Anticonvulsant drugs for migraine prophylaxis (Review)

Transcription

1 Chronicle EP, Mulleners WM This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library 2009, Issue 1

2 T A B L E O F C O N T E N T S HEADER ABSTRACT PLAIN LANGUAGE SUMMARY BACKGROUND OBJECTIVES METHODS RESULTS DISCUSSION AUTHORS CONCLUSIONS ACKNOWLEDGEMENTS REFERENCES CHARACTERISTICS OF STUDIES DATA AND ANALYSES ADDITIONAL TABLES WHAT S NEW HISTORY DECLARATIONS OF INTEREST SOURCES OF SUPPORT INDEX TERMS i

3 [Intervention Review] Anticonvulsant drugs for migraine prophylaxis Edward P Chronicle 2, Wim M Mulleners 1 1 Department of Neurology, Canisius Wilhelmina Ziekenhuis, Nijmegen, Netherlands. 2 (Deceased), Department of Psychology, University of Hawaii at Manoa, Manoa, USA Contact address: Wim M Mulleners, Department of Neurology, Canisius Wilhelmina Ziekenhuis, PO Box 9015, Nijmegen, 6500 GS, Netherlands. w.mulleners@cwz.nl. w.mulleners@hetnet.nl. Editorial group: Cochrane Pain, Palliative and Supportive Care Group. Publication status and date: Edited (no change to conclusions), published in Issue 1, Review content assessed as up-to-date: 29 April Citation: Chronicle EP, Mulleners WM. Anticonvulsant drugs for migraine prophylaxis. Cochrane Database of Systematic Reviews 2004, Issue 3. Art. No.: CD DOI: / CD pub2. Background A B S T R A C T Anticonvulsant drugs seem to be useful in clinical practice for the prophylaxis of migraine. This might be explained by a variety of actions of these drugs in the central nervous system. Objectives To describe and assess the evidence from controlled trials on the efficacy and tolerability of anticonvulsants for preventing migraine attacks in adult patients with migraine. Search methods We searched PubMed (1966-December 2005), EMBASE (1974-December 2005) and the Cochrane Central Register of Controlled Trials (CENTRAL, Issue 3, 2005), and handsearched Headache and Cephalalgia through April Selection criteria Studies were required to be prospective, controlled trials of anticonvulsant drugs taken regularly to prevent the occurrence of migraine attacks and/or to reduce the intensity of those attacks. Data collection and analysis Studies were selected and data extracted by two independent reviewers. For migraine frequency data, standardized mean differences (SMDs) were calculated for individual studies and pooled across studies. For dichotomous data on significant reduction in migraine frequency, odds ratios (ORs) and numbers-needed-to-treat (NNTs) were similarly calculated. Adverse events were analyzed by calculating numbers-needed-to-harm (NNHs) for studies using similar agents. Main results Twenty-three papers met the inclusion criteria. In total, data from 2927 patients were considered. Analysis of data from 10 trials (n = 902) demonstrates that anticonvulsants, considered as a class, reduce migraine frequency by about 1.3 attacks per 28 days as compared to placebo (WMD -1.31; 95% confidence interval [CI] to -0.63). Data from 13 trials (n = 1773) show that anticonvulsants, considered as a class, also more than double the number of patients for whom migraine frequency is reduced by 50% or more relative to placebo (RR 2.25; 95% CI 1.79 to 2.84; NNT 3.9; 95% CI 3.4 to 4.7). For six trials of sodium valproate and divalproex sodium, NNHs for five clinically important adverse events ranged from 7.0 to For six trials of topiramate, NNHs for seven adverse events (100 mg dose) ranged from 2.4 to

4 Authors conclusions Anticonvulsants appear to be both effective in reducing migraine frequency and reasonably well tolerated. There is noticeable variation among individual agents, but there are insufficient data to know whether this is due to chance or variation in true efficacy. Acetazolamide, clonazepam, lamotrigine and vigabatrin were not superior to placebo (one trial each). Relatively few robust trials are available for agents other than sodium valproate/divalproex sodium and topiramate; gabapentin in particular needs further evaluation. Trials designed with sufficient power to compare different drugs are also necessary. P L A I N L A N G U A G E S U M M A R Y Anticonvulsant drugs for migraine prophylaxis Various medicines, collectively termed anticonvulsant drugs, are used to treat epilepsy. In recent years, some anticonvulsant drugs have also been used to reduce the frequency of migraine attacks. This review systematically examines the evidence supporting this practice. The authors conclude that anticonvulsant drugs are indeed effective in reducing the frequency of migraine attacks by approximately 1 to 2 attacks per month. Patients are also more than twice as likely to reduce the number of their migraine attacks by 50% or more with anticonvulsants than with an inactive placebo. There is, however, considerable variation among the available anticonvulsant drugs. Further research will be necessary to confirm the value of some drugs, and to compare the efficacy of drugs against each other. B A C K G R O U N D Migraine is a common and disabling health problem among children and predominantly young and middle-aged adults. Surveys from the U.S. and elsewhere suggest that 6% of men and 15% to 17% of women experience migraine headaches (Stewart 1994). These headaches result 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 in France were estimated to amount to 900 million Euros (one billion U.S. dollars) annually, or about 15 Euros (18 U.S. dollars) per inhabitant (Dartigues 2003). 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 goal of preventive therapy is to reduce the frequency and/or intensity of attacks, and thereby improve patient functioning and quality of life. 