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Convergent evolution provides insights into the selective drivers underlying evolutionary change. Snake venoms, with a direct genetic basis and clearly defined functional phenotype, provide a model system for exploring the repeated evolution of adaptations. While snakes use venom primarily for predation, and venom composition often reflects diet specificity, three lineages of cobras have independently evolved the ability to spit venom at adversaries. Using gene, protein, and functional analyses, we show that the three spitting lineages possess venoms characterized by an up-regulation of phospholipase A (PLA) toxins, which potentiate the action of preexisting venom cytotoxins to activate mammalian sensory neurons and cause enhanced pain. These repeated independent changes provide a fascinating example of convergent evolution across multiple phenotypic levels driven by selection for defense.
Learn More >The proper detection and behavioral response to painfully cold temperatures is critical for avoiding potentially harmful tissue damage. Cold allodynia and hyperalgesia, pain associated with innocuous cooling and exaggerated pain with noxious cold, respectively, are common in patients with chronic pain. In peripheral somatosensory afferents, the ion channels transient receptor potential melastatin 8 (TRPM8) and transient receptor potential ankyrin 1 (TRPA1) are candidate receptors for innocuous and noxious cold temperatures, respectively. However, the role of TRPA1 as a cold sensor has remained controversial, and recent evidence suggests that TRPM8 channels and afferents mediate the detection of both pleasant and painful cold. To determine the role of TRPA1 afferents in cold-induced mouse behaviors in vivo, we used functional phenotyping by targeted nerve conduction block with the cell-impermeant lidocaine derivative QX-314. Surprisingly, we find that injection of QX-314 with TRPA1 agonists reduces cold-induced behaviors in mice, but does so in a TRPM8-dependent manner. Moreover, this effect is sexually dimorphic and requires the glial cell line-derived neurotrophic factor receptor GFRα3, as does cold hypersensitivity produced by the activation of TRPA1 channels. Taken together, these results suggest that under conditions of neurogenic inflammation, TRPA1 works upstream of GFRα3 and TRPM8 to produce cold hypersensitivity, providing novel insights into the role of TRPA1 channels in cold pain.
Learn More >There is significant heterogeneity in pain outcomes following motor vehicle crashes (MVCs), such that a sizeable portion of individuals develop symptoms of chronic pain months after injury while others recover. Despite variable outcomes, the pathogenesis of chronic pain is currently unclear. Previous neuroimaging work implicates the dorsal anterior cingulate cortex (dACC) in adaptive control of pain, while prior resting state functional magnetic resonance imaging studies find increased functional connectivity (FC) between the dACC and regions involved in pain processing in those with chronic pain. Hyper-connectivity of the dACC to regions that mediate pain response may therefore relate to pain severity. The present study completed rsfMRI scans on N = 22 survivors of MVCs collected within 2 weeks of the incident to test whole-brain dACC-FC as a predictor of pain severity 6 months later. At 2 weeks, pain symptoms were predicted by positive connectivity between the dACC and the premotor cortex. Controlling for pain symptoms at 2 weeks, pain symptoms at 6 months were predicted by negative connectivity between the dACC and the precuneus. Previous research implicates the precuneus in the individual subjective awareness of pain. Given a relatively small sample size, approximately half of which did not experience chronic pain at 6 months, findings warrant replication. Nevertheless, this study provides preliminary evidence of enhanced dACC connectivity with motor regions and decreased connectivity with pain processing regions as immediate and prospective predictors of pain following MVC. PERSPECTIVE: This article presents evidence of distinct neural vulnerabilities that predict chronic pain in MVC survivors based on whole-brain connectivity with the dorsal anterior cingulate cortex.
Learn More >In the dorsal horn of the spinal cord, peripheral nerve injury induces structural and neurochemical alterations through which aberrant synaptic signals contribute to the formation of neuropathic pain. However, the role of injured primary afferent terminals in such plastic changes remain unclear. In this study, we investigated the effect of nerve injury on the morphology of cell adhesion molecule L1-CAM (total L1-CAM [tL1-CAM])-positive primary afferent terminals and on the synaptic contact pattern in the dorsal horn. In the confocal images, the tL1-CAM-positive terminals showed morphological changes leading to the formation of hypertrophic varicosities in the c-fiber terminal. These hypertrophic varicosities in the dorsal horn were co-labeled with phosphorylated (Ser1181) L1-CAM (pL1-CAM) and shown to store neurotransmitter peptides, but not when co-labeled with the pre-synaptic marker, synaptophysin. Quantitative analyses based on three-dimensional reconstructed confocal images revealed that peripheral nerve injury reduced dendritic synaptic contacts but promoted aberrant axo-axonic contacts on the tL1-CAM-positive hypertrophic varicosities. These tL1-CAM-positive varicosities co-expressed the injury-induced alpha2delta-1 (α2δ-1) subunit of the calcium channel in the dorsal horn. Administration of the anti-allodynic drug, pregabalin, inhibited accumulation of α2δ-1 and pL1-CAM associated with a reduction in hypertrophic changes of tL1-CAM-positive varicosities, and normalized injury-induced alterations in synaptic contacts in the dorsal horn. Our findings highlight the formation of aberrant spinal circuits that mediate the convergence of local neuronal signals onto injured c-fibers, suggesting that these hypertrophic varicosities may be important contributors to the pathological mechanisms underlying neuropathic pain. We describe, for the first time, morphological changes in L1-CAM-positive injured c-fiber terminals that lead to the formation of hypertrophic varicosities, in which we found phosphorylation of L1-CAM and increased expression of the calcium channel subunit α2δ-1. Moreover, we found alterations in synaptic contacts and discovered that peripheral nerve injury increased axo-axonic contacts onto L1-CAM-positive varicosities while decreasing axo-dendritic contacts. These plastic changes indicate the convergence of neuronal signals onto the pain pathway and may represent a pathological mechanism underlying neuropathic pain. Administration of the anti-allodynic drug pregabalin reversed the injury-induced synaptic alternations. These data highlight the unique role of injured c-fibers in peripheral nerve injury and their role as a possible therapeutic target for neuropathic pain.
Learn More >Primary headaches are one of the most common conditions; migraine being most prevalent. Recent work on the pathophysiology of migraine suggests a mismatch in the communication or tuning of the trigeminovascular system, leading to sensitization and the release of calcitonin gene-related peptide (CGRP). In the current Opinion, we use the up-to-date molecular understanding of mechanisms behind migraine pain, to provide novel aspects on how to modify the system and for the development of future treatments; acute as well as prophylactic. We explore the distribution and the expression of neuropeptides themselves, as well as certain ion channels, and most importantly how they may act in concert as modulators of excitability of both the trigeminal C neurons and the Aδ neurons.
Learn More >After surgery, acute pain is still managed insufficiently and may lead to short- and long-term complications including chronic postsurgical pain and an increased prescription of opioids. Thus, identifying new targets specifically implicated in postoperative pain is of utmost importance to develop effective and non-addictive analgesics. Here, we employed an integrated and multimethod workflow to reveal unprecedented insights into proteome dynamics in dorsal root ganglia (DRG) of mice after plantar incision (INC). Based on a detailed characterization of INC-associated pain-related behavior profiles, including a novel paradigm for non-evoked pain (NEP), we performed quantitative mass-spectrometry-based proteomics in DRG 1 day after INC. Our data revealed a hitherto unknown INC-regulated protein signature in DRG with changes in distinct proteins and cellular signaling pathways. In particular, we show the differential regulation of 44 protein candidates, many of which are annotated with pathways related to immune and inflammatory responses such as MAPK/ERK signaling. Subsequent orthogonal assays comprised multiplex western blotting, bioinformatic protein network analysis, and immunolabeling in independent mouse cohorts to validate (i) the INC-induced regulation of immune/inflammatory pathways and (ii) the high priority candidate Annexin A1 (Anxa1). Taken together, our results propose novel potential targets in the context of incision and, therefore, represent a highly valuable resource for further mechanistic and translational studies of postoperative pain.
Learn More >The ICD-11 chronic pain classification includes about 100 chronic pain diagnoses on different diagnostic levels. Each of these diagnoses requires specific operationalized diagnostic criteria to be present. The classification comprises more than 200 diagnostic criteria. The aim of the Classification Algorithm for Chronic Pain in ICD-11 (CAL-CP) is to facilitate the use of the classification by guiding users through these diagnostic criteria. The diagnostic criteria were ordered hierarchically and visualized in accordance with the standards defined by the Society for Medical Decision Making Committee on Standardization of Clinical Algorithms. The resulting linear decision tree underwent several rounds of iterative checks and feedback by its developers, as well as other pain experts. A preliminary pilot evaluation was conducted in the context of an ecological implementation field study of the classification itself. The resulting algorithm consists of a linear decision tree, an introduction form, and an appendix. The initial decision trunk can be used as stand-alone algorithm in primary care. Each diagnostic criterion is represented in a decision box. The user needs to decide for each criterion whether it is present or not, and then follow the respective yes or no arrows to arrive at the corresponding ICD-11 diagnosis. The results of the pilot evaluation showed good clinical utility of the algorithm. The CAL-CP can contribute to reliable diagnoses by structuring a way through the classification and by increasing adherence to the criteria. Future studies need to evaluate its utility further and analyze its impact on the accuracy of the assigned diagnoses.
Learn More >Children and adults with atopic dermatitis suffer from intractable chronic itch and can also experience acute itch flare ups that significantly increase itch intensity. In this issue of Cell, Wang et al. demonstrate that a subset of basophils activates sensory neurons to drive allergen-evoked itch flare ups in atopic dermatitis.
Learn More >Transient Receptor Potential Melastatin 3 (TRPM3) is a heat-activated ion channel in primary sensory neurons of the dorsal root ganglia (DRG). Pharmacological and genetic studies implicated TRPM3 in various pain modalities, but TRPM3 inhibitors were not validated in TRPM3 mice. Here we tested two inhibitors of TRPM3 in male and female wild type and TRPM3 mice in nerve injury-induced neuropathic pain. We found that intraperitoneal injection of either isosakuranetin, or primidone reduced heat hypersensitivity induced by chronic constriction injury (CCI) of the sciatic nerve, in wild type, but not in TRPM3 mice. Primidone was also effective when injected locally in the hind paw, or intrathecally. Consistently, intrathecal injection of the TRPM3 agonist CIM0216 reduced paw withdrawal latency to radiant heat in wild type, but not in TRPM3 mice. Intraperitoneal injection of 2 mg/kg, but not 0.5 mg/kg isosakuranetin, inhibited cold and mechanical hypersensitivity in CCI, both in wild-type and TRPM3 mice, indicating a dose dependent off target effect. Primidone had no effect on cold sensitivity, and only a marginal effect on mechanical hypersensitivity. Genetic deletion or inhibitors of TRPM3 reduced the increase in the levels of the early genes cFos and pERK in the spinal cord and DRG in CCI mice, suggesting spontaneous activity of the channel. Intraperitoneal isosakuranetin also inhibited spontaneous pain related behavior in CCI in the conditioned place preference assay, and this effect was eliminated in TRPM3 mice. Overall our data indicate a role of TRPM3 in heat hypersensitivity and in spontaneous pain after nerve injury.Neuropathic pain is a major unsolved medical problem. The heat-activated TRPM3 ion channel is a potential target for novel pain medications, but it is not clear what pain modalities it plays roles in. Here we used a combination of genetic and pharmacological tools to assess the role of this channel in spontaneous pain, heat-, cold- and mechanical hypersensitivity in a nerve injury model of neuropathic pain in mice. Our findings indicate a role for TRPM3 in heat hyperalgesia, and spontaneous pain, but not in cold, and mechanical hypersensitivity. We also find that not only TRPM3 located in the peripheral nerve termini, but also TRPM3 in the spinal cord, or proximal segments of DRG neurons is important for heat hypersensitivity.
Learn More >Central amygdala (CeA) neurons expressing protein kinase Cδ (PKCδ) or somatostatin (Som) differentially modulate diverse behaviors. The underlying features supporting cell-type-specific function in the CeA, however, remain unknown. Using whole-cell patch-clamp electrophysiology in acute mouse brain slices and biocytin-based neuronal reconstructions, we demonstrate that neuronal morphology and relative excitability are two distinguishing features between Som and PKCδ neurons in the laterocapsular subdivision of the CeA (CeLC). Som neurons, for example, are more excitable, compact, and with more complex dendritic arborizations than PKCδ neurons. Cell size, intrinsic membrane properties, and anatomic localization were further shown to correlate with cell-type-specific differences in excitability. Lastly, in the context of neuropathic pain, we show a shift in the excitability equilibrium between PKCδ and Som neurons, suggesting that imbalances in the relative output of these cells underlie maladaptive changes in behaviors. Together, our results identify fundamentally important distinguishing features of PKCδ and Som cells that support cell-type-specific function in the CeA.
Learn More >Diversity and equity in medicine remain pivotal to care delivery. Data analysis on sex and racial diversity of pain medicine fellowship trainees and faculty in the United States are scant. We sought to characterize demographic and retention patterns among pain medicine fellows and faculty, who represent the emerging chronic pain management workforce.
Learn More >Complex Regional Pain Syndrome (CRPS) is a disorder of severe chronic pain in one or more limb(s). People with CRPS report unusual perceptions of the painful limb suggesting altered body representations, as well as difficulty attending to their affected limb (i.e., a 'neglect-like' attention bias). Altered body representations and attention in CRPS might be related, however, existing evidence is unclear. We hypothesized that if there were a body-related visuospatial attention bias in CRPS, then any attention bias away from the affected side should be larger for or limited to circumstances when the (impaired) body representation is involved in the task versus when this is not the case.
Learn More >Some children with chronic pain struggle with fear of pain, avoidance behaviors, and associated disability; however, movement adaptations in the context of chronic pain in childhood is virtually unknown. Variability in adaptive movement responses previously observed between individuals might be largely explained by the presence of problematic psychological drivers (eg, fear, avoidance). The goals of this study were to (1) quantify the variability of gait and (2) examine relationships among pain, fear, avoidance, function, perceived and objective, and gait variability.
Learn More >Expectations contribute to cognitive pain modulation through opioidergically-mediated descending inhibition. Mindfulness meditation reduces pain independent of endogenous opioids, engaging unique corticothalamo-cortical mechanisms. However, it remains unknown whether expectations for pain-relief predict mindfulness-induced analgesia and if these expectations are modified by endogenous opioids.
