Genetic impact of blood C-reactive protein levels on chronic spinal & widespread pain.

PURPOSE: 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. METHODS: 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%). Latent causal variable (LCV) and generalised summary data-based Mendelian randomisation (GSMR) analyses examined putative causal associations between chronic pain & CRP (FDR < 5%). RESULTS: Higher CRP levels were genetically correlated with chronic back, neck/shoulder & widespread pain (rG range 0.26-0.36; P ≤ 8.07E-9; 3/6 trait pairs). Although genetic causal proportions (GCP) did not explain this finding (GCP range - 0.32-0.08; P ≥ 0.02), GSMR demonstrated putative causal effects of higher CRP levels contributing to each pain type (beta range 0.027-0.166; P ≤ 9.82E-03; 3 trait pairs) as well as neck/shoulder pain effects on CRP levels (beta [S.E.] 0.030 [0.021]; P = 6.97E-04). CONCLUSION: This genetic evidence for higher CRP levels in chronic spinal (back, neck/shoulder) & widespread pain warrants further large-scale multimodal & prospective longitudinal studies to accelerate the identification of novel translational targets and more effective therapeutic strategies.

Genetic basis to structural grey matter associations with chronic pain.

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.

Associations Between Resting Heart Rate, Resting Blood Pressure, Psychological Variables and Pain Processing in Chronic Whiplash-Associated Disorder: A Cross-Sectional Study.

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.

Spinal cord injury is not a feature of chronic whiplash-associated disorder: a magnetic resonance spectroscopy study.

PURPOSE: Injury to the cervical spinal cord has been suggested as a mechanism that may underpin chronic whiplash-associated disorder (WAD). This study aimed to assess metabolite concentrations indicative of neuronal injury or pathology in the cervical cord in people with chronic WAD. METHODS: Forty-one people with chronic WAD (mean [SD] age 39.6 [11.0] years, 25 females) and 14 healthy controls (39.2 [12.6] years, 9 females) underwent cervical spinal cord magnetic resonance spectroscopy to measure the metabolites N-acetylaspartate (NAA), creatine (Cr) and choline (Cho). Participants with WAD completed clinical questionnaires on pain intensity (Visual Analogue Scale), disability (Neck Disability Index) and psychological factors (Pain Catastrophising Scale, Post-traumatic Diagnostic Scale), and underwent cervical range of motion assessment and pain threshold testing to cold and pressure stimuli. Data were analysed using hypothesis testing and Spearman correlations (p < 0.05). RESULTS: There were no differences between the WAD and control groups for NAA/Cr (median [IQR] WAD 1.73 [1.38, 1.97], controls 2.09 [1.28, 2.89], p = 0.37), NAA/Cho (WAD 1.50 [1.18, 2.01], controls 1.57 [1.26, 1.93], p = 0.91) or Cr/Cho (WAD 0.84 [0.64, 1.17], controls 0.76 [0.60, 0.91], p = 0.33). There were no significant correlations between NAA/Cr, NAA/Cho or Cr/Cho and any clinical variable (p ≥ 0.06). CONCLUSIONS: Findings are consistent with major metabolic changes not being present in chronic WAD.

Magnetic Resonance Imaging Investigation of Cervical-Spine Meniscoid Composition: A Validation Study.

OBJECTIVE: The composition of cervical-spine meniscoids may have clinical significance in neck-pain conditions, but the accuracy of assessment of meniscoid composition in vivo using magnetic resonance imaging has not been established. The aim of this study was to compare cervical-spine meniscoid composition by magnetic resonance imaging with histologic composition. METHODS: Four embalmed cadaveric cervical spines (mean [standard deviation] age, 79.5 [3.7] years; 1 female, 3 male) underwent magnetic resonance imaging, allowing radiologic classification of lateral atlantoaxial- and zygapophyseal-joint (C2-3 to C6-7) meniscoids as either mostly fatty, mixed tissue, or mostly connective tissue. Subsequently, each joint was dissected and disarticulated to allow excision of meniscoids for histologic processing. Each meniscoid was sectioned sagittally, stained with hematoxylin and eosin, examined using light microscopy, and classified as adipose, fibroadipose, or fibrous in composition. Data were analyzed using the kappa statistic with linear weighting. RESULTS: From dissection, 62 meniscoids were identified, excised, and processed; 46 of these 62 were visualized with magnetic resonance imaging. For single-rater identifying structures, agreement between assessment of meniscoid composition by magnetic resonance imaging and by microscopy was fair (κ = 0.24; 95% confidence interval, 0.02-0.46; P = .02). CONCLUSION: Findings suggest that the accuracy of this method of magnetic resonance imaging assessment of cervical-spine meniscoid composition may be limited. This should be considered when planning or interpreting research investigating meniscoid composition using magnetic resonance imaging.

