Validation of a questionnaire for Central nervous system Aspects of joint Pain: the CAP questionnaire.

BACKGROUND AND AIMS: Neuropathic-like pain, fatigue, cognitive difficulty, catastrophising, anxiety, sleep disturbance, depression, and widespread pain associate with a single factor in people with knee pain. We report the Central Aspects of Pain questionnaire (CAP) to characterise this across painful musculoskeletal conditions. METHODS: CAP was derived from the 8 item CAP-Knee questionnaire, and completed by participants with joint pain in the Investigating Musculoskeletal Health and Wellbeing survey. Subgroups had osteoarthritis, back pain or fibromyalgia. Acceptability was evaluated by feedback and data missingness. Correlation coefficients informed widespread pain scoring threshold in relation to the other items, and evaluated associations with pain. Factor analysis assessed CAP structure. Intraclass Correlation Coefficient (ICC) between paper and electronic administration assessed reliability. Friedman test assessed score stability over 4 years in people reporting knee osteoarthritis. RESULTS: Data were from 3579 participants (58% female, median age; 71 years), including subgroups with osteoarthritis (n = 1158), back pain (n = 1292) or fibromyalgia (n = 177). Across the 3 subgroups, ≥10/26 painful sites on the manikin scored widespread pain. Reliability was high (ICC= 0.89 (95% CI: 0.84-0.92)) and CAP scores fit to 1 and 2 factor model, with a total CAP score that was associated with pain severity and quality (r = 0.50-0.72). In people with knee pain, CAP scores were stable over 4 years at the group level, but displayed significant temporal heterogeneity within individual participants. CONCLUSIONS: Central Aspects of Pain is reliably measured by the CAP questionnaire across a range of painful musculoskeletal conditions, and is a changeable state.

Influence of central aspects of pain on self-management in people with chronic low back pain.

OBJECTIVE: This observational study investigated whether central aspects of pain are associated with self-management domains in individuals with chronic low back pain (CLBP) undertaking a pain management program. METHODS: Individuals with CLBP provided pain sensitivity and self-management data at baseline (n = 97) and 3-months (n = 87). Pressure pain detection threshold (PPT) at the forearm, temporal summation (TS) and conditioned pain modulation (CPM), Widespread Pain Index (WPI), and a Central Aspects of Pain factor (CAPf) were considered as central aspects of pain. Self-management was measured using the 8 domains of the Health Education Impact Questionnaire, as well as Pain Self Efficacy and Health Care Utilisation questionnaires. RESULTS: PPT, CPM, WPI and CAPf predicted worse performance in several self-management domains at 3-months (r = 0.21 to 0.54, p < 0.05 overall). In multivariable regression models (adjusted for baseline scores of self-management, depression, catastrophization, pain and fatigue) low PPT, high TS, and high CAPf at baseline predicted poorer self-management at 3 months (R2 =0.14 to 0.52, ß = -0.37 to 0.35, p < 0.05). CONCLUSIONS: Central aspects of pain are associated with impaired self-management, over and above effects of pain intensity, fatigue, depression and catastrophizing. PRACTICE IMPLICATIONS: Treatments that target central aspects of pain might help improve self-management in people with CLBP.

Associations of Muscle Strength with Central Aspects of Pain: Data from the Knee Pain and Related Health in the Community (KPIC) Cohort.

Knee pain is associated with lower muscle strength, and both contribute to disability. Peripheral and central neurological mechanisms contribute to OA pain. Understanding the relative contributions of pain mechanisms to muscle strength might help future treatments. The Knee Pain and related health In the Community (KPIC) cohort provided baseline and year 1 data from people with early knee pain (n = 219) for longitudinal analyses. A cross-sectional analysis was performed with baseline data from people with established knee pain (n = 103) and comparative data from people without knee pain (n = 98). Quadriceps and handgrip strength indicated local and general muscle weakness, respectively. The indices of peripheral nociceptive drive were knee radiographic and ultrasound scores. The indices associated with central pain mechanisms were Pressure Pain detection Threshold (PPT) distal to the knee, and a validated self-report Central Aspects of Pain Factor (CAPF). The associations were explored using correlation and multivariable regression. Weaker quadriceps strength was associated with both high CAPF and low PPT at baseline. Year 1 quadriceps weakness was predicted by higher baseline CAPF (ß = -0.28 (95% CI: -0.55, -0.01), p = 0.040). Weaker baseline and year 1 handgrip strength was also associated with higher baseline CAPF. Weaker baseline quadriceps strength was associated with radiographic scores in bivariate but not adjusted analyses. Quadriceps strength was not significantly associated with total ultrasound scores. Central pain mechanisms might contribute to muscle weakness, both locally and remote from the knee.

The interrater and test-retest reliability of 3 modalities of quantitative sensory testing in healthy adults and people with chronic low back pain or rheumatoid arthritis.

Introduction: Quantitative Sensory Testing (QST) modalities used to assess central pain mechanisms require different protocols in people with different musculoskeletal conditions. Objectives: We aimed to explore the possible effects of musculoskeletal diagnosis and test site on QST interrater and test-retest reliability. Methods: The study included participants with rheumatoid arthritis (RA, n = 18; QST conducted on lower leg) and low back pain (LBP, n = 25; QST conducted on forearm), plus 45 healthy control participants (n = 20 QST on lower leg and n = 25 QST on forearm). Test-retest reliability was assessed from QST conducted 1 to 3 weeks apart. Quantitative sensory testing modalities used were pressure pain detection threshold (PPT) at a site distant to tissue pathology, temporal summation (TS), and conditioned pain modulation (CPM). Temporal summation was calculated as difference or ratio of single and repeated punctate stimuli and unconditioned thresholds for CPM used single or mean of multiple PPTs. Intraclass correlation coefficients (ICCs) were compared between different subgroups. Results: High to very high reliability was found for all assessments of PPT and TS across anatomical sites (lower leg and forearm) and participants (healthy, RA, and LBP) (ICC ≥ 0.77 for PPT and ICC ≥ 0.76 for TS). Reliability was higher when TS was calculated as a difference rather than a ratio. Conditioned pain modulation showed no to moderate reliability (ICC = 0.01-0.64) that was similar between leg or forearm, and between healthy people and those with RA or LBP. Conclusion: PPT and TS are transferable tools to quantify pain sensitivity at different testing sites in different musculoskeletal diagnoses. Low apparent reliability of CPM protocols might indicate minute-to-minute dynamic pain modulation.

The bidirectional relationship between chronic joint pain and frailty: data from the Investigating Musculoskeletal Health and Wellbeing cohort.

BACKGROUND: Pain and frailty are associated, but this relationship is insufficiently understood. We aimed to test whether there is a unidirectional or bidirectional relationship between joint pain and frailty. METHODS: Data were from Investigating Musculoskeletal Health and Wellbeing, a UK-based cohort. Average joint pain severity over the previous month was assessed using an 11-point numerical rating scale (NRS). Frailty was classified as present/absent using the FRAIL questionnaire. Multivariable regression assessed the association between joint pain and frailty, adjusted for age, sex, and BMI class. Two-wave cross-lagged path modelling permitted simultaneous exploration of plausible causal pathways between pain intensity and frailty at baseline and 1-year. Transitions were assessed using t-tests. RESULTS: One thousand one hundred seventy-nine participants were studied, 53% female, with a median age of 73 (range 60 to 95) years. FRAIL classified 176 (15%) participants as frail at baseline. Mean (SD) baseline pain score was 5.2 (2.5). Pain NRS ≥ 4 was observed in 172 (99%) of frail participants. Pain severity was associated with frailty at baseline (aOR 1.72 (95%CI 1.56 to 1.92)). In cross-lagged path analysis, higher baseline pain predicted 1-year frailty [ß = 0.25, (95%CI 0.14 to 0.36), p < 0.001] and baseline frailty predicted higher 1-year pain [ß = 0.06, (95%CI 0.003 to 0.11), p = 0.040]. Participants transitioning to frailty over one year had higher mean pain scores (6.4 (95%CI 5.8 to 7.1)) at baseline than those who remained non-frail (4.7 (95%CI 4.5 to 4.8)), p < 0.001. CONCLUSIONS: The bidirectional relationship between pain and frailty could lead to a vicious cycle in which each accelerates the other's progression. This justifies attempts to prevent frailty by addressing pain and to include pain measures as an outcome in frailty studies.

How people with knee pain understand why their pain changes or remains the same over time: A qualitative study.

Objectives: Guidelines recommend knee osteoarthritis pain management based on biopsychosocial mechanisms. Treatment adherence and effectiveness may be affected if there is a mismatch between patient perspectives and treatment focus. We therefore examined patient perspectives on mechanisms of their knee pain, why it persisted or changed over the past year, whether their understanding had changed, and whether their understanding aligned with that of others with whom they interact. Methods: Individuals with chronic knee pain (n â€‹= â€‹50) were purposively recruited from the Knee Pain and related health In the Community (KPIC) cohort to represent worsened, improved, or unchanged pain or anxiety between baseline and one year later. Framework analysis, a comparative form of thematic analysis, was used across transcripts of semi-structured telephone interviews. Results: Data were collapsed into themes of diagnosis, joint structure, ageing, physical activity, weight management, and treatment. Participants focused on biomechanical rather than psychological pain mechanisms. Some participants attributed pain improvement to increased and others to decreased physical activity. Participants reported no change in their understanding of their pain during the preceding year, but that their attitudes to pain, for example acceptance, had changed. Participants reported that they and others around them lacked understanding of their pain and why it did or did not change. Conclusion: People report a predominantly biomechanical understanding of why their knee pain remains constant or changes over time. Clinicians should support patients to develop a biopsychosocial understanding of knee pain aligned to treatment across the range of biological, psychological, and social modalities.

Influence of Social Support, Financial Status, and Lifestyle on the Disparity Between Inflammation and Disability in Rheumatoid Arthritis.

OBJECTIVE: To investigate how social support, financial status, and lifestyle influence the development of excess disability in rheumatoid arthritis (RA). METHODS: Data were obtained from the Étude et Suivi des Polyarthrites Indifférenciées Récentes (ESPOIR) cohort study of people with RA. A previous analysis identified groups with similar inflammation trajectories but markedly different disability over 10 years; those in the higher disability trajectory groups were defined as having "excess disability." Self-reported data regarding contextual factors (social support, financial situation, lifestyle) were obtained from participants, and they completed patient-reported outcome measures (pain, fatigue, anxiety, depression) at baseline. The direct effect of the contextual factors on excess disability and the effect mediated by patient-reported outcome measures were assessed using structural equation models. Findings were validated in 2 independent data sets (Norfolk Arthritis Register [NOAR], Early Rheumatoid Arthritis Network [ERAN]). RESULTS: Of 538 included ESPOIR participants (mean age ± SD 48.3 ± 12.2 years; 79.2% women), 200 participants (37.2%) were in the excess disability group. Less social support (ß = 0.17 [95% confidence interval (95% CI) 0.08, 0.26]), worse financial situation (ß = 0.24 [95% CI 0.14, 0.34]), less exercise (ß = 0.17 [95% CI 0.09-0.25]), and less education (ß = 0.15 [95% CI 0.06, 0.23]) were associated with excess disability group membership; smoking, alcohol consumption, and body mass index were not. Fatigue and depression mediated a small proportion of these effects. Similar results were seen in NOAR and ERAN. CONCLUSION: Greater emphasis is needed on the economic and social contexts of individuals with RA at presentation; these factors might influence disability over the following decade.

An observational study of centrally facilitated pain in individuals with chronic low back pain.

