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.

To assess the analgesic efficacy of amitriptyline for relief of fibromyalgia, and the adverse events associated with its use in clinical trials.

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.

We included randomised, double-blind studies of at least four weeks’ duration comparing amitriptyline with placebo or another active treatment in fibromyalgia.

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.

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.

Our understanding of fibromyalgia (a condition of persistent, widespread pain and tenderness, sleep problems, and fatigue) is poor. Common pain relieving medicines such as paracetamol and ibuprofen are not usually considered effective in fibromyalgia. Medicines that are sometimes used to treat epilepsy or depression can be very effective in some people with fibromyalgia, as they are in some other forms of chronic pain where there may be nerve damage (neuropathic pain).

Amitriptyline is an antidepressant, and antidepressants are recommended for treating fibromyalgia. Although amitriptyline is commonly used to treat fibromyalgia, a review in 2012 found no good quality evidence to support its use. Most studies were small, old, and used methods or reported results that we now recognise as making benefits seem better than they are.

This review is an update of the 2012 review, which considered both fibromyalgia and neuropathic pain conditions. Neuropathic pain is now considered in a separate review. Here we examine how well amitriptyline worked in treating fibromyalgia, using a definition of what worked that involved both a high level of pain relief and the ability to take the tablets over a longer time without side effects being intolerable.

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.