Exploring the effect on primary endpoints in trials testing targeted therapy interventions for rheumatoid arthritis: a meta-epidemiological study on the appropriate use of a core outcome set.

OBJECTIVES: To explore which core domain is best associated with the American College of Rheumatology (ACR) 20% response in trials assessing the effect of targeted interventions in rheumatoid arthritis (RA). METHODS: A meta-epidemiological study was performed on randomised trials investigating biologics and targeted agents compared with placebo or conventional disease-modifying antirheumatic drugs in patients with RA. The main outcome measures were ORs for the ACR 20% response and at least one of the eight core domains according to the existing RA core outcome set (COS) analysed based on standardised mean differences. RESULTS: 115 trials involving 55 422 patients with RA were eligible. The OR for achieving ACR 20% response was 3.19 (95% CI 2.96 to 3.44) for the experimental interventions relative to the comparators. The median number of COS domains reported was 6; 18 trials reported only 1 domain, 17 all 8. Univariable meta-regression analyses indicated that each of the eight core domains was significantly associated with ACR 20% response, yet improvements in physical disability explain a successful ACR 20% response the most. Including only trials reporting on all eight core domains, univariable meta-regression analyses proved improvement in fatigue to explain a successful ACR 20% response the most. CONCLUSIONS: Within this dataset, it is evident that the conclusions concerning our primary objective were significantly influenced by both the amount and characteristics of missing data. Our data suggest that fatigue could be more important for the primary endpoint than previously assumed, but this is based on limited data.

Comorbidities, pain and fatigue in psoriatic arthritis, psoriasis and healthy controls: a clinical cohort study.

OBJECTIVES: To explore the prognostic value of pre-specified comorbidities on treatment outcomes in PsA, and to compare baseline data with cutaneous psoriasis without arthritis and healthy controls (HC). METHODS: Patients initiating conventional synthetic/biological disease-modifying antirheumatic drugs were enrolled in this clinical observational cohort study, and data on comorbidities, and clinical and patient-reported outcomes were retrieved at baseline and after 4 months. Pearson's chi-squared tests were performed to investigate the prognostic value of pre-specified comorbidities and achievement of ACR20, DAPSA50 and MDA. Mann-Whitney U tests were used to compare OMERACT PsA Core Outcome Set (COS) measures at baseline and follow-up for the pre-specified comorbidities. RESULTS: A total of 100 PsA patients were included at baseline. Statistically significantly fewer patients with obesity achieved DAPSA50 compared with patients without obesity (P =0.035), and fewer patients with hypertension (P =0.034) and Charlson Comorbidity Index (CCI) ≥1 (P =0.027), respectively, achieved MDA compared with patients without these comorbidities. Patients with obesity, hypertension, widespread pain, and CCI ≥1 had significantly worse COS measures at follow-up compared with patients without these comorbidities. At baseline, patients with PsA had higher disease burden compared with patients with cutaneous psoriasis and HC, including higher pain (P <0.001) and fatigue (P <0.001) scores, and more widespread pain (P =0.002). CONCLUSION: Obesity, hypertension and CCI ≥1 were prognostic factors for poorer treatment outcome rates in PsA. Pain and fatigue were more frequently reported among patients with PsA compared with patients with cutaneous psoriasis and HC. TRIAL REGISTRATION: The Danish National Committee on Health Research Ethics: H-15009080; Data Protection Agency: 2012-58-0004; ClinicalTrials.gov: NCT02572700.

Low-Dose Naltrexone for the Treatment of Fibromyalgia: Investigation of Dose-Response Relationships.

OBJECTIVE: This study explores dose-response relationships when treating fibromyalgia with low-dose naltrexone. DESIGN: A single-blinded clinical trial was carried out using the "up-and-down" method. SUBJECTS: Subjects included women with a diagnosis of fibromyalgia aged 18-60 years who had been referred to treatment at a public pain clinic at a Danish university hospital. METHODS: The test doses were in the range 0.75-6 mg, and the dosing interval was 0.75 mg. The method was sequential and allowed predicting the dose effective in 50% (ED50) and 95% (ED95) of the subjects when the dose had shifted direction 10 times, and six pairs of "up-and-down" data were available. RESULTS: A total of 27 subjects were included in the study; two subjects were withdrawn. After inclusion of 25 evaluable subjects, the dose estimates were calculated as 3.88 mg for ED50 and 5.40 mg for ED95. As a secondary outcome, the effects on 10 common fibromyalgia symptoms were evaluated. A high interindividual variation was observed both in the symptom presentation at baseline and in which symptoms were reduced by low-dose naltrexone. CONCLUSIONS: This study is the first to explore dose-response relationships in the treatment of fibromyalgia with low-dose naltrexone. Future placebo-controlled randomized clinical trials are needed, and according to our findings, 4.5 mg, which has previously been used, seems to be a relevant test dose. We recommend that future studies include additional nonpain fibromyalgia symptoms as outcome measures.

The benefit of adding a physiotherapy or occupational therapy intervention programme to a standardized group-based interdisciplinary rehabilitation programme for patients with chronic widespread pain: a randomized active-controlled non-blinded trial.

OBJECTIVE: To evaluate the benefit of adding occupational therapy or physiotherapy interventions to a standard rehabilitation programme targeted for chronic widespread pain. DESIGN: Randomized active-controlled non-blinded trial. SUBJECTS: Women with chronic widespread pain recruited in a tertiary outpatient clinic. METHODS: Participants were randomized to a two-week, group-based standard rehabilitation programme followed by 16 weeks of group-based occupational therapy (Group BOT, n = 43) or 16 weeks of group-based physiotherapy (Group BPT, n = 42). Group A only received the two-week rehabilitation programme acting as comparator (n = 96). OUTCOMES: Primary outcomes were the Assessment of Motor and Process Skills and Short Form-36 (SF36) Mental Component Summary score. RESULTS: Mean changes in motor and process ability measures were clinically and statistically insignificant and without differences across the three groups assessed 88 weeks from baseline. Motor ability measures: -0.006 (95% confidence interval (CI): -0.244 to 0.233) in Group BOT; -0.045 (95% CI: -0.291 to 0.202) in Group BPT; and -0.017 (95% CI: -0.248 to 0.213) in Group A, P = 0.903. Process ability measures: 0.087 (95% CI: -0.056 to 0.231) in Group BOT; 0.075 (95% CI: -0.075 to 0.226) in Group BPT; and 0.072 (95% CI: -0.067 to 0.211) in Group A, P = 0.924. Mean changes in patient-reported outcomes were likewise small; clinically and statistically insignificant; and independent of group allocation, except for the SF36 mental component summary score in the BPT group: 8.58 (95% CI: 1.75 to 15.41). CONCLUSION: Participants were on average stable in observation-based measures of functional ability and patient-reported outcomes, except in overall mental well-being, favouring the enhanced intervention. Efficacy of additional interventions on functional ability remains uncertain.

Psychometric properties of the painDETECT questionnaire in rheumatoid arthritis, psoriatic arthritis and spondyloarthritis: Rasch analysis and test-retest reliability.

BACKGROUND: Pain is inherent in rheumatoid arthritis (RA), psoriatic arthritis (PsA) and spondyloarthritis (SpA) and traditionally considered to be of nociceptive origin. Emerging data suggest a potential role of augmented central pain mechanisms in subsets of patients, thus, valid instruments that can identify underlying pain mechanisms are needed. The painDETECT questionnaire (PDQ) was originally designed to differentiate between pain phenotypes. The objectives were to evaluate the psychometric properties of the PDQ in patients with inflammatory arthritis by applying Rasch analysis and to explore the reliability of pain classification by test-retest. METHODS: For the Rasch analysis 900 questionnaires from patients with RA, PsA and SpA (300 per diagnosis) were extracted from 'the DANBIO painDETECT study'. The analysis was directed at the seven items assessing somatosensory symptoms and included: 1) the performance of the six-category Likert scale; 2) whether a unidimensional construct was defined; 3) the reliability and precision of estimates. Another group of 30 patients diagnosed with RA, PsA or SpA participated in a test-retest study. Intraclass Correlation Coefficients (ICC) and classification consistency were calculated. RESULTS: The Rasch analysis revealed: (1) Acceptable psychometric rating scale properties; the frequency distribution peaked in category 0 except for item 5, threshold calibration >10 observations per category, no disorder in the category measures for all items, scale category outfit Mnsq <2.0, small distances (<1.4 logits) between thresholds for category 1, 2 and 3 for all items. (2) The principal component analysis supported unidimensionality; the standardized residuals showed that 53.7% of total variance was explained by the measure and the magnitude of first contrast had an eigenvalue of 1.5, no misfitting items, clinical insignificant different item hierarchies across diagnoses (DIF < 0.5 logits). (3) A targeted item-person map, person and item separation indices of 1.88(reliability = 0.78), and 13.04 (reliability = 0.99). The test-retest revealed: ICC: RA 0.86(0.56-0.96), PsA 0.96(0.74-0.99), SpA 0.93(0.76-98), overall 0.94(0.84-0.98). Classification consistency was: RA 70%, PsA 80%, SpA 90%, overall 80%. CONCLUSION: The results support that the PDQ can be used as a classification instrument and assist identification of underlying pain-mechanisms in patients suffering from inflammatory arthritis.

Interventions for treating persistent pain in survivors of torture.

BACKGROUND: Persistent (chronic) pain is a frequent complaint in survivors of torture, particularly but not exclusively pain in the musculoskeletal system. Torture survivors may have no access to health care; where they do, they may not be recognised when they present, and the care available often falls short of their needs. There is a tendency in state and non-governmental organisations' services to focus on mental health, with poor understanding of persistent pain, while survivors may have many other legal, welfare, and social problems that take precedence over health care. OBJECTIVES: To assess the efficacy of interventions for treating persistent pain and associated problems in survivors of torture. SEARCH METHODS: We searched for randomised controlled trials (RCTs) published in any language in CENTRAL, MEDLINE, Embase, Web of Science, CINAHL, LILACS, and PsycINFO, from database inception to 1 February 2017. We also searched trials registers and grey literature databases. SELECTION CRITERIA: RCTs of interventions of any type (medical, physical, psychological) compared with any alternative intervention or no intervention, and with a pain outcome. Studies needed to have at least 10 participants in each arm for inclusion. DATA COLLECTION AND ANALYSIS: We identified 3578 titles in total after deduplication; we selected 24 full papers to assess for eligibility. We requested data from two completed trials without published results.We used standard methodological procedures expected by Cochrane. We assessed risk of bias and extracted data. We calculated standardised mean difference (SMD) and effect sizes with 95% confidence intervals (CI). We assessed the evidence using GRADE and created a 'Summary of findings' table. MAIN RESULTS: Three small published studies (88 participants) met the inclusion criteria, but one had been retracted from publication because of ethical problems concerned with confidentiality and financial irregularities. Since these did not affect the data, the study was retained in this review. Despite the search including any intervention, only two types were represented in the eligible studies: two trials used cognitive behavioural therapy (CBT) with biofeedback versus waiting list on unspecified persistent pain (58 participants completed treatment), and one examined the effect of complex manual therapy versus self-treatment on low back pain (30 participants completed treatment). Excluded studies were largely either not RCTs or did not report pain as an outcome.There was no difference for the outcome of pain relief at the end of treatment between CBT and waiting list (two trials, 58 participants; SMD -0.05, 95% CI -1.23 to 1.12) (very low quality evidence); one of these reported a three-month follow-up with no difference between intervention and comparison (28 participants; SMD -0.03, 95% CI -0.28 to 0.23) (very low quality evidence). The manual therapy trial also reported no difference between complex manual therapy and self-treatment (30 participants; SMD -0.48, 95% CI -9.95 to 0.35) (very low quality evidence). Two studies reported dropouts, one with partial information on reasons; none of the studies reported adverse effects.There was no information from any study on the outcomes of use of analgesics or quality of life.Reduction in disability showed no difference at the end of treatment between CBT and waiting list (two trials, 57 participants; SMD -0.39, 95% CI -1.17 to 0.39) (very low quality evidence); one of these reported a three-month follow-up with no difference between intervention and comparison (28 participants; SMD 0, 95% CI -0.74 to 0.74) (very low quality evidence). The manual therapy trial reported superiority of complex manual therapy over self-treatment for reducing disability (30 participants; SMD -1.10, 95% CI - 1.88 to -0.33) (very low quality evidence).Reduction in distress showed no difference at the end of treatment between CBT and waiting list (two trials, 58 participants; SMD 0.07, 95% CI -0.46 to 0.60) (very low quality evidence); one of these reported a three-month follow-up with no difference between intervention and comparison (28 participants; SMD -0.24, 95% CI -0.50 to 0.99) (very low quality evidence). The manual therapy trial reported superiority of complex manual therapy over self-treatment for reducing distress (30 participants; SMD -1.26, 95% CI - 2.06 to -0.47) (very low quality evidence).The risk of bias was considered high given the small number of trials, small size of trials, and the likelihood that each was underpowered for the comparisons it reported. We primarily downgraded the quality of the evidence due to small numbers in trials, lack of intention-to-treat analyses, high unaccounted dropout, lack of detail on study methods, and CIs around effect sizes that included no effect, benefit, and harm. AUTHORS' CONCLUSIONS: There is insufficient evidence to support or refute the use of any intervention for persistent pain in survivors of torture.

How can group-based multidisciplinary rehabilitation for patients with fibromyalgia influence patients' self-efficacy and ability to cope with their illness: a grounded theory approach.

AIMS AND OBJECTIVES: To describe how group-based multidisciplinary rehabilitation for patients with fibromyalgia can influence patients' self-efficacy and ability to cope with their illness. BACKGROUND: Multidisciplinary rehabilitation is recommended in the management of fibromyalgia. Self-efficacy is said to influence and predict adaptive coping behaviours and functioning. However, knowledge is lacking on how rehabilitation programmes may influence self-efficacy and ability to cope, from the patients' perspective. DESIGN: Grounded theory study of semi-structured focus group interviews. METHODS: Participants (n = 17) were included in four focus groups that had completed a two-week multidisciplinary rehabilitation programme together. Interviews were conducted four weeks after each group had completed the programme. The analysis was conducted constant comparatively applying open, axial and selective coding. RESULTS: Categories (in italics) were derived from data in which the explanatory core category was identified: Learning to accept and live with pain as a life condition, and linked to three categories mutually influencing each other: Increased self-acceptance of living with the illness, experiencing acceptance from others and developing new coping strategies. Thus, patients benefitted from multidisciplinary rehabilitation with stronger self-efficacy and expectations to their future coping. However, limitations in the programme were identified, as the programme was short and intensive with no subsequent follow-up, and social welfare was not sufficiently addressed. Participants also found it difficult to maintain knowledge and were lacking individual sessions with the psychologist and had waited long to receive rehabilitation. CONCLUSION: Multidisciplinary rehabilitation may advantageously be offered to patients with fibromyalgia. However, earlier action with longer programmes, in which patients' social situation is addressed, comprising individual sessions with the psychologist, with multiple repetitions of the content and follow-up sessions, may further enhance the patients' self-efficacy and coping with their illness.

Treatment of persistent pain from torture: review and commentary.

Torture and the conditions under which it is inflicted often leave persistent painful disorders. Because there may be no lasting signs, persistent pain is often misconceived as a somatic representation of psychological distress, also common after torture. This serious failure to understand the nature of persistent pain means that pain is largely overlooked and untreated in torture survivors. We carried out a systematic review on treatments for pain from torture, but found few studies and little use of current understanding and evidence. We discuss this in the context of treating pain associated with psychological distress and of the broader problems faced by the refugee and torture survivor that may take priority over pain. We propose clinical and research implications for this neglected field.

Association of Physical Fitness with Depression in Women with Fibromyalgia.

OBJECTIVE: The aim of this study was to examine the association between physical fitness and depressive symptoms in women with fibromyalgia (FM). We also assessed whether different fitness components present independent relationships with depressive symptoms. DESIGN: Cross-sectional study. SETTING: University facilities and FM associations. SUBJECTS: Four hundred and forty-four patients with FM according to the 1990 American College of Rheumatology criteria. METHODS: Depressive symptoms were assessed using the Beck Depression Inventory (BDI-II). Physical fitness (aerobic fitness, muscle strength, flexibility, and motor agility) was assessed using the standardized Senior Fitness Test battery and the handgrip strength test. A standardized composite score for fitness was computed and divided into quintiles. RESULTS: Overall, the fitness tests presented inverse associations with the total BDI-II score (P < 0.05). The patients in the highest fitness quintile had 8.4% lower depressive symptoms than the patients in the lowest fitness quintile (P = 0.014). The odds of severe symptoms of depression were between 3.7% and 16.9% lower for each performance unit in the back-scratch, handgrip, arm-curl, and eight-feet up-and-go tests. When all the fitness tests were simultaneously considered, the back-scratch test was the only one independently associated with the total BDI-II score (P = 0.001; R(2) = 0.023). CONCLUSIONS: Although higher physical fitness was generally associated with lower symptoms of depression in women with FM, the observed associations were somewhat weak and inconsistent, differing from those previously observed in healthy adults. Further research to determine the clinical relevance of the association between physical fitness and depression in FM is warranted.

The adaptation of a Danish version of the Pain Self-Efficacy Questionnaire: reliability and construct validity in a population of patients with fibromyalgia in Denmark.

The aim of this study was to translate, culturally adapt and evaluate the psychometric properties of the Pain Self-Efficacy Questionnaire (PSEQ) in a population of patients with fibromyalgia in Denmark. The study sample included 102 patients diagnosed with fibromyalgia referred to a specialist clinic. The PSEQ was translated and adapted to a Danish setting using a standard stepwise forward-backward translation procedure, followed by initial testing and focus group interview. Reliability was examined by analysing internal consistency and test-retest agreement. Construct validity was examined by investigating dimensionality, targeting, local independence, category functioning and differential item functioning (DIF). Reliability was high: Cronbach's alpha 0.88, test-retest correlation 0.93, intraclass correlation coefficient (ICC) 0.89 and item-total correlations 0.44-0.70. Factor analyses and item response (IRT) models indicated unidimensionality, and the PSEQ-DK was well targeted to the sample. High interitem correlation was observed between two items, indicating local dependence, and item misfit and DIF were observed for a few items. However, the overall fit of the scale to a single-factor model and IRT models supported acceptable construct validity. The PSEQ-DK showed acceptable psychometric properties and can therefore represent a reliable and valid measure for evaluating self-efficacy in patients with fibromyalgia in Denmark.

Association of different levels of depressive symptoms with symptomatology, overall disease severity, and quality of life in women with fibromyalgia.

PURPOSE: This study examined the associations of different levels of depression with pain, sleep quality, fatigue, functional exercise capacity, overall fibromyalgia (FM) severity, and health-related quality of life (HRQoL) in women with FM. METHODS: A total of 451 women with FM participated in this cross-sectional study. Depressive symptoms (Beck Depression Inventory; BDI-II), pain intensity (numerical rating scale; NRS), pain sensitivity (algometry), sleep quality (Pittsburgh Sleep Quality Index), fatigue (Multidimensional Fatigue Inventory), functional exercise capacity (6-min walk test), FM severity (revised Fibromyalgia Impact Questionnaire), and HRQoL (SF-36) were assessed. RESULTS: Participants with severe depressive symptoms had significantly higher pain intensity (NRS = 1.1; 95 % CI 0.3-1.8), fatigue (12.6-units; 95 % CI 8.2-17.1) and overall FM severity (12.6-units; 95 % CI 11.4-23.7), as well as poorer sleep quality (3.2-units; 95 % CI 1.7-4.7) and mental component of HRQoL (-17.0-units; 95 % CI -21.0 to -12.9) than participants with minimal signs of depression. There was no association of signs of depression with pain sensitivity, exercise capacity, or the physical component of HRQoL (P > 0.05). CONCLUSIONS: These results extend current knowledge on the association of signs of depression with FM severity and quality of life in women with FM, and suggest that severity of depressive symptoms could potentially be a prognostic factor to be considered in future prospective intervention studies.

Association of Physical Fitness With Fibromyalgia Severity in Women: The al-Ándalus Project.

OBJECTIVES: To assess the association between physical fitness and fibromyalgia (FM) severity in women with FM as well as to assess whether different fitness components present an independent relation with FM severity. DESIGN: Population-based cross-sectional study. SETTING: University facilities and FM associations. PARTICIPANTS: Women with FM (N=444). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: FM severity was assessed with the Revised Fibromyalgia Impact Questionnaire (FIQR). Aerobic fitness (6-min walk test), muscle strength (handgrip, chair stand, and arm curl tests), flexibility (chair sit and reach and back scratch tests), and motor agility (8 foot Up and Go test) were measured with the Senior Fitness Test battery and digital dynamometry. A standardized composite score (hereafter "global fitness profile") was calculated and divided into quintiles. RESULTS: Overall, physical fitness was significantly associated with the FIQR total and subscale scores, regardless of the fitness test used (all P<.05). The 6-minute walk and back-scratch tests were independently associated with the FIQR total score (R(2)=.88; both P<.005). The group with the highest global fitness profile had 16% lower FM severity than did the group with the lowest global fitness profile (P<.001). CONCLUSIONS: Our results suggest that higher physical fitness is consistently associated with lower FM severity in women with FM. Aerobic fitness and flexibility present independent associations with FM severity. However, the FIQR variability explained by these fitness tests was rather low (<10%), and further research on the potential disagreement between performance-based physical fitness and different self-reported outcomes in women with FM is warranted.

Health inequities and societal costs for patients with fibromyalgia and their spouses: a Danish cohort study.

OBJECTIVE: To assess the burden of illness of people with fibromyalgia (FM) and their spouses compared with selected match populations in Denmark. METHODS: Population-based, cohort case-control study using data from Danish registries from 1994 to 2021. Individuals with an FM diagnosis were identified from the National Patient Register (2008-2019) and randomly matched to a 1:4 general population comparator. Spouses or persons co-living with subjects with FM at the time of diagnosis were compared with matched comparator spouses. Healthcare and societal costs, socioeconomic status and occurrence of comorbidities were evaluated for subjects with FM, spouses and controls. RESULTS: 9712 subjects with FM (94.9% females, mean age 50 years) and 5946 spouses were included. At year of diagnosis, subjects with FM had significantly more comorbidities compared with controls, including significantly more comorbid rheumatic disorders. The highest risk at the time of FM diagnosis was a comorbid diagnosis of ankylosing spondylitis (OR 7.0, 95% CI 4.9 to 10.0). Significantly more comorbidities were also observed in spouses. Subjects with FM and spouses had higher healthcare and public transfer costs and lower income from employment at all timepoints. Loss of income from employment in subjects with FM occurred years before establishment of the FM diagnosis. The employment rate after diagnosis was 22%. 10 years after the FM diagnosis, 50% received disability pension as compared with 11% of matched controls. The observed net average increased societal cost for subjects with FM amounted to €27 193 per patient-year after diagnosis. CONCLUSION: FM has major health and socioeconomic consequences for patients, their partners and society and call for improved healthcare strategies matching patients' needs.

Naltrexone 6 mg once daily versus placebo in women with fibromyalgia: a randomised, double-blind, placebo-controlled trial.

BACKGROUND: Low-dose naltrexone is used to treat fibromyalgia despite minimal evidence for its efficacy. This trial aimed to investigate whether 12-week treatment with 6 mg low-dose naltrexone was superior to placebo for reducing pain in women with fibromyalgia. METHODS: We did a single-centre, randomised, double-blind, placebo-controlled trial in Denmark. We enrolled women aged 18-64 years who were diagnosed with fibromyalgia. Participants were randomly assigned 1:1 to receive low-dose naltrexone (6 mg) or an identical-appearing placebo, using a computerised algorithm with no stratifications applied. Participants, investigators, outcome assessors, and statistical analysts were all masked to treatment allocation. The primary outcome was change in pain intensity on an 11-point numeric rating scale from baseline to week 12, in the intention-to-treat population. Safety was assessed in participants in the intention-to-treat population who received at least one dose of their allocated intervention. This trial was registered with ClincalTrials.gov (NCT04270877) and EudraCT (2019-000702-30). FINDINGS: We screened 158 participants for eligibility from Jan 6, 2021, to Dec 27, 2022, and 99 patients were randomly assigned to low-dose naltrexone (n=49) or placebo (n=50). The mean age was 50·6 years (SD 8·8), one (1%) of 99 participants was Arctic Asian and 98 (99%) were White. No participants were lost to follow-up. The mean change in pain intensity was -1·3 points (95% CI -1·7 to -0·8) in the low-dose naltrexone group and -0·9 (-1·4 to -0·5) in the placebo group, corresponding to a between-group difference of -0·34 (-0·95 to 0·27; p=0·27, Cohen's d 0·23). Discontinuations due to adverse events were four (8%) of 49 in the low-dose naltrexone group and three (6%) of 50 in the placebo group. 41 (84%) of 49 patients in the low-dose naltrexone group had an adverse event versus 43 (86%) of 50 in the placebo group. One serious adverse event occurred in the placebo group and no deaths occurred. INTERPRETATION: This study did not show that treatment with low-dose naltrexone was superior to placebo in relieving pain. Our results indicate that low-dose naltrexone might improve memory problems associated with fibromyalgia, and we suggest that future trials investigate this further. FUNDING: The Danish Rheumatism Association, Odense University Hospital, Danielsen's Foundation, and the Oak Foundation.

Muscle fatigue in fibromyalgia is in the brain, not in the muscles: a case-control study of perceived versus objective muscle fatigue.

OBJECTIVE: To investigate relationships between perceived and objectively measured muscle fatigue during exhausting muscle contractions in women with fibromyalgia (FM) compared with healthy controls (HC). METHODS: Women with FM and HC completed an isometric muscle exhaustion task at 90° shoulder abduction. Surface electromyographic (EMG) activity in the deltoid muscle was recorded together with self-reported level of muscle fatigue. RESULTS: 25 participants with FM and 23 HC were included. Average time to exhaustion was 254 s shorter in participants with FM than in HC. Participants with FM did not exhibit the same level of objective signs of muscle fatigue, seen as fewer changes in the EMG activity, as the HC during the exhaustion task. The task did not provoke pain in the HC, while participants with FM reported a doubling of pain. CONCLUSIONS: Women with FM had shorter exhaustion times and showed fewer objective signs of muscle fatigue during an exhausting isometric shoulder abduction compared with younger HC. This indicates that perceived muscle fatigue may be of central origin and supports the notion of central nervous dysfunction as basic pathological changes in FM.

Assessment of pressure-pain thresholds and central sensitization of pain in lateral epicondylalgia.

OBJECTIVE.: To assess pain sensitivity and spreading hyperalgesia in lateral epicondylalgia (LE). SUBJECTS.: Twenty-two women with LE, and 38 controls were included. OUTCOME MEASURES.: Computerized cuff pressure algometry was used for assessment of pressure-pain threshold and tolerance. The stimulus was applied using a single (stimulation-area: 241 cm(2) ) or double-chambered (stimulation-area: 482 cm(2) ) tourniquet on the arm and leg. Spatial summation was expressed as the ratio between pressure-pain thresholds to single and double cuff-chamber stimulation. During 10-minute constant pressure stimulation at intensity relative to the individual pain threshold, the pain intensity was continuously recorded using an electronic visual analogue scale (VAS), and from this the degree of temporal summation was estimated. For LE, a Doppler ultrasound examination of the elbow was made to identify inflammation. RESULTS.: In LE compared with controls the pressure-pain threshold and tolerance were on average reduced by respectively 31% (nonsignificant) and 18% (nonsignificant) on the lower arm and by 32% (P < 0.05) and 22% (P < 0.05) on the lower leg (spreading sensitization). Within the LE group, pressure-pain thresholds were on average reduced by 20% (P < 0.05) and pain tolerance by 10% (nonsignificant) on the painful compared with the asymptomatic side. Spatial summation (P < 0.01) and temporal summation (P < 0.05) was facilitated in LE compared with controls. In LE patients without signs of peripheral inflammation assessed by Doppler ultrasound, temporal summation was significantly stronger than in patients with ongoing inflammation (P < 0.01). CONCLUSION.: Patients with LE may be subgrouped based on pain hypersensitivity and Doppler ultrasound into clinically meaningful subgroups with varying duration of symptoms and different degrees of central sensitization. These groups may require different pain management strategies.

How a group-based occupational therapy program works in woman with fibromyalgia: A process evaluation of the ADAPT program.

BACKGROUND: The ADAPT Program have improved activities of daily living (ADL) in women with fibromyalgia. To understand the functioning of the program, it is relevant to evaluate how program theory components are linked to outcomes (mechanisms) and how the randomised controlled trial (RCT) context, influenced delivery and outcomes. OBJECTIVE: To evaluate ADAPT in terms of dose, mechanisms of change and contextual factors. MATERIAL/METHODS: Dose was recorded on the n = 21 participants receiving ADAPT in the IMPROvE trial (NCT01352052). A subsample of n = 16 attended one of three 2-hour focusgroups, evaluating mechanisms of change and contextual factors. Interview questions explored participants' interaction with four program components, i.e. how the 'client-centred approach', 'group-based peer-exchange format', 'teaching-learning strategies' and 'long-term program format' triggered mechanisms facilitating/hindering outcomes. Moreover, how randomisation procedures influenced delivery and outcomes. RESULTS: Attending a long-term educational peer-exchange program, in which participants experienced met by a health professional that legitimised difficulties, facilitated participants knowledge, insights and motivation for changing habits. With time and support, participants experienced increased acceptance of their situation and began to implement more effective ways to perform ADL tasks. CONCLUSIONS/SIGNIFICANCE: Results support previous findings of improved ADL ability post-ADAPT and provide initial evidence to support the ADAPT Program theory.

Biopsychosocial Rehabilitation for Inflammatory Arthritis and Osteoarthritis Patients: A Systematic Review and Meta-Analysis of Randomized Trials.

OBJECTIVE: To assess the benefits and harms associated with biopsychosocial rehabilitation in patients with inflammatory arthritis and osteoarthritis (OA). METHODS: We performed a systematic review and meta-analysis. Data were collected through electronic searches of Cochrane CENTRAL, MEDLINE, Embase, PsycInfo, and CINAHL databases up to March 2019. Trials examining the effect of biopsychosocial rehabilitation in adults with inflammatory arthritis and/or OA were considered eligible, excluding rehabilitation adjunct to surgery. The primary outcome for benefit was pain and total withdrawals for harm. RESULTS: Of the 27 trials meeting the eligibility criteria, 22 trials (3,750 participants) reported sufficient data to be included in the quantitative synthesis. For patient-reported outcome measures, biopsychosocial rehabilitation was slightly superior to control for pain relief (standardized mean difference [SMD] -0.19 [95% confidence interval (95% CI) -0.31, -0.07]), had a small effect on patient global assessment score (SMD -0.13 [95% CI -0.26, -0.00]), with no apparent effect on health-related quality of life, fatigue, self-reported disability/physical function, mental well-being, and reduction in pain intensity ≥30%. Clinician-measured outcomes displayed a small effect on observed disability/physical function (SMD -0.34 [95% CI -0.57, -0.10]), a large effect on physician global assessment score (SMD -0.72 [95% CI -1.18, -0.26]), and no effect on inflammation. No difference in harms existed in terms of the number of withdrawals, adverse events, or serious adverse events. CONCLUSION: Biopsychosocial rehabilitation produces a significant but clinically small beneficial effect on patient-reported pain among patients with inflammatory arthritis and OA, with no difference in harm. Methodologic weaknesses were observed in the included trials, suggesting low-to-moderate confidence in the estimates of effect.

Neurophysiological and psychosocial mechanisms of fibromyalgia: A comprehensive review and call for an integrative model.

Research into the neurobiological and psychosocial mechanisms involved in fibromyalgia has progressed remarkably in recent years. Despite this, current accounts of fibromyalgia fail to capture the complex, dynamic, and mutual crosstalk between neurophysiological and psychosocial domains. We conducted a comprehensive review of the existing literature in order to: a) synthesize current knowledge on fibromyalgia; b) explore and highlight multi-level links and pathways between different systems; and c) build bridges connecting disparate perspectives. An extensive panel of international experts in neurophysiological and psychosocial aspects of fibromyalgia discussed the collected evidence and progressively refined and conceptualized its interpretation. This work constitutes an essential step towards the development of a model capable of integrating the main factors implicated in fibromyalgia into a single, unified construct which appears indispensable to foster the understanding, assessment, and intervention for fibromyalgia.

Emotion regulation and the salience network: a hypothetical integrative model of fibromyalgia.

Fibromyalgia is characterized by widespread pain, fatigue, sleep disturbances and other symptoms, and has a substantial socioeconomic impact. Current biomedical and psychosocial treatments are unsatisfactory for many patients, and treatment progress has been hindered by the lack of a clear understanding of the pathogenesis of fibromyalgia. We present here a model of fibromyalgia that integrates current psychosocial and neurophysiological observations. We propose that an imbalance in emotion regulation, reflected by an overactive 'threat' system and underactive 'soothing' system, might keep the 'salience network' (also known as the midcingulo-insular network) in continuous alert mode, and this hyperactivation, in conjunction with other mechanisms, contributes to fibromyalgia. This proposed integrative model, which we term the Fibromyalgia: Imbalance of Threat and Soothing Systems (FITSS) model, should be viewed as a working hypothesis with limited supporting evidence available. We hope, however, that this model will shed new light on existing psychosocial and biological observations, and inspire future research to address the many gaps in our knowledge about fibromyalgia, ultimately stimulating the development of novel therapeutic interventions.