Frontiers in Pain Research

Background: Pressure pain threshold (PPT) is commonly assessed using pressure algometry. Self-administered algometry could reduce examiner involvement and may facilitate repeated assessment outside specialist settings. Objective: To examine the concurrent agreement of a previously described syringe-based pneumatic algometer with a commercially available comparator during self-administered PPT measurement in healthy adults. Methods: Thirty healthy volunteers completed researcher-administered and self-administered pain threshold measurements utilizing an AMF-500 device and the syringe-based pneumatic algometer. Results: During self-administration, measurements from the two devices were strongly correlated (r = 0.82, p < 0.05); the mean paired difference was 6.01 N (95% CI, -0.58 to 12.59 N). Self-administered test values were lower than researcher-administered test values in the fixed-order comparison (p = 0.0029). Conclusion: According to our findings the proposed device is a valid tool for autoalgometry and may potentially be introduced as an element of routine self-assessment of PPT.

Cervical spondylotic myelopathy (CSM) is the most common cause of nontraumatic spinal cord dysfunction in adults and is an increasingly important source of disability as populations age. Gabapentin is widely prescribed for neuropathic pain and may therefore be used for symptoms related to known or undiagnosed CSM. However, there is sparse evidence related specifically to gabapentin's use for CSM-related pain. We investigate gabapentin use and trends over time in patients with CSM compared to matched controls. We observed that gabapentin prescriptions were higher in CSM patients compared to controls across two multi-hospital datasets. These results highlight the need for further research into pharmacologic treatment for chronic pain in CSM.

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.

Background: Neuropathic pain (NP) remains a therapeutic challenge, with conventional repetitive transcranial magnetic stimulation (rTMS) of the primary motor cortex (M1) yielding a response rate of approximately 40%. Personalised targeting based on dysfunctional neurocircuitry offers a promising strategy to enhance efficacy, yet its application in NP is unexplored. This open-label trial investigated a novel targeting approach guided by the recently described cingulo-opercular and somato-cognitive action (CON-SCAN) network, a circuit integrating cognitive and affective dimensions of pain. Methods: Twenty patients with NP received 10 sessions of M1-rTMS over two weeks, with the stimulation site individually localised based on maximal functional connectivity to a CON template. Results: Increased CON-SCAN connectivity from baseline to post-treatment was associated with reduction in pain interference, anxiety and depression scores. The response rate was 50% post-treatment, which was maintained at the 1-month follow-up. Improvements were also observed in neuropathic pain symptoms, negative affect, and overall health. Conclusions: As the first connectivity-guided rTMS trial for NP, this study provides preliminary evidence that personalised targeting of the CON-SCAN network is feasible and associated with the analgesic effects of M1-rTMS, supporting further investigation in randomised controlled trials. Trial registration: Chinese Clinical Trial Registry, ChiCTR2500104679. Registered 20 June 2025, http://www.chictr.org.cn. Chinese Clinical Trial Registry, ChiCTR2400094568. Registered 24 December 2024, http://www.chictr.org.cn. Keywords: Personalised TMS; Pain; M1; CON; SCAN

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.

Purpose: Fibromyalgia involves chronic widespread pain and heightened movement evoked pain (MEP), which can limit access to resistance training's functional and psychological benefits by hindering exercise participation and adherence. This study aimed to determine whether transcutaneous electrical nerve stimulation (TENS) applied during resistance exercise reduces MEP in women with fibromyalgia. Materials and methods: 21 women with fibromyalgia performed 2 sets of 10 leg press repetitions at 60% predicted 1 RM while receiving randomized active TENS (100 Hz) or sham TENS. Pain intensity and unpleasantness (0 to 10 numerical rating scales) were assessed at baseline, immediately post exercise, 15 min post-exercise, end-of-day, and 24h later. Results: Active TENS led to a greater reduction in post-exercise pain than sham, with 90% of participants experiencing at least a 15% decrease in whole body pain 15 minutes post-exercise, compared to none in the sham group. No group differences were observed at the end of the day or 24h after the exercise session. Conclusion: These results suggest that a single session of high frequency TENS during resistance exercise can produce short term reductions in MEP in women with fibromyalgia. While effects did not persist at 24h, these short-term effects may help mitigate acute exercise related pain and support early training adherence.

