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Anticonvulsivantes en profilaxis de migraña

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Review Article
Antiepileptics in migraine prophylaxis: An
updated Cochrane review
Cephalalgia
2015, Vol. 35(1) 51–62
! International Headache Society 2014
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DOI: 10.1177/0333102414534325
cep.sagepub.com
Wim M Mulleners1, Douglas C McCrory2,3 and Mattias Linde4,5
Abstract
Introduction: The efficacy of several antiepileptics in the preventive treatment of episodic migraine in adults has been
systematically reviewed. Because many trial reports have been published since then, an updated systematic review was
warranted.
Methods: We searched the Cochrane Central Register of Controlled Trials, PubMed/MEDLINE (1966 to January 15,
2013), MEDLINE In-Process (current week, January 15, 2013), and EMBASE (1974 to January 15, 2013) and handsearched Headache and Cephalalgia through January 2013. Prospective, controlled trials of antiepileptics taken regularly
to prevent the occurrence of migraine attacks, to improve migraine-related quality of life, or both, were selected.
Results: Mean headache frequency on topiramate and sodium valproate is significantly lower than placebo. Likewise,
topiramate and divalproex demonstrated favorable results for the proportion of subjects with 50% reduction of
migraine attacks. For topiramate, 100 mg and 200 mg outperformed 50 mg, but this was paralleled by a higher adverse
event rate. For valproate/divalproex, a dose-effect correlation could not be established. There was no unequivocal
evidence of efficacy for any of the other antiepileptics.
Conclusion: Topiramate, sodium valproate and divalproex are effective prophylactic treatments for episodic migraine in
adults. In contrast to previous reports, there is insufficient evidence to further support the use of gabapentin.
Keywords
Migraine, prophylaxis, prophylactic treatment, preventive treatment, antiepileptic
Date received: 3 February 2014; accepted: 28 March 2014
Introduction
The prevention of disease-related disability is the ultimate goal of successful migraine treatment. Currently
available prophylactic remedies for migraine may at
best lead to only partial reduction of frequency of headache attacks, often at the expense of significant adverse
experiences, and improving patient functioning and
quality of life to a limited extent only. Moreover, they
are used by only an estimated 3%–12% (1–3) of
patients, hence failing to meet the needs of migraine
sufferers worldwide (4).
Evidence-based guidelines on the drug treatment of
migraine have been developed and published by the
European Federation of Neurological Societies
(EFNS) (5). These guidelines suggest that prophylactic
therapy should be considered for patients with migraine
when quality of life, business duties, or school attendance are restricted; when attack frequency exceeds one
per month; in case of a lack of response to acute drug
treatment; and when frequent, long, or uncomfortable
auras occur. Moreover, patient preferences and
treatment costs should be considered when making
treatment decisions.
Based on a shared primary indication of use or rationale for development, drug treatments for epilepsy are
collectively known as ‘‘antiepileptics.’’ The use of antiepileptics for the prophylactic treatment of migraine is
theoretically warranted by several known modes of
action, which relate either to the general modulation of
1
Department of Neurology, Canisius Wilhelmina Ziekenhuis, The
Netherlands
2
Department of Medicine, Duke University Medical Center, NC, USA
3
Center for Health Services Research in Primary Care, Durham Veterans
Affairs Medical Center, NC, USA
4
Department of Neuroscience, Norwegian University of Science and
Technology (NTNU), Norway
5
Norwegian National Headache Centre, St. Olavs University Hospital,
Norway
Corresponding author:
Wim M Mulleners, Department of Neurology, Canisius Wilhelmina
Ziekenhuis, PO Box 9015, 6500 GS Nijmegen, The Netherlands.
Email: w.mulleners@cwz.nl
52
pain systems (6) or more specifically to systems involved
in the pathophysiology of migraine (7). However, it is not
currently possible to state with any certainty which particular mode or modes of action of antiepileptic drugs are
relevant to the prophylaxis of migraine. Thus, with
respect to a systematic review of migraine-preventive
treatments, the argument for considering them as a
class fails. It was therefore decided that the update of
an earlier Cochrane review (8) should be split into four.
