Gabapentin add-on for drug-resistant partial epilepsy

  • Review
  • Intervention

Authors


Abstract

Background

The majority of people with epilepsy have a good prognosis and their seizures are well controlled by a single antiepileptic drug, but up to 30% develop drug-resistant epilepsy, especially those with partial seizures. In this review we summarise the current evidence regarding the antiepileptic drug gabapentin, when used as an add-on treatment for drug-resistant partial epilepsy.

Objectives

To evaluate the efficacy and tolerability of gabapentin when used as an add-on treatment for people with drug-resistant partial epilepsy.

Search methods

This is an updated version of the original Cochrane review published in The Cochrane Library 2009, Issue 4. We searched the Cochrane Epilepsy Group's Specialised Register (14 May 2013), the Cochrane Central Register of Controlled Trials (CENTRAL 2013, Issue 4, The Cochrane Library) (April 2013) and MEDLINE (1946 to 14 May 2013). We imposed no language restrictions.

Selection criteria

Randomised, placebo-controlled, double-blind, add-on trials of gabapentin in people with drug-resistant partial epilepsy. Trials using an active drug control group or which compared doses of gabapentin were also included in the review.

Data collection and analysis

Two review authors independently selected trials for inclusion and extracted the relevant data. We assessed the following outcomes: (a) seizure frequency and seizure freedom; (b) treatment withdrawal (any reason); (c) adverse effects. Primary analyses were intention-to-treat. We also undertook sensitivity best and worst-case analyses. We estimated summary risk ratios for each outcome and evaluated dose-response in regression models.

Main results

Eleven trials were included representing 2125 randomised participants. We combined data from six trials in meta-analyses of 1206 randomised participants. The overall risk ratio (RR) for 50% or greater reduction in seizure frequency compared to placebo was 1.89 (95% confidence interval (CI) 1.40 to 2.55). Dose regression analysis (for trials in adults) shows increasing efficacy with increasing dose, with 25.3% (19.3 to 32.3) of people responding to 1800 mg of gabapentin compared to 9.7% on placebo, a 15.5% increase in response rate (8.5 to 22.5). The RR for treatment withdrawal compared to placebo was 1.05 (95% CI 0.74 to 1.49). Adverse effects were significantly associated with gabapentin compared to placebo. Risk ratios were as follows: ataxia 2.01 (99% CI 0.98 to 4.11), dizziness 2.43 (99% CI 1.44 to 4.12), fatigue 1.95 (99% CI 0.99 to 3.82) and somnolence 1.93 (99% CI 1.22 to 3.06). No significant differences were found for the adverse effects of headache (RR 0.79, 99% CI 0.46 to 1.35) or nausea (RR 0.95, 99% CI 0.52 to 1.73). Overall the studies together are rated as low/unclear risk of bias due to information on each risk of bias domain not being available.

Authors' conclusions

Gabapentin has efficacy as an add-on treatment in people with drug-resistant partial epilepsy. However, the trials reviewed were of relatively short duration and provide no evidence for the long-term efficacy of gabapentin beyond a three-month period. The results cannot be extrapolated to monotherapy or to people with other epilepsy types.

摘要

背景

Gabapentin作為添加療法來治療藥物難治的局部發作型癲癇

多數癲癇患者的預後良好,使用單一抗癲癇藥物就可以有效控制其癲癇發作,但是還有將近30%的人發展成為藥物難治的癲癇,尤其是局部發作型的患者。在本次回顧中,我們總結了Gabapentin(一個新一代的抗癲癇藥物)作為藥物難治的局部發作型癲癇的添加療法的臨床證據。

目標

評估Gabapentin作為添加療法來治療藥物難治的局部發作型癲癇的療效和耐受性。

搜尋策略

我們搜尋了Cochrane Epilepsy Group's Specialized Register(2005年5月)以及Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library,2005年第2期) 和MEDLINE (1966年2005年3月)。沒有設定任何語言限制。我們同時聯繫Gabapentin的製造商和該領域的研究者,尋找進行中或未發表的研究。

選擇標準

選擇比較添加Gabapentin或安慰劑來治療藥物難治的局部發作型癲癇患者的隨機雙盲對照試驗。

資料收集與分析

兩位回顧作者各自選擇收納試驗和摘錄數據。評估了下列治療成果:(a) 癲癇發作頻率降低50% 或以上;(b) 停止試驗用藥(不論任何原因);(c) 藥物不良反應。初步分析採用intentiontotreat方法’.同時實施了Sensitivity best and worst case analyses。對每項治療成果評估了總體的odds ratios。使用回歸模型評估劑量與反應的相關性,計算Number Needed to Treat (NNT)。

主要結論

總共收納了5個試驗,包括997位隨機挑選的受試者。相較於安慰劑,Gabapentin在達成癲癇發作頻率降低50% 或以上的odds ratio(OR)是1.93 (95% CI 1.37 −2.71)。劑量回歸分析指出,劑量越大療效越強;相較於安慰劑,28.5% (21.5 – 36.7) 的人對1800 mg Gabapentin的治療有反應,NNT為6.7 (3.0 10.5)。相較於安慰劑,停藥的OR為1.05 (95% CI 0.68 – 1.61)。相對於安慰劑,下列藥物不良反應的OR分別為:頭暈2.22 (99% CI 1.28 – 3.85);疲勞2.28 (99% CI 1.15 – 4.52),嗜睡2.01 (99% CI 1.24 – 3.28) 均顯著和Gabapentin相關。

作者結論

Gabapentin作為添加療法來治療藥物難治的局部發作型癲癇患者時確有其療效。但因本回顧中的臨床試驗,治療期間都相對較短,所以無法提供長期療效的證據。上述的結果也不能外推到單一藥物療法或患有其他癲癇類型的病人。

翻譯人

此翻譯計畫由臺灣國家衛生研究院(National Health Research Institutes, Taiwan)統籌。

總結

Gabapentin作為短期治療局部發作型癲癇患者的添加療法是有效的。癲癇是一種由於大腦放電異常引起的重覆發作的疾病。本試驗回顧發現,作為一種新一代的抗癲癇藥物,Gabapentin併用其他藥物,短期內可以有效治療藥物難治的局部發作型癲癇。較常見因Gabapentin引起的藥物不良反應包括運動失調(協調性不良,前後搖擺不定)、頭暈、疲勞、噁心、嗜睡和頭疼。至於長期使用Gabapentin的療效則需要更進一步的研究。

Résumé scientifique

Adjonction de gabapentine dans l'épilepsie partielle réfractaire aux médicaments

Contexte

Le pronostic pour la plupart des patients épileptiques est favorable et leurs crises sont correctement contrôlées grâce à un seul médicament antiépileptique, mais 30 % d'entre eux développent une épilepsie réfractaire aux médicaments, surtout ceux souffrant de crises partielles. Dans cette revue, nous avons résumé les preuves actuelles concernant la gabapentine, médicament antiépileptique, administrée comme traitement adjuvant dans l'épilepsie partielle réfractaire aux médicaments.

Objectifs

Évaluer l'efficacité et la tolérance de la gabapentine administrée comme traitement adjuvant à des patients souffrant d'épilepsie partielle réfractaire aux médicaments.

Stratégie de recherche documentaire

Cette version est une mise à jour de la revue Cochrane d'origine publiée dans The Cochrane Library 2009, numéro 4. Nous avons effectué des recherches dans le registre spécialisé du groupe Cochrane sur l'épilepsie (14 mai 2013), le registre central des essais contrôlés (CENTRAL 2013, numéro 4, The Cochrane Library) (avril 2013) et MEDLINE (de 1946 au 14 mai 2013). Nous n'avons imposé aucune restriction de langue.

Critères de sélection

Des essais randomisés en double aveugle, contrôlés par placebo, concernant l'adjonction de gabapentine chez des personnes atteintes d'épilepsie partielle réfractaire aux médicaments. Les essais utilisant un groupe témoin pour le médicament actif ou ceux comparant des doses de gabapentine étaient également inclus dans cette revue.

Recueil et analyse des données

Deux auteurs de la revue ont indépendamment sélectionné les essais à inclure et extrait des données pertinentes. Nous avons évalué les critères de jugement suivants : (a) la fréquence des crises et les périodes sans crises ; (b) l'arrêt du traitement (pour quelque raison que ce soit) ; (c) les effets indésirables. Les analyses principales ont été effectuées en intention de traiter. Nous avons procédé à des analyses de sensibilité pour un scénario optimiste et pessimiste. Nous avons évalué le récapitulatif des risques relatifs pour chaque critère de jugement et évalué le rapport dose-réponse dans des modèles de régression.

Résultats principaux

Onze essais ont été inclus et totalisaient 2 125 participants randomisés. Nous avons combiné les données de six essais dans des méta-analyses composées de 1 206 participants randomisés. Le risque relatif (RR) global d'une diminution d'au moins 50 % de la fréquence des crises comparé à un placebo était de 1,89 (intervalle de confiance (IC) à 95 % 1,40 à 2,55). L'analyse de régression des doses (pour les essais réalisés chez des adultes) montre une efficacité croissante à mesure que la dose augmente, avec 25,3 % (19,3 à 32,3) des patients répondant à 1 800 mg de gabapentine par rapport à 9,7 % sous placebo, soit une augmentation de 15,5 % du taux de réponse (8,5 à 22,5). Le RR lié à l'arrêt du traitement par rapport à un placebo était de 1,05 (IC à 95 % 0,74 à 1,49). Comparés à un placebo, les effets indésirables étaient significativement liés à la gabapentine. Les risques relatifs étaient les suivants : ataxie 2,01 (IC à 99 % 0,98 à 4,11), vertiges 2,43 (IC à 99 % 1,44 à 4,12), fatigue 1,95 (IC à 99 % 0,99 à 3,82) et somnolence 1,93 (IC à 99 % 1,22 à 3,06). Aucune différence significative n'a été constatée pour les effets indésirables dus à des céphalées (RR 0,79, IC à 99 % 0,46 à 1,35) ou à des nausées (RR 0,95, IC à 99 % 0,52 à 1,73). Dans l'ensemble, les risques de biais des études sont considérés comme étant faibles/incertains en raison de l'absence d'informations concernant chaque domaine de risque de biais.

Conclusions des auteurs

La gabapentine est efficace en tant que traitement adjuvant chez les personnes souffrant d'épilepsie partielle réfractaire aux médicaments. Toutefois, les essais passés en revue s'étendaient sur une durée relativement courte et ne montraient aucune preuve d'efficacité à long terme (période de plus de trois mois) de la gabapentine. Ces résultats ne peuvent pas être extrapolés à une monothérapie ou à des personnes souffrant d'autres types d'épilepsie.

Plain language summary

Gabapentin as an add-on for drug-resistant partial epilepsy

This review is an update of a previously published review and is now currently up to date as from 18/07/2013.

Epilepsy is a disorder where recurrent seizures are caused by abnormal electrical discharges from the brain. Evidence from randomised controlled trials are often used to examine how effective and safe antiepileptic drugs are in people who experience such seizures. In this review 11 studies were included and data from a total of 2125 people with partial seizures are presented. Data from 6 of the studies were combined together in the analysis. All the participants including adults and children were previously taking at least one antiepileptic drug and all were continuing to experience seizures. Either gabapentin or a placebo drug was then added to the drug regime. The results showed that gabapentin effectively reduced seizures when used as an additional treatment. Compared to a placebo gabapentin was almost twice as likely to reduce seizures by 50% or more. The most common adverse effects associated with gabapentin are ataxia (poor co-ordination and unsteady gait), dizziness, fatigue, and drowsiness. Overall the quality of evidence is moderate as several details regarding study methods were unclear in the reports. Research is needed into the effects of the long-term use of gabapentin.

Résumé simplifié

Gabapentine en tant qu'adjuvant dans l'épilepsie partielle réfractaire aux médicaments

La présente revue est une mise à jour d'une revue publiée précédemment et est désormais à jour depuis le 18/07/2013.

L'épilepsie est un trouble qui se caractérise par des convulsions récurrentes causées par des décharges électriques anormales dans le cerveau. Les preuves issues d'essais contrôlés randomisés permettent généralement d'examiner l'efficacité et l'innocuité des médicaments antiépileptiques chez les personnes victimes de ces convulsions. Dans cette revue, 11 études ont été incluses et des données provenant d'un total de 2 125 personnes atteintes de crises partielles sont présentées. Les données issues de 6 de ces études ont été combinées dans l'analyse. Tous les participants, y compris les adultes et les enfants, prenaient déjà au moins un médicament antiépileptique et tous constataient une persistance des crises. La gabapentine ou un placebo était alors ajouté(e) au schéma thérapeutique. Les résultats montraient que la gabapentine réduisait efficacement les crises lorsqu'elle était administrée comme traitement additionnel. La gabapentine avait presque deux fois plus de chances de réduire les crises d'au moins 50 % par rapport à un placebo. Les effets indésirables les plus fréquents associés à la gabapentine sont l'ataxie (mauvaise coordination et troubles de la marche), des vertiges, de la fatigue et des somnolences. Dans l'ensemble, les preuves sont de qualité moyenne car plusieurs détails concernant les méthodes de l'étude restaient flous dans les rapports. Des recherches seront nécessaires afin de déterminer les effets liés à l'administration de gabapentine à long terme.

Notes de traduction

Traduit par: French Cochrane Centre 4th September, 2013
Traduction financée par: Pour la France : Minist�re de la Sant�. Pour le Canada : Instituts de recherche en sant� du Canada, minist�re de la Sant� du Qu�bec, Fonds de recherche de Qu�bec-Sant� et Institut national d'excellence en sant� et en services sociaux.

Резюме на простом языке

Габапентин в качестве дополнения к [лечению] лекарственно-устойчивой парциальной эпилепсии

Этот обзор является обновлением ранее опубликованного обзора, и теперь актуален по 18/07/2013.

Эпилепсия - это расстройство, при котором повторяющиеся приступы вызваны аномальными электрическими разрядами в головном мозге. Доказательства из рандомизированных контролируемых испытаний часто используются, чтобы исследовать, касколько эффективны и безопасны противоэпилептические препараты для людей, которые испытывают такие приступы. В этот обзоре были включены 11 исследований и в общей сложности представлены данные от 2125 людей с парциальными приступами. Данные из 6 исследований были объединены в мета-анализе. Все участники, включая взрослых и детей, ранее принимали, по крайней мере, одно противоэпилептическое лекарство, и все продолжали испытывать приступы. Габапентин или плацебо добавляли к режиму лечения. Результаты показали, что габапентин эффективно уменьшал приступы при использовании в качестве дополнительной терапии. Габапентин сокращал частоту приступов (на 50% или более) с вероятностью почти в два раза большей, чем плацебо. Наиболее распространенными побочными эффектами, связанными с габапентином, являются атаксия (нарушение координации и шаткая походка), головокружение, усталость и сонливость. В целом качество доказательств является умеренным, поскольку некоторые детали относительно методов исследования были неясны в докладах. Необходимы исследования влияния долгосрочного использования габапентина.

Заметки по переводу

Перевод: Абакумова Татьяна Рудольфовна. Редактирование: Зиганшина Лилия Евгеньевна. Координация проекта по переводу на русский язык: Cochrane Russia - Кокрейн Россия (филиал Северного Кокрейновского Центра на базе Казанского федерального университета). По вопросам, связанным с этим переводом, пожалуйста, обращайтесь к нам по адресу: cochrane.russia.kpfu@gmail.com; cochranerussia@kpfu.ru

Summary of findings(Explanation)

Summary of findings for the main comparison. Gabapentin versus placebo for drug-resistant partial epilepsy patients
  1. 1Four studies had missing data and did not carry out intention-to-treat analysis.
    2Three studies had missing data and did not carry out intention-to-treat analysis.
    3One study with small number of events and wide confidence intervals; concern regarding the confidence in overall effect.
    4Two studies with small study effects and wide confidence intervals; concern regarding the confidence in overall effect.

Gabapentin versus placebo for drug-resistant partial epilepsy patients
Patient or population: drug-resistant partial epilepsy patients
Settings: outpatient
Intervention: gabapentin versus placebo
OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of participants
(studies)
Quality of the evidence
(GRADE)
Comments
Assumed riskCorresponding risk
Control Gabapentin
50% reduction in seizure frequency - primary analysis
Number of seizures reported in seizure diary
Study population RR 1.89
(1.4 to 2.55)
1206
(6 studies)
⊕⊕⊕⊝
moderate 1
 
12 per 100 23 per 100
(17 to 31)
Moderate
10 per 100 18 per 100
(13 to 24)
Drug withdrawal
Number of patients withdrawn for any reason
Study population RR 1.05
(0.74 to 1.49)
1206
(6 studies)
⊕⊕⊕⊝
moderate 1
 
10 per 100 11 per 100
(8 to 15)
Moderate
8 per 100 8 per 100
(6 to 11)
Adverse effects - ataxia
Number of patients experiencing ataxia
Study population 2.01
(0.98 to 4.11)
787
(3 studies)
⊕⊕⊝⊝
low 2,3
 
5 per 100 10 per 100
(5 to 20)
Moderate
3 per 100 6 per 100
(3 to 12)
Adverse effects - dizziness
Number of people experiencing dizziness
Study population 2.43
(1.44 to 4.12)
1206
(6 studies)
⊕⊕⊕⊝
moderate 1
 
6 per 100 14 per 100
(8 to 23)
Moderate
5 per 100 13 per 100
(7 to 21)
Adverse effects - fatigue
Number of patients experiencing fatigue
Study population 1.95
(0.99 to 3.82)
1161
(5 studies)
⊕⊕⊝⊝
low 1,4
 
4 per 100 7 per 100
(3 to 13)
Moderate
4 per 100 7 per 100
(4 to 14)
Adverse effects - nausea
Number of patients experiencing nausea
Study population 0.95
(0.52 to 1.73)
1034
(4 studies)
⊕⊕⊕⊝
moderate 2
 
7 per 100 7 per 100
(4 to 12)
Moderate
8 per 100 8 per 100
(4 to 14)
Adverse effects - somnolence
Number of patients experiencing somnolence
Study population 1.93
(1.22 to 3.06)
1206
(6 studies)
⊕⊕⊕⊝
moderate 1
 
7 per 100 14 per 100
(9 to 23)
Moderate
8 per 100 15 per 100
(10 to 24)
*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: confidence interval; RR: risk ratio
GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

Background

This review is an update of a previously published review in the Cochrane Database of Systematic Reviews (The Cochrane Library 2009, Issue 4) on 'Gabapentin add-on for drug-resistant partial epilepsy'. The purpose of this update is to summarise current understanding of the role of gabapentin as an add-on treatment in partial epilepsy resistant to at least one other antiepileptic drug (AED). Evidence has been taken from randomised controlled trials (RCTs) using placebo, other AED or varying doses of gabapentin to compare its efficacy in seizure control and tolerability. There is no internationally accepted definition of drug resistance, so for the purpose of this review we considered people drug-resistant if they have partial-onset seizures (simple partial and/or complex partial and/or secondary generalised tonic-clonic seizures) and have failed to respond to at least one monotherapy AED. In addition to work published previously, we report best and worse-case sensitivity analyses for the main efficacy outcome (50% or greater reduction in seizure frequency) and give estimates of the number needed to treat (NNT) for individual doses using robust methods.

Description of the condition

Epilepsy is a common neurological disorder characterised by recurrent seizures. The majority of people given a diagnosis of epilepsy have a good prognosis and their seizures will be controlled by treatment with a single AED (Reynolds 1981), however up to 30% will continue to have seizures despite treatment with adequate doses of AEDs, often requiring treatment with a combination (Cockerell 1995). These individuals represent a significant therapeutic problem when one realises that up to two to three per cent of the population will suffer from epilepsy at some time in their lives (Hauser 1993).

Description of the intervention

With the development of new AEDs clinicians are faced with an increasing number of drugs to choose from in the treatment of refractory individuals. Initially, new AEDs are tested in people with refractory partial-onset epilepsy as add-on treatment, in randomised, placebo-controlled trials.This review is one in a series (also published elsewhere (Marson 1996; Marson 1997)) in which the efficacy and tolerability of six new AEDs (gabapentin, lamotrigine, tiagabine, topiramate, vigabatrin and zonisamide) are investigated in people with drug-resistant partial epilepsy. Current first-line treatment for partial epilepsy includes: lamotrigine, sodium valproate, carbamazepine, oxcarbazepine and levetiracetam. When first-line medications fail to achieve seizure freedom, add-on therapy is required.

How the intervention might work

The mechanism of action of gabapentin is uncertain (McClean 1995). It was licensed for add-on use in the UK in 1993. Gabapentin is a structural analogue of the neurotransmitter gamma-aminobutyric acid (GABA). It does, however, cross the blood brain barrier and its activities are believed not to be GABA-related. Gabapentin has a high volume of distribution, is not significantly protein-bound or metabolised, and does not induce or inhibit hepatic enzymes; thus it has minimal to no known interactions with other AEDs.

