Una; Yu, Yin Yin; Bradshaw, Heather B.; Coulombe, Pierre A.; Walker, J. Michael; Caterina, Michael J.

2009-01-01

The ability to sense changes in the environment is essential for survival because it permits responses such as withdrawal from noxious stimuli and regulation of body temperature. Keratinocytes, which occupy much of the skin epidermis, are situated at the interface between the external environment and the body's internal milieu, and have long been appreciated for their barrier function against external insults. The recent discovery of temperature-sensitive TRPV ion channels in keratinocytes has raised the possibility that these cells also actively participate in acute temperature and pain sensation. To address this notion, we generated and characterized transgenic mice that overexpress TRPV3 in epidermal keratinocytes under the control of the keratin 14 promoter. Compared to wild-type controls, keratinocytes overexpressing TRPV3 exhibited larger currents as well as augmented prostaglandin E2 (PGE2) release in response to two TRPV3 agonists, 2-aminoethoxydiphenyl borate (2APB) and heat. Thermal selection behavior and heat-evoked withdrawal behavior of naïve mice overexpressing TRPV3 were not consistently altered. Upon selective pharmacological inhibition of TRPV1 with JNJ-7203212, however, the keratinocyte-specific TRPV3 transgenic mice showed increased escape responses to noxious heat relative to their wild-type littermates. Co-administration of the cyclooxygenase inhibitor, ibuprofen, with the TRPV1 antagonist decreased inflammatory thermal hyperalgesia in transgenic but not wild-type animals. Our results reveal a previously undescribed mechanism for keratinocyte participation in thermal pain transduction through keratinocyte TRPV3 ion channels and the intercellular messenger PGE2. PMID:19091963

Language and the pain experience.

PubMed

Wilson, Dianne; Williams, Marie; Butler, David

2009-03-01

People in persistent pain have been reported to pay increased attention to specific words or descriptors of pain. The amount of attention paid to pain or cues for pain (such as pain descriptors), has been shown to be a major factor in the modulation of persistent pain. This relationship suggests the possibility that language may have a role both in understanding and managing the persistent pain experience. The aim of this paper is to describe current models of neuromatrices for pain and language, consider the role of attention in persistent pain states and highlight discrepancies, in previous studies based on the McGill Pain Questionnaire (MPQ), of the role of attention on pain descriptors. The existence of a pain neuromatrix originally proposed by Melzack (1990) has been supported by emerging technologies. Similar technologies have recently allowed identification of multiple areas of involvement for the processing of auditory input and the construction of language. As with the construction of pain, this neuromatrix for speech and language may intersect with neural systems for broader cognitive functions such as attention, memory and emotion. A systematic search was undertaken to identify experimental or review studies, which specifically investigated the role of attention on pain descriptors (as cues for pain) in persistent pain patients. A total of 99 articles were retrieved from six databases, with 66 articles meeting the inclusion criteria. After duplicated articles were eliminated, the remaining 41 articles were reviewed in order to support a link between persistent pain, pain descriptors and attention. This review revealed a diverse range of specific pain descriptors, the majority of which were derived from the MPQ. Increased attention to pain descriptors was consistently reported to be associated with emotional state as well as being a significant factor in maintaining persistent pain. However, attempts to investigate the attentional bias of specific pain descriptors highlighted discrepancies between the studies. As well as the diversity of pain descriptors used in studies, they were inconsistently categorized into domains of pain. A lack of consistent bias towards certain pain descriptors was observed, and may be explained simply by the fact that the words provided are not those which subjects themselves would use. These findings suggest that the multidimensional and individual nature of the persistent pain experience may not be adequately explained by pain questionnaires such as the MPQ. Personalized pain descriptors may communicate the pain experience more appropriately, but may also contribute to an increased sensitivity of cortical pain processing areas by capturing increased attention for that individual. The language used as part of communication between therapists and people with persistent pain may provide an, as yet, unexplored adjunct strategy in management. Copyright (c) 2008 John Wiley & Sons, Ltd.

A longitudinal study of pain, personality, and brain plasticity following peripheral nerve injury.

PubMed

Goswami, Ruma; Anastakis, Dimitri J; Katz, Joel; Davis, Karen D

2016-03-01

We do not know precisely why pain develops and becomes chronic after peripheral nerve injury (PNI), but it is likely due to biological and psychological factors. Here, we tested the hypotheses that (1) high Pain Catastrophizing Scale (PCS) scores at the time of injury and repair are associated with pain and cold sensitivity after 1-year recovery and (2) insula gray matter changes reflect the course of injury and improvements over time. Ten patients with complete median and/or ulnar nerve transections and surgical repair were tested ∼3 weeks after surgical nerve repair (time 1) and ∼1 year later for 6 of the 10 patients (time 2). Patients and 10 age-/sex-matched healthy controls completed questionnaires that assessed pain (patients) and personality and underwent quantitative sensory testing and 3T MRI to assess cortical thickness. In patients, pain intensity and neuropathic pain correlated with pain catastrophizing. Time 1 pain catastrophizing trended toward predicting cold pain thresholds at time 2, and at time 1 cortical thickness of the right insula was reduced. At time 2, chronic pain was related to the time 1 pain-PCS relationship and cold sensitivity, pain catastrophizing correlated with cold pain threshold, and insula thickness reversed to control levels. This study highlights the interplay between personality, sensory function, and pain in patients following PNI and repair. The PCS-pain association suggests that a focus on affective or negative components of pain could render patients vulnerable to chronic pain. Cold sensitivity and structural insula changes may reflect altered thermosensory or sensorimotor awareness representations.