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 5% in various studies (Clarke 1996; Edmeads 1993; Rasmussen 1992). It is hoped that this review and others like it will help to provide a systematic basis supporting the use of certain medications in the prevention of migraine. This review considers the evidence for the efficacy and tolerability of anticonvulsants for preventing migraine in adults. The prophylactic treatment of migraine in children is the subject of a separate Cochrane review (Victor 2003). Note that we use the term anticonvulsant 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 anticonvulsants was between 1935 and 1960, when 13 drugs were developed and marketed (Porter 1992). In the last decade, renewed interest has led to the development of several novel anticonvulsants which may confer advantages in tolerability (Marson 1996), and these are beginning to be used in migraine also. The use of anticonvulsants 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 (Wiffen 2000) or more specifically to systems involved in the pathophysiology of migraine. For example, Cutrer and colleagues identified nine stages of the migraine attack at which sodium valproate might potentially have a beneficial effect (Cutrer 1997). 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 anticonvulsant drugs as a class are relevant to the prophylaxis of migraine. The primary goals of migraine 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. Substantiated guidelines on the treatment of migraine have now 2

5 been developed and published by the American Academy of Neurology (Silberstein 2000). These guidelines suggest that prophylactic therapy should be considered for patients with frequent migraine attacks (more than two per month) or disabling migraine refractory to acute treatment, those who experience intolerable side effects of acute therapy, those with contraindications to acute medication and those at risk of overusing acute medication. The guidelines also suggest that patient preferences and the cost of acute and preventive medications should be taken into consideration in making treatment decisions. Anticonvulsant drugs are now marketed specifically for migraine relief in the U.S., and divalproex sodium (a stable combination of sodium valproate and valproic acid in a 1:1 molar ratio) has been approved by the U.S. Food and Drug Administration (FDA) for migraine prophylaxis since One study of prescriber preferences found that 10% of American neurologists consider divalproex sodium the first or second choice for prophylaxis of migraine (Ramadan 1997), although preferences may have shifted since the FDA approval of topiramate in Anticonvulsants are usually prescribed off-license for migraine in the UK, but our impression is that they are becoming more popular there, and the British Association for the Study of Headache lists sodium valproate and topiramate as second-line prophylactics (BASH 2004). O B J E C T I V E S To describe and assess the evidence from controlled trials on the efficacy and tolerability of anticonvulsants for preventing migraine attacks in adult patients with migraine. M E T H O D S 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 (IHS Trials 2000). 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. Studies were required to be prospective, controlled trials of selfadministered drug treatments taken regularly to prevent the occurrence of migraine attacks and/or to reduce the intensity of those attacks. Trials were included only if allocation to treatment groups was randomized or pseudo-randomized (based on some non-random process unrelated to the treatment selection or expected response). Trials were not required to be blinded. Concurrent cohort comparisons and other non-experimental designs were excluded. Types of participants Study participants were required to be adults over 18 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. The use of a specific set of diagnostic criteria (e.g., Ad Hoc Cttee 1962; IHS Cttee 1988) was not required, but migraine diagnoses needed to be based on at least some of the distinctive features of migraine, e.g., nausea/vomiting, severe head pain, throbbing character, unilateral location, phono/ photophobia, or aura. Secondary headache disorders had to be excluded using reasonable criteria. It was anticipated that some of the trials identified would include patients described as having mixed migraine and tensiontype headaches or combination headaches. It is not always clear whether such descriptions refer to patients with discrete episodes of migraine and discrete episodes of tension-type headache, or to patients with headaches which (in the view of the investigators) combine features of migraine and tension-type headache. The IHS criteria would assign a dual diagnosis of migraine and tensiontype headache to patients in the former category, and a diagnosis of migrainous disorder or chronic migraine to those in the latter (ICHD-II 2004). The inclusion of patients of either type in a migraine trial is at least potentially problematic. For trials or treatment groups including patients with mixed or combination headaches, then, we intended to describe the headache pattern denoted by these terms as clearly as possible and justify the inclusion of such trials or treatment groups in, or their exclusion from, the larger migraine analysis on a case-by-case basis. Likewise, whenever separate results were reported for migraine and mixed or combination patients in a single trial, we intended to describe and analyze these results separately. In the event, no such precautions were required. In any case, studies evaluating treatments for chronic migraine, transformed migraine or chronic daily headache were regarded unsuitable for this review. The reasons for this are that (a) the definition of chronic migraine is still heavily debated, and a revision of the 2004 IHS criteria for this condition has recently been proposed (Olesen 2006); (b) transformed migraine and chronic daily headache are, although widely used, insufficiently validated terms; (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 the episodic forms. Trials and treatment groups including only patients with tension-type headache were explicitly excluded. 3

