The Journal of Pain

Objective: Myofascial pain (MP) is a leading cause of disability globally. Pain quality and severity vary widely for people with MP, making it difficult to accurately assess the spectrum of symptoms and develop appropriate treatments. We assessed potential contributors to variability in the clinical spectrum of unexplained neck/shoulder pain and associated myofascial component(s). Design: Prospective cross-sectional study of adults reporting neck/shoulder pain and pain-free individuals. Outcomes Measures: Pain intensity and interference (PEG); Symptom burden measured using patient-reported outcomes and objective measures: pain catastrophizing (PCS); PROMIS physical function (PF); sleep disturbance; anxiety (GAD-2); depression (PHQ-2); hypermobility (Beighton/Brighton); Objective measures in the medial upper trapezius: pressure pain threshold (PPT) and quantitative sensory testing (QST). Results: Of the 96 adults recruited for the study, 82 had complete records (age 32.2 +/-13.1 years, 57% women). On physical exam, 23 were assessed to be in an active group (those with spontaneous MP without provocation), 38 in a latent group (those with MP upon provocation), and 21 in a normal group (no MP in neck and shoulder). The symptom burden explained 75% of the variance in PEG in the overall sample, 85% in the active group and 92% in the normal group. PF and PCS are key predictors of PEG. Network analysis identified unique symptom clusters in the active and latent groups. Conclusions: The symptom burden explains the variability in the clinical spectrum of pain intensity and interference in unexplained neck/shoulder MP. Network analysis can further improve clinical risk stratification. These findings represent a step towards an eventual goal of developing multidisciplinary clinical guidance for managing the whole patient, rather than the current emphasis on regional pain contributors in MP.

IntroductionIrritable bowel syndrome (IBS) is a prevalent disorder whose most debilitating symptom is pain. The complex, multifactorial nature of IBS pain leads to highly variable and often inadequate responses to self-management, underscoring the urgent need for personalized prediction models. MethodsThis ancillary analysis of a randomized controlled trial (NCT03332537) utilized data from 80 young adults with IBS. We applied the Bayesian Additive Regression Trees machine learning algorithm to develop 27 distinct predictive models for pain severity, pain interference, and quality of life (QOL) at baseline and post-intervention. Predictors included a comprehensive, multi-domain set of variables spanning genetics, quantitative sensory testing, gut microbiota, psychosocial factors, and food intake. ResultsModel performance was strong, with area under the curve (AUC) values ranging from 0.753 to 0.981. A consistent hierarchy of predictors emerged. The COMT rs4680 polymorphism was the most significant predictor, featuring in 26 models, followed by ADRA1D rs1556832 in 24 models. The mechanical pain threshold was a key predictor of pain severity, while psychosocial factors, particularly pain catastrophizing, were crucial for pain interference and QOL. Gut microbiota features and food intake were also consistently important. DiscussionThis study establishes a comprehensive, multi-omics framework that explains individual differences in IBS pain and treatment response. The identified predictors provide a practical tool for advancing precision medicine. By classifying patients based on their distinct profiles, clinicians can proactively customize self-management strategies, potentially transforming care for this complex condition. WHAT IS KNOWNO_LIIBS pain involves complex, dysregulated gut-brain interactions. C_LIO_LITreatment response is highly variable and difficult to predict. C_LIO_LIMachine learning can help phenotype complex pain conditions. C_LI WHAT IS NEW HEREO_LIMachine learning based hierarchical models identify a core neurogenetic predisposition for IBS pain. C_LIO_LIMachine learning based prediction of individual response to self-management before treatment begins. C_LIO_LIThis provides a direct pathway to precision pain management in IBS. C_LI

IntroductionChronic pain is the most common qualifying condition found in states with medical cannabis (MC). We conducted a study assessing the geographic distribution of MC certifications for severe chronic or intractable pain in Pennsylvania (PA) between 2018 to 2024, identifying relationships between median household income and ethnic background with the percentage of adults with a MC certification for pain. MethodsUsing data from the PA Department of Health (PDOH) from 2018 to 2024 (N = 44,645 to 165,740 certifications for pain / year), we mapped Zip codes associated with MC certifications for pain to counties and Zip code tabulation areas (ZCTAs). The difference between the highest and lowest counties was determined. A linear regression evaluated correlations between community variables and the percentage of adults in geographical areas with a MC certification for pain in 2024. ResultsThere was an almost a four-fold difference in the percent of adults with a MC certification for pain in the highest (Perry = 2.3%) versus lowest (Tioga = 0.6%) counties in 2024. Bradford and Tioga County had a significantly (p < 0.05) lower percentage certified relative to the county-wide average. There was a significantly higher proportion of certifications for pain in counties with larger population densities of adults (1.76 +/- 0.12%) than counties with smaller population densities (1.38% +/- 0.14%) of adults (t(65) = 4.66, p < 0.001, d = 1.14). At the county level, higher median household income was associated with a greater percentage of adults with MC (r(65) = +0.34, p < 0.01). At the ZCTA level, the proportion of non-White individuals, including Hispanics, showed a modest, but significant, inverse association with MC certification (r(1,722) = -0.07, p < 0.01). ConclusionsThis study identified four-fold county level disparities in MC certifications for pain. The association between median household income and MC pain certifications may indicate differences in accessibility of MC based on financial status. Further research may be warranted pending any changes to the legal status or demand for MC.

We performed the first systematic review and meta-analysis of the prevalence of pain with neuropathic characteristics using Bayesian methods to correct prevalence estimates for the use of screening tools with imperfect sensitivity and specificity (CRD42023416845). We searched major databases for national or regional epidemiological studies that reported the prevalence of pain with neuropathic characteristics, as identified by the PainDETECT, S-LANSS, or DN4-interview. Of the 1,251 unique records retrieved, 8 were finally extracted. The uncorrected (apparent) prevalence data were pooled using a random-effects meta-analysis for proportions. The corrected (true) prevalence was estimated using Bayesian models incorporating sensitivity and specificity distributions under non-informative [beta(1,1)] and informative priors [beta(4.389, 29.522); based on apparent prevalence]. Using the mean values from Bayesian credible intervals, a pooled estimate of true prevalence was generated using a random-effects model. The pooled estimate for the apparent prevalence was 10.6% (95% CI: 8.5; 12.9). The pooled estimate for true prevalence was 4.9% (95% CI: 3.8; 6.1) using informative priors, and 2.3% (95% CI: 1.5; 3.2) using non-informative priors. The use of imperfect screening tools may have overestimated the prevalence of neuropathic pain. PerspectiveThe prevalence of neuropathic pain may be lower than previously estimated. A lower prevalence should not be equated with reduced societal or clinical significance, but it may have implications for healthcare resource allocation and research funding policies for neuropathic pain.

Persistent pain has a significant impact on quality of life and places considerable demand on the NHS (National Health Service). In 2023, Welsh Government published their guidance Living with Persistent Pain, marking persistent pain as a national priority. The research aimed to provide evidence to help inform NHS leads in Wales around current and future services, capacity planning, and to aid in implementing health policies. We conducted a retrospective cohort study covering the period 2010-2023. Anonymised, individual- level, population-scale linked routinely-collected electronic health records and administrative data from the SAIL Databank was used. The population included people living in Wales and registered with a General Practice (GP) that provides data to SAIL. Three cohorts of people were created. These were i) people with diagnostic codes relevant to persistent pain, ii) people prescribed opioids or gabapentinoids for 3 months or more, and iii) people referred to specialist outpatient pain services. A comparator group included people who did not meet any of these criteria. We measured the proportion of the population living with persistent pain, demographic details, and health status. Healthcare use data included GP appointments and prescriptions, hospital admissions, emergency department visits, and outpatient appointments. The results showed that 15% of the population of Wales are living with persistent pain. Persistent pain was more common among older adults, women, and individuals living in more deprived areas. A higher burden of frailty and comorbid conditions was observed in the persistent pain cohort compared to the general population. People living with persistent pain had 63% more GP events than those without. Those referred to pain services had more healthcare interactions overall and were younger and less frail compared to those not referred. Trends over time showed small but statistically significant decline was observed in the prevalence of persistent pain over the study period. After adjusting for demographics and seasonal changes--there were small but significant monthly increases in GP events, hospital admissions, emergency attendances, for the persistent pain cohort. Outpatient attendances showed small but statistically significant month-on-month decreases. Findings may point to unmet need in accessing specialist care, particularly among older adults and individuals from more deprived areas. Patterns of pain prevalence and service use reflect existing inequalities across age, sex, and socioeconomic status. There is a need for further research, service improvements and policy development. Funding statementThe authors and their Institutions were funded for this work by the Health and Care Research Wales Evidence Centre, itself funded by Health and Care Research Wales on behalf of Welsh Government.

