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Itch is a common clinical symptom and major driver of disease-related morbidity across a wide range of medical conditions. A substantial unmet need is for objective, accurate measurements of itch. In this article, we present a noninvasive technology to objectively quantify scratching behavior via a soft, flexible, and wireless sensor that captures the acousto-mechanic signatures of scratching from the dorsum of the hand. A machine learning algorithm validated on data collected from healthy subjects ( = 10) indicates excellent performance relative to smartwatch-based approaches. Clinical validation in a cohort of predominately pediatric patients ( = 11) with moderate to severe atopic dermatitis included 46 sleep-nights totaling 378.4 hours. The data indicate an accuracy of 99.0% (84.3% sensitivity, 99.3% specificity) against visual observation. This work suggests broad capabilities relevant to applications ranging from assessing the efficacy of drugs for conditions that cause itch to monitoring disease severity and treatment response.
Learn More >Chronic pain is a disabling disease with limited treatment options. While animal models have revealed important aspects of pain neurobiology, therapeutic translation of this knowledge requires our understanding of these cells and networks of pain in humans. We propose a multi-institutional collaboration to rigorously and ethically address this challenge.
Learn More >How genetic loss of the sodium channel Na1.7 results in painlessness is puzzling. MacDonald et al. (2021) demonstrate that instead of impairing peripheral excitability, Na1.7 channels at central terminals of pain-sensing afferents play a pivotal role in the balance between pain and analgesia.
Learn More >Fibromyalgia is a prevalent pain condition that is associated with cognitive impairments including in attention, memory, and executive processing. It has been proposed that fibromyalgia may be caused by altered central pain processing characterised by a loss of endogenous pain modulation. We tested whether attentional analgesia, where cognitive engagement diminishes pain percept, was attenuated in fibromyalgia patients (n=20) compared to matched healthy controls (n=20). An individually calibrated, attentional analgesia paradigm with a 2×2 block design was used with brain and brainstem-focussed fMRI. Fibromyalgia patients had both lower heat pain thresholds and speeds in a visual attention task. When this was taken into account for both attentional task and thermal stimulation, then both groups exhibited an equivalent degree of attentional analgesia. fMRI analysis showed similar patterns of activation in the main effects of pain and attention in the brain and brainstem (with the sole exceptions of increased activation in the control group in frontopolar cortex and the ipsilateral locus coeruleus). The attentional analgesic effect correlated with activity in the periaqueductal grey and rostroventromedial medulla. These findings indicate that fibromyalgia patients can engage the descending pain modulatory system if the attentional task and noxious stimulus intensity is appropriately titrated.
Learn More >Sympathoneuronal outflow into dorsal root ganglia (DRG) is suggested to be involved in sympathetically maintained chronic pain, which is mediated by norepinephrine (NE) action on DRG cells. The present study combined in vitro and in vivo approaches to identify the cell types of DRG that received NE action and examined cell-type specific expression of adrenergic receptors (ARs) in DRG. Using DRG explants, we identified that NE acted on satellite glial cells (SGCs) to induce the phosphorylation of cAMP response element-binding (CREB). Using primarily cultured SGCs, we identified that beta (β)2AR but not alpha (α)AR nor other βAR isoforms mediated NE-induced CREB phosphorylation and CRE-promoted luciferase transcriptional activity. Using fluorescence in situ hybridization and affinity purification of mRNA from specific cell types, we identified that β2AR was expressed by SGCs but not DRG neurons. We further examined β2AR expression and CREB phosphorylation in vivo in a model of colitis in which sympathetic nerve sprouting in DRG was observed. We found that β2AR expression and CREB phosphorylation were increased in SGCs of thoracolumbar DRG on day 7 following colitis induction. Inhibition but not augmentation of β2AR reduced colitis- induced calcitonin gene-related peptide (CGRP) release into the spinal cord dorsal horn and colonic pain responses to colorectal distention. Prolonged activation of β2AR in naïve DRG increased CGRP expression in DRG neurons. These findings provide molecular basis of sympathetic modulation of sensory activity and chronic pain that involves β2AR-mediated signaling in SGCs of DRG.
Learn More >Harnessing placebo and nocebo effects has significant implications for research and medical practice. Placebo analgesia and nocebo hyperalgesia, the most well-studied placebo and nocebo effects, are thought to initiate from the dorsal lateral prefrontal cortex (DLPFC) and then trigger the brain's descending pain modulatory system and other pain regulation pathways. Combining repeated transcranial direct current stimulation (tDCS), an expectancy manipulation model, and functional MRI, we investigated the modulatory effects of anodal and cathodal tDCS at the right DLPFC on placebo analgesia and nocebo hyperalgesia using a randomized, double-blind and sham-controlled design. We found that compared with sham tDCS, active tDCS could 1) boost placebo and blunt nocebo effects and 2) modulate brain activity and connectivity associated with placebo analgesia and nocebo hyperalgesia. These results provide a basis for mechanistic manipulation of placebo and nocebo effects and may lead to improved clinical outcomes in medical practice.
Learn More >Peripheral nerve regeneration is associated with pain in several preclinical models of neuropathic pain. Some neuropathic pain conditions and preclinical neuropathic pain behaviors are improved by sympathetic blockade. In this study we examined the effect of a localized "microsympathectomy," i.e., cutting the gray rami containing sympathetic postganglionic axons where they enter the L4 and L5 spinal nerves, which is more analogous to clinically used sympathetic blockade compared to chemical or surgical sympathectomy. We also examined manipulations of CCL2 (monocyte chemoattractant protein 1; MCP-1), a key player in both regeneration and pain. We used rat tibial nerve crush as a neuropathic pain model in which peripheral nerve regeneration can occur successfully. CCL2 in the sensory ganglia was increased by tibial nerve crush and reduced by microsympathectomy. Microsympathectomy and localized siRNA-mediated knockdown of CCL2 in the lumbar DRG had very similar effects: partial improvement of mechanical hypersensitivity and guarding behavior; reduction of regeneration markers growth-associated protein 43 (GAP43) and activating transcription factor 3 (ATF3); and reduction of macrophage density in the sensory ganglia and regenerating nerve. Microsympathectomy reduced functional regeneration as measured by myelinated action potential propagation through the injury site and denervation-induced atrophy of the tibial-innervated gastrocnemius muscle at day 10. Microsympathectomy plus CCL2 knockdown had behavioral effects similar to microsympathectomy alone. The results show that local sympathetic effects on neuropathic pain may be mediated in large part by the effects on expression of CCL2, which in turn regulates the regeneration process.
Learn More >Activation of transient receptor potential ankyrin 1 (TRPA1) channels by both environmental irritants and endogenous inflammatory mediators leads to excitation of the nerve endings, resulting in acute sensation of pain, itch, or chronic neurogenic inflammation. As such, TRPA1 channels are actively pursued as therapeutic targets for various pathological nociception and pain disorders. We uncovered that exon 27 of human TRPA1 (hTRPA1) could be alternatively spliced into hTRPA1_27A and hTRPA1_27B splice variants. The resulting channel variants displayed reduced expression, weakened affinity to interact with WT, and suffered from complete loss of function because of disruption of the C-terminal coiled-coil domain. Using a human minigene construct, we revealed that binding of splicing factor serine/arginine-rich splicing factor 1 (SRSF1) to the exonic splicing enhancer was critical for the inclusion of intact exon 27. Knockdown of SRSF1, mutation within exonic splicing enhancer, or masking SRSF1 binding with antisense oligonucleotides promoted alternative splicing within exon 27. Finally, antisense oligonucleotides-induced alternative splicing produced transcript and protein variants that could be functionally determined as diminished endogenous TRPA1 activity in human Schwann cell-line SNF96.2 and hiPSCs-derived sensory neurons. The outcome of the work could potentially offer a novel therapeutic strategy for treating pain by targeting alternative splicing of hTRPA1.
Learn More >Chronic widespread musculoskeletal pain (CWP) is a symptom of fibromyalgia and a complex trait with poorly understood pathogenesis. CWP is heritable (48%-54%), but its genetic architecture is unknown and candidate gene studies have produced inconsistent results. We conducted a genome-wide association study to get insight into the genetic background of CWP.
Learn More >The therapeutic utility of opioids is diminished by their ability to induce rewarding behaviors that may lead to opioid use disorder. Recently, the endogenous cannabinoid system has emerged as a hot topic in the study of opioid reward but relatively little is known about how repeated opioid exposure may affect the endogenous cannabinoid system in the mesolimbic reward circuitry. In the present study, we investigated how sustained morphine may modulate the endogenous cannabinoid system in the ventral tegmental area (VTA) of Sprague Dawley rats, a critical region in the mesolimbic reward circuitry. Studies here using proteomic analysis and quantitative real-time PCR (qRT-PCR) found that the VTA expresses 32 different proteins or genes related to the endogenous cannabinoid system; three of these proteins or genes (PLCγ2, ABHD6, and CB2R) were significantly affected after repeated morphine exposure (CB2R was only detected by qRT-PCR but not proteomics). We also identified that repeated morphine treatment does not alter either anandamide (AEA) or 2-arachidonoylglycerol (2-AG) levels in the VTA compared to saline treatment; however, there may be diminished levels of anandamide (AEA) production in the VTA 4 h after a single morphine injection in both chronic saline and morphine pretreated cohorts. Treating the animals with an inhibitor of 2-AG degradation significantly decreased repeated opioid rewarding behavior. Taken together, our studies reveal a potential influence of sustained opioids on the endocannabinoid system in the VTA, suggesting that the endogenous cannabinoid system may participate in the opioid-induced reward.
Learn More >Tissue injury induces a long-lasting latent sensitization (LS) of spinal nociceptive signaling that is kept in remission by an opposing µ-opioid receptor (MOR) constitutive activity. To test the hypothesis that supraspinal sites become engaged, we induced hindpaw inflammation, waited 3 weeks for mechanical hypersensitivity to resolve, and then injected the opioid receptor inhibitors naltrexone, CTOP or β-funaltrexamine subcutaneously, and/or into the cerebral ventricles. Intracerebroventricular injection of each inhibitor reinstated hypersensitivity and produced somatic signs of withdrawal, indicative of LS and endogenous opioid dependence, respectively. In naïve or sham controls, systemic naloxone (3 mg/kg) produced conditioned place aversion, and systemic naltrexone (3 mg/kg) increased Fos expression in the central nucleus of the amygdala (CeA). In LS animals tested 3 weeks after plantar incision, systemic naltrexone reinstated mechanical hypersensitivity and produced an even greater increase in Fos than in sham controls, particularly in the capsular subdivision of the right CeA. One third of Fos+ profiles co-expressed protein kinase C delta (PKCδ), and 35% of PKCδ neurons co-expressed tdTomato+ in Oprm1 ::tdTomato transgenic mice. CeA microinjection of naltrexone (1 µg) reinstated mechanical hypersensitivity only in male mice and did not produce signs of somatic withdrawal. Intra-CeA injection of the MOR-selective inhibitor CTAP (300 ng) reinstated hypersensitivity in both male and female mice. We conclude that MORs in the capsular subdivision of the right CeA prevent the transition from acute to chronic postoperative pain.
Learn More >Chronic abdominal pain is a common clinical condition experienced by patients with irritable bowel syndrome (IBS). A general lack of suitable treatment options for the management of visceral pain is the major contributing factor to the debilitating nature of the disease. Understanding the underlying causes of chronic visceral pain is pivotal to identifying new effective therapies for IBS. This review provides the current evidence demonstrating that mediators and receptors that induce itch in the skin also act as 'gut irritants' in the gastrointestinal tract. Activation of these receptors trigger specific changes in the neuronal excitability of sensory pathways responsible for the transmission of nociceptive information from the periphery to the central nervous system leading to visceral hypersensitivity and visceral pain. As accumulating evidence points to significant roles of these irritant mediators and their receptors in visceral hypersensitivity, they may constitute potential targets for the development of more effective therapeutic options for IBS.
Learn More >Chronic pain is a common condition among people with haemophilia (PWH), associated with joint deterioration due to repeated joint bleeds. This systematic review and meta-analysis aimed to determine the prevalence of chronic pain due to haemophilia and to analyze its interference in the lives of patients. A systematic search was performed in May and June 2019 and updated in February 2021, using PubMed, EMBASE, Web of Science and SciElo. The search included terms related to haemophilia, pain, pain prevalence and pain interference. Studies were included if they reported data referring to haemophilia-related chronic pain among adult males (age≥18). From 3258 identified studies, 11 met the inclusion criteria. Three studies used a proposed definition for haemophilia-related chronic pain and 8 used direct questions developed by the authors. For the global samples, prevalence ranged from 17% to 84%. The random-effects meta-analysis including all studies demonstrated a pooled prevalence of chronic pain of 46% (95% Confidence Interval, CI=34%-58%). Subgroup analysis of samples including all disease severities or including only severe patients revealed a pooled prevalence of 48% (95% CI=29%-67%) and 53% (95% CI=38%-69%), respectively. High heterogeneity between studies was observed in all models. Information concerning chronic pain interference was retrieved from 1 study, reporting a mean interference of 3.7 (0-10 numerical rating scale from the Brief Pain Inventory). This systematic review revealed a wide prevalence range of haemophilia-related chronic pain across studies, varying methodologies and sample characteristics. Research in the haemophilia field should clearly distinguish between acute and chronic pain and provide complete characterization of study samples. Perspective: Pain is a central issue in the lives of people with haemophilia, posing a significant challenge for healthcare providers. A clear picture of chronic pain due to haemophilia is precluded by high heterogeneity among studies and various definitions used to investigate its prevalence.
Learn More >To compare the quality and acceptability of a new headache-specific patient-reported measure, the Chronic Headache Quality of Life Questionnaire (CHQLQ) with the six-item Headache Impact Test (HIT-6), in people meeting an epidemiological definition of chronic headaches.
Learn More >The failure of past practices and policies related to opioid prescribing for chronic pain has led federal agencies and professional organizations to recommend multimodal approaches that prioritize evidence-based nonpharmacological pain treatments (NPTs). These multimodal approaches, which include both traditional and complementary/integrative approaches, hold great promise for reducing the burden of chronic pain and reducing opioid use. Unfortunately, NPT approaches are underutilized due to a daunting array of interrelated barriers including the public's attitudes and beliefs about chronic pain and its treatment. Given the dual crises of chronic pain and opioid use, there is a critical need for a national public health campaign on chronic pain and its treatment to help educate the American public about NPT pain management options, while countering the misleading messages promulgated by the pharmaceutical industry, including but not limited to messages promoting the broad use of prescription opioids and minimizing its risks. Despite these dual crises of chronic pain and opioid use in the U.S., there has never been a concerted effort to broadly educate the American public about these issues and NPT pain management options. Perspectives: Given the dual crises of chronic pain and opioid use, there is a critical need for a national public health campaign on chronic pain and its treatment, to educate the public about current treatment guidelines, which prioritize multi-modal, nonpharmacological pain treatment approaches, and counter the influence of pharmaceutical promotional efforts.
