European Journal of Pain

Objective: There is a bidirectional relationship between emotional distress and pain. However, this relationship is understudied in people with HIV in low-resource settings. This study sought to describe the temporal relationship between emotional distress and pain in people with HIV. Design: Longitudinal observational study. Methods: Participants with virally suppressed HIV, reporting either no pain or persistent pain at baseline, provided weekly remote ratings of distress, worst pain, and average pain using 0-10 visual analogue scales. Within-individual fluctuations in distress and pain were visualised over time. Group-level correlations were determined using Spearman's correlation tests. Cumulative link mixed models assessed whether distress and pain each predicted the other in the following week. Results: 72 participants provided responses over 49 weeks. The participants had a median (IQR) age of 43 (37-51) years, 63% (n=45) were unemployed and most were females (n=51;71%). Distress and pain fluctuated concurrently within individuals: distress was positively correlated with worst pain ({rho}=0.66, 95% CI= 0.60-0.72, p<0.001) and average pain ({rho}=0.70, 95% CI=0.64-0.75, p<0.001) intensity within the same week. Worst pain (OR=1.42, 95% CI=1.17-1.71, p<0.001) and average pain (OR=1.43, 95% CI=1.20-1.71, p<0.001) intensity both predicted distress in the next week. Distress predicted worst pain intensity (OR=1.25, 95% CI=1.07-1.46, p=0.023) but not average pain intensity (OR=1.19, 95% CI=1.01-1.40, p=0.152) in the next week. Conclusions: The temporal relationship between distress and worst pain intensity was bidirectional, whereas distress did not temporally predict average pain intensity. Both pain and emotional distress should receive attention from HIV research and clinical care in low-resource settings.

Chronic pain is highly heterogeneous, with individuals varying substantially in symptoms. pain severity, disability, affective distress, cognitive functioning, and trauma-related symptoms. This study examined whether working memory, post-traumatic stress symptoms (PTSS), trauma exposure, and pain modulation explain distinct or shared dimensions of chronic pain variability. Individuals with chronic pain completed clinical, cognitive, trauma-related, and behavioural pain modulation measures, as well as resting-state functional magnetic resonance imaging. Multivariate regressions were used to determine whether working memory, PTSS, trauma exposure, and pain modulation independently predicted chronic pain outcomes. Principal component analysis was used to identify latent dimensions of chronic pain, and mediation analyses tested whether behavioural pain modulation explained relationships between dlPFC to vlPAG resting-state functional connectivity and clinical pain outcomes. PTSS independently predicted affective outcomes, including depression, state anxiety, and trait anxiety, whereas working memory independently predicted pain severity and pain interference. Trauma exposure was associated with greater PTSS and poorer working memory, but did not independently predict core pain outcomes after accounting for these more proximal factors. Principal component analysis identified partially distinct affective and sensory-disability dimensions, while trauma exposure loaded primarily on a separate component characterized by greater PTSS and poorer working memory. Behavioural pain modulation showed broader relationships across symptom dimensions and was associated with dlPFC to vlPAG connectivity. Exploratory mediation analyses demonstrated that pain modulation mediated relationships between dlPFC to vlPAG connectivity and both pain severity and affective distress. These findings support an integrated model where PTSS and working memory are more proximal predictors of affect and severity respectively, and trauma exposure represents a more distal vulnerability factor that predicts both. Thus, pain modulation represents a shared mechanism linking cortico-brainstem connectivity to chronic pain intensity and affect. These variables need further testing for phenotyping people with chronic pain based on their specific clinical needs.

Background: Chronic pain affects hundreds of millions worldwide and remains a major clinical challenge, despite numerous available treatments. Advances in brain imaging offer a promising path toward identifying neural signatures of chronic pain, potentially enhancing diagnosis and guiding treatment. However, while a core set of brain regions, including the insula, cingulate, and somatosensory cortices, has been repeatedly implicated, findings regarding other regions and connectivity patterns involved remain inconsistent, with limited robust replication. Objective: To address these gaps, the present work characterizes resting-state functional connectivity and gray matter volume differences between chronic pain patients and pain-free controls. Methods: In this secondary analysis of publicly available data, anatomical and resting-state functional MRI were analyzed from 56 patients with chronic knee pain due to osteoarthritis and 20 pain-free controls. Group comparisons used Network-Based Statistic (NBS) and Bayesian multivariate regression models, controlling for demographic covariates. Results: In the pain group, about 75% of parcellated brain regions exhibited increased functional connectivity compared to controls. The 30 highest degree centrality regions in the NBS network were concentrated in regions consistent with prior pain neuroimaging findings. Additionally, chronic pain patients exhibited reduced gray matter volume (-3.98%; SD 1.2%) across 33% of parcellated brain regions, including key regions implicated in pain processing. Conclusions: These findings demonstrate widespread functional and anatomical neural alterations in chronic pain, revealing a global pattern of reorganization extending beyond previously reported network-pair effects. Characterizing such alterations may contribute to ongoing efforts to identify neuroimaging markers of chronic pain, with potential translational relevance.

