Gabapentin for chronic neuropathic pain and fibromyalgia in adults

  • Review
  • Intervention

Authors

  • R Andrew Moore,

    Corresponding author
    1. University of Oxford, Pain Research and Nuffield Department of Clinical Neurosciences (Nuffield Division of Anaesthetics), Oxford, Oxfordshire, UK
    • R Andrew Moore, 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. andrew.moore@ndcn.ox.ac.uk.

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  • 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,

    1. University of Oxford, Pain Research and Nuffield Department of Clinical Neurosciences (Nuffield Division of Anaesthetics), Oxford, Oxfordshire, 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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Abstract

Background

This review is an update of a review published in 2011, itself a major update of previous reviews published in 2005 and 2000, investigating the effects of gabapentin in chronic neuropathic pain (pain due to nerve damage). Antiepileptic drugs are used to manage chronic neuropathic pain and fibromyalgia.

Objectives

To assess the analgesic efficacy and adverse effects of gabapentin in chronic neuropathic pain and fibromyalgia.

Search methods

We identified randomised trials of gabapentin for chronic neuropathic pain or fibromyalgia by searching the databases MEDLINE (1966 to March 2014), EMBASE (1980 to 2014 week 10), and CENTRAL in The Cochrane Library (Issue 3 of 12, 2014). We obtained clinical trial reports and synopses of published and unpublished studies from Internet sources, and searched Clinicaltrials.gov. Searches were run originally in 2011 and the date of the most recent search was 17 March 2014.

Selection criteria

Randomised, double-blind studies reporting the analgesic and adverse effects of gabapentin in neuropathic pain or fibromyalgia with assessment of pain intensity, pain relief, or both, using validated scales. Participants were adults.

Data collection and analysis

Three review authors independently extracted efficacy and adverse event data, examined issues of study quality, and assessed risk of bias. 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), concentrating on at least 50% pain intensity reduction, and Initiative on Methods, Measurement and Pain Assessment in Clinical Trials (IMMPACT) definitions of at least moderate and substantial benefit. For harm we calculated number needed to treat for harm (NNH) for adverse effects and withdrawal. Meta-analysis was undertaken using a fixed-effect model. We emphasised differences between conditions now defined as neuropathic pain, and other conditions like masticatory pain, complex regional pain
syndrome type 1 (CRPS-1), and fibromyalgia.

Main results

Seven new studies with 1919 participants were added. Another report (147 participants) provided results for a study already included, but which previously had no usable data. A further report (170 participants) used an experimental formulation of intrathecal gabapentin. Thirty-seven studies (5633 participants) studied oral gabapentin at daily doses of 1200 mg or more in 12 chronic pain conditions; 84% of participants were in studies of postherpetic neuralgia, painful diabetic neuropathy or mixed neuropathic pain. There was no first tier evidence.

Second tier evidence for the outcome of at least 50% pain intensity reduction, considered valuable by patients with chronic pain, showed that gabapentin was significantly better than placebo in postherpetic neuralgia (34% gabapentin versus 21% placebo; NNT 8.0, 95% CI 6.0 to 12) and painful diabetic neuropathy (38% versus 21%, NNT 5.9, 95% CI 4.6 to 8.3). There was insufficient information in other pain conditions to reach any reliable conclusion. There was no obvious difference between standard gabapentin formulations and recently-introduced extended-release or gastro-retentive formulations, or between different doses of gabapentin.

Adverse events occurred significantly more often with gabapentin. Persons taking gabapentin could expect to have at least one adverse event (62%), withdraw because of an adverse event (11%), suffer dizziness (19%), somnolence (14%), peripheral oedema (7%), and gait disturbance (9%). Serious adverse events (3%) were no more common than with placebo.

There were insufficient data for direct comparisons with other active treatments, and only third tier evidence for other painful conditions.

Authors' conclusions

There was no top tier evidence that was unequivocally unbiased. Second tier evidence, with potentially important residual biases, showed that gabapentin at doses of 1200 mg or more was effective for some people with some painful neuropathic pain conditions. The outcome of at least 50% pain intensity reduction is regarded as a useful outcome of treatment by patients, and the achievement of this degree of pain relief is associated with important beneficial effects on sleep interference, fatigue, and depression, as well as quality of life, function, and work. About 35% achieved this degree of pain relief with gabapentin, compared with 21% for placebo. Over half of those treated with gabapentin will not have worthwhile pain relief. Results might vary between different neuropathic pain conditions, and the amount of evidence for gabapentin in neuropathic pain conditions except postherpetic neuralgia and painful diabetic neuropathy, and in fibromyalgia, is very limited.

The levels of efficacy found for gabapentin are consistent with those found for other drug therapies in postherpetic neuralgia and painful diabetic neuropathy.

摘要

慢性神經病變痛和纖維肌痛成人患者的gabapentin治療

背景

本次文獻回顧為更新2011年發表的文獻回顧資料,該次文獻回顧本身即為2005年和2000年發表之文獻回顧的重大更新,探討gabapentin對慢性神經病變痛 (chronic neuropathic pain) (因神經受損而導致疼痛) 的療效。醫師會使用抗癲癇藥物 (antiepileptic drug),治療慢性神經病變痛和纖維肌痛 (fibromyalgia)。

目的

評估gabapentin對慢性神經病變痛和纖維肌痛的止痛效果及不良作用。

搜尋策略

我們搜尋MEDLINE (1966年至2014年3月)、EMBASE (1980年至2014年第10週) 和考科藍圖書館的CENTRAL(2014年第3次發行 [共12次]) 等資料庫,找出以gabapentin治療慢性神經病變痛或纖維肌痛的隨機試驗。我們自網路來源取得臨床試驗報告及摘要 (已發表和未發表試驗),並搜尋Clinicaltrials.gov。我們自2011年開始執行搜尋,最近一次搜尋日期為2014年3月17日。

選擇標準

隨機雙盲試驗,報告gabapentin對神經病變痛或纖維肌痛的止痛效果和不良作用,採用有效量表評估疼痛強度、疼痛緩解程度或兩者。試驗受試者為成人。

資料收集與分析

由3位文獻回顧作者,獨立萃取療效和不良事件資料、檢視試驗品質的相關問題,並評估偏差風險。本次文獻回顧採用三級證據 (three tiers of evidence) 進行分析。第一級證據源自符合現行最佳準則且偏差風險極低的資料 (結果相當於大幅減輕疼痛強度、不受退出試驗受試者影響的治療意向分析法 [intention-to-treat analysis];至少有200名受試者接受比較,試驗持續8至12週,採平行分組設計);第二級證據來自未能符合1項或多項上述準則,雖具一些偏差風險,但所進行的比較數量適當的資料;至於第三級證據則來自受試者人數少,因此極可能出現偏差,或使用臨床效用有限的結果,或兩者皆具的資料。

我們計算療效的益一需治數 (NNT),著重於至少減輕50%的疼痛強度,以及按臨床試驗的方法、測量和疼痛評估創議 (Initiative on Methods, Measurement and Pain Assessment in Clinical Trials, IMMPAC) 定義,至少具有中等和大幅效益。我們也針對不良作用和退出試驗的情況,計算傷害的益一需治數 (NNH)。採固定效果模式 (fixed-effect model) 進行後設分析 (meta-analysis)。我們強調如今定義為神經病變痛的疾病,與其他例如咀嚼疼痛 (masticatory pain)、第一型複合性局部疼痛症候群 (complex regional pain syndrome type 1, CRPS-1) 及纖維肌痛等疾病之間的差異。

主要結果

本次文獻回顧新增7篇新試驗,包含1919名受試者。有1篇論文 (147名受試者) 雖為先前文獻回顧中已納入的試驗,但當時並無可使用的資料。另有1篇論文 (170名受試者) 使用gabapentin脊髓腔止痛 (intrathecal gabapentin) 的實驗配方。有37篇試驗 (5633名受試者) 探討口服gabapentin,採用每日劑量1200 mg以上,針對12種慢性疼痛疾病進行探究;有84%的試驗受試者患有帶狀皰疹後神經痛 (postherpetic neuralgia)、會疼痛的糖尿病性神經病變,或混合型神經病變痛。並無第一級證據。

關於疼痛程度至少降低50%的結果,若將慢性疼痛患者的評價納入考慮,則第二級證據顯示,gabapentin對帶狀皰疹後神經痛 (34%相對於21%;NNT為8.0,95% CI為6.0至12) 和會疼痛的糖尿病性神經病變 (38%相對於21%,NNT為5.9,95% CI為4.6至8.3) 的療效,顯著優於安慰劑。至於其他疼痛疾病則因資訊不足,無法得出可靠結論。標準gabapentin劑型和近期推出的緩釋劑型或胃滯留劑型,或各種劑量的gabapentin之間,並無明顯差異。

gabapentin的不良事件發生率顯著較高。預期使用gabapentin的患者至少會發生1項不良事件 (62%)、因不良事件而退出試驗 (11%)、感覺暈眩 (19%)、想睡 (14%)、周邊水腫 (7%) 和步態障礙 (gait disturbance) (9%)。嚴重不良事件的發生率 (3%),與安慰劑相似。

並無充分資料足以和其他有效治療進行直接比較,而其他疼痛疾病則僅有第三級證據。

作者結論

並未發現確實無偏差的頂級證據。可能具有重要殘餘偏差 (residual bias) 的第二級證據顯示,使用1200 mg以上劑量的gabapentin,可有效治療罹患某些疼痛性神經病變痛疾病的部分患者。疼痛強度至少降低50%的結果,被患者視為有效的治療結果,但必須能對睡眠不受干擾、疲倦和沮喪,以及生活品質、功能和工作產生重大的有利作用,才能達到此種程度的疼痛緩解效果。gabapentin治療組約有35%的患者,可達到此種疼痛緩解程度,相較之下安慰劑組患者則有21%的患者,疼痛程度至少降低50%。接受gabapentin治療的患者中,有一半以上的人疼痛並未得到滿意的緩解。不同的神經病變性疼痛疾病,可能會產生不同的結果,而且除了帶狀皰疹後神經痛、會疼痛的糖尿病性神經病變和纖維肌痛以外,關於gabapentin治療神經病變性疼痛疾病的證據,數量也非常有限。

gabapentin的止痛效果,與帶狀皰疹後神經痛和會疼痛的糖尿病性神經病變的其他藥物治療一致。

譯註


翻譯者:臺北醫學大學實證醫學研究中心
本翻譯計畫由衛生福利部補助經費,臺北醫學大學實證醫學研究中心、台灣實證醫學學會及東亞考科藍聯盟(EACA)統籌執行。

Resumo

Gabapentina para dor neuropática crônica e fibromialgia em adultos

Introdução

Esta revisão é uma atualização de uma revisão publicada em 2011, que era também uma grande atualização de revisões anteriores publicadas em 2005 e 2000, investigando os efeitos da gabapentina na dor neuropática crônica (dor devida a lesões nos nervos). Drogas antiepilépticas são usadas para controlar a dor neuropática crônica e a fibromialgia.

Objetivos

Avaliar a eficácia analgésica e os efeitos adversos da gabapentina para o tratamento da dor neuropática crônica e da fibromialgia.

Métodos de busca

Identificamos ensaios clínicos randomizados sobre a gabapentina em dor crônica neuropática ou fibromialgia nas bases MEDLINE (1966 a março de 2014), EMBASE (1980 a 2014, semana 10) e CENTRAL (na Cochrane Library, Issue 3 de 10, 2014). Procuramos na internet e na plataforma de registro de ensaios clínicos Clinicaltrials.gov por relatos de ensaios clínicos e resumos de estudos publicados ou não. As buscas foram originalmente feitas em 2011 e a data da busca mais recente foi 17 de março de 2014.

Critério de seleção

Incluímos estudos randomizados, duplo-cegos que apresentavam os efeitos analgésicos e adversos da gabapentina para dor neuropática ou fibromialgia nos quais a avaliação da intensidade da dor e/ou alívio da dor foi feita usando escalas validadas. Os participantes eram adultos.

Coleta dos dados e análises

Três revisores, de forma independente, extraíram os dados de eficácia e efeitos adversos, avaliaram a qualidalidade dos estudos e calcularam o risco de viés. Foram realizadas análises utilizando três níveis de evidência. No primeiro nível, utilizamos evidências a partir de dados de estudos com a melhor qualidade e sujeitos ao menor risco de viés, isto é: desfechos equivalentes a uma redução substancial da intensidade da dor, análise por intenção de tratar sem imputação para os participantes desistentes, pelo menos 200 participantes na comparação, 8 a 12 semanas de duração e ensaio clínico com desenho paralelo. No segundo nível, examinamos evidências de estudos que não conseguiram cumprir um ou mais desses critérios e foram considerados como tendo algum risco de viés, mas com números adequados na comparação. Por fim, num terceiro nível, trabalhamos a partir de dados de estudos com poucos participantes e que foram considerados como tendo alta probabilidade de viés ou que usaram desfechos de relevância clínica limitada, ou ambas as situações.

Para medir a eficácia da intervenção, calculamos o número necessário para tratar para promover benefício (NNT), focando em pelo menos 50% de redução da dor. Também consideramos as definições de benefício pelo menos moderado ou substancial conforme definido pelo IMMPACT (Initiative on Methods, Measurement and Pain Assessment in Clinical Trials). Quanto aos efeitos adversos, calculamos o número necessário para tratar para causar dano (NNH) e para abandono. O modelo de efeito fixo foi usado nas metanálises. Enfatizamos as diferenças entre as condições agora definidas como dor neuropática e outras condições, tais como dor mastigatória, dor complexa regional,
síndrome tipo 1 (CRPS-1) e fibromialgia.

Principais resultados

Sete novos estudos com 1.919 participantes foram incluídos. Outra publicação (147 participantes) apresentou resultados de um estudo já incluído, mas que anteriormente não tinha dados que pudessem ser usados. Um estudo adicional (170 participantes) usou uma formulação experimental de gabapentina intratecal. Trinta e sete estudos (com 5.633 participantes) examinaram o uso da gabapentina oral em doses diárias de 1.200 mg ou mais em 12 condições de dor crônica; 84% dos participantes faziam parte de estudos sobre neuralgia pós-herpética, neuropatia diabética dolorosa e dor neuropática mista. Não encontramos evidência do primeiro nível de qualidade.

De acordo com evidência de segundo nível para o desfecho redução de pelo menos 50% na intensidade da dor (considerado importante pelos pacientes com dor crônica), a gabapentina é significativamente melhor que placebo na neuralgia pós-herpética (34% com gabapentina versus 21% com placebo; NNT 8,0; intervalo de confiança de 95%, 95% CI, de 6,0 a 12,0) e na neuropatia diabética dolorosa (38% versus 21%, NNT 5,9; 95% CI de 4,6 a 8,3). Não havia informação suficiente para que se pudesse chegar a conclusões confiáveis sobre outras condições dolorosas. Nâo encontramos diferença evidente entre as formulações padrão de gabapentina e as formulações recentemente lançadas (de liberação enteral prolongada) ou entre diferentes doses de gabapentina.

A ocorrência de eventos adversos foi significativamente maior com a gabapentina. Pessoas tomando gabapentina podem esperar ter pelo menos um efeito adverso em 62% dos casos, desistir de participar do estudo por causa de um evento adverso (11%), ter tontura (19%), sonolência (14%), edema periférico (7%) e distúrbios da marcha (9%). Os eventos adversos graves ocorreram em 3% dos participantes que tomavam gabapentina e não foram mais comuns do que com placebo.

Os dados foram insuficientes para que se pudesse fazer comparações diretas com outros tratamentos ativos. Havia somente evidência de terceiro nível para outras condições dolorosas.

Conclusão dos autores

Não encontramos evidência de primeiro nível que fosse totalmente livre de viés. Evidência de segundo nível, com viés residual potencialmente importante, mostrou que gabapentina em doses de 1.200 mg ou mais foi eficaz para alguns pacientes com condições neuropáticas dolorosas. A redução de pelo menos 50% na intensidade da dor é vista como um desfecho útil pelos pacientes. Esse nível de alívio da dor é associado com efeitos benéficos importantes na redução dos distúrbios do sono, da fadiga e da depressão, assim como melhora na qualidade de vida, função e trabalho. Cerca de 35% dos pacientes conseguiram atingir esse nível de alívio da dor com a gabapentina, comparados com 21% dos pacientes que receberam placebo. Mais da metade das pessoas tratadas com gabapentina não vai conseguir ter alívio satisfatório da dor. Os resultados podem variar em diferentes tipos de dor neuropática. Existe pouquíssima evidência sobre o efeito da gabapentina para fibromialgia e para outros tipos de dores neuropáticas além da neuralgia pós-herpética e da neuropatia diabética dolorosa.

Os níveis de eficácia da gabapentina são semelhantes àqueles de outros tratamentos medicamentosos para neuralgia pós-herpética e neuropatia diabética dolorosa.

Notas de tradução

Traduzido pelo Centro Cochrane do Brasil (Arnaldo Alves da Silva e Patricia Logullo).

Plain language summary

Gabapentin for chronic neuropathic pain and fibromyalgia in adults

Neuropathic pain is pain coming from damaged nerves. It differs from pain messages carried along healthy nerves from damaged tissue (a fall, 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 with neuropathic pain. Our understanding of fibromyalgia (a condition of persistent, widespread pain and tenderness, sleep problems, and fatigue) is poor, but fibromyalgia can respond to the same medicines as neuropathic pain.

Gabapentin was developed to treat epilepsy, but it is now used to treat various forms of chronic pain. On 17 March 2014 we performed searches to look for clinical trials where gabapentin was used to treat neuropathic pain or fibromyalgia. We found that 5633 participants had been involved in 37 studies of reasonable quality. They tested gabapentin against placebo for four weeks or more. Studies lasting only one or two weeks are unhelpful when pain can last for years.

Only two conditions had useful amounts of data - postherpetic neuralgia (chronic pain following shingles) and painful diabetic neuropathy (where nerves are damaged in diabetes). Gabapentin helped 3 or 4 people in 10 by reducing their pain by at least half, while with placebo only 2 in 10 had this result.

With gabapentin 6 people in 10 can expect to have some adverse events, including dizziness (2 in 10), somnolence (1 or 2 in 10), peripheral oedema (1 in 10), and gait disturbance (1 in 10). Serious adverse events (1 in 33) were no more common than with placebo. One person in 10 withdrew because of adverse events. Persons taking gabapentin can expect to have at least one adverse event (6 in 10), or stop taking gabapentin because of an adverse event (about 1 in 10).

Gabapentin is helpful for some people with chronic neuropathic pain or fibromyalgia. It is not possible to know beforehand who will benefit and who will not. Current knowledge suggests that a short trial is the best way of telling.

Резюме на простом языке

Габапентин при хронической невропатической боли и фибромиалгии у взрослых

Невропатическая боль – это боль, исходящая из поврежденных нервов. Она отличается от боли, передающейся здоровыми нервами из поврежденной ткани (падение, порез или артрит коленного сустава). Невропатическая боль лечится другими лекарствами, нежели боль от поврежденной ткани. Лекарственные средства, такие как парацетамол или ибупрофен не эффективны при невропатической боли, в то время как лекарства, применяемые для лечения депрессии или эпилепсии, могут быть очень эффективными у некоторых пациентов с невропатической болью. Наше понимание фибромиалгии (состояние постоянной, широко распространенной боли и болезненности [при дотрагивании или давлении], c проблемами со сном и утомляемостью) оставляет желать лучшего, но фибромиалгия может отзываться на те же лекарства, что и невропатическая боль.

Габапентин был разработан для лечения эпилепсии, но в настоящее время используется и для лечения различных форм хронической боли. 17 марта 2014 мы провели поиск клинических исследований, в которых габапентин применялся для лечения невропатической боли или фибромиалгии. Мы обнаружили, что 5633 участника были включены в 37 исследований приемлемого качества. Они [исследования] проверяли габапентин против плацебо в течение четырех недель и более. Учитывая, что боль [хроническая] может длиться годами, исследования продолжительностью только одну или две недели бесполезны.

Только при двух состояниях (нарушениях здоровья) были пригодные объемы данных - постгерпетическая невралгия (хроническая боль при опоясывающем лишае) и болезненная диабетическая невропатия (поражение нервов при диабете). Габапентин помогал 3 или 4 людям из 10, уменьшая их боль, по крайней мере, наполовину, в то время как в группе плацебо только у 2 из 10 был такой же результат.

При приеме габапентина 6 человек из 10 могут ожидать некоторые неблагоприятные события, в том числе головокружение (2 из 10), сонливость (1 или 2 из 10), периферические отеки (1 из 10), и нарушения походки (1 из 10). Серьезных неблагоприятных событий (1 из 33) было не больше, чем при приеме плацебо. Один человек в 10 вышел из исследований из-за неблагоприятных событий. Лица, принимающие габапентин, могут ожидать, по крайней мере, одно неблагоприятное событие (6 из 10), или прекратят прием габапентина из-за неблагоприятного события (примерно 1 из 10).

Габапентин полезен некоторым людям с хронической невропатической болью или фибромиалгией. Нельзя знать заранее, кому поможет, а кому нет. Современные знания позволяют предполагать, что краткосрочные исследования – лучший способ убедиться в этом.

Заметки по переводу

Перевод: Абакумова Татьяна Рудольфовна. Редактирование: Александрова Эльвира Григорьевна, Зиганшина Лилия Евгеньевна. Координация проекта по переводу на русский язык: Казанский федеральный университет. По вопросам, связанным с этим переводом, пожалуйста, свяжитесь с нами по адресу: lezign@gmail.com

淺顯易懂的口語結論

慢性神經病變痛和纖維肌痛成人患者的gabapentin治療

神經病變痛 (neuropathic pain) 是由於神經受損所導致的疼痛,有別於來自受損組織 (跌倒、割傷或膝關節炎) 並沿健康神經傳遞的疼痛訊息。神經病變痛的治療藥物,與治療受損組織所造成的疼痛不同。諸如paracetamol或 ibuprofen之類的藥物,對神經病變痛無效,但有時用來治療憂鬱症或癲癇的藥物,卻對部分神經病變痛的患者極為有效。我們對纖維肌痛 (fibromyalgia) (一種會出現持續性的廣泛性疼痛和壓痛、睡眠障礙和疲倦等症狀的疾病) 的瞭解不深,但可使用治療神經病變痛的藥物治療纖維肌痛。

藥廠研發gabapentin是為了治療癲癇,但如今則用來治療各種慢性疼痛。本次文獻回顧於2014年3月17日進行搜尋,找尋使用gabapentin治療神經病變痛和纖維肌痛的臨床試驗。我們找到37篇品質適當的試驗,共計包含5633名受試者。這些試驗的研究者讓受試者接受gabapentin或安慰劑治療4週以上,然後比較兩組患者的狀況。由於患者的疼痛可能持續數年,因此僅持續1或2週的試驗並無幫助。

只有2種疾病具有適當的資料量,即帶狀皰疹後神經痛 (postherpetic neuralgia) (罹患帶狀皰疹後的慢性疼痛),和會疼痛的糖尿病性神經病變 (神經受損的糖尿病患者)。gabapentin治療組中,每10人約有3至4人的疼痛程度可降低至少一半,但安慰劑組中則每10人中只有2人如此。

預期接受gabapentin治療時,每10人約有6人會發生一些不良事件,包括暈眩 (每10人有2人發生)、想睡 (每10人有1或2人發生)、周邊水腫 (每10人有1人發生) 和步態障礙 (每10人有1人發生)。gabapentin治療組的嚴重不良事件發生率 (33人中有1人發生),與安慰劑組相似。在10名退出試驗的患者中,有1人是因為不良事件而退出。預期使用gabapentin的患者至少會發生1項不良事件 (每10人中有6人發生),或因不良事件而停用gabapentin治療 (每10人中約有1人)。

gabapentin對某些慢性神經病變痛或纖維肌痛的患者的確有幫助,但無法事先得知gabapentin對哪些患者有效,對哪些患者無效。現有的知識顯示,短期試驗是解決這個問題的最佳方式。

譯註


翻譯者:臺北醫學大學實證醫學研究中心
本翻譯計畫由衛生福利部補助經費,臺北醫學大學實證醫學研究中心、台灣實證醫學學會及東亞考科藍聯盟(EACA)統籌執行。

Resumo para leigos

Gabapentina para adultos com dor neuropática crônica e fibromialgia

A dor neuropática é a dor que vem de nervos que sofreram lesão. Ela difere das mensagens de dor conduzidas ao longo de nervos sadios a partir de tecidos com lesões (por uma queda, corte ou por um joelho com artrite, por exemplo). A dor neuropática é tratada por remédios diferentes dos utilizados para a dor que vem de tecidos lesionados. Remédios como paracetamol ou ibuprofeno não são eficazes para a dor neuropática. Por outro lado, os medicamentos que são às vezes usados para tratar depressão ou epilepsia podem ser muito eficazes em algumas pessoas com dor neuropática. Ainda não sabemos tudo sobre a fibromialgia, uma condição de dor persistente e generalizada, acompanhada de fadiga e problemas para dormir. Mas sabemos que a fibromialgia pode responder aos mesmos remédios usados para tratar a dor neuropática.

A gabapentina foi desenvolvida para tratar epilepsia, mas agora está sendo utilizada para tratar várias formas de dor crônica. Em março de 2014, realizamos buscas na literatura à procura de ensaios clínicos em que a gabapentina foi usada para tratar a dor neuropática ou a fibromialgia. Encontramos 37 estudos de qualidade razoável com 5.633 participantes. Esses estudos testaram os efeitos do uso da gabapentina por pelo menos quatro semanas, comparados com o uso de um placebo. Os estudos com duração de apenas uma ou duas semanas nao são adequados para pessoas que têm dores há anos.

Havia dados suficientes para apenas duas condições: a neuralgia pós-herpética (dor persistente no lugar onde havia bolhas do herpes, ou cobreiro), e neuropatia diabética dolorosa (uma condição em que os nervos sofrem lesões por causa do diabetes). De cada 10 pessoas que tomaram a gabapentina, 3 a 4 tiveram uma redução de pelo menos 50% na sua dor. Esse mesmo efeito foi observado em apenas 2 a cada 10 pessoas que tomaram um placebo.

De cada 10 pessoas que tomam a gabapentina, 6 podem esperar ter algum efeito adverso, incluindo tontura (2 em 10), sonolência (1 ou 2 em 10), inchaço periférico (1 em 10) e problemas com a marcha (1 em 10). A taxa de efeitos adversos sérios foi semelhante entre as pessoas que tomaram gabapentina ou placebo (1 caso em cada 33 pessoas). Uma pessoa a cada 10 abandonou o estudo por causa de efeitos adversos. Espera-se que pessoas tomando gabapentina tenham pelo menos um efeito adverso (6 em 10) ou abandonem o tratamento por causa de um efeito adverso (1 em 10).

A gabapentina pode auxiliar algumas pessoas com dor crônica neuropática ou fibromialgia. Não é possível saber de antemão quem vai se beneficiar e quem não vai. O conhecimento atual sugere que um ensaio clínico curto é a melhor maneira de responder essa pergunta.

Notas de tradução

Traduzido pelo Centro Cochrane do Brasil (Arnaldo Alves da Silva e Patricia Logullo).

Laički sažetak

Gabapentin za kroničnu neuropatsku bol i fibromijalgiju odraslih

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.

Gabapentin je lijek razvijen za liječenje epilepsije, ali se danas koristi i za liječenje različitih oblika kronične (dugotrajne) boli. Tijekom izrade ovog Cochrane sustavnog pregleda 17. ožujka 2014. godine je pretražena literatura kako bi se pronašle kliničke studije u kojima je ispitan gabapentin za liječenje neuropatske boli ili fibromijalgije. Pronađeno je 37 studija s ukupno 5633 ispitanika; studije su bile odgovarajuće kvalitete. U tim je studijama istražen gabapentin i uspoređen s placebom tijekom 4 tjedna ili duljeg razdoblja. Studije koje traju 1-2 tjedna nisu od velike koristi jer se radi o stanjima kod kojih bol može trajati godinama.

