Effectiveness of tizanidine for migraine prophylaxis: a double-blind, placebo-controlled study

Tizanidine has been used for chronic daily headache, but its preventive efficacy in episodic migraine remains uncertain. This study conducted a randomized, double-blind, placebo-controlled trial to evaluate the efficacy and safety of low-dose tizanidine for episodic migraine, with an exploratory pharmacokinetic analysis to assess interindividual exposure variability. Patients were assigned 1:1:1 to placebo, tizanidine 1 mg or 2 mg, each administered three times daily for 12 weeks. The primary endpoint was change in a prespecified headache index from baseline to week 12. 150 patients were randomized, and 123 completed all follow-ups. Over 12 weeks, there was no significant between-group difference in the headache index ( P = 0.610) and no time-by-group interaction ( P = 0.077), although a transient improvement at week 4 favored tizanidine 1 mg versus placebo. Subgroup analysis suggested that male participants experienced a greater reduction in the headache index across treatment groups by week 12. Exploratory pharmacokinetic analysis suggested that smoking was associated with higher apparent clearance and male sex with a larger apparent volume of distribution, indicating potential exposure variability within the study population. Tizanidine was well tolerated; adverse events were predominantly somnolence or dry mouth with no excess laboratory or cardiovascular abnormalities. The results showed that uncertain preventive benefit of low-dose tizanidine for episodic migraine, with a possible sex-specific signal that may relate to pharmacokinetic differences. Future studies should further evaluate dose optimization and prospectively investigate whether exposure variability contributes to heterogeneous clinical response. Trial registration: ChiCTR2000040075; First Posted 20/11/2020.