Background: Fluctuations in pain intensity are intrinsic to non-specific chronic low back pain (nsCLBP). Nevertheless, pain fluctuations have rarely been considered when investigating pathophysiological mechanisms. Therefore, a novel study protocol was developed and implemented to systematically assess the impact of fluctuating pain states on pain-related measures. Methods: The final study cohort consisted of 45 nsCLBP patients and 47 age- and sex-matched healthy controls (HCs). Patients participated in three visits, conducted during different pain states (i.e. clinically relevant pain, low-intensity clinical pain / pain-free, clinically irrelevant pain induced using a Qutenza 8% capsaicin patch). Pain fluctuations were monitored through online assessments every four days and guided the pseudorandomized visit scheduling. HCs participated in a single visit. Each study visit comprised a multimodal battery of pain-related measures. Results: 93.33% of patients completed all three visit types in a pseudorandomized order (chi-squared=1.50, p=0.826). Visit scheduling was possible due to the high self-report adherence (median=93.48%), unrelated to self-report burden (rho=-0.097, p=0.53). Study visits were conducted during different pain states, as indicated by: i) the significantly higher low back pain intensity in the clinically relevant pain visit (mean[SD]: 3.98[0.90]), compared to the low-intensity clinical pain (1.03[0.86]) and clinically irrelevant pain (1.13[0.82]) visits (p-values<0.001), as well as by ii) the successful induction of a moderate-to-high clinically irrelevant pain across assessments. Conclusion: Despite scheduling complexity and pain state transition uncertainty, a pain state-dependent pseudorandomized study design is feasible and could improve the understanding of nsCLBP mechanisms.

Background: Sleep, pain, affect, cognition and energy (SPACE) has been described as a latent symptom-severity construct in chronic overlapping pain conditions. Its population-level structure and associations with chronic pain interference and functional disability remain uncertain. Methods: We conducted a cross-sectional analysis of UK Biobank participants. Prespecified standardised symptom domains were examined using correlation analysis, principal component analysis, exploratory factor analysis and k-means clustering. Associations with chronic pain interference, current work disability, poor self-rated health and longstanding illness or disability were assessed using covariate-adjusted logistic regression. A four-domain score excluding pain tested whether associations extended beyond the pain domain. Secondary analyses examined convergence with actigraphy, biomarkers, polygenic risk scores and brain magnetic resonance imaging phenotypes. Results: Of 501,935 eligible participants, 475,134 had complete domain data. Domains were modestly intercorrelated (r=0.04-0.46). Clustering identified lower- and higher-burden phenotypes comprising 70.5% and 29.5% of participants; current work disability occurred in 1.3% and 10.3%, respectively. Adding the four non-pain domains increased the area under the curve for chronic pain interference from 0.593 to 0.672 and for work disability from 0.748 to 0.850. Inclusion of pain increased the work-disability area under the curve to 0.863. Multimodal measures added smaller increments. Conclusions: A multidimensional symptom profile was identifiable at population scale and was concurrently associated with chronic pain interference and work disability, with non-pain domains contributing information beyond pain burden alone.