Learn More >"Pain interference" and "headache impact" refer to negative consequences that pain and headache have on one's life. This study investigated determinants of these negative impacts in a large patient cohort who have chronic migraine with medication overuse.
Learn More >Chronic pain is a frequent, yet under-recognised and under-assessed problem in people with muscular dystrophies (MDs). Knowledge of the prevalence and characteristics of chronic pain, and its impact on function and quality of life is limited and lacks systematic exploration. This article aims to systematically review and synthesise existing literature that addresses chronic pain prevalence, characteristics and impact in people with different types of MDs. The present meta-analysis showed that the estimated prevalence of chronic pain in MDs is high and appears to be similar across different diagnostic groups: 68% (95% CI: 52% to 82%) in FSHD, 65% (95% CI: 51% to 77%) in DM, 62% (95% CI: 50% to 73%) in BMD/DMD, and 60% (95% CI: 48% to 73%) in LGMD, although it should be noted that heterogeneity was high in some diagnostic groups. On average, people with FSHD and DM present with moderate pain intensity. The lumbar spine, shoulders and legs are the most frequent sites of chronic pain among people with FSHD, DM, BMD/DMD, and LGMD, with little variation. Diffuse pain across multiple body sites was reported by a notable proportion of these individuals. Chronic pain has a negative impact on daily life activities in people with MDs, and may also contribute to decreased quality of life. The protocol for this review has been published on PROSPERO (CRD42020168096). PERSPECTIVES: This is the first systematic review and meta-analysis exploring the prevalence, and nature and impact of chronic pain in people with MDs. The present study demonstrates how common chronic pain is across various MD populations and highlights the need for better recognition and understanding of the nature and impact of pain from health professionals.
Learn More >Throughout the body, damage to peripheral nerves normally involved in nociception may produce a constellation of symptoms-including irritation, itchiness and pain. The neurobiological processes involved in corneal symptoms of dry eye (DE) and neuropathic corneal pain (NCP) have not been clearly considered in terms of nociceptive processing. The conventional underlying presumption is that a labelled line principle is responsible; that these distinct perceptions are hard coded by primary afferent inputs to the central nervous system. This presumption oversimplifies the neurobiological mechanisms underlying somatosensory perception. The labelled line perspective that DE represents a chronic pain condition does not make intuitive sense: how can an eye condition that is not painful in most cases be considered a pain condition? Does not chronic pain by definition require pain to be present? On the other hand, NCP, a term that clearly denotes a painful condition, has historically seemed to resonate with clinical significance. Both DE and NCP can share similar features, yet their differentiation is not always clear. As is often the case, clinical terms arise from different disciplines, with DE evolving from ophthalmological findings and NCP inspired by pain neurophysiology. This review evaluates the current definition of these terms, the rationale for their overlap and how the neurophysiology of itch impacts our understanding of these conditions as a continuum of the same disease. Despite the complexity of nociceptive physiology, an understanding of these mechanisms will allow us a more precise therapeutic approach.
Learn More >Persistent post-traumatic headache most commonly has symptoms that overlap those of migraine. In some cases, it can be clinically difficult to differentiate persistent post-traumatic headache with a migraine phenotype from migraine. The objective of this study was to develop a classification model based on questionnaire data and structural neuroimaging data that distinguishes individuals with migraine from those with persistent post-traumatic headache.
Learn More >Neuropathic pain is a common disorder of the somatosensory system that affects 7%-10% of the general population. The disorder places a large social and economic burden on patients as well as healthcare services. However, not everyone with a relevant underlying aetiology develops corresponding pain. DOLORisk Dundee, a European Union-funded cohort, part of the multicentre DOLORisk consortium, was set up to increase current understanding of this variation in onset. In particular, the cohort will allow exploration of psychosocial, clinical and genetic predictors of neuropathic pain onset.
Learn More >Pain is the hallmark symptom of knee osteoarthritis (OA), and varies widely across individuals. Previous research has demonstrated both fluctuating and stable pain trajectories in knee OA using various time periods. Changes in pain assessed quarterly (i.e. 3-month intervals) in knee OA are relatively unknown. The current study aimed to investigate temporal variations in pain over a one and a half year period (18 months) based on quarterly characteristic pain assessments, and to examine differences in pain patterns by sociodemographic and baseline pain characteristics.
Learn More >African American (AA) older adults with knee osteoarthritis experience more severe chronic pain and advanced physical disability. One of the most prominent stimuli that provoke knee pain is movement. Research suggests that compared to White Americans, AAs report significantly higher movement-evoked pain (MEP) in the knee. However, little is known about the biopsychosocial-behavioral mechanisms underlying MEP.
Learn More >To assess the effects and reliability of sham procedures in manual therapy (MT) trials in the treatment of back pain (BP) in order to provide methodological guidance for clinical trial development.
Learn More >To determine whether our E-diary can be used to diagnose migraine and provide more reliable migraine-related frequency numbers compared to patients' self-reported estimates.
Learn More >To better address sociodemographic-related health disparities, this study examined which sociodemographic variables most strongly correlate with self-reported health in patients with chronic musculoskeletal pain.
Learn More >Pediatric chronic post-surgical pain is a surgical complication associated with various levels of functional limitation. Two commonly used measures of functional limitations in youth are the Functional Disability Inventory (FDI) and the PROMIS Pediatric Pain Interference Scale (PPIS), where the former is general, and the latter, pain specific. The aim of the present study was to prospectively compare pre-surgical youth and parent risk factors for youth functional limitations, assessed by the FDI and PPIS, 12 months after major pediatric surgery. Risk factors for the FDI and PPIS were compared in 79 dyads consisting of youth (58% female, = 14.56 years; SD = 2.31) undergoing major surgery and one of their parents. The FDI and PPIS were highly correlated prior to surgery ( = 0.698, < 0.001) and even more so 12 months after surgery ( = 0.807, < 0.001). Parent pre-surgical anxiety sensitivity and youth pre-surgical functional disability significantly predicted 12-month FDI ((6,56) = 4.443, = 0.001, Adjusted R = 0.25), whereas parent pre-surgical anxiety sensitivity, trait anxiety, pain anxiety, as well as youth pain-related anxiety and worry significantly predicted 12-month PPIS ((6,45) = 4.104, = 0.002, Adjusted R = 0.27). Risk factors for 12-month general and pain-specific functional limitations differ by dyad member and type. Functional limitations in youth after surgery are predicted by youth and parent factors, however the risk factors differ between the FDI and the PPIS.
Learn More >Cluster headaches can occur with considerable clinical variability. The inter- and intra-individual variability could contribute to the fact that the clinical headache phenotype is not captured by too strict diagnostic criteria, and that the diagnosis and the effective therapy are thereby delayed. The aim of the study was to analyze the severity and extent of the clinical symptoms of episodic and chronic cluster headaches with regard to their variability and to compare them with the requirements of the International Classification of Headache Disorders 3rd edition (ICHD-3) diagnostic criteria.
Learn More >The 22-item PROMIS®-Rx Pain Medication Misuse item bank (Bank-22) imposes a high response burden. This study aimed to characterize the performance of the Bank-22 in a computer adaptive testing (CAT) setting based on varied stopping rules.
