Gabapentin for chronic neuropathic pain in adults

  • Review
  • Intervention

Authors

  • Philip J Wiffen,

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

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

    1. Haukeland University Hospital, Regional Centre of Excellence in Palliative Care, Bergen, Norway
  • Andrew SC Rice,

    1. Imperial College London, Pain Research, Department of Surgery and Cancer, Faculty of Medicine, London, UK
  • Thomas Rudolf Tölle,

    1. Technische Universität München, Department of Neurology, Klinikum Rechts der Isar, Munich, Germany
  • Tudor Phillips,

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


Abstract

Background

Gabapentin is commonly used to treat neuropathic pain (pain due to nerve damage). This review updates a review published in 2014, and previous reviews published in 2011, 2005 and 2000.

Objectives

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

Search methods

For this update we searched CENTRAL), MEDLINE, and Embase for randomised controlled trials from January 2014 to January 2017. We also searched the reference lists of retrieved studies and reviews, and online clinical trials registries.

Selection criteria

We included randomised, double-blind trials of two weeks' duration or longer, comparing gabapentin (any route of administration) with placebo or another active treatment for neuropathic pain, with participant-reported pain assessment.

Data collection and analysis

Two review authors independently extracted data and assessed trial quality and potential bias. Primary outcomes were participants with substantial pain relief (at least 50% pain relief over baseline or very much improved on Patient Global Impression of Change scale (PGIC)), or moderate pain relief (at least 30% pain relief over baseline or much or very much improved on PGIC). We performed a pooled analysis for any substantial or moderate benefit. Where pooled analysis was possible, we used dichotomous data to calculate risk ratio (RR) and number needed to treat for an additional beneficial outcome (NNT) or harmful outcome (NNH). We assessed the quality of the evidence using GRADE and created 'Summary of findings' tables.

Main results

We included four new studies (530 participants), and excluded three previously included studies (126 participants). In all, 37 studies provided information on 5914 participants. Most studies used oral gabapentin or gabapentin encarbil at doses of 1200 mg or more daily in different neuropathic pain conditions, predominantly postherpetic neuralgia and painful diabetic neuropathy. Study duration was typically four to 12 weeks. Not all studies reported important outcomes of interest. High risk of bias occurred mainly due to small size (especially in cross-over studies), and handling of data after study withdrawal.

In postherpetic neuralgia, more participants (32%) had substantial benefit (at least 50% pain relief or PGIC very much improved) with gabapentin at 1200 mg daily or greater than with placebo (17%) (RR 1.8 (95% CI 1.5 to 2.1); NNT 6.7 (5.4 to 8.7); 8 studies, 2260 participants, moderate-quality evidence). More participants (46%) had moderate benefit (at least 30% pain relief or PGIC much or very much improved) with gabapentin at 1200 mg daily or greater than with placebo (25%) (RR 1.8 (95% CI 1.6 to 2.0); NNT 4.8 (4.1 to 6.0); 8 studies, 2260 participants, moderate-quality evidence).

In painful diabetic neuropathy, more participants (38%) had substantial benefit (at least 50% pain relief or PGIC very much improved) with gabapentin at 1200 mg daily or greater than with placebo (21%) (RR 1.9 (95% CI 1.5 to 2.3); NNT 5.9 (4.6 to 8.3); 6 studies, 1277 participants, moderate-quality evidence). More participants (52%) had moderate benefit (at least 30% pain relief or PGIC much or very much improved) with gabapentin at 1200 mg daily or greater than with placebo (37%) (RR 1.4 (95% CI 1.3 to 1.6); NNT 6.6 (4.9 to 9.9); 7 studies, 1439 participants, moderate-quality evidence).

For all conditions combined, adverse event withdrawals were more common with gabapentin (11%) than with placebo (8.2%) (RR 1.4 (95% CI 1.1 to 1.7); NNH 30 (20 to 65); 22 studies, 4346 participants, high-quality evidence). Serious adverse events were no more common with gabapentin (3.2%) than with placebo (2.8%) (RR 1.2 (95% CI 0.8 to 1.7); 19 studies, 3948 participants, moderate-quality evidence); there were eight deaths (very low-quality evidence). Participants experiencing at least one adverse event were more common with gabapentin (63%) than with placebo (49%) (RR 1.3 (95% CI 1.2 to 1.4); NNH 7.5 (6.1 to 9.6); 18 studies, 4279 participants, moderate-quality evidence). Individual adverse events occurred significantly more often with gabapentin. Participants taking gabapentin experienced dizziness (19%), somnolence (14%), peripheral oedema (7%), and gait disturbance (14%).

Authors' conclusions

Gabapentin at doses of 1800 mg to 3600 mg daily (1200 mg to 3600 mg gabapentin encarbil) can provide good levels of pain relief to some people with postherpetic neuralgia and peripheral diabetic neuropathy. Evidence for other types of neuropathic pain is very limited. 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. Around 3 or 4 out of 10 participants achieved this degree of pain relief with gabapentin, compared with 1 or 2 out of 10 for placebo. Over half of those treated with gabapentin will not have worthwhile pain relief but may experience adverse events. Conclusions have not changed since the previous update of this review.

Résumé scientifique

La gabapentine pour les douleurs neuropathiques chroniques chez l'adulte

Contexte

La gabapentine est couramment utilisée pour traiter les douleurs neuropathiques (des douleurs dues à des lésions nerveuses). Cette revue est une mise à jour d'une revue publiée en 2014, et des revues précédentes, publiées en 2011, 2005 et 2000.

Objectifs

Évaluer l'efficacité analgésique et les effets indésirables de la gabapentine pour la douleur neuropathique chronique chez l'adulte.

Stratégie de recherche documentaire

Pour cette mise à jour, nous avons effectué des recherches dans CENTRAL, MEDLINE et Embase pour identifier des essais contrôlés randomisés de janvier 2014 à janvier 2017. Nous avons également effectué des recherches dans les références bibliographiques des études et revues identifiées, et dans des registres d'essais cliniques en ligne.

Critères de sélection

Nous avons inclus des essais randomisés en double aveugle d'une durée de deux semaines ou plus, comparant la gabapentine (via n'importe quelle voie d'administration) à un placebo ou à un autre traitement actif contre les douleurs neuropathiques, avec une évaluation de la douleur rapportée par les participants.

Recueil et analyse des données

Deux auteurs de la revue ont indépendamment extrait les données et évalué la qualité des essais et les biais potentiels. Les critères de jugement principaux étaient les participants présentant un important soulagement des douleurs (au moins 50 % de soulagement des douleurs par rapport aux douleurs initiales ou une très grande amélioration sur l'échelle Patient Global Impression of Change (PGIC)), ou un soulagement modéré des douleurs (au moins 30 % de soulagement des douleurs par rapport aux douleurs initiales ou une amélioration importante ou très importante sur l'échelle PGIC). Nous avons effectué une analyse combinée pour tout bénéfice substantiel ou modéré. Lorsqu'une analyse groupée était possible, nous avons utilisé les données dichotomiques pour calculer le risque relatif (RR) et le nombre de sujets à traiter pour obtenir un résultat bénéfique supplémentaire (NSTb) ou un effet néfaste (NNN). Nous avons évalué la qualité des preuves en utilisant l'approche GRADE et créé des tableaux « Résumé des résultats ».

Résultats principaux

Nous avons inclus quatre nouvelles études (530 participants), et nous avons exclu trois études précédemment incluses (126 participants). Dans l'ensemble, 37 études ont fourni des informations sur 5914 participants. La plupart des études utilisaient la gabapentine par voie orale ou la gabapentine encarbil à des doses de 1200 mg ou plus par jour pour différents types de douleurs neuropathiques, principalement la névralgie post-herpétique et la neuropathie diabétique douloureuse. La durée des études était généralement de quatre à 12 semaines. Certaines des études n'ont pas rapporté d'importants critères de jugement d'intérêt. Un risque de biais élevé apparaissait principalement en raison de la petite taille des études (en particulier dans les études croisées), et en raison des manipulations des données lorsque des participants ont quitté l'étude.

Dans la névralgie post-herpétique, davantage de participants (32 %) ont obtenu un bénéfice substantiel (au moins 50 % de soulagement des douleurs ou une amélioration très importante sur l'échelle PGIC) avec la gabapentine à 1200 mg par jour ou plus par rapport au placebo (17 %) (RR 1,8 (IC à 95 % 1,5 à 2,1) ; NST = 6,7 (5,4 à 8,7) ; 8 études, 2260 participants, preuves de qualité modérée). Davantage de participants (46 %) ont obtenu un bénéfice modéré (au moins 30 % de soulagement des douleurs ou une amélioration significative ou très significative sur l'échelle PGIC) avec la gabapentine à 1200 mg par jour ou plus par rapport au placebo (25 %) (RR 1,8 (IC à 95 % 1,6 à 2,0) ; NST = 4,8 (4,1 à 6,0) ; 8 études, 2260 participants, preuves de qualité modérée).

Dans la neuropathie diabétique douloureuse, davantage de participants (38 %) ont obtenu un bénéfice substantiel (au moins 50 % de soulagement des douleurs ou une amélioration très importante sur l'échelle PGIC) avec la gabapentine à 1200 mg par jour ou plus par rapport au placebo (21 %) (RR 1,9 (IC à 95 % 1,5 à 2,3) ; NST = 5,9 (4,6 à 8,3) ; 6 études, 1277 participants, preuves de qualité modérée). Davantage de participants (52 %) ont obtenu un bénéfice modéré (au moins 30 % de soulagement des douleurs ou une amélioration significative ou très significative sur l'échelle PGIC) avec la gabapentine à 1200 mg par jour ou plus par rapport au placebo (37 %) (RR 1,4 (IC à 95 % 1,3 à 1,6) ; NST = 6,6 (4,9 à 9,9) ; 7 études, 1439 participants, preuves de qualité modérée).

Pour toutes les pathologies combinées, les abandons en raison d'événements indésirables étaient plus fréquents avec la gabapentine (11 %) qu'avec le placebo (8,2 %) (RR 1,4 (IC à 95 % 1,1 à 1,7) ; NNN = 30 (20 à 65) ; 22 études, 4346 participants, preuves de qualité élevée). Les événements indésirables graves n'étaient pas plus fréquents avec la gabapentine (3,2 %) qu'avec le placebo (2,8 %) (RR 1,2 (IC à 95 % 0,8 à 1,7) ; 19 études, 3948 participants, preuves de qualité modérée) ; il y a eu huit décès (preuves de très faible qualité). Plus de participants recevant de la gabapentine ont rapporté au moins un événement indésirable (63 %) par rapport au placebo (49 %) (RR 1,3 (IC à 95 % 1,2 à 1,4) ; NNN = 7,5 (6,1 à 9,6) ; 18 études, 4279 participants, preuves de qualité modérée). Les événements indésirables individuels sont plus souvent survenus avec la gabapentine. Les participants prenant de la gabapentine ont souffert d'étourdissements (19 %), de somnolence (14 %), d'œdèmes périphériques (7 %) et de troubles de la marche (14 %).

Conclusions des auteurs

La gabapentine à des doses de 1800 mg à 3600 mg par jour (1200 mg à 3600 mg de gabapentine encarbil) peut fournir un bon niveau de soulagement des douleurs à certaines personnes ayant une névralgie post-herpétique et une neuropathie diabétique périphérique. Les preuves pour d'autres types de douleurs neuropathiques sont très limitées. Le critère de jugement d'au moins 50 % de réduction de l'intensité des douleurs est considéré comme étant un résultat pertinent par les patients, et l'obtention de ce degré de soulagement de la douleur est associée à des effets bénéfiques importants au niveau des troubles du sommeil, de la fatigue et de la dépression, ainsi que sur la qualité de vie, le fonctionnement, et au travail. Environ 3 ou 4 participants sur 10 ont obtenu ce niveau de soulagement des douleurs avec la gabapentine, par rapport à 1 ou 2 personnes sur 10 avec le placebo. Plus de la moitié des personnes traitées avec la gabapentine n'obtiennent pas un soulagement suffisant des douleurs et peuvent présenter des événements indésirables. Les conclusions n'ont pas changé depuis la dernière mise à jour de cette revue.

Plain language summary

Gabapentin for chronic neuropathic pain in adults

Bottom line

There is moderate-quality evidence that oral gabapentin at doses of 1200 mg daily or more has an important effect on pain in some people with moderate or severe neuropathic pain after shingles or due to diabetes.

Background

Neuropathic pain comes from damaged nerves. It is different from pain messages that are carried along healthy nerves from damaged tissue (for example, from a fall or cut, or arthritic knee). Neuropathic pain is often treated by different medicines (drugs) to those used for pain from damaged tissue, which we often think of as painkillers. Medicines that are sometimes used to treat depression or epilepsy can be effective in some people with neuropathic pain. One of these is gabapentin. Our definition of a good result was someone with a high level of pain relief and able to keep taking the medicine without side effects making them stop.

Study characteristics

In January 2017 we searched for clinical trials in which gabapentin was used to treat neuropathic pain in adults. We found 37 studies that satisfied the inclusion criteria, randomising 5914 participants to treatment with gabapentin, placebo, or other drugs. Studies lasted 4 to 12 weeks. Most studies reported beneficial outcomes that people with neuropathic pain think are important. Results were mainly in pain after shingles and pain resulting from nerve damage in diabetes.

Key results

In pain after shingles, 3 in 10 people had pain reduced by half or more with gabapentin and 2 in 10 with placebo. Pain was reduced by a third or more for 5 in 10 with gabapentin and 3 in 10 with placebo. In pain caused by diabetes, 4 in 10 people had pain reduced by half or more with gabapentin and 2 in 10 with placebo. Pain was reduced by a third or more for 5 in 10 with gabapentin and 4 in 10 with placebo. There was no reliable evidence for any other type of neuropathic pain.

Side effects were more common with gabapentin (6 in 10) than with placebo (5 in 10). Dizziness, sleepiness, water retention, and problems with walking each occurred in about 1 in 10 people who took gabapentin. Serious side effects were uncommon, and not different between gabapentin and placebo. Slightly more people taking gabapentin stopped taking it because of side effects.

Gabapentin is helpful for some people with chronic neuropathic pain. 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.

Quality of the evidence

The evidence was mostly of moderate quality. This means that the research provides a good indication of the likely effect. The likelihood that the effect will be substantially different is moderate.

Résumé simplifié

La gabapentine pour les douleurs neuropathiques chroniques chez l'adulte

Bilan

Il existe des preuves de qualité modérée indiquant que la gabapentine par voie orale à des doses de 1200 mg par jour ou plus a un effet important sur les douleurs chez certaines personnes ayant des douleurs neuropathiques modérées ou sévères suite à un zona ou en raison d'un diabète.

Contexte

La douleur neuropathique est due à des lésions nerveuses. Celle-ci est différente des messages transmettant la douleur convoyés par les nerfs sains à partir d'une lésion des tissus biologiques (par exemple, lors d'une chute, d'une coupure ou en cas d'arthrite au genou). La douleur neuropathique est traitée avec des médicaments différents de ceux utilisés pour les douleurs survenant lorsqu'un tissu est endommagé (les médicaments dits « antidouleurs » ou « analgésiques »). Les médicaments qui sont parfois utilisés pour traiter la dépression ou l'épilepsie peuvent être efficaces chez certaines personnes ayant des douleurs neuropathiques. L'un de ces médicaments est la gabapentine. Notre définition d'un bon résultat correspondait à une personne ayant un niveau élevé de soulagement de la douleur et étant capable de continuer à prendre ses médicaments sans effets secondaires la menant à arrêter des les prendre.

Caractéristiques de l'étude

En janvier 2017, nous avons recherché des essais cliniques dans lesquels la gabapentine avait été utilisée pour traiter la douleur neuropathique chez l'adulte. Nous avons trouvé 37 études remplissant les critères d'inclusion, randomisant 5914 participants à un traitement à base de gabapentine, à un placebo ou à d'autres médicaments. Les études duraient de 4 à 12 semaines. La plupart des études ont rapporté des effets bénéfiques que les personnes ayant des douleurs neuropathiques estiment comme étant importants. Les résultats portaient principalement sur les douleurs survenant suite à un zona et celles dues à des lésions nerveuses en cas de diabète.

Principaux résultats

Au niveau des douleurs survenant suite à un zona, 3 personnes sur 10 recevant de la gabapentine ont eu des douleurs réduites de moitié ou plus par rapport à 2 personnes sur 10 recevant un placebo. Les douleurs étaient réduites d'un tiers ou plus pour 5 personnes sur 10 recevant de la gabapentine et 3 personnes sur 10 recevant un placebo. Au niveau des douleurs causées par un diabète, 4 personnes sur 10 recevant de la gabapentine ont eu des douleurs réduites de moitié ou plus par rapport à 2 personnes sur 10 recevant un placebo. Les douleurs étaient réduites d'un tiers ou plus pour 5 personnes sur 10 recevant de la gabapentine par rapport à 4 personnes sur 10 recevant un placebo. Il n'y avait aucune preuve fiable pour n'importe quel autre type de douleur neuropathique.

Les effets secondaires étaient plus fréquents avec la gabapentine (6 personnes sur 10) qu'avec un placebo (5 personnes sur 10). Des vertiges, une somnolence, une rétention d'eau, et des problèmes lors de la marche sont survenus chez environ 1 personne sur 10 ayant pris de la gabapentine. Les effets indésirables graves étaient rares, et n'étaient pas différents entre la gabapentine et le placebo. Légèrement plus de personnes prenant de la gabapentine ont arrêté le traitement en raison d'effets secondaires.

La gabapentine est utile pour certaines personnes ayant des douleurs neuropathiques chroniques. Il n'est pas possible de déterminer préalablement quelle personne obtiendra un bénéfice ou non. Les connaissances actuelles suggèrent qu'une courte période de test est la meilleure façon de le savoir.

