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Chronic pain is highly prevalent worldwide and imparts a significant socioeconomic and public health burden. Factors influencing susceptibility to, and mechanisms of, chronic pain development, are not fully understood, but sex is thought to play a significant role, and chronic pain is more prevalent in women than in men. To investigate sex differences in chronic pain, we carried out a sex-stratified genome-wide association study of Multisite Chronic Pain (MCP), a derived chronic pain phenotype, in UK Biobank on 178,556 men and 209,093 women, as well as investigating sex-specific genetic correlations with a range of psychiatric, autoimmune and anthropometric phenotypes and the relationship between sex-specific polygenic risk scores for MCP and chronic widespread pain. We also assessed whether MCP-associated genes showed expression pattern enrichment across tissues. A total of 123 SNPs at five independent loci were significantly associated with MCP in men. In women, a total of 286 genome-wide significant SNPs at ten independent loci were discovered. Meta-analysis of sex-stratified GWAS outputs revealed a further 87 independent associated SNPs. Gene-level analyses revealed sex-specific MCP associations, with 31 genes significantly associated in females, 37 genes associated in males, and a single gene, DCC, associated in both sexes. We found evidence for sex-specific pleiotropy and risk for MCP was found to be associated with chronic widespread pain in a sex-differential manner. Male and female MCP were highly genetically correlated, but at an rg of significantly less than 1 (0.92). All 37 male MCP-associated genes and all but one of 31 female MCP-associated genes were found to be expressed in the dorsal root ganglion, and there was a degree of enrichment for expression in sex-specific tissues. Overall, the findings indicate that sex differences in chronic pain exist at the SNP, gene and transcript abundance level, and highlight possible sex-specific pleiotropy for MCP. Results support the proposition of a strong central nervous-system component to chronic pain in both sexes, additionally highlighting a potential role for the DRG and nociception.
Learn More >The opioid crisis represents a major worldwide public health crisis that has accelerated the search for safer and more effective opioids. Over the past few years, the identification of biased opioid ligands capable of eliciting selective functional responses has provided an alternative avenue to develop novel therapeutics without the side effects of current opioid medications. However, whether biased agonism or other pharmacological properties, such as partial agonism (or low efficacy), account for the therapeutic benefits remains questionable. Here, we provide a summary of the current status of biased opioid ligands that target the μ- and κ-opioid receptors and highlight advances in preclinical and clinical trials of some of these ligands. We also discuss an example of structure-based biased ligand discovery at the μ-opioid receptor, an approach that could revolutionize drug discovery at opioid and other receptors. Last, we briefly discuss caveats and future directions for this important area of research.
Learn More >Deletion of SCN9A encoding the voltage-gated sodium channel Na1.7 in humans leads to profound pain insensitivity and anosmia. Conditional deletion of Na1.7 in sensory neurons of mice also abolishes pain, suggesting that the locus of analgesia is the nociceptor. Here we demonstrate, using in vivo calcium imaging and extracellular recording, that Na1.7 knockout mice have essentially normal nociceptor activity. However, synaptic transmission from nociceptor central terminals in the spinal cord is greatly reduced by an opioid-dependent mechanism. Analgesia is also reversed substantially by central but not peripheral application of opioid antagonists. In contrast, the lack of neurotransmitter release from olfactory sensory neurons is opioid independent. Male and female humans with Na1.7-null mutations show naloxone-reversible analgesia. Thus, inhibition of neurotransmitter release is the principal mechanism of anosmia and analgesia in mouse and human Nav1.7-null mutants.
