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ORIGINAL CONTRIBUTION |
From the Diamond Headache Clinic in Chicago, Ill, and Midwestern University Chicago College of Osteopathic Medicine in Downers Grove, Ill (Dr Freitag); North Shore Pain Services in Valley Stream, NY (Dr Forde); Johnson & Johnson Pharmaceutical Research and Development LLC in Raritan, NJ (Drs Neto and Wang, Ms Schmitt); and Ortho-McNeil Neurologics Inc in Titusville, NJ (Drs Wu and Hulihan).
Address correspondence to Fred G. Freitag, DO, Diamond Headache Clinic, 467 W Deming Place, Chicago, IL 60614-1881. E-mail: dhcdoc{at}aol.com
Context: A substantial proportion of the patient population with migraine headache should be considered for preventive treatment based on the frequency and disability associated with this disorder. Use of the anticonvulsant topiramate was previously examined in two large, double-blind, randomized, placebo-controlled clinical trials of a subset of patients who have 3 to 12 migraine episodes per month.
Objective: To better characterize the efficacy of topiramate for prevention of migraine, with or without aura, by pooling and analyzing data from the two large clinical trials.
Methods: The pooled intent-to-treat population included 937 patients receiving topiramate at one of three dosages (50 mg/d, 100 mg/d, 200 mg/d) or placebo. Outcome measures included change in mean monthly migraine frequency and categorical responder rate throughout the 26-week doubleblind phase.
Results: At daily doses of 100 and 200 mg, topiramate was associated
with significant reductions in mean monthly migraine frequency throughout the
double-blind phase compared with placebo (P<.001). Significantly
more patients treated with these topiramate doses exhibited high-percentage
reductions in monthly migraine frequency (
50% [P<.001],
75% [P<.001], 100% [P=.049]) versus placebo. The most
common adverse events included anorexia, cognitive deficits, diarrhea,
fatigue, nausea, and paresthesia. Topiramate (100 mg/d, 200 mg/d) was
associated with significant and sustained reductions in mean monthly migraine
frequency beginning as early as 1 week into therapy.
Conclusion: Pooled efficacy data from two large, similarly designed,
placebo-controlled migraine-prevention trials demonstrated that a
statistically significant proportion of patients using topiramate met or
exceeded two main outcome guidelines recommended by the International Headache
Society (50% and 75% reduction in frequency of monthly attacks). Based
on efficacy and tolerability, topiramate at a dosage of 100 mg per day (50 mg
twice daily) should be the target dosage for most patients with migraine.
A holistic approach to migraine therapy would include assessment of the patient's headache frequency, severity, and duration, as well as the level of overall functional impairment experienced by the patient both during and between attacks. The patient's views on treatment should also be taken into consideration when deciding upon an appropriate course of therapy. Appropriate musculoskeletal examination should be included in the patient assessment to determine the potential role of osteopathic manipulative treatment (OMT). Many patients with migraine may benefit from OMT, though there is a paucity of clinical trial data on this matter. Comprehensive therapy should also include acute treatments, behavioral interventions, and trigger-factor avoidance as part of migraine management. Preventive medication should be used as appropriate with patients.
According to generally accepted clinical guidelines,7,8 indications for migraine prevention include the following:
Preventive therapy may reduce the risk of medication-overuse (ie, rebound) headache resulting from frequent usage.7,8 Studies have also shown that effective migraine-prevention therapy is associated with improvements in health-related quality of life.9,10 In addition, an indirect evaluation of productivity data pooled from pivotal migraine-prevention trials estimates that medication therapy led to productivity gains of nearly 14.5 days over the course of 1 year.11
Topiramate, an anticonvulsant, is approved in more than 50 countries, including the United States, for the prevention of migraine headache in adults. Other medications approved for this indication include divalproex sodium (another anti-convulsant) and propranolol (a ß-adrenergic blocking agent).12 Several large clinical studies have demonstrated the efficacy of topiramate for the prevention of migraine with or without aura.13-15 These studies include two randomized, placebo-controlled, 26-week trials in the United States and Canada of identical design.13,14 Compared with placebo in these trials, topiramate at dosages of 100 mg per day and 200 mg per day was associated with significantly reduced mean monthly migraine frequency after the first month of treatment (P<.001).13,14 Adverse events were mild to moderate in severity and included anorexia, cognitive deficits, diarrhea, fatigue, nausea, and paresthesia.13,14
The present study analyzes pooled efficacy data from these two pivotal North American migraine-prevention trials13,14 to characterize primary and secondary efficacy measures used to assess topiramate therapy.
