Intervention Review

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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

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Characteristics of included studies [ordered by study ID]
Afshari 2012

MethodsProspective, randomised, double-blind, parallel-group trial. The study consisted of a 4-week baseline period (possibly retrospective) and a prospective treatment period of 12 weeks

Discontinuation rate: sodium valproate 22%, topiramate 30%

Compliance (adherence) data: not available

Rule for use of acute medication: during the acute attacks, patients were allowed to use acetaminophen, NSAIDs, ergotamine, triptans, and opioids. Dosing frequency not limited

Methodological quality score: 3


ParticipantsInclusion: migraine with or without aura according to ICHD-II; migraine onset at least 6 months prior to study and before age 50; migraine frequency 4 to 10 attacks per month; attacks separated by 48 h pain-free interval. Ages 18 to 65. Non-pregnant, non-lactating, adequate contraception. Migraine prophylaxis withdrawn at least 1 month prior to study entry

Exclusion: non-migraine headaches; > 8 treatment days/month of ergots, NSAIDs, or triptans. No rule reported for exclusion of CDH. Other exclusions: alcohol/drug dependence. Hemiplegic, basilar, or ophthalmoplegic migraine. Serious medical conditions

Setting: single-centre

Country: Iran

Intention-to-treat analysis of 56 patients. Of these, 9 had migraine with aura and 47 migraine without aura (ie, not stated that some had both). 44 females and 12 males included in the ITT analysis; mean age among ITT participants treated with sodium valproate 29.2 ± 9.6; mean age among ITT participants treated with topiramate 32.1 ± 10.2. 36 allocated to receive sodium valproate; 40 allocated to receive topiramate


InterventionsSodium valproate 400 mg/day versus topiramate 50 mg/day (12 weeks). Sodium valproate initiated with 200 mg/day for 1 week, thereafter 400 mg/day until study end. Dosing frequency not stated. Topiramate initiated with 25 mg/day for 1 week, thereafter 50 mg/day until study end. Dosing frequency not stated


OutcomesHeadache frequency (4 weeks). Headache severity. Duration of episode. Weight. MIDAS at baseline and 8 weeks. HIT-6 at baseline and 8 weeks. Responder rate

Time point(s) considered in the review: last (third) month of double-blind phase for frequency; entire double-blind phase for MIDAS


NotesA migraine attack persisting longer than 72 hours was counted as a new distinct migraine period. This outcome measure runs the risk of confounding reductions in migraine frequency with reductions in attack duration. Since it is unclear if the baseline was prospective, change scores from baseline were excluded from the analyses of this review. Complementary information requested by email (twice) and ordinary letter (once) but not provided by corresponding author

Funders of the trial: Kermanshah University of Medical Sciences, Iran


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskComputer-generated randomisation schedule

Allocation concealment (selection bias)Low riskMedication prescribed with preprinted medication code labels

Blinding of participants and personnel (performance bias)
All outcomes
High riskStated that both participants and clinicians were blinded by the use of preprinted medication code labels. However, there is no mention of equally appearing tablets. It is thus possible that standard medication was provided by third party according to allocation label

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNo information

Incomplete outcome data (attrition bias)
All outcomes
Unclear risk20 randomised patients did not contribute to the ITT analysis: 8 AEs; 10 lack of efficacy (whereof 8 were allocated to topiramate); 2 moved

Selective reporting (reporting bias)Low riskNo suspicion of selective reporting of outcomes, time points, or analyses

Freitag 2002

MethodsProspective, randomised, double-blind, parallel trial. 5 half-lives washout period for previous migraine prophylactic medication. 4-week baseline period. Duration of treatment: 2 weeks titration then 10 weeks stable dosage

Discontinuation rate: dropout 17% for active treatment; 12% for placebo

Compliance (adherence) data: compliance, defined as "generally took study drug as directed", 75% for active treatment, 74% for placebo

Rule for use of acute medication: was permitted but restrictions not reported

Methodological quality score: 5


ParticipantsInclusion: migraine according to ICHD-I; migraine onset more than 6 months before screening; average of 2 or more attacks per month in the 3 months before screening

