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Abstract The studies of different antiepileptic drugs
(AEDs) in the prophylaxis of episodic migraine, cluster
headache (CH) and chronic headache forms (chronic daily
headache, transformed or chronic migraine, chronic ten-
sion-type headache) are reviewed. The main results from
published trials are summarised focusing on responder
rates as reported in placebo-controlled, double-blind stud-
ies. Most common adverse events are also discussed. This
review indicated that robust evidence supports the use of
sodium valproate-divalproex and of topiramate (TPM) in
the prophylaxis of migraine, while definitive conclusions
about the real effects of other AEDs in migraine cannot be
drawn. Overall, evidence of efficacy of different AEDs in
chronic headache forms and in CH is still lacking, moststudies being open-label, small-sample trials. Neverthe-
less, encouraging data from controlled trials are emerging
for TPM in the treatment of chronic headache forms.
Key words Antiepileptic drugs (AEDs) Responder rate
Adverse events (AEs) Migraine Cluster headache (CH)
Chronic headache forms
Introduction
The treatment of migraine and of other primary headaches
is based on three main steps [1, 2]. Elimination of any fac-
tor or condition which could precipitate or exacerbate
headaches is the first step. The second step is acute thera-
py, which should reduce the severity and duration of indi-
vidual headache episodes. While these two steps are virtu-
ally indicated for all patients, prophylactic therapy is
required in most severely affected patients, in those in
which attacks are very frequent, and when there is a
marked impact on daily functioning. The main aim of pro-
phylaxis is the reduction in headache frequency, the ulti-
mate target being to improve functioning and well-being ofpatients. Thus, successful implementation of prophylaxis
requires appropriate patient selection, and the possibility
of using drugs with an evidence-based efficacy and a
favourable tolerability profile [1, 2]. Antiepileptic drugs
(AEDs) are among those medications that are currently
used for migraine prophylaxis [35]. Furthermore, the effi-
cacy of some drugs of this class in cluster headache (CH)
and in chronic headache forms has been recently suggest-
ed by several reports [639].
Objective and methods
The aim of this paper is to briefly review the studies of different
AEDs in the prophylaxis of episodic migraine, CH and chronic
headache forms (chronic daily headache, CDH; transformed
migraine, TM; chronic migraine, CM; and also chronic tension-
type headache). Studies included in this review were individuat-
ed by a MEDLINE search of the words headacheand migraine
along with the names of different AEDs. Additional studies pub-
lished as abstracts from international congresses on headache
disorders and from other sources were included.
Data acquired in open, uncontrolled trials will be summarised
particularly when these were the only available studies for an
Neurol Sci (2007) 28:S188S197
DOI 10.1007/s10072-007-0775-3
D. DAmico
Antiepileptic drugs in the prophylaxis of migraine, chronic headacheforms and cluster headache: a review of their efficacy and tolerability
J O I N T M E E T I N G A N I R C E F & H C N E
D. DAmico ()Fondazione IRCCS Istituto Neurologico C. Besta
Via Celoria 11, I-20123 Milan, Italy
e-mail: [email protected]
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D. DAmico: Antiepileptic drugs in headache prophylaxis S189
individual drug. The results obtained in placebo (PLO)-con-
trolled, double-blind (DB) studies will be discussed, focusing on
the reported responder rates, i.e., the proportion of treated
patients who experienced a reduction in migraine frequency of
50% or more. The main adverse events (AEs) due to AEDs will
also be reported for each drug.
Discussion on the efficacy of AEDs in other forms of headand facial pain that are currently treated with these drugs, name-
ly trigeminal neuralgia [40] and SUNCT [41], is beyond the
scope of the present paper.
Antiepileptic drugs in migraine prophylaxis
Sodium valproate (SV)/divalproex (DV)
Several trials with valproic acid either as SV or as DV (a
stable combination of SV and valproic acid in a 1:1 molar
ratio) are available. Sorensen reported for the first time the
positive effect of SV in migraine prevention in an open
trial [42]. In another prospective open study this drug was
found to be effective in migraineurs who had no benefit
from other prophylactic medications [43].
The first controlled trial was published in 1992 [44].
It was a DB, PLO-controlled, crossover trial. The results
showed a reduction in headache attacks in the majority
(86.2%) of the 29 migraineurs on SV 800 mg/day who
completed the study. In a triple-blind, PLO-controlled
crossover study with slow-release SV (10001500
mg/day) [45] the responder rate was 50% in the SV groupand 18% in the PLO group. The responder rates after
SV/DV therapy were evaluated in another 3 controlled,
DB trials [4648]. In the first two studies [46, 47],
responder rates after DV 5001600 mg/day, ranging from
43% to 48%, were significantly superior to the rates
found in the PLO group. In the third study [48], although
the mean reduction in migraine attacks was significantly
higher in patients on SV/DV than in those on PLO
(p=0.006), the responder rate was lower than those
reported in previous studies and not significantlygreater than that found in the PLO group (30% vs. 24%,
p=0.25) (Table 1).