The anterior cingulate cortex (ACC) is a key brain center involved in cognitive and emotional processing that is implicated in a variety of neuropsychiatric disorders including chronic pain and depression. Circuit-targeted diagnosis and treatment of these disorders will require the capacity to precisely modulate ACC subregions. Toward that end, we recently developed and validated a novel low-intensity transcranial focused ultrasound device that can noninvasively and directly modulate ACC subdivisions in humans with millimeter precision. Here we describe the subjective reports of 36 individuals diagnosed with either chronic pain or major depression who received repeated brief stimulation trials (807 active, 797 sham; duration 30s-3min) spanning the dorsoventral extent of the ACC. Sonication immediately altered cognitive-emotional states (odds ratio 5.6, active versus sham), eliciting a positive-valence experience more often than negative (29% versus 8%) in both diagnostic groups. Sham-adjusted response rate varied across ACC targets, with the largest effects (Cohen's d ~ 0.8) observed in pregenual and subgenual ACC in subjects with chronic pain and depression, respectively. These rapid trial-by-trial responses to ACC stimulation predicted subsequent improvements in pain and depression severity at 24 hours. Collectively, these findings reveal that transcranial ultrasound can robustly evoke immediate, target-specific, clinically meaningful changes in cognitive-emotional state, demonstrating the potential of ultrasonic neuromodulation as a tool for individualized probing of circuit function and dysfunction.

Background Chronic postsurgical pain (CPSP) affects between 7-23% and 13-44% of patients after hip and knee arthroplasty, respectively. Standardised methods of pain assessment provide superior evaluation of pain, including the Oxford Joint Score Pain Subscale (OJS-PS). We aim to estimate the proportion of patients with a phenotype consistent with CPSP through a k-medoids clustering technique and identify a threshold on the OJS-PS to highlight such patients at a population level. Methods In this cross-sectional study Patient Reported Outcomes Measures data 6-months after hip and knee arthroplasty from 2017 to 2025 were examined. An adapted k-medoid clustering technique utilising subsampling, batch assignment and probabilistic consensus allocated clusters. A receiver operator characteristic analysis identified a threshold on the OJS-PS noting the lowest scoring cluster. Our categorisation was compared to self-reported severe or moderate pain; sensitivity, specificity and accuracy of this categorisation were calculated. Results We analysed 109,542 hip and 113,799 knee arthroplasty patients; three clusters were used in each analysis. After hip arthroplasty: 14.4% of patients were assigned to the cluster with the lowest median OJS-PS of 11 [IQR 8 - 13]. A threshold of 15.5 classified patients as severe or moderate pain with 60.6% sensitivity, 91.0% specificity and 85.7% accuracy. Similarly, after knee arthroplasty, 25.3% were assigned to the cluster with the lowest median OJS-PS of 14 [IQR 11 - 16]. A threshold of 18.5 on the OJS-PS had an 85.4% sensitivity, 88.4% specificity and 87.8% accuracy for classifying patients with self-reported severe or moderate pain. Conclusions This robust and scalable clustering technique on ordinal clinical data estimates the proportion of patients reporting a phenotype consistent with CPSP. On a population level the thresholds identified on the OJS-PS could aid screening for potential CPSP patients 6 months after hip and knee arthroplasties.

Background: Chronic pain is associated with impaired muscle health, but whether these changes reflect site-specific factors, broader systemic factors, or both remains unclear. The purpose of this study is to determine whether normative markers of muscle health derived from MRI show site-specific patterns in chronic pain. Methods: UK Biobank participants who underwent whole-body MRI from 2006 to 2010 were included in this retrospective cross-sectional study. The MuscleMap Toolbox quantified volume and intramuscular fat (IMF) in 42 muscles of the abdomen, pelvis, and thigh. Normative models trained on a no pain group generated muscle-specific deviations from normal (i.e., Z-scores) for single- and multi-site chronic and acute pain. Results: Of 17,843 participants, the primary site-specific analysis included 9,704 no pain, 885 single-site chronic back pain (CBP), 438 single-site chronic hip pain (CHP), and 1,315 single-site chronic knee pain (CKP) participants (n=12,342; mean age 63.7{+/-}7.5 years; 52.7% female). Additional analyses included single-site chronic neck/shoulder pain, acute pain, and multi-site chronic pain groups. In CBP, deviations were localized to abdominal muscles, with decreased volume in 6/8 and increased IMF in 6/8. In CHP, deviations were broad, with decreased volume in 3/8 of the abdominal and 14/26 of the thigh muscles, and increased IMF in 6/8 of the abdominal, 5/8 of the pelvic, and 4/26 of the thigh muscles. In CKP, deviations were localized to thigh muscles, with decreased volume in 8/26 and increased IMF in 6/26. Acute pain groups showed no significant differences except for decreased volume in one thigh muscle in acute knee pain. With each additional chronic pain site, volume decreased ({beta}=-.078;IQR:-0.100-0.051), and IMF increased ({beta}=.085;IQR:0.066-0.101). Combined Z-scores classified chronic pain groups better than chance (accuracy: 48.6%;p<.001), but not acute pain groups (accuracy: 39.0%;p=.20). Conclusions: Whole-body MRI combined with AI-driven muscle segmentation and normative modeling revealed site-specific patterns of muscle health in single-site chronic pain.

The Acute to Chronic Pain Signatures (A2CPS) project is a large, multisite, longitudinal observational study designed to identify biomarkers that predict the transition from acute to chronic pain following surgery in more than 2200 patients. Two participant cohorts were recruited before undergoing either knee arthroplasty or thoracic surgery. A unique feature of this study is its comprehensive evaluation of pain, including evoked and recall pain measures collected at baseline, 6-weeks, and 3-months following surgery, in addition to the primary pain outcome assessed remotely at 6 months. This paper describes the acquisition, quality control procedures, and available pain and pain sensitivity variables included in the A2CPS study. Self-report pain assessments include surgical site (i.e., index) pain intensity, pain interference and quality, spatial distribution of pain using body maps, and pain-related dysfunction specific to each cohort. Quantitative sensory testing yielded evoked pain sensitivity data including pressure pain thresholds, temporal summation of pain, dynamic mechanical allodynia, and conditioned pain modulation at both index and common sites across cohorts. Movement-evoked pain was assessed for each cohort using relevant functional tasks (knee: 10m walk and five-time-sit-to-stand tests, thoracic: deep breathing and coughing). Using baseline data from release v2.1.0, comprising approximately 1,400 participants, we evaluated interrelationships among pain variables. Overall, the A2CPS pain and pain sensitivity data provide a robust, comprehensive set of variables that supports the study goal of uncovering predictive biomarkers of post-operative chronic pain and enables broader exploration relative to other study outcomes, including imaging, psychosocial, and omics data.

Objectives To analyse the long-term effects of a cruciate ligament (CL) injury on health and socioeconomic outcomes. Methods We used a comprehensive national injury insurance database to identify CL injuries occurring in New Zealand between 2009 and 2022, and employed a doubly robust staggered difference-in-differences research design to identify the effects of these injuries on outcomes up to 10 years after injury. The outcomes of interest were healthcare use (hospitalisations, emergency department visits, medications, knee replacement surgery for osteoarthritis), associated healthcare costs, and labour market outcomes (employment rates, income, and government benefit payments). Results We identified 61 344 CL injuries for inclusion in the analysis. Over 10-year follow-up, a CL injury resulted in increased healthcare use (0.6 more hospitalizations [95%CI 0.4 to 0.7], 1.7 more days spent in hospital [95%CI 1.3 to 2.1], 0.4 more emergency department visits [95%CI 0.3 to 0.6], 2.5 more outpatient visits [95%CI 1.8 to 3.2], and 4.7 more medications dispensed [95%CI -1.8 to 11.2]) and public healthcare costs ($7 537; 95%CI 5 888 to 9 186), reduced income (-$6 060; 95%CI -11 644 to -475), and increased benefit payments ($1 152; 95%CI 542 to 1 761). Conclusion CL injuries have long-term impacts on healthcare use and socioeconomic outcomes. Strategies to reduce the incidence of CL injuries have the potential to realise large health and economic benefits.

Placebo analgesia varies substantially across individuals, yet the sources of this heterogeneity remain incompletely understood. Pain-reporting variability may represent an underrecognized predictor of placebo responsiveness. This study examined whether variability and reliability of pain reporting predict placebo analgesia in an experimental pain setting. Eight hundred and three participants (401 individuals with temporomandibular disorder and 400 healthy controls) completed a standardized thermal pain paradigm involving calibration, placebo conditioning, and testing phases. We obtained repeated heat temperatures (four) during thermal calibration and pain ratings during conditioning test (24 trials). We used these measurements to quantify within-person pain-reporting variability using standard deviation (SD) and coefficient of variation (CoV), and reliability using intraclass correlation coefficients (ICC). Placebo analgesia was calculated as the difference in pain ratings between control and placebo cue trials during testing. Regression models examined associations between reporter characteristics and placebo analgesia controlling for age, sex, race and experimenters. Variability of thermal pain responses during calibration did not predict placebo analgesia. Greater pain-reporting variability during conditioning was associated with reduced placebo analgesia (higher SD and CoV), and this effect was mediated by slower acquisition of the cue pain contingency. Conditioning-phase reliability was not associated with placebo analgesia, whereas three clusters of learning profiles predicted placebo effects. Thus, individual differences in pain-reporting variability during conditioning, rather than baseline sensory variability, contribute to heterogeneity in placebo analgesia. These findings suggest that variability during acquisition processing matters more than general sensory variability influencing the magnitude of placebo effects.