Objectives

To evaluate the efficacy and tolerability of gabapentin when used as an add-on treatment for people with drug-resistant partial epilepsy.

Methods

Criteria for considering studies for this review

Types of studies

To be included in our review, studies had to meet all of the following criteria:

  1. randomised controlled trials, in which an adequate method of concealment of randomisation was used (e.g. allocation of sequentially sealed packages of medication, sealed opaque envelopes, telephone randomisation);

  2. double-blind trials, in which both patient and clinician treating or assessing outcome are blinded to treatment allocated;

  3. placebo-controlled or alternative AED or range of gabapentin doses used as controls;

  4. parallel-group or cross-over studies.

Types of participants

People of any age with drug-resistant partial epilepsy (i.e. experiencing simple partial, complex partial or secondary generalised tonic-clonic seizures).

Types of interventions

  1. The active treatment group receive treatment with gabapentin in addition to conventional antiepileptic drug treatment.

  2. The control group receive matched placebo/different dose of gabapentin/alternative AED in addition to conventional antiepileptic drug treatment.

Types of outcome measures

Primary outcomes
50% or greater reduction in seizure frequency

We chose the proportion of people with a 50% or greater reduction in seizure frequency in the treatment period compared to the pre-randomisation baseline period as the primary outcome. It was chosen as it is commonly reported in this type of study and can be calculated for studies that do not report it, provided that baseline seizure data were reported.

Seizure freedom

The proportion of people with complete cessation of seizures during the treatment period.

Secondary outcomes
Treatment withdrawal

We used the proportion of people having treatment withdrawn during the course of the treatment period as a measure of global effectiveness. Treatment is likely to be withdrawn due to adverse effects, lack of efficacy or a combination of both, and this is an outcome to which the individual makes a direct contribution. In trials of short duration it is likely that adverse effects will be the most common reason for withdrawal.

Adverse effects

(a) The proportion of individuals experiencing the following five adverse effects:

(i) ataxia;
(ii) dizziness;
(iii) fatigue;
(iv) nausea;
(v) somnolence.

We chose these adverse effects as we considered them to be common and important adverse effects of antiepileptic drugs.

(b) The proportion of individuals experiencing the five most common adverse effects if different from (a) above.

Search methods for identification of studies

Electronic searches

We searched the Cochrane Epilepsy Group's Specialised Register (14 May 2013). In addition we searched the following databases:

  • Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library 2013, Issue 4) (April 2013) using the strategy set out in Appendix 1;

  • MEDLINE (Ovid) (1946-14 May 2013) using the strategy outlined in Appendix 2.

There were no language restrictions.

Searching other resources

We reviewed the reference lists of included studies to search for additional reports of relevant studies.

Data collection and analysis

Selection of studies

Two review authors (SA and JP) independently assessed trials for inclusion. Any disagreements were resolved by mutual discussion; failing this we sought an opinion from a third party. The same two review authors independently carried out data extraction and assessed risk of bias. Again disagreements were resolved through mutual discussion; failing this we sought a third party opinion.

Data extraction and management

We extracted the following information for each trial using a data extraction sheet:

Methodological/trial design
  • Method of randomisation and allocation concealment.

  • Method of double-blinding.

  • Whether any participants had been excluded from reported analyses.

  • Duration of baseline period.

  • Duration of treatment period.

  • Dose(s) of gabapentin tested.

Participant/demographic information
  • Total number of participants allocated to each treatment group.

  • Age/sex.

  • Number with partial/secondary generalised seizures.

  • Seizure types.

  • Seizure frequency during the baseline period.

  • Number of background drugs.

Most trials found were sponsored by Parke Davis whom we asked to confirm the following information:

  • the method of randomisation;

  • the total number randomised to each group;

  • the number of participants in each group achieving a 50% or greater reduction in seizure frequency per treatment group;

  • the number of participants having treatment withdrawn post-randomisation per treatment group;

  • for those excluded:

    • the reason for exclusion;

    • whether any of those excluded completed the treatment phase;

    • whether any of those excluded had a 50% or greater reduction in seizure frequency during the treatment phase.

Outcomes

We recorded the number of participants experiencing each outcome (see Types of outcome measures) per randomised group.

We contacted authors of trials for any missing information.

Assessment of risk of bias in included studies

Two review authors independently made an assessment of risk of bias for each trial using Cochrane 'Risk of bias' tables as described in Higgins 2011. We rated included studies as adequate, inadequate or unclear on six domains applicable to randomised controlled trials: randomisation method, allocation concealment, blinding methods, incomplete outcome data, selective outcome reporting and other sources of bias. We created a 'Summary of findings' table and employed the GRADE approach for assessing quality of evidence.

We have outlined studies failing to meet the criteria to be included in the meta-analysis in narrative form; statistics for those included in the meta-analysis are outlined below.

Measures of treatment effect

The primary outcome of seizure reduction is presented as a risk ratio. Secondary outcomes, including treatment withdrawal and adverse effects, are also presented as risk ratios.

Dealing with missing data

We sought any missing data from study authors. We carried out intention-to-treat, best-case and worst-case analysis to account for any missing data. All analyses are presented in the main report.

Assessment of heterogeneity

We assessed clinical heterogeneity by comparing the distribution of important individual participant factors among trials (e.g. age, seizure type, duration of epilepsy) and trial factors (e.g. methods of randomisation and blinding, missing data). We examined statistical heterogeneity using a Chi2 test (P > 0.10) and the I2 statistic.

Assessment of reporting biases

We requested all protocols from study authors to enable a comparison of outcomes of interest. We investigated outcome reporting bias using the ORBIT matrix system (Kirkham 2010).

We examined reporting biases, such as publication bias, by identifying certain aspects of each study (e.g. sponsors of research, research teams involved). We intended to examine funnel plots in the event that it was possible for an appropriate number of studies to be combined.

Data synthesis

We employed a fixed-effect meta-analysis to synthesise the data. Comparisons we expected to carry out included:

  1. intervention group versus controls on seizure reduction;

  2. intervention group versus controls on seizure freedom;

  3. intervention group versus controls on treatment withdrawal;

  4. intervention group versus controls on adverse effects.

We stratified each comparison by type of control group (i.e. placebo or active control group) and study characteristics to ensure appropriate combination of data.

The preferred estimate was the Mantel-Haenszel risk ratio (RR). For the outcomes 50% or greater reduction in seizure frequency and treatment withdrawal, we used 95% confidence intervals (CIs). For individual adverse effects we used 99% CIs to make an allowance for multiple testing by using wider confidence intervals. This is not a strict formal adjustment, as the number of individual adverse effects is not known in advance.

All our analyses included all participants in the treatment group to which they had been allocated. For the efficacy outcome (50% or greater reduction in seizure frequency) we undertook three analyses.

  • Primary (intention-to-treat) analysis: participants not completing follow-up or with inadequate seizure data were assumed to be non-responders. To test the effect of this assumption, we undertook the following sensitivity analyses:

    • worst-case analysis: participants not completing follow-up or with inadequate seizure data were assumed to be non-responders in the gabapentin group and responders in the placebo group;

    • best-case analysis: participants not completing follow-up or with inadequate seizure data were assumed to be responders in the gabapentin group and non-responders in the placebo group.

Dose regression analysis

We examined dose-response relationships using logistic regression (for the five adult trials) and calculated probabilities for the following for differing doses: (i) the percentage of participants having a 50% response; (ii) the difference in the percentage of participants responding to each dose compared to placebo. A binary variable was defined with value 0 if the response was less than 50% and value 1 otherwise. We examined dose-response relationships using logistic regression, in the framework of generalised linear models, using the package GLIM, with this binary variable as the outcome variable (McCullagh 1989). Trial effects were not included in the regression models as it was generally not possible to do so as some doses are confounded with trials. As none of the tests for heterogeneity reached a significance level of less than 30%, it seemed reasonable to proceed without trial effects.

Subgroup analysis and investigation of heterogeneity

We undertook subgroup analysis for individual adverse effects. We intended to investigate heterogeneity using sensitivity analysis if deemed appropriate.

Sensitivity analysis

We also intended to carry out sensitivity analysis if peculiarities were found between study quality, characteristics of participants, interventions and outcomes.

Results

Description of studies

Results of the search

The search revealed 466 records identified from the databases outlined in Electronic searches. After duplicates were removed, 316 records remained; all were screened for inclusion in the review. We excluded 302 at this point and 2 studies are awaiting classification leaving 12 full-text articles to be assessed for eligibility. Following this, one was excluded (see Figure 1 and Characteristics of excluded studies for reasons for exclusion). A total of 11 studies were included in the review, six of which were included in meta-analyses. The data from the five remaining studies were not combined in meta-analysis due to the differences in comparisons investigated.

Figure 1.

Study flow diagram.

Included studies

There were seven trials which compared gabapentin to a placebo (Anhut 1994; Appleton 1999; Leach 1997; Sivenius 1991; UK Gabapentin 1990; US Gabapentin 1993; Yamauchi 2006), two trials which examined two different doses of gabapentin (Fisher 2001; Tomovic 1999), one trial which compared gabapentin to vigabatrin (Lindberger 2000) and one trial which compared gabapentin to lamotrigine (Sethi 2002). All patients had drug-resistant partial epilepsy and were taking at least one monotherapy AED. Pre-existing AED regimes remained unchanged throughout the study period. All outcome measures included seizure reduction and adverse events.

One parallel trial (Anhut 1994) had a 12-week pre-randomisation baseline period and a 12-week treatment period of gabapentin 900 mg/day (n = 111) or gabapentin 1200 mg/day (n = 52) or placebo (109). Study medication was administered three times daily (TDS). Included patients had a minimum of six partial seizures within the baseline period and were aged 12 years or over. Women of childbearing potential on adequate contraception and patients with additional seizure types were also included in this study.

The baseline period in one parallel trial (Appleton 1999) was six weeks in duration and had a treatment period of 12 weeks. Gabapentin (600 to 1200 mg/day) was administered TDS and this was dependent on the weight of the patient. One hundred and twenty-eight patients were randomised to the placebo group and 119 were randomised to gabapentin. Patients were children who were aged less than 12 years old and had a minimum of four seizures during the baseline period.

