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Host protection against cutaneous herpes simplex virus 1 (HSV-1) infection relies on the induction of a robust adaptive immune response. Here, we show that Nav sensory neurons, which are involved in pain perception, control the magnitude of CD8 T cell priming and expansion in HSV-1-infected mice. The ablation of Nav-expressing sensory neurons is associated with extensive skin lesions characterized by enhanced inflammatory cytokine and chemokine production. Mechanistically, Nav sensory neurons are required for the downregulation of neutrophil infiltration in the skin after viral clearance to limit the severity of tissue damage and restore skin homeostasis, as well as for eliciting robust CD8 T cell priming in skin-draining lymph nodes by controlling dendritic cell responses. Collectively, our data reveal an important role for the sensory nervous system in regulating both innate and adaptive immune responses to viral infection, thereby opening up possibilities for new therapeutic strategies.
Learn More >People report substituting cannabis for pain medications, but whether cannabidiol (CBD) is used similarly remains unknown. CBD products can be CBD alone (isolate), hemp extract (containing <0.3% Δ-9-tetrahydrocannabinol [THC], other cannabinoids, and terpenes), or CBD-cannabis (containing >0.3% THC). In a secondary analysis from a cross-sectional survey, we examined substitution patterns among n = 878 individuals with fibromyalgia who currently used CBD. We sub-grouped participants by most commonly used CBD product (CBD isolate, hemp, CBD-cannabis, no preference) and whether they substituted CBD for medications. We investigated rationale for substituting, substitution-driven medication changes, CBD use patterns, and changes in pain-related symptoms (e.g., sleep, anxiety). The study population was 93.6% female and 91.5% Caucasian, with an average age of 55.5 years. The majority (n = 632, 72.0%) reported substituting CBD products for medications, most commonly NSAIDs (59.0%), opioids (53.3%), gabapentanoids (35.0%), and benzodiazepines (23.1%). Most substituting participants reported decreasing or stopping use of these pain medications. The most common reasons for substitution were fewer side effects and better symptom management. Age, hemp products, past-year use of marijuana, and higher somatic burden were all associated with substituting (p's ≤ 0.05). Those who substituted reported larger improvements in health and pain than those who did not. Participants using CBD-cannabis reported significantly more substitutions than any other group (p's ≤ 0.001) and larger improvements in health, pain, memory, and sleep than other subgroups. This widespread naturalistic substitution for pain medications suggests the need for more rigorous study designs to examine this effect. Perspective: This article shows that people with fibromyalgia are deliberately substituting CBD products for conventional pain medications despite the dearth of evidence suggesting CBD products may be helpful for fibromyalgia. CBD's medication-sparing and therapeutic potential should be examined in more rigorous study designs.
Learn More >To test whether contralateral sensory abnormalities in the clinically unaffected area of patients with unilateral neuropathic pain are due to the neuropathy or pain mechanisms.
Learn More >Humans with loss-of-function mutations in the Na1.7 channel gene (SCN9A) show profound insensitivity to pain, whereas those with gain-of-function mutations can have inherited pain syndromes. Therefore, inhibition of the Na1.7 channel with a small molecule has been considered a promising approach for the treatment of various human pain conditions. To date, clinical studies conducted using selective Na1.7 inhibitors have not provided analgesic efficacy sufficient to warrant further investment. Clinical studies to date used multiples of in vitro IC values derived from electrophysiological studies to calculate anticipated human doses. To increase the chance of clinical success, we developed rhesus macaque models of action potential propagation, nociception, and olfaction, to measure Na1.7 target modulation in vivo. The potent and selective Na1.7 inhibitors SSCI-1 and SSCI-2 dose-dependently blocked C-fiber nociceptor conduction in microneurography studies and inhibited withdrawal responses to noxious heat in rhesus monkeys. Pharmacological Na1.7 inhibition also reduced odor-induced activation of the olfactory bulb (OB), measured by functional magnetic resonance imaging (fMRI) studies consistent with the anosmia reported in Na1.7 loss-of-function patients. These data demonstrate that it is possible to measure Na1.7 target modulation in rhesus macaques and determine the plasma concentration required to produce a predetermined level of inhibition. The calculated plasma concentration for preclinical efficacy could be used to guide human efficacious exposure estimates. Given the translatable nature of the assays used, it is anticipated that they can be also used in phase 1 clinical studies to measure target modulation and aid in the interpretation of phase 1 clinical data.
Learn More >Migraine is one of the leading causes of years lived with disability and considered to be a major global health concern. Pharmacological preventive treatment often causes side effects that limit the adherence to longer-term treatment regiments. Both experimental and clinical evidence suggests that positive expectations can modulate pain and analgesic treatment effects. However, the role of expectations in migraine prophylactic treatment has not systematically been investigated. Here, we examined the influence of treatment expectation prior to commencing pharmacological preventive treatment on its efficacy and tolerability in N=134 episodic (30%) and chronic migraine (70%) patients in a prospective, longitudinal observational study over the course of six months. The migraine prophylaxis reduced the number of headache and migraine days with acceptable tolerability. Positive treatment expectation was associated with a generally lower number of headache and migraine days and a stronger reduction in headache days over the course of the treatment in chronic but not in episodic migraine patients. Moreover, patients with prior treatment showed a stronger reduction in headache days with higher expectation as compared to patients without prior experience. Our results underscore the relevance of further exploring the role of treatment expectation and its systematic modulation in migraine patients and other pain conditions.
Learn More >Opioids are perhaps the most effective analgesics in medicine. However, between 1999 to 2018, over 400,000 people in the United States died from opioid overdose. Excessive opioids make breathing lethally slow and shallow, a side-effect called opioid induced respiratory depression. This doubled-edged sword has sparked the desire to develop novel therapeutics that provide opioid-like analgesia without depressing breathing. One such approach has been the design of so-called 'biased agonists' that signal through some, but not all pathways downstream of the µ-opioid receptor (MOR), the target of morphine and other opioid analgesics. This rationale stems from a study suggesting that MOR-induced ß2-arrestin dependent signaling is responsible for opioid respiratory depression, whereas adenylyl cyclase inhibition produces analgesia. To verify this important result that motivated the 'biased agonist' approach, we re-examined breathing in ß2-arrestin deficient mice and instead find no connection between ß2-arrestin and opioid respiratory depression. This result suggests that any attenuated effect of 'biased agonists' on breathing is through an as-yet defined mechanism.
Learn More >Data from the Global Burden of Disease Study 2019 were used to report the burden of migraine in 204 countries and territories during the period 1990 to 2019, through a systematic analysis of point prevalence, annual incidence, and years lived with disability (YLD). In 2019, the global age-standardised point prevalence and annual incidence rate of migraine were 14,107.3 (95% Uncertainty Interval [UI] 12,270.3-16,239) and 1142.5 (95% UI 995.9-1289.4) per 100,000, an increase of 1.7% (95% UI 0.7%-2.8%) and 2.1% (95% UI 1.1%-2.8%) since 1990, respectively. Moreover, the global age-standardised YLD rate in 2019 was 525.5 (95% UI 78.8-1194), an increase of 1.5% (95% UI -4.4% to 3.3%) since 1990. The global point prevalence of migraine in 2019 was higher in females and increased by age up to the 40 to 44 age group, then decreased with increased age. Belgium (22,400.6 [95% UI: 19,305.2-26,215.8]), Italy (20,337.7 [95% UI: 17,724.7-23,405.8]), and Germany (19,436.4 [95% UI: 16,806.2-22,810.3]) had the 3 highest age-standardised point prevalence rates for migraine in 2019. In conclusion, there were large intercountry differences in the burden of migraine, and this burden increased significantly across the measurement period. These findings suggest that migraine care needs to be included within the health system to increase population awareness regarding the probable risk factors and treatment strategies especially among young adults and middle-aged women, as well as to increase the data on migraines.