Learn More >Despite a century of research on the physiology/pathophysiology of the spinal cord in chronic pain condition, the properties of the spinal cord were rarely studied at the large-scale level from a neurovascular point of view. This is mostly due to the limited spatial and/or temporal resolution of the available techniques. Functional ultrasound imaging (fUS) is an emerging neuroimaging approach that allows, through the measurement of cerebral blood volume, the study of brain functional connectivity or functional activations with excellent spatial (100 μm) and temporal (1 msec) resolutions and a high sensitivity. The aim of this study was to increase our understanding of the spinal cord physiology through the study of the properties of spinal hemodynamic response to the natural or electrical stimulation of afferent fibers. Using a combination of fUS and ultrasound localization microscopy, the first step of this study was the fine description of the vascular structures in the rat spinal cord. Then, using either natural or electrical stimulations of different categories of afferent fibers (Aβ, Aδ, and C fibers), we could define the characteristics of the typical hemodynamic response of the rat spinal cord experimentally. We showed that the responses are fiber-specific, located ipsilaterally in the dorsal horn, and that they follow the somatotopy of afferent fiber entries in the dorsal horn and that the C-fiber response is an N-methyl-D-aspartate receptor-dependent mechanism. Finally, fUS imaging of the mesoscopic hemodynamic response induced by natural tactile stimulations revealed a potentiated response in inflammatory condition, suggesting an enhanced response to allodynic stimulations.
Learn More >Many patients with diabetic peripheral neuropathy experience chronic pain and inadequate relief despite best available medical treatments.
Learn More >We aimed to identify differences in network properties of white matter microstructure between asymptomatic ulcerative colitis (UC) participants who had a history of chronic gut inflammation, healthy controls (HCs) and a disease control group without gut inflammation (irritable bowel syndrome; IBS).
Learn More >Chronic pain-related sickness absence is an enormous socioeconomic burden globally. Optimized interventions are reliant on a lucid understanding of the distribution of social insurance benefits and their predictors. This register-based observational study analyzed data for a seven-year period from a population-based sample of 44,241 chronic pain patients eligible for interdisciplinary treatment (IDT) at specialist clinics. Sequence analysis was used to describe the sickness absence over the complete period and to separate the patients into subgroups based on their social insurance benefits over the final two years. The predictive performance of features from various domains was then explored with machine learning-based modeling in a nested cross-validation procedure. Our results showed that patients on sickness absence increased from 17% five years before to 48% at the time of the IDT assessment, and then decreased to 38% at the end of follow-up. Patients were divided into three classes characterized by low sickness absence, sick leave, and disability pension, with eight predictors of class membership being identified. Sickness absence history was the strongest predictor of future sickness absence, while other predictors included a 2008 policy, age, confidence in recovery, and geographical location. Information on these features could guide personalized intervention in the specialized healthcare. PERSPECTIVE: This study describes sickness absence in patients who visited a Swedish pain specialist interdisciplinary treatment clinic during the period 2005-2016. Predictors of future sickness absence are also identified that should be considered when adapting IDT programs to the patient's needs.
Learn More >Adverse life events (ALEs) are a risk factor for chronic pain; however, mechanisms underlying this association are not understood. This study examined whether cumulative ALE exposure impairs endogenous inhibition of pain (assessed from pain report) and spinal nociception (assessed from nociceptive flexion reflex; NFR) in healthy, pain-free Native Americans (n=124) and non-Hispanic Whites (n=129) during a conditioned pain modulation (CPM) task. Cumulative ALE exposure was assessed prior to testing by summing the number of potentially traumatic events experienced by each participant across their lifespan. Multilevel modeling found that ALEs were associated with NFR modulation during the CPM task even after controlling for general health, body mass index, sex, age, blood pressure, sleep quality, stimulation intensity, stimulus number, perceived stress, and psychological distress. Low exposure to ALEs was associated with NFR inhibition, whereas high exposure to ALEs was associated with NFR facilitation. By contrast, pain perception was inhibited during the CPM task regardless of the level of ALE exposure. Race/ethnicity did not moderate these results. Thus, ALEs may be pronociceptive for both Native Americans and non-Hispanic Whites by impairing descending inhibition of spinal nociception. This could contribute to a chronic pain risk phenotype involving latent spinal sensitization. Perspective: This study found that adverse life events were associated with impaired descending inhibition of spinal nociception in a sample of Native Americans and non-Hispanic Whites. These findings expand on previous research linking adversity to chronic pain risk by identifying a proximate physiological mechanism for this association.
Learn More >Limited understanding of pruritus mechanisms in cholestatic liver diseases hinders development of anti-pruritic treatments. Previous studies implicated lysophosphatidic acid (LPA) as a potential mediator of cholestatic pruritus.
Learn More >To evaluate the impact of two calcitonin gene-related peptide (CGRP)-targeted monoclonal antibodies (mAbs), erenumab and galcanezumab, on the pharmacokinetic (PK) profile, safety, and tolerability of ubrogepant.
Learn More >Persistent pain after total knee replacement is an underestimated outcome leading to significant health burden. Sensory testing has been explored to help surgeons in decision making and better patient selection. Patients with different chronic pain syndromes exhibit a poor descending pain inhibition that can be quantified through experimental paradigms (conditioned pain modulation). A poor preoperative descending pain inhibition response predicted persistence of pain after surgery in previous studies.
Learn More >Migraine is a complex, multifaceted, and disabling headache disease that is often complicated by gastrointestinal (GI) conditions, such as gastroparesis, functional dyspepsia, and cyclic vomiting syndrome (CVS). Functional dyspepsia and CVS are part of a spectrum of disorders newly classified as disorders of gut-brain interaction (DGBI). Gastroparesis and functional dyspepsia are both associated with delayed gastric emptying, while nausea and vomiting are prominent in CVS, which are also symptoms that commonly occur with migraine attacks. Furthermore, these gastric disorders are comorbidities frequently reported by patients with migraine. While very few studies assessing GI disorders in patients with migraine have been performed, they do demonstrate a physiological link between these conditions.
Learn More >Atopic dermatitis (AD) patients have heterogeneous clinical phenotypes, including different combinations of itch and lesional severity. Little is known about the characteristics and course of these subtypes.
Learn More >Migraine has been associated with many comorbidities. However, lifestyle factors and the presence of comorbid diseases have not previously been extensively studied in the same sample. This study aimed to compare the prevalence of unhealthy lifestyle factors and comorbid diseases between patients with migraine and migraine-free controls with subgroup analyses to determine the pathophysiology and possible consequences.
Learn More >Oxaliplatin-induced peripheral neuropathy negatively affects the quality of life for patients with gastrointestinal cancers and may cause neuropathic pain. Measures of peripheral nerve structure or function, such as intraepidermal nerve fiber density (IENFD) during treatment could reduce neuropathy severity through individualized dose reduction.
Learn More >Persistent inflammation and persistent pain are major medical, social and economic burdens. As such, related pharmacotherapy needs to be continuously improved. The peptide ERα17p, which originates from a part of the hinge region/AF2 domain of the human estrogen receptor α (ERα), exerts anti-proliferative effects in breast cancer cells through a mechanism involving the hepta-transmembrane G protein-coupled estrogen receptor (GPER). It is able to decrease the size of xenografted human breast tumors, in mice. As GPER has been reported to participate in pain and inflammation, we were interested in exploring the potential of ERα17p in this respect. We observed that the peptide promoted anti-hyperalgesic effects from 2.5 mg/kg in a chronic mice model of paw inflammation induced by the pro-inflammatory complete Freund's adjuvant (CFA). This action was abrogated by the specific GPER antagonist G-15, leading to the conclusion that a GPER-dependent mechanism was involved. A systemic administration of a Cy5-labeled version of the peptide allowed its detection in both, the spinal cord and brain. However, ERα17p-induced anti-hyperalgesia was detected at the supraspinal level, exclusively. In the second part of the study, we have assessed the anti-inflammatory action of ERα17p in mice using a carrageenan-evoked hind-paw inflammation model. A systemic administration of ERα17p at a dose of 2.5 mg/kg was responsible for reduced paw swelling. Overall, our work strongly suggests that GPER inverse agonists, including ERα17p, could be used to control hyperalgesia and inflammation.
