Pain

Approximately 1 in 4 women with chronic pelvic pain (CPP) report persistent pelvic pain after hysterectomy. Centralized symptoms-fatigue, multisite pain, and sleep disturbance, quantified using the Fibromyalgia Survey Score (FSS)-often co-occur with this risk, but the trajectory of centralized symptom burden after surgery, independent of pelvic pain outcome, is not well understood. Whether presurgical differences in central nervous system pain processing distinguish women whose centralized symptoms improve (improvers) from those whose do not (non-improvers) has not been tested. In this observational study, we assessed whether individuals who do and do not report improvement in FSS scores six months post-operatively differ in their baseline/pre-operative phenotypes and brain function. Sensory sensitivity scores were significantly higher in non-improvers than in improvers at baseline. We identified no significant, presurgical differences in age, average pelvic pain intensity, widespread pain, or pain interference between improvers and non-improvers. Functional connectivity was examined at rest and during the application of a distal, sustained pressure pain. We identified no significant group differences at rest. During sustained pressure pain, non-improvers showed greater connectivity than improvers between primary somatosensory cortex and posterior thalamic seeds with frontal, motor, cerebellar and limbic regions, but lower connectivity between the periaqueductal gray and subgenual cingulate cortex. Non-improvers also showed a greater pain-evoked increase in connectivity between the pelvic and leg representations of the primary sensory cortex and other sensorimotor regions in the pain-versus-rest contrast. Overall, non-improvers showed increased functional connectivity between regions associated with the multisensory integration of ascending pain, and decreased connectivity between regions associated with descending pain modulation. In exploratory analyses, some of these connections were additionally associated with symptom burden: sensory sensitivity, number of painful regions, and pain interference. This work may inform mechanisms of persistent symptom burden and guide surgical decision-making in patients with high central sensitization.

Endometriosis is a common yet understudied condition in which sex hormones play a key role in the etiology and pathophysiology of the disease. Sex hormones are dysregulated in endometriosis and are pharmacologically targeted to reduce symptoms including pain, but the relationships between endometriosis-related pain with sex hormone levels and their receptors are not clear. In 60 women previously diagnosed or undergoing laparoscopic surgery for the diagnosis of endometriosis, we collected patient-reported endometriosis/pelvic pain intensity in the last 30 days, pain interference scale, and the Endometriosis Health Profile 30 (EHP30) pain subscale. In a sub-sample of 38 participants, biopsies from control non-lesion pelvic peritoneum and endometrial lesion tissues were collected during surgery to analyze the tissue abundance of the primary receptors for estrogen, as well as androgen, progesterone, and prolactin receptors. Serum was collected to analyze systemic sex hormone levels including estradiol, prolactin, progesterone, and testosterone. Between tissues, we found elevated transcript levels for estrogen receptor alpha (ESR1) in lesions, but no difference in estrogen receptor beta (ESR2) transcript levels between tissue samples were found. Relating tissue receptor transcript levels to clinical pain revealed that only ESR1 and PGR in lesions were negatively associated with endometriosis/pelvic pain intensity, however, following false discovery rate correction the association with ESR1 was no longer statistically significant. No other tissue or systemic factors were associated with clinical pain outcomes. Together, these data demonstrate unique alterations in receptor abundance in lesions yet select transcript levels only weakly relate to pain in endometriosis.