Learn More >Clinical models of chronic low back pain (cLBP) highlight the role of excessive attention to pain and kinesiophobia on the origin of disability. At the motor control level, various mechanisms are involved in the impairments observed in patients with cLBP. We aimed to assess the role of maladaptative attentional behaviors by using a complex systems approach and a visual display as a distraction during walking. Sixteen patients with cLBP with no previous surgery or significant leg pain and 16 healthy matched controls were included. Patients walked on a treadmill at preferred walking speed with and without distraction. Stride time (ST) fractal complexity was assessed using detrended fluctuation analysis. A two-way analysis of variance with repeated measures on distraction was performed on fractal exponents. We found a significant group × distraction interaction effect on fractal complexity of ST series (F(1,30) = 9.972, P = 0.004). Post hoc analysis showed that, without distraction, patients with cLBP had significantly lower ST complexity than controls, but when distracted, they regained gait complexity, recovering the level of controls. Our results suggest that excessive attention to pain causes loss of complexity and adaptability in cLBP and explain alterations of motor control with pain. Fractal analysis seems to be a promising method to explore movement variability and individual adaptability in musculoskeletal disorders.
Learn More >Persistent postsurgical pain (PPSP) is common after breast and thoracic surgeries. Understanding which risk factors consistently contribute to PPSP will allow clinicians to apply preventive strategies, as they emerge, to high-risk patients. The objective of this work was to systematically review and meta-analyze the literature on risk factors of PPSP after breast and thoracic surgeries. A systematic literature search using Ovid Medline, Cochrane Central Register of Controlled Trials, Cumulative Index to Nursing and Allied Health Literature, Embase, PsycINFO, and Scopus databases was conducted. Study screening with inclusion and exclusion criteria, data extraction, and risk of bias assessment was performed independently by 2 authors. The data for each surgical group were analyzed separately and meta-analyzed where possible. The literature search yielded 5584 articles, and data from 126 breast surgery and 143 thoracic surgery articles were considered for meta-analysis. In breast surgery, younger age, higher body mass index, anxiety, depression, diabetes, smoking, preoperative pain, moderate to severe acute postoperative pain, reoperation, radiotherapy, and axillary lymph node dissection were the main factors associated with higher risk of PPSP. In thoracic surgery, younger age, female sex, hypertension, preoperative pain, moderate to severe acute postoperative pain, surgical approach, major procedure, and wound complications were associated with PPSP. This systematic review demonstrated certain consistent risk factors of PPSP after breast and thoracic surgeries, as well as identified research gaps. Understanding the factors that increase susceptibility to PPSP can help selectively allocate resources to optimize perioperative care in high-risk patients and help develop targeted, risk-stratified interventions for PPSP prevention.
Learn More >Chronic pain is associated with reduced quality of life, increased medical expenditures, and significant economic costs. Chronic pain is among the most common chronic conditions in the United States, although estimates vary widely regarding its precise prevalence. Understanding the scope of the problem using the most contemporaneous data is therefore an important goal. This study sought to determine the prevalence of chronic pain and its impacts among adults in the United States using the National Health Interview Survey, a household-based annual survey of self-reported health status of U.S. adults that can be used to generate national-level estimates. Using a chronic pain module introduced in the 2019 edition of National Health Interview Survey, we found that 50.2 million adults (20.5%) reported pain on most days or every day. The most common pain locations were back pain and hip, knee, or foot pain. The most commonly used management strategies for chronic pain were physical therapy and massage. Respondents with chronic pain reported limitations in daily functioning, including social activities and activities of daily living. Respondents with chronic pain reported significantly more workdays missed compared with those without chronic pain (10.3 vs 2.8, P < 0.001). Overall, these findings indicate that more than 1 in 5 adults in America experiences chronic pain; additional attention to managing the burden of this disease is warranted.
Learn More >Afferents from the C2 spinal nerve (SN) and trigeminal nerve (TN) innervate neighboring cranial territories and their convergence on the upper cervical dorsal horn neurons represents neural substrate of pain referral in primary headache disorders. Unfortunately, little is known about trigeminocervical input to the major spinal nociceptive-projection area lamina I. Here we used ex-vivo brainstem-cervical cord preparation for the visually-guided whole-cell recording from the upper cervical lamina I neurons. We show that 50% of them receive convergent monosynaptic input from both nerves, whereas 35% and 11% of neurons receive specific supply from the C2 SN and TN, respectively. Altogether, ten distinct patterns of synaptic input from the C2 SN and TN to lamina I neurons could be identified. Although stimulation of both nerves evoked excitatory/inhibitory responses, more numerous pure inhibitory inputs arose from the TN. We show that cervical and trigeminal nociceptors converge on to lamina I projection and inhibitory neurons. Thus, trigeminocervical input in lamina I is processed in both nerve-specific and convergent circuitries. Afferent convergence on to inhibitory interneurons serves as a feedforward mechanism balancing excitatory drive to projection neurons. Disruption of this balance may cause pain in primary headache syndromes.
Learn More >Dorsal root ganglion field stimulation (GFS) relieves evoked and spontaneous neuropathic pain by use-dependent blockade of impulse trains through the sensory neuron T-junction, which becomes complete within less than 1 minute for C-type units, also with partial blockade of Aδ units. We used this tool in the spinal nerve ligation (SNL) rat model to selectively block sensory neuron spontaneous activity (SA) of axotomized neurons at the fifth lumbar (L5) level vs blockade of units at the L4 level that remain uninjured but exposed to inflammation. In vivo dorsal root single-unit recordings after SNL showed increased SA in L5 units but not L4 units. Ganglion field stimulation blocked this SA. Ganglion field stimulation delivered at the L5 dorsal root ganglion blocked mechanical hyperalgesia behavior, mechanical allodynia, and ongoing spontaneous pain indicated by conditioned place preference, whereas GFS at L4 blocked evoked pain behavior but not spontaneous pain. In vivo single-unit recordings of spinal cord dorsal horn (DH) wide-dynamic-range neurons showed elevated SA after SNL, which was reduced by GFS at the L5 level but not by GFS at the L4 level. In addition, L5 GFS, but not L4 GFS, increased mechanical threshold of DH units during cutaneous mechanical stimulation, while L5 GFS exceeded L4 GFS in reducing evoked firing rates. Our results indicate that SA in injured neurons supports increased firing of DH wide-dynamic-range neurons, contributing to hyperalgesia, allodynia, and ongoing pain. Ganglion field stimulation analgesic effects after nerve injury are at least partly attributable to blocking propagation of this SA.
Learn More >Tapering opioids for chronic pain can be challenging for both patients and prescribers, both of whom may be unsure of what to expect in terms of pain, distress, activity interference, and withdrawal symptoms over the first few weeks and months of the taper. In order to better prepare clinicians to provide patient-centred tapering support, the current research used prospective longitudinal qualitative methods to capture individual-level variation in patients' experience over the first few months of a voluntary physician-guided taper. The research aimed to identify patterns in individuals' experience of tapering, and explore whether patient characteristics, readiness to taper, opioid-tapering self-efficacy, or psychosocial context were related to tapering trajectory. Twenty-one patients with chronic non-cancer pain commencing tapering of long-term opioid therapy were recruited from a metropolitan tertiary pain clinic (n = 13) and a regional primary care practice (n = 8). Semi-structured phone interviews were conducted a mean of 8 times per participant over a mean duration of 12 weeks (N = 173). Four opioid tapering trajectories were identified, which we characterised as thriving, resilient, surviving, and distressed. High and low readiness to taper were a defining characteristic of "thriving" and "distressed" trajectories, respectively. Life adversity was a prominent theme of "resilient" and "distressed" trajectories, with supportive relationships buffering the effects of adversity for those who followed a "resilient" trajectory. Discussion focuses on the implications of these findings for the preparation and support of patients with chronic pain who are commencing opioid tapering.
