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

  • Review
  • Overview


  • Philip J Wiffen,

    1. University of Oxford, Pain Research and Nuffield Department of Clinical Neurosciences (Nuffield Division of Anaesthetics), Oxford, Oxfordshire, UK
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  • Sheena Derry,

    Corresponding author
    1. University of Oxford, Pain Research and Nuffield Department of Clinical Neurosciences (Nuffield Division of Anaesthetics), Oxford, Oxfordshire, UK
    • Sheena Derry, Pain Research and Nuffield Department of Clinical Neurosciences (Nuffield Division of Anaesthetics), University of Oxford, Pain Research Unit, Churchill Hospital, Oxford, Oxfordshire, OX3 7LE, UK.

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  • R Andrew Moore,

    1. University of Oxford, Pain Research and Nuffield Department of Clinical Neurosciences (Nuffield Division of Anaesthetics), Oxford, Oxfordshire, UK
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  • Dominic Aldington,

    1. Royal Hampshire County Hospital, Winchester, UK
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  • Peter Cole,

    1. Churchill Hospital, Oxford University Hospitals NHS Trust, Oxford Pain Relief Unit, Oxford, UK
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  • Andrew SC Rice,

    1. Imperial College London, Pain Research, Department of Surgery and Cancer, Faculty of Medicine, London, UK
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  • Michael PT Lunn,

    1. National Hospital for Neurology and Neurosurgery, Department of Neurology and MRC Centre for Neuromuscular Diseases, London, UK
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  • Katri Hamunen,

    1. Helsinki University Central Hospital, Department of Anaesthesia, Intensive Care Medicine, Emergency Medicine and Pain Medicine, Helsinki, Finland
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  • Maija Haanpaa,

    1. Helsinki University Central Hospital, Pain Clinic and Department of Neurosurgery, Helsinki, Finland
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  • Eija A Kalso

    1. Helsinki University and Helsinki University Hospital, Department of Anaesthesia, Intensive Care and Pain Medicine, Helsinki, Finland
    2. University of Helsinki, Institute of Clinical Medicine, Helsinki, Finland
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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.


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.


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.

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.

Laički sažetak

Lijekovi antiepileptici za ublažavanje neuropatske boli i fibromijalgije - prikaz Cochrane sustavnih pregleda

Neuropatska bol nastaje zbog oštećenih živaca. Razlikuje se od boli koja se širi zdravim živcima i posljedica je oštećenja tkiva (primjerice, zbog pada, porezotine ili artritisa koljena). Neuropatska bol se liječi lijekovima koji se razlikuju od lijekova protiv boli koja nastaje zbog oštećenja tkiva. Lijekovi kao što su paracetamol ili ibuprofen obično nisu učinkoviti za ublažavanje neuropatske boli, dok nekad lijekovi koji se koriste za liječenje depresije ili epilepsije mogu biti vrlo učinkoviti kod nekih osoba koje pate od neuropatske boli. Fibromijalgija je poremećaj koji uzrokuje trajnu bol i osjetljivost diljem tijela, probleme sa spavanjem i umor. O toj se bolesti još uvijek ne zna dovoljno, ali ponekad dobro odgovara na iste lijekove koji se koriste i za neuropatsku bol.

Lijekovi antiepileptici (koji su se ranije nazivali antikonvulzivi) koriste se za liječenje epilepsije, ali također su se propisivali za liječenje neuropatske boli i fibromijalgije. Većina lijekova iz te skupine pojedinačno su analizirani u zasebnim Cochrane sustavnim pregledima. U kolovozu 2013. prikupljeni su svi ti Cochrane sustavni pregledi o antiepilepticima za neuropatsku bol ili fibromijalgiju te se u ovom prikazu njihovi rezultati zajedno analiziraju. Pojedini antiepileptici djeluju na različite načine i nitko ne očekuje da su svi ti lijekovi jednako djelotvorni.

Pregledom svih Cochrane sustavnih pregleda na temu antiepileptika za neuropatsku bol ili fibromijalgiju utvrđeno je da jedino za gabapentin i pregabalin ima nekih dokaza da djeluju na dugotrajnu bol u živcima uzrokovanu dijabetesom (bolna dijabetička neuropatija) i bol nakon infekcije herpes zosterom (postherpetična neuralgija). Za pregabalin je također utvrđeno da može biti djelotvoran za centralnu neuropatsku bol (koja se tipično javlja nakon moždanog udara) i kod fibromijalgije. Lijekovi su dobro djelovali kod nekih osoba s tim bolnim stanjima, tako da je bol ublažena za najmanje 50%. Međutim, samo između 1 od 10 i 1 od 4 osobe će iskusiti takvu korist od lijeka, ovisno o njihovom stanju i lijeku koji se koristi. Većini ljudi ti lijekovi neće ublažiti bol.

Antiepileptici izazivaju nuspojave kod većine osoba koje ih uzimaju, i otprilike 1 od 4 osobe te nuspojave ne može podnositi te zbog njih prekida uzimanje lijeka. Ozbiljne nuspojave češće su zabilježene u skupinama ispitanika koje su uzimale antiepileptike nego kod onih koji su dobivali lažni lijek (placebo).

Dokazi koji su pronađeni ne odgovaraju najboljim standardima znanstvene metodologije, zbog čega su rezultati možda precijenjeni. Najveći je problem manjak dokaza o većini lijekova iz skupine antiepileptika i njihovu djelovanju na najčešće vrste neuropatske boli i na fibromijalgiju. Za lijekove lakozamid i lamotrigin pronađeni su dokazi da ti lijekovi nisu djelotvorni, a za druge antiepileptike (uključujući karbamazepin, kloanazepam, fenitoin, valproat) nisu nađeni dokazi o učinku ili su nađeni nedostatni dokazi o učinku.

Bilješke prijevoda

Hrvatski Cochrane
Prevela: Livia Puljak
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