Importance: Pain varies in its intensity and course, yet much of our understanding of pain is based on cross-sectional assessments or longitudinal studies of selected clinical populations. Routinely collected electronic health record data may enable characterization of longitudinal pain patterns at scale. Objective: To identify longitudinal pain profiles among U.S. Veterans and characterize their clinical and polygenic correlates. Design: Cohort study using electronic health record and genomic data from the Million Veteran Program, with up to 16 years of pain assessments collected between 2000 to 2025. Setting: U.S. Department of Veterans Affairs health care system. Participants: Million Veteran Program participants assigned to African-like, Admixed American-like, East Asian-like, European-like, or South Asian-like genetically inferred ancestry groups who have at least three years of outpatient numeric rating scale pain records. Exposures: Outpatient pain ratings and polygenic scores for psychiatric, sleep, and substance use traits. Main Outcomes and Measures: Pain profiles were identified using Gaussian finite mixture modeling of pain intensity, directional change, and within-person variability. Profiles were characterized by pain, psychiatric and substance use diagnoses, opioid exposure, body mass index, and polygenic scores. Results: Among 624,996 participants (Mean [SD] age at first pain rating=53.4 [13.5] years; 568,833 [91.0%] male), 51,731,567 outpatient pain ratings were analyzed. Three profiles were identified: stable no pain, stable mild pain, and mild-to-moderate increasing pain. Compared with the stable no pain profile, the increasing pain profile had higher odds of chronic pain (OR=21.14 [95% CI: 18.96-23.57]), opioid use disorder (OR=9.32 [95% CI: 8.31-10.45]), opioid exposure (OR=8.61 [95% CI: 8.41-8.83]), major depressive disorder (OR=3.77 [95% CI: 3.67-3.87]), and posttraumatic stress disorder (OR=3.72 [95% CI: 3.61-3.84]). Associations were attenuated but remained after adjustment for mean pain severity. Polygenic scores for depression, insomnia, attention-deficit/hyperactivity disorder, and tobacco use disorder were the most consistent predictors of increasing pain across the three largest genetically inferred ancestry groups. Conclusions and Relevance: Longitudinal modeling of routinely collected pain scores identified pain profiles associated with clinical burden and polygenic liability. These profiles captured clinically meaningful information beyond mean pain severity alone, highlighting the value of longitudinal pain phenotyping in electronic health record data.

Pain is associated with dynamic brain reorganization. Electroencephalographic microstates can characterize transient large-scale brain states, yet findings across pain studies are inconsistent. Two features may contribute: conditions have been studied in isolation, and analytical pipelines vary widely. We applied a harmonized analysis pipeline across three pain conditions: capsaicininduced pain, assessed within participants against a pain-free baseline, and non-chronic and chronic back pain, each compared with matched controls. Using a five-minute resting-state electroencephalographic recordings we examined microstate topography, temporal expression and transition probabilities, and directly compared pain related differences across pain states. We identified five microstates (A-E), corresponding to auditory, visual, salience, and attentional networks. Capsaicin pain showed increased expression of microstate C and reduced expression of microstates A, D and E. Transitions were redistributed towards microstate C, indicating a shift toward salience-related processing at the expense of sensory and attentional dynamics. In clinical back pain, effects were smaller and diverged by pain type: non-chronic back pain showed lower microstate C occurrence, opposite in direction to the capsaicin effect, whereas chronic back pain showed lower microstate D global explained variance, suggesting salience and attentional differences in clinical pain. Direct comparisons showed weaker pain-related increases in microstate C expression in both clinical back pain groups than capsaicin pain, with additional differences involving microstates A, D and E. These findings argue against a unitary EEG microstate signature of pain and instead reveal pain-type-specific patterns of large-scale brain dynamics, with microstate C providing the clearest distinction between experimental and clinical pain.

Despite urgent need for better analgesics, drug development has been complicated by incomplete bench-to-bedside translation. A likely contributing factor is the poor connection between the experimenter-evoked pain-related measures often used in preclinical models, and the clinical symptoms, like broader functional impairment, reported by patients. Here, we asked whether vertical climbing, a species-specific elective behaviour in mice, could serve as a measure of pain-related impairment. We tested male and female mice in a wide range of pain-related models including models of post-operative pain, inflammatory injury, osteoarthritis, rheumatoid arthritis, cancer-induced bone pain, fibrous dysplasia, neuropathic pain, migraine-related pain and facial neuropathy. Vertical climbing was reduced in all models, across five different laboratories, demonstrating the robustness and consistency of this type of behaviour as a novel pain-related outcome measure. Reduced climbing correlated significantly with established pain-related measures, but its time course diverged from that of evoked mechanical allodynia, while aligned more closely with other non-evoked behaviours, like burrowing, home cage activity, wheel running or weight bearing. Pharmacological validation was bidirectional: gabapentin restored climbing in mice with neuropathic injury, and naltrexone reinstated the climbing deficit in mice that had recovered from intraplantar CFA, consistent with persistent pain held in remission by endogenous opioid signalling. Overall, our results indicate that voluntary vertical climbing is a stable, elective behaviour that provides a robust and translationally relevant measure of pain-related functional impairment in mice.

While progress has been made in identifying pain biomarkers using neuroimaging, the development of reliable EEG-based biomarkers remains challenging, limited by small sample sizes and the lack of adequate control conditions. We present a comprehensive dataset from 125 pain-free adults, comprising electroencephalogram (EEG) recordings, and behavioural, sociodemographic, and psychological data. Galvanic skin response and electrocardiogram data were also recorded in a subset of participants (n = 76). Participants received two sustained painful stimulations (thermal, chemical) and two sustained aversive non-painful stimulations (auditory, taste), each delivered twice (with and without continuous intensity ratings). Data are provided in Brain Imaging Data Structure format, where all physiological, stimulus-related, and behavioural data are synchronized within the EEG data files for easy access and analysis. Technical validation confirmed data integrity, with spectral and physiological analyses showing responses associated with stimulus intensity and subjective pain/unpleasantness levels. By providing multimodal physiological data across painful and non-painful aversive conditions, this initiative represents a valuable resource for developing or validating biomarkers and exploring the multidimensional nature of pain perception.

Interoception is described as the sensitivity to internal bodily stimuli, and plays an important role in pain perception. Heightened interoceptive sensibility (i.e. self-reported interoceptive abilities) may reinforce misinterpretation of stimuli, enhancing pain perception. This study aimed to investigate the relationship between interoceptive sensibility and acute postoperative pain. Interoceptive sensibility was measured using the Private Body Consciousness Scale in two prospective observational surgical cohorts: a Caesarean delivery cohort (C-section cohort) of 146 patients, and a lower extremity orthopaedic surgery cohort (Ortho cohort) of 70 patients. One day after surgery, patients rated pain (primary outcome) and other postoperative symptoms (secondary outcomes) on a 0-10 scale. Bonferroni corrections were applied to secondary outcomes. Interoception positively correlated with pain (C-section cohort: Spearmans rho = 0.182, P = 0.028; Ortho cohort: rho = 0.259, P = 0.031), and with dizziness (C-section cohort: rho = 0.309, P = 0.002; Ortho cohort: rho = 0.348 P = 0.041) in both cohorts. In the C-section cohort, interoception correlated with shivering (rho = 0.321, P < 0.001). In the Ortho cohort, interoception correlated with nausea (rho = 0.366, P = 0.023) and helplessness (rho = 0.363, P = 0.026); whereas no correlation with pain catastrophising was found (rho = 0.240, P = 0.539). In pooled multiple linear regression analysis (n = 216), interoception predicted pain after controlling for age, sex and anaesthetic technique (B = 0.119, 95% CI [0.027-0.210], P = 0.011). These findings highlight the potential role of interoception in identifying patients at risk for acute postsurgical pain.

Chronic pain is frequently accompanied by anxiety and other affective disturbances, but the molecular and cellular changes linking peripheral injury to persistent alterations in brain function remain incompletely defined. The hippocampal extracellular matrix (ECM) regulates synaptic plasticity, cellular signaling, and neuroimmune interactions and may therefore contribute to pain-related central plasticity. We used a tibial fracture/cast immobilization model to examine temporal changes in hippocampal ECM, glial morphology, and affective behavior following peripheral injury. Behavioral testing was performed at 3, 7, and 20 weeks after injury, while high-dimensional morphometric analysis of microglia and astrocytes was performed at 1, 3, 7, and 20 weeks. Hippocampal ECM associated molecular signals were mapped at the chronic stage using decellularization coupled with MALDI-TOF mass spectrometry imaging. Injured mice developed mechanical hypersensitivity and reduced exploration in two anxiety related paradigms during the early and chronic stages, with these behavioral phenotypes no longer detected at 20 weeks. At 7 weeks, injury was associated with changes in hippocampal ECM-associated peptide signals, including reduced signals corresponding to four ECM-associated proteins. Microglia and astrocytes exhibited distinct, time-dependent changes in density and multidimensional morphology, with some alterations persisting after behavioral measures returned toward control levels. In vitro, BV2 microglia exhibited rigidity-dependent changes in morphology, phagocytic behavior, and calcium signaling. Together, these findings define a temporally evolving hippocampal ECM and glial phenotype following peripheral injury and identify matrix biomechanics as a candidate regulator of microglial function.

Background: Chronic musculoskeletal pain (CMP) is a common and debilitating symptom of Long COVID (LC), which shares several clinical features with Fibromyalgia Syndrome (FMS). Aims: This longitudinal study investigated whether the symptom overlap between LC-CMP and FMS persists over time, whether patterns differ according to pre-COVID CMP history, and the extent to which neuropathic pain features are present. Methods: Individuals with LC completed questionnaires assessing the symptom-based component of the 2010 American College of Rheumatology criteria for FMS and the presence of neuropathic pain features (PainDetect Questionnaire, PDQ) at baseline, 6- and 12-month follow-ups. Participants were grouped according to pre-COVID CMP history. Group differences were analysed using mixed-effects logistic regression. Results: 240 individuals completed the baseline assessment at a mean of 2.61 years after LC onset, including 131 (100 females) with new-onset CMP and 94 (87 females) with pre-existing CMP. The prevalence of participants meeting the symptom-based criteria for FMS remained high across follow-up (67.5-78.6%), with 50.0-61.0% of those with complete follow-up data fulfilling criteria at all timepoints. No significant subgroup differences were observed (OR = 0.43, 95% CI [0.14 1.39], p = 0.160). Across follow-up, 22.2-36.1% of participants reported likely neuropathic pain features, with significantly higher odds in the pre-existing CMP group (OR = 3.17, 95% CI [1.22 8.18], p = 0.017). Conclusions: FMS-like symptoms remain highly prevalent several years after acute COVID-19 and persist over a further 12 months, suggesting that LC-CMP frequently represents a persistent long-term condition with substantial overlap with FMS. These findings support closer integration of LC and chronic pain rehabilitation services and add to the wider literature linking post-infectious processes with FMS-like symptoms.

Trigeminal pain produces persistent facial hypersensitivity that is difficult to treat. Ion channels contribute to the pathology of trigeminal pain, but the consequences of their modulation remain poorly understood. We previously demonstrated that voltage-gated sodium channel Nav1.7 is a therapeutic target that can be indirectly modulated via interaction with collapsin mediated response protein 2 (CRMP2) to reduce membrane expression of Nav1.7 and trigeminal ganglion neuronal excitability. We used the Foramen Rotundum Inflammatory Constriction of the Trigeminal InfraOrbital Nerve (FRICT-ION) model of trigeminal neuropathic pain to characterize behavioral and supraspinal effects of indirectly modulating the peripheral CRMP2-Nav1.7 interaction via our novel Compound 194 (C194). FRICT-ION produced mechanical and cold allodynia, which were reduced by C194, but had no effect on non-evoked affective behaviors. Despite behavioral improvement, C194 did not normalize heightened glutamatergic activity in the parabrachial nucleus (PBN), revealing a dissociation between behavioral analgesia and activity of a central pain circuit. These findings extend mechanistic studies of C194 in the trigeminal system and demonstrate efficacy of CRMP2-Nav1.7 disruption in modulating facial pain-like behavior. These results support the CRMP2-Nav1.7 axis as a promising therapeutic target while highlighting the need to define how peripheral and central adaptations interact to shape persistent facial pain.

Adverse side effects of chronic opioid use, including analgesic tolerance, opioid-induced hyperalgesia, and addiction, are serious clinical challenges for pain management and opioid deprescribing. Microglia have been implicated in the development of these adverse effects, but the extent to which opioids alter microglia and the mechanisms behind opioid effects on microglia are poorly understood. We performed morphological and single-cell transcriptomic analysis on spinal microglia from opioid-withdrawn and saline-treated mice, and found that while morphological changes recapitulated prior reports, transcriptomic changes in these cells were modest. Furthermore, peripherally, but not centrally, restricted opioid administration was sufficient to induce both hyperalgesia and microglial morphological changes in mice. Finally, complete loss of microglia in Csf1r{Delta}{Delta}FIRE mice did not prevent the development of opioid-induced hyperalgesia, analgesic tolerance, and somatic withdrawal symptoms. These data argue against any microglial involvement in the development of these phenomena.

Background: Opioids remain the cornerstone of acute postoperative pain management but are associated with potentially serious adverse effects. We aimed to investigate the effect of oxycodone patient-controlled analgesia with adjunctive S-ketamine on pain after lumbar fusion surgery. Methods: In this secondary analysis, we examined oxycodone and S-ketamine exposure and PCA behaviour during the first 24 h. We assessed current pain versus subsequent PCA activity and whether the association between plasma oxycodone and adequate analgesia changed with postoperative time. Results: Plasma concentrations of administered drugs rose rapidly after PCA initiation, but variation was large. Metabolite concentrations accumulated over time. PCA attempt and delivered-dose rates decreased over postoperative time (RR 0.965 and 0.966 per hour, respectively; both P<0.001). Older age was associated with a lower delivered-dose rate (RR 0.905 per 10 years, 95% CI 0.829-0.987). Each 1-point higher current pain score was associated with more subsequent PCA attempts (RR 1.09, 95% CI 1.04-1.14) and delivered doses (RR 1.07, 95% CI 1.03-1.11). The oxycodone-analgesia association weakened over time [interaction P <0.001; odds ratios (Ors) per 10 ng/mL 1.16, 1.13, and 1.00 at 1, 4, and 24 h, respectively]. In active S-ketamine groups, including S-ketamine, norketamine, and 6-hydroxynorketamine concentrations left the pain-PCA association unchanged (RR 1.09 and 1.07) and preserved the time-dependent oxycodone association (ORs 1.30, 1.26, and 1.02). Conclusions: During PCA, drug exposure develops from patient-generated dosing histories while pain and recovery change. Current pain was associated with subsequent PCA activity, and the oxycodone-analgesia association was time-dependent.

Introduction: Chronic pelvic pain disorders (CPPDs) affect up to one in four reproductive-age women and are characterized by fluctuating, heterogeneous symptoms that complicate engagement in regular physical exercise. Standard programs rarely adjust to daily symptom variability. WorkoutCPP is a pilot series of N-of-1 trials evaluating the feasibility of an adaptive mobile-health (mHealth) intervention using reinforcement learning (RL) to personalize exercise for individuals with CPPDs. Methods and Analysis: This pilot study consists of a series of N-of-1 trials employing a randomized ABAB or BABA design, in which 45 participants (aged 18-55 years) with CPPDs each serve as their own control. Each participant completes one baseline week followed by four alternating 2-week intervention phases (A = generic exercise guidance; B = adaptive RL-generated recommendations), totaling 9 weeks. The RL agent integrated into the ehive app suggests daily exercise recommendations based on participant-reported pain and prior exercise behavior. Primary outcomes are exercise recommendation adherence rate and participant retention rate; safety and additional feasibility indicators are also monitored. Secondary outcomes assess algorithm interpretability. Exploratory outcomes assess contextual sensitivity of the RL algorithm and changes in pain and behavioral engagement. Ethics and Dissemination: Ethical approval was granted by the Icahn School of Medicine IRB (Protocol # STUDY-23-00721). Electronic informed consent will be obtained. Findings will be shared via peer-reviewed publications, conferences, and de-identified data summaries. Registration: This study protocol was publicly registered on the Open Science Framework (OSF) Registries (URL: https://osf.io/d9f36) prior to participant enrollment, to support international open-science data transparency and reproducibility standards for mobile health adaptive intervention trials. The study was subsequently registered on ClinicalTrials.gov (NCT07810218), consistent with ICMJE recommendations for trials informing future confirmatory research. All documented study procedures match the baseline human subjects tracking mechanisms approved by the Icahn School of Medicine at Mount Sinai Institutional Review Board (Protocol # STUDY-23-00721).

Background: Although opioids are frequently prescribed for refractory chronic neuropathic pain, few data are available on baseline factors that may identify individuals more likely to respond and inform individually tailored practice. Methods: This was a post hoc, exploratory analysis of individual-level data from a placebo-controlled trial of methadone for chronic neuropathic pain (NCT05235191). Baseline clinical, psychological, psychophysical and radiological variables were tested for association with 30% or more pain reduction in the methadone group. The correlation between expectation of improvement and pain reduction was examined in both groups. Results: Of the 81 participants completing the 8-week follow-up, 28 (70%) on methadone and 14 (34.1%) on placebo achieved 30% or more pain reduction. In the methadone group, responders had higher baseline expectation of improvement (median 100 [80-100] vs. 55 [50-81]; p=0.004), which correlated moderately with percentage pain reduction (rs=0.508; p<0.001). Neither finding was observed in the placebo group (p=0.211 and p=0.161, respectively), although the correlation did not differ significantly between groups (p for interaction=0.728). Other clinical, sociodemographic, psychological and psychophysical variables were not associated with response. In the subsample with peripheral neuropathic pain and structural MRI (n=37), lower left precentral cortex volume was associated with response to methadone (p=0.041), and lower right paracentral volume with response to placebo (p=0.003). Conclusions: Baseline expectation may influence treatment outcomes, supporting its inclusion as a covariate to improve the precision of treatment effect estimates in trials, and its use in clinical practice to help tailor treatment to individual patients. These exploratory findings require confirmation in larger studies.

The external parabrachial nucleus (elPBN) contributes to diverse behaviors, including pain and stress. Neurons in this region use glutamatergic and neuropeptidergic signaling, with pituitary adenylate cyclase-activating polypeptide (PACAP) expressed in a subset of glutamatergic neurons. Deletion of PACAP in elPBN neurons attenuates behavioral responses to stress, but the contribution of PACAP to pain sensitization and of glutamatergic neurotransmission to pain- and stress-related responses remain poorly understood. Here, we show that constitutive loss of PACAP markedly attenuated nerve injury-induced hypersensitivity across heat, pressure, cold and tactile modalities without altering baseline nociception, while also reducing inflammation-induced spontaneous pain-related behavior. Notably, selective deletion of PACAP within elPBN neurons phenocopied the suppression of injury-induced hypersensitivity, but left inflammation- induced pain-related behavior unaffected. Ex vivo optogenetic-assisted circuit mapping showed that activation of PACAP-expressing elPBN terminals elicited glutamatergic transmission onto central amygdala (CeA) PKC{delta}-expressing neurons. Selective deletion of VGluT2 in elPBN neurons reduced nerve injury-induced hypersensitivity but, unlike PACAP deletion, also reduced inflammation-induced pain-related behavior, while leaving stress-induced hypophagia intact. Together, these findings reveal differential requirements for PACAP and glutamatergic neurotransmission within the elPBN across pain- and stress-related behaviors.