Learn More >Different pathophysiological mechanisms contribute to the pain development in osteoarthritis (OA). Sensitization mechanisms play an important role in the amplification and chronification of pain and may predict the therapeutic outcome. Stratification of patients according to their pain mechanisms could help to target pain therapy. This study aimed at developing an easy-to-use, bedside tool-kit to assess sensitization in patients with chronic painful knee OA or chronic pain after total knee replacement (TKR).In total, 100 patients were examined at the most affected knee and extra-segmentally by use of four standardized quantitative sensory testing parameters reflecting sensitization (mechanical pain threshold, mechanical pain sensitivity, dynamic mechanical allodynia, pressure pain threshold), a bedside testing battery of equivalent parameters including also temporal summation and conditioned pain modulation, and pain questionnaires. Machine learning techniques were applied to identify an appropriate set of bedside screening tools.Approximately half of the patients showed signs of sensitization (46%). Based on machine learning techniques a composition of tests consisting of three modalities were developed. The most adequate bedside tools to detect sensitization were pressure pain sensitivity (pain intensity at 4 ml pressure using a 10 ml blunted syringe), mechanical pinprick pain sensitivity (pain intensity of a 0.7 mm nylon-filament) over the most affected knee, and extra-segmental pressure pain sensitivity (pain threshold).This pilot study presents a first attempt to develop an easy-to-use bedside test to probe sensitization in patients with chronic OA knee pain or chronic pain after TKR. This tool may be used to optimize individualized, mechanism-based pain therapy.
Learn More >Normalization of the excitatory and inhibitory balance by increasing the levels of endogenous inhibitory neurotransmitters by blocking their reuptake is a promising therapeutic strategy for relieving chronic pain. Pharmacological blockade of spinal GABA transporter subtypes 1 and 3 (GAT1 and GAT3) has been reported to generate analgesic effects in animal models of neuropathic pain. Here we explored the synaptic mechanisms underlying their analgesic effects in the spinal dorsal horn. Whole-cell recordings were made from dorsal horn neurons in spinal slices with attached dorsal roots from adult mice, and the effects of GAT inhibitors on miniature and evoked postsynaptic currents were examined. Behaviorally, GAT inhibitors were intrathecally applied to assess their effects on mechanical hypersensitivity in mice developing neuropathic pain after partial sciatic nerve ligation. The GAT1 inhibitor NNC-711 reduced the frequency of mEPSCs and the amplitude of C-fiber-mediated EPSCs, and the GAT3 inhibitor SNAP-5114 reduced the amplitude of A- and C-fiber-mediated EPSCs. These effects were antagonized by the GABAB receptor antagonist CGP55845. Consistently, the analgesic effect of intrathecally injected NNC-711 and SNAP-5114 in mice developing mechanical hypersensitivity after partial sciatic nerve ligation was abolished by CGP55845. Thus, GAT1 and GAT3 inhibitors exert distinct GABAB receptor-mediated inhibitory effects on excitatory synaptic transmission in the spinal dorsal horn, which most likely contributes to their analgesic effects.
Learn More >Deprescribing is the systematic process of discontinuing drugs when harms outweigh the benefits. We conducted semi-structured telephone interviews with twenty-two general practitioners (GPs) who had prescribed or deprescribed opioids in patients with chronic non-cancer pain within the last six months to investigate the barriers and facilitators to deprescribing opioid analgesics in patients with chronic non-cancer pain. We also explored GPs' perspectives on the available resources to assist them with opioid deprescribing. Interviews were audio-recorded, transcribed verbatim and then coded using an iterative process until data saturation reached. The thematic analysis process identified themes, first as concepts, then refined to overarching themes after the merging of similar subthemes.Themes exploring barriers to deprescribing highlighted the difficulties GPs face while considering patient factors and varying prescribing practices within the confines of the health system. Patient motivation and doctor-patient rapport were central factors to facilitate deprescribing and GPs considered the most important deprescribing resource to be a multidisciplinary network of clinicians to support themselves and their patients. Therefore, although GPs emphasised the importance of deprescribing opioid analgesics, they also expressed many barriers relating to managing complex pain conditions, patient factors and varying prescribing practices between clinicians. Some of these barriers could be mitigated by GPs having time and resources to educate and build rapport with their patients. This suggests the need for further development of multimodal resources and improved support through the public health system to enable GPs to prioritise patient-centred care.
Learn More >To quantify the change in quality of life, disease-specific indicators, health, and lifestyle before and during the COVID19 pandemic amongst people with musculoskeletal diagnoses and symptoms.
Learn More >This study aims to analyse the effect of the discontinuation of anti-calcitonin gene-related peptide antibodies on monthly migraine days after 12 treatment months.
Learn More >Chronic pain, highly prevalent throughout the course of Parkinson's disease (PD), has been ranked as one of the top ten most bothersome symptoms people with Parkinson's (PwP) are experiencing. Yet, robust evidence-based treatment strategies are lacking. This unmet need is partly attributable to the multifaceted nature of PD-related pain, which results in part from a complex and poorly understood interplay involving a range of neurotransmitter pathways. Degeneration of nigrostriatal dopaminergic pathways and alterations of central nervous system extra-striatal dopaminergic, noradrenergic, serotoninergic, glutamatergic, opioidergic and endocannabinoid circuits may all promote a heightened experience of pain in PwP. Thus, the potential targets for mechanism-based pain-relieving strategies in PwP are several. These targets are discussed herein.
Learn More >Patients with chronic pain who are tapering prescription opioids report a need for greater support for coping with symptoms of pain and withdrawal. Mobile health (mHealth) technologies (SMS text messaging- or app-based) have the potential to provide patients with educational, emotional, and motivational support for opioid tapering beyond what is offered by their health care provider. However, it is not known whether patients with chronic pain who are tapering opioids would be willing or able to engage with technology-based support.
Learn More >Potential fremanezumab doses for pediatric patients were evaluated using pharmacokinetic modeling and simulation. An open-label phase 1 pharmacokinetic and safety study was conducted in pediatric patients with migraine. This study's results together with refinement of the adult population pharmacokinetic model were used to determine fremanezumab dose recommendations for phase 3 pediatric studies.
Learn More >Although the European Medicines Agency and the US Food and Drug Administration have cleared several devices that use neuromodulation to provide clinical benefits in the acute or preventive treatment of migraine, the Clinical Trials Committee of the International Headache Society has not developed guidelines specifically for clinical trials of neuromodulation devices. In recognition of the distinct needs and challenges associated with their assessment in controlled trials, the Committee provides these recommendations for optimizing the design and conduct of controlled trials of neuromodulation devices for the acute and/or preventive treatment of migraine.
Learn More >Photophobia is one of the most common symptoms in migraine, and the underlying mechanism is uncertain. The discovery of the intrinsically-photosensitive retinal ganglion cells which signal the intensity of light on the retina has led to discussion of their role in the pathogenesis of photophobia. In the current review, we discuss the relationship between pain and discomfort leading to light aversion (traditional photophobia) and discomfort from flicker, patterns, and colour that are also common in migraine and cannot be explained solely by the activity of intrinsically-photosensitive retinal ganglion cells. We argue that, at least in migraine, a cortical mechanism provides a parsimonious explanation for discomfort from all forms of visual stimulation, and that the traditional definition of photophobia as pain in response to light may be too restrictive. Future investigation that directly compares the retinal and cortical contributions to photophobia in migraine with that in other conditions may offer better specificity in identifying biomarkers and possible mechanisms to target for treatment.
