In total, 2979 titles were identified. From these, 571 abstracts and then 275 full papers were selected for review, and 107 reviews evaluated as eligible for consideration in making recommendations for management (figure 1).

Information on the reviews informing these recommendations on pharmacological therapy and on non-pharmacological and complementary and alternative medicines/therapies is collated in online supplementary tables A and B, respectively, while information from one review, for each medicine/therapy, selected based on recency and quality is provided in tables 1 and 2, respectively.

The literature search did not identify any reviews on corticosteroids, strong opioids, cannabinoids and antipsychotics. The committee made a ‘strong against’ evaluation (100% agreement) regarding the use of strong opioids and corticosteroids in patients with fibromyalgia on the basis of lack of evidence of efficacy and high risk of side effects/addiction reported in individual trials.

Tramadol, a weak opioid with mild serotonin-noradrenalin reuptake inhibitor (SNRI) activity was considered by two reviews. Roskell et al 22 identified a single study of tramadol with paracetamol. Those in the active arm were more likely to have 30% improvement in pain (RR 1.77, 95% CI 1.26 to 2.48). Tramadol evaluation: weak for (100% agreement).

A single systematic review of five studies including 1535 patients reported small effects sizes on pain (0.44; 0.31 to 0.58), sleep problems (0.47; 0.28 to 0.66) and fatigue (0.48; 0.35 to 0.60). The European Medicines Agency and the US Food and Drug Administration refused the approval for FM because of safety concerns. 16 The drug is only approved for narcolepsy. Sodium oxybate evaluation: strong against (94% agreement).

Seven systematic reviews included up to 11 trials and a maximum of 521 subjects. Given that reviews have not focused on specific drugs or comparisons, drugs within this class were considered together. A recent review of medium quality included seven trials and reported a moderate effect on pain (−0.40; −0.73, to −0.07), sleep (−0.31; −0.60 to −0.02) and no effect on fatigue (−0.17; −0.46 to 0.11). 36 Selective serotonin reuptake inhibitor (SSRI) evaluation: weak against (94% agreement).

Eight systematic reviews were identified, which presented data separately for duloxetine. The largest review of 2249 subjects 32 reported duloxetine, short term (up to 12 weeks) and long term (up to 28 weeks), was more effective than placebo at reducing pain (RR >30% pain, RR 1.38, 95% CI 1.22 to 1.56), although there was no significant effect at 20–30 mg/day and no difference between doses of 60 and 120 mg/day. NNTB, based on 60 mg/day up to 12 weeks, was 6, 95% CI 3 to 12. A previous review reported small effects on sleep (−0.24; −0.37, to −0.12) and disability (−0.33; −0.43, to −0.24) but no effect on fatigue. 30 Seven systematic reviews were identified of milnacipran, a recent one of which evaluated five trials. 30 Patients taking milnacipran were more likely, at the end of treatment, to have 30% pain reduction (RR 1.38, 95% CI 1.25 to 1.51) but there was only a small benefit on fatigue (−0.14; −0.19 to −0.08), disability (−0.16; −0.23 to −0.10) and no effect on sleep. Duloxetine and milnacipran evaluation: weak for (100% agreement).

Four reviews identified up to three studies and 241 patients. Häuser et al 26 reported a moderate effect on pain across the studies (−0.54; −1.02, to −0.07), but the single studies that evaluated fatigue and sleep showed no effect. There were no differences in dropouts or adverse events compared with placebo. There was no comparison between compounds. Life-threatening interactions have been documented. Monoamine oxidase inhibitors (MAOIs) evaluation: weak against (81% agreement).

A single systematic review of two studies involving 74 patients reported an effect size on pain of 1.36 (0.01 to 1.34). 16 The improvement in functional deficit was not statistically significant (1.24; −0.36 to 2.84). There are concerns on safety (sleep apnoea, carpal tunnel syndrome). The drug is not approved for fibromyalgia (FM) or related disorders in Europe. Growth hormone evaluation: strong against (94% agreement).

A single systematic review of five studies involving 312 patients reported that of those taking cyclobenzaprine 85% experienced side effects and only 71% completed the studies. They were more likely to report themselves as ‘improved’ (NNT 4.8, 95% CI 3.0 to 11.0). Only two studies reported an ‘intention-to-treat’ (ITT) analysis. Sleep, but not pain, showed a significant, very small, improvement relative to baseline at the longest outcome considered (12 weeks: SMD 0.34) and patients on placebo showed similar improvement (SMD 0.52). 25 Cyclobenzaprine evaluation: weak for (75% agreement).

Nine reviews of pregabalin included up to seven studies and a maximum of 3344 patients. A recent Cochrane review 24 reported patients receiving active treatment were more likely to have 30% pain reduction, RR 1.37, 95% CI 1.22 to 1.53, with a ‘number needed to benefit’ (NNTB) over placebo of 9, 95% CI 7 to 13. There was a very small effect on fatigue (−0.17; −0.25 to −0.09) and small effect on sleep (−0.35; −0.43 to −0.27) but no effect on disability (−0.01; −0.11 to 0.09). A single, moderate quality, study of gabapentin in 150 subjects (eg, in ref. 104 ) showed a significant effect on 30% pain reduction (RR 1.65, 95% CI 1.10 to 2.48), a small effect on sleep (−0.71; −1.08 to −0.24) and a large effect on disability (−0.94; −1.32 to −0.56). Anticonvulsant evaluation: pregabalin—weak for (94% agreement); gabapentin—research only (100% agreement).

Five reviews included up to 13 trials and a maximum of 919 subjects. Häuser et al 12 reported that patients receiving amitriptyline were more likely to achieve 30% pain reduction (risk ratio (RR) 1.60, 95% CI 1.15 to 2.24), equivalent to a ‘number needed to treat’ (NNT) of 3.54, 95% CI 2.74 to 5.01. There was a moderate effect on sleep (standardised mean difference (SMD) −0.56, 95% CI −0.78, to −0.34) i and small effect on fatigue (−0.44; −0.71 to −0.16). There was no difference in discontinuation rates compared with patients receiving placebo. Nishishinya et al 13 in their high-quality review concluded that 25 mg/day improved pain, sleep and fatigue at 6–8 weeks of treatment but not at 12 weeks while 50 mg/day did not demonstrate efficacy. Amitriptyline evaluation: weak for, at low dose (100% agreement).

Evaluation of non-pharmacological therapies; complementary and alternative medicines and therapies

Acupuncture Eight reviews included up to 16 trials and 1081 participants. One high-quality review included nine trials, with 395 patients, and demonstrated that acupuncture, added to standard therapy, resulted in a 30% (21%, 39%) improvement in pain.70 Electric acupuncture was also associated with improvements in pain (22%; 4% to 41%) and fatigue (11%; 2% to 20%). Some adverse events were reported, but these were commonly mild and transient. There is little understanding of the active component of acupuncture, and the evidence supporting the use of real versus sham acupuncture was less consistent. Acupuncture evaluation: weak for (93% agreement).

Biofeedback Two reviews included up to seven trials and 307 participants. Glombiewski et al92 reviewed seven studies, comprising 321 participants. Treatment sessions varied from 6 to 22; with control therapy comprising sham biofeedback, attention control, medication and treatment as usual. Biofeedback was effective in reducing pain intensity (Hedges' g=0.79; 0.22 to 1.36), although all trials were poor quality. There was no evidence of effectiveness in terms of fatigue or sleep and subgroup analysis suggested that any effect was limited to electromyographic (0.86; 0.11 to 1.62) rather than electroencephalographic biofeedback (0.71; −0.37 to 1.8). Biofeedback evaluation: weak against (100% agreement).

Capsaicin Two reviews included two trials and 153 participants. The most recent review, a narrative review of two trials, considered data on 153 patients.94 Both showed some evidence of positive effect in terms of pain relief, although results were not consistent for other outcomes. Capsaicin gel is generally considered safe, although many users report a mild burning sensation when applied to the skin. However, the number of patients and trials was small and was therefore limited in the extent to which they can provide evidence for toxicity. Capsaicin evaluation: weak against (86% agreement).

Chiropractic Three reviews included up to 13 trials and 102 participants. The most recent review summarised three studies.89 One study was an open pilot study, one quasi-randomised and in the third no between-group differences were observed in terms of pain. The studies were poor quality and lacked robust interpretable data. Chiropractic evaluation: strong against (93% agreement).

Cognitive behavioural therapies Five reviews included up to 30 trials and at least 2031 participants. One high-quality review included 23 trials, comprising >2000 patients, although the quality of individual trials was reported as generally poor.58 Cognitive behavioural therapies (CBTs) were effective in reducing pain (−0.29; −0.49 to −0.17) and disability (−0.30; −0.51 to −0.08) at the end of treatment compared with a variety of controls groups, and results were sustained long term. Behavioural therapy evaluation: weak for (100% agreement).

Exercise Twenty reviews included up to 34 trials and at least 2494 participants.ii The largest, a Cochrane review, considered 47 different exercise interventions.41 Aerobic exercise was associated with improvements in pain (0.65; −0.09 to 1.39) and physical function (0.66; 0.41 to 0.92). Busch et al42 reviewed five trials with 219 participants and concluded that resistance training resulted in a significant improvement in pain (−3.3 cm on a 10 cm scale; −6.35 to −0.26) as well as function compared with control. There is some consistency with regard to aerobic and strengthening exercises, although insufficient evidence to suggest superiority of one over the other; land and aquatic exercise appear equally effective.56 Exercise therapy evaluation: strong for (100% agreement).

Hydrotherapy/spa therapy Four reviews included up to 21 trials and 1306 participants. One high-quality review included 10 trials, 446 participants and compared a median of 4-hour hydrotherapy (range 200–300 min) against various comparators.76 There was a significant improvement in pain (−0.78; −1.42 to −0.13) at the end of therapy, maintained in the longer term (median 14 weeks), although the review authors noted that no trials conducted an ITT analysis. There was consistency with regard to the evidence for hydrotherapy and balneotherapy, although little evidence to suggest superiority of one over the other.77 Hydrotherapy evaluation: weak for (93% agreement).

Hypnotherapy One review included four trials, although the number of participants is unclear.91 Although six trials of hypnotherapy and/or guided imagery were reviewed, only four examined hypnotherapy in isolation. Median treatment duration (where reported) was 360 min and hypnotherapy was compared with a variety of control therapies: cognitive intervention, active control (physical therapy/massage/relaxation/autogenic training) and treatment as usual. A meta-analysis is presented on all six trials, and isolated data for hypnotherapy are not presented. Two of the four hypnotherapy trials report some significant benefit in terms of pain, the other two demonstrate null, non-significant results. Hypnotherapy evaluation: weak against (86% agreement).

Massage Six reviews have been reported and one meta-analysis with nine trials and 404 patients63 with sessions lasting 25–90 min, and treatment duration ranging from 1 to 24 weeks (median 5 weeks). Comparator treatments included transcutaneous electrical nerve stimulation (TENS), standard care, guided relaxation and acupuncture. Methodological problems were noted with all of the studies, only four were at low risk of bias in terms of random allocation and only two were analysed as ITT. Overall, massage was not associated with a significant improvement in pain (0.37; −0.19 to 0.93), and of the two ITT analyses, one favoured massage and one favoured control (both significant). A subgroup analysis revealed some evidence of a positive effect with massage of ≥5 weeks duration, although this was based solely on lower-quality trials. Massage evaluation: weak against (86% agreement).

Meditative movement Six reviews, including up to eight trials and 559 participants, focused on qigong, yoga, tai chi or a combination of these therapies. However, there was insufficient evidence to make individual recommendations. One review included seven trials, with 362 participants randomised to tai chi, yoga, qigong or body awareness therapy.80 Total treatment time ranged from 12 to 24 hours and was compared with a variety of controls, including treatment as usual and active control groups (aerobics, wellness education and stretching). At the end of therapy, improvements were seen in sleep (−0.61; −0.95 to −0.27) and fatigue (−0.66; −0.99 to −0.34) some of which were maintained in the longer term. Meditative movement evaluation: weak for (71% agreement).

Mindfulness/mind–body therapy Six reviews included up to 13 trials and 1209 participants. One recent review, a meta-analysis of six trials, with 674 patients84 provided evidence that mindfulness-based stress reduction resulted in improvements in pain (−0.23; −0.46 to −0.01) immediately post treatment compared with usual care and compared with active control interventions (−0.44; −0.73 to −0.16). However, these effects were not robust against bias. Mindfulness/mind–body therapy evaluation: weak for (73% agreement).

Multicomponent therapy Two reviews including up to 27 trials and 2407 participants examined the additional benefit of combining therapies compared with individual therapy. Häuser et al60 conducted a review of management involving both educational or psychological therapies and exercise. In a meta-analysis of nine trials and 1119 patients, multicomponent therapy was effective in reducing pain (−0.37; −0.62 to −0.13), and fatigue, immediately post treatment, compared with waiting list, relaxation, treatment as usual and education. However, effects were short-lived. Multicomponent therapy evaluation: weak for (93% agreement).

S-Adenosyl methionine Two reviews each included one trial with, in combination, 74 participants. De Silva et al93 reported that, after the end of treatment, significant improvements were observed in pain and fatigue compared with placebo. Sim and Adams52 reviewed a trial comparing S-adenosyl methionine (SAMe) with TENS but data on the main trial comparison are omitted. Side effects are usually mild and infrequent. However, the number of patients and trials was small and therefore cannot provide a robust assessment of toxicity and safety. SAMe evaluation: weak against (93% agreement).