Learn More >Cyclic GMP (cGMP) is a second messenger that regulates numerous physiological and pathophysiological processes. In recent years, more and more studies have uncovered multiple roles of cGMP signalling pathways in the somatosensory system. Accumulating evidence suggests that cGMP regulates different cellular processes from embryonic development through adulthood. During embryonic development, a cGMP-dependent signalling cascade in the trunk sensory system is essential for axon bifurcation, a specific form of branching of somatosensory axons. In adulthood, various cGMP signalling pathways in distinct cell populations of sensory neurons and dorsal horn neurons in the spinal cord play an important role in the processing of pain and itch. Some of the involved enzymes might serve as a target for future therapies. In this review, we summarize the knowledge regarding cGMP-dependent signalling pathways in dorsal root ganglia and the spinal cord during embryonic development and adulthood, and the future potential of targeting these pathways.
Learn More >This post-hoc analysis was conducted to evaluate the effect of erenumab on monthly migraine days, monthly migraine attacks, and attack duration in patients with episodic migraine to investigate whether erenumab actually prevents the occurrence of migraine attacks and/or shortens them.
Learn More >Burn injury is one of the main causes of mortality worldwide and frequently associated with severe and long-lasting pain that compromises the quality of patient life. Several studies have shown that the mu-opioid system plays an important role in burn pain relief. In this study, we investigated the spinal antinociception induced by the endogenous mu-opioid receptor (MOR) agonists endomorphins and explored their mechanisms of actions in burn injury-induced pain model. Our results showed that intrathecal injection of endomorphin-1 and -2 dose-dependently attenuated mechanical allodynia and thermal hyperalgesia via the mu-opioid receptor in mice on day 3 after burn injury, which was consistent with the data obtained from the mu-opioid receptor knockout mice. Western blot showed that the phosphorylation levels of extracellular signal-regulated kinase1/2 (ERK1/2) and p38 mitogen-activated protein kinase (p38 MAPK) in ipsilateral spinal cord tissues were significantly up-regulated after burn injury. Intrathecal injection of endomorphins selectively inhibited the activation of p38 MAPK on day 3 after burn injury via the mu-opioid receptor. Further studies found that repeated application of the specific p38 MAPK inhibitor SB203580 dose-dependently inhibited burn-injury pain, as well as the activation of spinal p38 MAPK. Taken together, our present study demonstrates that intrathecal injection of endomorphins attenuates burn-injury pain in male mice by affecting the spinal activation of p38 MAPK via the mu-opioid receptor.
Learn More >Osteoarthritis (OA) is a highly prevalent musculoskeletal condition worldwide. More than 300 million individuals are affected by OA, and pain is the most common and challenging symptom to manage. Although many new advances have led to improved OA-related pain management, smart technology offers additional opportunities to enhance symptom management. This narrative review identifies and describes the current literature focused on smart technology for pain management in individuals with OA. In collaboration with a health sciences librarian, an interdisciplinary team of clinician-scientists searched multiple databases (e.g. PubMed, CINAHL and Embase), which generated 394 citations for review. After inclusion criteria were met, data were extracted from eight studies reporting on varied smart technologies, including mobile health, wearables and eHealth tools to measure or manage pain. Our review highlights the dearth of research in this crucial area, the implications for clinical practice and technology development, and future research needs.
Learn More >It has been established that the endogenous cannabinoid (endocannabinoid) system plays key modulatory roles in a wide variety of pathological conditions. The endocannabinoid system comprises both cannabinoid receptors, their endogenous ligands including 2-arachidonoylglycerol (2-AG), N-arachidonylethanolamine (anandamide, AEA), and enzymes that regulate the synthesis and degradation of endogenous ligands which include diacylglycerol lipase alpha (DAGL-α), diacylglycerol lipase beta (DAGL-β), fatty acid amide hydrolase (FAAH), monoacylglycerol lipase (MAGL), α/β hydrolase domain 6 (ABHD6). As the endocannabinoid system exerts considerable involvement in the regulation of homeostasis and disease, much effort has been made towards understanding endocannabinoid-related mechanisms of action at cellular, physiological, and pathological levels as well as harnessing the various components of the endocannabinoid system to produce novel therapeutics. However, drug discovery efforts within the cannabinoid field have been slower than anticipated to reach satisfactory clinical endpoints and raises an important question into the validity of developing novel ligands that therapeutically target the endocannabinoid system. To answer this, we will first examine evidence that supports the existence of an endocannabinoid system role within inflammatory diseases, neurodegeneration, pain, substance use disorders, mood disorders, as well as metabolic diseases. Next, this review will discuss recent clinical studies, within the last 5 years, of cannabinoid compounds in context to these diseases. We will also address some of the challenges and considerations within the cannabinoid field that may be important in the advancement of therapeutics into the clinic.
Learn More >We conducted a systematic review/meta-analysis to evaluate noninvasive brain stimulation (NIBS) efficacy to alleviate pain and improve disability in low back pain (LBP).
Learn More >Pain disorders and psychiatric illness are strongly comorbid, particularly in the context of Major Depressive Disorder (MDD). While these disorders account for a significant amount of global disability, the mechanisms of their overlap remain unclear. Understanding these mechanisms is of vital importance to developing prevention strategies and interventions that target both disorders. Of note, brain reward processing may be relevant to explaining how the comorbidity arises, given pain disorders and MDD can result in maladaptive reward responsivity that limits reward learning, appetitive approach behaviours and consummatory response. In this review, we discuss this research and explore the possibility of reward processing deficits as a common diathesis to explain the manifestation of pain disorders and MDD. Specifically, we hypothesize that contextual physical or psychological events (e.g. surgery, divorce) in the presence of a reward impairment diathesis worsens symptoms and results in a negative feedback loop that increases the chronicity and probability of developing the other disorder. We also highlight the implications for treatment and provide a framework for future research.
Learn More >Chronic pain in children is a serious issue, therefore calling for effective prevention/intervention measures. This study aimed to evaluate the efficacy of an educational movie on pain knowledge in school children in general and on pain-related behaviours and pain intensity in those who are affected by chronic pain. Regarding those affected, the association between pain knowledge and intensity, as well as the potential mediating effect of pain-related behaviours, were investigated.
Learn More >Ubrogepant is a small-molecule calcitonin gene-related peptide (CGRP) receptor antagonist that received Food and Drug Administration (FDA) approval for the acute treatment of migraine with and without aura in adults. The ACHIEVE I and ACHIEVE II Phase III clinical trials showed that ubrogepant was superior to placebo for pain freedom and freedom of the most bothersome migraine-associated symptom at 2 hours after medication intake. The 52-week open label extension of the Phase III trials demonstrated safety of ubrogepant. A real-world study conducted at a tertiary headache center also confirmed the efficacy and safety of ubrogepant. Adverse event rates were higher in the real-world population. Studies are needed to evaluate its long-term efficacy and safety, especially in the setting of co-administration with other CGRP modulating therapies such as the CGRP monoclonal antibodies.
