Methods

Prospective, 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: topiramate 30%, sodium valproate 22%

Compliance (adherence) data: not available

Rule for use of acute medication: during acute attacks, patients were allowed to use acetaminophen, NSAIDs, ergotamine, triptans, and opioids

Methodological quality score: 3

Participants

Inclusion: 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 Migraine prophylaxis withdrawn at least 1 month prior to study entry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 topiramate 32.1 ± 10.2; mean age among ITT participants treated with sodium valproate 29.2 ± 9.6. 40 allocated to receive topiramate; 36 allocated to receive sodium valproate

Interventions

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

Outcomes

Headache 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

Notes

A 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

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Computer‐generated randomisation schedule

Allocation concealment (selection bias)

Low risk

Medication prescribed with preprinted medication code labels

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Stated 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 risk

No information

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

20 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 risk

No suspicion of selective reporting of outcomes, time points, or analyses

Methods

Prospective, randomised, double‐blind, parallel‐group trial. Retrospective baseline (presumably 1 month) followed by 8 weeks prospective treatment phase

Discontinuation rate in double‐blind phase: topiramate 3%, propranolol 3%

Compliance (adherence) data: not available

Rule for use of acute medication: no mention

Methodological quality score: 3

Participants

Inclusion: migraine with or without aura according to ICHD‐I; migraine onset at least 1 year prior to study and before age 50; migraine frequency 3 or more attacks per month during the 3 months prior to study entry; pain‐free interval of at least 48 h between attacks; concomitant migraine prophylactics withdrawn 1 month prior to study entry. Ages 18 to 65

Exclusion: no adequate rule reported for exclusion of CDH or overuse of acute medication. Other exclusions: pregnancy; breast feeding; general and neurologic diseases

Setting: single‐centre

Country: Iran

Complete case analysis of 60 patients. Not reported how many had migraine with aura. 49 females and 11 males; mean age in topiramate group 31.7 ± 8; mean age in propranolol group 29.9 ± 9. 31 allocated to receive topiramate and 31 allocated to receive propranolol

Interventions

Topiramate 50 mg/day versus propranolol 80 mg/day (8 weeks). Topiramate initiated with 25 mg/day for 1 week, thereafter 50 mg/day until study end. Dosing frequency not stated. Propranolol initiated with 40 mg/day for 1 week, thereafter 80 mg/day until study end. Dosing frequency not stated

Outcomes

Migraine attack frequency per 4 weeks; attack duration (hours); headache intensity (VAS, not mentioned if at prespecified time points or maximum); AEs

Time point(s) considered in the review: last (second) month of double‐blind phase

Notes

Since the baseline was retrospective, change scores from baseline were excluded from the analyses of this review. Complementary information requested twice but not provided by corresponding author

Funders of the trial: not reported

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

The study was randomised (1:1). Presumably sequence generation was by a lottery procedure (see below under 'Allocation concealment')

Allocation concealment (selection bias)

Unclear risk

After selection of 1 of 62 sealed envelopes, half of which contained medication codes for topiramate and the other half those for propranolol, a tear‐off label was removed, revealing the randomisation number. The medication code was removed from the envelope. It is not clear who delivered the study medication according to the medication code

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Both participants and clinicians were blinded. It is unclear how this was maintained

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

No information

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

1 subject dropped out in each group (both due to AEs) and they were excluded from the data available for this review

Selective reporting (reporting bias)

Unclear risk

AEs of propranolol (not included in this review) are inadequately reported

Methods

Prospective, randomised, double‐blind, parallel‐group trial. 28‐day baseline period. Duration of treatment: 8 weeks titration, then 18 weeks stable dosage, followed by open‐label extension

Discontinuation rate: dropout reported as 47% for combined active treatment groups; 48% for placebo, but unclear how many patients completed the entire trial

Compliance (adherence) data: only reported as percentage of patients achieving target dose

Rule for use of acute medication: analgesics, ergot derivatives, triptans and opioids allowed

Methodological quality score: 5

Participants

Inclusion: IHS migraine criteria; migraine frequency of 3 to 12 in 28‐day baseline phase; women practising adequate contraception or unable to bear children

Exclusion: secondary headaches, daily headache, and analgesic overuse headache were all adequately excluded. Other exclusions: failure to respond to more than 2 previous migraine‐prophylactic regimens, migraine onset after age 50, continued use of various CNS‐active and other drugs, history of nephrolithiasis, previous exposure to topiramate, use of experimental drug or device within 30 days of screening

Setting: multicentre

Country: 52 North American clinical centres

Intention‐to‐treat analysis of 468 patients. Patients both with and without aura recruited, but percentages not reported. 406 females and 62 males; age range 12 to 65. 117 received 50 mg/day dose, 120 received 100 mg/day dose, 117 received 200 mg/day dose and 114 received placebo

Interventions

Topiramate 50 mg/day versus topiramate 100 mg/day versus topiramate 200 mg/day versus placebo (18 weeks). Dosage started at 25 mg/day and increased by 25 mg each week to reach assigned dose or maximum tolerated dose

Outcomes

Headache frequency per 28 days. Proportion of responders (50% reduction in frequency). Severity and duration of attacks. Month of onset of drug action. Quality of life (average maintenance AUC of MSQ and SF‐36 scores). AEs

Time points considered in the review: through entire double‐blind phase (migraine frequency, response rate, AEs); week 8 to 26 of double‐blind phase (MSQ, SF‐36)

Notes

Lowest allowable age was 12 years; hence some patients not adult. Headache frequency defined as the number of migraine periods per 28 days, where a migraine period is any occurrence of migraine headache that started, ended, or recurred with 24 hours. A migraine attack persisting into a second 24‐hour period 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

Funders of the trial: Johnson & Johnson Pharmaceutical Research and Development, LLC

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Computer‐generated randomisation schedule balanced by using permutated blocks of 4 and stratified by centre

Allocation concealment (selection bias)

Low risk

An interactive voice response system was used to assign randomisation numbers to patients

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Patients and clinicians were blinded to study medication. Study medication packaged and labelled according to a medication code schedule generated before the trial. Each bottle had a 2‐part, tear‐off label; study medication identification was concealed and could be revealed only in case of emergency