SV and DV were compared to other prophylactic
agents: they were equally effective as propranolol in an
open study [49] and in a single-investigator, single-blind,
crossover study [50]; SV was similar to flunarizine in a
small-sample, randomised, double-open, parallel-group
clinical trial [51].
The long-term efficacy of DV was evaluated in an
open-label extension phase of a DB study, in which 163
patients were invited to use this drug for up to 3 years [52].
Only 33% of them completed the study, while 16% with-
drew from the study due to insufficient effectiveness, 21%
because of drug intolerance and 31% for other reasons.
Treatment lasted more than 180 days for 72% of patients
and more than 360 days for 48% of patients. Improvements
were observed during each of the 3- and 6-month follow-
up intervals. Responder rates were 49% in patients treated
up to three months, and 70% for patients receiving DV for
longer periods.
The most common AEs of SV/DV were gastrointesti-
nal problems, hair loss, tremor, sedation, changes in cog-
nitive performance, weight gain, fatigue and dizziness
[4648]. In the above-mentioned long-term study [52],
dyspepsia was present in 25% of patients, nausea in 42%of patients and alopecia in 31% of patients. The incidence
of these side effects was lower after 3 and 6 months of
treatment, while other AEs were stable during the differ-
ent treatment periods: tremor (present in 28% of
Table 1 Responder rates (i.e., the percentage of patients experiencing 50% or more reduction in attack frequency) reported in large
randomised, controlled, double-blind trials of different AEDs in the prophylaxis of migraine
Trial (first Randomised Duration of AED Daily Responder Responder Difference,
author, year) patients (n), treatment dose (mg) rate (%), rate (%), AED vs. PLO
diagnosis (weeks) AED PLO
Jensen, 1994 43, MO 12 SV 10001500 50 18 SignificantMathew, 1995 107, MO, MA 12 DV Mean 1087 48 14 Significant
Klapper, 1997 176, MO, MA 12 DV 5001500 4344 21 Significant
Freitag, 2003 234, MO, MA 12 DV 1000 30 24 Not significant
Silberstein, 2004 487, MO, MA 26 TPM 50 36 Not significant
100 54 23 Significant
200 52 Significant
Brandes, 2003 483, MO, MA 26 TPM 50 39 Significant
100 49 23 Significant
200 47 Significant
Diener, 2004 575, MO, MA 26 TPM 100 37 Significant
200 35 Significant
Propranolol 160 43 23 Significant
Mathew, 2001 143, MO, MA 12 GBP 2400 46 16 Significant
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S190 D. DAmico: Antiepileptic drugs in headache prophylaxis
patients), somnolence, asthenia and dyspepsia (in about
25% of patients), and weight gain (in 19%). Hepatoto-
xicity, ovarian dysfunction, hyperandrogenism and alter-
ations in coagulation factors have been occasionally
reported. Irreversible hepatic dysfunction and pancreati-
tis are very rare in migraine patients.Discontinuation rates because of intolerance were
rather low (8%13%) in controlled trials [46, 48], but they
were higher (21%) in the long-term study [52].
Topiramate (TPM)
TPM has been extensively studied in migraine patients.
Open-label and small PLO-controlled studies of TPM in
migraine were published between 1999 and 2002 [5356],
which suggested that TPM may be effective in migraineurs
when used at different daily doses.
These preliminary studies were followed by large DB
trials published in 2004, which led to the indication of the
100 mg/day dose as the optimal treatment choice, based on
the balance between efficacy and tolerability [5759]. The
MIGR-001 [57] and MIGR-002 [58] studies were both
multicentre, randomised, DB, PLO-controlled trials. The
treatment period included a 8-week titration phase and an
18-week maintenance phase. They were also dose-finding
studies, as different daily doses were tested. The intent to
treat populations included 469 patients in MGR-001 and
468 patients in MGR-002. TPM treatment was associated
with significant improvements in the 100 mg/day and inthe 200 mg/day arms. Reduction in migraine frequency
(assessed using migraine periods, i.e., migraine headache
that started and ended or recurred and ended within 24 h)
was significantly greater in the TPM 100 mg/day and 200
mg/day arms than in the PLO arms (in MGR-001: p
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Gabapentin (GBP)
GBP was investigated in two controlled trials [65, 66]. One
small-sample, single-centre trial on 63 patients [65]
reported a significative reduction of frequency and inten-
sity of migraine in 30 patients treated with GBP(1200 mg/day). The other study [66] was a multicentre
trial in which 143 patients were included in a 4-week, sin-
gle-blind, PLO baseline period, followed by a 12-week,
DB, treatment period. The median migraine frequency was
significantly lower in the active medication group than in
the PLO group (p=0.006). Additionally, responder rates
were 46.4% among patients receiving GBP 2400 mg/day
and 16.1% among patients on PLO (p=0.008).
