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Medication overuse headache (MOH) is a disabling, globally prevalent disorder representing a well-known and debated clinical problem. Evidence for the most effective treatment strategy is needed.
Learn More >Although most patients with chronic pain are women, the preclinical literature regarding pain processing and the pathophysiology of chronic pain has historically been derived overwhelmingly from the study of male rodents. This Review describes how the recent adoption by a number of funding agencies of policies mandating the incorporation of sex as a biological variable into preclinical research has correlated with an increase in the number of studies investigating sex differences in pain and analgesia. Trends in the field are analysed, with a focus on newly published findings of qualitative sex differences: that is, those findings that are suggestive of differential processing mechanisms in each sex. It is becoming increasingly clear that robust differences exist in the genetic, molecular, cellular and systems-level mechanisms of acute and chronic pain processing in male and female rodents and humans.
Learn More >Pancreatic ductal adenocarcinoma (PDAC) is frequently accompanied by excruciating pain, which has been associated with attraction of cancer cells and their invasion of intrapancreatic sensory nerves. Neutralization of the chemokine CCL2 reduced cancer-associated pain in a clinical trial, but there have been no systematic analyses of the highly diverse chemokine families and their receptors in PDAC.
Learn More >With over 30% of current medications targeting this family of proteins, G-protein-coupled receptors (GPCRs) remain invaluable therapeutic targets. However, due to their unique physicochemical properties, their low abundance, and the lack of highly specific antibodies, GPCRs are still challenging to study in vivo. To overcome these limitations, we combined here transgenic mouse models and proteomic analyses in order to resolve the interactome of the δ-opioid receptor (DOPr) in its native in vivo environment. Given its analgesic properties and milder undesired effects than most clinically prescribed opioids, DOPr is a promising alternative therapeutic target for chronic pain management. However, the molecular and cellular mechanisms regulating its signaling and trafficking remain poorly characterized. We thus performed liquid chromatography-tandem mass spectrometry (LC-MS/MS) analyses on brain homogenates of our newly generated knockin mouse expressing a FLAG-tagged version of DOPr and revealed several endogenous DOPr interactors involved in protein folding, trafficking, and signal transduction. The interactions with a few identified partners such as VPS41, ARF6, Rabaptin-5, and Rab10 were validated. We report an approach to characterize in vivo interacting proteins of GPCRs, the largest family of membrane receptors with crucial implications in virtually all physiological systems.
Learn More >This randomized, double-blind, Phase 3 study (56-week treatment; 24-week follow-up) assessed tanezumab in patients with chronic low back pain (CLBP) and history of inadequate response to standard-of-care analgesics (NCT02528253). Patients received placebo, subcutaneous tanezumab (5mg or 10mg every 8 weeks), or oral tramadol prolonged-release (100-300mg/day). Primary endpoint was change in Low Back Pain Intensity (LBPI) at week 16 for tanezumab versus placebo. Key secondary endpoints were proportion of patients with ≥50% decrease in LBPI at week 16, change in Roland Morris Disability Questionnaire (RMDQ) at week 16, and change in LBPI at week 2 for tanezumab versus placebo. Adverse events and joint safety were assessed through weeks 56 and 80, respectively. Tanezumab 10mg met the primary endpoint by significantly improving LBPI at week 16 versus placebo; least squares (LS) mean (95% CI) difference = -0.40 (-0.76, -0.04; P=0.0281). Tanezumab 10mg significantly improved all key secondary endpoints. Tanezumab 5mg did not meet the primary endpoint (LS mean [95% CI] treatment difference versus placebo = -0.30 [-0.66, 0.07; P=0.1117]), preventing formal testing of key secondary endpoints for this dose. The proportion of patients with ≥50% improvement in LBPI at week 16 was 37.4% in the placebo group, 43.3% in the tanezumab 5mg group (Odds ratio [95% CI] vs placebo = 1.28 [0.97, 1.70; P=0.0846]) and 46.3% in the tanezumab 10mg group (Odds ratio [95% CI] vs placebo = 1.45 [1.09, 1.91; P=0.0101]). Prespecified joint safety events were more frequent with tanezumab 10mg (2.6%) than tanezumab 5mg (1.0%), tramadol (0.2%), or placebo (0%). Seven patients, all in the tanezumab 10mg group (1.4%), underwent total joint replacement. In conclusion, tanezumab 10mg significantly improved pain and function versus placebo in patients with difficult-to-treat CLBP. Tanezumab was associated with a low rate of joint safety events, some requiring joint replacement. Sponsored by Pfizer Inc. and Eli Lilly & Company.
Learn More >Diseases and disorders such as Parkinson's, schizophrenia, and chronic pain are characterized by altered mesolimbic dopaminergic neurotransmission. Dopamine release in the nucleus accumbens (NAc) influences behavior through both tonic and phasic signaling. Tonic dopamine levels are hypothesized to inversely regulate phasic signals via dopamine D2 receptor feedback inhibition. We tested this hypothesis directly in the context of ongoing pain. Tonic and phasic dopamine signals were measured using fast-scan controlled-adsorption voltammetry and fast-scan cyclic voltammetry, respectively, in the NAc shell of male rats with standardized levels of anesthesia. Application of capsaicin to the cornea produced a transient decrease in tonic dopamine levels. During the pain-induced hypodopaminergic state, electrically evoked phasic dopamine release was significantly increased when compared to baseline evoked phasic release. A second application of capsaicin to the same eye had a lessened effect on tonic dopamine suggesting desensitization of TRPV1 channels in that eye. Capsaicin treatment in the alternate cornea, however, again produced coincident decreased dopaminergic tone and increased phasic dopamine release. These findings occurred independently of stimulus lateralization relative to the hemisphere of dopamine measurement. Our data show that (a) the mesolimbic dopamine circuit reliably encodes acute noxious stimuli; (b) ongoing pain produces decreases in dopaminergic tone; and (c) pain-induced decreases in tonic dopamine correspond to augmented evoked phasic dopamine release. Enhanced phasic dopamine neurotransmission resulting from salient stimuli, may contribute to increased impulsivity and cognitive deficits often observed in conditions associated with decreased dopaminergic tone, including Parkinson's disease and chronic pain.