Samo su dva poremećaja ispitana na način da su studije u kojima su istraženi dala dovoljno podataka za ovaj sustavni pregled - postherpetična neuralgija (dugotrajna bol koja se javlja nakon herpes zoster infekcije) i bolna dijabetička neuropatija (stanje kod kojeg su živci oštećeni zbog dijabetesa). Gabapentin je bio koristan kod 3-4 osobe od 10 za ublažavanje boli barem za 50%, dok je u placebo skupini samo 2 od 10 ispitanika imalo takav rezultat.

Ako uzimaju gabapentin, 6 od 10 osoba može očekivati neke nuspojave, uključujući vrtoglavicu (2 od 10), pospanost (1-2 od 10), periferne otekline (1 od 10) i poremećaje hoda (1 od 10). Ozbiljne nuspojave (1 od 33) nisu bile češće u skupini koja je primala gabapentin u usporedbi sa skupinom koja je primala placebo. Jedna osoba od 10 odustala je od sudjelovanja u studiji zbog nuspojava. Osobe koje uzimaju gabapentin mogu očekivati barem jednu nuspojavu (6 od 10) ili prestanu uzimati gabapentin zbog nuspojava (1 od 10).

Gabapentin može pomoći nekim pacijentima koji pate od kronične neuropatske boli ili fibromijalgije. Međutim, nije moguće unaprijed znati kojim pacijentima će lijek pomoći, a kojima neće. Prema trenutnim spoznajama, potrebno je pacijentu dati lijek kroz kraće vrijeme pa procijeniti da li pomaže.

Bilješke prijevoda

Hrvatski Cochrane
Prevela: Livia Puljak
Ovaj sažetak preveden je u okviru volonterskog projekta prevođenja Cochrane sažetaka. Uključite se u projekt i pomozite nam u prevođenju brojnih preostalih Cochrane sažetaka koji su još uvijek dostupni samo na engleskom jeziku. Kontakt: cochrane_croatia@mefst.hr

எளியமொழிச் சுருக்கம்

நாள்பட்ட நரம்பு சார்ந்த வலி மற்றும் ஃபைப்ரோமையால்ஜியா உடைய பெரியவர்களுக்கு காபாபேண்டின்

சேதமடைந்த நரம்புகளால் நரம்பு சார்ந்த வலி உண்டாகிறது. அது சேதமடைந்த திசுக்களில் (ஒரு வீழ்ச்சி, வெட்டு, அல்லது முழங்கால் கீல்வாதம்) இருந்து ஆரோக்கியமான நரம்புகள் மூலம் எடுத்துச் செல்லப்படும் வலி சமிக்ஞைகளில் இருந்து வேறுபடுகிறது. நரம்பு சார்ந்த வலிக்கு சேதமடைந்த திசுவினால் ஏற்படும் வலிக்கு கொடுக்கப்படும் மருந்துகளில் இருந்து வேறுபட்ட மருந்துகள் மூலம்சி கிச்சையளிக்கப்படுகிறது. பாராசெட்டமால் அல்லது இபுப்ரோஃபென் போன்ற மருந்துகள், நரம்பு சார்ந்த வலிக்கு பயனுள்ளதாக இராது. சில நேரங்களில் மன அழுத்தம் அல்லது வலிப்பு சிகிச்சைக்கு பயன்படுகின்ற மருந்துகள் நரம்புநோய் வலி கொண்ட சிலருக்கு மிகவும் பயனுள்ளதாக இருக்கும். ஃபைப்ரோமையால்ஜியா (தொடர், பரவலான வலி மற்றும் தொடு அழுத்த வலி, தூக்கச் சிக்கல்கள், மற்றும் சோர்வு உண்டாக்கும் ஒரு நோய்) பற்றிய நம்முடைய புரிதல் குறைவே, ஆனால் ஃபைப்ரோமையால்ஜியா நரம்பு சார்ந்த வலிக்கு கொடுக்கப்படும் அதே மருந்துகளுக்கு குறையலாம்.

காபாபெண்டின் வலிப்பு சிகிச்சைக்காக உருவாக்கப்பட்டது, ஆனால் அது இப்போது பல்வேறுபட்ட நாள்பட்ட வலி சிகிச்சைக்கு பயன்படுத்தப்படுகிறது. 17 மார்ச் 2014 அன்று நாங்கள் நரம்பு சார்ந்த வலி அல்லது ஃபைப்ரோமையால்ஜியா சிகிச்சைக்கு காபாபெண்டின் பயன்படுத்தப்பட்ட மருத்துவ அய்வுகளை தேடினோம். நாங்கள் ஓரளவு தரம் கொண்ட 5633 பங்கேற்பாளர்கள் கொண்ட 37 ஆய்வுகளை கண்டறிந்தோம். அவர்கள் நான்கு வாரங்கள் அல்லது அதற்கும் மேலாகவோ மருந்துப்போலிக்கு எதிராக காபாபெண்டினை ஒப்பிட்டு பரிசோதித்தனர். வருடக்கணக்கில் வலி இருப்பதால் ஒன்று அல்லது இரண்டு வாரங்கள் மட்டும் நீடித்த ஆய்வுகளினால் பயனில்லை.

இரண்டு நோய்களுக்கு மட்டும்தான் போதுமான தரவுகள் உள்ளன.-கெர்பஸ்- வைரஸ் பாதிப்பிற்கு பின் நரம்பு வலி (சிங்க்லஸ் (கொப்புளப் புண்கள் உண்டாக்கும் ஒருவகைத் தோல் நோய்) தொடர்ந்து நாள்பட்ட வலி) மற்றும் வலியுடன் கூடிய நீரிழிவு நரம்புநோய் (நீரிழிவு நோயினால் நரம்புகள் சேதமடைதல்) காபாபெண்டின் பத்தில்3 அல்லது 4 வருக்கு வலியை குறைந்தது பதியாக குறைத்தது, மருந்தற்ற குளிகை உட்கொண்டோரில் பத்தில் 2 வர்க்கு மட்டும் அதே முடிவுக் கிட்டியது.

காபாபெண்டினால் 10 ல் 6 பேருக்கு, (மயக்கம் (10ல் 2 பேருக்கு), அரைத்தூக்கம்10 ல்1 வர் அல்லது 2வருக்கு), புற வீக்கம் ( 10ல் 1வருக்கு),மற்றும் நடை இடையூறு (10 ல் 1வருக்கு) உட்பட, சில பாதகமான விளைவுகள் இருக்க, எதிர்பார்க்கலாம். தீவிர பாதகமான விளைவுகள் ( 33ல் 1வருக்கு ) மருந்து போலியை விட பொதுவாக அதிகமாக இல்லை. 10 இல் ஒருவர் பாத்கமான விளைவுகளினால் விலகினர் காபாபெண்டின் எடுக்கும் நபர்கள் குறைந்தது ஒரு தீங்கு விளைவிக்கும் நிகழ்வை (10 ல் 6 பேருக்கு) எதிர்பார்க்கலாம், அல்லது எதிர்விளைவின் காரணமாக (சுமார்10 ல் 1வர் ) காபாபெண்டின் எடுப்பதை நிறுத்தலாம்.

நாள்பட்ட நரம்பு சார்ந்த வலி மற்றும் ஃபைப்ரோமையால்ஜியா உடைய சிலருக்கு காபாபேண்டின் உதவக்கூடும். ஆனால் எவருக்கு நன்மை பயக்கும் என்று முன்னதாகவே தெரிந்து கொள்ள சாத்தியம் இல்லை. தற்போதைய அறிவு குறுகியகால ஆய்வுகளே சொல்வதற்கு சிறந்த வழி என அறிவுறுத்துகிறது .

மொழிபெயர்ப்பு குறிப்புகள்

மொழிபெயர்ப்பு: சி.இ.பி.என்.அர் குழு

Laienverständliche Zusammenfassung

Gabapentin zur Behandlung von neuropathischen Schmerzen und Fibromyalgie bei Erwachsenen

Neuropathische Schmerzen werden auf Schädigungen von Nerven zurückgeführt. Sie werden unterschieden von Schmerzsignalen aufgrund einer Gewebeschädigung (zum Beispiel durch einen Sturz, eine Schnittverletzung oder eine Kniegelenksentzündung), welche entlang gesunder Nervenfasern geleitet werden. Neuropathische Schmerzen werden auch mit anderen Medikamenten behandelt als Schmerzen, die von geschädigtem Gewebe verursacht werden. Medikamente wie Paracetamol oder Ibuprofen sind bei neuropathischen Schmerzen nicht wirksam. Hingegen können Medikamente, die manchmal bei Depression oder Epilepsie eingesetzt werden, bei einigen Menschen mit neuropathischen Schmerzen sehr wirksam sein. Unser Verständnis der Fibromyalgie (einer Erkrankung mit anhaltenden, ausgedehnten Schmerzen, Berührungsempfindlichkeit, sowie Schlafstörungen und Erschöpfung) ist unzureichend. Doch es ist bekannt, dass Fibromyalgie auf die gleichen Medikamente ansprechen kann, welche auch bei neuropathischen Schmerzen wirken.

Gabapentin wurde ursprünglich zur Therapie von Epilepsie entwickelt, wird aber inzwischen auch zur Behandlung verschiedener Formen von chronischen Schmerzen verwendet. Am 17. März 2014 führten wir eine Literatursuche nach klinischen Studien durch, die Gabapentin zur Behandlung neuropathischer Schmerzen oder von Fibromyalgie einsetzten. Wir fanden 37 Studien von befriedigender Qualität mit insgesamt 5633 Teilnehmern. Gabapentin wurde jeweils über mindestens vier Wochen mit Placebo verglichen. Studien mit einer Behandlungsdauer von nur ein bis zwei Wochen sind im Hinblick auf chronische Schmerzen, die oft jahrelang anhalten, nicht hilfreich.

Lediglich für zwei Erkrankungen fanden wir eine ausreichende Menge Daten: chronische Schmerzen nach dem Auftreten von Gürtelrose (postherpetische Neuralgie) und chronische Schmerzen durch Nervenschädigung bei Diabetes (diabetische Neuropathie). Gabapentin halbierte bei drei oder vier von zehn Teilnehmern die Schmerzen; Placebo hatte diese Wirkung nur bei zwei von zehn Personen.

Mit Gabapentin müssen sechs von zehn Personen mit Nebenwirkungen, wie zum Beispiel Schwindel (zwei von zehn), Schläfrigkeit (einer oder zwei von zehn), Schwellung der Beine (einer von zehn) oder Gangunsicherheit (einer von zehn) rechnen. Ernste Nebenwirkungen (eine von 33 Personen) wurden aber nicht häufiger festgestellt als mit Placebo. Eine von zehn Personen beendete die Teilnahme an der Studie auf Grund von Nebenwirkungen. Wer Gabapentin nimmt, muss mit dem Auftreten mindestens einer Nebenwirkung rechnen (sechs von zehn Patienten waren betroffen), oder damit, die Behandlung wegen Nebenwirkungen abzubrechen (ungefähr einer von zehn Patienten).

Gabapentin hilft manchen Menschen, die an chronischen neuropathischen Schmerzen oder Fibromyalgie leiden. Es ist aber nicht möglich vorherzusagen, bei wem das Medikament helfen wird und bei wem nicht. Um das herauszufinden sollte nach heutigem Kenntnisstand am besten ein kurzer Therapieversuch durchgeführt werden.

Anmerkungen zur Übersetzung

C. Wildhagen, freigegeben durch Cochrane Schweiz

Ringkasan bahasa mudah

Gabapentin untuk sakit neuropatik kronik and mialgia otot dalam kalangan dewasa

Sakit neuropatik adalah sakit yang berpunca dari kecederaan saraf. Ia berbeza daripada mesej sakit yang dibawa oleh saraf yang sihat daripada tisu tercedera (jatuh, luka atau lutut artritik). Sakit neuropatik dirawat dengan pelbagai ubat yang berbeza dengan ubat untuk tisu tercedera. Ubat-ubat seperti parasetamol atau ibuprofen tidak berkesan untuk sakit neuropatik, manakala ubat-ubat yang kadangkala diguna untuk merawat kemurungan atau epilepsi boleh menjadi amat berkesan bagi sesetengah orang dengan sakit neuropatik. Kefahaman kami tentang mialgia otot (satu keadaan berterusan, sakit meluas, masalah tidur dan keletihan) adalah kurang, namun mialgia otot boleh dirawat dengan ubat-ubat yang sama bagi sakit neuropatik.

Gabapentin dibangunkan untuk merawat epilepsi, tetapi ia kini digunakan untuk merawat pelbagai jenis sakit kronik. Pada 17 Mac 2014 kami melakukan carian kajian klinikal di mana gabapentin digunakan untuk merawat sakit neuropatik atau mialgia otot. Kami mendapati 5633 peserta telah terlibat dalam 37 kajian yang kualitinya munasabah. Kajian-kajian tersebut menguji gabapentin berbanding plasebo selama empat minggu atau lebih. Kajian yang bertempoh hanya satu atau dua minggu tidak membantu kerana sakit boleh bertahan bertahun-tahun.

Hanya dua keadaan yang mempunyai jumlah data yang berguna - neuralgia postherpetik (sakit kronik selepas kayap) dan sakit akibat neuropati diabetik (kerosakan saraf akibat diabetes). Gabapentin telah membantu 3 atau 4 orang dalam 10 dengan mengurangkan kesakitan sekurang-kurangnya separuh, manakala plasebo hanya 2 dalam 10 orang mempunyai keputusan begini.

Dengan gabapentin 6 orang dalam 10 boleh mengalami beberapa peristiwa buruk, termasuk pening (2 dalam 10); mengantuk (1 atau 2 dalam 10), edema periferi (1 dalam 10), dan gangguan gaya jalan (1 dalam 10). Peristiwa buruk serius (1 dalam 33) adalah tidak lebih lazim dengan plasebo. Satu orang dalam 10 menarik diri kerana peristiwa buruk. Orang yang mengambil gabapentin boleh mengalami sekurang-kurangnya satu peristiwa buruk (6 dalam 10), atau berhenti mengambil gabapentin kerana satu peristiwa buruk (kira-kira 1 dalam 10).

Gabapentin amat berguna untuk sesetengah orang yang mengalami nyeri neuropatik atau nyeri otok. Namun demikian, kami tidak mungkin akan mengetahui siapa yang boleh bermanfaat daripada ubat ini dan siapa yang tidak. Pengetahuan yang kami dapat kini bercadang bahawa kajian singkat merupakan cara terbaik untuk menentukan kesesuaian gabapentin dalam kalangan pesakit.

Catatan terjemahan

Diterjemahkan oleh Phang Yee Lin (International Medical University). Disunting oleh Noorliza Mastura Ismail (Kolej Perubatan Melaka-Manipal). Untuk sebarang pertanyaan berkaitan terjemahan ini sila hubungi Phang.YeeLin@student.imu.edu.my.

Summary of findings(Explanation)

Summary of findings for the main comparison. 
  1. LOCF: last observation carried forward; NNT: number needed to treat for an additional beneficial effect: NNH: number needed to treat for an additional harmful effect; RR: risk ratio

Gabapentin compared with placebo for neuropathic pain and fibromyalgia

Patient or population: adults with postherpetic neuralgia or painful diabetic neuropathy

Settings: community

Intervention: gabapentin ≥ 900 mg daily

Comparison: placebo

OutcomeProbable outcome with interventionProbable outcome with placeboNNT or NNH and/or relative effect (95% CI)No of participantsQuality of the evidence
(GRADE)
Comments
Postherpetic neuralgia: gabapentin ≥ 1800 mg daily or gabapentin encarbil 1200 mg daily
At least 50% reduction in pain or equivalent340 in 1000210 in 1000

RR 1.6 (1.3 to 1.9)

NNT 8.0 (6.0 to 12)

1816

(6 studies)

Moderate

Imputation method used (LOCF) and small study size could influence results to reduce gabapentin efficacy.

Range of doses and dosing regimens pooled to obtain these results, so no guidance regarding efficacy or harm of particular doses

IMMPACT definition - any substantial pain benefit340 in 1000200 in 1000

RR 1.7 (1.4 to 2.0)

NNT 6.8 (5.4 to 9.3)

2045

(7 studies)

Moderate
Patient Global Impression of Change much or very much improved390 in 1000290 in 1000

RR 1.3 (1.2 to 1.5)

NNT 9.7 (6.9 to 16)

2013

(7 studies)

Moderate
IMMPACT definition - any at least moderate pain benefit440 in 1000270 in 1000

RR 1.6 (1.4 to 1.8)

NNT 5.7 (4.6 to 7.5)

2045

(7 studies)

Moderate
Painful diabetic neuropathy
At least 50% reduction in pain or equivalent380 in 1000210 in 1000

RR 1.9 (1.5 to 2.3)

NNT 5.9 (4.6 to 8.3)

1277

(6 studies)

Moderate

Imputation method used (LOCF) and small study size could influence results to reduce gabapentin efficacy.

Range of doses and dosing regimens pooled to obtain these results, so no guidance regarding efficacy or harm of particular doses

IMMPACT definition - any substantial pain benefit380 in 1000210 in 1000

RR 1.9 (1.5 to 2.3)

NNT 5.9 (4.6 to 8.3)

1277

(6 studies)

Moderate
Patient Global Impression of Change much or very much improved500 in 1000300 in 1000

RR 1.7 (1.4 to 2.0)

NNT 4.9 (3.6 to 7.6)

695

(5 studies)

Moderate
IMMPACT definition - any at least moderate pain benefit520 in 1000370 in 1000

RR 1.4 (1.3 to 1.6)

NNT 6.6 (4.9 to 9.9)

1439

(7 studies)

Moderate
All conditions - pooled data
Adverse event withdrawals110 in 100079 in 1000

RR 1.4 (1.1 to 1.7)

NNH 31 (20 to 66)

4448

(22 studies)

HighUnlikely new research would change this finding
Serious adverse events32 in 100028 in 1000RR 1.2 (0.83 to 1.7)

3952

(19 studies)

ModerateSmall number of events but no suggestion of difference
Death3 in max 3603 exposed5 in max 2377 exposednot calculatednot calculatedLowFew events, relatively short duration for drug possibly taken over periods of years
GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

Background

This is an update of a Cochrane review published in 2011. That review was an update of a previous Cochrane review titled 'Gabapentin for acute and chronic pain' (Wiffen 2005), which itself was an extension to a review previously published in The Cochrane Library on 'Anticonvulsant drugs for acute and chronic pain' (Wiffen 2000). The effects of gabapentin in established acute postoperative pain have been published as a separate review in 2010 (Straube 2010).

The decision to split the review in 2011 was undertaken after discussions with the Editor-in-Chief of The Cochrane Collaboration at a meeting in Oxford in early 2009. That meeting was in response to controversy in the United States of America (USA) over the effectiveness of gabapentin as an analgesic (Landefeld 2009) together with calls for the 2005 review to be updated with the inclusion of unpublished information made available through litigation (Vedula 2009). It was agreed to update the review by splitting the earlier one into two components: this review looking at the role of gabapentin in chronic neuropathic pain (including neuropathic pain of any cause, and fibromyalgia), and a second one to determine the effects of gabapentin in acute postoperative pain (Straube 2010). Other reviews may examine gabapentin in chronic musculoskeletal pain. After the review published in 2005, unpublished data were released by the licence holders of the first gabapentin product to be marketed, and these data were included in the 2011 review. This latest update has an expanded background, in line with other reviews of antiepileptic drugs used to treat neuropathic pain and fibromyalgia, and includes three new studies for oral gabapentin plus additional information on an already included study. We have also identified a number of ongoing studies.

The original chronic pain review on oral gabapentin included 14 studies with 1392 participants in 13 reports. The 2011 update involved 29 studies in 29 reports with 3571 participants. In this update we consider 33 studies in 34 reports, involving 4388 participants taking oral gabapentin.

Description of the condition

The 2011 International Association of the Study of Pain definition of neuropathic pain is "pain caused by a lesion or disease of the somatosensory system" (Jensen 2011) based on an earlier consensus meeting (Treede 2008). Neuropathic pain may be caused by nerve damage, but is often followed by changes in the central nervous system (CNS) (Moisset 2007). It is complex (Apkarian 2011; Tracey 2011), and neuropathic pain features can be found in patients with joint pain (Soni 2013). Moreover, neuropathic pain and fibromyalgia patients experience similar sensory phenomena (Koroschetz 2011).

Neuropathic pain tends to be chronic and may be present for months or years. Fibromyalgia is defined as widespread pain for longer than three months with pain on palpation at 11 or more of 18 specified tender points (Wolfe 1990), and is frequently associated with other symptoms such as poor sleep, fatigue, and depression. More recently, a definition of fibromyalgia has been proposed based on symptom severity and the presence of widespread pain (Wolfe 2010). The cause, or causes, are not well understood, but it has features in common with neuropathic pain, including changes in the CNS. Many people with these conditions are significantly disabled with moderate or severe pain for many years.

In primary care in the UK the incidences, per 100,000 person years observation, have been reported as 28 (95% CI 27 to 30) for postherpetic neuralgia, 27 (26 to 29) for trigeminal neuralgia, 0.8 (0.6 to 1.1) for phantom limb pain and 21 (20 to 22) for painful diabetic neuropathy (Hall 2008). They appear to be increasing over time (Hall 2013). Estimates vary between studies, often because of small numbers of cases. The incidence of trigeminal neuralgia has been estimated at 4 in 100,000 per year (Katusic 1991; Rappaport 1994), while more recently, a study of facial pain in The Netherlands found incidences per 100,000 person years of 12.6 for trigeminal neuralgia and 3.9 for postherpetic neuralgia (Koopman 2009). A systematic review of chronic pain demonstrated that some neuropathic pain conditions, such as painful diabetic neuropathy, can be more common, with prevalence rates up to 400 per 100,000 person years (McQuay 2007) illustrating how common the condition was as well as its chronicity. The prevalence of neuropathic pain was reported as being 3.3% in Austria (Gustorff 2008), 6.9% in France (Bouhassira 2008), as high as 8% in the UK (Torrance 2006), and about 7% in a systematic review of studies published since 2000 (Moore 2013a). Some forms of neuropathic pain, such as diabetic neuropathy and post surgical chronic pain (which is often neuropathic in origin) are increasing (Hall 2008). Fibromyalgia is common, especially in women, with an all-age prevalence of 12%, and a female to male ratio of 6:1 (McNally 2006).

Neuropathic pain and fibromyalgia are known to be difficult to treat effectively, with only a minority of individuals experiencing a clinically relevant benefit from any one intervention. A multidisciplinary approach is now advocated, with pharmacological interventions being combined with physical interventions, cognitive interventions, or both. Conventional analgesics are usually not effective (Tölle 2013). Some patients may derive some benefit from a topical lidocaine patch or low concentration topical capsaicin, though evidence for the benefits is uncertain (Derry 2012; Khaliq 2007). High concentration topical lidocaine may benefit some patients with postherpetic neuralgia (Derry 2013). Treatment is more usually by so-called unconventional analgesics such as antidepressants like duloxetine and amitriptyline (Lunn 2009; Moore 2012a; Sultan 2008) or antiepileptics like gabapentin or pregabalin (Moore 2009a; Wiffen 2013a). An overview of treatment guidelines points out some general similarities, but also differences in approach (O'Connor 2009). The proportion of patients who achieve worthwhile pain relief (typically at least 50% pain intensity reduction (Moore 2013b)) is small, generally 10% to 25% more than with placebo, with the number needed to treat for an additional beneficial outcome (NNTB) usually between 4 and 10. The finding of low treatment success rates with analgesics is common across a range of acute and chronic pain conditions (Moore 2013b).

Chronic painful conditions comprise five of the 11 top-ranking conditions for years lived with disability in 2010 (Vos 2012), and are responsible for considerable loss of quality of life, employment, and increased health costs (Moore 2013a).

Description of the intervention

Gabapentin is licensed for the treatment of peripheral and central neuropathic pain in adults in the UK at doses up to 3.6 grams (3600 mg) daily. It is given orally, usually as tablets or capsules, but sometimes as an oral solution (50 mg/ml). Guidance suggests that gabapentin treatment can be started at a dose of 300 mg per day for treating neuropathic pain. Based on individual patient response and tolerability, the dosage may be increased by 300 mg per day until pain relief is experienced or adverse effects make taking the drug intolerable (EMC 2009). US marketing approval for gabapentin was granted in 2002 for postherpetic neuralgia; in Europe, the label was changed to include peripheral neuropathic pain in 2006. Gabapentin has the trade name Neurontin, and is also available as generic products in some parts of the world.

Gabapentin has a half-life of five to seven hours. It is absorbed through a saturable transport system, so that absorption is not linear, and the transporter is found only in the proximal small bowel. This means that the drug needs to be administered at least three times daily, and may result in plasma trough levels. Two new formulations have attempted to improve the availability of the drug. The first is an extended release, gastro-retentive formulation, designed to provide continuous delivery at the optimal site of absorption over 8 to 10 hours (Sang 2013). The second uses an extended-release prodrug (gabapentin encarbil) that is absorbed through a high capacity transport system found throughout the intestine, and then undergoes rapid hydrolysis to gabapentin. It is claimed to provide sustained, dose-proportional gabapentin exposure (Backonja 2011), and can be administered twice daily.

Gabapentin can also be formulated as an aqueous solution for injection. This formulation is not available commercially or licensed for treatment of any type of neuropathic pain or fibromyalgia.

How the intervention might work

Gabapentin is thought to act by binding to calcium channels and modulating calcium influx. This mode of action confers antiepileptic, analgesic and sedative effects. The most recent research indicates that gabapentin acts by blocking new synapse formation (Barres 2009).

Why it is important to do this review

Gabapentin is widely prescribed for neuropathic pain and it is common practice in some countries to aim for the maximum tolerated dose. There is growing controversy over whether this practice is justified by experimental evidence from double-blind randomised trials.

The original review of antiepileptic drugs for neuropathic pain has been withdrawn (Wiffen 2010, originally published in 2005), and split into reviews for individual drugs, including carbamazepine (Wiffen 2011a), lamotrigine (Wiffen 2011b), topiramate (Wiffen 2013b) pregabalin (Moore 2009a), valproic acid (Gill 2011), phenytoin (Birse 2012), and clonazepam (Corrigan 2012). These separate reviews for individual drugs use more stringent criteria of validity, which include the level of response obtained, the duration of study and method of imputation of missing data (Moore 2012a).

There have been several changes in how the efficacy of both conventional and unconventional treatments is assessed in chronic painful conditions. The outcomes used today are better defined, particularly with new criteria for what constitutes moderate or substantial benefit (Dworkin 2008); older trials may only report participants with 'any improvement'. Newer trials tend to be larger, avoiding problems from the random play of chance. Newer trials also tend to be longer, up to 12 weeks, and longer trials provide a more rigorous and valid assessment of efficacy in chronic conditions. New standards have evolved for assessing efficacy in neuropathic pain, we are now applying stricter criteria for inclusion of trials and assessment of outcomes, and we are more aware of problems that may affect our overall assessment.

To summarise, some of the recent insights into studies in neuropathic pain and chronic pain more generally that make a new review necessary, over and above including more trials, are the following:

  1. Pain relief results tend to have a U-shaped distribution rather than a bell-shaped distribution, with participants either achieving very good levels of pain relief, or little or none. This is the case for acute pain (Moore 2005a), fibromyalgia (Straube 2010), and arthritis (Moore 2009b); in all cases average results usually describe the actual experience of almost no-one in the trial. Continuous data expressed as averages should be regarded as potentially misleading, unless it can be proved to be suitable. Systematic reviews now frequently report results for responders (Lunn 2009; Moore 2010a; Straube 2008; Sultan 2008).