The most common AEs after GBP were somnolence,
dizziness, tremor, fatigue and ataxia. They were generally
transient and mild to moderate in severity, although they
resulted in patient withdrawal in 13.3% of the GBP-treat-
ed patients in the multicentre trial [66]. Weight gain was
not a common complaint, although in the same study 3.1%
of patients reported an increase in body weight.
Lamotrigine (LTG)
The first trial of LTG in migraine prophylaxis was a nega-
tive study [67]. It was a randomised, PLO-controlled, DB
parallel-group trial: 37 subjects were on LTG 200 mg/day,
and 37 were on PLO, for 3 months. Mean attack frequency
was reduced from 3.6 episodes to 3.2 on LTG and from 4.4episodes to 3.0 on PLO during the last month of treatment
vs. baseline. Thus, it was concluded that LTG is ineffective
for migraine prophylaxis. After this study, some open-
label studies have indicated that this AED may be very
effective in patients who experience migraine aura. In two
small open pilot studies [68, 69] LTG 100 mg/day signifi-
cantly reduced the frequency of migraine with aura. In more
than 50% of cases in the study by DAndrea et al. [68] the
attacks were completely abolished at the third month of
treatment in a sample of 21 subjects who had a rather high
frequency of aura attacks (6.14.1/month). Furthermore, a
significant increase in aura frequency was observed byLampl et al. [69] in all the 15 studied patients after cessa-
tion of LTG during a 3-month post-treatment observation
period. LTG was effective in another open study [70] in
which also rather severe forms of migraine with aura (pro-
longed aura, frequent episodes, basilar-type migraine,
hemiplegic migraine) were treated. Also in this sample
auras tended to reappear after LTG was stopped, and ceased
as soon as this drug was reintroduced. The efficacy of LTG
in migraine with aura was recently evaluated in a larger
sample (59 patients) and on a prolonged treatment period (3
years) in a prospective, open study [71]. The mean frequen-
cy of migraine aura was significantly reduced after treat-
ment (p
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S192 D. DAmico: Antiepileptic drugs in headache prophylaxis
Antiepileptic drugs in patients with chronic headache
forms
SV/DV
Encouraging results were found in a retrospective analysis of
207 patients with refractory chronic headaches who were treat-
ed with SV/DV [17], as well as in subsequent prospective tri-
als [18, 19]. Substantial improvement based on headache index
and headache-free days was found in two thirds of patients
with persistent CDH after a 3-month treatment period [18], and
more than 50% of patients with frequent migraines or TM
improved after a 6-week treatment period with DV [20].
The efficacy and safety of DV in the long-term treat-
ment of CDH were assessed in a retrospective chart review
which included patients suffering from migraine associat-
ed with tension-type headache or from TM who were treat-
ed for up to 6 years as add-on therapy or as only treatment
[20]. A reduction in headache frequency of at least 50%
was reported by 93 of the 138 patients receiving only DV.
AEs occurred in approximately 35% of the patients. None
were severe, and hepatotoxicity did not occur.
TPM
The first report on chronic headache sufferers was published
in 2002 [21]. It was a retrospective chart analysis that includ-
ed 96 TM patients in whom TPM was used as add-on therapy.The mean number of headache days/month decreased from
22.1 to 9.6 (p=0.001), and the mean number of symptomatic
medications decreased from 28.7/month to 10.6 (p=0.001). A
3-month therapy with either SV/DV 750 mg/day or TPM 75
mg/day in 49 CM patients without medication overuse led to
a reduction in headache frequency (p
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GBP
After a small open study in patients with CDH [29], a multi-
centre, randomised, PLO-controlled, crossover study was
published [30]. Ninety-five patients (out of the 133 who were
enrolled) completed the study. Analyses on these completersshowed a significant difference in headache-free rates
favouring GBP 2400 mg/day over PLO (p=0.0005). The
active drug was superior to PLO also for other end points
(headache-free days/month, disability, quality of life, etc.).
Analyses on intention-to-treat population were not reported.
