Topiramate Treatment of Chronic Migraine: A Randomized, Placebo-Controlled Trial of Quality of Life and Other Efficacy Measures

Authors

  • Stephen Silberstein MD,

    1. From the Thomas Jefferson University – Neurology, Philadelphia, PA, USA (S. Silberstein); Albert Einstein College of Medicine – Neurology, Bronx, New York, NY, USA (R. Lipton and M. Bigal); Mayo Clinic, Scottsdale – Neurology, Scottsdale, AZ, USA (D. Dodick); Diamond Headache Clinic, Chicago, IL, USA (F. Freitag); Houston Headache Clinic, Houston, TX, USA (N. Mathew); Nashville Neuroscience Group, Pc – Neurology, Nashville, TN, USA (J. Brandes); Merck Research Laboratories, Whitehouse Station, NJ, USA (M. Bigal); Ortho-McNeil Janssen – Scientific Affairs, Titusville, NJ, USA (S. Ascher, J. Morein, P. Wright, and J. Hulihan); EMD Serono – Neurology, Rockland, MA, USA (S. Greenberg).
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  • Richard Lipton MD,

    1. From the Thomas Jefferson University – Neurology, Philadelphia, PA, USA (S. Silberstein); Albert Einstein College of Medicine – Neurology, Bronx, New York, NY, USA (R. Lipton and M. Bigal); Mayo Clinic, Scottsdale – Neurology, Scottsdale, AZ, USA (D. Dodick); Diamond Headache Clinic, Chicago, IL, USA (F. Freitag); Houston Headache Clinic, Houston, TX, USA (N. Mathew); Nashville Neuroscience Group, Pc – Neurology, Nashville, TN, USA (J. Brandes); Merck Research Laboratories, Whitehouse Station, NJ, USA (M. Bigal); Ortho-McNeil Janssen – Scientific Affairs, Titusville, NJ, USA (S. Ascher, J. Morein, P. Wright, and J. Hulihan); EMD Serono – Neurology, Rockland, MA, USA (S. Greenberg).
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  • David Dodick MD,

    1. From the Thomas Jefferson University – Neurology, Philadelphia, PA, USA (S. Silberstein); Albert Einstein College of Medicine – Neurology, Bronx, New York, NY, USA (R. Lipton and M. Bigal); Mayo Clinic, Scottsdale – Neurology, Scottsdale, AZ, USA (D. Dodick); Diamond Headache Clinic, Chicago, IL, USA (F. Freitag); Houston Headache Clinic, Houston, TX, USA (N. Mathew); Nashville Neuroscience Group, Pc – Neurology, Nashville, TN, USA (J. Brandes); Merck Research Laboratories, Whitehouse Station, NJ, USA (M. Bigal); Ortho-McNeil Janssen – Scientific Affairs, Titusville, NJ, USA (S. Ascher, J. Morein, P. Wright, and J. Hulihan); EMD Serono – Neurology, Rockland, MA, USA (S. Greenberg).
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  • Fred Freitag DO,

    1. From the Thomas Jefferson University – Neurology, Philadelphia, PA, USA (S. Silberstein); Albert Einstein College of Medicine – Neurology, Bronx, New York, NY, USA (R. Lipton and M. Bigal); Mayo Clinic, Scottsdale – Neurology, Scottsdale, AZ, USA (D. Dodick); Diamond Headache Clinic, Chicago, IL, USA (F. Freitag); Houston Headache Clinic, Houston, TX, USA (N. Mathew); Nashville Neuroscience Group, Pc – Neurology, Nashville, TN, USA (J. Brandes); Merck Research Laboratories, Whitehouse Station, NJ, USA (M. Bigal); Ortho-McNeil Janssen – Scientific Affairs, Titusville, NJ, USA (S. Ascher, J. Morein, P. Wright, and J. Hulihan); EMD Serono – Neurology, Rockland, MA, USA (S. Greenberg).
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  • Ninan Mathew MD,