6 Types of interventions Included studies were required to have at least one arm in which an anticonvulsant (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 and/or reducing the intensity of such attacks in adult patients with migraine. Acceptable comparator groups included placebo, no intervention, other drug treatments, same drug treatments with a clinically relevant different dose and behavioral or physical therapies. The analysis included only drugs and dosages that are commercially available. Studies of drugs that have been withdrawn from the market worldwide were excluded. The list of target drugs included the following, in alphabetical order: acetazolamide, carbamazepine, chlormethiazole, clobazam, clonazepam, clorazepate, diazepam, divalproex sodium, ethosuximide, felbamate, fosphenytoin, gabapentin, lamotrigine, levetiracetam, lidocaine, lignocaine, lorazepam, mephobarbital, methsuximide, midazolam, nitrazepam, oxcarbazepine, paraldehyde, pentobarbital, phenobarbital, phenytoin, primidone, sodium valproate, tiagabine, topiramate, valproic acid, vigabatrin, zonisamide. It was not necessary to add any other target drugs during the identification of studies. While some of the agents on this list also fall into other drug categories (e.g., lidocaine and lignocaine are local anaesthetic agents; acetazolamide is a diuretic; lorazepam and nitrazepam are benzodiazepines; mephobarbital, pentobarbital and phenobarbital are barbiturates), they are used as anticonvulsants in the treatment of epilepsy or status epilepticus in either Europe or the U.S. and were therefore included in the search process. Only one publication included in this review reported a trial of one of these drugs (acetazolamide). 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 the analysis. Types of outcome measures Authors collected trial data on symptomatic outcomes related to head pain (frequency, intensity and duration) and other symptoms of migraine (nausea, vomiting, photophobia, phonophobia). We did not envisage that sufficient quality-of-life data would be available to allow a rigorous analysis. This was kept under review as studies were selected, and indeed no meaningful quality-of-life analysis was possible. For the efficacy analysis, the following outcomes were considered: (1) Headache frequency; and (2) Headache index. 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. Among headache index measures, we preferred those that incorporate frequency as a component (along with intensity and/or duration), but considered other types of indexes when these were not available. The formula used to calculate headache index was recorded whenever it was described by investigators. We anticipated that trials would vary in length, that outcomes would be measured over various units of time (e.g., number of attacks per 2 weeks vs. number of attacks per 4 weeks), and that results would be reported for numerous different time points (e.g., 4-week headache frequency at 2 months vs. at 4 months). We attempted to standardize the unit of time over which headache frequency was measured at 28 days (4 weeks) wherever possible. We recorded outcomes beginning 4 weeks after the start of treatment and continued through all later assessment periods that were not compromised by problems with dropouts (an overall dropout rate of 20% or an imbalance in dropout rates between treatment groups). A decision about which time points to include in the final analysis was made once the data had been collected. 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. Where data on adverse events were missing or inadequate, we intended to obtain these data by correspondence with authors, but in several cases this was not possible because of the age of studies. Search methods for identification of studies For the identification of studies included or considered for this review, detailed search strategies were developed for each database searched. These were based on the search strategies for PubMed, but revised appropriately for each database. The search strategies combined the subject search (see Appendix 1) with the Cochrane highly sensitive search strategy for RCTs (Alderson 2004). The subject search used a combination of controlled vocabulary and freetext terms based on the search strategy for searching PubMed presented in Appendix 1. Databases that were searched are: Cochrane Pain, Palliative & Supportive Care Trials Register; Cochrane Central Register of Controlled Trials (CENTRAL) (Issue 3, 2005); PubMed 1966-December 2005; EMBASE 1974-December