Introduction: Central pain facilitation can hinder recovery in people with chronic low back pain (CLBP). Objectives: The objective of this observational study was to investigate whether indices of centrally facilitated pain are associated with pain outcomes in a hospital-based cohort of individuals with CLBP undertaking a pain management programme. Methods: Participants provided self-report and pain sensitivity data at baseline (n = 97) and again 3 months (n = 87) after a cognitive behavioural therapy-based group intervention including physiotherapy. Indices of centrally facilitated pain were pressure pain detection threshold, temporal summation and conditioned pain modulation at the forearm, Widespread Pain Index (WPI) classified using a body manikin, and a Central Mechanisms Trait (CMT) factor derived from 8 self-reported characteristics of anxiety, depression, neuropathic pain, fatigue, cognitive dysfunction, pain distribution, catastrophizing, and sleep. Pain severity was a composite factor derived from Numerical Rating Scales. Cross-sectional and longitudinal regression models were adjusted for age and sex. Results: Baseline CMT and WPI each was associated with higher pain severity (CMT: r = 0.50, P < 0.001; WPI: r = 0.21, P = 0.04) at baseline and at 3 months (CMT: r = 0.38, P < 0.001; WPI: r = 0.24, P = 0.02). High baseline CMT remained significantly associated with pain at 3 months after additional adjustment for baseline pain (ß = 2.45, P = 0.04, R 2 = 0.25, P < 0.0001). Quantitative sensory testing indices of pain hypersensitivity were not significantly associated with pain outcomes at baseline or at 3 months. Conclusion: Central mechanisms beyond those captured by quantitative sensory testing are associated with poor CLBP outcome and might be targets for improved therapy.

Exploring the disparity between inflammation and disability in the 10-year outcomes of people with rheumatoid arthritis.

OBJECTIVES: To identify groups of people with RA with different disability trajectories over 10 years, despite comparable levels of inflammation. METHODS: Data for this analysis came from three European prospective cohort studies of people with RA [Norfolk Arthritis Register (NOAR), Early RA Network (ERAN), Étude et Suivi des Polyarthrites Indifférenciées Récentes (ESPOIR)]. Participants were assessed regularly over 8 (ERAN) to 10 (NOAR/ESPOIR) years. Inclusion criteria were: recruited after 1 January 2000, <24 months baseline symptom duration, and disability (HAQ) and inflammation [two-component DAS28 (DAS28-2C)] recorded at baseline and at one other follow-up. People in each cohort also completed patient-reported outcome measures at each assessment (pain, fatigue, depressive symptoms). Group-based trajectory models were used to identify distinct groups of people with similar HAQ and DAS28-2C trajectories over follow-up. RESULTS: This analysis included 2500 people with RA (NOAR: 1000, ESPOIR: 766, ERAN: 734). ESPOIR included more women and the participants were younger [mean (standard deviation) age: NOAR: 57.1 (14.6), ESPOIR: 47.6 (12.5), ERAN: 56.8 (13.8); women: NOAR: 63.9%, ESPOIR: 76.9%, ERAN: 69.1%). Within each cohort, two pairs of trajectories following the hypothesized pattern (comparable DAS28-2Cs but different HAQs) were identified. Higher pain, fatigue and depressive symptoms were associated with increased odds of being in the high HAQ trajectories. CONCLUSION: Excess disability is persistent in RA. Controlling inflammation may not be sufficient to alleviate disability in all people with RA, and effective pain, fatigue and mood management may be needed in some groups to improve long-term function.

The efficacy of systemic glucocorticosteroids for pain in rheumatoid arthritis: a systematic literature review and meta-analysis.

OBJECTIVES: Glucocorticosteroids (GCs) are recommended to suppress inflammation in people with active RA. This systematic review and meta-analysis aimed to quantify the effects of systemic GCs on RA pain. METHODS: A systematic literature review of randomized controlled trials (RCTs) in RA comparing systemic GCs to inactive treatment. Three databases were and spontaneous pain and evoked pain outcomes were extracted. Standardized mean differences (SMDs) and mean differences were meta-analysed. Heterogeneity (I2, tau statistics) and bias (funnel plot, Egger's test) were assessed. Subgroup analyses investigated sources of variation. This study was pre-registered (PROSPERO CRD42019111562). RESULTS: A total of 18 903 titles, 880 abstracts and 226 full texts were assessed. Thirty-three RCTs suitable for the meta-analysis included 3123 participants. Pain scores (spontaneous pain) decreased in participants treated with oral GCs; SMD = -0.65 (15 studies, 95% CI -0.82, -0.49, P <0.001) with significant heterogeneity (I2 = 56%, P =0.0002). Efficacy displayed time-related decreases after GC initiation. Mean difference visual analogue scale pain was -15 mm (95% CI -20, -9) greater improvement in GC than control at ≤3 months, -8 mm (95% CI -12, -3) at >3-6 months and -7 mm (95% CI -13, 0) at >6 months. Similar findings were obtained when evoked pain outcomes were examined. Data from five RCTs suggested improvement also in fatigue during GC treatment. CONCLUSION: Oral GCs are analgesic in RA. The benefit is greatest shortly after initiation and GCs might not achieve clinically important pain relief beyond 3 months. Treatments other than anti-inflammatory GCs should be considered to reduce the long-term burden of pain in RA.

Central Aspects of Pain in Rheumatoid Arthritis (CAP-RA): protocol for a prospective observational study.

BACKGROUND: Pain and fatigue are persistent problems in people with rheumatoid arthritis. Central sensitisation (CS) may contribute to pain and fatigue, even when treatment has controlled inflammatory disease. This study aims to validate a self-report 8-item questionnaire, the Central Aspects of Pain in Rheumatoid Arthritis (CAP-RA) questionnaire, developed to measure central pain mechanisms in RA, and to predict patient outcomes and response to treatment. A secondary objective is to explore mechanisms linking CS, pain and fatigue in people with RA. METHODS/DESIGN: This is a prospective observational cohort study recruiting 250 adults with active RA in secondary care. The CAP-RA questionnaire, demographic data, medical history, and patient reported outcome measures (PROMs) of traits associated with central sensitization will be collected using validated questionnaires. Quantitative sensory testing modalities of pressure pain detection thresholds, temporal summation and conditioned pain modulation will be indices of central sensitization, and blood markers, swollen joints and ultrasound scans will be indices of inflammation. Primary data collection will be at baseline and 12 weeks. The test-retest reliability of CAP-RA questionnaire will be determined 1 week after the baseline visit. Pain and fatigue data will be collected weekly via text messages for 12 weeks. CAP-RA psychometric properties, and predictive validity for outcomes at 3 months will be evaluated. DISCUSSION: This study will validate a simple self-report questionnaire against psychophysical indices of central sensitization and patient reported outcome measures of traits associated with CS in a population of individuals with active RA. The application of this instrument in the clinical environment could provide a mechanism-based stratification tool to facilitate the provision of targeted therapy to individuals with pain and fatigue in RA, alongside treatments that target joint inflammation. TRIAL REGISTRATION: Clinicaltrials.gov NCT04515589 . Date of registration 17 August 2020.

Association of subchondral bone marrow lesion localization with weight-bearing pain in people with knee osteoarthritis: data from the Osteoarthritis Initiative.

BACKGROUND: Subchondral bone marrow lesions (BMLs) detected on MRI in knee osteoarthritis (OA) are associated with knee pain. The prevalence and progression of subchondral BMLs are increased by mechanical knee load. However, associations of subchondral BML location with weight-bearing knee pain are currently unknown. In this study, we aim to demonstrate associations of subchondral BML location and size with weight-bearing knee pain in knee OA. METHODS: We analyzed 1412 and 582 varus knees from cross-sectional and longitudinal Osteoarthritis Initiative datasets, respectively. BML scores were semi-quantitatively analyzed with the MRI Osteoarthritis Knee Score for 4 subchondral regions (median and lateral femorotibial, medial and lateral patellofemoral) and subspinous region. Weight-bearing and non-weight-bearing pain scores were derived from WOMAC pain items. Correlation and negative binomial regression models were used for analysis of associations between the BML scores and pain at baseline and changes in the BML scores and changes in pain after 24-month follow-up. RESULTS: Greater BML scores at medial femorotibial and lateral patellofemoral compartments were associated with greater weight-bearing pain scores, and statistical significance was retained after adjusting for BML scores at the other 4 joint compartments and other OA features, as well as for non-weight-bearing pain, age, sex, and body mass index (BMI) (medial femorotibial; B = 0.08, p = 0.02. patellofemoral; B = 0.13, p = 0.01). Subanalysis revealed that greater medial femorotibial BML scores were associated with greater pain on walking and standing (B = 0.11, p = 0.01, and B = 0.10, p = 0.04, respectively). Lateral patellofemoral BML scores were associated with pain on climbing, respectively (B = 0.14, p = 0.02). Increases or decreases over 24 months in BML score in the medial femorotibial compartment were significantly associated with increases or decreases in weight-bearing pain severity after adjusting for non-weight-bearing pain, age, sex, baseline weight-bearing pain, BMI, and BML at the other 4 joint compartments (B = 0.10, p = 0.01). CONCLUSIONS: Subchondral BML size at the medial femorotibial joint compartment was specifically associated with the severity and the change in weight-bearing pain, independent of non-weight-bearing pain, in knee OA. Specific associations of weight-bearing pain with subchondral BMLs in weight-bearing compartments of the knee indicate that BMLs in subchondral bone contribute to biomechanically induced OA pain.

Investigating musculoskeletal health and wellbeing; a cohort study protocol.

BACKGROUND: In an ageing population, pain, frailty and disability frequently coexist across a wide range of musculoskeletal diagnoses, but their associations remain incompletely understood. The Investigating Musculoskeletal Health and Wellbeing (IMH&W) study aims to measure and characterise the development and progression of pain, frailty and disability, and to identify discrete subgroups and their associations. The survey will form a longitudinal context for nested research, permitting targeted recruitment of participants for qualitative, observational and interventional studies; helping to understand recruitment bias in clinical studies; and providing a source cohort for cohort randomised controlled trials. METHODS: IMH&W will comprise a prospective cohort of 10,000 adults recruited through primary and secondary care, and through non-clinical settings. Data collection will be at baseline, and then through annual follow-ups for 4 years. Questionnaires will address demographic characteristics, pain severity (0-10 Numerical Rating Scale), pain distribution (reported on a body Manikin), pain quality (McGill Pain Questionnaire), central aspects of pain (CAP-Knee), frailty and disability (based on Fried criteria and the FRAIL questionnaire), and fracture risk. Baseline characteristics, progression and associations of frailty, pain and disability will be determined. Discrete subgroups and trajectories will be sought by latent class analysis. Recruitment bias will be explored by comparing participants in nested studies with the eligible IMH&W population. DISCUSSION: IMH&W will elucidate associations and progression of pain, frailty and disability. It will enable identification of people at risk of poor musculoskeletal health and wellbeing outcomes who might be suitable for specific interventions, and facilitate generalisation and comparison of research outcomes between target populations. The study will benefit from a large sample size and will recruit from diverse regions across the UK. Purposive recruitment will enrich the cohort with people with MSK problems with high representation of elderly and unwell people. TRIAL REGISTRATION: Clinicaltrials.gov NCT03696134. Date of Registration: 04 October 2018.

Disease activity flares and pain flares in an early rheumatoid arthritis inception cohort; characteristics, antecedents and sequelae.

BACKGROUND: RA flares are common and disabling. They are described in terms of worsening inflammation but pain and inflammation are often discordant. To inform treatment decisions, we investigated whether inflammatory and pain flares are discrete entities. METHODS: People from the Early RA Network (ERAN) cohort were assessed annually up to 11 years after presentation (n = 719, 3703 person-years of follow up). Flare events were defined in 2 different ways that were analysed in parallel; DAS28 or Pain Flares. DAS28 Flares satisfied OMERACT flare criteria of increases in DAS28 since the previous assessment (≥1.2 points if active RA or ≥ 0.6 points if inactive RA). A ≥ 4.8-point worsening of SF36-Bodily Pain score defined Pain Flares. The first documented episode of each of DAS28 and Pain Flare in each person was analysed. Subgroups within DAS28 and Pain Flares were determined using Latent Class Analysis. Clinical course was compared between flare subgroups. RESULTS: DAS28 (45%) and Pain Flares (52%) were each common but usually discordant, with 60% of participants in DAS28 Flare not concurrently in Pain Flare, and 64% of those in Pain Flare not concurrently in DAS28 Flare. Three discrete DAS28 Flare subgroups were identified. One was characterised by increases in tender/swollen joint counts (14.4%), a second by increases in symptoms (13.1%), and a third displayed lower flare severity (72.5%). Two discrete Pain Flare subgroups were identified. One occurred following low disease activity and symptoms (88.6%), and the other occurred on the background of ongoing active disease and pain (11.4%). Despite the observed differences between DAS28 and Pain Flares, each was associated with increased disability which persisted beyond the flare episode. CONCLUSION: Flares are both common and heterogeneous in people with RA. Furthermore our findings indicate that for some patients there is a discordance between inflammation and pain in flare events. This discrete flare subgroups might reflect different underlying inflammation and pain mechanisms. Treatments addressing different mechanisms might be required to reduce persistent disability after DAS28 and Pain Flares.

CGRP and Painful Pathologies Other than Headache.

CGRP has long been suspected as a mediator of arthritis pain, although evidence that CGRP directly mediates human musculoskeletal pain remains circumstantial. This chapter describes in depth the evidence surrounding CGRP's association with pain in musculoskeletal disorders and also summarises evidence for CGRP being a direct cause of pain in other conditions. CGRP-immunoreactive nerves are present in musculoskeletal tissues, and CGRP expression is altered in musculoskeletal pain. CGRP modulates musculoskeletal pain through actions both in the periphery and central nervous system. Human observational studies, research on animal arthritis models and the few reported randomised controlled trials in humans of treatments that target CGRP provide the context of CGRP as a possible pain biomarker or mediator in conditions other than migraine.

Quantitative sensory testing and predicting outcomes for musculoskeletal pain, disability, and negative affect: a systematic review and meta-analysis.

Hypersensitivity due to central pain mechanisms can influence recovery and lead to worse clinical outcomes, but the ability of quantitative sensory testing (QST), an index of sensitisation, to predict outcomes in chronic musculoskeletal disorders remains unclear. We systematically reviewed the evidence for ability of QST to predict pain, disability, and negative affect using searches of CENTRAL, MEDLINE, EMBASE, AMED, CINAHL, and PubMed databases up to April 2018. Title screening, data extraction, and methodological quality assessments were performed independently by 2 reviewers. Associations were reported between baseline QST and outcomes using adjusted (ß) and unadjusted (r) correlations. Of the 37 eligible studies (n = 3860 participants), 32 were prospective cohort studies and 5 randomised controlled trials. Pain was an outcome in 30 studies, disability in 11, and negative affect in 3. Meta-analysis revealed that baseline QST predicted musculoskeletal pain (mean r = 0.31, 95% confidence interval [CI]: 0.23-0.38, n = 1057 participants) and disability (mean r = 0.30, 95% CI: 0.19-0.40, n = 290 participants). Baseline modalities quantifying central mechanisms such as temporal summation and conditioned pain modulation were associated with follow-up pain (temporal summation: mean r = 0.37, 95% CI: 0.17-0.54; conditioned pain modulation: mean r = 0.36, 95% CI: 0.20-0.50), whereas baseline mechanical threshold modalities were predictive of follow-up disability (mean r = 0.25, 95% CI: 0.03-0.45). Quantitative sensory testing indices of pain hypersensitivity might help develop targeted interventions aiming to improve outcomes across a range of musculoskeletal conditions.

Discrete Trajectories of Resolving and Persistent Pain in People With Rheumatoid Arthritis Despite Undergoing Treatment for Inflammation: Results From Three UK Cohorts.

Rheumatoid arthritis (RA) is an example of human chronic inflammatory pain. Modern treatments suppress inflammation, yet pain remains a major problem for many people with RA. We hypothesized that discrete RA subgroups might display favorable or unfavorable pain trajectories when receiving treatment, and that baseline characteristics will predict trajectory allocation. Growth mixture modelling was used to identify discrete trajectories of Short Form-36 bodily pain scores during 3 years in 3 RA cohorts (Early RA Network (n = 683), British Society for Rheumatology Biologics Register Biologics (n = 7,090) and nonbiologics (n = 1,720) cohorts. Logistic regression compared baseline predictor variables between trajectories. The role of inflammation was examined in a subgroup analysis of people with normal levels of inflammatory markers after 3 years. The mean Short Form-36 bodily pain scores in each cohort improved but remained throughout 3 years of follow-up of >1 standard deviation worse than the UK general population average. Discrete persistent pain (59-79% of cohort participants) and resolving pain (19-27%) trajectories were identified in each cohort. In Early RA Network, a third trajectory displaying persistently low pain (23%) was also identified. In people with normal levels of inflammatory markers after 3 years, 65% were found to follow a persistent pain trajectory. When trajectories were compared, greater disability (adjusted odds ratio = 2.3-2.5 per unit baseline Health Assessment Questionnaire score) and smoking history (adjusted odds ratio = 1.6-1.8) were risk factors for persistent pain trajectories in each cohort. In conclusion, distinct trajectories indicate patient subgroups with very different pain prognosis during treatment for RA. Inflammation does not fully explain the pain trajectories, and noninflammatory factors as well as acute phase response predict which trajectory an individual will follow. Targeted treatments additional to those which suppress inflammation might reduce the long-term burden of arthritis pain. PERSPECTIVE: Immunosuppression decreases inflammation in RA, but pain outcomes are less favorable. Discrete persistent and resolving pain trajectories were identified after treatment, both in early and established RA. Smoking and greater disability at baseline predicted persistent pain. Identifying patient subgroups with a poor pain prognosis could enable adjunctive treatment to improve outcomes.

Associations of Symptomatic Knee Osteoarthritis With Histopathologic Features in Subchondral Bone.

OBJECTIVE: Subchondral bone and the osteochondral junction are thought to contribute to osteoarthritis (OA) knee pain. We undertook this study to identify osteochondral pathologies specifically associated with symptomatic human knee OA. METHODS: Medial tibial plateau samples from 2 groups of subjects (n = 31 per group) were matched for macroscopic chondropathy scores. The symptomatic chondropathy group had undergone total knee replacement for OA knee pain, at which time specimens of the medial tibial plateau were obtained. The asymptomatic chondropathy group included subjects who died of unrelated illness (specimens were obtained at postmortem examination) and who had not previously sought help for knee pain. OA histopathology, immunoreactivity for nerve growth factor (NGF) and CD68 (macrophages), tartrate-resistant acid phosphatase-positive subchondral osteoclasts, and synovitis were compared between groups. RESULTS: Mankin scores, subchondral bone density, and subchondral CD68-immunoreactive macrophage infiltration were similar between the 2 groups. NGF-like immunoreactivity was found in subchondral mononuclear cells and osteoclasts, as well as in chondrocytes. NGF in osteochondral channels and osteoclast densities in subchondral bone were higher in the symptomatic chondropathy group than in the asymptomatic chondropathy group (P < 0.01 and P = 0.02, respectively), as were synovitis scores (P < 0.01). Osteochondral pathology was not significantly associated with synovitis score. The differences in NGF expression and in osteoclast density remained significant after adjustment for age and synovitis score (P = 0.01 and P = 0.04, respectively). Osteochondral NGF and osteoclast densities, together with synovitis scores, explained ~28% of sample allocation to symptomatic or asymptomatic groups. CONCLUSION: Subchondral pathology was associated with symptomatic knee OA, independent of chondropathy and synovitis. Increased NGF expression in osteochondral channels and increased osteoclast density appear to be key features associated with bone pain in knee OA.

Traits associated with central pain augmentation in the Knee Pain In the Community (KPIC) cohort.

This study aimed to identify self-report correlates of central pain augmentation in individuals with knee pain. A subset of participants (n = 420) in the Knee Pain and related health In the Community (KPIC) baseline survey undertook pressure pain detection threshold (PPT) assessments. Items measuring specific traits related to central pain mechanisms were selected from the survey based on expert consensus, face validity, item association with underlying constructs measured by originating host questionnaires, adequate targeting, and PPT correlations. Pain distribution was reported on a body manikin. A "central pain mechanisms" factor was sought by factor analysis. Associations of items, the derived factor, and originating questionnaires with PPTs were compared. Eight self-report items measuring traits of anxiety, depression, catastrophizing, neuropathic-like pain, fatigue, sleep disturbance, pain distribution, and cognitive impact were identified as likely indices of central pain mechanisms. Pressure pain detection thresholds were associated with items representing each trait and with their originating scales. Pain distribution classified as "pain below the waist additional to knee pain" was more strongly associated with low PPT than were alternative classifications of pain distribution. A single factor, interpreted as "central pain mechanisms," was identified across the 8 selected items and explained variation in PPT (R = 0.17) better than did any originating scale (R = 0.10-0.13). In conclusion, including representative items within a composite self-report tool might help identify people with centrally augmented knee pain.