Chronic overlapping pain conditions (COPCs), internalizing (INT) disorders, and opioid use disorder (OUD) are common, comorbid, and difficult to phenotype at scale. Electronic health record (EHR) studies commonly define cases using Any Code (AC; ≥1 ICD-9/10 code) and Multiple Code (MC; ≥1 inpatient or ≥2 outpatient codes) phenotyping strategies, but it is unclear whether these thresholds change only case numbers or also the clinical relationships among conditions. This cross-sectional study included 950,000 Million Veteran Program participants with ≥2 visits. AC and MC phenotypes for 17 conditions spanning COPCs, INT, and OUD conditions were compared in prevalence, case characteristics, comorbidity, and latent structure. Random-thinning analysis compared AC-MC differences to case reduction alone. Construct validity was evaluated through correspondence with expected patterns of association and latent organization. Back pain (AC=58.1%; MC=48.1%), major depressive disorder (41.5%; 36.2%), and post-traumatic stress disorder (32.6%; 29.1%) were most prevalent. MC excluded 33.5% of AC cases on average, and MC cases had greater healthcare utilization, diagnostic burden, opioid exposure, and psychiatric medication use than AC-only cases. The observed mean absolute correlation change (mean |Δr|=0.014) was smaller than in all 1,000 random-thinning replicates. Both strategies supported a correlated, four-factor model consistent with "Anxious Misery," "Fear," "Diffuse Pain," and "Head Pain" for both strategies (AC: CFI=0.987, RMSEA=0.015; MC: CFI=0.987, RMSEA=0.014). The MC strategy reduced prevalence and altered case composition but maintained the expected comorbidity and latent organization patterns among conditions. Findings provide evidence of phenotype construct validity and inform selection of EHR phenotyping strategies for epidemiological and genomic research. PERSPECTIVE: Commonly used EHR phenotyping strategies tested in nearly one million Veterans produce broadly similar latent organization across comorbid and prevalent chronic overlapping pain conditions, internalizing disorders, and opioid use disorder. Findings support construct validity and clarify trade-offs involving case inclusion, recorded burden, and healthcare observation in large-scale research.
Adolescents' perceived uncertainty regarding diagnosis and its causes are significant barriers to acceptance of their knee pain and formation of self-management skills. This study uses a repeated interview design to explore how adolescents with longstanding non-traumatic knee pain experience and perceive changes over time in their condition, needs, understanding of knee pain, and self-management. Ten adolescents with longstanding, non-traumatic knee pain were included. Each adolescent participated in two semi-structured online interviews. The first interview took place 1-3 days after the consultation, followed by a second interview 11-17 days later. Data were analyzed using reflexive thematic analysis, and findings from both time points were synthesized using a matrix analysis. Ten adolescents aged 12 to 15 years were included in the study. Most were female (n= 8). The analysis generated five themes for each interview time point. The matrix analysis generated key areas that illustrated how adolescents' perceptions and experiences evolved over time: (1) Limited recall and understanding of medical information; (2) Seeking proof: validation, reassurance and diagnostic confirmation; (3) Diagnosis as normalization and validation over time; (4) Reinforced beliefs: a rigid dichotomy between activity and rest; (5) Trial-and-error approach to pain management strategies; (6) Uncertainty and frustration in the absence of a clear recovery timeline. Adolescents' experiences and perceptions are dynamic; they are maintained, reinforced, and changed over time. These findings raise questions about how healthcare professionals should communicate and support adolescents to enhance their understanding of pain and adapt recommended self-management strategies. PERSPECTIVE: The key areas illustrate how adolescents' uncertainty, experiences, perceptions, and trial-and-error self-management evolve over time. These processes become integrated into the trajectory of living with knee pain and lay the foundation for how adolescents understand and manage their pain. Findings may inform more personalized communication and interventions to support self-management.
