Flunarizine for the prevention of migraine – a new look at an old drug

Randomized, double-blind, placebo-controlled trials remain the cornerstone in evaluating the efficacy of medications in migraine prophylaxis. Among the large number of drugs that may be used in the prevention of migraine, flunarizine, topiramate, and to a lesser degree propranolol have been shown to be effective in childhood trials.1, 2 The International Headache Society’s guidelines on controlled trials rightly suggest that ‘the subjective nature of migraine and a high placebo effect invalidates open and single-blind trials’. It also acknowledges that ‘there is no special guidance available on selection of children or adolescents for trials of migraine prophylactic drugs’.3 Furthermore, the paucity of research into the efficacy of new drugs in childhood migraine, the lack of commercial interest in old orphan drugs, and the high cost of randomized studies make the availability of evidence-based medications for the prevention of migraine in children extremely limited. Therefore, it is not unreasonable to assess drugs, with proven efficacy and safety in adults, in open trials to establish their roles in children and adolescents. The International Headache Society accepted that ‘open studies and clinical observations may be hypothesis-generating for possible prophylactic effects’.3 Flunarizine has been shown to be superior to placebo in several controlled trials in adults and in one controlled trial in children for the prevention of migraine.4 Flunarizine is a calcium channel blocker with selective effects on the cerebrovascular circulation. Most therapeutic trials were in the prophylaxis of migraine, occlusive peripheral vascular disease, and vertigo of central or peripheral origin. Its mechanism of action in the prevention of migraine is not well understood and may involve both vascular (smooth muscle inhibition) and neuronal effects (5-hydroxytryptamin antagonism). Flunarizine is widely prescribed for the prevention of migraine in continental Europe, but it is not licensed in the UK or the USA. In a recent study, flunarizine was the third most commonly prescribed drug for the prevention of migraine in adult patients after propronalol and pizotifen in the Netherlands.5 Similar data on its use in children are not available. Concerns about the associated side effects (despite its effectiveness) were the main limiting factor for its use in the UK. An open study of flunarizine in children and adolescents shows good preventative value in migraine, but more importantly a superior effect in a subgroup of children with hemiplegic migraine.6 It also shows that flunarizine is relatively well tolerated with a reasonable safety profile similar to previous studies in Europe. Depression, mood swings, drowsiness (which may be avoided by taking the dose at night), tiredness, and excessive weight gain were in keeping with side effects reported by other studies. Extrapyramidal symptoms are less common. Other drugs used in the prevention of migraine can also cause side effects: pizotifen is associated with drowsiness and weight gain; propranolol causes depression, mood swings, and hypotension; and topiramate may cause mood swings, weight loss, and drowsiness. The long half-life of flunarizine makes it possible for it to be taken once a day (in the evening) in order to minimize the effect of drowsiness during daytime. Also, a once-a-day dose is likely to be more acceptable to patients and may improve adherence to treatment. A treatment course of 2 to 3 months is necessary before the efficacy of medication can be judged. Once proven effective the course of treatment may continue for 6 to 12 months, but longer if necessary. Regular clinical reviews are necessary while the child is on treatment for early detection of side effects, mainly low mood and depression. No blood tests are needed. Flunarizine can offer children and adolescents a treatment option in the prevention of migraine and it deserves to be evaluated afresh.