Antiepileptics other than gabapentin, pregabalin, topiramate, and valproate for the prophylaxis of episodic migraine in adults

  • Review
  • Intervention

Authors

  • Mattias Linde,

    Corresponding author
    1. Norwegian University of Science and Technology, Department of Neuroscience, Trondheim, Norway
    2. St. Olav’s University Hospital, Norwegian Advisory Unit on Headaches, Trondheim, Norway
    • Mattias Linde, Department of Neuroscience, Norwegian University of Science and Technology, Trondheim, Norway. mattias.linde@ntnu.no.

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  • Wim M Mulleners,

    1. Canisius Wilhelmina Ziekenhuis, Department of Neurology, Nijmegen, Netherlands
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  • Edward P Chronicle,

    1. University of Hawaii at Manoa, (Deceased) Department of Psychology, Manoa, USA
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  • Douglas C McCrory

    1. Duke University Medical Center, Department of Medicine, Durham, NC, USA
    2. Durham Veterans Affairs Medical Center, Center for Health Services Research in Primary Care, Durham, NC, USA
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Abstract

Background

Some antiepileptic drugs but not others are useful in clinical practice for the prophylaxis of migraine. This might be explained by the variety of actions of these drugs in the central nervous system. The present review is part of an update of a Cochrane review first published in 2004, and previously updated (conclusions not changed) in 2007.

Objectives

To describe and assess the evidence from controlled trials on the efficacy and tolerability of antiepileptic drugs other than gabapentin, pregabalin, topiramate, and valproate (which are the subjects of separate Cochrane reviews) for preventing migraine attacks in adult patients with episodic migraine.

Search methods

We searched the Cochrane Central Register of Controlled Trials (CENTRAL; The Cochrane Library 2012, Issue 12), PubMed/MEDLINE (1966 to 15 January 2013), MEDLINE In-Process (current week, 15 January 2013), and EMBASE (1974 to 15 January 2013) and handsearched Headache and Cephalalgia through January 2013.

Selection criteria

Studies were required to be prospective, controlled trials of antiepileptic drugs other than gabapentin, pregabalin, topiramate, and valproate taken regularly to prevent the occurrence of migraine attacks, to improve migraine-related quality of life, or both.

Data collection and analysis

Two review authors independently selected studies and extracted data. For headache frequency data, we calculated mean differences (MDs) between antiepileptic drugs and comparators (placebo, active control, or same drug in a different dose) for individual studies and pooled these across studies. For dichotomous data on responders (patients with ≥ 50% reduction in headache frequency), we calculated odds ratios (ORs) and numbers needed to treat (NNTs). We also summarised data on adverse events from placebo-controlled trials and calculated risk differences (RDs) and numbers needed to harm (NNHs).

Main results

Eleven papers describing 10 unique trials met the inclusion criteria. The 10 trials reported results for nine antiepileptic drugs other than gabapentin, pregabalin, topiramate, and valproate. Six of the eight drugs investigated in placebo-controlled trials were not better than placebo in reducing headache frequency per 28-day period during treatment (clonazepam, lamotrigine, oxcarbazepine, and vigabatrin) and/or in the proportion of responders (acetazolamide, carisbamate, lamotrigine, oxcarbazepine). One prospective, randomised, double-blind, single cross-over trial of 48 patients demonstrated a significant superiority of carbamazepine over placebo in the proportion of responders (OR 11.77; 95% confidence interval (CI) 3.92 to 35.32). The NNT was 2 (95% CI 2 to 3). In a small prospective, randomised, double-blind, parallel-group trial, levetiracetam 1000 mg was significantly superior to placebo in reducing headache frequency per 28-day period during treatment (MD -2.40; 95% CI -4.52 to -0.28; 26 patients), as well as in the proportion of responders (OR 26.07; 95% CI 1.30 to 521.91; 26 patients). The NNT was 2 (95% CI 1 to 4). The same trial examined levetiracetam 1000 mg versus topiramate 100 mg and found a small but significant difference favouring topiramate in headache frequency per 28-day period during treatment (MD 1.40; 95% CI 0.14 to 2.66; 28 patients). There was no significant difference between levetiracetam and topiramate in the proportion of responders (OR 0.71; 95% CI 0.16 to 3.23; 28 patients). Finally, one trial with 75 participants examined zonisamide versus topiramate (200 and 100 mg, respectively) and found no significant difference between them in reduction of headache frequency from baseline during the third month of treatment. Adverse events for active treatment versus placebo were available for all investigated drugs except levetiracetam, vigabatrin, and zonisamide. A high prevalence of adverse events was noted for carbamazepine, with a NNH of only 2 (95% CI 2 to 4).

Authors' conclusions

Available evidence does not allow robust conclusions regarding the efficacy of antiepileptic drugs other than gabapentin, pregabalin, topiramate, and valproate in the prophylaxis of episodic migraine among adults. Acetazolamide, carisbamate, clonazepam, lamotrigine, oxcarbazepine, and vigabatrin were not more effective than placebo in reducing headache frequency. In one trial each, carbamazepine and levetiracetam were significantly superior to placebo in reducing headache frequency, and there was no significant difference in proportion of responders between zonisamide and active comparator. These three positive studies suffer from considerable methodological limitations.

Résumé scientifique

Antiépileptiques autres que la gabapentine, la prégabaline, le topiramate et le valproate pour la prophylaxie des épisodes migraineux chez l'adulte

Contexte

Certains médicaments antiépileptiques, mais pas d'autres, sont utiles dans la pratique clinique pour la prophylaxie de la migraine. Cela pourrait s'expliquer par la diversité des actions de ces médicaments dans le système nerveux central. La présente revue fait partie d'une mise à jour d’une revue Cochrane publiée pour la première fois en 2004 et précédemment mise à jour en 2007 (conclusions inchangées).

Objectifs

Décrire et évaluer les preuves issues des essais contrôlés sur l'efficacité et la tolérance des médicaments antiépileptiques autres que la gabapentine, la prégabaline, le topiramate et le valproate (qui font l'objet de revues Cochrane distinctes) pour la prévention des crises de migraine chez les patients adultes souffrant d'épisodes migraineux.

Stratégie de recherche documentaire

Nous avons effectué une recherche dans le registre Cochrane des essais contrôlés (CENTRAL ; The Cochrane Library 2012, numéro 12), PubMed/MEDLINE (de 1966 au 15 janvier 2013), MEDLINE In-Process (semaine actuelle, 15 janvier 2013), et EMBASE (de 1974 au 15 janvier 2013) et des recherches manuelles de Maux de tête et Céphalées jusqu'à janvier 2013.

Critères de sélection

Les études devaient impérativement être des essais contrôlés prospectifs portant sur des médicaments antiépileptiques autres que la gabapentine, la prégabaline, le topiramate et le valproate pris régulièrement pour prévenir la survenue de crises de migraine, pour améliorer la qualité de vie liée à la migraine ou les deux.

Recueil et analyse des données

Deux auteurs de la revue ont indépendamment sélectionné des études et extrait des données. Pour les données sur la fréquence des maux de tête, nous avons calculé la différence moyenne (DM) entre des médicaments antiépileptiques et des comparateurs (placebo, témoin actif, ou médicament identique à une dose différente) pour les études individuelles et regroupé celles-ci entre les études. Pour les données dichotomiques sur les répondants (patients obtenant au moins 50 % de réduction de la fréquence des maux de tête), nous avons calculé les rapports de cotes (RC) et le nombre de sujets à traiter (NST). Nous avons aussi résumé les données sur les événements indésirables figurant dans les essais contrôlés par placebo et calculé les différences de risque (DR) et le nombre de sujets à traiter pour observer un effet indésirable du traitement (NNN).

Résultats principaux

Onze articles décrivant 10 essais uniques répondaient aux critères d'inclusion. Les 10 essais ont rapporté des résultats pour neuf médicaments antiépileptiques autres que la gabapentine, la prégabaline, le topiramate et le valproate. Six médicaments sur les huit étudiés dans les essais contrôlés par placebo n'ont pas été plus efficaces que le placebo pour réduire la fréquence des maux de tête par période de 28 jours durant le traitement (clonazépam, lamotrigine, oxcarbazépine et vigabatrine) et/ou en termes de proportion de répondants (acétazolamide, carisbamate, lamotrigine, oxcarbazépine). Un unique essai croisé, prospectif, randomisé, en double aveugle, totalisant 48 patients a démontré que la carbamazépine est nettement plus efficace que le placebo en termes de proportion de répondants (RC 11,77 ; intervalle de confiance (IC) à 95 % 3,92 à 35,32). Le NST était de 2 (IC à 95 % 2 à 3). Dans un petit essai en groupes parallèles, prospectif, randomisé, en double aveugle, le lévétiracétam 1 000 mg a été nettement plus efficace que le placebo pour réduire la fréquence des maux de tête par période de 28 jours durant le traitement (DM -2,40 ; IC à 95 % -4,52 à -0,28 ; 26 patients), ainsi que pour la proportion de répondants (RC 26,07 ; IC à 95 % 1,30 à 521,91 ; 26 patients). Le NST était de 2 (IC à 95 % 1 à 4). Ce même essai a comparé le lévétiracétam 1 000 mg au topiramate 100 mg et a révélé une différence petite mais significative favorisant le topiramate dans la fréquence des maux de tête par période de 28 jours durant le traitement (DM 1,40 ; IC à 95 % 0,14 à 2,66 ; 28 patients). Il n'y avait aucune différence significative entre le lévétiracétam et le topiramate dans la proportion de répondants (RC 0,71 ; IC à 95 % 0,16 à 3,23 ; 28 patients). En dernier lieu, un essai totalisant 75 participants a comparé le zonisamide au topiramate (200 et 100 mg, respectivement) et n'a détecté aucune différence significative entre eux en termes de réduction de la fréquence des maux de tête par rapport aux valeurs initiales au cours du troisième mois de traitement. Les événements indésirables pour le traitement actif comparé au placebo avaient été consignés pour tous les médicaments étudiés à l'exception du lévétiracétam, de la vigabatrine et du zonisamide. Une forte prévalence des événements indésirables a été notée pour la carbamazépine, avec un NNN de 2 seulement (IC à 95 % 2 à 4).

Conclusions des auteurs

Les preuves disponibles ne permettent pas d'émettre des conclusions solides concernant l'efficacité des médicaments antiépileptiques autres que la gabapentine, la prégabaline, le topiramate et le valproate dans la prophylaxie des épisodes migraineux chez l'adulte. L'acétazolamide, le carisbamate, le clonazépam, la lamotrigine, l'oxcarbazépine et la vigabatrine n'ont pas été plus efficaces que le placebo pour réduire la fréquence des maux de tête. Dans un essai de chacun d'eux, la carbamazépine et le lévétiracétam ont été nettement plus efficaces que le placebo pour réduire la fréquence des maux de tête, et il n'y avait aucune différence significative dans la proportion de répondants entre le zonisamide et le comparateur actif. Ces trois études positives souffrent de limites méthodologiques considérables.

Notes de traduction

Translated by: French Cochrane Centre

Translation supported by: 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.

Plain language summary

Antiepileptics other than gabapentin, pregabalin, topiramate, and valproate for preventing migraine attacks in adults

Various medicines, collectively termed 'antiepileptics', are used to treat epilepsy. For several years, three antiepileptics have also been recommended as drugs of first choice (topiramate and valproate) or third choice (gabapentin) for preventing migraine attacks. These three drugs, along with one other (pregabalin), are the subject of separate Cochrane reviews. For the present review, researchers in The Cochrane Collaboration reviewed the evidence about the effect of other antiepileptics in adult patients (≥ 16 years of age) with 'episodic' migraine (headache on < 15 days per month). They examined research published up to 15 January 2013 and found 10 studies of nine different antiepileptics. The majority of these drugs were no better than placebo for migraine prophylaxis (acetazolamide, carisbamate, clonazepam, lamotrigine, oxcarbazepine, and vigabatrin). In one study each, carbamazepine and levetiracetam were better than placebo, and there was no significant difference between zonisamide and topiramate (a drug proven to be effective for migraine prophylaxis). None of these studies was of high methodological quality. The quantity and quality of the evidence were such that no firm conclusions could be drawn about the effect or lack of effect of any of the antiepileptics studied.

Résumé simplifié

Antiépileptiques autres que la gabapentine, la prégabaline, le topiramate et le valproate pour la prévention des crises de migraine chez l'adulte

Différents médicaments, collectivement désignés par le terme générique 'antiépileptiques', sont utilisés pour traiter l'épilepsie. Depuis plusieurs années, trois antiépileptiques sont aussi recommandés en tant que médicaments de premier choix (topiramate et valproate) ou de troisième choix (gabapentine) pour la prévention des crises de migraine. Ces trois médicaments, ainsi qu'un autre (prégabaline), font l'objet de revues Cochrane distinctes. Pour la présente revue, les chercheurs de la Cochrane Collaboration ont examiné les preuves sur l'effet d'autres antiépileptiques chez des patients adultes (âgés d'au moins 16 ans) souffrant 'd'épisodes migraineux' (maux de tête pendant moins de 15 jours par mois). Ils ont examiné la recherche publiée jusqu'au 15 janvier 2013 et trouvé 10 études portant sur neuf différents antiépileptiques. La majorité de ces médicaments n'ont pas été plus efficaces que le placebo pour la prophylaxie de la migraine (acétazolamide, carisbamate, clonazépam, lamotrigine, oxcarbazépine et vigabatrine). Dans une étude portant sur chacun d'eux, la carbamazépine et le lévétiracétam ont été plus efficaces que le placebo, et il n'y avait aucune différence significative entre le zonisamide et le topiramate (médicament dont l'efficacité est prouvée dans la prophylaxie de la migraine). Aucune de ces études n'était d'une grande qualité méthodologique. Compte tenu de la quantité et de la qualité des preuves insuffisantes, aucune conclusion définitive n'a pu être émise sur l'effet ou le manque d'effet de n'importe lequel des antiépileptiques étudiés.

Notes de traduction

Translated by: French Cochrane Centre

Translation supported by: 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.