This review considers the evidence for the efficacy
and tolerability of antiepileptics for preventing
migraine in adults and is a companion paper to four
recently published systematic reviews in the Cochrane
Database of Systematic Reviews on migraine prophylaxis, covering topiramate (9), valproate (10), gabapentin or pregabalin (11) and antiepileptics other than
those (12). It extends the findings of a previously
published review (13) with information from studies
published between 2005 and January 2013. The prophylactic treatment of migraine in children is the subject of
a separate Cochrane review (14).
Methods (additional details are in the
companion papers in the Cochrane
Database of Systematic Reviews (9–12))
Characteristics of eligible studies
Studies were required to be prospective, (pseudo-)randomized controlled trials of self-administered preventive drugs in adults 16 years or older. Trials were not
required to be blinded but results needed to be published in full; short conference and journal abstracts
were not included. Diagnosis needed to be based on
at least some of the distinctive features of migraine,
preferably a specific set of diagnostic criteria (e.g. Ad
Hoc Committee (15), International Classification of
Headache Disorders, first edition (ICHD-I) (16) or
second edition (ICHD-II) (17)).
Studies evaluating treatments for chronic migraine,
medication-overuse headache or any other chronic daily
headache were unsuitable for this review. Studies were
required to have at least one arm with an antiepileptic
drug. Acceptable comparator groups included placebo,
no intervention, active drug or non-pharmacological treatments (with proven efficacy), and same drug treatments
with a clinically relevant different dose. Only drugs used
for the treatment of epilepsy or status epilepticus, commercially available and suitable for outpatient use in either
Europe or the United States (US) were considered.
Types of outcome measures
Data on headache frequency (both in continuous
and dichotomous format), quality of life and adverse
Cephalalgia 35(1)
events (AEs), obtained directly from patients,
were collected.
For outcomes measured on a continuous scale
(headache frequency), we preferred number of migraine
attacks to number of days with migraine. We anticipated reporting in a variety of ways, e.g. as mean pretreatment, post-treatment, and/or change scores. When
variance associated with these means was not reported
or provided by the authors upon request, we attempted
to estimate variances based on primary data, test statistics, and/or error bars in graphs.
When efficacy outcomes were reported in dichotomous form (success/failure), we chose a 50% reduction
in headache frequency as the clinically relevant outcome. Reviewers recorded, for each treatment arm,
the number of patients included in the analysis and
the number with each outcome.
As we anticipated that frequency outcomes would be
measured over various units of time (e.g. number of
attacks per two weeks versus per four weeks), and for
numerous different time points (e.g. four-week headache frequency at two months versus at four months),
we attempted to standardize the unit of time over which
headache frequency was measured at 28 days (four
weeks) wherever possible.
For quality-of-life data, we envisaged that the
Migraine-Specific Quality of Life Questionnaire
(MSQ) and the Medical Outcomes Study 36-item
Short-Form Health Survey (SF-36) would most likely
be the preferred outcome scales. However, other types
of outcomes related to quality of life (e.g. work absenteeism) were not excluded a priori.
In addition, we tabulated AEs for each included
study. Where data on AEs were missing or inadequate,
we intended to obtain these data by correspondence
with authors, but in several cases this was not possible
because of the age of the studies.
Identification of studies
Databases searched were (a) The Cochrane Pain,
Palliative & Supportive Care Trials Register; (b) The
Cochrane Central Register of Controlled Trials
(CENTRAL) (Issue 12, 2012); (c) PubMed 1966–
December 2005; (d) MEDLINE (via OVID) 2005–
January 15, 2013; (e) MEDLINE In-Process (via
OVID) January 15, 2013; (f) EMBASE 1974–
December 2005; and (g) EMBASE 2005–January 15,
2013. In addition, the reference lists of review articles
and included studies, books related to headache, and
two journals (Headache and Cephalalgia) were handsearched. We attempted to identify all relevant published trials, irrespective of language.
Titles and abstracts of studies identified by the literature search were screened for eligibility by two
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Mulleners et al.
independent reviewers (WM, ML). Papers passing this
initial screening process were retrieved, and the full text
was reviewed independently by the reviewers.