Accurate opioid dispensing surveillance is critical for guiding public health interventions; however, claims data alone may underestimate opioid utilization and opioid-related quality measures. This study evaluated the impact of linking prescription drug monitoring program (PDMP) data with administrative claims on opioid prescription metrics, Concurrent Use of Opioids and Benzodiazepines (COB) quality measure reporting, and predictors of additional concurrent user identification. Trends in opioid prescription metrics were assessed using 2019-2022 PDMP-linked Mississippi (MS) Medicaid claims. A cohort study of COB measure performance was conducted among Medicaid beneficiaries who filled opioid prescriptions in 2021 without cancer or sickle cell disease. Predictors included sociodemographic, clinical, and prescription-level characteristics. Outcomes included opioid prescription metrics, COB quality measure reporting, and identification of additional concurrent users using PDMP-linked MS Medicaid claims data beyond MS Medicaid data alone. Overall, the proportion of opioid prescriptions paid by Medicaid declined from 68.8% to 58.3% between 2019 and 2022 with corresponding increases in cash and other payer sources. PDMP-linked MS Medicaid claims identified, on average, 12,339 beneficiaries with opioid prescriptions compared with 10,972 using Medicaid claims alone (p <.001). For COB measure reporting, PDMP-linked data identified more concurrent users than Medicaid claims alone (14,067 vs. 9,344), and the COB rate increased from 3.7% to 8.0%, a 4.3-percentage-point increase. Higher average daily opioid dose was associated with additional concurrent user identification, while Black race and concurrent psychotropic medication use were associated with lower odds. Integrating PDMP data with Medicaid claims enhances opioid dispensing surveillance and COB measure accuracy. PERSPECTIVE: This study shows that Medicaid claims alone underestimates opioid dispensing and quality measure estimation compared with PDMP-linked data. Linked data improves COB quality measure detection and surveillance accuracy. These findings underscore the need for policy that facilitate secure PDMP-claims integration to strengthen opioid quality measurement and public health surveillance.
Chronic low back pain is common among Veterans and is associated with functional impairment and prescription opioid misuse. Cognitive Behavioral Therapy for Chronic Pain is the VA's recommended nonpharmacologic treatment, yet many patients experience modest improvements, underscoring the need for adjunctive strategies. Transcranial Direct Current Stimulation, a low-risk neuromodulation technique, has demonstrated analgesic and cognitive-affective benefits and may augment behavioral pain treatment. This double-blind, randomized controlled trial (NCT02483468) examined whether adding Transcranial Direct Current Stimulation to Cognitive Behavioral Therapy for Chronic Pain improved pain, functional impairment, and opioid misuse among Veterans with chronic low back pain and prescription opioid misuse. Veterans (N=115) were randomized to real or sham Transcranial Direct Current Stimulation administered during 11 Cognitive Behavioral Therapy for Chronic Pain sessions and completed repeated assessments of pain, functional impairment, and opioid misuse from baseline through follow-up. Mixed-effects models indicated significant time × group interactions for both pain and functional impairment, with participants receiving real Transcranial Direct Current Stimulation demonstrating a steeper decline across study timepoints. Opioid misuse decreased significantly over time in both groups, without additional benefit from Transcranial Direct Current Stimulation. Transcranial Direct Current Stimulation may meaningfully enhance the trajectory of pain and functional recovery during Cognitive Behavioral Therapy for Chronic Pain. Although adding Transcranial Direct Current Stimulation did not improve opioid misuse over the study period, the accelerated gains in pain and functioning may have downstream effects. Overall, Transcranial Direct Current Stimulation appears to be a promising adjunct that may accelerate recovery during behavioral pain treatment. PERSPECTIVE: Adding Transcranial Direct Current Stimulation to Cognitive Behavioral Therapy for Chronic Pain accelerates reductions in pain and functional impairment among Veterans with chronic low back pain, even when end-of-treatment scores are similar. Faster treatment gains may enhance engagement and reduce disability burden, highlighting the clinical value of neuromodulation.
Pain and sleep symptoms commonly co-occur in later life, but their interdependence within couples remains understudied in low- and middle-income settings. This study analyzed cross-sectional dyadic data from Wave 1 of the Longitudinal Ageing Study in India, including 6,382 cohabiting opposite-sex married couples in which both partners were aged 60 years or older. The outcome was any frequent insomnia symptom-difficulty initiating sleep, difficulty maintaining sleep, or early-morning awakening-reported on at least 5 nights per week. Survey-weighted logistic models with couple-clustered standard errors estimated associations of respondent and spouse frequent pain with the respondent's outcome. In the primary model, respondent frequent pain was associated with higher odds of the outcome when spouse pain was absent (odds ratio, 3.12; 95% confidence interval, 2.53-3.83), whereas spouse frequent pain showed a smaller association when respondent pain was absent (odds ratio, 1.41; 95% confidence interval, 1.11-1.79). Adjusted probabilities were 7.03% when neither partner reported frequent pain, 9.58% for spouse-only pain, 18.69% for respondent-only pain, and 16.11% when both partners reported frequent pain. The additive interaction contrast was -5.13 percentage points (95% confidence interval, -8.70 to -1.56), indicating a subadditive joint pattern. Respondent pain was the dominant correlate, whereas spouse pain contributed a smaller conditional association. Longitudinal studies are needed to establish temporal direction. PERSPECTIVE: This survey-weighted dyadic analysis found that frequent pain was associated with frequent insomnia symptoms within respondents and, more modestly, across spouses. Considering pain in both partners may support couple-aware assessment, although these cross-sectional findings do not establish temporal direction, mechanisms, or treatment effects.