7 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. Two journals, Headache and Cephalalgia, were handsearched in their entirety, through April Data collection and analysis Eligibility Titles and abstracts of studies identified by the literature search were screened for eligibility by two independent reviewers. 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. Papers passing this initial screening process were retrieved, and the full text was reviewed independently by both reviewers. Disagreements at the full-text stage were resolved through discussion between the authors and, in a few cases, through correspondence with members of the editorial staff of the Cochrane Pain, Palliative and Supportive Care Review Group. Reviewers were not blinded to the 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). Both authors agreed that short abstracts of this kind would be excluded from consideration in this version of the review. Data extraction Information on patients, methods, interventions, outcomes and adverse events were abstracted from the original reports onto specially designed, pre-tested paper forms by two independent reviewers. Disagreements were again resolved through discussion. 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% or more reduction in headache frequency or headache index as meeting this criterion. In such cases, reviewers recorded, for each treatment arm, the number of patients included in the analysis and the number with each outcome. When outcome data were reported on an ordinal scale (e.g., for reduction in headache frequency: 0%, 1-24%, 25-49%, 50-74%, 75-99%, 100%), we selected a threshold based on the definition of clinically significant improvement (discussed immediately above) and converted these data into dichotomous form. If categorical data could not be split into dichotomous outcomes meeting our a priori definition, we intended to exclude them from the analysis; in practice, this never happened. For outcomes reported on a continuous scale, we anticipated that many trials would report pre- and post-treatment 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. A variety of possible treatments for pre- and post-treatment scores, change scores and the like was also anticipated, but in fact it was not necessary to implement any strategy for dealing with change scores, as they were rarely reported, and then only as an adjunct to dichotomous or continuous data as above. In the case of crossover trial designs, we anticipated that the data reported would normally not permit analysis of paired withinpatient data. Crossover trials were thus analyzed 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. Reviewers 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 methodological quality The internal validity of individual trials was assessed using the scale devised by Jadad and colleagues (Jadad 1996), which was operationalized as follows: (1) Was the study described as randomized? (1 = yes; 0 = no) (2) Was the method of randomization 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. Summarizing the results Dichotomous data meeting our definition of a clinically significant threshold were used to calculate odds ratios (ORs), with 95% 5

8 confidence intervals (CIs). We additionally computed numbersneeded-to-treat (NNTs), with 95% CIs. NNTs were calculated as the reciprocal of the absolute risk reduction (McQuay 1998). For unwanted effects (e.g., adverse events), the NNT becomes the number-needed-to-harm (NNH), and is calculated in the same way. We anticipated that continuous outcome measures of headache frequency or headache index would be reported on different and often incompatible scales. Although we attempted to standardize the extraction of headache frequency data to a 28-day (4-week) period, this was not possible in every case. We therefore analyzed these data using the standardized mean difference (SMD, with 95% CIs) rather than the weighted mean difference (WMD). Estimates of efficacy (both SMDs and ORs) were tested for homogeneity. If study estimates were homogeneous, they were combined using a fixed-effect model. When significant heterogeneity was present, an attempt was made to examine the differences based on the clinical characteristics of the included studies. Clinically dissimilar studies were not statistically combined. However, when a group of studies with statistically heterogeneous results appeared to be clinically similar, the study estimates were combined using a random-effects model. Although we prefer ORs and SMDs because of their statistical properties, some readers may find it simpler to interpret the clinical significance of our findings using relative risks (RRs) and WMDs. We provide clinical interpretations based on these statistics for the comparison of anticonvulsants as a class versus placebo (Comparison No. 01). Interested readers may view RRs and WMDs for additional comparisons by changing the settings on the relevant MetaView graphs. Subgroup analyses were undertaken by drug, and by dose where possible. We considered further subgroup analyses by method of randomization and by completeness of blinding, but did not undertake them because of insufficient data. Data on the proportion of patients reporting adverse events were used to calculate NNHs. It was only feasible to calculate NNHs for seven studies using valproate or divalproex, and six studies using topiramate. Further details are given in the Results section. R E S U L T S Description of studies See: Characteristics of included studies; Characteristics of excluded studies. The PubMed search strategy yielded 1089 studies as possible candidates for the review. In EMBASE, a total of 290 potentially eligible studies were found, while the CENTRAL search yielded 6952 studies to be considered. No additional studies were retrieved from Cochrane Pain, Palliative & Supportive Care Trials Register. After title-and-abstract screening, 58 published papers were obtained for full-text review. Of these, 35 were excluded, for the following reasons (see the Characteristics of excluded studies table): 11 because the trial did not include any appropriate control or comparison group; 7 were letters or abstracts; 4 because only case studies were reported; 3 were review papers; 3 reported data on only chronic migraine or chronic daily headache; 2 had no arm in which an anticonvulsant alone was given; 1 because there was insufficient evidence of random or pseudo-random allocation to groups; 1 because the publication was unobtainable; 1 because appropriate data were not extractable from the published information; 1 was a basic science paper; and 1 concatenated data from two included trials. Twenty-three papers were therefore included in the review. Of these, 19 reported trials comparing anticonvulsants with placebo, as follows: six trials of topiramate; four trials of divalproex sodium; two trials of sodium valproate; two trials of gabapentin; and one trial each of acetazolamide, carbamazepine, clonazepam, lamotrigine and vigabatrin. Five papers reported data that enabled dose comparisons of sodium valproate, gabapentin and topiramate. Four papers reported trials comparing different active drugs. The daily doses of anticonvulsants 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 daily; dose used in epilepsy mg; Carbamazepine - dose investigated not reported; dose used in epilepsy mg; Clonazepam - dose investigated 1 mg daily; dose used in epilepsy 2-4 mg; Divalproex sodium - doses investigated mg daily; dose used in epilepsy mg; Gabapentin - doses investigated mg daily; dose used in epilepsy mg; Lamotrigine - dose investigated 200 mg daily; dose used in epilepsy mg; Topiramate - doses investigated mg daily; dose used in epilepsy mg; Sodium valproate - doses investigated mg daily; dose used in epilepsy mg; Vigabatrin - dose investigated 1000 mg daily; dose used in epilepsy mg. The duration of the treatment phase of the included trials varied from 4 to 24 weeks, with a mean of 12.3 weeks. in included studies Methodological quality was scored as indicated in the Data collection and analysis section, with a maximum attainable score of 5. Each author scored the studies independently, and a consensus 6

9 score was then arrived at through discussion. The consensus score is reported for each study in the Characteristics of included studies table and is not used as a weighting in statistical analyses. The median quality score was 4 (range 1-5). Although the median quality score was relatively high, there were a few studies with serious methodological weaknesses such as lack of blinding (Mitsikostas 1997) or inadequate blinding (Kaniecki 1997). Furthermore, several important issues need to be taken into account in any assessment of the efficacy of a drug for migraine prophylaxis. Diagnostic criteria, baseline migraine frequency, washout periods for previous medication, rules for rescue medication, and the statistical power of the comparison were handled very variably in the 23 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 (IHS Trials 2000). 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. Effects of interventions Extraction of data Twenty-one of the 23 included studies provided sufficient information in the published paper to enable straightforward extraction of data, either as mean migraine frequency, number of patients reporting a 50% or more reduction in headache frequency, or both (six studies: Brandes 2004; Edwards 2000; Jensen 1994; Jimenez 2002; Silberstein 2004; Storey 2001). For one study (Steiner 1997), means were available but standard deviations were not: they were estimated from the range data provided. For the final study (Stensrud 1979), means and standard deviations were estimated from the graph provided. After reviewing the variety of methods used for calculating headache index, it was 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 IHS Trials Anticonvulsants versus placebo Methodological considerations Significant statistical heterogeneity was evident across trials for both efficacy outcomes. The clinical similarity of trials was therefore examined to determine whether studies should be combined for statistical meta-analysis. Although there was methodological variation, as described above (under Methodological quality of included studies ), the included trials were fundamentally similar with regard to basic design, patients and measures. Some heterogeneity may result simply from variation in true efficacy across different anticonvulsant drugs. It was therefore decided that it would be maximally informative to report analyses as follows: first, for all agents combined, and second, drug by drug. Note that three trials compared different doses of the same anticonvulsant drug with placebo (topiramate 50 mg, 100 mg and 200 mg daily in Brandes 2004 and Silberstein 2004, and topiramate 100 mg and 200 mg daily in Diener 2004). For these trials, the combined analyses contain data only for the dose judged by trial investigators to be most clinically advisable (100 mg daily). Complete data for all three doses studied are considered in separate analyses. Migraine frequency Anticonvulsants, considered as a class, reduce migraine frequency (per 28-day period) as compared to placebo (SMD -0.55; 95% CI to -0.26; Analysis 01.01). In clinical terms, the observed effect corresponds to a reduction in migraine frequency of 1.3 attacks per 28 days (WMD -1.31; 95% CI to -0.63; Analysis 01.01). Considerable variation appears to exist in the efficacy of different drugs, although it is important to stress that the number of trials of each drug is small and the number of patients in some trials is also small. Two trials of sodium valproate (Hering 1992; Jensen 1994; 63 patients in total) showed a significant reduction in migraine frequency in the active group compared to the placebo group (SMD -0.87; 95% CI to -0.50; Analyses and 03.01). Four trials of topiramate (Brandes 2004; Edwards 2000; Silberstein 2004; Storey 2001; 534 patients in total) also showed a significant reduction in migraine frequency in the active group compared to the placebo group in the combined analysis (SMD -0.37; 95% CI to -0.20; Analysis ). It should be noted that two of these trials (Edwards 2000; Storey 2001) reported significant reductions in migraine frequency in the active treatment group (topiramate 200 mg) compared to placebo, using analysis of covariance to control for baseline differences in frequency; by contrast, our analysis of the post-treatment SMDs were not statistically significant (Edwards 2000: SMD -0.48; 95% CI to 0.42; Storey 2001: SMD -0.27; 95% CI to 0.35). Separate analysis of all the data on the three topiramate doses studied found that the 200 mg dose led to significantly lower headache frequency than did placebo (SMD -0.49; 95% CI to -0.32), as did the 100 mg dose (SMD -0.37; 95% CI to -0.19); the 50 mg dose did not (Analysis 08.01). One trial of gabapentin (Di Trapani 2000; 63 patients) showed a statistically significant reduction in migraine frequency in the active treatment group as compared to the placebo group (SMD -1.94; 95% CI to -1.33; Analyses and 04.01). In a single trial (Steiner 1997; 77 patients), lamotrigine did not appear to be superior to 7

10 placebo, on either statistical or clinical grounds (SMD 0.09; 95% CI to 0.53; Analyses and 06.01). Likewise, in a study by Stensrud 1979 (37 patients), clonazepam was slightly but not significantly superior to placebo (SMD -0.41; 95% CI to 0.06; Analyses and 05.01). Finally, in a single trial (Ghose 2002; 30 patients) vigabatrin was not significantly superior to placebo (SMD -0.21; 95% CI to 0.50; Analyses and 09.01). Reduction of migraine frequency by 50% or more Anticonvulsants, considered as a class, also increase the number of patients for whom migraine frequency is reduced by 50% or more, relative to placebo (OR 3.53; 95% CI 2.46 to 5.06; Analysis 01.02). In clinical terms, the observed effect suggests that patients are 2.3 times more likely to experience a 50% or greater reduction in frequency with anticonvulsants than with placebo (RR 2.25; 95% CI 1.79 to 2.84; Analysis 01.02). Four trials of divalproex sodium (Freitag 2002; Kaniecki 1997; Klapper 1997; Mathew 1995; 574 patients in total) found, overall, that active treatment was significantly superior to placebo (OR 3.34; 95% CI 1.46 to 7.67; Analyses and 02.01). It is notable that the largest of these four studies (Freitag 2002) found no significant difference between active treatment and placebo. One trial of sodium valproate (Jensen 1994; 34 patients) showed that active treatment is significantly superior to placebo (OR 4.67; 95% CI 1.54 to 14.14; Analyses and 03.02). Six trials of topiramate (Brandes 2004; Diener 2004; Edwards 2000; Mei 2004; Silberstein 2004; Storey 2001; 898 patients in total) demonstrated overall superiority of treatment to placebo in the combined analysis (OR 3.34; 95% CI 2.36 to 4.73; Analysis ), although there is noticeable variability in the odds ratios across these studies. Separate analysis of all the data on the various topiramate doses studied showed that all three (50, 100 and 200 mg) significantly increased the number of patients for whom migraine frequency was reduced by 50% or more. Odds ratios (with 95% CIs) were as follows: for the 200 mg dose, 2.89 (2.03 to 4.12); for the 100 mg dose, 3.27 (2.21 to 4.85); and for the 50 mg dose, 2.03 (1.35 to 3.05) (Analysis 08.02). One trial of gabapentin (Mathew 2001; 87 patients) demonstrated a significant superiority of active treatment (OR 4.51; 95% CI 1.51 to 13.43; Analyses and 04.02), as did one of carbamazepine (Rompel 1970; 48 patients) (OR 11.77; 95% CI 3.92 to 35.32; Analyses and 07.01). One trial (Vahedi 2002; 53 patients) showed no significant difference between acetazolamide and placebo (OR 0.89; 95% CI 0.28 to 2.82; Analyses and 10.01), although it should be mentioned that this trial was discontinued prematurely. We calculated NNTs (with 95% CIs) for drugs with significant combined ORs versus placebo; these were as follows: All anticonvulsants combined: NNT 3.9 (3.4 to 4.7). Sodium valproate: NNT 3.1 (1.9 to 8.9). Divalproex sodium: NNT 4.8 (3.5 to 7.5). Gabapentin: NNT 3.3 (2.1 to 8.4). Carbamazepine: NNT 2.1 (1.6 to 3.3). Topiramate: NNT 3.9 (3.4 to 5.1). Dose comparisons for sodium valproate Kinze 2001 (45 patients) compared different doses of sodium valproate by measuring serum valproate concentrations. The study showed that lower (21-50 ug/ml) serum levels gave rise to slightly but significantly lower headache frequency than higher (> 50 ug/ ml) serum levels (SMD 0.83; 95% CI 0.22 to 1.44; Analysis 11.01). Dose comparisons for gabapentin Jimenez 2002 (135 patients) compared 1200 mg and 2000 mg daily doses of gabapentin. There were no significant differences between the groups, either in terms of headache frequency (SMD -0.26; 95% CI to 0.12; Analysis 12.01) or in the number of patients whose migraine frequency was reduced by 50% or more (OR 0.62; 95% CI 0.28 to 1.37; Analysis 12.02). Dose comparisons for topiramate Data from Brandes 2004 and Silberstein 2004 were used to directly compare the three doses of topiramate, with additional data from Diener 2004 contributing to the comparison between 200 mg and 100 mg doses (Analyses and 13.02). The 200 mg dose was significantly superior to the 50 mg dose both in terms of reducing migraine frequency (SMD -0.31; 95% CI to -0.12) and increasing the number of patients for whom migraine frequency was reduced by 50% or more (OR 1.66; 95% CI 1.15 to 2.41). Likewise, the 100 mg dose was superior to the 50 mg dose (SMD ; 95% CI to -0.03; and OR 1.80; 95% CI 1.25 to 2.60). The 200 mg dose was not significantly superior to the 100 mg dose for either outcome measure. It is important to note, however, that none of these studies was designed to have the statistical power to make comparisons between doses. Sodium valproate versus flunarizine One trial (Mitsikostas 1997) compared sodium valproate with an active comparator, flunarizine. There was no significant difference in the number of patients for whom migraine frequency reduced by 50% or more (OR 1.07; 95% CI 0.28 to 4.12; Analysis 14.01). Divalproex sodium versus propranolol A further trial using an active comparator examined divalproex sodium versus propranolol (Kaniecki 1997). There was no significant difference in the number of patients for whom migraine frequency was reduced by 50% or more (OR 1.15; 95% CI 0.41 to 3.18; Analysis 15.01). 8

11 Topiramate versus propranolol and versus sodium valproate Two trials examined topiramate versus an active comparator. Diener 2004 included an additional arm (propranolol 160 mg daily) in a trial of topiramate (200 mg and 100 mg daily) versus placebo. A comparison of propranolol with the 100 mg dose of topiramate (the dose judged by trial investigators to be most clinically advisable) shows no significant difference in the number of patients with a 50% or greater reduction in migraine frequency (OR 1.32; 95% CI 0.82 to 2.13; Analysis 16.01). Shaygannejad 2006 compared topiramate 50 mg daily with sodium valproate 400 mg daily. On the basis of their statistical analysis, the authors found no significant differences in efficacy between the two drugs. However, our analysis of post-treatment mean headache frequencies demonstrates a slight but significant advantage for topiramate over valproate (SMD -0.61; 95% CI to -0.10; Analysis 17.01). It should be noted that the doses used in this study are not those used in routine clinical practice for the management of migraine. Safety During the process of extracting safety data, it became clear that the range of adverse events considered, and the method of their reporting, varied very considerably from trial to trial. The following strategy for analyzing data was therefore adopted. For acetazolamide, carbamazepine, clonazepam, gabapentin and lamotrigine no further analysis was undertaken; all available safety data are simply summarized in Table 1. For the one trial of vigabatrin (Ghose 2002), no safety data were extractable from the published manuscript. Because of the fundamental similarity of sodium valproate and divalproex sodium, safety data from the six trials of these drugs against placebo were analyzed together. NNHs (with 95% CIs) were calculated for the five adverse events judged by both authors to be of greatest clinical importance, as follows: Nausea: NNH 7.0 (5.1 to 11.0). Asthenia/fatigue: NNH 15.0 (8.4 to 66.8). Tremor: NNH 12.5 (9.0 to 20.9). Weight gain: NNH 18.8 (8.7 to undefined upper bound). Dizziness/vertigo: NNH 16.3 (9.5 to 57.9). Five of these six trials of sodium valproate or divalproex sodium reported unambiguous data on the percentage of patients in active treatment groups who withdrew because of adverse events. These percentages ranged from 3% to 13%, with a mean of 9%. In the six trials of topiramate against placebo, seven adverse events were reported by at least three trials. NNHs and 95% CIs were analyzed by dose (50 mg, 100 mg, 200 mg per day) and are given in Table 2. Table 2 also reports, by dose, the percentages of patients in active treatment groups who withdrew because of adverse events in each trial. The mean percentage withdrawing because of adverse events at the 100 mg dose was 26%. D I S C U S S I O N Meta-analysis of the 23 studies included in this review suggests that anticonvulsants are efficacious for the prophylaxis of migraine. Mean migraine frequency is significantly reduced (by approximately 1 to 2 attacks per month) with anticonvulsants as compared to placebo (10 studies contributed to this analysis). Furthermore, and perhaps of greater clinical relevance, patients were more than twice as likely to have a 50% or greater reduction in the number of migraine attacks with anticonvulsants than with placebo (13 studies contributed to this analysis). Anticonvulsants do not appear to give rise to an unexpectedly high rate of adverse events when used for migraine prophylaxis, although clearly (a) nausea is a problem when trials of sodium valproate and divalproex sodium are considered together, and (b) a large percentage of patients taking topiramate report paresthesia. It should also be noted that dropouts due to adverse events are somewhat higher in trials of topiramate than would generally be expected on the basis of trials of other anticonvulsant drugs, particularly sodium valproate or divalproex sodium. These relatively straightforward results should be viewed with some caution. As usual in the context of clinical trials research, there is considerable heterogeneity in both headline results and general levels of analytic and statistical sophistication. It is appropriate, therefore, to review a number of caveats. Variability across anticonvulsants Topiramate has been investigated in six trials and with the largest number of patients. The three larger trials (Brandes 2004, Diener 2004, Silberstein 2004) all show unambiguous statistically significant superiority of 100 mg and 200 mg daily doses over placebo. The 50 mg dose appears to give rise to a significant increase in the number of patients reporting a 50% or greater reduction in migraine frequency, but not a significant overall decrease in monthly migraine frequency. One additional trial of the 100 mg dose showed significant superiority over placebo in 50% responder rates (Mei 2004). Two small preliminary trials of the 200 mg dose (Edwards 2000, Storey 2001) were equivocal in that the analysis for migraine frequency did not reveal a significant difference with placebo in either study, although one trial reported topiramate 200 mg to be significantly more efficacious considering 50% responder rates (Edwards 2000). Both trials were almost certainly underpowered. Sodium valproate and divalproex sodium have also received considerable attention: six of 23 trials compared these drugs with placebo. Five showed a statistically significant superiority of active treatment over placebo. We were unable to analyze data on reduction in mean migraine frequency from the most recent and largest trial of divalproex sodium (Freitag 2002), but the investigators analysis demonstrated a statistically significant difference between active treatment and placebo for this outcome. The clinical relevance of this effect was, however, less compelling, as both the 9

12 investigators analysis and our own found no significant difference between treatments in the number of patients reporting a 50% or greater reduction in migraine frequency. Gabapentin was investigated in two trials, both of which demonstrated reasonable to good efficacy (Di Trapani 2000; Mathew 2001). In a single trial, lamotrigine was no more effective than placebo in reducing migraine frequency, but this result is likely to have been influenced by a large difference in baseline frequency between active treatment and placebo groups (Steiner 1997). Also in single trials, acetazolamide (Vahedi 2002) and vigabatrin (Ghose 2002) were found to be no more effective than placebo. Two trials from the 1970s investigated older drugs, carbamazepine (Rompel 1970) and clonazepam (Stensrud 1979), of which only carbamazepine showed evidence of superiority over placebo. The age of these trials means that recent diagnostic standards (IHS Cttee 1988; ICHD-II 2004) could not be employed. Dose comparisons The studies including more than one dose of a single drug were generally not designed to enable direct dose comparisons, and the results of the dose comparisons reported here should therefore be viewed with some caution. The comparisons suggest that the 200 mg dose of topiramate is no more effective than the 100 mg dose, and also that a 2000 mg dose of gabapentin is no more effective than a 1200 mg dose. The finding of Kinze 2001, that lower serum valproate levels produced lower migraine frequency than higher serum levels, is somewhat counterintuitive, has not been replicated and should be regarded as preliminary. Trials with active comparators The four trials using active comparators found (a) no significant difference in efficacy between sodium valproate and flunarizine (Mitsikostas 1997); (b) no significant difference in efficacy between divalproex sodium and propranolol (Kaniecki 1997); (c) no significant difference in efficacy between topiramate and propranolol (Diener 2004); and (d) a slight but significant advantage of topiramate over valproate (Shaygannejad 2006). These trials are of relevance for two reasons. First, both flunarizine and propranolol have demonstrable efficacy in the prophylaxis of migraine (Linde 2004; Reveiz-Herault 2003). Second, little is yet known about the relative efficacy of different anticonvulsants. It should be noted that all four trials are potentially problematic for reasons including lack of blinding, insufficient statistical power and possibly incomplete statistical analysis. Further well-designed trials, both of anticonvulsants against other drug categories, and comparing different anticonvulsants, are desirable. Statistical analysis and reporting It is fair to say that the authors faced several difficulties in deriving adequate information from the results of the 23 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 labeled. 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 intent-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. A U T H O R S C O N C L U S I O N S 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 anticonvulsants for the preventive management of migraine headache in real-life clinical practice. It must be stressed, however, that this review does not provide definite evidence for the efficacy of anticonvulsant drugs in the management of other aspects of the condition (e.g., prodromal symptoms, aura symptoms), either because these aspects were not considered in the selected trials or were not adequately reported. It seems reasonable to assume that as anticonvulsants are successful in preventing the attack of migraine headache, they will equally likely delay or prevent the occurrence of the several non-headache symptoms. 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. Sodium valproate/divalproex sodium have been investigated in the largest number of independent clinical trials (eight), the results of which are generally consistent with each other. It can be concluded from this review that sodium valproate/divalproex sodium are of proven efficacy in migraine prevention and are suitable for routine clinical use. One important caveat should be noted: these drugs are known to be teratogenic (Morrell 2003), and appropriate caution must be used when prescribing to women of child-bearing age. As for topiramate, seven randomized controlled trials were considered in this review (two of these providing comparator data against propranolol and sodium valproate), and they provide good evidence to support the use of this drug in routine clinical management, mainly based on the data from three recently published large studies (the three largest trials of anticonvulsants in migraine prophylaxis). The two trials allowing comparisons with another active drug suggest that topiramate is marginally more effective 10