The aim of our meta-analysis was to compile the available evidence to evaluate the effect of physical exercise-based therapy (PEBT) on pain, impact of the disease, quality of life (QoL) and anxiety in patients with fibromyalgia syndrome (FMS), to determine the effect of different modes of physical exercise-based therapy, and the most effective dose of physical exercise-based therapy for improving each outcome. A systematic review and meta-analysis was carried out. The PubMed (MEDLINE), SCOPUS, Web of Science, CINAHL Complete and Physiotherapy Evidence Database (PEDro) databases were searched up to November 2022. Randomized controlled trials (RCTs) comparing the effects of physical exercise-based therapy and other treatments on pain, the impact of the disease, QoL and/or anxiety in patients with FMS were included. The standardized mean difference (SMD) and a 95% CI were estimated for all the outcome measures using random effect models. Three reviewers independently extracted data and assessed the risk of bias using the PEDro scale. Sixty-eight RCTs involving 5,474 participants were included. Selection, detection and performance biases were the most identified. In comparison to other therapies, at immediate assessment, physical exercise-based therapy was effective at improving pain [SMD-0.62 (95%CI, -0.78 to -0.46)], the impact of the disease [SMD-0.52 (95%CI, -0.67 to -0.36)], the physical [SMD 0.51 (95%CI, 0.33 to 0.69)] and mental dimensions of QoL [SMD 0.48 (95%CI, 0.29 to 0.67)], and the anxiety [SMD-0.36 (95%CI, -0.49 to -0.25)]. The most effective dose of physical exercise-based therapy for reducing pain was 21-40 sessions [SMD-0.83 (95%CI, 1.1--0.56)], 3 sessions/week [SMD-0.82 (95%CI, -1.2--0.48)] and 61-90 min per session [SMD-1.08 (95%CI, -1.55--0.62)]. The effect of PEBT on pain reduction was maintained up to 12 weeks [SMD-0.74 (95%CI, -1.03--0.45)]. Among patients with FMS, PEBT (including circuit-based exercises or exercise movement techniques) is effective at reducing pain, the impact of the disease and anxiety as well as increasing QoL. Systematic Review Registration: PROSPERO https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42021232013.
BACKGROUND: Chronic pain is common in adults, and often has a detrimental impact upon physical ability, well-being, and quality of life. Previous reviews have shown that certain antidepressants may be effective in reducing pain with some benefit in improving patients' global impression of change for certain chronic pain conditions. However, there has not been a network meta-analysis (NMA) examining all antidepressants across all chronic pain conditions.
OBJECTIVES: To assess the comparative efficacy and safety of antidepressants for adults with chronic pain (except headache).
SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, CINAHL, LILACS, AMED and PsycINFO databases, and clinical trials registries, for randomised controlled trials (RCTs) of antidepressants for chronic pain conditions in January 2022.
SELECTION CRITERIA: We included RCTs that examined antidepressants for chronic pain against any comparator. If the comparator was placebo, another medication, another antidepressant, or the same antidepressant at different doses, then we required the study to be double-blind. We included RCTs with active comparators that were unable to be double-blinded (e.g. psychotherapy) but rated them as high risk of bias. We excluded RCTs where the follow-up was less than two weeks and those with fewer than 10 participants in each arm. DATA COLLECTION AND ANALYSIS: Two review authors separately screened, data extracted, and judged risk of bias. We synthesised the data using Bayesian NMA and pairwise meta-analyses for each outcome and ranked the antidepressants in terms of their effectiveness using the surface under the cumulative ranking curve (SUCRA). We primarily used Confidence in Meta-Analysis (CINeMA) and Risk of Bias due to Missing Evidence in Network meta-analysis (ROB-MEN) to assess the certainty of the evidence. Where it was not possible to use CINeMA and ROB-MEN due to the complexity of the networks, we used GRADE to assess the certainty of the evidence. Our primary outcomes were substantial (50%) pain relief, pain intensity, mood, and adverse events. Our secondary outcomes were moderate pain relief (30%), physical function, sleep, quality of life, Patient Global Impression of Change (PGIC), serious adverse events, and withdrawal.
MAIN RESULTS: This review and NMA included 176 studies with a total of 28,664 participants. The majority of studies were placebo-controlled (83), and parallel-armed (141). The most common pain conditions examined were fibromyalgia (59 studies); neuropathic pain (49 studies) and musculoskeletal pain (40 studies). The average length of RCTs was 10 weeks. Seven studies provided no useable data and were omitted from the NMA. The majority of studies measured short-term outcomes only and excluded people with low mood and other mental health conditions. Across efficacy outcomes, duloxetine was consistently the highest-ranked antidepressant with moderate- to high-certainty evidence. In duloxetine studies, standard dose was equally efficacious as high dose for the majority of outcomes. Milnacipran was often ranked as the next most efficacious antidepressant, although the certainty of evidence was lower than that of duloxetine. There was insufficient evidence to draw robust conclusions for the efficacy and safety of any other antidepressant for chronic pain. Primary efficacy outcomes Duloxetine standard dose (60 mg) showed a small to moderate effect for substantial pain relief (odds ratio (OR) 1.91, 95% confidence interval (CI) 1.69 to 2.17; 16 studies, 4490 participants; moderate-certainty evidence) and continuous pain intensity (standardised mean difference (SMD) -0.31, 95% CI -0.39 to -0.24; 18 studies, 4959 participants; moderate-certainty evidence). For pain intensity, milnacipran standard dose (100 mg) also showed a small effect (SMD -0.22, 95% CI -0.39 to 0.06; 4 studies, 1866 participants; moderate-certainty evidence). Mirtazapine (30 mg) had a moderate effect on mood (SMD -0.5, 95% CI -0.78 to -0.22; 1 study, 406 participants; low-certainty evidence), while duloxetine showed a small effect (SMD -0.16, 95% CI -0.22 to -0.1; 26 studies, 7952 participants; moderate-certainty evidence); however it is important to note that most studies excluded participants with mental health conditions, and so average anxiety and depression scores tended to be in the 'normal' or 'subclinical' ranges at baseline already. Secondary efficacy outcomes Across all secondary efficacy outcomes (moderate pain relief, physical function, sleep, quality of life, and PGIC), duloxetine and milnacipran were the highest-ranked antidepressants with moderate-certainty evidence, although effects were small. For both duloxetine and milnacipran, standard doses were as efficacious as high doses. Safety There was very low-certainty evidence for all safety outcomes (adverse events, serious adverse events, and withdrawal) across all antidepressants. We cannot draw any reliable conclusions from the NMAs for these outcomes.
AUTHORS' CONCLUSIONS: Our review and NMAs show that despite studies investigating 25 different antidepressants, the only antidepressant we are certain about for the treatment of chronic pain is duloxetine. Duloxetine was moderately efficacious across all outcomes at standard dose. There is also promising evidence for milnacipran, although further high-quality research is needed to be confident in these conclusions. Evidence for all other antidepressants was low certainty. As RCTs excluded people with low mood, we were unable to establish the effects of antidepressants for people with chronic pain and depression. There is currently no reliable evidence for the long-term efficacy of any antidepressant, and no reliable evidence for the safety of antidepressants for chronic pain at any time point.
BACKGROUND: Chronic non-cancer pain, a disabling and distressing condition, is common in adults. It is a global public health problem and economic burden on health and social care systems and on people with chronic pain. Psychological treatments aim to reduce pain, disability and distress. This review updates and extends its previous version, published in 2012.
OBJECTIVES: To determine the clinical efficacy and safety of psychological interventions for chronic pain in adults (age > 18 years) compared with active controls, or waiting list/treatment as usual (TAU).
SEARCH METHODS: We identified randomised controlled trials (RCTs) of psychological therapies by searching CENTRAL, MEDLINE, Embase and PsycINFO to 16 April 2020. We also examined reference lists and trial registries, and searched for studies citing retrieved trials.
SELECTION CRITERIA: RCTs of psychological treatments compared with active control or TAU of face-to-face therapies for adults with chronic pain. We excluded studies of headache or malignant disease, and those with fewer than 20 participants in any arm at treatment end.
DATA COLLECTION AND ANALYSIS: Two or more authors rated risk of bias, extracted data, and judged quality of evidence (GRADE). We compared cognitive behavioural therapy (CBT), behavioural therapy (BT), and acceptance and commitment therapy (ACT) with active control or TAU at treatment end, and at six month to 12 month follow-up. We did not analyse the few trials of other psychological treatments. We assessed treatment effectiveness for pain intensity, disability, and distress. We extracted data on adverse events (AEs) associated with treatment.
MAIN RESULTS: We added 41 studies (6255 participants) to 34 of the previous review's 42 studies, and now have 75 studies in total (9401 participants at treatment end). Most participants had fibromyalgia, chronic low back pain, rheumatoid arthritis, or mixed chronic pain. Most risk of bias domains were at high or unclear risk of bias, with selective reporting and treatment expectations mostly at unclear risk of bias. AEs were inadequately recorded and/or reported across studies. CBT The largest evidence base was for CBT (59 studies). CBT versus active control showed very small benefit at treatment end for pain (standardised mean difference (SMD) -0.09, 95% confidence interval (CI) -0.17 to -0.01; 3235 participants; 23 studies; moderate-quality evidence), disability (SMD -0.12, 95% CI -0.20 to -0.04; 2543 participants; 19 studies; moderate-quality evidence), and distress (SMD -0.09, 95% CI -0.18 to -0.00; 3297 participants; 24 studies; moderate-quality evidence). We found small benefits for CBT over TAU at treatment end for pain (SMD -0.22, 95% CI -0.33 to -0.10; 2572 participants; 29 studies; moderate-quality evidence), disability (SMD -0.32, 95% CI -0.45 to -0.19; 2524 participants; 28 studies; low-quality evidence), and distress (SMD -0.34, 95% CI -0.44 to -0.24; 2559 participants; 27 studies; moderate-quality evidence). Effects were largely maintained at follow-up for CBT versus TAU, but not for CBT versus active control. Evidence quality for CBT outcomes ranged from moderate to low. We rated evidence for AEs as very low quality for both comparisons. BT We analysed eight studies (647 participants). We found no evidence of difference between BT and active control at treatment end (pain SMD -0.67, 95% CI -2.54 to 1.20, very low-quality evidence; disability SMD -0.65, 95% CI -1.85 to 0.54, very low-quality evidence; or distress SMD -0.73, 95% CI -1.47 to 0.01, very low-quality evidence). At follow-up, effects were similar. We found no evidence of difference between BT and TAU (pain SMD -0.08, 95% CI -0.33 to 0.17, low-quality evidence; disability SMD -0.02, 95% CI -0.24 to 0.19, moderate-quality evidence; distress SMD 0.22, 95% CI -0.10 to 0.54, low-quality evidence) at treatment end. At follow-up, we found one to three studies with no evidence of difference between BT and TAU. We rated evidence for all BT versus active control outcomes as very low quality; for BT versus TAU. Evidence quality ranged from moderate to very low. We rated evidence for AEs as very low quality for BT versus active control. No studies of BT versus TAU reported AEs. ACT We analysed five studies (443 participants). There was no evidence of difference between ACT and active control for pain (SMD -0.54, 95% CI -1.20 to 0.11, very low-quality evidence), disability (SMD -1.51, 95% CI -3.05 to 0.03, very low-quality evidence) or distress (SMD -0.61, 95% CI -1.30 to 0.07, very low-quality evidence) at treatment end. At follow-up, there was no evidence of effect for pain or distress (both very low-quality evidence), but two studies showed a large benefit for reducing disability (SMD -2.56, 95% CI -4.22 to -0.89, very low-quality evidence). Two studies compared ACT to TAU at treatment end. Results should be interpreted with caution. We found large benefits of ACT for pain (SMD -0.83, 95% CI -1.57 to -0.09, very low-quality evidence), but none for disability (SMD -1.39, 95% CI -3.20 to 0.41, very low-quality evidence), or distress (SMD -1.16, 95% CI -2.51 to 0.20, very low-quality evidence). Lack of data precluded analysis at follow-up. We rated evidence quality for AEs to be very low. We encourage caution when interpreting very low-quality evidence because the estimates are uncertain and could be easily overturned.
AUTHORS' CONCLUSIONS: We found sufficient evidence across a large evidence base (59 studies, over 5000 participants) that CBT has small or very small beneficial effects for reducing pain, disability, and distress in chronic pain, but we found insufficient evidence to assess AEs. Quality of evidence for CBT was mostly moderate, except for disability, which we rated as low quality. Further trials may provide more precise estimates of treatment effects, but to inform improvements, research should explore sources of variation in treatment effects. Evidence from trials of BT and ACT was of moderate to very low quality, so we are very uncertain about benefits or lack of benefits of these treatments for adults with chronic pain; other treatments were not analysed. These conclusions are similar to our 2012 review, apart from the separate analysis of ACT.
BACKGROUND: This is an updated version of the original Cochrane review published in Issue 12, 2012. That review considered both fibromyalgia and neuropathic pain, but the efficacy of amitriptyline for neuropathic pain is now dealt with in a separate review.Amitriptyline is a tricyclic antidepressant that is widely used to treat fibromyalgia, and is recommended in many guidelines. It is usually used at doses below those at which the drugs act as antidepressants.
OBJECTIVES: To assess the analgesic efficacy of amitriptyline for relief of fibromyalgia, and the adverse events associated with its use in clinical trials.
SEARCH METHODS: We searched CENTRAL, MEDLINE, and EMBASE to March 2015, together with reference lists of retrieved papers, previous systematic reviews and other reviews, and two clinical trial registries. We also used our own hand searched database for older studies.
SELECTION CRITERIA: We included randomised, double-blind studies of at least four weeks' duration comparing amitriptyline with placebo or another active treatment in fibromyalgia.
DATA COLLECTION AND ANALYSIS: We extracted efficacy and adverse event data, and two study authors examined issues of study quality independently. We performed analysis using three tiers of evidence. First tier evidence derived from data meeting current best standards and subject to minimal risk of bias (outcome equivalent to substantial pain intensity reduction, intention-to-treat analysis without imputation for dropouts; at least 200 participants in the comparison, 8 to 12 weeks duration, parallel design), second tier from data that failed to meet one or more of these criteria and were considered at some risk of bias but with adequate numbers in the comparison, and third tier from data involving small numbers of participants that were considered very likely to be biased or used outcomes of limited clinical utility, or both.For efficacy, we calculated the number needed to treat to benefit (NNT), and for harm we calculated the number needed to treat to harm (NNH) for adverse events and withdrawals. We used a fixed-effect model for meta-analysis.
MAIN RESULTS: We included seven studies from the earlier review and two new studies (nine studies, 649 participants) of 6 to 24 weeks' duration, enrolling between 22 and 208 participants; none had 50 or more participants in each treatment arm. Two studies used a cross-over design. The daily dose of amitriptyline was 25 mg to 50 mg, and some studies had an initial titration period.There was no first or second tier evidence for amitriptyline in the treatment of fibromyalgia. Using third tier evidence the risk ratio (RR) for at least 50% pain relief, or equivalent, with amitriptyline compared with placebo was 3.0 (95% confidence interval (CI) 1.7 to 4.9), with an NNT) of 4.1 (2.9 to 6.7) (very low quality evidence). There were no consistent differences between amitriptyline and placebo or other active comparators for relief of symptoms such as fatigue, poor sleep, quality of life, or tender points.More participants experienced at least one adverse event with amitriptyline (78%) than with placebo (47%). The RR was 1.5 (1.3 to 1.8) and the NNH was 3.3 (2.5 to 4.9). Adverse event and all-cause withdrawals were not different, but lack of efficacy withdrawals were more common with placebo (12% versus 5%; RR 0.42 (0.19 to 0.95)) (very low quality evidence).
AUTHORS' CONCLUSIONS: Amitriptyline has been a first-line treatment for fibromyalgia for many years. The fact that there is no supportive unbiased evidence for a beneficial effect is disappointing, but has to be balanced against years of successful treatment in many patients with fibromyalgia. There is no good evidence of a lack of effect; rather our concern should be of overestimation of treatment effect. Amitriptyline will be one option in the treatment of fibromyalgia, while recognising that only a minority of patients will achieve satisfactory pain relief.It is unlikely that any large randomised trials of amitriptyline will be conducted in fibromyalgia to establish efficacy statistically, or measure the size of the effect.
Objectives. Acupuncture is often used for relieving symptoms of fibromyalgia syndrome (FMS). Our aim is to ascertain whether verum acupuncture is more effective than sham acupuncture in FMS. Methods. We collected RCTs to investigate the effects of verum acupuncture and sham acupuncture on pain, sleep quality, fatigue, and general status in FMS patients. The databases used for data retrieval were PubMed, Central Cochrane, EMBASE, PsycINFO, CNKI, VIP, OASIS, KoreaMed, and RISS. Selection/exclusion from the retrieved records was performed according to prespecified criteria, and the final selected records were assessed according to the Cochrane risk of bias tool. The results of the included trials were synthesized on the basis of outcomes, and subgroup analysis depended on the type of add-on sham acupuncture that was performed. Results. Ten RCTs (690 participants) were eligible, and eight RCTs were eventually included in the meta-analysis. The synthesis showed a sizable effect of verum acupuncture compared with sham acupuncture on pain relief (standardized mean difference (SMD) -0.49, Z = 3.26, P=0.001; I2 = 59%), improving sleep quality (SMD -0.46, Z = 3.24, P=0.001; I2 = 0%), and reforming general status (SMD -0.69, Z = 6.27, P<0.00001; I2 = 4%). However, efficacy on fatigue was insignificant (SMD -0.10, Z = 0.51, P=0.61; I2 = 46%). When compared with a combination of simulation and improper location of needling, the effect of verum acupuncture for pain relief was the most obvious. Conclusions. Verum acupuncture is more effective than sham acupuncture for pain relief, improving sleep quality, and reforming general status in FMS posttreatment. However, evidence that it reduces fatigue was not found.
OBJECTIVES: Many interventions are available to manage chronic pain; understanding the durability of treatment effects may assist with treatment selection. We sought to assess which noninvasive nonpharmacological treatments for selected chronic pain conditions are associated with persistent improvement in function and pain outcomes at least 1 month after the completion of treatment.
DATA SOURCES: Electronic databases (Ovid MEDLINE®, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews) through November 2017, reference lists, and ClinicalTrials.gov.
REVIEW METHODS: Using predefined criteria, we selected randomized controlled trials of noninvasive nonpharmacological treatments for five common chronic pain conditions (chronic low back pain; chronic neck pain; osteoarthritis of the knee, hip, or hand; fibromyalgia; and tension headache) that addressed efficacy or harms compared with usual care, no treatment, waitlist, placebo, or sham intervention; compared with pharmacological therapy; or compared with exercise. Study quality was assessed, data extracted, and results summarized for function and pain. Only trials reporting results for at least 1 month post-intervention were included. We focused on the persistence of effects at short term (1 to <6 months following treatment completion), intermediate term (≥6 to <12 months), and long term (≥12 months).
RESULTS: Two hundred eighteen publications (202 trials) were included. Many included trials were small. Evidence on outcomes beyond 1 year after treatment completion was sparse. Most trials enrolled patients with moderate baseline pain intensity (e.g., >5 on a 0 to 10 point numeric rating scale) and duration of symptoms ranging from 3 months to >15 years. The most common comparison was against usual care. Chronic low back pain: At short term, massage, yoga, and psychological therapies (primarily CBT) (strength of evidence [SOE]: moderate) and exercise, acupuncture, spinal manipulation, and multidisciplinary rehabilitation (SOE: low) were associated with slight improvements in function compared with usual care or inactive controls. Except for spinal manipulation, these interventions also improved pain. Effects on intermediate-term function were sustained for yoga, spinal manipulation, multidisciplinary rehabilitation (SOE: low), and psychological therapies (SOE: moderate). Improvements in pain continued into intermediate term for exercise, massage, and yoga (moderate effect, SOE: low); mindfulness-based stress reduction (small effect, SOE: low); spinal manipulation, psychological therapies, and multidisciplinary rehabilitation (small effects, SOE: moderate). For acupuncture, there was no difference in pain at intermediate term, but a slight improvement at long term (SOE: low). Psychological therapies were associated with slightly greater improvement than usual care or an attention control on both function and pain at short-term, intermediate-term, and long-term followup (SOE: moderate). At short and intermediate term, multidisciplinary rehabilitation slightly improved pain compared with exercise (SOE: moderate). High-intensity multidisciplinary rehabilitation (≥20 hours/week or >80 hours total) was not clearly better than non–high-intensity programs. Chronic neck pain: At short and intermediate terms, acupuncture and Alexander Technique were associated with slightly improved function compared with usual care (both interventions), sham acupuncture, or sham laser (SOE: low), but no improvement in pain was seen at any time (SOE: llow). Short-term low-level laser therapy was associated with moderate improvement in function and pain (SOE: moderate). Combination exercise (any 3 of the following: muscle performance, mobility, muscle re-education, aerobic) demonstrated a slight improvement in pain and function short and long term (SOE: low). Osteoarthritis: For knee osteoarthritis, exercise and ultrasound demonstrated small short-term improvements in function compared with usual care, an attention control, or sham procedure (SOE: moderate for exercise, low for ultrasound), which persisted into the intermediate term only for exercise (SOE: low). Exercise was also associated with moderate improvement in pain (SOE: low). Long term, the small improvement in function seen with exercise persisted, but there was no clear effect on pain (SOE: low). Evidence was sparse on interventions for hip and hand osteoarthritis . Exercise for hip osteoarthritis was associated with slightly greater function and pain improvement than usual care short term (SOE: low). The effect on function was sustained intermediate term (SOE: low). Fibromyalgia: In the short term, acupuncture (SOE: moderate), CBT, tai chi, qigong, and exercise (SOE: low) were associated with slight improvements in function compared with an attention control, sham, no treatment, or usual care. Exercise (SOE: moderate) and CBT improved pain slightly, and tai chi and qigong (SOE: low) improved pain moderately in the short term. At intermediate term for exercise (SOE: moderate), acupuncture, and CBT (SOE: low), slight functional improvements persisted; they were also seen for myofascial release massage and multidisciplinary rehabilitation (SOE: low); pain was improved slightly with multidisciplinary rehabilitation in the intermediate term (SOE: low). In the long term, small improvements in function continued for multidisciplinary rehabilitation but not for exercise or massage (SOE: low for all); massage (SOE: low) improved long-term pain slightly, but no clear impact on pain for exercise (SOE: moderate) or multidisciplinary rehabilitation (SOE: low) was seen. Short-term CBT was associated with a slight improvement in function but not pain compared with pregabalin. Chronic tension headache: Evidence was sparse and the majority of trials were of poor quality. Spinal manipulation slightly improved function and moderately improved pain short term versus usual care, and laser acupuncture was associated with slight pain improvement short term compared with sham (SOE: low). There was no evidence suggesting increased risk for serious treatment-related harms for any of the interventions, although data on harms were limited.
CONCLUSIONS: Exercise, multidisciplinary rehabilitation, acupuncture, CBT, and mind-body practices were most consistently associated with durable slight to moderate improvements in function and pain for specific chronic pain conditions. Our findings provided some support for clinical strategies that focused on use of nonpharmacological therapies for specific chronic pain conditions. Additional comparative research on sustainability of effects beyond the immediate post-treatment period is needed, particularly for conditions other than low back pain.
BACKGROUND: Fibromyalgia is a chronic widespread pain condition affecting millions of people worldwide. Current pharmacotherapies are often ineffective and poorly tolerated. Combining different agents could provide superior pain relief and possibly also fewer side effects.
OBJECTIVES: To assess the efficacy, safety, and tolerability of combination pharmacotherapy compared to monotherapy or placebo, or both, for the treatment of fibromyalgia pain in adults.
SEARCH METHODS: We searched CENTRAL, MEDLINE, and Embase to September 2017. We also searched reference lists of other reviews and trials registries.
SELECTION CRITERIA: Double-blind, randomised controlled trials comparing combinations of two or more drugs to placebo or other comparators, or both, for the treatment of fibromyalgia pain.
DATA COLLECTION AND ANALYSIS: From all studies, we extracted data on: participant-reported pain relief of 30% or 50% or greater; patient global impression of clinical change (PGIC) much or very much improved or very much improved; any other pain-related outcome of improvement; withdrawals (lack of efficacy, adverse events), participants experiencing any adverse event, serious adverse events, and specific adverse events (e.g. somnolence and dizziness). The primary comparison was between combination and one or all single-agent comparators. We also assessed the evidence using GRADE and created a 'Summary of findings' table.
MAIN RESULTS: We identified 16 studies with 1474 participants. Three studies combined a non-steroidal anti-inflammatory drug (NSAID) with a benzodiazepine (306 participants); two combined amitriptyline with fluoxetine (89 participants); two combined amitriptyline with a different agent (92 participants); two combined melatonin with an antidepressant (164 participants); one combined carisoprodol, paracetamol (acetaminophen), and caffeine (58 participants); one combined tramadol and paracetamol (acetaminophen) (315 participants); one combined malic acid and magnesium (24 participants); one combined a monoamine oxidase inhibitor with 5-hydroxytryptophan (200 participants); and one combined pregabalin with duloxetine (41 participants). Six studies compared the combination of multiple agents with each component alone and with inactive placebo; three studies compared combination pharmacotherapy with each individual component but did not include an inactive placebo group; two studies compared the combination of two agents with only one of the agents alone; and three studies compared the combination of two or more agents only with inactive placebo.Heterogeneity among studies in terms of class of agents evaluated, specific combinations used, outcomes reported, and doses given prevented any meta-analysis. None of the combinations of drugs found provided sufficient data for analysis compared with placebo or other comparators for our preferred outcomes. We therefore provide a narrative description of results. There was no or inadequate evidence in any comparison for primary and secondary outcomes. Two studies only reported any primary outcomes of interest (patient-reported pain relief of 30%, or 50%, or greater). For each 'Risk of bias' item, only half or fewer of studies had unequivocal low risk of bias. Small size and selective reporting were common as high risk of bias.Our GRADE assessment was therefore very low for primary outcomes of pain relief of 30% or 50% or greater, PGIC much or very much improved or very much improved, any pain-related outcome, participants experiencing any adverse event, any serious adverse event, or withdrawing because of an adverse event.Three studies found some evidence that combination pharmacotherapy reduced pain compared to monotherapy; these trials tested three different combinations: melatonin and amitriptyline, fluoxetine and amitriptyline, and pregabalin and duloxetine. Adverse events experienced by participants were not serious, and where they were reported (in 12 out of 16 studies), all participants experienced them, regardless of treatment. Common adverse events were nausea, dizziness, somnolence, and headache.
AUTHORS' CONCLUSIONS: There are few, large, high-quality trials comparing combination pharmacotherapy with monotherapy for fibromyalgia, consequently limiting evidence to support or refute the use of combination pharmacotherapy for fibromyalgia.
BACKGROUND: Fibromyalgia (FM) is a syndrome whose primary symptoms include chronic widespread muscle pain and fatigue. The treatment of patients with FM aims to provide symptomatic relief and improvement in physical capacities to perform daily tasks and quality of life. Invasive or non-invasive electric stimulation (ES) is used for pain relief in patients with FM.
OBJECTIVE: This systematic review aimed to assess the effects of treatment with ES, combined or not combined with other types of therapy, for pain relief in patients with FM.
STUDY DESIGN: Systematic review and meta-analysis.
SETTING: Electronic search was conducted on databases (from the inception to April 2016): MEDLINE (accessed by PubMed), EMBASE, Cochrane Central Register of Controlled Trials (Cochrane CENTRAL), and Physiotherapy Evidence Database (PEDro).
METHODS: Two independent reviewers assessed the eligibility of studies based on the inclusion criteria: randomized controlled trials (RCTs) examining the effects of ES combined or not with other types of treatment for pain relief in patients with FM (according to the American College of Rheumatology), regardless of the ES dosages. The primary outcome was pain, assessed by the visual analogue scale (VAS). The secondary outcomes extracted were quality of life, assessed by short form-36 health survey (SF- 36), and fatigue, assessed by VAS.
RESULTS: Nine studies were included, with 301 patients. The meta-analysis for pain showed positive effect of ES treatment versus control [-1.24 (95% CI: -2.39 to -0.08; I²: 87%, P = 0.04) n = 8 RCTs]. The sensitivity analysis for pain showed significant results for invasive ES, combined or not with other types of therapy [-0.94 (95% CI, -1.50 to -0.38; I² 0%, P = 0.001) n = 3 RCTs]. No significant improvement was found regarding quality of life [-3.48 (95% CI: -12.58 to 5.62; I²: 0%, P = 0.45), n = 2 RCTs] or fatigue [-0.57 (95% CI, -1.25 to 0.11; I² 34%, P = 0.100; n = 4 RCTs].
LIMITATIONS: This systematic review included a small number of studies and reduced number of participants in each study. Furthermore, most of the studies showed some biases and lack of methodological quality.
CONCLUSIONS: This meta-analysis indicates that there is low-quality evidence for the effectiveness of ES for pain relief in patients with FM. However, moderate-quality evidence for the effectiveness of electroacupuncture (EA), combined or not combined with other types of treatment, was found for pain relief.
CLINICAL TRIAL REGISTRATION INFORMATION: PROSPERO under the identification CRD42015025323Key words: Electric stimulation, electroacupuncture, transcutaneous electric nerve stimulation, pain, fibromyalgia, review, physical therapy, rehabilitation.
IntroductionPrevious randomized controlled trials have led to conflicting findings regarding the effects of exercise on depressive symptoms in adults with arthritis and other rheumatic conditions (AORC). The purpose of this study was to use the meta-analytic approach to resolve these discrepancies.MethodsThe inclusion criteria were: (1) randomized controlled trials, (2) exercise (aerobic, strength training, or both) ¿4 weeks, (3) comparative control group, (4) adults with osteoarthritis, rheumatoid arthritis, fibromyalgia or systemic lupus erythematosus, (5) published and unpublished studies in any language since January 1, 1981 and (6) depressive symptoms assessed. Studies were located by searching 10 electronic databases, cross-referencing, hand searching and expert review. Dual-selection of studies and data abstraction was performed. Hedge¿s standardized mean difference effect size (g) was calculated for each result and pooled using random-effects models, an approach that accounts for heterogeneity. Non-overlapping 95% confidence intervals (CI) were considered statistically significant. Heterogeneity based on fixed-effect models was estimated using Q and I 2 with alpha values ¿0.10 for Q considered statistically significant.ResultsOf the 500 citations reviewed, 2,449 participants (1,470 exercise, 979 control) nested within 29 studies were included. Length of training, reported as mean¿±¿standard deviation (±SD) was 19¿±¿16 weeks, frequency 4¿±¿2 times per week and duration 34¿±¿17 minutes per session. Overall, statistically significant exercise minus control group reductions were found for depressive symptoms (g¿=¿¿0.42, 95% CI, ¿0.58, ¿0.26, Q¿=¿126.9, P <0.0001, I 2 ¿=¿73.2%). The number needed-to-treat was 7 (95% CI, 6 to 11) with an estimated 3.1 million (95% CI, 2.0 to 3.7) United States adults not currently meeting physical activity guidelines improving their depressive symptoms if they began and maintained a regular exercise program. Using Cohen¿s U3 Index, the percentile reduction was 16.4% (95% CI, 10.4% to 21.9%). All studies were considered to be at high risk of bias with respect to blinding of participants and personnel to group assignment.ConclusionsExercise is associated with reductions in depressive symptoms among selected adults with AORC. A need exists for additional, well-designed and reported studies on this topic.
BACKGROUND: Fibromyalgia is a clinically well-defined chronic condition with a biopsychosocial aetiology. Fibromyalgia is characterized by chronic widespread musculoskeletal pain, sleep problems, cognitive dysfunction, and fatigue. Patients often report high disability levels and poor quality of life. Since there is no specific treatment that alters the pathogenesis of fibromyalgia, drug therapy focuses on pain reduction and improvement of other aversive symptoms.
OBJECTIVES: The objective was to assess the benefits and harms of selective serotonin reuptake inhibitors (SSRIs) in the treatment of fibromyalgia.
SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL; 2014, Issue 5), MEDLINE (1966 to June 2014), EMBASE (1946 to June 2014), and the reference lists of reviewed articles.
SELECTION CRITERIA: We selected all randomized, double-blind trials of SSRIs used for the treatment of fibromyalgia symptoms in adult participants. We considered the following SSRIs in this review: citalopram, fluoxetine, escitalopram, fluvoxamine, paroxetine, and sertraline.
DATA COLLECTION AND ANALYSIS: Three authors extracted the data of all included studies and assessed the risks of bias of the studies. We resolved discrepancies by discussion.
MAIN RESULTS: The quality of evidence was very low for each outcome. We downgraded the quality of evidence to very low due to concerns about risk of bias and studies with few participants. We included seven placebo-controlled studies, two with citalopram, three with fluoxetine and two with paroxetine, with a median study duration of eight weeks (4 to 16 weeks) and 383 participants, who were pooled together.All studies had one or more sources of potential major bias. There was a small (10%) difference in patients who reported a 30% pain reduction between SSRIs (56/172 (32.6%)) and placebo (39/171 (22.8%)) risk difference (RD) 0.10, 95% confidence interval (CI) 0.01 to 0.20; number needed to treat for an additional beneficial outcome (NNTB) 10, 95% CI 5 to 100; and in global improvement (proportion of patients who reported to be much or very much improved: 50/168 (29.8%) of patients with SSRIs and 26/162 (16.0%) of patients with placebo) RD 0.14, 95% CI 0.06 to 0.23; NNTB 7, 95% CI 4 to 17.SSRIs did not statistically, or clinically, significantly reduce fatigue: standard mean difference (SMD) -0.26, 95% CI -0.55 to 0.03; 7.0% absolute improvement on a 0 to 10 scale, 95% CI 14.6% relative improvement to 0.8% relative deterioration; nor sleep problems: SMD 0.03, 95 % CI -0.26 to 0.31; 0.8 % absolute deterioration on a 0 to 100 scale, 95% CI 8.3% relative deterioration to 6.9% relative improvement.SSRIs were superior to placebo in the reduction of depression: SMD -0.39, 95% CI -0.65 to -0.14; 7.6% absolute improvement on a 0 to 10 scale, 95% CI 2.7% to 13.8% relative improvement; NNTB 13, 95% CI 7 to 37. The dropout rate due to adverse events was not higher with SSRI use than with placebo use (23/146 (15.8%) of patients with SSRIs and 14/138 (10.1%) of patients with placebo) RD 0.04, 95% CI -0.06 to 0.14. There was no statistically or clinically significant difference in serious adverse events with SSRI use and placebo use (3/84 (3.6%) in patients with SSRIs and 4/84 (4.8%) and patients with placebo) RD -0.01, 95% CI -0.07 to 0.05.
AUTHORS' CONCLUSIONS: There is no unbiased evidence that SSRIs are superior to placebo in treating the key symptoms of fibromyalgia, namely pain, fatigue and sleep problems. SSRIs might be considered for treating depression in people with fibromyalgia. The black box warning for increased suicidal tendency in young adults aged 18 to 24, with major depressive disorder, who have taken SSRIs, should be considered when appropriate.
The aim of our meta-analysis was to compile the available evidence to evaluate the effect of physical exercise-based therapy (PEBT) on pain, impact of the disease, quality of life (QoL) and anxiety in patients with fibromyalgia syndrome (FMS), to determine the effect of different modes of physical exercise-based therapy, and the most effective dose of physical exercise-based therapy for improving each outcome. A systematic review and meta-analysis was carried out. The PubMed (MEDLINE), SCOPUS, Web of Science, CINAHL Complete and Physiotherapy Evidence Database (PEDro) databases were searched up to November 2022. Randomized controlled trials (RCTs) comparing the effects of physical exercise-based therapy and other treatments on pain, the impact of the disease, QoL and/or anxiety in patients with FMS were included. The standardized mean difference (SMD) and a 95% CI were estimated for all the outcome measures using random effect models. Three reviewers independently extracted data and assessed the risk of bias using the PEDro scale. Sixty-eight RCTs involving 5,474 participants were included. Selection, detection and performance biases were the most identified. In comparison to other therapies, at immediate assessment, physical exercise-based therapy was effective at improving pain [SMD-0.62 (95%CI, -0.78 to -0.46)], the impact of the disease [SMD-0.52 (95%CI, -0.67 to -0.36)], the physical [SMD 0.51 (95%CI, 0.33 to 0.69)] and mental dimensions of QoL [SMD 0.48 (95%CI, 0.29 to 0.67)], and the anxiety [SMD-0.36 (95%CI, -0.49 to -0.25)]. The most effective dose of physical exercise-based therapy for reducing pain was 21-40 sessions [SMD-0.83 (95%CI, 1.1--0.56)], 3 sessions/week [SMD-0.82 (95%CI, -1.2--0.48)] and 61-90 min per session [SMD-1.08 (95%CI, -1.55--0.62)]. The effect of PEBT on pain reduction was maintained up to 12 weeks [SMD-0.74 (95%CI, -1.03--0.45)]. Among patients with FMS, PEBT (including circuit-based exercises or exercise movement techniques) is effective at reducing pain, the impact of the disease and anxiety as well as increasing QoL. Systematic Review Registration: PROSPERO https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42021232013.
Systematic Review Question»Systematic review of interventions