Learn More >Given the potential for obesity to complicate migraine treatment outcomes, there is a need to understand patterns and correlates of acute medication use among individuals with this comorbidity. Experience sampling methodology (ESM) was used to characterize patterns of acute medication use among those with migraine and overweight/obesity and to examine individual and momentary factors related to medication use (both migraine-specific and nonspecific medications). Women with migraine and overweight/obesity (N = 170) seeking behavioral migraine treatment completed questionnaires followed by 28 days of daily ESM headache diaries. Participants used medications to treat 71.9% of attacks, 20% of which were treated with migraine-specific medications. Participants were more likely to use medication in the context of longer and more severe attacks that started earlier in the day. Presence of aura and greater work-related pain interference uniquely related to migraine-specific medication use. Questionnaire-assessed factors were not related to medication use, although older age and higher educational attainment related to more frequent use. A substantial proportion of attacks were left untreated, suggesting unmet treatment needs in this population. Results also suggest that ESM-assessed factors are more salient correlates of medication use compared to questionnaires. Additional investigation of barriers to medication use is needed.
Learn More >The need for measuring emotional functioning in chronic pain patients was recognized decades ago. The Initiative on Methods, Measures, and Pain Assessment in Clinical Trials (IMMPACT) proposed the Profile of Mood States (POMS) for this purpose. However, to date, its factor structure has not been confirmed in these patients.
Learn More >The clinical impact of postoperative opioid use requires accurate prediction strategies to identify at-risk patients. We utilize preoperative claims data to predict postoperative opioid refill and new persistent use in opioid-naïve patients.
Learn More >Overlap of pathways enriched by single nucleotide polymorphisms and DNA-methylation underlying chronic postsurgical pain (CPSP), prompted pilot study of CPSP-associated methylation quantitative trait loci (meQTL). Children undergoing spine-fusion were recruited prospectively. Logistic-regression for genome- and epigenome-wide CPSP association and DNA-methylation-single nucleotide polymorphism association/mediation analyses to identify meQTLs were followed by functional genomics analyses. CPSP (n = 20/58) and non-CPSP groups differed in pain-measures. Of 2753 meQTLs, DNA-methylation at 127 cytosine-guanine dinucleotides mediated association of 470 meQTLs with CPSP (p < 0.05). At PARK16 locus, CPSP risk meQTLs were associated with decreased DNA-methylation at and increased DNA-methylation at Corresponding blood eQTLs (GTEx) and cytosine-guanine dinucleotide-loci enrichment for histone marks, transcription factor binding sites and ATAC-seq peaks suggest altered transcription factor-binding. CPSP-associated meQTLs indicate epigenetic mechanisms mediate genetic risk. Clinical trial registration: NCT01839461, NCT01731873 (ClinicalTrials.gov).
Learn More >Migraine sufferers often exhibit photophobia and physical hypoactivity in the postdrome and interictal periods, for which no effective therapy currently exists. Cortical spreading depolarization (CSD) is a neural phenomenon underlying migraine aura. We previously reported that CSD induced trigeminal sensitization, photophobia, and hypomobility at 24 h in mice. Here, we examined the effects of CSD induction on light sensitivity and physical activity in mice at 48 h and 72 h. Trigeminal sensitization was absent at both time points. CSD-subjected mice exhibited significantly less ambulatory time in both light (P = 0.0074, the Bonferroni test) and dark (P = 0.0354, the Bonferroni test) zones than sham-operated mice at 72 h. CSD-subjected mice also exhibited a significantly shorter ambulatory distance in the light zone at 72 h than sham-operated mice (P = 0.0151, the Bonferroni test). Neurotropin® is used for the management of chronic pain disorders, mainly in Asian countries. The CSD-induced reductions in ambulatory time and distance in the light zone at 72 h were reversed by Neurotropin® at 0.27 NU/kg. Our experimental model seems to recapitulate migraine-associated clinical features observed in the postdrome and interictal periods. Moreover, Neurotropin® may be effective in ameliorating postdromal/interictal hypoactivity, especially in a light environment.
