title: Efficacy and safety of topiramate for the treatment of chronic migraine: a randomized, double-blind, placebo-controlled trial.
abstract: OBJECTIVE
  To evaluate the efficacy and safety of topiramate (100 mg/day) compared with placebo for the treatment of chronic migraine.
  
  
  METHODS
  This was a randomized, placebo-controlled, parallel-group, multicenter study consisting of 16 weeks of double-blind treatment. Subjects aged 18 to 65 years with 15 or more headache days per month, at least half of which were migraine/migrainous headaches, were randomized 1:1 to either topiramate 100 mg/day or placebo. An initial dose of topiramate 25 mg/day (or placebo) was titrated upward in weekly increments of 25 mg/day to a maximum of 100 mg/day (or to the maximum tolerated dose). Concomitant preventive migraine treatment was not allowed, and acute headache medication use was not to exceed 4 days per week during the double-blind maintenance period. The primary efficacy endpoint was the change from baseline in the mean monthly number of migraine/migrainous days; the change in the mean monthly number of migraine days also was analyzed. A fixed sequence approach (ie, gatekeeper approach) using analysis of covariance was used to analyze the efficacy endpoints. Assessments of safety and tolerability included physical and neurologic examinations, clinical laboratory parameters, and spontaneous reports of clinical adverse events.
  
  
  RESULTS
  The intent-to-treat population included 306 (topiramate, n = 153; placebo, n = 153) of 328 randomized subjects who provided at least 1 efficacy assessment; 55.8% of the topiramate group and 55.2% on placebo were trial completers. The mean final topiramate maintenance dose was 86.0 mg/day. The mean duration of therapy was 91.7 days for the topiramate group and 90.6 days for the placebo group. Topiramate treatment resulted in a statistically significant mean reduction of migraine/migrainous headache days (topiramate -6.4 vs placebo -4.7, P= .010) and migraine headache days relative to baseline (topiramate -5.6 vs placebo -4.1, P= .032). Treatment-emergent adverse events occurred in 132 (82.5%) and 113 (70.2%) of topiramate-treated and placebo-treated subjects, respectively, and were generally of mild or moderate severity. Most commonly reported adverse events in the topiramate group were paresthesia (n = 46, 28.8%), upper respiratory tract infection (n = 22, 13.8%), and fatigue (n = 19, 11.9%). The most common adverse events in the placebo group were upper respiratory tract infection (n = 20, 12.4%), fatigue (n = 16, 9.9%), and nausea (n = 13, 8.1%). Discontinuations due to adverse events occurred in 18 (10.9%) topiramate subjects and 10 (6.1%) placebo subjects. There were no serious adverse events or deaths.
  
  
  CONCLUSIONS
  Topiramate treatment at daily doses of approximately 100 mg resulted in statistically significant improvements compared with placebo in mean monthly migraine/migrainous and migraine headache days. Topiramate is safe and generally well tolerated in this group of subjects with chronic migraine, a burdensome condition with important unmet treatment needs. Safety and tolerability of topiramate were consistent with experience in previous clinical trials involving the drug.
authors.affiliation: Jefferson Headache Center, Philadelphia, PA 19107, USA.
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Silberstein
authors.forename: Richard B
authors.initials: RB
authors.lastname: Lipton
authors.forename: David W
authors.initials: DW
authors.lastname: Dodick
authors.forename: Frederick G
authors.initials: FG
authors.lastname: Freitag
authors.forename: Nabih
authors.initials: N
authors.lastname: Ramadan
authors.forename: Ninan
authors.initials: N
authors.lastname: Mathew
authors.forename: Jan L
authors.initials: JL
authors.lastname: Brandes
authors.forename: Marcelo
authors.initials: M
authors.lastname: Bigal
authors.forename: Joel
authors.initials: J
authors.lastname: Saper
authors.forename: Steven
authors.initials: S
authors.lastname: Ascher
authors.forename: Donna M
authors.initials: DM
authors.lastname: Jordan
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Greenberg
authors.forename: Joseph
authors.initials: J
authors.lastname: Hulihan
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000927:Anticonvulsants / Q000009:adverse effects / Q000627:therapeutic use*; D002908:Chronic Disease; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D005632:Fructose / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D006801:Humans; D008297:Male; D008875:Middle Aged; D008881:Migraine Disorders / Q000188:drug therapy*; D000077236:Topiramate; D016896:Treatment Outcome
chemical_list: D000927:Anticonvulsants; D000077236:Topiramate; D005632:Fructose