Learn More >One of the potential mechanisms of motor cortex stimulation by non-invasive brain stimulation (NIBS) effects on pain is through the restoration of the defective endogenous inhibitory pain pathways. However, there is still limited data on quantitative sensory testing (QST), including conditioned pain modulation (CPM), supporting this mechanism. This systematic review and meta-analysis aimed to evaluate the effects of non-invasive motor cortex stimulation on pain perception as indexed by changes in QST outcomes. Database searches were conducted until July 2019 to included randomized controlled trials that performed sham-controlled NIBS on the motor cortex in either healthy and/or pain population and assessed the QST and CPM. Quality of studies was assessed through the Cochrane tool. We calculated the Hedge's effect sizes of QST and CPM outcomes, their 95% confidence intervals (95% CI) and performed random-effects meta-analyses. Thirty-eight studies were included (1178 participants). We found significant increases of pain threshold in healthy subjects (ES=0.16, 95% CI=0.02 to 0.31, I=22.2%) and pain population (ES=0.48, 95% CI=0.15 to 0.80, I=68.8%); and homogeneous higher CPM effect (pain ratings reduction) in healthy subjects (ES=-0.39, 95% CI=-0.64 to -0.14, I2=17%) and pain population (ES=-0.35, 95% CI=-0.60 to -0.11, I2=0%) in active NIBs group compared with sham. These results support the idea of top-down modulation of endogenous pain pathways by motor cortex stimulation as one of the main mechanisms of pain reduction assessed by QST, which could be a useful predictive and prognostic biomarker for chronic pain personalized treatment with NIBS.
Learn More >Both persistent pain and cognitive decline prevalence increase with advancing age and are associated with functional decline. However, the association of pain and cognitive decline has not been evaluated yet by a systematic assessment of longitudinal studies. We aimed to assess the association of persistent pain as a risk factor for cognitive decline in community older adults, using data from longitudinal studies in a systematic review and meta-analysis. Publications were identified using a systematic search on PubMed, EMBASE and Cochrane Library databases from inception to June 2019. Since heterogeneity across studies was high, we used random-effects meta-analysis to calculate the pooled relative risk for the association between persistent pain and cognitive decline incidence. We investigated sources of heterogeneity among studies using meta-regression and stratified analyses. We included ten prospective longitudinal studies with 57,495 participants with a mean age at the baseline ranging from 61.8 to 88.4 years old and mean follow-up times ranging from 2.75 to 11.8 years. Persistent pain at baseline was not associated with the development of cognitive decline during the follow-up (pooled RR = 1.05, 95% CI = 0.92-1.21). In sensitivity analyses, only length of follow-up time ≤ 4.5 years was associated with a higher risk of cognitive impairment (pooled RR = 1.19, 95% CI = 1.10-1.28). Persistent pain was not associated with the incidence of cognitive decline.
Learn More >In clinical trials of treatments for chronic pain, the percentage of participants who withdraw early can be as high as 50%. Major reasons for early withdrawal in these studies include perceived lack of efficacy and adverse events. Commonly employed strategies for accommodating missing data include last observation carried forward, baseline observation carried forward, and more principled methods such as mixed model repeated measures and multiple imputation. All of these methods require strong and untestable assumptions concerning the conditional distribution of outcomes after dropout given the observed data. We review recent developments in statistical methods for handling missing data in clinical trials, including implications of the increased emphasis being placed on precise formulation of the study objectives and the estimand (treatment effect to be estimated) of interest. A flexible method that appears to be well-suited for the analysis of chronic pain clinical trials is control-based imputation, which allows a variety of assumptions to be made concerning the conditional distribution of post-dropout outcomes that can be tailored to the estimand of interest. These assumptions can depend, for example, on the stated reasons for dropout. We illustrate these methods using data from four clinical trials of pregabalin for the treatment of painful diabetic peripheral neuropathy and postherpetic neuralgia. When planning chronic pain clinical trials, careful consideration of the trial objectives should determine the definition of the trial estimand, which in turn should inform methods used to accommodate missing data in the statistical analysis.
Learn More >Our goal was to examine the association between mental health disorders (MHD) and subsequent risk of opioid use among commercially insured youth and adults (ages 14-64) with co-morbid chronic non-cancer pain (CNCP) conditions. We conducted a retrospective cohort study utilizing IQVIA Health Plan Claims database from January 1, 2006 to December 31, 2015. CNCP was defined as any diagnosis of back, head, neck, arthritis, or chronic pain (index date). MHD was assessed in the 12-months prior to the index pain diagnosis. Based on days supply (none, acute, chronic) and average daily dose (none, low, medium, and high), we constructed a 7-level categorical dependent measure of opioid use. We estimated the overall prevalence of MHD and opioid receipt. Among those with CNCP, multinomial logistic regression (AOR; 95 CI) was used to estimate the association of MHD with opioid receipt. Among 879,815 individuals diagnosed with CNCP, 143,923 (16.4%) had co-morbid MHD. Chronic/high dose use of opioids was more common among those with CNCP and MHD compared to those with only CNCP. After adjusting for demographic and clinical factors, individuals with co-morbid CNCP and MHD were significantly more likely to be prescribed opioids compared to those with only CNCP conditions. This effect varied by average daily dose and days supply: acute/low dose (1.08; 1.07-1.08); chronic/low dose (1.49; 1.49-1.50); acute/medium dose (1.07; 1.07-1.08); chronic/medium dose (1.61; 1.61-1.62); acute/high dose (1.03; 1.02-1.03); and chronic/high dose (1.53; 1.53-1.54). In individuals with CNCP, having a MHD was a strong predictor of prescription opioid use, particularly chronic use.
Learn More >Chronic low back pain (cLBP) is a prevalent disorder. A growing body of evidence linking the pathology of the reward network to chronic pain suggests that pain sensitization may contribute to cLBP chronification via disruptions of mesocortical and mesolimbic circuits in the reward system. Resting-state (RS) functional magnetic resonance imaging (fMRI) data was acquired from 90 patients with cLBP and 74 matched pain-free controls (HCs) at baseline and after a manipulation for back pain intensification. The ventral tegmental area (VTA) was chosen as a seed region to perform RS functional connectivity (FC) analysis. Baseline rsFC of both the mesocortical (between the VTA and bilateral rostral anterior cingulate cortex (rACC) / and medial prefrontal cortex (mPFC)) and mesolimbic (between the VTA and bilateral hippocampus/parahippocampus) pathways was reduced in patients with cLBP (vs. HCs). In addition, patients exhibiting higher back pain intensity (compared to the relatively lower back pain intensity condition) also showed increases in both mesocortical and mesolimbic connectivity, implicating these pathways in pain downregulation in cLBP. Mediation analysis further isolated the mesolimbic (VTA-hippocampus/ parahippocampus) dysconnectivity as a neural mechanism mediating the association between mechanical pain sensitivity (indexed by P40 pressure) and cLBP severity. In sum, the current study demonstrates deficient mesocorticolimbic connectivity in cLBP, with the mesolimbic dysconnectivity potentially mediating the contribution of pain sensitization to pain chronification. These reward network dysfunctions and purportedly, dopaminergic dysregulations, may help us to identify key brain targets of neuromodulation in the treatment of cLBP.
