Intervention Review

You have free access to this content

Valproate (valproic acid or sodium valproate or a combination of the two) 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.CD010611


How to Cite

Linde M, Mulleners WM, Chronicle EP, McCrory DC. Valproate (valproic acid or sodium valproate or a combination of the two) for the prophylaxis of episodic migraine in adults. Cochrane Database of Systematic Reviews 2013, Issue 6. Art. No.: CD010611. DOI: 10.1002/14651858.CD010611.

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

SEARCH

 

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 valproate for preventing episodic migraine in adults. The prophylactic treatment of migraine in children is the subject of a separate Cochrane review (Victor 2003).

Valproic acid (2-Propylpentanoic acid) was first synthesised in 1882 as analogue of valeric acid, found naturally in valerian. It is a liquid at room temperature, but it can be reacted with a base such as sodium hydroxide to form the salt sodium valproate, which is solid. Valproic acid, sodium valproate, or a mixture of the two (divalproex sodium according to United States Adopted Names (USAN), valproate semisodium according to WHO International Nonproprietary Name (INN) nomenclature) are marketed under various brand names and are collectively referred to as 'valproate' in this review.

Sodium valproate is rapidly absorbed, reaching peak plasma concentrations within one to four hours and thereafter remaining stable for four to 14 hours. After oral administration, 85% to 100% of the administered dose is absorbed. Half-life is eight to 20 hours in most patients, but may occasionally be much longer. Renal impairment prolongs the half-life. The relationship between dose, plasma concentration, and effect are incompletely understood. The equilibrium concentration is usually achieved after three to five days of treatment. Sodium valproate is highly protein bound (approximately 90%). The concentration in the cerebrospinal fluid is approximately 10% of plasma concentrations. Sodium valproate is extensively metabolised and excreted in the urine as conjugated metabolites.

 

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). The mechanisms of action of valproate include enhanced neurotransmission of GABA (by inhibiting GABA transaminase) and blockage of voltage-gated sodium channels and T-type calcium channels. More than 15 years ago, Cutrer and colleagues identified nine stages of the migraine attack at which valproate might potentially have a beneficial effect (Cutrer 1997), but it is still not possible to state with certainty which particular mode or modes of action of valproate are relevant to the prophylaxis of migraine.

 

Why it is important to do this review

Some antiepileptic drugs are marketed specifically for migraine prophylaxis, and divalproex sodium 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 valproic acid among first-line migraine prophylactics.

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 (the present review, 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 (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 valproate (valproic acid or sodium valproate or a combination of the two) 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 valproate (valproic acid or sodium valproate or a combination of the two) 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 valproate (valproic acid or sodium valproate or combination of the two, 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. There were no quality of life data available for rigorous analysis, but one study (Afshari 2012) 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. We therefore analysed cross-over trials 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 were 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 AE) 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, 22 (nine included, 13 excluded) investigated 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, seven (one included, six excluded) investigated valproate.

Thus, for the present update, we reviewed a total of 29 papers on valproate at the full-text screening stage. Of these, we included 10 papers and excluded 19.

 

Included studies

The 10 included papers reported data from 10 unique studies, including four trials of divalproex sodium (Freitag 2002; Kaniecki 1997; Klapper 1997; Mathew 1995) and six trials of sodium valproate (Afshari 2012; Hering 1992; Jensen 1994; Kinze 2001; Mitsikostas 1997; Shaygannejad 2006). Six trials compared valproate with placebo (Freitag 2002; Hering 1992; Jensen 1994; Kaniecki 1997; Klapper 1997; Mathew 1995), four compared valproate to active intervention (Afshari 2012; Kaniecki 1997; Mitsikostas 1997; Shaygannejad 2006), and one reported data that enabled dose comparisons of valproate (Kinze 2001).

Four trials (Hering 1992; Jensen 1994; Kaniecki 1997; Shaygannejad 2006) had a cross-over design, whereas the other six trials had a parallel-group design (Afshari 2012; Freitag 2002; Kinze 2001; Klapper 1997; Mathew 1995; Mitsikostas 1997).

The doses of valproate investigated in the 10 included trials ranged from 400 to 1500 mg/day. This can be compared to the range of doses used in epilepsy, which is 750 to 4000 mg/day.

The duration of the treatment phase of the included trials varied from eight to 12 weeks, with a mean of 11 weeks.