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Treatment assignments were not revealed to investigators or study monitors until all patients had completed therapy and the database had been finalised. Not clearly stated that blinding included the stage of analysis

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Intention‐to‐treat analysis excluded 15 patients who did not provide any post‐baseline data, out of 483 randomised

Selective reporting (reporting bias)

Low risk

No suspicion of selective reporting of outcomes, time points, subgroups, or analyses

Methods

Prospective, randomised, double‐blind, parallel‐group trial. Two months baseline period. Duration of treatment: 2 months

Discontinuation rate: topiramate 20%, placebo 27%, levetiracetam 0%

Compliance (adherence) data: "non‐compliance" reported as the most common reason for dropping out (6/7), but the extent to which patients took medications as prescribed is not reported

Rule for use of acute medication: not reported

Methodological quality score: 3

Participants

Inclusion: migraine without aura according to ICHD‐II; attack frequency not specified. Ages 18 to 49. Consent to additional neurophysiological tests

Exclusion: no adequate rule reported for exclusion of secondary headaches, daily headache, or analgesic overuse headache. However, no included patient had CDH or other headache than migraine according to correspondence with the first author. Other exclusions: psychoactive drugs, general/neurological/psychiatric disorders

Setting: single‐centre

Country: Italy

Intention‐to‐treat analysis of 39 patients. Patients with aura not recruited. 35 females and 10 males included; mean age 37.9 ± 12.4, age range 18 to 49. 15 received topiramate, 15 received placebo, and 15 received levetiracetam

Interventions

Topiramate 100 mg/day (50 mg BID, presumably tablets) versus placebo versus levetiracetam (8 weeks). Dose escalation strategy not reported

Outcomes

Migraine days per month. 50% or greater reduction in headache frequency. Flicker frequency dependent α‐rhythm phase synchronisation (phase synchronisation index). Mean iCNV amplitude and iCNV habituation index

Time point(s) considered in the review: through entire treatment period (2 months)

Notes

Levetiracetam arm of trial excluded as comparator from this review, since the intervention is experimental. Study was not principally designed to obtain clinical outcome data of the interventions

Funders of the trial: not reported

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

No information

Allocation concealment (selection bias)

Unclear risk

No information

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Study was double‐blind, but methodological description is lacking

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

No information

Incomplete outcome data (attrition bias)
All outcomes

Low risk

No concern among the review authors over incomplete outcome data

Selective reporting (reporting bias)

Unclear risk

Means (SD) for migraine frequency during treatment period not presented in publications but provided by first author after request. No safety data reported for placebo‐group

Methods

Prospective, randomised, double‐blind, parallel‐group trial. 14‐day washout period then 28‐day baseline period. Duration of treatment: 8 weeks titration then 18 weeks maintenance

Discontinuation rate: dropouts: 32% for topiramate 100 mg, 55% for topiramate 200 mg, 29% for propranolol, 31% for placebo

Compliance (adherence) data: daily dose recorded; plasma concentration of topiramate recorded

Rule for use of acute medication: aspirin, paracetamol, NSAIDs, ergot compounds, triptans, and opioids permitted

Methodological quality score: 4

Participants

Inclusion: IHS migraine criteria, migraine onset more than 1 year prior to study, migraine frequency 3 to 12 per month during 28‐day baseline phase. Ages 12 to 65. No mixed or combination headaches included

Exclusion: daily headache was adequately excluded; no information given on the exclusion of secondary headache and analgesic overuse headache. Other exclusions: failure to respond to more than 2 previous migraine‐prophylactic regimens, asthma, bradyarrhythmia, uncontrolled diabetes, contraindications to beta‐blockers

Setting: multicentre

Country: 13 countries in Europe, Asia, Australia, and Africa

Intention‐to‐treat analysis of 568 patients. Patients both with and without aura recruited, but percentages not reported. 453 females and 115 males; age range 12 to 65. 139 received topiramate 100 mg/day, 143 received topiramate 200 mg/day, 143 received propranolol 160 mg/day, and 143 received placebo

Interventions

Topiramate 100 mg/day versus topiramate 200 mg/day versus propranolol 160 mg/day versus placebo (18 weeks). Dosages started at 25 mg/day (topiramate) and 20 mg/day (propranolol) and increased by 25 mg (topiramate) or 20 mg (propranolol) each week to reach assigned dose or maximum tolerated dose

Outcomes

Headache frequency per 28 days. Change in number of migraine days per month. Change in average monthly rate of rescue medication. Proportion of responders (50% reduction in frequency). Month of onset of drug action. Average duration

Time point(s) considered in the review: through the core double‐blind phase

Notes

Lowest allowable age was 12 years; hence some patients not adult. Headache frequency defined as the number of migraine periods per 28 days, where a migraine period is any occurrence of migraine headache that started, ended, or recurred with 24 hours. A migraine attack persisting into a second 24‐hour period 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

Funders of the trial: Johnson & Johnson Pharmaceutical Research and Development, LLC

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Randomisation, in equal proportions, to 1 of 4 treatment groups. Method not described

Allocation concealment (selection bias)

Unclear risk

No information

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Participants and clinicians were blinded. Method not described

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

No information

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Intention‐to‐treat analysis excluded 7 patients who did not provide any post‐baseline data, out of 575 randomised

Selective reporting (reporting bias)

Low risk

No suspicion of selective reporting of outcomes, time points, subgroups, or analyses

Methods

Prospective, randomised, double‐blind, parallel‐group trial. 26‐week open‐label phase at target dose of topiramate 100 mg/day (allowing 50 to 200 mg/day), then randomising to 26‐week, double‐blind, parallel‐group phase of prolonged topiramate treatment at individualised dose or placebo

Discontinuation rate in double‐blind phase: topiramate 18%, placebo 20%

Compliance (adherence) data: not available

Rule for use of acute medication: individuals with medication overuse not included; triptans, ergots, opiates, and other analgesics thereafter permitted

Methodological quality score: 5

Participants

Inclusion: migraine with or without aura according to ICHD‐II; history of migraine at least 1 year; migraine frequency of ≥ 4 attacks/month. Ages 18 to 80

