Antiepileptic drugs in migraine prophylaxis

Abstract

Research in the field of headache treatment has experienced a marked impetus in the last few years. In the era of the triptans, the treatment modality of this disease has been revolutionised, and though most of the studies conducted have investigated the symptomatic treatment of migraine, less attention has been dedicated to migraine prophylaxis. This review considers the current data available in the literature regarding the use of antiepileptic drugs in migraine prophylaxis, noting the clinical studies that have yielded statistically significant data. [PUBLICATION ABSTRACT]

J Headache Pain (2004) 5:S67S70

DOI 10.1007/s10194-004-0111-8Antiepileptic drugs in migraine prophylaxisGiovanni Mazzotta

Francesca Floridi

Andrea Alberti

Paola SarchielliReceived: Accepted in revised form: tic drugs in migraine prophylaxis,

noting the clinical studies that have

yielded statistically significant data.G. Mazzotta () F. Floridi A. AlbertiP. SarchielliDepartment of Neuroscience,

University of Perugia,

Via E. Dal Pozzo,I-06126 Perugia, Italy

e-mail: [email protected]

Tel.: [phone]

Fax: [phone]Abstract Research in the field of

headache treatment has experienced

a marked impetus in the last few

years. In the era of the triptans, the

treatment modality of this disease

has been revolutionised, and though

most of the studies conducted have

investigated the symptomatic treatment of migraine, less attention has

been dedicated to migraine prophylaxis. This review considers the

current data available in the literature regarding the use of antiepilep-Key words Migraine prophylaxis

AntiepilepticsIntroductionThe decision to begin prophylactic therapy for the treatment of migraine depends on the frequency and the severity of the attacks, and to what extent they alter the quality

of life of the patients. According to the Diagnostic and

Therapeutic Guidelines for migraine and cluster headache

of the Italian Society for the Study of Headaches [1], the

presence of at least 2 attacks of migraine per month or

lasting 4 or more days per month, which do not completely respond to symptomatic therapy, are indications to

begin prophylactic therapy.A state of hyperexcitability of the cerebral cortex is

considered the neuropathophysiologic basis of migraine,

as in epilepsy, and in fact the two pathologies are often

comorbid [2]. In a population study, Ottman and Lipton [3]

demonstrated that epilepsy and migraine are closely linked

pathologic conditions, independent of seizure aetiology,

age at first onset and type of crisis. These features, which

are shared by these pathologies characterised by attacks,

suggest a common pathogenesis involving membrane

excitability upon which the antiepileptic drugs can act.From this point of view, the studies of efficacy and tolerability confirm and delineate antiepileptics as very

promising drugs in the panorama of the prevention of

migraine and other head pain.Antiepileptic and antimigraine drugs act on the nociceptive mechanisms mediated by GABA or glutamate neurotransmission, or both [4]. GABA is the major inhibitory

neurotransmitter in the central nervous system and its presynaptic release occurs by a calcium-dependent mechanism[5]. Valproate and gabapentin interfere with GABA metabolism, inhibiting its degradation and transformation into

succinate [6], and topiramate potentiates GABA-mediated

inhibition by facilitating receptor action [7]. GABA binding

to its receptors causes cellular hyperpolarisation and inhibition of postsynaptic transmission. All these drugs modulate

the activity of calcium, sodium and potassium ion channels

by hyperpolarising and stabilising the membrane [4].S68Sodium valproateSodium valproate, more frequently marketed as its stable

coordination product, divalproate (divalproex sodium), is the

only antiepileptic drug in the United States approved by the

Food and Drug Administration for migraine prophylaxis, as

has been demonstrated with excellent results in randomised

clinical studies [5, 814]. In a more recent study conducted by

Freitag et al. [8], a reduction in the weekly frequency of

headache was significantly greater in the study group than in

the placebo group (p=0.006). The antiepileptic and antimigraine properties of sodium valproate are due to its effects on

GABA-mediated neurotransmission, blockade of sodium and

calcium ion channels, and modulation of the release of excitatory amino acids [15]. The strong membrane stabilising

effect makes valproate the prophylactic drug of first choice in

the case of headache with mood disturbance or epilepsy. The

main side effects are somnolence, nausea and other gastrointestinal disturbances, alopecia, tremor and weight gain [15]. It

may have possible teratogenic effects on neural tube development and thus it should not be used in case of pregnancy [15].

