The Journal of Pain

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

Temporomandibular disorder (TMD) and irritable bowel syndrome (IBS) are two highly comorbid, nociplastic pain conditions that belong to a broader group of commonly co-occurring chronic pain conditions. Most of these chronic overlapping pain conditions (COPCs), including TMD and IBS, disproportionately affect females and are highly stress sensitive. Our previous study illustrated sex differences in brain activity during colorectal distension specific to our model of comorbid pain hypersensitivity (CPH), in which masseter muscle inflammation followed by restraint stress elicits IBS-like visceral hypersensitivity. Since insular cortex (Ins) activity increased in female CPH rats only and abnormal Ins activity has been identified in TMD and IBS patients, we sought to characterize patterns of Ins-based functional connectivity (FC) by performing functional MRI (fMRI) scans at baseline, 1 week, and 7 weeks post-injury/stress in groups of male and female Sprague-Dawley rats randomized to the following conditions: CPH, stress-induced hypersensitivity (SIH), Complete Freunds Adjuvant (CFA)-induced masseter muscle inflammation, and naive. CPH females displayed extensive Ins FC with brain regions in the cortex and limbic system, including the thalamus. Compared to CPH males, CPH females showed robust insular-thalamo connectivity at week seven, a time point where visceral hypersensitivity and referred pain-like behavior persists in CPH females but not males. This trend is also apparent in CPH females week seven versus week one Ins FC, whereas CPH males tend to decrease Ins FC broadly. These findings potentially suggest sensitization within the insular-thalamo and -cortical networks in CPH females, warranting future investigation of Ins circuit involvement in comorbid pain.

BackgroundProteases and histamine, co-secreted by mast cells and bacteria, sensitize colonic nociceptors and contribute to irritable bowel syndrome (IBS) pain. ObjectiveTo determine whether irreversible proteolytic cleavage of protease-activated receptor-2 (PAR2) and its continued activity in endosomes amplify and sustain otherwise transient pronociceptive actions of histamine receptors (HRs) to cause recurrent pain, the defining symptom of IBS. DesignWe investigated the coexpression of PAR2 and H1R in nociceptors using RNAscope in situ hybridization and assessed the consequences of coactivation using electrophysiological assays of nociceptor sensitization and biophysical measurements of receptor and effector activity. ResultsPAR2 and H1R were coexpressed by human and mouse dorsal root ganglion nociceptors. Intracolonic infusion of fecal supernatants from IBS patients enhanced mechanosensitivity of colonic nociceptors in mice. Antagonists of PAR2 or H1-4R abolished this response. Combined administration of subthreshold concentrations of trypsin and histamine replicated the effects of fecal supernatant and caused hyperexcitability of isolated nociceptors. Pre-activation of PAR2 sensitized histamine-induced hyperexcitability. Endocytosis inhibitors prevented this hypersensitivity, consistent with sustained endosomal signaling of PAR2 and persistent nociceptor hyperexcitability. Trypsin amplified histamine-induced activation of H1R and {beta}-arrestin2 and Gq effectors at the plasmalemma and in endosomes. Conversely, histamine did not sensitize trypsin-induced hyperexcitability of neurons, in line with the inability of histamine to induce sustained nociceptor hypersensitivity. ConclusionsBy amplifying and maintaining the otherwise transient actions of H1R and possibly other pain receptors, persistent PAR2 endosomal signaling makes a dominant contribution to IBS-related colonic pain. Summary boxO_ST_ABSWhat is already known on this topicC_ST_ABSProteases and histamine are increased in IBS patients and cause visceral pain. What this study addsProlonged intracellular PAR2 signaling sensitizes and maintains H1R activity to amplify and maintain pain. How this might affect research, practice or policyAlthough neuroactive factors can act synergistically to amplify and maintain IBS pain, antagonists of dominant receptors (e.g., PAR2) can provide effective treatment.

BackgroundStress and pain are two adaptive mechanisms, driving human behavior and cognition. They are bidirectionally related, and modulating factors such as sleep or physical activity were identified. However, how stable individual differences in pain-related distress, including individual dispositions for pain catastrophizing, and person-specific pain sensitivities relate to the strength of stress responses remains unclear. This preregistered study closes this gap by investigating how trait pain-related distress and pain sensitivity changes relate to individuals stress response. MethodsTrait pain-related distress was assessed in 148 healthy males with the Pain Catastrophizing Scale, the Tampa Scale of Kinesiophobia, and the Fear of Pain Questionnaire. Baseline blood pressure, pulse rate, alpha-amylase, and cortisol were obtained as well as initial heat pain thresholds and tolerances. One participant group underwent the Maastricht Acute Stress Task, while a control group performed the placebo version of this task, and consecutively all stress- and experimental pain indicators were examined again. ResultsIndividuals with lower kinesiophobia demonstrated higher stress-induced increases in alpha-amylase. Furthermore, stress-induced changes in pain sensitivity showed high individual variability, but were not associated with the stress response. Finally, in individuals with a higher tendency to catastrophize and to fear pain, stronger alpha-amylase increases were associated with larger post-stressor increases in pain threshold, indicating reduced pain sensitivity. ConclusionOur study suggests that stable individual differences influence the stress-pain link beyond physiology. This underscores the importance of considering trait differences in future research on stress-pain interactions with the goal of better tailoring preventions and treatments for patients with chronic pain.

High-impact chronic pain (HICP), defined as persistent pain that substantially limits daily activities, affects millions of adults and poses a public health challenge. Yet relatively little is known about how HICP manifests in people's daily lives. To address this gap, this study used the comprehensive Ecological Momentary Assessment of pain (cEMAp) to assess pain-related experiences four times per day over 7 days in individuals with chronic low back pain. Based on the classification using the Graded Chronic Pain Scale-Revised, we compared individuals with HICP (n = 66) with those in the next most severe pain category, bothersome chronic pain (n = 41), defined as having similar pain frequency but less frequent interference with daily activities. On each prompt, participants completed 2-hour assessments of pain intensity, interference, catastrophizing, behaviors, coping strategies, and pain characteristics. In line with prior research, both groups reported similar pain intensity levels, but the HICP group reported more frequent interference with physical, mental, and social activities. There were no group differences in daily mood or catastrophizing. Exploratory analyses suggested that many daily experiences were similar across groups, with differences observed in selected pain qualities, coping strategies, and pain behaviors. Additional analyses of response distributions showed some similarity across groups in many experiences. Overall, although individuals with HICP on average experience higher pain interference in daily life, levels of many day-to-day experiences are similar between the two groups. Data obtained with cEMAp complement traditional retrospective assessment by providing a detailed view of chronic pain in everyday life.

Pain is commonly described in sensory terms, yet its spatial characteristics-localization and distribution-are rarely quantified. We investigated whether lay beliefs about pain distribution (PD) influence theoretical decisions to seek care and treatment preferences. In a representative cross-sectional survey (N=503; 49% with pain), participants completed thought experiments in which both visually presented PD patterns (small, moderate or large) and pain intensity (NRS 2, 5, 8/10) were systemically varied. For each scenario, they rated the likelihood of (i) seeking professional help (LoSH) and (ii) taking analgesic medication (LoTM). Participants also completed a spatial-intensity trade-off task (SITT), in which they chose between a fixed 20% reduction in intensity and variable reductions in PD (20-80%). A reversed version contrasted a fixed 80% reduction in PD with variable reductions in pain intensity. LoSH and LoTM increased significantly with greater PD (p<0.001), mirroring the gradient observed for pain intensity. In the SITT, participants' choice followed a sigmoid-like function (p<0.001): 1% reduction in intensity was treated as equivalent to approximately a 3% reduction in distribution, indicating a systematic valuation of PD. This ratio was lower in individuals experiencing pain compared to pain-free individuals. Moreover, 63% reported that PD should be routinely considered in pain management alongside intensity. Results suggest that PD is not merely a trivial descriptor, but a meaningful determinant of healthcare-related decision-making beliefs. Incorporating spatial metrics into clinical assessment and research may better capture how individuals implicitly evaluate pain severity.

Chronic pain involves natural intensity fluctuations that patients cannot control, contributing to learned helplessness and functional impairment. Detecting spontaneous pain decreases could enable precisely timed interventions that enhance perceived control. However, existing research on objective pain assessment has focused primarily on estimating static intensity from short, predictable stimuli rather than detecting moment-to-moment changes in ongoing pain. This study investigated whether pain decreases can be detected objectively using easily obtainable physiological signals during fluctuating pain. We recorded multiple physiological signals (8-channel EEG, electrodermal activity, heart rate, pupil diameter, facial expressions) from 42 healthy participants (Mage = 26.2 years, SD = 5.1) during calibrated tonic heat pain stimulation on the left forearm with unpredictable intensity fluctuations (0-70 on visual analogue scale; twelve 3-minute trials). Temperature changes lasted 5-20 seconds. Using minimal preprocessing suitable for real-time applications, we trained state-of-the-art deep learning models to classify pain decreases versus non-decreases from brief temporal windows on a held-out test set (9 participants). Combining electrodermal activity, heart rate, and pupil diameter yielded optimal classification performance using a transformer-based architecture (AUROC = 0.854, accuracy = 76.8%). Electrodermal activity emerged as the most informative single predictor. Continuous stream analysis demonstrated median detection latency of 5.75 seconds with 70.4% sensitivity, reducible to 4.25 seconds at the cost of increased false positives. Results indicate that electrodermal activity and heart rate enable straightforward practical deployment, while highly variable signals such as EEG and facial expressions require personalized fine-tuned models. These findings establish a basis for closed-loop interventions targeting spontaneous pain changes. SummaryDeep learning models detect pain decreases using electrodermal activity, heart rate, and pupil diameter (AUROC=0.854, 5.75s latency), facilitating precisely timed interventions for fluctuating tonic pain.

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

Nav1.7 voltage-gated sodium channels are strongly expressed in human primary painsensing neurons (nociceptors) and selective Nav1.7 inhibitors have been developed as possible therapeutic agents for treating pain, so far with disappointing clinical results. In contrast, a selective Nav1.8 channel inhibitor (suzetrigine) has had successful clinical trials. Because nociceptors express both Nav1.7 and Nav1.8 channels, it is of interest to compare effects of Nav1.7 and Nav1.8 inhibitors on the excitability of human nociceptors. To compare with previous results with suzetrigine, we characterized the effects of a selective Nav.7 inhibitor, AM-2099, on action potential generation and repetitive firing of dissociated human dorsal root ganglion neurons, studied at 37{degrees}C. Inhibition of Nav1.7 channels by 600 nM AM-2099 generally produced a substantial depolarizing shift of action potential threshold, an increase in rheobase, a decrease in action potential upstroke velocity, decrease in action potential peak, and prolongation of refractory period. Compared to inhibition of Nav1.8 channels, inhibition of Nav1.7 channels had larger effects on threshold and maximal upstroke velocity, while action potential peak was reduced similarly by both. Nav1.8 inhibition produced much more dramatic reduction of repetitive firing than Nav1.7 inhibition. The results show that although the excitability of human DRG neurons is affected by inhibition of Nav1.7 channels, most notably by an increase in threshold and increase in refractory period, repetitive firing of the neurons in response to strong stimuli is little affected. Significance statementNav1.7 sodium channels are highly expressed in primary pain-sensing neurons and humans with null mutations in Nav1.7 channels have loss of pain sensation. However, unlike the Nav1.8 inhibitor suzetrigine, Nav1.7 inhibitors have so far not reached clinical use. We compared effects of Nav1.7 on electrical excitability of human dorsal root ganglion neurons with those of suzetrigine and found that while Nav1.7 inhibition affects spike threshold more than suzetrigine, there is little effect on repetitive firing with strong stimuli.

