SECTION EDITOR: IRA SHOULSON, MD

Topiramate in Migraine Prevention

Results of a Large Controlled Trial
Stephen D. Silberstein, MD; Walter Neto, MD; Jennifer Schmitt, MS; David Jacobs, MD; for the MIGR-001 Study Group
Background: Open-label trials andsmall controlledstud-
ies report topiramates efficacy in migraine prevention.
Objective: To assess the efficacy and safety of topira-
mate as a migraine-preventive therapy.
Design: A26-week, randomized, double-blind, placebo-
controlled study.
Setting: Outpatient treatment at 49 US clinical centers.
Patients: Patients were aged 12 to 65 years, had a
6-month International Headache Society migraine his-
tory, and experienced 3 to 12 migraines per month, but
had 15 or fewer headache days per month during the 28-
day baseline period.
Interventions: Participants were randomized to pla-
cebo or topiramate, 50, 100, or 200 mg/d, titrated by 25
mg/wk to the assigned dose or as tolerated in 8 weeks;
maintenance therapy continued for 18 weeks.
Main Outcome Measures: The primary efficacy as-
sessment was a reduction in mean monthly migraine fre-
quency across the 6-month treatment phase. Secondary
end points were responder rate, time to onset of action,
mean change in migraine days per month, and mean
change in rescue medication days per month.
Results: Four hundred eighty-seven patients were ran-
domized, and 469 composed the intent-to-treat popula-
tion. The meanSD monthly migraine frequency de-
creased significantly for the 100-mg/d group (from
5.42.2 to 3.32.9; P.001) and the 200-mg/d group
(from5.62.6 to 3.32.9; P.001) vs the placebo group
(from5.62.3to4.63.0); improvements occurredwithin
the first treatment month. Significantly more topiramate-
treated patients (50 mg/d, 35.9% [P=.04]; 100 mg/d,
54.0% [P.001]; and 200 mg/d, 52.3% [P.001]) ex-
hibited a 50% or more reduction in monthly migraine
frequency than placebo-treated patients (22.6%). Ad-
verse events included paresthesia, fatigue, nausea, an-
orexia, and taste per version.
Conclusion: Topiramate, 100 or 200 mg/d, was effec-
tive as a preventive therapy for patients with migraine.
Arch Neurol. 2004;61:490-495
M
IGRAINE IS A COMMON,
episodic, disabling dis-
order occurring in17%
of women, 6% of men,
and 4% of children
yearly.
1
Approximately53%of patients with
severe migraines report that their attacks
require bed rest or are a source of severe
impairment.
2
The cost of missed work-
days and impaired performance because of
migraine is estimated at $18 billion.
1,2
Migraine preventioncanimprove care
and outcomes. The US Headache Consor-
tium recommends preventive treatment
whenthe followingoccurs: (1) migraine sig-
nificantly interferes with daily routine, de-
spite acute treatment; (2) acute medica-
tions fail, are contraindicated, or lead to
troublesome adverse events (AEs); (3) acute
medications are overused; (4) there are spe-
cial circumstances, such as hemiplegic mi-
graine or risk of permanent neurologic in-
jury; (5) the patient experiences frequent
headaches (2 per week); or (6) the pa-
tient prefers preventive treatment.
3
Effective preventive migraine treat-
ments include antiepileptic drugs (AEDs),
antidepressants, and -blockers. Topira-
mate (Topamax; Ortho-McNeil Pharma-
ceutical, Raritan, NJ), an AED, has dem-
onstrated potential utility in other
neurologic disorders.
4-8
Preliminary re-
ports
9-11
suggest that topiramate may be ef-
fective for migraine prevention. This study
evaluated the safety and efficacy of topira-
mate vs placebo in migraine prevention.
METHODS
This was a randomized, double-blind, placebo-
controlled, parallel-group, multicenter USstudy.
Topiramateat 50, 100, or 200mg/dor matching
CLINICAL TRIALS
Author affiliations and
financial disclosures are listed
at the end of this article. A list
of the clinical investigators of
the MIGR-001 Study Group
appears on page 494.
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490
2004 American Medical Association. All rights reserved.
placebowas givenfor a 26-weektotal treatment period. Enrolled
