Headache Medicine, v.2, n.4, p.173-181, Oct/Nov/Dec. 2011 173

Neuromodulators and its combinations for the

preventive treatment of migraine

Neurotransmissores e suas combinações para o tratamento preventivo

da migrânea

ABSTRACTABSTRACT

ABSTRACT

Migraine is a chronic, debilitating neurological disorder. It

affects nearly 15% of the adult population and it is

characterized by a range of symptom profiles and degrees of

disability. It is a disease generally believed to occur in

consequence of a genetically hyper excitable brain state, in

addition to a neurotransmitter dysfunction which results in

susceptibility to the occurrence of intermittent attacks of

headache with particular associated features. Pharmacotherapy

remains the mainstay for the prevention of the attacks and

despite the use of different classes of drugs, some older than

30 years and used by serendipity, some neuromodulators

represent the most modern option and the better studied drugs

for the prophylactic treatment of migraine. Supposedly acting

by targeting one or more molecular sites in the brain, these

drugs alter neurotransmission through effects on ion channels,

on specific receptors and on neurotransmitter metabolism.

Neuromodulators are considered the state of art in migraine

therapeutic and its combination may represent an upcoming

option for patients not responding well or presenting limiting

tolerability issues with full-dose monotherapy. In this review,

we explore the specificities of the different drugs belonging to

this pharmacological class, the evidence available for its use

in migraine as well as the fundamentals and potential for new

approaches combining two neuromodulators, even in lower

doses.

Keywords:Keywords:

Keywords: Neuromodulators; Combination; Migraine;

Preventive treatment

VIEW AND REVIEWVIEW AND REVIEW

VIEW AND REVIEW

Abouch Valenty Krymchantowski, Carla da Cunha Jevoux

Centro de Avaliação e Tratamento da Dor de Cabeça do Rio de Janeiro

(Headache Center of Rio)

Krymchantowski AV, Jevoux CC

Neuromodulators and its combinations for the preventive treatment of migraine.

Headache Medicine. 2011;2(4):173-81

RESUMORESUMO

RESUMO

A enxaqueca é uma doença neurológica crônica e incapa-

citante. Afeta em torno de 15% da população adulta e é

caracterizada por vários sintomas e graus diferentes de

incapacidade funcional. A enxaqueca é considerada uma

doença na qual há hiperexcitabilidade cerebral aliada à

disfunção de sistemas de neurotransmissão originando

susceptibilidade à ocorrência de crises intermitentes de cefaleia

com características peculiares. A farmacoterapia preventiva

é o eixo central do tratamento e, a despeito do uso de várias

classes de drogas, algumas com mais de 30 anos e consi-

deradas eficazes por acaso, alguns neuromoduladores repre-

sentam a opção mais moderna e mais estudada para esse

tratamento. Supostamente atuando em um ou mais sítios mole-

culares cerebrais, essas drogas alteram a neurotransmissão

através da ação em canais iônicos, em receptores específicos

ou no metabolismo de neurotransmissores. Os neuromodu-

ladores são considerados o "estado da arte" no tratamento da

enxaqueca e sua combinação pode representar uma opção

nova para pacientes não responsivos ou que apresentam

efeitos colaterais limitando o uso de doses plenas na mono-

terapia com esses fármacos. Nesta revisão, exploramos as

especificidades das diferentes drogas pertencentes a essa

classe, a evidência disponível para sua indicação e funda-

mentos para uma forma nova de utilizá-los através de sua

combinação.

alavrasalavras

alavras

chave:chave:

chave: Neuromoduladores; Associação; Migrânia;

Tratamento preventivo

174

Headache Medicine, v.2, n.4, p.173-181, Oct/Nov/Dec. 2011

KRYMCHANTOWSKI AV, JEVOUX CC

INTRODUCTION

Migraine is a highly prevalent primary headache,

which affects more women than men and may start during

childhood or adolescence. Those affected may experience

migraine throughout their lives.

(1,2)

Despite its life time

prevalence of 12 to 15% and its disabling nature, migraine

is an underdiagnosed and undertreated disease.

(1)

Migraine is a primary neurological disorder with a clear

genetic basis.

(3,4)

During migraine attacks neural events

result in the dilatation of meningeal blood vessels, which

in turn, results in pain, further nerve activation, and

inflammation.

(5)

It probably results from dysfunction of brainstem

involved in the modulation of craniovascular afferents.

(3-6)

Brainstem activation may also lead to activation of

ascending and descending pathways, with initiation of a

perimeningeal vasodilatation and neurogenic inflammation.

The resulting pain is felt as a combination of altered

perception (due to peripheral or central sensitization) of

stimuli that are usually not painful, as well as the activation

of a feed-forward neurovascular dilator mechanism in the

first division of the trigeminal nerve. Cortical spreading

depression is a presumed substrate of migraine aura;

spreading depression and central dysnociception may also

occur in migraine without aura.

(3-6)

Since the chemical cascade of migraine attacks is

believed to occur, at least in part, consequent to a

genetically hyper excitable brain state, neuromodulators

that decrease neuronal excitability should be effective

approach for the prevention of migrainous

symptoms.

(7-11)

NEUROMODULATORS IN MIGRAINE

Valproate (VLP) is simple, eight-carbon branched-

chain fatty acid with antiepileptic properties, which was

one of the first neuromodulators studied for migraine

prevention. Divalproex (DVP) has also been extensively

studied in controlled-studies. Studies have shown that DVP

decreases migraine headache frequency by 50% or

greater in 45%-50% of the patients after 3 months, versus

12%-15% among those receiving placebo.

(13)

Therefore,

the therapeutic gain of DVP is lower than 35%.

At clinical relevant doses, both VLP and DVP attenuate

plasma protein extravasion in migraine models of

meningeal neurogenic inflammation, and this effect is

reversed by GABA

-A

, but not by GABA

-B

receptor

antagonists.

(14)

Furthermore, the effect of VLP is mimicked

by the GABA

-A

agonist, muscimol, but not by the GABA

-B

agonist baclofen, suggesting a GABA

-A

mediated

mechanism. However, in higher doses it blocks the GABA

degradation by GABA transaminase, thereby increasing

GABA concentrations in both axon and in glial cells. The

role of these pharmacological properties in migraine

prevention is uncertain as it is the DVP action of blocking

voltage-dependent sodium ion-channels, therefore

modulating the release of excitatory amino acids, and of

blocking low-threshold T-type calcium ion channels.

(12)

Although VLP and DVP are more often used in the

preventive treatment of migraine, at least VLP seem also

to be effective for the acute treatment.

(15)

It is established

that the substantia gelatinosa of the spinal cord receives

descending 5-HT fibers from the rostroventral medulla

(RVM) and these fibers connect with spinothalamic

neurons.

(16,17)

Accordingly, VLP action in the acute treatment

of migraine may be partially due to serotoninergic

modulation.

Nowadays, DVP is much more commonly used than

VLP for the preventive treatment of migraine. It is typically

started at a dose of 250 mg bid, and can be brought up

to a dose of 500 mg bid. For the acute treatment, typical

doses range from 300 to 500 mg of intravenous VLP.

Adverse effects limit the use of DVP and include weight

gain, hair loss, potential liver dysfunction, teratogenicity,

among others.

(17)

Topiramate is the most recent medication approved

by the FDA for migraine prevention. It is a sulfamate-

substituted monosaccharide derived from D-fructose that

is structurally distinct from other neuromodulators.(

18)

It has

been proven to be an effective pharmacological agent

at doses ranging from 50 mg to 200 mg/day

(19-23)

(Table

1) for the prevention of migraine and recently for the

treatment of chronic migraine as well.

TPM has modulatory effects on voltage-sensitive

L-type calcium channels.

(12,18)

However, the observation

that TPM is more effective at 10 µM than at 50 µM in

reducing the L-type Calcium currents suggests that TPM

may have a different mode of action from traditional

Calcium channel blockers. The biphasic concentration-

response curve for the effect of TPM on L-type Calcium

currents is similar to that for the modulatory effect of

TPM on GABA

receptors.

(24)

Because TPM has no effect

on ionic currents in the absence of GABA, its effect on

GABA

receptors appears to be modulatory as well.

(24)

The effect of TPM is similar to that of the benzodiazepines

(BDZs) in that TPM increases the frequency of channel

activation. TPM has been reported to inhibit KA-evoked

Headache Medicine, v.2, n.4, p.173-181, Oct/Nov/Dec. 2011 175

whole-cell currents in hippocampal neurons and this is

associated with decrease in neuronal excitability.