Exclusion: secondary headaches were adequately excluded. Neither daily headache nor analgesic overuse headache were adequately excluded. Other exclusions: pregnancy, lactation, inadequate contraception, more than 15 headache days per month, cluster headache, previous adequate treatment with sodium valproate or divalproex sodium, significant CNS disorder, failed more than 2 adequate trials of migraine prophylactic medication

Setting: multicentre

Country: USA

Intention-to-treat analysis of 237 migraine patients. 229 had had attacks without aura; 86 had had attacks with aura (since migraine onset). 187 females and 50 males; age range 16 to 69. 122 received active treatment and 115 received placebo


InterventionsDivalproex sodium versus placebo (12 weeks). Dosage titrated up to 1000 mg/day then maintained at 1000 mg/day for 10 weeks, or 500 mg/day if higher dose could not be tolerated (14% of active group)


OutcomesNumber of migraine attacks per 28 days. Number of migraine days per 28 days

Time point(s) considered in the review: entire 3-month treatment phase


NotesFunders of the trial: Abbott Laboratories


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskThe randomisation schedule, which assigned a unique series of randomised (in a 1:1 ratio) subject numbers to each centre, was computer-generated by Abbott Laboratories Department of Clinical Statistics prior to study initiation

Allocation concealment (selection bias)Low riskThe randomisation schedule was used by Abbott Laboratories Investigational Drugs Services Department to package and label the study medication containers. Randomisation was accomplished by instructing investigators to assign the subject numbers in ascending numerical sequence as subjects qualified for randomisation. Treatment assignments were provided to the clinical sites in sealed envelopes that could have been opened if needed in an emergency. The integrity of these envelopes was verified at each clinical monitoring visit

Blinding of participants and personnel (performance bias)
All outcomes
Low riskBoth clinicians and participants were blinded. Placebo tablets were identical (grey, ovaloid) to active tablets

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNo information

Incomplete outcome data (attrition bias)
All outcomes
Low riskIntention-to-treat analysis includes all randomised participants

Selective reporting (reporting bias)Unclear riskThe information is not sufficient to come up with precise enough estimates to include mean migraine frequency in this meta-analysis. Only the 95% CI of the difference between (but not the SDs for) the changes in mean migraine frequency from baseline are given. The responder ratios are usable in this meta-analysis

Hering 1992

MethodsProspective, randomised, double-blind, single cross-over trial. 2-week washout period for previous migraine prophylactic medication. No baseline period. Total duration: 16 weeks

Discontinuation rate: dropout 3.1% for active treatment; 6.3% for placebo

Compliance (adherence) data: compliance assessed by pill count and blood valproate levels, but pill count data not reported

Rule for use of acute medication: patients' normal analgesics permitted

Methodological quality score: 4


ParticipantsInclusion: Ad Hoc Committee criteria; migraine onset more than 2 years prior to screening; at least 4 attacks per month for 2 years. No information about mixed or combination headaches

Exclusion: secondary headaches were adequately excluded. It is not reported whether daily headaches were excluded. Analgesic overuse headaches were not adequately excluded. Other exclusions: contraindications to valproate, renal or hepatic abnormality, psychiatric disorder, pregnancy or reproductive intentions, change in use of oral contraception, alcohol or drug abuse, participation in another headache study, other chronic medication use

Setting: single headache clinic

Country: Israel

32 migraine patients participated. Demographic data available on the 29 who completed the trial. 4 had migraine with aura, and 25 migraine without aura. 23 females and 6 males; age range 18 to 54 years


InterventionsSodium valproate versus placebo (8 weeks). Dosage: 800 mg/day


OutcomesNumber of migraine attacks per 8 weeks. Sum of individual attack severity (1 to 3) per 8 weeks. Sum of individual attack duration (hours) per 8 weeks

Time point(s) considered in the review: entire 8-week treatment phase


NotesFunders of the trial: not reported


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskDescription of method for random sequence generation is lacking

Allocation concealment (selection bias)Unclear riskNo information

Blinding of participants and personnel (performance bias)
All outcomes
Low riskBoth clinicians and participants were blinded. Placebo had same appearance as verum