Background Fibromyalgia (FM) is a disorder characterized by chronic pain and somatic symptoms that are not fully understood. Central sensitization, a process by which the central nervous system amplifies pain signals, is a key aspect of the pathophysiology of fibromyalgia. Despite its prevalence, effective treatment options are limited and the underlying pathophysiological mechanisms are not fully understood. Network pharmacology, which analyzes the interactions between diseases, targets, and biological pathways, can be used to identify potential molecular targets and pathways associated with fibromyalgia. In this study, we aimed to identify potential hub genes and the underlying biological pathways involved in fibromyalgia. Methods Four online databases, GeneCards, DisGeNET, OMIM, and PharmGKB, were initially screened for genes associated with fibromyalgia. GeneCards and DisGeNET were subsequently used to identify common genes, which were used to generate a protein association network using the STRING database. Cytoscape software was used to analyze the network, and the CytoHubba plugin was used to identify hub genes based on degree and betweenness centrality. Functional enrichment analysis was performed using ShinyGO to identify significantly enriched KEGG pathways. Results TNF and IL6 were identified as the top two hub genes with the highest degree of centrality. Functional enrichment analysis identified the Toll-like receptor (TLR) signaling pathway as a significantly enriched pathway among the prioritized hub genes, with a fold enrichment of 6.78 and FDR of 0.0346. Conclusion This study identified TNF, IL6 and other highly connected genes, along with TLR signaling as an enriched pathway in the fibromyalgia-associated gene network. These findings provide potential molecular targets and pathways for further investigation into the pathophysiology of fibromyalgia. Further experimental and clinical studies are required to independently validate these findings and determine their therapeutic relevance.

Phantom limb pain (PLP) is common after amputation, yet why poor sleep becomes pain in only some individuals is unknown. We hypothesized that a regulatory response is interpretable only against the reserve sustaining it, and thus we tested whether autonomic capacity relative to demand moderates the sleep-pain relationship in 121 amputee adults. Sleep was assessed with the Pittsburgh Sleep Quality Index; PLP, residual limb pain (RLP), and phantom limb sensation (PLS) on 0-10 scales. Heart rate variability was summarized as autonomic reserve (log-transformed SDNN, RMSSD, total and high-frequency power) and autonomic drive (normalized low-frequency power). Poorer sleep was associated with greater PLP and RLP, but not PLS. No single HRV index moderated these associations, but the sleep x reserve x drive interaction did for PLP (b =-0.51, p = 0.026). Poor sleep predicted pain most strongly under high drive with reduced reserve. PLP vulnerability reflects autonomic capacity relative to demand, instead of any single HRV marker alone.

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: Myofascial Pain Syndrome (MPS) is a common musculoskeletal pain condition associated with myofascial trigger points that has been reported to occur in 30-93% of patients who present with musculoskeletal pain. The current pharmacologic treatments (such as nonsteroidal anti-inflammatory drugs [NSAIDs], muscle relaxants, and tricyclic antidepressants) are only partially effective and have side effects. Shilajit, a mineral-organic exudate from the Himalayas, has antioxidant, anti-inflammatory, mitochondrial bioenergetic, and central analgesic effects and has not previously been examined as an analgesic in any musculoskeletal pain condition. METHODS: This was an exploratory pilot clinical trial with open-label design in a single arm for an 18-month period at All India Institute of Medical Sciences (AIIMS), Rishikesh, India. Patients aged 18 to 65 years with clinically diagnosed MPS (Simons et al. 1999 criteria) and a baseline visual analog scale (VAS) score >4 were enrolled. Native Himalayan Shilajit 250 mg daily was administered as add-on therapy for 49 days. The main outcome was the percentage of participants with more than or equal to 30% VAS reduction at Day 49. The intensity of pain, the dose of analgesics consumed, and the number of trigger points were evaluated at five time points (Day 0, 12, 24, 36, 49). Throughout, adverse events were monitored. RESULTS: Of 80 enrolled participants, 76 (95.0%) completed the per-protocol analysis. Mean age was 41.25 (SD 9.05) years; 52.6% were male. A total of 56 of 76 participants (73.7%; 95% CI: 62.1-82.8%) achieved the primary endpoint. Mean VAS score declined from 6.63 (SD 1.08) at baseline to 3.63 (SD 1.72) at Day 49 (mean reduction 45.3%; Friedman Chi-square= 278.5, p<0.001). The first signs of pain reduction were seen at Day 24. The number of analgesic doses consumed decreased by 75.5% during the study period (chi-square = 126.1, p<0.001). There was a significant reduction in trigger point count from baseline to Day 49 (p=0.031) of 23.4%. One Grade 2 adverse event (gastrointestinal irritation, Day 28, resolved within 24 hours, no drug discontinuation) occurred; no serious adverse events were reported. Trial registration: CTRI/2025/06/088636. The study was not funded by any external sources. CONCLUSIONS: Native Himalayan Shilajit 250 mg/day for 49 days was associated with clinically and statistically significant reductions in pain intensity, analgesic consumption, and trigger-point burden in patients with MPS, with a favorable safety profile. These findings warrant confirmation in a larger, randomized, placebo-controlled trial.

Background: Pain relief is the principal patient-centered goal of surgery for symptomatic lumbar synovial facet cysts, yet comparative reviews have often emphasized cyst recurrence. Whether adding fusion improves postoperative pain or reduces later surgery remains uncertain. Objective: To compare decompression alone with decompression plus fusion, with postoperative back- and leg-pain outcomes as the primary domain. Methods: PubMed, Embase, Scopus, Web of Science, and the Cochrane Library were searched from inception to 2 June 2026. Comparative cohorts and case series with at least five patients were eligible. Twenty-two studies were re-extracted for VAS/NRS scores, change scores, and persistent or recurrent pain. Random-effects restricted maximum likelihood models with Hartung-Knapp inference were used; clinically distinct pain outcomes were analyzed separately. Results: Twenty-two studies (16 cohorts, 6 case series; 51,899 participants) were included. Two studies provided compatible final VAS data. Fusion did not improve postoperative back pain (MD -0.04, 95% CI -0.17 to 0.10; I2=0%) or leg pain (MD -0.03, 95% CI -0.28 to 0.21; I2=0%). Postoperative back pain (RR 0.58, 95% CI 0.14-2.30) and leg/radicular symptoms (RR 0.75, 95% CI 0.42-1.32) were also not significantly reduced. Fusion decreased confirmed cyst recurrence (RR 0.29, 95% CI 0.15-0.57) but not reoperation or subsequent lumbar surgery (RR 0.80, 95% CI 0.42-1.50). Conclusion: Current comparative evidence does not demonstrate superior postoperative pain control with routine fusion. Fusion reduces cyst recurrence without clearly reducing reoperation, supporting selective use when instability is present or anticipated.

Background. Chronic pelvic pain with involuntary pelvic-floor hypertonicity is common, disabling, and inconsistently measured, and no validated condition-specific severity instrument exists. A refractory subset has been proposed to represent a focal dystonia of the pelvic musculature, termed pelvic dystonia. Purpose. To develop the Pelvic Dystonia Severity Scale (PDSS) and evaluate its measurement properties as a patient-reported measure of pelvic-pain symptom severity and burden, following the COSMIN guidelines. Methods. Cross-sectional study with a test-retest component in 102 adults from an outpatient multidisciplinary pain practice. We assessed data quality, structural validity, internal consistency, test-retest reliability, measurement error, and construct validity against the Global Dystonia Severity Rating Scale (GDS) and Brief Pain Inventory (BPI). Because no validated diagnostic criteria exist, a clinician blinded to PDSS responses rated each participant for clinical signs of pelvic dystonia (present/possible/absent) as a provisional reference standard. Results. 100 of 102 participants (98%) returned complete data, with 0% item-level missing data. Factor analysis supported a unidimensional structure (single factor, 68.6% of variance; loadings 0.56-0.93), with high subscale intercorrelations (r = 0.81-0.97). Internal consistency (Cronbach's 0.810-0.924) and test-retest reliability (ICC 0.857-0.953) were strong. Convergent validity was supported by correlations with GDS pelvic-region items (r = 0.56-0.68) and BPI severity (r = 0.44-0.55), and discriminant validity by weak correlations with anatomically remote regions (shoulder/arm r = 0.03-0.16). PDSS scores rose monotonically across blinded clinical-signs categories (absent 14.9, possible 32.7, present 52.0; Kruskal-Wallis p < 0.001), discriminating signs-present from signs-absent participants with a very large effect (Hedges g = 2.19; ROC AUC = 0.92). Conclusion. The PDSS is a psychometrically robust, unidimensional measure of pelvic-pain symptom severity and burden with strong data quality, reliability, and construct validity. It is suitable for characterizing symptom severity and, pending responsiveness testing, for monitoring treatment. The dystonia interpretation of the underlying phenotype is discussed as a hypothesis for future neurophysiologic and longitudinal study.