LTC
The utility of LTC as add-on therapy in patients with chron-
ic and/or refractory headaches was suggested in two open-
label studies reported in abstracts [6, 7]. In the first study [6]
14 out of 30 patients with refractory chronic headaches, and
additional cervical or lumbar symptoms, reported a 50% or
more reduction in frequency and severity after 3 months of
LTC (up to 20004500 mg/day). In the other study [7] the
majority of the 62 patients with refractory migraines or CDH
had a marked improvement after LTC 5001550 mg/day
therapy. Encouraging data were also reported in a retrospec-
tive chart review on patients with migraine [8] treated with
LTC 5002000 mg/day. A recent prospective, open trial
assessed LTC in the prevention of TM [9]. The intention-to-
treat population consisted of 36 patients. The mean headache
frequency per month at baseline was 24.9 days and a signif-icant reduction was obtained in 1 month (19.4, p
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S194 D. DAmico: Antiepileptic drugs in headache prophylaxis
some improvement in frequency and severity of attacks was
reported by 9 episodic CH patients, no change by 3 chronic
CH patients and complete remission by none of the evaluat-
ed subjects. In a prospective open-label study [38] in which
23 episodic and 10 chronic CH patients received TPM (daily
doses ranging from 25 to 250 mg/day) no significant changein mean headache frequency before and after treatment was
found, and the responder rate was low (21%). Response to
TPM was not dose related.
GBP
The efficacy of this drug in CH was assessed in an open-
label study on 8 patients with refractory CH (8 eight
patients with episodic CH; 4 with chronic CH). Remission
was obtained in all patients after treatment with GBP 900
mg/day after 8 days or less, with absence of attacks after a
4-month follow-up period [39].
Concluding remarks
The above-reported data indicate that there is a substantial
body of evidence supporting the efficacy of SV/DV and of
TPM in the prophylaxis of migraine. Both drugs have been
investigated in various open trials, in at least one long-
term open-label study [52, 62, 63], and in at least 3 con-
trolled trials [4447, 5759]. Responder rates (percentageof patients experiencing a reduction in migraine frequen-
cy of 50% or more) reported in randomised, DB, PLO-
controlled trials ranged from 30 to 50% for SV/DV (daily
dose between 500 and 1500 mg), and from 37 to 54% for
TPM (at the target dose of 100 mg/day) (Table 1). These
responder rates were significantly higher than those found
in patients on PLO in all three controlled trials of TPM,
and in 3 out of 4 controlled trials of SV/DV (Table 1).
Overall, the above-reported data may suggest a slight
superiority of TPM over SV/DV. Furthermore, results
from the TPM trials may be more easily interpreted and
transposed to clinical practice than those from the SV/DVstudies. In fact the DB, PLO-controlled studies of TPM
had the same design and were aimed also to define the
optimal target dose in migraine patients. Results were
evaluated with intention-to-treat analyses, and on large
populations (more than 450 patients in each study). On the
other hand, studies of SV/DV were characterised by dif-
ferent formulations and daily doses, different treatment
schedules, and rather small samples.
Definitive evidence of the efficacy of other AEDs in
migraine is still lacking. Encouraging data for GBP effi-
cacy were reported in two small-sample controlled trials
(a single-centre study in which 30 patients received GBP
1200 mg/day, and a multicentre trial in which 56 patients
received GBP up to 2400 mg/day) [65, 66]. Regarding
clonazepam, VIG, LTG and oxcarbazepine, one controlled
study is available for each of these agents, but results
showed a slight superiority [16, 72] or no superiority [67,
74] of the active drug vs. PLO. On the other hand, theresults of various studies [6871] indicated the efficacy of
LTG in patients suffering from aura symptoms: although
they were open-label studies the positive results in
patients who were affected also by high-frequency or
severe aura syndromes, the long-term efficacy and the ten-
dency of auras to reappear after LTG discontinuation
make this drug a valid treatment option in migraine with
aura. The efficacy of carbamazepine was reported in only
one controlled study [73], which has never been replicat-
ed in recent years.
Regarding chronic headache forms, clear evidence of
the efficacy of AEDs is still lacking. Only open-label stud-
ies are available for SV/DV [1721], LTC [69], ZNS
[1013] and TGB [14, 15], most of which were small-sam-
ple, retrospective studies (often published as abstracts), in
which AEDs were used as add-on therapy in patients
receiving other prophylactic compounds. Controlled trials
have been performed only for TPM and GBP. Fours stud-
ies of TPM are available: two single-centre, small-sample
studies [24, 25], and two well designed, multicentre, ran-
domised, DB, PLO-controlled, parallel trial, one published
in abstract form [26] and one as full-paper [27]. For GBP
only one controlled study (multicentre, randomised, DB,
PLO-controlled, crossover trial) was published [30]. Re-
levant problems in understanding the real efficacy of AEDsin chronic headaches also characterise the above-reported
controlled trials: non-homogeneous classification criteria
used across studies, inclusion of patients with and without
medication overuse, small studied samples, AED used as
add-on treatment and lack of data analyses on intention-to-
treat populations.