One cross-over trial (Leach 1997) was another placebo-controlled study which did not have a pre-randomised baseline period, however all patients reported at least four seizures per month for the previous three months. There were four treatment arms (gabapentin 1200 mg/day, 1800 mg/day, 2400 mg/day and placebo each administered on a TDS basis). All patients received all doses/placebo in a cross-over design with a four-week washout period between each treatment arm. Twenty-seven patients were recruited and 23 were analysed. In view of the lack of a pre-randomised baseline period it has not been included in the meta-analysis.

A parallel trial (Sivenius 1991) had a baseline period of three months in duration in which adults with partial epilepsy experienced four or more seizures a month. Patients were randomised to either 900 mg of gabapentin (n = 16), 1200 mg of gabapentin (n = 9) or placebo (n = 18). Treatment medication was administered TDS and lasted 12 weeks.

One further parallel trial (UK Gabapentin 1990) had a three-month baseline period where included patients had at least one partial seizure per week. This study had a two-week initiation phase of 600 mg/day of gabapentin or placebo administered TDS, after which patients began a 12-week treatment period of 1200 mg/day taken TDS. Sixty-six adults were randomised to placebo and 61 to gabapentin 1200 mg/day.

Another parallel trial (US Gabapentin 1993) recruited 306 adults, randomising 53 patients to gabapentin 600 mg/day, 101 patients to 1200 mg/day, 54 patients to 1800 mg/day and 98 to placebo. Treatment medication was administered TDS for 12 weeks. The study implemented an initiation period of two to three days of either 300 mg or 600 mg/day up to the required dose. The baseline period was three months and included patients who had a minimum of four partial seizures per month.

The last trial examining gabapentin versus placebo (Yamauchi 2006) had a baseline period of 12 weeks and included patients who had a minimum of eight partial seizures during baseline. Adults were randomised into one of three treatment arms: gabapentin 1200 mg/day (n = 86), 1800 mg/day (n = 41) and placebo (n = 82). Treatment medication was taken TDS over 12 weeks.

Two randomised controlled trials were gabapentin dose trials which had no placebo group (Fisher 2001; Tomovic 1999). Fisher 2001 compared slow initiation (300 mg on day one, 600 mg on day two and then 900 mg per day for five days) and rapid initiation of gabapentin (placebo for the first two days followed by 900 mg/day for five days). Three hundred and sixty were randomised to the slow initiation group and 360 were randomised to the rapid initiation dose. There was no baseline period; patients were required to have been taking at least one AED for one month prior to the study and were considered to have inadequate seizure control as defined by the authors. Patients were aged 12 years or older. The trial period was seven days. Tomovic 1999 compared 900 mg/day of gabapentin versus 1200 mg/day of gabapentin administered TDS over 12 weeks. Nine patients were randomised to each dose group. There was no formal baseline period; included patients were considered to have unsatisfactorily controlled seizures while taking at least one first-line AED for three months prior to the study, as defined by the authors.

One trial (Lindberger 2000) compared gabapentin to lamotrigine; it had an eight-week baseline period. All participants had tried no more than two AED monotherapy regimens and were on one AED at the time of study (this had to exclude phenytoin). A minimum seizure frequency of four seizures during an eight-week baseline period and two or more seizures during the last month was required. One hundred and two patients (aged 12 to 75) were randomised to receive either gabapentin or vigabatrin add-on treatment. A flexible dosing regime was established over the subsequent 24 weeks: gabapentin variable dose 1800 mg/day minimum, then 2400 mg and then a maximum of 3600 mg/day, increased every eight weeks as tolerated. The vigabatrin initial dose was 1000 mg, then 2000 mg, then 4000 mg, increased in the same manner (as tolerated by adverse effects) and increased if complete seizure freedom had not be attained. The total trial period was 24 weeks, however, outcome measures were taken at eight weeks (awaiting clarification from author).

One trial (Sethi 2002) compared gabapentin to lamotrigine treatment of patients refractory to the maximum tolerated dose of carbamazepine monotherapy, with a seizure duration of two years or less. Twenty-seven patients were randomised to the gabapentin group and 25 to lamotrigine and were aged 10 to 60. Baseline seizure frequency was at least four seizures despite treatment (unclear over what time frame). The baseline period was time of enrolment. The trial period was 12 weeks. Gabapentin was administered at a dose of 300 mg on day one, 300 mg twice daily (BD) on day two and thereafter an increment of 300 mg was made daily until seizures were controlled or toxic effects appeared. Lamotrigine was started at 50 mg per day for two weeks, then 50 mg BD for two weeks, then increased by 50 to 100 mg every two weeks until seizures were controlled or there were toxic effects.

Excluded studies

We excluded one randomised controlled trial of 25 participants (Crawford 1987), as seizure outcomes were not investigated, and one open-label study (Saidon 1997) of 40 patients which had a randomised baseline period of five months; responders within this period were then entered into the open-label study.

Risk of bias in included studies

See Figure 2 for a summary of the risk of bias in the included studies.

Figure 2.

Allocation

For six studies (Appleton 1999; Leach 1997; Lindberger 2000; Sethi 2002; Tomovic 1999; Yamauchi 2006) the method of allocation concealment was not described (authors have been contacted but we have been unable to clarify). For the remaining four studies randomisation was achieved by generating random lists using random permuted blocks and allocation was concealed by dispensing sequentially numbered packages to each patient allocated treatment.

Blinding

In four studies (Appleton 1999; Leach 1997; Sethi 2002; Tomovic 1999) the means of blinding is unclear. The remaining five studies achieved blinding by providing packaging and tablets that were identical for the gabapentin and placebo groups. No specific details were given regarding who was blinded (i.e. patients, study personnel or outcome assessors).

Incomplete outcome data

Two studies (Appleton 1999; Lindberger 2000) analysed results on an intention-to-treat basis. Five studies (Anhut 1994; Fisher 2001; Leach 1997; Sivenius 1991; Tomovic 1999) excluded participants from the study and analysis without providing reasons for this. The remaining studies analysed results on an 'as treated' basis but did report attrition.

Selective reporting

All the studies detailed outcomes within the methods of the paper and reported the data. We identified no evidence of publication bias through the examination of a funnel plot for the primary analysis, however there was significant evidence of bias for the worst-case scenario analysis (see Figure 3).

Figure 3.

Funnel plot of comparison: 1 Gabapentin versus placebo, outcome: 1.1 50% reduction in seizure frequency.

Effects of interventions

See: Summary of findings for the main comparison Gabapentin versus placebo for drug-resistant partial epilepsy patients

Gabapentin versus placebo

50% or greater reduction in seizure frequency

Given that all participants had drug-resistant partial epilepsy, it seemed reasonable to combine results from the paediatric and adult studies, for an overall estimate (irrespective of dose). Data from the paediatric study could not be included in dose regression models, as individuals were not randomised to a specific daily dose. Data for this outcome were provided by six trials (Anhut 1994; Appleton 1999; Sivenius 1991; UK Gabapentin 1990; US Gabapentin 1993; Yamauchi 2006). See Figure 4 for forest plots for this outcome. One trial (Leach 1997) was not deemed suitable for inclusion in the meta-analysis due to the cross-over design but has been discussed in narrative form below.

Figure 4.

Forest plot of comparison: 1 Gabapentin versus placebo, outcome: 1.1 50% reduction in seizure frequency.

Intention-to-treat analysis

An analysis pooling data from six studies shows no evidence of heterogeneity (Chi2 = 3.90, P = 0.56, I2 = 0%). The overall risk ratio (RR) for 50% or greater reduction in seizures is 1.89 (95% confidence interval (CI) 1.40 to 2.55).

Best and worst-case scenarios

Chi2 tests for heterogeneity for a response to gabapentin indicate no significant heterogeneity (best-case P = 0.08, worst-case P = 0.95). The overall risk ratios for 50% responders across all studies are 2.52 (95% CI 1.89 to 3.37) (best-case) and 1.35 (95% CI 1.04 to 1.76) (worst-case).

For all three analyses, the results suggest a significant treatment effect. However, there is a considerable difference between estimates.

Dose-response regression
Intention-to-treat analysis

A linear dose-response model gives a good summary (for the five adult trials) of the log odds of 50% response rate. After adjusting for dose, there is no difference in estimated dose response between studies. The log odds of response increase by 0.19 (standard error of the mean (SEM) 0.045) for a 300 mg increase in daily dose. This is roughly a 20% increase in the odds of response with a 300 mg increase in dose. The reduction in deviance due to dose is 19.1 on 1 degree of freedom, and the residual deviance is 10.9 on 13 degrees of freedom. The trial in children was not included, as the doses were prescribed to achieve particular levels of mg/kg/day.

The results are summarised in the following tables:

  • the estimated percentage of patients responding to each dose with 95% CI (intention-to-treat) (Table 1);

    Table 1. Estimated percentage responders per dose, intention-to-treat
    1. CI: confidence interval

    DoseResponders % (95% CI)
    0 mg (placebo)9.7 (7.2 to 12.9)
    600 mg13.6 (11.4 to 16.1)
    900 mg16.0 (13.7 to 18.6)
    1200 mg18.7 (15.8 to 22.1)
    1800 mg25.3 (19.3 to 32.3)
  • the percentage difference in patients responding to each dose compared to placebo with 95% CIs (intention-to-treat) (Table 2).

    Table 2. Percentage difference in responders per dose compared to placebo, intention-to-treat
    1. CI: confidence interval

    DoseDifference (95% CI)
    600 mg3.9 (1.6 to 6.2)
    900 mg6.3 (2.8 to 9.8)
    1200 mg9.0 4.4 to 13.7)
    1800 mg15.5 (8.5 to 22.5)
Best-case scenario

In the best-case analysis, there is roughly a 30% increase in the odds of response with a 300 mg increase in dose.

The results are summarised in the following tables:

  • the estimated percentage of patients responding to each dose with 95% CI (best-case) (Table 3);

    Table 3. Estimated percentage responders per dose, best-case
    1. CI: confidence interval

    DoseResponders % (95% CI)
    0 mg (placebo)10.9 (8.1 to 14.5)
    600 mg17.2 (14.6 to 20.2)
    900 mg21.4 (18.5 to 24.6)
    1200 mg26.2 (22.4 to 30.4)
    1800 mg37.6 (30.0 to 46.0)
  • the percentage difference in patients responding to each dose compared to placebo with 95% CI (best-case) (Table 4).

    Table 4. Percentage difference in responders per dose compared to placebo, best-case
    1. CI: confidence interval

    DoseDifference (95% CI)
    600 mg6.3 (3.9 to 8.8)
    900 mg10.5 (6.8 to 14.2)
    1200 mg15.3 (10.3 to 20.0)
    1800 mg26.7 (19.3 to 34.2)
Worst-case scenario

For the worst-case analysis, there is roughly a 10% increase in the odds of response with a 300 mg increase in dose.

