Tizanidine is an alpha2-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: