ABSTRACT:Developmental trajectories for neck disability after whiplash injury have been identified. Their relationship to cold and mechanical sensitivity trajectories is not known. We aimed to (1) identify recovery trajectories of cold and mechanical sensitivity, (2) explore their codevelopment with disability trajectories, (3) identify predictors of sensitivity trajectories, and (4) explore codevelopment of cold and mechanical sensitivity trajectories. Participants (n = 233) were assessed at <1, 3, 6, and 12 months after whiplash injury. Outcomes were cold pain detection threshold (CPT at neck), pressure pain detection thresholds (PPT, neck C5, and tibialis anterior), and the Neck Disability Index. We used group-based trajectory models to identify postinjury recovery trajectories and multinominal logistic regression to explore associations between baseline characteristics and trajectory membership. We identified the following trajectory groups: CPT (low [50.0%], moderate [29.7%], and high [20.4%] sensitivity); PPT C5 (low [10.8%] and high [89.2%] sensitivity); and PPT tibialis anterior (low [23.9%], moderate [39.0%], and high [37.1%] sensitivity); all were stable over the 12 months. There was good correspondence between disability and cold sensitivity trajectory groups but not for mechanical sensitivity; cold and mechanical sensitivity trajectories were not well associated. Higher baseline pain predicted membership of the high cold sensitivity trajectory (RR 1.27, 95% CI 1.01-1.59) and hyperarousal symptoms predicted membership of the moderate cold sensitivity trajectory (RR 1.17, 95% CI 1.01-1.36). We found no associations between baseline characteristics and mechanical sensitivity. There is an interplay between cold allodynia, pain, and hyperarousal symptoms in development of ongoing disability after whiplash injury. Different mechanisms likely underlie cold and mechanical sensitivity.

ABSTRACT:Small nerve fibre pathology has been observed in several chronic pain conditions not typically classified as neuropathic (e.g., fibromyalgia). This systematic review compared morphometric data of small nerve fibres in people with non-neuropathic chronic pain conditions, defined using ICD-11 classifications, with pain-free controls. MEDLINE, EMBASE, Cochrane, Web of Science, and CINAHL were searched. Two independent reviewers performed screening, risk of bias assessment, and data extraction. Outcomes of interest were intraepidermal nerve fibre density (IENFD) and metrics derived from corneal confocal microscopy (CCM), compared by meta-analysis. Quality of evidence was assessed using Grades of Recommendation, Assessment, Development, and Evaluation. Fifty-two studies were included, examining fibromyalgia (N = 28), complex regional pain syndrome I (N = 5), migraine (N = 4), and other conditions (N = 15). Intraepidermal nerve fibre density was assessed in 41 studies and CCM in 14 studies. Risk of bias was low in 24 studies and moderate in 28. Meta-analysis revealed lower IENFD (fibres/mm 2 ) at the distal leg (MD: -3.06 [95% CI: -3.80 to -2.31]; I 2 = 74%; 16 studies; 1123 participants) and proximal thigh (MD: -3.77 [-5.10 to -2.43]; I 2 = 86%; 12 studies; 896 participants) and reduced corneal nerve fibre density (MD: -7.14 [-13.56 to -0.72]; I 2 = 98%; 8 studies; 768 participants) in participants with non-neuropathic chronic pain compared with controls. Innervation measures differed in participants with chronic pain vs controls for other IENFD and CCM metrics. Quality of evidence ranged from high to low. Associations between clinical features (e.g., pain, disability) and IENFD/CCM data were less commonly examined, mostly indicating no relationships. There is morphological evidence of small nerve fibre pathology in non-neuropathic chronic pain conditions; however, the clinical significance of these findings is unclear.

Chronic pain (pain on most days or daily for at least 3 months) is prevalent among people living with Parkinson's disease (PD). We analysed data from 10,631 Australian individuals with PD to assess the prevalence, severity, anatomical distribution, clinical history, and associated factors. Two-thirds (66.2%) reported chronic pain, with females experiencing higher prevalence (70.8%) and severity (4.7 vs. 4.3 on a 10-point scale). Common pain sites included the buttocks (35.6%), lower back (25.4%), neck (19.4%), and knees (17.2%). Chronic pain was strongly linked to comorbid depression, sleep disorders, and osteoarthritis (p < 0.05). Environmental exposures such as pesticides, heavy metals, and alcohol were associated with higher pain prevalence, especially in males (p < 0.05). These findings emphasise the substantial burden of chronic pain in PD, highlighting sex differences and strong links to multimorbidity. Further research is warranted to clarify sex-specific treatments and identify novel therapeutic targets. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement APGS is supported by the Shake It Up Australia Foundation and the Michael J. Fox Foundation for Parkinson's Research (MJFF-021952). MER thanks the support from the Rebecca L. Cooper Medical Research Foundation (F20231230). LMGM is supported by a UQ Research Training Scholarship from the University of Queensland (UQ). KRK is supported by grants from the Medical Research Future Fund and the Ainsworth 4 Foundation (unrelated to the current study). JA is supported by grants from the National Health & Medical Research Foundation (unrelated to the current study). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The QIMR Berghofer Human Research Ethics Committee granted this study's ethical approval under project number P3711. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes The data supporting the findings of this study are not publicly accessible due to participant privacy considerations. However, anonymised datasets can be made available to qualified researchers upon request to the corresponding author. Data sharing will be contingent upon obtaining all necessary ethical approvals and signing an institutional data transfer agreement.

ABSTRACT:Health outcomes may be worse for individuals with whiplash-associated disorders (WAD) compared to nontraumatic neck pain (NTNP), and clinical characteristics may differ. This systematic review examined evidence comparing WAD and NTNP in terms of pain, disability, psychological status, quality of life, measures of nociceptive processing, movement, sensorimotor, and muscle function. Studies were identified through electronic database searches and included after screening against predefined eligibility criteria. Standardized mean differences (SMD) or mean differences (MD) and 95% confidence intervals (CI) were calculated. Associations between MDs with demographics and study characteristics were explored using meta-regression. Certainty of evidence was assessed using Grades of Recommendation, Assessment, Development, and Evaluation. Sixty-one studies were eligible with 45 included in meta-analysis. Individuals with WAD reported clinically relevant higher disability (100-point Neck Disability Index MD [95% CI] 11.15 [8.63, 13.68]), greater remote cold sensitivity (SMD 0.89 [0.57, 1.21]), lower quality of life (SMD -0.96 [-1.77, -0.16]), greater depression (SMD 0.60 [0.27, 0.93]), greater local (SMD -0.56 [-1.00, -0.13]) and remote (SMD -0.50 [-0.81, -0.19]) pressure sensitivity, less cervical flexion (MD -5.30° [-7.44, -3.16]) and extension (MD -5.43° [-9.31, -1.55]), higher pain intensity (100-point numerical rating scale: MD 8.15 [5.80, 10.50]), and greater kinesiophobia (SMD 0.35 [0.11, 0.59]). No between-group differences were found for dizziness symptoms, stress, anxiety, balance, and local cold sensitivity. Meta-regression indicated that disability differences were negatively associated with age (R 2 = 29.6%, P = 0.006). Certainty of evidence was mostly moderate. Individuals with chronic WAD have a worse clinical presentation compared to those with chronic NTNP, which has implications for patient assessment and management.

OBJECTIVE:Chronic pain is prevalent among people living with Parkinson's disease (PD). We analyzed data from 10,631 Australian individuals with PD to assess the prevalence, age and sex differences, severity, anatomical distribution, clinical history, and associated factors. METHODS:We analysed data from 10,631 participants with PD enrolled in the Australian Parkinson's Genetics Study (APGS), an ongoing nationwide cohort. Participants completed an online or paper-based questionnaire assessing sociodemographic factors, PD-related variables, and chronic pain characteristics. Chronic pain was defined as pain persisting for more than 3 months and occurring most days or daily. Statistical analyses included descriptive statistics, correlation analyses, and group comparisons using chi-squared tests, Fisher's exact tests, and independent samples t-tests. RESULTS:Two-thirds (66.2%) reported chronic pain, with females experiencing higher prevalence (70.8%) and severity (4.7 vs. 4.3 on a 10-point scale). Common pain sites included the buttocks (35.6%), lower back (25.4%), neck (19.4%), and knees (17.2%). Chronic pain was strongly linked to comorbid depression, sleep disorders, and osteoarthritis (p < 0.05). Environmental exposures such as pesticides, heavy metals, and alcohol were associated with higher pain prevalence, especially in males (p < 0.05). INTERPRETATION:These findings emphasise the substantial burden of chronic pain in PD, highlighting sex differences and strong links to multimorbidity. Further research is warranted to clarify sex-specific treatments and identify novel therapeutic targets.