Learn More >A growing body of evidence suggests Chronic Lower Back Pain (CLBP) is associated with cognitive dysfunction. Little is known, however, about the extent of cognitive impairment in CLBP. The present study explored the cognitive profile of people with CLBP and sought to determine the extent of Mild Cognitive Impairment (MCI) according to the DSM-V and the Movement Disorders Society criteria for MCI. Thirty-one participants with CLBP and 27 age and gender matched healthy controls completed a full neuropsychological battery, consisting of two tasks for each of the five cognitive domains (Executive Function, Attention/Working Memory, Memory, Language, and Visuospatial). Participants with CLBP performed worse, compared to controls, on measures of Attention/Working Memory, Memory, Language, and Visuospatial performance. Cognitive performance in CLBP was also compared to equivalent normative data to determine cognitive impairment. Sixteen CLBP participants were impaired on at least one cognitive measure, with 5 participants meeting criteria for MCI. MCI was not associated with pain-related experience, or psychological health. The present study supports and extends previous findings that CLBP is associated with cognitive dysfunction and some people with CLBP meet criteria for MCI. These findings support that rehabilitation in people with CLBP requires a multidisciplinary approach.
Learn More >The clinical benefit of galcanezumab, demonstrated in randomized clinical trials (RCTs), remains to be quantified in real life. This study aimed at evaluating the effectiveness, safety and tolerability of galcanezumab in the prevention of high-frequency episodic migraine (HFEM) and chronic migraine (CM) in a real-life setting.
Learn More >Trigeminal neuralgia (TN) is a rare condition for which there are multiple treatment options available. To date, there has been difficulty in comparing the outcomes of treatment due to the variety of patient-reported outcome measures (PROMs) and their inadequate psychometric testing. The aim of this review was to assess the psychometric properties of PROMs used to date in TN and make recommendations for their use in future studies.
Learn More >The conceptual paradigm of axial spondyloarthritis (axSpA) has evolved and now comprises an expanded spectrum that includes more females and patients with little or no radiographic changes in sacroiliitis or syndesmophyte formation in the spine. This broadened paradigm is often, but not always, characterized by an inflammatory magnetic resonance imaging (MRI) signature.
Learn More >A robust body of research has shown that traumatic experiences occurring during critical developmental periods of childhood when neuronal plasticity is high increase risks for a spectrum of physical and mental health problems in adulthood, including substance use disorders. However, until recently, relatively few studies had specifically examined the relationships between early life stress (ELS) and opioid use disorder (OUD). Associations with opioid use initiation, injection drug use, overdose, and poor treatment outcome have now been demonstrated. In rodents, ELS has also been shown to increase the euphoric and decrease antinociceptive effects of opioids, but little is known about these processes in humans or about the neurobiological mechanisms that may underlie these relationships. This review aims to establish a theoretical model that highlights the mechanisms by which ELS may alter opioid sensitivity, thereby contributing to future risks for OUD. Alterations induced by ELS in mesocorticolimbic brain circuits, and endogenous opioid and dopamine neurotransmitter systems are described. The limited but provocative evidence linking these alterations with opioid sensitivity and risks for OUD is presented. Overall, the findings suggest that better understanding of these mechanisms holds promise for reducing vulnerability, improving prevention strategies, and prescribing guidelines for high-risk individuals.
Learn More >The characteristics of self-reported functional limitations among older United States (US) adults with pain are currently unknown. This cross-sectional study aimed to determine the characteristics associated with functional limitations among non-institutionalized older (≥50 years) US adults with pain using 2017 Medical Expenditure Panel Survey (MEPS) data. Eligible subjects were alive for the calendar year, aged ≥50 years, and experienced pain within the past four weeks. Hierarchical logistic regression models were utilized to determine significant characteristics associated with functional limitations (outcome variable; yes, no). Functional limitations included difficulty with bending, stooping, climbing stairs, grasping objects, lifting, reaching overhead, standing for long periods of time, or walking. Extrapolation of national data values was possible by adjusting for the complex MEPS design. We found approximately 22 million of the 57 million older US adults (≥50 years) who reported pain had a functional limitation in 2017. Characteristics associated with functional limitations included: gender, race, ethnicity, employment status, marital status, pain intensity, physical health, number of chronic conditions, and frequent exercise status. Knowledge of characteristics associated with functional limitations may provide an opportunity to identify and resolve gaps in patient care among this population.
Learn More >Transcranial direct current stimulation (tDCS) may have therapeutic potential in the management of migraine. However, studies to date have yielded conflicting results. We reviewed studies using repeated tDCS for longer than 4 weeks in migraine treatment, and performed meta-analysis on the efficacy of tDCS in migraine.
Learn More >The consistency of the treatment effect of galcanezumab throughout the dosing interval is examined in patients with episodic and chronic migraine.
Learn More >Nicotinamide adenine dinucleotide phosphate oxidase 2 (NOX2)-induced oxidative stress, including the production of reactive oxygen species (ROS) and hydrogen peroxide, plays a pivotal role in neuropathic pain. Although the activation and plasma membrane translocation of protein kinase C (PKC) isoforms in dorsal root ganglion (DRG) neurons have been implicated in multiple pain models, the interactions between NOX2-induced oxidative stress and PKC remain unknown.
Learn More >To evaluate the impact of the Coronavirus disease of 2019 (COVID-19) pandemic on patients with migraine.
Learn More >Transient receptor potential ankyrin 1 (TRPA1) channel is expressed in a subset of nociceptive neurons. This channel integrates several nociceptive signals. Particularly, it is modulated by intracellular pH (pH). Na/H exchanger 1 (NHE1) contributes to the maintenance of pH in nociceptors. However, it is currently unknown whether the interaction between TRPA1 and NHE1 contributes to the nociceptive processing. Thus, the purpose of this study was to assess the functional interaction between NHE1 and TRPA1 in small dorsal root ganglion (DRG) neurons from primary culture obtained from adult rats. Moreover, we also evaluated their possible interaction in acute and inflammatory pain. Zoniporide (selective NHE1 inhibitor) reduced pH and increased intracellular calcium in a concentration-dependent fashion in DRG neurons. Zoniporide and allyl isothiocyanate (AITC, TRPA1 agonist) increased calcium transients in the same DRG neuron, whereas that A-967079 (TRPA1 antagonist) prevented the effect of zoniporide in DRG neurons. Repeated AITC induced TRPA1 desensitization and this effect was prevented by zoniporide. Both NHE1 and TRPA1 were localized at the membrane surface of DRG neurons in culture. Local peripheral zoniporide enhanced AITC-induced pronociception and this effect was prevented by A-967079. Likewise, zoniporide potentiated Complete Freund́s Adjuvant (CFA)-induced hypersensitivity, effect which was prevented by A-967079 in vivo. CFA paw injection increased TRPA1 and decresed NHE1 protein expression in DRG. These results suggest a functional interaction between NHE1 and TRPA1 in DRG neurons in vitro. Moreover, data suggest that this interaction participates in acute and inflamatory pain conditions in vivo.
Learn More >We examined the association between long-term (~10 years) changes in self-reported sleep quality and risk of any chronic musculoskeletal pain and chronic widespread pain. The study comprised data on 6,033 people who participated in three consecutive surveys in the Norwegian HUNT Study (1995-1997, 2006-2008 and 2017-2019) and who were without chronic musculoskeletal pain at the first two surveys. We used a modified Poisson regression model to calculate adjusted risk ratios for chronic pain at follow-up (2017-2019) associated with categories of poor and good sleep quality reported in 1995-1997 and 2006-2008. Compared with people who reported good sleep at both surveys (crude absolute risk: 32.4%), the risk ratios of any chronic pain were 1.20 (95% confidence interval: 1.02-1.41) for those who changed from poor to good sleep; 1.25 (95% confidence interval: 1.12-1.39) for those who changed from good to poor sleep; and 1.41 (95% confidence interval: 1.21-1.63) for those who reported long-term poor sleep. The corresponding risk ratios for chronic widespread pain were 1.35 (95% confidence interval: 0.82-2.23), 1.55 (95% confidence interval: 1.14-2.12) and 2.09 (95% confidence interval: 1.38-3.17), respectively. In conclusion, these findings indicate that people with long-term poor sleep quality have a markedly higher risk of chronic musculoskeletal pain and chronic widespread pain, compared with people who remain good sleep quality.