Learn More >Voltage-gated sodium channels are key players in neuronal excitability and pain signaling. Functional expression of the voltage-gated sodium channel Na1.7 is under the control of SUMOylated collapsin response mediator protein 2 (CRMP2). When not SUMOylated, CRMP2 forms a complex with the endocytic proteins Numb, the epidermal growth factor receptor pathway substrate 15 (Eps15), and the E3 ubiquitin ligase Nedd4-2 to promote clathrin-mediated endocytosis of Na1.7. We recently reported that CRMP2 SUMO-null knock-in (CRMP2) female mice have reduced Na1.7 membrane localization and currents in their sensory neurons. Preventing CRMP2 SUMOylation was sufficient to reverse mechanical allodynia in CRMP2 female mice with neuropathic pain. Here we report that inhibiting clathrin assembly in nerve-injured male CRMP2 mice precipitated mechanical allodynia in mice otherwise resistant to developing persistent pain. Furthermore, Numb, Nedd4-2 and Eps15 expression was not modified in basal conditions in the dorsal root ganglia (DRG) of male and female CRMP2 mice. Finally, silencing these proteins in DRG neurons from female CRMP2 mice, restored the loss of sodium currents. Our study shows that the endocytic complex composed of Numb, Nedd4-2 and Eps15, is necessary for non-SUMOylated CRMP2-mediated internalization of sodium channels in vivo.
Learn More >Chemotherapy-induced peripheral neuropathy (CIPN) is a common, debilitating side effect in cancer survivors. This study aimed to assess the characteristics of quantitative sensory testing (QST) and its correlation with patient-reported outcomes (PROs) in cancer patients with and without CIPN.
Learn More >Critical for the diagnosis and treatment of chronic pain is the anatomical distribution of pain. Several body maps allow patients to indicate pain areas on paper; however, each has its limitations.
Learn More >The relationship between pain and cognition has primarily been investigated in patients with chronic pain and healthy participants undergoing experimental pain. Recently, there has been interest in understanding the disruptive effects of non-experimental pain in otherwise healthy individuals. Recent studies suggest that healthy individuals reporting pain also demonstrate decrements in working memory (WM) performance, however factors contributing to this relationship remain poorly understood. The present study examined the association between everyday pain and WM in a large community-based sample of healthy individuals and investigated whether self-reported affective distress and medial frontal cortex activity might help to explain this relationship. To address these research questions, a large publicly available dataset from the Human Connectome Project (N = 416) was sourced and structural equation modeling was utilized to examine relationships between pain intensity experienced over the past 7 days, self-reported affective distress (composite measure), performance on a WM (n-back) task, and task-related activation in the medial frontal cortex. Examining participants who reported non-zero pain intensity in the last 7 days (n = 228), we found a direct negative association between pain intensity and performance on the WM n-back task, consistent with prior findings. Self-reported affective distress was not associated with WM performance. Additionally, pain intensity was indirectly associated with WM performance via WM task-related activity in the ventromedial prefrontal cortex (vmPFC). Our findings suggest that everyday pain experienced outside of the laboratory by otherwise healthy individuals may directly impact WM performance. Furthermore, WM task-related increases in vmPFC activity may be a factor contributing to this relationship.
Learn More >Multisensory hypersensitivity (MSH), which refers to persistent discomfort across sensory modalities, is a risk factor for chronic pain. Developing a better understanding of the neural contributions of disparate sensory systems to MSH may clarify its role in the development of chronic pain. We recruited a cohort of women ( =147) enriched with participants with menstrual pain at risk for developing chronic pain. Visual sensitivity was measured using a periodic pattern-reversal stimulus during EEG. Self-reported visual unpleasantness ratings were also recorded. Bladder pain sensitivity was evaluated with an experimental bladder-filling task associated with early clinical symptoms of chronic pelvic pain. Visual stimulation induced unpleasantness was associated with bladder pain and evoked primary visual cortex excitation; however, the relationship between unpleasantness and cortical excitation was moderated by bladder pain. Thus, future studies aimed at reversing the progression of MSH into chronic pain should prioritize targeting of cortical mechanisms responsible for maladaptive sensory input integration.
Learn More >Women with breast cancer in medically underserved areas are particularly vulnerable to persistent pain and disability. Behavioral pain interventions reduce pain and improve outcomes. Cancer patients in medically underserved areas receive limited adjunctive cancer care, as many lack access to pain therapists trained in behavioral interventions, face travel barriers to regional medical centers, and may have low literacy and limited resources. mHealth technologies have the potential to decrease barriers but must be carefully adapted for, and efficacy-tested with, medically underserved patients. We developed an mHealth behavioral pain coping skills training intervention (mPCST-Community). We now utilize a multisite randomized controlled trial to: 1) test the extent mPCST-Community reduces breast cancer patients' pain severity (primary outcome), pain interference, fatigue, physical disability, and psychological distress; 2) examine potential mediators of intervention effects; and 3) evaluate the intervention's cost and cost-effectiveness.
Learn More >Despite empirical support for interdisciplinary pain rehabilitation programs improving functioning and quality of life, access to this treatment approach has decreased dramatically over the last 20 years within the United States but has grown significantly in the Department of Veterans Affairs (VA). Between 2009 and 2019, VA pain rehabilitation programs accredited by the Commission on Accreditation of Rehabilitation Facilities increased 10-fold in the VA, expanding from two to 20. The aim of this collaborative observational evaluation was to examine patient outcomes across a subset of six programs at five sites.
Learn More >Migraine is the second largest cause of years lost to disability globally among all diseases, with a worldwide prevalence over 1 billion. Despite the global burden of migraine, few classes of therapeutics have been specifically developed to combat migraine. After 30 years of translational research, calcitonin gene-related peptide (CGRP) inhibitors have emerged as a promising new tool in the prevention of migraine. Like all new therapeutics; however, we have limited real-world experience and CGRP has several known systemic actions that warrant consideration. This article provides a narrative review of the evidence for CGRP antagonists and summarises the known and potential side effects that should be considered.
Learn More >Human voltage-gated sodium channel (VGSC) Na1.7 (hNa1.7) is involved in the generation and conduction of neuropathic and nociceptive pain signals. Compelling genetic and preclinical studies have validated that hNa1.7 is a therapeutic target for the treatment of pain, however there is a dearth of currently available compounds capable of targeting hNav1.7 with high potency and specificity. Hainantoxin-III (HNTX-III) is a 33-residue polypeptide from the venom of the spider Ornithoctonus hainana. It is a selective antagonist of neuronal tetrodotoxin-sensitive voltage-gated sodium channels. Here, we report the engineering of improved potency and Na selectivity of hNa1.7 inhibition peptides derived from the HNTX-III scaffold. Alanine scanning mutagenesis showed key residues for HNTX-III interacting with hNa1.7. Site-directed mutagenesis analysis indicated key residues on hNa1.7 interacting with HNTX-III. Molecular docking was conducted to clarify the binding interface between HNTX-III and Nav1.7 and guide the molecular engineering process. Ultimately, we obtained H4 [K0G1-P18K-A21L-V] based on molecular docking of HNTX-III and hNa1.7 with a 30-fold improved potency (IC 0.007 ± 0.001 μM) and > 1000-fold selectivity against Na1.4 and Na1.5. H4 also showed robust analgesia in the acute and chronic inflammatory pain model and neuropathic pain model. Thus, our results provide further insight into peptide toxins that may prove useful in guiding the development of inhibitors with improved potency and selectivity for Na subtypes with robust analgesia.