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Methods |
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Patients with diagnosed depression who were using a stable regimen of a selective serotonin reuptake inhibitor for at least 3 months were allowed to enter the trials. Female subjects included in the trials were postmenopausal women, those surgically incapable of childbearing, and those currently practicing a medically acceptable method of birth control.13,14
Patients were excluded from the trials if they had cluster headache or basilar, hemiplegic, ophthalmologic, or transformed migraine, or if the onset of migraines occurred after age 50 years. Patients were also excluded from trial entry if their headaches previously failed to respond to more than two adequately dosed migraine-prevention regimens or if they overused analgesics or agents designed for the acute treatment of migraine, such as triptans. In addition, patients who required the concomitant use of anticonvulsants, ß-blockers, calcium-channel blockers, monoamine oxidase inhibitors, tricyclic antidepressants, or daily nonsteroidal anti-inflammatory drugs (NSAIDs) were also excluded. Finally, patients with nephrolithiasis or those who participated in a previous topiramate study, used topiramate for 2 weeks or longer, or used an experimental drug or device within 30 days prior to screening were excluded.13,14
Eligible patients entered a maximum 14-day medication washout phase, during which any migraine-prevention medications were tapered, followed by a 28-day prospective baseline phase (Figure 1). After completion of these two phases and a review of headache records, 970 patients were randomly assigned to receive placebo or topiramate at one of three dosage levels (50 mg/d, 100 mg/d, or 200 mg/d).13,14
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All phases of the clinical trials were conducted with full approval by the institutional review boards at the respective sites. Each patient signed an informed consent form, which conformed to the current revision of the World Medical Association Declaration of Helsinki.13,14
The intent-to-treat (ITT) population included all randomized patients who received study medication and at least one postbaseline efficacy evaluation. The safety population comprised all randomized patients who received at least one postbaseline safety evaluation, while the per-protocol population included all patients who completed the study without major protocol violations.13,14
Outcome Measures
Efficacy and safety analyses were performed on data pooled from the two
North American migraine-prevention
trials.13,14
Pooling data from similarly designed trials may reveal significant treatment
differences that would otherwise be masked because of insufficient statistical
power.
The primary efficacy measure for the trials was the change in monthly
migraine frequency for the pooled ITT population, from the prospective
baseline phase through the entire double-blind phase. Primary- and
secondary-efficacy outcomes were based on the amount of time a patient
remained in the study, using the last-observation-carried-forward (LOCF)
method. Mean percent change in monthly migraine frequency and categorical
responder rates (number of patients [%] with 50%, 75%, or 100%
reduction in monthly migraine frequency) from baseline to study endpoint were
among several secondary efficacy measures analyzed for the ITT and
per-protocol
populations.13,14
To determine the onset of effect after initiation of topiramate therapy, a post hoc analysis of weekly migraine frequency during the first month of treatment (ie, first month of titration period) was performed. For this post hoc analysis, the onset of therapeutic action was defined as the earliest week after initiation of topiramate during which a statistically significant reduction in mean migraine frequency was observed when compared with placebo. During the initial month of the titration phase, patients who had been randomized to the highest topiramate-dosage groups (100 mg/d, 200 mg/d) received identical dosages of topiramate. Therefore, weekly migraine frequency data collected during this initial month were combined for these dosages. Adverse-event data from both trials were also pooled and analyzed.
Statistical Analyses
The primary efficacy outcome measure was assessed using a linear model,
with the treatment and analysis centers as factors and the baseline value as a
covariate. For patients who discontinued participation in the trials early,
the mean monthly migraine frequency during the entire double-blind treatment
phase was computed according to the frequency of migraine periods observed
before discontinuation. The least squares means, which are means adjusted for
the variables in the statistical model, were used to compare treatment groups.
