ORIGINAL ARTICLE
Efficacy of Topiramate and Valproate in
Chronic Migraine
Marco Bartolini, MD, Mauro Silvestrini, MD, Ruja Taffi, MD, Chiara Lanciotti, MD,
Roberta Luconi, MD, Marianna Capecci, MD, and Leandro Provinciali, MD
Objectives: The aim of this study was to compare the efficacy of
sodium valproate and topiramate in treating chronic migraine.
Methods: Forty-nine patients with chronic migraine were randomly
assigned to 1 of 2 groups of treatment: 750 mg/day valproate or 75
mg/day topiramate. Efficacy variables were number of days with
headache over a 30-day period and changes in Migraine Disability
Assessment (MIDAS) scores at 3 months.
Results: At baseline the 2 groups had similar numbers of days with
headache and mean MIDAS scores. At the end of the treatment
period, a significant reduction in 30-day headache frequency with
respect to baseline (P , 0.00001) and a significant reduction in
MIDAS scores (P , 0.00001) were recorded in both groups. There
were no significant differences in beneficial effects between the
2 drugs.
Discussion: Valproate and topiramate seem to be able to manage
successfully chronic migraine without substantial differences in
efficacy and tolerability. This affords clear practical advantages—in
the event of failure of or intolerance for one treatment, the patient may
be switched to the other.
Key Words: chronic migraine, topiramate, valproate
(Clin Neuropharmacol 2005;28:277–279)
A ccording to the new International Headache Society (IHS)
classification,1 chronic migraine (CM) is a condition in
which patients with a personal history of migraine experience
more than 15 days a month with pain lasting more than
4 hours. A progressive dysfunction of the central nervous
nociceptive system has been hypothesized to cause the shift
from episodic to chronic headache.2 Activation of brainstem
areas, especially the dorsal rostral pons, has a well-established
role in episodic migraine attacks.3,4 Chronic migraine may
share similar underlying pathophysiologic mechanisms and is
presumably the result of continuous rather than periodic
activation of brainstem nociceptive areas.5
From the Department of Neuroscience, Polytechnic University of Marche,
Ancona, Italy.
Reprints: Prof. Mauro Silvestrini, Clinica Neurologica, Università Politecnica
delle Marche, Azienda Ospedaliero-Universitaria Ospedali Riuniti, Via
Conca 71, 60020 Ancona (e-mail: masilvestrini@libero.it).
Copyright Ó 2005 by Lippincott Williams & Wilkins
Clin Neuropharmacol  Volume 28, Number 6, November - December 2005
Treatment indications for the increasing number of
patients with CM referred to headache centers are few. The
rationale for using antiepileptic drugs (AEDs) in these patients
derives from studies of the mechanisms of pain modulation in
chronic syndromes6 and from some shared pathophysiologic
features of migraine and epilepsy.7 As yet, however, available
data do not allow one to establish the optimal pharmacologic
approach with AEDs in terms of efficacy and tolerability.
The aim of this open-label, randomized, controlled study
was to compare the efficacy of 75 mg/day topiramate (Topamax)
and 750 mg/day slow-release valproate (Depakin Chrono) in
a group of patients with CM.
MATERIALS AND METHODS
Forty-nine consecutive patients with CM and a history
consistent with a diagnosis of episodic migraine without aura
fulfilling the diagnostic criteria for migraine of the IHS Clas-
sification of Head and Facial Pain1 referred to our headache
center from February 2004 to January 2005 were included in
the study. All patients had had preventive medications (basically
b-blockers and calcium antagonists) with poor results, but at
the moment of our observation they were without any pro-
phylactic treatment. Patients with analgesic drug overuse were
not included.
Patients were informed that the drug they would receive
was registered for the treatment of epilepsy and that there was
encouraging preliminary evidence for its effect in migraineurs.
The study was conducted in accordance with the Declaration of
Helsinki and was approved by the local ethics committee. After
giving their informed written consent to participate in the study,
patients were given a diary in which they recorded headache
frequency, duration, and severity; and use of symptomatic
drugs.