patients hadanestablishedhistory(6months) of migrainewith
or without aura (International Headache Society criteria).
INCLUSION CRITERIA
Patients were aged 12 to 65 years and experienced 3 to 12 mi-
graines during the prospective 28-day baseline phase.
12,13
Women
had to be postmenopausal, surgically incapable of childbear-
ing, or practicing a medically acceptable method of birth con-
trol for 1 month or longer before study enrollment.
EXCLUSION CRITERIA
Patients were excluded if they experienced headaches other than
migraine, episodic tension, or sinus headaches; experienced the
failure of more than 2 previous adequately dosed migraine-
preventive medications; had migraine onset after the age of 50
years; overused acute migraine treatments (8 treatment days
per month of ergots or triptans); or used -blockers, tricyclic
antidepressants, AEDs, calcium channel blockers, mono-
ami ne oxi dase i nhi bi tors, dai l y nonsteroi dal anti -
inflammatory drugs, high-dose magnesium supplements (600
mg/d), high-dose riboflavin (100 mg/d), corticosteroids, local
anesthetics, botulinumtoxin, or herbal preparations during the
study. 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 of screening were excluded.
STUDY DESIGN AND RANDOMIZATION AND BLINDING
Eligible subjects had a washout period of up to 14 days, dur-
ing which migraine-preventive medications were tapered off.
They then entered a 28-day prospective baseline phase. On
completion of the baseline phase, headache records were re-
viewed. Baseline phase completers who met the enrollment cri-
teria were randomized (permutation blocks of 4 stratified by
center) to placebo or topiramate, 50, 100, or 200 mg/d. Pa-
tients and clinicians were blinded to study medication with pre-
printed medication code labels. Sealed envelopes containing
study drug information were provided to investigators in case
such information was required on unblinding a patient. Pla-
cebo was identical in appearance and packaging to active drug.
The double-blindphase was dividedinto titration(8 weeks)
and maintenance (18 weeks). Topiramate was started at 25 mg/d
and increased by 25 mg/wk for 8 weeks, until the assigned or
maximum tolerated dose was reached. That dose was contin-
ued for 18 weeks. Study drug was administered daily in di-
vided doses (every morning and every night).
Duringthe double-blindphase, clinic visits were scheduled
every 4weeks, headache andmedicationrecords were collected
and reviewed and new records were dispensed, vital signs and
bodyweight weremeasured, aurinepregnancytest wasperformed,
andAEs were recorded. Unusedstudy medicationwas collected
and counted, and additional study medication was dispensed.
Subjects were permitted to take acute medications, record-
ing the type and amount used. Allowable medications included
aspirin, acetaminophen, nonsteroidal anti-inflammatory drugs,
ergot derivatives, triptans, and opioids.
The trial was conducted with full approval by the institu-
tional review boards at the respective sites. Each subject pro-
vided informed consent, which conformed to the current re-
vision of the Declaration of Helsinki.
EFFICACY MEASURES
The primary efficacy measure was a comparisonamong the topi-
ramate and placebo groups of the reduction in mean migraine
frequency frombaseline through the entire double-blind phase.
Patients recorded start and stop times for headache and mi-
graine aura. Migraine headache frequency was assessed using
migraine periods (migraine headache that started, ended, or re-
curred within 24 hours). If the headache persisted for longer
than 24 hours, it was considered a new migraine period. Aura
alone was not counted as a migraine headache unless acute mi-
graine treatment was used.
Secondary efficacy end points included the time to onset
of action, the proportion of subjects responding to treatment
(50% reduction in the monthly migraine frequency), mean
change inmonthly migraine days, and change innumber of days
per month requiring rescue medication fromthe end of the pro-
spective baseline phase through the double-blind phase. All ef-