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.

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.

BackgroundThis study aimed to determine if a rat osteotomy model elicits a measurable systemic response and to utilize this profile to evaluate the mechanism of action of preemptive analgesics with translational relevance to veterinary perioperative pain management. MethodsTwenty-five male rats were randomized into five groups: Sham, Surgery Control, Robenacoxib (2 mg/kg S.C.), Amantadine (30 mg/kg P.O.), and Combination. A femoral osteotomy was performed following ARRIVE 2.0 guidelines for refinement of surgical models. Serum levels of IL-6, PGE2, and cortisol were quantified via ELISA at baseline, 1-, 3-, and 6- hours post-surgery. Postoperative pain was assessed using the Rat Grimace Scale (RGS). ResultsThe osteotomy model did not induce a significant systemic inflammatory or stress response. Serum IL-6 and cortisol levels showed no significant changes over time (IL-6: p=0.219; Cortisol: p=0.187) or between groups. While PGE2 showed a temporal increase (F=6.52, p=0.001), it was unaffected by drug treatments. In stark contrast, the model successfully produced significant pain-related behaviors in the Control group (p=0.007), which were effectively reduced by both Robenacoxib (p=0.014) and amantadine (p=0.019) monotherapies. The combination group also showed significant pain reduction compared to Control at T6 (p=0.002), with an additive effect relative to monotherapies. Correlation analysis confirmed a dissociation between systemic biomarker levels and pain scores. ConclusionThe efficacy of Robenacoxib (a COX-2 inhibitor approved for veterinary use) and amantadine in the absence of altered systemic biomarkers suggests their analgesic actions are mediated predominantly through local or neurogenic pathways, with direct implications for optimizing perioperative analgesia protocols in companion animal orthopedic surgery.

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.

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 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.

Peripheral nerve injury induces long-lasting changes in sensory neurons that contribute to the development of neuropathic pain. Although the histamine H3 receptor (H3R) is best known for regulating neurotransmitter release in the central nervous system, its expression and role in dorsal root ganglia (DRG) remain poorly understood. In this study, we examined the expression, cellular distribution, and functional role of H3 R in DRG and implications in neuropathic pain. Sciatic nerve injury increased membrane-associated H3R protein expression in the DRG, suggesting enhanced receptor trafficking or stabilization at the neuronal membrane. Single-cell transcriptomic analysis revealed that H3R mRNA expression in DRG is predominantly restricted in peptidergic sensory neurons and C-LTMRs neurons. Fluorescence imaging and transcriptomic analysis also suggest that the majority of H3R co-express with TrkA (a NGF receptor) sensory neuron populations. These findings identify a subset of NGF-responsive nociceptors in which H3R may directly influence injury-induced sensitization. Pain behavior assessment demonstrated a paradoxical role of an H3R inverse agonist (GSK334429), which reduces mechanical hypersensitivity caused by chronic constriction injury (CCI) with no change in thermal pain. Patch-clamp recordings show that the GSK334429 attenuates NGF-induced hyperexcitability in DRG neuronal cultures. Overall, our work suggests a contributing role of H3R in modality-specific effects on sensory processing through its enrichment in specific neuronal populations in DRG.

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.