Regarding the real efficacy of different AEDs in CH, it
is not possible to draw any definitive conclusion. All stud-
ies but one [34] were open-label, small-sample and often
retrospective [21, 3133, 3539] in which AEDs were used
as add-on therapy in some patients. Despite the encourag-
ing results of most reports on SV/DV, TPM and GBP, neg-ative results were found in those studies with a more accu-
rate design, i.e., in the only controlled, DB study of SV [34]
and in a prospective open-label study of TPM characterised
by a 7-day run in period and a 20-day treatment period with
TPM as monotherapy during which patients completed
diary cards [38]. Controlled studies on larger samples are
needed, which should take into account several method-
ological issues that are peculiar to CH. Episodic and chron-
ic CH patients must be studied in separate trials. Attention
should be paid to the duration of previous active periods in
episodic CH patients: the reduction in attack frequency, or
their complete resolution, in episodic CH patients might be
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D. DAmico: Antiepileptic drugs in headache prophylaxis S195
due to spontaneous remission. On the other hand, the same
explanation could account for the high response rates in
patients on PLO, with consequent negative results for the
active drug in statistical analysis [34].
Overall, the safety and tolerability of AEDs in
headache patients were satisfactory, also in long-termtreatment studies. AEs were generally mild or well tolerat-
ed, although they were rather common in controlled trials
on migraine patients (e.g., in 8%23% of SV/DV-treated
patients, around in 25% of those on TPM 100 mg/day and
in 27%67% in those on GBP). Patients should be warned
in advance and reassured about the benign nature of most
AEs and about their tendency to decrease over time (as is
the case with nausea due to SV/DV and with paraesthesia
due to TPM) also because the clinical experience indi-
cates that many patients will better tolerate them. Howe-
ver, clinicians should be aware of some relevant, disturb-
ing or potentially serious AEs. For example, SV/DV may
cause hair loss, tremor and sedation; more serious events
like hepatic dysfunction, pancreatitis and abnormalities in
coagulation factors may occur, particularly in patients who
are receiving other medications; ovarian dysfunction,
hyperandrogenism and weight gain must be taken into
account in young female headache patients on SV/DV.
TPM can rarely induce metabolic acidosis, oligohydrosis
and hyperthermia. Patients should be advised that ade-
quate hydration is necessary when taking TPM, and that
physical exercise in high ambient temperature is to be
avoided. It is advisable to periodically measure serum
bicarbonate levels when conditions predisposing to acido-
sis are present (kidney disease, severe respiratory disorder,status epilepticus, diarrhoea, surgery, ketogenic diet, use
of other carbonic anhydrase inhibitors). Patients must con-
sult an ophthalmologist if difficulties in vision arise, in
order to rule out acute myopia and glaucoma syndrome,
which are rare, bilateral, easily recognisable and reversible
effects of TPM [64]. Dizziness, concentration difficulties,
somnolence, tremor and also psychiatric symptoms
(depression, nervousness, anxiety, etc.) may be treatment-
limiting AEs in patients receiving other AEDs, such as
ZNS, LTC, GBP and TGB.
It is important to note that slow dose-escalation gener-
ally reduces the frequency of most AEs, and the risk ofwithdrawal from treatment in clinical practice. For all drugs
of this class the starting dose should be low, with progres-
sive titration. For TPM, the suggested titration schedule is
to start with 25 mg at night, and to titrate by 25 mg/week to
the target dose (100 mg/day), with possible adjustments to
lower or higher doses if indicated on the basis of clinical
response and tolerability. Slow titration reduces the risk of
rash in patients on LTG, and the starting dose of 25 mg/day
should be preferably maintained for 12 weeks.
A major benefit of AEDs is that they can be prescribed
in conditions (such as depression, Raynauds disease, asth-
ma, hypotension, urinary retention) that prevent the use of
other prophylactic compounds, such as propranolol, vera-
pamil, flunarizine and amitriptyline. Furthermore, TPM is
the only migraine preventive medication that is not likely
to cause weight gain, and thus can be used in overwei-
ght/obese patients. AEDs are the first choice therapy in mi-
graineurs with co-morbid epilepsy, a drug of this class maybe indicated in those with psychiatric comorbidities, as
AEDS are effective in anxiety or bipolar disorders [75].
