Brandes JL, Saper JR, Diamond M, Couch JR, Lewis DW, Schmitt J, Neto W, Schwabe S, Jacobs D, for the MIGR-002 Study Group . Topiramate for Migraine PreventionA Randomized Controlled Trial. JAMA. 2004;291(8):965-973. doi:10.1001/jama.291.8.965
Author Affiliations: Nashville Neuroscience Group, Nashville, Tenn (Dr Brandes); Michigan Head Pain and Neurological Institute, Ann Arbor (Dr Saper); Diamond Headache Clinic, Chicago, Ill (Dr Diamond); University of Oklahoma Health Sciences Center, Oklahoma City (Dr Couch); Children's Hospital of the King's Daughters, Norfolk, Va (Dr Lewis); and Johnson & Johnson Pharmaceutical Research and Development, Raritan, NJ (Drs Neto, Schwabe, and Jacobs and Ms Schmitt).
Context Small open-label and controlled trials suggest that the antiepileptic
drug topiramate is effective for migraine prevention.
Objective To assess the efficacy and safety of topiramate for migraine prevention
in a large controlled trial.
Design, Setting, and Patients A 26-week, randomized, double-blind, placebo-controlled study was conducted
during outpatient treatment at 52 North American clinical centers. Patients
were aged 12 to 65 years and had a 6-month history of migraine (International
Headache Society criteria) and 3 to 12 migraines a month but no more than
15 headache days a month during a 28-day prospective baseline phase.
Interventions After a washout period, patients meeting entry criteria were randomized
to topiramate (50, 100, or 200 mg/d) or placebo. Topiramate was titrated by
25 mg/wk for 8 weeks to the assigned or maximum tolerated dose, whichever
was less. Patients continued receiving that dose for 18 weeks.
Main Outcome Measures The primary efficacy measure was change from baseline in mean monthly
migraine frequency. Secondary efficacy measures included responder rate (proportion
of patients with ≥50% reduction in monthly migraine frequency), reductions
in mean number of monthly migraine days, severity, duration, and days a month
requiring rescue medication, and adverse events. The month of onset of preventive
treatment action was assessed.
Results Of 483 patients randomized, 468 provided at least 1 postbaseline efficacy
assessment and comprised the intent-to-treat population. Mean monthly migraine
frequency decreased significantly for patients receiving topiramate at 100
mg/d (−2.1, P = .008) and topiramate at 200
mg/d (−2.4, P<.001) vs placebo (−1.1).
Statistically significant reductions (P<.05) occurred
within the first month with topiramate at 100 and 200 mg/d. The responder
rate was significantly greater with topiramate at 50 mg/d (39%, P = .01), 100 mg/d (49%, P<.001), and 200
mg/d (47%, P<.001) vs placebo (23%). Reductions
in migraine days were significant for the 100-mg/d (P =
.003) and 200-mg/d (P<.001) topiramate groups.
Rescue medication use was reduced in the 100-mg/d (P =
.01) and 200-mg/d (P = .005) topiramate groups. Adverse
events resulting in discontinuation in the topiramate groups included paresthesia,
fatigue, and nausea.