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNo information

Incomplete outcome data (attrition bias)
All outcomes
High riskAEs reported but number of safety evaluable participants on each drug unclear

Selective reporting (reporting bias)Low riskNo suspicion of selective reporting of outcomes, time points, or analyses

Jensen 1994

MethodsProspective, randomised, double-blind, single cross-over trial. Total duration 32 weeks. 4-week medication-free run-in period; 12-week treatment period; 4-week washout period; 12-week treatment period

Discontinuation rate: dropout 21%

Compliance (adherence) data: compliance data available only as mean blood valproate levels

Rule for use of acute medication: patients' usual treatment permitted

Methodological quality score: 4


ParticipantsInclusion: migraine according to ICHD-I; migraine onset more than 1 year prior to study; 2 to 10 days with migraine per month

Exclusion: secondary and daily headaches were adequately excluded. The criteria for excluding analgesic overuse headache were vague. Other exclusions: cluster headache, trigeminal neuralgia, other neurological or psychiatric disease, other migraine prophylaxis, drug dependency, previous participation in more than 2 migraine drug trials

Setting: single headache clinic

Country: Denmark

43 migraine patients participated; all had migraine without aura. 36 females and 7 males; allowed age range 18 to 70 years


InterventionsSodium valproate versus placebo (12 weeks). Dosage either 1000 mg/day or 1500 mg/day to maintain plasma concentration above 50 mg/L


OutcomesNumber of migraine days per 28 days. Intensity of headache (3-point scale). Duration

Time point(s) considered in the review: entire 12-week treatment phase


NotesFunders of the trial: Ercopharm Ltd Denmark


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskDescription of method for random sequence generation is lacking

Allocation concealment (selection bias)Unclear riskNo information

Blinding of participants and personnel (performance bias)
All outcomes
Low riskBoth clinicians and participants were blinded. Dose adjustments (differentiation between 2 doses) were performed by independent investigators based on serum levels of sodium valproate. Placebo and verum tablets were apparently identical

Blinding of outcome assessment (detection bias)
All outcomes
Low riskThe term 'triple-blind' presumably means that the statistician was blinded

Incomplete outcome data (attrition bias)
All outcomes
High riskPatients who dropped out after randomisation were excluded from statistical analysis

Selective reporting (reporting bias)Low riskNo suspicion of selective reporting of outcomes, time points, or analyses

Kaniecki 1997

MethodsProspective, randomised, single-blind, double cross-over trial. 4-week baseline period. Total duration: 32 weeks (4 weeks placebo, 12 weeks treatment, 4-week washout, 12 weeks treatment)

Discontinuation rate: dropout: 14% overall

Compliance (adherence) data: compliance data available only as mean blood valproate levels

Rule for use of acute medication: not reported

Methodological quality score: 2


ParticipantsInclusion: migraine according to ICHD-I; migraine onset more than 1 year prior to study; 2 to 8 attacks per month; maximum of 15 headache days per month. Patients unable to differentiate migraine from other headaches were not included

Exclusion: secondary headaches, daily headaches, and analgesic overuse headache were adequately excluded. Other exclusions: participation in previous trials of valproate or propanolol, failure of more than 2 other migraine prophylactic agents, severe medical or psychiatric illness, alcohol or drug abuse, inadequate contraception

Setting: single neurology clinic

Country: USA

37 migraine patients participated; all had migraine without aura. 30 females and 7 males; allowed age range 18 to 65


InterventionsPlacebo (4 weeks) versus divalproex sodium (12 weeks) versus propranolol hydrochloride (12 weeks). Dosage titrated for 8 weeks to goals of 1500 mg/day for divalproex sodium and 180 mg/day for propranolol hydrochloride, followed by 4-week maintenance period


OutcomesNumber of migraine attacks per 28 days. Number of migraine days per 28 days

Time point(s) considered in the review: entire 12-week treatment phase for active treatment (valproate or propranolol); 4-week treatment phase for placebo


NotesPlacebo tablets were continued throughout the trial

Funders of the trial: Abbott Laboratories


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskDescription of method for random sequence generation is lacking