Effects of transcranial random noise stimulation (tRNS) on affect, pain and attention in multiple sclerosis.

PubMed

Palm, Ulrich; Chalah, Moussa A; Padberg, Frank; Al-Ani, Tarik; Abdellaoui, Mohamed; Sorel, Marc; Dimitri, Dalia; Créange, Alain; Lefaucheur, Jean-Pascal; Ayache, Samar S

2016-01-01

Pain and cognitive impairment are frequent symptoms in patients with multiple sclerosis (MS). Neglecting experimental pain and paying attention to demanding tasks is reported to decrease the pain intensity. Little is known about the interaction between chronic neuropathic pain and attention disorders in MS. Recently, transcranial direct current stimulation (tDCS) was used to modulate various cognitive and motor symptoms in MS. We aimed to study the effects of transcranial random noise stimulation (tRNS), a form of transcranial electric stimulation, over the left dorsolateral prefrontal cortex (DLPFC) on attention and neuropathic pain in MS patients. 16 MS patients were included in a randomized, sham-controlled, cross-over study. Each patient randomly received two tRNS blocks, separated by three weeks of washout interval. Each block consisted of three consecutive daily sessions of either active or sham tRNS. The patients were evaluated for pain, attention and mood and further underwent an electrophysiological evaluation. Compared to sham, tRNS showed a trend to decrease the N2-P2 amplitudes of pain related evoked potentials and improve pain ratings. Attention performance and mood scales did not change after stimulations. This study suggests the role of tRNS in pain modulation, which could have been more evident with longer stimulation protocols.

The role of chronic psychosocial stress in explaining racial differences in stress reactivity and pain sensitivity

PubMed Central

Gordon, Jennifer L.; Johnson, Jacqueline; Nau, Samantha; Mechlin, Beth; Girdler, Susan S.

2016-01-01

Objective To examine the role of psychosocial factors in mediating the relationship between African American (AA) race and both increased pain sensitivity and blunted stress reactivity. Methods Participants included 133 AA and non-Hispanic White (nHW) individuals (mean (SD) age = 37 (9)) matched for age, sex and socioeconomic status. Participants underwent mental stress testing (Trier Social Stress Test) while cardiovascular, hemodynamic, and neuroendocrine reactivity were measured. Participants completed questionnaires assessing potential sources of psychosocial stress and were tested for pain responses to cold pain and the temporal summation of heat pulses. Mediation analyses were used to determine the extent to which exposure to psychosocial stress accounted for the observed racial differences in stress reactivity and pain. Results Chronic stress exposure and reactivity to mental stress was largely similar among AAs and nHWs; however, AAs exhibited heightened pain to both cold (p = .012) and heat (p = .004). Racial differences in the relationship between stress reactivity and pain were also observed: while greater stress reactivity was associated with decreased pain among nHWs, reactivity was either unrelated to or even positively associated with pain among AAs (e.g. r = −.21 among nHWs and r = .41 among AAs for stroke volume reactivity and cold pressor intensity). Adjusting for minor racial differences in chronic psychosocial stress did not change these findings. Conclusion Accounting for psychosocial factors eliminated racial differences in stress reactivity but not racial differences in sensitivity to experimental pain tasks. Increased exposure to chronic stress may not explain AAs’ increased pain sensitivity in laboratory settings. PMID:27669431

A clinical perspective on a pain neuroscience education approach to manual therapy.

PubMed

Louw, Adriaan; Nijs, Jo; Puentedura, Emilio J

2017-07-01

In recent years, there has been an increased interest in pain neuroscience education (PNE) in physical therapy. There is growing evidence for the efficacy of PNE to decrease pain, disability, fear-avoidance, pain catastrophization, limited movement, and health care utilization in people struggling with pain. PNE teaches people in pain more about the biology and physiology of their pain experience including processes such as central sensitization, peripheral sensitization, allodynia, inhibition, facilitation, neuroplasticity and more. PNE's neurobiological model often finds itself at odds with traditional biomedical models used in physical therapy. Traditional biomedical models, focusing on anatomy, pathoanatomy, and biomechanics have been shown to have limited efficacy in helping people understand their pain, especially chronic pain, and may in fact even increase a person's pain experience by increasing fear-avoidance and pain catastrophization. An area of physical therapy where the biomedical model is used a lot is manual therapy. This contrast between PNE and manual therapy has seemingly polarized followers from each approach to see PNE as a 'hands-off' approach even having clinicians categorize patients as either in need of receiving PNE (with no hands-on), or hands-on with no PNE. In this paper, we explore the notion of PNE and manual therapy co-existing. PNE research has shown to have immediate effects of various clinical signs and symptoms associated with central sensitization. Using a model of sensitization (innocuous, noxious, and allodynia), we argue that PNE can be used in a manual therapy model, especially treating someone where the nervous system has become increasingly hypervigilant. Level of Evidence : VII.