Learn More >To evaluate the efficacy of monthly or quarterly fremanezumab in patients with chronic migraine or episodic migraine and documented inadequate response to 2, 3, or 4 classes of prior migraine preventive medications.
Learn More >Many pain-triggering nociceptor neurons express TRPV1 or TRPA1, cation-selective channels with large pores that enable permeation of QX-314, a cationic analogue of lidocaine. Co-application of QX-314 with TRPV1 or TRPA1 activators can silence nociceptors. In this study, we describe BW-031, a novel more potent cationic sodium channel inhibitor, test whether its application alone can inhibit pain associated with tissue inflammation, and whether this strategy can also inhibit cough.
Learn More >It has been suggested that sensorimotor conflict contributes to the maintenance of some pathological pain conditions, implying that there are problems with the adaptation processes that normally resolve such conflict. We tested whether sensorimotor adaptation is impaired in people with Complex Regional Pain Syndrome (CRPS) by characterising their adaption to lateral prismatic shifts in vision. People with unilateral upper-limb CRPS Type I (n = 17), and pain-free individuals (n = 18; matched for age, sex, and handedness) completed prism adaptation with their affected/non-dominant and non-affected/dominant arms. We examined 1) the rate at which participants compensated for the optical shift during prism exposure (i.e., strategic recalibration), 2) endpoint errors made directly after prism adaptation (sensorimotor realignment) and the retention of these errors, and 3) kinematic markers associated with strategic control. Direct comparisons between people with CRPS and controls revealed no evidence of any differences in strategic recalibration, including no evidence for differences in a kinematic marker associated with trial-by-trial changes in movement plans during prism exposure. All participants made significant endpoint errors after prism adaptation exposure, indicative of sensorimotor realignment. Overall, the magnitude of this realignment did not differ between people with CRPS and pain-free controls. However, when endpoint errors were considered separately for each hand, people with CRPS made greater errors (indicating more rather than less realignment) when using their affected hand than their non-affected hand. No such difference was seen in controls. Taken together, these findings provide no evidence of impaired strategic control or sensorimotor realignment in people with CRPS. In contrast, they provide some indication that there could be a greater propensity for sensorimotor realignment in the CRPS-affected arm, consistent with more flexible representations of the body and peripersonal space. Our study challenges an implicit assumption of the theory that sensorimotor conflict might underlie some pathological pain conditions.
Learn More >The present study examined the role of attention control in understanding the development of negatively-biased pain memories as well as its moderating role in the relationship between pain catastrophizing and negatively-biased pain memories. Youth with chronic pain (N = 105) performed a cold pressor task (CPT) and completed self-report measures of state/trait pain catastrophizing and attention control, with the latter comprising both attention focusing and attention shifting. Two weeks after the CPT, youth's pain-related memories were elicited via telephone allowing to compute pain and anxiety memory bias indices (i.e., recalling pain intensity or pain-related anxiety, respectively, as higher than initially reported). Results indicated no main effects of attention control and pain catastrophizing on pain memories. However, both components of attention control (i.e., attention focusing and attention shifting) moderated the impact of pain catastrophizing on youth's memory bias, with opposite interaction effects. Specifically, whereas high levels of attention shifting buffered the influence of high pain catastrophizing on the development of pain memory bias, high levels of attention focusing strengthened the influence of high pain catastrophizing on the development of anxiety memory bias. Interaction effects were confined to trait catastrophizing (i.e., not state catastrophizing). Theoretical and clinical implications are discussed. PERSPECTIVE: This article investigates the role of attention control in the development of negatively-biased pain memories in children with chronic pain. Findings underscore the importance of targeting differential components of attention control and can inform intervention efforts to minimize the development of negatively biased pain memories in youth with chronic pain.
Learn More >This study compared perceptions of the burden of patient care and associated clinical judgments between physicians and people with chronic pain (PWCP) in a 2 × 3 × 2 between-subjects design that varied participant type, patient-reported pain severity (4-6-8/10), and supporting medical evidence (low/high). 109 physicians and 476 American Chronic Pain Association members were randomly assigned to one of six conditions. Respondents estimated the clinical burden they would assume as the treating physician of a hypothetical patient with chronic low back pain, and made clinical judgments regarding that patient. Physician burden ratings were significantly higher than PWCP ratings, and clinical impressions (e.g., trust in pain report, medical attribution) and management concerns (e.g., opioid abuse risk) were relatively less favorable. Neither pain severity nor medical evidence affected burden ratings significantly. High medical evidence was associated with more favorable clinical impressions; higher pain severity led to more discounting of patient pain reports. Burden was significantly correlated with a range of clinical judgments. Results indicate that physicians and people with chronic pain differ in their perceptions of provider burden and related clinical judgments in ways that could impact treatment collaboration. Further research is needed that examines provider burden in actual clinical practice. Perspective Physicians and people with chronic pain (PWCP) estimated the clinical burden of patient care and made judgments about a hypothetical patient with chronic pain. Physician burden ratings were higher and clinical judgments less favorable, relative to PWCP respondents. These differences could impact treatment collaboration and merit study in clinical practice.
Learn More >Complex Regional Pain Syndrome (CRPS) is characterised by pain, autonomic, sensory and motor abnormalities. It is associated with changes in the primary somatosensory cortex (S1 representation), reductions in tactile sensitivity (tested by two-point discrimination), and alterations in perceived hand size or shape (hand perception). The frequent co-occurrence of these three phenomena has led to the assumption that S1 changes underlie tactile sensitivity and perceptual disturbances. However, studies underpinning such a presumed relationship use tactile sensitivity paradigms that involve the processing of both non-spatial and spatial cues. Here, we used a task that evaluates anisotropy (i.e., orientation-dependency; a feature of peripheral and S1 representation) to interrogate spatial processing of tactile input in CRPS and its relation to hand perception. People with upper limb CRPS ( = 14) and controls with ( = 15) or without pain ( = 19) judged tactile distances between stimuli-pairs applied across and along the back of either hand to provide measures of tactile anisotropy. Hand perception was evaluated using a visual scaling task and questionnaires. Data were analysed with generalised estimating equations. Contrary to our hypotheses, tactile anisotropy was bilaterally preserved in CRPS, and the magnitude of anisotropic perception bias was comparable between groups. Hand perception was distorted in CRPS but not related to the magnitude of anisotropy or bias. Our results suggest against impairments in spatial processing of tactile input, and by implication S1 representation, as the cause of distorted hand perception in CRPS. Further work is warranted to elucidate the mechanisms of somatosensory dysfunction and distorted hand perception in CRPS.
Learn More >To describe the methodology and implications of the patient-identified most bothersome symptom (PI-MBS) measure used in the phase 3, multicenter, randomized, double-blind, placebo-controlled, and parallel-group PROMISE-2 trial and to evaluate the contribution of this measure to the assessment of the preventive migraine benefits of treatment.
Learn More >To examine the risk factors for new chronic opioid use in elderly patients who underwent hip fracture surgery.
Learn More >Calpain I is a calcium-dependent cysteine protease which has dual effects on tissue inflammation depending on its cellular location. Intracellularly, calpain I has pro-inflammatory properties but becomes anti-inflammatory when exteriorised into the extracellular space. In this study, the effect of calpain I on joint pain was investigated using the kaolin/carrageenan model of acute synovitis. Evoked pain behaviour was determined by von Frey hair algesiometry and non-evoked pain was measured using dynamic hindlimb weight bearing. Local administration of calpain I reduced secondary allodynia in the acute inflammation model and this effect was blocked by the cell impermeable calpain inhibitor E-64c. Calpain I also blocked the algesic effect of the protease activated receptor-2 (PAR-2) cleaving enzyme mast cell tryptase. The cell permeable calpain blocker E-64d also produced analgesia in arthritic joints. These data suggest that calpain I produces disparate effects on joint pain . analgesia when present extracellularly by disarming PAR-2, and pro-algesic when the enzyme is inside the cell.