Allocation concealment (selection bias)Unclear riskNo information

Blinding of participants and personnel (performance bias)
All outcomes
High riskClinician not blinded. Placebo, divalproex, and propranolol had different appearances, so even single-blinding is questionable

Blinding of outcome assessment (detection bias)
All outcomes
High riskThe single investigator was not blinded until he reviewed the diaries for outcomes assessment

Incomplete outcome data (attrition bias)
All outcomes
High riskPatients who dropped out after randomisation were excluded from statistical analysis

Selective reporting (reporting bias)Unclear riskAEs not reported for placebo treatment

Kinze 2001

MethodsProspective, open-label, parallel study of serum valproate levels. Baseline period of 1 to 3 months. Duration of treatment: unspecified titration period followed by 6 months stable dosage

Discontinuation rate: dropout/loss to follow-up: 7 of 52 patients

Compliance (adherence) data: compliance assessed by serum valproate level in relation to dose

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

Methodological quality score: 1


ParticipantsInclusion: migraine according to ICHD-I, migraine frequency of 2 to 5 attacks per month, sufficient therapy for acute attacks (not fully defined), age 18 or over

Exclusion: secondary headaches were adequately excluded. No clear information on the exclusion of daily headache or analgesic overuse headache. Other exclusions: pregnancy, breast-feeding, use of other migraine prophylaxis, history of liver disease or elevated liver enzymes, more than 10 days of tension-type headache per month

Setting: single outpatient headache clinic

Country: Germany

52 patients recruited, 7 with aura and 45 without aura. 49 females and 3 males; mean age 45 years


InterventionsPatients received differing doses of sodium valproate depending upon their assignment to a physician. Efficacy of low (21 to 50 micrograms/ml) versus high (> 50 micrograms/ml) serum valproate levels was the focus of analysis. Dosage started at 150 mg/day and was titrated upwards to individualised target dose (maximum 1200 mg/day)


OutcomesMigraine frequency per month. Migraine days per month. Headache intensity. Use of acute medication

Time point(s) considered in the review: last (sixth) month of stable dosage treatment phase


NotesFunders of the trial: not reported


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)High riskTwo participating physicians generally used doses up to 600 mg/day, whereas 2 others escalated up to 1200 mg/day without a predefined schedule

Allocation concealment (selection bias)High riskStudy not blinded

Blinding of participants and personnel (performance bias)
All outcomes
High riskStudy not blinded

Blinding of outcome assessment (detection bias)
All outcomes
High riskNo information

Incomplete outcome data (attrition bias)
All outcomes
High riskResults reflect a complete case analysis of 45 patients. Analysis was by serum valproate level; it was not reported whether patients assigned to the lower dose conditions were all in the low serum level group

Selective reporting (reporting bias)High riskNumerical information about adverse events not provided

Klapper 1997

MethodsProspective, randomised, double-blind, parallel trial. Five half-lives washout period. Total duration then 16 weeks. 4-week single-blind, placebo-only baseline period. 12-week treatment period

Discontinuation rate: dropout: 25% of randomised participants

Compliance (adherence) data: compliance data not reported

Rule for use of acute medication: fewer than 3 times per week, but no information about permitted medications

Methodological quality score: 4


ParticipantsInclusion: migraine according to ICHD-I; migraine onset at least 6 months prior to study; at least 2 attacks per month for previous 3 months

Exclusion: daily headaches and analgesic overuse headaches were adequately excluded. No information on the exclusion of secondary headaches is reported. Other exclusions: more than 15 days of non-migrainous headache per month, migraine symptoms without headache, pregnancy, inadequate contraception for women, previous treatment with valproate, failure of more than 2 other migraine prophylactic agents, significant medical or psychiatric disorder, many concomitant medications

Setting: multi-centre

Country: USA and Canada

176 migraine patients were randomised; 91% had had attacks without aura and 40% with aura. 157 females and 19 males; age range 17 to 76


InterventionsDivalproex sodium 500 mg versus 1000 mg versus 1500 mg versus placebo (12 weeks). Dosage titrated for 4 weeks, then maintained for 8 weeks


OutcomesNumber of headache days per 28 days. Number of migraine attacks per 28 days. Frequency of non-migraine headaches

