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Little is known about the evidence required by the U.S. Food and Drug Administration (FDA) for new approvals of opioid analgesics.
Learn More >The gut microbiome has been implicated in multiple human chronic gastrointestinal (GI) disorders. Determining its mechanistic role in disease has been difficult due to apparent disconnects between animal and human studies and lack of an integrated multi-omics view of disease-specific physiological changes. We integrated longitudinal multi-omics data from the gut microbiome, metabolome, host epigenome, and transcriptome in the context of irritable bowel syndrome (IBS) host physiology. We identified IBS subtype-specific and symptom-related variation in microbial composition and function. A subset of identified changes in microbial metabolites correspond to host physiological mechanisms that are relevant to IBS. By integrating multiple data layers, we identified purine metabolism as a novel host-microbial metabolic pathway in IBS with translational potential. Our study highlights the importance of longitudinal sampling and integrating complementary multi-omics data to identify functional mechanisms that can serve as therapeutic targets in a comprehensive treatment strategy for chronic GI diseases. VIDEO ABSTRACT.
Learn More >Mobile health (mHealth) apps have the potential to enhance pain management through the use of daily diaries, medication and appointment reminders, education, and facilitating communication between patients and providers. Although many pain management apps exist, the extent to which these apps utilize evidence-based behavior change techniques (BCTs) remains largely unknown, making it nearly impossible for providers to recommend apps with evidence-based strategies. The present study systematically evaluated commercially available pain management apps for evidence-based BCTs and app quality. Pain management apps were identified using the search terms "pain" and "pain management" in the App and Google Play Stores. Reviewed apps were specific to pain management, in English, for patients, and free. A total of 28 apps were coded using the taxonomy of BCTs. App quality was assessed using the Mobile App Rating Scale (MARS). Apps included 2-15 BCTs (M=7.36) and 1-8 (M=4.21) pain management specific BCTs. Prompt intention formation, instruction, behavioral-health link, consequences, feedback, and self-monitoring were the most common BCTs used in the reviewed apps. App quality from the MARS ranged from 2.27-4.54 (M=3.65) out of a possible 5 with higher scores indicating better quality. PainScale followed by Migraine Buddy demonstrated the highest number of overall and pain management BCTs as well as good quality scores. Although existing apps should be assessed through RCTs and future apps should include capabilities for electronic medical record integration, current pain management apps often use evidence-based pain management BCTs.
Learn More >Under some conditions, people persist in their attempts to control their pain even when no such control is possible. Theory suggests that such pain-control attempts arise from actual pain experiences. Across three experiments we examined how (a) losing control over pain and (b) instructions concerning pain, moderate pain-control attempts. In each experiment, participants completed a learning task. Before the task, one group of participants received instructions outlining a strategy via which they could control pain, whereas another group had to develop such a strategy via trial-and-error learning. During the first half of the task, the pain-control instructions allowed participants to successfully control pain, while during the second half of the task, this was no longer the case. Instead, participants lost control over pain due to an unannounced change in the learning task. Results indicate that when participants lost control over pain, they generally stuck to the previously effective pain-control strategy, and that this tendency was larger if they received instructions from others than when they developed a strategy by themselves. These findings suggest that when pain is no longer controllable, very persistent pain-control attempts might be the result of adherence to previously effective pain-control instructions.
Learn More >Fibromyalgia (FM) is characterized by widespread chronic pain, fatigue, and somatic symptoms. The influence of phenotypic changes in monocytes on symptoms associated with FM are not fully understood. The primary aim of this study was to take a comprehensive whole-body to molecular approach in characterizing relationships between monocyte phenotype and FM symptoms in relevant clinical populations. LPS-evoked and spontaneous secretion of IL-5 and other select cytokines from circulating monocytes was higher in women with FM compared to women without pain. Additionally, greater secretion of IL-5 was significantly associated with pain and other clinically relevant psychological and somatic symptoms of FM. Further, higher levels of pain and pain-related symptoms were associated with a lower percentage of intermediate monocytes (CD14/CD16) and a greater percentage of non-classical monocytes (CD14/CD16) in women with FM. Based on findings from individuals with FM, we examined the role of IL-5, an atypical cytokine secreted from monocytes, in an animal model of widespread muscle pain. Results from the animal model show that IL-5 produces analgesia and polarizes monocytes toward an anti-inflammatory phenotype (CD206). Taken together, our data suggest that monocyte phenotype and their cytokine profiles are associated with pain-related symptoms in individuals with FM. Furthermore, our data show that IL-5 has a potential role in analgesia in an animal model of FM. Thus, targeting anti-inflammatory cytokines such as IL-5 in secreted by circulating leukocytes could serve as a promising intervention to control pain and other somatic symptoms associated with FM.
Learn More >Development and characterization of a novel injury-free preclinical model of migraine-like pain allowing mechanistic assessment of both acute and preventive treatments.
Learn More >Neuropathy is a common complication of long-term diabetes that impairs quality of life by producing pain, sensory loss and limb amputation. The presence of neuropathy in both insulin-deficient (type 1) and insulin resistant (type 2) diabetes along with the slowing of progression of neuropathy by improved glycemic control in type 1 diabetes has caused the majority of preclinical and clinical investigations to focus on hyperglycemia as the initiating pathogenic lesion. Studies in animal models of diabetes have identified multiple plausible mechanisms of glucotoxicity to the nervous system including post-translational modification of proteins by glucose and increased glucose metabolism by aldose reductase, glycolysis and other catabolic pathways. However, it is becoming increasingly apparent that factors not necessarily downstream of hyperglycemia can also contribute to the incidence, progression and severity of neuropathy and neuropathic pain. For example, peripheral nerve contains insulin receptors that transduce the neurotrophic and neurosupportive properties of insulin, independent of systemic glucose regulation, while the detection of neuropathy and neuropathic pain in patients with metabolic syndrome and failure of improved glycemic control to protect against neuropathy in cohorts of type 2 diabetic patients has placed a focus on the pathogenic role of dyslipidemia. This review provides an overview of current understanding of potential initiating lesions for diabetic neuropathy and the multiple downstream mechanisms identified in cell and animal models of diabetes that may contribute to the pathogenesis of diabetic neuropathy and neuropathic pain.