Learn More >Diminished synaptic inhibition in the superficial spinal dorsal horn contributes to exaggerated pain responses that accompany peripheral inflammation and neuropathy. α2GABA receptors (α2GABAR) constitute the most abundant GABAR subtype at this site and are the targets of recently identified antihyperalgesic compounds. Surprisingly, hoxb8-α2 mice that lack α2GABAR from the spinal cord and peripheral sensory neurons exhibit unaltered sensitivity to acute painful stimuli and develop normal inflammatory and neuropathic hyperalgesia. Here, we provide a comprehensive analysis of GABAergic neurotransmission, of behavioral phenotypes and of possible compensatory mechanisms in hoxb8-α2 mice. Our results confirm that hoxb8-α2 mice show significantly diminished GABAergic inhibitory postsynaptic currents (IPSCs) in the superficial dorsal horn but no hyperalgesic phenotype. We also confirm that the potentiation of dorsal horn GABAergic IPSCs by the α2-preferring GABAR modulator HZ-166 is reduced in hoxb8-α2 mice and that hoxb8-α2 mice are resistant to the analgesic effects of HZ-166. Tonic GABAergic currents, glycinergic IPSCs, and sensory afferent-evoked EPSCs did show significant changes in hoxb8-α2 mice rendering a compensatory up-regulation of other GABAR subtypes or of glycine receptors unlikely. Although expression of serotonin and of the serotonin producing enzyme tryptophan hydroxylase (TPH2) was significantly increased in the dorsal horn of hoxb8-α2 mice, ablation of serotonergic terminals from the lumbar spinal cord failed to unmask a nociceptive phenotype. Our results are consistent with an important contribution of α2GABAR to spinal nociceptive control but their ablation early in development appears to activate yet-to-be identified compensatory mechanisms that protect hoxb8-α2 mice from hyperalgesia.
Learn More >Depression is a frequent comorbid condition in patients with persistent back pain and is associated with substantial adverse consequences, including the risk of developing opioid use disorders. Shifting the focus from depression treatment to preventing depression might be a viable way to reduce the disease burden.
Learn More >The evolution of therapeutics for and management of human immunodeficiency virus-1 (HIV-1) infection has shifted it from predominately manifesting as a severe, acute disease with high mortality to a chronic, controlled infection with a near typical life expectancy. However, despite extensive use of highly active antiretroviral therapy, the prevalence of chronic widespread pain in people with HIV remains high even in those with a low viral load and high CD4 count. Chronic widespread pain is a common comorbidity of HIV infection and is associated with decreased quality of life and a high rate of disability. Chronic pain in people with HIV is multifactorial and influenced by HIV-induced peripheral neuropathy, drug-induced peripheral neuropathy, and chronic inflammation. The specific mechanisms underlying these three broad categories that contribute to chronic widespread pain are not well understood, hindering the development and application of pharmacological and nonpharmacological approaches to mitigate chronic widespread pain. The consequent insufficiencies in clinical approaches to alleviation of chronic pain in people with HIV contribute to an overreliance on opioids and alarming rise in active addiction and overdose. This article reviews the current understanding of the pathogenesis of chronic widespread pain in people with HIV and identifies potential biomarkers and therapeutic targets to mitigate it.
Learn More >There is ample evidence for the role of the immune system in developing chronic pain following peripheral nerve injury. Especially Toll-like receptors (TLRs) and their associated signaling components and pro-inflammatory cytokines such as IL-1β, induced after injury, are involved in nociceptive processes and believed to contribute to the manifestation of chronic neuropathic pain states. Whereas the inhibition of the kinase function of IRAK-4, a central kinase downstream of TLRs and IL-1 receptors (IL-1Rs), seems efficacious in various chronic inflammatory and autoimmune models, it's role in regulating chronic neuropathic pain remained elusive to date. Here, we examined whether pharmacological inhibition of IRAK-4 kinase activity using PF-06650833 and BMS-986147, two clinical-stage kinase inhibitors, is effective for controlling persistent pain following nerve injury. Both inhibitors potently inhibited TLR-triggered cytokine release in human peripheral blood mononuclear cell (PBMC) as well as human and rat whole blood cultures. BMS-986147 showing favorable pharmacokinetic (PK) properties, significantly inhibited R848-triggered plasma TNF levels in a rat in vivo cytokine release model after single oral dosing. However, BMS-986147 dose dependently reversed cold allodynia in a rat chronic constriction injury (CCI) model following intrathecal administration only, supporting the notion that central neuro-immune modulation is beneficial for treating chronic neuropathic pain. Although both inhibitors were efficacious in inhibiting IL-1β- or TLR-triggered cytokine release in rat dorsal root ganglion cultures, only partial efficacy was reached in IL-1β-stimulated human glial cultures indicating that inhibiting IRAK-4́s kinase function might be partially dispensable for human IL-1β driven neuroinflammation. Overall, our data demonstrate that IRAK-4 inhibitors could provide therapeutic benefit in chronic pain following nerve injury, and the central driver for efficacy in the neuropathic pain model as well as potential side effects of centrally available IRAK-4 inhibitors warrant further investigation to develop effective analgesia for patients in high unmet medical need.
Learn More >Exercise training is an effective therapy for many pain-related conditions, and trained athletes have lower pain perception compared to unconditioned people. Some painful conditions, including strenuous exercise, are associated with elevated levels of protons, metabolites and inflammatory factors, which may activate receptors and/or ion channels, including acid-sensing ion channels (ASICs), on nociceptive sensory neurons. We hypothesized that ASICs are required for immediate exercise-induced muscle pain (IEIP), and that exercise training diminishes IEIP by modulating ASICs within muscle afferents. We found high-intensity interval training (HIIT) reduced IEIP in C57BL/6 mice, diminished ASICs mRNA levels in lumber dorsal root ganglia (DRG), and this downregulation of ASICs correlated with improved exercise capacity. Additionally, we found that ASIC3 -/- mice did not develop IEIP, however the exercise capacity of ASIC3 -/- was similar to wild-type mice. These results suggest that ASICs are required for IEIP, and that diminishment of IEIP after exercise training correlates with downregulation of ASICs in sensory neurons.