Cervical spine findings on MRI in people with neck pain compared with pain-free controls: A systematic review and meta-analysis.

BACKGROUND: There is uncertainty regarding the clinical significance of findings on MRI in patients with whiplash associated disorder (WAD) or nonspecific neck pain (NSNP). PURPOSE: To compare the presence of cervical spine MRI findings in people with WAD or NSNP with pain-free controls. STUDY TYPE: Systematic review and meta-analysis. POPULATION: Adults with WAD (n = 994), NSNP (n = 715), or pain-free controls (n = 2323). FIELD STRENGTH: 0.5T, 1.5T, and 3.0T. ASSESSMENT: Medline, EMBASE, CINAHL, Web of Science, SCOPUS, and Cochrane CENTRAL databases were searched. Two independent reviewers identified studies for inclusion and extracted data. Risk of bias was assessed using the Quality Assessment Tool for Observational Cohort and Cross-Sectional Studies. Overall quality of the evidence from meta-analysis was assessed using the Grades of Recommendation, Assessment, Development, and Evaluation approach. STATISTICAL TESTS: Meta-analysis was performed using a random-effects model to calculate odds ratios or standard mean differences (SMDs) for binary and continuous data. RESULTS: In total, 31 studies were included (eight comparing acute WAD to controls, 14 comparing chronic WAD to controls, 12 comparing chronic NSNP to controls) comprising 4032 participants. Rectus capitis posterior major cross-sectional area was smaller in people with chronic NSNP than controls (two studies: SMD -1.18 [95% confidence interval [CI] -1.65, -0.71]). The remaining meta-analysis comparisons showed no group differences in MRI findings. The quality of evidence was mostly low due to small sample sizes and high heterogeneity. DATA CONCLUSION: Given the typically low-quality evidence, definitive conclusions cannot be drawn on the presence of MRI findings in individuals with WAD or NSNP compared with pain-free controls. LEVEL OF EVIDENCE: 3 Technical Efficacy: Stage 3 J. Magn. Reson. Imaging 2018.

Quantitative magnetic resonance imaging assessment of lateral atlantoaxial joint meniscoid composition: a validation study.

PURPOSE: Lateral atlantoaxial (LAA) joint meniscoid composition may have clinical significance in patients following neck trauma. However, the existing method of radiologically assessing meniscoid composition has an inherent element of subjectivity, which could contribute to measurement variability. The present study sought to investigate the accuracy of two-point Dixon fat/water separation MRI as a quantitative assessment of LAA joint meniscoid composition. METHODS: Sixteen LAA joint meniscoids were excised from four cadavers (mean [SD] age 79.5 [3.7] years; one female) following cervical spine MRI (two-point Dixon, T1-weighted VIBE and T2-weighted SPACE sequences). Composition of LAA joint meniscoids was undertaken by (1) histological examination by light microscopy, (2) calculation of fat fraction by Dixon MRI (both in-phase/opposed-phase and fat/water methods), and (3) the existing method of considering VIBE and SPACE signal intensities. Analysis was performed using the kappa statistic with linear weighting. RESULTS: Microscopy revealed three, five, and eight meniscoids to be composed of adipose, fibroadipose, and fibrous tissues, respectively. Dixon sequence MRI classified 11 of these meniscoids correctly, with 'substantial' level of agreement (In-phase/Opp-phase kappa statistic = 0.78 [95% CI 0.38, 1.17]; fat/water kappa statistic = 0.72 [95% CI 0.32, 1.11]). Level of agreement between microscopy and the VIBE and SPACE method was 'slight' (kappa statistic = 0.02 [95% CI - 0.34, 0.38]). CONCLUSIONS: Findings suggest that Dixon fat/water separation MRI may have superior utility in the assessment of LAA joint meniscoid composition than the existing method of considering VIBE and SPACE signal intensities. These slides can be retrieved under Electronic Supplementary Material.

Sensorimotor Control in Individuals With Idiopathic Neck Pain and Healthy Individuals: A Systematic Review and Meta-Analysis.