Learn More >Many individuals who undergo limb amputation experience persistent phantom limb pain (PLP), but the underlying mechanisms of PLP are unknown. The traditional hypothesis was that PLP resulted from maladaptive plasticity in sensorimotor cortex that degrades the neural representation of the missing limb. However, a recent study of individuals with upper limb amputations has shown that PLP is correlated with aberrant electromyographic (EMG) activity in residual muscles, posited to reflect a retargeting of efferent projections from a preserved representation of a missing limb. Here, we assessed EMG activity in a residual thigh muscle (vastus lateralis, VL) in patients with trans-femoral amputations during cyclical movements of a phantom foot. VL activity on the amputated side was compared to that recorded on patients' intact side while they moved both the phantom and intact feet synchronously. VL activity in the patient group was also compared to a sample of control participants with no amputation. We show that phantom foot movement is associated with greater VL activity in the amputated leg than that seen in the intact leg as well as that exhibited by controls. The magnitude of residual VL activity was also positively related to ratings of PLP. These results show that phantom limb movement is associated with aberrant activity in a residual muscle after lower-limb amputation and provide evidence of a positive relationship between this activity and phantom limb pain.
Learn More >Stress can trigger symptoms in patients with irritable bowel syndrome (IBS). Previously we demonstrated that chronic psychological stress induced microglial remodeling in the central nucleus of amygdala (CeA), and contributed to the development of visceral hypersensitivity via synaptic engulfment. However, the specific signaling mechanisms that microglia depend upon to recognize target neurons to facilitate visceral pain remain unknown. Here we test the hypothesis that the microglia in the CeA contribute to chronic stress-induced visceral hypersensitivity via complement C1q/C3-CR3 signaling-mediated synaptic remodeling. In male and female Fischer-344 rats, micropellets of corticosterone (CORT) or cholesterol (control) were stereotaxically implanted bilaterally onto the CeA. After 7 days, microglial C1q, complement receptor 3 (CR3) expression and microglia-mediated synaptic engulfment were assessed via RNAscope, quantitative PCR and immunofluorescence. The microglial inhibitor minocycline, CR3 antagonist neutrophil inhibitory factor (NIF) or vehicle were daily infused into the CeA following CORT implantations. Visceral sensitivity was assessed via a visceromotor response (VMR) to graded pressures of isobaric colorectal distension (CRD). Our results suggest that chronic exposure to elevated CORT in the CeA induced visceral hypersensitivity and amygdala microglial morphological remodeling. CORT increased microglial C1q and CR3 expression, and increased microglia-mediated synaptic engulfment. Both groups of animals with minocycline or NIF infusions reversed microglia-mediated synaptic remodeling, and attenuated CORT-induced visceral hypersensitivity. Our findings demonstrate that C1q/C3-CR3 signaling is critical for microglia-mediated synaptic remodeling in the CeA and contributes to CORT-induced visceral hypersensitivity.
Learn More >Patients on long-term opioid therapy (LTOT) for pain have difficulty accessing primary care clinicians who are willing to prescribe opioids or provide multimodal pain treatment. Recent treatment guidelines and statewide policies aimed at reducing inappropriate prescribing may exacerbate these access issues, but further research is needed on this issue. This study aimed to understand barriers to primary care access and multimodal treatment for chronic pain from the perspective of multiple stakeholders.
Learn More >As a disorder of brain dysfunction, migraine has been associated with cognitive decline. However, no consistent results with respect to the attention function in migraineurs have been found, and the relationship between attentional inhibition and migraine is also unclear. In this study, the attentional inhibition function was evaluated using event-related potentials (ERPs) while migraine patients and healthy controls were performing the color-word Stroop task.
Learn More >Virtual reality (VR) facilitates physical therapy (PT) via improved engagement. While shown to benefit specific patient populations, such as stroke patients, it is less established in otherwise healthy adults and children receiving outpatient PT. The primary objective was to compare total PT-guided Movement supplemented with VR (PTMVR) to PT guided Movement alone, without VR (PTM).
Learn More >Migraine, endometriosis, and the comorbidity of both are frequent pain disorders of special relevance for women. The neuropeptide calcitonin gene-related peptide (CGRP) is critically involved in migraine, and circumstantial evidence suggests a role in endometriosis. We assessed CGRP levels at different times of menstrual cycle in four groups: healthy women, women with migraine or endometriosis and with the comorbidity of both.
Learn More >Chronic pruritus affects up to 70% of patients with immune-mediated hepatobiliary disorders. Antagonists of the μ-opioid receptor (MOR) and agonists of the κ-opioid receptor (KOR) are used to treat hepatic itch, albeit with limited success. An imbalance between ligands of MOR and KOR receptors has recently been suggested as a potential mechanism of hepatic pruritus. In this study, we therefore investigated systemic levels of important endogenous opioids such as β-endorphin, dynorphin A, Leu- and Met-enkephalin in plasma of a large cohort of well-characterized patients with immune-mediated cholestatic disorders, including patients with liver cirrhosis, and during effective anti-pruritic therapy. Plasma samples and clinical data were prospectively collected from well-characterized patients with primary/secondary sclerosing cholangitis (PSC/SSC), primary biliary cholangitis (PBC) and overlap syndromes suffering from pruritus ( = 29) and age-, gender- and disease-matched controls without pruritus ( = 27) as well as healthy controls ( = 20). General laboratory testing for hepatobiliary and renal function was performed. Levels of β-endorphin, dynorphin A, Leu- and Met-enkephalin were quantified in plasma by ELISA. Intensity of pruritus over the last week was evaluated using a visual analog scale (VAS, 0-10). PBC and PSC patients with or without pruritus did neither differ in disease entity, disease stage, nor in the presence of cirrhosis. While both dynorphin A and β-endorphin concentrations were lower in pruritic patients compared to those without pruritus and healthy controls, the MOR/KOR ligand ratio was unaltered. No significant differences were observed for Leu- and Met-enkephalin concentrations. Opioid levels correlated with neither itch intensity nor stage of disease. Cirrhotic patients displayed higher concentrations of MOR agonist Leu-enkephalin and KOR agonist dynorphin A. Endogenous opioid levels remained largely unchanged after successful treatment with the potent anti-pruritic drugs rifampicin and bezafibrate. Endogenous opioid levels and the MOR/KOR ligand ratio neither correlate with itch intensity nor differentiate pruritic from non-pruritic patients with immune-mediated liver diseases. Thus, endogenous opioids may modulate signaling pathways involved in hepatic pruritus, but are unlikely to represent the major pruritogens in liver disease.
Learn More >Musculoskeletal disorders often lead to chronic pain in Veterans. Chronic pain puts sufferers at risk for substance misuse, and early intervention is needed for both conditions. This pilot study tested the feasibility and acceptability of a Screening, Brief Intervention, and Referral to Treatment for Pain Management intervention (SBIRT-PM) to help engage Veterans seeking disability compensation for painful musculoskeletal disorders in multimodal pain treatment and to reduce risky substance use, when indicated.
