Flunarizine may be safe, effective, and well-tolerated as a prophylactic treatment for episodic migraine, according to a systematic review and pooled meta-analysis published in Pain.

Despite its effectiveness, excellent safety profile, and recommendation in guidelines as first-line prophylactic therapy, the calcium channel blocker flunarizine has not gained the same level of popularity as similar cardiovascular medications used for migraine prevention and has limited availability in certain countries. Investigators sought to characterize the safety and efficacy of this drug via an examination of available published trials, which they rated for quality and bias.

A systematic review of the literature published up to November 2017 on Embase, MEDLINE, and CENTRAL databases was conducted. In particular, randomized controlled trials (RCTs) that evaluated flunarizine for episodic migraine prophylaxis were examined. The primary outcome was the mean reduction in 28-day migraine attack frequency, expressed as the mean difference between groups. Secondary outcomes included treatment-related adverse events (AEs) and migraine intensity and duration, and the percentage of responders (ie, those reporting ≥50% decrease in headache frequency). Of the 879 studies identified, 25 were selected for inclusion and data synthesis.

A total of 175 risk for bias issues were identified, with 31 (17.7%) rated as high risk, 60 (34.3%) as low risk, and 84 (48.0%) with an unclear risk level. The most common risk for bias were attrition and reporting biases, suspected in 10 and 13 studies, respectively.

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Based on 5 trials (n=249), flunarizine was found to reduce the frequency of attacks by 0.4 per 28 days (mean difference, −0.44; 95% CI, −0.61 to −0.26). In 3 studies (n=113), the percentage of responders was greater in patients taking flunarizine vs placebo (OR, 8.86; 95% CI, 3.57-22.0). In 7 trials (n=1151), the prophylactic efficacy of flunarizine was comparable with that of propranolol (mean difference, −0.08; 95% CI, −0.34 to 0.18), in other studies, flunarizine and propranolol were found to have comparable efficacy on migraine intensity (2 studies; 135 participants; mean difference, 0.22; 95% CI, 0.12-0.57) and on migraine duration (5 studies; 1063 participants; mean difference, 0.60; 95% CI, −1.48 to 2.69).

Although only 2 trials (n=105) examined the efficacy of flunarizine in pediatric populations, they reported lower attack frequency (mean difference, −1.14; 95% CI, −1.51 to -0.77) and shorter headache duration (mean difference, −0.46; 95% CI, −0.77 to −0.16) compared with placebo.

Weight gain and daytime somnolence were the two most commonly reported adverse events. Patients taking flunarizine had a pooled risk for ≥1 adverse event that was comparable with placebo (risk difference, 0.04; 95% CI, −0.08 to 0.17). There were no serious adverse events reported in any RCTs. However, adverse event reporting was considered limited and inconsistent.

Study strengths include the use of strict inclusion criteria, comparisons with treatments with established efficacies, and thorough assessment of risk for bias.

Study limitations include insufficient power, data variability, and the presence of multiple biases.

“Ultimately, flunarizine seems to be a well-tolerated alternative for patients with contraindications for beta blockers,” noted the authors, who called for new RCTs that adhere to current methodologic standards.

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Stubberud A, Flaaen NM, Mccrory DC, Pedersen SA, Linde M. Flunarizine as prophylaxis for episodic migraine: a systematic review with meta-analysis. Pain. December 2018:1-11. doi:10.1097/j.pain.0000000000001456