Learn More >IL-31 is a major pruritogen associated with atopic dermatitis (AD). Although a specific antibody for IL-31 receptor has been shown to alleviate pruritus in patients with AD, therapeutic approaches to inhibit IL-31 production remain unexploited. IL-31 production by helper T cells critically depends on the transcription factor EPAS1, which mediates IL31 promoter activation in collaboration with SP1.
Learn More >Chronic, multisite pain is a common phenomenon in aging and is associated with a host of negative health outcomes. It is a complex and multifaceted condition that may be exacerbated by weight gain and long periods of inactivity. Unfortunately, older adults suffering from chronic pain have unique barriers limiting access to center-based behavior change interventions. The MORPH study first adapted and iteratively refined an evidence-based group-mediated intervention for delivery in the home via mHealth tools (a smartphone app, teleconferencing software, wearable activity monitor, smart weight scale). This was followed by a pilot randomized controlled trial (RCT) meant to assess feasibility of the MORPH intervention, and to examine initial effects on physical function, pain, weight, and sedentary behavior. We recruited low-active and obese older adults with multisite pain to partake in a series of N-of-1 refinement studies ( = 5 total) or a 12-week pilot RCT delivered largely in the home ( = 28 assigned to active intervention or wait-list control). The refinement phase identified several key technological (e.g., selection of a new smart weight scale) and user interface (e.g., clarification of in-app phrasing) modifications that were made before initiating the RCT phase. Analyses of covariance, controlling for baseline values, sex, and age indicated effects favoring the intervention across all domains of interest: there was a substantially clinically meaningful difference in short physical performance battery scores (0.63 points, = 0.08), a moderate-to-large difference in PROMIS pain intensity scores (5.52 points, = 0.12), a large difference in body weight (2.90 kg, = 0.207), and a moderate effect on adjusted ActivPAL-assessed sedentary time (64.90 min, = 0.07) with a small effect on steps (297.7 steps, = 0.01). These results suggest a largely-home delivered movement and weight loss program for older adults with pain is feasible and recommendations are provided for future programs of this nature.
Learn More >Spinal degenerative joint disease (DJD) is associated with lower back pain (LBP) arising from the degeneration of intervertebral discs (IVD), facet joints, intertransversarii muscles, and interspinous ligaments among other anatomical structures. To circumvent the socioeconomic burdens and often-problematic surgical options imposed by DJD therapy, cell-based biologic modalities like bone marrow aspirate concentrate (BMAC) have been investigated in pre-clinical and clinical settings, mostly for IVD degeneration (IDD), with encouraging outcomes. In this study, we evaluated the differences in therapeutic benefits of BMAC between IVD- and facet joint-originating chronic LBP. Eighteen patients diagnosed with chronic LBP met the selection criteria. Following discography and provocation testing, 13 patients tested positive and were assigned into IDD-associated LBP (1st arm), while the remaining 5 tested negative and were assigned into facetogenic LBP (2nd arm). Autologous BMAC was injected intradiscally in the 1st arm, while the 2nd arm received posterior spinal chain injections. No procedure-related serious events ensued. Clinical improvement was evaluated over 12 months based on pain and functionality questionnaires (VAS, BPI, RAND-36), opioid use, and changes in disc parameters assessed by magnetic resonance imaging (MRI). Ameliorated VAS and BPI scores differed significantly between both arms in favor of IDD patients who also took significantly less opioids. Average RAND-36 scores showed no significant difference between groups albeit a trend suggesting improvement was observed in IDD patients. MRI scans conducted on IDD patients demonstrated marked elevation in disc height and spinal canal space size without worsening disc quality. Overall, this is the first study investigating the potency of BMAC as an IDD treatment in Canada and the first globally for addressing facetogenic pain using cellular therapy.
Learn More >Childhood maltreatment is associated with pain catastrophizing. Both childhood maltreatment and pain catastrophizing are prevalent in certain immune-mediated inflammatory disease (IMID) populations. However, it is unknown whether childhood maltreatment contributes to the high rates of pain catastrophizing in IMID cohorts. We assessed the relationship between childhood maltreatment and pain catastrophizing in individuals with IMID, and whether this differed across IMID.
Learn More >Headache is one of the most disabling conditions in the world. Despite plentiful evidence supporting rehabilitation strategies, headache is significantly underassessed and undertreated. Obstacles to headache care include lack of available expertise in headache management, few available resources for effective assessment and treatment, and cost and disability that preclude treatment seeking in patients with headache. Telerehabilitation can allow providers to access expert consultation and gives patients easier access to assessment and treatment. This article covers existing telerehabilitation options for headache management and explores the strength of evidence supporting these approaches. Risks of telerehabilitation and recommendations for future development are discussed.
Learn More >Telerehabilitation for pain management uses communication technology to minimize geographic barriers. Access to such technology has proven critically important during the coronavirus disease-2019 pandemic and has been useful for patients with chronic pain disorders unable to travel. The evaluation and treatment of such disorders requires a whole health approach that individualizes treatment options and delivers care through a biopsychosocial approach. The goals of care are unchanged from an in-person patient-provider experience. Telerehabilitation can be successfully implemented in pain management with appropriate consideration for staging an evaluation, a structured approach to the visit, and application of standard clinical metrics.
Learn More >Endomorphin analogs containing unnatural amino acids have demonstrated potent analgesic effects in our previous studies. In the present study, the differences in antinociception and the mechanisms thereof for analogs 1-3 administered intracerebroventricularly and intrathecally were explored. All analogs at different routes of administration produced potent analgesia compared to the parent peptide endomorphin-1. Multiple antagonists and antibodies were used to explore the mechanisms of action of these analogs, and it was inferred that analogs 1-3 stimulated the µ opioid receptor to induce antinociception. Moreover, the antibody data suggested that analog 2 may induce the release of immunoreactive [Leu]-enkephaline and [Met]-enkephaline to produce a secondary component of antinociception at the spinal level and analog 3 may stimulate the the release of immunoreactive [Met]-enkephaline at the spinal level. Finally, analogs 2 and 3 produced no acute tolerance in the spinal cord. We hypothesize that the unique characteristics of the endomorphin analogs result from their capacities to stimulate the release of endogenous antinociceptive substances.
Learn More >Lidocaine continuous subcutaneous infusion (L-CSCI) for neuropathic pain in hospice patients has limited evidence for its safety and efficacy, and guidelines are lacking. This study assesses a series of patients admitted to a hospice over a six-month period that had neuropathic pain and received L-CSCI. The primary outcome was improvement in patient-rated distress from pain following L-CSCI titration. Also assessed were changes in oral morphine equivalent dose (OME), frequency of breakthrough medication, functional status, adverse effects and perception of response. Fifteen patients received L-CSCI for an average of 6.7 days (range 1-92). Average pain distress score decreased by 2 or more in six patients. Positive responses to L-CSCI were documented in the clinical notes of 10 patients. Opioid down-titration occurred in four patients. Lidocaine levels were performed in 3 patients but did not change management. Five patients experienced adverse effects attributable to lidocaine and all responded to simple measures. In conclusion, L-CSCI can help manage neuropathic pain in hospice patients, particularly in those who cannot swallow oral medications. Further systematic research is warranted to establish efficacy and tolerability, and to inform guideline development.
Learn More >The topical inflammatory soup can model the inflammation of the dura mater causing hypersensitivity and activation of the trigeminal system, a phenomenon present in migraineurs. Calcitonin gene-related peptide, transient receptor potential vanilloid-1 receptor, and neuronal nitric oxide synthase are important in the sensitization process there. 5-HT receptor agonists, triptans are used as a treatment of migraine. Kynurenic acid an NMDA antagonist can act on structures involved in trigeminal activation.
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