Qualité des preuves

Les preuves étaient généralement de qualité modérée. Cela signifie que les recherches apportent une bonne indication du véritable effet. La probabilité que l'effet soit sensiblement différent est modérée.

Notes de traduction

Traduction réalisée par Martin Vuillème et révisée par Cochrane France

淺顯易懂的口語結論

Gabapentin用於治療成人慢性神經病變痛

重點

有中等品質的證據表示口服劑量為每天1200毫克或更多的gabapentin,對一些中度或重度神經性疼痛的患者在帶狀皰疹後或由於糖尿病引起的疼痛具有重要影響。

背景

神經性疼痛來自受損的神經。有別於來自受損組織(例如:跌倒、割傷或膝關節炎造成)沿健康神經傳遞的疼痛訊息。神經病變痛經常以不同的藥物治療,這些藥物也被用於治療受損組織所造成的疼痛(我們經常認為是止痛藥)。有時候治療抑鬱症或癲癇的藥物對於一些神經病變痛的病人是有效的。其中之一便是gabapentin。我們對良好結果的定義是,具有高程度的疼痛緩解,並能不因副作用而停止、持續服用藥物。

研究特點

2017年1月,作者搜索了使用gabapentin治療成人神經性疼痛的臨床試驗。作者發現37個符合納入標準的研究,隨機分組5914名參與者使用gabapentin、安慰劑或其他藥物治療。研究為期4到12週。大多數研究報告神經病變痛病人認為有益的結果是重要的。研究主要為帶狀皰疹後及糖尿病病人神經損傷引起的疼痛。

主要結果

在帶狀皰疹後的疼痛中,10人中有3人使用gabapentin後減輕了一半以上的疼痛,而10人中有2人使用安慰劑後減輕了一半以上的疼痛;10人中有5人使用gabapentin後減輕了三份之一的疼痛,而10人中有3人使用安慰劑後也能減輕同等疼痛。在糖尿病引起的疼痛中,10人中有4人使用gabapentin後減輕了一半以上的疼痛,而10人中有2人使用安慰劑後也減輕了一半以上的疼痛;10人中有5人使用gabapentin後減輕了三份之一的疼痛,而10人中有4人使用安慰劑後也能減輕同等疼痛。其他類型的神經性疼痛並無可靠證據。

Gabapentin組別(10人中有6人)的副作用比安慰劑組(10人中有5人)更常見。服用gabapentin的人,大約各有10分之1的人會出現頭暈、嗜睡、水滯留以及行走問題。嚴重的副作用是罕見的,在gabapentin組別和安慰劑組別中沒有差異。服用gabapentin的組別稍為有多一些的人因為副作用而停止服藥。

Gabapentin對某些慢性神經病變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。目前的知識指出短期試驗是解決這個問題的最佳方式。

證據品質

大部分的證據品質為中等。這意味著這個研究為可能的效益提供了一個的好跡象。效果會有很大差異的可能性中等。

譯註

翻譯者:賴啟楹 (Cremilda Lai)
服務單位:澳門科大醫院
職稱:藥師

本翻譯計畫由臺北醫學大學考科藍臺灣研究中心(Cochrane Taiwan)、台灣實證醫學學會及東亞考科藍聯盟(EACA)統籌執行
聯絡E-mail:cochranetaiwan@tmu.edu.tw

எளியமொழிச் சுருக்கம்

நாள்பட்ட நரம்பு சார்ந்த வலி உடைய பெரியவர்களுக்கு காபாபேண்டின்

அடிப்படை கருத்து

தோல் கொப்புளங்கள்(shingles ) அல்லது நீரிழிவு நோய்க்குப் பின் உண்டாகும் மிதமான நரம்பு சார்ந்த வலிக்கு, ஒருநாளைக்கு 1200 மி .கி . வாய்வழி காபாபேண்டின் ஒரு சிலருக்கு முக்கிய வலி நிவாரணியாக இருக்கும் என்பதற்கு மிதமான தரம் கொண்ட ஆதாரம் உள்ளது.

பின்னணி

சேதமடைந்த நரம்புகளால் நரம்பு சார்ந்த வலி உண்டாகிறது. பாதிக்கப்பட்ட திசுக்களிலிருந்து (உதாரணத்திற்கு, கீழே விழுதல் அல்லது ஒரு வெட்டு காயம் அல்லது ஒரு முழங்கால் மூட்டு வாதம்)எடுத்து செல்லப்படும் தகவல்கள் , ஆரோக்கியமான நரம்புகள் வழியாக கடத்தி செல்லப்படும் வலி தகவல்களிலிருந்து வேறுபட்டிருக்கும். பாதிக்கப்பட்ட திசுக்களுக்குப் பயன்படுத்தப்படும் மருந்துகளிலிருந்து வேறுபட்டு நரம்பு நோய் வலிக்கு வேறு விதமான மருந்துகள் மூலம் சிகிச்சையளிக்கப்படும். சிலநேரங்களில் நரம்பு நோய் வலி கொண்ட சிலருக்கு , மனச்சோர்வு அல்லது வலிப்பு நோய்க்கு சிகிச்சையளிக்க பயன்படும் மருந்துகள் மிகவும் திறன் மிக்கதாக இருக்கக் கூடும். இதில் ஒன்று காபாபேண்டின். உயர் நிலை வலி நிவாரணம் மற்றும் பக்க விளைவுகள்இல்லாமல் மருந்து உட்கொள்வதை தொடர்ந்து மேற்கொண்டு மேலான நிலையில் வைத்திருப்பதே நல்ல விளைவு என்று வரையறைக்கப்படுகிறது .

ஆய்வு பண்புகள்

மே 2015-ல், நரம்பு நோய் வலி சிகிச்சைக்கு வாய் வழி ஸ்டிராய்டற்ற அழற்சி நீக்கி மருந்துகளை பயன்படுத்திய மருத்துவ சோதனைகளை நாங்கள் தேடினோம். தேர்வு அடிப்படைக் கூறுகளைப் பூர்த்திசெய்த 5914 பங்கேற்பாளர்களை கொண்ட 37 ஆராய்ச்சிகளை நாங்கள் கண்டறிந்தோம். 4 முதல் 12 வாரங்கள் வரைஆராய்ச்சிகள் நடந்தப்பட்டன. பெரும்பாலுமான ஆராய்ச்சிகள் நரம்பு சார்ந்த வலி உள்ளவர்களுக்கு் பயன் உள்ள விளைவுபயன் தருகிறது என்று தெரிவித்தது. சிங்கிள்ஸ்க்கு பின் உண்டாகும் வலி மற்றும் நீரிழிவு நோய் காரணமாக உண்டாகும் நரம்பு சேத வலி அடிப்படையிலே இந்த முடிவுகள் அமைந்தன.

முக்கிய முடிவுகள்

ஷிங்கில்ஸ்க்கு பின் வரும் வலிக்கு காபாபேண்டின் உட்கொண்டவர்களில் 10இல் 3வருக்கும் மருந்தற்ற குளிகை உட்கொண்டவர்களில் 10இல் 2 பேருக்கும் வலி பாதியாகவோ அல்லது கூடுதலாகவோ குறைந்தது. காபாபேண்டின் உட்கொண்டவர்களில் 10இல் 5பேருக்கும் மருந்தற்ற குளிகை உட்கொண்டவர்களில் 10இல் 3 பேருக்கும் வலி மூன்றில் ஒரு பங்காகவோ அல்லது அதைவிட அதிகமாகவோ குறைந்தது. நீரிழிவு நோயினால் வரும் வலிக்கு காபாபேண்டின் உட்கொண்டவர்களில் 10இல் 4 பேருக்கும் மருந்தற்ற குளிகை உட்கொண்டவர்களில் 10இல் 2 பேருக்கும் வலி பாதியாக குறைந்தது. காபாபேண்டின் உட்கொண்டவர்களில் 10இல் 5பேருக்கும் மருந்தற்ற குளிகை உட்கொண்டவர்களில் 10இல் 4 பேருக்கும் வலி மூன்றில் ஒரு பங்காக குறைந்தது. மற்ற நரம்பு சார்ந்த வலிகளுக்கு நம்பகமான ஆதாரம் எதுவும் இல்லை.

மருந்தற்ற குளிகையோடு ஒப்பிடுகையில் (10இல் 5) காபாபேண்டின்னிக்கு பக்க விளைவுகள் அதிகபடியாக வரும் (10 இல் 6). காபாபேண்டின் உட்கொண்டவர்களில் 10இல் ஒருவருக்கு கிறுகிறுப்பு, தூக்கக் கலக்கம், தண்ணீர் தக்கவைத்தல் (water retention) மற்றும் நடப்பதில் பிரச்சினை போன்றவை நேர்ந்துள்ளது. காபாபேண்டின் மற்றும் மருந்தற்ற குளிகைக்குஉட்கொண்டவர்களிடையே கடுமையான பக்க விளைவுகள் பொதுவாக வருவதில்லை. காபாபேண்டின் உட்கொண்டவவர்கள் சற்று அதிகமாகமாணவர்கள் பக்க விளைவுகள் காரணமாக மருந்தை நிறுத்தினர்.

நாள்பட்ட நரம்பு சார்ந்த வலி உடைய சிலருக்கு காபாபேண்டின் உதவக்கூடும். ஆனால் யாருக்கு நன்மை பயக்கும் என்று முன்னதாகவே தெரிந்து கொள்ள சாத்தியம் இல்லை. இன்றைய நிலையில் அறிந்துகொண்டபடி குறுகிய கால ஆய்வுகளே சொல்வதற்கு சிறந்த வழி வழி என அறிவுறுத்துகிறது .

ஆதாரங்களின் தரம்

ஆதாரம் பொதுவாக மிதமான தரம் கொண்டவையாக இருந்தது இதன் அர்த்தம் இந்த விளைவு ஏற்படுவதற்கான வாய்ப்பு நன்றாக இருப்பதாக ஆராய்ச்சி கூறுகிறது. இந்த விளைவு கணிசமாக வேறுபடுவதற்கான வாய்ப்பு மிதமானதாக இருக்கும்.

மொழிபெயர்ப்பு குறிப்புகள்

மொழிபெயர்ப்பு: சி.இ.பி.என்.அர் குழு

Laienverständliche Zusammenfassung

Gabapentin zur Behandlung chronischer neuropathischer Schmerzen bei Erwachsenen

Fazit

Wir fanden Evidenz von moderater Qualität, dass 1200 mg Gabapentin oder mehr täglich zur oralen Einnahme eine wesentliche Wirkung auf den Schmerz von einigen Menschen mit moderaten oder schweren neuropathischen Schmerzen nach Herpes Zoster (Gürtelrose) oder aufgrund von Diabetes hat.

Hintergrund

Neuropathische Schmerzen werden auf Schädigungen von Nerven zurückgeführt. Sie sind anders als die Botschaften durch Schmerzen, die von beschädigtem Gewebe (zum Beispiel durch einen Fall, einen Schnitt oder ein arthritisches Knie) entlang gesunder Nerven geleitet werden. Neuropathische Schmerzen werden oft mit anderen Medikamenten behandelt als jene Schmerzen, die durch beschädigtes Gewebe entstehen und mit Schmerzmitteln behandelt werden. Medikamente, die manchmal bei Depression oder Epilepsie eingesetzt werden, können bei einigen Menschen mit neuropathischen Schmerzen wirksam sein. Eines davon ist Gabapentin. Unsere Definition eines guten Ergebnisses war eine Person, die eine hohe Schmerzlinderung erfuhr und in der Lage war, das Medikament weiterhin einzunehmen, ohne dass Nebenwirkungen dazu geführt hätten, dass sie die Behandlung abbrechen musste.

Studienmerkmale

Wir suchten im Januar 2017 nach klinischen Studien, in denen Gabapentin zur Behandlung von neuropathischen Schmerzen bei Erwachsenen verwendet wurde. Wir fanden 37 Studien, die die Einschlusskriterien erfüllten. Sie randomisierten 5914 Teilnehmer zu Behandlungen mit Gabapentin, Placebo oder anderen Medikamenten. Die Studien dauerten 4 bis 12 Wochen. Die meisten Studien berichteten vorteilhafte Endpunkte, die Menschen mit neuropathischen Schmerzen für wichtig halten. Ergebnisse lagen vor allem für Schmerzen nach Gürtelrose und Schmerzen aufgrund von Nervenschädigungen bei Diabetes vor.

Hauptergebnisse

Schmerzen nach Gürtelrose wurden um die Hälfte oder mehr bei 3 von 10 Personen durch Gabapentin und bei 2 von 10 Personen durch Placebo reduziert. Die Schmerzen verringerten sich um ein Drittel oder mehr bei 5 von 10 Personen durch Gabapentin und bei 3 von 10 durch Placebo. Schmerzen, die durch Diabetes verursacht wurden, wurden um die Hälfte oder mehr bei 4 von 10 Personen durch Gabapentin und bei 2 von 10 durch Placebo reduziert. Die Schmerzen verringerten sich um ein Drittel oder mehr bei 5 von 10 durch Gabapentin und 4 von 10 durch Placebo. Es gab keine zuverlässige Evidenz für andere Arten von neuropathischen Schmerzen.

Nebenwirkungen waren häufiger bei Gabapentin (6 von 10) als bei Placebo (5 von 10). Schwindel, Schläfrigkeit, Wassereinlagerungen und Probleme mit dem Gehen traten jeweils bei etwa 1 von 10 Personen auf, die Gabapentin einnahmen. Schwerwiegende Nebenwirkungen waren selten und nicht unterschiedlich zwischen Gabapentin und Placebo. Etwas mehr Menschen brachen die Einnahme von Gabapentin wegen der Nebenwirkungen ab.

Gabapentin ist für manche Menschen mit chronischen neuropathischen Schmerzen hilfreich. 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.

Qualität der Evidenz

Die Evidenz war größtenteils von moderater Qualität. Dies bedeutet, dass die Forschung einen guten Hinweis für die wahrscheinliche Wirkung bietet. Die Wahrscheinlichkeit, dass die Wirkung wesentlich anders sein wird, ist moderat.

Anmerkungen zur Übersetzung

N. Tittlbach, freigegeben durch Cochrane Deutschland

Ringkasan bahasa mudah

Gabapentin untuk sakit neuropatik kronik dalam golongan dewasa

Kesimpulan

Terdapat bukti berkualiti sederhana bahawa gabapentin yang diambil melalui mulut pada dos 1200 mg setiap hari atau dos yang lebih tinggi mempunyai kesan yang penting terhadap kesakitan dalam golongan yang mengalami sakit neuropatik yang sederhana atau teruk akibat penyakit kayap atau kencing manis (diabetes).

Latar belakang

Sakit neuropatik berasal daripada saraf yang tercedera. Ia berbeza daripada mesej kesakitan yang dibawa oleh saraf yang sihat daripada tisu tercedera (contohnya, daripada jatuh, luka atau sakit sendi lutut). Sakit neuropatik sering dirawat dengan ubat-ubatan yang berlainan daripada ubat-ubatan yang digunakan untuk sakit daripada tisu yang tercedera, yang kita sentiasa anggap sebagai ubat penahan sakit. Ubat-ubatan yang kadang-kala digunakan untuk merawat kemurungan atau epilepsi boleh berkesan bagi sesetengah orang yang mengalami sakit neuropatik. Antaranya termasuk gabapentin. Definisi kami tentang kesan yang bagus merujuk kepada seseorang yang mencapai tahap peringanan kesakitan yang tinggi dan mampu mengambil ubat yang berkenaan tanpa kesan-kesan sampingan yang menyebabkan pemberhentian pengambilan ubat.

Ciri-ciri kajian

Pada Januari 2017 kami mencari kajian-kajian klinikal di mana gabapentin digunakan untuk merawat sakit neuropatik dalam kalangan golongan dewasa. Kami menemui 37 kajian yang memenuhi syarat kemasukan di mana 5914 orang peserta diberikan rawatan dengan gabapentin, plasebo atau ubat yang lain-lain secara rawak. Kajian-kajian berlangsung selama 4 hingga 12 minggu. Kebanyakan kajian melaporkan hasilan berfaedah yang dianggap penting oleh orang ramai yang mengalami sakit neuropatik. Hasilan yang utama adalah bagi sakit selepas penyakit kayap dan sakit akibat kecederaan saraf dalam diabetes.

Hasilan utama

Bagi sakit selepas penyakit kayap, 3 daripada 10 orang mengalami pengurangan sakit sebanyak separuh atau lebih dengan gabapentin berbanding dengan 2 daripada 10 orang dengan plasebo. Sakit dikurangkan sebanyak satu per tiga atau lebih bagi 5 daripada 10 orang dengan gabapentin dan 3 daripada 10 orang dengan plasebo. Bagi sakit yang disebabkan oleh diabetes, 4 daripada 10 orang mengalami pengurangan sakit sebanyak separuh atau lebih dengan gabapentin dan 2 daripada 10 orang dengan plasebo. Sakit dikurangkan sebanyak satu per tiga atau lebih bagi 5 daripada 10 orang dengan gabapentin dan 4 daripada 10 orang dengan plasebo. Tiada bukti yang boleh dipercayai bagi jenis sakit neuropatik yang lain.

Kesan-kesan sampingan adalah lebih kerap dengan gabapentin (6 daripada 10) berbanding dengan plasebo (5 daripada 10). Pening, mengantuk, pengekalan air dan masalah berjalan berlaku dalam kira-kira 1 daripada 10 orang yang mengambil gabapentin. Kesan-kesan sampingan yang serius adalah luar biasa dan tidak berbeza antara gabapentin dengan plasebo. Sedikit lebih banyak orang yang mengambil gabapentin berhenti mengambil gabapentin oleh sebab kesan-kesan sampingannya.

Gabapentin adalah berfaedah bagi sesetengah orang yang mengalami sakit neuropatik kronik. Kami tidak mungkin tahu dengan lebih awal tentang siapa yang akan mendapat manfaat daripada gabapentin dan siapa yang tidak akan mendapat manfaat. Pengetahuan setakat ini bercadang bahawa sebuah kajian singkat merupakan cara yang terbaik untuk menentukan kesesuaian gabapentin dalam kalangan pesakit.

