Flunarizine versus topiramate for chronic migraine prophylaxis: a randomized trial

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Migraine is a leading cause of disability worldwide, with a prevalence of 10%–15%.1 In a subset of patients with migraine, headache frequency increases gradually to daily or near daily occurrence.2 According to the second edition of the International Classification of Headache Disorders (ICHD‐II)4 and the revised ICHD‐II criteria (ICHD‐IIR),5 chronic migraine (CM) is defined as headache occurring on ≥15 days/mo for at least 3 months, with ≥8 headaches/mo fulfilling the criteria of migraine without aura or responding to migraine‐specific treatment (i.e., triptans or ergots). Epidemiological studies have shown that approximately 2% of the general population suffers from CM,6 with a 3% annual conversion rate from episodic migraine (EM) to CM.2 In a subgroup (30%–75%) of patients with CM, the clinical course may further be complicated by medication overuse headache (MOH), that is, frequent or regular use of acute abortive medications.8
Patients with CM face significant physical, psychological, and social distress and have reduced health‐related quality of life. Moreover, they represent a considerable healthcare expense for society.3 Not until recently, however, have randomized placebo‐controlled trials showed effective CM prophylaxis with topiramate,11 botulinum toxin injection,16 or acupuncture.17 The high cost, invasiveness, and inconvenience of botulinum toxin injection and acupuncture prevent their wide use. In addition, despite the efficacy of topiramate for CM prophylaxis, it is associated with a high rate (66%–82.5%) of adverse events at the recommended dose (100 mg/d).13 An unmet yet important need for CM prophylaxis thus persists. In CM patients with concomitant MOH, the situation is further complicated as previous studies suggested that they are more resistant to treatment.18 However, recent studies demonstrated that successful prophylaxis may take place in CM patients with or without MOH,13 leaving this issue under debate.
Pharmacological agents with multiple therapeutic actions may have greater potential for the treatment of CM, the pathophysiology of which may involve several mechanisms.19 Flunarizine may be a viable alternative. Flunarizine,20 like topiramate,22 exerts its pharmacological effects through different mechanisms, for example, dopamine receptor blockade and serotonin modulation, which are aligned with current understanding of migraine pathophysiology.
In several randomized, double‐blinded, placebo‐controlled trials involving adult24 and pediatric26 patients with EM, flunarizine treatment resulted in significant headache reduction, with efficacy observed within the first month of treatment. The results of these trials suggest that 5–10 mg/d flunarizine is an effective, safe, and generally well‐tolerated preventive treatment for EM. Thus, flunarizine has been approved and listed in several countries' guidelines for EM prevention, including those of the EU,28 Canada,29 and Taiwan.30 However, its efficacy in CM prophylaxis has yet to be evaluated.
To assess the possible therapeutic effect of flunarizine in CM prophylaxis in comparison with that of topiramate, and also the responses in subgroups of patients with CM with and without MOH, we designed the present active competitor, prospective, randomized, open‐label, blinded‐endpoint (PROBE) trial.31 Ten mg/d flunarizine was compared with 50 mg/d topiramate as topiramate has demonstrated its efficacy at dosage 25–75 mg/d with fewer adverse effects, especially in Asian populations.

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