American Indians/Alaska Natives (AI/AN) have higher rates of chronic pain than other U.S. groups. Research has attempted to uncover mechanisms behind this disparity, but risk factors for chronic pain have been delineated at the expense of examining resilience factors. Chronic pain resilience is typically defined as "the capacity to resist, adapt to, recover, or grow from a challenge." However, this conceptualization may not capture strengths inherent to AI/AN. To our knowledge, no investigations of AI/AN chronic pain resilience have been conducted to date. This project investigated the construct of chronic pain resilience among 27 AI/AN adults experiencing chronic pain. A semi-structured interview asked about personal definitions of resilience, experiences with chronic pain, and cultural influences. Interviews were conducted in-person or virtually, and transcripts of responses were generated, verified, and coded using 2 independent coders. Results produced 2 complementary sets of findings. First, participants indicated that pain was not a special form of adversity that would meaningfully change their definitions of resilience. Rather, pain was seen as another hardship requiring persistence, balance, and acceptance. Second, despite this general view, thematic analysis identified 4 interrelated themes describing how resilience is expressed in the context of chronic pain: Pain Management and Adaptation Strategies, Psychological and Behavioral Resilience Processes, AI/AN Cultural Resources and Practices Supporting Resilience, and System-Level Impacts on the Chronic Pain Experience. This study proposes the first model of AI/AN chronic pain resilience and provides a foundation for future investigations to clarify the interplay of the themes identified. PERSPECTIVE: This study provides the first model of chronic pain resilience in American Indians/Alaska Natives, showing that resilience is defined generally but expressed through culturally grounded practices and shaped by systemic inequities. These findings highlight the need for culturally centered interventions and greater attention to structural factors affecting pain experiences.
As a posttraumatic reaction after distal bone fracture, hypersensitivity to mechanical stimuli develops, spinal receptive fields enlarge mostly ipsilateral to the injury and the adrenergic receptor composition alters in peripheral and central nervous tissue. Many of these changes subside during fracture healing. In humans, CRPS can develop after distal bone fracture with long-lasting pain in the affected limb and, sometimes, contralaterally. This study shows contralateral effects after distal bone fracture in mice. Contralateral hypersensitivity develops in aging groups, in females earlier than in males. Aging males display contralateral spread of spinal changes to the neuronal network and activity. Field sizes can massively enlarge in a glove- or stocking-like distribution and cluster in the cord as early as in the posttraumatic phase. In these cases, clusters of fields shrink on the ipsilateral side long after trauma. Spinal neurons with abnormally large (in the posttraumatic phase) and later small (in the chronic phase) receptive fields respond strongly to pressure stimuli. Thus, hypersensitivity to pressure, occurring in many CRPS-like cases, might reflect a spinal status of altered connectivity. Further, alpha-adrenergic receptors are bilaterally differentially regulated in the spinal cord and locus coeruleus after bone trauma in aging male mice, potentially contributing to neuronal hyperexcitability in pain pathways during aging. Perspective Contralateral spread of hypersensitivity can occur after distal bone fracture in mice, primarily of female sex and/ or older age. Spinal network alterations and spinal and supraspinal adrenoceptor dysregulation also occurs in aging male mice.
Randomized controlled trials of acupuncture for pain management commonly rely on sham procedures intended to function as placebo controls. However, accumulating evidence suggests that widely used sham approaches, such as superficial needling or non-penetrating devices applied near therapeutic acupoints, may not be physiologically inert. Neuroimaging studies and clinical trials indicate that minimal needling or tactile stimulation can activate neural pathways involved in pain modulation, raising concern that sham acupuncture may represent a low-intensity intervention rather than a true placebo. This issue may attenuate observed differences between treatment and control groups and complicate interpretation of acupuncture trials for chronic pain conditions, including low back pain. In this Perspective, we discuss limitations of current sham acupuncture designs and propose reconsideration of an underutilized control strategy: random-point acupuncture. In this approach, real needling is performed at acupoints randomly selected from locations unrelated to the treatment protocol. This design preserves procedural credibility and participant blinding while minimizing overlap with protocol-specific therapeutic points. Importantly, comparing outcomes between true acupuncture and random-point acupuncture allows investigators to directly evaluate the role of acupoint specificity. We argue that incorporating such controls could improve the methodological rigor of acupuncture trials and provide clearer insights into the mechanisms underlying acupuncture analgesia. PERSPECTIVE: Random-point acupuncture offers a pragmatic sham-control strategy for acupuncture trials. By systematically excluding potentially therapeutic and condition-relevant acupoints and assigning participant-specific random-point sets, this approach may reduce unintended therapeutic effects while supporting blinding, thereby strengthening evaluation of acupuncture efficacy and acupoint specificity.
Chronic pain is common among refugees, who report challenges in accessing and engaging in care. As part of a wider program of research focussed primarily on refugee perspectives on this issue, we were interested in the insights and perspectives of healthcare professionals, who are key agents in improving refugees' health outcomes. We used an interpretivist ontology and a relativist social constructionist approach to analyse data from semi-structured interviews with 22 health and medical professionals who work with refugees across refugee resettlement settings in ten different countries. Interview transcriptions were analysed in NVivo using reflexive thematic analysis. We identified three broad themes that captured health professionals' perspectives: 1) 'Adversity and pain experiences are intertwined', suggested that health professionals saw pain in refugees as a manifestation of trauma, loss, and cultural dislocation. 2) 'Disempowerment shapes refugee engagement with care' suggested that health professionals saw that a loss of autonomy, invalidation and disruption of social networks disrupts refugees' engagement with pain care. 3) 'Barriers within and beyond the healthcare system' suggested that health professionals saw communication and cultural safety as significant barriers to access and engagement, and an unmet need for specific skills, training and support, with a focus on effective communication, cultural safety, the promotion of trauma-informed approaches to care and strategies to ensure health professional wellbeing. PERSPECTIVE: This article fills an important gap in understanding how resettlement countries can best provide care for refugees with chronic pain, by focusing on the perspectives of health professionals engaged in providing that care. Their perspectives contribute important considerations for the design and implementation of services to meet refugees' complex needs.
Chronic back pain (CBP) affects one in ten people worldwide, limiting mobility, productivity, and quality of life. Current treatments are often inadequate, partly due to an incomplete understanding of their mechanisms. This study explores pathophysiological contributions to CBP at the level of the DRG using the urokinase-type plasminogen activator (uPA) mouse model (uPA-CBP). We observed sustained mechanical hypersensitivity resembling clinical features of CBP in both male and female uPA-CBP mice with notable sex-specific effects on cold and heat sensitivity as well as gait and spontaneous pain behaviors. Whole-cell patch clamp electrophysiological recordings of lumbar DRG from male and female uPA-CBP mice reveal increased excitability compared to sham controls including a higher prevalence of multi- vs. single-firing and spontaneous activity. Analysis of action potential waveform, depolarizing spontaneous fluctuations (DSFs), and intrinsic properties revealed sex-specific differences in uPA-CBP compared to sham mice. Flow cytometry revealed increased CD45+CD11b+ myeloid cells in males and elevated CD45+CD3+CD4+ T cells in females. RNA sequencing identified upregulation of genes involved in immune response as well as sex-specific transcriptomic changes related to immune, glial, and neuronal functions and crosstalk, together suggesting altered DRG neuroimmune interactions in uPA-CBP. These findings highlight sex-specific neuroimmune pathophysiological changes in a model of CBP and uncover new potential targets for the development of analgesics for treatment. PERSPECTIVE This study highlights sex-specific pathophysiological changes in behavioral profiles in a mouse model of CBP attributed to differential electrophysiological, transcriptomic, and immune cell profiles at the level of the DRG. We uncover new potential targets along the neuroimmune axis for the development of analgesics for treatment of CBP.
Chronic pain is a common non-motor symptom in Parkinson's disease (PD), but its central neural mechanisms are not fully understood. Structural and resting-state functional MRI offer non-invasive insights into brain structural and functional correlates of pain. This systematic review synthesizes neuroimaging evidence on the neural correlates of pain in PD. A search of PubMed, Scopus, Google Scholar, and Web of Science identified eight case-control studies, including 432 PD patients with pain (PDP), 225 without pain (PDNP), and 257 healthy controls (HCs). Structural MRI revealed prefrontal cortical thinning and reduced insular gyrification, while resting-state functional MRI showed altered activity and connectivity across basal ganglia, limbic, brainstem, sensorimotor, cerebellar, insula-temporo-parietal and parahippocampal networks. Key findings included reduced putamen activity negatively correlated with pain, disrupted striatal-limbic connectivity, and increased raphe nucleus connectivity positively associated with pain. Other alterations included impaired sensorimotor-cerebellar integration and amygdala hypoconnectivity linked to pain severity. Dopamine-responsive and dopamine-unresponsive pain phenotypes displayed distinct connectivity patterns. Compared to HCs, PDP exhibited reduced connectivity in pain-related networks. Dynamic connectivity of default mode and frontoparietal networks showed no consistent links with pain. Two studies employed multimodal imaging approaches. Findings converged with unimodal evidence implicating prefrontal, insular, orbitofrontal, cerebellar, and striato-limbic circuits. White matter abnormalities were observed versus HCs but not consistently between PDP and PDNP. Overall, the findings support a network-based pathophysiological framework for PD-related pain and highlight the need for multimodal, longitudinal, and mechanism- and dopaminergic response-specific investigations to clarify underlying mechanisms and inform targeted therapeutic strategies. REGISTRATION: Registered on the PROSPERO site on November 13, 2025 (ID: CRD420251230685). PERSPECTIVE: This review identifies notable structural and functional alterations in striatal, limbic, brainstem, and sensorimotor-cerebellar networks underlying pain in PD. These findings support a network-based framework for PD-related pain and highlight the need for multimodal, longitudinal, and pain subtype- and treatment response-specific studies to clarify mechanisms and guide targeted interventions.
Chronic pain is both prevalent and debilitating. It is often treated with interdisciplinary pain rehabilitation programs (IPRPs). While research has largely focused on the effectiveness of IPRPs in improving patient outcomes, negative treatment effects remain under-explored. This study aims to investigate both the prevalence and types of negative outcomes following IPRPs for chronic pain. Data for the current study were obtained from the Swedish Quality Registry for Pain, with 22771 patients undergoing IPRPs between 2016 and 2023. We calculated the Reliable Change Index to find reliable deterioration across 18 patient-reported outcome measures, including pain intensity, physical function, psychological well-being, and vitality. Descriptive statistics were employed to determine the prevalence of deterioration, the prevalence of less severe deterioration, and the frequency of multiple deteriorations per patient. Results showed that while most participants did not report any areas of deterioration, about 23% of patients did experience reliable deterioration on at least one measure at the end of rehabilitation. Deterioration was most frequent in measures assessing physical status and pain, while psychological measures showed less deterioration. Mild deterioration on at least one measure was observed in 44.5% of patients. This study shows that a substantial proportion of patients experience at least some negative short-term outcomes following IPRPs, primarily in physical and pain-related outcomes. The findings underscore the importance of acknowledging and further investigating negative outcomes in chronic pain rehabilitation, and to take measures to address this issue. Perspective This large registry study reveals that almost one in four patients experiences a statistically reliable short-term worsening in at least one outcome, primarily physical and pain-related, after interdisciplinary pain rehabilitation. Thus, there is a need to identify these patients and the mechanisms behind deteriorations.
Although cognitive reappraisal is known to regulate pain-related affect, it remains unclear whether vicarious pain perception can also be modulated through behavior-oriented embodied processes. Using fMRI, we compared cognitive reappraisal and action simulation during vicarious pain in a within-subject design. Thirty-one participants completed a vicarious pain regulation task under three conditions: watch, cognitive reappraisal, and action simulation. Behaviorally, both strategies reduced vicarious pain ratings, with cognitive reappraisal producing stronger regulation but longer response times, indicating greater cognitive demands. Neuroimaging analyses revealed a shared regulatory network involving the dorsomedial prefrontal cortex (dmPFC), inferior parietal lobule (IPL), and anterior insula (AI). However, effective connectivity analyses using dynamic causal modeling (DCM) revealed strategy-specific pathways: cognitive reappraisal enhanced IPL-AI coupling while reducing dmPFC-IPL connectivity, suggesting a top-down cognitive control route. In contrast, action simulation primarily increased IPL-AI coupling. Generalized psychophysiological interaction (gPPI) analyses further showed that action simulation strengthened task-dependent functional coupling between the left dmPFC and postcentral gyrus, which was associated with faster regulatory responses, suggesting reliance on an embodied sensorimotor pathway. Additionally, the IPL showed differential lateralization: the left IPL predicted regulation success in cognitive reappraisal, whereas the right IPL was more engaged in action simulation. These findings support a dual-pathway account of pain-empathy regulation, in which action simulation provides a less cognitively demanding route for modulating vicarious pain responses alongside cognitive control, which may inform low-burden strategies for managing such responses in clinical contexts. Perspective Using fMRI with DCM and gPPI analyses, this study suggests that action simulation provides an embodied route for regulating vicarious pain perception, distinct from cognitively demanding reappraisal. These findings extend cognitive accounts of empathy regulation and underscore sensorimotor mechanisms supporting rapid responses to others’ pain.
Kinesiophobia plays a central role in understanding adult pain mechanisms, yet its assessment and theoretical relevance in pediatric pain remain poorly understood. Research to clarify the role of kinesiophobia in pediatric populations requires a valid and reliable measure of the construct. The most commonly used measure is the Tampa Scale of Kinesiophobia (TSK). Unfortunately, prior research in pediatric populations with different TSK versions has shown suboptimal psychometric performance, leaving the field without a reliable tool to evaluate fear-avoidance processes. This study provides the first comprehensive evaluation of the validity of the 11-item TSK (TSK-11) in pediatric populations. A total of 536 participants aged 8-18 years were recruited across three hospital units in Spain. Participants completed the TSK-11 in Spanish plus measures of pain intensity, pain interference, pain catastrophizing, pain anxiety, and physical functioning. A subsample (n=50) completed the TSK-11 again 3 months later. Internal consistency was good for the total score (α=.88) and the Activity Avoidance (α=.82) and Harm (α=.85) subscales. Test-retest reliability was excellent (ICC=.89). CFA supported the expected two-factor structure. Participants with chronic pain (totals score 24.70) and chronic post-surgical pain (M=27.81) had higher TSK-11 scores than participants without chronic pain (M=22.89), with significant differences for the total score and Harm subscale. Large correlations were observed with pain interference (r=.63), anxiety (r=.59), catastrophizing (r=.56), fear of pain (r=.58), and pain intensity (r=.55). Findings support the TSK-11 as a reliable, valid, and theoretically coherent brief kinesiophobia measure capable of advancing mechanistic and clinical research in pediatric populations. PERSPECTIVE: This study provides the first comprehensive validation of the TSK-11 in pediatric populations, supporting its reliability, validity, and theoretical coherence for assessing kinesiophobia. The findings offer researchers and clinicians a brief, psychometrically sound tool to advance understanding of fear-avoidance mechanisms in pediatric chronic pain.
Sleep and pain problems commonly co-occur yet few treatments address both. Behavioral pain interventions can improve sleep even when sleep is not explicitly targeted, but how these effects occur remains unclear. We conducted a secondary analysis of a 3-arm randomized trial (N=223) of 8-session cognitive behavioral therapy (CBT; n=76), 1-session Empowered Relief (ER; n=78), 1-session health education (HE; n=69) in chronic low back pain. We tested whether changes in pain intensity, interference, catastrophizing, and self-efficacy explain sleep improvement using self-report measures from baseline, 1, 2, and 3 months. Latent growth curve mediation models were used to estimate indirect effects (CBT or ER vs. no-skills → mediator → sleep). Preliminary mediation analyses showed similar indirect effects for CBT and ER; thus, both were pooled into a skills-based treatment group and compared with the no-skills HE for primary analyses. Reductions in pain interference and catastrophizing, but not pain intensity, were associated with significant indirect pathways to improved sleep disturbance, whereas improvements in pain self-efficacy contributed a partial indirect pathway. These findings suggest that improving pain interference and pain-related cognitions may explain how skills-based pain interventions improve sleep. Targeting pain interference and pain-related cognitions may yield cross-domain benefits for both sleep and pain. Perspective This study identifies candidate pathways through which behavioral pain interventions improve sleep despite minimal sleep-specific content. Reductions in pain interference and catastrophizing may help explain these effects, rather than reduction in pain intensity alone. Targeting functional and cognitive-emotional aspects of pain may offer meaningful benefits across sleep and pain domains.
Chronic musculoskeletal pain is a persistent condition that can reduce the quality of life and contribute to mental health disorders, leading to structural alterations in the central nervous system. On these grounds, the gray (GM) and white (WM) matter alterations in patients with non-specific chronic spinal pain (CSP) were examined using Magnetic Resonance Imaging (MRI), and explored their associations with clinical measures of mental health and quality of life. In this study, 60 controls (age 46.2 ± 11.8 years, 37 women) and 40 patients with CSP (age 49.5 ± 8.1 years, 31 women) were recruited. Before the MRI session, patients filled out multiple questionnaires and provided basic clinical information. The neuroimaging acquisition included a T1-weighted sequence, to extract the GM morphological features, and diffusion-weighted images (DWI) to calculate the WM diffusion parameters. The relationship of those measures with clinical variables was assessed with partial Spearman’s correlation coefficients. Patients with non-specific CSP exhibited significantly reduced GM volume in several brain regions involved in pain processing and modulation. Regarding WM, patients showed increased mean and axial diffusivity in a few regions implicated in proprioception and the sensation of pain. Moreover, significant correlations between these measures and scores from clinical tests were found. In conclusion, MRI-based parameters from GM morphometry and diffusion descriptors allowed to detect structural alterations in the GM and WM of patients with CSP. These MRI-based descriptors were correlated with multiple clinical parameters that suggested a worsening of the patient’s physical and mental health. Perspective This article assesses structural gray and white matter alterations of patients with non-specific chronic spinal pain and their relationship with clinical symptoms. Cerebellar and subcortical gray matter volume loss, and white matter altered diffusivity, were associated with reduced pain sensitivity, negative emotional and cognitive pain responses, and amplified pain experience.
Low back pain (LBP) is a leading cause of disability globally, with its impact amplified by the recurrent nature of the condition. It is unclear whether specific patient features are associated with future disability burden, following recovery from an episode of LBP. The current study explored prognostic factors of future disability over 12 months in patients recently recovered from an episode of LBP. Participants were adults from the no-intervention control group of the WalkBack trial. Fifteen candidate prognostic factors were collected at baseline. The outcome was disability, self-reported at 3, 6, 9 and 12 months using the Roland-Morris Disability Questionnaire and summarised as an area under the curve to quantify overall disability burden over 12 months. A single multivariable model was developed to identify prognostic factors. Three hundred and one of 350 control group participants (at least 3 of 4 disability measures available) were included. The sample had a mean age of 55 years, and most participants were female (81%). Higher body mass index (β = 0.27, 95% confidence interval [CI] 0.04-0.49; Kg/m2), worse pain intensity during the previous episode (β = 1.10, 95% CI 0.28-1.92; 0-10 scale), a higher perceived risk of recurrence (β = 0.71, 95% CI 0.14-1.28; 0-10 scale), and depressive symptoms (β = 0.61, 95% CI 0.18-1.05; 0-21 depression subscale) were associated with higher overall disability burden, controlling for other candidate prognostic factors. Each factor had a small, unique effect on overall disability. The findings inform risk assessment and prevention of future LBP-related disability.Perspective: The combination of psychological vulnerability, pain experience, and body composition is associated with future overall disability burden, even after apparent recovery from low back pain.
Acute dental pain contributes to ∼10% of opioid analgesic prescriptions in the U.S., highlighting a critical need for safer, non-opioid alternatives. This study supports the NIH HEAL initiative by developing a preclinical model to investigate behavioral depression as one class of behavioral signs that are both caused by dental pain and useful for analgesic discovery. Specifically, we assessed depression of locomotor and oral activity and stimulation of postural hunching and facial grimace as pain-related behaviors produced by a set of dental-pain manipulations. We then evaluated effectiveness of the nonsteroidal anti-inflammatory drug ketoprofen and opioid agonist morphine to alleviate these behavioral effects. Male and female ICR mice received one of four dental-pain manipulations: (1) Control - anesthesia only, (2) Open -pulp exposure, (3) Closed-Sal - pulp exposure with saline-soaked point and sealing, (4) Closed-CFA - pulp exposure with complete Freund's adjuvant-soaked point and sealing. Locomotor activity along with posture and grimace scores were assessed 6 h after surgery. Retrieval and consumption of sunflower seeds were assessed after 24 h to assess oral activity required to crush the hull and extract the kernel. Relative to control treatment, dental-pain manipulations produced significant, graded depression of locomotion and seed retrieval/consumption (Open<Closed-Sal<Closed-CFA) while increasing posture and grimace scores. Ketoprofen and morphine partially improved posture but did not alleviate behavioral depression or grimace. This model demonstrates translational relevance by capturing multiple dimensions of dental-pain models in mice. The limited efficacy of ketoprofen and morphine underscore the need for novel non-opioid analgesics capable of addressing the complex behavioral consequences of dental pain. PERSPECTIVE: This article describes the impact of a set of dental-pain manipulations on endpoints of translationally relevant and pain-related behavioral depression in mice. The procedure described here could be used as a preclinical platform for use in discovery of novel analgesics for treatment of dental pain.
Machine learning (ML) has been used to predict subjective pain intensity from electroencephalographic (EEG) data. However, few ML models for pain assessment have been externally validated, particularly for continuous pain prediction. We externally validated ML regression models using multi-stage validation to predict pain intensity from single-trial oscillatory EEG features. Ninety-one participants were recruited across three samples. Sample one (n = 40) was used for model development, sample two (n = 51) for cross-subject external validation, and sample three (n = 25), comprising additional recording sessions from sample one participants, for within-subject temporal external validation. Pneumatic pressure stimuli were delivered at 10 graded intensity levels. Single-trial EEG time-frequency features were used to train a Random Forest (RF) model and a long short-term memory (LSTM) network to predict pain intensity. Both models outperformed a random prediction model, with the RF achieving mean absolute errors (MAE) of 19.59, 21.29, and 18.90 for internal validation, cross-subject external validation, and within-subject external validation, respectively. However, neither model outperformed a baseline dummy model predicting the mean training-set rating. We also trained a RF classifier to distinguish low and high pain trials, achieving internal and external validation accuracies up to 64% and 58%, respectively. Overall, our results indicate that predicting continuous pain ratings from oscillatory EEG changes using ML remains highly challenging. Classification models demonstrated above-chance performance across validation samples but remained below clinically meaningful thresholds. Further methodological improvements, particularly the integration of composite measures, are required before ML can achieve clinical utility in pain assessment.
Pain management remains a significant challenge in pediatric care, where pain is frequently under-assessed and undertreated. Artificial intelligence is increasingly integrated into healthcare, yet its practical implementation in pediatric pain management remains limited. A systematic understanding of stakeholder perceptions is crucial for designing ethically sound, effective, and sustainable AI‑driven solutions in this sensitive domain. This study aimed to explore stakeholder needs, implementation priorities, and barriers regarding AI‑based pain assessment in pediatric care. Individual interviews guided by the Technology Acceptance Model were conducted from September to October 2025 with 35 participants: 11 children, 12 family caregivers, and 12 medical staff. Data were analyzed using a thematic analysis approach. All groups identified the core value of AI as providing objective, continuous monitoring to counter episodic human assessment. Priorities diverged: medical staff emphasized clinical decision support; family caregivers valued empowerment via real‑time information; children sought communication facilitation and emotional support. A consensus held that AI should aid, not replace, clinical judgment. Key adoption barriers included workload and integration challenges, with willingness to use hinging on proven accuracy, workflow compatibility, and safety. This study reveals significant disparities in stakeholder priorities for AI in pediatric pain care. Although all groups endorse AI as a clinical aid, its successful implementation hinges on seamless workflow integration and establishing trust. These findings provide stakeholder‑informed guidance to translate AI tools into clinical practice, with the goal of improving pain assessment accuracy, reducing under‑assessment, and enhancing the quality and equity of pediatric pain management. PERSPECTIVE: These findings offer critical clinical guidance for implementing AI tools that align with stakeholder needs, ultimately enhancing pain recognition, supporting timely interventions, and advancing person-centered pediatric pain care.
