Antiepileptic drugs for neuropathic pain and fibromyalgia ‐ an overview of Cochrane reviews

Abstract

Background

Antiepileptic drugs have been used for treating different types of neuropathic pain, and sometimes fibromyalgia. Our understanding of quality standards in chronic pain trials has improved to include new sources of potential bias. Individual Cochrane reviews using these new standards have assessed individual antiepileptic drugs. An early review from this group, originally published in 1998, was titled 'Anticonvulsants for acute and chronic pain'. This overview now covers the neuropathic pain aspect of that original review, which was withdrawn in 2009.

Objectives

To provide an overview of the relative analgesic efficacy of antiepileptic drugs that have been compared with placebo in neuropathic pain and fibromyalgia, and to report on adverse events associated with their use.

Methods

We included reviews published in theCochrane Database of Systematic Reviews up to August 2013 (Issue 7). We extracted information from each review on measures of efficacy and harm, and methodological details concerning the number of participants, the duration of studies, and the imputation methods used, in order to judge potential biases in available data.

We analysed efficacy data for each painful condition in three tiers, according to outcome and freedom from known sources of bias. The first tier met current best standards ‐ at least 50% pain intensity reduction over baseline (or its equivalent), without the use of last observation carried forward (LOCF) for dropouts, an intention‐to‐treat (ITT) analysis, in parallel group studies with at least 200 participants lasting eight weeks or more. The second tier used data from at least 200 participants where one or more of the above conditions were not met. The third tier of evidence related to data from fewer than 200 participants, or with several important methodological problems that limited interpretation.

Main results

No studies reported top tier results.

For gabapentin and pregabalin only we found reasonably good second tier evidence for efficacy in painful diabetic neuropathy and postherpetic neuralgia. In addition, for pregabalin, we found evidence of efficacy in central neuropathic pain and fibromyalgia. Point estimates of numbers needed to treat for an additional beneficial effect (NNTs) were in the range of 4 to 10 for the important outcome of pain intensity reduction over baseline of 50% or more.

For other antiepileptic drugs there was no evidence (clonazepam, phenytoin), so little evidence that no sensible judgement could be made about efficacy (valproic acid), low quality evidence likely to be subject to a number of biases overestimating efficacy (carbamazepine), or reasonable quality evidence indicating little or no effect (lamotrigine, oxcarbazepine, topiramate). Lacosamide recorded such a trivial statistical superiority over placebo that it was unreliable to conclude that it had any efficacy where there was possible substantial bias.

Any benefits of treatment came with a high risk of adverse events and withdrawal because of adverse events, but serious adverse events were not significantly raised, except with oxcarbazepine.

Authors' conclusions

Clinical trial evidence supported the use of only gabapentin and pregabalin in some neuropathic pain conditions (painful diabetic neuropathy, postherpetic neuralgia, and central neuropathic pain) and fibromyalgia. Only a minority of people achieved acceptably good pain relief with either drug, but it is known that quality of life and function improved markedly with the outcome of at least 50% pain intensity reduction. For other antiepileptic drugs there was no evidence, insufficient evidence, or evidence of a lack of effect; this included carbamazepine. Evidence from clinical practice and experience is that some patients can achieve good results with antiepileptics other than gabapentin or pregabalin.

There is no firm evidence to answer the important pragmatic questions about which patients should have which drug, and in which order the drugs should be used. There is a clinical effectiveness research agenda to provide evidence about strategies rather than interventions, to produce the overall best results in a population, in the shortest time, and at the lowest cost to healthcare providers.

Author(s)

Philip J Wiffen, Sheena Derry, R Andrew Moore, Dominic Aldington, Peter Cole, Andrew SC Rice, Michael PT Lunn, Katri Hamunen, Maija Haanpaa, Eija A Kalso

Abstract

Plain language summary

Antiepileptic drugs to treat neuropathic pain or fibromyalgia‐ an overview of Cochrane reviews

Neuropathic pain is pain coming from damaged nerves. It is different from pain messages carried along healthy nerves from damaged tissue (eg a fall, cut, or arthritic knee). Neuropathic pain is treated by different medicines than pain from damaged tissue. Medicines such as paracetamol or ibuprofen are probably not 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. 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.