Chronic use at elevated dosages may cause hepatic toxicity[15], and so it should be used with caution in subjects who are

taking antiaggregants or anticoagulants because the association with valproate can interfere with haemostasis and coagulation [15]. It was shown that 21% of patients in preventive

therapy with valproate stopped treatment due to undesirable

effects, and this has lead to a debate on the utility of identifying, even using serum dosages of the drug, a minimum effective dose that does not cause serious undesirable effects [16].

Recently, studies on valproate have evaluated the intravenous

administration of the drug, which seems to offer better results

for chronic headache and for acute phase therapy [17].Among the new generation of antiepileptic drugs,

many studies have investigated topiramate, gabapentin,

lamotrigine and levetiracetam.GabapentinGabapentin interferes with the metabolism of GABA into its

metabolite, succinate, and can modulate, as the other

antiepileptic drugs, GABA-mediated neurotransmission [31].

It may also be involved in the inhibition of sodium and calcium ion channels [31]. Gabapentin is currently used in the

treatment of chronic pain syndromes, such as SUNCT,

trigeminal neuralgia or cluster headache [32]. The study of

gabapentin in migraine, with recent randomised, open studies[33] and double-blind studies with placebo [34, 35], are yielding positive results. In the study of Jimenez-Hernandez et al.[33], a statistically significant difference was found between

the treatment with gabapentin and the baseline condition of

the patients, both for the reduction in the number of attacks

and for the reduction in intensity and increase in the pain-free

intervals. The most frequent side effects were somnolence

and vertigo, symptoms well tolerated by the patients [31].LamotrigineLamotrigine is an antagonist of glutamate-mediated activity

due to its blockade of voltage-dependent sodium ion channels [31]. It is a well-tolerated drug and the most undesirable

effect is skin rash [31]. Studies on the use of lamotrigine for

headache have yielded contrasting results; in one study it furnished significant data only for migraine with aura [3638].TopiramateTopiramate, introduced for the first time in 1995 in Anglo-

Saxon countries for the therapy of partial seizures, produces

a membrane-stabilising effect by blocking sodium, calcium

and potassium ion channels, and by modulating GABA and

glutamate-mediated activity. Many recent studies, even those

conducted in children [18], have shown efficacy in migraine

prophylaxis, both for migraine without aura and presently

also for that with aura [19], and also in other forms of primary headache, yielding good results both in terms of frequency

and efficacy at dosages of 100 mg/day [18, 2029]. In a study

just published, Brandes et al. [23] demonstrated that the average monthly headache crisis frequency was reduced significantly, even at the dosage of 100 mg/day of topiramate

(p=0.008) as well as at that of 200 mg/day (p<0.001) compared to placebo. The most frequent side effects [30] of

weight loss, paraesthesiae and dysgeusias were rarely caused

by the discontinuation of therapy. These results make topiramate a very interesting molecule for migraine prophylaxis.LevetiracetamLevetiracetam, a new antiepileptic drug used as adjunctive

therapy in the treatment of partial crises with or without generalisation, has a mechanism of action which is mostly unknown[31]. It acts selectively on autonomous neuronal activity, without any effect on normal neuronal characteristics. Specific

receptor binding has not been shown, although recently the

ability to selectively inhibit some voltage-dependent ion channels has been demonstrated [39]. The drug is well tolerated and

the undesirable effects, though rare, are: somnolence, asthenia

and postural instability [31]. For migraine therapy, few studiesS69are available in the literature regarding the use of levetiracetam

for both the prophylaxis and attack of migraine. These studies

have yielded encouraging results [4043], even in children,

with a recent retrospective study [44].The efficacy of many of these drugs has been confirmed

by diverse placebo-controlled studies.The mechanism that underlies the efficacy of

antiepileptic drugs in migraine prophylaxis seems to be

related to its ability to modulate GABA or glutamatemediated neurotransmission, or both, in the disequilibrium between neuronal inhibition and excitation, which has

been hypothesised for migraine. The data presented here

are very encouraging for the clinician, who thus possesses a valid alternative for consideration in the prophylactic

therapy of migraine.ConclusionsIn the last few years, the use of antiepileptic drugs in

migraine prophylaxis has become ever more widespread.References1. Societ Italiana per lo Studio delle

Cefalee (2002) Linee Guida

Diagnostiche e Terapeutiche dellemicrania e della cefalea a grappolo. In:

Gallai V, Pini LA (eds) Trattato delle

Cefalee. Centro Scientifico Editore,

Torino, pp L3L1412. Mazzotta G (2002) Ipereccitabilit

neuromuscolare latente e test dischemia nei pazienti cefalalgici. In:

Gallai V, Pini LA (eds) Trattato delle

Cefalee. Centro Scientifico Editore,

Torino, pp 1431513. Ottman R, Lipton RB (1994)

Comorbidity of migraine and epilepsy.