Disagreements at the full-text stage were resolved
through discussion.
Data extraction and analysis
Information on patients, methods, interventions, outcomes and AEs were abstracted by two independent
reviewers.
For outcomes reported on a continuous scale
(change in migraine frequency), pre- and post-treatment means and variances were analyzed and reported
as mean difference (MD) with 95% confidence
interval (CI).
Dichotomous data meeting our definition of a clinically significant threshold were used to calculate odds
ratios (ORs) with CIs. AEs and withdrawal rates due
AE were assessed, and data on the proportion of
patients reporting specific AEs were used to calculate
numbers-needed-to-harm (NNH).
Estimates of efficacy (both MDs and ORs) were
tested for homogeneity. If study estimates were homogeneous, they were combined using a fixed-effect model.
When significant heterogeneity was present, an attempt
was made to examine the differences based on the clinical characteristics of the included studies. Only when
studies with statistically heterogeneous results appeared
to be clinically similar were the study estimates combined using a random-effects model.
Results
The PubMed search strategy for the original review (8)
yielded 1089 potentially eligible citations, while the
EMBASE and CENTRAL searches yielded 290 and
6952 citations, respectively. No additional citations
were retrieved from the Cochrane Pain, Palliative &
Supportive Care Trials Register or from other sources.
After title-and-abstract screening, we obtained 58 published papers on antiepileptics for full-text scrutiny
(Figure 1).
The MEDLINE search strategy for the present
update (from 2005 on) yielded 188 citations as possible
candidates for the current series of reviews on antiepileptic drugs for migraine prophylaxis; the search of
MEDLINE In-Process identified an additional 20 citations. The EMBASE and CENTRAL updates identified 484 and 85 citations, respectively. Three additional
study reports (all unpublished and all pertaining to
gabapentin) were identified from other sources. After
title-and-abstract screening, we obtained 37 published
and three unpublished papers on antiepileptics for fulltext scrutiny.
Gabapentin and pregabalin (Table 1)
The original review included three papers reporting on
gabapentin (18–20). For the current update, no papers
investigating gabapentin or pregabalin, but one investigating gabapentin enacarbil (21), were identified. In
addition, three previously confidential research reports
investigating gabapentin (22–24) recently had become
public by virtue of being entered into evidence in a legal
proceeding in 2008. However, the inclusion of one of
the research reports led to the exclusion of a previously
included paper (19) as they reported on the same study.
Thus, six papers were included (18,20–24), enabling
comparison to placebo as well as dose comparisons of
gabapentin or gabapentin enacarbil. All six trials had
parallel-group designs and a median duration of the
treatment phase of 12 weeks (range 12–20 weeks).
The doses of gabapentin investigated in the trials were
900–2400 mg.
The risk of bias in the studies was generally judged
as low or unclear. However, three studies were at high
risk of selection bias (20), performance bias (20,22),
attrition bias (22) or reporting bias (20,21).
The pooled results did not demonstrate a significant
difference between gabapentin and either placebo or
different gabapentin doses on the outcomes ‘‘headache
frequency’’ or ‘‘responder rate’’ (Table 1). The sole trial
of gabapentin enacarbil (21) failed to demonstrate a
significant difference in responder rate across all dose
ranges.
Because the only placebo-controlled paper that
reported data on quality of life reported no significant difference with regard to reduction of headache frequency, no
further analyses were undertaken of these data (23).
Overall, 68% of subjects on active treatment
reported one or more AEs, as opposed to 57% on placebo. Withdrawal due to AEs ranged between 0% and
17%. NNHs for any as well as the five most prevalent
AEs for the pooled analyses of gabapentin 900 to
2400 mg versus placebo are presented in Table 1.
