antiepilepticos y cefalea cronica

7/29/2019 Antiepilepticos y Cefalea Cronica

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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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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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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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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.

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