Migraine prophylaxis: flunarizine

This evidence summary is based on 4 studies and a Cochrane review. Two of the studies were randomised controlled trials (RCTs): Diener et al. (2002) compared flunarizine with propranolol, and Luo et al. (2012) compared flunarizine, topiramate, and a combination of the two. The other 2 studies were identically designed double blind studies that compared flunarizine with propranolol (Lucking et al. 1988); it is unclear if these 2 studies were randomised. The Cochrane review (Victor et al. 2003) evaluated drug treatment for the prevention of migraine in children and young people. This was last updated in December 2002 and is not planned to be reviewed.

Diener et al. (2002) was an RCT conducted in 8 European countries. It compared the safety and efficacy of flunarizine at 2 different doses with propranolol over a 16-week period. The study included 810 adults aged 18 to 65 years with a history of migraine for at least 1 year. For the intention-to-treat (ITT) population, flunarizine 10 mg daily (with 2 consecutive 'drug-free' days from week 9 onwards) and flunarizine 5 mg daily were reported to be at least as effective as propranolol 160 mg daily for the efficacy outcome of mean migraine frequency per 4 weeks (p<0.001 in one-sided equivalence test; each group reduced the mean migraine frequency from around 3 at baseline to around 2 per 4 weeks). For the percentage of responders per 4 weeks for the ITT population, flunarizine 10 mg daily was reported to be at least as effective as propranolol (p=0.01 in one-sided equivalence test) but flunarizine 5 mg daily was not (p=0.344 in one-sided equivalence test). It is unclear if Diener et al. (2002) was a non-inferiority study or an equivalence study, and results from both the ITT population and the per protocol population would be needed to support this finding. The per protocol analysis was not presented.

Lucking et al. (1988) compared flunarizine 10 mg daily with propranolol 40 mg 3 times a day over a 16-week period in 2 identically designed double-blind studies in Germany in adults with a history of migraine. The first study included 87 people recruited from 12 hospital outpatient departments and the second study included 434 people recruited from 99 medical practices in primary care. In the primary care study, the frequency of migraine attacks was reduced in 54.5% of people in the flunarizine group and 53.1% of people in the propranolol group after 4 months of treatment. In the outpatient department study, the frequency of migraine attacks was reduced in 67.9% of people in the flunarizine group and 45.8% of people in the propranolol group after 4 months of treatment. No statistical analysis was presented.

Luo et al. (2012), an RCT conducted in China, compared flunarizine 5 mg daily alone with topiramate 25 mg to 100 mg daily alone and topiramate and flunarizine combined over a 12-month period in 150 adults aged 18 to 65 years with a history of migraine for at least a year. The proportion of people who had at least a 50% reduction in their mean monthly migraine frequency compared with baseline (the primary outcome) was 66.7% (26/39) in the flunarizine group, 72.7% (32/44) in the topiramate group and 76.7% (33/43) in the combined group. There was no statistically significant difference between the 3 groups (p=0.593).

Diener et al. (2002) and Luo et al. (2012) only included people aged 18 to 65 years. There is limited evidence available for people outside of this age range. The majority of people in the studies were female, however this reflects the higher prevalence rate of migraine in women. None of the studies was conducted in the UK and therefore may not be applicable to UK practice. The results of these studies may also not be applicable to people whose migraine has not responded to a number of different prophylactic treatments already.

A Cochrane review (Victor et al. 2003) included 2 RCTs that compared flunarizine with placebo and 4 RCTs that compared it with an active comparator. All of the studies were conducted in children and young people aged 3 to 17 years, but were small and of poor quality. There was a statistically significant reduction in migraine frequency with flunarizine compared with placebo in the 2 RCTs that compared flunarizine with placebo. In the 4 RCTs that compared flunarizine with an active comparator (propranolol, aspirin, nimodipine or dihydroergotamine), there was no statistically significant difference between flunarizine and the other treatments for reduction in migraine frequency.

The Irish summary of product characteristics for flunarizine dihydrochloride 5 mg tablets (Sibelium; Janssen-Cilag) states that flunarizine is contraindicated in people with a current depressive illness or with a history of recurrent depression and in people with pre-existing symptoms of Parkinson's disease or other extrapyramidal disorders. Weight gain is reported as a very common (1 in 10 or more) adverse effect; common (1 in 100 or more to less than 1 in 10) adverse effects include rhinitis, increased appetite, depression, insomnia, somnolence, constipation, stomach discomfort, nausea, myalgia, menstruation irregularities, breast pain and fatigue.