Conclusion Topiramate showed significant efficacy in migraine prevention within
the first month of treatment, an effect maintained for the duration of the
Migraine headache is a neurologic disorder associated with significant
disability and impaired quality of life,1,2 adversely
affecting daily activity and work-related productivity for many persons.3,4 Approximately 11% of the US population
experiences migraine,4 and a similar prevalence
is evident in other industrialized countries.5- 8 Many
migraineurs patients do not consult a physician for treatment, and even among
patients who are treated, less than one third report consistently effective
results with their current pharmacologic regimens, most of which include over-the-counter
analgesics.5 Furthermore, most migraine patients
require bed rest in addition to medication, indicating that migraine continues
to significantly affect their lives.5
The goals of managing migraine are to reduce migraine frequency, severity,
and disability; reduce reliance on poorly tolerated, ineffective, or unwanted
acute pharmacotherapies; improve quality of life; reduce headache-related
distress and psychologic symptoms; educate patients and enable them to manage
their disease; and avoid dose escalation of acute medications.9 Recent
studies suggest that habitual overuse of acute medications, including triptans,
ergots, and other analgesics, can lead to the development of chronic daily
headaches.10 Preventive medications can serve
an important role in the treatment of migraine by reducing migraine frequency
and by ameliorating dose escalation and the potential for overuse of acute
Topiramate is a broad-spectrum antiepileptic drug indicated as adjunctive
therapy and monotherapy for adults and pediatric patients and has shown efficacy
in the treatment of several other neurologic and psychiatric diseases, including
binge eating disorder,11 bulimia,12 and
essential tremor.13,14 Open-label15- 17 and small controlled18 studies with adult patients suggest that topiramate
may be efficacious for migraine prevention. Topiramate has multiple mechanisms
of action that could contribute to migraine prevention, including state-dependent
inhibition of voltage-gated sodium channels, inhibition of high-voltage–activated
calcium channels, inhibition of glutamate-mediated neurotransmission at α-amino-3-hydroxy-5-methylisoxazole-4-propionic
acid and kainate receptor subtypes, and enhancement of γ-aminobutyric-acidA-receptor–mediated chloride flux.19 It
is unclear which of these mechanisms (or which combination) is most important
in the prevention of migraine, but basic research into the pathophysiology
and genetics of migraine suggests that the disorder can develop through the
dysfunction of multiple systems. Recent research suggests that topiramate
may modulate trigeminovascular signaling, which could affect migraine pathogenesis.20
Patients were required to have an established history of migraine with
or without aura, as assessed by International Headache Society (IHS) criteria,
for at least 6 months before screening. Patients had to be aged 12 to 65 years
and to have between 3 and 12 migraines but no more than 15 headache days (migraine
or nonmigraine) per 28 days during the prospective baseline phase. A headache
day was defined as a calendar day during which the patient experienced headache
for at least 30 minutes. Women were required to be postmenopausal, surgically
incapable of bearing children, or practicing a medically acceptable method
of birth control for at least 1 month before study entry.
Patients were excluded from the study if they experienced headaches
other than migraine, episodic tension, or sinus headaches. Although episodic
tension and sinus headaches were not expected to respond to treatment, the
data were tabulated to confirm that these allowable headaches were accurately
captured. Patients were also excluded if their headaches failed to respond
to more than 2 adequate previous regimens of migraine-preventive medications,
if their onset of migraine occurred after age 50 years, or if they overused
analgesics or specific agents for the acute treatment of migraine episodes.
Examples of analgesic overuse included the following: more than 8 treatment
episodes (episode defined as any calendar day of usage) of ergot-containing
medications a month; more than 8 treatment episodes of triptans a month; or
more than 6 treatment episodes of potent opioids a month. The final decision
about analgesic use constituting overuse rested with the study investigators.
Patients also were excluded if they required continued use of the following
medications for any medical reason during the study: β-blockers, tricyclic
antidepressants, antiepileptics, calcium channel blockers, monoamine oxidase
inhibitors, nonsteroidal anti-inflammatory drugs (NSAIDs) daily, magnesium
supplements at high doses (eg, 600 mg/d), riboflavin at high doses (eg, 100
mg/d), corticosteroids, local anesthetics, botulinum toxin, or herbal preparations
such as feverfew or St John's wort. Nonpharmacologic prophylactic approaches
started at least 1 month before the prospective baseline phase could be continued
throughout the study. Patients with a history of nephrolithiasis were excluded,
as were patients who had participated in a topiramate study or had taken topiramate
for more than 2 weeks. Patients who had received an experimental drug or used
an experimental device within 30 days of screening also were excluded.
Eligible patients were assigned to 1 of 4 treatment groups according
to a computer-generated randomization schedule. Study medication was packaged
and labeled according to a medication code schedule generated before the trial.
