Abstract: 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). 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.

Plain-language summary: In March 2015 we performed searches to look for new studies, and found only two additional small studies to include. Neither provided any good quality evidence for benefit or harm. There were still no studies that could provide an answer that was trustworthy or reliable, because most were relatively old, and used methods or reported results that we now recognise as making benefits seem better than they are. This is disappointing, but we can still make useful comments about the drug. Amitriptyline probably does provide good levels of pain relief for some people with fibromyalgia, although we cannot be certain of this. Our best guess is that amitriptyline provides good pain relief in about 1 in 4 (25%) more people than does placebo. About 1 in 3 (31%) more people than with placebo report having one or more adverse events, which are usually not serious but may be troublesome and interfere with taking the treatment. We cannot trust either figure based on the information available. The most important message is that amitriptyline probably does give really good pain relief to some patients with fibromyalgia, but only a minority of them; amitriptyline will not work for most people.