Kualiti bukti

Kebanyakan bukti adalah berkualiti sederhana. Ini bermakna bahawa penyelidikan memberikan petunjuk yang baik tentang kemungkinan kesan gabapentin. Kemungkinan bahawa kesan gabapentin akan berbeza secara ketara adalah sederhana.

Catatan terjemahan

Diterjemahkan oleh Chew Jia En (Penang Medical College). Disunting oleh Tan May Loong (Penang Medical College). Untuk sebarang pertanyaan berkaitan terjemahan ini sila hubungi jiaen_c2017@ms.pmc.edu.my

Streszczenie prostym językiem

Gabapentyna w leczeniu przewlekłego bólu neuropatycznego u dorosłych

Najważniejsza informacja

Dane naukowe umiarkowanej jakości potwierdzają, że przyjmowanie doustne gabapentyny w dawce co najmniej 1200 mg/dobę ma istotny wpływ na ból u niektórych pacjentów odczuwających umiarkowany lub silny ból neuropatyczny w przebiegu półpaśca lub cukrzycy.

Wprowadzenie

Ból neuropatyczny powstaje wskutek uszkodzenia nerwów. Ból ten różni się od bólu przewodzonego przez zdrowe nerwy, spowodowanego uszkodzeniem tkanek (np. w wyniku upadku, skaleczenia lub zwyrodnienia stawów kolanowych). W leczeniu bólu neuropatycznego są często zalecane inne leki niż te stosowane w bólu spowodowanym uszkodzeniem tkanek (przeciwbólowe). Leki stosowane w przypadku depresji lub padaczki mogą być skuteczne u niektórych osób z bólem neuropatycznym. Jednym z takich leków jest gabapentyna. Według nas definicja dobrego wyniku zdrowotnego to pacjent z znaczną ulgą w zakresie odczuwanego bólu, który może przyjmować lek bez wystąpienia skutków ubocznych, które mogłyby skłonić go do zaprzestania dalszego leczenia.

Charakterystyka badań

W styczniu 2017 r. poszukiwaliśmy badań klinicznych dotyczących stosowania gabapentyny w bólu neuropatycznym u osób dorosłych. Odnaleźliśmy 37 badań spełniających nasze kryteria włączenia, w których 5914 chorych przydzielono losowo do jednej z dwóch grup, w których otrzymywali oni gabapentynę w porównaniu z placebo albo innym lekiem. Czas trwania wszystkich badań wynosił od 4 do 12 tygodni. W większości badań wykazano korzystne wyniki zdrowotne, które według oceny pacjentów mają duże znaczenie. Wyniki dotyczyły głównie bólu po przebytym półpaścu oraz bólu spowodowanego uszkodzeniem nerwów w przebiegu cukrzycy.

Główne wyniki

W przypadku bólu po półpaścu u 3 osób na 10 przyjmujących gabapentynę stwierdzono zmniejszenie natężenia bólu co najmniej o połowę w porównaniu z 2 osobami na 10 w grupie placebo. Natężenie bólu zmniejszyło się o co najmniej jedną trzecią u 5 na 10 osób leczonych gabapentyną oraz u 3 na 10 otrzymujących placebo. W grupie chorych na cukrzycę u 4 na 10 pacjentów leczonych gabapentyną stwierdzono zmniejszenie o co najmniej połowę natężenia bólu neuropatycznego w porównaniu z 2 osobami na 10 z grupy placebo. Natężenie bólu zmniejszyło się o co najmniej jedną trzecią u 5 osób na 10 w grupie gabapentyny oraz u 4 na 10 w grupie placebo. Nie posiadamy żadnych wiarygodnych danych naukowych w odniesieniu do innych rodzajów bólu neuropatycznego.

Działania niepożądane częściej obserwowano w przypadku gabapentyny (6 na 10 osób) niż placebo (5 na 10 osób). Zawroty głowy, senność, zatrzymanie wody w organizmie oraz trudności w poruszaniu się wystąpiły u 1 pacjenta na 10 leczonych gabapentyną. Poważne działania niepożądane występowały rzadko i nie różniły się między grupą leczonych gabapentyną i placebo. Nieznacznie więcej osób leczonych gabapentyną zdecydowało się przerwać leczenie z powodu skutków ubocznych.

Gabapentyna jest pomocna u niektórych pacjentów z przewlekłym bólem neuropatycznym. Nie ma możliwości określenia z wyprzedzeniem, u których pacjentów lek ten przyniesie korzyści, a u których nie. Według aktualnego stanu wiedzy najlepszym sposobem, aby to ocenić jest podjęcie próby leczenia.

Jakość danych naukowych

Jakość danych naukowych określono na umiarkowaną. Oznacza to, że badania dostarczyły dobrych informacji na temat przewidywanego efektu. Prawdopodobieństwo, że wynik będzie całkowicie odmienny, jest umiarkowane.

Uwagi do tłumaczenia

Tłumaczenie: Magdalena Siwek Redakcja: Piotr Szymczak, Karolina Moćko, Małgorzata Kołcz

Summary of findings(Explanation)

Summary of findings for the main comparison. Gabapentin compared with placebo for postherpetic neuralgia: efficacy
Gabapentin compared with placebo for postherpetic neuralgia: efficacy

Patient or population: adults with postherpetic neuralgia

Settings: community

Intervention: gabapentin ≥ 1800 mg daily or gabapentin encarbil 1200 mg daily

Comparison: placebo

OutcomeProbable outcome with gabapentinProbable outcome with placebo

RR and NNT

(95% CI)

Number of studies, participants Certainty of the evidence
(GRADE)
Comments
At least 50% reduction in pain or equivalent330 per 1000190 per 1000

RR 1.7 (1.4 to 2.0)

NNT 6.9 (5.5 to 9.4)

7 studies

2031 participants

ModerateDowngraded because of issues around dosing, formulation, and imputation
IMMPACT definition - any substantial pain benefit320 per 1000170 per 1000

RR 1.8 (1.5 to 2.1)

NNT 6.7 (5.4 to 8.7)

8 studies

2260 participants

ModerateDowngraded because of issues around dosing, formulation, and imputation
Patient Global Impression of Change much or very much improved390 per 1000290 per 1000

RR1.3 (1.2 to 1.5)

NNT 9.7 (6.9 to 16)

7 studies

2013 participants

ModerateDowngraded because of issues around dosing, formulation, and imputation

IMMPACT definition - any at least moderate pain benefit

(includes Gong 2008 at 25% pain relief)

46 per 100025 per 1000

RR 1.8 (1.6 to 2.0)

NNT 4.8 (4.1 to 6.0)

8 studies

2260 participants

ModerateDowngraded because of issues around dosing, formulation, and imputation
CI: confidence interval; IMMPACT: Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials; NNT: number needed to treat for an additional beneficial outcome; RR: risk ratio

Descriptors for levels of evidence (EPOC 2015):
High quality: this research provides a very good indication of the likely effect. The likelihood that the effect will be substantially different is low.
Moderate quality: this research provides a good indication of the likely effect. The likelihood that the effect will be substantially different is moderate.
Low quality: this research provides some indication of the likely effect. However, the likelihood that it will be substantially different is high.
Very low quality: this research does not provide a reliable indication of the likely effect. The likelihood that the effect will be substantially different is very high.

Substantially different: a large enough difference that it might affect a decision.

Summary of findings 2 Gabapentin compared with placebo for peripheral diabetic neuropathy: efficacy

Summary of findings 2. Gabapentin compared with placebo for peripheral diabetic neuropathy: efficacy
Gabapentin compared with placebo for peripheral diabetic neuropathy: efficacy

Patient or population: adults with peripheral diabetic neuropathy

Settings: community

Intervention: ≥ 1800 mg daily or gabapentin encarbil 1200 mg daily

Comparison: placebo

OutcomeProbable outcome with gabapentinProbable outcome with placebo

RR and NNT

(95% CI)

Number of studies, participants Certainty of the evidence
(GRADE)
Comments
At least 50% pain intensity reduction380 per 1000210 per 1000

RR 1.9 (1.5 to 2.3)

NNT 5.9 (4.6 to 8.3)

6 studies

1277 participants

ModerateDowngraded because of issues around dosing, formulation, and imputation
Any definition of substantial benefit (at least 50% pain intensity reduction or PGIC very much improved)380 per 1000210 per 1000

RR 1.9 (1.5 to 2.3)

NNT 5.9 (4.6 to 8.3)

6 studies

1277 participants

ModerateDowngraded because of issues around dosing, formulation, and imputation
PGIC much or very much improved500 per 1000300 per 1000

RR 1.7 (1.4 to 2.0)

NNT 4.9 (3.6 to 7.6)

5 studies

695 participants

ModerateDowngraded because of issues around dosing, formulation, and imputation
Any definition of moderate benefit (at least 30% pain intensity reduction or PGIC much or very much improved)520 per 1000370 per 1000

RR 1.4 (1.3 to 1.6)

NNT 6.6 (4.9 to 9.9)

7 studies

1439 participants

ModerateDowngraded because of issues around dosing, formulation, and imputation
CI: confidence interval; IMMPACT: Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials; NNT: number needed to treat for an additional beneficial outcome; RR: risk ratio

Descriptors for levels of evidence (EPOC 2015):
High quality: this research provides a very good indication of the likely effect. The likelihood that the effect will be substantially different is low.
Moderate quality: this research provides a good indication of the likely effect. The likelihood that the effect will be substantially different is moderate.
Low quality: this research provides some indication of the likely effect. However, the likelihood that it will be substantially different is high.
Very low quality: this research does not provide a reliable indication of the likely effect. The likelihood that the effect will be substantially different is very high.

Substantially different: a large enough difference that it might affect a decision.

Summary of findings 3 Gabapentin compared with placebo for neuropathic pain (all conditions pooled): adverse events and withdrawals

Summary of findings 3. Gabapentin compared with placebo for neuropathic pain (all conditions pooled): adverse events and withdrawals
Gabapentin compared with placebo for neuropathic pain (all conditions pooled): adverse events and withdrawals

Patient or population: adults with neuropathic pain

Settings: community

Intervention: gabapentin 1800 mg to 3600 mg daily (gabapentin encarbil 1200 mg to 3600 mg daily)

Comparison: placebo

OutcomeProbable outcome with gabapentinProbable outcome with placebo

RR and NNH

(95% CI)

Number of studies, participants Certainty of the evidence
(GRADE)
Comments
Participants experiencing at least one adverse event630 per 1000490 per 1000

RR 1.3 (1.2 to 1.4)

NNH 7.5 (6.1 to 9.6)

18 studies

4279 participants

ModerateMany events. Unlikely new research would change this finding
Adverse event withdrawals110 in 100082 in 1000

RR 1.4 (1.1 to 1.7)

NNH 30 (20 to 66)

22 studies

4346 participants

HighUnlikely new research would change this finding
Serious adverse events32 in 100028 in 1000

RR 1.2 (0.83 to 1.7)

NNH not calculated

19 studies

3948 participants

ModerateSmall number of events but no suggestion of difference
Death3 in max 3603 exposed5 in max 2377 exposedNot calculatedNot calculatedVery lowFew events, relatively short duration for drug possibly taken over periods of years
CI: confidence interval; NNH: number needed to treat for an additional harmful outcome; RR: risk ratio

Descriptors for levels of evidence (EPOC 2015):
High quality: this research provides a very good indication of the likely effect. The likelihood that the effect will be substantially different is low.
Moderate quality: this research provides a good indication of the likely effect. The likelihood that the effect will be substantially different is moderate.
Low quality: this research provides some indication of the likely effect. However, the likelihood that it will be substantially different is high.
Very low quality: this research does not provide a reliable indication of the likely effect. The likelihood that the effect will be substantially different is very high.

Substantially different: a large enough difference that it might affect a decision.

Background

This is an update of a Cochrane Review titled 'Gabapentin for chronic neuropathic pain and fibromyalgia in adults', published in 2014 (Moore 2014a). The review has now been split and this update will consider only neuropathic pain. A separate updated review of gabapentin for fibromyalgia has been published (Cooper 2017).

Earlier versions of this review include 'Gabapentin for chronic neuropathic pain and fibromyalgia in adults' (Moore 2011a), and 'Gabapentin for acute and chronic pain' (Wiffen 2005). That was itself split out of a review previously published in the Cochrane Library on 'Anticonvulsant drugs for acute and chronic pain' (Wiffen 2000), an update of yet an older systematic review (McQuay 1995).

At a meeting in Oxford in early 2009 with Cochrane's Editor-in-Chief, it was decided to create separate chronic pain and acute pain reviews from the then current review on acute and chronic pain together (Wiffen 2005). The meeting was in response to controversy in the 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 2005 review by splitting the earlier one into two components: one 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. Other reviews may examine gabapentin in chronic musculoskeletal pain. The unpublished data were included in the 2011 review on chronic neuropathic pain and fibromyalgia (Moore 2011a), and in established acute postoperative pain (Straube 2010).

This latest update is based on a template for drugs to treat neuropathic pain, using current standards for Cochrane Reviews, including assessment of the reliability of the evidence with GRADE, and based on criteria for what constitutes reliable evidence in chronic pain (Moore 2010a; Moore 2013a; Appendix 1).

Description of the condition

Neuropathic pain is a consequence of a pathological maladaptive response of the nervous system to 'damage' from a wide variety of potential causes (Colloca 2017). It is characterised by pain in the absence of an noxious stimulus, or where minor or moderate nociceptive stimuli evoke exaggerated levels of pain. Neuropathic pain may be spontaneous (continuous or paroxysmal) in its temporal characteristics or be evoked by sensory stimuli (dynamic mechanical allodynia where pain is evoked by light touch of the skin).

Neuropathic pain is heterogeneous in etiology, pathophysiology, and clinical appearance. The 2011 International Association for the Study of Pain definition of neuropathic pain is "pain caused by a lesion or disease of the somatosensory system" (Jensen 2011), based on a definition agreed at an earlier consensus meeting (Treede 2008). Neuropathic pain is associated with a variety of sensory loss (numbness) and sensory gain (allodynia) clinical phenomena, the exact patterns of which vary between people and disease, perhaps reflecting different pain mechanisms operating in an individual person and, therefore, potentially predictive of response to treatment (Demant 2014; Helfert 2015; von Hehn 2012). A new approach of subgrouping people with peripheral neuropathic pain of different etiologies according to intrinsic sensory profiles has generated three profiles that may be related to pathophysiological mechanisms and may be useful in clinical trial design to enrich the study population for treatment responders (Baron 2017).

Pre-clinical research hypothesises a bewildering array of possible pain mechanisms that may operate in people with neuropathic pain, which largely reflect pathophysiological responses in both the central and peripheral nervous systems, including neuronal interactions with immune cells (Baron 2012; Calvo 2012; von Hehn 2012). Overall, the treatment gains in neuropathic pain, to even the most effective of available drugs, are modest (Finnerup 2015; Moore 2013b), and a robust classification of neuropathic pain is not yet available (Finnerup 2013).

Neuropathic pain is usually classified according to the cause of nerve injury. There may be many causes, but some common causes of neuropathic pain include diabetes (painful diabetic neuropathy (PDN)), shingles (postherpetic neuralgia (PHN)), amputation (stump and phantom limb pain), neuropathic pain after surgery or trauma, stroke or spinal cord injury, trigeminal neuralgia, and HIV infection. Sometimes the cause is unknown.

Many people with neuropathic pain conditions are significantly disabled with moderate or severe pain for many years. Chronic pain conditions comprised 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 and employment, and increased healthcare costs (Moore 2014a). A US study found the healthcare costs were threefold higher for people with neuropathic pain than matched control subjects (Berger 2004). A UK study and a German study showed a two- to threefold higher level of use of healthcare services in people with neuropathic pain than those without (Berger 2012; Berger 2009). For PHN, for example, studies demonstrate large loss of quality of life and substantial costs (Scott 2006; Van Hoek 2009).

In systematic reviews, the overall prevalence of neuropathic pain in the general population is reported to be between 7% and 10% (Van Hecke 2014), and about 7% in a systematic review of studies published since 2000 (Moore 2014a). In individual countries, prevalence rates have been reported as 3.3% in Austria (Gustorff 2008), 6.9% in France (Bouhassira 2008), and up to 8% in the UK (Torrance 2006). Some forms of neuropathic pain, such as PDN and post-surgical chronic pain (which is often neuropathic in origin), are increasing (Hall 2008). The prevalence of PHN is likely to fall if vaccination against the herpes virus becomes widespread.

Estimates of incidence vary between individual studies for particular origins of neuropathic pain, often because of small numbers of cases. In primary care in the UK, between 2002 and 2005, the incidences (per 100,000 person-years' observation) were 28 (95% confidence interval (CI), 27 to 30) for PHN, 27 (95% CI, 26 to 29) for trigeminal neuralgia, 0.8 (95% CI, 0.6 to 1.1) for phantom limb pain, and 21 (95% CI, 20 to 22) for PDN (Hall 2008). Other studies have estimated an incidence of 4 in 100,000 per year for trigeminal neuralgia (Katusic 1991; Rappaport 1994), and 12.6 per 100,000 person-years for trigeminal neuralgia and 3.9 per 100,000 person-years for PHN in a study of facial pain in the Netherlands (Koopman 2009). One systematic review of chronic pain demonstrated that some neuropathic pain conditions, such as PDN, can be more common than other neuropathic pain conditions, with prevalence rates up to 400 per 100,000 person-years (McQuay 2007). It is also the case that pains not classified as neuropathic can have neuropathic features. In a community study of recent joint pain, features of neuropathic pain were common and were present in over half of those reporting pain of at least moderate severity (Soni 2013).

