The Journal of Pain

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

Chronic widespread pain (CWP) is highly prevalent among minoritized adults with clinical obesity, and symptom management is challenging. Weight loss via bariatric surgery is often recommended to improve musculoskeletal pain. However, there is significant variation in pain trajectories following bariatric surgery, and the impact of weight loss on movement-evoked pain is largely unknown. The current study aims to systematically characterize and quantify longitudinal changes in pain at rest and movement-evoked pain up to 6 months post-surgery, and to determine whether pain modulatory mechanisms, joint motion, and mechanical loading biosignatures mediate the relationship between weight loss and pain change. This study protocol details the research methodologies and procedures for a prospective observational cohort study of 60 individuals undergoing bariatric surgery for weight loss. Participants will complete questionnaires, anthropometric measurements, clinical and experimental pain testing, functional testing, and a standardized movement testing battery to assess joint motion and mechanical loading using camera-based motion capture before and at 3 and 6 months post-bariatric surgery. Generalized linear mixed models to assess the significance of changes in PAR, MEP, and all patient-reported outcome measures. Reduced models will treat the main effect of time as a fixed factor, and intra-individual repeated measures as random effects. Ethics and dissemination: This study protocol has been registered as an observational study with ClinicalTrials.gov (NCT0675386) in the United States and has been approved by the NYU Langone Health Institutional Review Board (IRB#: i21-01652) and the New York City Health + Hospitals/Bellevue Research Office (Bellevue Study ID #: STUDY00003739). Study results will be published in peer-reviewed journals and presented at national and international conferences and community events.

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.

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.

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.

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.

Spinal cord stimulation (SCS) is an established therapy for neuropathic pain, typically delivered at either low (60 Hz) or high (1 kHz) frequencies, with analgesic effects largely dependent on active stimulation. Here, we investigated whether combined-frequency SCS produces sustained analgesia beyond stimulation periods and explored the underlying mechanisms. Using a spared nerve injury (SNI) model in both rats and mice, we applied dual-frequency SCS (60 Hz + 1 kHz). This paradigm produced robust reversal of mechanical allodynia during stimulation and, notably, a progressive and long-lasting analgesic effect that persisted for days to weeks after stimulation cessation. RNA sequencing revealed pronounced immune-related transcriptional changes in the spinal cord, including upregulation of innate immune, pro-resolution, and neutrophil-associated pathways. Functional studies demonstrated that neutrophil depletion attenuated SCS-induced analgesia, whereas intrathecal S100A8 treatment mimicked therapeutic effects via CD69/SOCS3 signaling. These findings identify dual-frequency SCS as a promising strategy to prolong analgesia and highlight a critical role for neuroimmune modulation in sustained pain relief. HighlightsO_LICombined-frequency, not single-frequency SCS, sustains analgesia during washout C_LIO_LICombination SCS induces robust immune activation in spinal cord and DRG C_LIO_LICombination SCS increases spinal perfusion and promotes neutrophil recruitment C_LIO_LINeutrophil signaling contributes to sustained SCS analgesia C_LI

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.

Objective: To evaluate the clinical efficacy of non-invasive electrical pulsed radiofrequency (PRF) stimulation on diagnostic thresholds and subjective pain in chronic, pedal diabetic peripheral neuropathy (DPN). Methods: A randomized, single-blind, placebo-controlled trial (ClinicalTrials.gov: NCT07725419) enrolled 92 patients with pedal DPN naive to PRF and scoring [&ge;] 4/10 on the Douleur Neuropathique 4 (DN4) test. Participants received either active PRF stimulation (n = 46) or a non-stimulating placebo (n = 46) applied bilaterally to the sciatic nerve in the popliteal fossa for 10 minutes per limb, once weekly for three weeks. The primary outcome was clinical neuropathic resolution (DN4 < 4). Secondary outcomes included subjective pain tracking via the Brief Pain Inventory-Short Form (BPI-SF) Worst Pain scale over a 6-month follow-up window. Missing data were handled via Non-Responder Imputation (NRI). Longitudinal continuous trajectories were modeled using Linear Mixed-Effects Models (LMMs) adjusted for age, gender, and baseline medication use. Results: In the Intention-to-Treat population (N = 92), a significant diagnostic responder effect occurred at 3 months, with 39.1% of active patients dropping below the diagnostic threshold for neuropathy (DN4 < 4) versus 19.6% of placebo controls (p = 0.039). For subjective pain, 47.7% of active patients achieved a Minimally Clinically Important Difference ([&ge;] 3-point reduction) in BPI Worst Pain at 1 month compared to 19.4% of placebo controls (p = 0.008). Multivariable logistic regression identified active treatment as a significant independent predictor of clinical response (Adjusted OR = 4.86; 95% CI: 1.56 to 17.53; p = 0.010). Continuous LMM tracking confirmed a statistically significant treatment-by-timepoint interaction for BPI Worst Pain at 1 month (p = 0.046). Conclusion: A brief, three-week course of non-invasive PRF stimulation serves as a safe, effective, non-pharmacological adjunct that aids in managing the diagnostic presentation of neuropathic pain and mitigates worst pain experiences in patients suffering from pedal DPN.