In conclusion, the results of the present review indicate
that there is robust evidence to support the use of SV/DV
and of TPM in the prophylaxis of migraine in clinical prac-
tice. Definitive data about the efficacy of other AEDs in
migraine, as well as all AEDs in chronic headaches and
CH is still insufficient. Encouraging data from recent con-
trolled trials are emerging for TPM, in the treatment of
chronic headache forms. Overall, AEDs can be considered
as alternative options in those patients with either CH or
chronic headache forms who had poor response to other
standard treatments or in whom other agents are con-
traindicated.
References
1. Silberstein SD (2000) Practice parameter: evidence-based
guidelines for migraine headache (an evidence-based review):
report of the Quality Standards Subcommittee of the Ameri-
can Academy of Neurology. Neurology 55:754762
2. DAmico D, Lanteri-Minet M (2006) Migraine preventive
therapy: selection of appropriate patients and general princi-
ples of management. Expert Rev Neurother 6:11471157
3. Silberstein SD, Goadsby PJ (2002) Migraine: preventive treat-
ment. Cephalalgia 22:491512
4. Rapoport AM, Bigal ME (2005) Migraine preventive therapy:
current and emerging treatment options. Neurol Sci 26[Suppl
2]:S111S120
5. Chronicle E, Mulleners W (2004) Anticonvulsant drugs for
migraine prophylaxis. Cochrane Database of
Systematic Reviews, Issue 3. Art. No.: CD003226.
DOI:10.100214651858.CD003226.pub2
6. Krusz JC (2001) Levetiracetam as prophylaxis for resistant
headaches. Cephalalgia 21:373
7. Drake ME, Greathouse NI, Armentbright AD, Renner JB
(2001) Levetiracetam for preventive treatment of migraine.Cephalalgia 21:373
8. Cochran JW (2004) Levetiracetam as migraine prophylaxis.
Clin J Pain 20:198199
9. Rapoport AM, Sheftell FD, Tepper SJ, Bigal ME (2005)
Levetiracetam in the preventive treatment of transformed
migraine. Curr Ther Res 66:212221
10. Krusz JC (2001) Zonisamide in the treatment of headache dis-
orders. Cephalalgia 21:374375
11. Drake ME, Greathouse NI, Armentbright AD, Renner JB
(2001) Preventive treatment of migraine with zonisamide.
Cephalalgia 21:374
12. Smith TR (2001) Treatment of refractory chronic daily
headache with zonisamide: a case series. Cephalalgia 21:482
7/29/2019 Antiepilepticos y Cefalea Cronica
9/10
S196 D. DAmico: Antiepileptic drugs in headache prophylaxis
13. Ashkenazi A, Benlifer A, Korenblit J, Silberstein SD (2006)
Zonisamide for migraine prophylaxis in refractory patients.
Cephalalgia 26:11991202
14. Drake ME Jr, Kay AM, Knapp MS, Greathouse NI (1999) An
open-label trial of tiagabine for migraine prophylaxis.
Headache 39:352
15. Freitag FG, Diamond S, Diamond ML et al (1999) The pro-phylaxis of migraine with the GABA-agonist, tiagabine: a
clinical report. Headache 39:354
16. Ghose K, Niven BE, Berry D (2002) Double blind cross-over
comparison of the effects of vigabatrin with placebo in the
prevention of migraine headache. J Headache Pain 3:7985
17. Moore KL (1992) Valproate in the treatment of refractory
recurrent headaches: a retrospective analysis of 207 patients.
Headache Quarterly 3:323332
18. Mathew NT, Ali S (1991) Valproate in the treatment of persis-
tent chronic daily headache. An open label study. Headache
31:7174
19. Rothrock JF, Kelly NM, Brody ML, Golbeck A (1994) A dif-
ferential response to treatment with divalproex sodium in
patients with intractable headache. Cephalalgia 14:241244
20. Freitag FG, Diamond S, Diamond ML, Urban GJ (2001)
Divalproex in the long-term treatment of chronic daily
headache. Headache 41:271278
21. Mathew NT, Kailasan J, Meadors L (2002) Prophylaxis of
migraine, transformed migraine, and cluster headache with
topiramate. Headache 42:796803
22. Bartolini M, Silvestrini M, Taffi R et al (2005) Efficacy of top-
iramate and valproate in chronic migraine. Clin Neuro-
pharmacol 28:277279
23. Peres MF, Mercante JF, Tanuri FC et al (2006) Chronic
migraine prevention with topiramate. J Headache Pain
7:185187
24. Mei D, Ferraro D, Zelano G et al (2006) Topiramate and trip-tans revert chronic migraine with medication overuse to
episodic migraine. Clin Neuropharmacol 29:269275
25. Silvestrini M, Bartolini M, Coccia M, Baruffali R et al (2003)
Topiramate in the treatment of chronic migraine. Cephalalgia
23:820824
26. Grazzi L, Diener HC, van Oen JC et al (2006) Response to to-
piramate in the prevention of chronic migraine: results of a
double-blind, randomized, placebo-controlled trial. Cephalal-
gia 26:1368
27. Silberstein S, Lipton RB, Dodick DW et al (2007) Efficacy
and safety of topiramate in the treatment of chronic migraine:
a randomized, double-blind, placebo-controlled trial. Heada-
che 47:170180
28. Lampl C, Marecek S, May A, Bendtsen L (2006) A prospec-tive, open-label, long-term study of the efficacy and tolerabil-
ity of topiramate in the prophylaxis of chronic tension-type
headache. Cephalalgia 26:12031208
29. Fragoso YD, Carrazana EJ (2000) Low doses of gabapentin
may be helpful in the management of chronic daily headache.