The psychedelic psilocybin may have lasting therapeutic effects for patients with chronic pain syndromes. Some clinical and preclinical data suggest these putative benefits derive from direct analgesic effects. However, this possibility has not been comprehensively tested in preclinical models. Here, we show that psilocybin is not analgesic over a range of doses across multiple pain assays and models of acute and chronic inflammatory, neuropathic, or musculoskeletal pain in mice.

ObjectivesBack pain is a massive public health problem. The STarT Back Screening Tool (SBST) was developed for use in primary care to triage people with lumbar pain, classifying them as low, medium or high "risk" of prolonged symptoms. This classification guides non-surgical interventions including manual treatments, exercise and cognitive behavioural therapy. Claims suggest SBST brings generic health and cost benefits. National guidance recommends STarT Back is used at the first primary care consultation but can be used at any stage. For SBST to be an effective triage tool it should distinguish structural from non-structural pain. We tested this requirement in consecutive people referred to a single triage practitioner, hypothesising it was not possible conceptually. DesignAn observational study of the relationship between routine, prospectively collected triage data and diagnosis. SettingA secondary care spinal triage service based in a teaching hospital. ParticipantsWe studied consecutive referrals with lumbar pain triaged by a single extended scope practitioner (ESP) over 22 months (Nov 2015-Sept 2017). Main Outcome MeasuresSBST and pain visual analogue scores (VAS: 0-10) were collected at the initial consultation. We compared data for people with and without surgically remedial lesions. Results1041 people were seen (61% female, mean age 53), n=234 (28%) had surgically amenable explanations for pain. People with surgical lesions were older (58 v 51yrs), more likely male (48 v 35%) and had higher VAS scores (6.8 v 6.1). Surgery and non-surgery subgroups had similar SBST total and domain score distribution profiles. The surgery subgroup had less low risk (9%v21%) and more high risk (37% v 30%) classified people. ConclusionSBST scores did not differentiate surgical from non-surgical pathologies. It seems unlikely that symptom questionnaires can estimate prognosis accurately unless everyone has the same diagnosis, not just the same symptom. Diagnosis, rather than questionnaire scores, should guide treatment and inform prognosis. O_TEXTBOXSummary Box What is already known on this topic?The symptom of low back pain is a common cause of disability worldwide. The majority if people with low back pain probably do not have a structural problem in their lumbar spine to explain the extent of their disability. National guidelines throughout the world attempt to facilitate the identification and treatment of people with, "non-specific low back pain", and prescribe treatment for people given this label. What this study adds?It seems unlikely that symptom questionnaires can estimate prognosis accurately unless everyone has the same diagnosis, not just the same symptom. The practice of recommending treatment and prognosticating in the absence of a diagnosis needs further scrutiny. C_TEXTBOX

Objective: To evaluate whether glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are associated with improvements in pain severity, disability, quality of life, and physical function in adults with obesity and chronic low back pain (cLBP), and to explore potential mechanisms. Design: Prospective, single-arm cohort study. Subjects: Thirty-five adults (median age 41 years; 86% women) with obesity (median BMI 39.9 kg/m2) and cLBP initiating GLP-1 RAs (tirzepatide, n=24; semaglutide, n=11). Methods: Participants completed questionnaires at baseline, 3, 6, 9, and 12 months. The primary outcome was Brief Pain Inventory-Short Form (BPI-SF) pain severity. Secondary outcomes included body mass index (BMI), BPI-SF pain interference, Numerical Rating Scale (NRS) back pain, Oswestry Disability Index (ODI), and Short Form-12 (SF-12). At baseline and 6 months, a subset (n=24) underwent quantitative sensory testing, physical performance testing, and blood draws for inflammatory biomarkers (C-reactive protein, TNF-, IL-6, IL-10), adipokines (leptin, adiponectin), and hemoglobin A1c. Results: Over 12 months, BMI decreased by 12.5% (median 39.9 to 34.9 kg/m2, 95% CI [-6.6, -4.2]). BPI-SF pain severity improved (median 4.8 to 2.0, 95% CI [-2.1, -0.8]), as did pain interference, ODI, NRS back pain, and SF-12 physical component scores. Hemoglobin A1c, leptin, and C-reactive protein decreased. Adiponectin increased and physical performance improved, but neither reached significance. Experimental pain sensitivity was unchanged. Conclusions: GLP-1 RAs were associated with clinically meaningful improvements in pain, disability, and quality of life. These findings suggest GLP-1 RAs may be a promising nonsurgical therapy for cLBP; randomized controlled trials are needed to establish causality and mechanisms.

ObjectiveChronic low back pain (cLBP) is a leading cause of global disability, with current treatments offering limited and inconsistent relief. D-cycloserine (DCS), a partial NMDA receptor agonist and FDA-approved antimicrobial, has shown promise in preclinical models for reducing neuropathic pain and its negative emotional impact. Building on these findings and a positive pilot study, we conducted a randomized, double-blind, placebo-controlled phase 2 trial to evaluate the efficacy and safety of DCS in adults with cLBP. MethodsParticipants with cLBP (n=203) were randomized to receive 200 mg DCS or placebo twice daily for 12 weeks, followed by a 12-week placebo phase. The primary outcome was pain intensity (numeric rating scale, NRS) at 12 weeks; secondary outcomes included pain intensity at 24 weeks, safety, and patient-reported psychological measures. ResultsDCS had negligible effects on pain compared to placebo at both 12 weeks (adjusted effect: -0.07/10 NRS units, 95% CI: (-0.67, 0.53), p = 0.78) and at 24 weeks (adjusted effect: -0.22/10 NRS units, 95% CI: (-0.84, 0.40), p = 0.39). Adverse events were similar between groups. Exploratory outcomes also showed no significant effects. ConclusionOur results indicate that 12 weeks of DCS 400 mg/day does not provide clinically meaningful analgesia in cLBP, though it is well tolerated. These findings highlight the challenges of translating preclinical neuropathic pain results to heterogeneous clinical pain populations.

Treatments for chronic low back pain (LBP) provide only small improvements in pain and disability compared with placebo. Targeting mechanisms involved in the persistence of pain and disability following an episode of acute LBP (ALBP) may enhance treatment effectiveness. Sensorimotor alterations have been observed in individuals with chronic LBP (CLBP), but their role in the development of CLBP remains unclear. In this secondary analysis of longitudinal data from 99 participants with ALBP, the causal associations between pain sensitivity and erector spinae muscle activation measured in the acute phase of LBP and pain and disability at 6- and 12-month follow-ups were explored. Negative binomial regressions revealed that greater lumbar muscle activation at baseline was associated with lower disability at 6 months (incidence rate ratio [IRR] 0.33 [95% CI 0.13 to 0.85], p=0.02). Higher lumbar pressure pain threshold was also associated with lower disability at 6 months (IRR 0.87 [95% CI 0.79 to 0.97], p=0.009). At 12 months, greater lumbar and thoracic muscle activation were associated with lower disability (IRR 0.11 [95% CI 0.03 to 0.35], p<0.001 and IRR 0.09 [95% CI 0.02 to 0.33], p<0.001, respectively). The findings suggest that increased thoracolumbar muscle activation during the acute phase may act as a protective mechanism and support recovery. However, the association with pain sensitivity should be interpreted with caution, as only one of 16 models reached statistical significance. Longitudinal studies assessing the evolution of these sensorimotor factors could improve the understanding of their contribution in the development of CLBP. Perspective: This article presents exploratory analyses of causal associations between sensorimotor outcomes in acute low back pain and levels of pain and disability in the long-term. Increased muscle activation explained better long-term outcomes, whereas increased pain sensitivity explained poorer long-term outcomes.

Genetic deletion and pharmacological inhibition are distinct approaches to unravelling pain mechanisms, identifying targets and developing new analgesics. Both approaches have been applied to the voltage-gated sodium channels Nav1.7 and Nav1.8. Genetic deletion of Nav1.8 in mice leads to a loss of pain, and antagonists are effective analgesics. Complete embryonic loss of Nav1.7 in humans or in mouse sensory neurons leads to profound analgesia substantially mediated by endogenous opioid signaling, and anosmia that is opioid independent. Autonomic function appears to be normal. Adult deletion of Nav1.7 in sensory neurons also leads to analgesia with diminished sensory neuron excitability but there is no opioid component of analgesia. Pharmacological inhibition of Nav1.7 leads to dramatic side-effects on the autonomic nervous system. Here we compare and contrast the distinct embryonic and adult null mechanisms of Nav1.7 loss-of-function analgesia. We describe an endogenous opioid mechanism of analgesia that provides new opportunities for therapeutic intervention and pain relief. SummaryIn contrast to Nav1.8, Nav1.7, a genetically validated human pain target is unsuitable for small molecule drug development because of its wide spread expression both centrally and peripherally.

Objective: To quantify the effect size of four biopsychosocial amplifier loops on chronic pain outcomes through systematic review and meta-analysis, and to develop a logistic regression-based risk stratification tool for interventional pain medicine. Methods: We searched PubMed, Scopus, and Cochrane Library through March 2026 for studies reporting adjusted odds ratios for associations between (1) sleep disturbance, (2) pain catastrophizing, (3) metabolic/inflammatory markers, (4) preoperative opioid use/polypharmacy, and chronic pain chronification or treatment failure. Random-effects meta-analyses (DerSimonian-Laird) were performed for each loop. Effect sizes were translated into a composite logistic regression model, the Pain Amplifier Loop Framework (PALF), using ln(OR) as first-order coefficient approximations. Results: Forty-four studies with over 500,000 participants were included. Pooled odds ratios were: sleep disturbance OR=1.80 (95% CI 1.65-1.96; k=16), pain catastrophizing OR=2.11 (95% CI 1.71-2.61; k=8), metabolic/fat mass OR=2.02 (95% CI 1.32-3.09; k=7), preoperative opioid use OR=4.48 (95% CI 2.87-6.97; k=6), and opioid-benzodiazepine co-prescription OR=2.62 (95% CI 1.76-3.89; k=7). All four loops converge on TLR4/NF-kB microglial signaling. The PALF model produces a probability of interventional failure enabling stratification into low, moderate, and high risk categories. Conclusions: Four amplifier loops independently increase chronic pain risk. The PALF provides a transparent, clinically actionable risk score requiring prospective validation.

