Efficacy and Safety of Topiramate for the Treatment of Chronic Migraine: A Randomized, Double-Blind, Placebo-Controlled Trial

Authors

  • Stephen D. Silberstein MD,

  • Richard B. Lipton MD,

  • David W. Dodick MD,

  • Frederick G. Freitag DO,

  • Nabih Ramadan MD,

  • Ninan Mathew MD,

  • Jan L. Brandes MD,

  • Marcelo Bigal MD,

  • Joel Saper MD,

  • Steven Ascher PhD,

  • Donna M. Jordan RN,

  • Steven J. Greenberg MD,

  • Joseph Hulihan MD,

  • on behalf of the Topiramate Chronic Migraine Study Group


  • From the Jefferson Headache Center, Philadelphia, PA, USA (Dr. Silberstein); Albert Einstein College of Medicine, Bronx, NY, USA (Drs. Lipton and Bigal); Mayo Clinic, Scottsdale, AZ, USA (Dr. Dodick); Diamond Headache Clinic, Chicago, IL, USA (Dr. Freitag); Rosalind Franklin University of Medicine and Science, North Chicago, IL, USA (Dr. Ramadan); Houston Headache Clinic, Houston TX, USA (Dr. Mathew); Nashville Neuroscience Group, Nashville, TN, USA (Dr. Brandes); Michigan Head Pain and Neurological Institute, Ann Arbor, MI, USA (Dr. Saper); Ortho-McNeil Janssen Scientific Affairs, LLC, Titusville, NJ, USA (Dr. Ascher); PriCara, Unit of Ortho-McNeil, Inc., Raritan, NJ, USA (Ms. Jordan); Ortho-McNeil Neurologics, Titusville, NJ, USA (Drs. Greenberg and Hulihan);

  • Topiramate Chronic Migraine Study Group Investigators (listed alphabetically with the location of their trial sites): James Adelman, MD (Greensboro, NC, USA); James Banks, MD (Roanoke, VA, USA); Frank R. Berenson, MD (Atlanta, GA, USA); Tanya R. Bilchik, MD (Hartford, CT, USA); Harvey Blumenthal, MD (Tulsa, OK, USA); Bradley S. Boop, MD (Little Rock, AR, USA); Jan L. Brandes, MD (Nashville, TN, USA); Roger Cady, MD (Springfield, MO, USA); John E. Castaldo, MD (Allentown, PA, USA); John Cochran, MD (Alexandria, VA, USA); James Couch, MD (Oklahoma City, OK, USA); F. Michael Cutrer, MD (Rochester, MN, USA); Kathleen Digre, MD (Salt Lake City, UT, USA); David W. Dodick, MD (Scottsdale, AZ, USA); Robert A. Duarte, MD (Manhasset, NY, USA); Grace Forde, MD (Valley Stream, NY, USA); Frederick Freitag, DO (Chicago, IL, USA); Gerard Gary, MD (Toledo, OH, USA); Gordon Gibson, MD (Little Rock, AR, USA); Richard Hull, MD (Huntsville, AL, USA); Nancy Juopperi, DO (Madison Heights, MI, USA); Simmons L. Keith, DO (Tulsa, OK, USA); John R. Kirchner, MD (Omaha, NE, USA); David Kudrow, MD (Santa Monica, CA, USA); Howard LaRoche, MD (Lake Jackson, TX, USA); Hubert A. Leonard, MD (Portland, OR, USA); Robert S. Lipetz, DO (Spring Valley, CA, USA); Elizabeth W. Loder, MD (Boston, MA, USA); Morris Maizels, MD (Woodland Hills, CA, USA); Lisa Mannix, MD (West Chester, OH, USA); Herbert Markley, MD (Worcester, MA, USA); Ninan Mathew, MD (Houston, TX, USA); Peter McAllister, MD (Fairfield, CT, USA); Laszlo Mechtler, MD (Amherst, NY, USA); Marshall Nash, MD (Decatur, GA, USA); William Noran, MD (Jacksonville, FL, USA); James Patton, MD (Asheville, NC, USA); Eric Pearlman, MD, PhD (Savannah, GA, USA); Nabih Ramadan, MD (North Chicago, IL, USA); Alan Rapoport, MD (Stamford, CT, USA); John Rothrock, MD (Mobile, AL, USA); Todd Rozen, MD (Ann Arbor, MI, USA); Aurora Sheena, MD (Seattle, WA, USA); Stephen Silberstein, MD (Philadelphia, PA, USA); Richard P. Singer, MD (Plantation, FL, USA); Timothy Smith, MD (St. Louis, MO, USA); Kenneth Sokolski, MD (Santa Ana, CA, USA); Egilius Spierings, MD, PhD (Wellesley Hill, MA, USA); Alexandre Todorov, MD (Northport, AL, USA); Steve Wheeler, MD (Hialeah, FL, USA); Paul Winner, DO (West Palm Beach, FL, USA).

Address all correspondence to Dr. Stephen Silberstein, Jefferson Headache Center, 111 South 11th Street, Suite 8130 Gibbon, Philadelphia, PA 19107, USA.

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.

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