ABSTRACT:Patients with inflammatory arthritis (IA) often report pain not necessarily coupled to active inflammation. We previously demonstrated that a significant subset of patients with newly diagnosed IA report features of centrally mediated pain. In this prospective study following the same IA cohort, we tracked the relative contributions of inflammatory/noninflammatory mechanisms to pain over 2 years. We used patient-reported outcome measures (PROMs), clinical data (including ultrasound), and standardised quantitative sensory testing. Mixed-effects regression models examined longitudinal associations. We recruited 66 patients. At 6, 12, and 24 months, 62%, 57%, and 49% of individuals, respectively, reported persistent pain (numerical rating scale ≥3). Using factor-derived composite scores, baseline and longitudinal inflammation was not associated with subsequent pain (b -0.05, P = 0.87), whereas higher centrally mediated pain markers predicted less pain reduction (b 1.41, 95%, P < 0.001). Baseline PROMs of centrally mediated pain (fibromyalgia severity average marginal effect [AME]: 0.94, P < 0.001, painDETECT AME: 1.03, P < 0.001) and mental health (eg, Generalised Anxiety Disorder-7 AME: 1.08, P < 0.001) were the strongest predictors of persistent pain. Baseline trapezius pressure pain threshold (PPT) and conditioned pain modulation (CPM) pain detection threshold (PDT) effect showed modest association (trapezius PPT AME: -0.51, P = 0.054, CPM PDT effect AME: -0.49, P = 0.051) whereas temporal summation of pain (AME: 0.09, P = 0.756) and CPM pain tolerance threshold effect (AME: -0.01, P = 0.964) did not. In our cohort, persistent pain was associated with higher baseline and longitudinal scores for centrally mediated pain according to PROMs rather than inflammation according to joint ultrasound. In IA, early identification and treatment of features of centrally mediated pain may improve pain-related outcomes.
ABSTRACT:Characterizing the affective processes parents experience following a child's surgery and how these processes might predict their perceptions of children's pain and postoperative medication administration is critical for refining interventions to improve children's pain management. This study evaluated concurrent and lagged associations among parent affect (pain catastrophizing, negative affect, and positive affect), perceived child pain intensity, and opioid administration in the 7 days after tonsillectomy in a sample of youth ages 7 to 12 years (n = 138). Parents of potentially eligible patients were recruited before surgery and completed electronic diaries through a smartphone application 3 times daily for 7 days after surgery. Opioid administration was evaluated in the context of routine clinical care. Patients were generally prescribed a 3-day supply of liquid oxycodone for parents to administer if pain was uncontrolled by acetaminophen and ibuprofen. Of the 138 parents who completed ≥1 diary, 90 parents reported administering an opioid during the diary period (65.2%) and were included in opioid analyses. In multilevel models, both average and momentary levels of parent affect predicted parents' perceptions of their child's pain intensity, whereas only average negative affect and momentary levels of parent affect predicted odds of opioid administration. Parent pain catastrophizing had a bidirectional relation with perceived child pain in lagged analyses, with higher parent pain catastrophizing predicting higher perceived pain intensity at subsequent timepoints and vice versa. Assessing momentary levels of parent affect may be particularly important for capturing dynamic shifts that predict escalations in children's pain and opioid administration.
ABSTRACT:Music effectively reduces pain, yet the mechanisms underlying music-induced hypoalgesia remain poorly understood. We investigated how latent perceptual dimensions of music influence pain by examining both stimulus properties and subjective evaluations of those properties in 2 experiments. One hundred thirty-four participants listened to unfamiliar musical excerpts during thermal pain stimulation. Musical stimuli were systematically selected using the validated Arousal, Valence, Depth (AVD) model, which quantifies 3 key latent perceptual dimensions of music based on groups of descriptors such as "forceful" or "calming." Study A (n = 74) demonstrated that high arousal music increased pain unpleasantness, whereas high depth music provided relief, but crucially, these effects were completely mediated by participants' subjective ratings of musical pleasantness. Study B (n = 60) replicated the beneficial effect of musical depth and confirmed that participants' perceptions aligned with loadings of the AVD model dimensions. Individual differences in trait systemizing moderated the analgesic effect of depth in one study. Complete mediation by pleasantness ratings indicates that experiences of reward and subjective aesthetic evaluation, rather than perceived musical dimensions themselves, drives music-induced hypoalgesia. This suggests that musical pain interventions should prioritize deep and relaxing music that is well liked by the participant.
