Chronic daily headache prophylaxis with tizanidine: A double-blind, placebo-controlled, multicenter outcome study

Objective.-To assess the efficacy of tizanidine hydrochloride versus placebo as adjunctive prophylactic therapy for chronic daily headache (chronic migraine, migrainous headache, or tension-type headache). Background.-Tizanidine is an alpha(2) -adrenergic agonist that inhibits the release of norepinephrine at both the spinal cord and brain, with antinociceptive effects that are independent of the endogenous opioid system. Previous open-label studies have suggested the drug may be effective for treatment of chronic daily headache. Methods.-Two hundred patients completed a 4-week, single-blind, placebo baseline period, with 134 fulfilling selection criteria and then randomized to tizanidine or placebo. Ninety-two patients completed at least 8 weeks of treatment (tizanidine, n = 45; placebo, n = 47), and 85 patients completed 12 weeks of treatment (tizanidine, n = 44; placebo, n = 41). Most patients (77%) met the diagnostic criteria for migraine of the International Headache Society; 23% had either chronic migrainous headache or chronic tension-type headache. Tizanidine was slowly titrated over 4 weeks to 24 mg or the maximum dose tolerated (mean, 18 mg; SD, 6.4; median, 20.0; range, 2 to 24), divided equally over three dose intervals per day. Overall headache index ([headache days x average intensity x duration in hours]/28 days) was the primary end point. Results.-Tizanidine was shown to be superior to placebo in reducing the overall headache index (P = .0025), as well as mean headache days per week (P = .0193), severe headache days per week (P = .0211), average headache intensity (P = .0108), peak headache intensity (P = .0020), and mean headache duration (P = .0127). The mean percentage improvement during the last 4 weeks of treatment with tizanidine versus placebo was 54% versus 19% for the headache index (P = .0144), 55% versus 21% for severe headache days (P = .0331), 35% versus 19% for headache duration (P = .0142), 35% versus 20% for peak headache intensity (P = .0106), 33% versus 20% for average headache intensity (P = .0281), and 30% versus 22% for total headache days (P = .0593). Patients receiving tizanidine also scored higher ratings of overall headache improvement on a visual analog scale (P = .0069). There was no statistically significant difference in outcome for patients with chronic migraine versus those with only migrainous or tension-type headache. Adverse effects reported by more than 10% of the patients included somnolence (47%), dizziness (24%), dry mouth (23%), and asthenia (19%). Dropouts due to adverse events did not differ significantly between tizanidine and placebo. Conclusions.-The results support tizanidine as an effective prophylactic adjunct for chronic daily headache, including migraine, migrainous headache, and tension-type headache. These results also suggest the possible importance of an alpha(2) -adrenergic mechanism underlying the pathophysiology of this spectrum of headache disorders.