(25)

TPM is one of the only neuromodulators associated

with weight loss.

(26,27)

Adverse effects include paresthesias,

cognitive deficits, nephrolithiasis, acute closed angle

glaucoma, and non-anion gap metabolic acidosis-the

latter three considered idiosyncratic in nature. A dose of

50 mg bid has been shown to be optimal, but effects

have been shown at as little as 25 mg bid.

(19,20)

Topiramate's efficacy is similar to the efficacy of DVP,

and it has not been shown to be superior to beta-blockers

or tryciclic anti-depressants, although recent studies have

been suggesting that the combination of topiramate and

other traditional pharmacological agents for migraine

prevention promote better outcome figures for decreasing

the frequency of migraine attacks.

(28-31)

Gabapentin (GBP) is not approved by the FDA for

migraine prevention, but is often used in the treatment of

migraine. Its molecule is formed by the addition of a

cyclohexyl group to GABA, allowing this form of GABA to

cross the blood-brain barrier. It is not metabolized and

does not induce or inhibit hepatic metabolism. Gabapentin

has to be administered three times a day due to its half-

life of 4 to 9 hours and drug-drug interactions are not an

issue with GBP because of its pharmacokinetic profile of

not binding to plasma proteins and its lack of interference

with hepatic function. The mechanism of action of the

gabapentinoids is not fully understood yet. Despite its

structural similarity with GABA, it does not bind to GABA

receptors in the CNS. It does interact with the alfa-2-delta

subunit of voltage-gated ion calcium channels possibly

modulating their currents as well as increases the rate of

GABA synthesis in the brain. Gabapentin has also an

antinociceptive effect. It inhibits monoamine neuro-

transmitter release, including dopamine, serotonin and

noradrenaline in addition to total cellular calcium content.

At the spinal cord level, gabapentin alters N-methyl-D-

aspartate (NMDA) receptor-mediated responses. These

effects explain why GBP has been used in the treatment

of neuropathic pain conditions.

(32-36)

For the prevention of migraine, Gabapentin (1800-

2400 mg/day) was found to be superior to placebo in

reducing the frequency of migraine attacks in a controlled,

double-blind trial, supporting the results of previous open

trials. The responder rate was 36% for gabapentin and

14% for placebo

(37)

(Table 1). The most common adverse

events were dizziness and drowsiness. Clinical experience

does not corroborate the presumed efficacy of gabapentin

and it is not considered one of the neuromodulators

recommended for migraineurs.

Another gabapentinoid, pregabalin, which has a

longer half-life and, therefore, may be used in two-daily

dosages regimen, is also suggested as useful for migraine

prevention despite of the lack of published controlled

studies. Pregabalin is recommended for partial seizures,

pain of post-herpetic neuralgia, pain of the diabetes

mellitus neuropathy, fibromyalgia and generalized anxiety

disorder.

(38,39)

Levetiracetam (LCT) is a pyrrolidine, the racemically pure

S-enantiomer of alfa-ethyl-2-oxo-1-pyrrolidineacetamide.

It inhibits partial and secondarily generalized tonic-clonic

seizures in the kindling model. The mechanisms by which

it exerts this antiseizure effect are still unknown, but despite

its lack of effect on Na

channels or either on GABA- or

glutamate mediated synaptic transmission, LCT seems to

act on a binding site at the synaptic vesicle protein SV2A,

at least in rat brain membranes.

(40)

LCT is rapidly and

nearly completely absorbed after oral administration and

it is not bound to plasma proteins; peak serum

concentrations are achieved within 2 hours, and daily doses

are linearly related with plasma concentrations. An

advantage of this neuromodulator is the fact that LCT

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176 Headache Medicine, v.2, n.4, p.173-181, Oct/Nov/Dec. 2011

KRYMCHANTOWSKI AV, JEVOUX CC

neither induces nor is a high-affinity substrate for CYP

isoforms or glucuronidation enzymes and thus is devoid

of known interactions with other antiseizure medications,

oral contraceptives or anticoagulants.

(41)

LCT was studied for migraine and chronic migraine

prevention in few trials, mostly uncontrolled. Average dose

was 1,000 mg and results were not impressive, but a better

definition of effective doses in randomized controlled trials

is warranted before this neuromodulator can be excluded

from the migraine medication arsenal.