The Role of Chronic Psychosocial Stress in Explaining Racial Differences in Stress Reactivity and Pain Sensitivity.

PubMed

Gordon, Jennifer L; Johnson, Jacqueline; Nau, Samantha; Mechlin, Beth; Girdler, Susan S

To examine the role of psychosocial factors in mediating the relationship between African American (AA) race and both increased pain sensitivity and blunted stress reactivity. Participants included 133 AA and non-Hispanic white (nHW) individuals (mean [SD] age, 37 [9]) matched for age, sex, and socioeconomic status. Participants underwent mental stress testing (Trier Social Stress Test) while cardiovascular, hemodynamic, and neuroendocrine reactivity were measured. Participants completed questionnaires assessing potential sources of psychosocial stress and were tested for pain responses to cold pain and the temporal summation of heat pulses. Mediation analyses were used to determine the extent to which exposure to psychosocial stress accounted for the observed racial differences in stress reactivity and pain. Chronic stress exposure and reactivity to mental stress was largely similar among AAs and nHWs; however, AAs exhibited heightened pain to both cold (p = .012) and heat (p = .004). Racial differences in the relationship between stress reactivity and pain were also observed: while greater stress reactivity was associated with decreased pain among nHWs, reactivity was either unrelated to or even positively associated with pain among AAs (e.g., r = -.21 among nHWs and r = .41 among AAs for stroke volume reactivity and cold pressor intensity). Adjusting for minor racial differences in chronic psychosocial stress did not change these findings. Accounting for psychosocial factors eliminated racial differences in stress reactivity but not racial differences in sensitivity to experimental pain tasks. Increased exposure to chronic stress may not explain AAs' increased pain sensitivity in laboratory settings.

Modulation of the peripheral immune system after low-dose radon spa therapy: Detailed longitudinal immune monitoring of patients within the RAD-ON01 study.

PubMed

Rühle, Paul F; Wunderlich, Roland; Deloch, Lisa; Fournier, Claudia; Maier, Andreas; Klein, Gerhart; Fietkau, Rainer; Gaipl, Udo S; Frey, Benjamin

2017-03-01

The pain-relieving effects of low-dose radon therapies on patients suffering from chronic painful inflammatory diseases have been described for centuries. Even though it has been suggested that low doses of radiation may attenuate chronic inflammation, the underlying mechanisms remain elusive. Thus, the RAD-ON01 study was initiated to examine the effects of radon spa therapy and its low doses of alpha radiation on the human immune system. In addition to an evaluation of pain parameters, blood was drawn from 100 patients suffering from chronic painful degenerative musculoskeletal diseases before as well as 6, 12, 18, and 30 weeks after the start of therapy. We verified significant long-term pain reduction for the majority of patients which was accompanied by modulations of the peripheral immune cells. Detailed immune monitoring was performed using a multicolor flow cytometry-based whole blood assay. After therapy, the major immune cells were only marginally affected. Nevertheless, a small but long-lasting increase in T cells and monocytes was observed. Moreover, neutrophils, eosinophils and, in particular, dendritic cells were temporarily modulated after therapy. Regarding the immune cell subsets, cytotoxic T and NK cells, in particular, were altered. However, the most prominent effects were identified in a strong reduction of the activation marker CD69 on T, B, and NK cells. Simultaneously, the percentage of HLA-DR + T cells was elevated after therapy. The RAD-ON01 study showed for the first time a modulation of the peripheral immune cells following standard radon spa therapy. These modulations are in line with attenuation of inflammation.

Magnitude and Temporal Variability of Inter-stimulus EEG Modulate the Linear Relationship Between Laser-Evoked Potentials and Fast-Pain Perception

PubMed Central

Li, Linling; Huang, Gan; Lin, Qianqian; Liu, Jia; Zhang, Shengli; Zhang, Zhiguo

2018-01-01

The level of pain perception is correlated with the magnitude of pain-evoked brain responses, such as laser-evoked potentials (LEP), across trials. The positive LEP-pain relationship lays the foundation for pain prediction based on single-trial LEP, but cross-individual pain prediction does not have a good performance because the LEP-pain relationship exhibits substantial cross-individual difference. In this study, we aim to explain the cross-individual difference in the LEP-pain relationship using inter-stimulus EEG (isEEG) features. The isEEG features (root mean square as magnitude and mean square successive difference as temporal variability) were estimated from isEEG data (at full band and five frequency bands) recorded between painful stimuli. A linear model was fitted to investigate the relationship between pain ratings and LEP response for fast-pain trials on a trial-by-trial basis. Then the correlation between isEEG features and the parameters of LEP-pain model (slope and intercept) was evaluated. We found that the magnitude and temporal variability of isEEG could modulate the parameters of an individual's linear LEP-pain model for fast-pain trials. Based on this, we further developed a new individualized fast-pain prediction scheme, which only used training individuals with similar isEEG features as the test individual to train the fast-pain prediction model, and obtained improved accuracy in cross-individual fast-pain prediction. The findings could help elucidate the neural mechanism of cross-individual difference in pain experience and the proposed fast-pain prediction scheme could be potentially used as a practical and feasible pain prediction method in clinical practice. PMID:29904336

The impact of pediatric chronic pain on parents' health-related quality of life and family functioning: reliability and validity of the PedsQL 4.0 Family Impact Module.