Learn More >Opioids are effective analgesics in the management of severe pain. However, tolerance, leading to dose escalation and adverse effects are significant limiting factors in their use. The role of peripheral opioid receptors in analgesia has been discussed especially under inflammatory conditions. The results from pharmacological and conditional knockout studies together do not provide a clear picture of the contribution of peripheral opioid receptors on antinociceptive tolerance and this needs to be evaluated. Therefore, we studied whether the peripherally restricted opioid receptor antagonist, methylnaltrexone (MNTX), could prevent morphine tolerance without attenuating the antinociceptive effect of morphine. Male Sprague-Dawley rats were treated for 7 days with increasing subcutaneous doses of morphine (5-30 mg/kg) and were coadministered saline, MNTX (0.5 or 2 mg/kg), or naltrexone (NTX; 2 mg/kg). Nociception was assessed with tail-flick, hotplate, and von Frey tests. Morphine, MNTX, and NTX concentrations in the plasma, brain, and spinal cord were measured by liquid chromatography-tandem mass spectrometry. In acute coadministration, NTX, but not MNTX, abolished the acute antinociceptive effects of morphine in all nociceptive tests. The antinociceptive tolerance after repeated morphine administration was also prevented by NTX but not by MNTX. MNTX penetrated to the spinal cord and the brain to some extent after repeated administration. The results do not support the use of MNTX for preventing opioid tolerance and also suggest that morphine tolerance is mediated by central rather than peripheral opioid receptors in the rat.
Learn More >Pain is a common symptom in pediatric inflammatory bowel disease (IBD) and is associated with poor health outcomes, yet additional knowledge about the psychosocial correlates of pain is needed to optimize clinical care. The purpose of this study is to systematically review the psychosocial factors associated with pain and pain impact in youth diagnosed with IBD within a developmentally informed framework.
Learn More >We performed a detailed analysis of sensory function in patients with chronic post-surgical neuropathic pain (NP) after breast cancer treatments by quantitative sensory testing (QST) with DFNS (German Research Network on Neuropathic Pain) protocol and bed side examination (BE). The nature of sensory changes in peripheral NP may reflect distinct pathophysiological backgrounds that can guide the treatment choices. NP with sensory gain (i.e., hyperesthesia, hyperalgesia, allodynia) has been shown to respond to Na-channel blockers (e.g., oxcarbazepine).
Learn More >Targeted muscle reinnervation is an emerging surgical technique to treat neuroma pain whereby sensory and mixed motor nerves are transferred to nearby redundant motor nerve branches. In a recent randomized controlled trial, targeted muscle reinnervation was recently shown to reduce postamputation pain relative to conventional neuroma excision and muscle burying.
Learn More >Unilateral injection of Complete Freund's Adjuvant (CFA) into the intra-plantar surface of the rodent hindpaw elicits chronic inflammation and hyperalgesia in the ipsilateral hindlimb. Mechanisms contributing to this hyperalgesia may act over multiple time courses and can include changes in ion channel expression and post-translational SUMOylation. Hyperpolarization-activated, cyclic nucleotide-gated (HCN) channels mediate the hyperpolarization-activated current, I . An HCN2-mediated increase in C-nociceptor I contributes to mechanical hyperalgesia in the CFA model of inflammatory pain. Changes in HCN2 post-translational SUMOylation and protein expression have not been systematically documented for a given DRG throughout the time course of inflammation.
Learn More >It has been reported that a GM-CSF→CCL17 pathway, originally identified in vitro in macrophage lineage populations, is implicated in the control of inflammatory pain, as well as arthritic pain and disease. We explore, in this study and in various inflammation models, the cellular CCL17 expression and its GM-CSF dependence as well as the function of CCL17 in inflammation and pain. This study used models allowing the convenient cell isolation from reporter mice; it also exploited both CCL17-dependent and unique CCL17-driven inflammatory pain and arthritis models, the latter permitting a radiation chimera approach to help identify the CCL17 responding cell type(s) and the mediators downstream of CCL17 in the control of inflammation and pain. We present evidence that 1) in the particular inflammation models studied, CCL17 expression is predominantly in macrophage lineage populations and is GM-CSF dependent, 2) for its action in arthritic pain and disease development, CCL17 acts on CCR4 non-bone marrow-derived cells, and 3) for inflammatory pain development in which a GM-CSF→CCL17 pathway appears critical, nerve growth factor, CGRP, and substance P all appear to be required.
Learn More >Retrospective analysis of inpatient and outpatient medical insurance claims data from a database containing over 100 million individuals.
Learn More >Exposure-response (E-R) models were developed to provide a description of the time-course of treatment effect for monthly and quarterly dosing regimens of fremanezumab.
Learn More >Precise cannabis treatment dosing remains a major challenge, leading to physicians' reluctance to prescribe medical cannabis.
Learn More >People with migraine have historically been depicted as "frail and perfectionist women." While these presentations are from a different cultural context, we may today still be at risk of stereotyping and stigmatizing this patient group. Portrayals of people with migraine on the Internet and in mass media offer a window of how society today views this patient group. The aim of this study was to explore how persons with migraine are being portrayed according to 2 popular sources of photographic images.