Learn More >Adhesion-type GPCRs (aGPCRs) participate in a vast range of physiological processes. Their frequent association with mechanosensitive functions suggests that processing of mechanical stimuli may be a common feature of this receptor family. Previously, we reported that the aGPCR CIRL sensitizes sensory responses to gentle touch and sound by amplifying signal transduction in low-threshold mechanoreceptors (Scholz et al., 2017). Here, we show that is also expressed in high-threshold mechanical nociceptors where it adjusts nocifensive behaviour under physiological and pathological conditions. Optogenetic experiments indicate that CIRL lowers cAMP levels in both mechanosensory submodalities. However, contrasting its role in touch-sensitive neurons, CIRL dampens the response of nociceptors to mechanical stimulation. Consistent with this finding, rat nociceptors display decreased expression during allodynia. Thus, cAMP-downregulation by CIRL exerts opposing effects on low-threshold mechanosensors and high-threshold nociceptors. This intriguing bipolar action facilitates the separation of mechanosensory signals carrying different physiological information.
Learn More >Pain sensation is powerfully modulated by signal processing in the brain, and pain becomes chronic with the dysfunction of the pain modulatory system; however, the underlying mechanisms are unclear. We found that the metabotropic glutamate receptor 5 (mGluR5) in the periaqueductal gray (PAG), the key area of endogenous pain modulation, is persistently active in normal conditions to maintain an appropriate sensory perception. In the neuropathic pain condition, Homer1a, an activity-dependent immediate early gene product, disrupted the persistent mGluR5 activity resulting in chronic pain. Remarkably a single-time blockage of the mGluR5 resulted in chronic neuropathic pain-like symptoms even in the absence of nerve injury. The decline of mGluR5 activity induced the pain modulatory dysfunction with a profound reduction of excitability of PAG neurons. These findings uncover the role of the persistent mGluR5 activity in vivo and provide new insight into how pain becomes chronic with the maladaptive coping of the PAG to pain sensation.
Learn More >Chronic pain treatment remains a sore challenge, and in our aging society, the number of patients reporting inadequate pain relief continues to grow. Current treatment options all have their drawbacks, including limited efficacy and the propensity of abuse and addiction; the latter is exemplified by the ongoing opioid crisis. Extensive research in the last few decades has focused on mechanisms underlying chronic pain states, thereby producing attractive opportunities for novel, effective and safe pharmaceutical interventions. Members of the transient receptor potential (TRP) ion channel family represent innovative targets to tackle pain sensation at the root. Three TRP channels, TRPV1, TRPM3, and TRPA1, are of particular interest, as they were identified as sensors of chemical- and heat-induced pain in nociceptor neurons. This review summarizes the knowledge regarding TRP channel-based pain therapies, including the bumpy road of the clinical development of TRPV1 antagonists, the current status of TRPA1 antagonists, and the future potential of targeting TRPM3. Expected final online publication date for the , Volume 61 is January 7, 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
Learn More >The adult K/BxN transgenic mouse develops spontaneous autoimmune arthritis with joint remodeling and profound bone loss. We report that both males and females display a severe sustained tactile allodynia which is reduced by gabapentin but not the potent cyclooxygenase inhibitor ketorolac. In dorsal horn, males and females show increased GFAP astrocytic cells; however, only males demonstrate an increase in Iba1 microglia. In dorsal root ganglia (DRG), there is an increase in CGRP, TH, and Iba1 (macrophage) labeling, but no increase in ATF3 cells. At the ankle there is increased CGRP, TH, and GAP-43 fiber synovial innervation. Thus, based on the changes in dorsal horn, DRG and peripheral innervation, we suggest that the adult K/BxN transgenic arthritic mice display a neuropathic phenotype, an assertion consistent with the analgesic pharmacology seen in this animal. These results indicate the relevance of this model to our understanding of the nociceptive processing which underlies the chronic pain state that evolves secondary to persistent joint inflammation.
Learn More >To use an animal model of migraine to test whether migraine headache might arise from a brainstem-trigeminal nucleus pathway.
Learn More >Neuroinflammation and periphery-to-CNS neuroimmune cross-talk in patients with painful knee osteoarthritis (OA) are poorly understood. We utilized proximity extension assay to measure the level of 91 inflammatory proteins in CSF and serum from OA patients and controls. The patients had elevated levels of 48 proteins in CSF indicating neuroinflammation. Ten proteins were correlated between CSF and serum and potentially involved in periphery-to-CNS neuroimmune cross-talk. Seven CSF proteins, all with previously reported neuroprotective effects, were associated with lower pain intensity and milder knee-related symptoms. Our findings indicate that neuroinflammation in OA could be protective and associated with less severe symptoms.
Learn More >Vulvodynia is a prevalent chronic vulval pain condition affecting 10-28% of women, and significantly impacting their health and quality of life. It is currently poorly understood and biomedical treatments achieve only modest benefits for pain and sexual functioning. A wider psychosocial conceptualization of this condition may improve outcomes. There is currently no coherent understanding of how psychosocial factors may contribute to outcomes in Vulvodynia. The aim of this review is to identify and systematically review psychosocial factors associated with pain and sexual outcomes and to inform a psychosocial model of Vulvodynia.
Learn More >To characterize psychologic functioning across five chronic overlapping pain conditions (COPCs)-temporomandibular disorders, fibromyalgia, low back pain, headache, and irritable bowel syndrome-and their overlaps.
Learn More >To quantify the contributions of atopic disorders, sleep disturbance, and other health conditions to five common pain conditions.
Learn More >To investigate whether TMD-related characteristics are indeed specific to TMD or whether they are also associated with other chronic overlapping pain conditions (COPCs).
Learn More >To investigate associations between experimental pain sensitivity and five chronic pain conditions among 655 participants in the OPPERA study.
Learn More >Opioids form an important component of general anesthesia and perioperative analgesia. Discharge opioid prescriptions are identified as a contributor for persistent opioid use and diversion. In parallel, there is increased enthusiasm to advocate opioid-free strategies, which include a combination of known analgesics and adjuvants, many of which are in the form of continuous infusions. This article critically reviews perioperative opioid use, especially in view of opioid-sparing versus opioid-free strategies. The data indicate that opioid-free strategies, however noble in their cause, do not fully acknowledge the limitations and gaps within the existing evidence and clinical practice considerations. Moreover, they do not allow analgesic titration based on patient needs; are unclear about optimal components and their role in different surgical settings and perioperative phases; and do not serve to decrease the risk of persistent opioid use, thereby distracting us from optimizing pain and minimizing realistic long-term harms.
Learn More >Physical therapy visit number and timing following knee arthroplasty (KA) are variable in daily practice. The extent to which the number and timing of physical therapy visits are associated with current and future pain and function-and, alternatively, whether pain and function are associated with the number of future physical therapy visits following KA-are unknown. The purpose of this study was to determine temporal and reciprocal associations between the number of physical therapy visits and future pain and function in people with KA.
Learn More >Neuropathic pain is a debilitating secondary condition for many individuals with spinal cord injury. Spinal cord injury neuropathic pain often is poorly responsive to existing pharmacological and nonpharmacological treatments. A growing body of evidence supports the potential for brain-computer interface systems to reduce spinal cord injury neuropathic pain via electroencephalographic neurofeedback. However, further studies are needed to provide more definitive evidence regarding the effectiveness of this intervention.
Learn More >Recent guidance from the US Immigration and Customs Enforcement drastically altered the lives of international students in America, especially those who are matriculating. This commentary describes how international students still face uncertainty concerning their visa statuses and their place in American society.
Learn More >To compare different exercise prescriptions for patients with chronic pain along the continuum of nociplastic pain: fibromyalgia, chronic whiplash-associated disorders (CWAD), and chronic idiopathic neck pain (CINP).
Learn More >To describe the pain characteristics of five index chronic overlapping pain conditions (COPCs) and to assess each COPC separately in order to determine whether the presence of comorbid COPCs is associated with bodily pain distribution, pain intensity, pain interference, and high-impact pain of the index COPC.
Learn More >To assess cohort retention in the OPPERA project and to compare the degree of overlap between pairs of chronic overlapping pain conditions (COPCs) using a cross-sectional analysis of data from 655 adults who completed follow-up in the OPPERA study.
Learn More >Pain is a fundamental feature of inflammation. The immune system plays a critical role in the activation of sensory neurons and there is increasing evidence of neuro-inflammatory mechanisms contributing to painful pathologies. The inflammasomes are signaling multiprotein complexes that are key components of the innate immune system. They are intimately involved in inflammatory responses and their activation leads to production of inflammatory cytokines that in turn can affect sensory neuron function. Accordingly, the contribution of inflammasome activation to pain signaling has attracted considerable attention in recent years. NLRP3 is the best characterized inflammasome and there is emerging evidence of its role in a variety of inflammatory pain conditions. In vitro and in vivo studies have reported the activation and upregulation of NLRP3 in painful conditions including gout and rheumatoid arthritis, while inhibition of NLRP3 function or expression can mediate analgesia. In this review, we discuss painful conditions in which NLRP3 inflammasome signaling has been pathophysiologically implicated, as well as NLRP3 inflammasome-mediated mechanisms and signaling pathways that may lead to the activation of sensory neurons.
Learn More >Neuropathic pain is a common complication of diabetes with high morbidity and poor treatment outcomes. Accumulating evidence suggests the immune system is involved in the development of diabetic neuropathy, whilst neuro-immune interactions involving the kynurenine (KYN) and tetrahydrobiopterin (BH4) pathways have been linked to neuropathic pain pre-clinically and in several chronic pain conditions. Here, using a multiplex assay, we quantified serum levels of 14 cytokines in 21 participants with type 1 diabetes mellitus, 13 of which were classified as having neuropathic pain. In addition, using high performance liquid chromatography and gas chromatography-mass spectrometry, all major KYN and BH4 pathway metabolites were quantified in serum from the same cohort. Our results show increases in GM-CSF and IL-8, suggesting immune cell involvement. We demonstrated increases in two inflammatory biomarkers: neopterin and the KYN/TRP ratio, a marker of indoleamine 2,3-dioxygenase activity. Moreover, the KYN/TRP ratio positively correlated with pain intensity. Total kynurenine aminotransferase activity was also higher in the diabetic neuropathic pain group, indicating there may be increased production of the KYN metabolite, xanthurenic acid. Overall, this study supports the idea that inflammatory activation of the KYN and BH4 pathways occurs due to elevated inflammatory cytokines, which might be involved in the pathogenesis of neuropathic pain in type 1 diabetes mellitus. Further studies should be carried out to investigate the role of KYN and BH4 pathways, which could strengthen the case for therapeutically targeting them in neuropathic pain conditions.
Learn More >We aimed at evaluating the differential involvement of large myelinated Aβ-fibers, small myelinated Aδ- and unmyelinated C-fibers in patients with diabetic polyneuropathy and how they contribute to neuropathic pain.
Learn More >DTB drug reviews provide an overview of medicines that have been recently launched in the UK. The articles include a summary of the evidence of benefits and harms as well as details of the regulatory authority's assessment report.
Learn More >Oral β-blockers used for the prevention of migraine headache are not effective for the treatment of acute pain. Small case series have suggested that topically applied β-blockers may be useful in the management of acute migraine pain, warranting evaluation with randomized clinical trials.
Learn More >Dexamethasone is a drug used to prolong the postoperative analgesia in children after peripheral nerve blockade, although the dose usually used (0.2 mg/kg) has not been studied yet. This study is a monocentric, prospective, randomised, placebo-controlled, double-blinded study in a university hospital in France. The primary objective of the study is to evaluate the efficacy of 0.2 mg/kg intravenous dexamethasone on early postoperative pain in children aged 6-15 years, who require a lower limb peripheral nerve block following general anaesthesia.
Learn More >The purpose of this paper is to review and synthesize current literature in which neurochemical and structural brain imaging were used to investigate chronic migraine (CM) pathophysiology and to further discuss the clinical implications.
Learn More >Pain is one of the most disabling symptoms in multiple sclerosis. Chronic pain in multiple sclerosis is often neuropathic in nature, although a clear-cut distinction with nociceptive pain is not easy.
Learn More >Cyclooxygenase-2 (COX-2) is known to be involved in the pathogenesis of migraine, and some polymorphisms are known to affect the expression of COX-2. This retrospective case-control study aimed to explore the associations between the -765 G>C (rs20417), -1759 G>A (rs3218625), and -8473 C>T (rs5275) COX-2 polymorphisms and migraine in Chinese Han individuals. One hundred and ten unrelated Han Chinese patients with migraine and 108 healthy controls were recruited between 03/2014 and 08/2016 at the First Affiliated Hospital of Nanjing Medical University and the First People's Hospital of Lianyungang City. The genotypes of all polymorphisms in controls followed the Hardy-Weinberg equilibrium (P = 0.215, P = 0.884, and P = 0.689). There were differences in the genotype and allele distributions of the COX-2-1759G>A (Gly587Arg) polymorphism between the migraine and control groups (P = 0.038 and P = 0.040, respectively). Compared with the COX-2-1759AG genotype, GG genotype carriers had an increased risk of migraine (odds ratio (OR) = 8.720, 95% confidence interval (CI): 1.072-70.960, P = 0.038). The frequency of the COX-2-1759A allele in patients with migraine was significantly lower than the controls (OR = 0.119, 95%CI: 0.015-0.957, P = 0.040). Adjusted age and sex, a statistical difference was found in the dominant model of COX-2-1759 G>A (OR = 0.118, 95% CI 0.014 to 0.962, P = 0.046). No significant difference was detected regarding the -765G>C and -8473T>C polymorphisms between the two groups. The COX-2 1759A allele might be involved in the development of migraine in Chinese Han individuals, but this will have to be confirmed in large-scale studies.
Learn More >The purpose of the present systematic review is to provide a current understanding of the mechanism of action and the evidence available to support clinical decision-making. The focus is to summarize randomized controlled trials (RCTs) and nonrandomized or observational studies of spinal cord stimulation in chronic pain to understand clinical effectiveness and the mechanism of action.
Learn More >Orofacial pain or tenderness is a primary symptom associated with temporomandibular joint (TMJ) disorders (TMDs). To understand the pathological mechanisms underlying TMDs, several mouse models have been developed, including mechanical stimulus-induced TMD and genetic mouse models. However, a lack of feasible approaches for assessing TMD-related nociceptive behaviours in the orofacial region of mice has hindered the in-depth study of TMD-associated mechanisms. This study aimed to explore modifications of three existing methods to analyse nociceptive behaviours using two TMD mouse models: (1) mechanical allodynia was tested using von Frey filaments in the mouse TMJ region by placing mice in specially designed chambers; (2) bite force was measured using the Economical Load and Force (ELF) system; and (3) spontaneous feeding behaviour tests, including eating duration and frequency, were analysed using the Laboratory Animal Behaviour Observation Registration and Analysis System (LABORAS). We successfully assessed changes in nociceptive behaviours in two TMD mouse models, a unilateral anterior crossbite (UAC)-induced TMD mouse model and a β-catenin conditional activation mouse model. We found that the UAC model and β-catenin conditional activation mouse model were significantly associated with signs of increased mechanical allodynia, lower bite force, and decreased spontaneous feeding behaviour, indicating manifestations of TMD. These behavioural changes were consistent with the cartilage degradation phenotype observed in these mouse models. Our studies have shown reliable methods to analyse nociceptive behaviours in mice and may indicate that these methods are valid to assess signs of TMD in mice.
Learn More >The U.S. Department of Veterans Affairs (VA) has been training clinicians in its cognitive behavioral therapy for chronic pain (CBT-CP) structured protocol since 2012. The aim of this project was to review patient outcomes to determine the effectiveness of the VA's CBT-CP treatment. From 2012-2018, 1,331 Veterans initiated individual CBT-CP treatment as part of the training program. Patient outcomes were assessed with measures of patient-reported pain intensity, pain catastrophizing, depression, pain interference, and quality of life (physical, psychological, social, and environmental). Mixed models of the effects of time indicated significant changes across pretreatment, midtreatment, and treatment conclusion on all outcomes. There was a large effect size (Cohen's d = 0.78) for pain catastrophizing, and there were medium to large effect sizes ( > 0.60) for worst pain intensity, pain interference, depression, and physical quality of life. Systematic training of therapists and implementation of the VA's CBT-CP protocol yielded significant patient improvements across multiple domains. This offers strong support for the VA's CBT-CP as an effective, safe treatment for Veterans with chronic pain and highlights it as a model to increase the availability of training in standardized, pain-focused, evidence-based, behavioral interventions. The findings suggest that the broad dissemination of such training, including in routine, nonpain specialty settings, would improve patient access to effective, nonpharmacological treatment options in both the public and private sectors. (PsycInfo Database Record (c) 2020 APA, all rights reserved).
Learn More >Altered Gut Microbiota Composition Is Associated With Back Pain in Overweight and Obese Individuals.
Back pain is the leading cause of disability worldwide and is associated with obesity and chronic low-grade inflammation. Alterations in intestinal microbiota may contribute to the pathogenesis of back pain through metabolites affecting immune and inflammatory responses. We compared the gut microbiota composition in a cohort of 36 overweight or obese individuals with or without self-reported back pain in the preceding month. Participants were characterized for anthropometry; bone health; metabolic health; inflammation; dietary intake; and physical activity. Demographic, clinical, biochemical characteristics, diet and physical activity were similar between participants with ( = 14) or without ( = 22) back pain. Individuals with back pain had a higher abundance of the genera ( = 0.0008; FDR = 0.027) ( = 0.0098; FDR = 0.17), and ( = 0.02; FDR = 0.27) than those without back pain. abundance remained higher in individuals with back pain in the past 2 weeks, 6 months, and 1 year. was positively correlated with BMI (rho = 0.35, = 0.03), serum adipsin (rho = 0.33, = 0.047), and serum leptin (rho = 0.38, = 0.02). Our findings suggest that back pain is associated with altered gut microbiota composition, possibly through increased inflammation. Further studies delineating the underlying mechanisms may identify strategies for lowering abundance to treat back pain.
Learn More >Capsaicin is an agonist of transient receptor potential cation channel subfamily V member 1 (TRPV1). Strong TRPV1 stimulation with capsaicin causes mitochondrial damage in primary sensory neurons. However, the effect of repetitive and moderate exposure to capsaicin on the integrity of neuronal mitochondria remains largely unknown. Our electron microscopic analysis revealed that repetitive stimulation of the facial skin of mice with 10 mM capsaicin induced short-term damage to the mitochondria in small-sized trigeminal ganglion neurons. Further, capsaicin-treated mice exhibited decreased sensitivity to noxious heat stimulation, indicating TRPV1 dysfunction, in parallel with the mitochondrial damage in the trigeminal ganglion neurons. To analyze the capsaicin-induced mitochondrial damage and its relevant cellular events in detail, we performed cell-based assays using TRPV1-expressing PC12 cells. Dose-dependent capsaicin-mediated mitochondrial toxicity was observed. High doses of capsaicin caused rapid destruction of mitochondrial internal structure, while low doses induced mitochondrial swelling. Further, capsaicin induced a dose-dependent loss of mitochondria and autophagy-mediated degradation of mitochondria (mitophagy). Concomitantly, transcriptional upregulation of mitochondrial proteins, cytochrome oxidase subunit IV, Mic60/Mitofilin, and voltage-dependent anion channel 1 was observed, which implied induction of mitochondrial biogenesis to compensate for the loss of mitochondria. Collectively, although trigeminal ganglion neurons transiently exhibit mitochondrial damage and TRPV1 dysfunction following moderate capsaicin exposure, they appear to be resilient to such a challenge. Our data show a dose-response relationship in capsaicin-mediated mitochondrial toxicity. We postulate that induction of mitophagy and mitochondrial biogenesis in response to capsaicin stimulation play important roles in repairing the damaged mitochondrial system.
Learn More >The exposure of the nucleus pulposus (NP) causes an immune and inflammatory response, which is intrinsically linked to the pathogenesis of radicular pain. As a newly discovered pro-resolving lipid mediator, maresin 1 (MaR1) could exert powerful inflammatory resolution, neuroprotection, and analgesic activities. In the present research, the analgesic effect of MaR1 was observed. Then, the potential mechanism by which MaR1 attenuated radicular pain was also analyzed in a rat model.
Learn More >Apelin is the endogenous ligand for APJ, a G-protein-coupled receptor. Apelin gene and protein are widely distributed in the central nervous system and peripheral tissues. The role of apelin in chronic inflammatory pain is still unclear. In the present study, a mouse model of complete Freund's adjuvant (CFA)-induced inflammatory pain was utilized, and the paw withdrawal latency/threshold in response to thermal stimulation and Von Frey filament stimulation were recorded after intrathecal (i.t.) injection of apelin-13 (0.1, 1, and 10 nmol/mouse). The mRNA and protein expression, concentration of glutamic acid (Glu), and number of c-Fos immunol staining in lumbar spinal cord (L4/5) were determined. The results demonstrated that gene expression in the lumbar spinal cord was down-regulated in the CFA pain model. Apelin-13 (10 nmol/mouse, i.t.) alleviated CFA-induced inflammatory pain, and it exhibited a more potent antinociceptive effect than apelin-36 and (pyr)apelin-13. The antinociception of apelin-13 could be blocked by APJ antagonist apelin-13(F13A). I.T. apelin-13 attenuated the increased levels of , , and genes expression, Glu concentration, and NMDA receptor 2B (GluN2B) protein expression caused by CFA. Apelin-13 significantly reduced the number of Fos-positive cells in laminae III and IV/V of the dorsal horn. This study indicated that i.t. apelin-13 exerted an analgesic effect against inflammatory pain, which was mediated by activation of APJ, and inhibition of Glu/GluN2B function and neural activity of the spinal dorsal horn.
Learn More >Use of triptans for acute treatment of migraine is associated with insufficient efficacy and/or tolerability in approximately 30-40% of people. We conducted a systematic literature review (SLR) to synthesize definitions, terminology, subsequent treatment outcomes, and characteristics associated with this subpopulation.
Learn More >Modulation of 5-HT3 receptor in the central nervous system (CNS) is a promising approach for treatment of neuropathic pain. The goal was to evaluate the role of P-glycoprotein (Pgp) in limiting exposure of different parts of the CNS to ondansetron (5-HT3 receptor antagonist) using wild-type and genetic knockout rat model.
Learn More >The CB R agonist AM1710, examined in animal models of peripheral neuropathy, is effective in controlling aberrant light touch sensitivity, referred to as mechanical allodynia. However, nonspecific binding of AM1710 to CB R, either peripherally or centrally, could be partially responsible for the analgesic effects of AM1710. Thus, we sought to determine in mice whether spinal (intrathecal; i.t.) or peripheral AM1710 administration could lead to anti-allodynia by reducing the protein expression of spinal and dorsal root ganglia (DRG) proinflammatory cytokines and elevating the anti-inflammatory cytokine interleukin-10 (IL-10) in the absence of CB R. Macrophage cell cultures were examined to characterize AM1710-mediated suppression of the proinflammatory cytokine tumor necrosis factor-alpha (TNF-α). Either i.p. or i.t. AM1710 reversed CCI-induced mechanical allodynia to sham levels in CB R (-/-), (+/-), (+/+) mice. CCI-induced neuropathy decreased IL-10 immunoreactivity (IR) in the dorsal root ganglia (DRG) and the dorsal horn of the spinal cord, with i.t. AM1710 restoring basal IL-10 IR. CCI-induced elevations in proinflammatory cytokine IR were decreased within the spinal cord only after i.t. AM1710 in all mouse genotypes. Meanwhile, within DRG tissue from neuropathic mice, proinflammatory cytokines were decreased following either i.p. or i.t. AM1710. Analysis of cultured supernatants revealed AM1710 decreased TNF-alpha protein. We conclude that CB R is dispensable for either peripheral or central anti-allodynic actions of AM1710 in neuropathic mice. Cannabinoid CB R agonists produce heightened spinal IL-10 which may be clinically relevant to successfully treat neuropathic pain.
Learn More >von Frey hairs are important tools for the study of mechanisms of cutaneous stimulation-induced sensory input. Mechanical force is exerted via application of a particular hair to the cutaneous receptive field until buckling of the hair occurs. The most commonly used von Frey filaments are productive in evaluating behavioral responses of neuropathic pain in preclinical and clinical research. To reduce the potential experimenter bias, automated instruments are being developed for behavioral assessment.
Learn More >Patch clamp is an electrophysiological technique that allows to analyze the activity of ion channels in neurons. In this chapter, we provide a detailed description of patch clamp protocol to measure the effect of a μ-opioid receptor agonist on the activity of G protein-coupled inwardly rectifying potassium (GIRK or Kir3) channels. This is performed in peripheral sensory neurons isolated from dorsal root ganglia (DRG) of mice without or with a chronic constriction injury (CCI) of the sciatic nerve, which models neuropathic pain. We describe the induction of the CCI , isolation and culture of DRG neurons, performance of the patch clamp recordings, and identification of opioid-responding neurons.
Learn More >Real-time quantitative reverse transcription-PCR (qRT-PCR ) is a highly sensitive molecular biology method based on the amplification of the cDNA of mRNA to detect and quantify the levels of mRNA of interest. In this chapter, we describe real-time qRT-PCR to detect and quantify mRNA of opioid receptors in immune cells. Specifically, we analyze mouse immune cells isolated from the blood and sciatic nerves exposed to a chronic constriction injury, which represents a model of neuropathic pain. We describe in detail the requirements and techniques to induce the chronic constriction injury, to isolate immune cells from the blood and injured nerves, to isolate the total RNA from immune cells, to perform a cDNA reverse transcription from the total RNA, and to perform real-time qRT-PCR for μ-, δ-, and κ-opioid receptor mRNAs.
Learn More >Chronic pain is more common among veterans than among the general population. Expert guidelines recommend multimodal chronic pain care. However, there is substantial variation in the availability and utilization of treatment modalities in the Veterans Health Administration. We explored health care providers' and administrators' perspectives on the barriers to and facilitators of multimodal chronic pain care in the Veterans Health Administration to understand variation in the use of multimodal pain treatment modalities.
Learn More >Acceptance and Commitment Therapy (ACT) is an empirically supported treatment for chronic pain in adults. There is also a small but growing evidence base of ACT for pediatric chronic pain. However, because of limited access to psychological treatment for pain, and geographical distances from pain facilities, many patients will not receive such treatment.
Learn More >The life altering nature of major limb amputations may be further complicated by neuroma formation in up to 60% of the estimated 2 million major limb amputees in the United States. This can be a source of pain and functional limitation of the residual limb. Pain associated with neuromas may limit prosthetic limb use, require reoperation, lead to opioid dependence, and dramatically reduce quality of life. A number of management options have been described including excision alone, excision with repair, excision with transposition, and targeted muscle reinnervation. Targeted muscle reinnervation has been shown to reduce phantom limb and neuroma pain for patients with upper and lower extremity amputations. It may be performed at the time of initial amputation to prevent pain development or secondarily for the treatment of established pain. Encouraging outcomes have been reported, and targeted muscle reinnervation is emerging as a leading surgical technique for pain prevention in patients undergoing major limb amputations and pain management in patients with pre-existing amputations.
Learn More >The "gepants" are a class of calcitonin gene-related peptide (CGRP) receptor antagonist molecules that have been developed for the prevention and treatment of migraine. Rimegepant is reported to act at the CGRP receptor, has good oral bioavailability, and has had positive clinical trial results. However, there is very little data available describing its receptor pharmacology. Importantly, rimegepant activity at the AMY receptor, a second potent CGRP receptor that is known to be expressed in the trigeminovascular system, has not been reported. The ability of rimegepant to antagonize activation of human CGRP, AMY, and related adrenomedullin receptors was determined in transfected in Cos7 cells. Rimegepant was an effective antagonist at both the CGRP and AMY receptor. The antagonism of both CGRP and AMY receptors may have implications for our understanding of the mechanism of action of rimegepant in the treatment of migraine.
Learn More >Entraining alpha activity with rhythmic visual, auditory, and electrical stimulation can reduce experimentally induced pain. However, evidence for alpha entrainment and pain reduction in patients with chronic pain is limited. This feasibility study investigated whether visual alpha stimulation can increase alpha power in patients with chronic musculoskeletal pain and, secondarily, if chronic pain was reduced following stimulation. In a within-subject design, 20 patients underwent 4-min periods of stimulation at 10 Hz (alpha), 7 Hz (high-theta, control), and 1 Hz (control) in a pseudo-randomized order. Patients underwent stimulation both sitting and standing and verbally rated their pain before and after each stimulation block on a 0-10 numerical rating scale. Global alpha power was significantly higher during 10 Hz compared to 1 Hz stimulation when patients were standing ( = -6.08, < 0.001). On a more regional level, a significant increase of alpha power was found for 10 Hz stimulation in the right-middle and left-posterior region when patients were sitting. With respect to our secondary aim, no significant reduction of pain intensity and unpleasantness was found. However, only the alpha stimulation resulted in a minimal clinically important difference in at least 50% of participants for pain intensity (50%) and unpleasantness ratings (65%) in the sitting condition. This study provides initial evidence for the potential of visual stimulation as a means to enhance alpha activity in patients with chronic musculoskeletal pain. The brief period of stimulation was insufficient to reduce chronic pain significantly. This study is the first to provide evidence that a brief period of visual stimulation at alpha frequency can significantly increase alpha power in patients with chronic musculoskeletal pain. A further larger study is warranted to investigate optimal dose and individual stimulation parameters to achieve pain relief in these patients.
Learn More >Pain is a usual and troublesome non-motor symptom of Parkinson's disease, with a prevalence of 29-82%. Therefore, it's vital to find pharmacological treatments for managing PD-associated pain symptoms, to improve patients' quality of life. For this reason, we tested the possible synergy between L-DOPA and celecoxib in decreasing allodynia and hyperalgesia induced by unilateral lesioning with 6-OHDA into the SNpc in rats. We also tested whether the antiallodynic and antihyperalgesic effect induced by combination of L-DOPA and celecoxib is mediated by the NO-cGMP-ATP-sensitive K channel pathway. Tactile allodynia and mechanical hyperalgesia were evaluated using von Frey filament. Isobolographic analyses were employed to define the nature of the drug interaction using a fixed dose ratio (0.5: 0.5). We found that acute and sub-acute (10-day) treatment with a single dose of L-DOPA (3-25 mg/kg, i. p.) or celecoxib (2.5-20 mg/kg, i. p.) induced a dose-dependent antiallodynic and antihyperalgesic effect in parkinsonian rats. Isobolographic analysis revealed that the ED values obtained by L-DOPA + celecoxib combination was significantly less than calculated additive values, indicating that co-administration of L-DOPA with celecoxib produces synergistic interactions in its antiallodynic and antihyperalgesic effect in animals with nigrostriatal lesions. Moreover, the antiallodynic and antihyperalgesic effects induced by L-DOPA + celecoxib combination were blocked by intrathecal pre-treatment with L-NAME, ODQ, and glibenclamide. Taken together, the data suggest that L-DOPA + celecoxib combination produces an antiallodynic and antihyperalgesic synergistic interaction at the systemic level, and these effects are mediated, at the central level, through activation of the NO-cGMP-ATP-sensitive K channel pathway.
Learn More >In chronic pain conditions, the pressure pain threshold (PPT) has been utilized to investigate the presence of central sensitization (CS).
Learn More >Previous studies suggest that immigration may influence the experience of pain.
Learn More >Tralokinumab, a fully human monoclonal antibody, specifically neutralizes interleukin-13, a key cytokine driving peripheral inflammation in atopic dermatitis (AD). In phase II studies, tralokinumab combined with topical corticosteroids provided early and sustained improvements in AD signs and symptoms.
Learn More >Breast cancer continues to be the most commonly diagnosed cancer among Canadian women, with as many as 25-60% of women suffering from chronic neuropathic pain (CNP) as a pervasive consequence of treatment. While pharmacological interventions have shown limited efficacy for the management of CNP to date, psychological interventions, such as mindfulness-based stress reduction (MBSR), may be a promising alterative for improving pain-related problems. The purpose of this study was to use brain imaging methods to investigate this potential.
Learn More >Mindfulness has been shown to be beneficial for chronic pain. The underlying mechanisms of the mindfulness-pain link, however, are yet to be established. Particularly, the effects of mindfulness on pain modulation, which is shown to be dysfunctional among chronic pain patients, barely has been tested. This study investigated whether a short mindful attention training based on Langerian mindfulness mitigates reductions in pain modulation.
Learn More >New daily persistent headache (NDPH) is a subset of chronic headache where the pain is continuous from onset. Phenotypically it has chronic migraine or chronic tension type features. NDPH is considered to be highly refractory. Occipital nerve stimulation (ONS) has been used for treatment of refractory chronic migraine but there are no specific reports of its use for NDPH with migrainous features.
Learn More >The objective of this study was to analyze health outcomes, resource utilization, and costs in osteoarthritis patients with chronic nociceptive pain who began treatment with an opioid in real-world practice in Spain.
Learn More >Today immersive environments such as Virtual Reality (VR) offer new opportunities for serious gaming in exercise therapy and psychoeducation. Chronic back pain (CBP) patients could benefit from exergames in VR. The requirements in older CBP patients for a VR pain therapy have not yet been determined in studies. The aim of the study was to perform a requirements analysis for the user group of geriatric patients with CBP for a VR exergame. The objective was to find out the expectations, desires, preferences and barriers in order to collect them as requirements for this vulnerable group and to determine frameworks of therapy by physiotherapists and psychotherapists.
Learn More >The prevalence and burden of musculoskeletal (MSK) conditions are growing around the world, and low back pain (LBP) is the most significant of the five defined MSK disorders in the Global Burden of Disease (GBD) study. LBP has been the leading cause of non-fatal health loss for the last three decades. The objective of this study is to describe the current status and trends of the burden due to LBP in Brazil based on information drawn from the GBD 2017 study.
Learn More >A global My Migraine Voice survey was conducted in 31 countries among 11,266 adults who suffered from ≥4 monthly migraine days (MMD). The aim of this retrospective observational survey-based study was to analyse the country specific results in Finland in order to understand the impact of migraine based on disease severity.
Learn More >Trigeminal neuralgia (TN), the most common form of severe facial pain, may be confused with an ill-defined persistent idiopathic facial pain (PIFP). Facial pain is reviewed and a detailed discussion of TN and PIFP is presented. A possible cause for PIFP is proposed. (1) Methods: Databases were searched for articles related to facial pain, TN, and PIFP. Relevant articles were selected, and all systematic reviews and meta-analyses were included. (2) Discussion: The lifetime prevalence for TN is approximately 0.3% and for PIFP approximately 0.03%. TN is 15-20 times more common in persons with multiple sclerosis. Most cases of TN are caused by neurovascular compression, but a significant number are secondary to inflammation, tumor or trauma. The cause of PIFP remains unknown. Well-established TN treatment protocols include pharmacotherapy, neurotoxin denervation, peripheral nerve ablation, focused radiation, and microvascular decompression, with high rates of relief and varying degrees of adverse outcomes. No such protocols exist for PIFP. (3) Conclusion: PIFP may be confused with TN, but treatment possibilities differ greatly. Head and neck muscle myofascial pain syndrome is suggested as a possible cause of PIFP, a consideration that could open new approaches to treatment.
Learn More >Patients with Failed Back Surgery Syndrome (FBSS) report a considerably lower health- related quality of life (HRQoL), compared to the general population. Spinal cord stimulation (SCS) is an effective treatment to offer pain relief in those patients. Despite initial treatment success of SCS, its effect sometimes wears off over time. This study investigates the added value of high dose SCS (HD-SCS) in patients with unsatisfactory conventional SCS, from a quality of life perspective. Seventy-eight FBSS patients who were treated with conventional SCS that failed to provide pain relief, were recruited in 15 centers. HRQoL was assessed before converting to HD-SCS (baseline) and three times after converting to HD-SCS using the EuroQol-5D-3L. Quality adjusted life years (QALY) were calculated and compared with conventional SCS. An overall significant increase over time was seen in utility values of the EQ5D-3L, as the mean value at baseline 0.283 (±0.21) increased to 0.452 (±0.29) at 12 months of HD-SCS. This average increase in utility coincides with an average increase of 0.153 (±0.24) QALY's in comparison to continued conventional SCS. Besides the potential of HD-SCS to salvage patients with failed responses to conventional SCS, this treatment seems to be a more efficient treatment than conventional SCS.
