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Flunarizine as prophylaxis for episodic migraine

a systematic review with meta-analysis

Stubberud, Ankera,*; Flaaen, Nikolai Melsetha; McCrory, Douglas C.b,c,d; Pedersen, Sindre Andree; Linde, Mattiasa,f

doi: 10.1097/j.pain.0000000000001456
Systematic Reviews and Meta-Analyses

Based on few clinical trials, flunarizine is considered a first-line prophylactic treatment for migraine in several guidelines. In this meta-analysis, we examined the pooled evidence for its effectiveness, tolerability, and safety. Prospective randomized controlled trials of flunarizine as a prophylaxis against migraine were identified from a systematic literature search, and risk of bias was assessed for all included studies. Reduction in mean attack frequency was estimated by calculating the mean difference (MD), and a series of secondary outcomes—including adverse events (AEs)—were also analyzed. The database search yielded 879 unique records. Twenty-five studies were included in data synthesis. We scored 31/175 risk of bias items as “high,” with attrition as the most frequent bias. A pooled analysis estimated that flunarizine reduces the headache frequency by 0.4 attacks per 4 weeks compared with placebo (5 trials, 249 participants: MD −0.44; 95% confidence interval −0.61 to −0.26). Analysis also revealed that the effectiveness of flunarizine prophylaxis is comparable with that of propranolol (7 trials, 1151 participants, MD −0.08; 95% confidence interval −0.34 to 0.18). Flunarizine also seems to be effective in children. The most frequent AEs were sedation and weight increase. Meta-analyses were robust and homogenous, although several of the included trials potentially suffered from high risk of bias. Unfortunately, reporting of AEs was inconsistent and limited. In conclusion, pooled analysis of data from partially outdated trials shows that 10-mg flunarizine per day is effective and well tolerated in treating episodic migraine—supporting current guideline recommendations.

Flunarizine is considered an effective prophylactic treatment for migraine, but guideline recommendations and up-to-date meta-analytical evidence are based on often outdated trials with high risk of bias.

aDepartment of Neuromedicine and Movement Sciences, NTNU Norwegian University of Science and Technology, Trondheim, Norway

bDuke Evidence Synthesis Group, Duke Clinical Research Institute, Durham, NC, United States,

cDepartment of Medicine, Duke University School of Medicine, Durham, NC, United States,

dCenter for Health Services Research in Primary Care, Durham Veterans Affairs Medical Center, Durham, NC, United States,

eLibrary Section for Medicine and Health Sciences, NTNU University Library, NTNU Norwegian University of Science and Technology, Trondheim, Norway

fNorwegian Advisory Unit on Headaches, St. Olavs Hospital, Trondheim, Norway

Corresponding author. Address: Department of Neuroscience and Movement Sciences, NTNU Norwegian University of Science and Technology, Nevro Øst, Edvard Griegs gt 8, Trondheim 7030, Norway. Tel.: 004745229174. E-mail address: (A. Stubberud).

Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Web site (

A. Stubberud and N.M. Flaaen contributed equally as co-first authors.

Received October 15, 2018

Received in revised form November 24, 2018

Accepted November 29, 2018

© 2019 International Association for the Study of Pain
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