The study design was as follows:
 A 1-month observation period during which patients kept
the diary
 Baseline (T0), at which time the 49 patients selected were
randomized 1:1 to receive topiramate or valproate, with
induction doses of 25 mg/day and 250 mg/day respectively;
patients also filled in the Migraine Disability Assessment
(MIDAS) questionnaire8 for headache-related disability
 A 3-week titration phase at the end of which patients
received 75 mg topiramate or 750 mg valproate daily (25 mg
and 250 mg in the morning, and 50 mg and 500 mg in the
evening respectively);
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Bartolini et al Clin Neuropharmacol  Volume 28, Number 6, November - December 2005
 A control at 1 month (T1) from the administration of the full
dose to evaluate side effects and efficacy
 Final assessment (T2) at 3 months
A help line was available to the patients throughout the
study.
Statistical analysis was performed using multivariate
analysis of variance with repeated measures (MIDAS and
number of days with headache over a 30-day period before
and after treatment). The Scheffé test was used for post hoc
comparisons.
RESULTS
At T1, 3 patients withdrew from valproate treatment
because of drowsiness; in the topiramate group, 2 patients
dropped out for the same reason and 1 for gastric discomfort
and paresthesias. The baseline demographic and clinical char-
acteristics of the patients who completed the study are reported
in Table 1. With regard to gender distribution, females were more
numerous in the valproate group. By contrast, there were no
significant differences in headache frequency and MIDAS
scores between the groups.
Mean number of days with headache over a 30-day
period at baseline (T0) and at 1 month (T1) and 3 months (T2)
from the administration of the full dose is reported in Table 2.
All patients experienced a progressive, significant reduction
in headache frequency. Post hoc intragroup analysis showed
similar significant improvements at T0 to T1 and T0 to T2 for
both drugs (P , 0.00001). Although the improvement from T1
to T2 was greater in the topiramate than in the valproate group
(P , 0.00001), at T1 valproate was more effective (P , 0.02)
according to intergroup analysis. MIDAS scores fell signif-
icantly from T0 (27.8 6 12.1 points for the topiramate group;
25.2 6 3.6 points for the valproate group) to T2 (7.1 6 10.3
points for the topiramate group; 5.7 6 6.4 points for the
valproate group) in both groups (P , 0.00001). Post hoc
comparisons (Scheffé test) confirmed significant improve-
ments in both groups from T0 to T2 (intragroup analysis).
Intergroup analysis showed no differences between the groups
in MIDAS scores at T2.
At T1, 21 patients on valproate and 20 patients on
topiramate had a reduction of at least 50% in days with
headache. This trend was confirmed at T2, with 21 patients on
topiramate achieving this result.
TABLE 1. Demographic and Baseline Characteristics
of Patients
Topiramate, Valproate,
Characteristics n = 22 n = 22
Gender, n
Women 13 18
Men 9 4
Age, y 6 SD 41.7 6 9.8 41.9 6 10.1
Time from beginning of CDH, y, 6 SD 5.3 6 1.5 5.6 6 1.4
30-day headache frequency, mean 6 SD 26.1 6 2.3 27.0 6 1.3
MIDAS score, pt, mean 6 SD 27.8 6 12.1 25.2 6 3.6
CDH, chronic daily headache.
278
TABLE 2. Thirty-day Headache Frequency (mean 6 SD) at
Baseline (B) and After 1 Month (T1) and 3 Months (T2)
From starting 75 mg Daily of Topiramate or 750 mg Daily
of Valproate
Topiramate Valproate
B T1 T2 B T1 T2
26.1 6 2.3 10.4 6 9.3 2.76 6 3.9 27.0 6 1.3 6.1 6 4.5 3.2 6 2.9
Given the different gender distribution in the 2 groups,
a gender covariate multiple analysis of variance was applied to
test the possible role of gender on the effect of treatment, but
its influence on outcome was not demonstrated.