BackgroundPersistent Spinal Pain Syndrome (PSPS) type II represents a challenging clinical entity with limited therapeutic options. Various spinal cord stimulation (SCS) modalities have emerged as potential treatments, but their comparative effectiveness remains unclear. ObjectiveOur goal in this paper is to systematically evaluate and compare the efficacy of different SCS modalities in patients with PSPS type II through meta-analysis of available randomized controlled trials. Evidence ReviewWe conducted a systematic review following PRISMA guidelines, searching major databases for randomized controlled trials evaluating SCS modalities in PSPS type II patients until the end of May 2025(search updated on October 3rd). Primary outcomes included pain intensity (VAS) and functional disability (ODI) at 6 and 12 months. Subgroup analyses compared tonic versus burst stimulation and high-frequency versus low-frequency SCS. FindingsNine randomized controlled trials were included, encompassing 565 patients across different SCS modalities. For the primary outcome of clinically meaningful pain relief ([&ge;]50% reduction), pooled analysis demonstrated that 45% (95% CI: 18-75%, I{superscript 2} = 92.2%) of patients achieved this threshold for back pain and 55% (95% CI: 45-65%, I{superscript 2} = 0%) for leg pain. Subgroup analysis revealed significant differences in back pain responder rates by stimulation modality: High-frequency SCS demonstrated responder rates of 92% (95% CI: 79-98%) versus 28% (95% CI: 13-49%) for conventional frequencies (p < 0.001). For leg pain, no significant difference was observed between tonic (51%, 95% CI: 37-65%) and burst stimulation (60%, 95% CI: 45-74%, p = 0.36) and mean VAS scores demonstrated significantly lower pain with high-frequency SCS (13.30, 95% CI: 8.82-17.78) compared to conventional frequency (28.42, 95% CI: 24.02-32.88, p<0.0001). For back pain, mean VAS scores decreased from a baseline of 73.03 to 41.67 (95% CI: 36.12-47.22, I{superscript 2}=22.8%) at 6 months and remained stable at 35.66 (95% CI: 25.39-45.93, I{superscript 2}=75.0%) at 12 months. Leg pain showed more pronounced improvement, with VAS scores declining from a baseline of 61.81 to 23.75 (95% CI: 17.69-29.81, I{superscript 2}=78.8%) at 6 months and 29.16 (95% CI: 24.81-33.52, I{superscript 2}=0%) at 12 months). Meta-regression identified longer pain duration and older age as positive predictors of response, while higher baseline leg pain predicted lower responder rates. Serious adverse events occurred in 10%, with a 16% revision surgery rate. Only two studies demonstrated a low risk of bias across all domains. ConclusionsCurrent evidence demonstrates that various SCS modalities provide clinically meaningful pain relief in PSPS type II patients, with approximately half achieving [&ge;]50% pain reduction. High-frequency SCS shows significantly superior responder rates for back pain compared to conventional tonic stimulation, while burst stimulation yields significantly superior reductions in continuous pain intensity metrics. However, the limited number of studies, substantial heterogeneity, and lack of head-to-head comparisons prevent definitive recommendations regarding optimal stimulation parameters. Future large-scale randomized trials with standardized protocols and responder-based outcomes are needed to establish evidence-based treatment algorithms for PSPS type II patients.