Comparisons of topiramate with placebo were made using the
Tukey-Ciminera-Heyse trend
test16 performed in
a step-down manner, which included all topiramate doses and placebo at the
first stage. This analytic method takes into account multiple comparisons.
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Results |
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TopMethodsResultsCommentConclusionReferences |
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The predominance of white patients in the ITT study population (approximately 90%) reflects both the major racial population distributions in the United States and the prevalence of migraine among different racial groups. The prevalence of migraine in the United States is highest among whites (women, 20.4%; men, 8.6%), intermediate among African Americans (women, 16.2%; men, 7.2%), and lowest among Asian Americans (women, 9.2%; men, 4.8%).17 The approximately 10% minority ITT population, stratified into the various topiramate groups and the placebo group, provided too few patients to perform inferential comparative statistical efficacy analyses. Nevertheless, we are not aware of any data that suggest topiramate preventive treatment is more or less effective, or more or less well-tolerated, in any minority population compared with the mostly white ITT population in the analyzed trials.
Additional patient information, including more details on specific inclusion and exclusion criteria and results of individual efficacy and safety analyses, can be obtained from the original published trials.13,14
Efficacy Measures
The pooled analysis of the data from the two trials revealed that
topiramate at dosages of 100 mg per day and 200 mg per day significantly
reduced mean monthly migraine frequency throughout the double-blind phase,
compared with placebo (P
.002)
(Figure 2). Topiramate
at 50 mg per day was also associated with a reduction in monthly migraine
frequency, though treatment with this dosage did not reach statistical
significance (P=.397). A sustained clinical response was observed for
the two highest topiramate dosages, beginning with the first month of
treatment and lasting until the end of the double-blind phase
(Figure 2). For
example, 100 mg of topiramate per day was associated with significant median
percent reductions in monthly migraine frequency from baseline to the end of
the double-blind phase, compared with placebo (P<.001)
(Figure 3). Efficacy
outcomes obtained from the cohort receiving 200 mg per day were not
statistically different than those observed with the cohort receiving 100 mg
per day.
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.002). For all three dosage
levels, the proportion of ITT patients who had a minimum 50% reduction or a
minimum 75% reduction in monthly migraine frequency was significantly greater
than the proportion of placebo responders at those levels
(P.011). A minimum 50% reduction in monthly migraine frequency
was achieved by 52% of patients treated with 100 mg of topiramate per day,
compared with 23% of patients given placebo (P<.001)
(Figure 4). The
percentage of patients with a minimum 75% reduction in monthly migraine
frequency was 27% for those treated with 100 mg of topiramate per day,
compared with 11% for those given placebo (P<.001)
(Figure 5).
Furthermore, the percentage of patients reporting a 100% reduction in monthly
migraine frequency was 5.7% for those treated with 100 mg of topiramate per
day, compared with 2.2% for those given placebo (P=.049).
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Paresthesia was the most common topiramate-associated adverse event, occurring in 48% of patients receiving 100 mg of topiramate per day. Patients treated with 100 mg of topiramate per day exhibited a mean weight loss of 2.8 kg (6.2 lb) from baseline to the last measurement in the double-blind phase, while placebo-treated patients lost a mean of 0.3 kg (0.7 lb) over the same time period (P<.001). A comprehensive assessment of topiramate safety and tolerability can be found in the original trial data.13,14
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Comment |
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When compared with placebo, the two highest dosages of topiramate (100 mg/d, 200 mg/d) significantly reduced mean migraine frequency from the first month of treatment to the study endpoint at week 26. The lowest dosage of topiramate (50 mg/d) was not statistically superior to placebo in efficacy for the primary outcome. When weekly efficacy data from the first month of treatment were combined for those patients receiving 100 mg and 200 mg of topiramate per day, a statistically significant difference from placebo in weekly migraine frequency was observed as early as the first week of treatment. This difference, however, is not necessarily clinically meaningful. Further reductions in migraine frequency occurred over the ensuing 3 to 4 weeks of treatment.