Learn More >Children with amplified musculoskeletal pain (AMPS) experience significant functional disability, with impairment in their ability to participate in age-appropriate activities of daily living. Parental factors play an important role in a child's pain symptoms and treatment outcomes, with parental pain catastrophizing and protective behaviors linked to several maladaptive outcomes for children. Aims of the current study were to examine how parental pain catastrophizing, child pain catastrophizing, and parental protective behaviors longitudinally impacted functional disability for children with AMPS.
Learn More >Pain is a common symptom accompanying the coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Nonspecific discomfort such as sore throat and body ache are frequent. Parainfectious pain such as headache, myalgia, or neuropathic pain has also been reported. The latter seems to be associated with an autoimmune response or an affection of the peripheral neuromuscular system or the central nervous system because of the viral infection. Furthermore, chronic pain can be a complication of intensive care unit treatment due to COVID-19 itself (such as intensive care-acquired weakness) or of secondary diseases associated with the SARS-CoV-2 infection, including Guillain-Barré syndrome, polyneuritis, critical illness polyneuropathy, or central pain following cerebrovascular events. Data on long-lasting painful symptoms after clinically manifest COVID-19 and their consequences are lacking. In addition, preexisting chronic pain may be exacerbated by limited and disrupted health care and the psychological burden of the COVID-19 pandemic. Medical providers should be vigilant on pain during and after COVID-19.
Learn More >Most patients with amputation (up to 80%) suffer from phantom limb pain postsurgery. These are often multimorbid patients who also have multiple risk factors for the development of chronic pain from a pain medicine perspective. Surgical removal of the body part and sectioning of peripheral nerves result in a lack of afferent feedback, followed by neuroplastic changes in the sensorimotor cortex. The experience of severe pain, peripheral, spinal, and cortical sensitization mechanisms, and changes in the body scheme contribute to chronic phantom limb pain. Psychosocial factors may also affect the course and the severity of the pain. Modern amputation medicine is an interdisciplinary responsibility.
Learn More >We previously reported promising results for a 4-month patient-centered voluntary opioid tapering study. Key questions remain about the durability of effects and possible risks after opioid reduction. We provide the longest follow-up data to date for prospective opioid tapering: 2- to 3-year follow-up for pain intensity and daily opioid use in a subset of patients from our original 4-month opioid tapering study.
Learn More >Physical activity has become a first-line treatment in rehabilitation settings for individuals with chronic pain. However, research has only recently begun to elucidate the mechanisms of exercise-induced analgesia. Through the study of animal models, exercise has been shown to induce changes in the brain, spinal cord, immune system, and at the site of injury to prevent and reduce pain. Animal models have also explored beneficial effects of exercise through different modes of exercise including running, swimming, and resistance training. This review will discuss the central and peripheral mechanisms of exercise-induced analgesia through different modes, intensity, and duration of exercise as well as clinical applications of exercise with suggestions for future research directions.
Learn More >Osteoarthritis (OA)-associated pain is often poorly managed, as our understanding of the underlying pain mechanisms remains limited. The known variability from patient to patient in pain control could be a consequence of a neuropathic component in OA.
Learn More >Complex regional pain syndrome (CRPS) is a condition that occurs after minor trauma characterized by sensory, trophic, and motor changes. Although preclinical studies have demonstrated that CRPS may be driven in part by autoinflammation, clinical use of immune-modulating drugs in CRPS is limited. Hydroxychloroquine (HCQ) is a disease-modifying antirheumatic drug used to treat malaria and autoimmune disorders that may provide benefit in CRPS.
Learn More >Posttraumatic stress disorder (PTSD) is a known risk factor for the development of chronic pain conditions, and almost 1 in 5 individuals with chronic pain fulfills the criteria for PTSD. However, the relationship between PTSD and pain is poorly understood and studies on pain perception in patients with PTSD show inconsistent results suggesting that different sensory profiles exist among individuals with PTSD. Here, we (1) systematically summarize the current literature on experimentally evoked pain perception in patients with PTSD compared to subjects without PTSD, and (2) assess whether the nature of the traumatic event is associated with different patterns in pain perception. The main outcome measures were pain threshold, pain tolerance, and pain intensity ratings as well as measures of temporal summation of pain and conditioned pain modulation. A systematic search of MEDLINE, EMBASE, Web of Science, PsycINFO, and CINAHL identified 21 studies for the meta-analysis, including 422 individuals with PTSD and 496 PTSD-free controls. No main effect of PTSD on any outcome measure was found. However, stratification according to the nature of trauma revealed significant differences of small to medium effect sizes. Combat-related PTSD was associated with increased pain thresholds, whereas accident-related PTSD was associated with decreased pain thresholds. No clear relationship between PTSD and experimentally evoked pain perception exists. The type of trauma may affect pain thresholds differently indicating the presence of different subgroups with qualitative differences in pain processing.
Learn More >Psychologically informed physical therapy (PIPT) blends psychological strategies within a physical therapist's treatment approach for the prevention and management of chronic musculoskeletal pain. Several randomized trials have been conducted examining the efficacy of PIPT compared to standard physical therapy on important patient-reported outcomes of disability, physical function, and pain. In this review, we examine recent trials published since 2012 to describe current PIPT methods, discuss implications from findings, and offer future directions. Twenty-two studies, representing 18 trials, were identified. The studied PIPT interventions included (1) graded activity or graded exposure (n = 6), (2) cognitive-behavioral-based physical therapy (n = 9), (3) acceptance and commitment-based physical therapy (n = 1), and (4) internet-based psychological programs with physical therapy (n = 2). Consistent with prior reviews, graded activity is not superior to other forms of physical activity or exercise. In a few recent studies, cognitive-behavioral-based physical therapy had short-term efficacy when compared to a program of standardized exercise. There is a need to further examine approaches integrating alternative strategies including acceptance-based therapies (ie, acceptance and commitment therapy or mindfulness) or internet-based cognitive-behavioral programs within physical therapy. Although PIPT remains a promising care model, more convincing evidence is needed to support widespread adoption, especially in light of training demands and implementation challenges.
Learn More >Chronic pain is a complicated condition which causes substantial physical, emotional, and financial impacts on individuals and society. However, due to high cost, lack of efficacy and safety problems, current treatments are insufficient. There is a clear unmet medical need for safe, nonaddictive and effective therapies in the management of pain. Epoxy-fatty acids (EpFAs), which are natural signaling molecules, play key roles in mediation of both inflammatory and neuropathic pain sensation. However, their molecular mechanisms of action remain largely unknown. Soluble epoxide hydrolase (sEH) rapidly converts EpFAs into less bioactive fatty acid diols in vivo; therefore, inhibition of sEH is an emerging therapeutic target to enhance the beneficial effect of natural EpFAs. In this review, we will discuss sEH inhibition as an analgesic strategy for pain management and the underlying molecular mechanisms.
Learn More >Pharmacological treatment for peripheral neuropathic pain has only modest effects and is often limited by serious adverse responses. Alternative treatment approaches including physiotherapy management have thus gained interest in the management of people with peripheral neuropathies. This narrative review summarises the current literature on the efficacy and safety of physiotherapy to reduce pain and disability in people with radicular pain and chemotherapy-induced peripheral neuropathy, 2 common peripheral neuropathies. For chemotherapy-induced peripheral neuropathy, the current evidence based on 8 randomised controlled trials suggests that exercise may reduce symptoms in patients with established neuropathy, but there is a lack of evidence for its preventative effect in patients who do not yet have symptoms. For radicular pain, most of the 21 trials investigated interventions targeted at improving motor control or reducing neural mechanosensitivity. The results were equivocal, with some indication that neural tissue management may show some benefits in reducing pain. Adverse events to physiotherapy seemed rare; however, these were not consistently reported across all studies. Although it is encouraging to see that the evidence base for physiotherapy in the treatment of peripheral neuropathic pain is growing steadily, the mixed quality of available studies currently prevents firm treatment recommendations. Based on promising preliminary data, suggestions are made on potential directions to move the field forward.
Learn More >Background: Chronic low back pain is the most prevalent chronic pain condition worldwide and access to behavioral pain treatment is limited. Virtual reality (VR) is an immersive technology that may provide effective behavioral therapeutics for chronic pain.
Learn More >Pediatric sickle cell disease (SCD) management can result in considerable caregiver distress. Parents of youth with chronic SCD pain may face the additional challenge of managing children's chronic pain and chronic illness. This study examined associations between parent psychological distress and child functioning and the moderating role of chronic pain among youth with SCD.
Learn More >Distal diabetic sensorimotor polyneuropathy (DSP) is a common complication of diabetes with many patients showing a reduction of intraepidermal nerve fibre density (IENFD) from skin biopsy, a validated and sensitive diagnostic tool for the assessment of DSP. Axonal swelling ratio is a morphological quantification altered in DSP. It is, however, unclear if axonal swellings are related to diabetes or DSP. The aim of this study was to investigate how axonal swellings in cutaneous nerve fibres are related to type 2 diabetes mellitus, DSP and neuropathic pain in a well-defined cohort of patients diagnosed with type 2 diabetes.
Learn More >This study aimed to investigate the cross-sectional association between arthritis and migraine in a large representative sample of the US adult population. The study used data from adults who participated in the RAND American Life Panel (ALP). Arthritis (excluding rheumatoid arthritis) and migraine were self-reported. Control variables included sex, age, ethnicity, marital status, education, employment, annual family income, stroke, epilepsy, coronary artery disease, asthma, depression, anxiety, bipolar disorder, and alcohol dependence. The association between arthritis and migraine was investigated using multivariable logistic regression models, while sex and age interaction analyses were also conducted. This study included 2649 adults (51.7% women; mean (SD) age 50.6 (15.9 years). The prevalence of migraine was 10.7% in the sample. After adjusting for several potential confounders, there was a significant association between arthritis and migraine (OR = 1.83, 95% CI = 1.20-2.81). Further sensitivity analyses revealed that the association was significant in women, adults aged ≤45 years, and those aged >65 years. The mere fact that arthritis and migraine may coexist is problematic, as this could lead to an important medical and economic burden. Therefore, strategies should be implemented to reduce the cooccurrence of these two chronic conditions.
Learn More >The International Headache Society criteria were written in order to help physicians establish a headache diagnosis. However, sometimes children with headache do not seem to fit any diagnosis. The purpose of our study was to assess the application of the criteria in a clinical setting.
Learn More >Painful procedures in early life cause acute pain and can alter pain processing at a spinal level lasting into adulthood. Current methods of analgesia seem unable to prevent both acute and long-term hypersensitivity associated with neonatal pain. The current study aims to prevent acute and long-term hypersensitivity associated with neonatal procedural pain using methadone analgesia in rat pups.
Learn More >Advanced age and obesity are reported to increase the risk of opioid-induced respiratory depression (OIRD). Oliceridine, an intravenous opioid, is a G-protein-biased agonist at the µ-opioid receptor that may provide improved safety. The recent phase 3 ATHENA open-label, multicenter study evaluated postoperative use of oliceridine in patients with moderate-to-severe acute pain. This exploratory analysis of the ATHENA data examined the incidence of OIRD in older (≥ 65 years) and/or obese (BMI ≥ 30 kg/m) patients and analyzed risk factors of OIRD.
Learn More >This study examined which patient characteristics are associated with travelling further to attend a metropolitan, publicly-funded pain management service, and whether travel distance was associated with differences in treatment profile, duration, and percentage of appointments attended.
Learn More >Cortical thickness (CTh) via surface-based morphometry analysis is a popular method to characterize brain morphometry. Many studies have been performed to investigate CTh abnormalities in migraine. However, the results from these studies were not consistent and even conflicting. These divergent results hinder us to obtain a clear picture of brain morphometry regarding CTh alterations in migraine. Coordinate-based meta-analysis (CBMA) is a promising technique to quantitatively pool individual neuroimaging studies to identify consistent brain areas involved. Electronic databases (PubMed, EMBASE, Web of Science, China National Knowledge Infrastructure, WanFang, and SinoMed) and other sources (bioRxiv and reference lists of relevant articles and reviews) were systematically searched for studies that compared regional CTh differences between patients with migraine and healthy controls (HCs) up to May 15, 2020. A CBMA was performed using the Seed-based d Mapping with Permutation of Subject Images approach. In total, we identified 16 studies with 17 datasets reported that were eligible for the CBMA. The 17 datasets included 872 patients with migraine (average sample size 51.3, mean age 39.6 years, 721 females) and 949 HCs (average sample size 59.3, mean age 44.2 years, 680 females). The CBMA detected no statistically significant consistency of CTh alterations in patients with migraine relative to HCs. Sensitivity analysis and subgroup analysis verified this result to be robust. Metaregression analyses revealed that this CBMA result was not confounded by age, gender, aura, attack frequency per month, and illness duration. Our CBMA adds to the evidence of the replication crisis in neuroimaging research that is increasingly recognized. Many potential confounders, such as underpowered sample size, heterogeneous patient selection criteria, and differences in imaging collection and methodology, may contribute to the inconsistencies of CTh alterations in migraine, which merit attention before planning future research on this topic.
Learn More >Resilience, a personality construct that reflects capacities to persevere, maintain a positive outlook and/or thrive despite ongoing stressors, has emerged as an important focus of research on chronic pain (CP). Although behavior studies have found more resilient persons with CP experience less pain-related dysfunction than less resilient cohorts do, the presence and nature of associated brain structure differences has received scant attention. To address this gap, we examined gray matter volume (GMV) differences between more versus less resilient adults with chronic musculoskeletal pain. Participants (75 women, 43 men) were community-dwellers who reported ongoing musculoskeletal pain for at least three months. More (n = 57) and less (n = 61) resilient subgroups, respectively, were identified on the basis of scoring above and below median scores on two validated resilience questionnaires. Voxel-based morphology (VBM) undertaken to examine resilience subgroup differences in GMV indicated more resilient participants displayed significantly larger GMV in the (1) bilateral precuneus, (2) left superior and inferior parietal lobules, (3) orbital right middle frontal gyrus and medial right superior frontal gyrus, and (4) bilateral median cingulate and paracingulate gyri, even after controlling for subgroup differences on demographics and measures of pain-related distress. Together, results underscored the presence and nature of specific GMV differences underlying subjective reports of more versus less resilient responses to ongoing musculoskeletal pain.