Nerve growth factor (NGF) is a key mediator of pain through activation of the high-affinity tropomyosin receptor kinase A (TrkA) and the low-affinity neurotrophin receptor (p75NTR). Although neuronal TrkA signaling is well established, the contribution of non-neuronal cells to NGF- dependent pain remains unclear. Here, we show that NGF and its precursor proNGF engage distinct cellular mechanisms. Intraplantar NGF induced acute nociception, heat hyperalgesia, mechanical allodynia, and cold hypersensitivity, whereas cleavage-resistant proNGF selectively evoked mechanical allodynia and cold hypersensitivity. Pharmacological and cell-specific genetic approaches demonstrated that acute nociception and heat hyperalgesia require neuronal TrkA, whereas mechanical and cold hypersensitivity depend on p75NTR activation in Schwann cells. In Schwann cells, NGF and proNGF induced p75NTR-dependent calcium release, followed by TRPA1 activation, mitochondrial ROS production, and NOX1-dependent oxidative amplification. Inhibition of ROS or TRPA1, or Schwann cell-specific Trpa1 deletion, markedly reduced mechanical allodynia and cold hypersensitivity without affecting acute nociception or heat hyperalgesia. These findings identify a Schwann cell p75NTR-ROS-TRPA1 pathway sustaining persistent pain and highlight non-neuronal p75NTR signaling as a potential therapeutic target.

Urinary tract infections (UTIs) are a major risk factor for interstitial cystitis/bladder pain syndrome (IC/BPS), yet the mechanisms driving chronic pelvic pain and associated symptoms remain poorly understood. Here, we investigated the role of microglia and Toll-like receptor 4 (TLR4) in a mouse model of post-UTI chronic pelvic pain (PUPP). Infection with E. coli induced persistent pelvic allodynia that was significantly attenuated by microglial depletion (PLX5622) or inhibition (minocycline), indicating a key role for microglia in pain maintenance. In contrast, microglial depletion did not improve urinary dysfunction or anxiety- and depression-like behaviors. Prefrontal cortex microglia of PUPP mice exhibited reduced microglial branching complexity and a less ramified phenotype, indicative of an activated microglial state. Transcriptomic profiling of brain CD11b+ cells revealed a reactive microglial signature enriched for chemokines, NFKB-related genes, and immediate early response genes, alongside pathways involved in immune regulation and leukocyte recruitment. Both general and microglia-specific TLR4 deletion reduced pelvic allodynia and reduced microglial morphological features of activation. Consistent with this, pharmacological TLR4 inhibition in vitro suppressed LPS-induced NFKB activation, cytokine secretion, and CD68 expression. Together, these findings identify microglial TLR4 as a critical mediator of post-UTI chronic pelvic pain.

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.

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.

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.

Endometriosis is a prevalent condition characterized by chronic pelvic pain that is frequently refractory to treatment. While the mechanisms underlying this pain remain poorly defined, clinical evidence often indicates that lesion innervation, but not disease stage (e.g. number and depth of lesions), correlate with pelvic pain severity. However, characterization of lesion-innervating neurons is incomplete, revealing an opportunity to identify novel, disease-modifying therapeutics. Here, we coupled functional analyses of lesion-innervating neurons in a mouse model with concurrent identification and characterization of lesion-innervating neurons from pain-phenotyped endometriosis patients. Following the confirmation of abdominal-directed pain-like behaviors in the mouse model, electrophysiological analysis revealed that lesion-innervating dorsal root ganglion (DRG) neurons are hyperexcitable compared to matched controls. These neurons are predominantly small-diameter and bind Isolectin B4, an established marker of the GDNF Family Ligand receptor, Ret. GDNF is concentrated within the stromal layer of both mouse and human lesions, adjacent to axons expressing the GDNF co-receptor, GFR1. Critically, clinical pain correlates with lesion GDNF level, axonal density, and neuronal GFR1 levels. These data provide evidence that endometrial lesions may recruit the Ret-positive subpopulation of nociceptors where they become sensitized and increase patient pain.