Learn More >Temporomandibular joint disorder (TMD) is associated with pain in the joint (temporomandibular joint, TMJ) and muscles involved in mastication. TMD pain dissipates following menopause but returns in some women undergoing estrogen replacement therapy. Progesterone has both anti-inflammatory and antinociceptive properties, while estrogen's effects on nociception are variable and highly dependent on both natural hormone fluctuations and estrogen dosage during pharmacological treatments, with high doses increasing pain. Allopregnanolone, a progesterone metabolite and positive allosteric modulator of the GABA receptor, also has antinociceptive properties. While progesterone and allopregnanolone are antinociceptive, their effect on estrogen-exacerbated TMD pain has not been determined. We hypothesized that removing the source of endogenous ovarian hormones would reduce inflammatory allodynia in the TMJ of rats and both progesterone and allopregnanolone would attenuate the estrogen-provoked return of allodynia. Baseline mechanical sensitivity was measured in female Sprague-Dawley rats (150-175 g) using the von Frey filament method followed by a unilateral injection of complete Freund's adjuvant (CFA) into the TMJ. Mechanical allodynia was confirmed 24 h later; then rats were ovariectomized or received sham surgery. Two weeks later, allodynia was reassessed and rats received one of the following subcutaneous hormone treatments over 5 days: a daily pharmacological dose of estradiol benzoate (E2; 50 μg/kg), daily E2 and pharmacological to sub-physiological doses of progesterone (P4; 16 mg/kg, 16 μg/kg, or 16 ng/kg), E2 daily and interrupted P4 given every other day, daily P4, or daily vehicle control. A separate group of animals received allopregnanolone (0.16 mg/kg) instead of P4. Allodynia was reassessed 1 h following injections. Here, we report that CFA-evoked mechanical allodynia was attenuated following ovariectomy and daily high E2 treatment triggered the return of allodynia, which was rapidly attenuated when P4 was also administered either daily or every other day. Allopregnanolone treatment, whether daily or every other day, also attenuated estrogen-exacerbated allodynia within 1 h of treatment, but only on the first treatment day. These data indicate that when gonadal hormone levels have diminished, treatment with a lower dose of progesterone may be effective at rapidly reducing the estrogen-evoked recurrence of inflammatory mechanical allodynia in the TMJ.
Learn More >Damaged or degenerated vertebral endplates are a significant cause of vertebrogenic chronic low back pain (CLBP). Modic changes are one objective MRI biomarker for these patients. Prior data from the treatment arm of a sham-controlled, RCT showed maintenance of clinical improvements at 2 years following ablation of the basivertebral nerve (BVN). This study reports 5-year clinical outcomes.
Learn More >Patients with co-morbid chronic pain and post-traumatic stress disorder (PTSD) pose significant treatment challenges. This study evaluated the effectiveness of an interdisciplinary pain rehabilitation program (IPRP) in improving pain and PTSD outcomes, as well as reducing medication use. In addition, the mediating effect of pain catastrophizing, which is theorized to underlie the pain and PTSD comorbidity, was examined. Participants included 83 completers of an IPRP with chronic pain and a provisional PTSD diagnosis. Significant improvements were found for pain outcomes, PTSD symptomatology, depressive symptoms, physical performance, and medication use (i.e., opioids and benzodiazepines). At discharge, 86.7% of participants reliably improved in at least one key measure of functioning and 50.6% demonstrated reliable improvement in PTSD symptomatology. Change in pain catastrophizing mediated improvements in pain interference and PTSD symptomatology. Results support the potential utility of an interdisciplinary pain treatment approach in the treatment of patients with comorbid pain and PTSD.
Learn More >Emotional awareness and expression therapy (EAET) emphasizes the importance of the central nervous system and emotional processing in the etiology and treatment of chronic pain. Prior trials suggest EAET can substantially reduce pain; however, only one has compared EAET with an established alternative, demonstrating some small advantages over cognitive behavioral therapy (CBT) for fibromyalgia. The current trial compared EAET with CBT in older, predominately male, ethnically diverse veterans with chronic musculoskeletal pain.
Learn More >Pain evoked by visceral inflammation is often 'referred' to the somatic level. Transient receptor potential ankyrin 1 (TRPA1) has been reported to contribute to visceral pain-like behavior in dextran sulfate sodium (DSS)-evoked colitis. However, the role of TRPA1 in somatic component of hypersensitivity due to visceral inflammation is unknown. The present study investigated the role of TRPA1 in colitis-evoked mechanical hypersensitivity at the somatic level. Colitis was induced in mice by adding DSS to drinking water for one week. Control and DSS-treated mice were tested for various parameters of colitis as well as mechanical pain sensitivity in abdominal and facial regions. DSS treatment caused mechanical hypersensitivity in the abdominal and facial skin. Pharmacological blockade or genetic deletion of TRPA1 prevented the colitis-associated mechanical hypersensitivity in the abdominal and facial skin areas although the severity of colitis remained unaltered. DSS treatment increased expression of TRPA1 mRNA in cultured dorsal root ganglion (DRG) neurons, but not trigeminal ganglion neurons, and selectively enhanced currents evoked by the TRPA1 agonist, allyl isothiocyanate, in cultured DRG neurons. Our findings indicate that the TRPA1 channel contributes to colitis-associated mechanical hypersensitivity in somatic tissues, an effect associated with upregulation of TRPA1 expression and responsiveness in DRG nociceptors.
Learn More >Chronic pain and co-occurring disorders, such as sleep disorders, anxiety, depression, post-traumatic stress disorder and substance use disorders, are among the most common conditions for which cannabis and cannabinoid-based products derived from the cannabis plant (CBP) are used for therapeutic purposes. However, healthcare providers report that they lack sufficient information on the risks, benefits and appropriate use of cannabis and CBP derived from the cannabis plant for therapeutic purposes.
Learn More >Headache is a common complication of traumatic brain injury. The International Headache Society defines post-traumatic headache as a secondary headache attributed to trauma or injury to the head that develops within seven days following trauma. Acute post-traumatic headache resolves after 3 months, but persistent post-traumatic headache usually lasts much longer and accounts for 4% of all secondary headache disorders.
Learn More >Exogenous cannabinoid receptor agonists are clinically effective for treating chronic pain but frequently cause side effects in the central nervous system. Fatty acid amide hydrolase (FAAH) is a primary catabolic enzyme for anandamide, an endogenous cannabinoid agonist. 3-Pyridyl 4-(phenylcarbamoyl)piperidine-1-carboxylate (ASP8477) is a potent and selective FAAH inhibitor that is orally active and able to increase the brain anandamide level and is effective in rat models of neuropathic and osteoarthritis pain without causing motor coordination deficits. In the present study, we examined the pharmacokinetics and pharmacodynamics, analgesic spectrum in pain models, and the anti-nociceptive mechanism of ASP8477. Single and four-week repeated oral administration of ASP8477 ameliorated mechanical allodynia in spinal nerve ligation rats with similar improvement rates. Further, single oral administration of ASP8477 improved thermal hyperalgesia and cold allodynia in chronic constriction nerve injury rats. ASP8477 also restored muscle pressure thresholds in reserpine-induced myalgia rats. This analgesic effect of ASP8477 persisted for at least 4 h, consistent with the inhibitory effect observed in an ex vivo study using rat brain as well as the increasing effect on oleoylethanolamide and palmitoylethanolamide levels but not the ASP8477 concentration in rat brain. ASP8477 also improved α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-, N-methyl-D-aspartic acid (NMDA)-, prostaglandin E-, prostaglandin F-, and bicuculline-induced allodynia in mice, showing broader analgesic spectra than existing drugs. In contrast, however, ASP8477 did not affect acute pain. These results indicate that the FAAH inhibitor ASP8477 exerts analgesic effects on neuropathic and dysfunctional pain, and its pharmacological properties are suitable for use in treating chronic pain.