Learn More >Visceral pain is a highly complex experience and is the most common pathological feature in patients suffering from inflammatory gastrointestinal disorders. Whilst it is increasingly recognized that aberrant neural processing within the gut-brain axis plays a key role in development of neurological symptoms, the underlying mechanisms remain largely unknown. Here, we investigated the cortical activation patterns and effects of non-invasive chemogenetic suppression of cortical activity on visceral hypersensitivity and anxiety-related phenotypes in a well-characterized mouse model of acute colitis induced by dextran sulfate sodium (DSS). We found that within the widespread cortical network, the mid-cingulate cortex (MCC) was consistently highly activated in response to innocuous and noxious mechanical stimulation of the colon. Furthermore, during acute experimental colitis, impairing the activity of the MCC successfully alleviated visceral hypersensitivity, anxiety-like behaviors and visceromotor responses to colorectal distensions (CRDs) via downregulating the excitability of the posterior insula (PI), somatosensory and the rostral anterior cingulate cortices (rACC), but not the prefrontal or anterior insula cortices. These results provide a mechanistic insight into the central cortical circuits underlying painful visceral manifestations and implicate MCC plasticity as a putative target in cingulate-mediated therapies for bowel disorders.
Learn More >To discuss recent advances of vasoactive intestinal peptide/pituitary adenylate cyclase-activating polypeptide (VIP/PACAP) receptors in the selected central nervous system (CNS) and inflammatory disorders.
Learn More >To evaluate the measurement properties of all three domains of the Migraine-Specific Quality of Life questionnaire version 2.1 (MSQ v2.1) electronic patient-reported outcome (ePRO) to assess the functional impact of migraine in patients with episodic or chronic migraine (CM); and identify meaningful within-patient change thresholds for the Role Function-Restrictive (RFR), Role Function-Preventive (RFP), and Emotional Function (EF) domains.
Learn More >Low back pain (LBP) is the leading cause of years lived with disability worldwide. Most people with LBP receive the diagnosis of nonspecific LBP or sciatica. Medications are commonly prescribed but have limited analgesic effects and are associated with adverse events. A novel treatment approach is to target neurotrophins such as nerve growth factor (NGF) to reduce pain intensity. NGF inhibitors have been tested in some randomized controlled trials (RCTs) in recent years, showing promise for the treatment of chronic LBP; however, their efficacy and safety need to be evaluated to guide regulatory actions.
Learn More >Spinal cord stimulation is frequently used for the treatment of intractable chronic pain conditions. Trialing of the spinal cord stimulator device is recommended to assess the patient's response to neurostimulation before permanent implantation. The trial response is often assessed by Numeric Rating Scale changes and patient-reported percentage pain improvement. Using number rating scale changes between prespinal and postspinal cord stimulation trial, a calculated percentage pain improvement can be obtained. The aim of this study was to assess the difference between calculated and patient-reported percentage improvement in pain scale during spinal cord stimulation trials.
Learn More >Concentration difficulties, forgetfulness and mental slowness are common in fibromyalgia syndrome (FMS); initial findings suggest that rheumatoid arthritis (RA) may also be accompanied by cognitive impairments. This study aimed to compare attentional performance between patients with FMS and RA. Attention was quantified in the domains of alerting, orienting and executive control using the Attentional Network Test-Interaction (ANT-I) in 56 women with FMS, 41 women with RA and 50 healthy women. Pain severity was statistically controlled in the group comparison. While FMS patients exhibited longer reaction times and made more errors on the ANT-I than RA patients and healthy women, performance did not differ between RA patients and healthy women. The magnitude of group differences did not vary by the experimental conditions of the ANT-I, suggesting a general attentional deficit in FMS rather than specific impairments in the domains of alerting, orienting and executive control. Differences between patient groups may relate to the different pathogenetic mechanisms involved in the disorders, i.e. inflammatory processes in RA and central nervous sensitization in FMS. In FMS, heightened activity in the pain neuromatrix may interfere with attention, because it requires enhanced neural resources in brain areas that are involved in both pain and attentional processing.
Learn More >Inflammatory pain associates with spinal glial activation and central sensitization. Systemic administration of IMT504, a non-CpG oligodeoxynucleotide originally designed as an immunomodulator, exerts remarkable anti-allodynic effects in rats with complete Freund´s adjuvant (CFA)-induced hindpaw inflammation. However, the anti-nociceptive mechanisms of IMT504 remain unknown. Here we evaluated whether IMT504 blocks inflammatory pain-like behavior by modulation of spinal glia and central sensitization. The study was performed in Sprague Dawley rats with intraplantar CFA, and a single lumbosacral intrathecal (i.t.) administration of IMT504 or vehicle was chosen to address if changes in glial activation and spinal sensitization relate to the pain-like behavior reducing effects of the ODN. Naïve rats were also included. Von Frey and Randall-Selitto tests, respectively, exposed significant reductions in allodynia and mechanical hypersensitivity, lasting at least 24 h after i.t. IMT504. Analysis of electromyographic responses to electrical stimulation of C fibers showed progressive reductions in wind-up responses. Accordingly, IMT504 significantly downregulated spinal glial activation, as shown by reductions in the protein expression of glial fibrillary acidic protein, CD11b/c, Toll-like receptor 4 (TLR4) and the phosphorylated p65 subunit of NFκB, evaluated by immunohistochemistry and western blot. In vitro experiments using early post-natal cortical glial cultures provided further support to in vivo data and demonstrated IMT504 internalization into microglia and astrocytes. Altogether, our study provides new evidence on the central mechanisms of anti-nociception by IMT504 upon intrathecal application, and further supports its value as a novel anti-inflammatory ODN with actions upon glial cells and the TLR4/NFκB pathway. Intrathecal administration of the non-CpG ODN IMT504 fully blocks CFA-induced mechanical allodynia and hypersensitivity, in association with reduced spinal sensitization. Administration of the ODN also results in downregulated gliosis and reduced TLR4-NF-κB pathway activation. IMT504 uptake into astrocytes and microglia support the concept of direct modulation of CFA-induced glial activation.
Learn More >While the majority of indications and approvals for dorsal root ganglion stimulation (DRGS) are for the refractory management of complex regional pain syndrome (CRPS), emerging evidence has suggested that DRGS may be favorably used for a plethora of other chronic pain phenomena. Consequently, we aimed to characterize the use and efficacy of DRGS for these non-CRPS-related chronic pain syndromes.
Learn More >Brain-derived neurotrophic factor (BDNF) is critically involved in the pathophysiology of chronic pain. However, the mechanisms of BDNF action on specific neuronal populations in the spinal superficial dorsal horn (SDH) requires further study. We used chronic BDNF treatment (200 ng/ml, 5-6 days) of defined-medium, serum-free spinal organotypic cultures to study intracellular calcium ([Ca]) fluctuations. A detailed quantitative analysis of these fluctuations using the Frequency-independent biological signal identification (FIBSI) program revealed that BDNF simultaneously depressed activity in some SDH neurons while it unmasked a particular subpopulation of 'silent' neurons causing them to become spontaneously active. Blockade of gap junctions disinhibited a subpopulation of SDH neurons and reduced BDNF-induced synchrony in BDNF-treated cultures. BDNF reduced neuronal excitability assessed by measuring spontaneous excitatory postsynaptic currents. This was similar to the depressive effect of BDNF on the [Ca] fluctuations. This study reveals novel regulatory mechanisms of SDH neuronal excitability in response to BDNF.