In human dorsal root ganglia (DRG), and trigeminal (TG) neurons, the various voltage-gated sodium channel (Nav) isoforms play critical roles in the firing of action potentials, which drive electrical impulses that encode somatosensations including, itch, and pain. The SCN11A gene encodes the tetrodotoxin (TTX)-resistant voltage-gated sodium channel Nav1.9, characterized by unique gating properties. Unlike other isoforms, the Nav1.9 channel activates and inactivates slowly and has a hyperpolarized voltage-dependence of activation and depolarized voltage-dependence of inactivation. This leads to a large window current that has been suggested to function as a regulator of the resting membrane potential of neurons. Mutations in Nav1.9 channels lead to congenital insensitivity to pain (gain-of-function) or familial episodic pain syndrome (loss-of-function) suggesting the channel is a critical mediator of pain. Despite its relevance in pain pathophysiology, most existing data relies on rodent models or heterologous expression systems, leaving the specific pharmacology and biophysical behavior of these channels in human primary neurons largely unknown. In this study, we pharmacologically isolated and characterized native Nav1.9 channel currents in human DRG and TG neurons to compare their biophysical profiles. Our findings reveal significant kinetic and voltage-dependent differences between the two populations. Specifically, Nav1.9 channels in TG neurons exhibit a right-shifted steady-state inactivation curve, a larger window current, and faster activation kinetics compared to those in DRG neurons. In addition, conditions that simulate inflammatory states in-vivo greatly potentiates the Nav1.9 currents consistent with similar observations in rodent models. By detailing these distinct biophysical properties, this research offers crucial insights into Nav1.9 channel function relevant for drug discovery efforts aimed at developing analgesics for both acute and chronic pain.

Background: People with disabilities (PWD) represent over one-quarter of the US population and disproportionately experience chronic pain, yet limited research explores disparities they face in opioid use disorder (OUD) treatment. Objective: To examine disparities across disability status regarding opioid use disorder (OUD)-related outcomes and understand how chronic pain interacts with these associations. Methods: We completed a cross-sectional, secondary analysis of data from the All of Us Research Program, including 370,722 adults with electronic health record data available between January 2021-September 2023. We identified prevalence of disability, chronic pain, OUD, receipt of medications for OUD (MOUD), and OUD remission using diagnostic codes. We performed interaction analyses between chronic pain, disability subtype, and MOUD receipt in affecting OUD outcomes. Results: OUD was more common among individuals with physical (aOR: 2.74, 95% CI: 2.54-2.95), cognitive (2.19, 1.94-2.45), and multiple disabilities (2.43, 2.19-2.68), compared to those without disabilities. Among patients with OUD, those with physical disabilities were less likely to receive MOUD (0.81, 0.69-0.94). Compared to those without disabilities, chronic pain was associated with higher probabilities of OUD diagnosis and lower probabilities of MOUD and OUD remission across all subjects. These relationships were stronger for OUD diagnosis in cognitive disabilities, MOUD in multiple disabilities, and OUD remission in physical disabilities. Conclusions: Disability and chronic pain jointly shape disparities in OUD treatment and underscore the urgent need for care models that integrate OUD treatment with pain management and address the unique access challenges faced by people with disabilities.