Chronic pain in later life may be accompanied by alterations in brain structure and cognition, but whether pain extent and central sensitization symptoms identify distinct brain-behavior patterns remains unclear. We examined associations of pain extent and central sensitization symptoms, assessed using the 9-item Central Sensitization Inventory (CSI-9), with regional gray matter volume and cognitive function in community-dwelling older adults. This cross-sectional study included 272 participants with chronic pain from the Bunkyo Health Study. Participants were classified as having single-site or multisite pain and by CSI-9 score as having lower or higher scores, with 12 or higher defining the higher group. Regional gray matter volume was quantified using 0.3-Tesla magnetic resonance imaging, and cognition was assessed using the Trail Making Test Part B (TMT-B), processing speed, and global and domain-specific measures. Pain extent and CSI-9 group interacted for TMT-B performance, with the longest completion time in participants with single-site pain and a higher CSI-9 score. No other cognitive outcome remained significant after correction for multiple testing. In categorical analyses, the higher CSI-9 group had smaller volumes in the right middle frontal gyrus, bilateral anterior cingulate cortex, right insula, right hippocampus, and bilateral amygdala, whereas pain extent and the interaction were not associated with regional volume. In a contextual comparison, only the single-site/higher CSI-9 group showed slower TMT-B performance than participants with no current pain. Pain extent and central sensitization symptoms may represent partly distinct dimensions of chronic pain, although the small single-site/higher CSI-9 group and attenuation in several sensitivity analyses warrant caution. Significance StatementChronic pain is often described by where it hurts, but location alone may miss important differences between patients. In older adults, pain extent and symptoms measured by the 9-item Central Sensitization Inventory captured partly different aspects of chronic pain. Participants with pain at one site and a higher CSI-9 score performed most slowly on a task requiring attention and mental flexibility, whereas differences in regional brain structure were related mainly to CSI-9 score rather than pain extent. These findings support a multidimensional approach to chronic pain and may inform future research on cognitive vulnerability and brain health across pain conditions. Graphical Abstract Text O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=120 SRC="FIGDIR/small/742487v1_ufig1.gif" ALT="Figure 1"> View larger version (47K): org.highwire.dtl.DTLVardef@17eacb7org.highwire.dtl.DTLVardef@17d535borg.highwire.dtl.DTLVardef@ebb79forg.highwire.dtl.DTLVardef@16464b7_HPS_FORMAT_FIGEXP M_FIG C_FIG Among older adults with chronic pain, pain extent and CSI-9 score captured different aspects of vulnerability. Slower performance on a task requiring attention and cognitive flexibility was concentrated in those with single-site pain and higher CSI-9 scores, whereas regional brain-volume differences tracked CSI-9 category more broadly.

Nociceptive pain is the most common pain condition, and moderate-to-severe nociceptive pain substantially impacts daily functioning, constituting a significant public health burden. Despite this, most studies investigating the neural mechanisms underlying somatosensory processing and inhibition have focused on other pain conditions (e.g., neuropathic, nociplastic, or mixed pain). Thus, the extent to which neural aberrancies detected in these other populations extend to or differentiate from nociceptive pain conditions remains largely unknown. In this study, 29 individuals with moderate-to-severe nociceptive pain (MSNP) and 47 pain-free (PF) controls underwent magnetoencephalography (MEG) alongside a paired-pulse somatosensory stimulation paradigm to examine somatosensory cortical processing and functional inhibition. Pain status and intensity were determined using validated pain questionnaires, painDETECT and PROMIS-29, respectively. MEG oscillatory responses were source localized via a beamformer to the primary somatosensory cortex (S1) and time series data were extracted from the peak voxel to quantify the dynamics of somatosensory gating (SG; index of cortical inhibitory processing), oscillatory response power, and spontaneous power. We found that adults with MSNP exhibit aberrant theta SG in contralateral S1 compared to PF controls, reflecting reduced functional inhibition of innocuous stimulus processing in this region. Additionally, individuals with MSNP demonstrated exaggerated gamma responses but blunted alpha responses in contralateral S1 to innocuous stimulation. Finally, individuals with MSNP were characterized by weaker spontaneous alpha in contralateral S1 that scaled with self-reported pain intensity. Together, these findings suggest that experiencing MSNP is associated with disrupted somatosensory and cortical inhibitory processing.