Learn More >Spinal cord stimulation (SCS) is an effective method to treat neuropathic pain; however, it is challenging to compare different stimulation modalities in an individual patient, and thus, it is largely unknown which of the many available SCS modalities is most effective. Specifically, electrodes leading out through the skin would have to be consecutively connected to different, incompatible SCS devices and be tested over a time period of several weeks or even months. The risk of wound infections for such a study would be unacceptably high and blinding of the trial difficult. The PARS-trial seizes the capacity of a new type of wireless SCS device, which enables a blinded and systematic intra-patient comparison of different SCS modalities over extended time periods and without increasing wound infection rates.
Learn More >The onset of chemotherapy-induced peripheral neurotoxicity (CIPN) is a leading cause of the dose reduction or discontinuation of cancer treatment due to sensory symptoms. Paclitaxel (PTX) can cause painful peripheral neuropathy, with a negative impact on cancer survivors' quality of life. While recent studies have shown that neuroinflammation is involved in PTX-induced peripheral neurotoxicity (PIPN), the pathophysiology of this disabling side effect remains largely unclear and no effective therapies are available. Therefore, here we investigated the effects of human intravenous immunoglobulin (IVIg) on a PIPN rat model. PTX-treated rats showed mechanical allodynia and neurophysiological alterations consistent with a severe sensory axonal polyneuropathy. In addition, morphological evaluation showed a reduction of intra-epidermal nerve fiber (IENF) density and evidenced axonopathy with macrophage infiltration, which was more prominent in the distal segment of caudal nerves. Three weeks after the last PTX injection, mechanical allodynia was still present in PTX-treated rats, while the full recovery in the group of animals co-treated with IVIg was observed. At the pathological level, this behavioral result was paralleled by prevention of the reduction in IENF density induced by PTX in IVIg co-treated rats. These results suggest that the immunomodulating effect of IVIg co-treatment can alleviate PIPN neurotoxic manifestations, probably through a partial reduction of neuroinflammation.
Learn More >Chronic spinal pain is the most prevalent chronic disease with employment of multiple modes of interventional techniques including epidural interventions. Multiple randomized controlled trials (RCTs), observational studies, systematic reviews, and guidelines have been published. The recent review of the utilization patterns and expenditures show that there has been a decline in utilization of epidural injections with decrease in inflation adjusted costs from 2009 to 2018. The American Society of Interventional Pain Physicians (ASIPP) published guidelines for interventional techniques in 2013, and guidelines for facet joint interventions in 2020. Consequently, these guidelines have been prepared to update previously existing guidelines.
Learn More >Posttraumatic headache (PTH) is a common debilitating condition arising from head injury and is highly prevalent among military service members and veterans with traumatic brain injury (TBI). Diagnosis and treatment for PTH is still evolving, and surprisingly little is known about the putative mechanisms that drive these headaches. This manuscript describes the design of a randomized clinical trial of two nonpharmacological (i.e., behavioral) interventions for posttraumatic headache. Design of this trial required careful consideration of PTH diagnosis and inclusion criteria, which was challenging due to the lack of standard clinical characteristics in PTH unique from other types of headaches. The treatments under study differed in clinical focus and dose (i.e., number of treatment sessions), but the trial was designed to balance the treatments as well as possible. Finally, while the primary endpoints for pain research can vary from assessments of pain intensity to objective and subjective functional measures, this trial of PTH interventions chose carefully to establish clinically relevant endpoints and to maximize the opportunity to detect significant differences between groups with two primary outcomes. All these issues are discussed in this manuscript.
Learn More >Chronic pain has a significant impact on functioning and results in the disruption of one's assumed life trajectory, potentially altering their self-perceived identity. The present research is designed to determine whether identity-related issues are associated with common chronic pain cognitions and pain-related disability, which may help inform understanding of clinical chronic pain populations.
Learn More >Introduction of a smartphone based behavioral intervention for migraine in the emergency department.
To determine whether a smartphone application (app) with an electronic headache diary and a progressive muscle relaxation (PMR) intervention is feasible and acceptable to people presenting to the Emergency Department (ED) with migraine.
Learn More >Patient-Reported Outcomes Measurement Information System Global Health (PGH) was validated to assess health-related quality of life (HRQOL) in several diseases. Little is known about its measurement properties in adult atopic dermatitis (AD).
Learn More >Spinal cord stimulation (SCS) has been considered as an alternative therapy to reduce opioid requirements in certain chronic pain disorders. However, information on long-term opioid consumption patterns and their impact on SCS device explantation is lacking. We conducted a retrospective study of 45 patients to characterize long-term patterns of opioid usage after SCS implantation. Daily morphine equivalent dosage (MED) increased, decreased, and remained the same in 40%, 40%, and 20% of patients at 1-year follow-up, respectively. Twelve (27%) underwent explantation due to treatment failure at a median of 18 months after implantation. Pre-operative opioid status (naïve vs. active use) was not associated with explantation (18% vs. 29%, p = 0.699) and neither was the daily MED change status (i.e. increased, decreased, unchanged) at 1-year (p = 0.499, 1.000, 0.735, respectively). Following explantation, reduction in the daily MED was seen in 92% of patients with dosages falling below pre-operative baseline in nine. Among the opioid naïve patients, 55% were on opioids at last follow-up (average 32.4 ± 14.6 months). Our results indicate that daily opioid consumption does not decrease in most patients 1-year after SCS implantation. Furthermore, post-operative evaluation beyond 1-year is necessary to assess the efficacy and durability of SCS therapy as well as its impact on opioid requirement. Lastly, rigorous patient selection and pre-operative risk assessment for misuse and dependence are paramount to improving outcome after SCS implantation.
Learn More >Atopic dermatitis (AD) is chronic, pruritic, inflammatory skin disease that affects a significant portion of the population in industrialized nations. For non-responders to conventional therapies, AD can significantly reduce sleep quality and quality of life. AD pathogenesis is multifactorial and involves multiple immune pathways, with recent evidence of Th2, Th17, and Th22 axis attenuation in various AD endotypes and racial subtypes. Inhibition of the conserved Janus Kinase (JAK) signaling pathways represents a promising therapeutic avenue to reduce the activation of multiple pro-inflammatory mediators involved in AD pathogenesis. JAK inhibitors exist in both oral and topical forms with variable specificity for the receptor tyrosine kinases JAK1, JAK2, JAK3, and tyrosine kinase 2. Oral formulations include abrocitinib, upadacitinib, baricitinib, and gusacitinib and are most appropriate for patients with moderate-to-severe AD. Emerging topical formulation in development include ruxolitinib and deglocitinib, which may be used in patients with localized AD and also adjunctively with systemic therapy in patients with more severe disease. With observed rapidity in itch relief and accompanying dramatic reduction in inflammatory lesion count, JAK inhibitors represent a promising new treatment modality to revolutionize the management of AD.