Learn More >The δ-opioid receptor (DOP) is an attractive pharmacological target due to its potent analgesic, anxiolytic and anti-depressant activity in chronic pain models. However, some but not all selective DOP agonists also produce severe adverse effects such as seizures. Thus, the development of novel agonists requires a profound understanding of their effects on DOP phosphorylation, post-activation signaling and dephosphorylation. Here we show that agonist-induced DOP phosphorylation at threonine 361 (T361) and serine 363 (S363) proceeds with a temporal hierarchy, with S363 as primary site of phosphorylation. This phosphorylation is mediated by G protein-coupled receptor kinases 2 and 3 (GRK2/3) followed by DOP endocytosis and desensitization. DOP dephosphorylation occurs within minutes and is predominantly mediated by protein phosphatases (PP) 1α and 1β. A comparison of structurally diverse DOP agonists and clinically used opioids demonstrated high correlation between G protein-dependent signaling efficacies and receptor internalization. In vivo, DOP agonists induce receptor phosphorylation in a dose-dependent and agonist-selective manner that could be blocked by naltrexone in DOP-eGFP mice. Together, our studies provide novel tools and insights for ligand-activated DOP signaling in vitro and in vivo and suggest that DOP agonist efficacies may determine receptor post-activation signaling.
Learn More >Patients with chronic fatigue syndrome (CFS) and chronic whiplash associated disorders (cWAD) present a reduced ability to activate central descending nociceptive inhibition after exercise, compared to measurements before exercise. It was hypothesised that a dysfunctional motor-induced inhibition of nociception partly explains this dysfunctional exercise-induced hypoalgesia. This study investigates if engagement of the motor system during movement preparation inhibits nociception-evoked brain responses in these patients as compared to healthy controls (HC).
Learn More >Schwannomatosis is the third form of neurofibromatosis and characterized by the occurrence of multiple schwannomas. The most prominent symptom is chronic pain. We aimed to test whether pain in schwannomatosis might be caused by small-fiber neuropathy. Twenty patients with schwannomatosis underwent neurological examination and nerve conduction studies. Levels of pain perception as well as anxiety and depression were assessed by established questionnaires. Quantitative sensory testing (QST) and laser-evoked potentials (LEP) were performed on patients and controls. Whole-body magnetic resonance imaging (wbMRI) and magnetic resonance neurography (MRN) were performed to quantify tumors and fascicular nerve lesions; skin biopsies were performed to determine intra-epidermal nerve fiber density (IENFD). All patients suffered from chronic pain without further neurological deficits. The questionnaires indicated neuropathic symptoms with significant impact on quality of life. Peripheral nerve tumors were detected in all patients by wbMRI. MRN showed additional multiple fascicular nerve lesions in 16/18 patients. LEP showed significant faster latencies compared to normal controls. Finally, IENFD was significantly reduced in 13/14 patients. Our study therefore indicates the presence of small-fiber neuropathy, predominantly of unmyelinated C-fibers. Fascicular nerve lesions are characteristic disease features that are associated with faster LEP latencies and decreased IENFD. Together these methods may facilitate differential diagnosis of schwannomatosis.
Learn More >Social touch is important for interpersonal interaction. Gentle touch and slow brushing are typically perceived as pleasant, the degree of pleasantness is linked to the activity of the C-tactile (CT) fibers, a class of unmyelinated nerves in the skin. The inability to experience pleasure in general is called anhedonia, a common phenomenon in the chronic pain condition fibromyalgia. Here, we studied the perception and cortical processing of gentle touch in a well-characterized cohort of fibromyalgia. Patients and controls participated in functional brain imaging while receiving tactile stimuli (brushing) on the forearm. They were asked to provide ratings of pleasantness of the tactile stimulus and ongoing pain. We found high distress, pain catastrophizing, and insomnia, and a low perceived state of health in fibromyalgia. Further, patients rated both slow (CT-optimal) and fast (CT-suboptimal) brushing as less pleasant than healthy participants. While there was no difference in brain activity during touch, patients showed deactivation in the right posterior insula (contralateral to the stimulated arm) during pleasantness rating and activation during pain rating. The opposite pattern was observed in healthy participants. Voxel-based morphometry analysis revealed reduced grey matter density in patients, in the bilateral hippocampus and anterior insula. Our results suggest anhedonia to gentle touch in fibromyalgia with intact early-stage sensory processing but dysfunctional evaluative processing. These findings contribute to our understanding of the mechanisms underlying anhedonia in fibromyalgia.
Learn More >Previous studies have demonstrated that continuous substance P (SP) infusion into the rat striatum attenuated hind paw formalin-induced nociceptive behaviors and mechanical hypersensitivity via a neurokinin-1 (NK1) receptor dependent mechanism. However, whether there is a role of striatal infusion of SP on chronic, neuropathic pain has yet to be demonstrated. The present study investigated the effect of continuous SP infusion into the rat striatum using a reverse microdialysis method is antinociceptive in a rat model of chronic, mononeuropathic pain. Two weeks after partial sciatic nerve injury, the ipsilateral hind paw demonstrated mechanical hypersensitivity. Infusion of SP (0.2, 0.4, or 0.8 µg/mL, 1 µL/min) for 120 min into the contralateral striatum dose-dependently relieved mechanical hypersensitivity. The antinociceptive effect of SP infusion was inhibited by co-infusion with the NK1 receptor antagonist CP96345 (10 µM). Neither ipsilateral continuous infusion nor acute microinjection of SP (10 ng) into the contralateral striatum was antinociceptive. A role of striatal muscarinic cholinergic neurons is suggested since co-infusion of SP with atropine (10 µM), but not the nicotinic receptor mecamylamine (10 µM), blocked antinociception. The current study suggests that activation of striatal muscarinic receptors through NK1 receptors could be a novel approach to managing chronic pain.