ficacy measures were prospectively designated.
SAFETY EVALUATIONS
Safety was assessed by AE occurrence, physical and neuro-
logic examinations, and clinical laboratory tests. Adverse events
were recorded after study medication was initiated and were
followed up until resolved or at a clinically stable end point.
Clinical laboratory tests were performed at selected intervals
throughout the 26-week study.
STATISTICAL ANALYSIS
Based on pilot placebo-controlled studies,
11
a sample size of 120
subjects per treatment group was calculated to give 95% power
to detect at the 5% 2-sided significance level a treatment differ-
ence of 1.19 change from baseline in migraine frequency be-
tween any pair of treatment groups, assuming 2.50 as the com-
mon standard deviation.
The primary efficacy measure was assessed using a linear
model with treatment and analysis center as factors and base-
line value as a covariate. The least squares means, which are
means adjusted for the variables in the statistical model, were
used to compare treatment groups. Comparisons of topira-
mate doses with placebo were made using the Tukey-
Ciminera-Heyse trend test,
14
performed in a step-down fash-
ion, including all doses and placebo at the first stage. Key
secondary efficacy measures were analyzed using the same
linear model, and unadjusted pairwise comparisons were
made between placebo and each topiramate group. The pro-
portion of subjects responding to treatment was analyzed
using the Cochran-Mantel-Haenszel pairwise test procedure.
Efficacy analyses were conducted on the intent-to-treat popu-
lation, which was defined as those randomized patients who
had at least 1 postbaseline efficacy assessment. For subjects
discontinuing the study early, the average monthly migraine
period rate was computed based on the migraine periods
observed before discontinuation.
RESULTS
Patients (N=487) were randomized to placebo (n=117)
or topiramate, 50 mg/d (n=125), 100 mg/d (n=128), or
200mg/d(n=117). The intent-to-treat population(n=469)
had at least 1 postbaseline efficacy assessment. During the
6-monthtreatment phase, 204 participants withdrew. Rea-
sons included patient choice, lost to follow-up, AEs, and
lack of efficacy (Figure 1).
Baseline anddemographic characteristics were evenly
balanced among groups (Table 1). The meanSDdaily
double-blind phase dose of topiramate was 44.76.4 mg
for the 50-mg/d group, 78.321.2 mg for the 100-mg/d
group, 116.246.9 mg for the 200-mg/d group, and
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491
2004 American Medical Association. All rights reserved.
143.343.4 mg for the placebo group (based on the al-
gorithmused for the topiramate, 200 mg/d, group). Most
(96.6%) of the subjects treated with topiramate, 50 mg/d,
achieved the target dose; 87.2% of the topiramate, 100
mg/d, and 58.0% of the topiramate, 200 mg/d, groups
reached their respective target doses.
EFFICACY MEASURES
Topiramate was associated with a significantly greater de-
crease than placebo in meanSD monthly migraine fre-
quency: topiramate, 100 mg/d, decreased the frequency
from 5.42.2 at baseline to 3.32.9 during the double-
blind phase; 200 mg/d, from5.62.6 to 3.32.9; 50 mg/d,
from 5.42.4 to 4.13.6; and placebo, from 5.62.3 to
4.63.0. The mean change frombaseline in migraine fre-
quency (Figure 2) was significantly greater for pa-
tients treated with either 100 or 200 mg/d of topiramate
(P.001 vs placebo) but not for those treated with 50
mg/d of topiramate (P=.24).
Secondary end points also demonstrated statisti-
cally significant improvements. The onset of action was
evident at the first month of treatment (Figure 3).
Topiramate, 100 or 200 mg/d, was associated with sta-
tistically significant reductions in migraine frequency
compared with placebo from the first month of treat-
ment through the end of the double-blind phase
(P.02). Although a significant difference (P=.03)
Screened (N= 658)
Excluded (n= 171)
Topiramate,
50 mg/d (n= 125)
Placebo
(n= 117)
Topiramate,
100 mg/d (n= 128)
Topiramate,
200 mg/d (n = 117)