The results are summarised in the following tables:

  • the estimated percentage of patients responding to each dose with 95% CIs (worst-case) (Table 5);

    Table 5. Estimated percentage responders per dose, worst-case
    1. CI: confidence interval

    DoseResponders % (95% CI)
    0 mg (placebo)13.8 (10.4 to 18.2)
    600 mg16.4 (13.8 to 19.2)
    900 mg17.8 (15.3 to 20.5)
    1200 mg19.2 (16.2 to 22.7)
    1800 mg22.5 (17.1 to 29.0)
  • the percentage difference in patients responding to each dose compared to placebo with 95% CIs (worst-case) (Table 6).

    Table 6. Percentage difference in responders per dose compared to placebo, worst-case
    1. CI: confidence interval

    DoseDifference % (95% CI)
    600 mg2.5 (-0.3 to 5.3)
    900 mg3.9 (-0.3 to 8.1)
    1200 mg5.4 (-0.2 to 11.0)
    1800 mg8.6 (0.3 to 17.0)

All three analyses (intention-to-treat, best and worst-case) show a significant increase in therapeutic effect with increasing dose. There is, however, a striking difference in the proportion of responders estimated.

Seizure freedom

Only two trials comparing gabapentin to placebo reported seizure freedom data (Appleton 1999; Yamauchi 2006). Yamauchi 2006 reported no patients attaining seizure freedom, whereas Appleton 1999 reported 3 of 119 patients receiving gabapentin as seizure-free compared to 1 of 128 patients receiving placebo.

Treatment withdrawal

A Chi2 test of heterogeneity suggests no significant statistical heterogeneity (Chi2 = 4.13, df = 4, P = 0.53, I2 = 0%). The overall RR for withdrawal for any reason is 1.05 (95% CI 0.74 to 1.49), hence there is insufficient evidence to conclude that individuals are more likely to withdraw from gabapentin than placebo, but there could be a substantial withdrawal rate.

Adverse effects

In addition to reports of ataxia, dizziness, fatigue, nausea and somnolence, headache was amongst the five most common adverse effects and has been included in our analysis. Significant differences between gabapentin and placebo were found for the following adverse effects: ataxia (RR 2.01, 99% CI 0.98 to 4.11); dizziness (RR 2.43, 99% CI 1.44 to 4.12); fatigue (RR 1.95, 99% CI 0.99 to 3.82) and somnolence (RR 1.93, 99% CI 1.22 to 3.06). No significant differences were found for headache (RR 0.79, 99% CI 0.46 to 1.35) or nausea (RR 0.95, 99% CI 0.52 to 1.73).

Cross-over trial, not included in meta-analysis
50% or greater reduction in seizure frequency and seizure freedom

In Leach 1997, 23 out of the 27 patients were evaluated (although there were a total of six withdrawals, two withdrew sufficiently late in the study to provide analysable data). Two patients achieved total seizure control throughout the active treatment phase and none in the placebo phase. For simple partial seizures two patients showed 'in excess' of 50% reduction in seizure frequency. The median monthly frequency for simple partial seizures was not significantly reduced in the treatment group (P = 0.80). Complex partial seizures with secondary generalisation were reported separately; five out of 17 patients had in excess of 50% reduction in seizure frequency (non-significant).

Treatment withdrawal

Six patients withdrew, five due to adverse events (four on placebo, one on gabapentin) and one of which withdrew consent to participate after the second visit. One did not provide complete data for seizure frequency and was withdrawn from the study.

Adverse effects

Nineteen patients (79%) reported 47 adverse events on gabapentin and 15 patients (63%) reported 30 adverse events on placebo. There was a statistically significant difference (P = 0.006) at 2400 mg/day. The types of adverse events have not been reported.

Dose comparison trials with no placebo group

For one study (Tomovic 1999) we sent a data extraction form to a translator. Our understanding is that the outcomes for the two treatment arms were combined, thus a comparison between the two treatment groups cannot be made. Another study (Fisher 2001) only measured adverse events at day two and day seven of a slow initiation regime and a rapid initiation regime, therefore this will be presented narratively narrative below.

50% or greater reduction in seizure frequency

In the Tomovic 1999 study 13 of 18 participants (72.2%) experienced 50% or greater reduction in seizures (two of which achieved a 100% reduction). Three patients had a 26% to 49% reduction in seizure frequency. Two patients had worse seizure control.

This was not an outcome measured in the Fisher 2001 study.

Seizure freedom

Two out of 18 patients were reported to be seizure-free during the treatment period, however it was not reported in which dose group this was achieved.

Treatment withdrawals

Tomovic 1999 did not report any treatment withdrawals. Fisher 2001 reported only patients who had full exposure to the study medication during the whole time period of assessment (i.e. details of withdrawals were not provided).

Adverse effects

In Tomovic 1999 adverse effects were reported in three patients, two of whom had dizziness and one excessive sleepiness (they were excluded from the study therefore not included in the total number of patients). They also noted bulimia, tremor, diplopia, headache, nausea and ataxia. Fisher 2001 reported adverse events on day three and day seven of a slow and rapid initiation regime of gabapentin. See Table 7 for the proportion of people with adverse effects with percentages. There were no statistically significant differences between the two dose regimes, apart from more dizziness in the rapid initiation group compared to the slow initiation group at day three only.

Table 7. Adverse events Fisher 2001
 Slow initiation (day 2)%Rapid initiation (day 2)%Slow initiation (day 7)%Rapid initiation (day 7)%
Fatigue9/2803.212/2944.119/2746.922/2947.5
Dizziness18/2806.431/29410.545/27616.359/29319.1
Somnolence13/2804.616/2945.427/2759.831/29310.6
Ataxia2/2800.74/2941.49/2753.39/2943.1

In addition, Tomovic 1999 reported 24-hour electroencephalogram (EEG) recordings pre- and post-intervention and revealed a reduction in total epileptiform discharges from 229.87 to 167.13.

Gabapentin versus vigabatrin

50% or greater reduction in seizure frequency and seizure freedom

Lindberger 2000 noted a reduction in 27 out of 50 patients (54%) and 34 out of 52 patients (56%) in the gabapentin and vigabatrin groups respectively (on an intention-to-treat basis); the 90% and 95% confidence intervals were wide and this was not deemed statistically significant. The proportion of seizure-free patients without side effects was 13 out of 50 (26%) and 18 out of 52 (35%) in the gabapentin and vigabatrin groups respectively; again not statistically significant. An extra variable of 'improvement rate' (proportion of patients with 50% or greater seizure reduction without side effects) was measured and was 24 out of 50 (48%) and 29 out of 52 (56%) respectively. Thirteen out of 50 patients were reported as seizure-free in the gabapentin arm compared to 18 of 52 patients taking vigabatrin.

Treatment withdrawals

There were 14 withdrawals from the study as a result of adverse events, seven in each group. In the gabapentin group status epilepticus, psychiatric problems, epigastric pain, diplopia, vertigo and dizziness (three patients); in the vigabatrin group depression, generalised seizure, rash, numbness and dizziness (three patients).

Adverse effects

In the gabapentin group, three patients experienced serious adverse events which were status epilepticus, pyelonephritis and psychiatric problems. In the vigabatrin group, four patients had serious adverse effects which were agitation depression, weight gain, mononucleosis and a secondary generalised seizure. Thirty-eight (76%) of gabapentin patients and 45 (86.5%) of vigabatrin patients experienced adverse events of any type. The five most common adverse events were similar in both groups (tiredness, dizziness, respiratory infection, headache and diarrhoea). Specific proportions of individual side effects were not provided.

Gabapentin versus lamotrigine

50% or greater reduction in seizure frequency and seizure freedom

In Sethi 2002 (intention-to-treat analysis) a 50% or greater reduction in seizure frequency was achieved by 77.7% and 92% in the gabapentin and lamotrigine groups respectively. Complete seizure control was seen in 29.6% (8 out of 27 patients) in the gabapentin group and not specified in the lamotrigine group.

Adverse effects

Twenty-two out of 27 (81.5%) and 18 out of 25 (72%) patients reported adverse effects in the gabapentin and lamotrigine groups respectively. The most common side effects were neurotoxic: dizziness (22.2% and 28%), diplopia (11.11% and 24%), weakness (14.8% and 24%), headache (25.9% and 20%), drowsiness (14.8% and 12%), tiredness (14.8% and 4%), amnesia (11.11% and 12%), tingling sensation (11.11% and 0%) and anorexia (11.11% and 8%).

No serious adverse effects were noted in the gabapentin group. Two serious adverse effects of Steven Johnson syndrome and anxiety neurosis (corresponding with an increase in seizure frequency) were noted in the lamotrigine group. An increase in the number of seizures was seen in one patient receiving 2400 mg/day of gabapentin. In the gabapentin group a change of seizure type from partial seizures to myoclonic jerks or atypical seizures was noted in five patients during treatment. In the lamotrigine group seizure type changed to atypical absence (two patients) and pseudoseizures (two patients).

Additionally it was noted that the benefit of gabapentin was more pronounced in patients with simple partial seizures with secondary generalisation than in patients with simple and complex partial seizures without secondary generalisation, whereas all subtypes of epilepsy responded similarly in the lamotrigine group.

Discussion

All trials included in this review were sponsored by Parke Davis, apart from Sethi 2002 and Tomovic 1999. Five out of the 11 studies used adequate methods of concealment of randomisation. All trials were double-blind, however often little information was reported as to how personnel/outcome assessors were blinded. For the studies included in the meta-analysis, apart from Yamauchi 2006, published reports referred to their analyses as being intention-to-treat, with a total of 99 (of the 1206 participants recruited) excluded from analyses. Reported analyses would perhaps be better called 'exploratory', as participants who (a) had treatment withdrawn during the treatment period; and (b) did not meet the original trial inclusion criteria, were excluded from the reported analyses, despite completing the treatment period with adequate seizure data. Additional data, supplied by Parke Davis, reveal that a total of 38 did not complete the treatment phase and nine had inadequate seizure data recorded, hence the percentage reduction in seizure frequency could not be calculated for 47 of these participants. The Yamauchi 2006 study does state that 19 participants were not included in the study and provides reasons. Similarly, there was a high risk of attrition bias in the remaining studies which we discussed in narrative form (Fisher 2001; Leach 1997; Tomovic 1999), apart from the Lindberger 2000 study for which analysis was completely intention-to-treat. The Sethi 2002 study did not give any information related to drop-outs and therefore the risk is uncertain. Selective outcome reporting bias was unclear in Leach 1997, Lindberger 2000, Sethi 2002 and Tomovic 1999 as they mention 'seizure activity recorded' without details of the methodology. There are also discrepancies between study designs which may be reflected in the variability of the results. These potential biases have been outlined in each of the outcome measures below.