PubMed

Jastrowski Mano, Kristen E; Khan, Kimberly Anderson; Ladwig, Renee J; Weisman, Steven J

2011-06-01

To evaluate the psychometric properties of the Family Impact Module (FIM), a parent self-report measure of health-related quality of life (HRQOL) and family functioning, among parents of youth with chronic pain. Parents (N = 458) completed the FIM (Total Impact, HRQOL, and Family Functioning scales); parents and youth (N = 332) completed measures of pain catastrophizing, pediatric quality of life, and emotional/behavioral functioning. The FIM demonstrated strong internal consistency and item-total correlations. All FIM scales were positively associated with pain catastrophizing, functional disability, and emotional/behavioral problems; and inversely related to pediatric quality of life. Mothers reported significantly worse HRQOL than fathers. Mothers and fathers did not differ on reports of Family Functioning. HRQOL and Family Functioning did not differ as a function of pain diagnosis. The FIM appears to be a suitable measure of parent self-reported HRQOL and family functioning in pediatric chronic pain.

[Phosphorylation of protein kinase C in cerebrospinal fluid-contacting nucleus modulates the inflammatory pain in rats].

PubMed

Zhou, Fang; Wang, Jia-You; Tian, En-Qi; Zhang, Li-Cai

2015-12-25

The present study was aimed to investigate the role of cerebrospinal fluid-contacting nucleus (CSF-CN) neurons in modulation of inflammatory pain and underlying mechanism. The inflammatory pain model was made by subcutaneous injection of the complete Freund's adjuvant (CFA) into the left hind paw of rats. The phosphorylation level of PKC (p-PKC) was examined by Western blot. Thermal withdrawal latency (TWL) of the rats was measured to assess inflammatory pain. The results showed that, compared with the sham controls, the inflammatory pain model rats showed shortened TWL on day 1, 3, and 7 after CFA injection, as well as increased level of p-PKC in CSF-CN neurons at 24 h after CFA injection. The administration of GF109203X, a PKC inhibitor, into lateral ventricle decreased the level of p-PKC protein expression and increased TWL in the model rats. These results suggest that blocking the PKC pathway in CSF-CN neurons may be an effective way to reduce or eliminate the inflammatory pain.

Relationship of Corneal Pain Sensitivity With Dry Eye Symptoms in Dry Eye With Short Tear Break-Up Time.

PubMed

Kaido, Minako; Kawashima, Motoko; Ishida, Reiko; Tsubota, Kazuo

2016-03-01

The purpose of this prospective comparative study was to investigate corneal sensitivity in subjects with unstable tear film, with and without dry eye (DE) symptoms. Forty-one eyes of 41 volunteers (mean age: 45.1 ± 9.4 years; age range, 23-57 years), with normal tear function and ocular surface except for tear stability, were studied. The eyes were divided into two groups depending on the presence or absence of DE symptoms: 21 eyes with DE symptoms (symptomatic group); and 20 eyes without DE symptoms (asymptomatic group). Three types of corneal sensitivity values were measured using a Cochet-Bonnet esthesiometer: the sensitivity for perception of touch (S-touch), the sensitivity for blinking (S-blink), and the sensitivity for pain (S-pain). Mean S-blink and S-pain were significantly higher in the symptomatic group than in the asymptomatic group (P < 0.05), whereas there was no significant difference in mean S-touch between these groups (P > 0.05). Corneal sensitivity for blinking and pain evoked by increased stimuli was higher in the symptomatic group (subjects with short break-up time DE) compared with subjects who have no DE symptoms despite decreased tear stability. The presence of both tear instability and hyperesthesia, rather than tear instability alone, may contribute to DE pathogenesis.

Clinical descriptors for the recognition of central sensitization pain in patients with knee osteoarthritis.

PubMed

Lluch, Enrique; Nijs, Jo; Courtney, Carol A; Rebbeck, Trudy; Wylde, Vikki; Baert, Isabel; Wideman, Timothy H; Howells, Nick; Skou, Søren T

2017-08-02

Despite growing awareness of the contribution of central pain mechanisms to knee osteoarthritis pain in a subgroup of patients, routine evaluation of central sensitization is yet to be incorporated into clinical practice. The objective of this perspective is to design a set of clinical descriptors for the recognition of central sensitization in patients with knee osteoarthritis that can be implemented in clinical practice. A narrative review of original research papers was conducted by nine clinicians and researchers from seven different countries to reach agreement on clinically relevant descriptors. It is proposed that identification of a dominance of central sensitization pain is based on descriptors derived from the subjective assessment and the physical examination. In the former, clinicians are recommended to inquire about intensity and duration of pain and its association with structural joint changes, pain distribution, behavior of knee pain, presence of neuropathic-like or centrally mediated symptoms and responsiveness to previous treatment. The latter includes assessment of response to clinical test, mechanical hyperalgesia and allodynia, thermal hyperalgesia, hypoesthesia and reduced vibration sense. This article describes a set of clinically relevant descriptors that might indicate the presence of central sensitization in patients with knee osteoarthritis in clinical practice. Although based on research data, the descriptors proposed in this review require experimental testing in future studies. Implications for Rehabilitation Laboratory evaluation of central sensitization for people with knee osteoarthritis is yet to be incorporated into clinical practice. A set of clinical indicators for the recognition of central sensitization in patients with knee osteoarthritis is proposed. Although based on research data, the clinical indicators proposed require further experimental testing of psychometric properties.