DISCUSSION
Patients with CM exhibit high rates of unresponsiveness
to symptomatic therapies, and a large proportion of these
patients are at risk for developing analgesic or abortive med-
ication overuse. Symptomatic drugs are suspected of contrib-
uting to headache chronicity. For these reasons, preventive
treatment is indicated in patients with CM. Unfortunately,
traditional drugs currently used in the prophylaxis of migraine,
including b-blockers, calcium-channel blockers, and antide-
pressants, are rarely effective.9 Recent evidence for the pos-
sibility of ameliorating conditions characterized by chronic pain
using AEDs has stimulated the interest in exploring the effects
of this approach in different headache conditions, including
migraine.10 The mechanisms underpinning the response
obtained with the same drugs in 2 clinical conditions as dif-
ferent as migraine and epilepsy, which also carry a very high
rate of comorbidity, are being investigated.11 One possible
explanation is that migraine and epilepsy share common patho-
physiologic mechanisms, including an increased genetic vul-
nerability to neuronal hyperexcitability.12 In this regard, an
alteration of the mechanisms involved in the central control of
pain has been hypothesized in migraine.13 There is also evi-
dence for anatomic changes occurring in some critical brain
regions like the periaqueductal gray matter.14 These changes
would sustain the hyperexcitability of brain regions critical for
migraine attack onset.15
Although administration of AEDs to migraine patients
has given encouraging results,10 it is not cost-effective in
patients with sporadic migraine, who would benefit more from
other options, including symptomatic drugs and traditional
prophylactic therapies.16 It is otherwise with patients with
more disabling illnesses who are unresponsive to these
treatments. This is the case of CM, in which the changes
invoked to justify the use of AEDs could be further
accentuated. Indeed, pathophysiologic evidence suggests that
the shift from episodic to chronic headache may be the result
of progressive damage to the central nociceptive system.2 The
large number of days with headache, the heavy social impact,
and, above all, the unsatisfactory response to conventional
treatment would thus justify a more aggressive and expensive
therapeutic approach.
q 2005 Lippincott Williams & Wilkins
Clin Neuropharmacol  Volume 28, Number 6, November - December 2005
In this open study, we compared the efficacy of topiramate
and valproate in treating severely disabled patients with CM.
The possibility of using topiramate, a new-generation AED,
for pain treatment is based on some of the central effects of the
drug that include the blocking of voltage-sensitive sodium
channels and the kainate/d-amino-3-hydroxy-methyl-4-isoxozole
propionic acid species of glutamate receptor, the action on the
GABA neurotransmitter system, and the increase in human
cerebral GABA concentration.17 Valproate is a classic AED
with proven action on GABA-ergic reuptake in the central
nervous system.18 The mechanisms of action of the 2 drugs are
theoretically able to address a dysfunction that may be present
in central pain-regulating mechanisms. The most important
finding of the current investigation was that the 2 AEDs
were similarly effective in reducing the number of days with
headache, resulting in a significant improvement of disability
as measured by MIDAS score. However, there were slight
differences between the two AEDs. Valproate acted earlier than
topiramate. This effect might be ascribed to the wider SD mean
MIDAS scores in the topiramate group at baseline: the patients
in this group may thus have had a more severe condition,
requiring longer to improve. In this respect, previous inves-
tigations showed that topiramate was able to induce a sig-
nificant clinical improvement in migraine patients within the
first month of treatment.19,20 With reference to side effects,
both AEDs were well tolerated. Drowsiness and gastric
discomfort are well-known effects of both drugs.
Our results are in line with previous data on the 2 drugs,
whose effects on migraine attacks prevention were investi-
gated separately. To the best of our knowledge, this is the first
study prospectively comparing the effectiveness of topiramate
and valproate in a selected population of CM patients. There
are some limitations in our study that deserve consideration.
The most relevant is the lack of a placebo group. It is widely
accepted that double-blind, placebo-controlled studies support
the best evidence in a clinical trial. However, we have to
consider the difficulties and the ethical problems for placebo
use in patients with chronic pain. The current data confirm the
effectiveness, safety, and tolerability of both drugs in treating
CM. Their similar efficacy affords clear practical advantages,
because in the event of failure of or intolerance for 1 treatment
it allows a patient to switch to the other.
q 2005 Lippincott Williams & Wilkins
Topiramate and Valproate in Chronic Migraine
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