Exclusion: overuse of acute medication. Acceptable exclusion of secondary headaches. Other exclusions: prophylaxis in month preceding entry (3 months for flunarizine); prior poor response on > 2 prophylactics; pregnancy and breastfeeding

Setting: 88 centres

Country: 21 countries in Europe and the Middle East

Intention‐to‐treat analysis of 507 patients. Patients both with and without aura recruited, but percentages not reported. 445/512 females and 67/512 males; mean age among allocated to continuing on topiramate 40.1 ± 10.6; mean age among allocated to switching to placebo 40.1 ± 10.7, age range 18 to 69. 255 allocated to continuing on topiramate and 259 allocated to switching to placebo

Interventions

Topiramate 100 mg/day versus placebo (26 weeks). Topiramate target dose 100 mg/day (tablets 50 mg BID), individualised according to efficacy and tolerability between 50 and 200 mg/day; dose remaining stable 4 weeks prior to randomisation. Mean dose last month of double‐blind phase: 103 ± 37 mg/day. Matching placebo BID; topiramate meanwhile tapered out by 100 mg weekly. β‐blockers and amitriptyline were allowed in both groups for indications other than migraine

Outcomes

Number of days with migraine headache per 28 days. Duration and severity of migraines. Number of days with acute medication. Patient satisfaction over double‐blind phase. Proportion of responders (50% reduction in frequency) not investigated. MIDAS. HIT‐6. SF‐12

Time point(s) considered in the review: last 4 weeks of the double‐blind phase, ie, weeks 17 to 26

Notes

CDH was not an exclusion criterion, but the migraine frequencies (migraine days per 28 days) during the last month of the open‐label phase (group continuing with topiramate: 4.9 ± 3.7 (data provided by Janssen‐Cilag); group that switched to placebo: 4.6 ± 4.0) confirm that the absolute majority had episodic migraine

Funders of the trial: Janssen‐Cilag, EMEA

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Computer randomisation, medication randomised in blocks of 4; blocks provided per study centre

Allocation concealment (selection bias)

Low risk

Subjects sequentially allocated to next available medication number within block at randomisation (= entry into double‐blind phase)

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Both clinicians and patients blinded. Medication provided by number. Use of identical appearing tablets

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

No information

Incomplete outcome data (attrition bias)
All outcomes

Low risk

No concern among the review authors over incomplete outcome data

Selective reporting (reporting bias)

Low risk

Mean monthly migraine frequency during the last month of the double‐blind phase only given in publication for the group that switched to placebo but provided by drug company for the group that continued with topiramate. Variance measures for change in MIDAS scores only roughly indicated in a graph (Fig. 4)

Methods

Prospective, randomised, double‐blind, parallel‐group trial. 14 to 28‐day washout period then 28‐day baseline period. Duration of treatment: 4 weeks titration then 22 weeks maintenance followed by up to 2 weeks taper/exit phase

Discontinuation rate: topiramate 43%, amitriptyline 44%

Compliance (adherence) data: not available

Rule for use of acute medication: use of acute headache medications including over‐the‐counter analgesics, NSAIDs, triptans, ergot derivatives, and dihydroergotamine mesylate, was permitted for symptomatic relief of headaches throughout the study, but was not to exceed 4 days per week

Methodological quality score: 5

Participants

Inclusion: migraine with or without aura according to ICHD‐II, migraine onset at least 6 months prior to study, migraine frequency of 3 to 12 attacks/month during 3 months prior to screening and during baseline period. Ages 18 and above

Exclusion: CDH during baseline, analgesic overuse (> 15 treatment days per month with abortive medication). Acceptable exclusion of secondary headaches. Other exclusions: failed > 2 adequate trials of migraine preventive medication, prior lack of efficacy for topiramate and/or amitriptyline, migraine onset after the age of 50 years, aura without headache only, history of cluster headache, progressive neurological disorder, condition more painful than migraine, contraindication for amitriptyline, unstable medical condition within the past 2 years, major psychiatric disorder within the past 6 months, drugs/alcohol abuse within the past 2 years, nephrolithiasis, active liver disease, liver function tests ≥ 2 times the upper limit of normal, pregnancy, lactation, inadequate contraception

Setting: 32 centres

Country: USA

Intention‐to‐treat analysis of 331 patients. Patients both with and without aura recruited, but percentages not reported. 281 females and 50 males; mean age 38.8 ± 11.0, age range 18 to 70. 178 received topiramate and 169 received amitriptyline

Interventions

Topiramate 100 mg/day versus amitriptyline 100 mg/day (26 weeks). Dosages started at 25 mg/day and increased by 25 mg each week to reach 50 mg BID (topiramate) and 100 mg at night with morning placebos (amitriptyline) or the maximum tolerated dose. A stable dose of at least 50 mg/day was required

Outcomes

Mean 28‐day rate of migraine episodes defined as the period from the onset to the cessation of painful migraine symptoms, not to exceed 24 h. Response rates (≥ 25%, ≥ 50%, ≥ 75%, or 100% reduction) on 28‐day migraine and headache days (migraine and non‐migrainous headache). Mean 28‐day rate of days with headache, abortive medication use, migraine duration, migraine severity, severity of migraine‐associated symptoms, frequency of migraine‐associated vomiting. Severity of functional disability (MIDAS, MSQ, Q‐LES‐Q‐SF). Mean change in weight and BMI

Time point(s) considered in the review: through entire treatment period (26 weeks)

Notes

If painful migraine symptoms lasted > 24 hours, this was considered a new and distinct migraine episode. Such a definition runs the risk of confounding reduction in headache frequency with reduction in attack duration

Funders of the trial: Ortho‐McNeil Janssen

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Computer‐generated 5‐digit subject numbers and 4‐digit medication code numbers. Randomisation in permuted blocks of 4 by site

Allocation concealment (selection bias)

Low risk

Numbers were assigned as subjects qualified for participation; assigned medication code was retained for duration of study

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Double‐blind, double‐dummy. Capsules of identical appearance. Topiramate: 2 active capsules BID + 2 placebo capsules evening. Amitriptyline: 2 placebo capsules morning + 4 active capsules evening. Treatment assigned by medication code

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

No information

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Unclear how many participants in the topiramate group contributed to the endpoint ≥ 50% reduction in headache frequency. Complementary data requested twice but not provided by corresponding author

Selective reporting (reporting bias)

Unclear risk

Within‐group variance measures lacking for changes in least squares mean of migraine frequencies and MSQ scores. Complementary data requested twice but not provided by corresponding author

Methods

Prospective, randomised, double‐blind, parallel‐group trial. 4‐week baseline period. Duration of treatment: 6 weeks titration then 8 weeks stable dosage

Discontinuation rate: dropouts: 6 of 15 in topiramate group; 4 of 15 in placebo group

Compliance (adherence) data: compliance data reported as number of patients reaching target dose (11 of 15)

Rule for use of acute medication: acute medication permitted; allowed types not specified

Methodological quality score: 3

Participants

Inclusion: IHS migraine criteria, migraine onset before age 50, migraine for more than 1 year, migraine frequency 2 to 8 per month, negative pregnancy test

Exclusion: daily headaches and analgesic abuse headaches were adequately excluded. Other exclusions: pregnancy or lactation; substance‐related disorder in 3 months prior to study; Axis I disorders; other relevant medical conditions; history of renal calculi; participant in any other clinical trial within 30 days of study onset

Setting: not reported (appears to be single‐centre)

Country: USA

30 patients recruited and analysed; various analyses undertaken. Patients with and without aura recruited but percentages not reported. 29 females and 1 male; age range 30 to 62. 15 received topiramate and 15 received placebo

Interventions

Topiramate 200 mg/day versus placebo (14 weeks). Dosage started at 25 mg/day and increased by 25 mg each week to reach target dose

Outcomes

Number of migraine attacks per 28 days in entire double‐blind period. Number of migraine attacks per 28 days in last 10 weeks of study. Proportion of responders (50% reduction in frequency). Severity and disability scores

Time point(s) considered in the review: through entire double‐blind period

Notes

Funders of the trial: Ortho‐McNeil Pharmaceutical

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

No information

Allocation concealment (selection bias)

Unclear risk

No information

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Participants and clinician were blinded, and placebo was used. No more information

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

No information

Incomplete outcome data (attrition bias)
All outcomes

High risk

Data available only from abstract and poster presentation

Selective reporting (reporting bias)

High risk

Data available only from abstract and poster presentation

Methods

Prospective, randomised, double‐blind, triple cross‐over trial. Study duration 23 weeks (although stated 20 weeks); 4 weeks prospective baseline followed by 4 weeks with first intervention, 1‐week washout, cross‐over to 4 weeks with second intervention, 1‐week washout, cross‐over to 4 weeks with third intervention, 1‐week washout, and finally cross‐over to 4 weeks with fourth intervention. Each subject received all treatments in a specified order

Discontinuation rate: topiramate 7%, lamotrigine 7%, topiramate placebo 7%, lamotrigine placebo 7%

Compliance (adherence) data: not available

Rule for use of acute medication: patients were allowed to take tablets with a combination of paracetamol and diclofenac potassium (supplied to them) at their choice

Methodological quality score: 2

Participants

Inclusion: migraine with or without aura according to ICHD‐I; migraine frequency of 4 to 10 attacks/month, history of migraine at least 1 year, debut of migraine before age 50, at least 48 h pain free interval between attacks. Ages 18 to 65

Exclusion: headaches other than migraines. > 8 days/month of NSAIDs, ergots, or triptans. Paracetamol overuse and CDH not mentioned as exclusion criteria. Other exclusions: migraine prophylactic drug (or drug with such potential) last month, antipsychotic/antidepressant drug last 3 months, alcohol, or other drug dependence, nephrolithiasis, participated in earlier study of lamotrigine or topiramate, used lamotrigine or topiramate 2 weeks or longer, used experimental drug last month

Setting: single‐centre

Country: India

Intention‐to‐treat analysis of 57 patients. 32% (19/60) of included patients had migraine with aura. 47 females and 13 males; mean age 29.4 ± 7.7 years (range 16 to 48). 57 received topiramate, 57 received lamotrigine, 57 received topiramate placebo, and 57 received lamotrigine placebo

Interventions

Topiramate 50 mg/day versus topiramate placebo versus lamotrigine 50 mg/day versus lamotrigine placebo (4 weeks). Topiramate and lamotrigine were given as 25 mg tablet BID (stable dosage), and placebos as 1 tablet BID (stable dosage)

Outcomes

Change in migraine frequency per 28 days compared to baseline. Proportion of responders (50% reduction in frequency). Responder rate migraine intensity. Attack frequency. Attack duration. Intensity on VAS. Phonophobia. Photophobia. Rescue medication use. Response to rescue medication. Aura frequency. "Reports of AEs communicated historically during visits, as transcribed on headache diaries"

Time point(s) considered in the review: through entire treatment period (4 weeks)

Notes

Lamotrigine (and lamotrigine placebo) data excluded as comparator from this review, since the intervention is experimental. Unclear if any participants had CDH. Shorter treatment periods (1 month) than recommended (3 months) by IHS for evaluation of efficacy in clinical trials. Since 2 potentially active drugs were used, there is an obvious risk of carry‐over effect (analysis for order effects lacking)

Funders of the trial: not reported

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Computer‐generated schedule allocating participants to 1 of 4 treatment arms: LTG – LPLAC‐TOP‐TPLAC or LPLAC‐LTG‐TPLAC‐TOP or TOP‐TPLAC‐LTG‐LPLAC or TPLAC‐TOP‐LPLAC‐LTG

Allocation concealment (selection bias)

Low risk

Preprinted medication code labels. Sealed envelopes containing the code labels with a tear‐off label concealing the randomisation number were provided to the investigator

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Patients and clinicians were blinded. Placebo was identical in appearance and packaging to active drug, but since the lamotrigine and topiramate tablets were different in appearance, 2 different placebos were used. For effective blinding a double‐dummy design would be required. Study medication was packaged and labelled according to a medication code schedule generated before the trial. Each package had all 4 medications numbered according to the phase of the trial. Each bottle had a 2‐part, tear‐off label; study medication identification was concealed and could be revealed only in case of emergency

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

Investigators were blinded but not clearly stated that this included the stage of analysis

Incomplete outcome data (attrition bias)
All outcomes

Low risk

No concern among the review authors over incomplete outcome data

Selective reporting (reporting bias)

Low risk

No suspicion of selective reporting of outcomes, time points, subgroups, or analyses

Methods

Prospective, randomised, double‐blind, parallel‐group trial. Total study duration up to 266 days; consisting of a pretreatment phase of up to 70 days (screening/washout period, followed by a 28 to 35‐day baseline period), a 26‐week double‐blind phase (6‐week titration followed by 20‐week maintenance), and 1‐week taper/exit phase

Discontinuation rate: topiramate 37%, placebo 44%

Compliance (adherence) data: not available

Rule for use of acute medication: subjects were permitted to take acute headache medication as indicated. The type and method of acute headache medication use was as consistent as possible with that used by the subject prior to enrolment

Methodological quality score: 5

Participants

Inclusion: migraine with or without aura according to ICHD‐II; migraine frequency of 9 to 14 days/month; history of migraine at least 1 year; onset of migraine before age 50. Ages 18 to 65. Other inclusion criteria: good health, capable of taking oral medication, no risk of pregnancy

Exclusion: < 15 total headache days/month; had used a combination of acute headache medications for any reason for > 4 days/week on a regular basis during the 3 months before baseline period. Secondary headaches were adequately excluded. Other exclusions: previously failed > 2 adequate trials of migraine prophylactic drugs; use of migraine prophylactic drugs in the 6 weeks before baseline period; previously discontinued topiramate therapy due to lack of efficacy or AE; exclusively migraine aura without headache; other equally painful condition; cluster headache; basilar or hemiplegic migraine; progressive neurological disorder other than migraine; malignancy; significant medical history or medical condition of neurological, cardiovascular, hepatic, or renal disease; nephrolithiasis; unstable medical condition that may have impaired participation in the study or necessitate the use of drugs not permitted; abnormal renal, liver, or blood tests (specified); suicidality and/or psychiatric disease; drug or alcohol abuse within the past 2 years and positive urine drug screen

Setting: 87 centres

Country: not reported (all authors from USA)

Intention‐to‐treat analysis of 330 "efficacy‐evaluable" (EE) patients. Patients both with and without aura recruited, but percentages not reported. 294 females and 36 males; mean age topiramate group 39.6 ± 10.6; mean age placebo group 40.9 ± 11.2; age range not reported. 188 received topiramate and 197 received placebo

Interventions

Topiramate 100 mg/day versus placebo (26 weeks). Topiramate initiated with a single 25 mg tablet in the evening day 1 to 7, then increased each week by a single 25 mg tablet/day until a total dosage of 100 mg/day (two 25 mg tablets BID). The titration was adjusted at the discretion of the investigator on the basis of subject tolerability. Subjects must have maintained a dose of at least 3 tablets/day beginning at day 42 and throughout the study period. The mean dose used during maintenance period was 89.5 ± 14.2 mg/day. Placebo initiated with a single tablet in the evening day 1 to 7, then increased each week by a single tablet per day until a total dosage of 2 tablets BID. The titration was adjusted at the discretion of the investigator on the basis of subject tolerability. Subjects must have maintained a dose of at least 3 tablets/day beginning at day 42 and throughout the study period

Outcomes

Headache frequency per 28 days. Proportion of responders (≥ 50% and ≥ 75% reduction in headache days and migraine days). ≥ 15 headache days per 28‐day period (CDH) at month 6. CDH during the last 28‐day period of the double‐blind phase for those subjects that had completed at least 28 days of the double‐blind phase. Time to first reporting of CDH. CDH of which at least half of days with migraine headache. Time to first reporting of CDH of which at least half of days with migraine headache. 28‐day rate of headache days. 28‐day rate of acute medication days. Change in the 28‐day frequency of nausea, photophobia, and phonophobia. MSQ. MIDAS

Time point(s) considered in the review: through the 26‐week double‐blind phase

Notes

Funders of the trial: Ortho‐McNeil Janssen Scientific Affairs

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Subjects were assigned to either of the 2 treatment groups based on a computer‐generated predetermined randomisation schedule prepared by the sponsor before the study. Randomisation sequences were generated for each site

Allocation concealment (selection bias)

Low risk

Medication code numbers were preprinted on study medication labels and assigned as subjects qualified for the study and were randomised to treatment. Sealed envelopes containing the study medication identification (ie, active or placebo) were provided to the investigator and kept in a limited access area

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Participants and clinicians were blinded. The double‐blind study medication tablets were identical in appearance and packaged in identically appearing bottles

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

No information

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

Efficacy only reported for the subgroup (EE) of ITT participants who completed at least 28 days of the double‐blind phase

Selective reporting (reporting bias)

High risk

≥ 50% and ≥ 75% reduction in headache days and migraine days were collected but only reported as "higher in the topiramate group compared with the placebo treatment group". For MSQ and MIDAS results, the authors refer to www.clinicaltrials.gov (study identifier: NCT00212810). More than 5 years after study completion, no results from this study have yet been posted there. Corresponding author requested twice about the numbers of subjects with 50% or greater reduction in 28‐day migraine day frequency in both groups without providing data

Methods

Prospective, randomised, open, parallel‐group trial. Total study duration 13 months; 1‐month baseline period and 12‐month treatment period

Discontinuation rate: topiramate 12%, flunarizine 22%

Compliance (adherence) data: not available

Rule for use of acute medication: subjects were permitted to take acute headache medication as indicated. Allowed rescue drugs included aspirin, acetaminophen, oral NSAIDs, ergot derivatives, triptans and opioids

Methodological quality score: 2

Participants

Inclusion: migraine with aura, migraine without aura, and/or chronic migraine according to ICHD‐II; at least 2 attacks/month that produce disability lasting 3 or more days per month despite the use of acute treatment; history of migraine at least 1 year. Ages 18 to 65