Laički sažetak

Antiepileptici osim gabapentina, pregabalina, topiramata i valproata za sprječavanje napadaja migrene u odraslih

Razni lijekovi, zajedničkog naziva antiepileptici, koriste se u terapiji epilepsije. Već neko vrijeme tri se antiepileptika preporučuju kao lijekovi prvog izbora (topiramat i valproat) ili trećeg izbora (gabapentin) za sprečavanje napadaja migrene. Ta tri lijeka, zajedno s još jednim (pregabalin) su predmet zasebnih Cochrane pregleda. U ovom sustavnom pregledu istraživači Cochranea pregledali su dokaze o učinkovitosti drugih antiepileptika u odraslih pacijenata (≥16 godina starosti) s epizodnom migrenskom glavoboljom (glavobolja koja se javlja u manje od 15 dana u mjesecu). Ispitana su istraživanja objavljena do 15. siječnja 2013. i pronađeno je 10 studija u kojima je ispitano devet različitih antiepileptika. Većina tih lijekova nije bila bolja od placeba u sprječavanju pojave migrene (acetazolamid, karisbamat, klonazepam, lamotrigin, okskarbazepin i vigabatrin) U po jednoj studiji svaki, karbamazepin i levetiracetam bili su bolji od placeba i nije bilo značajne razlike između zonisamida i topiramata (lijek za koji je dokazano da je učinkovit u migrenskoj profilaksi). Niti jedna od tih studija nije bila visoke metodološke kvalitete. Kvantiteta i kvaliteta dokaza bile su takve da se ne mogu naći čvrsti dokazi o učinku ili nedostatku učinka za niti jedan od antiepileptika koji su proučavani.

Bilješke prijevoda

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

Background

Description of the condition

Migraine is a common and disabling health problem among children and predominantly young and middle-aged adults. Surveys from the main regions of the world suggest that the global prevalence of migraine is 14.7% (18.8% among women and 10.7% among men; GBD 2010 Study). This disorder results in significant disability and work loss, and several studies have addressed the issue of the costs of migraine. In one of the most recent publications, aggregate direct and indirect costs to society due to migraine among adults in the European Union were estimated to amount to 50 billion Euros (67 billion US dollars) annually, or about 1222 Euros (1634 US dollars) annually per sufferer (Linde 2012).

Description of the intervention

Drug therapy for migraine falls into two categories: acute and preventive. Acute therapy aims at the symptomatic treatment of the head pain and other symptoms associated with an acute attack of migraine. The primary goals of preventive treatment are to reduce attack frequency, severity, and duration. Moreover, such therapy is commonly employed in an attempt to improve responsiveness to acute treatment, enhance functional status, and reduce disability. Evidence-based guidelines on the drug treatment of migraine have been developed and published by the European Federation of Neurological Societies (EFNS; Evers 2009). These guidelines suggest that prophylactic therapy should be considered for patients with migraine when quality of life, business duties, or school attendance are severely impaired; when the frequency of attacks is two or more per month; when there is a lack of response to acute drug treatment; and when frequent, very long, or uncomfortable auras occur.

This review considers the evidence for the efficacy and tolerability of antiepileptic drugs other than gabapentin, pregabalin, topiramate, and valproate (which are the subjects of separate Cochrane reviews) for preventing episodic migraine in adults. The prophylactic treatment of migraine in children is the subject of a separate Cochrane review (Victor 2003).

How the intervention might work

We use the term 'antiepileptics' here to refer generally to those drugs in common use for the treatment of epilepsy. The pharmacological treatment of epilepsy can be traced back as far as 1857, but the period of greatest development of antiepileptics was between 1935 and 1960, when 13 drugs were developed and marketed (Porter 1992). In recent decades, renewed interest has led to the development of several novel antiepileptics which may confer advantages in tolerability (Dalkara 2012), and these are beginning to be used in migraine also.

The use of antiepileptics for the prophylactic treatment of migraine is theoretically warranted by several known modes of action which relate either to the general modulation of pain systems or more specifically to systems involved in the pathophysiology of migraine (Silberstein 2008; Wiffen 2010). It is necessary to point out, however, that it is not currently possible to state with any certainty which particular mode or modes of action of antiepileptics are relevant to the prophylaxis of migraine.

Why it is important to do this review

Some antiepileptic drugs are marketed specifically for migraine relief, and divalproex sodium (a stable combination of sodium valproate and valproic acid in a 1:1 molar ratio) has been approved by the US Food and Drug Administration (FDA) for migraine prophylaxis since 1996. The EFNS (Evers 2009) and the Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Society (Silberstein 2012) list topiramate and valproic acid among first-line prophylactics. The EFNS lists gabapentin as a drug of third choice (only probable efficacy; Evers 2009), and the Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Society (Silberstein 2012) list it as Level U (inadequate or conflicting data to support or refute medication use). Regarding other antiepileptics, the EFNS concludes that lamotrigine does not reduce the frequency of attacks, and that oxcarbazepine is without any efficacy (Evers 2009), and the Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Society (Silberstein 2012) list carbamazepine as possibly effective (Level C), clonazepam and oxcarbazepine as possibly not effective, and lamotrigine as ineffective (Level A), and conclude that data are inadequate or conflicting to support or refute use of acetazolamide (Level U).

There is a fairly substantial body of evidence from controlled trials supporting the efficacy of many of the agents used for preventing migraine, yet such therapies are used by only a small percentage of patients with migraine — 3% to 12% in various studies (Clarke 1996; Edmeads 1993; Mehuys 2012). It is hoped that this review and others like it will increase awareness of migraine prophylactic treatment options and help to provide a systematic basis for making the best possible choice of such therapy in those individuals in need of it.

The present review is part of a series of reviews which, taken together, represent an update of a Cochrane review on 'Anticonvulsant drugs for migraine prophylaxis' (Chronicle 2004; Mulleners 2008; first published in 2004, and previously updated (conclusions not changed) in 2007). The old review has been split into four separate reviews for updating:

  1. Topiramate for the prophylaxis of episodic migraine in adults (Linde 2013a)

  2. Valproate (valproic acid or sodium valproate or a combination of the two) for the prophylaxis of episodic migraine in adults (Linde 2013b)

  3. Gabapentin or pregabalin for the prophylaxis of episodic migraine in adults (Linde 2013c)

  4. Antiepileptics other than gabapentin, pregabalin, topiramate, and valproate for the prophylaxis of episodic migraine in adults (the present review, Linde 2013d)

Objectives

To describe and assess the evidence from controlled trials on the efficacy and tolerability of antiepileptic drugs other than gabapentin, pregabalin, topiramate, and valproate (which are the subjects of separate Cochrane reviews) for preventing migraine attacks in adult patients with episodic migraine.

Methods

Criteria for considering studies for this review

Types of studies

The International Headache Society (IHS) has provided a useful document setting out guidelines for the conduct of clinical trials in migraine, to which current investigators are encouraged to adhere (Tfelt-Hansen 2012). This document was not used as the sole basis for considering studies in this review, as too many potentially informative past studies would likely have been excluded on methodological grounds. However, many of its recommendations have been used as a basis for what follows.

Included studies were required to be prospective, controlled trials of self administered antiepileptic drugs other than gabapentin, pregabalin, topiramate, or valproate taken regularly to prevent the occurrence of migraine attacks, to improve migraine-related quality of life, or both. We included trials only if allocation to treatment groups was randomised or pseudo-randomised (based on some non-random process unrelated to the treatment selection or expected response). Blinding was not required. We excluded concurrent cohort comparisons and other non-experimental designs.

Types of participants

Study participants were required to be adults (at least 16 years of age) and to meet reasonable criteria designed to distinguish migraine from tension-type headache. If patients with both types of headache were included in a trial, results were required to be stratified by headache diagnosis. We did not require the use of a specific set of diagnostic criteria (eg, Ad Hoc Cttee 1962; IHS Cttee 1988; ICHD-II 2004), but migraine diagnoses had to be based on at least some of the distinctive features of migraine, eg, nausea/vomiting, severe head pain, throbbing character, unilateral location, phono/photophobia, or aura. Secondary headache disorders had to be excluded using reasonable criteria.

We anticipated that some of the trials identified would include patients described as having mixed migraine and tension-type headaches or combination headaches, and the protocol for this review described detailed procedures for dealing with such trials. In the end, no such precautions were necessary. We excluded studies evaluating treatments for chronic daily headache, chronic migraine, and transformed migraine. The reasons for this are: (a) the definition of chronic migraine is still heavily debated, and a revision of the 2004 IHS criteria for this condition has been proposed (Olesen 2006); (b) transformed migraine and chronic daily headache, although commonly used terms, are insufficiently validated diagnoses; (c) the separation of these conditions from headache due to medication overuse is not always clear in many studies; and (d) there is some evidence that suggests that chronic migraine may be more refractory to standard prophylactic treatment than episodic migraine. We explicitly excluded trials and treatment groups including only patients with tension-type headache.

Types of interventions

Included studies were required to have at least one arm in which an antiepileptic drug other than gabapentin, pregabalin, topiramate, or valproate (without concomitant use of other migraine prophylactic treatment) was given regularly during headache-free intervals with the aim of preventing the occurrence of migraine attacks, improving migraine-related quality of life, or both. Acceptable comparator groups included placebo, no intervention, active drug treatment (ie, with proven efficacy, not experimental), the same drug treatment with a clinically relevant different dose, and non-pharmacological therapies with proven efficacy in migraine. The analysis included only drugs and dosages that are commercially available.

We recorded any data reported on treatment compliance in the Characteristics of included studies table. After examination of these data, it did not seem necessary to stratify the analysis by compliance.

We anticipated that most trials would permit the use of medication for acute migraine attacks experienced during the trial period. We therefore recorded descriptions of trial rules concerning the use of acute medication in the Characteristics of included studies table whenever such information was provided. We did not otherwise model or adjust for this factor in our analysis.

Types of outcome measures

We collected and analysed trial data on headache frequency, responders (patients with ≥ 50% reduction in headache frequency), quality of life, and adverse events.

Search methods for identification of studies

Search strategies used in our earlier review (Chronicle 2004; Mulleners 2008) are detailed in Appendix 1 (last search date 31 December 2005). For the present update, trained information specialists developed detailed search strategies for each database searched (Appendix 2). The new searches overlapped the old searches by a full year to ensure complete coverage. The last search date for all updated searches was 15 January 2013.

Databases searched for this update were:

  • Cochrane Central Register of Controlled Trials (CENTRAL; The Cochrane Library 2012, Issue 12; years searched = 2005 to 2012);

  • MEDLINE (via OVID), 2005 to 15 January 2013;

  • MEDLINE In-Process (via OVID), current week, 15 January 2013;

  • EMBASE (via OVID), 2005 to 15 January 2013.

Additional strategies for identifying trials included searching the reference lists of review articles and included studies, searching books related to headache, and consulting experts in the field. We attempted to identify all relevant published trials, irrespective of language. We handsearched two journals, Headache and Cephalalgia, in their entirety through January 2013.

Data collection and analysis

Selection of studies

Two of us independently screened titles and abstracts of studies identified by the literature search for eligibility. Papers that could not be excluded with certainty on the basis of information contained in the title and/or abstract were retrieved in full for screening. Disagreements were resolved through discussion. We retrieved papers passing this initial screening process, and two of us independently reviewed the full texts. Disagreements at the full-text stage were resolved through internal discussion and, in a few cases, through correspondence with members of the editorial staff of the Cochrane Pain, Palliative and Supportive Care Review Group. We were not blinded to study investigators' names and institutions, journal of publication, or study results at any stage of the review.

The search strategy described above identified a large number of short conference and journal abstracts. The majority of these either (a) reported partial results of ongoing trials; (b) provided insufficient information on trial design or results; (c) were early reports of included studies; or (d) were reproductions of abstracts of papers published in full (for example, the journal Headache reproduces abstracts of interest to readers, and these are found by PubMed). We agreed that short abstracts of this kind would be excluded from consideration.

Data extraction and management

Two of us independently abstracted information on patients, methods, interventions, efficacy outcomes, and adverse events from the original reports onto specially designed, pre-tested paper forms. Disagreements were again resolved through discussion.

We anticipated that trials would vary in length, that outcomes would be measured over various units of time (eg, number of attacks per two weeks versus number of attacks per four weeks), and that results would be reported for numerous different time points (eg, four-week headache frequency at two months versus at four months). We attempted to standardise the unit of time over which headache frequency was measured at 28 days (four weeks) wherever possible. We recorded outcomes beginning four weeks after the start of treatment and continued through all later assessment periods. We made decisions about which time points to include in the final analysis once the data had been collected.

We anticipated that outcomes measured on a continuous scale (eg, headache frequency) would be reported in a variety of ways, eg, as mean pre-treatment, post-treatment, and/or change scores. Among change scores, we preferred the mean of within-patient changes (from baseline to on-treatment in a parallel-group trial) over the change in group means because the first both results in a lower variance (taking into account the correlation between baseline and post-treatment scores in each patient) and adjusts for imbalances in baseline headache frequencies, while the latter has only the second advantage. When neither type of change score was reported, we compared post–treatment means between groups, assuming that baseline data would be balanced due to randomisation. We anticipated that many trials would report group means, without reporting data on the variance associated with these means. In such cases, we attempted to calculate or estimate variances based on primary data, test statistics, and/or error bars in graphs.

When efficacy outcomes were reported in dichotomous form (success/failure), we required that the threshold for distinguishing between treatment success and failure be clinically significant; for example, we interpreted a ≥ 50% reduction in headache frequency as meeting this criterion. In such cases, we recorded, for each treatment arm, the number of patients included in the analysis and the number with each outcome.

The protocol for this review specified rules for dealing with outcome data reported on an ordinal scale (eg, for reduction in headache frequency: 0%, 1% to 24%, 25% to 49%, 50% to 74%, 75% to 99%, 100%) but, in fact, none of the included trials reported ordinal data for outcomes of interest.

We envisaged that the preferred methods of collecting and presenting data on quality of life would most likely be the Migraine-Specific Questionnaire (MSQ) and the Medical Outcomes Study 36-item Short-Form Health Survey (SF-36). However, other instruments and other types of outcomes related to quality of life (eg, work absenteeism) were not excluded a priori, and these data were kept under review before specifying rules for analysing outcome data in this domain.