ABSTRACT: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 electroencephalography, electrodermal activity, heart rate, pupil diameter, and facial expressions) from 42 healthy participants (mean age = 26.2 years, SD = 5.1) during calibrated tonic noxious heat stimulation on the left forearm with unpredictable intensity fluctuations (0-70 on visual analogue scale; twelve 3-minute trials). Temperature changes lasted 5 to 20 seconds. Using minimal preprocessing suitable for real-time applications, we trained deep learning models to classify pain decreases vs nondecreases from brief temporal windows, evaluated 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 (area under the receiver operating characteristic curve = 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 electroencephalography and facial expressions require personalized fine-tuned models. These findings establish a basis for closed-loop interventions targeting spontaneous pain changes.
ABSTRACT:Paradoxical heat sensation (PHS) is conventionally described as the perception of warmth elicited by innocuous cooling, yet the qualitative nature of this experience remains largely uncharacterised. To describe potential differences in how PHS is perceived, we compared 2 a priori profiles: "true perceivers," who experience PHS as a clear, warm percept, and "unsure perceivers," who experience it as an ambiguous sensation. Seventy-five healthy adults (21-80 years old) performed a perceptual decision-making task designed to elicit PHS by manipulating the thermal contrast between warm and cold temperatures. To test the PHS experience across the lifespan, we applied hierarchical multivariate Bayesian modelling in which perceptual choices, response times, and confidence ratings were expected to vary systematically across the 2 hypothesised perceptual profiles. At the group level, behaviour was best accounted for by the unsure perceiver model, indicating that PHS is most often an uncertain experience, rather than a categorical misperception. Both profiles were present across individuals, demonstrating substantial interindividual variability in perceptual patterns. Older adults reported PHS more frequently, and at lower thermal contrasts, but their perceptual profiles did not differ from those of younger participants. This suggests that ageing increases the likelihood of experiencing PHS without changing its qualitative nature. These findings show that PHS is a heterogeneous perceptual phenomenon defined by variability in certainty and subjective quality across individuals.
ABSTRACT:Cannabidiol (CBD) has both analgesic and anti-inflammatory properties. Because CBD is not psychotomimetic, it could be an excellent nonopioid alternative for various pain disorders. The aim was to assess the effectiveness of CBD as an analgesic for apical periodontitis-induced mechanical hypersensitivity (MH), its site of action (peripheral or central), and the potential involvement of transient receptor potential vanilloid 1 (TRPV1), using a mouse behavioral model of apical periodontitis (AP). Male and female mice underwent pulp exposure of the left maxillary first molar (AP group) or sham surgery (Sham group). Mechanical hypersensitivity was assessed 21 days after surgery using von Frey filaments on the left vibrissal pad. Apical periodontitis mice that received a single dose of oral CBD (AP [CBD]) experienced a significant reduction in MH at 45 minutes and 120 minutes compared with AP mice that received vehicle (AP [Veh]). The analgesic effect in males was significantly greater than in females at this CBD dose. Intrathecal and intracisternal (IC), but not ipsilateral intraoral, CBD injections reduced MH in the male AP (CBD) group, indicating a central site of action of CBD in this model of odontogenic pain. Furthermore, intraperitoneal and IC injection of AMG 517 (TRPV1 antagonist) before an oral CBD dose blocked the CBD analgesic effect in male mice, suggesting TRPV1's involvement. Overall, this study shows, for the first time, that oral CBD can be an effective analgesic for apical periodontitis-induced MH. This analgesic effect was mediated through a central site of action and involved the TRPV1 channel.
ABSTRACT:Accumulating evidence indicates that glial cells play a critical role in the initiation, maintenance, and resolution of neuropathic pain. However, there is lack of glia-specific molecular targets for pain management. We recently identified the G protein-coupled receptor GPR37-like 1 (GPR37L1) as a glia-selective receptor expressed in astrocytes and satellite glial cells (SGCs), and GPR37L1 protects against the development of neuropathic pain, highlighting it as a promising target for neuroglial modulation. Building on our discovery that the proresolving lipid mediator Maresin1 acts as an endogenous ligand for GPR37L1, this study aimed to identify small-molecule GPR37L1 agonists with improved synthetic accessibility and analgesic duration. Using virtual screening combined with molecular dynamics simulations, we identified compound P06 as a top candidate with the highest predicted binding affinity. In vitro, P06 induced a dose-dependent potassium influx in cells expressing GPR37L1. The analgesic efficacy of P06 was evaluated in mouse models of neuropathic pain after chemotherapy-induced peripheral neuropathy and spared nerve injury (SNI). A single intrathecal injection of P06 produced robust and long-lasting inhibition of chemotherapy-induced mechanical allodynia for more than 24 hours. This effect was completely abolished in Gpr37l1 knockout mice, confirming a receptor-dependent mechanism. P06 also alleviated SNI-induced mechanical/cold allodynia and mitigated nerve injury-induced reactive gliosis in SGCs of dorsal root ganglia. Mechanistically, P06 directly acted on human and mouse SGCs to enhance potassium levels and suppress paclitaxel-induced Interleukin-1β release. Together, these findings establish GPR37L1 as a glia-specific therapeutic target and demonstrate that small-molecule activation of GPR37L1 provides effective relief from neuropathic pain.
ABSTRACT:Substantial evidence from animal and human studies supports the hippocampus' role in pain, positioning it as a key contributor to the pain experience. Here, we comprehensively incorporate the hippocampus in our understanding of pain perception and provide critical insight and novelty for future interdisciplinary research in pain.
ABSTRACT:Pain perception involves complex sensory and emotional processes, yet the supraspinal circuits that sustain neuropathic pain remain incompletely understood. Here, we demonstrate that parabrachial nucleus (PBN) neurons expressing the inhibitory G-protein-coupled neuropeptide Y Y1 receptor (Npy1r) are critical modulators of neuropathic pain. Approximately 19% of lateral PBN neurons express Npy1r. Stimulus-evoked Fos activation and calcium dynamics of these neurons increases in mice with spared nerve injury (SNI) compared to sham controls. Pharmacological activation of Y1 receptors or chemogenetic inhibition of Npy1r neurons attenuates SNI-induced mechanical and cold allodynia, without altering baseline sensitivity or conditioned place preference (a measure of affective pain). Preemptive ablation of parabrachial Npy1r neurons before SNI delayed the development of neuropathic hypersensitivity. Conversely, repeated chemogenetic activation of Npy1r neurons produced persistent mechanical and cold hypersensitivity in uninjured animals; this outlasted neuronal activation, indicating sufficiency to drive pain-like states. Viral tracing revealed dense Npy1r projections from lateral parabrachial neurons to forebrain regions including the central amygdala, lateral hypothalamus, zona incerta, and ventromedial thalamus, sites implicated in the sensory and affective dimension of pain. These findings demonstrate that Npy1r-expressing PBN neurons selectively regulate the sensory-discriminative component of neuropathic pain and can maintain long-lasting hypersensitivity even in the absence of injury.
ABSTRACT:Trigeminal neuralgia (TN), a devastating neuropathic pain condition, profoundly affects human well-being. Despite an initial response to carbamazepine (CBZ), many patients become refractory to pharmacotherapy and subsequent invasive procedures. Although preclinical trigeminal neuropathic pain models following extracranial chronic constriction injury (CCI) of the trigeminal nerve have been developed, the injury-induced facial hypersensitivity is rarely CBZ-responsive, questioning the models' relevance to TN. In recent reports, CBZ-responsive facial pain can be induced by intracranial CCI that better mimics the compression observed in classical TN. Nevertheless, behavioral assessment of persistent pain in these models often requires a restrained setting that could trigger unpredictable behaviors that are not necessarily pain associated. Here, we focused on spontaneous and evoked measures of pain in unrestrained mice after a CBZ-sensitive intracranial CCI, namely the FRICT-ION model. To measure these behaviors long-term, we developed a high-frame rate videography analysis that reliably captures increased chronic spontaneous asymmetric grooming and mechanically evoked facial rubbing, ipsilateral to the injury. Notably, this altered behavioral phenotype was significantly reversed by a nonsedating dose of CBZ. Using DeepLabCut tracking, we also found that the speed of head movement after facial mechanical stimulation is a significant CBZ-sensitive behavioral correlate of TN allodynia. Importantly, these behavioral measures accurately recapitulated the clinical outcomes-both success and failure-of a cohort of specific nonopioid analgesics that have previously been tested in the clinical management of TN. Together, these measures should greatly facilitate the research development of innovative TN therapies.
Abstract In pain and other research fields, placebos have traditionally been associated with deception, although harnessing placebo effects does not necessarily require deception. Open-label placebos (OLPs) represent a novel approach in which inert treatments are administered openly and transparently, allowing patients to knowingly receive an inert treatment while still experiencing therapeutic benefits (eg, pain relief). As OLP research grows, concerns have been raised regarding methodological rigor and the unique challenges posed by unblinded designs in both experimental and clinical contexts. Given the inherent transparency regarding treatment group allocation in OLP trials, particular attention is needed when defining appropriate control groups, implementing feasible blinding strategies, and providing a treatment rationale to adequately explain OLPs. Addressing these challenges is crucial to advancing both the scientific understanding of the psychoneurobiological mechanisms underlying OLP effects and their clinical relevance in pain. In this review, we outline key methodological considerations for designing and conducting OLP studies in pain research and beyond, providing guidance on control group selection, blinding strategies, and reporting standards. In addition, we integrate insights from the patient advisory board of the transregional Collaborative Research Center (CRC/TRR) 289 “Treatment Expectation” to incorporate patient perspectives on the feasibility and acceptability of OLPs. Aligning study designs with patient needs and expectations may foster a more meaningful, patient-centered approach to OLP research. By combining methodological guidance and emphasizing patient-centered insights, this review aims to enhance the quality, relevance, and clinical translation of OLP research in pain.
Abstract Group-based randomized controlled trials (RCTs) in clinical pain research in low- and middle-income settings (LMIS) face distinct challenges, including resource-related limitations and contextual barriers. In addition, evidence garnered through RCTs in high-income settings is often not directly relevant to LMIS. We briefly discuss alternative group-based study designs that can address some of these challenges. We then introduce single-case experimental designs as a complementary approach that may be more efficient than traditional group-based methods in these contexts. Single-case experimental designs focus on the individual person in relation to at least one independent variable over time under different conditions. Unlike RCTs, they require small sample sizes and provide more granular insights into how a pain intervention affects each individual rather than the average group response. Single-case experimental designs can also accommodate more diverse participants in terms of age, ethnic backgrounds, and comorbidities, making them resource-efficient, clinically relevant, and pragmatic, which can facilitate more clinical trials in LMIS, and thereby a better understanding and scientific evidence for the effects of treatments in these settings.
ABSTRACT:Results suggest that psychosocial treatments for chronic pain work via several mechanisms, and that they often do so to similar degrees and in similar ways. Extant research, however, has focused on individual and/or independent effects of mechanisms on outcomes. Whether successful outcomes are also partly because of sequential and meaningful relationships among and between mechanisms-mechanism-to-mechanism effects-has not been examined. Secondary analyses were conducted of an RCT that compared cognitive therapy, mindfulness-based stress reduction, and behavior therapy to treatment as usual in a sample (N = 521) of people with chronic low back pain. Results of hierarchical linear modeling revealed that (1) Treatment Condition × Mechanism interactions predicting changes in other mechanisms were nonsignificant; (2) lagged prior session mechanism changes predicted next session changes in another mechanism; (3) lagged relationships between pain catastrophizing and pain self-efficacy were reciprocal, whereas links between lagged pain catastrophizing and mindfulness changes and lagged pain catastrophizing changes and behavioral activation changes were unidirectional; and (4) individual differences in the strengths of mechanism-to-mechanism relationships predicted pre- to post-treatment changes in outcomes. Results reveal heretofore hidden therapeutic processes that cognitive therapy, mindfulness-based stress reduction, and behavior therapy may share. Namely, that mechanism-to-mechanism lagged effects do indeed emerge beyond mechanism-to-outcome effects. Findings show not only that mechanisms may change in definable sequences relative to each other but that individual differences in the strengths of mechanism-to-mechanism relationships may themselves be predictive of outcomes.
ABSTRACT:Peripheral neuropathy is a global health concern that markedly impairs quality of life. Peripheral nerve injury triggers complex interactions between the immune and nervous systems, driving persistent neuroinflammation and neuropathic pain. Macrophage migration inhibitory factor (MIF), a proinflammatory cytokine, has emerged as a key mediator in this process. Macrophage migration inhibitory factor binds to its primary receptor CD74, promotes cytokine release, recruits macrophages into the inflammatory milieu, and amplifies inflammatory responses. ISO-1, a small-molecule, high-affinity MIF inhibitor, targets the tautomerase active site of MIF, disrupts MIF-receptor (including canonical receptor CD74) binding, and thereby mitigates downstream inflammatory response. In this study, we investigated the anti-inflammatory and analgesic effects of ISO-1 in both male and female mice subjected to chronic constriction injury (CCI) of the sciatic nerve. A battery of behavioral, electrophysiological, immunohistochemical, and molecular approaches was used to evaluate the impact of systemic ISO-1 treatment on neuroinflammation and neuropathic pain. Electrophysiological recordings from the superficial dorsal horn neurons in acute spinal cord slices revealed that ISO-1 largely prevented the CCI-induced imbalance between excitatory and inhibitory postsynaptic currents. ISO-1 significantly reduced macrophage infiltration at the sciatic nerve injury site and within dorsal root ganglia. Notably, ISO-1 alleviated mechanical allodynia and thermal hyperalgesia in male mice, but not in female mice, a sex-specific effect corroborated by quantitative PCR analysis of inflammatory mediators. Together, these findings identify ISO-1 as a promising MIF-targeted strategy to counteract neuroinflammation and neuropathic pain after peripheral nerve injury and highlight the importance of sex-specific responses for the development of personalized immunomodulatory therapies.
ABSTRACT:Fear of movement (FoM), or kinesiophobia, is associated with functional disability in individuals with chronic pain. The Tampa Scale of Kinesiophobia (TSK) is among the most widely used instruments for assessing FoM and has undergone several revisions; however, its psychometric properties have not been evaluated in youth with chronic pain, and there is currently no consensus on the optimal version to use in pediatric pain populations. We examined data from youth with a range of chronic pain conditions (N = 1252; Mage = 14.55 years, 79.2% female sex assigned at birth) who were receiving clinical care or participating in studies across 3 study centers in the United States and Canada. Participants completed the 11- or 17-item version of the TSK as well as measures of mobility, functional disability, depressive symptoms, and pain catastrophizing. Using a combination of classical item theory techniques, Rasch analytic methods, and expert consensus, we identified a robust set of 7 TSK items (ie, the TSK-7-Y) based on item difficulty, point-measure correlations across items, and coverage of key measurement dimensions. The TSK-7-Y was compared with the 11-item set using predictive validation techniques including exploratory factor analysis and Pearson correlations with scores on 4 criterion-related instruments. Results indicated that TSK-7-Y items loaded onto 2 distinct factors comparably with the TSK-11. The total score correlated moderately with pain catastrophizing (r = 0.51) and weakly with depressive symptoms (r = 0.07). The TSK-7-Y is a brief yet psychometrically sound instrument for assessing FoM in youth with chronic pain.
ABSTRACT:Complex regional pain syndrome (CRPS) is a chronic, treatment-refractory neuropathic disorder associated with substantial functional impairment and socioeconomic burden. Although socioeconomic conditions have been implicated in vulnerability to chronic pain, evidence on the association between income dynamics and the risk of developing CRPS remains limited. Using the Korean National Health Insurance Service database, we conducted a nationwide cohort study including 3,437,021 adults in South Korea who underwent national health screening in 2012 and were followed through to 2022. Income-related indicators-including baseline income level, cumulative income exposure, income change, and income volatility during the 5 years preceding baseline-were assessed. Incident CRPS was identified using Korean Standard Classification of Diseases codes combined with registration in the Rare Intractable Disease program. Compared with the highest income quartile, individuals in the lowest income quartile had a higher CRPS risk (adjusted hazard ratio [aHR], 3.74; 95% confidence interval [CI], 3.07-4.56). Risk increased with longer duration of low-income status (aHR, 1.91; 95% CI, 1.48-2.45 for 5 vs 0 years) and decreased with longer duration of high-income status (aHR, 0.55; 95% CI, 0.44-0.70 for 5 vs 0 years). In addition, high-income volatility (highest vs lowest quartile aHR, 1.48; 95% CI, 1.23-1.78) and downward income changes (peak aHR, 1.84; 95% CI, 1.24-2.73) were independently associated with increased CRPS risk. These findings suggest that income dynamics represent an important socioeconomic risk factor for CRPS and highlight the relevance of longitudinal socioeconomic vulnerability in the development of disabling chronic pain conditions.