Neuropathic pain is difficult to treat effectively, with only a minority of people experiencing a clinically relevant benefit from any one intervention (Kalso 2013; Moore 2013b). A multidisciplinary approach is now advocated, combining pharmacological interventions with physical or cognitive (or both) interventions. The evidence for more invasive interventional therapies such as neural blockade or intrathecal medication is very weak, or non-existent (Dworkin 2013). Conventional analgesics such as paracetamol (acetaminophen) and nonsteroidal anti-inflammatory drugs (NSAID) are not thought to be effective, but without evidence to support or refute that view (Moore 2015a; Wiffen 2016). Some people may derive some benefit from a topical lidocaine patch or low-concentration topical capsaicin, although evidence about benefits is uncertain (Derry 2012; Derry 2014). High-concentration topical capsaicin may benefit some people with PHN (Derry 2017). Treatment is often by so-called 'unconventional analgesics' (pain modulators) such as antidepressants (duloxetine and amitriptyline; Lunn 2014; Moore 2014b; Moore 2015b; Sultan 2008), or antiepileptics (gabapentin or pregabalin; Moore 2009; Moore 2014b; Wiffen 2013). Evidence for efficacy of opioids is unconvincing (Derry 2016; Gaskell 2016; Stannard 2016; Wiffen 2015).

The proportion of people who achieve worthwhile pain relief (typically at least 50% pain intensity reduction; Moore 2014c) is small, generally only 10% to 25% more than with placebo, with numbers needed to treat for an additional beneficial outcome (NNT) usually between 4 and 10 (Kalso 2013; Moore 2013b). Neuropathic pain is not particularly different from other chronic pain conditions in that only a small proportion of trial participants have a good response to treatment (Moore 2013b).

The current National Institute for Health and Care Excellence (NICE) guidance for the pharmacological management of neuropathic pain suggests offering a choice of amitriptyline (Moore 2012b), duloxetine (Lunn 2014), gabapentin, or pregabalin (Moore 2009) as initial treatment for neuropathic pain (with the exception of trigeminal neuralgia), with switching if the first, second, or third drugs tried are not effective or not tolerated (NICE 2013). This concurs with other recent guidance (Finnerup 2015).

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 2017). 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 NeurontinTM, 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.

Gabapentin misuse has been reported, and the consequences documented and systematically reviewed (Evoy 2017; Quintero 2017).

How the intervention might work

Gabapentin's mechanism of action is primarily attributed to its effect on calcium channels located throughout the peripheral and central nervous systems, which modify the release of neurotransmitters and reduce excitability of nerve cells (Boyle 2014; Chang 2014). This mode of action confers antiepileptic, analgesic, and sedative effects. Research also indicates that gabapentin acts by blocking new synapse formation (Eroglu 2009).

Why it is important to do this review

Some, but not all, antiepileptics can reduce neuropathic pain (Wiffen 2010). Gabapentin is an antiepileptic 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. Guidance on prescribing typically puts gabapentin amongst the first-line agents (Finnerup 2015; NICE 2013). Despite this guidance based on good evidence, prescribing for neuropathic pain often involves paracetamol or paracetamol combined with opioids (Hall 2013), for which there is no evidence of efficacy (Wiffen 2016).

The standards used to assess evidence in chronic pain trials have evolved substantially in recent years, with particular attention being paid to trial duration, withdrawals, and statistical imputation following withdrawal, all of which can substantially alter estimates of efficacy (Appendix 1). The most important change is the move from using mean pain scores, or mean change in pain scores, to the number of people who have a large decrease in pain (by at least 50%) and who continue in treatment, ideally in trials of 8 to 12 weeks' duration or longer. Pain intensity reduction of 50% or more correlates with improvements in co-morbid symptoms, function, and quality of life. These standards are set out in the PaPaS Author and Referee Guidance for pain studies of Cochrane Pain, Palliative and Supportive Care (PaPaS 2012).

This Cochrane Review assesses the evidence using methods that make both statistical and clinical sense, and uses developing criteria for what constitutes reliable evidence in chronic pain (Moore 2010a). Trials included and analysed meet a minimum of reporting quality (blinding, randomisation), validity (duration, dose and timing, diagnosis, outcomes, etc), and size (ideally at least 500 participants in a comparison in which the NNT is 4 or above; Moore 1998). This approach sets high standards for the demonstration of efficacy and marks a departure from how reviews were conducted previously.

Objectives

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

Methods

Criteria for considering studies for this review

Types of studies

We included 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 eight weeks or longer. We required full journal publication, with the exception of online clinical trial results summaries of otherwise unpublished clinical trials, and abstracts with sufficient data for analysis.

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, with one or more chronic neuropathic pain condition including (but not limited to):

  1. cancer-related neuropathy;

  2. central neuropathic pain;

  3. complex regional pain syndrome (CRPS) Type II;

  4. HIV neuropathy;

  5. painful diabetic neuropathy;

  6. phantom limb pain;

  7. postherpetic neuralgia;

  8. postoperative or traumatic neuropathic pain;

  9. spinal cord injury;

  10. trigeminal neuralgia.

Where we included studies with more than one type of neuropathic pain, we analysed results according to the primary condition if identifiable.

Types of interventions

Gabapentin in any dose, by any route, administered for the relief of neuropathic pain and compared to placebo or any other active comparator.

Types of outcome measures

We anticipated that studies would use a variety of outcome measures, with most 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 were defined as:

  1. at least 30% pain relief over baseline (moderate);

  2. at least 50% pain relief over baseline (substantial);

  3. much or very much improved on Patient Global Impression of Change scale (PGIC; moderate);

  4. very much improved on PGIC (substantial).

These outcomes concentrate 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% pain intensity reduction, and ideally having no worse than mild pain (Moore 2013c; O'Brien 2010).

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

  2. Participant-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, adverse events, and for any cause.

  3. Participants experiencing any adverse event.

  4. Participants experiencing any serious adverse event. Serious adverse events typically include any untoward medical occurrence or effect that at any dose results in death, is life-threatening, requires hospitalisation or prolongation of existing hospitalisation, results in persistent or significant disability or incapacity, is a congenital anomaly or birth defect, is an 'important medical event' that may jeopardise the patient, or may require an intervention to prevent one of the above characteristics or consequences.

  5. Specific adverse events, particularly somnolence and dizziness.

Search methods for identification of studies

Electronic searches

For this update we searched the following databases, without language restrictions:

  1. Cochrane Central Register of Controlled Trials (CENTRAL) via the Cochrane Register of Studies Online (CRSO), 1 January 2014 to 16 January 2017;

  2. MEDLINE via Ovid, 1 January 2014 to 16 January 2017;

  3. Embase via Ovid, 1 January 2014 to 16 January 2017.

See Appendix 2 for the CENTRAL search strategy, Appendix 3 for the MEDLINE search strategy, and Appendix 4 for the Embase search strategy.

Searching other resources

We reviewed the bibliographies of any RCTs identified and review articles, and searched clinical trial databases (ClinicalTrials.gov (ClinicalTrials.gov) and World Health Organization (WHO) International Clinical Trials Registry Platform (ICTTRP) (apps.who.int/trialsearch/)) to identify additional published or unpublished data. We did not contact investigators or study sponsors.

Data collection and analysis

We performed separate efficacy analyses according to particular neuropathic pain conditions, and combined different neuropathic pain conditions in analyses for adverse events and withdrawals only.

Selection of studies

We determined eligibility by reading the abstract of each study identified by the search. We eliminated studies that clearly did not satisfy the inclusion criteria, and we obtained full copies of the remaining studies. Two review authors made the decisions. Two review authors (RAM, SD) then read these studies independently and reached agreement by discussion. We did not anonymise the studies in any way before assessment. We have provided a PRISMA flow chart to illustrate the flow of studies (Moher 2009) (Figure 1).

Figure 1.

Study flow diagram

Data extraction and management

Three review authors (RAM, PW, SD) extracted data independently, using a standard data extraction form, and agreed data before entry into Review Manager (RevMan) 5 (RevMan 2014) or any other analysis method. We 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, particular adverse events, or a serious adverse event).

Assessment of risk of bias in included studies

We used the Oxford Quality Score as the basis for inclusion (Jadad 1996), limiting inclusion to studies that were randomised and double-blind as a minimum.

Two review authors (SD, PW) independently assessed risk of bias for each study, using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Chapter 8, Higgins 2011), and adapted from those used by Cochrane Pregnancy and Childbirth, with any disagreements resolved by discussion. We assessed the following for each study:

  1. Random sequence generation (checking for possible selection bias). We assessed the method used to generate the allocation sequence as: low risk of bias (any truly random process: random number table or computer random-number generator); unclear risk of bias (when the method used to generate the sequence was not clearly stated). We excluded studies at a high risk of bias that used a non-random process (odd or even date of birth; hospital or clinic record number).

  2. Allocation concealment (checking for possible selection bias). The method used to conceal allocation to interventions prior to assignment determines whether intervention allocation could have been foreseen in advance of, or during, recruitment, or changed after assignment. We assessed the methods as: low risk of bias (telephone or central randomisation; consecutively-numbered, sealed, opaque envelopes); unclear risk of bias (when method not clearly stated). We excluded studies that did not conceal allocation and were therefore at a high risk of bias (open list).

  3. Blinding of participants and personnel (checking for possible performance bias), and blinding of outcome assessment (checking for possible detection bias). We assessed the methods used to blind study personnel and participants (all outcomes were self-assessed) from knowledge of which intervention a participant received. We assessed the methods as: low risk of bias (study stated that it was blinded and described the method used to achieve blinding, for example, identical tablets, matched in appearance and smell); unclear risk of bias (study stated that it was blinded but did not provide an adequate description of how it was achieved). We excluded studies at a high risk of bias that were not double-blind.

  4. Incomplete outcome data (checking for possible attrition bias due to the amount, nature, and handling of incomplete outcome data). We assessed the methods used to deal with incomplete data as: low risk of bias (fewer than 10% of participants did not complete the study or used 'baseline observation carried forward' (BOCF) analysis, or both); unclear risk of bias (used 'last observation carried forward' (LOCF) analysis); or high risk of bias (used 'completer' analysis).

  5. Size of study (checking for possible biases confounded by small size (Dechartres 2013; Dechartres 2014; Moore 1998; Nüesch 2010; Thorlund 2011)). We assessed studies as being at low risk of bias (200 participants or more per treatment arm); unclear risk of bias (50 to 199 participants per treatment arm); or high risk of bias (fewer than 50 participants per treatment arm).

Measures of treatment effect

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 was calculated in the same manner. 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 did not use continuous data in analyses.

Unit of analysis issues

The unit of analysis was the individual participant. For cross-over studies we planned to use first period data where possible, but otherwise to use available data and consider any potential bias that this study design presented.

Dealing with missing data

We used intention-to-treat (ITT) analysis where the ITT population consisted of participants who were randomised, took at least one dose of the assigned study medication, and provided at least one post-baseline assessment. We assigned zero improvement (baseline observation carried forward (BOCF)) to missing participants wherever possible.

We paid particular attention to methods used for imputation of missing data due to withdrawals for adverse events and lack of efficacy.

Assessment of heterogeneity

We dealt with clinical heterogeneity by combining studies that examined similar conditions. We assessed statistical heterogeneity visually (L'Abbé 1987) and with the use of the I2 statistic (Higgins 2003). When the I² value was greater than 50%, we considered possible reasons for this.

Assessment of reporting biases

The aim of this review was to use dichotomous outcomes of known utility and of value to people with neuropathic pain (Hoffman 2010; Moore 2010a; Moore 2010b; Moore 2010c; Moore 2014c). The review did not depend on what the authors of the original studies chose to report or not, and studies that did not report dichotomous results for an outcome did not contribute to pooled analyses for that outcome. We extracted and used continuous data, which probably reflect efficacy and utility poorly, for illustrative purposes only.

We assessed publication bias using a method designed to detect the amount of unpublished data with a null effect required to make any result clinically irrelevant (usually taken to mean a NNT of 10 or higher in this condition; Moore 2008).

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 used a fixed-effect model for meta-analysis, unless there was significant clinical heterogeneity and it was still considered appropriate to combine studies. In such cases we would use a random-effects model.

Quality of evidence
Quality of the evidence

We used the GRADE system to assess the quality of the evidence related to the key outcomes listed in Types of outcome measures, as appropriate (Appendix 6). Two review authors (RAM, SD) independently rated the quality of the evidence for each outcome.

We paid particular attention to inconsistency, where point estimates varied widely across studies or confidence intervals (CIs) of studies showed minimal or no overlap (Guyatt 2011), and potential for publication bias, based on the amount of unpublished data required to make the result clinically irrelevant (Moore 2008).

In addition, there may be circumstances where the overall rating for a particular outcome needs to be adjusted as recommended by GRADE guidelines (Guyatt 2013a). For example, where there were so few data that the results were highly susceptible to the random play of chance, or if a study used last observation carried forward (LOCF) imputation in circumstances where there were substantial differences in adverse event withdrawals, one would have no confidence in the result, and would need to downgrade the quality of the evidence by three levels, to very low quality. In circumstances where there were no data reported for an outcome, we would have reported the level of evidence as very low quality (Guyatt 2013b).

In addition, we are aware that many Cochrane Reviews are based largely or wholly on small underpowered studies, and the danger of making conclusive assessments of evidence based on inadequate information (AlBalawi 2013; Brok 2009; Roberts 2015; Turner 2013).

'Summary of findings' table

We have included a 'Summary of findings' table as set out in the PaPaS author guide (PaPaS 2012), and recommended in the Cochrane Handbook for Systematic Reviews of Interventions (Chapter 11, Schünemann 2011a). The table includes, where possible, outcomes equivalent to moderate or substantial benefit of at least 30% and at least 50% pain intensity reduction, PGIC (possibly at least substantial improvement and at least moderate improvement) (Dworkin 2008), withdrawals due to lack of efficacy, withdrawals due to adverse events, serious adverse events, and death (a particular serious adverse event).

For the 'Summary of findings' table we used the following descriptors for levels of evidence (EPOC 2015):

High: this research provides a very good indication of the likely effect. The likelihood that the effect will be substantially different is low.

Moderate: this research provides a good indication of the likely effect. The likelihood that the effect will be substantially different is moderate.

Low: this research provides some indication of the likely effect. However, the likelihood that it will be substantially different is high.

Very low: this research does not provide a reliable indication of the likely effect. The likelihood that the effect will be substantially different is very high.

Substantially different: a large enough difference that it might affect a decision.

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 2009). We also planned subgroup analysis according to dose of gabapentin, and duration of study if sufficient data were available.

Sensitivity analysis

In the 2014 review we considered a sensitivity analysis for formulation of gabapentin (standard, gastroretentive, slow-release), but there were insufficient data for meaningful analysis, and there were no additional data for these formulations. We planned no other 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 participant level (Tölle 2013). No such data were expected to be available.

Results

Description of studies

Results of the search

In the previous version of this review we considered 36 studies in 37 reports examining oral gabapentin, involving 5483 participants with chronic neuropathic pain in various different conditions, mainly PHN, PDN, or mixed neuropathic pain.

Updated database searches from January 2014 to 17 January 2017 identified 107 potentially relevant reports in CENTRAL, 237 in MEDLINE, and 484 in Embase. No additional studies were identified in clinical trials registries or reference lists of included studies or reviews.

After de-duplication and screening of titles and abstracts, we obtained the full text of seven reports. Of these, we included three new studies, with 468 participants (Atkinson 2016; Cohen 2015; Gong 2008). We also identified one report that was a secondary analysis of a study that was already included (Calkins 2016, see Zhang 2013), and two reports of pooled analyses of two studies that were already included (Freeman 2015 and Metha 2016, see Sang 2013; Wallace 2010).

One study that was previously ongoing has now completed. We could not identify a published article for this study, but we did find a synopsis with some results on the pharmaceutical company's website (NCT00904202). The study satisfied our inclusion criteria and was therefore included in this review (62 participants). We could not find any updated information on the remaining three ongoing studies (Fleckstein 2009; IRCT201212019014N14; NCT00674687).

We reassessed and excluded one study that had been included in the earlier review (Ho 2009). This small (18 participants) cross-over study in small fibre sensory neuropathy used a one-week titration period, followed by one week at the maximum dose and one week of wash-out, then crossed over to repeat the sequence with the other treatment. We excluded it because of the very short treatment periods (only one week at a stable dose), there was some uncertainty about the dosing schedule (although the maximum dose was clearly stated), and participants could take additional gabapentin to a maximum of 1200 mg daily if they required rescue medication and paracetamol was inadequate. There was no information about the use of this additional gabapentin, or how data from participants using it were analysed. Two further studies from the previous review are in conditions not now considered neuropathic pain (Kimos 2007; Van de Vusse 2004).

Figure 1 illustrates the flow of studies for this update.

Included studies

This update therefore includes four additional studies involving 530 participants, bringing the total for the review to 37 studies involving 5914 participants, although not all of the participants took all the study medication, and not all the participants were included in results.

The majority of studies involved participants with PHN and PDN. Other neuropathic pain conditions studied were spinal cord injury, phantom limb pain, cancer, nerve injury pain, CRPS, HIV, and radicular leg pain. Four studies enrolled participants with a mixture of types of neuropathic pain.

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-five studies had a parallel-group design and 12 had a cross-over design (Bone 2002; Gilron 2005; Gilron 2009; Gordh 2008; Gorson 1999; Harden 2013; Levendoglu 2004; Morello 1999; Rao 2007; Rintala 2007; Smith 2005; Tai 2002). 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 25 parallel-group studies involved 5298 participants (mean 204, median 162 participants, range 26 to 452), while the 12 cross-over studies involved 621 participants (mean 48, median 40 participants, range 14 to 120). Not all studies reported the results on an ITT basis, and this was particularly the case for cross-over studies with multiple comparisons.

Twenty-eight studies either described enrolment processes that were not enriched, or had no exclusion criteria that would raise the possibility of enrichment (Straube 2008). Seven studies were partially enriched (Caraceni 2004; Irving 2009; Rice 2001; Sang 2013; Serpell 2002) or excluded participants with previous inadequate response to treatment with gabapentin or pregabalin as an exclusion criterion, which may have led to enrichment (Cohen 2015; Wallace 2010). Two studies enriched for tolerance to gabapentin, but not response (Backonja 2011; Harden 2013), which is probably equivalent to partial enrichment. Participants in these two studies were treated with gabapentin encarbil, a prodrug of gabapentin; these are analysed alongside the other studies, but with a view to sensitivity analysis.

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). Thirty-one studies either made no mention of an imputation method for missing data (19) or declared use of LOCF (12). Others performed analyses on completers only (Atkinson 2016 (for responder analysis); Rintala 2007), and one presented results without imputation (Rao 2007).

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

Excluded studies

We excluded 25 studies from this review. The earlier review excluded 21 studies because they were open-label studies, were studies in chronic conditions not considered for this review, investigated related acute conditions or preventive strategies, or did not have an appropriate comparator.

We excluded one new study because it did not have an appropriate comparator and did not appear to be blinded (Ding 2014). We reassessed and excluded three previously included studies, one because of its short duration, use of gabapentin as rescue medication, and unclear methods of analysis (Ho 2009), and two because definitions of chronic neuropathic pain had changed, and these two were now outside the current definitions (Kimos 2007; Van de Vusse 2004).

Risk of bias in included studies

The risk of bias assessments identified that adequate sequence generation and allocation concealment were often inadequately reported. Additional risk of bias also derived from studies being small, and rarely describing how efficacy data were handled on withdrawal (Figure 2).

Figure 2.

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

Allocation

All studies were described as randomised, but only 22 adequately described the method used to generate the random sequence. Only 19 adequately described how the sequence was concealed. We judged studies with inadequate descriptions at unclear risk, although in most cases the methods were probably adequate but not reported.

Blinding

All studies were described as double-blind (participants, who also assessed outcomes, and personnel), but six did not adequately describe the method used to achieve and maintain blinding (Gorson 1999; Harden 2013; Mishra 2012; Perez 2000; Sandercock 2012; Simpson 2001). We judged studies with inadequate descriptions at unclear risk, although in most cases the methods were probably adequate but not reported.

Incomplete outcome data

We judged four studies at high risk of bias because they reported only on participants who completed treatment phases (Atkinson 2016; Rintala 2007), did not report groups or reasons for withdrawal and used LOCF imputation where there was 7% attrition (Gong 2008), or did not report all expected outcomes in the results synopsis and used LOCF imputation (NCT00904202). We judged five studies at low risk of bias for this domain (Rao 2007; Rauck 2013b; Sandercock 2012; Sang 2013; Wallace 2010), and the remaining 28 at unclear risk, mainly because they used LOCF imputation for early withdrawals.

Other potential sources of bias

We judged one study to be at low risk of bias due to study size (more than 200 participants each treatment arm; Sang 2013), 18 at unknown risk, with between 50 and 200 participants per treatment arm, and 18 of the included studies at high risk of bias due to study size smaller than 50 participants per treatment arm.

Effects of interventions

See: Summary of findings for the main comparison Gabapentin compared with placebo for postherpetic neuralgia: efficacy; Summary of findings 2 Gabapentin compared with placebo for peripheral diabetic neuropathy: efficacy; Summary of findings 3 Gabapentin compared with placebo for neuropathic pain (all conditions pooled): adverse events and withdrawals

Appendix 7 contains details of withdrawals, efficacy, and adverse events in the individual studies.

Efficacy

We report efficacy results where data were available, or where there was sufficient information to justify analysis, defined as information from 200 participants or more, ideally from at least two studies.

Analyses 1.1 to 1.5 show results for the following outcomes: at least 50% reduction in pain (Analysis 1.1; Figure 3); Patient Global Impression of Change (PGIC) very much improved (Analysis 1.2; Figure 4); PGIC much or very much improved (Analysis 1.3; Figure 5); IMMPACT outcome of substantial improvement in pain (Analysis 1.4; Figure 6); IMMPACT outcome of at least moderate improvement in pain (Analysis 1.5; Figure 7).

Figure 3.

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

Figure 4.

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

Figure 5.

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

Figure 6.

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

Figure 7.

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

Postherpetic neuralgia (PHN)

Of the 11 studies in PHN, nine (Backonja 2011; Gong 2008; 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 nine 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 mg to 3600 mg daily.

In seven studies reporting the outcome, at least 50% pain intensity reduction occurred in 33% of participants given gabapentin and 19% of those given placebo by the end of the study, with considerable consistency between studies (Summary of results A; Figure 8). 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 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 8.

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

Only two of these studies (Gong 2008; Rice 2001; 24% of participants) used a standard formulation of gabapentin, and removing them from the analysis did not significantly change the result. Similarly, removing the two studies using gabapentin encarbil (Backonja 2011; Zhang 2013; 21% of participants) did not affect the result. There were insufficient data for subgroup analyses based on dose or duration of studies.

We assessed the quality of evidence as moderate. Results were consistent between studies, but there were uncertainties and differences between dosing and dosing schedules, formulation, and imputation methods used.

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 reduction7203133191.7 (1.4 to 2.0)6.9 (5.5 to 9.4)
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)8226032171.8 (1.5 to 2.1)6.7 (5.4 to 8.7)
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 25% pain intensity reduction or PGIC much or very much improved)8226046251.8 (1.6 to 2.0)4.8 (4.1 to 6.0)

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%) with gabapentin and 14/38 (37%) with 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 participants given gabapentin and 21% of those given placebo by the end of the study, with considerable consistency between studies (Summary of results B; 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 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. We obtained very similar results when we omitted data from Simpson 2001 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 9.

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.

We assessed the quality of evidence as moderate. Results were consistent between studies, but there were uncertainties and differences between dosing and dosing schedules, formulation, and imputation methods used.

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.

Four studies examined the effects of oral gabapentin in mixed neuropathic painful conditions (Gilron 2005; Gilron 2009; NCT00904202; Serpell 2002); two included participants with PHN and PDN (Gilron 2005; Gilron 2009); in another the most common conditions were CRPS and PHN (Serpell 2002); and the fourth study enrolled participants with PHN, DN, CRPS, carpel tunnel syndrome, HIV neuropathy, idiopathic sensory neuropathy, and other peripheral neuropathy (proportions not reported, NCT00904202). One had a parallel-group comparison with placebo over eight weeks (Serpell 2002), and one had a parallel-group comparison with placebo, lidocaine patch, and gabapentin in combination with lidocaine patch over five weeks (NCT00904202). 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).

One parallel-group comparison with placebo used gabapentin titrated to a maximum of 2400 mg daily in 305 participants (Serpell 2002). 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)not calculated

The other parallel-group comparison used gabapentin titrated to 1800 mg daily over one week in 62 participants (NCT00904202), and did not report any of our specified efficacy outcomes. It did report the group mean change in pain intensity at the end of the study as 44% for gabapentin alone, 39% for lidocaine patch alone, 50% for the combination, and 26% for placebo (ITT analysis assumed). The number of participants who were satisfied or very satisfied with treatment were 65% for gabapentin alone, 69% for lidocaine patch alone, 69% for the combination, and 64% for placebo. There were no statistically significant differences between treatment groups.

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 reliefStudiesParticipantsGabapentin, morphine, of their combinationPlaceboRisk ratio
(95% CI)
NNT
(95% CI)
Gabapentin alone19661252.5 (1.5 to 4.2)not calculated
Morphine alone19680253.2 (1.9 to 5.2)not calculated
Gabapentin plus morphine19378253.1 (1.9 to 5.1)not calculated

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.

We assessed the quality of evidence as very low with a small number of studies, participants, and events.

Radicular leg pain

One study compared gabapentin, titrated to a maximum of 3600 mg daily, with placebo over 12 weeks in 108 participants, 46 of whom had radicular pain (Atkinson 2016). Although results were not reported separately for these participants, the investigators did report that there was no difference between those with and without radicular pain. In an exploratory analysis of completers, 36% of participants in both groups reported a 30% or more decrease in pain intensity, and 26% and 29% reported a 50% or more decrease with gabapentin (34 participants) and placebo (38 participants), respectively. There was also no difference between groups for 'patient estimation of pain improvement' at the end of the study.

Another study compared gabapentin, titrated to a target of 1800 to 3600 mg daily, with epidural steroid over three months (Cohen 2015). The study reported only group mean decreases in average and worst leg pain at the end of treatment, which ranged from 1.6 to 2.7, with large variation within groups. There were no significant differences between the groups.

We assessed the quality of evidence as very low with a small number of studies, participants, and events.

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).

We assessed the quality of evidence as very low with a small number of studies, participants, and events.

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%) with gabapentin and 9 (9%) with placebo, which did not reach statistical significance. At least 30% pain intensity reduction was achieved by 29 (29%) with gabapentin and 19 (19%) with placebo, which did not reach statistical significance.

We assessed the quality of evidence as very low with a small number of studies, participants, and events.

Phantom limb pain

Two cross-over studies evaluated the efficacy of gabapentin compared with placebo in phantom limb pain (Bone 2002; Smith 2005). 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. 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.

We assessed the quality of evidence as very low with a small number of studies, participants, and events.

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 or 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 (Mishra 2012). 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.

We assessed the quality of evidence as very low with a small number of studies, participants, and events.

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.

We assessed the quality of evidence as very low with a small number of studies, participants, and events.

Withdrawals (see Summary of results E)

We pooled data from participants with different types of neuropathic pain for analyses of withdrawals.

All-cause withdrawals

Twenty-two studies with 4617 participants reported on withdrawals for any cause, which occurred in 20% of participants with gabapentin at daily doses of 1200 mg or more, and in 19% with placebo (Analysis 2.1). The risk ratio was 1.0 (0.92 to 1.2). The NNH was not calculated.

Adverse event withdrawals

Twenty-two studies with 4346 participants reported on adverse event withdrawals, which occurred in 11% of participants with gabapentin at daily doses of 1200 mg or more, and in 8.2% with placebo (Analysis 2.2). The risk ratio was 1.4 (1.1 to 1.7), and the NNH was 30 (20 to 66).

Lack of efficacy withdrawals

Fifteen studies with 3559 participants reported on lack of efficacy withdrawals, which occurred in 1.9% of participants with gabapentin at daily doses of 1200 mg or more, and in 3.3% with placebo (Analysis 2.3). The risk ratio was 0.57 (0.37 to 0.88), and the number needed to treat to prevent one withdrawal (NNTp) NNTp was 73 (41 to 360).

We assessed the quality of evidence for withdrawals as high, based on a reasonable number of events and generally good reporting.

Adverse events (see Summary of results E)

We pooled data from participants with different types of neuropathic pain for analyses of adverse events.

Participants experiencing at least one adverse event

Eighteen studies with 4279 participants reported on participants experiencing at least one adverse event, which occurred in 63% of participants with gabapentin at daily doses of 1200 mg or more, and in 49% with placebo (Analysis 3.1). The risk ratio was 1.3 (1.2 to 1.4), and the NNH was 7.5 (6.1 to 9.6). We assessed the quality of evidence as moderate, based on a reasonable number of events and consistency, but limited quality of reporting adverse events.

Serious adverse events

NIneteen studies reported on 3948 participants experiencing a serious adverse event, which occurred in 3.2% of participants with gabapentin at daily doses of 1200 mg or more, and in 2.8% with placebo (Analysis 3.2). The risk ratio was 1.2 (0.83 to 1.7). The NNH was not calculated. We assessed the quality of evidence as moderate due to the limited number of events.

Particular adverse events

Somnolence, drowsiness, or sedation was reported as an adverse event in 20 studies with 4288 participants, and it occurred in 14% of participants with gabapentin at doses of 1200 mg daily or more, and in 5.2% with placebo (Analysis 3.3). The risk ratio was 2.8 (2.3 to 3.5), and the NNH was 11 (9.4 to 14).

Dizziness was reported as an adverse event in 21 studies with 4739 participants, and it occurred in 19% of participants with gabapentin at doses of 1200 mg daily or more, and in 6.6% with placebo (Analysis 3.4). The risk ratio was 2.9 (2.4 to 3.4), and the NNH was 8.0 (7.0 to 9.4).

Peripheral oedema was reported as an adverse event in 12 studies with 3325 participants, and it occurred in 6.7% of participants with gabapentin at doses of 1200 mg daily or more, and in 1.7% with placebo (Analysis 3.5). The risk ratio was 4.1 (2.7 to 6.4), and the NNH was 20 (16 to 27).

We assessed the quality of evidence for these outcomes as moderate. While there was a reasonable number of events, definitions of adverse events and reporting was not consistent.

Ataxia or gait disturbance was reported as an adverse event in four studies with 510 participants. It occurred in 14% of participants with gabapentin at doses of 1200 mg daily or more, and in 2.6% with placebo (Analysis 3.6). The risk ratio was 5.5 (2.5 to 12), and the NNH was 8.5 (6.1 to 14).

We assessed the quality of evidence for ataxia as low. There was a small number of studies and events.

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-cause22461720191.0 (0.91 to 1.2)Not calculated
Withdrawal due to adverse events224346118.21.4 (1.1 to 1.7)30 (20 to 66)
At least one adverse event18427963491.3 (1.2 to 1.4)7.5 (6.1 to 9.6)
Serious adverse event1939483.22.81.2 (0.83 to 1.7)Not calculated
Somnolence/drowsiness204288145.22.8 (2.3 to 3.5)11 (9.4 to 14)
Dizziness214739196.62.9 (2.4 to 3.4)8.0 (7.0 to 9.4)
Peripheral oedema1233256.71.74.1 (2.7 to 6.4)20 (16 to 27)
Ataxia/gait disturbance4510142.65.5 (2.5 to 12)8.5 (6.1 to 14)
Outcome Studies Participants Gabapentin Placebo Risk ratio
(95% CI)
NNTp
(95% CI)
Withdrawal - lack of efficacy1535591.93.30.57 (0.37 to 0.88)73 (41 to 360)
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. We assessed the quality of evidence as very low due to the very small number of events.

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 for an additional beneficial outcome (NNTs) were between 5 and 7 for substantial and at least moderate improvement in PHN and PDN (moderate-quality evidence). Results were consistent across the major neuropathic pain conditions tested, though gabapentin was tested only in small numbers in uncommon neuropathic pain conditions. 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. 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 (high-quality evidence), and participants taking gabapentin experienced more adverse events (high-quality evidence), including somnolence, dizziness, peripheral oedema, and gait disturbance than did those taking placebo (moderate-quality evidence). Serious adverse events were no more common with gabapentin than placebo (moderate-quality evidence), and death was an uncommon finding in these studies (very low-quality evidence).

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 equivalent to one or both of the IMMPACT outcomes of at least moderate or substantial benefit. Clearly, analysis at the level of the individual participant would facilitate a more robust estimate (Moore 2013a). Such analysis can also demonstrate a link between benefit in terms of pain and benefit in other outcomes, including quality of life (Hoffman 2010).

Possible sources of bias that could have affected the results of the review included the following.

  • Duration - NNT estimates of efficacy in chronic pain studies tend to increase (get worse) with increasing duration (Moore 2010e). 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 25 parallel-group studies involved 5298 participants (median 204), while the 12 cross-over studies involved 621 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 the number of participants with zero benefit would be 2448 for a moderate response and 1113 for a substantial response in PHN, and 741 for a moderate response and 887 for a substantial response in PDN. With median study size for parallel-group studies of about 200 participants, this would require a minimum of seven unavailable studies in PHN and four in PDN. While not impossible, this seems unlikely given the paucity of new data in the last three years.

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 overestimate treatment effects when adverse event withdrawals with drug are 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 2014b).

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), and 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 (McQuay 1996; Moore 2010a; Moore 2013a). This study design can provide useful and clinically relevant information, such as the relatively rapid onset of effect of therapies in neuropathic pain, or how individual patients respond to several different drugs. However, they are difficult to include in pooled analyses, and their small size and brevity come with significant potential biases. Small size has become a particular issue, with increasing association of small study size with positive bias (Dechartres 2013; Dechartres 2014; Fanelli 2017; Nguyen 2017). Cochrane Reviews have received criticism for being overly confident with inadequate data (AlBalawi 2013; Brok 2009; Roberts 2015; Turner 2013).

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 people may respond to one drug, but not another (Moore 2013b).

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 participant-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 less than 10% at week 5 was the best early predictor of lack of response at week 10 (Jensen 2012).

While there was considerable information about withdrawals and adverse events, rare but serious adverse events could not be addressed in these studies. 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. Moreover, the included studies did not address gabapentin misuse (Evoy 2017; Quintero 2017).

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, appropriate analysis of data for participants who withdrew, and 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 participant analysis could overcome some of the shortcomings of reporting.

Potential biases in the review process

We know of no potential biases in the review process.

Agreements and disagreements with other studies or reviews

The results for neuropathic pain in this review have not changed noticeably since the last updates in 2014 and 2011.

Summary of results F. Comparison of NNTs (95% CI) from previous and present reviews

 2005 review2011 update2014 Update2017 update
OutcomesAny improvement

IMMPACT

moderate benefit

IMMPACT

substantial benefit

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 reviewNot 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)5 (5 to 6)7 (6 to 9)
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)7 (5 to 10)6 (5 to 9)

Other systematic reviews

A number of guidelines based on systematic reviews have concluded that gabapentin is helpful in neuropathic pain (Finnerup 2015; Moulin 2014; NICE 2013; SIGN 2013). In PHN, a systematic review found that higher gabapentin doses may not provide greater benefit, but may increase the risk of adverse events (Wang 2017).

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 have NNTs in the region of 5 to 6 for at least 50% pain relief over eight to 12 weeks compared with placebo in PHN and PDN (Lunn 2009; Moore 2009; 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 gave 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 review 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. 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 if pain relief is not forthcoming (NICE 2013).