New-onset chronic pain is a common and debilitating symptom of Long COVID (LC) that remains not fully understood in terms of pathophysiology and therapeutic targets. A growing body of evidence in chronic pain syndromes similar to LC demonstrates an association between EEG alpha oscillatory activity and the experience of pain, with clinical studies showing maladaptive changes in oscillatory activity, particularly a slowing of alpha activity. This study aims to investigate the association between EEG alpha oscillatory activity and pain perception in new-onset LC-chronic pain. We recruited 31 individuals (20 females) with a clinical diagnosis of LC reporting new-onset chronic pain and 31 healthy pain-free age-and sex-matched controls. Participants completed questionnaires regarding symptoms and psychological functioning prior to recording eyes-open resting-state EEG. Peak alpha frequency (PAF) and spectral power within the alpha band (8-13 Hz) were extracted from EEG signals. Lower PAF over the posterior scalp region was significantly associated with higher LC-chronic pain severity when controlling for age and depression. This observation was consistent across PAF estimation methods. PAF was significantly increased, particularly in the posterior region, in the moderate pain LC subgroup compared to both severe pain subgroup and controls, while alpha power did not differ between the three groups and was not associated with pain severity. Our findings highlight associations between PAF and pain symptoms in a new post-infection chronic pain syndrome. PAF can thus be explored as a potential biomarker and therapeutic target for EEG-based neuromodulation interventions in LC-chronic pain. These results may have implications for other similar chronic pain syndromes. SummaryLower resting-state EEG peak alpha frequency in posterior scalp region is associated with higher severity of new-onset Long COVID chronic pain.

Suzetrigine, a selective Nav1.8 blocker, despite its significant role as a non-opioid analgesic, exhibits modest efficacy. The potential enhancement of Nav1.8 blocker efficacy through engagement of Nav1.8 at central terminals remains uncertain. We established a donor-derived human organotypic nociceptive circuit to determine where and how clinically relevant analgesics suppress pain signaling. Using ELISA and immunohistochemistry, we quantified calcitonin gene-related peptide (CGRP) release from acute explants of adult human spinal cord, dorsal root ganglia (DRG), and an intact DRG-spinal cord preparation preserving primary afferent anatomy and directional signaling. In isolated spinal cords, capsaicin evoked concentration-dependent spinal CGRP release without compromising viability, and clinically used analgesics inhibited it, validating the assay. In the intact circuit, the application of capsaicin to the DRG cell bodies triggered CGRP release exclusively in the spinal cord, consistent with compartmentalized neuropeptide release at central terminals. Selective Nav1.8 inhibition with suzetrigine reduced spinal CGRP release only when applied to the DRG or nerve root, not the spinal cord, indicating that Nav1.8 regulates peripheral action potential propagation rather than presynaptic transmitter release. These findings establish the first intact human pain circuit-based assay to study analgesics and demonstrate that the analgesic efficacy of Nav1.8 inhibitors is unlikely to increase with improved CNS penetration.

BackgroundUnderstanding the associations among biopsychosocial factors is essential for improving research and treatment of chronic low back pain (CLBP). Here we characterized interrelations among biopsychosocial domains using network analysis and identified the most influential features in CLBP. MethodsData came from Quebec Low Back Pain Study, comprising 4,489 CLBP participants. We modeled relationships among baseline biopsychosocial features as networks, where nodes represent features and edges encode statistical or causal dependencies among them. Undirected network was inferred using distance correlation. Directed network was constructed using the Linear Non-Gaussian Acyclic Model, which estimates plausible causal directions. Influence maximization was performed using the Independent Cascade (IC) model to identify the most influential features in each network. ResultsIn the undirected network, physical function and pain interference were the most central nodes, followed by depression. In the directed network, fear of movement, catastrophizing, and widespread pain emerged as key downstream hubs receiving multiple causal inputs, whereas pain interference, physical function, and depression acted as major upstream drivers exerting broad causal influence. IC diffusion simulations further identified pain interference and physical function as the most influential features in the undirected and directed networks, respectively. ConclusionsPain interference, physical function, and depression consistently emerged as key components of the CLBP biopsychosocial network. These features exert causal effects on fear of movement, catastrophizing, and widespread pain, with diffusion analyses confirming their roles as system-wide drivers. Interventions targeting functionality and pain interference, rather than pain intensity alone, may yield broader benefits across psychological and functional domains.