ImportanceSpinal disorders are common and associated with high rates of low value care. Efforts to improve guideline concordance and value benefit from understanding the influence of population and environmental factors. ObjectiveQuantify geographic variation in population race/ethnicity, socioeconomic status, and health care professional (HCP) availability, and associated variation in service utilization and total cost for management of spinal disorders. Design, Setting, and ParticipantsThis retrospective cohort study examines a national sample of 1,534,280 complete episodes of a spinal disorder experienced in 2017-2019 using zip code and episode of care. Risk ratio (RR) and 95% confidence interval (CI), and ridge regression were used to examine associations between independent and dependent measures. ExposuresZip code level measures of population race/ethnicity and socioeconomic status were the primary independent measures. Main Outcomes and MeasuresAvailability of and access to 17 types of HCPs, use of 14 types of health care services, and total cost were the primary dependent measures. Results1,075,204 continuously insured individuals aged 18 years and older from 29,318 zip codes were associated with 1,534,280 episodes of a spinal disorder involving 531,115 HCPs generating $2,022,124,695 in expenditures. Compared to those in primarily white, middle income zip codes, individuals in non-white, disadvantaged zip codes were more likely to initially contact an emergency medicine physician (RR 2.23, 95% CI 2.11-2.36) or primary care provider (RR 1.40, 95% CI 1.38-1.42) and less likely to contact a chiropractor (RR 0.36, 95% CI 0.34-0.37). These individuals had higher exposure to prescription NSAIDs (RR 1.99, 95% CI 1.95-2.02), skeletal muscle relaxants (RR 1.57, 95% CI 1.52-1.59), opioids (RR 1.18, 95% CI 1.15-1.20), and CT scans (RR 1.94, 95% CI 1.84-2.04). Conclusions and RelevanceIndividuals in affluent, primarily non-Hispanic white zip codes have an abundance of options for managing a spinal disorder. Use of first line non-pharmacological and non-interventional options should be reinforced before second- and third-line services are considered. Individuals in low-income, non-white zip codes have less availability of non-pharmacological options, leading to greater use of emergency department and primary care and resulting in pharmaceutical management of spinal disorders. Sustainable models that increase availability of non-pharmaceutical options warrant further study. Key PointsO_ST_ABSQuestionC_ST_ABSCompared to the middle-income zip codes with a primarily non-Hispanic white population, do individuals with a spinal disorder living in zip codes characterized by socioeconomic disadvantage and a primarily non-white population have different care experiences? FindingsIndividuals with low back pain living in non-white, low-income zip codes have less availability of chiropractors, physical therapists and licensed acupuncturists and are more likely to seek initial treatment from an emergency department or primary care provider. These same individuals are more likely to receive pharmaceutical management, including prescription opioids, and less likely to receive guideline recommended non-pharmaceutical and non-interventional first line treatments. MeaningThese findings suggest the need to create economically sustainable models that ensure access to guideline concordant non-pharmaceutical treatment options in non-white, low-income communities.

Introduction: Pain catastrophizing and pain self-efficacy are well-established predictors of health outcomes in chronic pain. Higher pain catastrophizing, a maladaptive cognitive process, predicts worse health outcomes, whereas higher pain self-efficacy, an adaptive cognitive process, predicts better health outcomes. This study examined whether pain catastrophizing and pain self-efficacy interactions predict physical and psychosocial health outcomes at 3 months and their change over 3-months among patients with chronic pain who sought care at a tertiary pain clinic. Methods: Adults with chronic pain (N = 181; 66.7% female; Mage = 58.7) completed baseline assessments of the Pain Catastrophizing Scale (PCS), Chronic Pain Self-Efficacy Scale (CPSS), and PROMIS measures of physical (pain intensity, pain interference, physical function) and psychosocial health (depression, anxiety, anger, loneliness). PROMIS measures were repeated at 3 months. Hierarchical multiple regression analyses tested PCS, CPSS, and their interaction as predictors of outcomes at 3 months and change scores from baseline to 3 months. Results: The PCS by CPSS interaction significantly improved prediction for physical function (Change in R2 = 0.02, p = .02). Higher baseline self-efficacy predicted better physical function (Beta = 0.65, p < .001), but this effect weakened with higher levels of pain catastrophizing. The interaction also predicted change scores in physical function (p = .025) but was marginal after false discovery rate correction (p = .059). Additionally, a significant interaction emerged for loneliness change scores (p = .01): higher self-efficacy predicted greater reductions in loneliness, attenuated by higher catastrophizing. Conclusion: Pain self-efficacy interacted with pain catastrophizing to predict physical function and loneliness at 3 months. Greater self-efficacy was associated with better outcomes, with associations diminished with higher levels of pain catastrophizing. Findings highlight the moderating role of adaptive and maladaptive cognitions and suggest interventions should address both processes to optimize recovery in physical and social functioning.