Antiepileptic drugs (previously called anticonvulsants) are used for treating epilepsy, but have also been used for treating neuropathic pain and fibromyalgia. Many of the drugs have been the subject of individual Cochrane reviews. In August 2013 we collected all these Cochrane reviews on antiepileptic drugs together to provide an overview. Individual antiepileptic drugs work in different ways, and there is no expectation that they are equally effective.

We found that only for gabapentin and pregabalin was there some evidence that they worked in long‐term nerve pain with diabetes (painful diabetic neuropathy) and pain after shingles (postherpetic neuralgia). Pregabalin also had evidence of efficacy in central neuropathic pain (typically pain after stroke) and in fibromyalgia. The drugs work very well in some people with these painful conditions, with pain reduced by half. However, only between 1 in 10 and 1 in 4 people will get this level of benefit, depending on the pain condition and the drug. Most people will get no pain relief.

The antiepileptic drugs produced side effects in most people taking them, and for about 1 in 4 these could not be tolerated so they stopped taking the drug. Serious side effects were no more common with antiepileptic drugs than with a harmless placebo.

The evidence we found did not meet current best standards, and as a result it may overestimate benefit. The biggest concern is a lack of any evidence for most drugs in most types of neuropathic pain and fibromyalgia. For lacosamide and lamotrigine there is evidence of a lack of effect; for other antiepileptic drugs (including carbamazepine, clonazepam, phenytoin, valproate) there is no evidence of effect or insufficient evidence of effect.

Author(s)

Philip J Wiffen, Sheena Derry, R Andrew Moore, Dominic Aldington, Peter Cole, Andrew SC Rice, Michael PT Lunn, Katri Hamunen, Maija Haanpaa, Eija A Kalso

Reviewer's Conclusions

Authors' conclusions 

Implications for practice 

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. Only a minority of patients will achieve acceptably good pain relief with either drug, but the evidence we have is that quality of life and function improve markedly with the outcome of at least 50% pain intensity reduction (Moore 2013a; Moore 2013b). For lacosamide and lamotrigine there is evidence of a lack of effect; for other antiepileptic drugs, including carbamazepine, there is no evidence of effect or insufficient evidence of effect.

Numbers needed to treat (NNTs) for gabapentin and pregabalin at doses typically used in painful diabetic neuropathy were above 6. This estimate was based on second tier evidence with the potential to overestimate efficacy. For pregabalin in fibromyalgia a large overestimation of treatment effects using last observation carried forward (LOCF) imputation is known, and this imputation method was also used in painful diabetic neuropathy trials with gabapentin and pregabalin. The best evidence for antidepressants is from duloxetine (Lunn 2009) with an NNT of 6, supported by almost identical NNT estimates from newer analyses using top tier evidence and baseline observation carried forward (BOCF) (Moore 2013e). This might be sufficient to convince some practitioners that duloxetine is a better first line choice in painful diabetic neuropathy.

Implications for research 

The knowledge that some antiepileptic (and antidepressant) drugs can give good pain relief raises some important questions, namely in which patients, and in which order, the drugs should be used. There is no firm evidence to support these important pragmatic questions. A wider examination of analgesic efficacy of drugs indicates that analgesic failure is common, should be expected, and alternative strategies pursued in the face of analgesic failure (Moore 2013c). This needs to be supported by pragmatic research to provide evidence about strategies rather than interventions, to produce the overall best results in a population, in the shortest time, and at lowest cost to healthcare providers. A clinical effectiveness for such a study has been proposed (Moore 2010c).

There is, in addition, an important research agenda regarding the reasons why some patients respond to a particular drug, while others do not. This knowledge could be used to improve treatment performance if it could be easily applied. While this is unlikely to be an easy research agenda, it is nonetheless one that needs attention, possibly by examining genetic associations or deep phenotyping of responder versus non‐responder characteristics, or both. 

A final research agenda relates to clinical trial design. Classical randomised controlled trials lack sensitivity to demonstrate efficacy when response rates are low and may be of limited use in these circumstances (Moore 2013d). Evidence from clinical practice and experience indicates that a few patients can achieve good results with antiepileptics other than gabapentin or pregabalin, despite classical trial designs failing to demonstrate those antiepileptics having any greater efficacy than placebo. What is needed are new trial designs that are able to detect low but important rates of response reliably. Enriched enrolment randomised withdrawal designs have the theoretical ability to do this, but they are few in number and heterogeneous in design and quality (McQuay 2008; Moore 2013d). Adaptive designs may also have some use in these circumstances.

Get full text at The Cochrane Library