MedGenMed 2:E52
30. Spira PJ, Beran RG, Australian Gabapentin Chronic Daily
Headache Group (2003) Gabapentin in the prophylaxis of
chronic daily headache: a randomized, placebo-controlled
study. Neurology 61:17531759
31. Hering R, Kuritzky A (1989) Sodium valproate in the treat-
ment of cluster headache: an open clinical trial. Cephalalgia
9:195198
32. Freitag FG, Diamond S, Diamond ML et al (2000) Divalproex
sodium in the preventative treatment of cluster headache.
Headache 40:408
33. Gallagher RM, Mueller LL, Freitag FG (2002) Divalproex
sodium in the treatment of migraine and cluster headaches.
J Am Osteopath Assoc 102:9294
34. El Amrani M, Massiou H, Bousser MG (2002) A negative trialof sodium valproate in cluster headache: methodological
issues. Cephalalgia 22:205208
35. Wheeler SD, Carrazana EJ (1999) Topiramate-treated cluster
headache. Neurology 53:234236
36. Forderreuther S, Mayer M, Straube A (2002) Treatment of
cluster headache with topiramate: effects and side-effects in
five patients. Cephalalgia 22:186189
37. Lainez MJ, Pascual J, Pascual AM et al (2003) Topiramate in
the prophylactic treatment of cluster headache. Headache
43:784789
38. Leone M, Dodick D, Rigamonti A et al (2003) Topiramate in
cluster headache prophylaxis: an open trial. Cephalalgia
23:10011002
39. Leandri M, Luzzani M, Cruccu G, Gottlieb A (2001) Drug-
resistant cluster headache responding to gabapentin: a pilot
study. Cephalalgia 21:744746
40. Cheshire WP Jr (2007) Trigeminal neuralgia. Curr Pain
Headache Rep 11:6974
41. Pareja JA, Cuadrado ML (2005) SUNCT syndrome: an
update. Expert Opin Pharmacother 6:591599
42. Sorensen KV (1988) Valproate: a new drug in migraine pro-
phylaxis. Acta Neurol Scand 78:346348
43. Erdemoglu AK, Ozbakr S (2000) Valproic acid in prophylax-
is of refractory migraine. Acta Neurol Scand 101:354358
44. Hering R, Kuritzky A (1992) Sodium valproate in the prophy-
lactic treatment of migraine: a double-blind study versus
placebo. Cephalalgia 12:818445. Jensen R, Brinck T, Olesen J (1994) Sodium valproate has a
prophylactic effect in migraine without aura: a triple-blind,
placebo-controlled crossover study. Neurology 44:647651
46. Mathew NT, Saper JR, Silberstein SD et al (1995) Migraine
prophylaxis with divalproex. Arch Neurol 52:281286
47. Klapper J (1997) Divalproex sodium in migraine prophylaxis:
a dose-controlled study. Cephalalgia 17:103108
48. Freitag FG, Collins SD, Carlson HA et al (2002) Migraine
Study Group. A randomized trial of divalproex sodium
extended-release tablets in migraine prophylaxis. Neurology
58:16521659
49. Kozubski W, Prusinski A (1995) Sodium valproate versus pro-
pranolol in the prophylactic treatment of migraine. Neurol
Neurochir Pol 29:93794750. Kaniecki RG (1997) A comparison of divalproex with propra-
nolol and placebo for the prophylaxis of migraine without
aura. Arch Neurol 54:11411145
51. Mitsikostas DD, Polychronidis I (1997) Valproate versus flu-
narizine in migraine prophylaxis: a randomized, double-open,
clinical trial. Funct Neurol 12:267276
52. Silberstein SD, Collins SD (1999) Safety of divalproex sodi-
um in migraine prophylaxis: an open-label, long-term study.
Long-term Safety of Depakote in Headache Prophylaxis
Study Group. Headache 39:633643
53. Shuaib A, Ahmed F, Muratoglu M, Kochanski P (1999)
Topiramate in migraine prophylaxis: a pilot study. Cephalal-
gia 19:379380
7/29/2019 Antiepilepticos y Cefalea Cronica
10/10
D. DAmico: Antiepileptic drugs in headache prophylaxis S197
54. Edwards KR, Glantz MJ, Shea P et al (2000) A double-blind,
randomized trial of topiramate versus placebo in the prophy-
lactic treatment of migraine headache with and without aura.
Cephalalgia 20:316
55. Potter BL, Hart DE, Calder CS, Storey JR (2000) A double-
blind, randomized, placebo-controlled, parallel study to deter-
mine the efficacy of topiramate in the prophylactic treatmentof migraine. Neurology 54:A15
56. Young WB, Hopkins MM, Shechter AL, Silberstein SD
(2002) Topiramate: a case series study in migraine prophylax-
is. Cephalalgia 22:659663
57. Silberstein SD, Neto W, Schmitt J et al (2004) Topiramate in
migraine prevention: results of a large controlled trial. Arch
Neurol 61:490495
58. Brandes JL, Saper JR, Diamond M et al (2004) Topiramate for
migraine prevention: a randomized controlled trial. JAMA
291:965973
59. Diener HC, Tfelt-Hansen P, Dahlof C et al (2004) Topiramate
in migraine prophylaxis. Results from a placebo-controlled
trial with propranolol as an active control. J Neurol
251:943950
60. Bussone G, Diener HC, Pfeil J et al (2005) Topiramate 100
mg/day in migraine prevention: a pooled analysis of double-
blind randomised controlled trials. Int J Clin Pract 59:961968
61. Silberstein SD, Ben-Menachem E, Shank RP et al (2005)
Topiramate monotherapy in epilepsy and migraine prevention.
Clin Ther 27:154165
62. Rapoport A, Mauskop A, Diener HC et al (2006) Long-term
migraine prevention with topiramate: open-label extension of
pivotal trials. Headache 46:11511160
63. Lanteri-Minet M, Agosti R, Diener HC et al (2006) Prolonged
migraine prevention with topiramate (PROMPT): results of the
initial 6-month open-label treatment phase. Cephalalgia 26:1368
64. Brandes JL (2005) Practical use of topiramate for migraineprevention. Headache 45[Suppl 1]:S66S73
65. Di Trapani G, Mei D, Marra C et al (2000) Gabapentin in the
prophylaxis of migraine: a double-blind randomized placebo-
controlled study. Clin Ter 151:145148
66. Mathew NT, Rapoport A, Saper J et al (2001) Efficacy of
gabapentin in migraine prophylaxis. Headache 41:119128
67. Steiner TJ, Findley LJ, Yuen AW (1997) Lamotrigine versus
placebo in the prophylaxis of migraine with and without aura.Cephalalgia 17:109112
68. DAndrea G, Granella F, Cadaldini M, Manzoni GC (1999)
Effectiveness of lamotrigine in the prophylaxis of migraine
with aura: an open pilot study. Cephalalgia 19:6466
69. Lampl C, Buzath A, Klinger D, Neumann K (1999)
Lamotrigine in the prophylactic treatment of migraine aura
a pilot study. Cephalalgia 19:5863
70. Pascual J, Caminero AB, Mateos V et al (2004) Preventing
disturbing migraine aura with lamotrigine: an open study.
Headache 44:10241028
71. Lampl C, Katsarava Z, Diener HC, Limmroth V (2005)
Lamotrigine reduces migraine aura and migraine attacks in
patients with migraine with aura. J Neurol Neurosurg
Psychiatry 76:17301732
72. Stensrud P, Sjaastad O (1979) Clonazepam (rivotril) in
migraine prophylaxis. Headache 19:333334
73. Rompel H, Bauermeister PW (1970) Aetiology of migraine
and prevention with carbamazepine (Tegretol): results of a
double-blind, cross-over study. S Afr Med J 44:7580
74. Saper JS, Silberstein S, Somogyi M, McCague K (2005)
Efficacy and safety of oxcarbazepine in patients with migraine
headache: a multicenter, double-blind, randomized, placebo-
controlled study. Poster presented at the annual Meeting of
The American Academy of Neurology, New Orleans, LA.
April (P05.152)
75. Ettinger AB, Argoff CA (2007) Use of antiepileptic drugs for
nonepileptic conditions: psychiatric disorders and chronicpain. Neurotherapeutics 4:7583