Nervous System Sensitization as a Predictor of Outcome in the Treatment of Peripheral Musculoskeletal Conditions: A Systematic Review.

PubMed

O'Leary, Helen; Smart, Keith M; Moloney, Niamh A; Doody, Catherine M

2017-02-01

Research suggests that peripheral and central nervous system sensitization can contribute to the overall pain experience in peripheral musculoskeletal (MSK) conditions. It is unclear, however, whether sensitization of the nervous system results in poorer outcomes following the treatment. This systematic review investigated whether nervous system sensitization in peripheral MSK conditions predicts poorer clinical outcomes in response to a surgical or conservative intervention. Four electronic databases were searched to identify the relevant studies. Eligible studies had a prospective design, with a follow-up assessing the outcome in terms of pain or disability. Studies that used baseline indices of nervous system sensitization were included, such as quantitative sensory testing (QST) or questionnaires that measured centrally mediated symptoms. Thirteen studies met the inclusion criteria, of which six were at a high risk of bias. The peripheral MSK conditions investigated were knee and hip osteoarthritis, shoulder pain, and elbow tendinopathy. QST parameters indicative of sensitization (lower electrical pain thresholds, cold hyperalgesia, enhanced temporal summation, lower punctate sharpness thresholds) were associated with negative outcome (more pain or disability) in 5 small exploratory studies. Larger studies that accounted for multiple confounders in design and analysis did not support a predictive relationship between QST parameters and outcome. Two studies used self-report measures to capture comorbid centrally mediated symptoms, and found higher questionnaire scores were independently predictive of more persistent pain following a total joint arthroplasty. This systematic review found insufficient evidence to support an independent predictive relationship between QST measures of nervous system sensitization and treatment outcome. Self-report measures demonstrated better predictive ability. Further high-quality prognostic research is warranted. © 2016 World Institute of Pain.

Short-term changes in neck pain, widespread pressure pain sensitivity, and cervical range of motion after the application of trigger point dry needling in patients with acute mechanical neck pain: a randomized clinical trial.

PubMed

Mejuto-Vázquez, María J; Salom-Moreno, Jaime; Ortega-Santiago, Ricardo; Truyols-Domínguez, Sebastián; Fernández-de-Las-Peñas, César

2014-04-01

Randomized clinical trial. To determine the effects of trigger point dry needling (TrPDN) on neck pain, widespread pressure pain sensitivity, and cervical range of motion in patients with acute mechanical neck pain and active trigger points in the upper trapezius muscle. TrPDN seems to be effective for decreasing pain in individuals with upper-quadrant pain syndromes. Potential effects of TrPDN for decreasing pain and sensitization in individuals with acute mechanical neck pain are needed. Methods Seventeen patients (53% female) were randomly assigned to 1 of 2 groups: a single session of TrPDN or no intervention (waiting list). Pressure pain thresholds over the C5-6 zygapophyseal joint, second metacarpal, and tibialis anterior muscle; neck pain intensity; and cervical spine range-of-motion data were collected at baseline (pretreatment) and 10 minutes and 1 week after the intervention by an assessor blinded to the treatment allocation of the patient. Mixed-model analyses of variance were used to examine the effects of treatment on each outcome variable. Patients treated with 1 session of TrPDN experienced greater decreases in neck pain, greater increases in pressure pain threshold, and higher increases in cervical range of motion than those who did not receive an intervention at both 10 minutes and 1 week after the intervention (P<.01 for all comparisons). Between-group effect sizes were medium to large immediately after the TrPDN session (standardized mean score differences greater than 0.56) and large at the 1-week follow-up (standardized mean score differences greater than 1.34). The results of the current randomized clinical trial suggest that a single session of TrPDN may decrease neck pain intensity and widespread pressure pain sensitivity, and also increase active cervical range of motion, in patients with acute mechanical neck pain. Changes in pain, pressure pain threshold, and cervical range of motion surpassed their respective minimal detectable change values, supporting clinically relevant treatment effects. Level of Evidence Therapy, level 1b-.

Development of the Sensory Hypersensitivity Scale (SHS): a self-report tool for assessing sensitivity to sensory stimuli

PubMed Central

Dixon, Eric A.; Benham, Grant; Sturgeon, John A.; Mackey, Sean; Johnson, Kevin A.; Younger, Jarred

2016-01-01

Sensory hypersensitivity is one manifestation of the central sensitization that may underlie conditions such as fibromyalgia and chronic fatigue syndrome. We conducted five studies designed to develop and validate the Sensory Hypersensitive Scale (SHS); a 25-item self-report measure of sensory hypersensitivity. The SHS assesses both general sensitivity and modality-specific sensitivity (e.g. touch, taste, and hearing). 1202 participants (157 individuals with chronic pain) completed the SHS, which demonstrated an adequate overall internal reliability (Cronbach’s alpha) of 0.81, suggesting the tool can be used as a cross-modality assessment of sensitivity. SHS scores demonstrated only modest correlations (Pearson’s r) with depressive symptoms (0.19) and anxiety (0.28), suggesting a low level of overlap with psychiatric complaints. Overall SHS scores showed significant but relatively modest correlations (Pearson’s r) with three measures of sensory testing: cold pain tolerance (−0.34); heat pain tolerance (−0.285); heat pain threshold (−0.271). Women reported significantly higher scores on the SHS than did men, although gender-based differences were small. In a chronic pain sample, individuals with fibromyalgia syndrome demonstrated significantly higher SHS scores than did individuals with osteoarthritis or back pain. The SHS appears suitable as a screening measure for sensory hypersensitivity, though additional research is warranted to determine its suitability as a proxy for central sensitization. PMID:26873609

Arthropod toxins and their antinociceptive properties: From venoms to painkillers.