Topiramate (Table 2)
In addition to the six papers included in the previous
review, 14 were included in the update process, yielding
a total of 20 papers considered for this review. These
reported data from 17 unique studies, 10 comparing
topiramate with placebo (25–34), three comparing different doses of topiramate (25,27,33), and seven comparing topiramate to another active intervention
(27,35–40). Two trials (30,39) had a cross-over design;
the doses of topiramate ranged from 50 to 200 mg/day
across studies. The study protocol of the three largest
trials allowed for a sub-target study dose in case the
prespecified dose escalation proved challenging because
54
Cephalalgia 35(1)
Figure 1. PRISMA flow diagram: paper selection, stages and numbers.
PRISMA: Preferred Reporting Items for Systematic Reviews and Meta-Analyses. From: Moher D, Liberati A, Tetzlaff J, et al. Preferred
Reporting Items for Systematic Reviews and Meta-Analyses: The PRISMA Statement. PLoS Med 2009; 6: e1000097. For more information, visit www.prisma-statement.org.
of AEs. The duration of the treatment phase of the
included trials varied from four to 52 weeks, with a
mean of 19 weeks.
We judged nine studies to be at high risk of bias for
at least one of six attributes (randomization, allocation,
performance, detection, attrition and reporting) (29–
32,35,38–41).
The combined analysis of nine trials (25–31,33,34)
showed a significant reduction in headache frequency
in the active group compared to placebo of about one
attack per 28 days. Likewise, patients were twice as
likely to experience a 50% reduction in frequency
with topiramate as with placebo. The 100 and 200 mg
target doses were significantly superior to 50 mg in both
outcomes, but did not differ from each other (25,33).
The combined analyses of two studies found favorable
results of topiramate across dose ranges for quality of life
on various domains of the disease-specific MSQ, but the
generic SF-36 was more equivocal (only two of 24
analyses pointed in this direction) (25,33). A correlation
between dose and increasing response was not apparent.
Based on the risk differences for the various doses of
topiramate versus placebo, we calculated NNHs where
appropriate, and these are reported in Table 2. AE rates
increased with the topiramate dose, the mean percentage of participants withdrawing because of AEs at
100 mg was 20%.
Seven trials examined several doses of topiramate
against active comparators (amitriptyline 50–100 mg (37),
flunarizine 5 mg (38), propranolol 80 mg (36) and 160 mg
(27), sodium valproate 400 mg (35,39) and relaxation therapy (40)). Mean headache frequencies demonstrated a
slight but significant advantage for topiramate over valproate, and relaxation was superior in change from baseline
in MSQ. It should be noted that most of these studies were
probably not powered to detect superiority of any
compound, and that the doses in some studies were lower
than those used in routine clinical management.
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Mulleners et al.
Table 1. Gabapentin main outcomes.
Efficacy vs placebo
Responders (OR (95% CI))
Frequency (MD (95% CI))
1.59 (0.57, 4.46)
0.44 ( 1.43, 0.56)
Dose ranges vs placebo
Responders (OR (95% CI))
Daily dose titrated up to
1800 mg
1800–2400 mg
Frequency (MD (95% CI))
Daily dose titrated up to
900 mg
1200 mg
1800 mg
1800–2400 mg
Quality of life
No pooled data
AEs
Any AE
Asthenia/fatigue
Dizziness/vertigo
Flu syndrome
Somnolence
Abnormal thinking
Withdrawal due to AE
NNH (95% CI)
ns
ns
7 (5 to 13)
7 (4, 25)
9 (6 to 33)
20 (11 to 100)
0%–17%
MD: mean difference; OR: odds ratio; CI: confidence interval; NNH: numbers-needed-to-harm; AE: adverse event;
ns: not significant.
Valproate (Table 3)
The present update added one trial to the nine unique
studies in the previous review. Four addressed divalproex
sodium (42–45) and six documented sodium valproate
(35,39,46–49). Six trials compared valproate with placebo
(42–47) and four compared valproate to active intervention (35,39,43,49), and one reported data that enabled
dose comparisons of valproate (40). Four trials
(39,43,46,47) had a cross-over design, whereas the other
six trials had a parallel-group design (35,42,44,45,48,49).
The doses of valproate investigated in the 10 included
trials ranged from 400 to 1500 mg/day. The duration of
the treatment phase of the included trials varied from
eight to 12 weeks, with a mean of 11 weeks.