(42-45)

LCT was also

studied for the prevention of migraine in children. In an

open label prospective trial (n=20), levetiracetam was

used in two daily dosages of 20 mg/kg after an initial

daily dose of 20 mg/kg during one month. In a

retrospective chart review of 19 children, who received

125-700 mg twice daily, migraine frequency was reduced

and headaches attacks were eliminated in 52.6% of the

treated patients.

(46)

Asthenia/somnolence, irritability,

hostility and dizziness were associated with the use of LCT

in this population.

The side effects of LCT reported in initial clinical trials

for epilepsy occurred in at least 3% of the patients and

presented as fatigue or tiredness, somnolence, dizziness

and infection (common cold or upper respiratory tract

infection).

(41,47)

Zonisamide (ZNS), a sulfonamide analog, is a

neuromodulator recently approved as an adjunctive

therapy for partial seizures in adults.

(48)

It has a high oral

bioavailability and a long half-life (63 hours), allowing

therapeutic regimens of once- or twice-daily dosages.

Similarly to topiramate, zonisamide promotes blockade

of voltage-gated sodium channels, inhibition of

potassium-mediated release of glutamate, facilitation of

serotonergic and dopaminergic neurotransmissions and

enhancement of gamma-aminobutyric acid release.

Additionally, it also seems to reduce ion flow through

T-Type calcium channels.

(49,50,51)

ZNS was primarily been tested for the treatment of

refractory migraine. Thirty four patients reported statistically

significant improvement of headache frequency, severity

and duration with a daily dosage of 400 mg/day

(initiation with 100 mg/day and titration till 400 mg/day)

after three months of treatment. Four patients (11.8%)

stopped the treatment due to adverse events, which include

dysphoria and difficulty concentrating.

(47,52)

In a retrospective chart review study of 33 patients

(23 with transformed migraine and 10 with episodic

migraine) who had failed over six preventive drugs prior

to ZNS, an average daily dosage of 340 mg for 6 months

of treatment, provided reduction in the number of

headache days. Adverse events were reported by 14

patients (14.4%), being fatigue the most common.

(53)

Recently, 34 patients with good response to the use

of Topiramate, but interrupting it due to intolerable side

effects, were evaluated after a one-month wash-out period.

Zonisamide was used during 6 consecutive months in a

dose up to 100 mg/day. The mean number of days with

headache per month was reduced from 14,9 ± 5.3 during

the wash-out period to 2,5 ± 0.6 after the treatment

period. Headache severity and disability, as assessed by

visual analog scale and migraine disability assessment

scale, were also significantly reduced. The use of rescue

medications at the end of the study was reduced as well.

Four patients (12%) reported side effects not responsible

for interrupting the treatment.

(51)

Lamotrigine (LTG) is a neuromodulator of the

phenyltriazine class chemically unrelated to existing

neuromodulators. Its chemical structure is 3,5-diamino-

6-(2,3-dichlorophenyl)-as-triazine and has a molecular

formula expressed as C9H7N5Cl2 with a molecular

weight of 256.09. Lamotrigine is very slightly soluble in

water and is well absorbed orally, with up to 98 percent

bioavailability. Absorption is not affected by food.

Approximately 55 percent of the drug is protein bound;

therefore, clinical interaction with other protein-bound

drugs is unlikely. Ninety percent of the drug undergoes

glucuronic acid conjugation in the liver, with the conjugate

and the remaining 10 percent of unmetabolized drug

excreted in the urine.

(54)

The Clearance of LTG is markedly increased by the

co-administration of other antiepileptic drugs that induce

hepatic enzymes. These include carbamazepine,

phenobarbital, phenytoin and primidone. The half-life of

lamotrigine may be reduced by about 50 percent with

concomitant use of one or more of these medications

(Table 2). However, when combined with valproic acid,

its elimination is decreased, and its half-life may be more

than doubled.

(55)

LTG is used as adjunctive therapy or monotherapy

in adults with partial seizures with or without secondary

generalization. The mechanism of action is unknown,

but it stabilizes neural membranes and inhibits the release

of excitatory neural transmitters as glutamate release,

possibly through modulation of voltage-sensitive sodium

channels.