Learn More >In our efforts to identify orally bioavailable CGRP receptor antagonists, we previously discovered a novel series of orally available azepinone derivatives that unfortunately also exhibited the unwanted property of potent time-dependent human CYP3A4 inhibition. Through heterocyclic replacement of the indazole ring, we discovered a series of heterocycle derivatives as high-affinity CGRP receptor antagonists. Some of them showed reasonable oral exposures, and the imidazolone derivatives that showed good oral exposure also exhibited substantially reduced time-dependent CYP3A4 inhibition. Several compounds showed strong in vivo efficacy in our marmoset facial blood flow assay with up to 87% inhibition of CGRP-induced activity. However, oral bioavailability generally remained low, emphasizing the challenges we and others encountered in discovering clinical development candidates for this difficult Class B GPCR target.
Learn More >Heart rate variability (HRV) is an important physiological measure of the capacity for neurogenic homeostatic regulation, and an indirect measure of emotional processing. We aimed to investigate whether HRV parameters are altered in people with chronic low back pain when compared to healthy controls.
Learn More >Diabetic peripheral neuropathy (DPN) is a chronic complication of diabetes mellitus associated with high morbidity and mortality. Major risk factors for DPN include metabolic changes, duration of diabetes, nerve ischaemia and derangements in regeneration and nerve repair programs. Chemokines have been previously implicated in the pathogenesis of various neuropathies and neuropathic pain processes. The aim of this pilot study was to evaluate the association between plasma levels of chemokines (CXCL9, CXCL10 and CXCL11) with the presence of DPN in a cohort of type 2 diabetes (T2D) patients.
Learn More >TNF-α-inducible protein 8-like 2 (TIPE2) is a recently discovered regulator of inflammation that can maintain immune homeostasis, exerting a significant role in the development of inflammation-related diseases. Here, we aimed to explore the role and potential regulatory mechanism of TIPE2 in the progression of inflammatory pain. In the present study, a mouse BV2 microglia cell activation-mediated inflammatory model was developed with LPS induction, and a mouse inflammatory pain model was established with complete Freund's adjuvant (CFA) injection. In vitro, the TIPE2 expression was decreased in LPS-induced BV2 cells. Overexpression of TIPE2 mitigated LPS-medicated microglial activation via decreasing nitric oxide (NO) generation and the expression of microglia marker IBA-1. Notably, increasing TIPE2 expression alleviated microglial activation-triggered expression levels and releases of proinflammatory factors such as TNF-α, IL-1β, and IL-6. Mechanism analysis verified that overexpression of TIPE2 blunted Rac1-mediated activation of NF-κB pathway following LPS stimulation. More importantly, CFA injection reduced the expression of TIPE2 in a mouse inflammatory pain model and overexpression of TIPE2 alleviated CFA-mediated pain hypersensitivity and inflammatory response, and inactivated microglia cell in vivo. Furthermore, overexpression of TIPE2 decreased Rac1 expression and suppressed the activation of NF-κB pathway in spinal cord after CFA injection. In summary, the present study revealed that overexpression of TIPE2 mitigated inflammatory pain through suppressing microglial activation-induced inflammation by inactivating Rac1/NF-κB pathway. The study provides a novel theoretical foundation for the therapy of inflammatory pain.
Learn More >Craniofacial neuropathic pain affects millions of people worldwide and is often difficult to treat. Two key mechanisms underlying this condition are a loss of the negative control exerted by inhibitory interneurons and an early microglial reaction. Basic features of these mechanisms, however, are still poorly understood. Using the chronic constriction injury of the infraorbital nerve (CCI-IoN) model of neuropathic pain in mice, we have examined the changes in the expression of GAD, the synthetic enzyme of GABA, and GlyT2, the membrane transporter of glycine, as well as the microgliosis that occur at early (5 days) and late (21 days) stages post-CCI in the medullary and upper spinal dorsal horn. Our results show that CCI-IoN induces a down-regulation of GAD at both postinjury survival times, uniformly across the superficial laminae. The expression of GlyT2 showed a more discrete and heterogeneous reduction due to the basal presence in lamina III of 'patches' of higher expression, interspersed within a less immunoreactive 'matrix', which showed a more substantial reduction in the expression of GlyT2. These patches coincided with foci lacking any perceptible microglial reaction, which stood out against a more diffuse area of strong microgliosis. These findings may provide clues to better understand the neural mechanisms underlying allodynia in neuropathic pain syndromes.
Learn More >Acute postoperative pain is associated with adverse short and long-term outcomes among women undergoing surgery for breast cancer. Previous studies identified preexisting pain as a predictor of postoperative pain, but rarely accounted for pain location or chronicity. This study leveraged a multinational pain registry, PAIN OUT, to: (1) characterize patient subgroups based on preexisting chronic breast pain status and (2) determine the association of preexisting chronic pain with acute postoperative pain-related patient-reported outcomes and opioid consumption following breast cancer surgery. The primary outcome was a composite score comprising the mean of pain intensity and pain interference items from the International Pain Outcomes Questionnaire. The secondary outcome was opioid consumption in the recovery room and ward. Among 1889 patients, we characterized three subgroups: no preexisting chronic pain ( = 1600); chronic preexisting pain elsewhere ( = 128) and; chronic preexisting pain in the breast with/without pain elsewhere ( = 161). Controlling for covariates, women with preexisting chronic breast pain experienced more severe acute postoperative pain and pain interference (β = 1.0, 95% CI = 0.7-1.3, < 0.001), and required higher doses of opioids postoperatively (β = 2.7, 95% CI = 0.6-4.8, = 0.013). Preexisting chronic breast pain may be an important risk factor for poor pain-related postoperative outcomes. Targeted intervention of this subgroup may improve recovery.
Learn More >Fatigue is a cardinal symptom in fibromyalgia. Fatigue is assumed to be the result of genetic susceptibility and environmental factors. We aimed at examining the role of genetic susceptibility for fatigue in southern Spanish women with fibromyalgia, by looking at single nucleotide polymorphisms in 34 fibromyalgia candidate-genes, at the interactions between genes, and at the gene-physical activity interactions. We extracted DNA from saliva of 276 fibromyalgia women to analyze gene-polymorphisms. Accelerometers registered physical activity and sedentary behavior. Fatigue was assessed with the Multidimensional Fatigue Inventory. Based on the Bonferroni's and False Discovery Rate values, we found that the genotype of the rs4453709 polymorphism (sodium channel protein type 9 subunit alpha, , gene) was related to reduced motivation (AT carriers showed the highest reduced motivation) and reduced activity (AA carriers showed the lowest reduced activity). Carriers of the heterozygous genotype of the rs1801133 (methylene tetrahydrofolate reductase, , gene) or rs4597545 ( gene) polymorphisms who were physically active reported lower scores on fatigue compared to their inactive counterparts. Highly sedentary carriers of the homozygous genotype of the rs7607967 polymorphism (AA/GG genotype; gene) presented more reduced activity (a dimension of fatigue) than those with lower levels of sedentary behavior. Collectively, findings from the present study suggest that the contribution of genetics and gene-physical activity interaction to fatigue in fibromyalgia is modest.