PubMed

Monge-Fuentes, Victoria; Arenas, Claudia; Galante, Priscilla; Gonçalves, Jacqueline Coimbra; Mortari, Márcia Renata; Schwartz, Elisabeth Ferroni

2018-03-29

The complex process of pain control commonly involves the use of systemic analgesics; however, in many cases, a more potent and effective polypharmacological approach is needed to promote clinically significant improvement. Additionally, considering side effects caused by current painkillers, drug discovery is once more turning to nature as a source of more efficient therapeutic alternatives. In this context, arthropod venoms contain a vast array of bioactive substances that have evolved to selectively bind to specific pharmacological targets involved in the pain signaling pathway, playing an important role as pain activators or modulators, the latter serving as promising analgesic agents. The current review explores how the pain pathway works and surveys neuroactive compounds obtained from arthropods' toxins, which function as pain modulators through their interaction with specific ion channels and membrane receptors, emerging as promising candidates for drug design and development. Copyright © 2018 Elsevier Inc. All rights reserved.

Medical Exercise Therapy for Treating Musculoskeletal Pain: A Narrative Review of Results from Randomized Controlled Trials with a Theoretical Perspective.

PubMed

Lorås, H; Østerås, B; Torstensen, T A; Østerås, H

2015-09-01

The purpose of this narrative review is to present an overview and theoretical rationale of medical exercise therapy (MET) as a physiotherapeutic rehabilitation treatment for musculoskeletal pain conditions. Results from randomized controlled trials (RCTs) conducted on MET are also presented. Computerized searches for any RCTs were conducted on the MET concept in the databases PubMed, Medline, Embase and ISI Web of science up to 2013. Overall findings from five included MET RCTs are long-term (≥1 year) reductions in pain and improved physical and functional capabilities. These results are interpreted in the context of the biopsychosocial model, advancing the view of a dynamic interaction among physiologic, psychological and social factors that influence pain modulation. MET is a biopsychosocial treatment that reduces pain and improves activities of daily living in patients with a musculoskeletal pain condition. Pain modulation is a key feature of MET, and an important area for further research is to elucidate the specific mechanisms behind the treatment effects. Copyright © 2015 John Wiley & Sons, Ltd.

An Integrative Neuroscience Framework for the Treatment of Chronic Pain: From Cellular Alterations to Behavior.

PubMed

Greenwald, Jess D; Shafritz, Keith M

2018-01-01

Chronic pain can result from many pain syndromes including complex regional pain syndrome (CRPS), phantom limb pain and chronic low back pain, among others. On a molecular level, chronic pain syndromes arise from hypersensitization within the dorsal horn of the spinal cord, a process known as central sensitization. Central sensitization involves an upregulation of ionotropic and metabotropic glutamate receptors (mGluRs) similar to that of long-term potentiation (LTP). Regions of the brain in which LTP occurs, such as the amygdala and hippocampus, are implicated in fear- and memory-related brain circuity. Chronic pain dramatically influences patient quality of life. Individuals with chronic pain may develop pain-related anxiety and pain-related fear. The syndrome also alters functional connectivity in the default-mode network (DMN) and salience network. On a cellular/molecular level, central sensitization may be reversed through degradative glutamate receptor pathways. This, however, rarely happens. Instead, cortical brain regions may serve in a top-down regulatory capacity for the maintenance or alleviation of pain. Specifically, the medial prefrontal cortex (mPFC), which plays a critical role in fear-related brain circuits, the DMN, and salience network may be the driving forces in this process. On a cellular level, the mPFC may form new neural circuits through LTP that may cause extinction of pre-existing pain pathways found within fear-related brain circuits, the DMN, and salience network. In order to promote new LTP connections between the mPFC and other key brain structures, such as the amygdala and insula, we propose a holistic rehabilitation program including cognitive behavioral therapy (CBT) and revolving around: (1) cognitive reappraisals; (2) mindfulness meditation; and (3) functional rehabilitation. Unlike current medical interventions focusing upon pain-relieving medications, we do not believe that chronic pain treatment should focus on reversing the effects of central sensitization. Instead, we propose here that it is critical to focus on non-invasive efforts to promote new neural circuits originating from the mPFC.

Central Sensitization and Neuropathic Features of Ongoing Pain in a Rat Model of Advanced Osteoarthritis.

