Could a lower, better-tolerated dose of an established muscle relaxant help prevent episodic migraine? A randomized trial tested the approach while exploring whether sex, smoking, and differences in drug exposure might shape treatment response.
Study: Effectiveness of tizanidine for migraine prophylaxis: a double-blind, placebo-controlled study. Image Credit: Tunatura / Shutterstock
In a recent study published in the journal Scientific Reports, researchers assessed the safety and efficacy of tizanidine for episodic migraine (EM).
Migraines affect about 15% of the population worldwide and are the second leading cause of disability. Approximately one-third of patients experience at least two migraine attacks monthly. Frequent attacks substantially impair productivity and quality of life. While multiple prophylactic medications are recommended for frequent attacks, prolonged use is constrained by poor tolerability and adverse effects.
Tizanidine, which has muscle-relaxant and antinociceptive properties, is widely used for pain and spasticity. Previous clinical trials suggest that higher-dose tizanidine may decrease the severity and frequency of chronic daily headaches. Nevertheless, sustained benefit hinges on long-term use, and premature discontinuation of treatment due to adverse effects is a significant limitation. Furthermore, whether tizanidine is effective in migraine, especially EM, is unknown.
About the study
In the present study, researchers evaluated the safety and efficacy of tizanidine in EM. This single-center, randomized, double-blind, placebo-controlled trial was conducted at West China Hospital of Sichuan University in China between April 2021 and June 2023. Individuals aged 18–65 years, with a diagnosis of EM and an attack frequency of over two episodes per month, were included. Subjects with familial hemiplegic migraine, secondary headaches, ophthalmoplegic migraine, medication-overuse headaches, or other specific migraine types were excluded.
Participants were randomized to receive 1 mg tizanidine, 2 mg tizanidine, or a placebo three times per day for 12 weeks. The trial entailed a four-week run-in period (baseline), a 12-week treatment period, and a three-week follow-up period. Participants received a placebo during the run-in period and were asked to document headache and related symptoms, acute analgesic use, mood, and sleep.
Subjects completed on-site visits at treatment weeks 4, 8, and 12, and at week 3 post-treatment. The Pittsburgh Sleep Quality Index, Hamilton Anxiety and Depression Scales, and Headache Impact Test-6 were administered at each visit. Electrocardiograms, physical examinations, and blood chemistry tests were also performed for safety monitoring. Plasma tizanidine levels were measured at 0.5, 1, and 1.5 hours after its administration at each visit.
The primary outcome was the change from baseline in the headache index (a composite measure reflecting the overall headache burden) at week 12 of treatment. Secondary outcomes were changes in monthly migraine days, headache days, severe headache days, acute analgesic use, and the frequency of related symptoms. The analyses also assessed changes over time and differences between treatment groups.
Adverse events (AEs) were compared between groups. Exploratory subgroup analyses were performed in patients with a greater burden (i.e., 4–14 attacks per month); sex-stratified analyses were also performed in this subgroup. An exploratory pharmacokinetic analysis was also conducted.
Findings
The study included 150 participants, 50 per group. Eight participants discontinued during the placebo run-in before receiving study medication and were excluded from the full analysis set, while 123 participants completed all study visits. The three groups were well balanced in baseline characteristics, except for higher body weight in the 2 mg tizanidine group. The headache index changed over time, but there was no sustained overall difference between the treatment groups.
Notably, the headache index differed between the 1 mg tizanidine and placebo groups only at treatment week 4. Secondary outcomes did not differ meaningfully between the tizanidine and placebo groups. Subgroup analysis in patients with 4–14 monthly attacks yielded consistent results. Sex-stratified analyses within this subgroup suggested differences in the headache index among females at treatment week 4.
Among males, the headache index also differed across groups at treatment week 12, although the sex-stratified analyses were exploratory and the findings were considered hypothesis-generating. Tizanidine was well tolerated, with most AEs being mild to moderate. Dry mouth and drowsiness were the most common treatment-related AEs. In an exploratory pharmacokinetic analysis based on 68 participants, smokers had higher apparent tizanidine clearance than non-smokers, while males had a larger apparent volume of distribution than females.
Conclusions
Taken together, there was no sustained preventive benefit on the headache index over 12 weeks of low-dose tizanidine administration, despite a transient improvement at week 4 with 1 mg tizanidine. Exploratory pharmacokinetic findings suggested that smoking and male sex were associated with higher apparent clearance rates and larger apparent distribution volume, respectively, suggesting heterogeneity in tizanidine exposure in the study population.
The study's limitations include the low dosage, which may have been below the threshold needed for sustained efficacy, and the 12-week treatment window, which may have been insufficient to capture long-term effects. The low entry threshold of more than two attacks per month may also have increased participant heterogeneity and placebo responsiveness, while the sex-specific efficacy and pharmacokinetic findings were not externally validated. Further research is needed to optimize dosing and determine whether tizanidine has a role in personalized migraine prevention.
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