We judged seven studies as having a ‘‘high’’ risk of
bias for at least one item in the domains allocation
(48,49),
randomization
(48,49),
performance
(35,43,48,49), detection (43,48), attrition (43,47–49)
and reporting (43,48,49).
Two cross-over trials of sodium valproate (46,47)
showed a significant reduction in headache frequency
in the active compared to the placebo group of approximately four headaches per 28 days. Four placebo-controlled divalproex sodium trials (42–45) showed that
with active treatment patients are twice as likely to
experience a 50% reduction in headache frequency.
One trial (47) found that sodium valproate was significantly superior to placebo for this outcome. We have
not identified any placebo-controlled studies reporting
quality-of-life outcome measures. One small trial compared different doses of sodium valproate by measuring
serum valproate concentrations (48), showing that
lower serum levels gave rise to slightly but significantly
lower headache frequencies. Comparisons with flunarizine (49) and propranolol (43) were not significantly
different between treatments.
56
Cephalalgia 35(1)
Table 2. Topiramate main outcomes.
Efficacy against placebo
Responders (OR (95% CI))
Frequency (MD (95% CI))
3.18 (2.10, 4.82)
1.20 ( 1.59, 0.80)
Dose ranges vs placebo
Responders (OR (95% CI))
daily dose titrated up to
50 mg
100 mg
200 mg
Frequency (MD (95% CI))
daily dose titrated up to
50 mg
100 mg
200 mg
Quality of life
Daily dose titrated up to
MSQ-role function restrictive
MSQ-role function preventive
MSQ-emotional function
SF-36 role physical
SF-36 bodily pain
50 mg/d
(MD (95% CI))
100 mg/d
(MD (95% CI))
200 mg/d
(MD (95% CI))
5.83 (2.25, 9.41)
ns
4.58 (0.61, 8.54)
ns
4.35 (0.04, 8.66)
10.08 (6.55, 13.60)
6.39 (3.37, 9.41)
10.22 (6.31, 14.14)
ns
ns
10.36 (6.68, 14.04)
5.06 (1.87, 8.25)
8.45 (4.38, 12.52)
8.59 (0.65, 16.52)
ns
50 mg/d
(NNH (95% CI))
100 mg/d
(NNH (95% CI))
200 mg/d
(NNH (95% CI))
ns
ns
ns
ns
ns
ns
7 (5, 14)
25 (14, 100)
2%–17%
11 (7, 33)
17 (10, 50)
25 (17, 100)
25 (17, 100)
ns
3 (2, 6)
14 (8, 100)
17 (11, 33)
8%–29%
5 (3, 12)
12 (8, 20)
12 (8, 25)
12 (9, 17)
17 (9, 50)
2 (2, 3)
7 (5, 11)
11 (8, 14)
11%–44%
AEs
Daily dose titrated up to
Any AE
Anorexia
Fatigue
Memory problems
Nausea
Paresthesia
Taste disturbance
Weight loss
Withdrawals due to AE
MSQ: Migraine-Specific Quality of Life Questionnaire; MD: mean difference; OR: odds ratio; CI: confidence interval; SF-36: Medical Outcomes Study
36-item Short-Form Health Survey; NNH: numbers-needed-to-harm; AE: adverse event; ns: not significant.
AE rates for sodium valproate and divalproex
sodium were higher than for placebo and resulted
in withdrawal rates between 8% and 19%. NNHs
for any AE, and for the five specific AEs we judged
to be of greatest clinical importance, are summarized
in Table 3.
Other antiepileptics (Table 4)
Five of the 11 included papers investigating antiepileptic drugs other than gabapentin, pregabalin, topiramate, or valproate were already included in the
previous review. The included papers reported data
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Mulleners et al.
endpoint (55). Analyses of AEs were undertaken for
carbamazepine only, as that was the sole drug with a
significant effect that provided safety data that enabled
a comparison to placebo. For this compound, NNHs
are reported in Table 4.
Table 3. Valproate main outcomes.