See the Characteristics of included studies for further details.

 

Excluded studies

Of the 29 papers obtained for full-text scrutiny, 19 were excluded for reasons given in the Characteristics of excluded studies table. The most common reasons for exclusion were: no control group (five papers), comparator an experimental intervention (three papers), and review article (two papers).

 

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 3.2; range 1 to 5).

Of 60 risk of bias items scored for the 10 studies, the majority of ratings were either 'unclear' (23 (38%)) or 'low' (20 (33%)) (Figure 1; Figure 2); we judged seven studies (Afshari 2012; Hering 1992; Jensen 1994; Kaniecki 1997; Kinze 2001; Klapper 1997; Mitsikostas 1997) as having a 'high' risk of bias for at least one item (Figure 2). One of these studies (Kinze 2001) was judged as having a high risk of bias for all six items assessed.

 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

Only two studies (Afshari 2012; Freitag 2002) provided an adequate methodological description (computer-generated randomisation schedule) of how allocation sequences were generated (see the Characteristics of included studies table). Likewise, only Afshari 2012 and Freitag 2002 provided an adequate methodological description (preprinted medication code labels and sealed envelopes) of attempts to conceal allocation of intervention assignment (see the Characteristics of included studies table). A high risk of selection bias was valued for Kinze 2001 and Mitsikostas 1997 due to their open-label design in combination with a lack of description of predefined randomisation schedules.

 

Blinding

Both participants and clinicians were blinded during the conduct of the majority of studies (7/10), and adequate methodological descriptions are reported for five of them (see Figure 2 and Characteristics of included studies table). Double-blinding was typically achieved by packaging and labelling identical appearing tablets according to the randomisation codes. In Afshari 2012, there is no mention of identical appearing tablets, and it is thus possible that standard medication was provided by third party according to allocation label. We therefore judged this study as suffering from a high risk of performance bias. In Kaniecki 1997, even the stated single-blinding is questionable, since divalproex, propranolol, and placebo had different appearances. Kinze 2001 and Mitsikostas 1997 were open-label studies and therefore also had a high risk of performance bias. In Kaniecki 1997, the single investigator was not blinded until he reviewed the diaries for outcomes assessment. Since the sample of this study was small, and non-completers were excluded from the analysis, he could possibly have recognised some of the participants and the interventions they were using. Remarkably, no paper clearly stated that the analyst was effectively blinded. The risk of detection bias in all studies is therefore unclear.

 

Incomplete outcome data

Only in four of the 10 studies was completeness of data adequately reported (Figure 2). Usually in these papers an intention-to-treat (ITT) analysis was applied (see the Characteristics of included studies table). We were particularly concerned about incomplete outcome data in Jensen 1994, Kaniecki 1997, Kinze 2001, and Mitsikostas 1997, which considered complete cases only, excluding the other participants from analysis. In addition, Hering 1992 does not report the size of the safety evaluable sample.

 

Selective reporting

We judged the risk of reporting bias as low in six of the 10 studies (Figure 2). Selective availability of data was encountered in Kaniecki 1997 (nocebo effect not reported, precluding calculation of NNHs), Kinze 2001 (inadequate reporting of adverse events), and Klapper 1997 (dose comparisons not possible, as insufficient data were provided).

 

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

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 (Risk of bias in included studies), the included trials were fundamentally similar with regard to basic design, patients, and measures.

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

 

Valproate versus placebo

 

Divalproex sodium

None of the four trials comparing divalproex sodium with placebo (Freitag 2002; Kaniecki 1997; Klapper 1997; Mathew 1995) reported sufficient data for us to calculate mean differences (MDs) for headache frequency, our preferred outcome measure.

All four trials did, however, report data on responders. Analysis of these data showed, overall, that active treatment was significantly superior to placebo for this outcome (odds ratio (OR) 3.34; 95% confidence interval (CI) 1.46 to 7.67; 542 patients (one cross-over study had 32 patients);  Analysis 1.1). In clinical terms, the observed effect suggests that patients are approximately twice as likely to experience a ≥ 50% reduction in headache frequency with divalproex sodium as with placebo. Details are as follows:

  • The proportion of responders with divalproex sodium was 42% (147/349; range: 30% to 66%);
  • The proportion of responders with placebo was 21% (48/225; range 14% to 24%);
  • The risk ratio (RR) for divalproex sodium versus placebo was 2.18 (95% CI 1.28 to 3.72;  Analysis 1.2);
  • The number needed to treat (NNT) for divalproex sodium versus placebo was 4 (95% CI 2 to 11).