In the pooled results for the ITT patients who completed at least 2 weeks of treatment and for the per-protocol population, additional efficacy analyses revealed that 100 mg of topiramate per day significantly reduced mean migraine frequency during the last 28 days of treatment. Thus, patients who could benefit from topiramate should remain on this migraine-prevention medication for at least 2 to 3 months to establish clinical efficacy.7
Data from the pooled analysis showed that 52% of patients treated with 100 mg of topiramate per day achieved a minimum 50% reduction in monthly migraine frequency—the standard measure by which the efficacy of migraine-prevention medications is judged. Twenty-seven percent of patients treated with 100 mg of topiramate per day exceeded this standard by achieving a minimum 75% reduction in monthly migraine frequency. Overall, the pooled analysis demonstrated that topiramate was associated with a significant reduction in mean monthly migraine frequency compared with placebo. This reduction in migraine frequency was observed as early as 1 week after initiation of topiramate therapy and continued throughout the 26-week double-blind phase.
Topiramate was shown to be effective, safe, and generally well tolerated throughout the 26-week double-blind phase of the two pivotal trials. The most common topiramate-associated adverse events included anorexia, cognitive deficits, diarrhea, fatigue, nausea, paresthesia, and taste alteration.13,14 An analysis of pooled safety data derived from more than 1500 patients enrolled in four multicenter, randomized, double-blind, placebo-controlled clinical trials of migraine prevention revealed that most of the adverse events associated with topiramate were mild or moderate in severity.18 Moreover, adverse events occurred more frequently during the titration period than during the maintenance period of the double-blind phase, and they did not usually lead to treatment discontinuation.18
A number of migraine-prevention medications are associated with weight gain, which many potential users find undesirable.19 Topiramate, by contrast, was associated with moderate weight loss during the two trials analyzed in the present study.13,14 Patients maintained on 100 mg of topiramate per day had a mean weight loss of 2.8 kg (6.2 lb) from baseline to the last measurement of the double-blind phase, compared to a mean weight loss of 0.3 kg (0.7 lb) for patients on placebo.
The efficacy of topiramate for migraine prevention is believed to be a result of its neurostabilizing properties, which may act to reduce neuronal hyperexcitability and cortical-spreading depression.20 Topiramate appears to fulfill Group 1 criteria for a first-line migraine-prevention medication, as described in evidence-based guidelines published by the US Headache Consortium.7 In the comprehensive management of frequent migraine headache, an approach using treatments individualized for each patient should be developed. This approach optimally uses multiple strategies, which may include education of the patient in self-help approaches and other nonpharmacologic treatments, as well as the use of appropriate first-line acute and preventive medications.
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Conclusion |
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TopMethodsResultsCommentConclusionReferences |
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50%
and 75% reductions in frequency of monthly attacks), according to pooled
efficacy data from two large, similarly designed, placebo-controlled
migraine-prevention trials. Based on its efficacy and tolerability profile,
topiramate at 100 mg per day (50 mg twice daily) should be the target dosage
for most patients with migraine. |
Footnotes |
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This research study was sponsored by Johnson & Johnson Pharmaceutical Research and Development LLC.
Submitted March 13, 2006; revision received September 6, 2006; accepted September 7, 2006.
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References |
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migraine in the United States: disability and economic costs. Arch
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7. Ramadan NM, Silberstein SD, Freitag FG, Gilbert TT, Frishberg BM. Evidence-based guidelines for migraine headache in the primary care setting: pharmacological management for prevention of migraine; 2000. American Academy of Neurology Web site. Available at: http://www.aan.com/professionals/practice/pdfs/gl0090.pdf. Accessed June 23, 2005.
8. Snow V, Weiss K, Wall EM, Mottur-Pilson C; for the American Academy of Family Physicians and American College of Physicians-American Society of Internal Medicine. Pharmacologic management of acute attacks of migraine and prevention of migraine headache. Ann Intern Med. 2002;137:840-849. Available at: http://www.annals.org/cgi/reprint/137/10/840.pdf. Accessed April 21, 2007.
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P=.002.
P<.001.