Each bottle had a 2-part tear-off label; study medication identification was
concealed and could be revealed only in case of emergency. An interactive
voice response system was used to assign randomization numbers to patients,
and treatment assignments were not revealed to study patients, investigators,
clinical staff, or study monitors until all patients had completed therapy
and the database had been finalized.
The trial was 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 Declaration of Helsinki.
After evaluation for inclusion and exclusion criteria, eligible patients
entered a washout period of up to 14 days, during which any migraine-preventive
medications were tapered. This period was followed by a prospective baseline
phase of 28 days, during which headache and medication record information
completed by patients was reviewed. During the baseline phase, patients were
permitted to take rescue medication. Patients who completed the prospective
baseline phase and met all entry criteria were randomized to 1 of 4 treatment
groups: placebo or topiramate at 50 mg/d, 100 mg/d, or 200 mg/d.
Randomization was balanced by using permutated blocks of 4 and stratified
by center. Patients and clinicians were blinded to study medication. Patients
randomized to topiramate started at a dose of 25 mg/d; the daily dose was
increased by 25 mg weekly (for a total of 8 weeks) until patients reached
either their assigned dose or maximum tolerated dose, whichever was less.
Patients then continued receiving that amount for 18 weeks in 2 divided doses
(morning and evening). Patients who completed the 18-week maintenance period
or who exited the double-blind phase for lack of efficacy were eligible to
enter an open-label extension after a blinded transition period of 7 weeks.
In the event of tolerability problems, patients were given the opportunity
to reduce study medication by a maximum of 2 dose levels during the entire
26-week treatment phase.
The frequency, severity, and symptoms of all headaches or auras were
recorded by each patient in a diary, which was then transcribed into the patient's
case record form at each clinical visit. The transcription of each patient's
diary into the case record form was performed on days 1, 29, 57, 85, 113,
141, and 183 of the study. Across all treatment groups, headaches were classified
by using the patient's own judgment. Patients were permitted to take rescue
medication for headaches during the study, including during the baseline phase.
Each patient recorded the type and amount of rescue medication used. Allowable
medications included aspirin, acetaminophen, NSAIDs, ergot derivatives, triptans,
Hematologic (red blood cell count, white blood cell count, platelet
count, and hemoglobin and hematocrit levels), serum chemistry (including glucose,
sodium, potassium, serum urea nitrogen, and total protein levels), and liver
function tests (alkaline phosphatase, aspartate aminotransferase, alanine
aminotransferase, and bilirubin levels) were performed for all patients at
specific intervals throughout the study, and physical examinations were performed
at the beginning and end of the study. Hematologic and serum chemistry tests
were performed at the first, third, and final visits of the double-blind phase.
Liver function tests were performed each clinic visit. A urinalysis was performed
at baseline only. Vital signs and weight were recorded at each clinic visit.
Adverse events during the study were recorded and followed up until resolved
or until a clinically stable end point was achieved.
The primary efficacy measure was a comparison of the reduction in mean
28-day monthly migraine frequency from the baseline phase through the entire
double-blind phase between the groups treated with topiramate and placebo.
Patients recorded the times and dates on which migraine symptoms started and
stopped. Migraine frequency was assessed by the number of migraine periods.
A migraine period was defined as any occurrence of migraine headache that
started, ended, or recurred within 24 hours. Pain persisting more than 24
hours after its initial onset was considered to be a new, distinct migraine
period. Aura was not counted as a migraine headache unless acute treatment
was used during aura symptoms.
Secondary efficacy measures included proportion of patients responding
to treatment (as measured by a 50% or more reduction in monthly migraine frequency);
the mean change in monthly migraine days, severity, and duration; and the
change in number of days requiring rescue medication per month. A migraine
day was defined as any calendar day during which a patient had a migraine
headache lasting at least 30 minutes.
The month of onset of action for each topiramate dose was assessed.
Analyses were performed to identify the first cumulative monthly period (ie,
month 1, months 1 and 2, up to months 1 through 6) during which there was
a statistically significant reduction in the monthly migraine frequency for
that topiramate group compared with placebo. In addition, this difference
was required to be maintained for all subsequent cumulative periods. This
month would then be identified as the onset of action.
Safety was assessed by reports of adverse events, physical and neurologic
examinations, and clinical laboratory tests.
According to pilot placebo-controlled studies, a sample size of 120
patients per treatment group was calculated to give a 95% power to detect
a difference of 1.19 in change from baseline in mean monthly migraine frequency
between dose group and placebo at the 5% 2-sided significance level, assuming
2.50 as the common SD. Efficacy analyses were conducted on the intent-to-treat
population, which was defined as randomized patients who had at least 1 postbaseline
efficacy assessment. For patients discontinuing early, the mean monthly migraine
frequency during the entire double-blind treatment phase and the cumulative
monthly periods were computed according to the migraine periods observed before
The primary efficacy measure was assessed with a linear model, with
treatment and analysis center as factors and the baseline value as a covariate.
As is done in the Tukey-Ciminera-Heyse trend test,21 treatment
groups were compared by using equally spaced contrasts of treatment effects
within the linear model. To control the type I error, linear contrasts were
implemented with a step-down procedure. The hypothesis of a trend in dose
response among all doses and placebo was tested by the corresponding equally
spaced contrast at the first step at the .05 level. If the first step was
statistically significant, then the 200-mg/d group would be declared different
from placebo and the procedure would proceed to the second step, in which
the hypotheses of a trend among placebo, the mid dose, and the low dose would
be similarly tested. Finally, the low dose would be compared with placebo
only if the second step test was statistically significant.
For all secondary variables and migraine frequencies during cumulative
monthly periods, comparisons of each topiramate group with placebo were analyzed
with pairwise comparisons, and nominal P values are
given. The proportions of patients responding to treatment were analyzed with
the Cochran-Mantel-Haenszel test stratified by analysis center. All other
secondary variables, as well as the analyses for onset of action, were based
on linear models corresponding to the model used for the primary efficacy
measure. Estimates of various treatment effects and their graphical depictions
are based on the treatments' least squares means, which are the means adjusted
for the variables in the statistical model. Analyses were done with SAS (version
6.12; SAS Institute Inc, Cary, NC) at a significance level of .05.
Figure 1 depicts patient disposition
during the study. Of 693 patients enrolled, 210 did not meet screening criteria,
although specific reasons for exclusion were not tabulated. Four hundred eighty-three
patients were randomized to 4 treatment groups; 468 were in the intent-to-treat
population. Fifteen patients (3%) were randomized but did not provide postbaseline
efficacy data and were not included in the intent-to-treat population. Fifty-seven
of 120 randomized patients (48%) in the placebo group, 61 of 120 (51%) in
the topiramate at 50 mg/d group, 59 of 122 (48%) in the topiramate at 100
mg/d group, and 51 of 121 (42%) in the topiramate at 200 mg/d group withdrew
during the study.
Placebo patients withdrew most often because of lack of efficacy, and
topiramate patients withdrew most often because of adverse events. Twenty-one
of 114 placebo-treated patients (18%) withdrew because of lack of efficacy
compared with 15 of 117 (13%) in the topiramate at 50 mg/d group, 11 of 120
(9%) in the topiramate at 100 mg/d group, and 12 of 117 (10%) in the topiramate
at 200 mg/d group. Fourteen of 114 (12%) patients in the placebo group withdrew
because of adverse events compared with 20 of 117 (17%) in the topiramate
at 50 mg/d group, 32 of 120 (27%) in the topiramate at 100 mg/d group, and
25 of 117 (21%) in the topiramate at 200 mg/d group. No patients were required
to be unblinded during the study. Two hundred fifty-five patients completed
the study. For patients discontinuing early, the mean monthly migraine frequency
during the double-blind treatment phase was computed according to the migraine
periods observed before discontinuation because no data were available beyond
The mean (SD) monthly migraine frequency for all patients at baseline
was 5.5 (2.33; range, 1.0-14.5), and the mean monthly number of migraine days
was 6.5 (2.83; range, 1.0-18.0) (Table 1).