Learn More >The dissemination of cancer to bone can cause significant cancer-induced bone pain (CIBP), severely impairing the patient's quality of life. Several rodent models have been developed to explore the nociceptive mechanisms of CIBP, including intratibial inoculation of breast carcinoma cells in syngeneic Sprague Dawley rats. Using this model, we investigated whether resident spinal microglial cells are involved in the transmission and modulation of CIBP, a long-debated disease feature. Immunohistochemical staining of ionizing calcium-binding adaptor molecule 1 (Iba-1) and phosphorylated p38-mitogen-activated protein kinase (P-p38 MAPK) showed no spinal microglial reaction in cancer-bearing rats, independently of disease stage, sex, or carcinoma cell line. As a positive control, significant upregulation of both Iba-1 and P-p38 was observed in a rat model of neuropathic pain. Additionally, intrathecal administration of the microglial inhibitor minocycline did not ameliorate pain-like behaviors in cancer-bearing rats, in contrast to spinal morphine administration. Our results indicate that microglial reaction is not a main player in CIBP, adding to the debate that even within the same models of CIBP, significant variations are seen in disease features considered potential drug targets. We suggest that this heterogeneity may reflect the clinical landscape, underscoring the need for understanding the translational value of CIBP models.
Learn More >Nociplastic pain has been recently introduced as a third mechanistic descriptor of pain arising primarily from alterations of neural processing, in contrast to pain due to tissue damage leading to nociceptor activation (nociceptive) or due to lesion or disease of the somatosensory nervous system (neuropathic). It is characterized by hyperalgesia and allodynia, inconsistency and reversibility, as well as dynamic cross-system interactions with biological and psychobehavioral factors. Along with this renewed understanding, functional pain disorders, also classified as chronic primary pain, are being reframed as biopsychosocial conditions that benefit from multimodal treatment.
Learn More >After traumatic brain injury (TBI), a host of symptoms of varying severity and associated functional impairment may occur. One of the most commonly encountered and challenging to treat are the post-traumatic cephalalgias. Post-traumatic cephalalgia (PTC) or headache is often conceptualized as a single entity as currently classified using the ICHD-3. Yet, the terminology applicable to the major primary, non-traumatic, headache disorders such as migraine, tension headache, and cervicogenic headache are often used to specify the specific type of headache the patients experiences seemingly disparate from the unitary definition of post-traumatic headache adopted by ICHD-3. More complex post-traumatic presentations attributable to brain injury as well as other headache conditions are important to consider as well as other causes such as medication overuse headache and medication induced headache. Treatment of any post-traumatic cephalalgia must be optimized by understanding that there may be more than one headache pain generator, that comorbid traumatic problems may contribute to the pain presentation and that pre-existing conditions could impact both symptom complaint, clinical presentation and recovery. Any treatment for PTC must harmonize with ongoing medical and psychosocial aspects of recovery.
Learn More >Exercise is recommended to promote and maintain health and as treatment for more than 25 diseases and pain conditions. Exercise-induced hypoalgesia (EIH), a measure of descending pain inhibitory control, has been found to be impaired in some chronic pain conditions, but it is currently unclear if EIH is modifiable. This study investigated whether a long-term exercise intervention could modulate EIH in healthy subjects.
Learn More >This systematic review aimed to evaluate the effectiveness of different interventions at reducing pain-related fear in people with fibromyalgia and to analyze whether the included trials reported their interventions in full detail.
Learn More >Epigenetic modulation by DNA methylation is associated with aberrant gene expression in sensory neurons, which consequently leads to pathological pain responses. In this study, we sought to investigate whether peripheral inflammation alters global DNA methylation in trigeminal ganglia (TG) and results in abnormal expression of pro-nociceptive genes. Our results show that peripheral inflammation remotely reduced the level of global DNA methylation in rat TG with a concurrent reduction in and expression. Using unbiased steps, we selected the following pro-nociceptive candidate genes that are potentially regulated by DNA methylation: , and . Inhibition of DNMT with 5-Aza-dC in dissociated TG cells produced dose-dependent upregulation of , and . Systemic treatment of animals with 5-Aza-dC significantly increased the expression of , and in TG. Furthermore, the overexpression of DNMT3a, as delivered by a lentiviral vector, significantly downregulated and expression and also reliably decreased and transcripts. MeDIP revealed that this overexpression also significantly enhanced methylation of CGIs associated with and . In addition, bisulfite sequencing data indicated that the CGI associated with was methylated in a pattern catalyzed by DNMT3a. Taken together, our results show that all 4 pro-nociceptive genes are subject to epigenetic modulation via DNA methylation, likely via DNMT3a under inflammatory conditions. These findings provide the first evidence for the functional importance of DNA methylation as an epigenetic factor in the transcription of pro-nociceptive genes in TG that are implicated in pathological orofacial pain responses.
Learn More >The aims of this study were to: (a) identify differences in serum and cerebrospinal fluid (CSF) glucocorticoids among episodic migraine (EM) and chronic migraine (CM) patients compared with controls; (b) determine longitudinal changes in serum glucocorticoids in CM patients; and (c) determine migraine-related clinical features contributing to glucocorticoid levels.
Learn More >Children aged ≥6 to <12 years with severe atopic dermatitis (AD) have limited treatment options. In a 16-week, randomized, placebo-controlled, phase III trial in children, dupilumab, a monoclonal antibody inhibiting interleukin (IL)-4/IL-13 signaling, significantly improved signs and symptoms with acceptable safety; longer-term safety and efficacy data are lacking.
Learn More >The self-management of osteoarthritis (OA) and low back pain (LBP) through activity and skills (SOLAS) theory-driven group-based complex intervention was developed primarily for the evaluation of its acceptability to patients and physiotherapists and the feasibility of trial procedures, to inform the potential for a definitive trial.
Learn More >Diabetic peripheral neuropathy (DPN) is a chronic microvascular complication of diabetes. The purpose of this study is to find the underlying mechanism for the effects of acupuncture in DPN rats. Rats were rendered diabetic with a single injection of 35 mg/kg streptozotocin (STZ). These STZ-diabetic rats were treated with acupuncture for 20 min once daily. The therapeutic efficacy of acupuncture was assessed using mechanical withdrawal threshold (MWT) and thermal withdrawal latency (TWL) evaluations. After 14 days treatment, acupuncture markedly reduced the pathological injury in STZ-diabetic rats. Moreover, it significantly down-regulated P2X4 and OX42 expression along with the reduced levels of inflammatory factors (CXCR3, TNF-α, IL-1β, IL-6), GSP and lipid metabolisms in the spinal cord of the DPN rats. Acupuncture could relieve DPN in rats by regulating P2X4 expression and inflammation in spinal microglia.
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