Accurate assessment of pain in animal models is essential for understanding pain mechanisms, developing analgesics, and ensuring animal welfare. The Mouse Grimace Scale (MGS) provides a sensitive, non-invasive measure of spontaneous pain by quantifying pain-related facial expressions, but its utility is limited by labor-intensive manual scoring, observer variability, and reliance on static images that fail to capture the temporal dynamics of facial behavior. Existing automated approaches improve throughput but typically rely on highly standardized imaging conditions, selected viewing angles, and static facial appearance, while providing limited temporal resolution and little insight into the relative contributions of individual facial action units. Here, we introduce LabGrymace, an open-source, artificial intelligence-powered framework for automated, frame-by-frame analysis of pain-related facial dynamics in freely moving mice. Built on the LabGym behavioral analysis platform, LabGrymace uses deep-learning-based facial feature detection and tracking to quantify ear, eye, and nose movements continuously from video recordings. To generate a quantitative pain metric and facilitate reproducibility, we calibrated facial dynamics against graded chemogenetic activation of nociceptors and identified the kinematic features most strongly associated with pain intensity. These features were integrated into a weighted composite pain score that reflects the differential contributions of individual facial action units. LabGrymace accurately classified pain-related facial actions and generated continuous pain scores without manual frame selection or restrictive recording conditions. The resulting pain scale exhibited dose-dependent responses generalized across distinct pain modalities, including visceral pain induced by MgSO and somatic pain induced by capsaicin. By combining automated facial-feature analysis with quantitative temporal modeling, LabGrymace provides an objective, scalable, interpretable, and flexible tool for assessing spontaneous pain in laboratory mice.

Background: Stroke remains a leading cause of death and disability worldwide. Matrix metalloproteinases (MMPs), particularly MMP-9 and MMP-12, contribute to early blood-brain barrier (BBB) disruption, neuroinflammation, haemorrhagic transformation, and intracerebral haemorrhage (ICH). Intravenous thrombolysis is the only widely used pharmacological therapy for acute ischaemic stroke, but its utility is limited by narrow eligibility criteria and haemorrhagic risk. Inhibition of MMPs in the acute phase may offer a complementary neurovascular protective strategy. Methods: AZD1236, a selective dual MMP-9/-12 inhibitor, was evaluated in transient and permanent middle cerebral artery occlusion models and in a collagenase-induced ICH model in young, aged, obese, and female mice. Drug or vehicle was administered 2-6 hours after stroke onset. Outcomes included infarct or haematoma volume, BBB integrity, neurological function, and pain-related behaviours. Results: AZD1236 given within 2-4 hours after ischaemic or haemorrhagic insult significantly reduced infarct and haematoma volumes, improved short- and long-term neurological scores, and preserved BBB integrity, whereas treatment at 6 hours was largely ineffective. AZD1236 also attenuated the development of post-stroke mechanical allodynia and thermal hyperalgesia. Mechanistically, treatment reduced MMP-9 and MMP-12 activity, increased tight junction protein expression, and dampened inflammatory responses. Conclusions: Dual inhibition of MMP-9/-12 with AZD1236 confers robust neurovascular protection and mitigates post-stroke pain across clinically relevant models of ischaemic and haemorrhagic stroke. These findings provide a strong preclinical rationale for clinical evaluation of dual MMP-9/12 inhibition as an adjunctive neuroprotective strategy for acute stroke.

Background and purpose: Patellofemoral pain syndrome (PFPS) is a multifaceted condition where proximal, local, and distal factors may contribute to symptoms and limitations. How these factors collectively contribute to PFPS remains poorly understood. Therefore, this study compared proximal, local, and distal mechanical characteristics between individuals with and without PFPS and investigated their association with pain intensity and functional disability. Methods: Eighty participants were included: 40 individuals with unilateral or bilateral PFPS, 40 healthy controls. Isometric muscle strength of hip, trunk, and ankle was assessed using a handheld dynamometer. Joint alignment (Q-angle, rearfoot angle, pelvic tilt) and muscle flexibility (iliotibial band, hamstrings, quadriceps, gastrocnemius, and soleus) were measured using standard clinical techniques. Pain severity was assessed using a visual analog scale (VAS), and functional disability was evaluated using the Kujala score. Results: Individuals with PFPS showed reduced iliotibial band flexibility, decreased hamstring and soleus length, lower hip abductor strength, and greater anterior and lateral pelvic tilt (all p < 0.02). Multivariate analysis identified reduced iliotibial band flexibility (OR = 7.48) and greater anterior pelvic tilt (OR = 11.75) as independent associates of PFPS. Anterior pelvic tilt predicted pain severity, while anterior trunk muscle strength and Q-angle predicted disability. Discussion: Reduced iliotibial band flexibility and increased anterior pelvic tilt were independently associated with PFPS, while anterior pelvic tilt predicted pain severity and anterior trunk muscle strength and Q-angle predicted functional disability. Clinical assessment and rehabilitation of PFPS should therefore extend beyond the knee to include iliotibial band flexibility, pelvic alignment, and trunk muscle strength.