Eighty-seven percent (406/468) of patients were women. At baseline,
patients had a mean (SD) weight of 76.5 (19.55) kg and a mean body mass index
of 27.8 (6.51). Baseline clinical and demographic characteristics were balanced
between treatment groups. During the 3 months before the prospective baseline
phase, 15%, 18%, and 19% of patients in the topiramate treatment groups at
50 mg, 100 mg, and 200 mg, respectively, and 24% of patients in the placebo
group were receiving preventive medications. However, the differences were
not statistically significant. The most common preventive medications taken
during that time included β-blocking agents (propranolol, atenolol, nadolol),
antiepileptics (valproate, gabapentin), tricyclic antidepressants (amitriptyline,
nortriptyline, imipramine), and selective serotonin reuptake inhibitors.
Topiramate-treated patients received therapy for a mean duration of
127 days during the double-blind phase, whereas those receiving placebo received
therapy for a mean duration of 137 days. The median daily dose of topiramate
was 46.5 mg/d for the 50 mg/d group (97.4% achieved target dose), 85.6 mg/d
for the 100 mg/d group (85.8% achieved target dose), and 150.2 mg/d for the
200 mg/d group (69.2% achieved target dose). For the placebo group, 85.1%
achieved the target dose.
The primary analysis showed that topiramate was associated with greater
reductions in mean monthly migraine frequency than placebo. Mean (SD) monthly
migraine frequency decreased from 5.4 (2.4) at baseline to 4.1 (3.6) during
the double-blind phase for patients treated with topiramate at 50 mg/d, from
5.8 (2.6) to 3.5 (3.5) for patients treated with topiramate at 100 mg/d, and
from 5.1 (2.0) to 3.0 (2.2) for patients treated with topiramate at 200 mg/d
compared with a decrease from 5.6 (2.2) to 4.5 (2.9) for patients treated
with placebo. The change from baseline (Figure
2) was statistically significant for patients treated with topiramate
at either 100 mg/d (P = .008) or 200 mg/d (P<.001) in comparison with placebo but was not statistically
significant for patients treated with topiramate at 50 mg/d (P = .48) in comparison with placebo.
The month of onset of preventive treatment action between topiramate
groups and placebo is shown in Figure 3,
in which migraine frequencies during cumulative monthly periods are presented
by treatment group and monthly period. For the topiramate groups at 100 mg/d
and 200 mg/d, statistically significant (P<.05)
reductions in migraine frequency, compared with those of the placebo group,
occurred by month 1 of treatment and remained statistically significant for
all subsequent monthly periods through the end of the double-blind phase.
For the topiramate at 50 mg/d group, no statistically significant differences
compared with placebo were seen for any cumulative monthly periods.
The proportion of patients with at least a 50% reduction in monthly
migraine frequency (responder rate) for patients treated with topiramate was
significantly larger than placebo at all doses assessed. Patients treated
with topiramate at 50 mg/d (39%, P = .01), 100 mg/d
(49%, P<.001), or 200 mg/d (47%, P<.001) exhibited a significantly better response than patients
treated with placebo (23%).
Topiramate was also associated with larger reductions compared with
placebo in the mean monthly number of migraine days and mean monthly number
of days when rescue medication was needed. Compared with that for placebo,
the mean reduction in the monthly number of migraine days was statistically
significant for the topiramate at 100 mg/d group (P =
.003) and the 200 mg/d group (P<.001); the respective
least squares means (SEs) for the topiramate at 100 mg/d, 200 mg/d, and placebo
groups were −2.6 (0.31), −2.9 (0.32), and −1.3 (0.32) (Figure 4). The mean reduction in the monthly
number of days when acute rescue medication was used was also significantly
greater for patients treated with topiramate at 100 mg/d (P = .01) or 200 mg/d (P = .005) compared with
placebo; the respective least squares means (SEs) for the topiramate at 100
mg/d and 200 mg/d and placebo groups were −2.1 (0.29), −2.2 (0.29),
and −1.0 (0.29). The mean reductions in the monthly number of migraine
days and monthly number of days when acute rescue medication was used were
not statistically significant for the topiramate at 50 mg/d group compared
with that for the placebo group.
