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

Mattias Linde; Wim M Mulleners; Edward P Chronicle; Douglas C McCrory

doi:10.1002/14651858.CD010608

. 2013 Jun 24;2013(6):CD010608. doi: 10.1002/14651858.CD010608

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

Mattias Linde ^1,^2,^✉, Wim M Mulleners ³, Edward P Chronicle ⁴, Douglas C McCrory ^5,⁶

Editor: Cochrane Pain, Palliative and Supportive Care Group

PMCID: PMC8221229 PMID: 23797674

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.

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.

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:

Topiramate for the prophylaxis of episodic migraine in adults (Linde 2013a)
Valproate (valproic acid or sodium valproate or a combination of the two) for the prophylaxis of episodic migraine in adults (Linde 2013b)
Gabapentin or pregabalin for the prophylaxis of episodic migraine in adults (Linde 2013c)
Antiepileptics other than gabapentin, pregabalin, topiramate, and valproate for the prophylaxis of episodic migraine in adults (the present review, Linde 2013d)

Objectives

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:

Was the study described as randomised? (1 = yes; 0 = no)
Was the method of randomisation well described and adequate? (0 = not described; 1 = described and adequate; ‐1 = described, but not adequate)
Was the study described as double‐blind? (1 = yes; 0 = no)
Was the method of double‐blinding well described and adequate? (0 = not described; 1 = described and adequate; ‐1 = described, but not adequate)
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).

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

'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.

1. Numbers (percentages) of adverse events (AEs) in single dosage placebo‐controlled studies.

Study	Type of AE	Antiepileptic	Placebo
Vahedi 2002		Acetazolamide (n = 26)	Placebo (n = 27)
	Paresthesia	21 (81)	2 (7)
	Fatigue/drowsiness/memory problems/malaise	15 (58)	4 (15)
	Gastrointestinal intolerance	3 (12)	2 (7)
	Hypokalaemia	1 (4)	0 (0)
	Hyperuricaemia	1 (4)	0 (0)
	Skin eruption	0 (0)	2 (7)
	Fever and shivering	0 (0)	1 (4)
	Dry mouth	1 (4)	1 (4)
	Breast tension	0 (0)	1 (4)
	Rhinitis	1 (4)	2 (7)
	Tinnitus	0 (0)	1 (4)
	Miscellaneous	1 (4)	3 (11)
Rompel 1970		Carbamazepine (n = 45)	Placebo (n = 48)
	Any AE	30 (67)	11 (23)
	Vertigo, giddiness	23 (51)	2 (4)
	Drowsiness	5 (11)	1 (2)
	Nausea	4 (9)	3 (6)
	Dry mouth	2 (4)	0 (0)
	Heavy eyes	2 (4)	0 (0)
	Constipation	2 (4)	0 (0)
	Vomiting	1 (2)	0 (0)
	Weight gain	1 (2)	1 (2)
	Sweating	1 (2)	0 (0)
	Transient rash	1 (2)	0 (0)
	Dysuria	1 (2)	0 (0)
	Blocked nose	0 (0)	1 (2)
	Flushing	0 (0)	1 (2)
	Blunted feeling	0 (0)	1 (2)
	Heavy head	0 (0)	1 (2)
Cady 2009		Carisbamate (n = 238)	Placebo (n = 78)
	Any AE	183 (77)	58 (74)
	Fatigue	41 (17)	5 (6)
	Nasopharyngitis	30 (13)	9 (12)
	Nausea	21 (9)	6 (8)
	Back pain	12 (5)	1 (1)
	Diarrhoea	11 (5)	2 (3)
	Dizziness	11 (5)	3 (4)
	Somnolence	8 (3)	4 (5)
	Upper abdominal pain	7 (3)	2 (3)
	Vomiting	7 (3)	2 (3)
	Hepatic enzyme increased	6 (3)	0
	Migraine	6 (3)	5 (6)
	Insomnia	4 (2)	4 (5)
Stensrud 1979		Clonazepam (n = 38)	Placebo (n = 38)
	Sedation	23 (61)	Unclear
	Dizziness	10 (26)	Unclear
	Irritability	2 (5)	Unclear
Steiner 1997		Lamotrigine (n = 37)	Placebo (n = 40)
	Rash	11 (30)	1 (3)
	Dizziness	4 (11)	2 (5)
	Asthenia	2 (5)	2 (5)
	Somnolence	2 (5)	0 (0)
	Thinking abnormality	1 (3)	0 (0)
	Tremor	0 (0)	1 (3)
	Leukopenia	1 (3)	1 (3)
	Nausea	0 (0)	3 (8)
	Weight gain	0 (0)	3 (8)
	Allergy	0 (0)	1 (3)
Gupta 2007		Lamotrigine (n = 57)	Placebo (n = 57)
	Sleepiness and concentration difficulty	2 (4)	0
	Paresthesias	2 (4)	Unclear
	Gastrointestinal intolerance	2 (4)	1
	Anorexia	1 (2)	2 (4)
	Giddiness	2 (4)	1 (2)
	Rash	2 (4)	1 (2)
	Palpitations	0	2 (4)
	Menorrhagia	0	0
	Hair loss	0	0
	Pain in lower limbs	0	1 (2)
de Tommaso 2007		Levetiracetam (n = 15)	Placebo (n = 15)
	Sedation and dizziness	5 (33)	Unclear
Silberstein 2008		Oxcarbazepine (n = 85)	Placebo (n = 85)
	Any AE	68 (80)	55 (65)
	Fatigue	17 (20)	6 (7)
	Dizziness	15 (18)	6 (7)
	Nausea	14 (16)	4 (5)
	Somnolence	7 (8)	6 (7)
	Balance disorder	5 (6)	2 (2)
	Insomnia	5 (6)	6 (7)
	Migraine	5 (6)	2 (2)
	Paresthesias	5 (6)	1 (1)
	Sinusitis	2 (2)	5 (6)