Chronic low back pain (CLBP) is persistent and refractory, affecting 20-30% of population worldwide. Neurofeedback has been explored as a potential non-pharmacological intervention for chronic pain, although evidence in CLBP remains limited. This study evaluated PainWaive, a consumer-grade digitally-delivered neurofeedback intervention targeting multiple pain-related frequency bands recorded over the sensorimotor cortex in individuals with CLBP. In a multiple-baseline experimental design, four participants completed daily assessments of pain severity and pain interference during randomly-assigned baseline phases of 7, 10, 14, and 20 days, followed by 20 sessions of the PainWaive intervention over four weeks. Daily pain assessments continued during the post-intervention and follow-up phases. Participants rated PainWaive's usability and acceptability at post-intervention. Anxiety, depression, wellbeing, and sleep disturbance were assessed at three timepoints. Aggregated Tau-U analyses indicated a large effect (-0.67) on pain severity from baseline to intervention and very large from baseline to post-intervention (-0.92) and follow-up (-0.92) phases. Large effects (-0.63, -0.62, and -0.70) were also observed for pain interference. Individual-level analyses showed significant reductions across all participants, with visual inspection confirming progressive decreases over time. The intervention was rated usable and acceptable by all participants, while psychological outcomes were mixed and varied across participants. The findings provide promising evidence that the PainWaive neurofeedback intervention may reduce pain severity and pain interference in some individuals with CLBP. By prioritising accessibility, usability, and self-administration, PainWaive supports a foundation for more patient-centred, technology-enabled approaches to chronic pain management. Further evaluation of this approach in randomised trials is required to establish efficacy.

BackgroundConventional local anesthetics (LAs) provide pain relief but also block motor and non-nociceptive fibers, causing undesirable side effects. Approaches using permanently charged derivatives, such as QX-314, delivered via TRPV1 channels, selectively target nociceptors but are limited by neurotoxicity. We hypothesized that clinically approved LAs with high pKa and low toxicity, such as 2-chloroprocaine (chloroprocaine), which is predominantly protonated and membrane-impermeant at physiological pH, would preferentially enter TRPV1-expressing nociceptors when co-administered with a TRPV1 agonist, thereby producing prolonged pain-selective anesthesia without neurotoxicity. MethodsWhole-cell voltage-clamp recordings from rat dorsal root ganglion (DRG) neurons assessed sodium current inhibition. Behavioral experiments in male Sprague-Dawley rats (N=6 -12/group) evaluated sensitivity to noxious thermal and mechanical stimuli and motor function following intraplantar and perisciatic injections of 0.5% or 2% chloroprocaine combined with capsaicin or cannabidiol (CBD). TRPV1 activation was examined by calcium imaging in hTRPV1-expressing HEK293 cells and in capsaicin- and AITC-sensitive DRG neurons. Neurotoxicity was assessed using propidium iodide uptake, long-term behavioral monitoring (35 days), and immunohistochemistry for TRPV1, ATF-3, and GFAP. ResultsCo-application of chloroprocaine with capsaicin enhanced sodium current blockade (76{+/-}15%) compared to either drug alone (p<0.05). Perisciatic injection produced thermal analgesia that persisted for 4 hours, whereas motor block resolved within 30 minutes. Unlike other LAs, chloroprocaine did not activate TRPV1 (98% non-responders) and showed no cytotoxicity. Long-term evaluation revealed no hypersensitivity, neuronal loss, or ATF-3 upregulation. Replacing capsaicin with CBD preserved prolonged ([~] 3.5 h) pain-selective anesthesia without motor impairment. ConclusionsTRPV1-mediated delivery of high-pKa LA chloroprocaine produces prolonged, nociceptor-selective anesthesia without neurotoxicity. Combining a clinically approved high-pKa LAs with low intrinsic toxicity and TRPV1 agonists such as CBD offers a potentially safe strategy for pain-selective regional anesthesia, with implications for perioperative and chronic pain management.