There was a statistically significant difference in the mean change
from baseline through the double-blind phase in migraine duration between
the topiramate at 200 mg/d group and placebo (P =
.007) but no significant differences between placebo and the topiramate at
50 mg/d (P = .61) or 100 mg/d groups (P = .19). The respective least squares means (SEs) for the topiramate
at 200 mg/d, 100 mg/d, and 50 mg/d and placebo groups were −1.2 (0.17),
−0.8 (0.17), −0.6 (0.17), and −0.5 (0.18). There was a statistically
significant difference in mean migraine severity between placebo and the topiramate
at 100 mg/d group (P = .04) but not between placebo
and the topiramate at 50 mg/d (P = .61) or 200 mg/d
(P = .46) groups (respective least squares means
[SEs] for the 200 mg/d, 100 mg/d, 50 mg/d, and placebo groups were −0.1
[0.04], −0.2 [0.04], −0.1 [0.04], and −0.1 [0.04]).
Treatment-emergent adverse events commonly associated with topiramate
use observed to occur in 10% or more of patients treated with topiramate at
100 mg/d included paresthesia (59, 50%), fatigue (17, 14%), anorexia (16,
13%), diarrhea (13, 11%), weight loss (13, 11%), hypesthesia (13, 11%), difficulty
with memory (12, 10%), and nausea (12, 10%; Table 2). Among these, events leading to discontinuation in patients
treated with topiramate at 100 mg/d included paresthesia (10, 8%), fatigue
(9, 8%), diarrhea (3, 3%), hypesthesia (3, 3%), difficulty with memory (4,
3%), and confusion (5, 4% [treatment-emergent incidence, 6%]). All other events
leading to discontinuation were reported at an incidence of 2% or less. Most
adverse events were mild to moderate. Three cases of renal calculus were reported,
with treatment being discontinued in 2 patients. There were no reports of
glaucoma (primary or secondary) or acute myopia in any patients. There were
no clinically important mean changes in laboratory values or vital signs.
Small mean changes in serum bicarbonate and chloride levels were consistent
with topiramate's activity as a carbonic anhydrase inhibitor.
Patients treated with topiramate lost weight compared with the placebo
group. The mean (SD) change in weight percentage was significantly greater
for patients treated with topiramate at 50 mg/d (−2.2% [4.39%]; P<.001), 100 mg/d (−3.3% [4.19%]; P<.001), or 200 mg/d (−4.6% [4.65%]; P<.001)
compared with placebo-treated patients, who gained a mean of 0.2% (3.82%)
of their weight.
Within the first month of treatment, topiramate at doses of 100 or 200
mg/d showed significant reductions compared with placebo in the primary measure
of migraine frequency, and this effect was maintained for the entire double-blind
treatment phase. Treatment with topiramate at doses of 100 or 200 mg/d was
associated with significant improvements during the entire double-blind treatment
phase for several other migraine efficacy measures, including migraine days
per month and acute rescue medication days per month, and demonstrated a significantly
higher responder rate than placebo. Most treatment-emergent adverse events
were mild to moderate; those occurring in 10% or more of patients and those
associated with discontinuation are listed in Table 2.
The number of patients experiencing adverse advents, including those
resulting in study discontinuation, is acknowledged, although this outcome
is not unexpected for drugs of this class and would not prevent the use of
topiramate in the population of patients requiring preventive migraine treatment.