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.

Understanding the complex network that regulates pain is fundamental to develop strategies to combat its growing prevalence and increase useful therapeutics. Although extensive literature identifies the importance of cannabinoid receptors and endocannabinoids in controlling pain, their efficacy and loci of action remain debated. To directly test the actions of peripherally restricted cannabinoids and elucidate the minimal circuitry capable of producing cannabinoid-mediated analgesia, we utilized a novel genetic approach that allows for cell-specific reactivation of cannabinoid receptor 1 (CB1R) selectively in peripheral sensory neurons using newly developed CB1R floxed-stop-floxed mice (CB1RLOXTB) crossed with Nav1.8-cre mice (Nav1.8+/-:CB1RLOXTB). Ex vivo and in vivo experiments confirmed successful knockout and reactivation of CB1R. Wildtype littermate controls, but neither Nav1.8+/-:CB1RLOXTB nor CB1RLOXTB animals, exhibited robust analgesia after systemic WIN55,212-2 (WIN) treatment in the tail flick assay. Furthermore, the presence of CB1R on Nav1.8 neurons was not associated with either a difference in the development of inflammatory pain or the response to WIN. However, after neuropathic injury, CB1RLOXTB animals displayed an earlier onset of both mechanical and thermal hypersensitivity than their Nav1.8+/-:CB1RLOXTB or wildtype counterparts, suggesting a dual role for CB1R in inflammatory and neuropathic pain. These studies represent an important approach to further improve our mechanistic understanding of cannabinoid modulation of pain in the nervous system and begins to settle long-standing controversies in cannabinoid literature. Table of ContentsPeripherally restricted cannabinoids show strong preclinical analgesic efficacy but have not translated clinically. Using a genetic model restricting CB1R to Nav1.8-expressing sensory neurons, we show peripheral neuronal endocannabinoid signaling is required for chronic, but not acute pain modulation. This dissociation suggests clinical failures may reflect testing peripheral cannabinoids in acute rather than chronic pain paradigms, informing future translational strategies.

Background. Pain influences motor function and has been proposed to reduce corticospinal and intracortical excitability. At the same time, performance can be maintained during pain, at the cost of increased perceived effort, a centrally generated signal reflecting resource engagement. Here, we tested whether contralateral thermal heat pain-related changes in corticospinal and intracortical excitability contribute to increased effort perception. Methods. In this preregistered transcranial magnetic stimulation (TMS) study, twenty-one healthy participants received single and paired pulse TMS at rest and during submaximal isometric right wrist flexions performed at 20% maximal peak force. Trials were conducted under a control condition or during contralateral thermal stimulation (painful or non-painful warm) applied to the left forearm. After each contraction, participants rated the intensity of their perceived effort. Corticospinal and intracortical excitability of the right wrist flexor was assessed at rest and during submaximal contractions. Results. Contralateral heat pain significantly increased perceived effort compared with the control and warm conditions. Contralateral heat pain did not reduce corticospinal or intracortical excitability. Conversely, contralateral heat pain increased corticospinal excitability, reflected primarily in decreased cortical silent period duration. Perceived effort was associated with the subjective experience of pain rather than with TMS-derived variables. Conclusions. These findings suggest that increased effort during contralateral heat pain cannot be attributed to inhibition of the primary motor cortex or the corticospinal pathway. The higher perceived effort in the presence of contralateral heat pain likely reflects the cognitive cost of pain rather than alterations in the transmission of the motor command.

Effective pain relief is a central goal of medical care, yet objective biomarkers of pain relief are lacking. Using task-based functional MRI and a capsaicin-induced tonic heat pain model, we experimentally elicited both pain exacerbation and pain relief within the same individuals. Existing brain-based signatures, including the Neurologic Pain Signature (NPS), reliably detected pain increases, but failed to capture pain relief. We therefore developed the PAin and RElief Signature (PARES), a multivariate brain signature trained to predict bidirectional changes in pain perception in n = 61 healthy controls. PARES robustly predicted both pain increases and relief and generalized to an independent cohort of people with chronic back pain (n = 58), who underwent the same experimental procedures. Together these findings establish a neural signature of pain relief and provide a potential biomarker for treatment stratification and analgesic development.