PubMed

Havelin, Joshua; Imbert, Ian; Cormier, Jennifer; Allen, Joshua; Porreca, Frank; King, Tamara

2016-03-01

Osteoarthritis (OA) pain is most commonly characterized by movement-triggered joint pain. However, in advanced disease, OA pain becomes persistent, ongoing and resistant to treatment with nonsteroidal anti-inflammatory drugs (NSAIDs). The mechanisms underlying ongoing pain in advanced OA are poorly understood. We recently showed that intra-articular (i.a.) injection of monosodium iodoacetate (MIA) into the rat knee joint produces concentration-dependent outcomes. Thus, a low dose of i.a. MIA produces NSAID-sensitive weight asymmetry without evidence of ongoing pain and a high i.a. MIA dose produces weight asymmetry and NSAID-resistant ongoing pain. In the present study, palpation of the ipsilateral hind limb of rats treated 14 days previously with high, but not low, doses of i.a. MIA produced expression of the early oncogene, FOS, in the spinal dorsal horn. Inactivation of descending pain facilitatory pathways using a microinjection of lidocaine within the rostral ventromedial medulla induced conditioned place preference selectively in rats treated with the high dose of MIA. Conditioned place preference to intra-articular lidocaine was blocked by pretreatment with duloxetine (30 mg/kg, intraperitoneally at -30 minutes). These observations are consistent with the likelihood of a neuropathic component of OA that elicits ongoing, NSAID-resistant pain and central sensitization that is mediated, in part, by descending modulatory mechanisms. This model provides a basis for exploration of underlying mechanisms promoting neuropathic components of OA pain and for the identification of mechanisms that might guide drug discovery for treatment of advanced OA pain without the need for joint replacement. Difficulty in managing advanced OA pain often results in joint replacement therapy in these patients. Improved understanding of mechanisms driving NSAID-resistant ongoing OA pain might facilitate development of alternatives to joint replacement therapy. Our findings suggest that central sensitization and neuropathic features contribute to NSAID-resistant ongoing OA joint pain. Copyright © 2016 American Pain Society. Published by Elsevier Inc. All rights reserved.

Initial accuracy assessment of the modified S-LANSS for the detection of neuropathic orofacial pain conditions.

PubMed

Herrero Babiloni, Alberto; Nixdorf, Donald R; Law, Alan S; Moana-Filho, Estephan J; Shueb, Sarah S; Nguyen, Ruby H; Durham, Justin

2017-01-01

To evaluate the accuracy of a questionnaire modified for the identification of intraoral pain with neuropathic characteristics in a clinical orofacial pain sample population. 136 participants with at least one of four orofacial pain diagnoses (temporomandibular disorders [TMD, n = 41], acute dental pain [ADP, n = 41], trigeminal neuralgia [TN, n = 19], persistent dentoalveolar pain disorder [PDAP, n = 14]) and a group of pain-free controls (n = 21) completed the modified S-LANSS, a previously adapted version of the original questionnaire devised to detected patients suffering from intraoral pain with neuropathic characteristics. Psychometric properties (sensitivity, specificity, positive predictive value [PPV], negative predictive value [NPV]) were calculated in two analyses with two different thresholds: (1) Detection of pain with neuropathic characteristics: PDAP + TN were considered positive, and TMD + ADP + controls were considered negative per gold standard (expert opinion). (2) Detection of PDAP: PDAP was considered positive and TMD + ADP were considered negative per gold standard. For both analyses, target values for adequate sensitivity and specificity were defined as ≥ 80%. For detection of orofacial pain with neuropathic characteristics (PDAP + TN), the modified S-LANSS presented with the most optimistic threshold sensitivity of 52% (95% confidence interval [CI], 34-69), specificity of 70% (95% CI, 60-79), PPV of 35% (95% CI, 22-51), and NPV of 82% (95% CI, 72-89). For detection of PDAP only, with the most optimistic threshold sensitivity was 64% (95% CI, 35-87), specificity 63% (95% CI, 52-74), PPV 23% (95% CI, 11-39) and NPV 91% (95% CI, 81-97). Based on a priori defined criteria, the modified S-LANSS did not show adequate accuracy to detect intraoral pain with neuropathic characteristics in a clinical orofacial pain sample.

The effect of culture on pain sensitivity.

PubMed

Al-Harthy, M; Ohrbach, R; Michelotti, A; List, T

2016-02-01

Cross-cultural differences in pain sensitivity have been identified in pain-free subjects as well as in chronic pain patients. The aim was to assess the impact of culture on psychophysical measures using mechanical and electrical stimuli in patients with temporomandibular disorder (TMD) pain and pain-free matched controls in three cultures. This case-control study compared 122 female cases of chronic TMD pain (39 Saudis, 41 Swedes and 42 Italians) with equal numbers of age- and gender-matched TMD-free controls. Pressure pain threshold (PPT) and tolerance (PPTo) were measured over one hand and two masticatory muscles. Electrical perception threshold and electrical pain threshold (EPT) and tolerance (EPTo) were recorded between the thumb and index fingers. Italian females reported significantly lower PPT in the masseter muscle than other cultures (P < 0.001) and in the temporalis muscle than Saudis (P = 0.003). Swedes reported significantly higher PPT in the thenar muscle than other cultures (P = 0.017). Italians reported significantly lower PPTo in all muscles than Swedes (P ≤ 0.006) and in the masseter muscle than Saudis (P < 0.001). Italians reported significantly lower EPTo than other cultures (P = 0.01). Temporomandibular disorder cases, compared to TMD-free controls, reported lower PPT and PPTo in all the three muscles (P < 0.001). This study found cultural differences between groups in the PPT, PPTo and EPTo. Overall, Italian females reported the highest sensitivity to both mechanical and electrical stimulation, while Swedes reported the lowest sensitivity. Mechanical pain thresholds differed more across cultures than did electrical pain thresholds. Cultural factors may influence response to type of pain test. © 2015 John Wiley & Sons Ltd.