One further review in the public domain (Perry 2008) was performed as part of a legal case in the USA ending in 2009. Perry 2008 considered similar outcomes to this review; NRS or VAS pain score was given hierarchical priority between 50% or greater 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

For people with neuropathic pain

Gabapentin at a dose of 1800 to 3600 mg daily (1200 to 3600 mg gabapentin encarbil) can provide good levels of pain relief to some people with postherpetic neuralgia and peripheral diabetic neuropathy. Evidence for other types of neuropathic pain is very limited. The outcome of at least 50% pain intensity reduction is regarded as a useful outcome of treatment by people with chronic neuropathic pain, 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. Around 3 to 4 out of 10 achieved this degree of pain relief with gabapentin, compared with 1 to 2 out of 10 for placebo. Over half of those treated with gabapentin will not have worthwhile pain relief.

For clinicians

Gabapentin at a dose of 1800 to 3600 mg daily (1200 to 3600 mg gabapentin encarbil) can provide good levels of pain relief to some people with postherpetic neuralgia and peripheral diabetic neuropathy. Evidence for other types of neuropathic pain is very limited. 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. Over half of those treated with gabapentin will not have worthwhile pain relief.

For policy makers

Gabapentin at a dose of 1800 to 3600 mg daily (1200 to 3600 mg gabapentin encarbil) can provide good levels of pain relief to some people with postherpetic neuralgia and peripheral diabetic neuropathy. Evidence for other types of neuropathic pain is very limited. The level of efficacy found for gabapentin is consistent with the efficacy estimates for other drug therapies in these conditions. Over half of those treated with gabapentin will not have worthwhile pain relief.

For funders

Gabapentin at a dose of 1800 to 3600 mg daily (1200 to 3600 mg gabapentin encarbil) can provide good levels of pain relief to some people with postherpetic neuralgia and peripheral diabetic neuropathy. Evidence for other types of neuropathic pain is very limited. The outcome of at least 50% pain intensity reduction is regarded as a useful outcome of treatment by people with chronic neuropathic pain, 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. Around 3 to 4 out of 10 achieved this degree of pain relief with gabapentin, compared with 1 to 2 out of 10 for placebo. Over half of those treated with gabapentin will not have worthwhile pain relief. The level of efficacy found for gabapentin is consistent with the efficacy estimates for other drug therapies in these conditions.

Implications for research

General

The design of studies in neuropathic pain, and the outcomes, are well understood, but as the number of people experiencing good pain relief with gabapentin over the longer term (12 weeks) is likely to be small, an enriched-enrolment randomised-withdrawal (EERW) design might provide the highest sensitivity to detect a signal (Moore 2015c). Since combination therapy for neuropathic pain has been reported to be more effective than monotherapy with any drug (Chaparro 2012), and combination therapy is common clinical practice, studies examining gabapentin in combination with an antidepressant could be of interest. Combinations with strong opioids are likely to be used less, owing to their limited efficacy and known harms. More interesting might be the combined use of gabapentin with tricyclic antidepressants, weak opioids, or tramadol, and examination of the timings and sequencing of these drugs with gabapentin.

More research is warranted into 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.

Design

Reporting of clinically relevant outcomes using appropriate imputation for withdrawal would improve the relevance of the findings for clinical practice. The use of EERW designs for comparison with classic trial designs indicates that good quality EERW designs of long duration may be appropriate for neuropathic pain.

Stratification by phenotype might be an interesting possibility for future studies (Baron 2017), as well as the possibility of measuring pain scores with activity (including dynamic tactile allodynia) versus at rest or on average/worst/best over prior 24 hours. Participant-level data might be of importance in identifying responder clusters and characteristics.

While pain is important, other outcomes relating to function, sleep, fatigue, and quality of life are also important, and are probably closely linked (Hoffman 2010). Participant-level data could shed light on these relationships.

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 people 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 2010f).

Measurement (endpoints)

Assessment of neuropathic pain and other symptoms should be based on dichotomous participant-reported outcomes of proven clinical utility.

Comparison between active treatments

There seems little point in comparing gabapentin directly with other treatments; the issue is what works for whom.

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 previous versions and provided considerable help and guidance throughout.

We are extremely grateful to Ke Deng for timely help with translation and data extraction for one of the included studies (Gong 2008).

The review followed the agreed template for neuropathic pain, which was developed in collaboration with Cochrane Musculoskeletal and Cochrane Neuromuscular Diseases. The editorial process was managed by Cochrane Pain, Palliative and Supportive Care.

Cochrane Review Group funding acknowledgement: this project was supported by the National Institute for Health Research, via Cochrane Infrastructure funding to Cochrane Pain, Palliative and Supportive Care (PaPaS). The views and opinions expressed therein are those of the authors and do not necessarily reflect those of the Systematic Reviews Programme, NIHR, NHS or the Department of Health.

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 neuralgia72031Risk Ratio (M-H, Fixed, 95% CI)1.69 [1.43, 2.00]
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]
2 Very much improved6 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 Nerve injury pain1196Risk Ratio (M-H, Fixed, 95% CI)3.6 [1.39, 9.31]
3 Much or very much improved14 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]
4 IMMPACT outcome of substantial improvement17 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
4.1 Postherpetic neuralgia82260Risk Ratio (M-H, Fixed, 95% CI)1.75 [1.49, 2.07]
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 Nerve injury pain1196Risk Ratio (M-H, Fixed, 95% CI)1.44 [0.65, 3.22]
4.5 Phantom pain148Risk Ratio (M-H, Fixed, 95% CI)2.6 [1.10, 6.16]
5 IMMPACT outcome of at least moderate improvement18 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
5.1 Postherpetic neuralgia82260Risk Ratio (M-H, Fixed, 95% CI)1.77 [1.56, 2.00]
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 Nerve injury pain1196Risk Ratio (M-H, Fixed, 95% CI)1.53 [0.92, 2.53]
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 withdrawal224617Risk Ratio (M-H, Fixed, 95% CI)1.03 [0.92, 1.16]
2 Adverse event withdrawal224346Risk Ratio (M-H, Fixed, 95% CI)1.38 [1.14, 1.67]
3 Lack of efficacy withdrawal153559Risk Ratio (M-H, Fixed, 95% CI)0.57 [0.37, 0.88]
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 event184279Risk Ratio (M-H, Fixed, 95% CI)1.28 [1.22, 1.36]
2 Serious adverse events193948Risk Ratio (M-H, Fixed, 95% CI)1.19 [0.83, 1.71]
3 Somnolence204288Risk Ratio (M-H, Fixed, 95% CI)2.82 [2.27, 3.50]
4 Dizziness214739Risk Ratio (M-H, Fixed, 95% CI)2.87 [2.40, 3.44]
5 Peripheral oedema123325Risk Ratio (M-H, Fixed, 95% CI)4.12 [2.66, 6.39]
6 Ataxia or gait disturbance4510Risk Ratio (M-H, Fixed, 95% CI)5.53 [2.49, 12.28]
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. Methodological considerations for chronic pain

There have been several changes in how the efficacy of conventional and unconventional treatments is assessed in chronic painful conditions. The outcomes are now 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 of longer duration, 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, and we are now applying stricter criteria for the inclusion of trials and assessment of outcomes, and are more aware of problems that may affect our overall assessment. To summarise some of the recent insights that must be considered in this new review:

  1. Pain results tend to have a U-shaped distribution rather than a bell-shaped distribution. This is true in acute pain (Moore 2011b), back pain (Moore 2010d), and arthritis (Moore 2010e), as well as in fibromyalgia (Straube 2010); in all cases average results usually describe the experience of almost no-one in the trial. Data expressed as averages are potentially misleading, unless they can be proven to be suitable.

  2. As a consequence, we have to depend on dichotomous results (the individual either has or does not have the outcome) usually from pain changes or patient global assessments. The Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) group has helped with their definitions of minimal, moderate, and substantial improvement (Dworkin 2008). In arthritis, trials of less than 12 weeks' duration, and especially those shorter than eight weeks, overestimate the effect of treatment (Moore 2010d); the effect is particularly strong for less effective analgesics, and this may also be relevant in neuropathic-type pain.

  3. The proportion of people with at least moderate benefit can be small, even with an effective medicine, falling from 60% with an effective medicine in arthritis to 30% in fibromyalgia (Moore 2009; Moore 2010d; Moore 2010e; Moore 2013b; Moore 2014b; Straube 2008; Sultan 2008). One 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 2009). 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 reasons for doing so.

  4. Individual patient analyses indicate that people who get good pain relief (moderate or better) have major benefits in many other outcomes, affecting quality of life in a significant way (Moore 2010c; Moore 2014b).

  5. Imputation methods such as last observation carried forward (LOCF), used when participants withdraw from clinical trials, can overstate drug efficacy especially when adverse event withdrawals with drug are greater than those with placebo (Moore 2012a).

Appendix 2. CENTRAL search strategy

  1. (gabapentin* or neurontin* or neurotonin*):TI,AB,KY (1184)

  2. MESH DESCRIPTOR Neuralgia EXPLODE ALL TREES (718)

  3. MESH DESCRIPTOR Peripheral Nervous System Diseases EXPLODE ALL TREES (2963)

  4. MESH DESCRIPTOR Somatosensory Disorders EXPLODE ALL TREES (796)

  5. ((pain* or discomfort*) adj10 (central or complex or nerv* or neuralg* or neuropath*)):TI,AB,KY (3931)

  6. ((neur* or nerv*) adj6 (compress* or damag*)):TI,AB,KY (732)

  7. 2 OR 3 OR 4 OR 5 OR 6 (7377)

  8. 1 AND 7 (215)

  9. 01/01/2014 TO 16/01/2017:CD (269940)

  10. 8 AND 9 (107)

Appendix 3. MEDLINE (via OVID) search strategy

  1. (gabapentin* or neurontin* or neurotonin*).mp. (5327)

  2. exp NEURALGIA/ (18298)

  3. exp PERIPHERAL NERVOUS SYSTEM DISEASES/ (142504)

  4. exp SOMATOSENSORY DISORDERS/ (20859)

  5. ((pain* or discomfort*) adj10 (central or complex or nerv* or neuralg* or neuropath*)).mp. (50119)

  6. ((neur* or nerv*) adj6 (compress* or damag*)).mp. (59288)

  7. 2 or 3 or 4 or 5 or 6

  8. randomized controlled trial.pt. (484826)

  9. controlled clinical trial.pt. (97360)

  10. randomized.ab. (371343)

  11. placebo.ab. (182076)

  12. drug therapy.fs (2092559)

  13. randomly.ab. (255301)

  14. trial.ti. (167136)

  15. groups.ab (1572017)

  16. 8 or 9 or 10 or 11 or 12 or 13 or 14 or 15 (3937255)

  17. 1 and 7 and 16 (1363)

  18. limit 17 to yr="2014 -Current" (237)

Appendix 4. Embase (via OVID) search strategy

  1. gabapentin/ (25201)

  2. (gabapentin* or neurontin* or neurotonin*).mp. (35892)

  3. 1 or 2 (25892)

  4. exp neuralgia/ (93025)

  5. exp peripheral neuropathy/ (62561)

  6. exp somatosensory disorder/ (83900)

  7. ((pain* or discomfort*) adj10 (central or complex or nerv* or neuralg* or neuropath*)).mp. (94901)

  8. ((neur* or nerv*) adj6 (compress* or damag*)).mp. (81121)

  9. 4 or 5 or 6 or 7 or 8 (330939)

  10. clinical trial/ (1025277)

  11. controlled clinical trial/ (468659)

  12. randomized controlled trial/ (469523)

  13. double-blind procedure/ (140238)

  14. (clin* adj25 trial*).mp. (1445057)

  15. ((doubl* or trebl* or tripl*) adj25 (blind* or mask*)). mp. (222270)

  16. placebo*.ti.ab. (252536)

  17. random*.ti,ab. (1172190)

  18. 10 or 11 or 12 or 13 or 14 or 15 or 16 or 17 (2247471)

  19. 3 and 9 and 18 (2998)

  20. limit 19 to yr="2014 -Current" (484)

Appendix 5. 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 participants per treatment arm50 to 199 participants per treatment arm≥ 200 participants per treatment arm

Appendix 6. GRADE: criteria for assigning grade of evidence

The GRADE system uses the following criteria for assigning a quality level to a body of evidence (Cochrane Handbook of Systematic Reviews of Interventions, Chapter 12, Schünemann 2011b).

  1. High: randomised trials; or double-upgraded observational studies

  2. Moderate: downgraded randomised trials; or upgraded observational studies

  3. Low: double-downgraded randomised trials; or observational studies

  4. Very low: triple-downgraded randomised trials; or downgraded observational studies; or case series/case reports

Factors that may decrease the quality level of a body of evidence are:

  1. limitations in the design and implementation of available studies suggesting high likelihood of bias;

  2. indirectness of evidence (indirect population, intervention, control, outcomes);

  3. unexplained heterogeneity or inconsistency of results (including problems with subgroup analyses);

  4. imprecision of results (wide confidence intervals);

  5. high probability of publication bias.

Factors that may increase the quality level of a body of evidence are:

  1. large magnitude of effect;

  2. all plausible confounding would reduce a demonstrated effect or suggest a spurious effect when results show no effect;

  3. dose-response gradient.

Appendix 7. Summary of outcomes in individual studies

StudyWithdrawalsEfficacyAdverse events
(general)
Adverse events
(specific)
Postherpetic neuralgia
Backonja 2011

All-cause withdrawal
GabaEn 2/47
Placebo 7/54

AE withdrawal
GabaEn 0/47
Placebo 4/54 (inc pain 2, dizziness 1, noncardiac chest pain 1)

No LoE withdrawals in double-blind phase

Gabapentin phase (titration)
AE withdrawal 3/116 (4 later: dizziness 2, lethargy 1, tachycardia 1)
LoE withdrawal 1/116

At least 30% reduction in pain
GabaEn 26/47
Placebo 15/54

At least 50% reduction in pain
GabaEn 13/47
Placebo 10/54

PGIC much and very much improved
GabaEn 20/47
Placebo 7/54
At least one AE
GabaEn 25/47
Placebo 25/47

No SAE

No deaths

In gabapentin phase 48/115 had ≥ one AE
Dizziness
GabaEn 10/47
Placebo 3/54
Nausea
GabaEn 5/47
Placebo 2.54
Headache
GabaEn 4/47
Placebo 4/54
Diarrhoea
GabaEn 3/47
Placebo 1/54
Fatigue
GabaEn 2/47
Placebo 4/54

In gabapentin phase
dizziness 16/115, nausea 2, headache 5, diarrhoea 4, fatigue 2
Chandra 2006All-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
Gabapentin 4/38
Nortriptyline 6/38

Giddiness
Gabapentin 1/38
Nortriptyline 0/38
Gong 200816 participants withdrew because of AEs, lack of
analgesic effect, or other reasons

No further details
25% to ≤ 50% pain relief
Gabapentin 45/109
Placebo 13/106

≥ 50% pain relief
Gabapentin 30/109
Placebo 4/106

"Patient evaluation"
"Mild effective"
Gabapentin 37/109
Placebo 28/106
"Excellent"
Gabapentin 48/109
Placebo 5/106

At least one AE

Gabapentin 78/109
Placebo 31/106

Most appeared in the first week, and symptoms relieved gradually as the treatment continued

Dizziness

Gabapentin 27/109

Placebo 10/106

Somnolence

Gabapentin 19/109

Placebo 3/106

Peripheral oedema

Gabapentin 6/109

Placebo 1/106

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 Gabapentin 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

Irving 2009All-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
Gabapentin 1800 single dose 14/55
Gabapentin 1800 split dose 15/52
Placebo 6/51

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

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

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

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

Dizziness
Gabapentin 1800 single dose: 12/55
Gabapentin 1800 split dose: 6/52
Placebo: 5/51

Gait disturbance
Gabapentin 1800 single dose: 4/55
Gabapentin 1800 split dose: 2/52
Placebo: 0/51

Peripheral oedema
Gabapentin 1800 single dose: 4/55
Gabapentin 1800 split dose: 1/52
Placebo: 0/51
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
No significant difference between Gabapentin and cream
Cream marginally better than placebo

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

No SAE
Assume no deaths
Vertigo
Gabapentin 2/144
Cream 7/144
Placebo 1/76
No other AEs reported
Rice 2001Gabapentin 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
Gabapentin 1800: 37/115
Gabapentin 2400: 37/108
Placebo: 16/111

PGIC very much or much improved
Gabapentin 1800: 44/115
Gabapentin 2400: 42/108
Placebo: 24/111

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

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

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

SAE
Gabapentin 1800: 3/115
Gabapentin 2400: 1/108
Placebo: 1/111

Death:
Gabapentin 1800: 0/115
Gabapentin 2400: 1/108
Placebo: 0/111
Somnolence
Gabapentin 1800: 20/115
Gabapentin 2400: 22/108
Placebo: 7/111

Dizziness
Gabapentin 1800: 36/115
Gabapentin 2400: 36/108
Placebo: 11/111

Asthenia
Gabapentin 1800: 7/115
Gabapentin 2400: 6/108
Placebo: 4/111

Peripheral oedema
Gabapentin 1800: 6/115
Gabapentin 2400: 12/108
Placebo: 0/111
Rowbotham 1998Gabapentin
All-cause 24
AE 21
LoE 0

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

PGIC CTR much improved
Gabapentin: 21/113
Placebo: 6/116

PGIC CTR moderately improved
Gabapentin: 26/113
Placebo: 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
Gabapentin 84/113
Placebo 60/116

Minor AE (treatment-related)
Gabapentin: 62/113
Placebo: 32/116

SAE (treatment-related)
Gabapentin: 0/113 (10/113 CTR)
Placebo: 0/116 (5/116 CTR)

Death:
Gabapentin: 0/113
Placebo: 1/116
Somnolence
Gabapentin: 31/113
Placebo: 6/116