It is notable that the largest of the four studies analysed (Freitag 2002; 234 patients) found no significant difference between active treatment and placebo.

 

Sodium valproate

Two cross-over trials of sodium valproate (Hering 1992; Jensen 1994; 63 patients) showed a significant reduction in headache frequency (per 28-day period) in the active group compared to the placebo group (MD -4.31; 95% CI -8.32 to -0.30;  Analysis 2.1). In clinical terms, the observed effect corresponds to a reduction in headache frequency of approximately four headaches per 28 days. The mean baseline headache frequency in the valproate group (reported only by Jensen 1994, and only for completers) was 6.1 headaches per 28 days.

One cross-over trial (Jensen 1994; 34 patients) reported data on responders; these showed that sodium valproate was significantly superior to placebo for this outcome (OR 4.67; 95% CI 1.54 to 14.14;  Analysis 2.2). In clinical terms, the observed effect suggests that patients are nearly three times as likely to experience a ≥ 50% reduction in headache frequency with sodium valproate as with placebo. Details are as follows:

  • The proportion of responders with sodium valproate was 50% (17/34);
  • The proportion of responders with placebo was 18% (6/34);
  • The RR for sodium valproate versus placebo was 2.83 (95% CI 1.27 to 6.31;  Analysis 2.3);
  • The NNT for sodium valproate versus placebo was 3 (95% CI 2 to 9).

 

Dose comparisons for sodium valproate

One parallel-group trial (Kinze 2001) compared different doses of sodium valproate by measuring serum valproate concentrations. The study showed that lower (21 to 50 µg/ml) serum levels gave rise to slightly but significantly lower headache frequency than higher (> 50 µg/ml) serum levels (MD 0.80; 95% CI 0.24 to 1.36; 45 patients;  Analysis 3.1). In clinical terms, the observed effect corresponds to a reduction in headache frequency of approximately one headache per 28 days in the lower versus the higher serum level group. The mean baseline headache frequency (reported only for the study population as a whole) was 3.5 headaches per 28 days.

 

Sodium valproate versus flunarizine

One parallel-group trial (Mitsikostas 1997) compared sodium valproate with flunarizine. Data were insufficient for us to calculate MDs for headache frequency, our preferred outcome measure. There was no significant difference between sodium valproate and flunarizine in the proportion of responders (OR 1.07; 95% CI 0.28 to 4.12; 41 patients;  Analysis 4.1).

 

Divalproex sodium versus propranolol

A further (cross-over) trial using an active comparator examined divalproex sodium versus propranolol (Kaniecki 1997). Data were insufficient for us to calculate MDs for headache frequency, our preferred outcome measure. There was no significant difference between treatments in the proportion of responders (OR 1.15; 95% CI 0.41 to 3.18; 32 patients;  Analysis 5.1).

 

Sodium valproate versus topiramate

Two fairly small studies compared topiramate 50 mg with sodium valproate 400 mg. Afshari 2012 did not demonstrate a significant difference in mean headache frequency during treatment (MD -0.60; 95% CI -1.57 to 0.37; 56 participants;  Analysis 6.1). On the basis of their statistical analysis, the authors of Shaygannejad 2006 found no significant differences in efficacy between the two drugs. However, our analysis of post-treatment mean headache frequencies demonstrated a slight but significant advantage for topiramate over valproate (MD -1.20; 95% CI -2.16 to -0.24; 32 (cross-over) participants;  Analysis 6.1). The pooled results of these two studies indicate a significant difference between topiramate and sodium valproate, in favour of topiramate, for this outcome (MD -0.90; 95% CI -1.58 to -0.22;  Analysis 6.1). In clinical terms, the observed effect corresponds to a reduction in headache frequency of approximately one headache per 28 days with topiramate versus sodium valproate. The median baseline headache frequency in the topiramate groups of the two trials was 6.1 headaches per 28 days (mean 6.1; range: 5.4 to 6.8). It should be noted that the doses used in these two studies are not those used in routine clinical practice for the management of migraine.