Learn More >Chronic low back pain (cLBP) is the leading cause of disability. Interdisciplinary pain management is recommended for patients with severe cLBP. Such programs are expensive, not easily accessible, and have limited effect and therefore new cost-effective strategies are warranted. Cognitive Functional Therapy (CFT) has shown promising results, but has not been compared with an interdisciplinary pain management approach. The primary aim of this randomized controlled trial (RCT) is to investigate if a pathway starting with CFT including psychologist support (CFT+) with the option of additional usual care (if needed), is superior in improving disability and more cost-effective at 12 months compared with an interdisciplinary pain management pathway (usual care).
Learn More >Trigeminal neuralgia (TN) is a severe facial pain disease of unknown cause and unclear genetic background. To examine the existing knowledge about genetics in TN, we performed a systematic study asking about the prevalence of familial trigeminal neuralgia, and which genes that have been identified in human TN studies and in animal models of trigeminal pain. MedLine, Embase, Cochrane Library and Web of Science were searched from inception to January 2021. 71 studies were included in the systematic review. Currently, few studies provide information about the prevalence of familial TN; the available evidence indicates that about 1-2% of TN cases have the familial form. The available human studies propose the following genes to be possible contributors to development of TN: CACNA1A, CACNA1H, CACNA1F, KCNK1, TRAK1, SCN9A, SCN8A, SCN3A, SCN10A, SCN5A, NTRK1, GABRG1, MPZ gene, MAOA gene and SLC6A4. Their role in familial TN still needs to be addressed. The experimental animal studies suggest an emerging role of genetics in trigeminal pain, though the animal models may be more relevant for trigeminal neuropathic pain than TN per se. In summary, this systematic review suggests a more important role of genetic factors in TN pathogenesis than previously assumed.
Learn More >A significant portion of individuals living with traumatic spinal cord injury (SCI) experiences some degree of debilitating neuropathic pain (NP). This pain remains largely intractable in a majority of cases, due in part to an incomplete understanding of its underlying mechanisms. Central sensitization, an increase in excitability of pain transmission neurons located in superficial dorsal horn (sDH), plays a key role in development and maintenance of SCI-induced NP. Resident microglia and peripheral monocyte-derived macrophages (referred to collectively as MMΦ) are involved in promoting SCI-induced DH neuron hyperexcitability. Importantly, these MMΦ consist of populations of cells that can exert pro-inflammatory or anti-inflammatory signaling within injured spinal cord. It is critical to spatiotemporally characterize this heterogeneity to understand MMΦ contribution to NP after SCI. Given that a majority of SCI cases are cervical in nature, we used a model of unilateral C5/C6 contusion that results in persistent at-level thermal hyperalgesia and mechanical allodynia, two forms of NP-related behavior, in the forepaw. The aim of this study was to characterize the sDH MMΦ response within intact cervical spinal cord segments caudal to the lesion (i.e. the location of primary afferent nociceptive input from the forepaw plantar surface). Cervical SCI promoted a persistent MMΦ response in sDH that coincided with the chronic NP phenotype. Using markers of pro- and anti-inflammatory MMΦ, we found that the MMΦ population within sDH exhibited significant heterogeneity that evolved over time post-injury, including a robust and persistent increase in pro-inflammatory MMΦ that was especially pronounced at later times. C5/C6 contusion SCI also induced below-level thermal hyperalgesia and mechanical allodynia in the hindpaw; however, we did not observe a pronounced MMΦ response in sDH of L4/L5 spinal cord, suggesting that different inflammatory cell mechanisms occurring in sDH may be involved in at-level versus below-level NP following SCI. In conclusion, our findings reveal significant MMΦ heterogeneity both within and across pain transmission locations after SCI. These data also show a prominent and persistent pro-inflammatory MMΦ response, suggesting a possible role in DH neuron hyperexcitability and NP.
Learn More >Opioid overdose intervention by naloxone, a high affinity receptor antagonist, reverses opioid-induced respiratory depression (OIRD) and analgesia by displacing opioids. Systemic naloxone stimulates release of the hypothalamic neuropeptide oxytocin, which has analgesic properties and participates in cardiorespiratory homeostasis. To test the hypothesis that oxytocin can reverse OIRD, we assessed the rescue potential of graded doses (0, 0.1, 2, 5, 10, 50 nmol/kg, i.v) of oxytocin to counter fentanyl (60 nmol/kg, i.v.)-induced depression of neural inspiration indexed by recording phrenic nerve activity (PNA) in anesthetized (urethane/α-chloralose), vagotomized, and artificially ventilated rats. Oxytocin dose-dependently rescued fentanyl OIRD by almost immediately reversing PNA burst arrest (=0.0057) and restoring baseline burst frequency (=0.0016) and amplitude (=0.0025) at low, but not high doses, resulting in inverted bell-shaped dose-response curves. Oxytocin receptor antagonism (40 nmol/kg, i.v.) prevented oxytocin reversal of OIRD (Arrest: =0.0066, Frequency: =0.0207, Amplitude: =0.0022). Vasopressin 1A receptor (V1aR) antagonism restored high-dose oxytocin efficacy to rescue OIRD (=0.0170 – <0.0001), resulting in classic sigmoidal dose-response curves, and prevented (=0.0135) transient hypertension from V1aR cross-activation (=0.0275). Alone, vasopressin (5 nmol/kg, i.v.) failed to reverse fentanyl respiratory arrest (=0.6184). The non-peptide oxytocin receptor agonist WAY-267464 (75 nmol/kg, i.v.), which has V1aR antagonist properties, quickly reversed fentanyl OIRD (<0.0001), with rapid recovery of PNA frequency (=0.0011) and amplitude (=0.0044) without adverse hemodynamic consequences (=0.9991). Findings indicate that peptide and non-peptide agonist activation of oxytocin receptors without V1aR cross-activation rescues fentanyl OIRD. Oxytocin receptor agonists could be lifesaving resuscitation agents that enhance rather than interrupt opioid analgesia. Oxytocin receptor activation produces analgesia. Here, we demonstrate that activation by the FDA-approved agonist oxytocin and the non-peptide partial agonist WAY-267464 can each reverse fentanyl cardiorespiratory depression. Selective targeting of oxytocin receptors for resuscitation from opioid overdose, alone or in combination with an opioid antagonist, could eliminate or attenuate negative side effects associated with traditional opioid receptor antagonism.
Learn More >N-acylethanolamine acid amidase (NAAA) is an N-terminal cysteine hydrolase that stops the physiological actions of palmitoylethanolamide (PEA), an endogenous lipid messenger that activates the transcription factor, peroxisome proliferator-activated receptor-α. We have previously reported that the compound ARN19702 ((2-ethylsulfonylphenyl)-[(2S)-4-(6-fluoro-1,3-benzothiazol-2-yl)-2-methylpiperazin-1-yl]methanone) is an orally active, reversible NAAA inhibitor (median inhibitory concentration, IC, on human NAAA = 230 nM) that produces remarkable protective effects against multiple sclerosis in mice. In the present study, we assessed the profile of ARN19702 in mouse and rat models of acute and neuropathic pain. Oral administration in male mice attenuated in a dose-dependent manner the spontaneous nocifensive response elicited by intraplantar formalin injection and the hypersensitivity caused by intraplantar carrageenan injection, paw incision or the sciatic nerve ligation. In male rats, ARN19702 reduced nociception associated with paclitaxel-induced neuropathy without development of sub-acute antinociceptive tolerance. Finally, ARN19702 (30 mg/kg, oral) did not produce place-preference or alter exploratory motor behavior in male mice. The findings support the conclusion that NAAA is a suitable molecular target for the discovery of efficacious analgesic drugs devoid of rewarding potential. We evaluated the pharmacological profile of the orally bioavailable NAAA inhibitor ARN19702 in mouse and rat models of neurogenic and inflammatory pain. The compound's potential rewarding and sedative effects were also examined. We conclude that ARN19702 exhibits a broad analgesic profile that can be generalized across rodent species. Our findings point to NAAA as a control node in the processing of neuropathic and inflammatory pain, and to ARN19702 as a lead to uncover novel pain therapeutics devoid of addictive potential.
Learn More >Flotation restricted environmental stimulation therapy (REST) is an emerging therapeutic intervention that, to our knowledge, has never been directly compared with an indistinguishable placebo in patients with chronic pain.
Learn More >Acute pain is the main complication of sickle cell disease. Chronic and neuropathic pain may also be experienced but have not been formally described in Jamaican patients. A cross-sectional study was conducted to determine their prevalence and characteristics, and to determine the common pain locations and modalities of management.
Learn More >Medication overuse headache (MOH), the development or worsening of chronic headache resulting from frequent and excessive intake of medications used for acute treatment of headache, is a common secondary headache disorder and is associated with significant personal and societal burdens. The plausible physiologic mechanism is that chronic exposure to acute care migraine treatment leads to suppression of endogenous antinociceptive systems, consequently facilitating the trigeminal nociceptive process via up-regulation of the calcitonin gene-related peptide (CGRP) system. Recognizing and preventing its development is an integral aspect of migraine management, as medication overuse is a modifiable risk factor in the progression from episodic to chronic migraine. Over the years, MOH has been difficult to treat and has generated much controversy. Ongoing debates exist over the diagnostic criteria and treatment strategies, particularly regarding the roles of formal detoxification and preventive treatment. The arrival of the anti-CGRP monoclonal antibodies has also challenged our views of MOH and its treatment. This review outlines the evolution of MOH diagnostic criteria, presents the current understanding of MOH pathogenesis and discusses the debates over its development and treatment. Data on the efficacy of anti-CGRP monoclonal antibodies in the setting of medication overuse is also presented. These results indicate that patients with medication overuse, who are treated with these new medications, may not need to be detoxified in order to treat MOH. In light of these developments, it is likely that in the future MOH will be more readily diagnosed and treatment will result in better outcomes.
Learn More >Fibromyalgia syndrome is one of the most common causes of chronic widespread pain, but pain accompanies a wide range of ancillary symptoms. To date, its aetiopathogenesis remains elusive, and diagnosis is exquisitely clinical, due to the lack of biomarkers or specific laboratory alterations in fibromyalgia patients. This position paper has the purpose to summarise the current scientific knowledge and expert opinions about the main controversies regarding fibromyalgia syndrome, namely: (i) fibromyalgia definition and why it is still not recognised in many countries as a distinct clinical entity; (ii) fibromyalgia severity and how to evaluate treatment outcome; (iii) how to treat fibromyalgia and which is a correct approach to fibromyalgia patients.
Learn More >Although opioids are potent analgesics, a consequence of chronic opioid use is hyperalgesia during withdrawal, which may contribute to opioid misuse. Dynorphin, the endogenous ligand of κ-opioid receptors (KORs), is upregulated in opioid-dependent rats and in animal models of chronic pain. However, the role of KORs in opioid withdrawal-induced hyperalgesia remains to be determined. We hypothesized that KOR antagonism would reverse opioid withdrawal-induced hyperalgesia in opioid-dependent rats. Male and female Wistar rats received daily injections of heroin (2-6 mg/kg, SC) and were tested for mechanical sensitivity in the electronic von Frey test 4-6 h into withdrawal. Female rats required significantly more heroin than male rats to reach comparable levels of both heroin-induced analgesia and hyperalgesia (6 mg/kg 2 mg/kg). Once hyperalgesia was established, we tested the effects of the KOR antagonists nor-binaltorphimine (norBNI; 30 mg/kg, SC) and 5'-guanidinonaltrindole (5'GNTI; 30 mg/kg, SC). When the animals continued to receive their daily heroin treatment (or saline treatment in the repeated saline group) five times per week throughout the experiment, both KOR antagonists reversed heroin withdrawal-induced hyperalgesia. The anti-hyperalgesia effect of norBNI was more prolonged in males than in females (14 days 7 days), whereas 5'GNTI had more prolonged effects in females than in males (14 days 4 days). The behavioral effects of 5'GNTI coincided with higher 5'GNTI levels in the brain than in plasma when measured at 24 h, whereas 5'GNTI did not reverse hyperalgesia at 30 min posttreatment when 5'GNTI levels were higher in plasma than in the brain. Finally, we tested the effects of 5'GNTI on naloxone-induced and spontaneous signs of opioid withdrawal and found no effect in either male or female rats. These findings indicate a functional role for KORs in heroin withdrawal-induced hyperalgesia that is observed in rats of both sexes.
Learn More >: Chronic low back pain (CLBP) is a major cause of disability globally. Stratified care has been proposed as a means to improve prognosis and treatment but is generally based on limited aspects of pain, including biopsychosocial drivers. : Following Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) recommendations, the present study explored pain phenotypes with a sample of workers with CLBP, a population for which no pain phenotypes have been derived to date. : A cross-sectional design was used with a sample of 154 workers with CLBP attending a rehabilitation clinic, recruited in person and from social media. Latent class analysis was used to identify subgroups of patients with different pain profiles based on ten pain indicators (pain variability, pain intensity, pain quality, somatization, sleep quality, depression, fatigue, pain catastrophizing, neuropathic pain, and central sensitization). : The majority of the sample (85%) were recruited through social media. Both the two-class and three-class solutions were found to be satisfactory in distinguishing phenotypes of workers with CLBP. Three variables proved particularly important in distinguishing between the pain phenotypes-pain quality, fatigue, and central sensitization-with higher scores on these indicators associated with pain phenotypes with higher pain burden. Increased chronic pain self-efficacy, work-related support, and perceived work abilities were protective risk factors for being in a higher pain burden class. : The present study is the first to explore IMMPACT recommendations for pain phenotyping with workers with CLBP. Future prospective research will be needed to validate the proposed pain phenotypes.
Learn More >Increased symptoms related to central sensitization have previously been reported in inflammatory bowel disease (IBD) patients, identified by the original central sensitization inventory (CSI-25). However, the recently developed CSI short form (CSI-9) may be more clinically useful. The aim of the present study was to evaluate the performance of CSI-9 compared to the original CSI-25 in individuals with IBD. Study objectives were to investigate the criterion validity of the CSI-9 to the CSI-25, assess individual association of the CSI measures with clinical features of IBD and pain presentations, and to establish disease-specific CSI-9 and CSI-25 cut-off scores for discriminating the presence of self-reported pain in individuals with IBD.
Learn More >Chronic pain is a common symptom experienced during cancer progression. Additionally, some patients experience bone pain caused by cancer metastasis, which further complicates the prognosis. Cancer pain is often treated using opioid-based pharmacotherapy, but these drugs possess several adverse effects. Accordingly, new mechanisms for cancer pain management are being explored, including transient receptor potential channels (TRPs). TRP ion channels are expressed in several tissues and play a key role in pain detection, especially TRP vanilloid 1 (TRPV1) and TRP ankyrin 1 (TRPA1). In the present review, we describe the role of TRPV1 and TRPA1 involved in cancer pain mechanisms. Several studies have revealed that the administration of TRPV1 or TRPA1 agonists/antagonists and TRPV1 or TRPA1 knockdown reduced sensitivity to nociception in cancer pain models. TRPV1 was also found to be involved in various models of cancer-induced bone pain (CIBP), with TRPV1 expression reportedly enhanced in some models. These studies have demonstrated the TRPV1 or TRPA1 association with cancer pain in models induced by tumour cell inoculation into the bone cavity, hind paw, mammary fat pad, and sciatic nerve in mice or rats. To date, only resiniferatoxin, a TRPV1 agonist, has been evaluated in clinical trials for cancer pain and showed preliminary positive results. Thus, TRP channels are potential targets for managing cancer-related pain syndromes.
