Amitriptyline for neuropathic pain in adults Stable (no update expected for reasons given in 'What's new')
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 effects of amitriptyline for fibromyalgia are now dealt with in a separate review.
Amitriptyline is a tricyclic antidepressant that is widely used to treat chronic neuropathic pain (pain due to nerve damage). It is recommended as a first line treatment in many guidelines. Neuropathic pain can be treated with antidepressant drugs in doses below those at which the drugs act as antidepressants.Objectives
To assess the analgesic efficacy of amitriptyline for relief of chronic neuropathic pain, and the adverse events associated with its use in clinical trials.Search methods
We searched CENTRAL, MEDLINE, and EMBASE to March 2015, together with two clinical trial registries, and the reference lists of retrieved papers, previous systematic reviews, and other reviews; 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 chronic neuropathic pain conditions.Data collection and analysis
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.Main results
We included 15 studies from the earlier review and two new studies (17 studies, 1342 participants) in seven neuropathic pain conditions. Eight cross‐over studies with 302 participants had a median of 36 participants, and nine parallel group studies with 1040 participants had a median of 84 participants. Study quality was modest, though most studies were at high risk of bias due to small size.
There was no first‐tier or second‐tier evidence for amitriptyline in treating any neuropathic pain condition. Only third‐tier evidence was available. For only two of seven studies reporting useful efficacy data was amitriptyline significantly better than placebo (very low quality evidence).
More participants experienced at least one adverse event; 55% of participants taking amitriptyline and 36% taking placebo. The risk ratio (RR) was 1.5 (95% confidence interval (CI) 1.3 to 1.8) and the number needed to treat for an additional harmful outcome was 5.2 (3.6 to 9.1) (low quality evidence). Serious adverse events were rare. Adverse event and all‐cause withdrawals were not different, but were rarely reported (very low quality evidence).Authors' conclusions
Amitriptyline has been a first‐line treatment for neuropathic pain for many years. The fact that there is no supportive unbiased evidence for a beneficial effect is disappointing, but has to be balanced against decades of successful treatment in many people with neuropathic pain. There is no good evidence of a lack of effect; rather our concern should be of overestimation of treatment effect. Amitriptyline should continue to be used as part of the treatment of neuropathic pain, but only a minority of people will achieve satisfactory pain relief. Limited information suggests that failure with one antidepressant does not mean failure with all.
R Andrew Moore, Sheena Derry, Dominic Aldington, Peter Cole, Philip J Wiffen
Plain language summary
Amitriptyline for neuropathic pain in adults
Neuropathic pain is pain coming from damaged nerves, and can have a variety of different names. Some of the more common are painful diabetic neuropathy, postherpetic neuralgia, or post‐stroke pain. It is different from pain messages that are carried along healthy nerves from damaged tissue (for example, a fall, or cut, or arthritic knee). Neuropathic pain is treated by different medicines to those used for pain from damaged tissue. Medicines such as paracetamol or ibuprofen are not usually effective in neuropathic pain, while medicines that are sometimes used to treat depression or epilepsy can be very effective in some people with neuropathic pain.
Amitriptyline is an antidepressant, and antidepressants are widely recommended for treating neuropathic pain. Amitriptyline is commonly used to treat neuropathic pain conditions, but an earlier review found no good quality evidence to support its use. Most studies were small, relatively old, and used methods or reported results that we now recognise as making benefits seem better than they are.
In March 2015 we performed searches to look for new studies in adults with neuropathic pain of at least moderate intensity. We found only two additional small studies that did not provide any good quality evidence for either benefit or harm. This is disappointing, but we can still make useful comments about the drug.
Amitriptyline probably does not work in neuropathic pain associated with human immunodeficiency virus (HIV) or treatments for cancer. Amitriptyline probably does work in other types of neuropathic pain, though we cannot be certain of this. Our best guess is that amitriptyline provides pain relief in about 1 in 4 (25%) more people than does placebo, and about 1 in 4 (25%) more people than placebo report having at least one adverse event, which may be troublesome, but probably not serious. 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 people with neuropathic pain, but only a minority of them; amitriptyline will not work for most people.
R Andrew Moore, Sheena Derry, Dominic Aldington, Peter Cole, Philip J Wiffen
Implications for practice
For people with chronic neuropathic pain
Amitriptyline has been a first‐line treatment for neuropathic pain for many years. The fact is that there is no supportive unbiased evidence for substantial pain relief has to be balanced against decades of successful treatment in many tens of thousands of people with neuropathic pain. There is no reliable evidence of a lack of effect: rather our concern should be of overestimation of treatment effect.For clinicians
Amitriptyline should continue to be used as part of the treatment of neuropathic pain, but we should be cognisant of the fact that only a small number of people will achieve satisfactory pain relief.For policy makers
Amitriptyline should continue to be used as part of the treatment of neuropathic pain, but a range of drugs will be needed to provide good pain relief for a population of people with neuropathic pain.For funders
Amitriptyline should continue to be used as part of the treatment of neuropathic pain, but a range of drugs will be needed to provide good pain relief for a population of people with neuropathic pain.
Implications for research
There is no convincing evidence about effectiveness of the most commonly used first line therapy for neuropathic pain.
It is unlikely that any large randomised trials of amitriptyline will be conducted in specific neuropathic pain conditions to prove efficacy. Such trials are expensive. The bigger implication is for research in clinical practice, to determine whether there is a sequence of using drugs that will provide overall better clinical effectiveness (Moore 2010c). Another area for research, though extremely difficult, is to identify characteristics that predict which patients are likely to benefit from amitriptyline.Design
This review highlights the design weaknesses of trials in neuropathic pain. It is notable that probably the only treatment in neuropathic pain that reaches first tier level of evidence is duloxetine in painful diabetic neuropathy, and then because of a post‐hoc individual patient level analysis to change last observation carried forward (LOCF) to baseline observation carried forward (BOCF), and use a common defined outcome (Moore 2014c).Measurement (endpoints)
There are no lessons here about endpoints. We know that individuals with high levels of pain relief obtain benefit in a range of other areas, like sleep, depression, quality of life, and function.Comparison between active treatments
A comparison between active treatments is not possible given the present state of knowledge, with generally inadequate trials and reporting.Get full text at The Cochrane Library
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