The results of the overall efficacy analysis show that gabapentin reduces seizure frequency when used as an add-on antiepileptic drug (AED) in people with drug-resistant partial epilepsy. The dose-response regression analysis shows increasing efficacy with increasing dose. There is considerable discrepancy between the results of the intention-to-treat and best and worst-case analyses, hence the intention-to-treat analyses need to be interpreted with some caution (see Implications for research). Results suggest that the therapeutic effect of 600 mg per day, although statistically significant, is small and 900 mg would seem a better initial dose. In addition, there is no plateauing of therapeutic effects at the doses tested and it may well be that optimal doses of gabapentin have not been tested. This is also reflected to a much greater extent by the studies described in narrative form. The Tomovic 1999 study reported 72.2% of the 18 patients evaluated as having a 50% or greater reduction in seizure frequency outcome (compared to 16% to 22% taken from meta-analysis studies) even though the demographics and treatment doses were comparable. Similarly, the head-to-head trials reported a 54% and 77% response rate (Lindberger 2000 and Sethi 2002 respectively). This could potentially be due to two key differences in methodology: the definition of 'drug-resistant' partial epilepsy and to the dosing regimes. Lindberger 2000 defined drug resistance as failure to respond to no more than two AED monotherapy regimes and gabapentin was always added to monotherapy. Sethi 2002 only recruited patients refractory to carbamazepine monotherapy and 88% of participants in the Tomovic 1999 study were on one other AED only. As the remaining studies used patients with refractory partial seizures who were established on one or two AEDs and stable doses (apart from Appleton 1999 who allowed three AEDs), the former patient populations are likely to have a less refractory epilepsy. In addition, Lindberger 2000 and Sethi 2002 used a flexible dosing regime, allowing doses of gabapentin to be increased as tolerated. This high flexibility made dose adjustments possible in response to a lack of seizure control, with doses of 3600 mg gabapentin per day allowed. This may be reflective of the increased efficacy of gabapentin at higher doses yet this flexible dosing method does result in complexity when interpreting the results as the final doses achieved to maintain seizure control have not been specified. At the other end of the spectrum in the Leach 1997 study, despite allowing doses of 2400 mg, only two out of 23 (8.7%) patients achieved 50% or greater partial seizure control; this may be reflective of the small sample size and the cross-over design. All patients received all doses (1200 mg, 1800 mg and 2400 mg) with a washout period of four weeks between doses; this dosing pattern may have influenced the efficacy of gabapentin, which may have resulted in period and carry-over effects.

The studies reviewed were all of short duration and no conclusions can be drawn regarding the long-term efficacy of gabapentin. Only one trial recruited children only (Appleton 1999) and the estimate for seizure reduction was low in that study. Caution is required when extrapolating the results of this trial to adults.

Results for the outcome 'withdrawal of allocated treatment' suggest that gabapentin is well tolerated, as no significant difference was found between gabapentin and placebo. However, the efficacy results suggest that optimal doses of gabapentin may not have been tested and it may well be that higher doses of gabapentin are less well tolerated.

With respect to adverse effects, dizziness, fatigue and somnolence were significantly more likely to occur in the gabapentin-treated group. There were insufficient data available for this review to delineate the precise adverse effect profile of this drug.

The results of this review indicate that gabapentin is an effective add-on treatment. Only two head-to-head trials were found (Lindberger 2000; Sethi 2002) with both studies not indicating a significant difference between gabapentin and the alternative AED (vigabatrin and lamotrigine). As clinicians are faced with an ever increasing number of antiepileptic drugs to choose from, more head-to-head trials are required to provide the evidence that is needed to enable clinicians to make an evidence-based choice between AEDs.

It still remains difficult to predict the differences between a rapid and slow initiation of gabapentin, as the Fisher 2001 study only observed the effects of rapid initiation on the first day of starting the maximum dose and four days later. However, they did contact patients for the subsequent two weeks to report any serious outcomes. These have not been documented in the report, therefore it is difficult to extrapolate data beyond this period.

In terms of seizure subtypes, Sethi 2002 reported gabapentin's more pronounced effects on simple partial seizures and secondary generalised as opposed to complex partial seizures. This is contrary to the US Gabapentin 1993 study, which observed gabapentin to be more efficacious in complex partial seizures.

The Kwan 2000 and Shapiro 2000 papers have been placed in the awaiting classification section as only abstracts are obtainable, therefore it is not possible to critique the study design (Characteristics of studies awaiting classification).

This review focuses on the use of gabapentin in drug-resistant partial epilepsy and the results cannot be generalised to add-on treatment in people with generalised epilepsy. Likewise, no inference can be made about the efficacy and tolerability of gabapentin when used as monotherapy.

Authors' conclusions

Implications for practice

In people with drug-resistant partial epilepsy, gabapentin has efficacy as an add-on treatment. Our results suggest that a dose of 1800 mg per day will reduce seizure frequency by at least 50% in 25.3% of people (95% confidence interval 19.3 to 32.3). Although our results suggest that 600 mg has a statistically significant effect on seizure frequency, that effect is small and 900 mg per day would seem a more reasonable initial dose. Regression analyses show no plateauing of therapeutic effect and it is likely that optimal doses need to be tested in a more standardised manner and final doses provided so that such results can be included in meta-analyses in the future. Doses of up to 2400 mg per day are currently recommended in the British National Formulary.

Dizziness, fatigue and somnolence were significant adverse effects although gabapentin is generally well tolerated.

Implications for research

(1) The conduct of future 'add-on' trials

The striking differences between the intention-to-treat, worst and best-case analyses for 50% responder rates has important implications for the conduct of further 'add-on' studies. For the intention-to-treat analysis in this review, all participants lost to follow-up or excluded from analyses due to inadequate seizure recording are assumed to be 'non-responders'. The best-case and worst-case analyses, although representing the extreme, test the effect of making that assumption. When large discrepancies are found, as in this case, the accuracy of individual trials and hence this review is challenged.

The main problem here is that participants having trial treatment withdrawn are no longer followed up. This provides a data set which allows an explanatory 'on treatment analysis', but precludes a robust intention-to-treat analysis. To minimise this problem, every attempt must be made to follow individuals up, even if trial treatment has been withdrawn. This provides the maximum data set from which analyses other than intention-to-treat may be undertaken.

(2) Further evaluation of gabapentin as an antiepileptic drug

To further evaluate the place of gabapentin in the armamentarium of available antiepileptic drugs, further studies are required which address the following:

  • the efficacy and tolerability of add-on doses higher than 1800 mg per day in people with drug-resistant partial epilepsy, in clearly specified doses and a clarification as to maximum doses achieved when flexible regimes are employed;

  • the long-term efficacy and tolerability of add-on gabapentin beyond three months;

  • how gabapentin compares with other add-on treatments in drug-resistant partial epilepsy;

  • the role of gabapentin in childhood epilepsies; and

  • how gabapentin compares with other standard antiepileptic drugs, such as sodium valproate, as monotherapy in generalised epilepsy.

Acknowledgements

We would like to acknowledge Zakaria Kadir and David Chadwick for contributing to the original review and Miloš Stojadinović for providing the translation of the Serbian paper.

Data and analyses

Download statistical data

Comparison 1. Gabapentin versus placebo
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 50% reduction in seizure frequency6 Risk Ratio (M-H, Fixed, 95% CI)Subtotals only
1.1 Primary analysis61206Risk Ratio (M-H, Fixed, 95% CI)1.89 [1.40, 2.55]
1.2 Sensitivity (best-case)61206Risk Ratio (M-H, Fixed, 95% CI)2.52 [1.89, 3.37]
1.3 Sensitivity (worst-case)61206Risk Ratio (M-H, Fixed, 95% CI)1.35 [1.04, 1.76]
2 Drug withdrawal61206Risk Ratio (M-H, Fixed, 95% CI)1.05 [0.74, 1.49]
3 Adverse effects6 Risk Ratio (M-H, Fixed, 99% CI)Subtotals only
3.1 Ataxia3787Risk Ratio (M-H, Fixed, 99% CI)2.01 [0.98, 4.11]
3.2 Dizziness61206Risk Ratio (M-H, Fixed, 99% CI)2.43 [1.44, 4.12]
3.3 Fatigue51161Risk Ratio (M-H, Fixed, 99% CI)1.95 [0.99, 3.82]
3.4 Headache61206Risk Ratio (M-H, Fixed, 99% CI)0.79 [0.46, 1.35]
3.5 Nausea41034Risk Ratio (M-H, Fixed, 99% CI)0.95 [0.52, 1.73]
3.6 Somnolence61206Risk Ratio (M-H, Fixed, 99% CI)1.93 [1.22, 3.06]
Analysis 1.1.

Comparison 1 Gabapentin versus placebo, Outcome 1 50% reduction in seizure frequency.

Analysis 1.2.

Comparison 1 Gabapentin versus placebo, Outcome 2 Drug withdrawal.

Analysis 1.3.

Comparison 1 Gabapentin versus placebo, Outcome 3 Adverse effects.

Appendices

Appendix 1. CENTRAL search strategy

#1 (gabapentin or Neurontin)
#2 MeSH descriptor Epilepsy explode all trees
#3 MeSH descriptor Seizures explode all trees
#4 epilep* or seizure* or convulsion*
#5 (#2 OR #3 OR #4)
#6 (#1 AND #5)

Appendix 2. MEDLINE search strategy

The following search was based on the Cochrane highly sensitive search strategy for MEDLINE as set out in Appendix 5b of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011).

1. randomized controlled trial.pt.

2. controlled clinical trial.pt.

3. exp Randomized Controlled Trials/

4. exp Random Allocation/

5. exp Double-Blind Method/

6. exp Single-Blind Method/

7. clinical trial.pt.

8. Clinical Trial/

9. (clin$ adj trial$).ab,ti.

10. ((singl$ or doubl$ or trebl$ or tripl$) adj (blind$ or mask$)).ab,ti.

11. exp PLACEBOS/

12. placebo$.ab,ti.

13. random$.ab,ti.

14. exp Research Design/

15. or/1-14

16. (animals not humans).sh.