Learn More >Coping strategies are essential for the outcome of chronic pain. This study evaluated religiosity in a cohort of patients with fibromyalgia syndrome (FMS), its effect on pain and other symptoms, on coping and FMS-related disability. A total of 102 FMS patients were recruited who filled in questionnaires, a subgroup of 42 patients participated in a face-to-face interview, and data were evaluated by correlation and regression analyses. Few patients were traditionally religious, but the majority believed in a higher existence and described their spirituality as "transcendence conviction". The coping strategy "praying-hoping" and the ASP dimension "religious orientation" (r = 0.5, P < 0.05) showed a significant relationship independent of the grade of religiosity (P < 0.05). A high grade of belief in a higher existence was negatively associated with the choice of ignoring as coping strategy (r = - 0.4, P < 0.05). Mood and affect-related variables had the highest impact on disability (b = 0.5, P < 0.05). In this cohort, the grade of religiosity played a role in the choice of coping strategies, but had no effects on health and mood outcome.
Learn More >The Patient-Reported Outcomes Meaurement Information System (PROMIS®) measures have been translated into many languages and have been shown to have strong measurement properties across a wide range of clinical conditions. However, Nepali translations of the PROMIS short forms are not yet available. The aim of this study was to translate and cross-culturally adapt the PROMIS Pain Intensity, Pain Interference, Pain Behavior, Depression, and Sleep Disturbance short forms into Nepali.
Learn More >The present study aimed to explore associations between brain activity in the auditory cortex and clinical and psychiatric characteristics in patients with migraine without aura (MwoA) during interictal periods. Resting-state data were acquired from patients with episodic MwoA (n = 34) and healthy controls (n = 30). Independent component analysis was used to extract and calculate the resting-state auditory network. Subsequently, we analyzed the correlations between spontaneous activity in the auditory cortex and clinical and psychiatric features in interictal MwoA. Compared with healthy controls, patients with MwoA showed increased activity in the left superior temporal gyrus (STG), postcentral gyrus (PoCG) and insula. Brain activity in the left STG was positively correlated with anxiety scores, and activity in the left PoCG was negatively correlated with anxiety and depression scores. No significant differences were found in intracranial volume between the two groups. This study indicated that functional impairment and altered integration linked to the auditory cortex existed in patients with MwoA in the interictal period, suggesting that auditory-associated cortex disruption as a biomarker may be implemented for the early diagnosis and prediction of neuropsychiatric impairment in interictal MwoA patients.
Learn More >Mas-related G protein-coupled receptor-X2 (MRGPRX2) is known as a novel receptor to activate mast cells (MCs). MRGPRX2 plays a dual role in promoting MC-dependent host defense and immunomodulation and contributing to the pathogenesis of pseudo-allergic drug reactions, pain, itching, and inflammatory diseases. In this article, we discuss the possible signaling pathways of MCs activation mediated by MRGPRX2 and summarize and classify agonists and inhibitors of MRGPRX2 in MCs activation. MRGPRX2 is a low-affinity and low-selectivity receptor, which allows it to interact with a diverse group of ligands. Diverse MRGPRX2 ligands utilize conserved residues in its transmembrane (TM) domains and carboxyl-terminus Ser/Thr residues to undergo ligand binding and G protein coupling. The coupling likely initiates phosphorylation cascades, induces Ca mobilization, and causes degranulation and generation of cytokines and chemokines via MAPK and NF-κB pathways, resulting in MCs activation. Agonists of MRGPRX2 on MCs are divided into peptides (including antimicrobial peptides, neuropeptides, MC degranulating peptides, peptide hormones) and nonpeptides (including FDA-approved drugs). Inhibitors of MRGPRX2 include non-selective GPCR inhibitors, herbal extracts, small-molecule MRGPRX2 antagonists, and DNA aptamer drugs. Screening and classifying MRGPRX2 ligands and summarizing their signaling pathways would improve our understanding of MRGPRX2-mediated physiological and pathological effects on MCs.
Learn More >Fibromyalgia and myalgic encephalomyelitis / chronic fatigue syndrome (ME/CFS) are poorly understood conditions with overlapping symptoms, fuelling debate as to whether they are manifestations of the same spectrum or separate entities. Both are associated with hypermobility, but this remains significantly undiagnosed, despite impact on quality of life.
Learn More >In this review, we explore the challenges of chronic pain and fatigue in clinical practice. Both pain and fatigue are common, troubling and frequently overlapping symptoms, and we describe both the clinical burden and the 'clinical problem'. We explore commonly associated symptoms and possible pathological associations, including variant connective tissue (joint hypermobility), small fibre neuropathy, mast cell activation, dysregulated inflammatory and interoceptive processes, which may inform treatment targets. We suggest a multidisciplinary management approach.
Learn More >There is evidence that people with persistent shoulder pain exhibit findings consistent with the presence of sensorimotor dysfunction. Sensorimotor impairments can manifest in a variety of ways, and further developing our understanding of sensorimotor dysfunction in shoulder pain may improve current models of care. The Fremantle Back Awareness Questionnaire (FreBAQ) has been developed to assess disturbed body perception specific to the back. The purpose of the present study was to develop a shoulder-specific self-perception questionnaire and evaluate the questionnaire in people with persistent shoulder pain.
Learn More >Bortezomib, a first-generation proteasome inhibitor widely used in chemotherapy for hematologic malignancy, has effective anti-cancer activity but often causes severe peripheral neuropathy. Although bortezomib-induced peripheral neuropathy (BIPN) is a dose-limiting toxicity, there are no recommended therapeutics for its prevention or treatment. One of the most critical problems is a lack of knowledge about pathological mechanisms of BIPN. Here, we summarize the known mechanisms of BIPN based on preclinical evidence, including morphological abnormalities, involvement of non-neuronal cells, oxidative stress, and alterations of transcriptional programs in both the peripheral and central nervous systems. Moreover, we describe the necessity of advancing studies that identify the potential efficacy of approved drugs on the basis of pathological mechanisms, as this is a convincing strategy for rapid translation to patients with cancer and BIPN.
Learn More >Nerve growth factor (NGF) and glial cell line-derived neurotrophic factor (GDNF) are essential for neuronal development and survival in embryo. However, after birth they play pivotal roles in generation of hyperalgesia in many painful conditions. Both factors are believed to act on different groups of primary afferents, and no interaction has been studied. Here we show a synergism of both factors. Intramuscular injection of a mixture of both factors of low concentration, each of which alone had no effect, induced a significant muscular mechanical hyperalgesia in rats. We show synergism occurs in the primary afferent neurons and find about 25 % primary afferents innervating the muscle express both TrkA (NGF receptor) and GFRα1 (GDNF receptor). We show by pharmacological means that afferent neurons with TrkA and GFRα1 express both TRPV1 and ASICs. Our data establish a basis for synergism of NGF and GDNF.
Learn More >A comprehensive approach to pain management often requires multimodal therapy and a combination of medications. Oncology patients may be prescribed methadone and duloxetine as single agents or in combination for cancer-related pain, particularly neuropathic pain. Duloxetine is also prescribed for depression or anxiety in patients with cancer.
Learn More >Recently, the role of electroacupuncture (EA) in chronic neuropathic pain has been widely reported. However, its specific mechanisms and ability to mitigate depression-like behaviors induced by chronic pain remains unclear. This study aims to determine the analgesic and antidepressant effect of EA.
Learn More >High-dose spinal cord stimulation (HD-SCS) revealed positive results for obtaining pain relief in patients with failed back surgery syndrome (FBSS). However, it is less clear whether HD-SCS also is able to reduce pain medication use. The aim of this registry-based cohort study is to explore the impact of HD-SCS on pain medication use in FBSS patients.
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