Withdrew
(n= 2)

Withdrew
(n= 8)

Withdrew
(n = 3)

Withdrew
(n = 5)
Intent-to-Treat
Population
(n= 115)
Intent-to-Treat
Population
(n= 117)
Intent-to-Treat
Population
(n = 125)
Intent-to-Treat
Population
(n= 112)
Withdrew (n= 46)
Subject Choice
(n= 3)
Lost to Follow-up
(n = 5)
Adverse Event
(n = 11)
Lack of Efficacy
(n = 21)
Other (n= 6)
Withdrew (n= 49)
Subject Choice
(n = 10)
Lost to Follow-up
(n = 4)
Adverse Event
(n = 21)
Lack of Efficacy
(n = 10)
Other (n= 4)
Withdrew (n= 42)
Subject Choice
(n= 6)
Lost to Follow-up
(n= 2)
Adverse Event
(n= 24)
Lack of Efficacy
(n= 6)
Other (n= 4)
Withdrew (n = 67)
Subject Choice
(n = 8)
Lost to Follow-up
(n = 6)
Adverse Event
(n = 38)
Lack of Efficacy
(n = 8)
Other (n= 7)
Completed (n= 69) Completed (n= 68) Completed (n= 83) Completed (n= 45)
Randomized (n= 487)
Figure 1. Patient disposition. The asterisk indicates patients who did not
provide at least 1 postbaseline efficacy assessment.
0
1.0
0.5
1.5
2.0
2.5
Placebo Group
0.8
1.3
2.1
2.2
50 100 200
Topiramate-Treated Groups, mg/d
M
e
a
n

C
h
a
n
g
e

F
r
o
m

B
a
s
e
l
i
n
e

i
n
M
o
n
t
h
l
y

M
i
g
r
a
i
n
e

F
r
e
q
u
e
n
c
y
Figure 2. Mean (least squares value) change from baseline in monthly
migraine frequency. Missing data were computed based on the frequency of
migraines observed before discontinuation. The asterisk indicates P.001 vs
placebo.
0
1.0
0.5
1.5
2.0
2.5
0 1 2 3 4 5 6
Treatment Month
M
e
a
n

C
h
a
n
g
e

F
r
o
m

B
a
s
e
l
i
n
e

i
n
M
o
n
t
h
l
y

M
i
g
r
a
i
n
e

F
r
e
q
u
e
n
c
y
Placebo
Group
Topiramate,
50 mg/d,
Group
Topiramate,
100 mg/d,
Group
Topiramate,
200 mg/d,
Group

Figure 3. Mean (least squares value) change from baseline in monthly

migraine frequency. The asterisk indicates P.02 vs placebo; and the
dagger, P=.03 for topiramate, 50 mg/d, vs placebo.
Table 1. Demographic and Baseline Characteristics*
Characteristic
Placebo
Group
(n = 115)
Topiramate-Treated Groups, mg/d
50
(n = 117)
100
(n = 125)
200
(n = 112)
Age, y 40.4 11.5 40.2 11.5 40.6 11.0 40.5 11.4
Sex
Male 12 (10.4) 10 (8.5) 13 (10.4) 18 (16.1)
Female 103 (89.6) 107 (91.5) 112 (89.6) 94 (83.9)
Body weight, kg 75.6 18.5 75.7 18.9 78.9 19.3 76.7 20.1
Migraine frequency/mo 5.6 2.3 5.4 2.4 5.4 2.2 5.6 2.6
Migraine days/mo 6.4 2.6 6.4 2.7 6.4 2.7 6.6 3.1
Rescue medication use, d/mo 6.1 3.0 5.8 2.5 5.9 2.5 6.1 2.6
*Data are given as mean SD unless otherwise indicated.
Data are given as number (percentage) of patients.
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492
2004 American Medical Association. All rights reserved.
between topiramate, 50 mg/d, and placebo was
observed at month 1, no significant differences were
seen after that (P.12).
The responder rate (50%reductioninmonthly mi-
graine frequency) for the 100-mg/d topiramate group was
54.0% (P.001 vs placebo); for the 200-mg/d group,
52.3% (P.001 vs placebo); and for the 50-mg/d group,
35.9%(P=.04 vs placebo). The rate for the placebo group
was 22.6%.
The meanSDmonthly migraine days were signifi-
cantly reduced for the groups treated with topiramate,
100 mg/d (from6.42.7 to 3.73.3; P.001) or 200 mg/d
(from6.63.1 to 3.93.4; P.001), compared with pla-
cebo (from6.42.6 to 5.33.6), but not for those treated
with topiramate, 50 mg/d (from 6.42.7 to 4.84.0;
P=.13). The meanSD monthly acute rescue medica-
tion days decreased significantly for patients treated with
topiramate, 100 mg/d (from5.92.5 to 4.03.4; P=.005),
or 200 mg/d (from 6.12.6 to 4.02.8; P=.002), vs pla-
cebo (from6.13.0 to 5.23.3), but not for those treated
with topiramate, 50 mg/d (from 5.82.5 to 4.53.1;
P=.12).
SAFETY MEASURES
The most common AEs observed were paresthesia, fa-
tigue, anorexia, taste perversion, and nausea (Table 2).
There was a trend toward higher AE incidences for pa-
tients who received 200-mg/d topiramate. Adverse events
such as language problems and difficulty concentrating
occurred in less than 10%of patients in the 50- and 100-
mg/d topiramate groups.
Renal calculi were reported in 4 patients; however,
in only 1 patient (in the 200-mg/d topiramate group) was
medication discontinued and lithotripsy performed. The
meanSDbody weight (vs baseline values) in all 3 topi-
ramate groups (50 mg/d, 2.4%4.4%, P=.004; 100 mg/d,
3.8%4.1%, P.001; and 200 mg/d, 3.9%5.1%,
P.001) showed a statistically significant reduction vs
placebo (0.3%11.5%) (Figure 4).
COMMENT
To our knowledge, this is the first completed multi-
center, prospective, placebo-controlled, randomizedclini-
cal trial of topiramate in migraine prevention. Topira-
mate, 100 or 200 mg/d, was associated with statistically
significant reductions in migraine frequency, migraine
days, and acute medication use and with significantly
higher responder rates vs placebo. Some benefits were
observed with topiramate, 50 mg/d, but statistical dif-
ferences from placebo were achieved only for the re-
sponder rate end point.
Antiepileptic drugs are increasingly recommended
for migraine prevention because of placebo-controlled
double-blind trials that prove them effective.
3
In its evi-
dence-based guidelines for migraine headache treat-
ment, the US Headache Consortium Level I criteria for
clinical studies require independent blind comparisons
and accepted standards of diagnosis among many con-
secutive patients.
3
To our knowledge, at the time of its
completion, this randomized, double-blind, placebo-
controlled topiramate trial for migraine prevention rep-
resented the largest set of patients involved in con-
1
0
1
3
2
4
5
Placebo Group
0.3
2.4

3.8

3.9

50 100 200
Topiramate-Treated Groups, mg/d
%

C
h
a
n
g
e

i
n

M
e
a
n

B
o
d
y

W
e
i
g
h
t

v
s
B
a
s
e
l
i
n
e
Figure 4. Mean (least squares value) percentage change from baseline in
body weight. The asterisk indicates P=.004 vs placebo; the dagger, P.001
vs placebo.
Table 2. Relevant Treatment-Emergent Adverse Events*
WHO Dictionary
Preferred Term
Placebo Group
(n = 116)
Topiramate, 50 mg/d,
Group (n = 118)
Topiramate, 100 mg/d,
Group (n = 126)
Topiramate, 200 mg/d,
Group (n = 113)
Total
Events
Events Led to
Withdrawal
Total
Events
Events Led to
Withdrawal
Total
Events
Events Led to
Withdrawal
Total
Events
Events Led to
Withdrawal
Paresthesia 8 (6.9) 2 (1.7) 43 (36.4) 5 (4.2) 59 (46.8) 6 (4.8) 53 (46.9) 7 (6.2)
Fatigue 12 (10.3) 2 (1.7) 11 (9.3) 2 (1.7) 14 (11.1) 3 (2.4) 20 (17.7) 3 (2.7)
Nausea 14 (12.1) 2 (1.7) 8 (6.8) 2 (1.7) 20 (15.9) 0 16 (14.2) 6 (5.3)
Anorexia 5 (4.3) 1 (0.9) 13 (11.0) 1 (0.8) 16 (12.7) 0 16 (14.2) 3 (2.7)
Taste perversion 2 (1.7) 0 23 (19.5) 1 (0.8) 13 (10.3) 2 (1.6) 16 (14.2) 0
Language problems 1 (0.9) 0 7 (5.9) 1 (0.8) 10 (7.9) 3 (2.4) 15 (13.3) 3 (2.7)
Difficulty with
memory
3 (2.6) 0 11 (9.3) 3 (2.5) 9 (7.1) 3 (2.4) 14 (12.4) 1 (0.9)
Weight loss 1 (0.9) 0 6 (5.1) 0 12 (9.5) 0 13 (11.5) 0
Difficulty with
concentration
1 (0.9) 0 3 (2.5) 0 5 (4.0) 0 11 (9.7) 0
Somnolence 7 (6.0) 3 (2.6) 9 (7.6) 0 11 (8.7) 2 (1.6) 10 (8.8) 3 (2.7)
Abbreviation: WHO, World Health Organization.
*Data are given as number (percentage) of patients.
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2004 American Medical Association. All rights reserved.
trolled trials of any migraine-preventive agent to date and
meets that level of evidence.
Other controlled clinical studies
15-17
have examined
the efficacy of AEDs in migraine prevention. Divalproex
sodium had a responder rate of 48%,
15
44%,
16
and 41%
17
in3placebo-controlleddouble-blindtrials. Gabapentinhad
a responder rate of 36% compared with 14% for pla-
cebo.
18
These studies support the clinical utility of AEDs
for migraine prevention.
Many older propranolol hydrochloride and amitrip-
tyline hydrochloride clinical studies, conducted before
1991 (before the publication of the first International
Headache Society guidelines
19
), used completer analy-
ses instead of intent-to-treat analyses to evaluate effi-
cacy. An amitriptyline completer analysis study
20
had a
responder rate of 50%to 55%. Acrossover study
21
of timo-
lol maleate, propranolol, and placebo used data only from
patients completing 12 weeks of treatment.
Topiramate at 100 mg/d provided a better tolerabil-
ity profile than did topiramate at 200 mg/d in this study.
Two of the more common AEs associated with topiramate
usewereparesthesiaanddifficultywithconcentration. These
events seemed to be dose dependent and generally re-
solved over time or with discontinuation. Other notable
AEs includedanorexia andweight loss, whichare alsoseen
inpatients withepilepsy. Although19.2%of patients treated
with 100-mg/d topiramate discontinued treatment be-
cause of AEsa rate comparable tothose observedinsome
previously publisheddivalproexstudies
15,16
patients who
tolerated topiramate continued to do well. The increased
discontinuation rate was likely affected by the duration of
the double-blind treatment phase, which at 6 months was
longer, to our knowledge, than that in all previous mi-
graine prevention studies in other drugs.
Topiramate was generally tolerable when titrated in
25-mg increments. The possibility of improving toler-
ability with slower titration and/or other dose adjust-
ments was not examined. Also, the development of drug-
relatedAEs canresult inunblinding of the active treatment
in placebo-controlled studies and may lead to a bias.
This study establishes the efficacy of topiramate in
migraine prevention. Based on its efficacy herein and
the tolerability profile established from its use in pa-
tients with epilepsy, topiramate should be considered a
first-line treatment option for the prevention of mi-
graine headaches.
Accepted for publication November 14, 2003.
Fromthe Jefferson Headache Center, Philadelphia, Pa
(Dr Silberstein); and Johnson & Johnson Pharmaceutical
Research and Development, LLC, Raritan, NJ (Drs Neto and
Jacobs and Ms Schmitt). Dr Silberstein is on the advisory
panel of, speakers bureau of, or serves as a consultant for
Abbott Laboratories, Allergan, Inc, AstraZeneca, Elan Phar-
maceutical Research Corp, Eli Lilly, Ortho-McNeil Phar-
maceutical, Merck & Co, and GlaxoSmithKline; receives
research support fromAllergan, Inc, AstraZeneca, Eli Lilly,
GlaxoSmithKline, Janssen Pharmaceutica, Merck &Co, Or-
tho-McNeil Pharmaceutical, Pfizer, Inc, UCB Pharma, and
Vernalis; and has received educational grants from Abbott
MIGR-001 Study Group
Frederick Bahls, MD, PhD, Neurological Associates of Des Moines, PC, Des Moines, Iowa; Stephen Baker, MD, Neurology
and Neurosciences, Inc, Columbus, Ind; Harvey Blumenthal, MD, Neurological Associates of Tulsa, Inc, Tulsa, Okla; Diane
Book, MD, Medical College of Wisconsin, Milwaukee; John Castaldo, MD, Lehigh Valley Hospital, Allentown, Pa; Angel
Chinea, MD, Santurce, Puerto Rico; Kathleen Digre, MD, University of Utah, Health Sciences Center, Salt Lake City; David
W. Dodick, MD, Mayo Clinic Arizona, Scottsdale; Douglas Dulli, MD, University of Wisconsin, Madison; William Ferrell,
MD, Raleigh Neurology Associates, PA, Raleigh, NC; Grace Forde, MD, Biomedical Research Alliance of New York, Great
Neck; Ruth K. Fredericks, MD, Mississippi Center for Clinical Research, LLC, Jackson; Jerome Goldstein, MD, San Fran-
cisco Clinical Research Center, San Francisco, Calif; Kenneth Goodwich, MD, Research Pharma Solutions, Lutherville, Md;
Norman Gordon, MD, CNS Research, Inc, East Providence, RI; James Grisolia, MD, DRC of San Diego, San Diego, Calif;
Carolyn Hart, MD, Mecklenburg Neurological Associates, Charlotte, NC; Jessica Heiring, MD, Minneapolis Clinic of Neu-
rology, Golden Valley, Minn; Richard Hull, MD, North Alabama Neuroscience Research Associates, Huntsville; Jack A. Klapper,
MD, ColoradoNeurology andHeadache Center, Denver; Shashidhar H. Kori, MD, Duke HealthCenter at Morreene Road, Durham,
NC; John C. Krusz, MD, PhD, Anodyne PainCare, Dallas, Tex; Howard LaRoche, MD, R/DClinical Research, Lake Jackson, Tex;
Hubert Leonard, MD, The Neurological Clinic, Portland, Ore; Peter LeWitt, MD, Royal Oak, Mich; Elizabeth Loder, MD, Spauld-
ing Rehabilitation Hospital, Boston, Mass; Antoinette Mangione, MD, Radiant Research, Philadelphia, Pa; Herbert Markley, MD,
New England Regional Headache Center, Inc, Worcester, Mass; Ninan Mathew, MD, Houston Headache Clinic, Houston, Tex;
Alexander Mauskop, MD, New York Headache Center, New York; Denis MeeLee, MD, Hawaii Clinical Research Center,
Honolulu; Joseph Nicolas, MD, Aring Neurology, Cincinnati, Ohio; William H. Noran, MD, Jacksonville Center for Clinical
Research, Jacksonville, Fla; Margarita Nunez, MD, Comprehensive NeuroScience, Inc, St Petersburg, Fla; William M.
Patterson, MD, BirminghamResearch Group, Inc, Birmingham, Ala; Eric Pearlman, MD, Memorial Health University, Medi-
cal Center, Savannah, Ga; Robert Rubinstein, MD, The Doctors Clinic, Bremerton, WVa; Curtis P. Schreiber, MD, Headache
Care Center/Integrated Healthcare Clinic, Springfield, Mo; Elliot Schulman, MD, Center for Headache Management, Neu-
rological Associates of Delaware Valley, Upland, Pa; Michael P. Sethna, MD, Noran Neurological Clinic, PA, Fridley, Minn;
Stephen D. Silberstein, MD, Jefferson Headache Center, Philadelphia, Pa; Allen Spiegel, MD, Tampa Bay Medical Research,
Inc, Clearwater, Fla; Stuart Stark, MD, The Innovative Clinical Research Center, Alexandria, Va; James R. Storey, MD, Up-
state Clinical Research, LLC, Albany, NY; James P. Sutton, MD, California Medical Clinic for Movement Disorders, Oxnard;
Martin Throne, MD, Radiant Research, Inc, Atlanta, Ga; Kerri Wilks, MD, Innovative Medical Research, Towson, Md; Paul
Winner, MD, Premiere Research Institute, West Palm Beach, Fla; Bradley Wrubel, MD, East Bay Region Associates in Neu-
rology, Berkeley, Calif.
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2004 American Medical Association. All rights reserved.
Laboratories, Allergan, Inc, AstraZeneca, Bristol-Myers
Squibb, Eli Lilly, GlaxoSmithKline, Merck & Co, Ortho-
McNeil Pharmaceutical, and Parke-Davis. Drs Neto and Ja-
cobs and Ms Schmitt hold shares in Johnson &Johnson Phar-
maceutical Research and Development, LLC, a subsidiary
of Johnson & Johnson Corporation.
Author contributions: Study concept and design (Drs
Silberstein, Neto, and Jacobs); acquisition of data (Drs Sil-
berstein, Neto, and Jacobs); analysis and interpretation of
data (Drs Silberstein, Neto, and Jacobs and Ms Schmitt);
drafting of the manuscript (Drs Silberstein, Neto, and Ja-
cobs and Ms Schmitt); critical revision of the manuscript
for important intellectual content (Drs Silberstein, Neto,
and Jacobs); statistical expertise (Ms Schmitt); obtained
funding (Dr Neto); administrative, technical, and mate-
rial support (Drs Silberstein, Neto, and Jacobs); study su-
pervision (Drs Silberstein, Neto, and Jacobs).
This study was supported by Johnson &Johnson Phar-
maceutical Research and Development, LLC, Raritan, NJ
Corresponding author and reprints: Stephen D. Silber-
stein, MD, Jefferson Headache Center, Thomas Jefferson Uni-
versity Hospital, 8130 Gibbon Bldg, 111 S 11th St, Philadel-
phia, PA 19107 (e-mail: stephen.silberstein@jefferson.edu).
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