European Headache Federation (EHF) critical reappraisal and meta-analysis of oral drugs in migraine prevention - part 3: topiramate

Abstract

Objective: Topiramate is a repurposed first-line treatment for migraine prophylaxis. The aim of this systematic review and meta-analysis is to critically re-appraise the existing evidence supporting the efficacy and tolerability of topiramate.

Methods: A systematic search in MEDLINE, EMBASE, Cochrane CENTRAL, and ClinicalTrials.gov was performed for trials of pharmacological treatment in migraine prophylaxis as of August 13, 2022, following the Preferred Reporting Items for Systematic Reviews (PRISMA). Randomized controlled trials in adult patients that used topiramate for the prophylactic treatment of migraine, with placebo as active comparator, were included. Two reviewers independently screened the retrieved studies and extracted all data. Outcomes of interest were the 50% responder rates, the reduction in monthly migraine days, and adverse events leading to treatment discontinuation. Results were pooled and meta-analyzed, with sensitivity analysis based on the risk of bias of the studies, the monthly migraine days at baseline, and the previous use of other prophylactic treatments. Certainty evidence was judged according to the GRADE framework.

Results: Eight out of 10,826 studies fulfilled the inclusion/exclusion criteria, accounting for 2,610 randomized patients. Six studies included patients with episodic migraine and two with chronic migraine. Topiramate dose ranged from 50 to 200 mg/day, and all studies included a placebo arm. There was a high certainty that topiramate: 1) increased the proportion of patients who achieved a 50% responder rate in monthly migraine days, compared to placebo [relative risk: 1.61 (95% confidence interval (CI): 1.29-2.01); absolute risk difference: 168 more per 1,000 (95% CI: 80 to 278 more)]; 2) was associated with 0.99 (95% CI: 1.41-0.58) fewer migraine days than placebo; 3) and had a higher proportion of patients with adverse events leading to treatment discontinuation [absolute risk difference 80 patients more per 1,000 (95% CI: 20 to 140 more patients)].

Conclusions: There is high-quality evidence of the efficacy of topiramate in the prophylaxis of migraine, albeit its use poses a risk of adverse events that may lead to treatment discontinuation, with a negative effect on patient satisfaction and adherence to care.

Fig. 1

Potential mechanisms of action for the anti-migraine effect of topiramate. Topiramate is proposed to act via inhibition of nociceptive neuronal firing in the trigeminocervical complex in animal models [12]. Firstly, excitatory neurotransmission is reduced via downregulation of postsynaptic AMPA/kainate receptors and Na + channels [–15]. Moreover, topiramate enhances GABA_A receptor activity, thereby promoting inhibitory GABAergic neurotransmission [14, 15]. By inhibition of voltage-gated Ca²⁺ channels, topiramate may prevent the release of vasoactive neuropeptides including CGRP [16]. Collectively, by altering activation and sensitization of neurons, these mechanisms could prevent migraine attacks and cortical spreading depression [8, 17]

Fig. 2

Flow diagram of screened, included, excluded and analyzed studies for the European Headache Federation (EHF) critical re-appraisals and meta-analyses of oral drugs in migraine prevention

Fig. 3

Forest plot showing meta-analysis comparing topiramate with placebo for the reduction of monthly migraine days

Fig. 4

Risk of bias ratings for the randomized controlled trials of topiramate vs. placebo included in this meta-analysis

Fig. 5

Forest plot showing meta-analysis comparing topiramate with placebo for 50% responder rates

Fig. 6

Forest plot showing meta-analysis comparing topiramate with placebo for adverse events leading to discontinuation