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Topiramate for migraine prevention

Clinical bottom line

Topiramate at doses up to 100 mg daily significantly reduces the frequency of chronic migraine. The proportion of patients with at least 50% reduction in headache frequency is 46%, and 26% have at least 75% reduction in frequency. Compared with placebo, NNTs are 4.1 for a 50% reduction, and 6.2 for a 75% reduction.


Background

Topiramate is an anticonvulsant, and this class of compounds has previously been shown to reduce the frequency of chronic migraine headaches, though the randomised trial evidence base is limited.

Systematic review

Randomised trials comparing topiramate with placebo or active comparator were sought in PubMed, to the end of 2005. Any trial was accepted that was randomised and double blind, used any dose regimen of topiramate, in patients with chronic migraine headache (at least two episodes a month), used standard diagnostic classification, and was at least of four weeks duration. The main outcomes sought were the number or proportion of patients with migraine frequency reduced by at least 50%, and adverse events.

Results

Two randomised trials, and one pooled analysis of other three randomised trials, were found (details in Table 1). Two of the trials in the pooled analysis were also published individually, but these were not included.

Table 1: Details of randomised trials with topiramate for migraine prevention

Reference Study design Patients Efficacy Adverse events
Bussone et al. Int J Clin Pract 2005 59: 961-968 Pooled analysis of 3 randomised, double blind, trials comparing topiramate with placebo
After 14 days without drugs, 28 days baseline phase, followed by 8 weeks titration and 18 weeks of maintenance
Topiramate 50-200 mg/day (n=386)
Placebo(n=372)
Migraine with or without aura , 12-65 years, established history of migraine using HIS criteria for 6-12 months. No more than 15 headache days per 28 days
Mean migraine days 6.4
Topiramate significantly reduce migraine days and duration by about 45%
At least 50% reduction 177/382 with topiramate, 85/372 with placebo
At least 75% reduction 96/382, 37/372
Days with migraine medication decreased to 13 from 20 days per month
Adverse event withdrawal was higher with topiramate (24%) than placebo (11%). Lack of efficacy withdrawal higher for placebo (15%) than topiramate (5%)
Main adverse events were parasthesia, fatigue, anorexia, and mood problems. Mean weight loss 2.5 kg on topiramte, no change with placebo
Silvestrini et al. Cephalalgia 2003 23: 820-824 Randomised, double blind trials of topiramate and placebo, consisting of 8 week baseline pahase, 1 week titration phase, and 8 week maintenance phase
Topiramate 50 mg (n=14)
Placebo (n=14)
Patients with chronic migraine with medication overuse, with at least 10 year history of chronic migraine, and who had failed to respond to at least four preventative medications at adequate dose and for adequate duration
Mean headache days 20/28 days, analgesic intake 26/28 days
Topiramate significantly reduced headache froquency from 21/28 days at baseline to 8/28 days at end, with no change with placebo
At least 50% reduction 10/14 topiramate, 1/14 placebo
At least 75% reduction 6/14, 0/14
At least 90% reduction 4/14, 0/14
Adverse event withdrawal with topiramate 1/14, 0/14 with placebo.
Adverse events 5/14 topiramate, 1/14 placebo
Storey et al. Headache 2001 41: 968-975 Randomised, double blind comparison of topiramate and placebo consisting of 4 week baseline phase, 8 week titration, and 8 weeks maintenance
Topiramate up to 100 mg daily (n=19)
Placebo (n=21)
Patients with established migraine using HIS criteria, for more than one year, at frequency of 2 or more attacks per month. Age 18-65 years Mean monthly migraine frequeny fell significantly more with topiramate than placebo, from 5.1 to 3.3 days on average
At least 50% reduction 5/19 topiramate, 2/21 placebo
Adverse event discontinuations 2/19 topiramate, 0/21 placebo
Total discontinuation 3/19, 2/21
Adverse events included parasthesia, weight loss, and altered taste. Weight loss with topiramate was about 2.5 kg

 

Overall, 192/415 (46%) patients on topiramate had at least 50% reduction in headache frequency, compared with 88/407 (22%) on placebo. The relative benefit was 2.1 (95% CI 1.7 to 2.6) and the number needed to treat for one additional patient to have reduced frequency was 4.1 (3.2 to 5.4).

Overall, 102/396 (26%) patients on topiramate had at least 75% reduction in headache frequency, compared with 37/386 (9.7%) on placebo. The relative benefit was 2.7 (95% CI 1.8 to 3.8) and the number needed to treat for one additional patient to have reduced frequency was 6.2 (4.7 to 9.1).

Adverse events included parasthesia, fatigue, mood swings and anorexia, with about one patient in five discontinuing because of adverse events on topiramate. On average, patients on topiramate lost about 2.5 kg over eight weeks.

Comment

These consistent results from clinical trials are similar to those found in clinical practice [1]. In this study of 115 patients who had not responded to or tolerated beta-blockers, amitriptyline, flunarizine, or valproate, 65 (56%) had at least 50% reduction in frequency, and 34 (30%) at least 75% reduction. Adverse events were also similar, with 21% withdrawing because of adverse events (mostly cognitive difficulties), and with weight loss of 3-13 kg in 16 (14%), 10 of whom were initially overweight.

References:

  1. J Pascuel et al. Topiramate for patients with refractory migraine: an observational, multicentre study in Spain. Neurologia 2003 18: 364-367.