  2. This means we have to depend on dichotomous results usually from pain changes or patient global assessments. The IMMPACT group has helped with their definitions of minimal, moderate, and substantial improvement (Dworkin 2008). In arthritis, trials shorter than 12 weeks, and especially those shorter than eight weeks, overestimate the effect of treatment (Moore 2009b); the effect is particularly strong for less effective analgesics. What is not always clear is how withdrawals are reported. Withdrawals can be high in some chronic pain conditions (Moore 2005b; Moore 2010b).

  3. The proportion with at least moderate benefit can be small, falling from 60% with an effective medicine in arthritis, to 30% in fibromyalgia (Moore 2009b; Straube 2008; Sultan 2008). A Cochrane Review of pregabalin in neuropathic pain and fibromyalgia demonstrated different response rates for different types of chronic pain (higher in diabetic neuropathy and postherpetic neuralgia and lower in central pain and fibromyalgia) (Moore 2009a). This indicates that different neuropathic pain conditions should be treated separately from one another, and that pooling should not be done unless there are good grounds for doing so.

  4. Finally, individual patient analyses indicate that patients who get clinically useful pain relief (moderate or better) have major benefits in many other outcomes, affecting quality of life in a major way (Hoffman 2010; Moore 2010c). A good response to pain predicts good effects for other troublesome symptoms like sleep, fatigue and depression.

These are by no means the only issues of trial validity that have been raised recently. A summary of what constitutes evidence in trials and reviews in chronic pain has been published (Moore 2010d). This review has attempted to address all of them, so that the review is consistent with current best practice.

This Cochrane review concentrates on evidence in ways that make both statistical and clinical sense. Studies included and analysed meet a minima of reporting quality (blinding, randomisation), validity (duration, dose and timing, diagnosis, outcomes, etc.), and size (ideally a minimum of 500 participants in a comparison with the number needed to treat to benefit (NNT) of four or greater (Moore 1998)).

This review covers chronic neuropathic pain and fibromyalgia, concentrating for efficacy on dichotomous responder outcomes. We consider conditions individually, as there is evidence of different effects in different neuropathic pain conditions for some interventions like pregabalin (Moore 2009a), though less so for others (Lunn 2009). The review also considers additional risks of bias. These include issues of withdrawal (Moore 2010b), size (Moore 1998; Nuesch 2010), and duration (Moore 2010a) in addition to standard risks of bias. In this 2014 update we emphasise the difference between first tier and second tier evidence, and also emphasise the differences between conditions now defined as neuropathic pain, and other conditions like masticatory pain, CRPS-1, and fibromyalgia.

The review is one of a series, and will be included in an overview of antiepileptic drugs for neuropathic pain and fibromyalgia (Wiffen 2013a).

Objectives

To assess the analgesic efficacy and adverse effects of gabapentin in chronic neuropathic pain and fibromyalgia.

Methods

Criteria for considering studies for this review

Types of studies

We included studies if they were randomised controlled trials (RCTs) with double-blind (participant and observers) assessment of participant-reported outcomes, following two weeks of treatment or longer, although the emphasis of the review was on studies of six weeks or longer. Full journal publication was required, with the exception of extended abstracts of otherwise unpublished clinical trials (for example detailed information from PDFs of posters that typically include all important details of methodology used and results obtained), otherwise unpublished clinical trial reports obtained from clinicaltrials.gov or similar sources, or clinical trial reports disclosed during the course of legal proceedings.

We did not include short abstracts (usually meeting reports with inadequate or no reporting of data). We excluded studies of experimental pain, case reports, and clinical observations.

Types of participants

We included adult participants aged 18 years and above. Participants could have one or more of a wide range of chronic neuropathic pain conditions including (but not limited to):

  • painful diabetic neuropathy (PDN);

  • postherpetic neuralgia (PHN);

  • trigeminal neuralgia;

  • phantom limb pain;

  • postoperative or traumatic neuropathic pain

  • cancer-related neuropathy;

  • HIV-neuropathy;

  • spinal cord injury;

and

  • complex regional pain syndrome type 1 (CRPS-1);

  • fibromyalgia.

We also included studies of participants with more than one type of neuropathic pain. We analysed results according to the primary condition.

Types of interventions

Gabapentin in any dose, by any route, administered for the relief of neuropathic pain or fibromyalgia, and compared to placebo, no intervention or any other active comparator. We did not include studies using gabapentin to treat pain resulting from the use of other drugs.

Types of outcome measures

Studies had to report pain assessment as either a primary or secondary outcome.

We anticipated that studies would use a variety of outcome measures, with the majority of studies using standard subjective scales (numerical rating scale (NRS) or visual analogue scale (VAS)) for pain intensity or pain relief, or both. We were particularly interested in Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) definitions for moderate and substantial benefit in chronic pain studies (Dworkin 2008). These are defined as at least 30% pain relief over baseline (moderate), at least 50% pain relief over baseline (substantial), much or very much improved on Patient Global Impression of Change (PGIC) (moderate), and very much improved on PGIC (substantial). These outcomes are different from those set out in the earlier review (Wiffen 2005), concentrating as they do on dichotomous outcomes where pain responses do not follow a normal (Gaussian) distribution. People with chronic pain desire high levels of pain relief, ideally more than 50%, and with pain not worse than mild (O'Brien 2010).

We include a 'Summary of findings' table as set out in the Cochrane Pain, Palliative and Supportive Care Group author guide (AUREF 2012). The 'Summary of findings' table includes outcomes of at least 30% and at least 50% pain intensity reduction, PGIC, adverse event withdrawals, serious adverse events and death.

Primary outcomes
  1. Patient-reported pain intensity reduction of 30% or greater

  2. Patient-reported pain intensity reduction of 50% or greater

  3. Patient-reported global impression of clinical change (PGIC) much or very much improved

  4. Patient-reported global impression of clinical change (PGIC) very much improved

Secondary outcomes
  1. Any pain-related outcome indicating some improvement

  2. Withdrawals due to lack of efficacy

  3. Participants experiencing any adverse event

  4. Participants experiencing any serious adverse event

  5. Withdrawals due to adverse events

  6. Specific adverse events, particularly somnolence and dizziness

These outcomes were not eligibility criteria for this review, but are outcomes of interest within whichever studies are included.

Search methods for identification of studies

Electronic searches

We ran the searches for the original review in 2011. For this update, the following databases were searched:

  • Cochrane Central Register of Controlled Trials (CENTRAL) (2014, Issue 3) in The Cochrane Library;

  • MEDLINE (via Ovid) (1966 to 17 March 2014);

  • EMBASE (via Ovid) (1980 to 17 March 2014);

  • Clinicaltrials.gov (on 17 March 2014).

See Appendix 1 for the CENTRAL search strategy, Appendix 2 for the MEDLINE search strategy, and Appendix 3 for the EMBASE search strategy.

There were no language restrictions.

Searching other resources

We searched reference lists of retrieved articles and reviews for any additional studies. We searched the Pharmaceutical
Research and Manufacturers of America (PhRMA) clinical study results database (www.clinicalstudyresults.org) and the World Health Organization (WHO) International Clinical Trials Registry Platform (apps.who.int/trialsearch/) for trial results of gabapentin in painful conditions, and information about ongoing studies.

Data collection and analysis

Selection of studies

All potentially relevant studies identified by the search were read independently by two review authors to determine eligibility, and agreement reached by discussion. The studies were not anonymised in any way before assessment. All publications that could not clearly be excluded by screening the title and abstract were obtained in full and read (Figure 1).

Figure 1.

Study flow diagram.

Data extraction and management

Three review authors extracted data (RAM, PW, SD) using a standard data extraction form, and agreed data before entry into RevMan (RevMan 2012) or any other analysis method. Data extracted included information about the pain condition and number of participants treated, drug and dosing regimen, study design, study duration and follow up, analgesic outcome measures and results, withdrawals and adverse events (participants experiencing any adverse event, or serious adverse event).

Assessment of risk of bias in included studies

We used the 'Risk of bias' tool to assess the likely impact on the strength of the evidence of various study characteristics relating to methodological quality (randomisation, allocation concealment and blinding), study validity (duration, outcome reporting, and handling of missing data), and size (Appendix 4).

We also scored each report independently for quality using a three-item scale (Jadad 1996) that considers randomisation, blinding and reporting of withdrawals. We then met to agree a 'consensus' score for each report. Low quality scores of two (out of a maximum of five) and below have been associated with greater estimates of efficacy than studies of higher quality (Khan 1996). Quality scores were not used to weight the results in any way.

Measures of treatment effect

We used dichotomous data to calculate risk ratio (RR) with 95% confidence intervals (CI) using a fixed-effect model unless significant statistical heterogeneity was found (see below). We calculated the number needed to treat for an additional beneficial outcome (NNT) as the reciprocal of the absolute risk reduction (ARR) (McQuay 1998). For unwanted effects, the NNT becomes the number needed to treat for an additional harmful outcome (NNH) and is calculated in the same manner. We did not use continuous data in analyses.

The following terms are used to describe adverse outcomes in terms of harm or prevention of harm:

  • When significantly fewer adverse outcomes occurred with gabapentin than with control (placebo or active) we use the term the number needed to treat to prevent one event (NNTp).

  • When significantly more adverse outcomes occurred with gabapentin compared with control (placebo or active) we use the term the number needed to harm or cause one event (NNH).

Unit of analysis issues

The control treatment arm would be split between active treatment arms in a single study if the active treatment arms were not combined for analysis.

Dealing with missing data

We used intention-to-treat (ITT) analysis wherever possible. The ITT population consisted of participants who were randomised, took the assigned study medication and provided at least one post-baseline assessment. Missing participants were assigned zero improvement (baseline observation carried forward (BOCF)) where this could be done. We were aware that imputation methods might be problematical and examined trial reports for information about them.

Assessment of heterogeneity

We dealt with clinical heterogeneity by combining studies that examined similar conditions. We assessed statistical heterogeneity visually (L'Abbe 1987) and with the use of the I2 statistic.

Assessment of reporting biases

The aim of this review was to use dichotomous data of known utility (Moore 2009b). The review did not depend on what the authors of the original studies chose to report or not report, though clearly there were difficulties with studies failing to report any dichotomous results. Continuous data, which probably poorly reflect efficacy and utility, were extracted and used only when useful for illustrative purposes.

We undertook no statistical assessment of publication bias.

We looked for effects of possible enrichment, either complete or partial, in enrolment of participants into the studies. Enrichment typically means including participants known to respond to a therapy, and excluding those known not to respond, or to suffer unacceptable adverse effects, though for gabapentin no significant effects have been shown from partial enrichment (Straube 2008). Enriched enrolment randomised withdrawal studies, known to produce higher estimates of efficacy, would not be pooled (McQuay 2008).

Data synthesis

We considered individual painful conditions separately because placebo response rates with the same outcome can vary between conditions, as can the drug-specific effects (Moore 2009a). We planned to use a fixed-effect model for meta-analysis, but no pooling of data was possible. We have included a ‘Summary of findings’ table according to recommendations described in Chapter 10 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011).

We analysed data for each painful condition in three tiers, according to outcome and freedom from known sources of bias.

  1. The first tier uses data meeting current best standards, where studies report the outcome of at least 50% pain intensity reduction over baseline (or its equivalent), without the use of last observation carried forward (LOCF) or other imputation method for dropouts, report an ITT analysis, last eight or more weeks, have a parallel-group design, and have at least 200 participants (preferably at least 400) in the comparison (Moore 2010a; Moore 2012b). These top-tier results are reported first.

  2. The second tier uses data from at least 200 participants but where one or more of the above conditions is not met (eg reporting at least 30% pain intensity reduction, using LOCF or a completer analysis, or lasting four to eight weeks).

  3. The third tier of evidence relates to data from fewer than 200 participants, or where there are expected to be significant problems because, for example, of very short duration studies of less than four weeks, where there is major heterogeneity between studies, or where there are shortcomings in allocation concealment, attrition, or incomplete outcome data. For this third tier of evidence, no data synthesis is reasonable, and may be misleading, but an indication of beneficial effects might be possible.

Subgroup analysis and investigation of heterogeneity

We planned for all analyses to be according to individual painful condition, because placebo response rates with the same outcome can vary between conditions, as can the drug-specific effects (Moore 2009a). We also planned subgroup analysis according to dose of gabapentin and duration of study if sufficient data were available.

Sensitivity analysis

We planned no sensitivity analyses because the evidence base was known to be too small to allow reliable analysis. Performing analyses that might inform on which patients were most likely to benefit from gabapentin treatment would require efficacy data together with detailed assessment of the exact nature and type of neuropathic pain at the individual patient level (Tölle 2013). No such data were expected to be available.

The 2011 review included three studies using a new gastroretentive formulation of gabapentin, two of which provided efficacy data. At that time we judged that there was no obvious difference from the standard oral formulation. Results now available from the third study, together with those in two new studies using the gastroretentive formulation and a prodrug formulation may make a sensitivity analysis based on formulation sensible if sufficient data were available.

Results

Description of studies

In the split update of the original review (Moore 2011), and for this update we made no attempt to contact authors or manufacturers of gabapentin. Clinical trial reports or synopses from previously unpublished studies became available as a result of legal proceedings in the USA. In the previous update, an author confirmed that one study was randomised but could provide no additional data (Perez 2000).

Included studies

The original chronic pain review included 14 studies with 1392 participants in 13 reports. The 2011 update involved 29 studies in 29 reports with 3571 participants. For this 2014 update we have added seven new studies of oral gabapentin with 1919 participants (Backonja 2011; Harden 2013; Mishra 2012; NCT00475904; Rauck 2013a; Sang 2013; Zhang 2013) and another publication (Sandercock 2012) that provided results for a study of oral gabapentin that was already included but did not provide usable data (Sandercock 2009); this more recent publication becomes the primary reference. We also identified a small study, with 170 participants, using an experimental formulation of injected (intrathecal) gabapentin (Rauck 2013b).

In this update we considered 37 studies in 38 reports examining oral gabapentin, involving 5633 participants (Figure 1). A number of chronic painful conditions were studied:

and

  • Masticatory myalgia; one study, 50 participants (Kimos 2007).

  • Complex regional pain syndrome type I (CRPS-1); one study, 58 participants (van de Vusse 2004).

  • Fibromyalgia; one study, 150 participants (Arnold 2007).

More than four fifths (84%) of the participants (4711) were enrolled in studies of PHN, PDN, or mixed neuropathic pain. The other nine neuropathic pain conditions were studied in 922 participants, with the largest numbers in cancer-related neuropathic pain (356 participants), fibromyalgia (150) and nerve injury pain (120).

Four studies (Irving 2009; Sandercock 2012; Sang 2013; Wallace 2010) used a gastroretentive, extended release formulation of gabapentin, and four others (Backonja 2011; Harden 2013; Rauck 2013a; Zhang 2013) used an extended release prodrug, gabapentin encarbil.

Twenty-three studies had a parallel-group design and 14 had a cross-over design (Bone 2002; Gilron 2005; Gilron 2009; Gordh 2008; Gorson 1999; Harden 2013; Ho 2009; Levendoglu 2004; Morello 1999; Rao 2007; Rintala 2007; Smith 2005; Tai 2002; van de Vusse 2004). We used whatever data were available from the cross-over studies, including first period or multiple periods, though there are major issues with what constitutes the ITT denominator where there are significant withdrawals.

Parallel-group trials were larger than cross-over trials. The 23 parallel-group studies involved 4563 participants (mean 207, median 162 participants, range 26 to 452), while the 14 cross-over studies involved 1041 participants (mean 74, median 39 participants, range 7 to 400). Not all studies reported the results on an ITT basis, and this was particularly the case for cross-over studies with multiple comparisons.

Twenty-three studies either described enrolment processes that were not enriched, or had no exclusion criteria that would raise the possibility of enrichment (Straube 2008). Eight studies were partially enriched (Caraceni 2004; Irving 2009; Rice 2001; Sandercock 2012; Sang 2013; Serpell 2002) or had previous treatment with gabapentin or pregabalin as an exclusion criterion, which may have led to enrichment (Arnold 2007; Wallace 2010). Two studies enriched for tolerance to gabapentin, but not response (Backonja 2011; Harden 2013), which is probably equivalent to partial enrichment. Participants were treated with gabapentin encarbil, a prodrug of gabapentin; it is analysed alongside the other studies, but with a view to sensitivity analysis. One study had complete enrichment (Ho 2009).

Three studies reported using baseline observation carried forward (BOCF) imputation for the primary outcome (Sandercock 2012; Sang 2013; Wallace 2010), sometimes alongside last observation carried forward (LOCF) analyses, and one reported using BOCF imputation for the responder analyses (Rauck 2013b). Twenty-five studies either made no mention of an imputation method for missing data (18) or declared use of LOCF (11). Others performed analyses on completers only (Rintala 2007; van de Vusse 2004), one presented results without imputation (Rao 2007), and in one we could not decide how data had been treated (Ho 2009).

Details of all eligible studies are given in the 'Characteristics of included studies' table.

Excluded studies

Several other studies were considered but excluded for various reasons. These included open studies (Arai 2010; Dallocchio 2000; Jean 2005; Kasimcan 2010; Keskinbora 2007; Ko 2010; NCT00634543; Salvaggio 2008; Sator-Katzenschlager 2005; Tanenberg 2011; Yaksi 2007), studies in chronic conditions not considered for this review (McCleane 2001; Pandey 2002; Pandey 2005; Sator-Katzenschlager 2005; Yaksi 2007), acute treatment of herpes zoster (Berry 2005; Dworkin 2009), and trials in surgery to prevent chronic phantom pain (Nikolajsen 2006). Two did not have an appropriate comparator (NCT01263132; NCT01623271). We also excluded an n-of-1 study in chronic neuropathic pain (Yelland 2009) with complete enrichment, high withdrawals, and short (two-week) treatment periods because this design is rare and interpretation very difficult. Details of excluded studies are given in the 'Characteristics of excluded studies' table.

Searches also identified several ongoing studies (Fleckstein 2009; IRCT201212019014N14; NCT00674687; NCT00904202).

Risk of bias in included studies

Reporting quality was largely good. On the five point Oxford Scale (Jadad 1996) addressing randomisation, blinding, and withdrawals, one study scored 2/5 points, four 3/5 points, 11 4/5 points, and 21 5/5 points. Studies with scores of 3/5 and above are considered unlikely to be subject to major systematic bias (Khan 1996). Points were lost mainly for inadequate descriptions of randomisation. The risk of bias assessments (Figure 2; Figure 3) emphasised this, with adequate sequence generation and allocation concealment being most often inadequately reported. Additional risk of bias also derived from studies being small, reporting unhelpful outcomes, rarely describing how efficacy data were handled on withdrawal, and being of short duration.

Figure 2.

Methodological quality graph: review authors' judgements about each methodological quality item presented as percentages across all included studies.

Figure 3.

Methodological quality summary: review authors' judgements about each methodological quality item for each included study.

Effects of interventions

See: Summary of findings for the main comparison

Appendix 5 contains details of withdrawals, efficacy, and adverse events in the individual studies.

Efficacy

Efficacy results are reported where data are available, or where there is sufficient information to justify analysis, defined as information from 200 participants or more, ideally from at least two studies.

First tier evidence

There was no first tier evidence of efficacy.

Second tier evidence

Second tier evidence was available for analyses of postherpetic neuralgia (PHN), painful diabetic neuropathy (PDN), and mixed neuropathic pain. The evidence was second tier mainly because of imputation using the LOCF method following withdrawal.

Analyses 1.1 to 1.5 show results for the following outcomes: at least 50% reduction in pain (Analysis 1.1; Figure 4); PGIC very much improved (Analysis 1.2; Figure 5); PGIC much or very much improved (Analysis 1.3; Figure 6); IMMPACT outcome of substantial improvement in pain (Analysis 1.4; Figure 7); IMMPACT outcome of at least moderate improvement in pain (Analysis 1.5; Figure 8).

Figure 4.

Forest plot of comparison: 1 All placebo-controlled studies, outcome: 1.1 At least 50% pain reduction over baseline.

Figure 5.

Forest plot of comparison: 1 All placebo-controlled studies, outcome: 1.2 Very much improved.

Figure 6.

Forest plot of comparison: 1 All placebo-controlled studies, outcome: 1.3 Much or very much improved.

Figure 7.

Forest plot of comparison: 1 All placebo-controlled studies, outcome: 1.4 IMMPACT outcome of substantial improvement.

Figure 8.

Forest plot of comparison: 1 All placebo-controlled studies, outcome: 1.5 IMMPACT outcome of at least moderate improvement.

Postherpetic neuralgia (PHN)

Of the 10 studies in PHN, eight (Backonja 2011; Irving 2009; NCT00475904; Rice 2001; Rowbotham 1998; Sang 2013; Wallace 2010; Zhang 2013) had a placebo control, and two (Chandra 2006; Harden 2013) an active control only. All eight placebo-controlled studies had a parallel-group design, with study duration of four to 12 weeks; daily gabapentin doses varied between 1800 mg and 3600 mg, while the dose of gabapentin encarbil was 1200 to 3600 mg daily.

At least 50% pain intensity reduction occurred in 34% of patients given gabapentin and 21% of those given placebo by the end of the study, with considerable consistency between studies (Summary of results A; Figure 9). Available data on dosing regimens were too sparse to establish a dose-response relationship. A number of outcomes consistent with IMMPACT recommendations for substantial and moderate benefit were reported in two or more placebo-controlled studies, and the results showed gabapentin at doses of 1800 mg daily or more, or gabapentin encarbil at 1200 mg daily, to be more effective than placebo (Summary of results A). For a Patient Global Impression of Change (PGIC) of much or very much improved, 39% of participants achieved this level of improvement with gabapentin and 29% with placebo. Other outcomes are reported in Summary of results A.

Figure 9.

Postherpetic neuralgia: Percentage of participants achieving at least 50% pain intensity reduction (PIR) over baseline with gabapentin 1200-3600 mg daily, or placebo

Only one of these studies (Rice 2001; 18% of participants) used a standard formulation of gabapentin, and removing it from the analysis did not significantly change the result. Similarly, removing the two studies using gabapentin encarbil (Backonja 2011; Zhang 2013; 26% of participants) did not affect the result. There were insufficient data for subgroup analyses based on dose or duration of studies.

Summary of results A. Efficacy outcomes with gabapentin in postherpetic neuralgia (PHN)

 Number ofPercent with outcome 
OutcomeStudiesParticipantsGabapentinPlaceboRisk ratio
(95% CI)
NNT
(95% CI)
Substantial benefit
At least 50% pain intensity reduction6181634211.6 (1.3 to 1.9)8.0 (6.0 to 12)
PGIC very much improved25631562.7 (1.5 to 4.8)11 (7.0 to 22)
Any definition of substantial benefit (at least 50% pain intensity reduction or PGIC very much improved)7204534201.7 (1.4 to 2.0)6.8 (5.4 to 9.3)
Moderate benefit
At least 30% pain intensity reduction252954381.4 (1.1 to 1.7)6.5 (4.0 to 16)
PGIC much or very much improved7201339291.3 (1.2 to 1.5)9.7 (6.9 to 16)
Any definition of moderate benefit (at least 30% pain intensity reduction or PGIC much or very much improved)7204544271.6 (1.4 to 1.8)5.7 (4.6 to 7.5)

In the active controlled study involving 76 participants, gabapentin at doses of up to 2700 mg daily was compared to nortriptyline at doses of up to 150 mg daily over nine weeks. At least 50% improvement in pain over baseline using a VAS pain scale was achieved by 13/38 (34%) on gabapentin and 14/38 (37%) on nortriptyline, broadly in line with event rates in placebo-controlled studies (Chandra 2006). Harden 2013 compared two dosing regimens of gabapentin encarbil in previous low dose treatment failures and found that about 13% did respond at the 50% pain reduction level.

Painful diabetic neuropathy (PDN)

Seven of the nine studies in PDN were of parallel-group design (Backonja 1998; CTR 945-1008; CTR 945-224; Perez 2000; Rauck 2013a; Sandercock 2012; Simpson 2001); two had a cross-over design (Gorson 1999; Morello 1999). Eight had a placebo comparator, while one (Morello 1999) had an active control only. Seven placebo-controlled parallel-group studies had a study duration between four and 14 weeks; all but one (Sandercock 2012) of seven weeks or longer. Daily gabapentin doses varied between 600 mg and 3600 mg; doses below 1200 mg were used in two studies, 900 mg daily as the only gabapentin dose in one (Gorson 1999), and 600 mg daily in one arm of another (CTR 945-224). Gabapentin encarbil at doses of 1200 and 3600 mg daily was compared with pregabalin 300 mg daily and placebo in one study (Rauck 2013a).

At least 50% pain intensity reduction occurred in 38% of patients given gabapentin and 21% of those given placebo by the end of the study, with considerable consistency between studies (Summary of findings B; Figure 10). Available data on dosing regimens were too sparse to establish a dose-response relationship. A number of outcomes consistent with IMMPACT recommendations for substantial and moderate benefit were reported in two or more placebo-controlled studies, and the results showed gabapentin at doses of 1200 mg daily or more to be more effective than placebo (Summary of results B). For PGIC much or very much improved; 50% of participants achieved this level of improvement with gabapentin and 30% with placebo, with very similar results when results from Simpson 2001 were omitted because of concerns one peer reviewer expressed about this study in a previous version of the review; no other efficacy outcome data were included from this study. Other outcomes are reported in Summary of results B.

Figure 10.

Painful diabetic neuropathy: Percentage of participants achieving at least 50% pain intensity reduction (PIR) over baseline with gabapentin 1200-3600 mg daily, or placebo

Two studies (Rauck 2013a; Sandercock 2012; 35% of participants) used the gabapentin encarbil or gastroretentive formulations. Removing these from the analysis did not change the result. There were insufficient data for subgroup analyses based on dose or duration of studies.

Summary of results B. Efficacy outcomes with gabapentin in painful diabetic neuropathy (PDN) (1200 mg daily or greater)

 Number ofPercent with outcome 
OutcomeStudiesParticipantsGabapentinPlaceboRisk ratio
(95% CI)
NNT
(95% CI)
Substantial benefit
At least 50% pain intensity reduction6127738211.9 (1.5 to 2.3)5.9 (4.6 to 8.3)
PGIC very much improved240824141.9 (1.3 to 3.0)9.6 (5.5 to 35)
Any definition of substantial benefit (at least 50% pain intensity reduction or PGIC very much improved)6127738211.9 (1.5 to 2.3)5.9 (4.6 to 8.3)
Moderate benefit
At least 30% pain intensity reduction274454431.2 (1.1 to 1.5)9.4 (5.6 to 29)
PGIC much or very much improved569550301.7 (1.4 to 2.0)4.9 (3.6 to 7.6)
PGIC much or very much improved (excluding Simpson 2001)463551311.6 (1.3 to 2.0)5.1 (3.7 to 8.3)
Any definition of moderate benefit (at least 30% pain intensity reduction or PGIC much or very much improved)7143952371.4 (1.3 to 1.6)6.6 (4.9 to 9.9)

Gabapentin 600 mg daily produced lesser effects than 1200 mg and 2400 mg daily in a study that compared them (CTR 945-224). In one placebo-controlled cross-over study involving 40 randomised participants, moderate or excellent pain intensity reduction was achieved by 17/40 (43%) with gabapentin 900 mg daily over six weeks, compared with 9/40 (23%) with placebo (Gorson 1999).

In one active-controlled study involving 25 participants, gabapentin at 1800 mg daily was compared to amitriptyline 75 mg daily over six weeks. Complete or a lot of pain relief was achieved by 6/21 (29%) with gabapentin and 5/21 (24%) with amitriptyline (Morello 1999).

Mixed neuropathic pain

One exploratory study (Rauck 2013b) examined the effects of intrathecal gabapentin in participants with chronic, intractable non cancer pain, the majority (147/170; 86%) of whom were classified as having pain of neuropathic or mixed types. Three different doses (1 mg, 6 mg, and 30 mg daily) were compared with placebo. There was no significant reduction in group mean pain scores within and between groups over the 22 day treatment period. The number of participants experiencing at least 30% reduction in pain was 4/42, 4/41, 1/41, and 2/44 for the 1 mg, 6 mg, 30 mg, and placebo groups respectively.

Three studies examined the effects of oral gabapentin in mixed neuropathic painful conditions (Gilron 2005; Gilron 2009; Serpell 2002); two included participants with PHN and PDN (Gilron 2005; Gilron 2009) and in the other the most common conditions were CRPS and PHN (Serpell 2002). One had a parallel-group comparison with placebo over eight weeks (Serpell 2002). The others had cross-over designs that included placebo and morphine alone and in combination with gabapentin over five weeks (Gilron 2005), and nortriptyline alone or in combination with gabapentin over six weeks (Gilron 2009).

The parallel-group comparison with placebo (Serpell 2002) used gabapentin titrated to a maximum of 2400 mg daily in 305 participants. Only for the PGIC outcome of much or very much improved was there a significant benefit of gabapentin (Summary of results C).

Summary of results C. Efficacy outcomes with gabapentin in mixed neuropathic pain (Serpell 2002)

 Number ofPercent with outcome 
OutcomeStudiesParticipantsGabapentinPlaceboRisk ratio
(95% CI)
NNT
(95% CI)
At least 50% pain intensity reduction130521141.5 (0.9 to 2.4)not calculated
PGIC very much improved13051262.0 (0.9 to 4.3)not calculated
PGIC much or very much improved130531142.2 (1.4 to 3.4)5.9 (3.8 to 13)

One placebo-controlled cross-over study (Gilron 2005) over five weeks provided results for moderate pain relief for participants who completed a given treatment period. Gabapentin alone (target dose 3200 mg daily), morphine alone (target dose 120 mg daily), and the combination (target dose gabapentin 2400 mg plus 60 mg morphine daily) were significantly better than placebo (Summary of results D). These results were calculated from the numbers and percentages with a moderate response. The total was larger than the 57 randomised, because some participated in more than one treatment arm.

Summary of results D. Efficacy outcomes with gabapentin in mixed neuropathic pain (Gilron 2005)

 Number ofPercent with outcome 
At least moderate pain reliefStudiesParticipantsGabapentinPlaceboRisk ratio
(95% CI)
NNT
(95% CI)
Gabapentin alone19661252.5 (1.5 to 4.2)2.8 (1.8 to 5.6)
Morphine alone19680253.2 (1.9 to 5.2)1.8 (1.4 to 2.7)
Gabapentin plus morphine19378253.1 (1.9 to 5.1)1.9 (1.4 to 2.8)

The other cross-over study compared gabapentin alone (target dose 3600 mg daily), nortriptyline (target dose 100 mg daily) and the combination (target dose 3600 mg gabapentin plus 100 mg nortriptyline daily) over six weeks (Gilron 2009). Pain intensity was significantly lower with the combination, by less than 1 point out of 10 on a numerical rating pain scale.

Third tier evidence

This was the only evidence available for several other pain conditions. Here the issues were the imputation method and small numbers.

Spinal cord injury

The efficacy of gabapentin in spinal cord injury pain at maximum doses of 1800 mg or 3600 mg daily was compared with placebo in three cross-over trials (Levendoglu 2004; Rintala 2007; Tai 2002) over periods of four and eight weeks. None of the studies reported dichotomous outcomes equivalent to moderate or substantial pain relief.

One eight-week study randomised 20 participants to a maximum of 3600 mg gabapentin daily or placebo over eight weeks (Levendoglu 2004) and reported a 62% average fall in pain with gabapentin compared with a 13% fall with placebo.

A second eight-week study randomised 38 participants to a maximum of 3600 mg gabapentin daily, amitriptyline 150 mg daily, or placebo over eight weeks (Rintala 2007). It claimed statistical superiority for amitriptyline for the 22 participants completing all three phases, and no benefit of gabapentin over placebo.

The final study comparing gabapentin with placebo over four weeks in seven participants had no interpretable results (Tai 2002).

Nerve injury pain

A single cross-over study evaluated the efficacy of gabapentin at a maximum of 2400 mg daily compared with placebo over five-week treatment periods (Gordh 2008). Among the 98 participants of the 120 randomised who completed both treatment periods, at least 50% pain intensity reduction was achieved by 13 (13%) on gabapentin and 9 (9%) on placebo, which did not reach statistical significance, risk ratio 1.4 (0.7 to 3.2). At least 30% pain intensity reduction was achieved by 29 (29%) on gabapentin and 19 (19%) on placebo, which did not reach statistical significance, risk ratio 1.5 (0.9 to 2.5).

Phantom limb pain

Two cross-over studies evaluated the efficacy of gabapentin compared with placebo in phantom limb pain (Bone 2002; Smith 2005). One (Bone 2002) randomised 19 participants to a maximum of 2400 mg gabapentin daily, or the maximum tolerated dose, with six-week treatment periods. Using an ITT approach, weekly VAS pain scores were lower at week six only with gabapentin, but not at any other time, nor with categorical pain measures. The other (Smith 2005) randomised 24 participants to gabapentin titrated to a maximum daily dose of 3600 mg. A "meaningful decrease in pain" (the top of a five-point scale) was achieved by 13 participants (54%) with gabapentin and 5 (21%) with placebo, a statistically significant difference, with risk ratio 2.6 (1.1 to 6.2).

Cancer-related neuropathic pain

Three studies examined gabapentin in the short term in cancer-related neuropathic pain (Caraceni 2004; Mishra 2012; Rao 2007). A parallel-group study (Caraceni 2004) randomised 121 participants to titration to a maximum of gabapentin 1800 mg daily or placebo, with 10 days of treatment. The average pain intensity was somewhat lower with gabapentin than with placebo, but the number of participants described as having pain under control was very similar with both treatments after six days, with 50% to 60% with pain under control over six to 10 days. A cross-over study (Rao 2007) compared gabapentin titrated to 2700 mg daily with placebo in chemotherapy-induced neuropathic pain over three weeks. There was no significant difference between gabapentin and placebo, but the study did recruit participants both with pain and sensory loss or paraesthesia, and baseline pain scores were only about 4/10 on a numerical rating scale. The study probably lacked sensitivity to detect any difference.

The third study compared gabapentin 1800 mg daily with pregabalin 600 mg daily and amitriptyline 100 mg daily for a total of four weeks. No dichotomous data were reported; a decrease in pain scores in all groups in all weeks was reported, together with a morphine-sparing effect and improvement in functional capacity. Morphine-sparing and functional capacity were significantly better with pregabalin than the other treatments.

HIV-associated sensory neuropathies

A single parallel-group study compared gabapentin titrated to 2400 mg daily with placebo over four weeks in 24 participants with painful HIV-associated neuropathies (Hahn 2004). On average, pain and sleep improved substantially with both gabapentin and placebo, though the time courses differed. After four weeks, there was no difference in median pain scores, though the placebo response had an unusual time course in 11 participants.

Small fibre sensory neuropathies

A single cross-over study with complete enrichment, compared gabapentin at doses up to 4800 mg daily with tramadol 50 mg (probably four times a day), and placebo in 18 participants with small fibre sensory neuropathies using two-week treatment periods (Ho 2009). The number achieving at least 50% pain intensity reduction was 4/18 (22%) with gabapentin, 4/18 (22%) with tramadol, and 1/18 (6%) with placebo. Similar results were obtained for those feeling very much better.

Chronic masticatory myalgia

A single parallel-group study compared gabapentin titrated to 4200 mg daily with placebo over 12 weeks in 50 participants with painful chronic masticatory myalgia, where pain is associated with central sensitisation (Kimos 2007). Gabapentin was significantly better than placebo for VAS pain, pain reduction, and VAS function, and an NNT of 3.4 for gabapentin compared with placebo was reported, though no details were recorded about outcome.

Complex regional pain syndrome (CRPS)

The efficacy of gabapentin in CRPS at maximum doses of 1800 mg daily was compared with placebo in 58 participants in a single placebo-controlled cross-over study lasting three weeks in each period (van de Vusse 2004). Over both periods, and using per protocol reporting, "much" pain improvement (undefined) was achieved by 8/46 (17%) with gabapentin compared with 2/46 (4%) with placebo. There was no significant difference, with a relative benefit of 4.0 (0.9 to 18).

Fibromyalgia

The efficacy of gabapentin in fibromyalgia at maximum doses of 2400 mg daily was compared with placebo in 150 participants in a single placebo (diphenhydramine) controlled parallel-group study lasting 12 weeks (Arnold 2007). The outcome of 30% reduction in pain over baseline was reported, with 38/75 participants (49%) achieving the outcome with gabapentin compared with 23/75 (31%) with placebo. The relative benefit was 1.6 (1.1 to 2.4) and the NNT was 5.4 (2.9 to 31).

Overall efficacy across all conditions

For the 2011 review it was considered appropriate to produce an analysis of the efficacy of gabapentin across all chronic pain conditions included. The reason for this was that there was a suggestion that partial reporting of studies and outcomes had overestimated gabapentin effectiveness (Vedula 2009), perhaps to the extent that it may be of little value when considering benefits and harms together (Perry 2008). Estimating efficacy across all conditions is of little value when sufficient information exists for estimation of efficacy in particular conditions, which is where the real-world interest lies. For this reason no results of overall efficacy across all conditions were included in this updated review.

Withdrawals (see Summary of results E)

All-cause withdrawals

Twenty-three studies with 4709 participants reported on withdrawals for any cause, which occurred in 20% of participants on gabapentin at daily doses of 1200 mg or more, and in 18% on placebo (Analysis 2.1). The risk ratio was 1.04 (0.90 to 1.2).

Adverse event withdrawals

Twenty-two studies with 4448 participants reported on adverse event withdrawals, which occurred in 11% of participants on gabapentin at daily doses of 1200 mg or more, and in 7.9% on placebo (Analysis 2.2). The risk ratio was 1.4 (1.1 to 1.7), and the NNH 31 (20 to 66).

Lack of efficacy withdrawals

Sixteen studies with 3693 participants reported on lack of efficacy withdrawals, which occurred in 1.6% of participants on gabapentin at daily doses of 1200 mg or more, and in 3.1% on placebo (Analysis 2.3). The risk ratio was 0.5 (0.3 to 0.8), and the NNTp 67 (40 to 205).

Adverse events (see Summary of results E)

Participants experiencing at least one adverse event

Seventeen studies with 4002 participants reported on participants experiencing at least one adverse event, which occurred in 62% of participants on gabapentin at daily doses of 1200 mg or more, and in 50% on placebo (Analysis 3.1). The risk ratio was 1.25 (1.2 to 1.3), and the NNH was 8.6 (6.8 to 12).

Serious adverse events

NIneteen studies reported on 3952 participants experiencing a serious adverse event, which occurred in 3.2% of participants on gabapentin at daily doses of 1200 mg or more, and in 2.8% on placebo (Analysis 3.2). The risk ratio was 1.2 (0.8 to 1.7).

Particular adverse events

Somnolence, drowsiness, or sedation was reported as an adverse event in 20 studies with 4125 participants, and it occurred in 14% of participants on gabapentin at doses of 1200 mg daily or more, and in 5% on placebo (Analysis 3.3). The risk ratio was 2.9 (2.3 to 3.6), and the NNH was 11 (9.4 to 14).

Dizziness was reported as an adverse event in 22 studies with 4576 participants, and it occurred in 19% of participants on gabapentin at doses of 1200 mg daily or more, and in 6.1% on placebo (Analysis 3.4). The risk ratio was 3.1 (2.6 to 3.8), and the NNH was 7.6 (6.6 to 8.8).

Peripheral oedema was reported as an adverse event in 12 studies with 3220 participants, and it occurred in 7.0% of participants on gabapentin at doses of 1200 mg daily or more, and in 2.2% on placebo (Analysis 3.5). The risk ratio was 3.3 (2.2 to 4.9), and the NNH was 21 (16 to 30).

Ataxia or gait disturbance was reported as an adverse event in five studies with 544 participants. It occurred in 26/295 (8.8%) participants on gabapentin at doses of 1200 mg daily or more, and in 3/249 (1.1%) on placebo, though all but one study reported no events with placebo (Analysis 3.6). This produced a risk ratio of 4.5 (1.9 to 11), and the NNH was 13 (9 to 24).

Summary of results E: Withdrawals and adverse events with gabapentin (1200 mg daily or more) compared with placebo

 Number ofPercent with outcome 
OutcomeStudiesParticipantsGabapentinPlaceboRisk ratio
(95% CI)
NNH
(95% CI)
Withdrawal - all-cause23470920181.04 (0.90 to 1.2)Not calculated
Withdrawal due to adverse events224448117.91.4 (1.1 to 1.7)31 (20 to 66)
At least one adverse event17400262501.25 (1.2 to 1.3)8.6 (6.8 to 12)
Serious adverse event1939523.22.81.2 (0.8 to 1.7)Not calculated
Somnolence/drowsiness204125145.02.9 (2.3 to 3.6)11 (9.4 to 14)
Dizziness224576196.13.1 (2.6 to 3.8)7.6 (6.6 to 8.8)
Peripheral oedema1232207.02.23.3 (2.2 to 4.9)21 (16 to 30)
Ataxia/gait disturbance55448.81.24.5 (1.9 to 11)13 (9 to 24)
OutcomeStudiesParticipantsGabapentinPlaceboRisk ratio
(95% CI)
NNTp
(95% CI)
Withdrawal - lack of efficacy1636931.63.10.5 (0.3 to 0.8)67 (40 to 205)
Death

Deaths were rare in these studies. Five deaths occurred in PHN studies; three with placebo: one in 231 participants (Sang 2013), one in 116 (Rowbotham 1998) and one in 133 (Wallace 2010); two with gabapentin: one in 223 participants (Rice 2001), and one in 107 (Irving 2009). An unpublished study (CTR 945-1008) reported two deaths: one of 200 participants treated with gabapentin, and one of 189 treated with placebo. A further study reported two deaths in 152 participants taking placebo (Serpell 2002). Overall, three deaths occurred with gabapentin and five with placebo.

Discussion

Summary of main results

Gabapentin is a reasonably effective treatment for a variety of neuropathic pain conditions. It has been demonstrated to be better than placebo across all studies for IMMPACT outcomes of substantial and at least moderate improvement, producing almost identical results for all trials and those in parallel-group studies lasting six weeks or longer. Numbers needed to treat to benefit (NNTs) were between 5 and 7 for substantial and at least moderate improvement in PHN and PDN. Results were consistent across the major neuropathic pain conditions tested, though gabapentin was tested only in small numbers in uncommon neuropathic pain conditions and fibromyalgia. The review concentrated on doses of gabapentin of 1200 mg daily or greater, though a wide range of fixed doses and dose titration regimens were used.

Gabapentin was tested in nine different chronic pain conditions generally considered to be neuropathic in origin, and three other chronic pain conditions where the aetiology may be different (masticatory myalgia, CRPS-1, and fibromyalgia). For only three neuropathic pain conditions was there sufficient information to be confident that it worked satisfactorily, namely PHN, PDN, and mixed neuropathic pain, itself principally, though not exclusively, PHN and PDN.

Benefit was balanced by more withdrawals due to adverse events, and participants taking gabapentin experienced more adverse events, including somnolence, dizziness, peripheral oedema, and gait disturbance than did those taking placebo. Serious adverse events were no more common with gabapentin than placebo, and death was an uncommon finding in these studies.

Overall completeness and applicability of evidence

Efficacy and adverse event outcomes were not consistently reported across the studies, and this limited the analyses to some extent. However, for the most important efficacy and adverse event outcomes, analyses across all conditions were mostly based on between 1000 and about 4700 participants. All the larger studies (typically those with more than 100 participants) reported some efficacy outcome that fitted one or both of the IMMPACT outcomes of at least moderate or substantial benefit. Clearly, analysis at the level of the individual patient would facilitate a more robust estimate.

There is one important unknown for most studies, namely whether the definition of response in the trials included only participants who had both an analgesic response and were able to take gabapentin. If response included an LOCF assessment of efficacy from those who discontinued, this could have affected the results (Moore 2012a). LOCF tends to generate overestimation of treatment effects when adverse event withdrawals with drug is higher than that with placebo. For gabapentin, the excess adverse withdrawal over placebo was about 3%. This is not likely to result in significant overestimation in treatment effect (Moore 2012a). In a similar situation, duloxetine produced little different NNTs using LOCF and BOCF in four different chronic pain conditions (Moore 2014).

Another issue is how to deal with relatively short term, small, multiple cross-over studies that intensively study participants on a daily basis (Gilron 2005; Gilron 2009), but do not report outcomes of clinical relevance (participants with adequate pain relief), but rather average pain scores, whose relevance has been questioned because of underlying skewed distributions (Moore 2010d). This study design can provide useful and clinically relevant information, like the relatively rapid onset of effect of therapies in neuropathic pain, or how individual patients respond to several different drugs, they are difficult to include in pooled analyses, and their small size and brevity come with significant potential biases (Moore 2012b).

There were almost no data for direct comparisons with other active treatments. It is questionable how important direct comparisons may be; they compare average efficacy rates between different active therapies, but individual patients may respond to one drug, but not another (Moore 2013b).

We are aware that erectile dysfunction has been a cause for concern for younger men treated with antiepileptic drugs for epilepsy (Smalldone 2004), and anorgasmia has been reported with gabapentin (Perloff 2011). Adverse event reporting of erectile dysfunction or anorgasmia in these trials was sparse or not present, and the effects of gabapentin on sexual function may not be well represented.

Finally, there was no way to incorporate into the review important observations on the timing and consistency of analgesia with gabapentin in neuropathic pain. In PHN, individual patient level pooled analyses of several large trials have demonstrated that, judged by the proportion of participants with a 1 out of 10 point pain intensity reduction, around 20 to 40 days is needed for effects to be seen (Rauck 2013c). Early response, defined as a 30% pain intensity reduction or greater, was predictive of response after 10 weeks, while pain intensity reduction of <10% at week 5 was the best early predictor of lack of response at week 10 (Jensen 2012).

Quality of the evidence

The studies included in this review covered a large number of different painful conditions. The main quality issues involve reporting of outcomes of interest, particularly dichotomous outcomes equivalent to IMMPACT, as well as better reporting of adverse events. The earliest study was published in 1998, and the past decade or so has seen major changes in clinical trial reporting. The studies themselves appear to be well-conducted, and individual patient analysis could overcome some of the shortcomings of reporting.

Potential biases in the review process

The review was restricted to randomised double-blind studies, thus limiting the potential for bias. Other possible sources of bias that could have affected the review included the following:

  • Duration - NNT estimates of efficacy in chronic pain studies tend to increase (get worse) with increasing duration (Moore 2010a). However, limiting studies to those of six weeks or longer did not change the main efficacy outcomes, mainly because most participants were in longer duration studies.

  • Outcomes may affect estimates of efficacy, but the efficacy outcomes chosen were of participants achieving the equivalent of IMMPACT-defined moderate or substantial improvement, and it is likely that lesser benefits, such as 'any benefit' or 'any improvement', are potentially related to lesser outcomes, though this remains to be clarified.

  • The dose of gabapentin used differed between studies, in terms of maximum allowable dose, and whether the dose was fixed, titrated to effect, or titrated up to the maximum irrespective of beneficial or adverse effects. We chose to pool data irrespective of dose, within broad limits, because it was the only practical way to deal with dose in a pooled analysis, and because of a lack of good evidence of any clear dose-response effect for gabapentin in neuropathic pain.

  • In some circumstances cross-over trials have been shown to exaggerate treatment effects in comparison with parallel-group designs (Khan 1996), but the extent is unclear, and it is unlikely to be the source of major bias (Elbourne 2002). Withdrawals from cross-over studies meant that any results were likely to be per protocol for completers rather than a true ITT analysis. Parallel-group studies were larger than cross-over studies, and dominated the analyses in terms of number of participants. The 20 parallel-group studies involved 3811 participants (median 162 ), while the 13 cross-over studies involved 633 participants (median 40 participants). Additionally, few cross-over studies reported outcomes that could be used in the analyses.

  • The absence of publication bias (unpublished trials showing no benefit of gabapentin over placebo) can never be proven. However, we can calculate the number of participants in studies of zero benefit (risk ratio of 1) required for the absolute benefit to reduce beneficial effects to a negligible amount (Moore 2008). If an NNT of 10 were considered a level that would make gabapentin clinically irrelevant, then across all types of neuropathic pain and for the outcome of at least 50% pain intensity reduction for PHN and PDN combined (6.9 in 3093 participants), there would have to be 1390 participants in zero effect studies. With median study size for parallel-group studies of about 220 participants, this would require a minimum of six or seven unavailable studies. We know of no unpublished studies, and none of the ongoing studies identified through Clinicaltrials.gov would be relevant to efficacy assessment.

Agreements and disagreements with other studies or reviews

Previous version of this review

This review differs in two major respects from the original review (Wiffen 2005) from which it was split into two parts (acute pain (Straube 2010) and this review on chronic neuropathic pain and fibromyalgia (Moore 2011)).

  1. The 2011 review (Moore 2011) and this update use strict definitions of what constitutes at least moderate and substantial benefit as defined by the 2008 IMMPACT criteria (Dworkin 2008). The 2005 review used a hierarchy of outcomes (pain intensity reduction of 50% or greater, global impression of clinical change, pain on movement, pain on rest or any other pain-related measure) that would have allowed any pain benefit to have been counted. That was reasonable, and continued a process of demonstrating that antiepileptic drugs effectively relieved pain in neuropathic pain conditions that began a decade earlier (McQuay 1995). This update uses developing considerations that people with chronic pain want high levels of pain relief, ideally with more than 50% pain relief, and pain not worse than mild (Moore 2013c). Use of more stringent outcomes is likely to lead to lower estimates of efficacy, as has been described in acute migraine (Oldman 2002).

  2. The 2011 review and this update together have more than three times the number of participants as the 2005 review, including several large long duration studies with different gabapentin formulations. These more modern studies have better reporting, especially of dichotomous efficacy outcomes. The review includes previously unpublished information, as has been recommended (Vedula 2009), and we have extended our search strategy for ongoing studies, in Clinicaltrials.gov for example.

A consequence of the stringent definition of outcome and the larger numbers available has resulted in a reduction in estimates of efficacy over all studies, and for PHN and PDN analysed separately, as shown by increased NNTs (Summary of results F). The decreased estimate of efficacy was most noticeable for PDN in the 2011 update, for which previously unpublished results made a major contribution to the updated review. The results have not changed noticeably since 2011.

Summary of findings F. Comparison of NNTs from previous and present reviews

 2005 review2011 update2014 Update
OutcomesAny improvement

IMMPACT

moderate benefit

IMMPACT

substantial benefit

IMMPACT

moderate benefit

IMMPACT

substantial benefit

All studies4.3 (3.5 to 5.7)5.8 (4.8 to 7.2)6.8 (5.6 to 8.7)Not calculated in this review
PHN3.9 (3.0 to 5.7)5.5 (4.3 to 7.7)7.5 (5.2 to 14)5.7 (4.6 to 7.5)6.8 (5.4 to 9.3)
PDN2.9 (2.2 to 4.3)8.1 (4.7 to 28)5.8 (4.3 to 9.0)6.6 (4.9 to 9.9)5.9 (4.6 to 8.3)

Other systematic reviews

One other review has provided NNTs for gabapentin in different neuropathic pain conditions based on 50% pain relief, quoting NNTs of 4.7 and 4.3 for neuropathic pain and peripheral pain, and 4.6 for PHN and 3.9 for PDN (Finnerup 2005). A systematic review of therapies for PHN considered gabapentin effective, with an NNT of 4.6 (Hempenstall 2005). These efficacy estimates are more optimistic than NNTs for the IMMPACT substantial benefit calculated for this review, and more optimistic than NNTs calculated for the same outcome of at least 50% pain relief for PHN of 5.7 and PDN of 5.8. The use of more stringent criteria for efficacy, and availability of more information from longer duration studies has led to more conservative efficacy results. Both pregabalin and duloxetine produce NNTs in the region of five to six for at least 50% pain relief over eight to 12 weeks compared with placebo in PHN and PDN (Lunn 2009; Moore 2009a; Sultan 2008).

A number of other systematic reviews have examined the efficacy of gabapentin in neuropathic pain. Systematic reviews of gabapentin for neuropathic pain in spinal cord injury (Tzellos 2008) and fibromyalgia (Hauser 2009; Tzellos 2010) found no more studies than those reported here. An examination of the effects of enriched enrolment found no more studies, and produced similar results for withdrawals and adverse events based on a more limited data set (Straube 2008). A review comparing gabapentin and duloxetine in PDN was limited to two gabapentin studies, was statistical in nature, and restricted to average changes in some efficacy parameters (Quilici 2009). The most directly relevant was a comparison between gabapentin and tricyclic antidepressants (Chou 2009), in which a meta-analysis of six placebo-controlled gabapentin studies in PHN, PDN, and mixed neuropathic pain was performed. Using a mixture of outcomes the relative benefit compared with placebo was 2.2, similar to the benefits found for the 'all studies' analysis and for analyses for PHN, PDN, and mixed neuropathic pain in this review. A systematic review of pregabalin and gabapentin in fibromyalgia (Hauser 2009) reported only on the single study identified in this review, but reported overall good reductions in pain and other outcomes, with no major difference between gabapentin and pregabalin. Phillips 2010 examined the same single study of gabapentin (Hahn 2004) as part of a wider review of pharmacological interventions for HIV neuropathy and came to similar conclusions. The UK NICE guidance on pharmacological management of neuropathic pain has gabapentin as one of four drugs to try initially, with early switching when pain relief is not forthcoming (NICE 2013).

There is one further review in the public domain (Perry 2008) which was performed as part of a legal case in the United States ending in 2009. Perry 2008 considered similar outcomes to this review; NRS or VAS pain score was given hierarchical priority between ≥50% reduction in pain score (higher priority) and PGIC (lower priority) mainly because it was the pre-defined primary end point in almost all studies, and for some studies it was difficult to determine how the secondary endpoints were manipulated during post hoc changes in statistical analysis plans. The Perry conclusions are very similar to those of the present review. The likely real differences would lie in the fact that Perry excluded Perez 2000 and Simpson 2001, and did not have access to Sandercock 2012, Irving 2009, and Wallace 2010.

Perry's conclusion on effectiveness was a clinical judgement based on balancing NNH against NNT, using the Cochrane glossary definition of effectiveness, and presuming that inherent biases in the studies (enrichment, exclusion of many typical real world patients) implied that on balance the benefit of gabapentin use on average does not exceed the harm, which is a somewhat different issue than addressed by this Cochrane review.

Authors' conclusions

Implications for practice

There was no first tier evidence that was unequivocally unbiased. Second tier evidence, with potentially important residual biases, showed that gabapentin at doses of 1200 mg or more was effective for some people with painful neuropathic pain conditions. No evidence regarding a dose-response effect was available for doses above 1200 mg daily, but limited evidence suggested that doses lower than 1200 mg daily were less effective. The outcome of at least 50% pain intensity reduction is regarded as a useful outcome of treatment by patients, and the achievement of this degree of pain relief is associated with important beneficial effects on sleep interference, fatigue, and depression, as well as quality of life, function, and work. About 35% achieved this degree of pain relief with gabapentin, compared with 21% for placebo. Over half of those treated with gabapentin will not have worthwhile pain relief. Results might vary between different neuropathic pain conditions, and the amount of evidence for gabapentin in some conditions (all except PHN, PDN, and mixed) is low, excluding any confidence that it works or does not work.

The level of efficacy found for gabapentin is consistent with the efficacy estimates for other drug therapies in these conditions.

Implications for research

The main research directions that would help improve clinical practice are as follows:

  1. Analysis of all gabapentin studies at the level of the individual participant in order to have consistent outcomes, and analyses based on them. Individual patient analyses can provide important information, for example showing that good pain response delivers large functional and quality of life benefits beyond pain (Moore 2010c). Studies already concluded contain outcomes important to patients and clinical practice, but not reported or expressed in these terms. It would be of questionable efficacy to undertake new studies when data should be available for reasonably rapid analysis.

  2. Participant level data might also be of importance in identifying responder clusters and characteristics.

  3. More research in to the efficacy of gabapentin in painful neuropathic pain conditions where there is currently inadequate information. These conditions tend to be uncommon, and studies can be difficult, with few possible participants. Others, though, like fibromyalgia, are common.

  4. The main issue, though, is not whether gabapentin is effective, but how best to use it in clinical practice to generate the best results for most patients with a chronic neuropathic pain condition, in the shortest time, and at the lowest cost. New study designs have been proposed to examine this (Moore 2009c).

Acknowledgements

We wish to thank Dr Thomas Perry for directing us to clinical trial reports and synopses of published and unpublished studies of gabapentin, and Dr Mike Clarke and colleagues for their advice and support relating to the 2011 update. Professor Henry McQuay was an author and contributor on all previous versions and provided considerable help and guidance throughout.

Data and analyses

Download statistical data

Comparison 1. Efficacy - placebo-controlled studies
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 At least 50% pain reduction over baseline15 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
1.1 Postherpetic neuralgia61816Risk Ratio (M-H, Fixed, 95% CI)1.56 [1.31, 1.85]
1.2 Painful diabetic neuropathy61277Risk Ratio (M-H, Fixed, 95% CI)1.86 [1.53, 2.27]
1.3 Mixed neuropathic pain1305Risk Ratio (M-H, Fixed, 95% CI)1.45 [0.88, 2.37]
1.4 Nerve injury pain1196Risk Ratio (M-H, Fixed, 95% CI)1.44 [0.65, 3.22]
1.5 Small fibre sensory neuropathy136Risk Ratio (M-H, Fixed, 95% CI)5.0 [0.65, 38.65]
2 Very much improved8 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
2.1 Postherpetic neuralgia2563Risk Ratio (M-H, Fixed, 95% CI)2.70 [1.51, 4.82]
2.2 Painful diabetic neuropathy2408Risk Ratio (M-H, Fixed, 95% CI)1.94 [1.26, 2.99]
2.3 Mixed neuropathic pain1305Risk Ratio (M-H, Fixed, 95% CI)1.99 [0.92, 4.28]
2.4 Complex regional pain syndrome I192Risk Ratio (M-H, Fixed, 95% CI)4.0 [0.90, 17.83]
2.5 Nerve injury pain1196Risk Ratio (M-H, Fixed, 95% CI)3.6 [1.39, 9.31]
2.6 Small fibre sensory neuropathy136Risk Ratio (M-H, Fixed, 95% CI)5.0 [0.65, 38.65]
3 Much or very much improved15 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
3.1 Postherpetic neuralgia72013Risk Ratio (M-H, Fixed, 95% CI)1.32 [1.16, 1.50]
3.2 Painful diabetic neuropathy5695Risk Ratio (M-H, Fixed, 95% CI)1.66 [1.36, 2.03]
3.3 Mixed neuropathic pain1305Risk Ratio (M-H, Fixed, 95% CI)2.17 [1.38, 3.41]
3.4 Nerve injury pain1196Risk Ratio (M-H, Fixed, 95% CI)2.21 [1.26, 3.90]
3.5 Small fibre sensory neuropathy136Risk Ratio (M-H, Fixed, 95% CI)1.5 [0.67, 3.34]
4 IMMPACT outcome of substantial improvement18 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
4.1 Postherpetic neuralgia72045Risk Ratio (M-H, Fixed, 95% CI)1.63 [1.37, 1.93]
4.2 Painful diabetic neuropathy61277Risk Ratio (M-H, Fixed, 95% CI)1.86 [1.53, 2.27]
4.3 Mixed neuropathic pain1305Risk Ratio (M-H, Fixed, 95% CI)1.45 [0.88, 2.37]
4.4 Complex regional pain syndrome I192Risk Ratio (M-H, Fixed, 95% CI)4.0 [0.90, 17.83]
4.5 Nerve injury pain1196Risk Ratio (M-H, Fixed, 95% CI)1.44 [0.65, 3.22]
4.6 Phantom pain148Risk Ratio (M-H, Fixed, 95% CI)2.6 [1.10, 6.16]
4.7 Small fibre sensory neuropathy136Risk Ratio (M-H, Fixed, 95% CI)5.0 [0.65, 38.65]
5 IMMPACT outcome of at least moderate improvement19 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
5.1 Postherpetic neuralgia72045Risk Ratio (M-H, Fixed, 95% CI)1.59 [1.40, 1.82]
5.2 Painful diabetic neuropathy71439Risk Ratio (M-H, Fixed, 95% CI)1.41 [1.24, 1.59]
5.3 Mixed neuropathic pain2391Risk Ratio (M-H, Fixed, 95% CI)2.10 [1.49, 2.95]
5.4 Fibromyalgia1150Risk Ratio (M-H, Fixed, 95% CI)1.61 [1.07, 2.42]
5.5 Nerve injury pain1196Risk Ratio (M-H, Fixed, 95% CI)1.53 [0.92, 2.53]
5.6 Small fibre sensory neuropathy136Risk Ratio (M-H, Fixed, 95% CI)2.25 [0.84, 5.99]
Analysis 1.1.

Comparison 1 Efficacy - placebo-controlled studies, Outcome 1 At least 50% pain reduction over baseline.

Analysis 1.2.

Comparison 1 Efficacy - placebo-controlled studies, Outcome 2 Very much improved.

Analysis 1.3.

Comparison 1 Efficacy - placebo-controlled studies, Outcome 3 Much or very much improved.

Analysis 1.4.

Comparison 1 Efficacy - placebo-controlled studies, Outcome 4 IMMPACT outcome of substantial improvement.

Analysis 1.5.

Comparison 1 Efficacy - placebo-controlled studies, Outcome 5 IMMPACT outcome of at least moderate improvement.

Comparison 2. Withdrawals - placebo-controlled studies
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 All-cause withdrawal234709Risk Ratio (M-H, Fixed, 95% CI)1.04 [0.92, 1.17]
2 Adverse event withdrawal224448Risk Ratio (M-H, Fixed, 95% CI)1.37 [1.13, 1.66]
3 Lack of efficacy withdrawal163693Risk Ratio (M-H, Fixed, 95% CI)0.49 [0.31, 0.77]
Analysis 2.1.

Comparison 2 Withdrawals - placebo-controlled studies, Outcome 1 All-cause withdrawal.

Analysis 2.2.

Comparison 2 Withdrawals - placebo-controlled studies, Outcome 2 Adverse event withdrawal.

Analysis 2.3.

Comparison 2 Withdrawals - placebo-controlled studies, Outcome 3 Lack of efficacy withdrawal.

Comparison 3. Adverse events
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 At least one adverse event174002Risk Ratio (M-H, Fixed, 95% CI)1.25 [1.18, 1.32]
2 Serious adverse events193952Risk Ratio (M-H, Fixed, 95% CI)1.19 [0.83, 1.71]
3 Somnolence204125Risk Ratio (M-H, Fixed, 95% CI)2.88 [2.30, 3.61]
4 Dizziness214576Risk Ratio (M-H, Fixed, 95% CI)3.11 [2.58, 3.76]
5 Peripheral oedema123220Risk Ratio (M-H, Fixed, 95% CI)3.30 [2.23, 4.89]
6 Ataxia or gait disturbance5544Risk Ratio (M-H, Fixed, 95% CI)4.47 [1.85, 10.82]
Analysis 3.1.

Comparison 3 Adverse events, Outcome 1 At least one adverse event.

Analysis 3.2.

Comparison 3 Adverse events, Outcome 2 Serious adverse events.

Analysis 3.3.

Comparison 3 Adverse events, Outcome 3 Somnolence.

Analysis 3.4.

Comparison 3 Adverse events, Outcome 4 Dizziness.

Analysis 3.5.

Comparison 3 Adverse events, Outcome 5 Peripheral oedema.

Analysis 3.6.

Comparison 3 Adverse events, Outcome 6 Ataxia or gait disturbance.

Appendices

Appendix 1. CENTRAL search strategy

  1. (gabapentin* or neurontin* or neurotonin*):ti,ab,kw

  2. MESH descriptor PAIN explode all trees

  3. (pain* or discomfort* or analgesi*):ti,ab,kw

  4. 2 OR 3

  5. 1 AND 4

  6. Limit 5 to Clinical Trials (CENTRAL)

Appendix 2. MEDLINE (via OVID) search strategy

  1. (gabapentin* or neurontin* or neurotonin*).mp.

  2. exp PAIN/

  3. (pain* or discomfort* or analgesi*).mp.

  4. 2 OR 3

  5. 1 AND 4

  6. randomized controlled trial.pt.

  7. controlled clinical trial.pt.

  8. randomized.ab.

  9. placebo.ab.

  10. drug therapy.fs

  11. randomly.ab.

  12. trial.ti.

  13. groups.ab

  14. OR/6-13

  15. 5 AND 13

Appendix 3. EMBASE (via OVID) search strategy

  1. Gabapentin/ OR (gabapentin* or neurontin* or neurotonin*).mp.

  2. exp PAIN/ OR exp chronic pain/ OR exp neuropathic pain/

  3. (pain* or discomfort* or analgesi*).mp.

  4. 2 OR 3

  5. clinical trials.sh.

  6. controlled clinical trials.sh.

  7. randomized controlled trial.sh.

  8. double-blind procedure.sh.

  9. (clin* adj25 trial*)

  10. ((doubl* or trebl* or tripl*) adj25 (blind* or mask*))

  11. placebo*

  12. random*

  13. OR/6-13

  14. 1 AND 4 AND 13

Appendix 4. Potential sources of bias in studies of chronic pain used in the 'Risk of bias' table

ItemHighUnclearLow
RandomisationNot randomisedClaims randomisation, but no method givenRandomised by adequate method
Allocation concealmentNot reportedReported but not describedAllocation undertaken independently and blind to investigator
BlindingNot double-blindClaims double-blind, but no methodConvincingly double-blind
Duration2 weeks or less3 to 6 weeks7 weeks or more
OutcomeAnything less than 30% pain intensity reduction
Pain state ≥ 50/100 mm or equivalent or undefined
Responder: pain intensity reduction of ≥ 30% from baseline
State: final pain intensity < 50/100 mm, or equivalent
Responder: pain intensity reduction of ≥ 50% from baseline
State: final pain intensity < 30/100 mm, or equivalent
State: no worse than mild pain
Incomplete outcome assessmentAverage results onlyResponder or state with last observation carried forward or imputation method for missing data or after withdrawal not statedResponder or state response, using baseline observation carried forward (zero improvement after withdrawal)
Size< 50 patients per treatment arm50 to 199 patients per treatment arm≥ 200 patients per treatment arm

Appendix 5. Summary of outcomes in individual studies

StudyWithdrawalsEfficacyAdverse events
(general)
Adverse events
(specific)
Postherpetic neuralgia

Rowbotham 1998

Rowbotham et al. JAMA 1998 280: 1837-1842

Parke-Davis 945-211 CTR additional data

Multicentre

Gabapentin
All-cause 24
AE 21
LoE 0

Placebo
All-cause 21
AE 14
LoE 2
PGIC moderate or much improved
Gaba: 47/113
Plac: 14/116

PGIC CTR much improved
Gaba: 21/113
Plac: 6/116

PGIC CTR moderately improved
Gaba: 26/113
Plac: 8/116

No change in pain 60% placebo, 23% gabapentin
No change or worse in pain 68% placebo, 26% gabapentin

Significant improvement over placebo in 5/9 SF-36 QoL and 5/7 mood states
At least one AE
Gaba 84/113
Plac 60/116

Minor AE (treatment related)
Gaba: 62/113
Plac: 32/116

SAE (treatment related)
Gaba: 0/113   (10/113 CTR)
Plac: 0/116 (5/116 CTR)

Death:
Gaba: 0/113
Plac: 1/116
Somnolence
Gaba: 31/113
Plac: 6/116

Dizziness
Gaba: 27/113
Plac: 6/116

Ataxia
Gaba: 8/113
Plac: 0/116

Peripheral oedema
Gaba: 11/113
Plac: 4/116

Rice 2001

Rice et al. Pain 2001 94: 215-224

Parke-Davis 945-295 CTR additional data

Multicentre

Gabapentin 1800 mg
All-cause 22
AE 15
LoE 4

Gabapentin 2400 mg
All-cause 23
AE 19
LoE 1

Placebo
All-cause 17
AE 7
LoE 4
At least 50% reduction in mean pain score
Gaba 1800: 37/115
Gaba 2400: 37/108
Plac: 16/111

PGIC very much or much improved
Gaba 1800: 44/115
Gaba 2400: 42/108
Plac: 24/111

PGIC very much  improved (CTR)
Gaba 1800: 18/115
Gaba 2400: 12/108
Plac: 7/111

PGIC much improved (CTR)
Gaba 1800: 26/115
Gaba 2400: 30/108
Plac: 17/111

Some significant differences in QoL measures and sleep
At least one AE
Gaba 1800: 81/115
Gaba 2400: 81/108
Plac: 55/111

SAE
Gaba 1800: 3/115
Gaba 2400: 1/108
Plac: 1/111

Death:
Gaba 1800: 0/115
Gaba 2400: 1/108
Plac: 0/111
Somnolence
Gaba 1800: 20/115
Gaba 2400: 22/108
Plac: 7/111

Dizziness
Gaba 1800: 36/115
Gaba 2400: 36/108
Plac: 11/111

Asthenia
Gaba 1800: 7/115
Gaba 2400: 6/108
Plac: 4/111

Peripheral oedema
Gaba 1800: 6/115
Gaba 2400: 12/108
Plac: 0/111

Chandra 2006

Chandra et al. Int J Clin Pharm Ther 2006 44: 358-363

All-cause withdrawal
Gabapentin 3/38
Nortriptyline 2/38

AE withdrawal
Gabapentin 0/38
Nortriptyline 1/38

LoE withdrawal
Gabapentin 0/38
Nortriptyline 1/38
At least 50% improvement over baseline pain (Likert)
Gabapentin 7/38
Nortriptyline 9/38

At least 50% improvement over baseline pain (VAS)
Gabapentin 13/38
Nortriptyline 14/38
No serious AE reported

No deaths reported
Sleepiness
Gaba 4/38
Nort 6/38

Giddiness
Gaba 1/38
Nort 0/38

Irving 2009

Irving et al. Clin J Pain 2009 25: 185-192
Jensen et al. Clin J Pain 2009 25: 185-192

Multicentre
Extended release

All-cause withdrawal 15 total

AE withdrawal
Gabapentin 1800 single dose 4/44
Gabapentin 1800 split dose 6/52
Placebo 1/51
At least 50% reduction in pain score
Gaba 1800 single dose 14/55
Gaba 1800 split dose 15/52
Placebo 6/51

At least 30% reduction in pain score
Gaba 1800 single dose 24/55
Gaba 1800 split dose 25/52
Placebo 16/51

PGIC very much or much improved
Gaba 1800 single dose 18/55
Gaba 1800 split dose 21/52
Placebo 11/5

Significantly better sleep with gabapentin compared with placebo
Serious AE
Gaba 1800 single dose 4/55
Gaba 1800 split dose 3/52
Placebo 1/51

Deaths
Gaba 1800 single dose 0/55
Gaba 1800 split dose 1/52
Placebo 0/51
Somnolence
Gaba 1800 single dose: 5/55
Gaba 1800 split dose: 4/52
Plac: 4/51

Dizziness
Gaba 1800 single dose: 12/55
Gaba 1800 split dose: 6/52
Plac: 5/51

Gait disturbance
Gaba 1800 single dose: 4/55
Gaba 1800 split dose: 2/52
Plac: 0/51

Peripheral oedema
Gaba 1800 single dose: 4/55
Gaba 1800 split dose: 1/52
Plac: 0/51

Wallace 2010

Wallace et al. Clin Drug Invest 2010 30: 765-776

Extended release. Note that two different gabapentin regimens have been combined, both 1800 mg daily

All-cause withdrawal
Gabapentin 56/269
Placebo 30/131

AE withdrawal
Gabapentin 31/269
Placebo 14/131

At least 50% improvement over baseline pain (Likert)
Gabapentin 95/269
Placebo 36/131

Much or very much improved on PGIC

Gabapentin 99/269
Placebo 32/131

At least one AE
Gaba 155/272
Plac 64/133

Serious AE
Gaba 10/272
Plac 4/133

Deaths
Gaba  0/272
Plac  1/133

Dizziness
Gaba 34/272
Plac 4/133

Somnolence
Gaba 13/272
Plac 3/133

Peripheral oedema
Gaba 13/272
Plac 0/133

Harden 2013All cause
GabaEn 1200 12/91
GabeEn 3600 3/85
GabaEn 2400 1 (cross-over)

AE withdrawal
GabaEn 1200 3/91
GabaEn 3600  0/85

LoE withdrawal
GabaEn 1200  4/91
GabaEn 3600 0/85 
≥ 50% red in PI
At end of period 1
GabaEn 1200 7/49
GabaEn 3600 5/44
At end of period 2
GabaEn 1200 8/41
GabaEn 3600 11/41

≥ 30% red in PI
At end of period 1
GabaEn 1200 13/49
GabaEn 360013/44
At end of period 2
GabaEn 120015/41
GabaEn 3600 19/41

PGIC much or v much improved
GabaEn 1200  17/63
GabaEn 3600 28/61
[paper says ITT - not sure where denominator comes from; summary says 'at last week of treatment' - completer?]
Overall incidence of AEs and changes in safety parameters were small and similar  between doses

One SAE during down titration (auditory hallucination)

At least 1 AE
B'line Gaba 1800 2/94
GabaEn 1200 15/91
GabaEn 2400 2.82
GabaEn 3600 14/85
Down-titration 2/80

Dizziness
GabaEn 1200 0/91
GabaEn 3600  3/85

Somnolence
GabaEn 1200 3/91
GabaEn 3600  2/85

Peripheral oedema
GabaEn 1200 1/91
GabaEn 3600  1/85

NCT00475904All cause
Gabapentin 13/144
A+K cream 15/140
Placebo 4/76

No reasons for withdrawal given
Reduction in PI from baseline
Mean data only
NSD between gaba and cream
Cream marginally better than placebo

Note - claims ITT analysis with LOCF, but numbers analysed are fewer than randomised (Gaba 6, Cream 5)
At least 1 AE
Gaba 2/144
Cream 7/144
Placebo 1/76

No SAE
Assume no deaths
Vertigo
Gaba 2/144
Cream 7/144
Placebo 1/76
No other AEs reported
Sang 2013All cause withdrawal
Gabapentin 35/221
Placebo 37/231

AE withdrawal
Gabapentin 19/221
Placebo 10/231

LoE withdrawal
Gabapentin 7/221
Placebo 12/231
At least 50% reduction in pain
Gabapentin 65/221
Placebo 52/231

PGIC very much or much improved
Gabapentin 94/221
Placebo 77/231
At least one AE
Gabapentin 118/221
Placebo 92/231

Serious AE
Gabapentin 4/221
Placebo 6/231
none attributed to study drug

Deaths
Gabapentin 0/221
Placebo 1/231
Dizziness
Gabapentin 25/221
Placebo 4/231

Somnolence
Gabapentin 12/221
Placebo 7/231

Headache
Gabapentin 10/221
Placebo 9.231

Nausea
Gabapentin 10/221
Placebo 7/231

Peripheral oedema
Gabapentin 7/221
Placebo 1/231

Nasopharyngitis
Gabapentin 5/221
Placebo 6/231
Zhang 2013To end of maintenance phase

All cause withdrawal
GabaEr1200 20/107
GabaEr 2400 21/82
GabaEr 3600 30/87
Placebo 30/95

AE withdrawal
GabaEr1200 6/107
GabaEr 2400 12/82
GabaEr 3600 16/87
Placebo 11/95

LoE
GabaEr1200 1/107
GabaEr 2400 1/82
GabaEr 3600 4/87
Placebo 6/95

Withdrawal of consent and protocol deviation most common other reasons
At least 50% reduction in pain by end maintenance
GabaEr1200 44/107
GabaEr 2400 28/82
GabaEr 3600 37/87
Placebo 22/95

At least 30% reduction in pain by end maintenance
GabaEr1200 57/107
GabaEr 2400 48/82
GabaEr 3600 52/87
Placebo 40/95

PGIC much and very much improved
GabaEr1200 24/85
GabaEr 2400 45/103
GabaEr 3600 35/78
Placebo 39/76
Note not ITT
At least 1 AE
GabaEr1200 75/107
GabaEr 2400 64/82
GabaEr 3600 71/87
Placebo 63/95

SAE:
GabaEr1200 0/107
GabaEr 2400 4/82
GabaEr 3600 2/87
Placebo 2/95

No deaths

Dizziness
GabaEr120018/107
GabaEr 2400 21/82
GabaEr 3600 26/87
Placebo 14/95

Somnolence
GabaEr120011/107
GabaEr 2400 9/82
GabaEr 3600 12/87
Placebo 8/95

Peripheral oedema
GabaEr1200 6/107
GabaEr 2400 6/82
GabaEr 3600 5/87
Placebo 0/95

Other AEs in ≥ 5% reported

Painful diabetic neuropathy

Backonja 1998

Backonja et al. JAMA 1998 280: 1831-1836

Parke-Davis Pfizer 945-210

Multicentre

All-cause withdrawal
Gabapentin 14/84
Placebo 16/81

AE withdrawal
Gabapentin 7/84
Placebo 5/81

LoE withdrawal
Gabapentin 1/84
Placebo 5/81
PGIC much or moderately improved
Gabapentin 47/84
Placebo 25/81

At least 50% reduction in pain (CTR)
Gabapentin 39/84
Placebo 16/81

PGIC much improved (CTR)
Gabapentin 33/84
Placebo 12/81

PGIC moderately or much improved (CTR)
Gabapentin 47/84
Placebo 25/81
At least one AE
Gaba 70/84
Plac 54/81

Serious AE
Gaba 3/84
Plac 2/81

Deaths
Gaba  0/84
Plac  0/81
Dizziness
Gaba 20/84
Plac 4/81

Somnolence
Gaba 19/84
Plac 5/81

Gorson 1999

Gorson et al. J Neurol, Neurosurg Psych 1999 66:251-252

 Moderate or excellent pain relief (both phases)
Gabapentin 17/40
Placebo 9/40
At least one AE
Gaba 12/40
Plac 4/40

Serious AE
Gaba 0/40
Plac 0/40

Deaths (inferred)
Gaba 0/40
Plac 0/40
 

Morello 1999

Morello et al. Archives of Internal Medicine 1999 159: 1931-1937

All-cause withdrawal/early cross-over
Gabapentin 3/25
Amitriptyline 4/25

AE withdrawal/early cross-over
Gabapentin 2/25
Amitriptyline 3/25

LoE withdrawal/early cross-over
Gabapentin 0/25
Amitriptyline 1/25
No significant difference at end of treatment

Pain relief at end of treatment (6-point global score), complete, a lot
Gabapentin 6/21
Amitriptyline 5/21

Pain relief at end of treatment (global score), at least moderate
Gabapentin 11/21
Amitriptyline 14/21
At least one AE
Gabapentin 18/23
Amitriptyline 17/24

No serious AEs or deaths noted
Sedation
Gaba 12/23
Amit 8/24

Dizziness
Gaba 7/23
Amit 2/24

Ataxia
Gaba 5/23
Amit 2/24

Peripheral oedema
Gaba 3/23
Amit 2/24
CTR 945-224

Multicentre

All-cause withdrawal
Gabapentin 600 12/82
Gabapentin 1200 6/82
Gabapentin 2400 19/84
Placebo 12/77

AE withdrawal
Gabapentin 600 8/82
Gabapentin 1200 3/82
Gabapentin 2400 11/84
Placebo 8/77

LoE withdrawal
Gabapentin 600 0/82
Gabapentin 1200 0/82
Gabapentin 2400 4/84
Placebo 1/77

At least 50% reduction in pain score
Gabapentin 600 13/82
Gabapentin 1200 33/82
Gabapentin 2400 25/84
Placebo 19/77

PGIC very much improved
Gabapentin 600 9/82
Gabapentin 1200 14/82
Gabapentin 2400 14/84
Placebo 10/77

PGIC much or very much improved
Gabapentin 600 22/82
Gabapentin 1200 36/82
Gabapentin 2400 36/84
Placebo 26/77
At least 1 AE
Gabapentin 600 40/82
Gabapentin 1200 35/82
Gabapentin 2400 45/84
Placebo 36/77

Serious AE
Gabapentin 600 5/82
Gabapentin 1200 2/82
Gabapentin 2400 3/84
Placebo 4/77

There were no deaths
Somnolence
Gabapentin 600 4/82
Gabapentin 1200 3/82
Gabapentin 2400 11/84
Placebo 1/77

Dizziness
Gabapentin 600 7/82
Gabapentin 1200 4/82
Gabapentin 2400 6/84
Placebo 2/77

Peripheral oedema
Gabapentin 600 4/82
Gabapentin 1200 1/82
Gabapentin 2400 2/84
Placebo 2/77
CTR 945-1008

Multicentre
All-cause withdrawal
Gabapentin 64/200
Placebo 54/189

AE withdrawal
Gabapentin 27/200
Placebo 18/189

LoE withdrawal
Gabapentin 1/200
Placebo 4/189
At least 30% reduction in pain
Gabapentin 113/200
Placebo 77/189

At least 50% reduction in pain
Gabapentin 77/200
Placebo 46/189
At least one AE
Gaba 159/200
Plac 126/189

Serious AE
Gaba 15/200
Plac 15/189

Deaths
Gaba 1/200
Plac 1/189
Somnolence
Gaba 31/200
Plac 8/189

Dizziness
Gaba 38/200
Plac 15/189

Asthenia
Gaba 22/200
Plac 8/189

Peripheral oedema
Gaba 33/200
Plac 7/189

Simpson 2001

Simpson J Clin Neuromusc Dis 2001 3: 53-62.

All-cause withdrawal
Gabapentin 3/30
Placebo  3/30

Lack of efficacy
Gabapentin 1/30
Placebo 1/30

Adverse event
Gabapentin 2/30
Placebo 2/30
PGIC moderate or much improved
Gaba: 15/30
Plac: 7/30
No deaths reported, and no serious adverse events reportedSomnolence
Gaba 6/27
Plac 1/27

Dizziness
Gaba 6/27
Plac 1/28

Perez 2000

Perez & Sanchez. American Journal of Medicine 2000 108: 689

No withdrawals apparentAt least 50% reduction in pain by 4 weeks
Gabapentin 14/17
Placebo 2/15
No major side effects reported for gabapentin groupNo data

Sandercock 2012

Sandercock et al. Diabetes Care 2009 32: e20

All cause withdrawal
Gabapentin [1] 4/46
Gabapentin [2] 3/50
Placebo 2/51

Adverse event
Gabapentin [1] 2/46
Gabapentin [2] 2/50
Placebo 2/51

No lack of efficacy withdrawals - remaining 3 were protocol violation (1) and withdrew consent (2)
At least 50% reduction in pain from baseline to week 4 (BOCF)
Gabapentin [1] 34.8% = 16/46
Gabapentin [2] 26.0% = 13/50
Placebo 7.8% = 4/51

PGIC much or very much improved
Gabapentin [1] 55.3% = 25/45
Gabapenti [2] 67.4% = 34/50
Placebo 34% = 17/51

Similar results for sleep interference
At least one AE
Gabapentin [1] 27/47
Gabapentin [2] 23/49
Placebo 20/51

Serious AE
Gabapentin [1] 0/47
Gabapentin [2] 0/49
Placebo 1/51 (judged not related)

No deaths

Dizziness
Gabapentin [1] 8/47
Gabapentin [2] 6/49
Placebo 0/51

Somnolence
Gabapentin [1] 6/47
Gabapentin [2] 2/49
Plaeboc 0/51

Nausea
Gabapentin [1] 2/47
Gabapentin [2] 3/49
Plaeboc 0/51

Headache
Gabapentin [1] 2/47
Gabapentin [2] 3/49
Plaeboc 2/51

Rauck 2013aAll cause withdrawal
GabaEr1200 15/62
GabaEr 2400 19/56
GabaEr 3600 38/117
Pregab 300 19/66
Placebo 30/120

AE withdrawal
GabaEr1200 5/62
GabaEr 2400 12/56
GabaEr 3600 21/117
Pregab 300 6/66
Placebo 11/120

LoE withdrawal
GabaEr1200 2/62
GabaEr 2400 0/56
GabaEr 3600 4/117
Pregab 300 3/66
Placebo 4/120

Protocol deviation most common other cause for not completing
At least 50% reduction in pain by end M week 12
GabaEr1200 26/62
GabaEr 2400 15/56
GabaEr 3600 46/117
Pregab 300 14/66
Placebo 35/120

At least 30% reduction in pain by end M week 12
GabaEr1200 31/62
GabaEr 2400 25/56
GabaEr 3600 66/117
Pregab 300 28/66
Placebo 57/120
At least 1 AE
GabaEr1200 45/62
GabaEr 2400 38/56
GabaEr 3600 86/117
Pregab 300 47/66
Placebo 79/120

SAE:
22 participants reported 29 nonfatal SAEs -  no clear differences between groups

No deaths

Dizziness
GabaEr1200 9/62
GabaEr 2400 8/56
GabaEr 3600 16/117
Pregab 300 9/66
Placebo 7/120

Somnolence
GabaEr1200 2/62
GabaEr 2400 7/56
GabaEr 3600 16/117
Pregab 300 9/66
Placebo 5/120

Peripheral oedema
GabaEr1200 2/62
GabaEr 2400 0/56
GabaEr 3600 11/117
Pregab 300 3/66
Placebo 5/120

Details of  other AEs occurring in at least 5% of any group

Mixed neuropathic pain

Serpell 2002

Serpell. Pain 2002 99: 557-566

Parke_Davis/Pfizer 945-430-306

All-cause withdrawals
Gabapentin 32/153
Placebo 41/152

AE withdrawals
Gabapentin 24/153
Placebo 25/152

LoE withdrawals
Gabapentin 1/153
Placebo 5/152
At least 50% reduction in pain
Gabapentin 32/153
Placebo 22/152

PGIC very much or much improved
Gabapentin 48/153
Placebo 22/152

PGIC very much  improved CTR
Gabapentin 18/153
Placebo 9/152

PGIC much improved CTR
Gabapentin 30/153
Placebo 13/152
At least one AE
Gabapentin 117/153
Placebo 103/152

Serious AE
Gabapentin 4/153
Placebo 4/152

Deaths
Gabapentin 0/153
Placebo 2/152
Somnolence
Gabapentin 22/153
Placebo 8/152

Dizziness
Gabapentin 37/153
Placebo 12/152

Gilron 2005

Gilron et al. NEJM 2005 352: 1324-1334.

16 withdrawals during treatmentAt least moderate pain relief (5-point scale) for those completing a given treatment:
Placebo 13/42
Gabapentin 27/44
Morphine 35/44
gabapentin/morphine 32/41
Not interpretableNot interpretable

Gilron 2009

Gilron et al. Lancet 2009 374:1252-1261

All-cause withdrawals
Gabapentin 8/54
Nortriptyline 2/52
Combination 1/52

AE withdrawals
Gabapentin 7/54
Nortriptyline 1/52
Combination 1/52
Pain significantly lower with combination than either drug alone, by < 1/10 pointsNo serious AE recordedIndividual AE reporting showed higher incidence during titration than at maximum tolerated dose
Fibromyalgia

Arnold 2007

Arnold et al. Arthritis & Rheumatism 2007 56: 1336-1344

Multicentre

All-cause withdrawals
Gabapentin 18/75
Placebo 13/75

AE withdrawals
Gabapentin 12/75
Placebo 7/75

LoE withdrawals
Gabapentin 1/75
Placebo 2/75
At least 30% reduction in pain
Gabapentin 38/75
Placebo 23/75

PG any improvement (7-point scale)
Gabapentin 78%
Placebo 36%
"no significant differences in the percentage of serious treatment emergent adverse events"Sedation
Gaba 18/75

Somnolence
Gaba 14/75
Placebo 6/75

Dizziness
Gaba 19/75
Plac 7/75

Asthenia
Gaba 6/75
Plac 5/751

Peripheral oedema
Gaba 12/75
Plac 6/75
Complex Regional Pain Syndrome type 1

van de Vusse 2004

van de Vusse et al 20 BMC Neurology 2004 4:13

Both periods
AE withdrawal
Gabapentin 3/46
Placebo 0/46

LoE withdrawal
Gabapentin 0/46
Placebo 0/46
Much improved (per protocol) both periods
Gabapentin 8/46
Placebo 2/46

Much improved (per protocol) first period
Gabapentin 3/22
Placebo 1/24
At least one AE
First period
Gaba 21/22
Placebo 14/24
Both periods

Somnolence
Gaba 15/54
Plac 3/51

Dizziness
Gaba 20/54
Plac 2/51

Disturbed gait
Gaba 4/54
Plac 0/51

Oedema
Gaba 1/54
Plac 3/51
Spinal cord injury

Tai 2002

Tai - J Spinal Cord Medicine 2002 25:100-5.

Discontinuations
All-cause 7/14
Urinary retention 1/14
Not interpretableNo data
"No significant side effects noted at the maximum dosage"
No data

Levendoglu 2004

Levendoglu et al. Spine 2004 29: 743-751

All completedAverage fall in pain 62% with gabapentin, 13% with placebo

Mean scores without SD. No dichotomous results
All-cause AE
Gaba 13/20
Plac 5/20
Sedation
Gaba 3/20
Plac 0/20

Oedema
Gaba 3/20
Plac 0/20

Rintala 2007

Rintala et al. Arch Phys Med Rehabil 2007 88: 1547-1560

16/38 withdrewNo dichotomous data.
The paper claims statistical superiority of amitriptyline over gabapentin using paired t-tests for 22 patients completing all 3 phases. It also claims no benefit of gabapentin over placebo
No dichotomous dataNo dichotomous data
Nerve injury pain

Gordh 2008

Gordh et al. Pain 2008 138: 255-266

Multicentre

All-cause withdrawal
Gabapentin 11/120
Placebo 11/120

AE withdrawal
Gabapentin 7/120
Placebo 3/120

LoE withdrawal
Gabapentin 1/120
Placebo 2/120
Marked pain relief
Gabapentin 18/98
Placebo 5/98

Marked or moderate pain relief
Gabapentin 31/98
Placebo 14/98

No pain relief
Gabapentin 54/98
Placebo 70/98

At least 50% pain relief
Gabapentin 11 13/98
Placebo 7 9/98

At least 30% pain relief
Gabapentin 20 29/98
Placebo 10 19/98

Benefits from gabapentin over placebo for sleep and some aspects of quality of life
Serious AE
Gaba 5/120
Plac 1/120
Dizziness
Gaba 39/120
Plac 9/120
Phantom

Smith 2005

Smith  et al. Journal of Rehabilitation Research & Development 2005 42: 645-654

No apparent withdrawals"Meaningful decrease in pain" (top of 5-point scale)
Gabapentin 13/24
Placebo 5/24
No dataNo data

Bone 2002

Bone et al. Regional Anesthesia and Pain medicine 2002 27: 481-486

No data on where withdrawals occurredNo dichotomous data
Significant benefit for gabapentin by week 6 for pain
No dataSomnolence
Gaba 7/19
Plac 2/19

Dizziness
Gaba 2/19
Plac 1/19
Cancer associated neuropathic pain

Caraceni 2004

Caraceni et al. Journal of Clinical Oncology 2004 22: 2909-2917

All-cause withdrawal
Gabapentin 21/80
Placebo 10/41

AE withdrawal
Gabapentin 6/80
Placebo 3/41

LoE withdrawal
Gabapentin 0/80
Placebo 0/41
Somewhat better pain responses with gabapentin than placeboNo data

Any AE
Gaba 35/79
Placebo 10/41
Somnolence
Gaba 18/79
Plac 4/41

Dizziness
Gaba 7/89
Plac  0/41

Rao 2007

Rao et al. Cancer 2007 110: 2110-2118

All-cause withdrawal
Gabapentin 23/115
Placebo 26/115
No significant difference between gabapentin and placebo, but pain scores were low and the study may have lacked sensitivityNo dataDizziness
Gaba 8/91
Plac 4/89
HIV

Hahn 2004

Hahn et al. Journal of Neurology 2004 251: 1260-1266

All-cause withdrawal
Gabapentin 1/15
Placebo 1/11

AE withdrawal
Gabapentin 1/15
Placebo 0/11
Improvement in pain and sleep interference with gabapentin and placebo, with sustained difference in sleep but not painNo serious AE or deaths reportedSomnolence
Gaba 12/15
Plac 2/11

Dizziness
Gaba 9/15
Plac 5/11

Disturbed gait
Gaba 7/15
Plac 3/11
Other

Kimos 2007

Kimos et al. Pain 2007 127: 151-160

Chronic masticatory myalgia

All-cause withdrawal
Gabapentin 6/25
Placebo 8/25

6 did not return after initial visit
NNT calculated for clinically significant reported pain reduction (pain reduction of 30% or more) 3.4No dataDrowsiness
Gaba 7/25
Plac 5/25

Dizziness
Gaba 7/25
Plac 2/25

Ataxia
Gaba 1/25
Plac 0/25

Ho 2009

Ho et al. Pain 2009 141: 19-24

Small fibre sensory neuropathy

All-cause withdrawal 3/18 in first 4 weeks (withdrawn consent)At least 50% improvement in pain
Gabapentin 4/18
Tramadol 4/18
Placebo 1/18

At least 30% improvement in pain
Gabapentin 9/18
Tramadol 8/18
Placebo 4/18

Very much better
Gabapentin 5/18
Tramadol 3/18
Placebo 1/18

Much or very much better
Gabapentin 9/18
Tramadol 6/18
Placebo 2/18
No serious AE or deaths reportedAE not ascribed consistently to drugs
AE = adverse event; Amit = amitriptyline; Gaba = gabapentin; Nort = nortriptyline; PGIC = Patient Global Impression of Change; Plac = placebo; QoL = quality of life; SAE = serious adverse event; VAS = visual analogue scale; CTR = clinical trial report; LOE = lack of efficacy

Feedback

Feedback submitted 2015, 29 May 2015

Summary

Date of Submission: 29-May-2015

Name: Michael Chan BSc(Pharm); Danielle Ghag BSc(Pharm); Aaron Tejani PharmD

Affiliation: UBC

Role: Pharmacist

Comment: Written by Michael Chan BSc(Pharm), Danielle Ghag BSc(Pharm), Aaron Tejani PharmD

Dear Cochrane Review Team,

We read with great interest the systematic review of Gabapentin for chronic neuropathic pain and fibromyalgia in adults by Moore 2014. Although this systematic review has taken on the arduous task of ascertaining the highest level of available evidence, it is made difficult by the inherent bias that plagues the trials in the literature. This was evidenced upon further analysis of the 6 trials that were included in outcome 1.1, “At least 50% pain reduction over baseline”. The results of this outcome were subject to the limitations of the methodology in these studies that were not adequately accounted for in this review article.

The five-point Oxford Scale was included for each study to assess the risk of bias. This scale has been shown to provide unreliable validity assessments and its use is discouraged because it does not address important biases such as allocation concealment. Moreover, since gabapentin has a profound side effect profile, participants may have correctly anticipated which treatment they received. Thus, we feel that blinding is not adequately assessed through the Oxford scale, as points are allocated for double blinding without considering whether blinding was maintained throughout the study. In these cases, the risk of bias due to blinding may be better represented as an unclear risk or as some may argue, high risk. This would lead to reclassification of Sang 2013, Wallace 2010 and Zhang 2013 from low risk to unclear or high risk of bias, which may impact our interpretation of outcome 1.1. Furthermore, the effect size of gabapentin may be an overestimation as compromised blinding may account for an exaggerated effect of 13% (Savović 2012).

The aforementioned risk of bias due to blinding may be exacerbated by partial enrichment of the population that was enrolled. Studies by Sang 2013, Wallace 2010 and Zhang 2013 included patients who had previously responded to gabapentin, and excluded those who did not respond or tolerate gabapentin. This subset of participants who have already received the active drug, may be able to determine which drug they are receiving based on their knowledge of its anticipated effects, therefore jeopardizing blinding. Thus, enrichment can introduce performance and selection bias, which falsely inflates the proportion of patients who respond to active treatment.

This review assumed that treatment effects were not significantly affected by partial enrichment based on the results of the systematic review by Straube 2008, which examined the effects of enrichment in 21 trials of gabapentin or pregabalin. Of the 12 studies that examined gabapentin specifically, 10 were not enriched and 2 were partially enriched. A limitation of Straube 2008 was that the 2 partially enriched studies did not provide the proportion of patients taking gabapentin at baseline. This makes it difficult to determine the degree and implications of enrichment. Also, Straube 2008 stated it was difficult to make meaningful comparisons between trials using different doses of gabapentin and enrolment strategies.

The issue of enriched enrolment is exemplified by the poorly described baseline characteristics in most of the studies for outcome 1.1. Although, Sang 2013 specified that 43.6% and 39.6% of those in the gabapentin and placebo groups respectively had received gabapentin or pregabalin prior to enrolment, other studies did not disclose this information. Due to the uncertainty surrounding the impact that enrichment has on the treatment effects of gabapentin, we believe that a subgroup analysis may be appropriate to analyze enriched and non-enriched studies independently. The impact of enrichment may jeopardize internal and external validity, which we feel were not adequately addressed in the “Overall Completeness and Applicability of the Evidence”.

The majority of the included studies reported in outcome 1.1 did not disclose the proportion of patients receiving tricyclic antidepressants concomitantly or specify whether the dose was altered during the study. Since there is uncertainty surrounding the maintenance of blinding, this could lead to researchers favoring the gabapentin group by altering TCAs or other analgesics accordingly.

The review article stated that a fixed-effects model would be used if statistically significant heterogeneity was found. Despite this, even though there was statistically significant heterogeneity for outcomes 1.2.2 and 1.3.1, a fixed effects model was still used. Moreover, the review did not provide an assessment of possible reasons for heterogeneity. A random-effects model meta-analyses would be a more conservative approach to address the heterogeneity to provide a more meaningful conclusion (Higgins 2011).

For outcome 1.1 Baseline Observation Carried Forward (BOCF) was utilized to address attrition in two of the six studies, which accounted for over half of the weight. Although deemed a conservative approach, it can lead to an overestimation or underestimation of the number of patients with greater than 50% improvement from baseline. For example, the BOCF may indirectly overestimate the treatment effect of gabapentin by not taking into account the proportion of those receiving placebo who experienced a 50% improvement. This is of particular concern since we believe that blinding may have been compromised in these trials as described above. This unclear risk of bias is not captured in the summary tables which classifies BOCF as low risk. Moreover, the Summary of Findings Table for Main Comparisons for postherpetic neuralgia states that “Imputation method used [was] (LOCF) and small study size could influence results to reduce gabapentin efficacy”. This statement is not entirely accurate as Sang 2013 and Wallace 2010, which account for approximately 58.1% of the weight of outcome 1.1, use BOCF. Even so, we disagree with the fact that the Last Observation Carried Forward (LOCF) would reduce the treatment as it may in fact increase or decrease it. Despite our best efforts to postulate whether or not LOCF and BOCF would alter treatment effects, the best approach would be delving into the individual studies and contacting the authors for missing information.

One possible intervention to increase the confidence of the results in this review would be to conduct a sensitivity analysis. We would have liked to see a sensitivity analysis performed regardless of the number of studies available. Sensitivity analysis would help to characterize the impact of methodological limitations on the results of the systematic review.

Best Regards,

Michael Chan BSc(Pharm),

Danielle Ghag BSc(Pharm) and

Aaron M Tejani PharmD

References:

1. Zhang L, Rainka M, Freeman R, Harden RN, Bell CF, Chen C, et al. A Randomized, Double-Blind, Placebo-Controlled Trial to Assess the Efficacy and Safety of Gabapentin Enacarbil in Subjects With Neuropathic Pain Associated With Postherpetic Neuralgia (PXN110748). J Pain. 2013 Jun;14(6):590–603.

2. Straube S, Derry S, McQuay HJ, Moore RA. Enriched enrolment: definition and effects of enrichment and dose in trials of pregabalin and gabapentin in neuropathic pain. A systematic review. Br J Clin Pharmacol. 2008 Aug;66(2):266–75.

3. Wallace MS, Irving G, Cowles VE. Gabapentin Extended-Release Tablets for the Treatment of Patients with Postherpetic Neuralgia. Clin Drug Investig. 2010;30(11):765–76.

4. Moore RA, Wiffen PJ, Derry S, Toelle T, Rice ASC. Gabapentin for chronic neuropathic pain and fibromyalgia in adults. In: The Cochrane Collaboration, editor. Cochrane Database of Systematic Reviews [Internet]. Chichester, UK: John Wiley & Sons, Ltd; 2014 [cited 2015 May 29]. Available from: http://doi.wiley.com/10.1002/14651858.CD007938.pub3

5. Rice ASC, Maton S, Group1UK PNS, others. Gabapentin in postherpetic neuralgia: a randomised, double blind, placebo controlled study. Pain. 2001;94(2):215–24.

6. Sang CN, Sathyanarayana R, Sweeney M, Investigators D-1796 S, others. Gastroretentive gabapentin (G-GR) formulation reduces intensity of pain associated with postherpetic neuralgia (PHN). Clin J Pain. 2013;29(4):281–8.

7. Savović J, Jones H, Altman D, Harris R, Jűni P, Pildal J et al. Influence of reported study design characteristics on intervention effect estimates from randomised controlled trials: combined analysis of meta-epidemiological studies. Health Technology Assessment. 2012;16(35). .

8. Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011]. The Cochrane Collaboration, 2011. Available from www.cochrane-handbook.org.

I agree with the conflict of interest statement below:

I certify that I have no affiliations with or involvement in any organization or entity with a financial interest in the subject matter of my feedback.

Reply

Chan and colleagues begin by suggesting that the presence of adverse events with an active drug may compromise an overall blinding of the trial by an external observer, as they would anticipate that a person with adverse events had had an active drug, while those without had placebo. That would be even when, as in the three studies you mentioned, there was a matched placebo so that neither patients nor observers were aware of the allocation initially.

Of course, for the individual patient, who cannot see the overall picture, that would not be the case. And since the individual patient makes their own judgment about pain and other outcomes, the position of the outside observer is irrelevant. Moreover, when you look at the actual event rates for adverse events in these three trials, and overall, there is a rather low increase in adverse event rates (RR 1.25 overall). Wallace and Zhang showed no difference in event rates between gabapentin and placebo, which makes it especially hard to see how this suggested bias would act.

In this circumstance, it is hard to see what justification they can have for their statements, unless supported with empirical evidence from elsewhere. We have been looking for some years now, as we have an interest in the methodology of systematic reviews and sources of bias, and are aware of none.

In passing, we use both the Oxford Quality Score (to help justify inclusion and exclusion – studies must be randomised and double blind to be accepted) and a version of Risk of Bias. The OQS now has well over 10,000 citations, and is validated. Cochrane RoB omits several important, and possibly crucial, sources of bias. Neither is perfect, but when detecting bias we need all the tools at our disposal.

They also make a point about partial enrichment. The situation right now is that there is zero empirical evidence that partial enrichment makes any difference to results of clinical trials in neuropathic pain. It may well be, as they say, that some residual bias is not accounted for, but that is speculation, and not fact. The fact is that the three studies that they seem to be concerned about are not out of line with others in the analyses, and one of them, for analysis of PGIC, was not different from placebo.

Chan and colleagues are also concerned with patients receiving TCAs. Actually, it is very unlikely that TCA prescribing changes affected the results. Most trials indicated that any concomitant therapies would not be changed during the course of the trial. It is an interesting speculation, but since tricyclic efficacy is as low as all others in NP (based on the rather inadequate evidence we have, as well as clinical experience), one would really need to push this to an extreme to explain any result. Is there any evidence that increasing doses of TCAs has any dramatic effect on analgesia? We know of none, and we also know that most people do not respond to TCAs while many suffer adverse events, which often make them desist. It is a hard argument to maintain.

Issues around statistics refer to situations with only a handful of studies, or where one study (Zhang) gave a result favouring placebo. Random effects models are more appropriate where there is clinical heterogeneity, which we try to avoid. Changing to random effects does not change the result, but we might revisit this. Actually RE is more appropriate where there are a number of small studies, which is where heterogeneity can occur – but there are number of issues intertwined here, so it isn't simple. For example, examples of fraudulent research often show high degrees of homogeneity, and heterogeneity tests can be used to detect fraud. We may need to reword the methods and revisit thinking on this.

We found their point about imputation rather difficult to understand. We cannot see why that should be because the imputation is applied equally to both active and placebo. In several individual patient level calculations that have used LOCF and BOCF there has been little effect of imputation method on placebo, only on active treatments where there is a large adverse event withdrawal rate, as we pointed out in our analysis in Pain. And there is good evidence of potentially very large positive bias for opioids in chronic non-cancer pain.

We are sorry Chan and colleagues disagree with the current evidence on imputation method. We use BOCF to produce a result where patients who are able to remain on treatment with tolerable adverse events have a high degree of pain relief. That makes clinical sense, and is what systematic reviews tell us that patients want. It also makes sound economic sense. Using LOCF to impute results where up to 65% of patients drop out over 12 weeks (as in opioid studies in chronic non-cancer pain) might be of some statistical interest, and might produce significant results where BOCF does not, but it takes some explaining as to its relevance to the real world. Unless and until that is explained to us and supported with empirical evidence, we are more than happy to stick to our guns on this.

As to contacting authors, we have done – or rather had discussions with pharmaceutical companies about the possibility of obtaining individual patient level data for gabapentin. This will not be possible. It is a shame, because in other circumstances where we could obtain patient level data we have been able to make some interesting and important methodological advances, even though you appear not to agree with them.

We find it hard to understand why Chan and colleagues would want sensitivity analysis with inadequate data. What we know is that small studies, and small numbers of small studies, can give us the wrong answer. This has been evident for at least 20 years, and is supported by several recent major studies, often in pain topics. To use unreliable evidence on which to base judgments like that seems retrograde.

Andrew Moore, Sheena Derry, Phil Wiffen

Editorial note: this review will be assessed for updating in 2019, and may then be split into two reviews: neuropathic pain, and fibromyalgia.

Contributors

Feedback Editor Kate Seers, Managing Editor Anna Hobson, and review authors.

What's new

DateEventDescription
13 March 2017AmendedDeleted error in Summary table A.

History

Protocol first published: Issue 3, 2009
Review first published: Issue 3, 2011

DateEventDescription
23 July 2015AmendedThis review is being split; see Published notes
6 July 2015Feedback has been incorporatedSee Feedback section for details.
19 May 2014AmendedMistake in Summary of findings table corrected
28 April 2014Review declared as stableThis review will be assessed for updating in 2019.
17 March 2014New search has been performed

New searches. New studies added. Minor methodological amendments made, in line with current standards.

The original chronic pain review included 14 studies with 1392 participants in 13 reports. The 2011 update involved 29 studies in 29 reports with 3571 participants. In this update we consider 33 studies in 34 reports, involving 4388 participants taking oral gabapentin.

We have added seven new studies of oral gabapentin with 1919 participants (Backonja 2011; Harden 2013; Mishra 2012; NCT00475904; Rauck 2013a; Sang 2013; Zhang 2013) and another new publication (Sandercock 2012) that provided results for a study that was already included but did not provide usable data (Sandercock 2009). We also identified a small study, with 170 participants, using an experimental formulation of injected (intrathecal) gabapentin (Rauck 2013b).

17 March 2014New citation required but conclusions have not changedAdditional studies did not change efficacy or harm estimates in any clinically significant way

Contributions of authors

PW registered the title. PW, RAM, and SD wrote the 2011 protocol.

PW, SD, and RAM assessed inclusion of papers and extracted data.

RAM wrote up the 2011 review and SD made changes for the 2014 update.

TRT and AR commented on clinical aspects relating to gabapentin.

All authors contributed to the final draft and approved the published version.

PW will be responsible for the update.

Declarations of interest

SD and PW have received research support from charities, government and industry sources at various times.

RAM has consulted for various pharmaceutical companies and received lecture fees from pharmaceutical companies related to analgesics and other healthcare interventions, including (in the past five years) AstraZeneca, Eli Lilly, Flynn Pharma, Furtura Medical, Grünenthal, GSK, Horizon Pharma, Lundbeck, Menarini, MSD, Pfizer, Reckitt Benckiser, Sanofi Aventis, Urgo, Astellas, Novartis, and Vifor Pharma.

TRT has consulted for various pharmaceutical companies and received lecture fees from pharmaceutical companies related to chronic pain and analgesics, including (in the past five years) Allergan, Astellas, AstraZeneca, Boeringer, Eli Lilly, Grünenthal, GSK, Janssen-Cilag, Pfizer, Mundipharma.TRT is an Principal Investigator in the EuroPain consortium. EuroPain has received support from the Innovative Medicines Initiative Joint Undertaking under grant agreement n° 115007, a European Union's Seventh Framework Programme (FP7/20072013) and EFPIA companies (www.imieuropain.org). TRT is a site investigator for the Neuropain project, funded by Pfizer.

ASCR undertakes Consultancy work through Imperial College Consultants. In last two years this has included work for Astellas, Spinifex and Servier. ASCR has share options in Spinifex. ASCR is a Principal Investigator in the EuroPain consortium. EuroPain has received support from the Innovative Medicines Initiative Joint Undertaking under grant agreement n° 115007, resources for which are composed of financial contribution from the European Union's Seventh Framework Programme (FP7/20072013) and EFPIA companies (www.imieuropain.org). Specifically, research funding for ASCR’s laboratory  has been received from Pfizer and Astellas. ASCR is a site investigator for the Neuropain project, funded by Pfizer.ASCR is Chair of the IASP Special Interest Group on Neuropathic Pain (www.neupsig.org). ASCR serves on the Executive Committee of ACTTION (Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks; www.acttion.org).

None of the authors have received any funds from any company with an interest in gabapentin for research on gabapentin, and none from any source for the production of this review.

Sources of support

Internal sources

  • No sources of support supplied

External sources

  • NHS Cochrane Collaboration Programme Grant Scheme, UK.

  • European Union Biomed 2 Grant no. BMH4 CT95 0172, UK.

Differences between protocol and review

The protocol for the original gabapentin review (Wiffen 2005) was superceded and split, and an updated protocol produced for the 2011 review (Moore 2011), to reflect, at least in part, the more recent developments in understanding of potential biases in chronic pain trials, and new outcomes of direct relevance to patients. The main difference between the original review and the updated protocol was more emphasis being given to a set of core outcomes, although all of those outcomes were included in the updated protocol.

In this 2014 update we emphasise the difference between first tier and second tier evidence, and also emphasise the differences between conditions now defined as neuropathic pain, and other conditions like masticatory pain, CRPS-1, and fibromyalgia.

Notes

This review is being split into separate reviews on fibromyalgia and neuropathic pain. A new protocol is in development for fibromyalgia. In due course, this version of the review will be updated to focus only on neuropathic pain.

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Arnold 2007

Methods

Multicentre, randomised, double-blind, placebo-controlled, parallel-group, partial enrichment, LOCF

Titration to limit of tolerability or maximum 2400 mg daily over 6 weeks, then 6 weeks stable dose (12 weeks in total)

Participants

Fibromyalgia (ACR criteria for diagnosis). N = 150 , median age 48 years, 90% women. PI at randomisation ≥4/10, initial pain score 5.8/10

Excluded: individuals with prior treatment with gabapentin or pregabalin

Interventions

Gabapentin 2400 mg daily (max), n = 75

Placebo, n = 75

Maximum dose 2400 mg daily, placebo was diphenhydramine

Paracetamol and OTC NSAIDs allowed (no dose limit stated)

Outcomes

≥ 30% reduction in pain

Adverse events

Withdrawals

NotesOxford Quality Score: R = 1, DB = 2, W = 1, Total = 4
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot described
Allocation concealment (selection bias)Unclear riskNot described
Blinding (performance bias and detection bias)
All outcomes
Low risk"matching placebo"
Incomplete outcome data (attrition bias)
Efficacy
Unclear riskLOCF
Size
Efficacy
Low risk229
Study duration
Efficacy
Low risk8 weeks
Outcomes reportedUnclear risk≥30% reduction in pain

Backonja 1998

Methods

Multicentre, randomised, double-blind, placebo-controlled, parallel-group, not enriched, LOCF

Titration to maximum tolerated dose or 3600 mg daily over 4 weeks, then stable dose for 4 weeks (8 weeks in total)

ParticipantsPainful diabetic neuropathy. N = 165, mean age 53 years, 40% women. Pain duration > 3 months before treatment, PI ≥40/100 at randomisation, initial mean pain score 6.4/10
Interventions

Gabapentin 3600 mg daily (max), n = 84

Placebo, n = 81

Medication for diabetes control remained stable during study. Paracetamol (max 3 g daily) allowed

Outcomes

PGIC much or moderately improved

≥ 50% reduction in pain (CTR)

PGIC much improved (CTR)

PGIC moderately or much improved (CTR)

Adverse events

Withdrawals

Notes

Oxford Quality Score: R = 2, DB = 2, W = 1, Total = 5

Parke-Davies/Pfizer sponsored

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskComputer-generated random code
Allocation concealment (selection bias)Unclear riskNot reported
Blinding (performance bias and detection bias)
All outcomes
Low risk"supplied in identical capsules in blinded fashion". "All participants were supplied with an equal number of capsules".
Incomplete outcome data (attrition bias)
Efficacy
Unclear riskLOCF
Size
Efficacy
Unclear risk165
Study duration
Efficacy
Low risk8 weeks
Outcomes reportedLow riskAt least 50% reduction in pain

Backonja 2011

Methods

Randomised, double blind, placebo controlled, parallel group, enriched for tolerance (but not response), LOCF

Open label titration with gabapentin from 300 mg at night to maximum 600 mg three times daily (1800 mg/d) over 4 days, maintained on maximum tolerated dose for 7 days, then randomised to double blind treatment with 600 mg gabapentin encarbil twice daily or placebo for 2 weeks

ParticipantsPostherpetic neuralgia. N = 102 in double-blind phase, and 116 in open-label phase, mean age 65 years, 51% women. Pain > 3 months after healing of skin rash. PI at randomisation ≥ 40/100, initial average daily pain score 6.1/10, and 4.5 before randomisation
Interventions

Gabapentin encarbil 1200 mg daily, n = 47 (equivalent to 624 mg gabapentin, given as divided dose)

Placebo, n = 54

Antiepileptic medication discontinued ≥7 days before open label phase. Antidepressant and narcotic analgesics continued if stable > 1 month

Outcomes

≥ 50% reduction in pain

≥ 30% reduction in pain

PGIC much and very much improved

Withdrawals

Adverse events

Notes

Oxford Quality Score: R = 1, DB = 2, W = 1, Total = 4

XenoPort sponsored

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot described
Allocation concealment (selection bias)Unclear riskNot reported
Blinding (performance bias and detection bias)
All outcomes
Low risk"matching placebo"
Incomplete outcome data (attrition bias)
Efficacy
Unclear riskLOCF
Size
Efficacy
High risk< 50 participants per treatment arm
Study duration
Efficacy
High risk2 weeks of double blind treatment
Outcomes reportedLow risk≥ 50% and ≥ 30% reduction in pain

Bone 2002

Methods

Randomised, double-blind, placebo-controlled, cross-over, not enriched. No imputation method mentioned

Titration to maximum tolerated dose or 2400 mg daily over 1 week, then stable dose for 5 weeks (6 weeks total); 1-week washout, then cross-over

Participants

Established phantom limb pain ≥ 6 months, N = 19, mean age 56 years, 21% women. PI before treatment > 3/10, initial pain score 6.4/10

14 completed both treatment periods

Interventions

Gabapentin 2400 mg daily (max)

Placebo

Paracetamol + codeine 500 mg/30mg (max 12 tablets daily) allowed as rescue medication. Stable, low doses of TCAs continued

Outcomes

No dichotomous efficacy data

Adverse events

NotesOxford Quality Score: R = 2, DB = 2, W = 1, Total = 5
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskComputer-generated
random numbers
Allocation concealment (selection bias)Low risk"The hospital pharmacists were also responsible for issuing identical, coded medication bottles containing identical tablets of gabapentin or placebo"
Blinding (performance bias and detection bias)
All outcomes
Low risk"identical, coded medication bottles containing identical tablets of gabapentin or placebo"
Incomplete outcome data (attrition bias)
Efficacy
Unclear riskNo imputation mentioned
Size
Efficacy
High risk19 randomised
Study duration
Efficacy
Unclear risk6 weeks each period
Outcomes reportedHigh riskNo dichotomous data

Caraceni 2004

Methods

Randomised, double-blind, placebo-controlled, parallel-group, partial enrichment. No imputation method mentioned

Titration to pain ≤ 3/10 or limit of tolerability, or maximum 1800 mg daily (10 days in total)

ParticipantsNeuropathic cancer pain despite regular systemic opioid therapy. N = 121, mean age 60 years, 56% women. Pain at randomisation ≥ 5/10, initial pain intensity 7.3/10
Interventions

Gabapentin 1800 mg daily (max), n = 80

Placebo, n = 41

Any previous analgesics continued unchanged. One additional dose of opioid allowed for rescue medication

Outcomes

No dichotomous efficacy data

Adverse events

Withdrawals

NotesOxford Quality Score: R = 2, DB = 2, W = 1, Total = 5
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskBlock of three randomisation list
Allocation concealment (selection bias)Low riskRemote pharmacy department provided numbered containers
Blinding (performance bias and detection bias)
All outcomes
Low risk"identical capsules"
Incomplete outcome data (attrition bias)
Efficacy
Unclear riskImputation not mentioned
Size
Efficacy
Unclear risk121 randomised
Study duration
Efficacy
High risk10 days
Outcomes reportedHigh riskNo dichotomous outcomes

Chandra 2006

Methods

Randomised, double-blind, active controlled, parallel-group, no enrichment

Dose escalation every 2 weeks until adequate pain relief obtained or limit of tolerability, to maximum nortriptyline 150 mg daily or gabapentin 2700 mg daily by 4 weeks, then stable dose for 5 weeks (9 weeks in total)

ParticipantsPostherpetic neuralgia. N = 76, mean age 54 years, 50% women. Pain > 2 months after healing of skin rash. PI at randomisation ≥ 40/100, initial average daily pain score 5.7/10
Interventions

Gabapentin 2700 mg daily (max), n = 38

Nortriptyline 150 mg daily (max), n = 38

Of 'responders' ˜80% gabapentin took 2700 mg daily, ˜66% nortriptyline took 75 mg daily

Outcomes

≥ 50% pain relief over baseline pain

≥ 50% pain relief over (VAS)

Adverse events

Withdrawals

Notes

Oxford Quality Score: R = 2, DB = 2, W = 1, Total = 5

Sponsored Pfizer/independent

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk"block-of-three randomization list was used"
Allocation concealment (selection bias)Low risk"code supplied in sealed envelopes, opened at time of enrolment", "drugs dispensed in sealed envelopes"
Blinding (performance bias and detection bias)
All outcomes
Low risk"drugs placed in identical capsules", "matching placebo of nortriptyline" to blind different dosing schedules
Incomplete outcome data (attrition bias)
Efficacy
Unclear riskImputation not mentioned
Size
Efficacy
Unclear risk76 randomised
Study duration
Efficacy
Low risk9 weeks
Outcomes reportedLow riskAt least 50% reduction in pain

CTR 945-1008

Methods

Multicentre, randomised, double-blind, placebo-controlled, parallel-group, no obvious enrichment, LOCF

Titration from 300 mg/day to maximum tolerated dose or 3600 mg daily over 3 weeks, then stable dose for 12 weeks (15 weeks total)

ParticipantsPainful diabetic neuropathy. N =389, mean age 58 years, "more men than women". Pain duration > 3 months, PI at randomisation ≥ 40/100
Interventions

Gabapentin 3600 mg daily (max), n = 200

Placebo, n = 189

Outcomes

≥ 30% reduction in pain

≥ 50% reduction in pain

Adverse events

Withdrawals

Notes

Oxford Quality Score: R = 1, DB = 2, W = 1, Total = 4

Pfizer sponsored

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot described
Allocation concealment (selection bias)Unclear riskNot described
Blinding (performance bias and detection bias)
All outcomes
Low riskMatching placebo
Incomplete outcome data (attrition bias)
Efficacy
Unclear riskLOCF
Size
Efficacy
Low risk389 randomised
Study duration
Efficacy
Unclear risk14 weeks
Outcomes reportedLow riskAt least 50% reduction in pain

CTR 945-224

Methods

Multicentre, randomised, double-blind, placebo-controlled, parallel-group, no enrichment, probably LOCF

Titration over 3 weeks to 600, 1200, or 2400 mg daily, then stable dose to 4 weeks (7 weeks total)

ParticipantsPainful diabetic neuropathy for 1 to 5 years. N = 325, mean age 60 years, 44% women. PI at randomisation ≥ 40/100, initial pain score 6.2/10
Interventions

Gabapentin 600 mg, n = 82

Gabapentin 1200 mg, n = 82

Gabapentin 2400 mg, n = 84

Placebo, n = 77

Outcomes

≥ 50% reduction in pain score

PGIC very much improved

PGIC much or very much improved

Adverse events

Withdrawals

Notes

Oxford Quality Score: R = 2, DB = 2, W = 1, Total = 5

Parke-Davis/Pfizer sponsored

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskRandomisation code
Allocation concealment (selection bias)Low riskRandomisation code broken after last patient completed
Blinding (performance bias and detection bias)
All outcomes
Low riskMatching placebo
Incomplete outcome data (attrition bias)
Efficacy
Unclear riskProbably LOCF
Size
Efficacy
Low risk325 randomised
Study duration
Efficacy
Unclear risk7 weeks
Outcomes reportedLow riskAt least 50% reduction in pain

Gilron 2005

Methods

Randomised, double-blind, placebo-controlled 4-period cross-over, no enrichment. No imputation method mentioned (but if half of scores missing, outcome considered missing)

Titration to target doses or limit of tolerability over 3 weeks, then stable dose for 1 week, and tapered dose for 1 week (5 weeks in total); 3-day washout and cross-over to next treatment

ParticipantsPDN and PHN. N = 57, median age 62 years, 44% women. Pain ≥ moderate for 3 months, initial mean pain score 5.8/10
Interventions

Gabapentin 3200 mg daily (max)

Morphine 120 mg daily (max)

Gabapentin plus morphine 2400 mg/60 mg daily (max)

Placebo (lorazepam) 1.6 mg

Mean maximum tolerated doses: gabapentin alone 2207 ± 89 mg, morphine alone 45.3 ± 3.9 mg, gabapentin + morphine 1705 ± 83 + 34.4 ± 2.6 mg

Outcomes

Pain relief for those completing a given treatment (5-point scale)

Withdrawals

NotesOxford Quality Score: R = 2, DB = 2, W = 1, Total = 5
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskBalanced Latin-square crossover design
Allocation concealment (selection bias)Low risk"concealed allocation schedule" prepared remotely
Blinding (performance bias and detection bias)
All outcomes
Low risk"identical appearing blue and grey capsules .... in accord with a double-dummy design"
Incomplete outcome data (attrition bias)
Efficacy
Unclear riskImputation not mentioned
Size
Efficacy
High riskAlthough 57 randomised, data available 40-44 completing a given treatment
Study duration
Efficacy
Unclear risk5 weeks each period
Outcomes reportedUnclear riskAt least moderate pain relief

Gilron 2009

Methods

Randomised, double-blind, placebo-controlled 3-period cross-over, no enrichment. No imputation method mentioned

Titration to target doses or limit of tolerability over 24 days, then stable dose for 1 week, and tapered dose for 1 week (6 weeks in total); 6-day washout and cross-over to next treatment

ParticipantsPDN and PHN. N = 56, median age 64 years, 40% women. Pain ≥ moderate for 6 months, initial mean pain score 5.4/10
Interventions

Gabapentin 3600 mg daily (max)

Nortriptyline 100 mg daily (max)

Gabapentin plus nortriptyline 3600 mg/100 mg daily (max)

Mean (SE) maximum tolerated doses: gabapentin alone 2433 ± 106 mg, nortriptyline alone 62 ± 3.6 mg, gabapentin + nortriptyline 2180 ± 108 + 50 ± 3.5 mg

Outcomes

Pain relief (average)

Withdrawals

Adverse events

NotesOxford Quality Score: R = 2, DB = 2, W = 1, Total = 5
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskBalanced Latin-square crossover design
Allocation concealment (selection bias)Low risk"concealed allocation"
Blinding (performance bias and detection bias)
All outcomes
Low risk"double dummy"
Incomplete outcome data (attrition bias)
Efficacy
Unclear riskImputation not mentioned
Size
Efficacy
High riskReporting on < 50 completing 2 periods
Study duration
Efficacy
Unclear risk5-week period on treatment
Outcomes reportedHigh riskNo dichotomous data

Gordh 2008

Methods

Multicentre, randomised, double-blind, placebo-controlled, cross-over, not enriched. No imputation method mentioned

Titration over 2 weeks from 300 mg to maximum pain relief at a tolerable dose or 2400 mg daily, then stable dose for 3 weeks (5 weeks total); 3-week washout, then cross-over

Participants

Peripheral nerve injury with pain ≥ 6 months. N = 120, mean age 49 years, 53% women. PI at randomisation > 30/100, initial pain intensity 53/100

Efficacy analysis based on 98 who completed both treatment periods

Interventions

Gabapentin 2400 mg daily (max)

Placebo

Mean daily dose of gabapentin 2243 ± 402 mg

Paracetamol ± codeine and dextropropoxyphene permitted as rescue medication

Analgesics and NSAIDs used by ˜50% during study

Outcomes

≥ 50% pain relief (weekly mean pain score)

≥ 30% pain relief

Marked pain relief (5-point scale)

Marked or moderate pain relief (5-point scale)

Adverse events

Withdrawals

NotesOxford Quality Score: R = 2, DB = 2, W = 1, Total = 5
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskRandomization list was generated by the Clinical Pharmaceutical Operation Center in Freiburg
Allocation concealment (selection bias)Low riskCentral, remote allocation, "sealed code envelope"
Blinding (performance bias and detection bias)
All outcomes
Low risk"capsules that were identical in appearance"
Incomplete outcome data (attrition bias)
Efficacy
Unclear riskImputation not mentioned
Size
Efficacy
Unclear risk120 randomised
Study duration
Efficacy
Unclear risk5-week period
Outcomes reportedLow riskAt least 50% reduction in pain

Gorson 1999

Methods

Randomised, double-blind, placebo-controlled, cross-over, not enriched. No imputation method mentioned

Titration over 3 days to 900 mg, then fixed dose for remainder of 6-week period; 3 week washout, then cross-over

ParticipantsPainful diabetic neuropathy 1 to 5 years, pain ≥ moderate for over 3 months. N = 40, mean age 62 years, 23% women. Pain intensity at randomisation ≥ 40/100, initial pain intensity not reported
Interventions

Gabapentin 900 mg, n = 19 (first phase)

Placebo, n = 21 (first phase)

Medication for diabetes control remained stable during study. Stable doses of NSAID or narcotics allowed

Outcomes

Pain relief at end of treatment (4-point global score) moderate or excellent

Adverse events

Notes

Oxford Quality Score: R = 1, DB = 1, W = 0, Total = 3

Sponsored by Warner Lambert/Parke-Davis

Note: no separate data for first period, small group sizes, non standard global scale

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot reported
Allocation concealment (selection bias)Unclear riskNot reported
Blinding (performance bias and detection bias)
All outcomes
Unclear riskNot reported
Incomplete outcome data (attrition bias)
Efficacy
Unclear riskImputation not mentioned
Size
Efficacy
High risk40 randomised
Study duration
Efficacy
Unclear risk6-week period
Outcomes reportedUnclear riskModerate or excellent pain relief

Hahn 2004

Methods

Randomised, double-blind, placebo-controlled, parallel-group, not enriched. No imputation method mentioned

Titration over 2 weeks to adequate pain relief or 2400 mg daily, then stable dose for 2 weeks (4 weeks in total)

ParticipantsPainful HIV sensory neuropathy by standard definitions. N = 26, mean age 45 years, 23% women. Pain at any level including mild pain at randomisation, initial mean pain score 4.9/10 (lower limit of range 1.5)
Interventions

Gabapentin 2400 mg daily (max), n = 15 (10 participants took max dose)

Placebo, n = 11

Outcomes

No dichotomous efficacy data

Adverse events

Withdrawals

NotesOxford Quality Score: R = 2, DB = 2, W = 1, Total = 5
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk"Randomisation was performed by producing a randomisation schedule that assigned each patient to GBP or a matching placebo"
Allocation concealment (selection bias)Low riskRemote allocation
Blinding (performance bias and detection bias)
All outcomes
Low risk"identically appearing capsules"
Incomplete outcome data (attrition bias)
Efficacy
Unclear riskImputation not mentioned
Size
Efficacy
High risk26 randomised
Study duration
Efficacy
Unclear risk4 weeks
Outcomes reportedHigh riskNo dichotomous data

Harden 2013

MethodsRandomised, double blind, crossover, dose-comparison. Two 4-week treatments plus 4 day washout
ParticipantsPostherpetic neuralgia for at least 3 months after rash healing, with inadequate response to gabapentin 1800 mg daily, but not no response to either gabapentin or pregabalin. Mean age 63 years, 39% women, mean baseline pain 6/10. N = 138
InterventionsGabaoentin encarbil at two different dose ranges
Outcomes≥50% and ≥30% pain reduction at end of treatment periods. Adverse events
NotesOxford Quality Score: R = 2, DB = 1, W = 1, Total = 5
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskComputer generated
Allocation concealment (selection bias)Low riskRemote allocation
Blinding (performance bias and detection bias)
All outcomes
Unclear riskNo details
Incomplete outcome data (attrition bias)
Efficacy
Unclear riskLOCF
Size
Efficacy
Unclear risk50-200
Study duration
Efficacy
Unclear risk4 weeks
Outcomes reportedLow risk≥50% pain reduction

Ho 2009

Methods

Randomised, double-blind, active placebo-controlled, cross-over. Analyses included all data available assuming that missing data were missing at random

Titration over 1 week of gabapentin at pre-study dose (up to 4800 mg daily), tramadol 50 mg "q.i.d." (probably once daily in USA - officially 4 times daily), or diphenhydramine 50 mg "qhs" (qh = every hour, but more likely 4 x daily) as active placebo, then stable dose for 1 week (2 weeks in total); 1-week washout, then cross-over to next treatment

ParticipantsPainful small fibre sensory neuropathy with gabapentin-sensitive pain that worsened with placebo, in a complete enrichment design. N = 18, mean age 59 years, 44% women. Pain at randomisation > 3, initial mean pain score 4.9/10
Interventions

Gabapentin 4800 mg daily (max)

Tramadol 200 mg daily (max)

Placebo

Stable pain medication other than gabapentin was continued

Paracetamol (325 mg tablets, dose not specified) allowed for rescue medication. If inadequate patient could take additional 400 mg gabapentin, up to 1200 mg daily

Outcomes

≥ 50% improvement in pain

≥ 30% improvement in pain

PGIC very much better

PGIC much or very much better

Withdrawals

NotesOxford Quality Score: R = 2, DB = 2, W = 1, Total = 5
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskComputer-generated random allocation schedule
Allocation concealment (selection bias)Low riskRemote allocation
Blinding (performance bias and detection bias)
All outcomes
Low risk"matching capsules"
Incomplete outcome data (attrition bias)
Efficacy
Unclear riskImputation not mentioned
Size
Efficacy
High risk54 randomised to 3 groups. Gabapentin comparison with placebo 36 patients maximum
Study duration
Efficacy
High risk2 weeks
Outcomes reportedLow riskAt least 50% reduction in pain

Irving 2009

Methods

Multicentre, randomised, double-blind, placebo-controlled, parallel-group, partial enrichment, LOCF, extended release formulation

Gradual titration to 1800 mg over 2 weeks, then stable for 2 weeks (4 weeks in total)

ParticipantsPostherpetic neuralgia. N = 158, mean age 70 years, 53% women. Pain > 3 months after healing of skin rash, PI at randomisation ≥ 4/10, initial average daily pain score 6.5/10
Interventions

Gabapentin ER 1800 mg daily, n = 55

Gabapentin ER 1800 mg daily in split doses, n = 52

Placebo, n = 51

Rescue with paracetamol up to 4000 mg daily, or paracetamol plus hydrocodone 500 mg/5 mg up to 8 tablets daily

Outcomes

≥ 50% reduction in pain score

≥ 30% reduction in pain score

PGIC much or very much improved

Adverse events

Withdrawals

Notes

Oxford Quality Score: R = 2, DB = 2, W = 1, Total = 5

Sponsored by Depomed

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskComputer generated list
Allocation concealment (selection bias)Unclear riskNot described
Blinding (performance bias and detection bias)
All outcomes
Low riskDouble-dummy method
Incomplete outcome data (attrition bias)
Efficacy
Unclear riskLOCF
Size
Efficacy
Unclear risk158 randomised
Study duration
Efficacy
Unclear risk4 weeks
Outcomes reportedLow riskAt least 50% reduction in pain

Kimos 2007

Methods

Randomised, double-blind, placebo-controlled, parallel-group, not enriched. No imputation method mentioned

Titration to adequate pain relief, limit of tolerability or 4200 mg daily, then stable dose for remainder of 12-week study

ParticipantsChronic masticatory myalgia (pain classification based on defined criteria) lasting ≥ 6 months, not resulting from trauma or active inflammatory cause. N = 50, mean age 34 years, 100% women. PI at randomisation ≥ 50/100, initial average daily pain score 6.2/10
Interventions

Gabapentin 4200 mg daily (max), n = 25

Placebo, n = 25

Stable doses of antidepressants continued

Paracetamol (max 4000 mg daily) allowed as rescue medication

Outcomes

≥ 30% reduction in pain

Adverse events

Withdrawals

Notes

Oxford Quality Score: R = 2, DB = 2, W = 1, Total = 5

Note: withdrawals > 10%

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk"computer-generated randomization code list"
Allocation concealment (selection bias)Low risk"concealed randomization and the according allocation were implemented by a research assistant" (not involved with patients or investigators)
Blinding (performance bias and detection bias)
All outcomes
Low risk"identical looking capsules ... packaged in identical clear bottles"
Incomplete outcome data (attrition bias)
Efficacy
Unclear riskImputation not mentioned
Size
Efficacy
Unclear risk50 randomised
Study duration
Efficacy
Low risk12 weeks
Outcomes reportedUnclear riskPain reduction of 30% or more

Levendoglu 2004

Methods

Randomised, double-blind, placebo-controlled, cross-over, not enriched. No imputation method mentioned

Titration to limit of tolerability or maximum of 3600 mg over 4 weeks, then stable dose for remainder of 8-week period; 2-week washout then cross-over

ParticipantsComplete traumatic SCI at lumbar or thoracic level. N = 20, mean age 36 years, 35% women. Pain duration before treatment ≥ 6 months, PI at randomisation > 4/10, initial average daily pain 9/10
Interventions

Gabapentin 3600 mg daily (max)

Placebo

Mean max tolerated dose of gabapentin 2850 ± 751 mg

No concurrent analgesics allowed

Outcomes

Pain reduction (mean data only)

Adverse events

Withdrawals

NotesOxford Quality Score: R = 1, DB = 2, W = 1, Total = 4
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot reported
Allocation concealment (selection bias)Unclear riskNot reported
Blinding (performance bias and detection bias)
All outcomes
Low risk"identically appearing capsules"
Incomplete outcome data (attrition bias)
Efficacy
Unclear riskImputation not mentioned
Size
Efficacy
High risk20 randomised
Study duration
Efficacy
Low risk8-week period
Outcomes reportedHigh riskNo dichotomous data

Mishra 2012

Methods

Randomised, double blind, active and placebo controlled, parallel group. Not enriched. No imputation method mentioned

Three active treatments, with low starting dose and increases at start of weeks 2 and 3. total duration 4 weeks

Gabapentin 900 mg/d (divided x2) increasing to 1800 mg/d (divided x3)

Pregabalin 150 mg/d (divided x2) increasing to 600 mg (divided x2)

Amitriptyline 50 mg/d increasing to 100 mg/d at bedtime

ParticipantsCancer with neuropathic pain. N = 120, age and sex distribution not reported. Baseline pain 7.6/10
Interventions

Gabapentin 1800 mg daily, n = 30

Pregabalin 600 mg daily, n = 30

Amitriptyline 100 mg daily, n = 30

Placebo, n = 30

OutcomesMean changes for pain functional capacity and opioid sparing
NotesOxford Quality Score: R = 2, DB = 1, W = 0, Total = 3
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskComputerised random list
Allocation concealment (selection bias)Unclear riskNot reported
Blinding (performance bias and detection bias)
All outcomes
Unclear riskAll drugs encapsulated, but no mention of equal numbers and regimen or double dummy method
Incomplete outcome data (attrition bias)
Efficacy
Unclear riskImputation not mentioned
Size
Efficacy
High risk< 50 participants per treatment arm
Study duration
Efficacy
Unclear risk4 weeks
Outcomes reportedHigh riskMean data or P-values reported

Morello 1999

Methods

Randomised, double-blind, placebo-controlled, cross-over, not enriched. No imputation method mentioned

Titration over 2 days and adjusted thereafter until adequate pain relief obtained or limit of tolerability to maximum 1800 mg gabapentin or 75 mg amitriptyline daily, then stable dose for remainder of 6-week period; 1-week washout, then cross-over

Participants

Painful diabetic neuropathy. N = 25, mean age 60 years, 4% women. Pain duration > 3 months before treatment, no initial PI at inclusion, initial pain intensity mild/moderate

19 completed 6 weeks with both study drugs

Interventions

Gabapentin 1800 mg daily (max)

Amitriptyline 75 mg daily (max)

Paracetamol allowed as rescue medication (max 1300 mg daily)

Outcomes

Pain relief at end of treatment (6-point global score), complete or a lot

Pain relief at end of treatment (6-point global score), at least moderate

Adverse events

Withdrawal

Notes

Oxford Quality Score: R = 1, DB = 2, W = 1, Total = 4

Note: no separate data for first period, small group sizes, non standard global scale

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot reported
Allocation concealment (selection bias)Unclear riskNot reported (all except clinical research pharmacist remained blinded until study termination)
Blinding (performance bias and detection bias)
All outcomes
Low risk"all capsules were identical in taste, color, size, and shape"
Incomplete outcome data (attrition bias)
Efficacy
Unclear riskImputation not mentioned
Size
Efficacy
High risk25 randomised
Study duration
Efficacy
Unclear risk6-week period
Outcomes reportedLow riskComplete, a lot of pain relief

NCT00475904

MethodsRandomised, double-blind, double-dummy, placebo-controlled, parallel-group, 4 weeks
ParticipantsPostherpetic neuralgia at least 3 months after healing of rash. Age ≥18 years. Mean age 53 years, 38% women. N = 360
InterventionsGabapentin 1800 mg daily, topical cream with amitriptyline and ketamine, placebo for oral and cream
OutcomesMean reduction in PI from baseline
NotesOxford Quality Score: R = 1, DB = 2, W = 1, Total = 4
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNo details
Allocation concealment (selection bias)Unclear riskNo details
Blinding (performance bias and detection bias)
All outcomes
Low riskDouble dummy
Incomplete outcome data (attrition bias)
Efficacy
Unclear riskLOCF
Size
Efficacy
Unclear risk50-200
Study duration
Efficacy
Unclear risk4 weeks
Outcomes reportedUnclear riskMean data only

Perez 2000

Methods

Randomised, double-blind, placebo-controlled, parallel-group, not obviously enriched. No imputation method mentioned

Dose adjusted on clinic successive visits, "based on clinical symptoms", to a maximum of 1200 mg daily (12 weeks total)

ParticipantsPainful diabetic neuropathy. N = 32, mean age 54 years, 53% female. Failed conventional treatment. PI ≥ 60/100 at randomisation
Interventions

Gabapentin 1200 mg daily (max), n = 17

Placebo, n = 15

All participants continued with non-opioid analgesia

Outcomes≥ 50% pain reduction
Notes

Oxford Quality Score: R = 1, DB = 1, W = 0, Total = 2

Published as letter, some details confirmed by correspondence

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot reported
Allocation concealment (selection bias)Unclear riskNot reported
Blinding (performance bias and detection bias)
All outcomes
Unclear riskNot reported
Incomplete outcome data (attrition bias)
Efficacy
Unclear riskImputation not mentioned
Size
Efficacy
High risk32 randomised
Study duration
Efficacy
Low risk12-week period
Outcomes reportedLow riskAt least 50% reduction in pain

Rao 2007

Methods

Randomised, double-blind, placebo-controlled, cross-over, not enriched. Missing data handled in a number of ways, and results presented without imputation

Titration over 3 weeks to limit of tolerability or 2700 mg daily, then stable dose for 3 weeks (6 weeks total); then 2-week weaning-off and washout, and cross-over

ParticipantsChemotherapy-induced peripheral neuropathy lasting ≥ 1 month. N = 115, mean age 59 years, 73% women. PI at randomisation ≥ 4/10, initial average daily pain 4/10
Interventions

Gabapentin 2700 mg daily (max)

Placebo

Usual cancer therapy continued

Outcomes

No dichotomous data

Adverse events

Withdrawals

NotesOxford Quality Score: R = 1, DB = 2, W = 1, Total = 4
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot reported
Allocation concealment (selection bias)Unclear riskNot described
Blinding (performance bias and detection bias)
All outcomes
Low risk"identical placebo capsules"
Incomplete outcome data (attrition bias)
Efficacy
Low riskResults presented without imputation
Size
Efficacy
Unclear risk115 randomised
Study duration
Efficacy
Unclear risk6-week period
Outcomes reportedHigh riskNo dichotomous data

Rauck 2013a

MethodsRandomised, double-blind, double-dummy, parallel-group, placebo and active controlled. Screening 4 weeks, baseline 1 week, up titration 1 week, maintenance 12 weeks, down titration 1 week
ParticipantsPainful diabetic neuropathy for ≥6 months, ≥18 years, PI ≥4/10. N = 420. Mean age 59 years, 41% women, baseline PI 6.5/10
InterventionsGabaEn 1200 mg daily, GabaEn 2400 mg daily, GabeEn 3600 mg daily, pregabalin 300 mg daily, placebo

Titration over 1 week
OutcomesPain intensity reduction of at least 50% and at least 30% end of maintenance over baseline. Adverse events
Notes

Oxford Quality Score: R = 2, DB = 2, W = 1, Total = 5

GSK sponsored

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskComputer generated
Allocation concealment (selection bias)Low riskThird party pharmacist
Blinding (performance bias and detection bias)
All outcomes
Low riskDouble dummy
Incomplete outcome data (attrition bias)
Efficacy
Unclear riskLOCF
Size
Efficacy
Unclear risk50-200
Study duration
Efficacy
Low risk12 weeks
Outcomes reportedLow risk≥50% pain reduction

Rauck 2013b

Methods

Randomised, double-blind, placebo-controlled, parallel-group, not enriched. Both LOCF and BOCF imputation methods used in analyses

Itrathecal drug delivery system implanted and filled with saline until randomisation. Fixed dose of gabapentin (1 mg, 6 mg or 30 mg/d) or placebo for 22 days, followed by 7-day taper

ParticipantsChronic intractable pain below neck for ≥ 1 year (86% classified as neuropathic or mixed). N = 170, mean age 50 years, 58% women. PI at randomisation 7.5/10, initial average daily pain ≥ 5/10
Interventions

Gabapentin injection 1 mg, 6 mg, 30 mg daily, n = 42, 41, 43 respectively

Placebo (saline) injection, n = 44

Outcomes

Pain intensity reduction

Adverse events

Withdrawals

NotesOxford Quality Score: R = 1, DB = 2, W = 1, Total = 4
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot reported
Allocation concealment (selection bias)Low risk"coded drug syringe labels, stored in sealed, sequentially numbered randomization envelopes". Pharmacist took next sequential envelope, prepared assigned drug, and attached coded label before sending to clinic
Blinding (performance bias and detection bias)
All outcomes
Low riskBoth treatments were clear liquids. Saline (placebo) "seemed identical to gabapentin"
Incomplete outcome data (attrition bias)
Efficacy
Low riskBOCF analysis reported alongside LOCF
Size
Efficacy
High risk< 50 participants per treatment group
Study duration
Efficacy
High risk22 days
Outcomes reportedUnclear risk≥ 30% reduction in pain

Rice 2001

Methods

Multicentre, randomised, double-blind, placebo-controlled, parallel-group, partial enrichment, LOCF

4 day forced titration, then further titration over 2 weeks to target dose, and stable dose for 4 weeks (7 weeks in total). Participants unable to tolerate dosing regimen were withdrawn

ParticipantsPostherpetic neuralgia. N = 334, median age 75 years, 59% women. Pain > 3 months after healing of rash, PI ≥ 40/100 at randomisation, initial average daily pain 6.5/10
Interventions

Gabapentin 1800 mg daily, n = 115

Gabapentin 2400 mg daily, n = 108

Placebo, n = 111

Outcomes

≥ 50% reduction in mean pain score

PGIC much or very much improved

PGIC much and very much improved (CTR)

Adverse events

Withdrawals

Notes

Oxford Quality Score: R = 2, DB = 2, W = 1, Total = 5

Pfizer sponsored

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk"computer generated randomisation list"
Allocation concealment (selection bias)Low riskList held securely and released only after study completion
Blinding (performance bias and detection bias)
All outcomes
Low risk"identical-appearing capsules"
Incomplete outcome data (attrition bias)
Efficacy
Unclear riskLOCF
Size
Efficacy
Low risk334 randomised
Study duration
Efficacy
Unclear risk7-week period
Outcomes reportedLow riskAt least 50% reduction in pain

Rintala 2007

Methods

Randomised, double-blind, placebo-controlled, 3-way cross-over, not enriched. No imputation method mentioned

Titration over 4 weeks to pain control, limit of tolerability, or maximum amitriptyline 150 mg daily, gabapentin 3600 mg daily, then stable dose for remainder of 8-week period; 1-week washout then cross-over

Analysis for completers only

ParticipantsSCI at any level and degree of completeness. N = 38, only 22 patients completed all three cross-overs. Mean age 43 years, 9% women. Pain duration before treatment > 6 months, PI at randomisation > 5/10, initial pain intensity 5.6/10
Interventions

Amitriptyline 150 mg daily (max)

Gabapentin 3600 mg daily (max)

Placebo (diphenhydramine) 75 mg daily

Oxycodone + paracetamol 5/325 mg (max 8 tablets daily) allowed for rescue medication

Outcomes

No dichotomous data for efficacy or harm

Withdrawals

NotesOxford Quality Score: R = 2, DB = 2, W = 1, Total = 5
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk"table of random numbers"
Allocation concealment (selection bias)Low riskPrepared, packaged and labelled by remote, commercial compounding pharmacy
Blinding (performance bias and detection bias)
All outcomes
Low risk"identical capsules"
Incomplete outcome data (attrition bias)
Efficacy
High riskCompleters only
Size
Efficacy
High risk38 randomised
Study duration
Efficacy
Low risk8-week period
Outcomes reportedHigh riskNo dichotomous data

Rowbotham 1998

Methods

Multicentre, randomised, double-blind, placebo-controlled, parallel-group, no enrichment, LOCF

4-week titration to maximum tolerated dose, or 3600 mg then stable dose for 4 weeks (8 weeks in total)

ParticipantsPostherpetic neuralgia. N = 229, median age 73 years, 48% women. Pain > 3 months after healing of rash, PI at randomisation ≥ 40/100, initial average daily pain 6.4/10
Interventions

Gabapentin 3600 mg daily (max), n = 113. (83% had ≥ 2400 mg daily)

Placebo, n = 116

Outcomes

PGIC moderate or much improved

PGIC CTR moderate and much improved

No change in pain

SF36 and QoL

Adverse events

Withdrawals

Notes

Oxford Quality Score: R = 1, DB = 2, W = 1, Total = 3

Parke-Davies sponsored

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot reported
Allocation concealment (selection bias)Low risk"subject-specific bottles based on randomisation schedule"
Blinding (performance bias and detection bias)
All outcomes
Low risk"identically appearing capsules"
Incomplete outcome data (attrition bias)
Efficacy
Unclear riskLOCF
Size
Efficacy
Low risk229 randomised
Study duration
Efficacy
Low risk8-week period
Outcomes reportedLow riskPGIC much improved (top level)

Sandercock 2012

Methods

Randomised, double-blind, placebo-controlled, parallel-group, no obvious enrichment.

Gabapentin titrated over 2 weeks to 3000 mg daily, then stable dose for 2 weeks (4 weeks total)

ParticipantsPainful diabetic neuropathy. N = 147, mean age 59 years, 45% women. PI at randomisation ≥ 4/10, initial PI 6.8/10
Interventions

Gabapentin ER, 3000 mg daily (as single dose), n = 46

Gabapentin ER, 3000 mg daily (as divided dose), n = 50

Placebo, n = 51

Outcomes

≥ 50% decrease in average daily pain

PGIC much or very much improved

Adverse events

Withdrawals

Notes

Oxford Quality Score: R = 1, DB = 2, W = 1, Total = 4

Full publication of study previously partially published as letter (Sandercock 2009)

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot reported
Allocation concealment (selection bias)Unclear riskNot described
Blinding (performance bias and detection bias)
All outcomes
Unclear risk"All patients received an appropriate combination of active and placebo tablets to achieve the required dosing and maintain the study blind - implies active and placebo were indistinguishable"
Incomplete outcome data (attrition bias)
Efficacy
Low riskBOFC analysis provided for primary outcome
Size
Efficacy
Unclear risk147 randomised
Study duration
Efficacy
Unclear risk4-week period
Outcomes reportedLow riskAt least 50% reduction in pain

Sang 2013

Methods

Multicentre, randomised, double-blind, placebo-controlled, parallel-group, partial enrichment, BOCF

2-week titration to maximum tolerated dose, or 3600 mg then stable dose for 8 weeks (10 weeks in total), then 1 week taper

ParticipantsPostherpetic neuralgia. N = 452, mean age 65 years, 63% women. Pain > 6 months and < 5 years after healing of rash, PI at randomisation ≥ 40/100, initial average daily pain 6.5/10
Interventions

Gabapentin ER, 1800 mg daily (as single dose), n = 221

Placebo, n = 231

Outcomes≥ 50% reduction in pain
NotesOxford Quality Score: R = 2, DB = 2, W = 1, Total = 5
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk"electronic randomization scheme that was stratified by site"
Allocation concealment (selection bias)Unclear riskNot described
Blinding (performance bias and detection bias)
All outcomes
Low risk"matched placebo"
Incomplete outcome data (attrition bias)
Efficacy
Low riskBOCF for primary endpoint
Size
Efficacy
Low risk> 200 participants per treatment group
Study duration
Efficacy
Low risk10 week treatment period
Outcomes reportedLow risk≥ 50% reduction in pain

Serpell 2002

Methods

Multicentre, randomised, double-blind, placebo-controlled, parallel-group, partial enrichment. No imputation method mentioned. Patients withdrawing due to lack of efficacy were defined as non-responders (n = 6), but treatment of substantial AE withdrawals (n = 49) and all-cause withdrawals (n = 73) not reported

Titration over 5 weeks from 900 mg daily until pain controlled, or to maximum of 2400 mg daily, then fixed dose (8 weeks in total)

Participants

Mixed neuropathic pain, most common conditions were CRPS (28%), PHN (14%). N = 305, median age 57 years, 53% women. PI at randomisation ≥ 4/10, initial mean pain score 7.2/10

Excluded: individuals who had previously failed to respond to gabapentin at ≥ 900 mg daily, or had experienced intolerable side effects at any dose

Interventions

Gabapentin 2400 mg daily (max), n = 153

Placebo, n = 152

101 took 2400 mg, 189 took 1800 mg, 27 took 900 mg

Stable antidepressant therapy and NSAID/opioid therapy for other conditions allowed

Paracetamol 500 mg/codeine 30 mg or paracetamol 500 mg (max 8 tablets daily) allowed as rescue medication

Outcomes

≥ 50% reduction in pain

PGIC much or very much improved

PGIC much improved and very much improved (CTR)

Adverse events

Withdrawals

Notes

Oxford Quality Score: R = 2, DB = 2, W = 1, Total = 5

Parke-Davies sponsored

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskComputer generated randomization list
Allocation concealment (selection bias)Low riskRandomisation list centrally held - remote allocation
Blinding (performance bias and detection bias)
All outcomes
Low risk"identical capsules"
Incomplete outcome data (attrition bias)
Efficacy
Unclear riskImputation not mentioned
Size
Efficacy
Low risk305 randomised
Study duration
Efficacy
Low risk8-week period
Outcomes reportedLow riskAt least 50% reduction in pain

Simpson 2001

Methods

Randomised, double-blind, placebo-controlled, parallel-group, not obviously enriched (part 1 of study only)

Titration over 4 weeks to maximum tolerated dose, then stable dose for 4 weeks (8 weeks in total)

ParticipantsPainful diabetic neuropathy. N = 60, mean age 50 years, 40% female. Pain duration > 3 months before treatment, PI ≥ 40/100 at randomisation, initial pain score 6.5/10
Interventions

Gabapentin 3600 mg daily (max), n = 30

Placebo, n = 30

Outcomes

PGIC moderate or much improved

Adverse events

Withdrawals

NotesOxford Quality Score: R = 1, DB = 1, W = 1, Total = 3
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot reported
Allocation concealment (selection bias)Unclear riskNot reported
Blinding (performance bias and detection bias)
All outcomes
Unclear riskNot reported
Incomplete outcome data (attrition bias)
Efficacy
Unclear riskImputation not mentioned
Size
Efficacy
Unclear risk60 randomised
Study duration
Efficacy
Low risk8-week period
Outcomes reportedUnclear riskModerate or much improved

Smith 2005

Methods

Randomised, double-blind, placebo-controlled, cross-over, no enrichment. No imputation method mentioned

Titration in 300 mg increments every 2 to 3 days until pain intensity of 0 or uncomfortable side effects, or maximum 3600 mg daily, then stable dose for remainder of 6-week treatment period, followed by titration off medication in week 7; 5-week washout, then cross-over

ParticipantsPhantom limb pain and residual limb pain. N = 24, mean age 52 years, 25% women. Time since amputation ≥ 6 months, PI before randomisation > 3/10, initial pain intensity 4.4/10
Interventions

Gabapentin 3600 mg daily (max), (19/24 took max dose)

Placebo

OutcomesMeaningful decrease in pain (5-point scale)
NotesOxford Quality Score: R = 2, DB = 2, W = 0, Total = 4
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskComputer generated random numbers
Allocation concealment (selection bias)Unclear riskNot described
Blinding (performance bias and detection bias)
All outcomes
Low risk"capsules that were identical in appearance"
Incomplete outcome data (attrition bias)
Efficacy
Unclear riskImputation not mentioned
Size
Efficacy
High risk24 randomised
Study duration
Efficacy
Unclear risk6-week period
Outcomes reportedUnclear riskMeaningful decrease in pain (probably top of 5-point scale)

Tai 2002

Methods

Randomised, double-blind, placebo-controlled, cross-over, no enrichment. No imputation method mentioned

Titration to limit of tolerability or maximum 1800 mg over 3 weeks, then stable for remainder of 4-week period; 2-week washout then cross-over

ParticipantsTraumatic spinal cord injury. N = 14, 7 patients with data, age 27 to 48 years, 6/7 male. Pain duration before treatment > 4/10
Interventions

Gabapentin 1800 mg daily (max)

Placebo

NSAID, TCA and narcotics allowed for rescue medication as needed

OutcomesWithdrawals
NotesOxford Quality Score: R = 2, DB = 2, W = 1, Total = 5
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskRandom distribution table
Allocation concealment (selection bias)Unclear riskNot reported
Blinding (performance bias and detection bias)
All outcomes
Low riskCapsules with "identical shape and colour"
Incomplete outcome data (attrition bias)
Efficacy
Unclear riskImputation not mentioned
Size
Efficacy
High risk7 patients with data of 14
Study duration
Efficacy
Unclear risk4-week period
Outcomes reportedHigh riskNo dichotomous data

van de Vusse 2004

Methods

Randomised, double-blind, placebo-controlled, cross-over, no enrichment

Gabapentin titrated to maximum of 1800 mg daily over 5 days, then stable dose for remainder of 3-week treatment period; 2-week washout then cross-over

Participants

Complex regional pain syndrome type 1 (IASP criteria for diagnosis). N = 58, mean age 44 years, 17% women. Pain duration before treatment > 3/10, initial pain intensity 6.3/10

46 patients completed both periods, with 12 excluded from analysis because they withdrew at some stage. Analysis performed only on complete data sets

Interventions

Gabapentin 1800 mg daily

Placebo

Usual analgesics continued without dose changes

Outcomes

Much improved (per protocol)

Adverse events

Withdrawals

NotesOxford Quality Score: R = 2, DB = 2, W = 1, Total = 5
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskTable of random numbers
Allocation concealment (selection bias)Low risk"closed envelopes containing assignments were prenumbered and kept at the pharmacy"
Blinding (performance bias and detection bias)
All outcomes
Low risk"identical placebo capsules"
Incomplete outcome data (attrition bias)
Efficacy
High riskAnalysis performed on completers
Size
Efficacy
High riskOnly 46 in final analysis
Study duration
Efficacy
Unclear risk3-week period
Outcomes reportedUnclear riskMuch improved

Wallace 2010

Methods

Randomised, double-blind, placebo-controlled, cross-over, partial enrichment, with exclusion of participants known not to respond to gabapentin or pregabalin, or who experienced dose limiting adverse events with gabapentin

Gabapentin extended release given in fixed doses of 1800 mg, either as a single morning dose, or divided between 600 mg morning plus 1200 mg evening. No titration

ParticipantsNeuropathic pain at least 3 months after healing of acute herpes zoster skin rash. N = 400, mean age 66 years, 52% women. Initial pain ≥4/10 on 0 to 10 scale. Mean initial pain 6.5/10
Interventions

Gabapentin ER 1800 mg daily

Placebo

Outcomes

A range of pain measures were used, but main results reported on numeric 0-10 rating scale, as well as patient global impression of change

Adverse events

Withdrawals

Notes

Oxford Quality Score: R = 1, DB = 2, W = 1, Total = 4

Sponsored by Depomed

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot reported
Allocation concealment (selection bias)Low riskUse of blinded medication carton
Blinding (performance bias and detection bias)
All outcomes
Low riskIdentical blister packs
Incomplete outcome data (attrition bias)
Efficacy
Low riskBOCF used for main results, with LOCF also
Size
Efficacy
Unclear riskOver 100 per treatment group
Study duration
Efficacy
Low risk10-week duration
Outcomes reportedLow riskAt least 50% pain reduction over baseline

Zhang 2013

  1. a

    AE = adverse event; CRPS = complex regional pain syndrome; DB = double-blinding; ER = extended release; LOCF = last observation carried forward; BOCF = baseline observation carried forward; NSAID = non-steroidal anti-inflammatory drug; OTC = over the counter; PDN = painful diabetic neuropathy; PGIC = Patient Global Impression of Change; PHN = postherpetic neuralgia; QoL = quality of life; R = randomisation; W = withdrawals; ACR = American College of Rheumatology; CTR = clinical trial report; IASP = International Association for the Study of Pain; PI = pain intensity; SCI = spinal cord injury; TCA = tricyclic antidepressants; OTC = over the counter

MethodsRandomised, double-blind, placebo-controlled, parallel-group. Screening 4 weeks, baseline 1 week, up titration 1 week, maintenance 12 weeks, down titration 1 week
Participants

PHN ≥ 3 months after healing of rash, PI ≥ 4/10, age ≥ 18 years. Mean age 62 years, 48% women, baseline PI 6/10

N = 371

InterventionsGabaEn 1200 mg daily, GabaEn 2400 mg daily, GabeEn 3600 mg daily, placebo. Titration over 1 week
OutcomesAt least 50% and at least 30% pain intensity reduction by end of maintenance over baseline. PGIV much or very much improved. Adverse events
Notes

Oxford Quality Score: R = 2, DB = 2, W = 1, Total = 5

Sponsored by GSK XenoPort

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskComputer generated
Allocation concealment (selection bias)Low riskInteractive voice response system
Blinding (performance bias and detection bias)
All outcomes
Low riskMatching placebo
Incomplete outcome data (attrition bias)
Efficacy
Unclear riskLOCF
Size
Efficacy
Unclear risk80-110 per group
Study duration
Efficacy
Low risk12 weeks
Outcomes reportedLow riskAt least 50% pain reduction over baseline

Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion
Arai 2010No mention of blinding of therapies in gabapentin plus imipramine additions to opioids in cancer pain
Berry 2005Single dose of gabapentin for treatment of acute herpes zoster
Dallocchio 2000Painful diabetic neuropathy, open comparison of gabapentin and amitriptyline
Dworkin 2009Study for acute herpes zoster pain
Jean 2005Postherpetic neuralgia, with open administration of gabapentin
Kasimcan 2010Acute and chronic radicular pain, with open administration of gabapentin
Keskinbora 2007Neuropathic cancer pain, with open administration of gabapentin
Ko 2010Open comparison of gabapentin and tramadol/paracetamol in painful diabetic neuropathy
McCleane 2001Low back pain
NCT00634543Open label study
NCT01263132No active or placebo comparator, randomised for B vitamins not gabapentin
NCT01623271Single group cohort without comparator
Nikolajsen 2006Trial of gabapentin in surgery to test whether use in surgery prevents development of phantom pain. There was no beneficial effect
Pandey 2002Guillain-Barré syndrome
Pandey 2005Guillain-Barré syndrome
Salvaggio 2008Facial pain, open administration of gabapentin plus tramadol
Sator-Katzenschlager 2005Chronic pelvic pain, with open administration of gabapentin
Tanenberg 2011Open label study
Yaksi 2007Lumbar spinal stenosis, with open administration of gabapentin
Yelland 2009No-of-1 study with short treatment periods of 2 weeks in chronic neuropathic pain, and with high withdrawal rate. Study design highly unusual and difficult to interpret
Yildrim 2003Not double-blind. Radiculopathy, not classic neuropathic pain

Characteristics of ongoing studies [ordered by study ID]

Fleckstein 2009

Trial name or titleAcupuncture in acute herpes zoster pain therapy (ACUZoster) – design and protocol of a randomised controlled trial
MethodsDouble blinded, randomised controlled trial, parallel groups
ParticipantsConfirmed diagnosis of acute herpes zoster, pain intensity > 30 mm on a visual analogue scale (VAS 0–100
mm), standardised antiviral therapy. Male and female, ≥ 18 years old
InterventionsSemi-standardised acupuncture, sham laser acupuncture, gabapentin with individualised dosage between 900–3600 mg/d
OutcomesAlteration of pain intensity before and 1 week after treatment sessions
Starting dateRecruitment for the trial started in November 2008
Contact informationdominik.irnich@med.uni-muenchen.de
NotesNCT00885586 - still recruiting as of March 2013

IRCT201212019014N14

Trial name or titleEffect of gabapentin on heart rate variability in diabetic painful peripheral neuropathy: a double blinded randomized clinical trial
MethodsDouble blinded, randomised controlled trial, parallel groups
ParticipantsDiabetic painful peripheral neuropathy. Male and female, ≥ 18 years old
Interventions

Gabapentin capsule 100 mg in the first day, 200 mg in the second day, and 300 mg daily from third day for three months plus moisturizing cream (as placebo) with a phalanx size three times a day for three months

Capsule like gabapentin including starch (as placebo) daily for three months plus Kapsycin cream for reducing pain with a phalanx size three times a day for three months

Outcomes

Standard deviation of N-N (SDNN) using 24 hours Holter monitoring device

Orthostatic hypotension

Resting tachycardia

Any adverse events

Starting dateRecruitment stared 21 December 2012, expected to end March 2013
Contact informationm.vasheghani@umsha.ac.ir
NotesRecruitment complete

NCT00674687

Trial name or titleA study of the efficacy of gabapentin in neuropathic pain patients as measured by quantitative sensory testing
MethodsRandomised, double blind, crossover
ParticipantsMale and female, ≥ 18 years old. Neuropathic pain of peripheral origin as a consequence of either post-herpetic neuralgia or post-traumatic neuropathic pain. Pain ≥4/10 for von Frey filament-evoked allodynia at the skin area
InterventionsGabapentin titrated to 1800 mg/day, placebo
OutcomesPresence/intensity of punctate allodynia (von Frey filament)
Starting dateJuly 2004, completed 2006
Contact informationDirector, Clinical Trial Disclosure Group, Pfizer, Inc.
NotesPossible exclude as response to evoked pain, but inadequate information to judge. 23 enrolled

NCT00904202

Trial name or titleA study of lidocaine patch 5% alone, gabapentin alone, and lidocaine patch 5% and gabapentin in combination for the relief of pain in patients with diverse peripheral neuropathic pain conditions
MethodsDouble blinded, double dummy, randomised controlled trial, parallel groups. Male and female, ≥ 18 years old
ParticipantsVarious peripheral neuropathic pain conditions
InterventionsGabapentin, lidocaine patch, placebo for both
OutcomesAverage daily pain intensity
Starting dateJanuary 2003 - completed 2006
Contact informationSr Director, Clinical R&D, Endo Pharmaceuticals Inc
Notes62 enrolled