Efficacy
Responders (OR (95% CI))
100%
3.34 [1.46, 7.67]
Frequency (MD (95% CI))
Discussion
100%
4.31 [ 8.32,
030]
Dose ranges: no pooled data
Quality of life
No pooled data
AEs
Any AE
Asthenia/fatigue
Dizziness/vertigo
Nausea
Tremor
Weight gain
Withdrawal due to AE
NNH (95% CI)
ns
ns
14 (8, 100)
7 (4, 25)
14 (8, 100)
ns
8%–19%
MD: mean difference; OR: odds ratio; CI: confidence interval;
NNH: numbers-needed-to-harm; AE: adverse event; ns: not significant.
from 10 unique studies. Of these, there were two trials
of lamotrigine (30,50) and one trial each of acetazolamide (51), carbamazepine (52), carisbamate (53), clonazepam (54), levetiracetam (26), oxcarbazepine (55),
vigabatrin (56), and zonisamide (57). All except the
trial of zonisamide included a placebo comparator.
Three trials included a comparison to active intervention (26,30,57), and one reported data that enabled
dose comparisons of the antiepileptic drug (carisbamate) under investigation (53). Four trials had a
cross-over design (30,52,54,56), while the other six
trials had a parallel-group design (26,50,51,53,55,57).
The duration of the treatment phase of the included
trials varied from four to 15 weeks, with a mean of 10
weeks. We judged eight studies as having a ‘‘high’’ risk
of bias for at least one of the items performance bias
(30), detection bias (54), attrition bias (52,56,57), and
reporting bias (51,53,55,57).
Of all investigated compounds, two drugs were
better than placebo, while zonisamide was not different
from topiramate 100–200 mg. Carbamazepine (dose
unknown) had a higher responder rate than placebo
(52), levetiracetam 1000 mg outperformed placebo
with regard to post-treatment mean headache frequency and responder rate, while headache frequency
was slightly but significantly higher with levetiracetam
compared to topiramate 100 mg (26).
One trial provided data on quality of life but was not
further analyzed as it failed to reach its primary
In this review, the results of the meta-analyses of 43
unique studies (57 reports) of 15 antiepileptic compounds are summarized. The results may be boiled
down to the following highlights:
. Both sodium valproate and topiramate significantly
reduced mean monthly headache frequency compared to placebo by approximately four and one
days, respectively.
. Furthermore, and perhaps of greater clinical relevance (though less informative scientifically),
patients were more than twice as likely to have a
50% reduction in headache frequency with divalproex sodium or topiramate than with placebo.
. All three target doses of topiramate significantly
improved three or more domains of quality of life
compared to placebo; for valproate, no placebo-controlled quality-of-life data were available.
. For topiramate and valproate, there is insufficient
evidence to support a relation between dose and
effect size.
. There may be a slight but significant advantage of
topiramate 50 mg daily over valproate 400 mg (both
doses lower than routinely used).
. Neither topiramate nor valproate appear to give rise
to an unexpectedly high rate of AEs when used for
migraine prophylaxis.
. For the other currently marketed antiepileptic drugs,
there is no robust evidence to support the use of any
of them in the preventive management of episodic
migraine.
. Although single studies of other antiepileptics may
attest to the efficacy of carbamazepine and levetiracetam, this evidence is considered insufficient
because of methodological issues (small sample size
(26,52), dose used not reported (52)), and efficacy
offset by AEs (52).
. Despite a small but significant effect in one trial of
gabapentin 1800–2400 mg (26), this evidence is considered insufficient because of the results from the
pooled analyses, findings from other trials, and lacking evidence for a clear dose-response trend.
There are, however, several findings that require special emphasis. For topiramate, some of the included
trials were almost certainly underpowered (26,29,34).
The studies including more than one dose of topiramate
58
Cephalalgia 35(1)
Table 4. Other antiepileptics main outcomes.
Efficacy vs placebo
Active compound
Acetazolamide 500 mg
Carbamazepine?