Exclusion: other primary headache including TTH (confirmed by corresponding author); overuse of analgesics, triptans, or other specific agents for the acute treatment of migraine, including simple analgesics > 15 days/month and combined analgesics > 10 days/month. Secondary headaches were adequately excluded. Other exclusions: use of migraine prophylactic medications in the month before trial entry or flunarizine in the 3 months before trial entry. Prior poor or no efficacy of > 2 migraine prophylactic medications. History of depressive illness, extrapyramidal disorders, chronic obstructive pulmonary disease, bronchospasm, asthma, heart failure, sinus bradycardia, second‐degree atrioventricular block, hypotension or peripheral vascular disease, serious diseases (diabetes, serious hepatic, renal, cardiovascular, respiratory, or malignant illness). Pregnancy, lactation, or childbearing potential without adequate contraception. History of allergy to flunarizine or topiramate

Setting: single‐centre

Country: China

Total number of randomised participants: 150, of which 50 assigned to topiramate (44 contributed to results), 50 to flunarizine (39 contributed to results), and 50 to topiramate + flunarizine. No information on proportion with migraine with aura. Among topiramate completers 30 were females and 14 males; among flunarizine completers 29 were females and 10 males; mean age topiramate completers 42.2 ± 12.4 (range 21 to 65); mean age flunarizine completers 43.2 ± 13.9 (range 20 to 64)

Interventions

Topiramate 100 mg/day versus flunarizine 5 mg/day versus a combination of both (12 months). Topiramate (presumably tablets) were initiated at 25 mg/day and thereafter increased weekly by 25 mg until reaching target a dose of 100 mg/day. If there was any significant AE, patients were instructed to decrease to the previously tolerated dose. Mean topiramate dose was 62.5 ± 24.4 mg/day. Flunarizine (presumably capsules) was given in a 5 mg/day dose

Outcomes

The primary efficacy parameter was the reduction in mean monthly migraine frequency of at least 50% as compared with baseline. Secondary efficacy parameters were mean monthly frequency of attacks, accumulated monthly migraine duration, and severity of head pain. Weight. Other AEs

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

Notes

According to the publication, only patients who had chronic migraine were to be included, but the corresponding author reports that only a small minority (7/126 completers; 6%) had chronic migraine according to ICHD‐II

Funders of the trial: National Natural Science Foundation, Science and Technology Item of Guandong Province of China, and Natural Science Foundation of Guandong Province of China

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

No information on method for random sequence generation except for resulting 1:1:1 ratio

Allocation concealment (selection bias)

Unclear risk

No information

Blinding of participants and personnel (performance bias)
All outcomes

High risk

Open‐label trial

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

No information

Incomplete outcome data (attrition bias)
All outcomes

High risk

Subjects who discontinued prematurely (6 in topiramate group whereof 5 due to AEs and 1 lost to follow‐up; 9 in flunarizine group whereof 8 due to lack of efficacy and 3 lost to follow‐up) were excluded from efficacy analyses

Selective reporting (reporting bias)

Unclear risk

In Tables 1 and 2, migraine frequency data are mislabelled. Corresponding author confirmed it should be attacks (not days) per month in Table 1 and absolute means (not change) in Table 2. AEs (not included in this review) are inadequately reported

Methods

Prospective, randomised, double‐blind, parallel‐group trial. One month baseline period. Duration of treatment: 4 weeks titration, then 12 weeks stable dosage

Discontinuation rate: dropout 35% for active treatment group, 40% for placebo

Compliance (adherence) data: no description of how compliance was assessed

Rule for use of acute medication: NSAID and triptan use monitored; unclear as to whether other drugs were permitted Methodological quality score: 4

Participants

Inclusion: IHS migraine criteria, migraine frequency of 2 to 6 per month

Exclusion: renal pathology, women taking oral contraceptives, women with the possibility of becoming pregnant during the study period, commencement of any migraine prophylactic medication in the 2 months prior to the trial

Setting: single‐centre

Country: Italy

Complete case analysis of 72 patients. Percentages of patients with aura: 23% in active treatment group, 16% in placebo. 39 females and 33 males; age range 20 to 60. 35 received 100 mg/day topiramate, 37 received placebo

Interventions

Topiramate 100 mg/day versus placebo (16 weeks). Dosage started at 25 mg/day then increased by 25 mg each week until 100 mg dose reached

Outcomes

Headache frequency per 28 days. Proportion of responders (50% reduction in frequency). Severity and duration of attacks, consumption of rescue medications, days of disability

Time point(s) considered in the review: last 4 weeks of the double‐blind phase

Notes

Funders of the trial: not reported

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Randomisation (ratio 1:1) in balanced blocks of 2 using a computer‐generated random number scheme

Allocation concealment (selection bias)

Unclear risk

No information

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Study was double‐blinded, and placebo was used. No more information provided

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

No information

Incomplete outcome data (attrition bias)
All outcomes

High risk

Analysis of responder rate appears to consider complete cases only, and safety data are only presented for a vaguely defined subgroup of participants

Selective reporting (reporting bias)

Unclear risk

Standard deviations lacking for migraine frequency during treatment phase

Methods

Prospective, randomised, double‐blind, double‐cross‐over trial. 1‐month baseline period. Duration of treatment: 1 week titration, followed by 7 weeks stable dose of first drug. 2 months washout, then 1‐week titration, followed by 7 weeks 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

Participants

Inclusion: IHS migraine criteria, 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

Interventions

Topiramate 50 mg/day versus sodium valproate 400 mg/day (8 weeks); 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

Outcomes

Headache frequency per month; migraine intensity; migraine duration

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

Notes

Study 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

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

No information

Allocation concealment (selection bias)

Unclear risk

No information

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Patients and clinicians were blinded, but method description is lacking

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

No information

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

No dropouts are acknowledged

Selective reporting (reporting bias)

High risk

Only 2 types of AEs are reported for topiramate

Methods

Prospective, randomised, double‐blind, parallel‐group trial. 28‐day baseline period. Duration of treatment: 8 weeks titration, then 18 weeks stable dosage

Discontinuation rate: dropout reported as 47% for combined active treatment groups; 41% for placebo. It is unclear how many patients contributed to efficacy data but in fact discontinued the study early

Compliance (adherence) data: compliance data reported only as percentage of patients achieving target dose

Rule for use of acute medication: analgesics, ergot derivatives, triptans, and opioids allowed

Methodological quality score: 5

Participants

Inclusion: IHS migraine criteria; migraine frequency of 3 to 12 in 28‐day baseline phase; women practicing adequate contraception or unable to bear children