Learn More >To evaluate the analgesic efficacy of a portable, disposable and home self-applied transcutaneous electrical nerve stimulation device during migraine attacks.
Learn More >Persistent pain after mild traumatic brain injury (mTBI) is widely experienced, yet little is known about who is at risk for experiencing persistent pain after their injury.
Learn More >Opioid-based drugs are frequently used for pain management in both males and females despite the known risk of prefrontal cortex dysfunction and cognitive impairments. Although poorly understood, loss of cognitive control following chronic drug use has been linked to decreased activation of frontal cortex regions. Here, we show that self-administration of the potent opioid, remifentanil, causes a long-lasting hypoactive basal state evidenced by a decrease in ex vivo excitability that is paralleled by an increase in firing capacity of layer 5/6 pyramidal neurons in the prelimbic, but not infralimbic region of the medial prefrontal cortex. This phenomenon was observed in females after as few as 5 days and up to 25-30 days of self-administration. In contrast, pyramidal neurons in males showed increased excitability following 10-16 days of self-administration, with hypoactive states arising only following 25-30 days of self-administration. The emergence of a hypoactive, but not hyperactive basal state following remifentanil self-administration aligned with deficits in cognitive flexibility as assessed using an operant-based attentional set-shifting task. In females, the hypoactive basal state is driven by a reduction in excitatory synaptic transmission mediated by AMPA-type glutamate receptors. Alternatively, hyper- and hypoactive states in males align selectively with decreased and increased GABA signaling, respectively. Chemogenetic compensation for this hypoactive state prior to testing restored cognitive flexibility, basal hypoactive state, and remifentanil-induced plasticity. These data define cellular and synaptic mechanisms by which opioids impair prefrontal function and cognitive control; indicating that interventions aimed at targeting opioid-induced adaptations should be tailored based on biological sex.
Learn More >To determine the long-term safety and tolerability profile of M207 in the acute treatment of migraine.
Learn More >The need for safer pain-management therapies with decreased abuse liability inspired a novel drug design that retains μ-opioid receptor (MOR)-mediated analgesia, while minimizing addictive liability. We recently demonstrated that targeting the dopamine D receptor (DR) with highly selective antagonists/partial agonists can reduce opioid self-administration and reinstatement to drug seeking in rodent models without diminishing antinociceptive effects. The identification of the DR as a target for the treatment of opioid use disorders prompted the idea of generating a class of ligands presenting bitopic or bivalent structures, allowing the dual-target binding of the MOR and DR. Structure-activity relationship studies using computationally aided drug design and binding assays led to the identification of potent dual-target leads (, , and ), based on different structural templates and scaffolds, with moderate (sub-micromolar) to high (low nanomolar/sub-nanomolar) binding affinities. Bioluminescence resonance energy transfer-based functional studies revealed MOR agonist-DR antagonist/partial agonist efficacies that suggest potential for maintaining analgesia with reduced opioid-abuse liability.
Learn More >To identify the potential biomarkers of interstitial cystitis/painful bladder syndrome (IC), a chronic syndrome of bladder-centric pain with unknown etiology that has an adverse impact on quality of life, we analyzed the urine and serum metabolomes of a cohort of IC patients and non-disease controls (NC).
Learn More >Atopic dermatitis(AD) causes sleep disturbance, yet the epidemiology is not known.
Learn More >To evaluate the efficacy and safety of lasmiditan in Japanese adults with migraine.
Learn More >The reported use of cannabis within surgical population is increasing. Cannabis use is potentially associated with increased harms and varied effects on pain control. These have important implications to perioperative care.
Learn More >RFamide-related peptide-3 (RFRP-3) and neuropeptide FF (NPFF) target two different receptor subtypes called neuropeptide FF1 (NPFF1R) and neuropeptide FF2 (NPFF2R) that modulate several functions. However, the study of their respective role is severely limited by the absence of selective blockers. We describe here the design of a highly selective NPFF1R antagonist called RF3286, which potently blocks RFRP-3-induced hyperalgesia in mice and luteinizing hormone release in hamsters. We then showed that the pharmacological blockade of NPFF1R in mice prevents the development of fentanyl-induced hyperalgesia while preserving its analgesic effect. Altogether, our data indicate that RF3286 represents a useful pharmacological tool to study the involvement of the NPFF1R/RFRP-3 system in different functions and different species. Thanks to this compound, we showed that this system is critically involved in the development of opioid-induced hyperalgesia, suggesting that NPFF1R antagonists might represent promising therapeutic tools to improve the use of opioids in the treatment of chronic pain.
Learn More >α-Conotoxins are small disulfide-rich peptides found in the venom of marine cone snails and are potent antagonists of nicotinic acetylcholine receptors (nAChRs). They are valuable pharmacological tools and have potential therapeutic applications for the treatment of chronic pain or neurological diseases and disorders. In the present study, we synthesized and functionally characterized a novel α-conotoxin Bt1.8, which was cloned from Conus betulinus. Bt1.8 selectively inhibited ACh-evoked currents in Xenopus oocytes expressing rat(r) α6/α3β2β3 and rα3β2 nAChRs with an IC of 2.1 nM and 9.4 nM, respectively, and similar potency for human (h) α6/α3β2β3 and hα3β2 nAChRs Additionally, Bt1.8 had higher binding affinity with a slower dissociation rate for the rα6/α3β2β3 subtype compared to rα3β2. The amino acid sequence of Bt1.8 is significantly different from other reported α-conotoxins targeting the two nAChR subtypes. Further Alanine scanning analyses demonstrated that residues Ile9, Leu10, Asn11, Asn12 and Asn14 are critical for its inhibitory activity at the α6/α3β2β3 and α3β2 subtypes. Moreover, the NMR structure of Bt1.8 indicated the presence of a relatively larger hydrophobic zone than other α4/7-conotoxins which may explain its potent inhibition of α6/α3β2β3 nAChRs.
Learn More >Preclinical studies demonstrate that the NK1 receptor is involved in opioid reinforcement and withdrawal expression. Few studies have examined the impact of treatment with NK1 antagonists on opioid response in humans.
Learn More >The medium spiny neurons (MSNs) in the nucleus accumbens (NAc) integrate excitatory and inhibitory synaptic inputs and gate motivational and emotional behavior output. Here we report that the relative intensity of excitatory and inhibitory synaptic inputs to MSNs of the NAc shell was decreased in mice with neuropathic pain induced by spinal nerve ligation (SNL). SNL increased the frequency, but not the amplitude of spontaneous inhibitory postsynaptic currents (sIPSCs), and decreased both the frequency and amplitude of spontaneous excitatory postsynaptic currents (sEPSCs) in the MSNs. SNL also decreased the paired-pulse ratio (PPR) of evoked IPSCs but increased the PPR of evoked EPSCs. Moreover, acute bath application of C-C motif chemokine ligand 2 (CCL2) increased the frequency and amplitude of sIPSCs and sEPSCs in the MSNs, and especially strengthened the amplitude of N-methyl-D-aspartate receptor (NMDAR)-mediated miniature EPSCs. Further Ccl2 overexpression in the NAc in vivo decreased the peak amplitude of the sEPSC/sIPSC ratio. Finally, Ccr2 knock-down improved the impaired induction of NMDAR-dependent long-term depression (LTD) in the NAc after SNL. These results suggest that CCL2/CCR2 signaling plays a role in the integration of excitatory/inhibitory synaptic transmission and leads to an increase of the LTD induction threshold at the synapses of MSNs during neuropathic pain.