Date	Event	Description
1 July 2016	Review declared as stable	See Published notes.
8 May 2014	Amended	Minor edit made to numbers reported in Results of the search.
20 June 2013	New search has been performed	Searches updated on 15 January 2013. Five new included studies added (Cady 2009; de Tommaso 2007; Gupta 2007; Mohammadianinejad 2011; Silberstein 2008).
20 June 2013	New citation required but conclusions have not changed	Conclusions regarding antiepileptics other than gabapentin, pregabalin, topiramate, and valproate essentially unchanged.
26 August 2008	Amended	Converted to new review format.
11 May 2007	New 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

Outcome or subgroup title	No. of studies	Statistical method	Effect size
2.1 OR for responders (patients with ≥ 50% reduction in headache frequency)	1	Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
2.2 RR for responders (patients with ≥ 50% reduction in headache frequency)	1	Risk Ratio (M‐H, Random, 95% CI)	Totals not selected
2.3 Any adverse event	1	Risk Difference (M‐H, Random, 95% CI)	Totals not selected
2.4 Drowsiness	1	Risk Difference (M‐H, Random, 95% CI)	Totals not selected
2.5 Nausea	1	Risk Difference (M‐H, Random, 95% CI)	Totals not selected
2.6 Vertigo/giddiness	1	Risk Difference (M‐H, Random, 95% CI)	Totals not selected

Outcome or subgroup title	No. of studies	Statistical method	Effect size
3.1 Responders (patients with ≥ 50% reduction in headache frequency)	1	Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
3.1.1 Carisbamate titrated to 100 mg/day	1	Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
3.1.2 Carisbamate titrated to 300 mg/day	1	Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
3.1.3 Carisbamate titrated to 600 mg/day	1	Odds Ratio (M‐H, Random, 95% CI)	Totals not selected

Outcome or subgroup title	No. of studies	Statistical method	Effect size
4.1 Responders (patients with ≥ 50% reduction in headache frequency)	1	Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
4.1.1 Carisbamate 300 mg/day versus 100 mg/day	1	Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
4.1.2 Carisbamate 600 mg/day versus 100 mg/day	1	Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
4.1.3 Carisbamate 600 mg/day versus 300 mg/day	1	Odds Ratio (M‐H, Random, 95% CI)	Totals not selected

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
6.1 Headache frequency (change from baseline to post‐treatment, or post‐treatment alone)	2	190	Mean Difference (IV, Random, 95% CI)	‐0.49 [‐1.83, 0.85]
6.1.1 Lamotrigine 50 mg/day	1	113	Mean Difference (IV, Random, 95% CI)	‐1.17 [‐2.17, ‐0.17]
6.1.2 Lamotrigine titrated to 200 mg/day	1	77	Mean Difference (IV, Random, 95% CI)	0.20 [‐0.81, 1.21]
6.2 Responders (patients with ≥ 50% reduction in headache frequency)	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
7.1 Headache frequency (change from baseline to post‐treatment)	1		Mean Difference (IV, Random, 95% CI)	Totals not selected
7.2 Responders (patients with ≥ 50% reduction in headache frequency)	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected

Outcome or subgroup title	No. of studies	Statistical method	Effect size
8.1 Headache frequency (post‐treatment; headache days per month)	1	Mean Difference (IV, Random, 95% CI)	Totals not selected
8.2 OR for responders (patients with ≥ 50% reduction in headache frequency)	1	Odds Ratio (M‐H, Random, 95% CI)	Totals not selected
8.3 RR for responders (patients with ≥ 50% reduction in headache frequency)	1	Risk Ratio (M‐H, Random, 95% CI)	Totals not selected

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
9.1 Headache frequency (post‐treatment; headache days per month)	1		Mean Difference (IV, Random, 95% CI)	Totals not selected
9.2 Responders (patients with ≥ 50% reduction in headache frequency)	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
10.1 Headache frequency (change from baseline to post‐treatment)	1		Mean Difference (IV, Random, 95% CI)	Totals not selected
10.2 Responders (patients with ≥ 50% reduction in headache frequency)	1		Odds Ratio (M‐H, Random, 95% CI)	Totals not selected

*Study characteristics*
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
Interventions	Carisbamate 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
Outcomes	Headache 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)
Notes	Funders of the trial: Johnson & Johnson Pharmaceutical Research & Development
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	1:1:1:1 randomisation, balanced by using randomly permuted blocks, stratified by centre, computer‐generated schedule
Allocation concealment (selection bias)	Low risk	Coded treatment allocation, code implemented via IVRS, codes maintained at IVRS centre.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Clinicians 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 risk	No information
Incomplete outcome data (attrition bias) All outcomes	Low risk	No concern among the review authors over incomplete outcome data
Selective reporting (reporting bias)	High risk	No means (SD) for the treatment period provided, only percentages (range) for changes from baseline. Corresponding author requested twice for complementary data without replying

*Study characteristics*
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
Interventions	Vigabatrin (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
Notes	Funders of the trial: Marion Merrell Dow Pharmaceuticals New Zealand Limited
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	No information on method for random sequence generation
Allocation concealment (selection bias)	Unclear risk	No information
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Both 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 risk	No information
Incomplete outcome data (attrition bias) All outcomes	High risk	Complete case analysis of 15 patients
Selective reporting (reporting bias)	Low risk	No suspicion of selective reporting of outcomes, time points, or analyses

*Study characteristics*
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
Interventions	Lamotrigine 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*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Computer‐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 risk	Preprinted 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 risk	Patients 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 risk	Investigators were blinded but not clearly stated that this included the stage of analysis
Incomplete outcome data (attrition bias) All outcomes	Low risk	No concern among the review authors over incomplete outcome data
Selective reporting (reporting bias)	Low risk	No suspicion of selective reporting of outcomes, time points, subgroups, or analyses

*Study characteristics*
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
Interventions	Carbamazepine (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*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	A randomised table of numbers was used for sequence generation
Allocation concealment (selection bias)	Low risk	Randomisation codes were unavailable to the trialist
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Both 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 risk	No information
Incomplete outcome data (attrition bias) All outcomes	High risk	Withdrawals were excluded from statistical analysis
Selective reporting (reporting bias)	Low risk	No suspicion of selective reporting of outcomes, time points, or analyses

*Study characteristics*
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
Interventions	Acetazolamide 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*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Study was randomised, but method for sequence generation not described
Allocation concealment (selection bias)	Low risk	Randomisation was performed centrally by fax
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Both 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 risk	No information
Incomplete outcome data (attrition bias) All outcomes	Low risk	Intention‐to‐treat analysis of randomised patients
Selective reporting (reporting bias)	High risk	Variance measures lacking for migraine attack frequency during treatment

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

PERMALINK

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

Mattias Linde

Wim M Mulleners

Edward P Chronicle

Douglas C McCrory

Abstract

Background

Objectives

Search methods

Selection criteria

Data collection and analysis

Main results

Authors' conclusions

Plain language summary

Background

Description of the condition

Description of the intervention

How the intervention might work

Why it is important to do this review

Objectives

Methods

Criteria for considering studies for this review

Types of studies

Types of participants

Types of interventions

Types of outcome measures

Search methods for identification of studies

Data collection and analysis

Selection of studies

Data extraction and management

Assessment of risk of bias in included studies

Measures of treatment effect

Unit of analysis issues

Dealing with missing data

Assessment of heterogeneity

Data synthesis

Subgroup analysis and investigation of heterogeneity

Results

Description of studies

Results of the search

Included studies

Excluded studies

Risk of bias in included studies

1.

2.

Allocation

Blinding

Incomplete outcome data

Selective reporting

Other potential sources of bias

Effects of interventions

Methodological considerations

1. Numbers (percentages) of adverse events (AEs) in single dosage placebo‐controlled studies.

Acetazolamide

1.1. Analysis.

Carbamazepine

2.1. Analysis.

2.2. Analysis.

2.3. Analysis.

2.4. Analysis.

2.5. Analysis.

2.6. Analysis.

Carisbamate

3.1. Analysis.

4.1. Analysis.

Clonazepam

5.1. Analysis.

Lamotrigine

6.1. Analysis.

6.2. Analysis.

7.1. Analysis.

7.2. Analysis.

Levetiracetam

8.1. Analysis.

8.2. Analysis.

8.3. Analysis.

9.1. Analysis.

9.2. Analysis.

Oxcarbazepine