We recorded the proportion of patients reporting adverse events for each treatment arm wherever possible. The identity and rates of specific adverse events were also recorded. We anticipated that reporting of adverse events would vary greatly across trials with regard to the terminology used, method of ascertainment, and classification of adverse events as drug-related or not and as severe or not.

Assessment of risk of bias in included studies

We completed a 'Risk of bias' table for each study, using assessments of random sequence generation (selection bias), allocation concealment (selection bias), blinding of participants and personnel (performance bias), blinding of outcome assessment (detection bias), incomplete outcome data (attrition bias), and selective reporting (reporting bias). For new studies identified in the present update, two of us completed this assessment independently; for older studies, one of us performed the assessment and a second author reviewed and commented on it. Disagreements were resolved through discussion.

We also assessed the methodological quality of individual trials using the scale devised by Jadad and colleagues (Jadad 1996), operationalised as follows:

  1. Was the study described as randomised? (1 = yes; 0 = no)

  2. Was the method of randomisation well described and adequate? (0 = not described; 1 = described and adequate; -1 = described, but not adequate)

  3. Was the study described as double-blind? (1 = yes; 0 = no)

  4. Was the method of double-blinding well described and adequate? (0 = not described; 1 = described and adequate; -1 = described, but not adequate)

  5. Was there a description of withdrawals and dropouts sufficient to determine the number of patients in each treatment group entering and completing the trial? (1 = yes; 0 = no)

Each trial thus received a score of 0 to 5 points, with higher scores indicating higher quality in the conduct or reporting of the trial. Two review authors scored the studies independently, and a consensus score was then arrived at through discussion. The consensus score is reported for each study in the Characteristics of included studies table and was not used as a weighting in statistical analyses.

Measures of treatment effect

The primary outcome considered for the efficacy analysis was headache frequency. Among headache frequency measures, we preferred number of migraine attacks to number of days with migraine. The latter measure confusingly incorporates attack duration into the measure of headache frequency. Moreover, attack duration is affected by the use of symptomatic medication, which is permitted in most trials. We also analysed headache frequency in terms of a responder rate, or the proportion of patients with a ≥ 50% reduction in headache frequency from pre- to post-treatment.

As noted above (Data extraction and management), we kept patient-reported quality of life data under review as studies were selected. The only quality of life data available for a rigorous analysis were measured in Silberstein 2008 using the SF-36 (physical health measure and mental health measure). The same study also reported Migraine Disability Assessment (MIDAS) scores.

The analysis considered only outcome data obtained directly from the patient and not those judged by the treating physician or study personnel. Efficacy data based on contemporaneous and timed (usually daily) recording of headache symptoms were preferred to those based on global or retrospective assessments.

In addition, we tabulated adverse events for each included study.

Unit of analysis issues

In the case of cross-over trial designs, we anticipated that the data reported would normally not permit analysis of paired within-patient data. Cross-over trials were thus analysed as if they were parallel-group trials, combining data from all treatment periods. If a carry-over effect was found and data were reported by period, then the analysis was restricted to period-one data only. In no trial was complete within-patient data reported, so within-patient improvement scores were not calculated.

Dealing with missing data

Where data were missing or inadequate, we attempted to obtain these data by correspondence with study authors.

Assessment of heterogeneity

We tested estimates of efficacy (both mean differences (MDs) and odds ratios (ORs)) for homogeneity. When significant heterogeneity was present, we made an attempt to explain the differences based on the clinical characteristics of the included studies. We did not statistically combine studies that were clinically dissimilar. However, when a group of studies with statistically heterogeneous results appeared to be clinically similar, we did combine study estimates. We performed all pooled analyses using a random-effects model.

As a sensitivity analysis, we also planned to calculate a pooled effect estimate using a fixed-effect model for major outcomes (headache frequency, responder rate, and any adverse event) when the random-effects result was near-significant (0.05 ≤ P ≤ 0.15) and the pooled studies were homogeneous (heterogeneity statistics: P > 0.15/I2 < 30%). Such a sensitivity analysis would evaluate whether conclusions might differ based on the statistical model used for pooling in situations where a fixed-effect model might reasonably be considered instead of a random-effects model. In fact, however, no such sensitivity analyses were warranted in the present review.

Data synthesis

We anticipated that continuous outcome measures of headache frequency would be reported on different and often incompatible scales. Although we attempted to standardise the extraction of headache frequency data to a 28-day (four-week) period, this was not possible in every case. In our previous review (Chronicle 2004; Mulleners 2008), we therefore analysed these data using the standardised mean difference (SMD, with 95% confidence intervals (CIs)) rather than the mean difference (MD). The introduction of change scores in the newly included studies for some of the reviews in this series necessitated a change in the analysis plan from SMDs to MDs. The latter also has the advantage of giving a result in clinically meaningful units (ie, x fewer migraines per 28 days).

We used dichotomous data meeting our definition of a clinically significant threshold to calculate odds ratios (ORs), with 95% CIs. Although we prefer ORs because of their statistical properties, some readers may find it simpler to interpret the clinical significance of our findings using risk ratios (RRs); we have therefore calculated RRs where appropriate. We additionally computed numbers needed to treat (NNTs), with 95% CIs, as the reciprocal of the risk difference (RD) versus placebo (McQuay 1998).

In the same way, we used data on the proportion of patients reporting adverse events to calculate RDs and numbers needed to harm (NNHs).

Subgroup analysis and investigation of heterogeneity

We undertook subgroup analyses by dose where possible. We considered further subgroup analyses by method of randomisation and by completeness of blinding, but did not undertake them because of insufficient data.

Results

Description of studies

Results of the search

The PubMed search strategy for our previous review (Chronicle 2004; Mulleners 2008) yielded 1089 potentially eligible citations, while the EMBASE and CENTRAL searches yielded 290 and 6952 citations, respectively. No additional citations were retrieved from the Cochrane Pain, Palliative & Supportive Care Trials Register or from other sources. After title and abstract screening, we obtained 58 published papers on antiepileptics for full-text scrutiny. Of these, 16 (five included, 11 excluded) investigated antiepileptic drugs other than gabapentin, pregabalin, topiramate, or valproate.

The MEDLINE search strategy for the present update (from 2005 on) yielded 188 citations as possible candidates for the current series of reviews on antiepileptic drugs for migraine prophylaxis; the search of MEDLINE In-Process identified an additional 20 citations. The EMBASE and CENTRAL updates identified 484 and 85 citations, respectively. Three additional study reports (all unpublished and all pertaining to gabapentin) were identified from other sources. After title and abstract screening, we obtained 37 published and three unpublished papers on antiepileptics for full-text scrutiny. Of these, six (all included) investigated antiepileptic drugs other than gabapentin, pregabalin, topiramate, or valproate.

Thus, for the present update, we reviewed a total of 22 papers on antiepileptic drugs other than gabapentin, pregabalin, topiramate, or valproate at the full-text screening stage. Of these, we included 11 papers and excluded 11.

Included studies

The 11 included papers reported data from 10 unique studies. Of these, there were two trials of lamotrigine and one trial each of acetazolamide, carbamazepine, carisbamate, clonazepam, levetiracetam (two publications), oxcarbazepine, vigabatrin, and zonisamide. Nine of the 10 studies included a placebo comparator (all except the trial of zonisamide (Mohammadianinejad 2011)), three included a comparison to active intervention (de Tommaso 2007; Gupta 2007; Mohammadianinejad 2011), and one reported data that enabled dose comparisons of the antiepileptic drug (carisbamate) under investigation (Cady 2009).

Four trials had a cross-over design (Ghose 2002; Gupta 2007; Rompel 1970; Stensrud 1979), while the other six trials had a parallel-group design (Cady 2009; de Tommaso 2007; Mohammadianinejad 2011; Silberstein 2008; Steiner 1997; Vahedi 2002).

The daily doses of antiepileptics used in the included trials are given below; for convenience, the standard clinical doses used in the routine management of epilepsy are also given:

  • acetazolamide: dose investigated 500 mg; dose used in epilepsy 250 to 1000 mg;

  • carbamazepine: dose investigated not reported; dose used in epilepsy 600 to 1200 mg;

  • carisbamate: 100 to 600 mg; dose used in epilepsy 300 to 1600 mg;

  • clonazepam: dose investigated 1 mg; dose used in epilepsy 2 to 4 mg;

  • lamotrigine: dose investigated 50 to 200 mg; dose used in epilepsy 100 to 400 mg;

  • levetiracetam: dose investigated 1000 mg; dose used in epilepsy 1000 to 3000 mg;

  • oxcarbazepine: doses investigated 1200 mg; dose used in epilepsy 600 to 2400 mg;

  • vigabatrin: dose investigated 1000 mg; dose used in epilepsy 2000 to 3000 mg;

  • zonisamide: dose investigated 200 mg; dose used in epilepsy 300 to 500 mg.

The duration of the treatment phase of the included trials varied from 4 to 15 weeks, with a mean of 9.9 weeks.

See the Characteristics of included studies table for further details.

Excluded studies

Of the 22 papers obtained for full-text scrutiny, 11 were excluded for reasons given in the Characteristics of excluded studies table. The most common reasons for exclusion were 'no control group' (five studies) and 'reports case studies only' (three studies).

Risk of bias in included studies

We scored methodological quality using the Jadad scale as indicated in the Assessment of risk of bias in included studies section, with a maximum attainable score of 5. The median quality score was 3.5 (mean 3.6; range 1 to 5).

Of 60 risk of bias items scored for the 10 studies, the majority of ratings were either 'low' (32 (53%)) or 'unclear' (19 (32%)) (Figure 1; Figure 2); we judged eight studies (Cady 2009; Ghose 2002; Gupta 2007; Mohammadianinejad 2011; Rompel 1970; Silberstein 2008; Stensrud 1979; Vahedi 2002) as having a 'high' risk of bias for at least one item (Figure 2).

Figure 1.

'Risk of bias' graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

Figure 2.

'Risk of bias' summary: review authors' judgements about each risk of bias item for each included study.

Allocation

Fewer than half (4/10) of studies (Figure 2) provided an adequate methodological description of how allocation sequences were generated. Most commonly this was achieved by a computer-generated randomisation schedule, balanced by using permuted blocks and stratification by centre (see the Characteristics of included studies table). More than half (6/10) of studies (Figure 2) provided an adequate methodological description of attempts to conceal allocation of intervention assignment. One common method was to keep sealed envelopes containing preprinted medication code labels in a limited access area until subjects qualified for participation, although interactive voice response systems were also used (see the Characteristics of included studies table). No study was valued to suffer from a high risk of selection bias.

Blinding

Participants and clinicians were reported as blinded during the conduct of all 10 studies, but adequate methodological details of how this was achieved are only given for seven of them (see Figure 2 and the Characteristics of included studies table). Double-blinding was typically achieved by packaging and labelling identical appearing tablets according to the randomisation codes. A high risk of performance bias was judged for Gupta 2007, since the lamotrigine and topiramate tablets were different in appearance, and two different placebos were used. For effective blinding a double-dummy design would be required. Remarkably, only one publication (Mohammadianinejad 2011) clearly stated that the analyst was effectively blinded. We were especially concerned about the high risk of detection bias in Stensrud 1979, where both treatment sequences incorporated a final four-week period in which all patients received the same 2 mg dose of clonazepam. The present review therefore only considers the results of the 1 mg dose versus placebo.

Incomplete outcome data

Completeness of data was adequately reported for most (7/10) studies (Figure 2). Usually an intention-to-treat (ITT) analysis was applied (see the Characteristics of included studies table). We were particularly concerned about a high risk of attrition bias in Ghose 2002, Mohammadianinejad 2011, and Rompel 1970, all of which considered complete cases only, excluding from statistical analyses those who discontinued treatment prematurely.

Selective reporting

We judged the risk of reporting bias as low in six of the 10 studies (Figure 2). A major obstruction for any meta-analysis is the lack of statistical variance measures as in Cady 2009 (only reporting percentages and range). Standard deviations (SDs) for changes in least squares means of migraine frequencies were lacking in the report of Silberstein 2008 but were estimated in this review by multiplying standard errors of the mean (SEMs) times the square root of the number of participants. Variance measures were lacking for migraine attack frequency during treatment in Vahedi 2002. The risk of reporting bias was also regarded as high for Mohammadianinejad 2011, where the numbers of 50% responders and adverse events were not adequately reported. We contacted the corresponding authors of these three papers repeatedly to request complementary statistical data, but without success.

Other potential sources of bias

Statistically significant results are more likely to be published than trials affirming a null result. This tendency for negative or inconclusive results to remain unpublished is inherently problematic also in the context of this review.

Effects of interventions

Methodological considerations

For one study (Steiner 1997), means were available but standard deviations (SDs) were not: we estimated them from the range of data provided. For another study (Stensrud 1979), we estimated means and SDs from the graph provided.

Although there was methodological variation as described above (Risk of bias in included studies), the included trials were fundamentally similar with regard to basic design, patients, and measures. Significant statistical heterogeneity was evident across trials for both efficacy outcomes. We therefore examined the clinical similarity of trials investigating the same antiepileptic drug to determine whether they should be combined for statistical meta-analysis.

During the process of extracting safety data, it became clear that the range of adverse events and the method of their reporting varied very considerably from trial to trial. For placebo-controlled trials, all available safety data are summarised in Table 1. For the one trial of vigabatrin (Ghose 2002), no safety data were extractable from the published manuscript. Further analyses were merely undertaken for carbamazepine, as that was the only drug with a significant effect providing safety data enabling a comparison to placebo.

Table 1. Numbers (percentages) of adverse events (AEs) in single dosage placebo-controlled studies
StudyType of AEAntiepilepticPlacebo
Vahedi 2002  Acetazolamide (n = 26)Placebo (n = 27)
 Paresthesia21 (81)2 (7)
 Fatigue/drowsiness/memory problems/malaise15 (58)4 (15)
 Gastrointestinal intolerance3 (12)2 (7)
 Hypokalaemia1 (4)0 (0)
 Hyperuricaemia1 (4)0 (0)
 Skin eruption0 (0)2 (7)
 Fever and shivering0 (0)1 (4)
 Dry mouth1 (4)1 (4)
 Breast tension0 (0)1 (4)
 Rhinitis1 (4)2 (7)
 Tinnitus0 (0)1 (4)
 Miscellaneous1 (4)3 (11)
Rompel 1970  Carbamazepine (n = 45)Placebo (n = 48)
 Any AE30 (67)11 (23)
 Vertigo, giddiness23 (51)2 (4)
 Drowsiness5 (11)1 (2)
 Nausea4 (9)3 (6)
 Dry mouth2 (4)0 (0)
 Heavy eyes2 (4)0 (0)
 Constipation2 (4)0 (0)
 Vomiting1 (2)0 (0)
 Weight gain1 (2)1 (2)
 Sweating1 (2)0 (0)
 Transient rash1 (2)0 (0)
 Dysuria1 (2)0 (0)
 Blocked nose0 (0)1 (2)
 Flushing0 (0)1 (2)
 Blunted feeling0 (0)1 (2)
 Heavy head0 (0)1 (2)
Cady 2009  Carisbamate (n = 238)Placebo (n = 78)
 Any AE183 (77)58 (74)
 Fatigue41 (17)5 (6)
 Nasopharyngitis30 (13)9 (12)
 Nausea21 (9)6 (8)
 Back pain12 (5)1 (1)
 Diarrhoea11 (5)2 (3)
 Dizziness11 (5)3 (4)
 Somnolence8 (3)4 (5)
 Upper abdominal pain7 (3)2 (3)
 Vomiting7 (3)2 (3)
 Hepatic enzyme increased6 (3)0
 Migraine6 (3)5 (6)
 Insomnia4 (2)4 (5)
Stensrud 1979  Clonazepam (n = 38)Placebo (n = 38)
 Sedation23 (61)Unclear
 Dizziness10 (26)Unclear
 Irritability2 (5)Unclear
Steiner 1997  Lamotrigine (n = 37)Placebo (n = 40)
 Rash11 (30)1 (3)
 Dizziness4 (11)2 (5)
 Asthenia2 (5)2 (5)
 Somnolence2 (5)0 (0)
 Thinking abnormality1 (3)0 (0)
 Tremor0 (0)1 (3)
 Leukopenia1 (3)1 (3)
 Nausea0 (0)3 (8)
 Weight gain0 (0)3 (8)
 Allergy0 (0)1 (3)
Gupta 2007  Lamotrigine (n = 57)Placebo (n = 57)
 Sleepiness and concentration difficulty2 (4)0
 Paresthesias2 (4)Unclear
 Gastrointestinal intolerance2 (4)1
 Anorexia1 (2)2 (4)
 Giddiness2 (4)1 (2)
 Rash2 (4)1 (2)
 Palpitations02 (4)
 Menorrhagia00
 Hair loss00
 Pain in lower limbs01 (2)
de Tommaso 2007  Levetiracetam (n = 15)Placebo (n = 15)
 Sedation and dizziness5 (33)Unclear
Silberstein 2008  Oxcarbazepine (n = 85)Placebo (n = 85)
 Any AE68 (80)55 (65)
 Fatigue17 (20)6 (7)
 Dizziness15 (18)6 (7)
 Nausea14 (16)4 (5)
 Somnolence7 (8)6 (7)
 Balance disorder5 (6)2 (2)
 Insomnia5 (6)6 (7)
 Migraine5 (6)2 (2)
 Paresthesias5 (6)1 (1)
 Sinusitis2 (2)5 (6)

All doses reported below are given in terms of mg/day.

Acetazolamide

A single parallel-group trial compared acetazolamide 500 mg and placebo (Vahedi 2002; 53 patients). Data were insufficient for us to calculate mean differences (MDs) for headache frequency, our preferred outcome measure. There was no significant difference between acetazolamide and placebo in the proportion of responders (odds ratio (OR) 0.89; 95% confidence interval (CI) 0.28 to 2.82; Analysis 1.1). It should be noted, however, that this trial was discontinued prematurely. Adverse events are summarised in Table 1.

Carbamazepine

One cross-over trial compared carbamazepine (dose not reported) and placebo (Rompel 1970; 48 patients). Data were insufficient for us to calculate MDs for headache frequency, our preferred outcome measure. Carbamazepine was significantly better than placebo in the proportion of responders (OR 11.77; 95% CI 3.92 to 35.32; Analysis 2.1). In clinical terms, the observed effect suggests that patients are approximately 5.5 times as likely to experience a ≥ 50% reduction in headache frequency with carbamazepine as with placebo. Details are as follows:

  • The proportion of responders with carbamazepine was 58% (26/45);

  • The proportion of responders with placebo was 10% (5/48);

  • The risk ratio (RR) for carbamazepine versus placebo was 5.55 (95% CI 2.33 to 13.19; Analysis 2.2);

  • The number needed to treat (NNT) for carbamazepine versus placebo was 2 (95% CI 2 to 3).

Adverse events (AEs) are summarised in Table 1. It is noteworthy that half of safety evaluable patients reported vertigo or giddiness on carbamazepine (23/45; 45%) as compared to only a few (2/48; 4%) on placebo. We calculated risk differences (RDs) for AEs occurring in at least 5% of carbamazepine-treated participants (Analysis 2.3; Analysis 2.4; Analysis 2.5; Analysis 2.6). NNHs (95% CIs) were:

  • any AE: NNH 2 (2 to 4);

  • drowsiness: NNH not calculated, since 95% CI for RD includes zero (Analysis 2.4);

  • nausea: NNH not calculated, since 95% CI for RD includes zero (Analysis 2.5);

  • vertigo/giddiness: NNH 2 (2 to 3).

Carisbamate

One parallel-group trial evaluated three doses of carisbamate (titrated to 100, 300, and 600 mg) versus placebo (Cady 2009; 317 patients). Data were insufficient for us to calculate MDs for headache frequency, our preferred outcome measure, for placebo or dose comparisons. This trial did not demonstrate a significant difference versus placebo in the proportion of responders for carisbamate titrated to 100 mg (OR 0.65; 95% CI 0.34 to 1.26; 162 patients), 300 mg (OR 0.59; 95% CI 0.30 to 1.16; 160 patients), or 600 mg (OR 0.74; 95% CI 0.38 to 1.44; 155 patients; Analysis 3.1). Dose comparisons in the same trial did not reveal a significant difference for this outcome between carisbamate 100 versus 300 mg (OR 0.91; 95% CI 0.46 to 1.83; 162 patients), carisbamate 100 versus 600 mg (OR 1.13; 95% CI 0.57 to 2.26; 157 patients), or carisbamate 300 versus 600 mg (OR 1.24; 95% CI 0.62 to 2.50; 155 patients; Analysis 4.1). AEs are summarised in Table 1.

Clonazepam

In a single cross-over trial by Stensrud 1979 (37 patients), clonazepam was not significantly different from placebo in reducing headache frequency per 28-day period during treatment (MD -4.10; 95% CI -8.68 to 0.48; Analysis 5.1). AEs are summarised in Table 1.

Lamotrigine

In a single cross-over trial by Gupta 2007 (57 patients, 56 of whom crossed over to the second therapy), lamotrigine 50 mg was slightly and significantly superior to placebo (MD -1.17; 95% CI -2.17 to -0.17) in reducing headache frequency per 28-day period during treatment. However, in another study of higher methodological quality (Steiner 1997; 77 patients), lamotrigine titrated up to 200 mg did not appear to be superior to placebo for this outcome (MD 0.20; 95% CI -0.81 to 1.21). The pooled results of these trials (MD -0.49; 95% CI -1.83 to 0.85; Analysis 6.1) do not support superiority of lamotrigine over placebo in reduction of attack frequency. In line with this, Gupta 2007 did not demonstrate a significant difference for lamotrigine 50 mg versus placebo in the proportion of responders (OR 1.63; 95% CI 0.76 to 3.49; 57 patients, 56 of whom crossed over to the second therapy; Analysis 6.2). AEs are summarised in Table 1.

Furthermore, Gupta 2007 examined low-dose lamotrigine (50 mg) versus low-dose topiramate (50 mg) and found no significant difference between them in headache frequency per 28-day period during treatment (MD 0.81; 95% CI -0.17 to 1.79; 57 patients, 56 of whom crossed over to the second therapy; Analysis 7.1) or in the proportion of responders (OR 0.50; 95% CI 0.24 to 1.07; 57 patients, 56 of whom crossed over to the second therapy; Analysis 7.2).

Levetiracetam

In a single parallel-group trial by de Tommaso 2007, levetiracetam 1000 mg was significantly superior to placebo in reducing headache frequency (MD -2.40; 95% CI -4.52 to -0.28; 26 patients; Analysis 8.1). In clinical terms, the observed effect corresponds to a reduction in headache frequency of more than two headache days per 28 days with levetiracetam. The mean baseline headache frequency in the levetiracetam group was 10.8 headache days per 28 days.

Levetiracetam was also significantly superior to placebo in the proportion of responders (OR 26.07; 95% CI 1.30 to 521.91; 26 patients; Analysis 8.2). In clinical terms, the effect observed suggests that patients are nearly 13 times as likely to experience a ≥ 50% reduction in headache frequency with levetiracetam as with placebo. Details are as follows:

  • The proportion of responders with levetiracetam was 53% (8/15);

  • The proportion of responders with placebo was 0% (0/11);

  • The RR for levetiracetam versus placebo was 12.75 (95% CI 0.81 to 199.98; Analysis 8.3);

  • The NNT for levetiracetam versus placebo was 2 (95% CI 1 to 4).

The same trial examined levetiracetam 1000 mg versus topiramate 100 mg and found a small but significant difference favouring topiramate (MD 1.40; 95% CI 0.14 to 2.66; 28 patients; Analysis 9.1) in headache frequency. In clinical terms, the observed effect corresponds to a reduction in headache frequency of more than one headache day per 28 days with topiramate versus levetiracetam. The mean baseline headache frequency in the topiramate group was 11.2 headache days per 28 days. There was no significant difference between levetiracetam and topiramate in the proportion of responders (OR 0.71; 95% CI 0.16 to 3.23; 28 patients; Analysis 9.2).

AEs were incompletely reported (Table 1), and no comparison between treatments was possible.

Oxcarbazepine

In a single parallel-group trial (Silberstein 2008; 170 patients), there was no significant difference between oxcarbazepine and placebo in reduction of mean headache frequency from baseline (MD 0.44; 95% CI -0.34 to 1.22; Analysis 10.1) or in the proportion of responders (OR 0.86; 95% CI 0.45 to 1.61; Analysis 10.2). Therefore, no further analyses were undertaken of the difference between oxcarbazepine and placebo on quality of life (SF-36) or disability (MIDAS) measures. AEs are summarised in Table 1.

Vigabatrin

In a single cross-over trial (Ghose 2002; 15 patients, all of whom crossed over to the second therapy) vigabatrin was not significantly superior to placebo (MD -0.42; 95% CI -1.78 to 0.94; Analysis 11.1) with regard to headache frequency per 28-day period during treatment. AEs were not reported.

Zonisamide

Finally, a single parallel-group trial (Mohammadianinejad 2011) examined zonisamide versus topiramate (200 and 100 mg, respectively) and found no significant difference between them in reduction of headache frequency from baseline during the third month of treatment (MD 0.10; 95% CI -0.68 to 0.88; 75 patients; Analysis 12.1). AEs were incompletely reported and no comparison between interventions was possible.

Discussion

Summary of main results

Available evidence does not allow robust conclusions regarding the efficacy of antiepileptic drugs other than gabapentin, pregabalin, topiramate, and valproate in the prophylaxis of episodic migraine among adults. The absence of studies showing superiority over placebo is not proof of a lack of effect, nor do single low-quality studies with positive findings provide proof of an effect. To the extent that the drugs reviewed here can be considered to be of a single pharmacological class (of antiepileptics), the weight of the evidence is against their efficacy for migraine prophylaxis.

Placebo-controlled trials

Six of the eight investigated drugs were not better than placebo in reducing headache frequency per 28-day period during treatment (clonazepam, lamotrigine, oxcarbazepine, and vigabatrin) and/or in the proportion of responders (acetazolamide, carisbamate, lamotrigine, oxcarbazepine). In one trial (Rompel 1970), carbamazepine was superior to placebo in the proportion of responders. One small study (de Tommaso 2007) showed superiority of levetiracetam over placebo both in headache frequency per 28-day period during treatment and in the proportion of responders.

Dose comparisons

Only one study (Cady 2009) included more than one dose of a single drug, thereby enabling direct dose comparisons. No significant differences were found between the 100, 300, or 600 mg doses of carisbamate.

Trials with active comparators

The three trials using active comparators found (a) no significant difference in efficacy between low doses of lamotrigine and topiramate (Gupta 2007); (b) a significant difference in headache frequency per 28-day period during treatment favouring topiramate over levetiracetam, but no corresponding significant difference in the proportion of responders (de Tommaso 2007); and (c) no significant difference between zonisamide and topiramate in reduction of headache frequency (Mohammadianinejad 2011).

Safety

Antiepileptic drugs other than gabapentin, pregabalin, topiramate, or valproate do not appear to give rise to an unexpectedly high rate of adverse events when used for migraine prophylaxis, although a large percentage of patients taking carbamazepine reported vertigo/giddiness (number needed to harm (NNH) 2; 95% confidence interval (CI) 2 to 3).

Overall completeness and applicability of evidence

The studies identified were sufficient to address the main objectives of the review. Our analysis did not demonstrate efficacy for the majority of antiepileptic drugs other than gabapentin, pregabalin, topiramate, or valproate in the prevention of attacks in adult patients with episodic migraine, and these results fit into the context of current practice. As usual in the context of clinical trials research, there is considerable heterogeneity in both headline results and general levels of analytical and statistical sophistication. The carbamazepine trial does not identify the dose used, so provides little information of clinical value. The trials with active comparator are of relevance for two reasons. First, topiramate has demonstrable efficacy in the prophylaxis of migraine (Edvinsson 2010). Second, little is known as of yet about the relative efficacy of different antiepileptics.

Quality of the evidence

The identified body of evidence does not allow robust conclusions of a lack of effect of acetazolamide, clonazepam, or vigabatrin. These drugs were all studied in single, small trials (numbers of participants ranging from 30 to 53). The negative single studies of carisbamate and oxcarbazepine were larger (numbers of participants 318 and 170, respectively), but still inconclusive, and need to be replicated. Lamotrigine was studied in two fairly large studies (numbers of participants 77 and 133, respectively) with equivocal results. The finding in Gupta 2007 that low-dose lamotrigine (50 mg) was effective in lowering headache frequency is somewhat counterintuitive, taking into consideration that the high dose (200 mg) of Steiner 1997 did not outperform placebo. Furthermore, the finding by Gupta 2007 should be regarded with caution, since the study had several methodological weaknesses (see the Characteristics of included studies table), and since there was no accompanying significant difference between lamotrigine 50 mg and placebo in the proportion of responders. It should also be mentioned, however, that the results of Steiner 1997 are likely to have been influenced by a large difference in baseline frequency between active treatment and placebo groups.

Neither does this review provide robust support of a favourable effect of carbamazepine, levetiracetam, or zonisamide. The age of the single carbamazepine trial (Rompel 1970) means that present-day diagnostic standards (IHS Cttee 1988; ICHD-II 2004) could not be employed. The study by de Tommaso 2007, which demonstrated superiority of levetiracetam over placebo, should be regarded with some caution, since it was not primarily designed to obtain clinical outcome data of the interventions. Mean headache frequency data was provided by the corresponding author upon request. The absence of a significant difference in effect between zonisamide and active comparator is not proof of an actual effect of zonisamide, which should be investigated in placebo-controlled trials. It should be noted that all three trials with active comparator are potentially problematic for reasons including important data being unpublished (de Tommaso 2007), a high risk of performance bias (Gupta 2007), and incomplete outcome data (Mohammadianinejad 2011) (see the Characteristics of included studies table). Further well-designed trials, both of antiepileptics against other effective interventions, and comparing different antiepileptics, are desirable.

Several important issues need to be taken into account in any assessment of the efficacy of a drug for migraine prophylaxis. Diagnostic criteria, baseline headache frequency, washout periods for previous medication, rules for rescue medication, and the statistical power of the comparison were handled very variably in the 10 included studies. As investigations of the efficacy of various agents become more commonplace, it seems increasingly important that scientists and clinicians are at least aware of the trial guidelines suggested by the International Headache Society (Tfelt-Hansen 2012). Even if these guidelines cannot — for operational or scientific reasons — be adhered to in their entirety, they provide a useful consultative framework at the early stages of trial design.

Potential biases in the review process

It is fair to say that we faced several difficulties in deriving adequate information from the results of 10 included studies. First, means and standard deviations were not always fully reported for each phase of trials. In tandem with this problem, reported measures of variability — either appearing in the text, tabulated, or as error bars in graphs — were not always adequately described or labelled. Second, methods of statistical analysis were generally under-specified, leading in some cases to a lack of clarity as to which comparisons were significant and which were not. Third, there was considerable variability in how intention-to-treat analyses were performed. In a few cases, this gave rise to uncertainty about the numbers of patients continuing to each phase of the trial.

Of 60 risk of bias items scored for the 10 studies, the majority of ratings were either 'low' (32 (53%)) or 'unclear' (19 (32%)) (Figure 1; Figure 2). As described in detail above (Risk of bias in included studies), we judged eight trials as having a 'high' risk of bias for at least one item, as follows: blinding of participants and personnel (Gupta 2007), blinding of outcome assessment (Stensrud 1979), incomplete outcome data (Ghose 2002; Mohammadianinejad 2011; Rompel 1970), and/or selective reporting (Cady 2009; Mohammadianinejad 2011; Silberstein 2008).

A strength of this review is that the methods used for searching and study selection make it highly likely most relevant trial results in the public domain were identified. There is nevertheless an obvious risk that the reports of some trials may have been classified as confidential and thus remain unobtainable.

Agreements and disagreements with other studies or reviews

To the extent that they overlap, the findings of this review are in line with the guideline recommendations summarised above (see Why it is important to do this review) of the EFNS (Evers 2009) and the Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Society (Silberstein 2012). It should be noted, however, that these guidelines do not cover the evidence now available for carisbamate, levetiracetam, vigabatrin, or zonisamide.

Authors' conclusions

Implications for practice

Bearing in mind the limitations invoked by the methodological and reporting issues mentioned above, this review nevertheless helps to provide a rational framework for the application of antiepileptic drugs other than gabapentin, pregabalin, topiramate, and valproate for the preventive management of migraine headache in clinical practice. There is, at present, either insufficient or no evidence to warrant their use in clinical practice.

It must be stressed, however, that this review does not provide definite evidence for the management of other aspects of the condition (eg, prodromal symptoms, aura symptoms), either because these aspects were not considered in the selected trials or were not adequately reported. Likewise, the conclusions in this review cannot be extrapolated to chronic migraine, transformed migraine, or chronic daily headache. None of these conditions was considered for this review, as properly validated definitions are as yet lacking.

Implications for research

At present, there is an inadequate number of trials of antiepileptic drugs other than topiramate and valproate in the prophylaxis of migraine. Based on the identified evidence, carbamazepine, levetiracetam, and zonisamide are drugs that could be considered for further investigation in methodologically stringent trials. However, the fact that a drug has antiepileptic activity should not, per se, be considered good reason to expect antimigraine activity or sufficient reason to subject patients to a clinical trial. Little is definitely known about the mechanism of action of the antiepileptics that are effective in migraine prophylaxis, eg, topiramate and valproate. A considerable amount of basic science research in both animal models and human neuroscience laboratories will be necessary in order to discover which of the many potential actions of antiepileptic drugs are causative in the reduction of headache frequency or severity. A programme of research aimed at improving efficacy and tolerability by designing prophylactic drugs targeted at known migraine mechanisms would be worthwhile.

In general, we feel that the quality of both methods and reporting is disappointing in this area of investigation. In particular, investigators wishing to report intention-to-treat analyses should carefully consider the recommendations of medical statisticians (eg, Hollis 1999). Future trialists should also be encouraged to follow the recommendations of the International Headache Society (Tfelt-Hansen 2012) with regard to both trial design and reporting of data.

Acknowledgements

Professor EP Chronicle, PhD, sadly passed away on 9 February 2007. We wish to acknowledge Professor Chronicle's major contribution and tremendous effort in compiling all statistical analyses and much of the text of the original review on antiepileptics (Chronicle 2004; Mulleners 2008). Without his relentless dedication it would have never seen the light of day.

The protocol for the original review was developed while Dr Chronicle was a Visiting Scholar at the University of California, Berkeley. Dr Sally Hollis, Lancaster University, and Dr Kentaro Hayashi, University of Hawaii at Manoa, provided helpful advice on statistical matters. Several pharmaceutical companies kindly provided information about trials in progress.

We thank Ruth Foxlee, Jane Hayes, and Joanne Abbott for assistance in designing search strategies and running searches; Prof Timothy Steiner for editorial guidance; and Dr Rebecca Gray for editorial assistance and technical support.

Lifting The Burden: the Global Campaign against Headache and the International Headache Society provided financial support for the editorial process (see Sources of support).

Data and analyses

Download statistical data

Comparison 1. Acetazolamide versus placebo
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Responders (patients with ≥ 50% reduction in headache frequency)1 Odds Ratio (M-H, Random, 95% CI)Totals not selected
Analysis 1.1.

Comparison 1 Acetazolamide versus placebo, Outcome 1 Responders (patients with ≥ 50% reduction in headache frequency).

Comparison 2. Carbamazepine versus placebo
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 OR for responders (patients with ≥ 50% reduction in headache frequency)1 Odds Ratio (M-H, Random, 95% CI)Totals not selected
2 RR for responders (patients with ≥ 50% reduction in headache frequency)1 Risk Ratio (M-H, Random, 95% CI)Totals not selected
3 Any adverse event1 Risk Difference (M-H, Random, 95% CI)Totals not selected
4 Drowsiness1 Risk Difference (M-H, Random, 95% CI)Totals not selected
5 Nausea1 Risk Difference (M-H, Random, 95% CI)Totals not selected
6 Vertigo/giddiness1 Risk Difference (M-H, Random, 95% CI)Totals not selected
Analysis 2.1.

Comparison 2 Carbamazepine versus placebo, Outcome 1 OR for responders (patients with ≥ 50% reduction in headache frequency).

Analysis 2.2.

Comparison 2 Carbamazepine versus placebo, Outcome 2 RR for responders (patients with ≥ 50% reduction in headache frequency).

Analysis 2.3.

Comparison 2 Carbamazepine versus placebo, Outcome 3 Any adverse event.

Analysis 2.4.

Comparison 2 Carbamazepine versus placebo, Outcome 4 Drowsiness.

Analysis 2.5.

Comparison 2 Carbamazepine versus placebo, Outcome 5 Nausea.

Analysis 2.6.

Comparison 2 Carbamazepine versus placebo, Outcome 6 Vertigo/giddiness.

Comparison 3. Carisbamate versus placebo
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Responders (patients with ≥ 50% reduction in headache frequency)1 Odds Ratio (M-H, Random, 95% CI)Totals not selected
1.1 Carisbamate titrated to 100 mg/day1 Odds Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]
1.2 Carisbamate titrated to 300 mg/day1 Odds Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]
1.3 Carisbamate titrated to 600 mg/day1 Odds Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]
Analysis 3.1.

Comparison 3 Carisbamate versus placebo, Outcome 1 Responders (patients with ≥ 50% reduction in headache frequency).

Comparison 4. Carisbamate dose comparisons
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Responders (patients with ≥ 50% reduction in headache frequency)1 Odds Ratio (M-H, Random, 95% CI)Totals not selected
1.1 Carisbamate 300 mg/day versus 100 mg/day1 Odds Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]
1.2 Carisbamate 600 mg/day versus 100 mg/day1 Odds Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]
1.3 Carisbamate 600 mg/day versus 300 mg/day1 Odds Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]
Analysis 4.1.

Comparison 4 Carisbamate dose comparisons, Outcome 1 Responders (patients with ≥ 50% reduction in headache frequency).

Comparison 5. Clonazepam versus placebo
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Headache frequency (post-treatment; headache days per month)1 Mean Difference (IV, Random, 95% CI)Totals not selected
Analysis 5.1.

Comparison 5 Clonazepam versus placebo, Outcome 1 Headache frequency (post-treatment; headache days per month).

Comparison 6. Lamotrigine versus placebo
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Headache frequency (change from baseline to post-treatment, or post-treatment alone)2190Mean Difference (IV, Random, 95% CI)-0.49 [-1.83, 0.85]
1.1 Lamotrigine 50 mg/day1113Mean Difference (IV, Random, 95% CI)-1.17 [-2.17, -0.17]
1.2 Lamotrigine titrated to 200 mg/day177Mean Difference (IV, Random, 95% CI)0.20 [-0.81, 1.21]
2 Responders (patients with ≥ 50% reduction in headache frequency)1 Odds Ratio (M-H, Random, 95% CI)Totals not selected
Analysis 6.1.

Comparison 6 Lamotrigine versus placebo, Outcome 1 Headache frequency (change from baseline to post-treatment, or post-treatment alone).

Analysis 6.2.

Comparison 6 Lamotrigine versus placebo, Outcome 2 Responders (patients with ≥ 50% reduction in headache frequency).

Comparison 7. Lamotrigine versus topiramate
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Headache frequency (change from baseline to post-treatment)1 Mean Difference (IV, Random, 95% CI)Totals not selected
2 Responders (patients with ≥ 50% reduction in headache frequency)1 Odds Ratio (M-H, Random, 95% CI)Totals not selected
Analysis 7.1.

Comparison 7 Lamotrigine versus topiramate, Outcome 1 Headache frequency (change from baseline to post-treatment).

Analysis 7.2.

Comparison 7 Lamotrigine versus topiramate, Outcome 2 Responders (patients with ≥ 50% reduction in headache frequency).

Comparison 8. Levetiracetam versus placebo
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Headache frequency (post-treatment; headache days per month)1 Mean Difference (IV, Random, 95% CI)Totals not selected
2 OR for responders (patients with ≥ 50% reduction in headache frequency)1 Odds Ratio (M-H, Random, 95% CI)Totals not selected
3 RR for responders (patients with ≥ 50% reduction in headache frequency)1 Risk Ratio (M-H, Random, 95% CI)Totals not selected
Analysis 8.1.

Comparison 8 Levetiracetam versus placebo, Outcome 1 Headache frequency (post-treatment; headache days per month).

Analysis 8.2.

Comparison 8 Levetiracetam versus placebo, Outcome 2 OR for responders (patients with ≥ 50% reduction in headache frequency).

Analysis 8.3.

Comparison 8 Levetiracetam versus placebo, Outcome 3 RR for responders (patients with ≥ 50% reduction in headache frequency).

Comparison 9. Levetiracetam versus topiramate
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Headache frequency (post-treatment; headache days per month)1 Mean Difference (IV, Random, 95% CI)Totals not selected
2 Responders (patients with ≥ 50% reduction in headache frequency)1 Odds Ratio (M-H, Random, 95% CI)Totals not selected
Analysis 9.1.

Comparison 9 Levetiracetam versus topiramate, Outcome 1 Headache frequency (post-treatment; headache days per month).

Analysis 9.2.

Comparison 9 Levetiracetam versus topiramate, Outcome 2 Responders (patients with ≥ 50% reduction in headache frequency).

Comparison 10. Oxcarbazepine versus placebo
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Headache frequency (change from baseline to post-treatment)1 Mean Difference (IV, Random, 95% CI)Totals not selected
2 Responders (patients with ≥ 50% reduction in headache frequency)1 Odds Ratio (M-H, Random, 95% CI)Totals not selected
Analysis 10.1.

Comparison 10 Oxcarbazepine versus placebo, Outcome 1 Headache frequency (change from baseline to post-treatment).

Analysis 10.2.

Comparison 10 Oxcarbazepine versus placebo, Outcome 2 Responders (patients with ≥ 50% reduction in headache frequency).

Comparison 11. Vigabatrin versus placebo
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Headache frequency (post-treatment)1 Mean Difference (IV, Random, 95% CI)Totals not selected
Analysis 11.1.

Comparison 11 Vigabatrin versus placebo, Outcome 1 Headache frequency (post-treatment).

Comparison 12. Zonisamide versus topiramate
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Headache frequency (change from baseline to post-treatment)1 Mean Difference (IV, Random, 95% CI)Totals not selected
Analysis 12.1.

Comparison 12 Zonisamide versus topiramate, Outcome 1 Headache frequency (change from baseline to post-treatment).

Appendices

Appendix 1. Search strategies for the previous review

For the identification of studies considered for the original review and the 2007 update (Chronicle 2004; Mulleners 2008), detailed search strategies were developed for each database searched. These were based on the search strategy for PubMed, but revised appropriately for each database. The search strategies combined the subject searches described below with the Cochrane highly sensitive search strategy for RCTs current at the time (Alderson 2004). The subject searches used a combination of controlled vocabulary and free-text terms based on the search strategy for PubMed presented below.

Databases searched were:

  • Cochrane Pain, Palliative & Supportive Care Trials Register;

  • Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library 2005, Issue 3);

  • PubMed 1966 to 31 December 2005;

  • EMBASE 1974 to 31 December 2005.

Additional strategies for identifying trials included searching the reference lists of review articles and included studies, searching books related to headache and consulting experts in the field. Two journals, Headache and Cephalalgia, were handsearched in their entirety, through April 2006.

Detailed descriptions of the subject search strategies used for PubMed, EMBASE, and CENTRAL are given below.

PubMed

Phase 1

#1 (randomized controlled trial [pt] OR controlled clinical trial [pt] OR randomized controlled trials [mh] OR random allocation [mh] OR double-blind method [mh] OR single-blind method [mh] OR clinical trial [pt] OR clinical trials [mh] OR ("clinical trial" [tw]) OR ((singl* [tw] OR doubl* [tw] OR trebl* [tw] OR tripl* [tw]) AND (mask* [tw] OR blind* [tw])) OR (placebos [mh] OR placebo* [tw] OR random* [tw] OR research design [mh:noexp] OR comparative study [mh] OR evaluation studies [mh] OR follow-up studies [mh] OR prospective studies [mh] OR control* [tw] OR prospectiv* [tw] OR volunteer* [tw]) NOT (animals [mh] NOT human [mh]) Limits: Humans

Phase 2

#2 HEADACHE Field: MeSH Terms, Limits: Humans
#3 HEADACHE DISORDERS Field: MeSH Terms, Limits: Humans
#4 headache* OR migrain* OR cephalgi* OR cephalalgi* Field: All Fields, Limits: Humans
#5 #2 OR #3 OR #4 Limits: Humans

Phase 3

#6 anticonvulsant* OR antiepileptic* OR acetazolamide OR carbamazepine OR chlormethiazole OR clobazam OR clonazepam OR clorazepate OR diazepam OR divalproex OR ethosuximide OR felbamate OR fosphenytoin OR gabapentin OR lamotrigine OR levetiracetam OR lidocaine OR lignocaine OR lorazepam OR mephobarbital OR methsuximide OR midazolam OR nitrazepam OR oxcarbazepine OR paraldehyde OR pentobarbital OR phenobarbital OR phenytoin OR primidone OR valproate OR tiagabine OR topiramate OR valproic OR vigabatrin OR zonisamide Field: All Fields, Limits: Humans
#7 #1 AND #5 AND #6

EMBASE

#1 'migraine'/exp AND [embase]/lim
#2 migrain* OR cephalgi* OR cephalalgi* AND [embase]/lim
#3 headache*:ti
#4 #1 OR #2 OR #3
#5 'anticonvulsive agent'/de AND [embase]/lim
#6 anticonvulsant* OR antiepileptic* OR 'acetazolamide'/de OR 'carbamazepine'/de OR 'chlormethiazole'/de OR 'clobazam'/de OR 'clonazepam'/de OR 'clorazepate'/de OR 'diazepam'/de OR 'divalproex'/de OR 'ethosuximide'/de OR 'felbamate'/de OR fosphenytoin OR 'gabapentin'/de OR 'lamotrigine'/de OR 'levetiracetam'/de OR 'lidocaine'/de OR 'lignocaine'/de OR 'lorazepam'/de OR 'mephobarbital'/de OR 'methsuximide'/de OR 'midazolam'/de OR 'nitrazepam'/de OR 'oxcarbazepine'/de OR 'paraldehyde'/de OR 'pentobarbital'/de OR 'phenobarbital'/de OR 'phenytoin'/de OR 'primidone'/de OR 'valproate'/de OR 'tiagabine'/de OR 'topiramate'/de OR valproic OR 'vigabatrin'/de OR 'zonisamide'/de AND [embase]/lim
#7 #5 OR #6
#8 #4 AND #7
#9 ((random*:ti,ab) OR (factorial*:ab,ti) OR (crossover*:ab,ti OR 'cross over':ab,ti OR 'cross over':ab,ti) OR (placebo*:ab,ti) OR ('double blind' OR 'double blind') OR ('single blind':ab,ti OR 'single blind':ab,ti) OR (assign*:ti,ab OR allocat*:ti,ab) OR (volunteer*:ab,ti) OR ('randomized controlled trial'/exp AND [embase]/lim) OR ('single blind procedure'/exp AND [embase]/lim) OR ('double blind procedure'/exp AND [embase]/lim) OR ('crossover procedure'/exp AND [embase]/lim)) NOT ((animal/ OR nonhuman/ OR 'animal'/de AND experiment/ AND [embase]/lim) NOT ((human/ AND [embase]/lim) AND (animal/ OR nonhuman/ OR 'animal'/de AND experiment/ AND [embase]/lim)) AND [embase]/lim) AND [embase]/lim
#10 #8 AND #9

CENTRAL

(migrain* OR headache*) AND (randomized controlled trial OR controlled clinical trial) Field: All Fields

Appendix 2. Search strategies for this update

CENTRAL

#1 MeSH descriptor: [Migraine Disorders] explode all trees
#2 (migrain* or cephalgi* or cephalalgi*)
#3 #1 or #2
#4 MeSH descriptor: [Anticonvulsants] explode all trees
#5 (anticonvulsant* or antiepileptic* or acetazolamide or carbamazepine or chlormethiazole or clobazam or clonazepam or clorazepate or diazepam or divalproex or ethosuximide or felbamate or fosphenytoin or gabapentin or lamotrigine or levetiracetam or lidocaine or lignocaine or lorazepam or mephobarbital or methsuximide or midazolam or nitrazepam or oxcarbazepine or paraldehyde or pentobarbital or phenobarbital or phenytoin or primidone or valproate or tiagabine or topiramate or valproic or vigabatrin or zonisamide or eslicarbazepine or lacosamide or perampanel or phenobarbitone or pregabalin or retigabine or rufinamide or stiripentol or *barbit*)
#6 #4 or #5
#7 #3 and #6
(search limited to years 2005-2012)

MEDLINE and MEDLINE In-Progress (via Ovid)

  1. exp Migraine Disorders/

  2. (migrain* or cephalgi* or cephalalgi*).tw.

  3. or/1-2

  4. exp Anticonvulsants/

  5. (anticonvulsant* or antiepileptic* or acetazolamide or carbamazepine or chlormethiazole or clobazam or clonazepam or clorazepate or diazepam or divalproex or ethosuximide or felbamate or fosphenytoin or gabapentin or lamotrigine or levetiracetam or lidocaine or lignocaine or lorazepam or mephobarbital or methsuximide or midazolam or nitrazepam or oxcarbazepine or paraldehyde or pentobarbital or phenobarbital or phenytoin or primidone or valproate or tiagabine or topiramate or valproic or vigabatrin or zonisamide or eslicarbazepine or lacosamide or perampanel or phenobarbitone or pregabalin or retigabine or rufinamide or stiripentol or $barbit$).tw.

  6. or/4-5

  7. 3 and 6

  8. randomized controlled trial.pt.

  9. controlled clinical trial.pt.

  10. randomized.ab.

  11. placebo.ab.

  12. clinical trials as topic.sh.

  13. randomly.ab.

  14. trial.ti.

  15. or/8-14

  16. exp animals/ not humans.sh.

  17. 15 not 16

  18. 7 and 17

For MEDLINE: limited 18 to yr="2005 -Current"
For MEDLINE In-Process: searched current week on 15 January 2013

EMBASE (via Ovid)

  1. exp Migraine/

  2. (migrain* or cephalgi* or cephalalgi*).tw.

  3. or/1-2

  4. exp Anticonvulsants/

  5. (anticonvulsant* or antiepileptic* or acetazolamide or carbamazepine or chlormethiazole or clobazam or clonazepam or clorazepate or diazepam or divalproex or ethosuximide or felbamate or fosphenytoin or gabapentin or lamotrigine or levetiracetam or lidocaine or lignocaine or lorazepam or mephobarbital or methsuximide or midazolam or nitrazepam or oxcarbazepine or paraldehyde or pentobarbital or phenobarbital or phenytoin or primidone or valproate or tiagabine or topiramate or valproic or vigabatrin or zonisamide or eslicarbazepine or lacosamide or perampanel or phenobarbitone or pregabalin or retigabine or rufinamide or stiripentol or $barbit$).tw.

  6. or/4-5

  7. 3 and 6

  8. random$.tw.

  9. factorial$.tw.

  10. crossover$.tw.

  11. cross over$.tw.

  12. cross-over$.tw.

  13. placebo$.tw.

  14. (doubl$ adj blind$).tw.

  15. (singl$ adj blind$).tw.

  16. assign$.tw.

  17. allocat$.tw.

  18. volunteer$.tw.

  19. Crossover Procedure/

  20. double-blind procedure.tw.

  21. Randomized Controlled Trial/

  22. Single Blind Procedure/

  23. or/8-22

  24. (animal/ or nonhuman/) not human/

  25. 23 not 24

  26. 7 and 25

  27. limit 26 to yr="2005 -Current"

What's new

DateEventDescription
1 July 2016Review declared as stableSee Published notes.

History

Review first published: Issue 6, 2013

DateEventDescription
8 May 2014AmendedMinor edit made to numbers reported in Results of the search.
20 June 2013New citation required but conclusions have not changedConclusions regarding antiepileptics other than gabapentin, pregabalin, topiramate, and valproate essentially unchanged.
20 June 2013New search has been performedSearches updated on 15 January 2013. Five new included studies added (Cady 2009; de Tommaso 2007; Gupta 2007; Mohammadianinejad 2011; Silberstein 2008).
26 August 2008AmendedConverted to new review format.
11 May 2007New search has been performed

May 2007 (Issue 3, 2007):

  • Electronic searches updated through December 2005

  • Handsearches updated through April 2006

  • Review revised to incorporate eight new included trials

  • Dr WM Mulleners took over as guarantor of the review

Contributions of authors

Prof Linde: Designing the review. Co-ordinating the review. Data collection for the review. Screening search results. Organising retrieval of papers. Screening retrieved papers against eligibility criteria. Appraising quality of papers. Extracting data from papers. Writing to authors of papers for additional information. Providing additional data about papers. Data management for the review. Entering data into RevMan. Analysis of data. Interpretation of data. Providing a clinical perspective. Writing the review.

Dr Mulleners: Conceiving the review. Designing the review. Data collection for the review. Screening search results. Organising retrieval of papers. Screening retrieved papers against eligibility criteria. Appraising quality of papers. Extracting data from papers. Interpretation of data. Providing a clinical perspective.

Prof Chronicle: Performing previous work that was the foundation of the current review.

Assoc Prof McCrory: Analysis of data. Interpretation of data. Providing a methodological perspective. Providing general advice on the review.

Declarations of interest

Prof Linde: During the process of preparing this review the author received a travel grant from Allergan in Sweden and was involved as an investigator in a clinical trial in Norway sponsored by AstraZeneca and comparing candesartan, propranolol, and placebo in the prophylaxis of migraine.

Dr Mulleners: The author was a paid consultant for the Merck Dutch Migraine Advisory Board and received a speaker's fee from Merck Sharp & Dohme Corp.

Prof Chronicle: Author deceased. During the process of preparing the original review the author was a paid consultant for Johnson & Johnson and NPS Pharmaceuticals in the USA.

Assoc Prof McCrory: During 2008, the author was a paid expert witness for the plaintiffs in a legal action against the manufacturer of Neurontin (gabapentin). In this capacity, he prepared a systematic review examining previously confidential research reports obtained from the manufacturer (through discovery), along with published trial reports of gabapentin for migraine prophylaxis, and testified at trial.

Sources of support

Internal sources

  • No sources of support supplied

External sources

  • International Headache Society, UK.

    Funding for administrative costs associated with editorial and peer review of the original and updated reviews

  • Lifting The Burden: the Global Campaign against Headache, UK.

    Funding for administrative costs associated with editorial and peer review of the updated review

Differences between protocol and review

After reviewing the variety of methods used for calculating headache index, we decided that no systematic analysis of headache index data would be undertaken, for two principal reasons. First, rarely was sufficient information given to allow a clear understanding of how the index was calculated, and second, even when indexes were clearly described, they were not always useful — for example, because they confounded severity scores with frequency scores. Avoiding the use of headache index measures is consistent with the recommendations of the International Headache Society (Tfelt-Hansen 2012).

After publication of the protocol, we decided not to extract trial data on pain intensity, duration of attacks, or associated symptoms of migraine (nausea, vomiting, photophobia, phonophobia). The reasons were that such information was rarely given, and that the methods used were not standardised.

Our methods for assessing and dealing with heterogeneity have evolved over time in line with changing Cochrane methods. The protocol for the original review specified that we would test estimates of efficacy for homogeneity, use a fixed-effect model to combine homogenous estimates, and use a random-effects model to combine estimates when a group of studies with statistically heterogeneous results appeared to be clinically similar. In the original review itself, and in the 2007 update (Chronicle 2004; Mulleners 2008), we in fact used a random-effects model throughout for pooled analyses. In the present review, we again use a random-effects model for pooling, but we have added a possible fixed-effect sensitivity analysis in select cases; see Assessment of heterogeneity for details.

Notes

An updated search in May 2016 identified one relevant study (Verma 2013) and two ongoing studies (NCT00440518 and NCT01820559). However, we did not identify any potentially relevant studies likely to change the conclusions. Therefore, this review has now been stabilised following discussion with the authors and editors. The review will be re-assessed for updating in five years. If appropriate, we will update the review before this date if new evidence likely to change the conclusions is published, or if standards change substantially which necessitate major revisions.

Verma, A., D. Srivastava, et al. (2013). "Levetiracetam in migraine prophylaxis: A randomized placebo-controlled study in a rural medical institute in northern India." Clinical Neuropharmacology 36(6): 193-197.

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Cady 2009

Methods

Prospective, randomised, double-blind, parallel-group trial. Two months baseline period. Duration of double-blind treatment phase: 14 weeks (2 weeks dose titration, 12 weeks maintenance)

Discontinuation rate: carisbamate 100 mg 35%, carisbamate 300 mg 28%, carisbamate 600 mg 29%, placebo 28%

Compliance (adherence) data: not available

Rule for use of acute medication: not reported

Methodological quality score: 5

Participants

Inclusion: migraine with or without aura according to ICHD-II; migraine frequency of 3 to 12 attacks/month; history of migraine at least 1 year; diagnosis of migraine before age 50. Ages 18 to 65

Exclusion: excessive use of acute medication ((> 15 days/month or beyond approved daily dose of ASA unless for cardiovascular indication, other NSAIDs, acetaminophen ± metheptane mucate) or (> 10 days/month or beyond approved daily dose of triptans, ergots opioids whether or not combined with other analgesics)). Acceptable exclusion of secondary headaches. CDH not a formal exclusion criterion, but baseline values + exclusion of medication overuse do not imply high proportion of CDH. Other exclusions: Failed > 2 adequate prophylactic courses. Requirement for continued use of β-blockers, TCAs, Ca-channel blockers, antiepileptics, 5-HT2-antagonists, MAO inhibitors, daily NSAIDs, high doses of magnesium or riboflavin, botulinum toxin, herbal preparations like St. John's Wort or feverfew
Setting: 42 centres
Countries: Germany, Spain, and USA
Intention-to-treat analysis of 318 patients. 47% (151/323) of randomised patients had migraine with aura. 276 females and 40 males randomised; mean age 41.3 ± 10.68, age range 18 to 64. 83 allocated to carisbamate 100 mg, 81 allocated to carisbamate 300 mg, 79 allocated to carisbamate 600 mg, 80 allocated to placebo

InterventionsCarisbamate 100 mg/day versus carisbamate 300 mg/day versus carisbamate 600 mg/day versus placebo (14 weeks). Dosing schedules not reported except for 2 weeks initial titration
OutcomesHeadache frequency using a 48-hour rule and a 24-hour rule (all migraine headaches starting within 48 or 24 hours, respectively, of the onset of the original migraine). 50% or greater reduction in migraine frequency. Frequency of migraine attacks lasting longer than 30 min. Migraine days with use of rescue medication
Time point(s) considered in the review: through double-blind-phase (14 weeks)
NotesFunders of the trial: Johnson & Johnson Pharmaceutical Research & Development
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low risk1:1:1:1 randomisation, balanced by using randomly permuted blocks, stratified by centre, computer-generated schedule
Allocation concealment (selection bias)Low riskCoded treatment allocation, code implemented via IVRS, codes maintained at IVRS centre.
Blinding of participants and personnel (performance bias)
All outcomes
Low riskClinicians and patients blinded. Study drugs provided according to treatment code, drugs and packaging of identical appearance
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNo information
Incomplete outcome data (attrition bias)
All outcomes
Low riskNo concern among the review authors over incomplete outcome data
Selective reporting (reporting bias)High riskNo means (SD) for the treatment period provided, only percentages (range) for changes from baseline. Corresponding author requested twice for complementary data without replying

de Tommaso 2007

Methods

Prospective, randomised, double-blind, parallel-group trial. Two months baseline period. Duration of treatment: two months

Discontinuation rate: levetiracetam 0%, topiramate 20%, placebo 27%

Compliance (adherence) data: "non-compliance" reported as the most common reason for dropping out (6/7), but the extent to which patients took medications as prescribed is not reported

Rule for use of acute medication: not reported

Methodological quality score: 3

Participants

Inclusion: migraine without aura according to ICHD-II; attack frequency not specified. Ages 18 to 49. Consent to additional neurophysiological tests

Exclusion: no adequate rule reported for exclusion of secondary headaches, daily headache, or analgesic overuse headache. However, no included patient had CDH or other headache than migraine according to correspondence with the first author. Other exclusions: psychoactive drugs, general/neurological/psychiatric disorders

Setting: single-centre

Country: Italy

Intention-to-treat analysis of 39 patients. Patients with aura not recruited. 35 females and 10 males included; mean age 37.9 ± 12.4, age range 18 to 49. 15 received levetiracetam, 15 received placebo, and 15 received topiramate

InterventionsLevetiracetam 1000 mg/day (500 mg BID, presumably tablets) versus topiramate 100 mg/day (50 mg BID, presumably tablets) versus placebo (8 weeks). Dose escalation strategy not reported
Outcomes

Migraine days per month. 50% or greater reduction in migraine frequency. Flicker frequency dependent α-rhythm phase synchronisation (phase synchronisation index). Mean iCNV amplitude and iCNV habituation index

Time point(s) considered in the review: through entire treatment period (2 months)

Notes

Study was not principally designed to obtain clinical outcome data of the interventions

Funders of the trial: not reported

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNo information
Allocation concealment (selection bias)Unclear riskNo information
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskStudy was double-blind, but methodological description is lacking
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNo information
Incomplete outcome data (attrition bias)
All outcomes
Low riskNo concern among the review authors over incomplete outcome data
Selective reporting (reporting bias)Low riskMeans (SD) for migraine frequency during treatment period not presented in publications but provided by first author after request

Ghose 2002

Methods

Prospective, randomised, double-blind cross-over trial. 4-week baseline period. Duration of treatment: 12 weeks of either vigabatrin or placebo, then 4-week placebo-only washout period, then cross-over medication for 12 weeks

Discontinuation rate: dropout: 4 of 23 patients

Compliance (adherence) data: compliance: 4 of 23 patients excluded by tablet count or serum vigabatrin levels

Rule for use of acute medication: triptans allowed, others not specified

Methodological quality score: 3

Participants

Inclusion: IHS migraine criteria, no other relevant physical or psychiatric disorder, normal CT scan of the head, no EEG evidence of epilepsy, non-smokers

Exclusions: secondary headache and analgesic overuse headache were adequately excluded. 5 patients with possible daily headache were included

Setting: single public hospital headache clinic

Country: not reported (likely New Zealand)

Complete case analysis of 15 patients. 8 patients with aura; 7 without. 10 females and 5 males, age range 28 to 66

InterventionsVigabatrin (12 weeks) versus placebo (12 weeks); repeat with cross-over. Dosage titrated up to 1000 mg twice/day
Outcomes

Number of migraine attacks per week. Severity (3-point scale), duration (hours), and a migraine index (frequency x duration x severity)

Time point(s) considered in the review: last (12th) week of treatment phase

NotesFunders of the trial: Marion Merrell Dow Pharmaceuticals New Zealand Limited
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNo information on method for random sequence generation
Allocation concealment (selection bias)Unclear riskNo information
Blinding of participants and personnel (performance bias)
All outcomes
Low riskBoth participants and clinicians blinded. Placebo tablets were identical to verum. Serum samples were coded to ensure that the analysis of drug levels was performed blindly
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNo information
Incomplete outcome data (attrition bias)
All outcomes
High riskComplete case analysis of 15 patients
Selective reporting (reporting bias)Low riskNo suspicion of selective reporting of outcomes, time points, or analyses

Gupta 2007

Methods

Prospective, randomised, double-blind, triple cross-over trial. Study duration 23 weeks (although stated 20 weeks); 4 weeks prospective baseline followed by 4 weeks with first intervention, 1 week washout, cross-over to 4 weeks with second intervention, 1 week washout, cross-over to 4 weeks with third intervention, 1 week washout, and finally cross-over to 4 weeks with fourth intervention. Each subject received all treatments in a specified order

Discontinuation rate: lamotrigine 7%, topiramate 7%, lamotrigine placebo 7%, topiramate placebo 7%

Compliance (adherence) data: not available

Rule for use of acute medication: patients were allowed to take tablets with a combination of paracetamol and diclofenac potassium (supplied to them) at their choice

Methodological quality score: 2

Participants

Inclusion: migraine with or without aura according to ICHD-I; migraine frequency of 4 to 10 attacks/month; history of migraine at least 1 year; debut of migraine before age 50; at least 48 h pain-free interval between attacks. Ages 18 to 65

Exclusion: headaches other than migraines. > 8 days/month of NSAIDs, ergots, or triptans. Paracetamol overuse and CDH not mentioned as exclusion criteria. Other exclusions: migraine prophylactic drug (or drug with such potential) last month, antipsychotic/antidepressant drug last 3 months, alcohol or other drug dependence, nephrolithiasis, participated in earlier study of lamotrigine or topiramate, used lamotrigine or topiramate 2 weeks or longer, used experimental drug last month

Setting: single-centre

Country: India

Intention-to-treat analysis of 57 patients. 32% (19/60) of included patients had migraine with aura. 47 females and 13 males; mean age 29.4 ± 7.7 years (range 16 to 48). 57 received lamotrigine, 57 received topiramate, 57 received lamotrigine placebo and 57 received topiramate placebo

InterventionsLamotrigine 50 mg/day, versus lamotrigine placebo, versus topiramate 50 mg/day, versus topiramate placebo (4 weeks). Lamotrigine and topiramate and were given as 25 mg tablet BID (stable dosage), and placebos as 1 tablet BID (stable dosage)
Outcomes

Change in migraine frequency per 28 days compared to baseline. Proportion of responders (50% reduction in frequency). Responder rate migraine intensity. Attack frequency. Attack duration. Intensity on VAS. Phonophobia. Photophobia. Rescue medication use. Response to rescue medication. Aura frequency. "Reports of AEs communicated historically during visits, as transcribed on headache diaries"

Time point(s) considered in the review: through entire treatment period (4 weeks)

Notes

Unclear if any participants had CDH. Shorter treatment periods (1 month) than recommended (3 months) by IHS for evaluation of efficacy in clinical trials. Since 2 potentially active drugs were used, there is an obvious risk of carry-over effect (analysis for order effects lacking)

Funders of the trial: not reported

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskComputer-generated schedule allocating participants to one of four treatment arms: LTG – LPLAC-TOP-TPLAC or LPLAC-LTG-TPLAC-TOP or TOP-TPLAC-LTG-LPLAC or TPLAC-TOP-LPLAC-LTG
Allocation concealment (selection bias)Low riskPreprinted medication code labels. Sealed envelopes containing the code labels with a tear-off label concealing the randomisation number were provided to the investigator
Blinding of participants and personnel (performance bias)
All outcomes
High riskPatients and clinicians were blinded. Placebo was identical in appearance and packaging to active drug, but since the lamotrigine and topiramate tablets were different in appearance, 2 different placebos were used. For effective blinding a double-dummy design would be required. Study medication was packaged and labelled according to a medication code schedule generated before the trial. Each package had all 4 medications numbered according to the phase of the trial. Each bottle had a 2-part tear-off label; study medication identification was concealed and could be revealed only in case of emergency
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskInvestigators were blinded but not clearly stated that this included the stage of analysis
Incomplete outcome data (attrition bias)
All outcomes
Low riskNo concern among the review authors over incomplete outcome data
Selective reporting (reporting bias)Low riskNo suspicion of selective reporting of outcomes, time points, subgroups, or analyses

Mohammadianinejad 2011

Methods

Prospective, randomised, double-blind, parallel-group trial. Study duration: prospective (confirmed by correspondence with author) baseline of unclear duration followed by a 3 months treatment phase

Discontinuation rate: zonisamide 8%, topiramate 5%

Compliance (adherence) data: not available

Rule for use of acute medication: not described

Methodological quality score: 3

Participants

Inclusion: migraine with or without aura according to ICHD (not stated which edition); migraine frequency of 4 to 15 attacks/month or < 4 attacks/month but so prolonged and debilitating that prophylaxis was required; history of migraine at least 1 year; debut of migraine before age 50. Age range not defined in publication, but corresponding author confirms that all were adults (17 to 58 years). Other inclusion: > 1 year since menopause (for postmenopausal women); negative pregnancy test and appropriate contraception; history of unsuccessful prophylactic treatment with one or more of the first-line migraine prophylaxis regimens; written informed consent obtained

Exclusion: any other primary headache, for example TTH or cluster headache. Overuse of acute medication and CDH not mentioned as exclusion criteria, but corresponding author confirms that no participant had CDH. Other exclusions: history of topiramate or zonisamide consumption; any other cause of pain that needs medications regularly, for example neuropathy or arthritis

Setting: single neurological clinic

Country: Iran

80 migraine patients participated. No information on proportion with migraine with aura. 63 females and 17 males; mean age zonisamide group 35.3 ± 9.5 years; mean age topiramate group 33.0 ± 9.2 years. 40 received zonisamide; 40 received topiramate

InterventionsZonisamide 200 mg/day versus topiramate 100 mg/day (12 weeks). Zonisamide capsules gradually titrated up from 50 mg/day to 200 mg/day within 1 month. Topiramate capsules gradually titrated up from 25 mg/day to 100 mg/day within 1 month
Outcomes

Headache frequency (number of migraine attacks per month). Response to treatment (decrease in frequency by more than 50%). Headache severity (VAS 1 to 10). Frequency of acute medication. MIDAS score. AEs

Time point(s) considered in the review: third month of treatment

NotesFunders of the trial: not reported
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskStudy was randomised (1:1), but method of sequence generation not described
Allocation concealment (selection bias)Low riskAn independent pharmacist packaged the drugs into numbered containers that were dispensed on the day of randomisation
Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskParticipants and clinicians were reported as blinded. Both drugs were capsules. Not stated that they were similar in appearance
Blinding of outcome assessment (detection bias)
All outcomes
Low riskAll active assessors were completely blinded
Incomplete outcome data (attrition bias)
All outcomes
High riskComplete case analysis, ie, patients discontinuing prematurely were excluded from efficacy analysis
Selective reporting (reporting bias)High riskThe percentages of 50% responders are not internally consistent. Absolute numbers requested twice from corresponding author but not provided. AEs are not adequately reported

Rompel 1970

Methods

Prospective, randomised, double-blind, single cross-over trial. No baseline or washout periods. Total duration: 12 weeks

Discontinuation rate: dropout 6% for active treatment; 0% for placebo

Compliance (adherence) data: no compliance data reported

Rule for use of acute medication not reported

Methodological quality score: 4

Participants

Inclusion: idiosyncratic criteria for migraine. Mixed and combination headaches may have been included, but subgroups cannot be distinguished

Exclusion: secondary headaches were adequately excluded. Neither daily headache nor analgesic overuse headache were adequately excluded

Setting: single migraine clinic

Country: South Africa

48 migraine patients participated; numbers with and without aura are not reported. 33 females, 15 males; age range 14 to 60. 45 received active treatment and 48 received placebo

InterventionsCarbamazepine (6 weeks) versus placebo (6 weeks). Precise dosage not reported
Outcomes

Number of migraine attacks in a 6-week period

Time point(s) considered in the review: through entire treatment phase (6 weeks)

Notes

Not all participants were adults over 16 years of age

Funders of the trial: not reported

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskA randomised table of numbers was used for sequence generation
Allocation concealment (selection bias)Low riskRandomisation codes were unavailable to the trialist
Blinding of participants and personnel (performance bias)
All outcomes
Low riskBoth participants and clinicians were blinded. Placebo and verum were indistinguishable (supplied by Geigy South Africa (Pty) Limited)
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNo information
Incomplete outcome data (attrition bias)
All outcomes
High riskWithdrawals were excluded from statistical analysis
Selective reporting (reporting bias)Low riskNo suspicion of selective reporting of outcomes, time points, or analyses

Silberstein 2008

Methods

Prospective, randomised, double-blind, parallel-group trial. Study duration: 4-week single-blind baseline phase (placebo given BID), thereafter a 15-week double-blind phase (6-week titration, 8-week maintenance, 1-week down-titration), followed by a 13-week open-label extension phase for patients who chose to continue or switch to oxcarbazepine therapy

Discontinuation rate: oxcarbazepine 34%, placebo 19%

Compliance (adherence) data: not available

Rule for use of acute medication: not reported

Methodological quality score: 5

Participants

Inclusion: migraine with or without aura according to ICHD-I; migraine frequency of 3 to 9 attacks/month; history of migraine at least 1 year; debut of migraine before age 50; at least 48 h pain-free interval between attacks. Ages 16 to 65. Serum sodium levels ≥ 135 mEq/L at visit 1. Ability to read, write, and understand English. Capability of satisfying the requirements of the protocol and willingness and ability to give informed consent/assent according to legal requirements. No risk of pregnancy

Exclusion: ≥ 14 headache days with each headache lasting > 4 hours (of either migraine or non-migraine type) during the last 28 days of the single-blind baseline phase. Required symptomatic (acute) therapy more than 3 days/7 consecutive day period for a non-migraine headache during the last 28 days of the single-blind baseline phase. Patients requiring acute treatment for > 3 days/week in any 28-day period were discontinued from the study. Acceptable exclusion of secondary headaches. Other exclusions: missed > 20% of their expected doses of placebo during the last 28 days of the single-blind baseline phase. Missed ≥ 3 migraine diary entries during the last 28 days of the single-blind baseline phase. Previously failed > 3 standard courses of a commonly effective preventive migraine treatment. Having taken antidepressants (except SSRIs), beta-blockers, verapamil, diuretics, other AEDs, magnesium, herbal supplements, or > 50 mg/day of vitamin B2 within 1 month of study entry

Setting: 23 centres

Country: USA

Intention-to-treat analysis of 170 patients. Not reported how many had migraine with aura and how many had migraine without aura. 144 females and 26 males; mean age: allocated to oxcarbazepine 40.6 years (SD not reported, range 17 to 63); allocated to placebo 40.3 years (SD NR, range 17 to 68). 85 allocated to oxcarbazepine, 85 allocated to placebo

Interventions

Oxcarbazepine 1200 mg/day versus placebo (15 weeks). During the 6-week titration period, oxcarbazepine was initiated at 150 mg/day and increased by 150 mg/day every 5 days to a to maximum tolerated dose of 1200 mg/day. At the investigator's discretion (based on poor tolerability), the dose could then be tapered downward, if necessary. Following step-down, the patient could be maintained at that dose level for the remainder of the titration phase, or the dose could be titrated up so the patient could reach his or her optimal dose. No further dose increases were allowed after the end of the 6-week titration period. At the end of the titration period, the median dose was 1200 mg/day (range 300 to 1200 mg/day). Upon completion of the 8-week maintenance period, or at premature discontinuation, patients were gradually withdrawn from study medication in a 1-week down-titration phase. Placebo tablets were administered BID during the baseline phase (not described for the double-blind period)

Time point(s) considered in the review: last 28-day period of the double-blind phase

Outcomes

Number of migraine attacks per 28-day period. Proportion of patients who responded to treatment with at least a 50% reduction in migraine attacks relative to baseline. Number of migraine days. Peak severity of migraine attacks. Acute therapy consumption. Number of non-migraine headache days during per 28 days. Migraine-related disability (MIDAS). Quality of life (SF-36). Clinical Global Impressions and Patient Global Impressions scales. AEs

Time point(s) considered in the review: last 4 weeks of the 15-week treatment phase

NotesFunders of the trial: Novartis Pharmaceuticals Corporation
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskRandomisation was performed by a contracted outside clinical research organisation using a validated system that automates the random assignment of treatment groups to randomisation numbers
Allocation concealment (selection bias)Low riskAs patients qualified for entry, the investigator called into the IVRS for assignment of randomisation numbers
Blinding of participants and personnel (performance bias)
All outcomes
Low riskDuring the single-blind baseline-phase, only the patients were blinded to the treatment being administered. During the double-blind phase, treatment assignments were not revealed to patients, investigators, clinical staff, or study monitors until all patients completed therapy and the database was finalised. The study drug was packaged and labelled according to a medication code generated before the trial. Each bottle had a two-part tear-off: study medication was concealed and only revealed in case of emergency. Placebo tablets were matched in size to verum
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNo information
Incomplete outcome data (attrition bias)
All outcomes
Low riskNo concern among the review authors over incomplete outcome data
Selective reporting (reporting bias)High riskSDs for changes in least squares means of migraine frequencies lacking in publication (only SEs given). Supplementary information requested twice from corresponding author, but no reply. Change from baseline in number of non-migraine headache days during the last 28 days of the double-blind phase and the entire double-blind phase stated as a secondary outcome, but data not given

Steiner 1997

Methods

Prospective, randomised, double-blind, parallel trial. Total duration: 4 months. 1-month single-blind, placebo-only baseline period. 3-month treatment period

Discontinuation rate: dropout: 31%

Compliance (adherence) data: compliance was assessed by count of returned tablets, but data are not reported

Rule for use of acute medication: Co-codamol encouraged, ergotamine discouraged, but some other medication also allowed

Methodological quality score: 5

Participants

Inclusion: IHS migraine criteria; migraine onset at least 2 years prior to study; 2 to 8 attacks per month in the previous 3 months

Exclusion: secondary headaches, daily headaches, and analgesic overuse headaches were adequately excluded. Other exclusions: chronic or recurrent pain, hepatic or renal disease, depression, other migraine prophylactic medication in last 2 months, pregnancy, change in use of oral contraception, previous participation in more than 2 clinical trials

Setting: 2 secondary-referral centres

Country: UK

77 patients were randomised; 31 with aura and 46 without. 63 females and 14 males; age range 18 to 60

InterventionsLamotrigine (3 months) versus placebo (3 months). Target dosage 200 mg/day, but see notes
Outcomes

Number of migraine attacks per 28 days. Number of migraine days per 28 days. Severity (3-point scale). Number of doses of escape medication

Time point(s) considered in the review: last (third) month of treatment phase

Notes

Initial protocol specified 200 mg dosage immediately, but adverse events led to an amendment in which dosage was titrated for the first 4 weeks

Funders of the trial: not reported

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskRandom sequence generation was generated separately at each centre, but method not described
Allocation concealment (selection bias)Unclear riskNo information
Blinding of participants and personnel (performance bias)
All outcomes
Low riskParticipants and clinicians were blinded. All medication was dispensed as matching hard-gelatin capsules manufactured by the Wellcome Foundation Ltd. To maintain blindness, equally many capsules of verum and placebo were given
Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNo information
Incomplete outcome data (attrition bias)
All outcomes
Low riskAll randomised patients were included in the analysis
Selective reporting (reporting bias)Low riskNo suspicion of selective reporting of outcomes, time points, subgroups, or analyses

Stensrud 1979

Methods

Prospective, randomised, double-blind, single cross-over trial. No washout period. 4-week baseline period. Total duration of double-blind period: 8 weeks. In an additional 4-week period, all participants received active treatment in higher dose

Discontinuation rate: dropout: 10.5% overall

Compliance (adherence) data: no compliance data reported

Rule for use of acute medication: analgesics or ergotamine

Methodological quality score: 1

Participants

Inclusion: Ad Hoc Committee criteria; at least 3 attacks per month

Exclusion: no criteria reported

Setting: single outpatient clinic

Coutnry: not reported (likely Norway)

38 migraine patients participated; numbers with and without aura are not reported. 27 females and 11 males; age range 20 to 60

InterventionsClonazepam (4 weeks) versus placebo (4 weeks). Dosage 1 mg/day, then 2 mg/day for additional 4-week higher dose period
Outcomes

Number of headache days per 28 days. Headache index: sum of individual headache severity grades (1 to 3 scale) per 28 days

Time point(s) considered in the review: first month of treatment phase

NotesFunders of the trial: not reported
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskStudy was randomised (to sequence A or B), but method of sequence generation not described
Allocation concealment (selection bias)Unclear riskNo information
Blinding of participants and personnel (performance bias)
All outcomes
Low riskParticipants and clinicians were blinded. Placebo was used
Blinding of outcome assessment (detection bias)
All outcomes
High riskNo information on blinding of analysts. Both sequences incorporated a final 4-week period in which all patients received same dose (2 mg) of clonazepam
Incomplete outcome data (attrition bias)
All outcomes
Low riskNo concern among the review authors over incomplete outcome data
Selective reporting (reporting bias)Low riskNo suspicion of selective reporting of outcomes, time points, subgroups, or analyses

Vahedi 2002

  1. a

    Abbreviations: AE = adverse event; AED = antiepileptic drug; ASA = acetylsalicylic acid; BID = twice (two times) a day; CDH = chronic daily headache; CT = computed tomography; EEG = electroencephalogram; h = hour; ICHD-I = International Classification of Headache Disorders, 1st Edition; ICHD-II = International Classification of Headache Disorders, 2nd Edition; IHS = International Headache Society; iCNV = initial contingent negative variation; IVRS = interactive voice response system; MIDAS = Migraine Disability Assessment; MAO = monoamine oxidase inhibitor; NSAIDs = non-steroidal anti-inflammatory drugs; SD = standard deviation; SE = standard error; SSRIs = selective serotonin re-uptake inhibitors; TCA = tricyclic antidepressant; TTH = tension-type headache; VAS = visual analogue scale

Methods

Prospective, randomised, double-blind parallel trial. 28-day baseline period. Duration of treatment: 12 weeks

Discontinuation rate: dropout 34% overall, 22% in placebo group and 46% in treatment group

Compliance (adherence) data: compliance data not reported

Rule for use of acute medication: patients' usual medication, except that more than 1 g aspirin daily was not permitted

Methodological quality score: 5

Participants

Inclusion: IHS migraine criteria; migraine for more than 1 year; migraine frequency of 2 to 8 per month; no more than 6 days per month of interval headache; age of onset of migraine 50 years or younger; discontinuation of other migraine prophylaxis at least 6 weeks prior to the trial

Exclusion: secondary headaches, daily headaches, and analgesic overuse headaches were adequately excluded. Other exclusions: depression, use of antidepressant or antipsychotic drugs; women of childbearing potential not using contraception; relevant allergies; use of medication likely to interfere with potassium or acid-base balances; history of renal lithiasis, renal or hepatic insufficiency, hyperuricaemia, diabetes, hypokalaemia

Setting: multicentre

Country: 7 sites in France

53 patients enrolled. 48 migraine without aura; 5 with aura. 40 females and 13 males, age range 19 to 60. 27 received placebo and 26 active drug

InterventionsAcetazolamide 250 mg twice/day versus placebo (12 weeks). Dose reduction to 125 mg twice/day permitted in the case of bothersome side effects
Outcomes

Headache frequency in the final 28 days of treatment. Proportion of responders (50% reduction in frequency of attacks). Severity and duration of attacks also recorded

Time point(s) considered in the review: last (third) month of treatment phase

Notes

Power calculations indicated the need for 90 patients in each arm of the trial. The study was discontinued prematurely because of the high frequency of adverse events. Hence only 53 patients were enrolled

Funders of the trial: Assistance Publique – Hôpitaux de Paris, GERMED GNE96003 at the Délégation à la Recherche Clinique of Saint-Louis Hospital and PHRCAOM97096 (Programme Hospitalier de Recherche Clinique of theFrench Ministry of Health)

Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskStudy was randomised, but method for sequence generation not described
Allocation concealment (selection bias)Low riskRandomisation was performed centrally by fax
Blinding of participants and personnel (performance bias)
All outcomes
Low riskBoth participants and clinicians were blinded. Each package of trial medication contained 3 boxes of 5 blisters of 14 placebo or verum tablets. These were delivered by a pharmacist at each centre
Blinding of outcome assessment (detection bias)
All outcomes
Low riskNo information
Incomplete outcome data (attrition bias)
All outcomes
Low riskIntention-to-treat analysis of randomised patients
Selective reporting (reporting bias)High riskVariance measures lacking for migraine attack frequency during treatment

Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion
Anthony 1972Insufficient evidence of randomisation or pseudo-randomisation
Chen 2001Reports case studies only
Cochran 2004Letter to editor
D'Andrea 1999No control group
Delvaux 2001No control group
Hedri 1975Reports case studies only
Lampl 1999Reports case studies only
Skupin 1975No control group
Smirne 1979No control group
Stieg 1977No arm of trial in which antiepileptic alone was given
Voto Bernales 1974No control group