Learn More >The most common and multifaceted migraine aura symptoms are visual disturbances. Health information is one of the most popular topics on the internet but the quality and reliability of publicized information is unknown. The aim of this study was to analyze images of migraine aura on Google to determine the frequency of correct presentations of visual aura and distribution of visual aura phenotypes.
Learn More >Migraine is associated with substantial functional impairment and affects many aspects of daily life.
Learn More >Physiological responses related to manual therapy (MT) treatment have been investigated over decades using various animal models. However, these studies have not been compiled and their collective findings appraised. The purpose of this scoping review was to assess current scientific knowledge on the physiological responses related to MT and/or simulated MT procedures in animal models so as to act as a resource to better inform future mechanistic and clinical research incorporating these therapeutic interventions. PubMed, Cumulative Index to Nursing and Allied Health Literature (CINAHL), Cochrane, Embase, and Index of Chiropractic Literature (ICL) were searched from database inception to August 2019. Eligible studies were: (a) published in English; (b) non-cadaveric animal-based; (c) original data studies; (d) included a form of MT or simulated MT as treatment; (e) included quantification of at least one delivery parameter of MT treatment; (f) quantification of at least one physiological measure that could potentially contribute to therapeutic mechanisms of action of the MT. MT studies were categorized according to three main intervention types: (1) mobilization; (2) manipulation; and (3) massage. Two-phase screening procedures were conducted by a pair of independent reviewers, data were extracted from eligible studies and qualitatively reported. The literature search resulted in 231 articles of which 78 met inclusion criteria and were sorted by intervention type. Joint mobilization induced changes in nociceptive response and inflammatory profile, gene expression, receptor activation, neurotransmitter release and enzymatic activity. Spinal manipulation produced changes in muscle spindle response, nocifensive reflex response and neuronal activity, electromyography, and immunologic response. Physiological changes associated with massage therapy included autonomic, circulatory, lymphatic and immunologic functions, visceral response, gene expression, neuroanatomy, function and pathology, and cellular response to simulated massage. Pre-clinical research supports an association between MT physiological response and multiple potential short-term MT therapeutic mechanisms. Optimization of MT delivery and/or treatment efficacy will require additional preclinical investigation in which MT delivery parameters are controlled and reported using pathological and/or chronic pain models that mimic neuromusculoskeletal conditions for which MT has demonstrated clinical benefit.
Learn More >Pain experience due to spinal degenerative disease decreases activity of daily living and quality of life. The present cross-sectional study was aimed at examining the sex-specific impact of pain severity, psychosocial factors, and insomnia on the disability due to chronic pain arising from spinal degenerative disease.
Learn More >Neuropathic pain is a very complex chronic pain state, the detailed molecular mechanisms of which remain unclear. In the present study, Shank3 was found to play an important role in neuropathic pain in rats following spared nerve injury (SNI). Shank3 was upregulated in the spinal dorsal horn of rats subjected to SNI, and mechanical hypersensitivity to noxious stimuli in these rats could be alleviated by knock down of Shank3. Shank3 also interacted with hyperpolarization-activated cyclic nucleotide-gated channel 2 (HCN2) and promoted the expression of HCN2 in central neurons of the spinal dorsal. Together with the SNI-dependent increase of HCN2, we also found that the postsynaptic protein of excitatory synapse (PSD95) was increased in rats following SNI. Taken together, our results showed that Shank3 modulated neuropathic pain by facilitating the SNI-dependent increase of HCN2 and the expression of PSD95 in spinal dorsal horn neurons. Our findings revealed new synaptic remodeling mechanisms linking Shank3 with neuropathic pain.
Learn More >Despite the wide body of research on the properties of the Oswestry Disability Index (ODI), only a few studies have investigated whether ODI scores can be interpreted similarly in both genders. A few previous studies suggested that the ODI may behave differently in different populations, e.g. in different age groups.
Learn More >Central post-stroke pain (CPSP) is defined as the neuropathic pain that arises either acutely or in the chronic phase of a cerebrovascular event and is a result of central lesions of the somatosensory tract. The aim of this systematic review and meta-analysis was to establish the prevalence of CPSP, to describe its characteristics, and to discuss the associated management challenges.
Learn More >Although opioids still remain the most powerful pain-killers, the chronic use of opioid analgesics is largely limited by their numerous side-effects, including opioid dependence. However, the mechanism underlying this dependence is largely unknown. In this study, we used the withdrawal symptoms precipitated by naloxone to characterize opioid dependence in mice. We determined the functional role of mu-opioid receptors (MORs) expressed in different subpopulations of neurons in the development of morphine withdrawal. We found that conditional deletion of MORs from glutamatergic neurons expressing vesicular glutamate transporter 2 (Vglut2) largely eliminated the naloxone-precipitated withdrawal symptoms. In contrast, conditional deletion of MORs expressed in GABAergic neurons had a limited effect on morphine withdrawal. Consistently, mice with MORs deleted from Vglut2 glutamatergic neurons also showed no morphine-induced locomotor hyperactivity. Furthermore, morphine withdrawal and morphine-induced hyperactivity were not significantly affected by conditional knockout of MORs from dorsal spinal neurons. Taken together, our data indicate that the development of morphine withdrawal is largely mediated by MORs expressed in Vglut2 glutamatergic neurons.
Learn More >Migraine is a disabling primary headache disorder often associated with triggers. Diet-related triggers are a common cause of migraine and certain diets have been reported to decrease the frequency of migraine attacks if dietary triggers or patterns are adjusted.