Learn More >The worldwide treatment gap for migraine before COVID-19 inevitably widens as attention focuses on an international emergency. Migraine hits people particularly in their early and middle years, potentially reduces quality of life and productivity, and remains a common emergency presentation. This article examines the impact of COVID-19 on migraine, and changing aspects of migraine care during and after the pandemic. Many risk factors for severe COVID-19-older age, male gender, cardiac and respiratory diseases, diabetes, obesity, and immunosuppression-are less frequent in migraineurs. Telemedicine is effective for migraine follow-up, and needs ongoing evaluation. Most migraine treatments can start or continue in acute COVID-19, with care to avoid drug interactions. Close contact procedures (botulinum toxin, acupuncture and steroid injections) are avoided in lockdown or in the vulnerable. Secondary effects of COVID-19, including long COVID and its economic impact, are probably equal or greater in people with migraine. Migraine and other long-term conditions need adequate resourcing to prevent personal, social and economic suffering. Treating migraine, a sequel of COVID, potentially reduces the impact of long COVID.
Learn More >Chronic post-surgical pain (CPSP) is a highly prevalent complication following thoracic surgery. This is a prospective cohort study that aims to describe the pain trajectories of patients undergoing thoracic surgery beginning preoperatively and up to 1 year after surgery METHODS: Two hundred and seventy nine patients undergoing elective thoracic surgery were enrolled. Participants filled out a preoperative questionnaire containing questions about their sociodemographic information, comorbidities as well as several psychological and pain-related statuses. They were then followed-up during their immediate postoperative period and at the three, six and 12 month time-points to track their postoperative pain, complications and pain-related outcomes. Growth mixture modeling was used to construct pain trajectories.
Learn More >The Symptom Impact Questionnaire (SIQR), now used for over a decade, has strong psychometric properties based on patients' subjective questionnaire data and correlations with other general measures of severity. However, the construct validity of the SIQR in assessing the central features of fibromyalgia (FM) has not been tested specifically with more objective measures. This study examined the construct validity of the SIQR using clinical examination of prominent features of FM, as well as patient questionnaire data.
Learn More >Self-compassion, defined as a mindful way of coping with pain and suffering by showing kindness, care, and concern towards the self, may improve psychological adjustment in people living with a chronic physical health condition (CPHC). Various studies illustrate that self-compassion is associated with positive outcomes in general. The aim of this systematic review is to establish the effect of compassion-related therapies on self-compassion specifically in people with CPHCs. Secondary aims are to (a) establish the effect on other psychological and physiological outcomes and (b) explore the relative effectiveness of different therapy types among those identified. Cochrane, Embase, Medline, PsycINFO, and CINAHL databases were searched using "compassion" AND "chronic disease" AND "psychological outcomes" and their synonyms, from 2004 to March 2019. Eligible studies had an experimental design using a self-compassion scale with an adult population. Risk of bias (RoB) was assessed using the Cochrane RoB tool. Effect sizes were calculated for study outcomes. Fifteen studies, including a total of 1,190 participants, 7 different CPHCs, and 11 types of therapies, were included in the review. Nearly all included therapies significantly increased self-compassion with medium to large effect sizes, and reported positive outcomes, such as decreased depression. None of the therapy types appeared clearly superior to the others. Findings from this review show that included therapies increased self-compassion and improved various outcomes, which may represent clinically significant benefits for patients. However, there is a need to further understand how self-compassion exerts its benefits and determine the best methods to increase self-compassion.
Learn More >The current definition of neuropathic pain is not sufficiently inclusive of the neuropathic pain conditions. There is a need in clinical practice and scientific research for the definition to not only cover conditions that are a direct consequence of a lesion or diseases affecting the somatosensory system but also those that are a direct consequence of a lesion or diseases affecting the visceral sensory system, as the IASP definition intends to. Here I propose to redefine neuropathic pain as "Pain caused by a lesion or disease of the sensory nervous system".
Learn More >In patients with chronic pain, a relative lower parasympathetic activity is suggested based on heart rate variability measurements. It is hypothesized that spinal cord stimulation (SCS) is able to influence the autonomic nervous system. The aim of this study is to further explore the influence of SCS on the autonomic nervous system by evaluating whether SCS is able to influence skin conductance, blood volume pulse, heart rate, and respiration rate.
Learn More >Accumulating evidence suggests Gulf War illness (GWI) is characterised by autonomic nervous system dysfunction (higher heart rate [HR], lower heart rate variability [HRV]). Yoga – an ancient mind-body practice combining mindfulness, breathwork, and physical postures – is proposed to improve autonomic dysfunction yet this remains untested in GWI. We aimed to determine (i) whether HR and HRV improve among Veterans with GWI receiving either yoga or cognitive behavioural therapy (CBT) for pain; and (ii) whether baseline autonomic functioning predicts treatment-related pain outcomes across follow-up.
Learn More >Postherpetic neuralgia (PHN) is the most common complication of acute herpes zoster. The treatment of PHN remains a challenge for clinical pain management. The present study investigated the P2X7 receptor antagonist brilliant blue G (BBG) whether inhibits endoplasmic reticulum stress and pyroptosis (a necrotic form of cell death) and alleviates PHN. Varicella zoster virus (VZV)-infected CV-1 cells were used to induce PHN model. Mechanical paw withdrawal thresholds were measured using an ascending series of von Frey filaments. Immunohistochemistry was used to detect the expression of P2X7R in nerve tissues. Western blot was used to determine the expression of endoplasmic reticulum (ER) stress and pyroptosis-related molecules. The expression of IL-1β and IL-18 in tissue homogenate was detected by ELISA. The PHN rat has the lower paw withdrawal threshold, but higher expression of P2X7 in nerve tissues. And, endoplasmic reticulum stress was activated and pyroptosis was increased in PHN rats. BBG can decrease pain thresholds and reduce ER stress and pyroptosis in PHN rats. In addition, ER stress activator tunicamycin (TM) can reverse the effect of BBG on the paw withdrawal thresholds, endoplasmic reticulum stress, and pyroptosis. Therefore, P2X7 receptor antagonist BBG alleviates PHN by activating ER stress and reducing pyroptosis.
Learn More >: The prevalence of inadequate treatments for chronic pain has necessitated the search for biological factors that influence the transition to chronicity. : Antecubital blood was drawn from those who experienced acute, noncatastrophic musculoskeletal trauma. Follow-up occurred at 1, 3, 6, and 12 months with the primary outcome being Brief Pain Inventory (BPI) Functional Interference scores. Eight markers were chosen for latent profile analysis: brain-derived neurotrophic factor (BDNF); transforming growth factor-beta 1 (TGF-β1); C-reactive protein (CRP); tumor necrosis factor-alpha (TNF-α); interleukins (ILs) 1-beta, 6, and 10; and the stress hormone cortisol. : Mean age of the 106 participants was 44.6 years and 58.5% were female. The final model indicated a three-class solution that could be adequately described by three of the eight markers: class 1 = low concentration of all markers (33.9% of the sample), class 2 = average concentration of all markers (47.7%), and class 3 = high concentration of BDNF and TGF-β1 (18.3%). BPI Pain Interference scores captured at both inception and 6-month follow-up were compared across the three groups. Mean scores were significantly higher in class 3 for the BPI Interference subscale at inception (27.0 [SD 16.4] vs. 35.8 [SD 17.3], = 0.05) and at 6-month follow-up (2.2 [SD 4.8] vs. 7.3 [SD 10.7], = 0.03) compared to those of the other two classes. : Although recovered populations are not significantly different in BDNF and TGF-β1 levels, those who experience persisting disability are more likely to have moderate to high levels in serum.
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