    1. From the Thomas Jefferson University – Neurology, Philadelphia, PA, USA (S. Silberstein); Albert Einstein College of Medicine – Neurology, Bronx, New York, NY, USA (R. Lipton and M. Bigal); Mayo Clinic, Scottsdale – Neurology, Scottsdale, AZ, USA (D. Dodick); Diamond Headache Clinic, Chicago, IL, USA (F. Freitag); Houston Headache Clinic, Houston, TX, USA (N. Mathew); Nashville Neuroscience Group, Pc – Neurology, Nashville, TN, USA (J. Brandes); Merck Research Laboratories, Whitehouse Station, NJ, USA (M. Bigal); Ortho-McNeil Janssen – Scientific Affairs, Titusville, NJ, USA (S. Ascher, J. Morein, P. Wright, and J. Hulihan); EMD Serono – Neurology, Rockland, MA, USA (S. Greenberg).
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  • Jan Brandes MD,

    1. From the Thomas Jefferson University – Neurology, Philadelphia, PA, USA (S. Silberstein); Albert Einstein College of Medicine – Neurology, Bronx, New York, NY, USA (R. Lipton and M. Bigal); Mayo Clinic, Scottsdale – Neurology, Scottsdale, AZ, USA (D. Dodick); Diamond Headache Clinic, Chicago, IL, USA (F. Freitag); Houston Headache Clinic, Houston, TX, USA (N. Mathew); Nashville Neuroscience Group, Pc – Neurology, Nashville, TN, USA (J. Brandes); Merck Research Laboratories, Whitehouse Station, NJ, USA (M. Bigal); Ortho-McNeil Janssen – Scientific Affairs, Titusville, NJ, USA (S. Ascher, J. Morein, P. Wright, and J. Hulihan); EMD Serono – Neurology, Rockland, MA, USA (S. Greenberg).
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  • Marcelo Bigal MD,

    1. From the Thomas Jefferson University – Neurology, Philadelphia, PA, USA (S. Silberstein); Albert Einstein College of Medicine – Neurology, Bronx, New York, NY, USA (R. Lipton and M. Bigal); Mayo Clinic, Scottsdale – Neurology, Scottsdale, AZ, USA (D. Dodick); Diamond Headache Clinic, Chicago, IL, USA (F. Freitag); Houston Headache Clinic, Houston, TX, USA (N. Mathew); Nashville Neuroscience Group, Pc – Neurology, Nashville, TN, USA (J. Brandes); Merck Research Laboratories, Whitehouse Station, NJ, USA (M. Bigal); Ortho-McNeil Janssen – Scientific Affairs, Titusville, NJ, USA (S. Ascher, J. Morein, P. Wright, and J. Hulihan); EMD Serono – Neurology, Rockland, MA, USA (S. Greenberg).
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  • Steven Ascher PhD,

    1. From the Thomas Jefferson University – Neurology, Philadelphia, PA, USA (S. Silberstein); Albert Einstein College of Medicine – Neurology, Bronx, New York, NY, USA (R. Lipton and M. Bigal); Mayo Clinic, Scottsdale – Neurology, Scottsdale, AZ, USA (D. Dodick); Diamond Headache Clinic, Chicago, IL, USA (F. Freitag); Houston Headache Clinic, Houston, TX, USA (N. Mathew); Nashville Neuroscience Group, Pc – Neurology, Nashville, TN, USA (J. Brandes); Merck Research Laboratories, Whitehouse Station, NJ, USA (M. Bigal); Ortho-McNeil Janssen – Scientific Affairs, Titusville, NJ, USA (S. Ascher, J. Morein, P. Wright, and J. Hulihan); EMD Serono – Neurology, Rockland, MA, USA (S. Greenberg).
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  • Jacqueline Morein,

    1. From the Thomas Jefferson University – Neurology, Philadelphia, PA, USA (S. Silberstein); Albert Einstein College of Medicine – Neurology, Bronx, New York, NY, USA (R. Lipton and M. Bigal); Mayo Clinic, Scottsdale – Neurology, Scottsdale, AZ, USA (D. Dodick); Diamond Headache Clinic, Chicago, IL, USA (F. Freitag); Houston Headache Clinic, Houston, TX, USA (N. Mathew); Nashville Neuroscience Group, Pc – Neurology, Nashville, TN, USA (J. Brandes); Merck Research Laboratories, Whitehouse Station, NJ, USA (M. Bigal); Ortho-McNeil Janssen – Scientific Affairs, Titusville, NJ, USA (S. Ascher, J. Morein, P. Wright, and J. Hulihan); EMD Serono – Neurology, Rockland, MA, USA (S. Greenberg).
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  • Pamela Wright,

    1. From the Thomas Jefferson University – Neurology, Philadelphia, PA, USA (S. Silberstein); Albert Einstein College of Medicine – Neurology, Bronx, New York, NY, USA (R. Lipton and M. Bigal); Mayo Clinic, Scottsdale – Neurology, Scottsdale, AZ, USA (D. Dodick); Diamond Headache Clinic, Chicago, IL, USA (F. Freitag); Houston Headache Clinic, Houston, TX, USA (N. Mathew); Nashville Neuroscience Group, Pc – Neurology, Nashville, TN, USA (J. Brandes); Merck Research Laboratories, Whitehouse Station, NJ, USA (M. Bigal); Ortho-McNeil Janssen – Scientific Affairs, Titusville, NJ, USA (S. Ascher, J. Morein, P. Wright, and J. Hulihan); EMD Serono – Neurology, Rockland, MA, USA (S. Greenberg).
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  • Steven Greenberg MD,

    1. From the Thomas Jefferson University – Neurology, Philadelphia, PA, USA (S. Silberstein); Albert Einstein College of Medicine – Neurology, Bronx, New York, NY, USA (R. Lipton and M. Bigal); Mayo Clinic, Scottsdale – Neurology, Scottsdale, AZ, USA (D. Dodick); Diamond Headache Clinic, Chicago, IL, USA (F. Freitag); Houston Headache Clinic, Houston, TX, USA (N. Mathew); Nashville Neuroscience Group, Pc – Neurology, Nashville, TN, USA (J. Brandes); Merck Research Laboratories, Whitehouse Station, NJ, USA (M. Bigal); Ortho-McNeil Janssen – Scientific Affairs, Titusville, NJ, USA (S. Ascher, J. Morein, P. Wright, and J. Hulihan); EMD Serono – Neurology, Rockland, MA, USA (S. Greenberg).
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  • Joseph Hulihan MD

    1. From the Thomas Jefferson University – Neurology, Philadelphia, PA, USA (S. Silberstein); Albert Einstein College of Medicine – Neurology, Bronx, New York, NY, USA (R. Lipton and M. Bigal); Mayo Clinic, Scottsdale – Neurology, Scottsdale, AZ, USA (D. Dodick); Diamond Headache Clinic, Chicago, IL, USA (F. Freitag); Houston Headache Clinic, Houston, TX, USA (N. Mathew); Nashville Neuroscience Group, Pc – Neurology, Nashville, TN, USA (J. Brandes); Merck Research Laboratories, Whitehouse Station, NJ, USA (M. Bigal); Ortho-McNeil Janssen – Scientific Affairs, Titusville, NJ, USA (S. Ascher, J. Morein, P. Wright, and J. Hulihan); EMD Serono – Neurology, Rockland, MA, USA (S. Greenberg).
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  • Conflict of Interest: Stephen Silberstein has received personal compensation for activities with: Johnson & Johnson, GlaxoSmithKline, Merck, UCB Pharma, AstraZeneca, Pfizer, Allergan, Pozen, Abbott Laboratories., Eli Lilly & Company, NPS, and Xcel Pharmaceuticals; has received personal compensation in an editorial capacity for Current Pain and Headache; and has received financial support for scholarly activities from GlaxoSmithKline, Johnson & Johnson, Merck, Pfizer, Allergan, and Abbott Laboratories.
    Richard B. Lipton has consulted for, conducted studies funded by, or received lecture honoraria from Allergan, Bristol-Myers Squibb, GlaxoSmithKline, Johnson & Johnson, Merck, Ortho-McNeill, Pfizer, and Pozen, among other companies.
    David W. Dodick has served as a consultant for GlaxoSmithKline, Merck, Allergan, Endo, Pfizer, Eli Lilly, Addex, Solvay, and Neuralieve and has received research support from Advanced Neurostimulation Systems, Medtronic, and St. Jude.
    Fred Freitag has received grants and research support from Advanced Bionics Corporation, Alzyer, AstraZeneca, CAPNIA, GlaxoSmithKline, Johnson & Johnson, Merck, Ortho-McNeil Pharmaceutical, Ortho-McNeil Neurologics, Solvay, and Vernalis Pharmaceuticals. He has served as a consultant for Allergan, AstraZeneca, CAPNIA, Endo Pharmaceuticals, Merck, Ortho-McNeil Pharmaceutical, Ortho-McNeil Neurologics, and Valeant Pharmaceuticals International. He has served on the speakers bureaus of AstraZeneca, GlaxoSmithKline, Merck, Ortho-McNeil Pharmaceutical, Ortho-McNeil Neurologics, Pfizer, and Valeant Pharmaceuticals International.
    Ninan Mathew has received personal compensation for activities involving continuing medical education and for advisory board participation from Ortho McNeil, Merck, Allergan, GlaxoSmithKline, Endo, and Valiant.
    Jan Brandes has received grants, research support, or served as a consultant to Merck, GlaxoSmithKline, UCB Pharma, Pfizer, Allergan, Johnson & Johnson, AstraZeneca, Bristol-Myers Squibb, Winston Laboratories, Sanofi-Aventis, Elan, Novartis, Endo, Pozen, Vernalis, Ortho-McNeil, Advanced Bionics, MedPointe, and Aradigm.
    Marcelo E. Bigal is a full-time employee of Merck Research Laboratories. This manuscript was written during his tenure at the Albert Einstein College of Medicine. He has received, in the past, compensation from Ortho-McNeil Pharmaceutical, AstraZeneca, GlaxoSmithKline, Merck, Allergan, MAP, NMT, and Endo, among other pharmaceutical companies.
    Steve Ascher, Jacqueline D. Morein, and Pamela Wright are employees of Ortho-McNeil Janssen Scientific Affairs, LLC.
    Steven J. Greenberg is an employee of EMD Serono Inc.