Background: Light hypersensitivity, or photophobia, affects nearly 80% of people with migraine and is the most prevalent symptom after headache. Despite its high prevalence, the neural pathways underlying migraine-associated light hypersensitivity remain poorly understood, in part due to the lack of behavioral assays that directly assess light sensitivity in mice. Consequently, whether nociceptors contribute to the development of photophobia remains unclear. Methods: We established a novel light sensitivity assay (LSA) to quantify the response to light in mice by measuring facial grimacing. The assay was applied to evaluate light hypersensitivity elicited by three established migraine triggers: calcitonin gene-related peptide (CGRP), nitric oxide donor (sodium nitroprusside), and repeated stress. To determine the contribution of TRPV1 nociceptors, mice were treated with resiniferatoxin (RTX) to ablate these neurons. Results: The LSA detected light hypersensitivity following administration of CGRP, sodium nitroprusside, and repeated stress in wild-type (WT) mice. Sex differences were not observed in CGRP- or stress-induced light hypersensitivity. Furthermore, ablation of TRPV1 nociceptors did not reduce light hypersensitivity induced by migraine triggers. Conclusions: These findings present the LSA as a robust, reproducible, and easy to implement behavioral assay for measuring light sensitivity in preclinical migraine models. Our results further demonstrate that TRPV1 nociceptors are dispensable for the development of migraine-associated light hypersensitivity. This assay provides a useful method for investigating the mechanisms underlying light sensitivity and for evaluating potential therapeutic strategies.

The genetic evidence for an essential role of sodium channel Nav1.7 in human pain conditions is compelling. Unfortunately, potent selective channel blockers of Nav1.7 are not useful analgesics because they have deleterious side effects, particularly on the autonomic nervous system. Here we have evaluated the downstream mechanisms induced by Nav1.7 loss in utero. Nav1.1 compensates for loss of Nav1.7 in sensory neurons and antisense Nav1.1 oligonucleotides diminish excitability in Nav1.7 embryonic null sensory neurons. Enhanced endogenous opioid signalling contributes substantially to analgesia. This is linked to altered gene expression that potentiates opioid signalling through lowered levels of proteins that terminate G-protein signalling (RGS4 and RGS8). There is also enhanced opioid drive through increased enkephalin levels linked to lowered sodium levels in Nav1.7 null neurons. Opioid signalling is the main driver of analgesia, but enhanced potassium channel expression (KCNC4 KCNK2, KCNMB2, KCNAB3) all implicated in pain control, may also contribute to the small level of naloxone-resistant analgesia. These findings suggest a potential new route to analgesia, through mimicking the events at Nav1.7 null sensory neuron terminals. Here we demonstrate potentiation of suzetrigine-evoked analgesia with RGS antagonists alone or in combination with normally inactive doses of morphine in formalin-evoked pain and CFA-induced inflammatory pain. Intriguingly, no analgesia is observed with acute pain. Cancer pain is under investigation. These data are of potential clinical interest.

BackgroundNeuropathic pain is a common and debilitating condition with persistently poor translation from preclinical research to effective clinical therapies. Preclinical systematic reviews and meta-analyses (SRMAs) can provide more robust estimates of intervention effects and help identify sources of bias and heterogeneity, but their use is limited by the time and effort required to synthesise rapidly expanding literatures. Automation may help overcome these barriers. MethodsWe developed Neuropathic Pain - Systematic Online Living Evidence Summaries (NP-SOLES), a machine-assisted approach used in this study to support systematic identification of animal studies relevant to neuropathic pain. Using NP-SOLES, we conducted a pilot systematic review and meta-analysis of controlled animal studies assessing the effects of citrus flavonoids on thermal and mechanical pain-related outcomes in streptozotocin-induced models of painful diabetic neuropathy. ResultsIn this pilot application, machine-assisted evidence synthesis supported reduced manual screening burden, illustrating the potential of such approaches to facilitate timely preclinical SRMAs. Fourteen studies met inclusion criteria for meta-analysis on thermal pain-related outcomes. Pooled estimates suggested a reduction in thermal pain-related behaviours following flavonoid treatment; however, substantial heterogeneity and widespread methodological limitations were observed. Nine studies were eligible for qualitative analysis on mechanical pain-related outcomes, which showed an overall reduction in pain-related behaviours following treatment but had similar methodological limitations. Reporting of key measures to reduce risk of bias, including randomisation and blinding, were consistently poor, and subgroup analyses were constrained by sparse data. ConclusionsAvailable evidence from preclinical animal studies suggests a potential analgesic effect of citrus flavonoids on thermal and mechanical pain-related outcomes in diabetic neuropathy models, but confidence in this estimate is limited by significant risks of bias. More rigorously designed and transparently reported preclinical studies are required before clinical translation can be justified.

Introduction: Observation of a partner in pain elicits empathy-related cortical responses and social support can modulate pain. Objective: The aim of this study was to investigate empathy and the cortical response during observation of a romantic partner in pain with and without consoling touch. Methods: A total of 40 participants (20 couples) completed validated measures of handedness, pain and empathy. Each member of the couple was randomly assigned to be either the recipient of cold pressor pain or the consoling partner undergoing EEG. EEG activity was recorded from the consoling partner during baseline and pain conditions (with and without consoling touch) to investigate how observation of a partner in pain could alter mu rhythms. Results: Observing a romantic partner in pain significantly enhanced mu at electrodes C4 and Cz, yet addition of consoling touch did not significantly change mu rhythms. Personal Distress was positively associated with mu rhythm enhancement at electrode C4 during pain without consoling touch (r = .576, p = .008). Conclusion: Viewing a romantic partner in pain significantly increased mu rhythms, that was not further changed by offering consoling touch. The association between increases in mu rhythms and Personal Distress in the current study suggests that self-oriented distress may be especially relevant to sensorimotor cortex responses when witnessing a partner in pain, particularly when consoling touch is not possible. Keywords: pain; empathy, EEG, mu rhythms, cold pressor

Non-pharmacological adjuncts are needed for chronic non-cancer pain in patients receiving long-term opioid therapy. Music listening may reduce pain, but most previous trials have used passive controls, limiting attribution of effects specifically to music. In this open-label, parallel- group, proof-of-concept randomized controlled trial, adults with chronic non-cancer pain receiving long-term opioid therapy were randomized 1:1 to four weeks of daily home-based music or audiobook listening. Analgesic outcomes included pain intensity, responder rates, quantity of pain relief, and multidimensional pain assessment; secondary outcomes included mood, quality of life, global impression of change, and safety. Of 70 participants entering the run-in period, 56 were randomized (28 per group). Adjusting for baseline pain intensity in a linear mixed-effects model, the between-group difference at end of treatment was -1.26 NRS points (95% CI -1.98 to -0.55; p<0.001; d=-0.70), favoring music. A [&ge;]30% pain-reduction criterion was met by 21.4% of participants in the music group and none in the audiobook group (p=0.023). An exploratory between-group difference in pain intensity favoring music was also observed at follow-up. Other analgesic and secondary outcomes showed no significant between-group differences, although exploratory within-group improvements in mood and health-related quality of life were observed with music. Both groups reported overall improvement in global perceived change, with ratings numerically favoring music. No intervention-related harms were observed. These findings support an analgesic benefit of music beyond the structured listening experience shared with the active comparator. Daily self-administered music listening may represent a feasible, low-cost adjunct for chronic non-cancer pain in patients receiving long-term opioid therapy.