OBJECTIVES: (1) To identify reported tests used to assess sensorimotor control in individuals with idiopathic neck pain and (2) to investigate whether these tests can quantify differences between individuals with idiopathic neck pain and healthy individuals. DATA SOURCES: Allied and Complementary Medicine Database, CINAHL, Cochrane Central Register of Controlled Trials, Embase, MEDLINE, Physiotherapy Evidence Database, Scopus, and SPORTDiscus. STUDY SELECTION: Studies reporting sensorimotor outcomes in individuals with idiopathic neck pain or healthy individuals were identified. There were 1,677 records screened independently by 2 researchers for eligibility: 43 studies were included in the review, with 30 of these studies included in the meta-analysis. DATA EXTRACTION: Methodologic quality was determined using the Quality Assessment Tool for Observational Cohort and Cross-Sectional Studies. Data were extracted using a standardized extraction table. DATA SYNTHESIS: Sensorimotor control was most commonly assessed by joint position error and postural sway. Pooled means for joint position error after cervical rotation in individuals with neck pain (range, 2.2°-9.8°) differed significantly (P=.04) compared with healthy individuals (range, 1.66°-5.1°). Postural sway with eyes open ranged from 4.85 to 10.5cm2 (neck pain) and 3.5 to 6.6cm2 (healthy) (P=.16), and postural sway with eyes closed ranged from 2.51 to 16.6cm2 (neck pain) and 2.74 to 10.9cm2 (healthy) (P=.30). Individual studies, but not meta-analysis, demonstrated differences between neck pain and healthy groups for postural sway. Other test conditions and other tests were not sufficiently investigated to enable pooling of data. CONCLUSIONS: The findings from this review suggest sensorimotor control testing may be clinically useful in individuals with idiopathic neck pain. However, results should be interpreted with caution because clinical differences were small; therefore, further cross-sectional research with larger samples is needed to determine the magnitude of the relation between sensorimotor control and pain and to assess any potential clinical significance.

The anatomy and morphometry of cervical zygapophyseal joint meniscoids.

PURPOSE: Meniscoids are folds of synovial membrane that project into the articular cavities of zygapophyseal joints throughout the cervical spine. These structures have been implicated in musculoskeletal neck pain; however, their anatomy has not been extensively investigated. The purpose of this study was to explore the morphometry and composition of the cervical zygapohyseal joint meniscoids. METHODS: Twelve adult cadaveric hemi-spines were dissected and their C2-3 to C6-7 zygapophyseal joints disarticulated (six female; six left; mean 81.5 years, SD 7.3 years). Meniscoids were identified and their surface area, protrusion length and articular cartilage degeneration measured. Specimens were then sectioned sagittally, stained with haematoxylin and eosin, and examined with a light microscope. Data were analysed descriptively and using non-parametric hypothesis testing (significance p < 0.05). RESULTS: Meniscoids were identified in 86% of zygapophyseal joints examined; 50% contained both ventral and dorsal meniscoids, 7% contained a ventral meniscoid only and 29% contained a dorsal meniscoid only. Meniscoids were classified as adipose (4%), fibrous (74%), or fibroadipose (22%) based upon histological composition. There were no significant associations between meniscoid size (surface area or protrusion length) and gender, position in joint, spinal level, or articular degeneration. Increased articular degeneration was associated with fibrous meniscoid classification. CONCLUSIONS: The morphological patterns observed, such as the association of fibrous meniscoids with cartilage degeneration, may provide insight into the significance of the zygapophyseal joint meniscoids in neck pathology. Further investigation is needed to explore the morphological qualities of these structures in a pathological population.

Serum Vitamin D and Chronic Musculoskeletal Pain: A Cross-Sectional Study of 349,221 Adults in the UK.

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. PERSPECTIVES: 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.

C-Reactive Protein (CRP) is Associated With Chronic Pain Independently of Biopsychosocial Factors.

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 C-reactive 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.

Poor sleep versus exercise: A duel to decide whether pain resolves or persists after injury.

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.

The influence of age, sex, and posture on the measurement of atlantodental interval in a normal population.

OBJECTIVE: The atlantodental interval (ADI) is used in assessing atlantoaxial stability. This measurement may potentially be affected by several features encountered during patient examination. This study examined the influence of 3 features: age, sex, and posture, on the measurement of ADI in a normal population. METHODS: The ADI was measured sequentially on 269 lateral cervical radiographs of adults with no demonstrated bony injury. Images were stratified by age and sex with equal representation in each age group. A further 25 asymptomatic adults were assessed for posture using craniovertebral angle measured from digital lateral photographs. The ADI was then measured from a lateral radiograph. The data were examined for correlation between age, craniovertebral angle, and ADI using Spearman rank correlation. The ADI of age groups was compared by Kruskal-Wallis test. The relationship between ADI and sex was examined using Wilcoxon rank sum test. Interaction between age and sex was explored using an interaction term in regression analysis. RESULTS: The ADI decreased with age, median measurements reducing from 2.07 to 0.85 mm across age groups (P < .01). No significant relationship was demonstrated between ADI and sex. No significant interaction was demonstrated between age and sex. Measurements of craniovertebral angle did not correlate with ADI (ρ = 0.03, P = .90). CONCLUSION: The magnitude of ADI decreases with advancing age. Age should be considered a modifying factor when interpreting measurement of ADI, particularly in consideration of potential minor instabilities. Patient sex does not appear to influence ADI, either independently or in interaction with age. Craniocervical posture variation does not influence ADI in an asymptomatic adult population.

Effectiveness of psychological interventions delivered by physiotherapists in the management of neck pain: a systematic review with meta-analysis.

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.

A Shared Genetic Signature for Common Chronic Pain Conditions and its Impact on Biopsychosocial Traits.

The multiple comorbidities & dimensions of chronic pain present a formidable challenge in disentangling its aetiology. Here, we performed genome-wide association studies of 8 chronic pain types 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. We report evidence of a shared genetic signature across chronic pain types as their genetic correlations and GCP directions were broadly consistent across an array of biopsychosocial traits. Across 5,942 significant genetic correlations, 570 trait pairs could be explained by a causal association (|GCP| >0.6; 5% false discovery rate), including 82 traits affected by pain while 410 contributed to an increased risk of chronic pain (cf. 78 with a decreased risk) such as certain somatic pathologies (eg, musculoskeletal), psychiatric traits (eg, depression), socioeconomic factors (eg, occupation) and medical comorbidities (eg, cardiovascular disease). This data-driven phenome-wide association analysis has demonstrated a novel and efficient strategy for identifying genetically supported risk & protective traits to enhance the design of interventional trials targeting underlying causal factors and accelerate the development of more effective treatments with broader clinical utility. PERSPECTIVE: Through large-scale phenome-wide association analyses of >1,400 biopsychosocial traits, this article provides evidence for a shared genetic signature across 8 common chronic pain types. It lays the foundation for further translational studies focused on identifying causal genetic variants and pathophysiological pathways to develop novel diagnostic & therapeutic technologies and strategies.

Pregabalin vs placebo to prevent chronic pain after whiplash injury in at-risk individuals: results of a feasibility study for a large randomised controlled trial.

ABSTRACT: 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.

Magnetic Resonance Spectroscopy Assessment of Brain Metabolite Concentrations in Individuals With Chronic Whiplash-associated Disorder: A Cross-sectional Study.

OBJECTIVES: Pathophysiologic mechanisms underpinning ongoing pain in whiplash-associated disorder (WAD) are not well understood, however, alterations in brain morphology and function have been observed in this population and in other chronic pain conditions. This study investigated metabolite profiles of brain regions in people with chronic WAD compared with controls. MATERIALS AND METHODS: Thirty-eight individuals with chronic WAD (mean [SD] age, 39.5 [11.3] years, 23 female individuals) and 16 pain-free controls (38.9 [12.7] years, 11 female individuals) underwent multivoxel brain magnetic resonance spectroscopy. At the anterior cingulate cortex (ACC), primary motor cortex (1MC), and somatosensory cortex (SSC), ratios of metabolite concentrations were calculated for N-acetylaspartate (NAA), creatine (Cr), choline (Cho), myo-inositol (Ins), and glutamate/glutamine (Glx). Chronic WAD group participants completed clinical questionnaires and cold and pressure pain threshold assessment. Data were analyzed with hypothesis testing and Spearman correlations (P≥0.05), with Benjamini-Hochberg corrections (5% false discovery rate). RESULTS: No group differences were observed for NAA:Cr, NAA:Cho, Cr:Cho, Glx:NAA, Glx:Cr, Glx:Cho, Ins:NAA, Ins:Cr, Ins:Cho or Ins:Glx for left or right ACC, 1MC, or SSC following correction for multiple comparisons. No significant correlations were observed between metabolite ratios and any clinical variable. DISCUSSION: These results suggest that ongoing pain and disability in this population may not be underpinned by metabolite aberrations in the brain regions examined. Further research is required to progress our understanding of cortical contributions to neurophysiologic mechanisms in chronic WAD.

Small fibre pathology in chronic whiplash-associated disorder: A cross-sectional study.

BACKGROUND: Mechanisms underpinning ongoing symptoms in chronic whiplash associated-disorder (WAD) are not well understood. People with chronic WAD can exhibit sensory dysfunction consistent with small nerve fibre pathology, including thermal hypoaesthesia and hyperalgesia. This study investigated small fibre structure and function in chronic WAD. METHODS: Twenty-four people with chronic WAD (median [IQR] age 49 [15] years, 16 females) and 24 pain-free controls (50 [17] years, 16 females) were recruited. Intraepidermal nerve fibre density (IENFD) and dermal innervation were assessed by skin biopsy. This was performed at (a) the lateral index finger on the primary side of pain and (b) superior to the lateral malleolus on the contralateral side. Quantitative sensory testing was performed over the hand. RESULTS: The WAD group exhibited lower IENFD at the finger (WAD: median [IQR] 4.5 [4.9] fibres/mm; control 7.3 [3.9]; p = .010), but not the ankle (WAD: mean [SD] 7.3 [3.7] fibres/mm; control 9.3 [3.8]; p = .09). Dermal innervation was lower in the WAD group at the finger (WAD: median [IQR] 3.7 [2.8] nerve bundles/mm2 ; controls: 4.9 [2.1]; p = .017) but not the ankle (WAD: median [IQR] 2.1 [1.9] nerve bundles/mm2 ; controls: 1.8 [1.8]; p = .70). In the WAD group, hand thermal and light touch detection were impaired, and heat pain thresholds were lowered (p ≤ .037). CONCLUSIONS: Findings suggest small fibre structural and functional deficits in chronic WAD, implicating potential involvement of small fibre pathology. SIGNIFICANCE: Our study found decreased intraepidermal nerve fibre density, reduced dermal innervation, thermal hypoaesthesia and hypersensitivity in people with chronic WAD, suggestive of small fibre pathology. This observation of peripheral nervous system pathology in chronic whiplash provides novel insights on mechanisms underpinning symptoms and challenges commonly held beliefs regarding this condition.

Systemic inflammatory markers in neck pain: A systematic review with meta-analysis.

BACKGROUND AND OBJECTIVE: Mechanisms underpinning symptoms in non-traumatic neck pain (NTNP) and whiplash-associated disorder (WAD) are not comprehensively understood. There is emerging evidence of systemic inflammation in musculoskeletal pain conditions, including neck and back pain. The aim of this systematic review was to determine if raised blood inflammatory markers are associated with neck pain. DATABASES AND DATA TREATMENT: MEDLINE, EMBASE, Cochrane Library, CINAHL and Web of Science databases were searched. Two independent reviewers identified studies for inclusion and extracted data. Meta-analysis was performed by random effects model to calculate standard mean differences (SMDs). Risk of bias of individual studies was assessed using the Newcastle-Ottawa Scale. Overall quality of evidence from meta-analysis was assessed by Grades of Recommendation, Assessment, Development and Evaluation approach. RESULTS: In total, 10 studies were included comprising 706 participants. Three studies provided data for acute WAD, two for chronic WAD, four for chronic NTNP and one for chronic mixed WAD and NTNP. Meta-analysis indicated increased interleukin 1ß (SMD: 0.84 [95% CI 0.24, 1.44], p = .01, I2  = 59%) and tumour necrosis factor α (SMD: 0.59 [0.09, 1.09], p = .02, I2  = 45%) in chronic neck pain compared to controls, but no increase in monocyte chemoattractant protein-1. Some inflammatory markers were associated with clinical variables (including pain intensity and disability). Quality of evidence was mostly low due to small samples and high heterogeneity. CONCLUSIONS: Findings imply that raised blood inflammatory markers are present in chronic neck pain, which may represent an ongoing inflammatory process in this population. SIGNIFICANCE: This systematic review advances our understanding of neck pain pathophysiology by demonstrating the presence of systemic inflammation in chronic neck pain, in the form of raised IL-1ß and TNFα. Further, numerous inflammatory markers were associated with clinical variables, including pain intensity, disability and hyperalgesia. These findings imply that systemic inflammation may contribute to mechanisms underlying neck pain.

Best Evidence Rehabilitation for Chronic Pain Part 4: Neck Pain.

Neck pain, whether from a traumatic event such as a motor vehicle crash or of a non-traumatic nature, is a leading cause of worldwide disability. This narrative review evaluated the evidence from systematic reviews, recent randomised controlled trials, clinical practice guidelines, and other relevant studies for the effects of rehabilitation approaches for chronic neck pain. Rehabilitation was defined as the aim to restore a person to health or normal life through training and therapy and as such, passive interventions applied in isolation were not considered. The results of this review found that the strongest treatment effects to date are those associated with exercise. Strengthening exercises of the neck and upper quadrant have a moderate effect on neck pain in the short-term. The evidence was of moderate quality at best, indicating that future research will likely change these conclusions. Lower quality evidence and smaller effects were found for other exercise approaches. Other treatments, including education/advice and psychological treatment, showed only very small to small effects, based on low to moderate quality evidence. The review also provided suggestions for promising future directions for clinical practice and research.