Exclusion: secondary headaches, daily headache, and analgesic overuse headache were all adequately excluded. Other exclusions: failure to respond to more than 2 previous migraine‐prophylactic regimens, migraine onset after age 50, continued use of various CNS‐active and other drugs, history of nephrolithiasis, previous exposure to topiramate, use of experimental drug or device within 30 days of screening

Setting: multicentre

Country: USA

Intention‐to‐treat analysis of 469 patients. Patients both with and without aura recruited, but percentages not reported. 416 females and 53 males; age range 12 to 65. 117 received 50 mg/day dose, 125 received 100 mg/day dose, 112 received 200 mg/day dose, and 115 received placebo

Interventions

Topiramate 50 mg/day versus topiramate 100 mg/day versus topiramate 200 mg/day versus placebo (18 weeks). Dosage started at 25 mg/day and increased by 25 mg each week to reach assigned dose or maximum tolerated dose

Outcomes

Headache frequency per 28 days. Proportion of responders (50% reduction in frequency). Number of days requiring rescue medication. Time to onset of drug action. Quality of life (average maintenance AUC of MSQ and SF‐36 scores). AEs

Time point(s) considered in the review: through entire double‐blind phase (migraine frequency, response rate, AEs); week 8 to 26 of double‐blind phase (MSQ, SF‐36)

Notes

Lowest allowable age was 12 years; hence some patients not adult. Headache frequency defined as the number of migraine periods per 28 days, where a migraine period is any occurrence of migraine headache that started, ended, or recurred with 24 hours. A migraine attack persisting into a second 24‐hour period 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

Funders of the trial: Johnson & Johnson Pharmaceutical Research and Development, LLC

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

Randomisation in permutation blocks of 4 stratified by centre

Allocation concealment (selection bias)

Low risk

Sealed envelopes containing study drug information were provided to investigators in case such information was required on unblinding a patient

Blinding of participants and personnel (performance bias)
All outcomes

Low risk

Patients and clinicians were blinded to study medication with preprinted medication code labels. Placebo was identical in appearance and packaging to active drug

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

No information

Incomplete outcome data (attrition bias)
All outcomes

Low risk

Intention‐to‐treat analysis excluded 18 patients who did not provide any post‐baseline data, out of 487 randomised

Selective reporting (reporting bias)

Low risk

No suspicion of selective reporting of outcomes, time points, subgroups, or analyses

Methods

Prospective, randomised, double‐blind, parallel‐group trial. Study duration up to 7 months; up to 1 month screening/washout, 1 month prospective baseline, and 5 months double‐blind phase (2 months titration and 3 months maintenance)

Discontinuation rate: topiramate 36%, placebo 18%

Compliance (adherence) data: not available

Rule for use of acute medication: use of acute medications was allowed for the symptomatic relief of breakthrough migraine pain

Methodological quality score: 3

Participants

Inclusion: migraine with or without aura according to ICHD‐I; average migraine frequency of 3 to 8 migraine episodes/month for 3 months before screening; history of migraine at least 1 year; migraine onset before age 50. Ages 18 to 65

Exclusion: > 15 headache days/month during the 3 months before screening, during screening, or during the prospective baseline period; overused acute migraine treatment (eg, triptan use on > 8 days/month); transformed migraine. Secondary headaches acceptably excluded. Other exclusions: previously failed to respond to topiramate therapy; preventive medication within 2 weeks of the start of baseline period; cluster headache; basilar, ophthalmoplegic, or hemiplegic migraine; migraine aura exclusively (without headache); previously failure to respond to > 2 adequately dosed migraine preventive medications; receipt of injected corticosteroids, local anaesthetics, or botulinum toxin within 60 days before screening; risk of pregnancy; lactation; serum alanine and/or aspartate aminotransferase levels > 2 times the upper limit of the normal range; active liver disease

Setting: 27 centres

Country: USA

Intention‐to‐treat analysis of 211 patients. 75 subjects (36%) in ITT group had migraine with aura. 181 females and 30 males; mean age 40.5 ± 11.1; age range 18 to 64. 140 received topiramate 73 received placebo

Interventions

Topiramate 200 mg/day versus placebo (20 weeks). Topiramate (presumably tablet) 25 mg/day for the first week, followed by weekly increases of 25 mg to a maximum of 100 mg BID or the maximum tolerated dose at week 8. Mean dosage during maintenance period: 161 ± 53 mg/day. Placebo (tablet?) 1/day for the first week, followed by weekly increases of 1 to a maximum of 4 BID or the maximum tolerated dose at week 8

Outcomes

Headache frequency per 28 days. Proportion of responders (those with ≥ 50%, ≥ 75%, or 100% reduction in monthly migraine frequency). Safety assessments included measurement of vital signs, physical examinations, clinical laboratory test, and evaluation of AEs

Time point(s) considered in the review: through the 20‐week double‐blind phase

Notes

Funders of the trial: Ortho‐McNeil Neurologics Inc., Titusville, New Jersey

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

No information in publication except for 2:1 ratio

Allocation concealment (selection bias)

Unclear risk

No information

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Patients and clinicians were blinded. No description of method except for the use of placebo

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

No information

Incomplete outcome data (attrition bias)
All outcomes

Low risk

No concern among the review authors over incomplete outcome data

Selective reporting (reporting bias)

High risk

Data on mean migraine frequencies during the double‐blind period lacking (only changes in least squares means without variance measures given in publication). Supplementary information requested twice from corresponding author, but no reply

Methods

Prospective, randomised, double‐blind, parallel trial. Total duration: 20 weeks. 4‐week baseline period, 8 weeks titration, 8‐week maintenance period

Discontinuation rate: dropout 16% for active treatment; 10% for placebo

Compliance (adherence) data: no compliance data reported

Rule for use of acute medication: abortive medications permitted (no further specification)

Methodological quality score: 3

Participants

Inclusion: IHS migraine criteria; migraine onset at least 1 year prior to trial; 2 or more attacks per month for previous 12 months; adequate contraception for women; negative pregnancy test 72 hours prior to trial

Exclusion: secondary headaches, daily headaches, and analgesic overuse headaches were adequately excluded. Other exclusions: substance‐related disorders, psychiatric disorder, carbonic anhydrase inhibitors, other experimental interventions, history of renal calculi, diagnosis of multiple sclerosis, other contraindications

Setting: single neurology clinic

Country: USA

40 migraine patients participated; numbers with and without aura not reported. 39 females and 1 male; allowed age range 18 to 65 years

Interventions

Topiramate versus placebo (16 weeks). Dosage titrated and maintained at 200 mg/day or maximum tolerated dose. Mean actual dose 125 mg/day

Outcomes

Number of migraine attacks per 28 days. Migraine severity (3‐point scale). Change in body weight

Time point(s) considered in the review: through entire double‐blind phase

Notes

Unusual feature of trial: concomitant migraine prophylactics were allowed if patients had been on stable dose for 3 months prior to start of trial, and no changes in dose took place during trial

Funders of the trial: Ortho‐McNeil Pharmaceutical, Raritan, New Jersey

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Unclear risk

No information except 1:1 ratio

Allocation concealment (selection bias)

Unclear risk

No information

Blinding of participants and personnel (performance bias)
All outcomes

Unclear risk

Patients and clinicians were blinded. No description of method except for the use of placebo

Blinding of outcome assessment (detection bias)
All outcomes

Unclear risk

No information

Incomplete outcome data (attrition bias)
All outcomes

Low risk

No concern among the review authors over incomplete outcome data

Selective reporting (reporting bias)

Low risk

No suspicion of selective reporting of outcomes, time points, subgroups, or analyses

Methods

Prospective, randomised, open, parallel‐group trial. Total study duration 10 to 12 months: 1 to 3 months baseline, 3 months treatment period, and 6 months additional follow‐up

Discontinuation rate: topiramate 32%, relaxation 13%

Compliance (adherence data on file provided by corresponding author): 77% in topiramate group (defined as using the drug > 2 months in accordance with the prescription and measured using self reports), 87% in relaxation group (defined as participating in 6 or more sessions at the clinic plus verbal confirmation of practice at home)

Rule for use of acute medication: medication overuse headache was an exclusion criterion. No restrictions were thereafter placed on the use of concomitant acute medication. Acute medication use (doses/month) was documented during the whole treatment period

Methodological quality score: 3

Participants

Inclusion: migraine with or without aura according to ICHD‐II; 2 to 8 migraine attacks/month; history of migraine at least 1 year; onset of migraine before 50 years of age. Ages 18 to 65

Exclusion: medication overuse headache according to ICHD‐II. Other secondary headaches adequately excluded. CDH not an exclusion criterion (1 patient had chronic migraine). Other exclusions: interval headaches not distinguishable from migraine; regular exercise (once or more per week during the 12 weeks prior to the study); earlier regular practice of relaxation; pregnancy; breastfeeding; use of daily migraine prophylaxis in the 12 weeks prior to the study; inability to understand Swedish; use of antipsychotic or antidepressive medication in the 12 weeks prior to the study; drug or alcohol abuse; topiramate intolerance

Setting: single‐centre

Country: Sweden

Intention‐to‐treat analysis of 91 patients; 7 had migraine with aura only, 44 had migraine without aura only, and 40 had both migraine with and without aura. 82 females and 9 males; mean age 44.3 ± 10.6; allowed age range 18 to 65 years. 31 received topiramate, 30 received relaxation and 30 received exercise

Interventions

Topiramate 200 mg/day versus relaxation versus exercise (36 weeks). Topiramate tablets started by 25 mg at night and thereafter increased weekly by 25 mg in dialogue with a neurologist until reaching the highest tolerable dose with a maximum of 100 mg BID. Participants in relaxation arm had to attend a scheduled individual appointment for relaxation with a registered physiotherapist once a week. The relaxation programme (Larsson 2002) is based on relaxation, breathing, and stress‐management techniques and includes a series of 6 exercises, each of which is based on the one before. Each relaxation exercise lasted for between 5 and 20 minutes, and verbal and written information was given before the introduction of a new relaxation exercise. After each session there was an opportunity for the participant to discuss their progress with the physiotherapist. If they were absent, they were contacted and informed about how to continue on their own. Between the scheduled sessions, the participants practised at home every day with a compact disc

Outcomes

Migraine attack frequency per 28 days. Proportion of responders (≥ 50% and 25% to 49% reduction in migraine attack frequency). Migraine days per 28 days. Mean pain intensity (VAS 0 to 100). Acute medication use (doses per 28 days). Quality of life (MSQoL, 0 to 100 points). Level of physical activity (MET‐minutes/week). Sedentary hours/day. Oxygen uptake. AEs

Time point(s) considered in the review: third month of treatment

Notes

Exercise arm of trial excluded as comparator from this review, since the intervention is experimental

Funders of the trial: The Swedish Research Council; The Gothenburg Research and Development Council; Praktikertjänst Inc, Stockholm, Sweden; The Minnesfonden at the Swedish Association of Registered Physiotherapists; The Renée Eander Fund; The Neurological Research Foundation; The Olle Engkvist Byggmästare Foundation; GlaxoSmithKline; AstraZeneca

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

The randomisation procedure was conducted by an independent person (separate from clinician and patient) according to a lottery procedure. Six pieces of paper, 2 for each group (n = 3), were folded twice and put into an opaque envelope. One piece of paper was taken each time a patient entered the study. After 6 participants had been included, the procedure started again

Allocation concealment (selection bias)

High risk

High number of withdrawals in topiramate arm ("refusal to start") suggests treatment selection bias by the subjects (predetermined treatment preference). Given the open nature of the study this may have influenced outcome reporting

Blinding of participants and personnel (performance bias)
All outcomes

High risk

As this study compared pharmacological and non‐pharmacological treatments, blindness to treatment was not possible to achieve

Blinding of outcome assessment (detection bias)
All outcomes

Low risk

The completed assessment forms were encoded and returned to the study secretary in sealed envelopes. The evaluator was effectively blinded

Incomplete outcome data (attrition bias)
All outcomes

Low risk

No concern among the review authors over incomplete outcome data

Selective reporting (reporting bias)

Low risk

No suspicion of selective reporting of outcomes, time points, subgroups, or analyses