Learn More >Chronic pain resulting from nerve injury, tissue inflammation, and tumor invasion or treatment, is a major health problem impacting the quality of life and producing a significant economic and social burden. However, the current analgesic drugs including non-steroidal anti-inflammatory drugs and opioids are inadequate to relieve chronic pain due to the lack of efficacy or severe side-effects. Chemokines are a family of small secreted proteins that bind to G protein-coupled receptors to trigger intracellular signaling pathways and direct cell migration, proliferation, survival, and inflammation under homeostatic and pathological conditions. Accumulating evidence supports the important role of chemokines and chemokine receptors in the peripheral and central nervous system in mediating chronic pain via enhancing neuroinflammation. In this review, we focus on recent progress in understanding the comprehensive roles of chemokines and chemokine receptors in the generation and maintenance of different types of chronic pain, including neuropathic pain, inflammatory pain, cancer pain, and visceral pain. The current review also summarizes the upstream signaling of transcriptional and epigenetic regulation on the expression of chemokines and chemokine receptors as well as the downstream signaling of chemokine receptors underlying chronic pain. As chronic itch and chronic pain share some common mechanisms, we also discuss the emerging roles of chemokines and chemokine receptors in chronic itch. Targeting specific chemokines or chemokine receptors by siRNAs, blocking antibodies, or small-molecule antagonists may offer new therapeutic potential for the management of chronic pain.
Learn More >Chronic pain is highly prevalent in the working population. People tend to attempt self-initiated treatments to manage their pain. The self-efficacy of behavioural change is a suitable model for guiding the development of an electronic pain management programme (ePain). The aim in this study is to develop ePain and to evaluate its effectiveness at improving pain self-efficacy, reducing pain intensity and negative emotions, and increasing quality of life.
Learn More >Vestibular symptoms and balance changes are common in patients with migraine, especially in the ones with aura and chronic migraine. However, it is not known if the balance changes are determined by the presence of vestibular symptoms or migraine subdiagnosis. Therefore, the aim of this study was to verify if the migraine subdiagnosis and/or the presence of vestibular symptoms can predict balance dysfunction in migraineurs.
Learn More >Complex regional pain syndrome type-I (CRPS-I) is a progressive and devastating pain condition. The mechanisms of CRPS-I still remain poorly understood. We aim to explore expression profiles of genes relevant to pain and neuroinflammation mechanisms involved in CRPS-I.
Learn More >Atopic Dermatitis (AD) is a common inflammatory disease with a genetic background. The prevalence of AD has been increasing in many countries. AD patients often have manifestations of pruritus, generalized skin dryness, and eczematous lesions. The pathogenesis of AD is complicated. The impaired skin barrier and immune imbalance play significant roles in the development of AD. Environmental factors such as allergens and pollutants are associated with the increasing prevalence. Many genetic and environmental factors induce a skin barrier deficiency, and this can lead to immune imbalance, which exacerbates the impaired skin barrier to form a vicious cycle (outside-inside-outside view). Genetic studies find many gene mutations and genetic variants, such as filaggrin mutations, which may directly induce the deficiency of the skin barrier and immune system. Epigenetic studies provide a connection between the relationship of an impaired skin barrier and immune and environmental factors, such as tobacco exposure, pollutants, microbes, and diet and nutrients. AD is a multigene disease, and thus there are many targets for regulation of expression of these genes which may contribute to the pathogenesis of AD. However, the epigenetic regulation of environmental factors in AD pathogenesis still needs to be further researched.
Learn More >Digital technologies connect young people with health services and resources that support their self-care. The lack of accessible, reliable digital resources tailored to young people with persistent musculoskeletal pain is a significant gap in the health services in Australia. Recognizing the intense resourcing required to develop and implement effective electronic health (eHealth) interventions, the adaptation of extant, proven digital technologies may improve access to pain care with cost and time efficiencies.
Learn More >Mounting evidence indicates that disruptions in bidirectional communication pathways between the central nervous system (CNS) and peripheral immune system underlie the etiology of pathologic pain conditions. The purpose of this review is to focus on the cross-talk between these two systems in mediating nociceptive circuitry under various conditions, including nervous system disorders. Elevated and prolonged proinflammatory signaling in the CNS is argued to play a role in psychiatric illnesses and chronic pain states. Here we review current research on the dynamic interplay between altered nociceptive mechanisms, both peripheral and central, and physiological and behavioral changes associated with CNS disorders.
Learn More >The effective management of pain is a longstanding public health concern. Although opioids have been frontline analgesics for decades, they also have well-known undesirable effects that limit their clinical utility, such as abuse liability and respiratory depression. The failure to develop better analgesics has, in some ways, contributed to the escalating opioid epidemic that has claimed tens of thousands of lives and has cost hundreds of billions of dollars in health-care expenses. A paradigm shift is needed in the pharmacotherapy of pain management that will require extensive efforts throughout biomedical science. The purpose of the present review is to highlight the critical role of the to devise improved translational models of pain for drug development. Despite high heterogeneity of painful conditions that involve cortical-dependent pain processing, current models often feature an overreliance on simple reflex-based measures and an emphasis on the absence, rather than presence, of behavior as evidence of analgesic efficacy. Novel approaches should focus on the restoration of operant and other CNS-mediated behavior under painful conditions.
Learn More >Native Americans (NAs) have a higher prevalence of chronic pain than other US racial/ethnic groups, but the mechanisms contributing to this pain disparity are under-researched. Pain catastrophizing is one of the most important psychosocial predictors of negative pain outcomes, and the Pain Catastrophizing Scale (PCS) has been established as a reliable and valid measure of the pain catastrophizing construct. However, before the PCS can be used to study pain risk in NAs, it is prudent to first determine whether the established 3-factor structure of the PCS also holds true for NAs.
Learn More >Pain is the most common symptom reported in clinical practice, meaning that it is associated with many pathologies as either the origin or a consequence of other illnesses. Furthermore, pain is a complex emotional and sensorial experience, as the correspondence between pain and body damage varies considerably. While these issues are widely acknowledged in clinical pain research, until recently they have not been extensively considered when exploring animal models, important tools for understanding pain pathophysiology. Interestingly, chronic pain is currently considered a risk factor to suffer psychiatric disorders, mainly stress-related disorders like anxiety and depression. Conversely, pain appears to be altered in many psychiatric disorders, such as depression, anxiety and schizophrenia. Thus, pain and psychiatric disorders have been linked in epidemiological and clinical terms, although the neurobiological mechanisms involved in this pathological bidirectional relationship remain unclear. Here we review the evidence obtained from animal models about the co-morbidity of pain and psychiatric disorders, placing special emphasis on the different dimensions of pain.
Learn More >In response to the opioid epidemic, the Centers for Disease Control and Prevention issued guidelines (CDCG) in 2016 for the prescription of opioids for chronic pain. To facilitate research into whether CDCG implementation will lead to reductions in opioid prescribing and improved patient safety, we sought to validate a tool that quantifies CDCG adherence based on clinical documentation.
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