Validated measures of pain catastrophizing primarily assess catastrophizing as a stable trait. However, emerging evidence suggests catastrophizing fluctuates with context, highlighting a need for ecologically valid methods to capture it. This study evaluated large language models (LLMs) as implicit markers of catastrophizing from free text responses from ninety-one adults with chronic pain receiving long-term opioid therapy (57.3 percent Female; mean age = 60.5 years). Patients completed baseline measures, including the trait pain catastrophizing scale (PCS), followed by a 10 minute writing task after random assignment to a negative, positive, or neutral pain-coping condition. State affect and pain were assessed before and after writing tasks and again after a cold pressor task (4 degrees C; <= 2 minutes). A state PCS followed the cold pressor task. Free text responses were analyzed using four LLMs (Claude Opus 4; GPT Mini 4o; Llama 4 Maverick; and Gemini 2.5 Pro). ANOVA based results supported discriminant validity, as all four LLM-derived pain catastrophizing scores differentiated negative from positive and neutral pain-coping conditions. Convergent validity was model dependent; only Gemini derived scores correlated with state catastrophizing (r = .22) and pain unpleasantness (r = .23). Divergent validity was mixed. LLM derived scores were unrelated to pain intensity, but Gemini and Claude derived scores showed small correlations with trait PCS (rs = .21; 28, respectively). All LLM-derived scores also correlated with negative affect (rs range = .29 - .41), comparable in magnitude to state PCS, suggesting limited specificity. These findings provide preliminary evidence that certain LLMs may serve as implicit markers of state pain catastrophizing, but further study is needed.

Background: Heatwrap is recommended for acute low back pain (ALBP), and previous research found heatwrap plus exercise more effective than each intervention alone. While recommended by clinical guidelines, their impact on mechanistic outcomes is unknown. This trial aimed to (i) assess immediate and short-term effects of heatwrap alone or combined with exercise, compared with a sham heatwrap, on pain sensitivity, lumbar muscle activity, current pain intensity, and trunk flexion range of motion, and (ii) explore whether changes in pain sensitivity and lumbar muscle activity are associated with changes in clinical symptoms from baseline to 1-week follow-up. Methods: A randomised controlled trial took place at a single research center. Of 315 individuals screened for eligibility, 99 adults with ALBP were recruited and assigned to one of three intervention groups: heatwrap plus exercise (n=34), heatwrap alone (n=33) or sham heatwrap (n=32). Interventions were applied for one hour at the first visit, and immediate effects were measured. Then, interventions were applied for 7 days, and short-term effects were measured at 1-week follow-up. Outcomes included pressure pain threshold, temporal summation of pain, flexion-relaxation ratio, trunk range of motion and current pain intensity. Results: Heatwrap and exercise did not produce greater effects over time than heatwrap alone or a sham heatwrap on all outcomes, and changes in sensorimotor outcomes at one week were not associated with changes in symptoms. Conclusions: Heatwrap and/or exercises did not influence specifically the potential sensorimotor mechanisms tested in individuals with ALBP. Trial registration: ClinicalTrials.gov; registration number: NCT03986047

Background: Chronic pain affects approximately 20% of children and youth worldwide and is associated with mental and physical health impacts. Canada-specific data on the prevalence of chronic pain in children and youth are limited, highlighting the need for current high-quality population-based estimates Aims: The aim of this study is to provide national estimates of self-reported chronic pain among Canadian children and youth by pain type (headache stomach ache, backache), sex (female, male), age group (5-11, 12-17 years) and province or territory. Methods: Publicly available data were used from the 2019 Canadian Health Survey on Children and Youth (CHSCY), a population-based survey conducted by Statistics Canada using a nationally representative sample of Canadian children and youth Results: Overall, headaches were the most commonly reported pain type (15.4%), followed by stomach aches (12.5%), and backaches (11.1%). Prevalence was consistently higher among females than males and among youth than children, with youth girls reporting the highest prevalence across all pain types. Prevalence also varied geographically, with some of the highest estimates observed in the Atlantic Provinces. Conclusions: Chronic pain affects substantial proportions of Canadian children and youth with disparities observed by pain type, sex, age, and geography. These findings under score pediatric chronic pain as an important public health issue and highlight the need for equity-oriented approaches that address the needs of populations experiencing the greatest burden.