Interpersonal affective touch, that preferentially engages C-tactile (CT) afferents, has been shown to produce analgesic effects, yet its role in pain sensitization remains poorly understood. This study explores whether touch delivered at CT-optimal parameters--either artificial or interpersonal--modulates secondary hyperalgesia (SH) induced by high-frequency stimulation (HFS). Two experimental studies were conducted. In Study 1, 46 participants underwent SH induction during two conditions: robot stroking at CT-optimal velocities and vibrotactile stimulation. In Study 2, 64 participants (32 couples) experienced SH in two separate sessions: alone or accompanied by their partner delivering affective touch. Pain reports, electroencephalographic activity (N-P complex and time-frequency activity), electrocardiographic (ECG) and electrodermal activity data (EDA) were collected. HFS successfully established SH in both studies; however, no significant differences were found in the SH area between CT-stimulation and control conditions. In Study 2, partner-delivered affective touch significantly reduced reported acute pain during HFS compared to the alone condition, whereas no such effect was observed in Study 1 (robotic vs. vibrotactile). At the neural level, no condition effects were observed in the N-P complex, EEG time-frequency data and ECG indexes in either study. Tonic EDA after HFS was higher when participants received stroking from their romantic partner compared to being alone. No sex differences were observed. Overall, while affective touch from a romantic partner may reduce acute pain during nociceptive stimulation -an effect not observed with robotic CT-stimulation- neither robotic nor interpersonal affective touch appeared to modulate the development of secondary hyperalgesia.

Neuropathic pain (NP) affects approximately 60% of individuals with spinal cord injury (SCI). Existing pharmacological treatments provide only modest relief and are often limited by adverse effects, while non-pharmacological options show small effects at best. As such, there remains a need for accessible, mechanism-informed treatments for SCI-NP. This protocol describes a trial evaluating two promising home-based neuromodulatory interventions for SCI-NP - electroencephalography neurofeedback (EEG-NF) and transcranial direct current stimulation (tDCS) - tested both independently and when applied in combination. We will employ a partially double-blinded (i.e. 1 treatment blinded, the other not), 2x2 factorial randomised controlled trial. Adults with chronic SCI-NP (N=192) will be randomised to: (1) EEG-NF + active tDCS, (2) EEG-NF + sham tDCS, (3) active tDCS alone, or (4) sham tDCS alone, in addition to treatment as usual. Participants will complete 20 home-based sessions over 5 weeks. The primary outcome is change in overall pain severity with the primary endpoint being 6 weeks post-randomisation, with secondary endpoints at 16, 26 and 52 weeks post-randomisation. Secondary outcomes (worst pain intensity, pain interference, sleep, depressive symptoms, health-related quality of life) will be assessed at 6 weeks, 16 weeks, 26 weeks and 52 weeks post-randomisation. This will be the first large-scale trial of home-based EEG-NF and tDCS for SCI-NP. If found to be effective, these scalable interventions could be integrated into routine care and inform further optimisation of neuromodulation strategies for managing SCI-NP.

Cognitive dysfunction is increasingly recognized as an important feature of chronic pain (CP). However, subjective cognitive complaints and objectively measured cognitive performance frequently diverge. Whether and how these two aspects of cognitive functioning differentially relate to the broad symptomatology and brain function in CP remains unclear. Here, 114 individuals with CP completed patient-reported outcome measures on cognitive functioning and multidimensional CP symptoms, as well as a visuospatial working memory task, and resting-state EEG. Bayesian correlations, network analyses, and Bayesian regression models examined how subjective and objective cognitive functioning relate to multidimensional CP symptoms and EEG activity/connectivity, while controlling for age and sex. Additional models tested whether EEG associations were independent of broader symptom burden. Results indicated that subjective and objective cognitive functioning were uncorrelated. Subjective cognitive functioning was strongly associated with psychosocial symptoms, whereas objective cognitive functioning was largely independent of broader symptom burden. EEG revealed associations between subjective cognitive functioning and bilateral frontotemporal beta connectivity; however, these relationships were substantially attenuated after accounting for broader CP symptom burden. Objective cognitive functioning showed no robust associations with EEG. These findings indicate a dissociation between subjective cognitive complaints and objective cognitive performance in CP. Subjective cognitive complaints were primarily associated with psychosocial symptom burden and beta-band hypoconnectivity. In contrast, objective cognitive performance was unrelated to the broader symptomatology of CP and EEG measures. This dissociation may inform more targeted interventions, optimize the allocation of cognitive assessment resources, and ultimately improve long-term functional outcomes in CP.

