Download efficacy of topiramate in migraine prophylaxis

PROCEEDINGS
EFFICACY OF TOPIRAMATE IN MIGRAINE PROPHYLAXIS:
A RANDOMIZED CONTROLLED STUDY*
—
Based on a presentation by Stephen D. Silberstein, MD†
ABSTRACT
Topiramate has been under investigation for
the past several years as a prophylactic agent
for migraine and other headache disorders.
Studies to date have shown it to be safe and
effective. As with other antiepileptic drugs, its
exact mechanisms of action are not yet known,
or at least, the mechanisms that are important in
its efficacy in migraine are not yet defined.
Topiramate acts on several receptors and ion
channels as well as neurotransmitter metabolism. As a result, it inhibits excitatory neurotransmission through several mechanisms. This
article briefly reviews the rationale for using
antiepileptic drugs in migraine and offers results
of a recent study of topiramate as migraine prophylaxis in 213 patients. The results support
earlier studies that topiramate is safe and effective. Based on the data reported here, the agent
appears to have particular benefit for those suffering from migraine with aura.
(Advanced Studies in Medicine 2002;2(21):758-761)
*This article is based on a presentation given by
Dr Silberstein at the 44th Annual Meeting of the American
Headache Society.
†Professor of Neurology and Director, Jefferson
Headache Center, Thomas Jefferson University Hospital;
Clinical Professor of Neurology, Temple University School of
Medicine, Philadelphia, Pennsylvania.
758
ntiepileptic drugs have long been
known as effective agents for migraine
prophylaxis. The exact mechanisms of
action in migraine are not known but
may involve cortical spreading depression and the similar rate of decrease in regional cerebral blood flow observed in migraine patients with
aura.1 Traditionally, migraine patients have been treated with valproate or carbamazepine as migraine prophylaxis. Although these agents offer headache relief,
relief is countered with sometimes unacceptable side
effects, including hair loss and weight gain.
More recently, gabapentin has been investigated
in migraine prophylaxis although it is not yet formally approved for this use. Studies have shown
it to be effective, with an improved side-effect profile compared with valproate, but these studies are
limited.2,3
Topiramate is one of the newer antiepileptic
drugs to be approved by the US Food and Drug
Administration. It too is under investigation for
migraine prophylaxis. Early results in small studies
and a randomized, controlled trial indicate that it
may be a safe and effective prophylactic alternative
for migraine.4
Topiramate, like other antiepileptic drugs, has
several mechanisms of action, any one or combination of which may be responsible for its efficacy in
migraine. The mechanisms of action all affect neurotransmission through ion channels, receptors, or
neurotransmitter metabolism (Table 1). Each of the
mechanisms is currently under investigation by
clinical researchers hoping to elucidate the pathophysiologic mechanisms behind a migraine attack.5,6
A
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PROCEEDINGS
CACNA1A was the first gene to be identified as
being involved in familial hemiplegic migraine, a rare
subtype of migraine, and may be involved in migraine
with aura as well. Located on chromosome 19, it
encodes the alpha-1A subunit of a voltage-dependent
calcium channel. CACNA1A is found in patients with
familial hemiplegic migraine and episodic ataxia,
another disorder with intermittent presentation in
otherwise healthy individuals.7,8 Long-QT syndrome is
a cardiac arrhythmia resulting from mutations in
either voltage-gated sodium or potassium channels.
Collectively, these types of diseases—episodic in otherwise healthy people with known mutations in ion
channels—are collectively referred to as channelopathies. They all respond to similar drug classes
and share common precipitating factors.5
Gamma-aminobutyric acid (GABA) and glutamate are also of great interest in migraine pathophysiology. Topiramate appears to activate GABA
receptors (type A), inhibiting glutamate excitatory
transmission. Glutamate may also be a player in
migraine onset; several investigators have discovered
increased plasma and cerebrospinal fluid levels of
glutamate, which increase even further during a
migraine attack, but the results sometimes vary.9-12
Glutamate binds to N-methyl-D-aspartate (NMDA)
and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA)/kainate receptors. Topiramate deactivates AMPA/kainate receptors, thus blocking
excitatory transmission.5
Interestingly, acetazolamide is another carbonic
anhydrase inhibitor that has been investigated in
familial hemiplegic migraine and episodic ataxia type
2. Positive effects on ataxia have been observed with
little or no prophylactic benefit for migraine.
Recent work suggests that topiramate may affect
migraine through all of these ion channels and receptors. Studies have shown that each of the channel/
receptor types are regulated by phosphorylation by
protein kinase A and other kinases. Each of the channels/receptors shares a homologous amino acid
sequence on the cytoplasmic side of the membranebound protein kinase A phosphorylation site, where
protein kinase A catalyzes phosphorylation and the
resulting cellular activation. It is thought that topiramate may bind at the protein kinase A phosphorylation site to prevent cellular activation and
neurotransmission or may bind at the site only in the
dephosphorylated state.13
Advanced Studies in Medicine
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STUDY DESIGN
The study reported here was a randomized, doubleblind, placebo-controlled, parallel-group study of 213
patients with migraine, as defined by the International
Headache Society, to assess the efficacy of topiramate.
Randomization was 2:1 (topiramate:placebo). After a
screening washout period of up to 28 days and a 28-day
baseline period, participants were treated for 20 weeks
with the study drug: an 8-week titration followed by 12
weeks of maintenance. The target dose of topiramate
was 200 mg after an initial starting dose of 25 mg, with
25-mg increments weekly.
Of the 213 patients who were randomized, 140
were in the topiramate group and 73 were in the
placebo group. At the end of the 20-week treatment
period, 95 (68%) remained in the topiramate group
and 60 (82%) remained in the placebo group. The
reasons for discontinuation were similar between
both groups and included lack of efficacy and protocol violation. Discontinuations were higher in the
topiramate group for patient choice (6% vs 1%),
adverse event (15% vs 5%), and loss to follow-up
Table 1.Topiramate Mechanisms of Action
Site
Action
Voltage-activated
Na+ channels
Limits sustained repetitive
firing via state-dependent
blockade of Na+ channels
Ca++ channel
subtypes
Reduces slightly the amplitude of
high voltage–activated CA++ currents
GABAA receptor
subtype(s)
Potentiates GABA-mediated inhibition
at GABAA site not modulated by
benzodiazepines or barbiturates
Glutamate receptor
subtypes (kainate and
AMPA)
Blocks glutamate-mediated
neuroexcitation with no apparent
effect on NMDA receptor activity
Carbonic anhydrase
Inhibits type II and type IV carbonic
anhydrase
AMPA = α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate; Ca++ =
calcium ion; GABAA = gamma-aminobutyric acid type A; Na+ = sodium
ion; NMDA = N-methyl-D-aspartate.
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PROCEEDINGS
(6% vs 0%). In the placebo group, discontinuations
were higher than the topiramate group for reasons
given as “other” (5% vs 1%).
Most of the patients in both groups achieved the
target dose of 200 mg (61.3% topiramate, 86.4%
placebo). The second most common dose for topiramate was 100 mg (12.3%), followed by 75 mg (9.4%).
The mean dose of topiramate was 161.3 mg; for place-
Figure. Migraine Frequency: Change From Baseline
*Least square mean.
†Analysis of covariance.
bo, the mean dose was 185.6 mg, clearly indicating a
placebo response.
RESULTS
The migraine frequency by month in the intention-to-treat population declined significantly during
the first 2 months in both groups, from about 5
migraines per month to about 3.5 migraines per
month. By month 3, the benefit reached a plateau for
the placebo group; the topiramate group continued
the decrease in monthly migraine frequency, but at a
lower rate. The migraine frequency in the intentionto-treat populations did not significantly change overall (–1.04 placebo, –1.43 topiramate; P = .29).
However, patients completing the study showed a significant change in overall migraine frequency between
the 2 treatment groups (Figure).
Interestingly, there was no significant difference in
the 50% response for both groups in the intention-totreat population, again suggesting a placebo effect.
However, significant differences in responder rates
were observed for those patients achieving a 75%
response or better (Table 2).
Of particular note, patients experiencing migraine
with aura had the greatest benefit with topiramate
treatment. The migraine frequency reduction was
–2.43 vs –0.79 for the topiramate and placebo groups
(intention-to-treat), respectively (P = .02).
All adverse events were greater in the topiramate
group, with ranges of 2-fold to 10-fold differences.
The most common adverse event with topiramate
was paresthesias; for placebo, it was dizziness. A total
of 14% of patients in the topiramate group experienced weight loss and nausea compared with 8% in
the placebo group.
CONCLUSION
Table 2. Migraine Responder Rates in the
Intention-to-Treat Population
These results support other studies showing that
topiramate is safe and effective for migraine prophylaxis. No serious adverse events were reported, and
most interesting is the particular efficacy for patients
suffering from migraine with aura.
Topiramate
n (%)
Placebo
n (%)
50
55 (40)
25 (34)
P = .26
75
27 (20)
6 (8)
P = .03
100
10 (7)
2 (3)
Response (%)
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