Neurology 44(11):210521104. Cutrer FM (2001) Antiepilectic drugs:

how they work in headache. Headache

41[Suppl 1]:S3S105. Ghose K, Niven B (1998) Prophylactic

sodium valproate therapy in patients

with drug-resistant migraine. Methods

Find Exp Clin Pharmacol

20(4):3533596. McNamara JO (2001) Drugs effective

in the therapy of the epilepsies. In:

Hardman JG, Limbird LE, Goodman

Gilman A (eds) The pharmacological

basis of therapeutics. McGraw Hill,

p 5367. Storey JR, Calder CS, Hart DE, Potter

DL (2001) Topiramate in migraine prevention: a double-blind placebo-controlled study. Headache

41(10):9689758. Freitag FG, Collins SD, Carlson HA,

Goldstein J, Saper J, Silberstein S,

Mathew N, Winner PK, Deaton R,

Sommerville K, Depakote ER:

Migraine Study Group (2002) A randomized trial of divalproex sodium

extended-release tablets in migraine

prophylaxis. Neurology

58(11):165216599. Mitsikostas DD, Polychronidis I

(1997) Valproate versus flunarizine in

migraine prophylaxis: a randomized,

double-open, clinical trial. Funct

Neurol 12(5):26727610. Kaniecki RG (1997) A comparison of

divalproex with propranolol and placebo for prophylaxis of migraine without

aura. Arch Neurol 54(9):1141114511. Klapper J (1997) Divalproex sodium in

migraine prophylaxis: a dose-controlled study. Cephalalgia

17(2):103108. Erratum in Cephalalgia

17(7):79812. Mathew NT, Saper JR, Silberstein SD,

Rankin L, Markley HG, Solomon S,

Rapoport AM, Silber CJ, Deaton RL

(1995) Migraine prophylaxis with

divalproex. Arch Neurol

52(3):28128613. 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(4):64765114. Hering R, Kuritzky A (1992) Sodium

valproate in prophylactic treatment of

migraine: a double-blind study versus

placebo. Cephalalgia 12(2):818415. McNamara JO (2001) Drugs effective

in the therapy of the epilepsies. In:

Hardman JG, Limbird LE, Goodman

Gilman A (eds) The pharmacological

basis of therapeutics. McGraw Hill,

p 53716. Cerbo R, Bruti G, Mostardini C, Di

Stani F, DAgostino V, Villani V, Lenzi

GL (2003) Il valproato di sodio. XVII

Congresso Nazionale della Societ

Italiana per lo Studio delle Cefalee,

Tirrenia (PI), 1113 maggio 2003.

Abstract Book, p 3617. Tanen DA, Miller S, French T,

Riffenburgh RH (2003) Intravenous

sodium valproate versus prochlorperazine for the emergency department

treatment of acute migraine headaches:

a prospective, randomized, doubleblind trial. Ann Emerg Med

41(6):84785318. Hershey AD, Powers SW, Vockell AL,

LeCates S, Kabbouche M (2002)

Effectiveness of topiramate in the prevention of childhood headaches.

Headache 42(8):81081819. Lampl C, Bonelli S, Ransmayr G

(2004) Efficacy of topiramate in

migraine aura prophylaxis: preliminary

results of 12 patients. Headache

44(2):17417620. Silvestrini M, Bartolini M, Coccia M,

Baruffaldi R, Taffi R, Provinciali L

(2003) Topiramate in the treatment of

chronic migraine. Cephalalgia

23(8):82082421. Edwards KR, Potter DL, Wu SC,

Kamin M, Hulihan J (2003) Topiramate

in the preventive treatment of episodic

migraine: a combined analysis from

pilot, double-blind, placebo-controlled

trials. CNS Spectr 8(6):428432S7022. Storey JR, Calder CS, Hart DE, Potter

DL (2001) Topiramate in migraine prevention: a double-blind, placebo-controlled study. Headache

41(10):96897523. Brandes JL, Saper JR, Diamond M,

Couch JR, Lewis DW, Schmitt J, Neto

W, Schwabe S, Jacobs D: MIGR 002

Study Group (2004) Topiramate for

migraine prevention: a randomized

controlled trial. JAMA 291(8):96597324. Martinez HR, Londono O, Cantu-

Martinez L, del Carmen Tarin L,

Castillo CD (2003) Topiramate as an

adjunctive treatment in migraine prophylaxis. Headache 43(10):1080108425. Pascual J, Sanchez del Rio M, Mateos

V, Lainez JM, Hernandez-Gallego J,

Leira R, Jimenez MD (2003)

Topiramate for patients with refractory migraine: an observational, multicenter study in Spain. Neurologia

18(7):36436726. Von Seggern RL, Mannix LK,

Adelman JU (2002) Efficacy of topiramate in migraine prophylaxis: a retrospective chart analysis. Headache

42(8):80480927. Mathew NT, Kailasam J, Meadors L

(2002) Prophylaxis of migraine, transformed migraine, and cluster headache

with topiramate. Headache

42(8):79680328. Young WB, Hopkins MM, Shechter

AL, Silberstein SD (2002) Topiramate:

a case series study in migraine prophylaxis. Cephalalgia 22(8):65966329. Matharu MS, Boes CJ, Goadsby PJ

(2002) SUNCT syndrome: prolonged

attacks, refractoriness and response to

topiramate. Neurology 58(8):130730. McNamara JO (2001) Drugs effective

in the therapy of the epilepsies. In:

Hardman JG, Limbird LE, Goodman

Gilman A (eds) The pharmacological

basis of therapeutics. McGraw Hill,

p 52431. McNamara JO (2001) Drugs effective

in the therapy of the epilepsies. In:

Hardman JG, Limbird LE, Goodman

Gilman A (eds) The pharmacological

basis of therapeutics. McGraw Hill,

pp 53954132. Pini LA, Brovia D (2002) Focus on:

gabapentin and headache. XVII

Congresso Nazionale della Societ

Italiana per lo Studio delle Cefalee,

Tirrenia (PI), 1113 maggio 2003.

Abstract Book, p 3433. Jimenez-Hernandez MD, Torrecillas

Narvaez MD, Friera Acebal G (2002)

[Effectiveness and safety of gabapentin

in the preventive treatment of

migraine]. Rev Neurol 35(7):603606

[article in Spanish]34. Mathew NT, Rapoport A, Saper J,

Magnus L, Klapper J, Ramadan N,

Stacey B, Tepper S (2001) Efficacy of

gabapentin in migraine prophylaxis.

Headache 41(2):11912835. Di Trapani G, Mei D, Marra C, Mazza

S, Capuano A (2000) Gabapentin in the

prophylaxis of migraine: a doubleblind randomized placebo-controlled

study. Clin Ter 151(3):14514836. Steiner TJ, Findley LJ, Yuen AW

(1997) Lamotrigine versus placebo in

the prophylaxis of migraine with and

without aura. Cephalalgia

17(2):10911237. 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(1):646638. Lampl C, Buzath A, Klinger D,

Neumann K (1999) Lamotrigine in the

prophylactic treatment of migraine aura

a pilot study. Cephalalgia

19(1):586339. Lukyanetz EA, Shkryl VM, Kostyuk

PG (2002) Selective blockade of N-

type calcium channels by levetiracetam. Epilepsia 43(1):91840. Krusz JC (2001) Levetiracetam as prophylaxis for resistant headaches.

Cephalalgia 373:P2I12 (Abstract)41. Drake ME (2001) Levetiracetam for

preventive treatment of migraine.

Cephalalgia 373:P2I13 (Abstract)42. Krusz JC (2002) Levetiracetam, given

intravenously, for acute intractable

migraines. Eur J Neurol 9[Suppl 2]:154

ABS P2177 (Abstract)43. Gallai V, Alberti A, Rossi C, Sarchielli P

(2002) Il Levetiracetam nella profilassi

dellemicrania. XVII Congresso

Nazionale della Societ Italiana per lo

Studio delle Cefalee, Tirrenia (PI), 1113

Maggio 2003. Abstract Book, p 3544. Miller GS (2004) Efficacy and safety

of levetiracetam in pediatric migraine.

Headache 44(3):238243