High-frequency stimulation (HFS) is a human surrogate model of secondary hyperalgesia and a key experimental tool for understanding the mechanisms and modulation of central nociceptive pathways. An emerging area of research focuses on the role of top-down endogenous analgesic systems during secondary hyperalgesia development. However, the test-retest reliability of the early temporal changes in sensitivity are poorly understood. In the present study, we investigated the between-session reliability of the early temporal dynamics and late-phase expression of HFS-induced changes in mechanical pinprick sensitivity in a heterotopic area on the volar forearm in 28 healthy participants across five time points relative to HFS conditioning: -15, 5, 20, 35, and 50 minutes. Homotopic changes in single-pulse electrically evoked responses were also assessed although no primary hyperalgesia was evident. Baseline conditioned pain modulation (CPM), temporal summation of pain (TSP), and state-trait anxiety (STAI) were also assessed to investigate potential influences on heterotopic and homotopic responses. The present findings demonstrate the consistent induction of mechanical pinprick secondary hyperalgesia by the end of the HFS window (50 minutes) across repeated test session. However, a distinct reduction in the development of sensitivity was present during session 2. Furthermore, pain during HFS conditioning, anxiety, CPM, and TSP demonstrated no influence on secondary hyperalgesia development and were inadequate to explain between-session variance. These results suggest that careful planning around experimental designs, and the counterbalancing of experimental conditions should be considered when investigating modulating factors over the development of secondary hyperalgesia. Further research into factors influencing habituation across sessions is needed. PerspectiveHigh-Frequency Stimulation evokes mechanical secondary hyperalgesia across repeated sessions; however, sensitivity development is diminished, and unexplained by pain intensity during HFS conditioning, anxiety, or cuff algometry CPM and TSP.

It is recognised that chronic pain is one of the leading causes of disabilities worldwide. However, statistics on mortality and causes of death in people with chronic noncancer pain (CNCP) have been difficult to determine. This systematic review aimed to determine the mortality rate in people with all types of CNCP and the associated causes and risk factors of death. MEDLINE (Ovid) and EMBASE (Ovid) were searched on 23 March 2023 to identify epidemiological studies reporting mortality in people with CNCP. Nineteen observational studies were included. There were 28,740 deaths (7%) reported in a population of 438,593 people with CNCP (n=16 studies), giving a mortality rate of 6,553 deaths per 100,000 people. An exploratory meta-analysis found that the relationship between mortality and CNCP was statistically significant (mortality risk ratio: 1.47; 95% CI: 1.22-1.77; n=11 studies) when comparing people with CNCP to those without pain. People with CNCP were more likely to die from cardiovascular disease whereas those without pain were more likely to die from malignancy, respiratory and gastrointestinal diseases. Smoking, lower physical activity levels, and opioid use were risk factors for death in people with CNCP. This systematic review found that people with CNCP have a higher risk of mortality than people without chronic pain. To reduce mortality rates in people with CNCP, cardiovascular diseases and risk factors for death should be considered when managing people with CNCP.