Learn More >(1) Background: Research has shown that thoughts about pain are important for the management of chronic pain in children. In order to monitor changes in thoughts about pain over time and evaluate the efficacy of treatments, we need valid and reliable measures. The aims of this study were to develop a questionnaire to assess a child's concept of pain and to evaluate its psychometric properties; (2) Methods: This is a cross-sectional, two-phase, mixed-method study. A total of 324 individuals aged 8 to 17 years old responded to the newly created questionnaire. The Conceptualization of Pain Questionnaire (COPAQ) was calibrated using the Rasch model. The chi-square test was used for the fit statistics. Underfit and overfit of the model were determined and a descriptive analysis of infit and outfit was conducted to identify who responded erratically. Internal consistency was measured using the Person Separation Index (PSI); (3) Results: Fit to the Rasch model was good. Suitable targeting indicated which items were simple to answer; Person Fit identified 9.56% children who responded erratically; PSI = 0.814; (4) Conclusions: The findings suggest that COPAQ is a measure of a child's concept of pain that is easy to administer and respond to. It has a good fit and a good internal consistency.
Learn More >The digital transformation of healthcare is advancing, leading to an increasing availability of clinical data for research. Perioperative big data initiatives were established to monitor treatment quality and benchmark outcomes. However, big data analyses have long exceeded the status of pure quality surveillance instruments. Large retrospective studies nowadays often represent the first approach to new questions in clinical research and pave the way for more expensive and resource intensive prospective trials. As a consequence, the utilization of big data in acute pain and regional anesthesia research has considerably increased over the last decade. Multicentric clinical registries and administrative databases (e.g., healthcare claims databases) have collected millions of cases until today, on which basis several important research questions were approached. In acute pain research, big data was used to assess postoperative pain outcomes, opioid utilization, and the efficiency of multimodal pain management strategies. In regional anesthesia, adverse events and potential benefits of regional anesthesia on postoperative morbidity and mortality were evaluated. This article provides a narrative review on the growing importance of big data for research in acute postoperative pain and regional anesthesia.
Learn More >The mechanism of pain chronicity is largely unknown in lumbar radiculopathy (LR). The anatomical location of nerve injury is one of the important factors associated with pain chronicity of LR. Accumulating evidence has shown constriction distal to the dorsal root ganglion (DRG) caused more severe radiculopathy than constriction proximal to the DRG; thereby, the mechanism of pain chronicity in LR could be revealed by comparing the differences in pathological changes of DRGs between nerve constriction distal and proximal to the DRG. Here, we used 2 rat models of LR with nerve constriction distal or proximal to the DRG to probe how the different nerve injury sites could differentially affect pain chronicity and the pathological changes of DRG neuron subpopulations. As expected, rats with nerve constriction distal to the DRG showed more persistent pain behaviors than those with nerve constriction proximal to the DRG in 50% paw withdraw threshold, weight-bearing test, and acetone test. One day after the operation, distal and proximal nerve constriction showed differential pathological changes of DRG. The ratios of activating transcription factor3 (ATF3)-positive DRG neurons were significantly higher in rats with nerve constriction distal to DRG than those with nerve constriction proximal to DRG. In subpopulation analysis, the ratios of ATF3-immunoreactivity (IR) in neurofilament heavy chain (NFH)-positive DRG neurons significantly increased in distal nerve constriction compared to proximal nerve constriction; although, both distal and proximal nerve constriction presented increased ratios of ATF3-IR in calcitonin gene-related peptide (CGRP)-positive DRG neurons. Moreover, the nerve constriction proximal to DRG caused more hypoxia than did that distal to DRG. Together, ATF3 expression in NHF-positive DRG neurons at the acute stage is a potential bio-signature of persistent pain in rat models of LR.
Learn More >The opioid epidemic is a major public health issue in the United States. Exposure of opioid naïve-patients to opioids in the perioperative period is a well-documented source of continued use with one in 20 opioid-naïve surgical patients continuing to use opioids beyond 90 days. There is no association with magnitude of surgery, major versus minor, and the strongest predictor of continued use is surgical exposure. Causal factors include over reliance on opioids for intraoperative and postoperative analgesia and excessive ambulatory opioid prescribing. Opioid-induced hyperalgesia can paradoxically result from intraoperative (anesthesia controlled) opioid administration. Increasing size of initial prescription is a strong predictor of continued use necessitating procedure specific supplies limited to under 3-days. Alternative multimodal pain management (non-opioid medications and regional anesthesia) that limit opioid use must be a high priority with opioids reserved for severe breakthrough pain. Barriers to implementation of opioid-sparing pathways include reluctance to adopt protocols and apprehension about opioid elimination. Considering the number of surgeries performed annually in the United States, perioperative physicians must aggressively address modifiable factors in surgical patients. Patient care pathways need to be constructed collaboratively by surgeons and anesthesiologists with continuing feedback to optimize patient outcomes including iatrogenic opioid dependence.
Learn More >The neuromodulator calcitonin gene-related peptide (CGRP) is known to facilitate nociceptive transmission in the superficial laminae of the spinal trigeminal nucleus caudalis (Sp5C). The central effects of CGRP in the Sp5C are very likely to contribute to the activation of central nociceptive pathways leading to attacks of severe headaches like migraine. To examine the potential impacts of CGRP on laminae I/II neurons at cellular and synaptic levels, we performed whole-cell patch-clamp recordings in juvenile mouse brainstem slices. First, we tested the effect of CGRP on cell excitability, focusing on neurons with tonically firing action potentials upon depolarizing current injection. CGRP (100 nM) enhanced tonic discharges together with membrane depolarization, an excitatory effect that was significantly reduced when the fast synaptic transmissions were pharmacologically blocked. However, CGRP at 500 nM was capable of exciting the functionally isolated cells, in a nifedipine-sensitive manner, indicating its direct effect on membrane intrinsic properties. In voltage-clamped cells, 100 nM CGRP effectively increased the frequency of excitatory synaptic inputs, suggesting its preferential presynaptic effect. Both CGRP-induced changes in cell excitability and synaptic drives were prevented by the CGRP receptor inhibitor BIBN 4096BS. Our data provide evidence that CGRP increases neuronal activity in Sp5C superficial laminae by dose-dependently promoting excitatory synaptic drive and directly enhancing cell intrinsic properties. We propose that the combination of such pre- and postsynaptic actions of CGRP might underlie its facilitation in nociceptive transmission in situations like migraine with elevated CGRP levels.
Learn More >: Pain is a multidimensional phenomenon with a wide range regarding the location, intensity and quality. Patients with chronic pain, in particular those suffering from mixed pain, often present a special challenge. The PainDETECT questionnaire (PD-Q) is a screening instrument designed to classify whether a patient has neuropathic pain (NP), often rated as more distressing compared to nociceptive pain. The objective of this study was to investigate whether the PD-Q score correlates with pain intensity, measured with the numeric rating scale (NRS), in chronic pain patients in an outpatient setting. : A questionnaire-based study was conducted to identify the associations between the unidimensional NRS scale for pain intensity and the PD-Q score for screening of an NP component in an outpatient setting. Participants were asked to fill in the questionnaire themselves. : One hundred seventy-six participants completed the PD-Q questionnaire and rated pain on the NRS scale at the baseline visit. The PD-Q and NRS scores significantly correlated at the baseline visit and the 1-month follow-up visit in chronic pain patients. The identification of a neuropathic component in chronic pain may permit more targeted and effective pain management. : The findings of our questionnaire suggest that a significant proportion of chronic pain patients had manifested features of NP at the first visit to the outpatient clinic. The PD-Q is a useful screening tool to alert clinicians of NP that may need further diagnostic evaluation or therapeutic intervention and may also help to predict treatment response. Further research is needed to investigate if a correlation is predictive of treatment response when pain therapy targets NP.
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