Clonazepam 1 mg
Lamotrigine 50 200 mg
Levetiracetam 1000 mg
Oxcarbazepine 1200 mg
Vigabatrin 1000 mg
Zonisamide 200 mga
Frequency (MD (95% CI))
Responders (OR (95% CI))
0.89 (0.28, 2.82)
11.77 (3.92, 35.32)
4.10 (
0.49 (
2.40 (
0.44 (
0.42 (
0.10 (
8.68, 0.48)
1.83, 0.85)
4.52, 0.28)
0.34, 1.22)
1.78, 0.94)
0.68, 0.88)
26.07 (1.30, 521.91)
0.86 (0.45, 1.61)
Dose ranges vs placebo
Responders (OR (95% CI))
Carisbamate 100 mg
Carisbamate 300 mg
Carisbamate 600 mg
Quality of life
No pooled data
AEs (carbamazepine only)
Any AE
Drowsiness
Nausea
Vertigo/giddiness
NNH (95% CI)
2 (2, 4)
ns
ns
2 (2, 3)
Statistically significant outcomes are highlighted as bold text.
MD: mean difference; OR: odds ratio; CI: confidence interval; NNH: numbers-needed-to-harm; AE: adverse event; ns: not significant.
a
vs topiramate 200 mg.
were generally not designed to enable direct dose comparisons, and the results of the dose comparisons
reported here should therefore be viewed with some
caution. For valproate, the largest trial of divalproex
sodium reported a statistically significant difference in
favor of active treatment (42). The clinical relevance of
this effect was, however, less compelling, as both the
investigators’ analysis and our own found no significant
difference between divalproex sodium and placebo in
the proportion of responders. Furthermore, the finding
that lower serum valproate levels produced lower headache frequency than higher serum levels (48) is somewhat counterintuitive, has not been replicated, and
should be regarded as preliminary.
Considering gabapentin, although the pooled results
of all gabapentin trials argue against a significant effect,
the highest gabapentin dose studied (1800 to 2400 mg/
day) demonstrated a small but significant effect in one
trial both with regard to reduction of mean headache
frequency and proportion of responders (24).
However, an evident dose-response relation was lacking.
It is remarkable that our analyses would have been
biased in favor of gabapentin had it not been for the
inclusion of previously confidential research reports
(22–24) that after several years became available in the
public domain by virtue of being entered into evidence in
a legal proceeding.
For the trials with acetazolamide, clonazepam, and
vigabatrin, these were certainly too small to allow any
conclusion. The finding that low-dose lamotrigine
(50 mg) was effective in lowering headache frequency
(30) while the high dose (200 mg) was not (50) should
also be interpreted with caution. The age of the single
carbamazepine trial is reason for concern and may
partly explain the outlying OR (52). The placebo-controlled levetiracetam study was not primarily designed
to obtain clinical outcome data of the interventions
(26). The equivalence in effect of zonisamide and
active comparator should be further investigated in placebo-controlled trials (57).
Two trials using active comparators found a slight
but significant advantage of topiramate over valproate.
It should be noted that these trials have various and
variable sorts of bias, notably insufficient statistical
power, performance, attrition reporting, and reporting
bias. Further well-designed trials, both of antiepileptics
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Mulleners et al.
against other drug categories, and comparing different
antiepileptics, are desirable.
Antiepileptic drugs do not appear to give rise to an
unexpectedly high rate of AEs when used for migraine
prophylaxis, although clearly (a) nausea is a problem
when trials of sodium valproate and divalproex sodium
are considered together, (b) a large percentage of patients
taking topiramate reported paresthesia, and (c) a large
percentage of patients taking carbamazepine reported vertigo/giddiness. Given the currently available evidence, in
our view the latter finding outweighs the very weak evidence in favor of carbamazepine. It should also be noted
that dropouts because of AEs are somewhat higher in
trials of topiramate than would generally be expected on
the basis of trials of other anticonvulsant drugs, particularly sodium valproate or divalproex sodium.
It can be concluded from this review that sodium
valproate, divalproex sodium, and topiramate are of
proven efficacy in migraine prevention and are suitable
for routine clinical use. Convincing evidence for efficacy
differences with amitriptyline, flunarizine, propranolol
or relaxation is lacking, although topiramate may be
marginally better than valproate. One important
caveat should be noted: These drugs are known to or
may be teratogenic, and appropriate caution must be
used when prescribing to women of child-bearing age.