Introduction Persistent musculoskeletal (MSK) pain conditions are highly prevalent and economically burdensome. Although extensive research has explored various management strategies for these conditions, most interventions yield only modest effects. Recently, there has been increasing recognition of neuro-immune contributions in several persistent MSK pain conditions not traditionally associated with such influences. Purpose The aim of this Masterclass is to provide an overview of some key neuro-immune factors that may contribute to persistent MSK pain whilst detailing both simple bedside and advanced novel methods to identify such neuro-immune contributions. It will also examine why an understanding of such contributions may be beneficial for the assessment and management of people with persistent MSK pain conditions. Implications Understanding neuro-immune contributions to persistent MSK pain and how to identify them will help clinicians to i). consider the involvement of the nervous and immune systems when managing people with persistent MSK pain conditions, ii). better understand the use of both simple bedside tests and novel methods to identify such mechanisms and iii). consider how neuro-immune contributions may inform management strategies.

Every 7 out of 10 people will experience neck pain at some point during their lifetime. A large proportion of these cases will develop into recurrent or chronic conditions. Typically, physical exercise for neck pain seems to be modestly beneficial, but differential effects across participants of randomised trials have not yet been appropriately considered. This individual participant data meta-analysis (IPD MA) will provide a consolidated synthesis of randomised controlled trials (RCTs) that have been conducted to date. We aim to investigate the effectiveness of exercise therapy for chronic non-specific neck pain. This study will address the following research questions: (1) what are the effects of exercise therapy compared to no intervention or control interventions on neck pain intensity, pain-related disability, and quality of life? (2) What are the responder and non-responder rates for exercise therapy? (3) What participant characteristics are associated with a clinically meaningful response to exercise therapy? (4) What are the minimal clinically important difference (MCID) and/or minimal detectable change (MDC) values for neck pain intensity, pain-related disability, and quality of life?. This study will follow the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. The raw data will be requested from the primary authors of included RCTs. The received original data will be collated into a main datasheet with all the details on every single study, including study details, methodological details, participant demographics, details about intervention and comparison groups, treatment effect modifiers (e.g. workload, medicine usage), and the main outcome measures: pain intensity, pain-related disability, and quality of life. This IPD MA will be performed following a one-step approach, where data from all studies are analysed together while considering the grouping of participants within each study. Risk of bias of included RCTs will be evaluated using the ROB 2.0 tool, and the Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) approach will be used to assess the certainty of evidence. We will analyse IPD of available RCTs exploring the exercise effectiveness for chronic non-specific neck pain. The expected large sample size and consistent presentation of data will allow for further analyses to investigate patient-level heterogeneity in treatment outcomes and the prognosis of chronic non-specific neck pain. PROSPERO CRD42022323359

PURPOSE OF REVIEW:Musculoskeletal pain following a road traffic crash is common and incurs substantial personal and economic costs. Current recommended treatments of reassurance and advice to stay active, exercise and simple analgesics are not very effective. This review describes the current evidence for health outcomes and potential processes involved in the persistence of pain. It also outlines promising current and future treatments aimed at the prevention of chronic pain after musculoskeletal injury. RECENT FINDINGS:Recent literature highlights a more complex clinical presentation including greater pain-related disability and nociplastic pain features of traumatic musculoskeletal pain compared to non-traumatic pain. Some studies have found evidence for the presence of neuropathic pain in a sub-group of patients. Accurate risk-prediction screening tools exist for neck pain following road traffic injury and clinical trials using these tools show promise where treatment is targeted to identified risk factors. SUMMARY:Traumatic musculoskeletal pain is characterised by a more complex, high-burden clinical presentation, with worse health outcomes compared to non-traumatic musculoskeletal pain. There is emerging evidence that multi-factorial stress-related processes, neuroimmune factors, and neuropathic pain may underlie these differences. Early treatments targeting risk factors for poor recovery, including stress symptoms and pro-nociceptive processes show promise in improving outcomes for injured people.

Poor sleep is thought to enhance pain via increasing peripheral and/or central sensitization. Aerobic exercise, conversely, relives pain via reducing sensitization, among other mechanisms. This raises two clinical questions: (1) does poor sleep contribute to the transition from acute-to-persistent pain, and (2) can exercise protect against this transition? This study tested these questions and explored underlying mechanisms in a controlled injury model. Twenty-nine adult female Sprague-Dawley rats performed an intensive lever-pulling task for 4 weeks to induce symptoms consistent with clinical acute-onset overuse injury. Rats were then divided into three groups and exposed for 4 weeks to either: voluntary exercise via access to a running wheel, sleep disturbance, or both. Pain-related behaviours (forepaw mechanical sensitivity, reflexive grip strength), systemic levels of brain derived neurotrophic factor (BDNF), estradiol and corticosterone, and white blood cells (WBC) were assessed pre-injury, post-injury and post-intervention. Mechanical sensitivity increased post-injury and remained elevated with sleep disturbance alone, but decreased to pre-injury levels with exercise both with and without sleep disturbance. Reflexive grip strength decreased post-injury but recovered post-intervention—more with exercise than sleep disturbance. BDNF increased with sleep disturbance alone, remained at pre-injury levels with exercise regardless of sleep, and correlated with mechanical sensitivity. WBCs and estradiol increased with exercise alone and together with sleep disturbance, respectively. Corticosterone was not impacted by injury/intervention. Findings provide preliminary evidence for a role of poor sleep in the transition from acute-to-persistent pain, and the potential for aerobic exercise to counter these effects. BDNF might have a role in these relationships.

Insufficient and deficient vitamin D may be associated with chronic musculoskeletal pain, but study findings are conflicting, and few account for important confounding factors. This cross-sectional study explored the association between serum vitamin D status and chronic musculoskeletal pain in various body sites, adjusting for a wide range and a number of potential confounding factors. Data collected at the baseline assessments of 349,221 UK Biobank participants between 2006 and 2010 were analyzed. Serum 25-hydroxyvitamin D was measured and categorized as <25.0 nmol/L (severe deficiency), 25.0 to 49.9 nmol/L (deficiency), 50.0 to 74.9 nmol/L (insufficiency), and ≥75.0 nmol/L (sufficiency). The outcome was self-reported chronic musculoskeletal pain at any site, neck/shoulder, back, hip, knee, or widespread pain that interfered with usual activities. Potential confounders were identified using directed acyclic graphs and included sociodemographic, lifestyle, psychological factors, and medical comorbidities. Simple models adjusted for age and sex showed significant associations between suboptimal vitamin D status and chronic pain across all sites (odds ratios [ORs] ranged 1.07-2.85). These associations were weakened or became insignificant after accounting for all confounding factors (ORs ≤ 1.01) for chronic regional musculoskeletal pain. Severe vitamin D deficiency remained a significant and positive association with chronic widespread pain after adjusting for all confounding factors (OR [95% confidence interval]: 1.26 [1.07, 1.49]). This study suggests that, while vitamin D status is not a key independent determinant of chronic regional musculoskeletal pain, severe vitamin D deficiency may be associated with chronic widespread pain. PERSPECTIVE: After accounting for various confounders, vitamin D deficiency was not associated with regional musculoskeletal pain. However, the relationship between chronic widespread pain severe vitamin D deficiency remained after confounder adjustment. Use of vitamin D supplements in individuals with chronic widespread pain and severe vitamin D deficiency warrants further exploration.

Inflammation is linked with chronic pain but the extent to which this relationship is associated with biopsychosocial factors is not known. We investigated relationships between blood Creactive protein (CRP) and regional chronic pain conditions adjusting for a large range and number of potential confounders. We performed cross-sectional analyses using the UK Biobank (N = 415,567) comparing CRP in people reporting any of 9 types of regional chronic pain with pain-free controls. Using logistic regression modelling, we explored relationships between CRP and the presence of chronic pain, with demographic, socioeconomic, psychological/lifestyle factors, and medical comorbidities as covariates. CRP was higher in chronic pain at any site compared with controls (Females: median [interquartile range] 1.60 mg/L [2.74] vs 1.17 mg/L [1.87], P < .001; Males: 1.44 mg/L [2.12] vs 1.15 mg/L [1.65], P < .001). In males, associations between CRP and all types of chronic pain were attenuated but remained significant after adjustment for biopsychosocial covariates (OR range 1.08-1.49, P <= .001). For females, adjusted associations between CRP and pain remained significant for most chronic pain types (OR range 1.07-1.34, P < .001) except for facial pain (OR 1.04, P = .17) and headache (OR 1.02, P = .07)-although these non-significant findings may reflect reduced sample size. The significant association between CRP and chronic pain after adjustment for key biopsychosocial confounders implicates an independent underlying biological mechanism of inflammation in chronic pain. The presence of yet unknown or unmeasured confounding factors cannot be ruled out. Our findings may inform better-targeted treatments for chronic pain. Perspective: Using a large-scale dataset, this article investigates associations between chronic pain conditions and blood C-reactive protein (CRP), to evaluate the confounding effects of a range of biopsychosocial factors. CRP levels were higher in those with chronic pain versus controls after adjusting for confounders-suggesting a possible independent biological mechanism. (R) 2023 Published by Elsevier Inc. on behalf of United States Association for the Study of Pain, Inc

PURPOSE:To evaluate the relative contributions of objective and subjective indicators of dry eye disease (DED) in individuals with chronic pain conditions compared with controls. METHODS:A systematic review and meta-analysis was conducted of studies that reported the signs and symptoms of DED and/or their prevalence in individuals with chronic pain compared with controls. International Association for the Study of Pain (IASP) International Classification of Diseases (ICD)-11 codes for chronic pain conditions were applied, and outcomes defined as DED signs and symptoms. A search strategy utilised the EMBASE, Web of Science, Cochrane Library and MEDLINE databases. Risk of bias assessment was performed with the Newcastle-Ottawa scale. Random effects meta-analysis calculated mean differences (MD) and odds ratios (OR), while subgroup analysis of different chronic pain conditions explored their relative association with the signs and symptoms of DED. Evidence certainty was evaluated using Grades of Recommendation, Assessment, Development, and Evaluation (GRADE). RESULTS:Fourteen observational studies comprising 3,281,882 individuals were included. Meta-analysis found high quality evidence that individuals with chronic pain were more likely to experience symptoms of DED than controls (OR = 3.51 [95 %CI: 3.45,3.57]). These symptoms were more severe (MD = 18.53 [95 %CI: 11.90, 25.15]) than controls with a clinically meaningful effect size. Individuals with chronic pain had more rapid tear film disruption (MD = -2.45 [95 %CI: -4.20, -0.70]) and reduced tear production (MD = -5.57 [95 %CI: -9.56, -1.57]) compared with controls (with moderate evidence quality). High quality evidence revealed individuals with chronic pain had lower basal tear production (anaesthetised) than controls (MD = -2.59 [95 %CI: -3.60, -1.58]). Tear film osmolarity showed no significant differences between the chronic pain and pain-free groups. Group differences for DED signs were not considered clinically meaningful. CONCLUSION:More severe, clinically meaningful symptoms of DED were reported in individuals with chronic pain than controls, however group differences for the signs of DED were typically of limited or questionable clinical relevance. This ocular phenotype where DED is felt more than it is seen in chronic pain may reflect underlying sensory hypersensitivity, shared by both conditions and contributing to their frequent comorbidity. Advancing understanding of this potential pathophysiological mechanism may guide clinical management.

Physiotherapists are increasingly using psychological treatments for musculoskeletal conditions. We assessed the effects of physiotherapist-delivered psychological interventions on pain, disability, and quality of life in neck pain. We evaluated quality of intervention reporting. We searched databases for randomized controlled trials (RCTs) comprising individuals with acute or chronic whiplash-associated disorder (WAD) or nontraumatic neck pain (NTNP), comparing physiotherapist-delivered psychological interventions to standard care or no treatment. Data were extracted regarding study characteristics and outcomes. Standardised mean difference (SMD) was calculated by random-effects meta-analysis. We evaluated certainty of evidence using Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) and intervention reporting using TIDieR. Fourteen RCTs (18 articles-4 detail additional outcome/follow-up data) were included comprising 2028 patients, examining acute WAD (n = 4), subacute/mixed NTNP (n = 3), chronic WAD (n = 2), and chronic NTNP (n = 5). Treatment effects on pain favoured psychological interventions in chronic NTNP at short-term (SMD -0.40 [95% CI -0.73, -0.07]), medium-term (SMD -0.29 [95% CI -0.57, 0.00]), and long-term (SMD -0.32 [95% CI -0.60, -0.05]) follow-up. For disability, effects favoured psychological interventions in acute WAD at short-term follow-up (SMD -0.39 [95% CI -0.72, -0.07]) and chronic NTNP at short-term (SMD -0.53 [95% CI -0.91, -0.15]), medium-term (SMD -0.49 [95% CI -0.77, -0.21]), and long-term (SMD -0.60 [95% CI -0.94, -0.26]) follow-up. GRADE ratings were typically moderate, and intervention reporting often lacked provision of trial materials and procedural descriptions. Psychological interventions delivered by physiotherapists were more effective than standard physiotherapy for chronic NTNP (small-to-medium effects) and, in the short term, acute WAD.

Causal mechanisms underlying systemic inflammation in spinal widespread pain remain an intractable experimental challenge. Here we examined whether: (i) associations between blood C-reactive protein (CRP) and chronic back, neck/shoulder widespread pain can be explained by shared underlying genetic variants; and (ii) higher CRP levels causally contribute to these conditions. Using genome-wide association studies (GWAS) of chronic back, neck/shoulder widespread pain (N = 6063–79,089 cases; N = 239,125 controls) and GWAS summary statistics for blood CRP (Pan-UK Biobank N = 400,094 PAGE consortium N = 28,520), we employed cross-trait bivariate linkage disequilibrium score regression to determine genetic correlations (rG) between these chronic pain phenotypes and CRP levels (FDR < 5

There are few effective treatments for acute whiplash-associated disorders (WADs). Early features of central sensitisation predict poor recovery. The effect of pregabalin on central sensitisation might prevent chronic pain after acute whiplash injury. This double blind, placebo-controlled randomised controlled trial examined feasibility and potential effectiveness of pregabalin compared with placebo for people with acute WAD. Twenty-four participants with acute WAD (<48 hours) and at risk of poor recovery (pain >= 5/10) were recruited from hospital emergency departments in Queensland, Australia, and randomly assigned by concealed allocation to either pregabalin (n = 10) or placebo (n = 14). Pregabalin was commenced at 75 mg bd, titrated to 300 mg bd for 4 weeks, and then weaned over 1 week. Participants were assessed at 5 weeks and 3, 6, and 12 months. Feasibility issues included recruitment difficulties and greater attrition in the placebo group. For the primary clinical outcome of neck pain intensity, attrition at 5 weeks was pregabalin: 10% and placebo: 36% and at 12 months was pregabalin: 10% and placebo: 43%. Pregabalin may be more effective than placebo for the primary clinical outcome of neck pain intensity at 3 months (mean difference: -4.0 [95% confidence interval -6.2 to -1.7]) on an 11-point Numerical Rating Scale. Effects were maintained at 6 months but not 12 months. There were no serious adverse events. Minor adverse events were more common in the pregabalin group. A definitive large randomised controlled trial of pregabalin for acute whiplash injury is warranted. Feasibility issues would need to be addressed with modifications to the protocol.

Background: The multifactorial heterogenous nature of chronic pain with its multiple comorbidities presents a formidable challenge in disentangling the aetiology underlying patient symptoms. Methods: Here, we performed genome-wide association studies (GWAS) of eight types of regional chronic pain using UK Biobank data (N=4,037-79,089 cases; N=239,125 controls), followed by bivariate linkage disequilibrium-score regression and latent causal variable analyses to determine (respectively) their genetic correlations and genetic causal proportion (GCP) parameters with 1,492 other complex traits. Findings: We report evidence of a shared genetic signature in common regional chronic pain types, with their genetic correlations and causal directions being broadly consistent across a wide array of biopsychosocial traits. Furthermore, we identified 5,942 significant genetic correlations, of which 570 trait pairs showed evidence of a likely causal association (|GCP| > 0.6; 5% false discovery rate), including 488 traits contributing to chronic pain while 82 were affected by pain. A range of somatic pathologies (e.g., musculoskeletal, visceral), psychiatric factors (e.g., depression, trauma, anxiety, mania, bipolar disorder), socioeconomic factors (e.g., occupation) and other medical comorbidities (e.g., cardiovascular disease) contributed to an increased risk of regional chronic pain. Conversely, each chronic pain type contributed to various other traits such as increased medication use (e.g., analgesics) and risk of ischaemic heart disease and depression. Interpretation: Findings of this data-driven study, through comprehensive analysis of a vast range of biopsychosocial factors, are indicative of a common genetic signature underlying eight regional chronic pain types. We identify a broad range of traits with genetic causal effects upon chronic pain, which may inform development of novel diagnostic and therapeutic strategies, as well as provide convergent support for various existing approaches.

Objective Autonomic nervous system dysfunction has been implicated in chronic whiplash-associated disorder (WAD). However, the relationship between autonomic variables (e.g., resting heart rate and blood pressure) and clinical factors in chronic WAD is not well understood. This study sought to examine the associations between resting heart rate, resting blood pressure, pain processing and psychological variables in chronic WAD and in pain-free controls. Design Secondary analysis of a cross-sectional study. Setting University clinical research laboratory. Subjects Thirty-six people with chronic WAD Grade II (mean [SD] age 40.1 [14.6] years, 28 females) and 25 pain-free controls (35.6 [13.0] years, 17 females). Methods Participants had resting heart rate, systolic and diastolic blood pressure measured. Pain processing measures comprised: (i) pain pressure threshold at the cervical spine, hand and leg, (ii) temporal summation at the cervical spine and hand, and (iii) conditioned pain modulation. Psychological outcomes included measures of kinesiophobia, pain catastrophizing and post-traumatic stress symptoms. Correlations between autonomic variables, pain processing and psychological variables were determined (P < .05, 5% FDR). Results No significant correlations between autonomic and pain processing variables, or autonomic and psychological variables were found in the chronic WAD group. In the control group, diastolic blood pressure was positively correlated with cervical spine pressure pain threshold (r = 0.53, P = .007). Conclusions An association between blood pressure and pain sensitivity was observed in the control group but not the chronic WAD group. Such an association appears to be disrupted in chronic WAD, which may infer involvement of autonomic pathways in the pathophysiology of this condition.

EDITORIAL article Front. Pain Res., 10 November 2022Sec. Musculoskeletal Pain Volume 3 - 2022 | https://doi.org/10.3389/fpain.2022.1071810

Structural neuroimaging studies of individuals with chronic pain conditions have often observed decreased regional grey matter at a phenotypic level. However, it is not known if this association can be attributed to genetic factors. Here we employed a novel integrative data-driven and hypothesis-testing approach to determine whether there is a genetic basis to grey matter morphology differences in chronic pain. Using publicly available genome-wide association study summary statistics for regional chronic pain conditions (n = 196 963) and structural neuroimaging measures (n = 19 629-34 000), we applied bivariate linkage disequilibrium-score regression and latent causal variable analyses to determine the genetic correlations (rG) and genetic causal proportion (GCP) between these complex traits, respectively. Five a priori brain regions (i.e. prefrontal cortex, cingulate cortex, insula, thalamus and superior temporal gyrus) were selected based on systematic reviews of grey matter morphology studies in chronic pain. Across this evidence-based selection of five brain regions, 10 significant negative genetic correlations (out of 369) were found (false discovery rate < 5%), suggesting a shared genetic basis to both reduced regional grey matter morphology and the presence of chronic pain. Specifically, negative genetic correlations were observed between reduced insula grey matter morphology and chronic pain in the abdomen (mean insula cortical thickness), hips (left insula volume) and neck/shoulders (left and right insula volume). Similarly, a shared genetic basis was found for reduced posterior cingulate cortex volume in chronic pain of the hip (left and right posterior cingulate), neck/shoulder (left posterior cingulate) and chronic pain at any site (left posterior cingulate); and for reduced pars triangularis volume in chronic neck/shoulder (left pars triangularis) and widespread pain (right pars triangularis). Across these negative genetic correlations, a significant genetic causal proportion was only found between mean insula thickness and chronic abdominal pain [rG (standard error, SE) = -0.25 (0.08), P = 1.06 × 10-3; GCP (SE) = -0.69 (0.20), P = 4.96 × 10-4]. This finding suggests that the genes underlying reduced cortical thickness of the insula causally contribute to an increased risk of chronic abdominal pain. Altogether, these results provide independent corroborating evidence for observational reports of decreased grey matter of particular brain regions in chronic pain. Further, we show for the first time that this association is mediated (in part) by genetic factors. These novel findings warrant further investigation into the neurogenetic pathways that underlie the development and prolongation of chronic pain conditions.