ObjectiveTo determine the incidence and transition patterns of local and spatial recurrence among youth athletes presenting with groin pain (GP), anterior knee pain (AKP), and heel pain (HP). DesignRetrospective observational study. SettingSingle sports medicine clinic. ParticipantsYouth athletes who visited the clinic between January 2017 and November 2025 for GP, AKP, or HP. A total of 769 clinical episodes were included. Independent VariablesPain-site transitions and laterality were extracted from electronic medical records. No therapeutic interventions were evaluated. Recurrence patterns were classified as local or spatial and further subclassified into contralateral same-site, adjacent-site, and remote-site recurrence. Main Outcome MeasureTrue recurrence, defined as an episode with at least one prior visit for GP, AKP, or HP within the preceding 12 months. ResultsAmong 769 episodes, 130 episodes (16.9%; 95% confidence interval [CI], 14.4- 19.7) represented true recurrence. Local recurrence accounted for 57 episodes (7.4%; 95% CI, 5.8-9.5), whereas spatial recurrence accounted for 73 episodes (9.5%; 95% CI, 7.6-11.8). Among spatial recurrences, 26 episodes (35.6%) were contralateral same-site, 42 (57.5%) adjacent-site, and 5 (6.8%) remote-site recurrence. Transitions most frequently occurred between GP and AKP and between AKP and HP, whereas direct transitions between GP and HP were uncommon. ConclusionsRecurrence after symptom resolution in youth athletes more often involves spatial transitions to anatomically adjacent sites rather than simple local recurrence. These findings support interpreting recurrence within a whole-body functional framework and may facilitate refined recurrence risk assessment and comprehensive intervention strategies. Clinical RelevanceClinicians should evaluate recurrent pain beyond the symptomatic region, which may improve recurrence prevention and return-to-sport decision-making.

There is evidence that adults with spinal cord injury (SCI) have deficits in mental body representations (e.g., altered visuospatial body maps and reduced body awareness), due to the diminished or lack of sensory information reaching the brain. These mental body representation deficits are important and need to be quantified, because they can impact daily functioning and they are associated with neuropathic pain. The currently available evaluation scales measure certain aspects of mental body representations with few having been assessed in adults with spinal cord injury. Furthermore, to our knowledge, no scales have been developed specifically for adults with spinal cord injury. Therefore, to address this gap, we completed two aims. First, we developed a novel evaluation scale (the SCI-BodyMap) to measure SCI-specific deficits in mental body representations. Second, we assessed the psychometric properties of inter-rater reliability, test-retest reliability, concurrent validity, with the Revised Body Awareness Rating Questionnaire, the Multidimensional Assessment of Interoceptive Awareness-2, and the Numeric pain rating scale. We also assessed feasibility, utility, and face validity with the QQ-10. We found good to excellent inter-rater and test-retest reliability, with the exception of two items showing moderate test-retest reliability. We did not find any correlations between the SCI-BodyMap with the Revised Body Awareness Rating Questionnaire or the Multidimensional Assessment of Interoceptive Awareness-2 and found fair correlations between high levels of neuropathic pain on the Numeric pain rating scale with highest level of neuropathic pain on the SCI-BodyMap. The scale proved to have high feasibility, utility, and face validity. Once more psychometric analyses are performed in a bigger sample, the SCI-BodyMap could be recommended for use in research and in the clinic.