Afshari 2012 was the only study to report data on migraine-related disability. These data showed no significant difference in Migraine Disability Assessment (MIDAS) scores between sodium valproate and topiramate (MD -3.90; 95% CI -8.72 to 0.92; 56 participants;  Analysis 6.2).

 

Safety

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. Because of the fundamental similarity of sodium valproate and divalproex sodium, safety data from trials of these drugs against placebo were analysed together. We calculated risk differences (RDs) for any adverse event ( Analysis 7.1), and for the five specific adverse events we judged to be of greatest clinical importance, namely, asthenia/fatigue ( Analysis 7.2), dizziness/vertigo ( Analysis 7.3), nausea ( Analysis 7.4), tremor ( Analysis 7.5), and weight gain ( Analysis 7.6). Numbers needed to harm (NNHs) (with 95% CIs) were as follows:

  • Any adverse event: NNH not calculated, since 95% CI for RD includes zero.
  • Asthenia/fatigue: NNH not calculated, since 95% CI for RD includes zero.
  • Dizziness/vertigo: NNH 14 (8 to 100).
  • Nausea: NNH 7 (4 to 25).
  • Tremor: NNH 14 (8 to 100).
  • Weight gain: NNH not calculated, since 95% CI for RD includes zero.

Five of the six placebo-controlled 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 8% to 19% (Freitag 2002, 8%; Jensen 1994, 9%; Kaniecki 1997, 11%; Klapper 1997, 19%; Mathew 1995, 13%), with a mean of 12% (median 11%).

 

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

 

Placebo-controlled trials

Meta-analysis of the studies included in this review suggests that valproate is efficacious for the prophylaxis of migraine. Mean headache frequency was significantly reduced (by approximately four headaches per month) with sodium valproate as compared to placebo (two studies contributed to this analysis, one of which reported a baseline frequency of six headaches per month). Furthermore, and perhaps of greater clinical relevance (though less informative scientifically), patients were more than twice as likely to have a ≥ 50% reduction in headache frequency with divalproex sodium than with placebo (four studies contributed to this analysis). Supporting the latter finding, one small study showed that patients were nearly three times as likely to experience a ≥ 50% reduction in headache frequency with sodium valproate as with placebo.

 

Dose comparisons

The data included did not demonstrate a direct dose-response relationship.

 

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); and (c) a slight but significant advantage of topiramate over valproate (pooled results of Afshari 2012 and Shaygannejad 2006).

 

Safety

Valproate does not appear to give rise to an unexpectedly high rate of adverse events when used for migraine prophylaxis, although nausea is clearly a problem when trials of sodium valproate and divalproex sodium are considered together.

 

Overall completeness and applicability of evidence

The studies identified were sufficient to address all of the objectives of the review. Our analysis demonstrates that valproate is efficacious for preventing attacks in adult patients with episodic migraine, and these results fit into the context of current practice. The trials with active comparator are of relevance since all three comparators have demonstrable efficacy in the prophylaxis of migraine (Edvinsson 2010; Linde 2004; Reveiz-Herault 2003).

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.

 

Quality of the evidence

The identified body of evidence allows a robust conclusion of an overall superiority of valproate over placebo with regard to reduction of mean headache frequency (two trials, 126 participants) and the proportion of responders (five trials, 576 participants). 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 fair to say that we faced several difficulties in deriving adequate information from the results of the 10 included studies. It is appropriate, therefore, to review a number of caveats. The largest trial of divalproex sodium (Freitag 2002) did not report sufficient data for us to calculate mean differences (MDs) for headache frequency (means were reported, but not standard deviations (SDs)), but the analysis reported by the study investigators demonstrated a statistically significant (P = 0.006) difference favouring active treatment over placebo for this outcome. The clinical relevance of this effect was, however, less compelling, as both the investigators' analysis and our own found no significant difference between treatments in the proportion of responders (patients with ≥ 50% reduction in headache frequency). The finding of Kinze 2001, that lower serum valproate levels produced lower headache frequency than higher serum levels, is somewhat counterintuitive, has not been replicated, and should be regarded as preliminary. It should be noted that all three trials with active comparator are potentially problematic for several reasons including lack of blinding. Further well-designed trials of valproate against other active drugs and non-pharmacological interventions are thus desirable.