BackgroundThe exact mechanisms underlying paediatric abdominal pain (AP) remain unclear due to patient heterogeneity. This study aimed to identify AP phenotypes and develop predictive models to explore associated factors. MethodsIn 13,790 children from a large birth cohort, data on paediatric and maternal demographics and comorbidities were extracted from general practitioner records. Machine learning (ML) clustering was used to identify distinct AP phenotypes, and an ML-based predictive model was developed using demographics and clinical features. Results1,274 children experienced AP (9.2 %) (average age: 8.4 {+/-} 1.1 years, male/female: 615/659), who clustered into three distinct phenotypes: Phenotype 1 with an allergic predisposition (n = 137), Phenotype 2 with maternal comorbidities (n = 676), and Phenotype 3 with minimal other comorbidities (n = 340). As the number of allergic diseases or maternal comorbidities increased, so did the frequency of AP, with 17.6% of children with [&ge;] 3 allergic diseases and 25.6% of children with [&ge;] 3 maternal comorbidities. The predictive model demonstrated moderate performance in predicting paediatric AP (AUC 0.67), showing that a childs ethnicity, paediatric allergic diseases, and maternal comorbidities were key predictive factors. When stratified by ML-predicted probability, observed AP rates were 18.9% in the <40% group, 44.8% in the 40-50% group, 60.6% in the 50-60% group, and 100.0% in the >60% group. ConclusionsOur findings reveal distinct phenotypes and associated factors of paediatric AP by an ML approach. These insights suggest potential targets for future research to clarify the underlying mechanisms of paediatric AP.

Structural neuroplasticity in the brain may contribute to the persistence of low back pain (LBP) symptoms and the disability associated with them. It is not known if structural adaptations are evident early in the lifespan in young adults with LBP. This study compared gray matter in cortical sensorimotor regions in young adults with and without persistent LBP and identified gray matter and clinical predictors of pain-related disability. Eighty-two individuals with and without a history of LBP participated. Peak and average gray matter density in cortical sensorimotor regions of interest was quantified using voxel-based morphometry. Pain-related disability, pain intensity, pain duration, and pain-related fear were also assessed. Multiple linear regression was used to determine independent predictors of pain-related disability. We document significantly greater peak gray matter density in individuals with LBP in the primary somatosensory cortex, angular gyrus, and the midcingulate cortex. Pain-related disability positively correlated with average gray matter density in the posterior cingulate cortex. The most robust predictors of disability were average gray matter in the posterior cingulate, pain intensity, and pain-related fear. We demonstrate that in young adults, persistent LBP, and pain-related disability, are linked with structural neuroplasticity in regions forming part of the brain network termed the pain matrix. In contrast with studies of LBP in older adults, our findings of increased rather than decreased gray matter in young adults with LBP suggest that gray matter may increase initially in response to nociceptive pain.

Chronic pain states are challenging to control with current drug therapies. Here, we demonstrate that a single dose of psilocybin can produce a sustained anti-nociceptive effect in a model of chronic neuropathic pain in male and female mice. Psilocybin anti-nociceptive effects were mediated by 5-HT2A receptors, although additional mechanisms might also be involved. Furthermore, a single dose of psilocybin caused a significant increase in the anti-nociceptive potential of gabapentin, a widely used treatment for neuropathic pain consistent with the establishment of longer lasting changes in network processing. Overall, these findings present the first preclinical evidence that psilocybin could be a valuable approach for treating chronic pain from nerve injury and serve as a new therapeutic addition for pain management.

Osteoarthritis (OA) represents a significant pain challenge globally, as current treatments are limited and come with substantial and adverse side effects. Voltage-gated calcium channels have proved to be pharmacologically effective targets, with multiple FDA-approved CaV2.2 modulators available for the treatment of pain. Although effective, drugs targeting CaV2.2 are complicated by the same obstacles facing other pain therapeutics-invasive routes of administration, narrow therapeutic windows, side effects, and addiction potential. We have identified a key regulator of CaV2.2 channels, collapsing response mediator protein 2 (CRMP2), that allows us to indirectly regulate CaV2.2 expression and function. We developed a peptidomimetic modulator of CRMP2, CBD3063, that effectively reverses neuropathic and inflammatory pain without negative side effects by reducing membrane expression of CaV2.2. Using a rodent model of OA, we demonstrate the intraperitoneal administration of CBD3063 alleviates both evoked and non-evoked behavioral hallmarks of OA pain. Further, we reveal that CBD3063 reduces OA-induced increased neural activity in the parabrachial nucleus, a key supraspinal site modulating the pain experience. Together, these studies suggest CBD3063 is an effective analgesic for OA pain.