Intervention Review

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

  1. Mattias Linde1,*,
  2. Wim M Mulleners2,
  3. Edward P Chronicle3,
  4. Douglas C McCrory4,5

Editorial Group: Cochrane Pain, Palliative and Supportive Care Group

Published Online: 24 JUN 2013

Assessed as up-to-date: 15 JAN 2013

DOI: 10.1002/14651858.CD010608

How to Cite

Linde M, Mulleners WM, Chronicle EP, McCrory DC. Antiepileptics other than gabapentin, pregabalin, topiramate, and valproate for the prophylaxis of episodic migraine in adults. Cochrane Database of Systematic Reviews 2013, Issue 6. Art. No.: CD010608. DOI: 10.1002/14651858.CD010608.

Author Information

  1. 1

    Norwegian University of Science and Technology, Department of Neuroscience, Trondheim, Norway

  2. 2

    Canisius Wilhelmina Ziekenhuis, Department of Neurology, Nijmegen, Netherlands

  3. 3

    University of Hawaii at Manoa, (Deceased) Department of Psychology, Manoa, USA

  4. 4

    Duke University Medical Center, Department of Medicine, Durham, NC, USA

  5. 5

    Durham Veterans Affairs Medical Center, Center for Health Services Research in Primary Care, Durham, NC, USA

*Mattias Linde, Department of Neuroscience, Norwegian University of Science and Technology, Trondheim, Norway. mattias.linde@ntnu.no.

Publication History

  1. Publication Status: Edited (no change to conclusions)
  2. Published Online: 24 JUN 2013

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Background

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms
 

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

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms

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

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms
 

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

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms
 

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).

 FigureFigure 1. 'Risk of bias' graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
 FigureFigure 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.

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

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms
 

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

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms

 

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

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms

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

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms
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)1Odds Ratio (M-H, Random, 95% CI)Totals not selected

 
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)1Odds Ratio (M-H, Random, 95% CI)Totals not selected

 2 RR for responders (patients with ≥ 50% reduction in headache frequency)1Risk Ratio (M-H, Random, 95% CI)Totals not selected

 3 Any adverse event1Risk Difference (M-H, Random, 95% CI)Totals not selected

 4 Drowsiness1Risk Difference (M-H, Random, 95% CI)Totals not selected

 5 Nausea1Risk Difference (M-H, Random, 95% CI)Totals not selected

 6 Vertigo/giddiness1Risk Difference (M-H, Random, 95% CI)Totals not selected

 
Comparison 3. Carisbamate versus placebo

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Responders (patients with ≥ 50% reduction in headache frequency)1Odds Ratio (M-H, Random, 95% CI)Totals not selected

    1.1 Carisbamate titrated to 100 mg/day
1Odds Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    1.2 Carisbamate titrated to 300 mg/day
1Odds Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    1.3 Carisbamate titrated to 600 mg/day
1Odds Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

 
Comparison 4. Carisbamate dose comparisons

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Responders (patients with ≥ 50% reduction in headache frequency)1Odds Ratio (M-H, Random, 95% CI)Totals not selected

    1.1 Carisbamate 300 mg/day versus 100 mg/day
1Odds Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    1.2 Carisbamate 600 mg/day versus 100 mg/day
1Odds Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

    1.3 Carisbamate 600 mg/day versus 300 mg/day
1Odds Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

 
Comparison 5. Clonazepam versus placebo

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Headache frequency (post-treatment; headache days per month)1Mean Difference (IV, Random, 95% CI)Totals not selected

 
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/day
1113Mean Difference (IV, Random, 95% CI)-1.17 [-2.17, -0.17]

    1.2 Lamotrigine titrated to 200 mg/day
177Mean Difference (IV, Random, 95% CI)0.20 [-0.81, 1.21]

 2 Responders (patients with ≥ 50% reduction in headache frequency)1Odds Ratio (M-H, Random, 95% CI)Totals not selected

 
Comparison 7. Lamotrigine versus topiramate

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Headache frequency (change from baseline to post-treatment)1Mean Difference (IV, Random, 95% CI)Totals not selected