In the clinical experience of the authors, slow upward titration, perhaps
even slower than that used in the trial, may enhance tolerability and help
to avoid many of the adverse events reported. Many of the events may also
be transient or manageable. For example, paresthesia associated with topiramate
therapy could be ameliorated with potassium supplements,22 although
this claim has not been confirmed in a controlled study. The weight loss associated
with topiramate therapy is not uncommon; a study in obese individuals found
that topiramate therapy was associated with significant weight loss through
76 weeks of treatment.23 Because many of the
agents used for prophylactic antimigraine therapy are associated with weight
gain, the availability of an agent associated with weight loss may be of benefit
to certain patient populations.
The study was not sized to detect differences in adverse event rates.
However, the sample size compares favorably with studies of preventive medications
for migraine, including a recent trial of extended-release valproate, which
had 239 randomized patients, and a small controlled trial of candesartan,
which had 60 patients.24,25
This is 1 of 2 large North American trials that together encompass 937
patients and constitute the largest controlled trial to date of a migraine-preventive
agent. The US Headache Consortium's evidence-based guidelines classify medications
for migraine prevention according to their established clinical efficacy,
adverse events, and safety profile, as well as the clinical experience of
US Headache Consortium participants.26 Drugs
assigned a level I designation are supported by clinical studies with independent,
blinded comparisons, accepted standards of physiology and diagnosis, and a
large number of consecutive patients. Clinical efficacy is also evaluated
on strength of evidence, scientific effect, and clinical impression of effect.
For example, strength of clinical evidence is graded A, B, or C, where "A"
designates the existence of multiple, well-designed, randomized clinical trials
that yield a consistent pattern of findings. This study and a concurrently
run controlled trial (Stephen Silberstein, MD, et al, unpublished data, 2003)
represent remarkably consistent results encompassing more than 900 patients
and fulfill the criteria for level I designation.
Patients in the 2 studies exhibited a significant reduction in migraine
frequency at a topiramate dose of either 100 or 200 mg/d. This response was
evident within the first month of treatment, which was also common to both
studies, and the reduction in migraine frequency for patients taking topiramate
at either 100 or 200 mg/d was significantly greater than that associated with
placebo at each monthly assessment (Stephen Silberstein, MD, et al, unpublished
data, 2003). Previous reports about the efficacy of divalproex sodium in migraine
prevention cited responder rates of 44% to 48%.27,28 An
extended-release formulation of divalproex was associated with a responder
rate of 41% during the final 4 weeks of treatment and a mean reduction of
1.7 migraine days a month from 6.3 at baseline.24 A
recent crossover study of candesartan, an angiotensin II receptor antagonist,
used the number of headache days as a primary efficacy measure and reported
a responder rate of 40%.25 However, these studies
were considerably smaller and shorter.
Many studies assessing older drugs for migraine prevention were conducted
before the IHS guidelines for clinical trials were published in 1991.29 Therefore, it is often difficult to place more current
results in context with earlier studies because methodologic procedures have
evolved. For example, some earlier studies used a headache index or score
to assess efficacy in migraine prevention.30,31 Others
used a single-blind placebo run-in period before randomization,32- 34 which
does not necessarily diminish the appropriateness of older medications for
migraine prevention; a recent report by Diener and colleagues,35 for
example, found that in a large trial (N = 808), 46% of patients treated with
flunarizine at 5 mg/d, 53% of patients treated with flunarizine at 10 mg/d,
and 48% of patients treated with controlled-release propranolol at 160 mg/d
exhibited at least a 50% reduction in monthly headache frequency.
In previous studies, before and after the IHS guidelines, agents with
class I data (including propranolol, amitriptyline, and valproate) showed
an approximately 50% responder rate.9 The results
of the current study demonstrate that topiramate is effective in migraine
prevention, with results at least comparable to those of these other agents.
Topiramate showed statistically significant efficacy in migraine prevention
within the first month of treatment, an effect maintained for the duration
of the double-blind phase. Topiramate appeared to be safe and had an acceptable
tolerability profile, although pooled analyses of a larger number of patients
and data on longer treatment duration should help complete the safety profile.
Among several treatment-emergent adverse events was dose-dependent weight
loss. According to these data, slow titration and an initial target dose of
100 mg/d in 2 divided doses appears advisable.