 

Potential biases in the review process

Of 60 risk of bias items scored for the 10 studies, the majority of ratings were either 'unclear' (23 (38%)) or 'low' (20 (33%)) (Figure 1; Figure 2). As described in detail above (Risk of bias in included studies), we judged seven trials as having a 'high' risk of bias for at least one item, as follows: random sequence generation (Kinze 2001), allocation concealment (Kinze 2001; Mitsikostas 1997), blinding of participants and personnel (Afshari 2012; Kaniecki 1997; Kinze 2001; Mitsikostas 1997), blinding of outcome assessment (Kaniecki 1997; Kinze 2001; Mitsikostas 1997), incomplete outcome data (Hering 1992; Jensen 1994; Kaniecki 1997; Kinze 2001; Mitsikostas 1997), and/or selective reporting (Kinze 2001; Klapper 1997) (Figure 2). A strength of this review is that the methods used for searching and study selection make it highly likely that the absolute majority of 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 and thus remain unobtainable.

 

Agreements and disagreements with other studies or reviews

The overall conclusion in this review, that valproate is efficacious for preventing attacks in adult patients with episodic migraine, is well in line with guideline recommendations of the EFNS (Evers 2009) and the Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Society (Silberstein 2012).

 

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 valproate for the preventive management of migraine headache in clinical practice. Valproate has been investigated in 10 independent clinical trials, the results of which are generally consistent. It can be concluded from this review that valproate is of proven efficacy in migraine prevention and is suitable for routine clinical use. It must be stressed, however, that this review does not provide definite evidence for the efficacy of valproate in the management of other aspects of the condition (eg, prodromal symptoms, aura 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.

Although adverse events were reported by a large proportion of migraine patients treated with valproate, these were usually mild and of a non-serious nature. Thus it can be concluded that valproate is reasonably well tolerated. One important caveat should be noted: valproate is known to be teratogenic (Morrell 2003), and appropriate caution must accordingly be used when prescribing to women of childbearing age.

 
Implications for research

There is a need for more studies designed specifically to compare the efficacy or safety of valproate to other interventions with proven efficacy in the prophylaxis of migraine. Also needed are (a) better studies of dose versus effect; (b) studies of which patients do and do not respond, and why; (c) long-term studies; and (d) studies post-withdrawal of valproate after effective use for several months.

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.

Little is definitely known about the mechanism of action of valproate in migraine prophylaxis. 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 this drug are causative in the reduction of headache frequency.

 

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. Divalproex sodium versus placebo

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

 1 ORs for responders (patients with ≥ 50% reduction in headache frequency)4574Odds Ratio (M-H, Random, 95% CI)3.34 [1.46, 7.67]

    1.1 Divalproex sodium titrated to 1500 mg/day
1105Odds Ratio (M-H, Random, 95% CI)5.68 [1.98, 16.34]

    1.2 Divalproex sodium titrated to maintain plasma concentration of 70 to 120 mg/L (mean 1087 mg/day)
164Odds Ratio (M-H, Random, 95% CI)8.27 [2.62, 26.10]

    1.3 Divalproex sodium titrated to 500 mg or 1000 mg/day, as tolerated
1234Odds Ratio (M-H, Random, 95% CI)1.35 [0.76, 2.40]

    1.4 Divalproex sodium 500 mg, 1000 mg, or 1500 mg/day (combined results)
1171Odds Ratio (M-H, Random, 95% CI)2.90 [1.29, 6.56]

 2 RRs for responders (patients with ≥ 50% reduction in headache frequency)4574Risk Ratio (M-H, Random, 95% CI)2.18 [1.28, 3.72]

    2.1 Divalproex sodium titrated to 1500 mg/day
1105Risk Ratio (M-H, Random, 95% CI)3.44 [1.47, 8.06]

    2.2 Divalproex sodium titrated to maintain plasma concentration of 70 to 120 mg/L (mean 1087 mg/day)
164Risk Ratio (M-H, Random, 95% CI)3.5 [1.63, 7.51]

    2.3 Divalproex sodium titrated to 500 mg or 1000 mg/day, as tolerated
1234Risk Ratio (M-H, Random, 95% CI)1.24 [0.81, 1.90]

    2.4 Divalproex sodium 500 mg, 1000 mg, or 1500 mg/day (combined results)
1171Risk Ratio (M-H, Random, 95% CI)2.06 [1.12, 3.80]

 
Comparison 2. Sodium valproate versus placebo

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

 1 Headache frequency (post-treatment)2126Mean Difference (IV, Random, 95% CI)-4.31 [-8.32, -0.30]

    1.1 Sodium valproate 1000 mg or 1500 mg/day (to maintain plasma concentration above 50 mg/L)
168Mean Difference (IV, Random, 95% CI)-2.60 [-4.07, -1.13]

    1.2 Sodium valproate 800 mg/day
158Mean Difference (IV, Random, 95% CI)-6.76 [-10.51, -3.01]

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

    2.1 Sodium valproate 1000 mg or 1500 mg/day (to maintain plasma concentration above 50 mg/L)
1Odds Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

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

    3.1 Sodium valproate 1000 mg or 1500 mg/day (to maintain plasma concentration above 50 mg/L)
1Risk Ratio (M-H, Random, 95% CI)0.0 [0.0, 0.0]

 
Comparison 3. Sodium valproate dose comparisons

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 4. Sodium valproate versus flunarizine

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 5. Divalproex sodium versus propanolol

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 6. Sodium valproate versus topiramate

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

 1 Headache frequency (post-treatment)2120Mean Difference (IV, Random, 95% CI)-0.90 [-1.58, -0.22]

 2 MIDAS score1Mean Difference (IV, Random, 95% CI)Totals not selected

 
Comparison 7. Safety of sodium valproate and divalproex sodium versus placebo

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

 1 Any adverse event3499Risk Difference (M-H, Random, 95% CI)0.03 [-0.08, 0.13]

 2 Asthenia/fatigue4606Risk Difference (M-H, Random, 95% CI)0.07 [-0.03, 0.17]

 3 Dizziness/vertigo2262Risk Difference (M-H, Random, 95% CI)0.07 [0.01, 0.13]

 4 Nausea4606Risk Difference (M-H, Random, 95% CI)0.15 [0.04, 0.26]

 5 Tremor3369Risk Difference (M-H, Random, 95% CI)0.07 [0.01, 0.13]

 6 Weight gain1Risk Difference (M-H, 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 valproate essentially unchanged.

20 June 2013New search has been performedSearches updated on 15 January 2013. One new included study added (Afshari 2012).

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.

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
Afshari 2012 {published data only (unpublished sought but not used)}
  • Afshari D, Rafizadeh S, Rezaei M. A comparative study of the effects of low-dose topiramate versus sodium valproate in migraine prophylaxis. International Journal of Neuroscience 2012;122(2):60-8. [MEDLINE: 21950578]
Freitag 2002 {published data only}
  • Freitag FG, Collins SD, Carlson HA, Goldstein J, Saper J, Silberstein S, et al. A randomized trial of divalproex sodium extended-release tablets in migraine prophylaxis. Neurology 2002;58(11):1652-9. [MEDLINE: 12058094]
Hering 1992 {published data only}
Jensen 1994 {published data only}
  • Jensen R, Brinck T, Olesen J. Sodium valproate has a prophylactic effect in migraine without aura: a triple-blind, placebo-controlled crossover study. Neurology 1994;44(4):647-51. [MEDLINE: 8164818]
Kaniecki 1997 {published data only}
  • Kaniecki RG. A comparison of divalproex with propanolol and placebo for the prophylaxis of migraine without aura. Archives of Neurology 1997;54(9):1141-5. [MEDLINE: 9311358]
Kinze 2001 {published data only}
Klapper 1997 {published data only}
  • Klapper J, on behalf of the Divalproex Sodium in Migraine Prophylaxis Study Group. Divalproex sodium in migraine prophylaxis: a dose-controlled study. Cephalalgia 1997;17(2):103-8. [MEDLINE: 9137847]
    Direct Link:
Mathew 1995 {published data only}
  • Mathew NT, Saper JR, Silberstein SD, Rankin L, Markley HG, Solomon S, et al. Migraine prophylaxis with divalproex. Archives of Neurology 1995;52(3):281-6. [MEDLINE: 7872882]
Mitsikostas 1997 {published data only}
  • Mitsikostas DD, Polychronidis I. Valproate versus flunarizine in migraine prophylaxis: a randomized, double-open, clinical trial. Functional Neurology 1997;12(5):267-76. [MEDLINE: 9439944]
Shaygannejad 2006 {published data only}

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
Arnold 1998 {published data only}
Bartolini 2005 {published data only}
Bavrasad 2010 {published data only}
  • Bavrasad R, Nejad SEM, Yarahmadi AR, Sajedi SI, Rahim F. Assessment of the middle dose of topiramate in comparison with sodium valproate for migraine prophylaxis: a randomized double-blind study. International Journal of Pharmacology 2010;6(5):670-5. [EMBASE: 2010449325]
Blumenfeld 2008 {published data only}
Cutrer 2001 {published data only}
Erdemoglu 2000 {published data only}
  • Erdemoglu AK, Ozbakir S. Valproic acid in prophylaxis of refractory migraine. Acta Neurologica Scandinavica 2000;102(6):354-8. [MEDLINE: 11125749]
    Direct Link:
Fragoso 2003 {published data only}
  • Fragoso YD. Low dose of sodium divalproate for the treatment of migraine. MedGenMed [electronic resource]: Medscape General Medicine 2003;5(1):32. [MEDLINE: 12827093]
Ghose 1998 {published data only}
Green 2005 {published data only}
Keyvan 2009 {published and unpublished data}
  • Keyvan G, Abolfazl MB. Comparison of treatment effect of sodium valproate, propranolol and tricyclic antidepressants in migraine. Pakistan Journal of Biological Sciences 2009;12(15):1098-101. [MEDLINE: 19943469]
Klapper 1994 {published data only}
  • Klapper JA. An open label cross-over comparison of divalproex sodium and propanolol HCl in the prevention of migraine headaches. Headache Quarterly 1994;5(4):50-3.
Krymchantowski 2011 {published data only}
Lenaerts 1996 {published data only}
  • Lenaerts M, Bastings E, Sianard J, Schoenen J. Sodium valproate in severe migraine and tension-type headache: an open study of long-term efficacy and correlation with blood levels. Acta Neurologica Belgica 1996;96(2):126-9. [MEDLINE: 8711985]
Millan-Guerrero 2007 {published data only}
Rothrock 1994 {published data only}
Rothrock 1997 {published data only}
Silberstein 1993 {published data only}
  • Silberstein SD, Saper JR, Mathew NT. The safety and efficacy of divalproex sodium in the prophylaxis of migraine headache: a multicenter, double-blind, placebo-controlled trial. Headache 1993;33(5):264-5.
Sørensen 1988 {published data only}
Togha 2008 {published data only}
  • Togha M, Rahmat Jirde M, Nilavari K, Ashrafian H, Razeghi S, et al. Cinnarizine in refractory migraine prophylaxis: Efficacy and tolerability. A comparison with sodium valproate. Journal of Headache & Pain 2008;9(2):77-82. [MEDLINE: 18286231]

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]
Cutrer 1997
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
  • Vos T, Flaxman AD, Naghavi M, Lozano R, Michaud C, Ezzati M, et al. Years lived with disability (YLDs) for 1160 sequelae of 289 diseases and injuries 1990-2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet 2013;380(9859):2163-96. [MEDLINE: 23245607]
ICHD-II 2004
  • Headache Classification Subcommittee of the International Headache Society. The International Classification of Headache Disorders: 2nd edition. Cephalalgia 2004;24 Suppl 1:1-160.
IHS Cttee 1988
  • Headache Classification Committee of the International Headache Society. Classification and diagnostic criteria for headache disorders, cranial neuralgias and facial pain. Cephalalgia 1988;8 Suppl 7:1-96.
Jadad 1996
Linde 2004
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
Morrell 2003
Olesen 2006
  • Olesen J, Bousser M-G, Diener H-C, Dodick D, First M, Goadsby PJ, et al. Headache Classification Committee. New appendix criteria open for a broader concept of chronic migraine. Cephalalgia 2006;26(6):742-6. [MEDLINE: 16686915]
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.
Reveiz-Herault 2003
  • Reveiz-Herault L, Cardona AF, Ospina EG, Carrillo P. Effectiveness of flunarizine in the prophylaxis of migraine: a meta-analytical review of the literature [Eficacia de flunaricina en la profilaxis de migrana: revision metaanalitica de la bibliografia]. Revista de Neurologia 2003;36(10):907-12. [MEDLINE: 12766861]
Silberstein 2008
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