17. 15 not 16

18. (gabapentin or neurontin).tw.

19. exp epilepsy/ or epilep$.tw.

20. exp seizures/ or seizure$.tw.

21. convulsion$.tw.

22. 19 or 20 or 21

23. 17 and 18 and 22 

What's new

DateEventDescription
14 May 2013New citation required but conclusions have not changedSix new studies included. Conclusions remain unchanged.
14 May 2013New search has been performedSearches updated 14 May 2013.

History

Protocol first published: Issue 1, 1999
Review first published: Issue 1, 1999

DateEventDescription
10 September 2008AmendedConverted to new review format.
1 July 2007New search has been performedWe re-ran our searches on 1 July 2007. One potential new study has been identified - this has been added to the 'Studies awaiting classification' section and will be assessed for inclusion at a later date.

Contributions of authors

Sarah Al-Bachari and Jennifer Pulman carried out the update of this review. Anthony Marson and Jane Hutton developed the original protocol. Jane Hutton carried out the dose-regression analysis.

Declarations of interest

Tony Marson has received hospitality from Parke Davis. No other conflicts of interest are declared.

Sources of support

Internal sources

  • No sources of support supplied

External sources

  • National Institute for Health Research, UK.

    This review presents independent research commissioned by the National Institute for Health Research (NIHR). The views expressed in this publication are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health.

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Anhut 1994

MethodsRandomised, double-blind, placebo-controlled, parallel-group study
3 treatment arms: 1 placebo and 2 gabapentin
Prospective pre-randomisation baseline period = 12 weeks
Treatment period = 12 weeks
ParticipantsAll adults
Cross-continent study
Total randomised 272; all with drug-resistant partial epilepsy
109 to placebo; 111 to 900 mg gabapentin; 52 to 1200 mg gabapentin
56% male
Age range 12 to 67 years
Other AEDs < 2
Median baseline seizure frequency/28 days 10.2 (range 0.5 to 634.3)
Interventions900 mg gabapentin per day
1200 mg gabapentin per day
Placebo
All treatments and packaging were identical
Outcomes

Proportion with a 50% reduction in seizure frequency
Response ratio*
Adverse effects

*Response ratio = (T-B)/(T+B) where T = number of seizures during the treatment period and B = number of seizure in the baseline period

Notes

27 participants excluded from published analyses: 10 from the placebo group; 15 from the 900 mg group; 2 from the 1200 mg group

Additional unpublished data allows the inclusion of participants excluded despite completing the treatment phase with adequate seizure data. The following participants contribute to the best and worst-case sensitivity analyses in this review.
Placebo = 7; 900 mg gabapentin = 9; 1200 mg gabapentin = 2

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskRandom permuted blocks to generate sequence for randomisation
Allocation concealment (selection bias)Low riskAllocated sequentially, sealed, numbered packages
Blinding (performance bias and detection bias)
All outcomes
Low riskIdentical tablets and packaging
Incomplete outcome data (attrition bias)
All outcomes
High risk'As treated' analysis. Disproportionate numbers excluded across groups 13:17:2 (P, 900 mg, 1200 mg), some excluded despite completing treatment phase. Exclusions not included in published analyses.
Selective reporting (reporting bias)Low riskSeizure diary for all groups, same outcomes. Published reports include all prespecified expected outcomes.

Appleton 1999

MethodsRandomised, double-blind, placebo-controlled, parallel-group study
Prospective pre-randomisation baseline period 6 weeks
Treatment period = 12 weeks
ParticipantsAll children
Cross-continent study. Total randomised 247; all with drug-resistant partial seizures (15% to 16% had generalised seizures also)
128 to placebo; 119 to gabapentin
54% male
Age range 3 to 12 years
Other AEDs < 3
Baseline seizure frequency per 28 days: median = 26.7, range = 1.3 to 2893
InterventionsPlacebo or gabapentin 600 to 1800 mg per day (equivalent to 23.2 to 35.3 mg/kg/day)
OutcomesProportion with a 50% reduction in seizure frequency
Response ratio
Adverse effects
Notes
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskMethod of randomisation not specified
Allocation concealment (selection bias)Unclear riskNo details provided
Blinding (performance bias and detection bias)
All outcomes
Unclear riskStudy mentions double-blinding - no details
Incomplete outcome data (attrition bias)
All outcomes
Low riskAll evaluated on an intention-to-treat basis
Selective reporting (reporting bias)Low risk

Published reports include all prespecified, expected outcomes

The parent/guardian and physician global assessment of patient seizure frequency and well-being

Fisher 2001

Methods

Randomised, double-blind, placebo-controlled, parallel-group study

No formal baseline period
Treatment period = 7 days

Participants

Participants at least 12 years of age
Multicentre study in USA

720 participants randomised. Initially 320 per dose initiation regime. Finally 280 slow initiation regime and 294 rapid initiation, after withdrawals and exclusions for not fulfilling pre-protocol criteria.

All participants with a recent history of partial seizures, with or without secondary generalisation with either inadequate seizure control on 1 or 2 anticonvulsants or had been judged to be unable to tolerate therapeutic dosages of these drugs (reaching maximum tolerated dose of at least 1 anticonvulsant)
280 slow initiation regime, 294 rapid initiation regime
Slow initiation 44.6% male, rapid initiation 44.2%
Age range 12 to 82 years

InterventionsSlow initiation (300 mg day 1, 600 mg day 2, then 900 mg/day) or a rapid initiation (2-day placebo lead-in followed by 900 mg/day). Total evaluated treatment period of 7 days
OutcomesReports of fatigue, dizziness, somnolence and ataxia
NotesThis study did not have a baseline period and only measured adverse outcomes over a 7-day period (day 3 (equivalent to 3rd day of active study medication for slow initiation group and first day for rapid initiation group) and day 7)), therefore unable to include in meta-analysis
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskRandomisation schedule that assigned each patient number to either the slow group or the rapid group in a one-to-one manner
Allocation concealment (selection bias)Low riskNumber specific blister packs
Blinding (performance bias and detection bias)
All outcomes
Low riskMatching placebo, all patients had a 2-day lead-in phase which was unknown to investigator and patient
Incomplete outcome data (attrition bias)
All outcomes
High riskPer protocol analysis stated to include patients who met the criteria for evaluation (not ITT analysis). 781 enrolled, only 574 analysed for 3 reasons: inadequate methods, inadequate reasons and reasons for withdrawal.
Selective reporting (reporting bias)Unclear riskExpected to report number of seizures, no baseline period

Leach 1997

Methods

The study was a double-blind, random order, cross-over, placebo-controlled study

12 weeks treatment/placebo

No baseline period, however all patients reported at least 4 seizures/month for 3 months and AED doses had remained unchanged for at least 3 months prior to study

Participants

Single centre (Western Infirmary in Glasgow)

Adults all with partial seizures refractory to 1 or 2 antiepileptic drugs

Total randomised 27; 23 analysed after withdrawals

Age 16 to 67, mean 28.4

37% male prior to withdrawals

InterventionsComparison of 3 sequential doses of GBP (400 mg, 600 mg and 800 mg all TDS, each dose increase after 4 weeks) with matched placebo
Outcomes

Seizure frequency

Seizure freedom

Adverse effects (scored, individual adverse effects not mentioned)

Neuropsychological tests (psychomotor, memory, cognition, dysphoria, temper, fatigue, worry, tiredness)

NotesNo baseline period therefore not included in meta-analysis
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNo details of randomisation provided
Allocation concealment (selection bias)Unclear riskNo details provided
Blinding (performance bias and detection bias)
All outcomes
Unclear riskDouble-blind and matched placebo but no further details provided
Incomplete outcome data (attrition bias)
All outcomes
High risk25% of participants excluded and not analysed on an ITT basis
Selective reporting (reporting bias)Low riskIncluded all prespecified expected outcomes

Lindberger 2000

Methods

A randomised, double-blind, dose titration study comparing gabapentin with vigabatrin

8-week baseline period

24-week treatment period, evaluation period at 8 weeks compared with baseline

To allow flexibility a dose adjustment regime was designed, with increases in doses of drug based on patient tolerance and seizure control, increased if required at 4-week periods, with a maximum treatment period at each dose of 8 weeks

Participants

Multicentre (34) Nordic countries

102 randomised, then 35 (gabapentin group) and 44 (vigabatrin group) post exclusions for not for fulfilling criteria

Patients with partial epilepsy who had tried no more than 2 AED monotherapy regimes

Interventions

Gabapentin variable dose 1800 mg/day minimum, then 2400 mg then max 3600 mg/day, increased every 8 weeks as tolerated

Vigabatrin initial 1000 mg then 2000 mg then 4000 mg increased in the same manner as gabapentin

Outcomes

Primary outcome: improvement rate: proportion of patients with 50% seizure reduction without side effects

Seizure reduction rate: proportion of patients with 50% seizure reduction irrespective of side effects

Responder rate: proportion of seizure-free patients without side effects

Secondary outcomes:quality of life measures, adverse events, perimetry

NotesResults provided do not indicate the doses the patients had achieved of each drug
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot specified
Allocation concealment (selection bias)Unclear riskNo details provided
Blinding (performance bias and detection bias)
All outcomes
Low riskDouble-dummy technique, patients received active drug and corresponding placebo
Incomplete outcome data (attrition bias)
All outcomes
Low riskAnalysed on an ITT basis
Selective reporting (reporting bias)Low riskSeizure activity reported

Sethi 2002

Methods

Randomised control trial

Head-to-head trial; 2 treatment arms gabapentin and lamotrigine

Treatment period of 12 weeks

No formal baseline period (however all had at least 4 seizures, unclear over what time period, despite treatment with maximum dose carbamazepine monotherapy)

Participants

52 children and adults

Indian study

Refractory partial seizures

48% male

27 gabapentin (19 M:8 F), 25 lamotrigine (6 M: 19F)

Age range 10 to 60

Interventions

Gabapentin: 300 mg day 1, 300 mg BD day 2, there after an increment of 300 mg daily until 50% reduction or more in seizures or toxic effects

Lamotrigine: 50 mg/day for two weeks, increased to 50 mg BD, subsequently an increase of 50 to 100 mg daily until above criteria met

Outcomes

Efficacy: seizure frequency, pattern of seizures, seizure-free interval. Including percentage change of seizure frequency from baseline, responder rate (50% or more reduction in seizure frequency), response ratio