Dizziness
Gabapentin: 27/113
Placebo: 6/116

Ataxia
Gabapentin: 8/113
Placebo: 0/116

Peripheral oedema
Gabapentin: 11/113
Placebo: 4/116
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

Wallace 2010

y

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
Gabapentin 155/272
Placebo 64/133

Serious AE
Gabapentin 10/272
Placebo 4/133

Deaths
Gabapentin 0/272
Placebo 1/133

Dizziness
Gabapentin 34/272
Placebo 4/133

Somnolence
Gabapentin 13/272
Placebo 3/133

Peripheral oedema
Gabapentin 13/272
Placebo 0/133

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 1998All-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
Gabapentin 70/84
Placebo 54/81

Serious AE
Gabapentin 3/84
Placebo 2/81

Deaths
Gabapentin  0/84
Placebo  0/81
Dizziness
Gabapentin 20/84
Placebo 4/81

Somnolence
Gabapentin 19/84
Placebo 5/81
CTR 945-224

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
Gabapentin 159/200
Placebo 126/189

Serious AE
Gabapentin 15/200
Placebo 15/189

Deaths
Gabapentin 1/200
Placebo 1/189
Somnolence
Gabapentin 31/200
Placebo 8/189

Dizziness
Gabapentin 38/200
Placebo 15/189

Asthenia
Gabapentin 22/200
Placebo 8/189

Peripheral oedema
Gabapentin 33/200
Placebo 7/189

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
Gabapentin 12/40
Placebo 4/40

Serious AE
Gabapentin 0/40
Placebo 0/40

Deaths (inferred)
Gabapentin 0/40
Placebo 0/40
 
Morello 1999All-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
Gabapentin 12/23
Amitriptyline 8/24

Dizziness
Gabapentin 7/23
Amitriptyline 2/24

Ataxia
Gabapentin 5/23
Amitriptyline 2/24

Peripheral oedema
Gabapentin 3/23
Amitriptyline 2/24
Perez 2000No 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
Rauck 2013aAll-cause withdrawal
GabaEn1200 15/62
GabaEn 2400 19/56
GabaEn 3600 38/117
Pregab 300 19/66
Placebo 30/120

AE withdrawal
GabaEn1200 5/62
GabaEn 2400 12/56
GabaEn 3600 21/117
Pregab 300 6/66
Placebo 11/120

LoE withdrawal
GabaEn1200 2/62
GabaEn 2400 0/56
GabaEn 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
GabaEn1200 26/62
GabaEn 2400 15/56
GabaEn 3600 46/117
Pregab 300 14/66
Placebo 35/120

At least 30% reduction in pain by end M week 12
GabaEn1200 31/62
GabaEn 2400 25/56
GabaEn 3600 66/117
Pregab 300 28/66
Placebo 57/120
At least 1 AE
GabaEn1200 45/62
GabaEn 2400 38/56
GabaEn 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
GabaEn1200 9/62
GabaEn 2400 8/56
GabaEn 3600 16/117
Pregab 300 9/66
Placebo 7/120

Somnolence
GabaEn1200 2/62
GabaEn 2400 7/56
GabaEn 3600 16/117
Pregab 300 9/66
Placebo 5/120

Peripheral oedema
GabaEn1200 2/62
GabaEn 2400 0/56
GabaEn 3600 11/117
Pregab 300 3/66
Placebo 5/120

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

Sandercock 2012All-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
Gabapentin (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
Placebo 0/51

Nausea
Gabapentin (1) 2/47
Gabapentin (2) 3/49
Placebo 0/51

Headache
Gabapentin (1) 2/47
Gabapentin (2) 3/49
Placebo 2/51

Simpson 2001All-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
Gabapentin: 15/30
Placebo: 7/30
No deaths reported, and no serious adverse events reportedSomnolence
Gabapentin 6/27
Placebo 1/27

Dizziness
Gabapentin 6/27
Placebo 1/28
Mixed neuropathic pain
NCT00904202AE withdrawals
Gabapentin 6/16
Lidocaine 3/14
Combination 6/16
Placebo 1/16

No statistically significant differences between groups for any efficacy parameter

% pain relief (mean change at end of study):
Gabapentin 43.6%
Lidocaine 39.2%
Combo 50%
Placebo 26.4%

Satisfaction with treatment (satisfied and very satisfied):
Gabapentin 65%
Lidocaine 69%
Combo 69%
Placebo 64%

Overall 61/62 participants reported at least one AE

No deaths

1 SAE (lidocaine (haemorrhagic stroke)
Most frequent AEs were fatigue, dizziness (excluding vertigo), weakness, somnolence, decreased appetite, nausea, confusion, vision blurred

Occurred at similar frequencies in each group except blurred vision (gabapentin 12/16, lidocaine 2/14, combination 8/16, placebo 8/16))
Gilron 200516 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 2009All-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
Serpell 2002All-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
Radicular leg pain
Atkinson 2016All-cause withdrawal
Gabapentin 19/55
Placebo 17/53

AE withdrawal
Gabapentin 7/55
Placebo 5/53

LoE withdrawal
Gabapentin 5/55
Placebo 1/53

Other (?Lost to follow-up):
Gabapentin 7/55
Placebo 11/53

≥ 30% decrease in pain intensity
Gabapentin 36% (n = 34)
Placebo 36% (n = 38)

≥ 50% decrease in pain intensity
Gabapentin 26% (n = 34)
Placebo 29% (n = 38)

No significant differences between those with (n = 46) and without (n = 62) radiating pain

Participant estimation of pain improvement at exit

≥ 30%
Gabapentin 43% (probably n =34)
Placebo 38% (probably n =38)

≥ 50%
Gabapentin 23% (probably n =34)
Placebo 20% (probably n =38)

At least one AE (possibly or probably attributed)
Gabapentin 49/55
Placebo 35/53
Most mild or moderate
Dizziness
Gabapentin 24/55
Placebo 14/53

Fatigue/Asthenia
Gabapentin 27/55
Placebo 15/53

Somnolence (inc sleep)
Gabapentin 21/55
Placebo 11/53

Loss of balance
Gabapentin 18/55
Placebo 2/53

Accomodation disturbance
Gabapentin 19/55
Placebo 3/53

Concentration difficulties
Gabapentin 21/55
Placebo 6/53

Dry mouth
Gabapentin 22/55
Placebo 10/53
Cohen 2015All-cause withdrawal
Gabapentin 40/72
Steroid 30/73

"Negative outcome"
Gabapentin 39/72
Steroid 23/73

"Withdrew"
Gabapentin 0/72
Steroid 7/73

Lost to follow-up
Gabapentin 1/72
Steroid 2/73

Decrease in average leg pain at 3 months
Gabapentin 1.6 (SD 2.7)
Steroid 2.0 (SD 2.6)

Decrease in worst leg pain at 3 months
Gabapentin 2.3 (SD 3.5)
Steroid 2.7 (SD 3.2)

At least one AE (injection-related)
Gabapentin 7/72
Steroid 6/73

At least one AE (drug-related)
Gabapentin 37/72
Steroid 30/73

Sedation/fatigue
Gabapentin 13/72
Placebo 8/73

Cognition
Gabapentin 7/72
Placebo 5/73

Swelling (oedema?)
Gabapentin 3/72
Placebo 0/73

Dizziness
Gabapentin 2/72
Placebo 0/73

Dry mouth
Gabapentin 2/72
Placebo 0/73
Spinal cord injury
Tai 2002Discontinuations
All-cause 7/14
Urinary retention 1/14
Not interpretableNo data
"No significant side effects noted at the maximum dosage"
No data
Levendoglu 2004All completedAverage fall in pain 62% with gabapentin, 13% with placebo

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

Oedema
Gabapentin 3/20
Placebo 0/20
Rintala 200716/38 withdrewNo dichotomous data.
The paper claims statistical superiority of amitriptyline over gabapentin using paired t-tests for 22 participants completing all 3 phases. It also claims no benefit of gabapentin over placebo
No dichotomous dataNo dichotomous data
Nerve injury pain
Gordh 2008All-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
Gabapentin 5/120
Placebo 1/120
Dizziness
Gabapentin 39/120
Placebo 9/120
Phantom
Smith 2005No apparent withdrawals"Meaningful decrease in pain" (top of 5-point scale)
Gabapentin 13/24
Placebo 5/24
No dataNo data
Bone 2002No data on where withdrawals occurredNo dichotomous data
Significant benefit for gabapentin by week 6 for pain
No dataSomnolence
Gabapentin 7/19
Placebo 2/19

Dizziness
Gabapentin 2/19
Placebo 1/19
Cancer-associated neuropathic pain
Caraceni 2004All-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
Gabapentin 35/79
Placebo 10/41
Somnolence
Gabapentin 18/79
Placebo 4/41

Dizziness
Gabapentin 7/89
Placebo  0/41
Rao 2007All-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
Gabapentin 8/91
Placebo 4/89
HIV
Hahn 2004All-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
Gabapentin 12/15
Placebo 2/11

Dizziness
Gabapentin 9/15
Placebo 5/11

Disturbed gait
Gabapentin 7/15
Placebo 3/11
AE: adverse event; CTR: clinical trial report; GabaEn: gabapentin encarbil; GabaEr: gabapentin extended-release; LoE: lack of efficacy; PGIC: Patient Global Impression of Change; QoL: quality of life; SAE: serious adverse event; VAS: visual analogue scale;

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
11 October 2017Review declared as stableSee Published notes.

History

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

DateEventDescription
28 April 2017New search has been performedThis review has been updated to include the results of a new search on 17 January 2017
25 April 2017New citation required but conclusions have not changedNew search resulting in four additional studies (530 participants). Modified inclusion and exclusion criteria, mainly concerned with newer definitions of neuropathic pain resulting in exclusion of three previously included studies
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 citation required but conclusions have not changedAdditional studies did not change efficacy or harm estimates in any clinically significant way
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).

Contributions of authors

For the 2011 update: PW, RAM, and SD wrote the 2011 protocol; PW, SD, and RAM carried out searches, assessed inclusion of papers, and extracted data. RAM wrote up the 2011 review and all authors contributed to the final draft and approved the published version.

For the 2014 update: RAM and SD carried out searches, selected studies, and added new data to the review. TRT and AR commented on clinical aspects relating to gabapentin. All authors contributed to the final draft and approved the published version.

For the 2017 update: RAM and SD carried out searches, selected studies, and added new data to the review. All authors contributed to the final draft and approved the published version.

PW will be responsible for the update.

Declarations of interest

PW: none known

SD: none known

RFB: none known. RFB is a retired specialist pain physician who has managed patients with neuropathic pain.

ASCR: undertakes consultancy and advisory board work for Imperial College Consultants - since June 2013 this has included remunerated work for: Spinifex, Abide, Astellas, Neusentis, Merck, Medivir, Mitsubishi, Aquilas, Asahi Kasei, Relmada, Novartis, and Orion. All consultancy activity relates to consultancy advice on the preclinical/clinical development of drugs for neuropathic pain. Neusentis was a subsidiary of Pfizer. He owned share options in Spinifex Pharmaceuticals which was acquired by Novartis in July 2015. ASCR was a Principal Investigator in the EuroPain consortium. EuroPain has received support from the Innovative Medicines Initiative Joint Undertaking under grant agreement number 115007, resources for which are composed of financial contribution from the European Union's Seventh Framework Programme (FP7/20072013) and European Federation of Pharmaceutical Industries and Associations (EFPIA) companies (www.imieuropain.org). Specifically, research funding for ASCR's laboratory has been received by Imperial College from Pfizer (manufacturer of gabapentin) and Astellas - both these grants were for projects related to improving the validity of animal models of neuropathic pain. ASCR is a site investigator for the Neuropain project, funded by Pfizer via Kiel University - Chief Investigator Prof Ralf Baron. He is Vice-Chair of the International Association for the Study of Pain (IASP) Special Interest Group on Neuropathic Pain (www.neupsig.org) and serves on the Executive Committee of ACTTION (Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks; www.acttion.org).

TRT is a site investigator for the Neuropain project, funded by Pfizer. Since 2014 TRT has consulted with or received lecture fees from pharmaceutical companies related to chronic pain and analgesics: Astellas, Eli Lilly, Grünenthal, Pfizer, and Mundipharma.

TP: none known. TP is a specialist pain physician who has managed patients with neuropathic pain.

RAM has received grant support from Grünenthal relating to individual participant-level analyses of trial data regarding tapentadol in osteoarthritis and back pain (2015) and from Novartis for network meta-analyses in acute pain. He has received honoraria for attending boards with Menarini concerning methods of analgesic trial design (2014), with Novartis (2014) about the design of network meta-analyses, and RB on understanding pharmacokinetics of drug uptake (2015). He has received honoraria from Omega Pharma (2016) and Futura Pharma (2016) for providing advice on trial and data analysis methods.

Sources of support

Internal sources

  • Oxford Pain Relief Trust, UK.

    General institutional support

External sources

  • NHS Cochrane Collaboration Programme Grant Scheme, UK.

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

  • The National Institute for Health Research (NIHR), UK.

    NIHR Cochrane Programme Grant: 13/89/29 - Addressing the unmet need of chronic pain: providing the evidence for treatments of pain.

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 2011a), 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 people with neuropathic pain. 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 the 2014 update we emphasised the difference between first tier and second tier evidence, and also emphasised the differences between conditions now defined as neuropathic pain, and other conditions such as masticatory pain, complex regional pain syndrome-1, and fibromyalgia.

In the 2017 update, we have removed tiers of evidence as these are now largely superceded by GRADE. We have set a minimum study duration of two weeks for this chronic pain condition, in keeping with other reviews in this area that now use only longer duration studies. We are using newer definitions for what constitutes neuropathic pain.

Notes

No new studies likely to change the conclusions are expected. Therefore, this review has now been stabilised following discussion with the authors and editors. If appropriate, we will update the review if new evidence likely to change the conclusions is published, or if standards change substantially which necessitate major revisions.

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Atkinson 2016

Methods

Randomised, double-blind, placebo-controlled, parallel groups, not enriched

Forced titration to target or maximum tolerated dose over 4 weeks, then stable to 12 weeks

Participants

Non-specific back pain with and without a radiating component, back pain primarily in lumbar region. Pain present on daily basis for ≥ 6 months, PI ≥ 2/10, impact on ≥ 2 aspects of daily life
Excluded: major coexisting illness, coexisting pain condition due to other disorders, contraindication to study medication, recent or planned surgery, history of alcohol or substance abuse, major depression, history of psychosis, cognitive impairment, pregnant or lactating

N = 108

Mean age 56 years, 23% women

Initial pain intensity "moderate"
Impact on everyday function "mild to moderate"
Mean duration of back pain 17 (± 15) years

Interventions

Gabapentin to maximum 3600 mg daily, n = 55

Placebo, n = 53

All muscle relaxants, antidepressants, opioids, discontinued ≥ 2 weeks before baseline assessment; NSAIDs permitted

Outcomes

≥ 30% and ≥ 50% reduction in PI

Participants estimation of pain improvement at exit (≥ 30%, ≥ 50%)

Adverse events

Withdrawals

Notes

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

US VA sponsored

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk"Computer-generated randomization tables, stratified by site"
Allocation concealment (selection bias)Low riskRemote allocation from central pharmacy; "sequentially numbered opaque sealed envelope"
Blinding (performance bias and detection bias)
All outcomes
Low riskGabapentin 300 mg over-capsulated and identical placebo capsules
Incomplete outcome data (attrition bias)
Efficacy
High riskUsed random-effects regression models for primary outcome, but reported only on completers (33% attrition)
Size
Efficacy
Unclear risk50-200 participants per treatment arm (55, 53)

Backonja 1998

Methods

Multicentre, randomised, double-blind, placebo-controlled, parallel groups, 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)

Participants

PDN. Pain duration > 3 months before treatment, PI ≥ 40/100 at randomisation

N = 165

Mean age 53 years, 40% women

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 imputation
Size
Efficacy
Unclear risk50-200 participants per treatment arm (81, 84)

Backonja 2011

Methods

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

Open-label titration with gabapentin from 300 mg at night to maximum 600 mg 3 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

Participants

PHN. Pain > 3 months after healing of skin rash. PI at randomisation ≥ 40/100

N = 102 in double-blind phase, and 116 in open-label phase

Mean age 65 years, 51% women

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 imputation
Size
Efficacy
High risk< 50 participants per treatment arm

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. PI before treatment > 3/10

N = 19 (14 completed both treatment periods)

Mean age 56 years, 21% women

Initial pain score 6.4/10

Interventions

Gabapentin 2400 mg daily (max)

Placebo

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

Outcomes

No dichotomous efficacy data

Adverse events

Notes

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

Pfizer Pharmaceuticals supplied gabapentin and placebo capsules. No other funding

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 risk< 50 participants per treatment arm (19 randomised, 14 completed both phases)

Caraceni 2004

Methods

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

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

Participants

Neuropathic cancer pain despite regular systemic opioid therapy. Pain at randomisation ≥ 5/10

N = 121

Mean age 60 years, 56% women

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

Notes

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

Sponsored/Pfizer Italy and Spain

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 risk< 50 participants per treatment arm (41, 80)

Chandra 2006

Methods

Randomised, double-blind, active-controlled, parallel groups, 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)

Participants

PHN. Pain > 2 months after healing of skin rash. PI at randomisation ≥ 40/100

N = 76

Mean age 54 years, 50% women

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
High risk< 50 participants per treatment arm

Cohen 2015

MethodsMulticentre, randomised, double-blind (double-dummy), active-controlled, parallel groups, partial enrichment. Titration to maximum tolerated dose (1800 mg to 3600 mg daily) over 15-24 days (3 months total)
Participants

Radicular leg pain for ≥ 6 weeks and < 4 years, PI ≥ 4/10 or ≥ 3/10 if leg pain ≥ back pain, symptoms of lumbosacral radicular pain. Findings of herniated disc or spinal stenosis on MRI concordant with presentation. Age ≥ 17 years
Excluded: neuropathic pain > 4 years, previous failed trial with gabapentin or pregabalin, steroid injections ≤ 3 years, cauda equina syndrome, planned surgery

N = 145

Mean age 43 years, 26% women
18% had pain ≤ 3 months, 25% taking opioids
Initial PI: worst leg 7.8/10; average leg 5.4/10

Interventions

Gabapentin capsule + saline injection, n = 72

Depomethylprednisolone 60 mg injection + 1 ml 0.25% bupivacaine + placebo capsule, n = 73

Gabapentin titrated to 1800 mg to 3600 mg/day (3 divided doses) over 15-24 days, but ≥ 5 days before follow-up

Steroid injected into epidural space (interlaminar or transforaminal), saline injected into posterior ligaments
Tramadol and NSAIDs "as needed" for rescue medication, or opioids increased by ≥ 20% for those taking them. No other co-interventions

Outcomes

Mean PI, for average and worst leg and back pain

Global evaluation (non-standard scales)

Adverse events

Withdrawals

Notes

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

Congressional grant from the Center for Rehabilitation Sciences Research, Bethesda

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskComputer-generated randomisation tables, stratified by site. Central pharmacy
Allocation concealment (selection bias)Low risk"sequentially numbered opaque sealed envelope"
Blinding (performance bias and detection bias)
All outcomes
Low risk"A central research pharmacy over-capsulated 300 mg gabapentin and placebo capsules to appear identical". Participants "visually shielded from the image screen" during injections", had no further contact with physician
Incomplete outcome data (attrition bias)
Efficacy
Unclear riskLOCF imputation
Size
Efficacy
Unclear risk50-200 participants per treatment arm

CTR 945-1008

Methods

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

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

Participants

PDN. Pain duration > 3 months, PI at randomisation ≥ 40/100

N = 389

Mean age 58 years, "more men than women"

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 imputation
Size
Efficacy
Unclear risk50-200 participants per treatment arm (189, 200)

CTR 945-224

Methods

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

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

Participants

PDN for 1-5 years. PI at randomisation ≥ 40/100

N = 325

Mean age 60 years, 44% women

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 participant completed
Blinding (performance bias and detection bias)
All outcomes
Low riskMatching placebo
Incomplete outcome data (attrition bias)
Efficacy
Unclear riskProbably LOCF
Size
Efficacy
Unclear risk50-200 participants per treatment arm (77-84)

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

Participants

PDN and PHN. Pain ≥ moderate for 3 months

N = 57

Median age 62 years, 44% women

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

Notes

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

Canadian Institutes of Health Research grant. Pharma supplied medicines

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskBalanced Latin-square cross-over 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 risk< 50 participants per treatment arm (data available 40-44 completing a given treatment)

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

Participants

PDN and PHN. Pain ≥ moderate for 6 months

N = 56

Median age 64 years, 40% women

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 (mean)

Withdrawals

Adverse events

Notes

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

Canadian Institutes of Health Research grant. Study drugs from pharma

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskBalanced Latin-square cross-over 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

Gong 2008

Methods

Multicentre, randomised, double-blind, placebo-controlled, parallel groups. No enrichment or imputation method mentioned

Forced titration from 300 mg daily to 1800 mg daily over 8 days, then stable dose to 6 weeks

Participants

PHN

N = 231

Mean age 66 years (± 12), 43% women

Mean baseline PI: 6.2/10 (± 1.3)

Interventions

Gabapentin 1800 mg daily, n = 109

Placebo, n = 106

Rescue medication: 2 x 100 mg tramadol if required 3 days after reaching maximum dose of gabapentin

Outcomes

≥ 25% and ≥ 50% pain relief

PGIC ("mild effective" and "excellent")

Sleep

Quality of life

Adverse events

Notes

Oxford Quality Score: R = 1, DB = 2, W = 0, Total = 4

Unknown funding

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot adequately described. "Patients were randomised to different groups according to their recruitment order", but then refers to "pre-determined code"
Allocation concealment (selection bias)Unclear riskNot adequately described. "Researchers allocated the treatments according to the pre-determined code"
Blinding (performance bias and detection bias)
All outcomes
Low risk"Identical-appearing capsules containing placebo were used to blind the patients"
Incomplete outcome data (attrition bias)
Efficacy
High riskWithdrawals (7%) and reasons for withdrawal not given per treatment group. No information about how data from withdrawals contributed to analyses
Size
Efficacy
Unclear risk50-199 participants per treatment arm (106, 109)

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. PI at randomisation > 30/100

N = 120 (efficacy analysis based on 98 who completed both treatment periods)

Mean age 49 years, 53% women

Initial pain intensity 53/100

Interventions

Gabapentin 2400 mg daily (max)

Placebo

Mean daily dose of gabapentin 2243 mg ± 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

Notes

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

Sponsored by Parke-Davis AB, later Pfizer AB

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskRandomisation 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 risk50-200 participants per treatment arm (98 completed both periods and included in efficacy analysis)

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

Participants

PDN 1-5 years, pain ≥ moderate for over 3 months. Pain intensity at randomisation ≥ 40/100

N = 40

Mean age 62 years, 23% women

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 risk< 50 participants per treatment arm (19, 21)

Hahn 2004

Methods

Randomised, double-blind, placebo-controlled, parallel groups, 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)

Participants

Painful HIV sensory neuropathy by standard definitions. Pain at any level including mild pain at randomisation

N = 26

Mean age 45 years, 23% women

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

Notes

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

Pfizer grant

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 risk< 50 participants per treatment arm (11, 15)

Harden 2013

MethodsRandomised, double blind, cross-over, dose-comparison. Two 4-week treatments plus 4 day washout
Participants

PHN for at least 3 months after rash healing, with inadequate response to gabapentin 1800 mg daily, but no response to either gabapentin or pregabalin

N = 93

Mean age 63 years, 39% women

Mean baseline pain 6/10

InterventionsGabapentin 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 imputation
Size
Efficacy
Unclear risk50-200 participants per treatment arm (93)

Irving 2009

Methods

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

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

Participants

PHN. Pain > 3 months after healing of skin rash, PI at randomisation ≥ 4/10

N = 158, mean age 70 years, 53% women

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 risk50-200 participants per treatment arm (51-55)

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

Participants

Complete traumatic SCI at lumbar or thoracic level. Pain duration before treatment ≥ 6 months, PI at randomisation > 4/10

N = 20

Mean age 36 years, 35% women

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

Notes

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

No funding

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 risk< 50 participants per treatment arm (20)

Mishra 2012

Methods

Randomised, double-blind, active- and placebo-controlled, parallel groups. 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 daily (divided x 2) increasing to 1800 mg daily (divided x 3)

Pregabalin 150 mg daily (divided x 2) increasing to 600 mg daily (divided x 2)

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

Participants

Cancer 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
Notes

Oxford Quality Score: R = 2, DB = 1, W = 0, Total = 3

Funding from Institute Research Grant of All India Institute of Medical Sciences

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 (30)

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

PDN. Pain duration > 3 months before treatment, no initial PI at inclusion

N = 25 (19 completed 6 weeks with both study drugs)

Mean age 60 years, 4% women

Initial pain intensity mild/moderate

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

No funding mentioned

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 risk< 50 participants per treatment arm (25 randomised, 19 completed both periods

NCT00475904

MethodsRandomised, double-blind, double-dummy, placebo-controlled, parallel groups, 4 weeks, not enriched
Participants

PHN ≥ 3 months after healing of rash. Age ≥ 18 years

N = 360

Mean age 53 years, 38% women

Interventions

Gabapentin 1800 mg daily, n = 144

Topical cream with amitriptyline and ketamine, n = 140

Placebo for oral and topical cream, n = 76

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 riskNot reported
Allocation concealment (selection bias)Unclear riskNot reported
Blinding (performance bias and detection bias)
All outcomes
Low riskDouble-dummy method
Incomplete outcome data (attrition bias)
Efficacy
Unclear riskLOCF imputation
Size
Efficacy
Unclear risk50-200 participants per treatment arm (76 to 144)

NCT00904202

Methods

Randomised, double-blinded, double-dummy, parallel groups, not enriched. Forced titration over 1 week

Duration of treatment: 5 weeks

Participants

Various peripheral neuropathic pain conditions (diagnosis of: PHN, PDN, CRPS, carpel tunnel syndrome, HIV neuropathy, idiopathic sensory neuropathy, other peripheral neuropathy). Age ≥ 18 years

N = 62

Age not reported, % women not reported

Baseline PI 4/10

Interventions

Gabapentin titrated to 1800 mg daily over first week + placebo patch, n = 16

Lidocaine patch 5% (up to 4 patches) applied once daily + placebo capsules, n = 14

Gabapentin 1800 mg + lidocaine 5% patch daily, n = 16

Placebo capsules + placebo patch, n = 16

Outcomes

Average daily pain intensity (BPS questions 3, 4, 5, 6)

PGIC

Patient satisfaction

Percent pain relief (BPI question 8)

Adverse events, dermal assessment

Notes

Oxford Quality Score: R = 1, DB = 2, W = 1, Total = 4 (from synopsis)

Endo Pharmaceuticals

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskMethod of sequence generation not reported
Allocation concealment (selection bias)Unclear riskMethod not reported
Blinding (performance bias and detection bias)
All outcomes
Low riskDouble-dummy method
Incomplete outcome data (attrition bias)
Efficacy
High risk2 participants did not provide efficacy data (1 lidocaine, 1 placebo). LOCF for early discontinuation. All outcomes not reported (synopsis)
Size
Efficacy
High risk< 50 participants per treatment arm (14-16)

Perez 2000

Methods

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

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

Participants

PDN. Conventional treatment unsuccessful. PI ≥ 60/100 at randomisation

N = 32

Mean age 54 years, 53% women

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

No funding mentioned

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 risk< 50 participants per treatment arm (15, 17)

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

Participants

Chemotherapy-induced peripheral neuropathy lasting ≥ 1 month. PI at randomisation ≥ 4/10

N = 115

Mean age 59 years, 73% women

Initial average daily pain 4/10

Interventions

Gabapentin 2700 mg daily (max)

Placebo

Usual cancer therapy continued

Outcomes

No dichotomous data

Adverse events

Withdrawals

Notes

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

No funding mentioned

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 risk50-200 participants per treatment arm (115)

Rauck 2013a

MethodsRandomised, double-blind (double-dummy), placebo- and active-controlled, parallel groups, not enriched. Screening 4 weeks, baseline 1 week, up titration 1 week, maintenance 12 weeks, down titration 1 week
Participants

PDN. Pain ≥ 6 months, ≥18 years, PI ≥ 4/10

N = 421

Mean age 59 years, 41% women

Baseline PI 6.5/10

Interventions

Gabapentin encarbil 1200 mg daily, n = 62

Gabapentin encarbil 2400 mg daily, n = 56

Gabapentin encarbil 3600 mg daily, n 117

Pregabalin 300 mg daily, n = 66

Placebo, n = 120

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 method
Incomplete outcome data (attrition bias)
Efficacy
Unclear riskLOCF imputation
Size
Efficacy
Unclear risk50-200 participants per treatment arm

Rauck 2013b

Methods

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

Intrathecal 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

Participants

Chronic intractable pain below neck for ≥ 1 year (86% classified as neuropathic or mixed). PI at screening 5/10

N = 170

Mean age 50 years, 58% women

Baseline PI ≥ 7.5/10

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

Notes

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

Medtronic

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 (41-44)

Rice 2001

Methods

Multicentre, randomised, double-blind, placebo-controlled, parallel groups, 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

Participants

PHN. Pain > 3 months after healing of rash, PI ≥ 40/100 at randomisation

N = 334

Median age 75 years, 59% women

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 imputation
Size
Efficacy
Unclear risk50-200 participants per treatment arm (108-115)

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

Participants

SCI at any level and degree of completeness. Pain duration before treatment > 6 months, PI at randomisation > 5/10

N = 38, only 22 participants completed all 3 cross-overs

Mean age 43 years, 9% women

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

Notes

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

Department of Veterans Affairs grant

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 risk< 50 participants per treatment arm (38 randomised, 22 completed 3 phases)

Rowbotham 1998

Methods

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

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

Participants

PHN. Pain > 3 months after healing of rash, PI at randomisation ≥ 40/100

N = 229

Median age 73 years, 48% women

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 imputation
Size
Efficacy
Unclear risk50-200 participants per treatment arm (113, 116)

Sandercock 2012

Methods

Randomised, double-blind, placebo-controlled, parallel groups, no obvious enrichment

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

Participants

PDN. PI at randomisation ≥ 4/10

N = 147

Mean age 59 years, 45% women

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

No obvious funding, but one author from what may be a pharmaceutical company

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
High risk< 50 participants per treatment arm (46-51)

Sang 2013

Methods

Multicentre, randomised, double-blind, placebo-controlled, parallel groups, 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

Participants

PHN. Pain > 6 months and < 5 years after healing of rash, PI at randomisation ≥ 40/100

N = 452

Mean age 65 years, 63% women

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
Notes

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

Supported by Depomed Inc

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 (221, 231)

Serpell 2002

Methods

Multicentre, randomised, double-blind, placebo-controlled, parallel groups, partial enrichment. No imputation method mentioned. Participants 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%). PI at randomisation ≥ 4/10

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

N = 305

Median age 57 years, 53% women

Initial mean pain score 7.2/10

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 randomisation 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
Unclear risk50-200 participants per treatment arm (152, 153)

Simpson 2001

Methods

Randomised, double-blind, placebo-controlled, parallel groups, 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)

Participants

PDN. Pain duration > 3 months before treatment, PI ≥ 40/100 at randomisation

N = 60

Mean age 50 years, 40% women

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

Notes

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

No funding mentioned

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 risk< 50 participants per treatment arm (30)

Smith 2005

Methods

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

Titration in 300 mg increments every 2-3 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

Participants

Phantom limb pain and residual limb pain. Time since amputation ≥ 6 months, PI before randomisation > 3/10

N = 24

Mean age 52 years, 25% women

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)
Notes

Oxford Quality Score: R = 2, DB = 2, W = 0, Total = 4

No funding mentioned

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 risk< 50 participants per treatment arm (24)

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

Participants

Traumatic spinal cord injury > 30 days. PI before treatment > 4/10

N = 14 (7 participants with data)

Age 27-48 years, 1/7 women

Interventions

Gabapentin 1800 mg daily (max)

Placebo

NSAID, TCA and narcotics allowed for rescue medication as needed

OutcomesWithdrawals
Notes

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

Grants from American Academy of Physical Medicine and Rehabilitation and Eastern Paralyzed Veterans Association

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 risk< 50 participants per treatment arm (7/14 with data)

Wallace 2010

Methods

Randomised, double-blind, placebo-controlled, parallel groups, 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. Total duration 10 weeks

Participants

PHN. Pain at least 3 months after healing of acute herpes zoster skin rash. Initial pain ≥ 4/10

N = 405

Mean age 66 years, 52% women

Mean initial pain 6.5/10

Interventions

Gabapentin ER 1800 mg daily, n = 272

Placebo, n = 133

Outcomes

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

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 risk50-200 per treatment arm (133, 272)

Zhang 2013

  1. a

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

MethodsRandomised, double-blind, placebo-controlled, parallel groups. 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

N = 371

Mean age 62 years, 48% women

Baseline PI 6/10

Interventions

Gabapentin encarbil 1200 mg daily, n = 107

Gabapentin encarbil 2400 mg daily, n = 82

Gabapentin encarbil 3600 mg daily, n = 87

Placebo, n = 95

Outcomes

At least 50% and at least 30% pain intensity reduction by end of maintenance over baseline

PGIC 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 imputation
Size
Efficacy
Unclear risk50-200 per group treatment arm (82-107)

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
Ding 2014Not indexed as blinded. Gabapentin assessed as add-on therapy to transdermal fentanyl
Dworkin 2009Study for acute herpes zoster pain
Ho 2009Short duration (1 week at stable dose), potential use of significant dose of gabapentin as rescue medication
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
Kimos 2007Condition (CRPS 1) not now defined as neuropathic pain
Ko 2010Open comparison of gabapentin and tramadol/paracetamol in painful diabetic neuropathy
McCleane 2001Low back pain, not specifically neuropathic
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
Van de Vusse 2004Condition (masticatory pain) not now defined as neuropathic pain
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

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. Men and women, ≥ 18 years old
InterventionsSemi-standardised acupuncture, sham laser acupuncture, gabapentin with individualised dosage between 900 mg and 3600 mg daily
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"; record verified February 2017

IRCT201212019014N14

Trial name or titleEffect of gabapentin on heart rate variability in diabetic painful peripheral neuropathy: a double blinded randomised clinical trial
MethodsDouble-blinded, randomised controlled trial, parallel groups
ParticipantsDiabetic painful peripheral neuropathy. Men and women, ≥ 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 3 months plus moisturizing cream (as placebo) with a phalanx size 3 times a day for three months

Capsule like gabapentin including starch (as placebo) daily for 3 months plus Kapsycin cream for reducing pain with a phalanx size 3 times a day for 3 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. No further update by February 2017

NCT00674687

  1. a

    VAS: visual analogue scale.

Trial name or titleA study of the efficacy of gabapentin in neuropathic pain patients as measured by quantitative sensory testing
MethodsRandomised, double-blind, cross-over
ParticipantsMen and women, ≥ 18 years old. Neuropathic pain of peripheral origin as a consequence of either postherpetic neuralgia or post-traumatic neuropathic pain. Pain ≥ 4/10 for von Frey filament-evoked allodynia at the skin area
InterventionsGabapentin titrated to 1800 mg daily, placebo
OutcomesPresence/intensity of punctate allodynia (von Frey filament)
Starting dateJuly 2004, completed 2006
Contact informationDirector, Clinical Trial Disclosure Group, Pfizer, Inc.
Notes

Possible exclude as response to evoked pain, but inadequate information to judge; 23 enrolled

No further update by February 2017, and no further information on Pfizer Clinical Study Results Synopses