Time point(s) considered in the review: entire 3-month treatment phase


NotesFunders of the trial: Abbott Laboratories


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskDescription of method for random sequence generation (1:1:1:1 ratio within each study centre) is lacking

Allocation concealment (selection bias)Unclear riskNo information

Blinding of participants and personnel (performance bias)
All outcomes
Low riskSingle-blind baseline phase followed by double-blind experimental phase. Placebo tablets were matched to verum

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNo information

Incomplete outcome data (attrition bias)
All outcomes
Low riskIntention-to-treat analysis includes all randomised participants who provided headache data during the double-blind phase

Selective reporting (reporting bias)High riskDose comparisons not possible, as insufficient data were provided

Mathew 1995

MethodsProspective, 2:1 randomised, double-blind, parallel trial. 5 half-lives washout period for previous migraine prophylactic medication. Total duration then 16 weeks: 4-week single-blind, placebo-only baseline period. 4 weeks titration, then 8 weeks stable dosage

Discontinuation rate: dropout 17% for active treatment, 14% for placebo

Compliance (adherence) data: compliance data available only as mean blood valproate levels

Rules for use of acute medication: reported as exclusions; analgesics and triptans permitted (but not daily)

Methodological quality score: 4


ParticipantsInclusion: migraine according to ICHD-I; migraine onset more than 6 months prior to study; 2 or more attacks per month for previous 3 months

Exclusion: secondary headaches, daily headaches, and analgesic overuse headache were adequately excluded. Other exclusions: migraine symptoms without headache, significant other medical or psychiatric disorder, history of poor compliance, history of valproate use, women of childbearing potential, failure of more than 2 other migraine prophylactic agents

Setting: multi-centre

Country: USA

107 migraine patients participated; 95% had had attacks without aura and 27% with aura. 83 females and 24 males; allowed age range 16 to 75


InterventionsDivalproex sodium versus placebo (12 weeks). Dosage titrated to maintain plasma concentration at 70 to 120 mg/L. Mean dose 1087 mg/day


OutcomesNumber of migraine attacks per 28 days. Number of migraine days per 28 days. Peak headache severity (0 to 4 scale). Headache duration (hours). Average analgesic use. Other composite measures

Time point(s) considered in the review: entire 3-month treatment phase


NotesFunders of the trial: Abbott Laboratories


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskDescription of method for random sequence generation (2:1 ratio of verum to placebo within each centre) is lacking

Allocation concealment (selection bias)Unclear riskNo information

Blinding of participants and personnel (performance bias)
All outcomes
Low riskSingle-blind baseline phase (patient was blinded, clinician was not) followed by double-blind treatment phase. Placebo tablets were identical in appearance to verum and dose-adjusted in a similar fashion. An unblinded designee reviewed plasma concentrations and informed personnel at each clinic of the results in a blinded manner. For patients receiving placebo, sham valproate concentrations were reported by the unblinded designee according to an algorithm designed to maintain the blind

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNo information

Incomplete outcome data (attrition bias)
All outcomes
Low riskAnalyses were performed using all data from randomised patients

Selective reporting (reporting bias)Low riskNo suspicion of selective reporting of outcomes, time points, subgroups, or analyses

Mitsikostas 1997

MethodsProspective, randomised, parallel trial. 4-week baseline period. Duration of treatment: 4 weeks titration, then 4 weeks stable dosage

Discontinuation rate: dropout 4.5% for active treatment; 9.1% for the comparison treatment

Compliance (adherence) data: compliance was assessed for the active treatment group only by serum valproate concentrations

Rule for use of acute medication: sumatriptan or anti-inflammatory agents only

Methodological quality score: 2


ParticipantsInclusion: migraine according to ICHD-I; migraine onset at least 6 months before screening; at least 3 attacks per month for 6 months; negative brain CT scan. Mixed headaches (with episodic TTH) were included; subgroups cannot be distinguished

Exclusion: secondary headaches, daily headaches, and analgesic overuse headache were adequately excluded. Other exclusions: other migraine prophylactic medication in last 6 months, study drug contraindications, hepatic or renal disorder, pregnancy or reproductive intention, chronic use of any other medication during study period

Setting: single headache clinic

Country: Greece

44 migraine patients participated; 9 with aura and 35 without. 31 females and 13 males; age range 15 to 60 years. 22 received active treatment and 22 received placebo


InterventionsSodium valproate versus flunarizine (8 weeks). Dosage titrated up to valproate 1000 mg/day or flunarizine 10 mg/day and maintained for 4 weeks


OutcomesNumber of migraine attacks per 28 days. Mean severity of attacks (0 to 10 scale). Mean attack duration (hours). Mean state of physical activity during attacks (0 to 100 scale). Average use of escape medication during 28 days (number of tablets)

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


NotesFunders of the trial: not reported


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskDescription of method for random sequence generation (1:1 ratio) is lacking

Allocation concealment (selection bias)High riskNo blinding

Blinding of participants and personnel (performance bias)
All outcomes
High riskThis trial is described as double-open, which appears equivalent to open-label

Blinding of outcome assessment (detection bias)
All outcomes
High riskNo information

Incomplete outcome data (attrition bias)
All outcomes
High riskParticipants not completing study were excluded from the analysis

Selective reporting (reporting bias)Low riskNo suspicion of selective reporting of outcomes, time points, or analyses

Shaygannejad 2006

MethodsProspective, randomised, double-blind, double cross-over trial. 1-month baseline period. Duration of treatment: 1 week titration, followed by 2 months stable dose of first drug. 2-month washout, then 2-month stable dose of second drug

Discontinuation rate: no dropouts were recorded

Compliance (adherence) data: compliance was reported as good, but no details or results of compliance measurement are given

Rule for use of acute medication: unspecified analgesics allowed, but not more than once per day. No other details provided

Methodological quality score: 3


ParticipantsInclusion: migraine according to ICHD-I, migraine for at least 6 months prior to trial, migraine frequency 3 or more per month in the 3 months prior to trial

Exclusion: no clear details given on the exclusion of secondary headache, daily headache, or analgesic overuse headache. Other exclusions: concurrent medical treatment; concurrent serious medical problems; other neurological disease; lactating or pregnant

Setting: single neurology clinic

Country: Iran

Complete case analysis of 64 patients. Patients with and without aura recruited, but percentages not reported. 36 males and 28 females; age range 14 to 57 years


InterventionsTopiramate 50 mg/day versus sodium valproate 400 mg/day; repeat in cross-over phase. Topiramate dose started at 25 mg/day and was incremented to 50 mg/day; sodium valproate was started at 200 mg/day and incremented to 400 mg/day


OutcomesMigraine frequency per month; migraine intensity; migraine duration

Time point(s) considered in the review: last (second) month of stable dosage treatment phase


NotesStudy appears to use doses of both topiramate and valproate that are lower than normal clinical doses

Funders of the trial: not reported


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskDescription of method for random sequence generation (1:1 ratio) is lacking

Allocation concealment (selection bias)Unclear riskNo information

Blinding of participants and personnel (performance bias)
All outcomes
Unclear riskParticipants and clinician were blinded. Information lacking about how this was adequately achieved

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNo information

Incomplete outcome data (attrition bias)
All outcomes
Low riskAll enrolled patients completed treatment and were available for follow-up

Selective reporting (reporting bias)Low riskNo suspicion of selective reporting of outcomes, time points, subgroups, or analyses

 
Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion

Arnold 1998Review paper

Bartolini 2005Reports data on chronic migraine only

Bavrasad 2010Serious flaws including selective outcome reporting and concerns about data integrity

Blumenfeld 2008Comparator is experimental

Cutrer 2001Basic science paper

Erdemoglu 2000No control group

Fragoso 2003Letter to editor

Ghose 1998No control group

Green 2005Post hoc analysis of Klapper 1997 (included)

Keyvan 2009Unknown number of participants were children. Lack of usable outcome data

Klapper 1994No extractable data published

Krymchantowski 2011No randomisation

Lenaerts 1996No control group

Millan-Guerrero 2007Comparator is experimental

Rothrock 1994No control group

Rothrock 1997Review paper

Silberstein 1993Conference abstract only

Sørensen 1988No control group

Togha 2008Comparator is experimental

 
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