Lubiprostone does not influence visceral pain thresholds in patients with irritable bowel syndrome.

PubMed

Whitehead, W E; Palsson, O S; Gangarosa, L; Turner, M; Tucker, J

2011-10-01

In clinical trials, lubiprostone reduced the severity of abdominal pain. The primary aim was to determine whether lubiprostone raises the threshold for abdominal pain induced by intraluminal balloon distention. A secondary aim was to determine whether changes in pain sensitivity influence clinical pain independently of changes in transit time. Sixty-two patients with irritable bowel syndrome with constipation (IBS-C) participated in an 8-week cross-over study. All subjects completed a 14-day baseline ending with a barostat test of pain and urge sensory thresholds. Half, randomly selected, then received 48 μg day(-1) of lubiprostone for 14 days ending with a pain sensitivity test and a Sitzmark test of transit time. This was followed by a 14-day washout and then a crossover to 14 days of placebo with tests of pain sensitivity and transit time. The other half of the subjects received placebo before lubiprostone. All kept symptom diaries. Stools were significantly softer when taking lubiprostone compared to placebo (Bristol Stool scores 4.20 vs 3.44, P < 0.001). However, thresholds for pain (17.36 vs 17.83 mmHg, lubiprostone vs placebo) and urgency to defecate (14.14 vs 14.53 mmHg) were not affected by lubiprostone. Transit time was not significantly different between lubiprostone and placebo (51.27 vs 51.81 h), and neither pain sensitivity nor transit time was a significant predictor of clinical pain. Lubiprostone has no effect on visceral sensory thresholds. The reductions in clinical pain that occur while taking lubiprostone appear to be secondary to changes in stool consistency. © 2011 Blackwell Publishing Ltd.

Examining the mediational role of psychological flexibility, pain catastrophizing, and visceral sensitivity in the relationship between psychological distress, irritable bowel symptom frequency, and quality of life.

PubMed

Cassar, G E; Knowles, S; Youssef, G J; Moulding, R; Uiterwijk, D; Waters, L; Austin, D W

2018-06-08

The aim of the current study was to use Structural Equation Modelling (SEM) to examine whether psychological flexibility (i.e. mindfulness, acceptance, valued-living) mediates the relationship between distress, irritable bowel syndrome (IBS) symptom frequency, and quality of life (QoL). Ninety-two individuals participated in the study (12 male, 80 female, M age  = 36.24) by completing an online survey including measures of visceral sensitivity, distress, IBS-related QoL, mindfulness, bowel symptoms, pain catastrophizing, acceptance, and valued-living. A final model with excellent fit was identified. Psychological distress significantly and directly predicted pain catastrophizing, valued-living, and IBS symptom frequency. Pain catastrophizing directly predicted visceral sensitivity and acceptance, while visceral sensitivity significantly and directly predicted IBS symptom frequency and QoL. Symptom frequency also had a direct and significant relationship with QoL. The current findings suggest that interventions designed to address unhelpful cognitive processes related to visceral sensitivity, pain catastrophizing, and psychological distress may be of most benefit to IBS-related QoL.

Effects of early human handling on the pain sensitivity of young lambs.

PubMed

Guesgen, Mirjam J; Beausoleil, Ngaio J; Stewart, Mairi

2013-01-01

Pain sensitivity of lambs changes over the first weeks of life. However, the effects of early treatments such as human handling on pain sensitivity are unknown for this species. This study investigated the effects of regular early gentle human handling on the pain sensitivity of lambs, indicated by their behavioural responses to tail docking. Prospective part-blinded experimental study. Twenty-nine singleton Coopworth lambs (females n=14, males n=15). Starting at one day of age, lambs were either handled twice daily for 2 weeks (Handled), were kept in the presence of lambs who were being handled but were not handled themselves (Presence), or were exposed to a human only during routine feeding and care (Control). At 3 weeks of age, all lambs were tail docked using rubber rings. Changes in behaviour due to docking were calculated and change data were analyzed using two-way anova with treatment and test pen as main factors. All lambs showed significant increases in the frequency and duration of behaviours indicative of pain, including 'abnormal' behaviours, and decreases in the frequency and duration of 'normal' behaviours after docking. Handled lambs showed a smaller increase in the time spent lying abnormally after docking than did Control lambs (mean transformed change in proportion of 30 minutes spent±SE: Control 0.55±0.04; Handled 0.38±0.03; Presence 0.48±0.03; C versus H t=3.45, p=0.007). These results provide some evidence that handling early in life may reduce subsequent pain sensitivity in lambs. While the behavioural effects of handling on pain behaviour were subtle, the results suggest, at the very least, that early handling does not increase pain sensitivity in lambs and suggests there is still flexibility postnatally in the pain processing system of a precocial species. © 2012 The Authors. Veterinary Anaesthesia and Analgesia. © 2012 Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesiologists.