Carbamazepine for chronic neuropathic pain and fibromyalgia in adults Stable (no update expected for reasons given in 'What's new')

Abstract

Abstract Background

This is an update of a Cochrane review entitled 'Carbamazepine for acute and chronic pain in adults' published in Issue 1, 2011. Some antiepileptic medicines have a place in the treatment of neuropathic pain (pain due to nerve damage). This updated review considers the treatment of chronic neuropathic pain and fibromyalgia only, and adds no new studies. The update uses higher standards of evidence than the earlier review, which results in the exclusion of five studies that were previously included.

Objectives

To assess the analgesic efficacy of carbamazepine in the treatment of chronic neuropathic pain and fibromyalgia, and to evaluate adverse events reported in the studies.

Search methods

We searched for relevant studies in MEDLINE, EMBASE and CENTRAL up to February 2014. Additional studies were sought from clinical trials databases, and the reference list of retrieved articles and reviews.

Selection criteria

Randomised, double blind, active or placebo controlled trials (RCTs) investigating the use of carbamazepine (any dose, by any route, and for at least two weeks' duration) for the treatment of chronic neuropathic pain or fibromyalgia, with at least 10 participants per treatment group. Participants were adults aged 18 and over.

Data collection and analysis

Two study authors independently extracted data on efficacy, adverse events, and withdrawals, and examined issues of study quality. Numbers needed to treat for an additional beneficial effect (NNT) or harmful effect (NNH) with 95% confidence intervals (CIs) were calculated from dichotomous data.

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, at least 8 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 was considered very likely to be biased or used outcomes of limited clinical utility, or both.

Main results

Ten included studies (11 publications) enrolled 480 participants with trigeminal neuralgia, diabetic neuropathy, and post stroke pain. Nine studies used a cross‐over design, and one a parallel group design. Most of the studies were of short duration, lasting four weeks or less.

No study provided first or second tier evidence for an efficacy outcome. Using third tier evidence, carbamazepine generally provided better pain relief than placebo in the three conditions studied, with some indication of pain improvement over mainly the short term, but with poorly defined outcomes, incomplete reporting, and in small numbers of participants. There were too few data in studies comparing carbamazepine with active comparators to draw any conclusions.

In four studies 65% (113/173) of participants experienced at least one adverse event with carbamazepine, and 27% (47/173) with placebo; for every five participants treated, two experienced an adverse event who would not have done so with placebo. In eight studies 3% (8/268) of participants withdrew due to adverse events with carbamazepine, and none (0/255) with placebo. Serious adverse events were not reported consistently; rashes were associated with carbamazepine. Four deaths occurred in patients on carbamazepine, with no obvious drug association.

Authors' conclusions

Carbamazepine is probably effective in some people with chronic neuropathic pain, but with caveats. No trial was longer than four weeks, had good reporting quality, nor used outcomes equivalent to substantial clinical benefit. In these circumstances, caution is needed in interpretation, and meaningful comparison with other interventions is not possible.

Author(s)

Philip J Wiffen, Sheena Derry, R Andrew Moore, Eija A Kalso

Abstract

Plain language summary

Carbamazepine for chronic neuropathic pain and fibromyalgia in adults

Neuropathic pain is pain coming from damaged nerves. It is different from pain messages carried along healthy nerves from damaged tissue (a fall, or cut, or arthritic knee). Neuropathic pain is treated by different medicines than pain from damaged tissue. Medicines like paracetamol or ibuprofen are not effective in neuropathic pain, while medicines that are sometimes used to treat depression or epilepsy can be very effective in some people. Our understanding of fibromyalgia (a condition of persistent, widespread pain and tenderness, sleep problems, and fatigue) is lacking, but fibromyalgia can respond to the same medicines as neuropathic pain.

Carbamazepine was developed to treat epilepsy, but it is now used to treat various forms of chronic pain. We performed searches (up to February 2014) to look for clinical trials where carbamazepine was used to treat neuropathic pain or fibromyalgia. We found 10 studies involving 418 people involved in testing carbamazepine. Studies were not generally of very good quality. Most were very small, as well as of short duration. Studies lasting only one or two weeks are unhelpful when pain can last for years.

There was not enough good quality evidence to say how well carbamazepine worked in any neuropathic pain condition. Pooling four small studies showed that it was better than placebo, but the result cannot be relied upon. There was not enough information from these studies to make any reliable comment on adverse events or harm.

Carbamazepine is probably helpful for some people with chronic neuropathic pain. It is not possible to know beforehand who will benefit and who will not.

Author(s)

Philip J Wiffen, Sheena Derry, R Andrew Moore, Eija A Kalso

Reviewer's Conclusions

Authors' conclusions

Implications for practice

Carbamazepine is probably effective in some people with chronic neuropathic pain, but with major caveats. Only third tier evidence was available, which is subject to potentially major bias in favour of active therapy. No trial was longer than four weeks, or of good reporting quality, nor used outcomes equivalent to substantial clinical benefit. In these circumstances, caution is needed in interpretation, and meaningful comparison with other interventions is not possible. An overview of antiepileptics in neuropathic pain and fibromyalgia concluded that, among antiepileptic drugs, clinical trial evidence supports only the use of gabapentin and pregabalin in some neuropathic pain conditions (painful diabetic neuropathy, postherpetic neuralgia, and central neuropathic pain) and fibromyalgia (Wiffen 2013b).

The use of carbamazepine in neuropathic pain has stood the test of time in the clinic, but carbamazepine usually does not now feature in treatment algorithms, other than for the treatment of trigeminal neuralgia. Current guidance in the UK states 'Despite the lack of trial evidence, it is perceived by clinicians to be efficacious. Further research should be conducted as described in the table below.' (NICE 2013)

Medical students are often taught that a positive response to carbamazepine is 'diagnostic' for trigeminal neuralgia. Even the suspect evidence we have indicates that this is not the case, with perhaps just over half of participants with trigeminal neuralgia having a good response to carbamazepine. Clinically it appears that trigeminal neuralgia can become refractory to carbamazepine.

The usual clinical decision for chronic neuropathic pain is a choice between antidepressant and antiepileptic as first‐line treatment, and there is insufficient evidence to support the use of carbamazepine as first line. In addition the need for laboratory monitoring and significant drug interactions with the use of carbamazepine have discouraged the use of carbamazepine with the emergence of newer antiepileptic drugs, such as gabapentin and pregabalin.

Implications for research

This review shows that there is still a need for large, high quality, long duration studies using sensible outcomes to establish relative effectiveness of different antiepileptics in chronic pain syndromes, and for comparisons of other treatments such as antidepressants with antiepileptics; appropriate trial designs have been suggested for this (Moore 2009c). The usefulness of such studies would be increased greatly by improvements in the quality of reporting, and particularly by use of clinically important end points rather than undefined improvement. Enriched enrolment randomised withdrawal studies have real potential (McQuay 2008).

For carbamazepine the particular interest lies in treating trigeminal neuralgia. For this condition, for all interventions, there have been only a handful of good quality studies reported. The major implication for research is therefore for trigeminal neuralgia as a specific condition, and using carbamazepine as an historically useful medicine to understand the parameters around the conduct of successful clinical trials in a debilitating and often poorly responding condition.

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