Safety: biochemical investigations and adverse effects

NotesAs no clear baseline period, excluded from meta-analysis
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNo details provided
Allocation concealment (selection bias)Unclear riskNo details provided
Blinding (performance bias and detection bias)
All outcomes
Unclear riskNo details provided
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskNo participants seem to be excluded from the results, ? 1 in gabapentin group that does not seem to be accounted for
Selective reporting (reporting bias)Low riskIncluded all prespecified expected outcomes

Sivenius 1991

MethodsRandomised, double-blind, placebo-controlled, parallel-group study
3 treatment arms: 1 placebo and 2 gabapentin
Prospective pre-randomisation baseline period = 12 weeks
Treatment period = 12 weeks
ParticipantsAll adults
Finland
Total randomised 45; all with drug-resistant partial epilepsy
18 to placebo; 18 to 900 mg gabapentin; 9 to 1200 mg gabapentin
47% male
Age range 16 to 59 years
Other AEDs < 2
Median baseline seizure frequency per 12-week baseline period: placebo = 36; 900 mg gabapentin = 26; 1200 mg gabapentin = 23
Interventions900 mg gabapentin per day, 1200 mg gabapentin per day, placebo
All treatments and packaging were identical
OutcomesMedian change in seizure frequency
Per cent change in seizure frequency
Adverse effects
Notes2 people in the 900 mg group were excluded from analysis, both excluded 2 weeks post-randomisation
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskAllocated sequentially, sealed, numbered packages
Allocation concealment (selection bias)Low riskRandom permuted blocks
Blinding (performance bias and detection bias)
All outcomes
Low riskIdentical tablets and packaging. Identical analysis of results.
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskNo reasons reported for exclusion of 2 patients in 900 mg group
Selective reporting (reporting bias)Low risk"... seizure frequency was recorded" - unclear how, otherwise includes all prespecified expected outcomes

Tomovic 1999

MethodsRandomised, parallel-group study
Participants

9 women and 9 men with refractory partial epilepsy. Serbian adults. Average age 24.7, range 17 to 47

Drug-resistant partial epilepsy

All had been treated with 1 or 2 first-line antiepileptic drugs during 3 months before introducing gabapentin with unsatisfactorily controlled seizures

Seizure frequency prior to treatment is unclear

Interventions2 treatment arms: 900 mg and 1200 mg gabapentin/day
Outcomes

Seizure frequency

Seizure freedom

Haematological and biochemical analyses (4th and 12th week) and 24-hour EEG on before therapy and on final week (W12) Frequency of epileptiform discharges noted

Reduction in seizure activity: 26% to 49%; 50% to 99%; 100%; worse state

Adverse effects

Notes3 people did not complete the study and so were not included in the study altogether (i.e. not included in demographics etc.)
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskMethod of randomisation unclear
Allocation concealment (selection bias)Unclear riskHow participants allocated to each group is unclear
Blinding (performance bias and detection bias)
All outcomes
Unclear riskUnclear if identical tablets and packaging
Incomplete outcome data (attrition bias)
All outcomes
High riskUnclear why 3 participants dropped out and excluded from analysis
Selective reporting (reporting bias)Low riskSeizure frequency recorded - unclear how seizure activity measured. Otherwise standardised tests for both groups.

UK Gabapentin 1990

MethodsRandomised, double-blind, placebo-controlled, parallel-group study
Prospective pre-randomisation baseline period = 12 weeks
Treatment period = 14 weeks
ParticipantsAll adults
Cross-continent study
Total randomised 127; all with drug-resistant partial epilepsy
66 to placebo; 61 to 1200 mg gabapentin
39% male
Age range 14 to 73 years
Other AEDs < 2
Median baseline seizure frequency/28 days: gabapentin = 13 (range 3 to 368); placebo = 13 (range 1 to 216)
Interventions1200 mg gabapentin per day
Placebo
All treatments and packaging were identical
OutcomesProportion with a 50% reduction in seizure frequency
Response ratio
Adverse effects
Notes

14 participants excluded from published analyses: 5 from the placebo group; 9 from the 1200 mg group

Additional unpublished data allows the inclusion of participants excluded despite completing the treatment phase with adequate seizure data. The following participants contribute to the best and worst-case sensitivity analyses in this review.
Placebo = 2; 1200 mg gabapentin = 8

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskUsed random permuted blocks to generate sequence for randomisation
Allocation concealment (selection bias)Low riskAllocated sequentially, sealed, numbered packages
Blinding (performance bias and detection bias)
All outcomes
Low riskUsed identical tablets and packaging
Incomplete outcome data (attrition bias)
All outcomes
High riskAttrition rate reported, 14 participants who withdrew were not included in published analyses. Does report withdrawals and gives reasons for withdrawal.
Selective reporting (reporting bias)Low riskIncluded all prespecified, expected outcomes

US Gabapentin 1993

MethodsRandomised, double-blind, placebo-controlled, parallel-group study
4 treatment arms: 1 placebo and 3 gabapentin
Prospective pre-randomisation baseline period = 12 weeks
Treatment period = 12 weeks
ParticipantsAll adults
USA study
Total randomised 306; all with drug-resistant partial epilepsy
98 to placebo; 53 to 600 mg gabapentin; 101 to 1200 mg gabapentin; 54 to 1800 mg gabapentin
66% male
Age range 16 to 70 years
Other AEDs < 2
Median baseline seizure frequency/28 days 10.8 (range 2.0 to 1092.7)
Interventions600 mg gabapentin per day
1200 mg gabapentin per day
1800 mg gabapentin per day
Placebo
All treatments and packages were identical
OutcomesProportion with a 50% reduction in seizure frequency
Response ratio
Adverse effects
Notes

18 participants were excluded from published analyses: 3 from the placebo group; 4 from the 600 mg group; 10 from the 1200 mg group; 1 from the 1800 mg group

Additional unpublished data allows the inclusion of participants excluded despite completing the treatment phase with adequate seizure data. The following participants contribute to the best and worst-case sensitivity analyses in this review Placebo = 2; 600 mg gabapentin = 4; 1200 mg gabapentin = 10; 1800 mg gabapentin = 1

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskUsed random permuted blocks to generate sequence for randomisation
Allocation concealment (selection bias)Low riskAllocated sequentially, sealed, numbered packages
Blinding (performance bias and detection bias)
All outcomes
Low riskUsed identical tablets and packaging
Incomplete outcome data (attrition bias)
All outcomes
High riskAttrition rate reported, 18 participants not included in published analyses and no reasons given
Selective reporting (reporting bias)Low riskIncluded all prespecified expected outcomes

Yamauchi 2006

  1. a

    AED: antiepileptic drug
    BD: twice a day
    EEG: electroencephalogram
    GBP: gabapentin
    ITT: intention-to-treat
    TDS: three times a day

Methods

Randomised, double-blind, placebo-controlled, parallel-group study
Prospective pre-randomisation baseline period 12 weeks
Treatment period = 12 weeks

Dose-reduction period lasting 8 days - 4 weeks instituted, followed by a 4-week post-dosing observation period

3 treatment arms - 1 placebo and 2 treatment (1200 mg TDS, 1800 mg TDS)

Participants

Adults (16+)

Majority between 18 and 44, mean age between 3 groups 31 to 33 years

Multicentre Japanese study March 2000-October 2002

Other AEDs greater than 1

Total randomised 209; all with drug-resistant partial epilepsy
82 to placebo (42 males, mean age 31.8 +/- 11.3, 25 secondary generalised seizures, mean duration epilepsy 19.5 years, mean seizure frequency/28 days 19.9, 1 other AED 19.5%, 80.5% 2 other)

86 to 1200 mg gabapentin (37 males, mean age 31.3 +/- 10.6, 26.3 secondary generalised seizures, mean duration epilepsy 19.8 years, mean seizure frequency/28 days 31.6, 1 other AED 14%, 86% 2 other AED)

41 to 1800 mg gabapentin (22 males, mean age 32.7 +/- 13.7, 13 secondary generalised seizures, mean duration epilepsy 21.2 years, mean seizure frequency/28 days 24.2, 1 other AED 4.9%, 95.1% 2 other AEDs)

19 excluded; after exclusion placebo = 75, 1200 mg = 80, 1800 mg = 35
Baseline seizure frequency/12 weeks: 8

Interventions1200 mg gabapentin per day
1800 mg gabapentin per day
Placebo
All treatments were identical (200 mg tablets)
Outcomes

Improvement in seizure frequency: completely (-100%), markedly improved (-99.9% to -75.0%), moderately improved (-74.9% to -50%), slightly improved (-49.9% to -25%), no change (-24.9% to 0%), aggravated (> +0.1%)

Response ratio

Seizure intensity/duration: better, no change and worse

Adverse effects

Serious treatment-related adverse events

*Response ratio = (T-B)/(T+B) where T = number of seizures during the treatment period, and B = number of seizure in the baseline period

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskLittle/no detail regarding randomisation given. Most variables between arms controlled (age, sex, frequency, no. of other AED, previous treatments etc.)
Allocation concealment (selection bias)Unclear riskInsufficient information provided
Blinding (performance bias and detection bias)
All outcomes
Low riskIdentical tablets, all outcomes blinded and monitored and followed up in the same way
Incomplete outcome data (attrition bias)
All outcomes
High riskITT analysis not employed; reasons for exclusions stated, however 19 patients not included
Selective reporting (reporting bias)Low riskSeizure diary for all groups, same outcomes. Published reports include all prespecified expected outcomes

Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion
Crawford 1987No seizure data recorded

Characteristics of studies awaiting assessment [ordered by study ID]

Kwan 2000

MethodsA double-blind, randomised, placebo-controlled, cross-over study in China
Participants43 adult patients with refractory partial seizures
InterventionsGabapentin 600 mg/day for 1 week and 1200 mg/day for 12 weeks with matching placebo controls
OutcomesConclusions were made that gabapentin is a safe and effective add-on therapy for drug-resistant partial epilepsy (-0.5 +/- 1.5, P = 0.04). Response ratio (-0.3 +/- 0.5, P = 0.02) and per cent change (-35.0% +/- 53.4%, P = 0.01) in complex partial seizures with secondary generalisation
NotesThere are no other data available for analysis; all data taken from abstract; author unable to provide further information

Shapiro 2000

  1. a

    TDS: three times a day

MethodsA randomised, placebo-controlled trial, USA
Participants76 young children with partial epilepsy
InterventionsSyrup formulation of gabapentin 40 mg/kg/day given TDS or placebo
OutcomesMain outcome was seizure reduction. Concluded that gabapentin was safe and well tolerated, and reduced the rate of partial seizures, however this finding did not reach significance.
NotesAll information taken from abstract, unable to contact study authors