Although AEs are reported by a large proportion of
migraine patients treated with sodium valproate/divalproex sodium or topiramate, these are usually mild and
of a non-serious nature. On a case-to-case basis,
rational prescriber preferences may be appreciated
because of differences in side effect profiles.
The evidence derived from trials of gabapentin provides insufficient grounds for advocating their use in clinical practice, even at higher dosing schemes. Similarly, for
all other antiepileptic drugs there is, at present, either
insufficient or no evidence concerning either efficacy or
tolerability to warrant their use in clinical practice.
Although a large number of antiepileptics, including the
newer ones, appear to be amply used in the management
of headache, as judged by the vast number of publications
of small retrospective series and studies in chronic daily
headache or transformed migraine, these results cannot
be translated as compelling evidence, and thus we would
like to argue against the liberal use of antiepileptics other
than topiramate and valproate.
Clinical implications
. Both sodium valproate and topiramate significantly reduce mean monthly headache frequency approximately four and one days, respectively.
. Patients are more than twice as likely to have a 50% reduction in headache frequency with divalproex
sodium or topiramate than with placebo.
. Topiramate significantly improves quality of life compared to placebo.
. There is insufficient evidence to further support the use of any dose of gabapentin.
. For the other currently marketed antiepileptic drugs, there is no robust evidence to support the use of any of
them.
Notes
This paper has been adapted from four systematic
Cochrane reviews published in the Cochrane Database of
Systematic Reviews 2013, Issue 6. Cochrane reviews are
regularly updated as new evidence emerges and in
response to feedback, and the Cochrane Database of
Systematic Reviews should be consulted for the most
recent version of the reviews. The four original reviews are:
Linde M, Mulleners WM, Chronicle EP, et al.
Topiramate for the prophylaxis of episodic migraine
in adults. Cochrane Database Syst Rev 2013; 6:
CD010610.
Linde M, Mulleners WM, Chronicle EP, et al.
Valproate (valproic acid or sodium valproate or a combination of the two) for the prophylaxis of episodic
migraine in adults. Cochrane Database Syst Rev 2013;
6: CD010611.
Linde M, Mulleners WM, Chronicle EP, et al.
Gabapentin or pregabalin for the prophylaxis of episodic migraine in adults. Cochrane Database Syst Rev
2013; 6: CD010609.
Linde M, Mulleners WM, Chronicle EP, et al.
Antiepileptics other than gabapentin, pregabalin, topiramate, and valproate for the prophylaxis of episodic
migraine in adults. Cochrane Database Syst Rev 2013;
6: CD010608.
Acknowledgments
Professor EP Chronicle, PhD, sadly passed away February 9,
2007. We wish to acknowledge Professor Chronicle’s major
contribution and tremendous effort in compiling all statistical
analyses and much of the text of the original review on
antiepileptics.
We thank the following members of the Cochrane Editorial
Unit (CEU) and the Cochrane Pain, Palliative and Supportive
60
Care Review Group (PaPaS) for their assistance: Ruth Foxlee
(CEU), Jane Hayes (PaPaS), and Joanne Abbott (PaPaS) for
assistance in designing search strategies and running searches,
Prof Timothy Steiner (PaPaS) for editorial guidance, and
Dr Rebecca Gray (PaPaS) for editorial assistance and technical support.
Funding
Lifting The Burden: The Global Campaign against Headache
and the International Headache Society provided financial support for the editorial process for the original Cochrane reviews.
Conflicts of interest
Dr Mulleners has nothing to disclose.
Dr Linde was involved as an investigator in a clinical trial
sponsored by AstraZeneca and comparing candesartan, propranolol, and placebo in the prophylaxis of migraine. Dr Linde
also received a travel grant from Allergan. Dr Linde was senior
investigator in one of the included studies (Varkey 2011).
Dr McCrory received personal fees from the Plaintiff’s
Sttering Committee in the Neurontin Marketing and Sales
Practices. Moreover, he received financial reimbursements for
committee and consultant activities from Cleveland Clinic,
MEDACorp and The College of American Pathologists.
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