 2 Responders (patients with ≥ 50% reduction in headache frequency)1Odds Ratio (M-H, Random, 95% CI)Totals not selected

 
Comparison 8. Levetiracetam versus placebo

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Headache frequency (post-treatment; headache days per month)1Mean Difference (IV, Random, 95% CI)Totals not selected

 2 OR for responders (patients with ≥ 50% reduction in headache frequency)1Odds Ratio (M-H, Random, 95% CI)Totals not selected

 3 RR for responders (patients with ≥ 50% reduction in headache frequency)1Risk Ratio (M-H, Random, 95% CI)Totals not selected

 
Comparison 9. Levetiracetam versus topiramate

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Headache frequency (post-treatment; headache days per month)1Mean Difference (IV, Random, 95% CI)Totals not selected

 2 Responders (patients with ≥ 50% reduction in headache frequency)1Odds Ratio (M-H, Random, 95% CI)Totals not selected

 
Comparison 10. Oxcarbazepine versus placebo

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Headache frequency (change from baseline to post-treatment)1Mean Difference (IV, Random, 95% CI)Totals not selected

 2 Responders (patients with ≥ 50% reduction in headache frequency)1Odds Ratio (M-H, Random, 95% CI)Totals not selected

 
Comparison 11. Vigabatrin versus placebo

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Headache frequency (post-treatment)1Mean Difference (IV, Random, 95% CI)Totals not selected

 
Comparison 12. Zonisamide versus topiramate

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Headache frequency (change from baseline to post-treatment)1Mean Difference (IV, Random, 95% CI)Totals not selected

 

Appendices

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms
 

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

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms

Last assessed as up-to-date: 15 January 2013.


DateEventDescription

8 May 2014AmendedMinor edit made to numbers reported in Results of the search.



 

History

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms

Review first published: Issue 6, 2013


DateEventDescription

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 performedMay 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

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms

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

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms

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

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms
 

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

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Results
  6. Discussion
  7. Authors' conclusions
  8. Acknowledgements
  9. Data and analyses
  10. Appendices
  11. What's new
  12. History
  13. Contributions of authors
  14. Declarations of interest
  15. Sources of support
  16. Differences between protocol and review
  17. Index terms

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.

* Indicates the major publication for the study

References

References to studies included in this review

  1. Top of page
  2. AbstractRésumé
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Characteristics of studies
  19. References to studies included in this review
  20. References to studies excluded from this review
  21. Additional references
  22. References to other published versions of this review
Cady 2009 {published data only (unpublished sought but not used)}
de Tommaso 2007 {published and unpublished data}
  • de Tommaso M, Guido M, Sardaro M, Serpino C, Vecchio E, De Stefano G, et al. Effects of topiramate and levetiracetam vs placebo on habituation of contingent negative variation in migraine patients. Neuroscience Letters 2008;442(2):81-5. [MEDLINE: 18620023]
  • de Tommaso M, Marinazzo D, Nitti L, Pellicoro M, Guido M, Serpino C, et al. Effects of levetiracetam vs topiramate and placebo on visually evoked phase synchronization changes of alpha rhythm in migraine. Clinical Neurophysiology 2007;118(10):2297-304. [MEDLINE: 17709295]
Ghose 2002 {published data only}
  • Ghose K, Niven BE, Berry D. A double-blind crossover comparison of the effects of vigabatrin with placebo in the prevention of migraine headache. Journal of Headache & Pain 2002;3(2):79-85.
Gupta 2007 {published data only}
Mohammadianinejad 2011 {published data only (unpublished sought but not used)}
  • Mohammadianinejad SE, Abbasi V, Sajedi SA, Majdinasab N, Abdollahi F, Hajmanouchehri R, et al. Zonisamide versus topiramate in migraine prophylaxis: a double-blind randomized clinical trial. Clinical Neuropharmacology 2011;34(4):174-7. [MEDLINE: 21738025]
Rompel 1970 {published data only}
  • Rompel H, Bauermeister PW. Aetiology of migraine and prevention with carbamazepine (Tegretol): results of a double-blind, cross-over study. South African Medical Journal 1970;44(4):75-80. [MEDLINE: 4905910]
Silberstein 2008 {published data only (unpublished sought but not used)}
Steiner 1997 {published data only}
Stensrud 1979 {published data only}
Vahedi 2002 {published data only}
  • Vahedi K, Taupin P, Djomby R, El-Amrani M, Lutz G, Filipetti V, et al. Efficacy and tolerability of acetazolamide in migraine prophylaxis: a randomized placebo-controlled trial. Journal of Neurology 2002;249(2):206-11. [MEDLINE: 11985388]

References to studies excluded from this review

  1. Top of page
  2. AbstractRésumé
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Characteristics of studies
  19. References to studies included in this review
  20. References to studies excluded from this review
  21. Additional references
  22. References to other published versions of this review
Anthony 1972 {published data only}
  • Anthony M, Lance JW, Somerville B. A comparative trial of prindolol, clonidine and carbamazepine in the interval therapy of migraine. Medical Journal of Australia 1972;1(26):1343-6. [MEDLINE: 4404482]
Chen 2001 {published data only}
Cochran 2004 {published data only}
D'Andrea 1999 {published data only}
  • D'Andrea G, Granella F, Cadaldini M, Manzoni GC. Effectiveness of lamotrigine in the prophylaxis of migraine with aura: an open pilot study. Cephalalgia 1999;19(1):64-6. [MEDLINE: 10099862]
    Direct Link:
Delvaux 2001 {published data only}
Hedri 1975 {published data only}
  • Hedri A. Rivotril in migraine [Rivotril bei Migräne]. Schweizerische Rundschau für Medizin Praxis 1975;64(33):1062-3. [MEDLINE: 1161753]
Lampl 1999 {published data only}
  • Lampl C, Buzath A, Klinger D, Neumann K. Lamotrigine in the prophylactic treatment of migraine aura—a pilot study. Cephalalgia 1999;19(1):58-63. [MEDLINE: 10099861]
    Direct Link:
Skupin 1975 {published data only}
  • Skupin G, Franzke HG. The role of chlorazepate dipotassium (Tranxilium) in the therapy of psychovegetative syndromes [Die Stellung von Dikalium-chlorazepat (Tranxilium) in der Therapie psychovegetativer Syndrome]. Medizinische Klinik 1975;70(31):1279-83. [MEDLINE: 54867]
Smirne 1979 {published data only}
  • Smirne S, Sinatra MG. Clonazepam in painful syndromes of the head [Il clonazepam nelle sindromi dolorose del distretto cefalico]. Rivista di Neurologia 1979;49(2):140-50. [MEDLINE: 451405]
Stieg 1977 {published data only}
Voto Bernales 1974 {published data only}
  • Voto Bernales J, Cruz G. Treatment of dysrhythmic migraines and other headaches with RO- 5-4023 [Tratamiento de la jaqueca distitmica y otras cefaleas con RO 5-4023]. Revista de Neuro-Psiquiatria 1974;37(1):1-8. [MEDLINE: 4453755]

Additional references

  1. Top of page
  2. AbstractRésumé
  3. Background
  4. Objectives
  5. Methods
  6. Results
  7. Discussion
  8. Authors' conclusions
  9. Acknowledgements
  10. Data and analyses
  11. Appendices
  12. What's new
  13. History
  14. Contributions of authors
  15. Declarations of interest
  16. Sources of support
  17. Differences between protocol and review
  18. Characteristics of studies
  19. References to studies included in this review
  20. References to studies excluded from this review
  21. Additional references
  22. References to other published versions of this review
Ad Hoc Cttee 1962
  • Ad Hoc Committee on the Classification of Headache of the National Institute of Neurological Diseases and Blindness. Classification of headache. JAMA 1962;179(9):717-8.
Alderson 2004
  • Alderson P, Green S, Higgins JPT, editors. Highly sensitive search strategies for identifying reports of randomized controlled trials in MEDLINE. Cochrane Reviewers' Handbook 4.2.2 [updated December 2003]; Appendix 5b. In: The Cochrane Library, Issue 1, 2004. Chichester, UK: John Wiley & Sons, Ltd.
Clarke 1996
  • Clarke CE, MacMillan L, Sondhi S, Wells NE. Economic and social impact of migraine. QJM 1996;89(1):77-84. [MEDLINE: 8730346]
Dalkara 2012
  • Dalkara S, Karakurt A. Recent progress in anticonvulsant drug research: strategies for anticonvulsant drug development and applications of antiepileptic drugs for non-epileptic central nervous system disorders. Current Topics in Medicinal Chemistry 2012;12(9):1033-71. [MEDLINE: 22352861]
Edmeads 1993
  • Edmeads J, Findlay H, Tugwell P, Pryse-Phillips W, Nelson RF, Murray TJ. Impact of migraine and tension-type headache on life-style, consulting behaviour, and medication use: a Canadian population survey. Canadian Journal of Neurological Sciences 1993;20(2):131-7. [MEDLINE: 8334575]
Edvinsson 2010
Evers 2009
GBD 2010 Study
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Hollis 1999
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ICHD-II 2004
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IHS Cttee 1988
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Jadad 1996
Linde 2012
Linde 2013a
  • Linde M, Mulleners WM, Chronicle EP, McCrory DC. Topiramate for the prophylaxis of episodic migraine in adults. Cochrane Database of Systematic Reviews 2013, Issue 6. [DOI: 10.1002/14651858.CD010610]
Linde 2013b
Linde 2013c
  • Linde M, Mulleners WM, Chronicle EP, McCrory DC. Gabapentin or pregabalin for the prophylaxis of episodic migraine in adults. Cochrane Database of Systematic Reviews 2013, Issue 6. [DOI: 10.1002/14651858.CD010609]
Linde 2013d
  • Linde M, Mulleners WM, Chronicle EP, McCrory DC. Antiepileptics other than gabapentin, pregabalin, topiramate, and valproate for the prophylaxis of episodic migraine in adults. Cochrane Database of Systematic Reviews 2013, Issue 6. [DOI: 10.1002/14651858.CD010608]
McQuay 1998
  • McQuay H, Moore R. An Evidence-based Resource for Pain Relief. Oxford: Oxford University Press, 1998.
Mehuys 2012
Olesen 2006
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Porter 1992
  • Porter RJ, Meldrum BS. Antiepileptic drugs. In: Katzung BG editor(s). Basic and Clinical Pharmacology. 5th Edition. Norwalk, CT: Appleton & Lange, 1992:331-49.
Silberstein 2012
  • Silberstein SD, Holland S, Freitag F, Dodick DW, Argoff C, Ashman E, Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Society. Evidence-based guideline update: pharmacologic treatment for episodic migraine prevention in adults: report of the Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Society. Neurology 2012;78(17):1337-45. [MEDLINE: 22529202]
Tfelt-Hansen 2012
  • Tfelt-Hansen P, Pascual J, Ramadan N, Dahlöf C, D'Amico D, Diener HC, et al. International Headache Society Clinical Trials Subcommittee. Guidelines for controlled trials of drugs in migraine: third edition. A guide for investigators. Cephalalgia 2012;32(1):6-38. [MEDLINE: 22384463]
Victor 2003
  • Victor S, Ryan S. Drugs for preventing migraine headaches in children. Cochrane Database of Systematic Reviews 2003, Issue 4. [DOI: 10.1002/14651858.CD002761]
Wiffen 2010