S. Silberstein, Department of Neurology, Thomas Jefferson University, Jefferson Headache Center, 111 South 11th Street, Suite 8130 Gibbon, Philadelphia, PA 19107, USA.

Abstract

Objective.— To define yet more clearly the utility of topiramate in the treatment of chronic migraine, we evaluated prespecified secondary endpoints from a recent randomized, double-blind, placebo-controlled, multicenter clinical trial.

Background.— We previously reported that topiramate 100 mg per day produced a statistically significant reduction in mean monthly migraine/migrainous and migraine headache days compared with placebo treatment and that it was safe and generally well tolerated.

Methods.— Variables analyzed included between-treatment group differences in percent responders, change in the mean monthly rate of total headache days and headache-free days, change in average and worst daily headache severity, change in the mean monthly use of acute headache medications, and absolute change and percent change in a headache index. Additional analyses included evaluation of changes in: the associated symptoms of photophobia, phonophobia, and nausea; Migraine-Specific Quality of Life Questionnaire scores; Migraine Disability Assessment Scale scores; and Physician's and Subjects Global Impression of Change.

Results.— The intent-to-treat population consisted of 306 patients (topiramate, n = 153; placebo, n = 153). Categorical responder rates of reductions in mean monthly migraine/migrainous days for topiramate- vs placebo-treated subjects were as follows: for ≥25% reduction: 68.6% vs 51.6% (P = .005); ≥50%: 37.3% vs 28.8% (P = .093); and ≥75%: 15.0% vs 9.2% (P = .061). The decrease in mean monthly total headache days and headache-free days for topiramate vs placebo treatment was 5.8 vs 4.7 days (P = .067). Compared with placebo, topiramate treatment resulted in statistically significant mean improvements in the Role Restrictive (P = .028) and Emotional Function (P = .036) domains of the Migraine-Specific Quality of Life Questionnaire, in the worst daily severity of migraine (P = .016), severity of photophobia (P = .032), frequency of vomiting (P = .018), photophobia (P = .038), phonophobia (P = .010), unilateral pain (P = .015), pulsatile pain (P = .023), and pain worsened because of physical activity (P = .047). In addition, there were trends observed (favoring topiramate) in average daily severity of migraine (P = .077), acute headache medication use (P = .127), severity of nausea (P = .098), frequency of nausea (P = .166), the Role Preventive domain of the Migraine-Specific Quality of Life Questionnaire (P = .061), and severity of phonophobia (P = .062).

Conclusions.— In addition to significantly reducing mean monthly migraine/migrainous and migraine headache days, treatment of chronic migraine with topiramate was effective with regard to several traditionally important and clinically relevant secondary outcomes in migraine prevention trials. Treatment with topiramate was well tolerated and not associated with serious adverse events.

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