(54)

A role for lamotrigine in the prophylactic treatment

of migraine has been suggested mostly by small open

trials, in which lamotrigine was suggested effective in

Headache Medicine, v.2, n.4, p.173-181, Oct/Nov/Dec. 2011 177

reducing the frequency of migraine with aura and aura

symptoms.

(56)

However, a larger double-blind randomized

study demonstrated that lamotrigine was ineffective in

migraine prophylaxis, even after three months of drug

use and more adverse effects were recorded in the

lamotrigine-treated group compared with placebo

(57)

(Table 1). In more recent small, open-label studies, in which

smaller doses were included, lamotrigine was effective in

reducing the frequency of migraine auras and the monthly

rate of migraine with aura attacks.

(58,59,60)

It does

corroborate the importance of larger controlled trials

investigating the true role of lamotrigine in migraine.

Lamotrigine does not impair cognition and the main

contraindication to its use is hypersensitivity to the drug.

The need for monitoring drug levels has not been

established. The most frequently encountered adverse

reactions include dizziness, ataxia, somnolence, headache,

blurred vision, nausea, vomiting and skin rash, which is

seen in approximately 10% of the patients. The risk of

more serious reactions, such as the Stevens-Johnson

syndrome, may be minimized by initializing the drug at a

low dose, escalating it slowly, and avoiding concomitant

use of divalproex or valproate sodium.

(47)

The adamantane derivative memantine (1-amino-

3,5-dimethylaminoadamantane, D-145, Akatinol) (MEM)

is a neuromodulator representing the first in a novel class

of Alzheimer's disease medications acting on the

glutamatergic system. MEM is a moderate-affinity voltage-

dependent noncompetitive antagonist at glutamatergic

N-methyl-D-aspartate (NMDA) receptors.

(61)

By binding

to the NMDA receptor with a higher affinity than

magnesium Magnesium ions, MEM is able to inhibit the

prolonged influx of calcium Calcium ions associated with

neuronal excitotoxicity. In addition, biochemical,

pharmacological, and electrophysiological studies show

that memantine interferes with the metabolism of the

neurotransmitters dopamine, noradrenaline, and

serotonin and modulates synaptic transmission.

(62)

MEM was studied for refractory migraineurs.

Subjects with migraine (episodic migraine with 8-14

days of headache per month or transformed migraine,

who had previously failed at least 2 trials of adequate

preventive therapy) were included. Other preventive

drugs were allowed if the patient had been on a stable

dose for more than 30 days. MEM dose ranged from

10 mg to 20 mg per day and the treatment phase lasted

3 months. The primary endpoint was number of days

with headache at month 3. In the ITT population (n =

28), monthly headache frequency was reduced from

21.8 days at baseline to 16.1 at 3 months (P < .01).

The mean number of days with severe pain was also

reduced from 7.8 to 3.2 at 3 months (P < .01) and

mean disability scores were significantly reduced at 3

months as well, when compared with baseline (36.6 vs

54.9, P < .01). Side effects were present in 37.5% of

the patients; 5.5% dropped out the study because of

poor tolerability. Most adverse events were mild. The

study, although not double-blind, posted preliminary

evidence that MEM could be useful for preventing

refractory migraine.

(62)

EXPERT COMMENTARY

Combining neuromodulators in migraine?Combining neuromodulators in migraine?

Combining neuromodulators in migraine?

Managing the migraine patient is sometimes difficult,

especially when they are referred to tertiary centers.

Guidelines recommendations suggest that the goal of

preventive treatment is to reduce headache frequency by

at least 50%, based on the assumption that this reduction

is likely clinically meaningful.

(63-65)

When patients fail to respond as expected to

appropriate therapy, or announces at the first consultation

that he or she has already tried everything and nothing

will work, it is important to identify the reason or reasons

that treatment has failed. Accordingly, although

NEUROMODULATORS AND ITS COMBINATIONS FOR THE PREVENTIVE TREATMENT OF MIGRAINE

178

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KRYMCHANTOWSKI AV, JEVOUX CC

monotherapy is usually recommended, rational

combination therapy is sometimes necessary.

(66,67)

In clinical practice, the use of the neuromodulators

TPM and DVP may be limited by tolerability issues and

optimal doses may not be achieved despite improvement

of headache. Phrases like "This drug helped me with the

headache but I was unable to function" or "I prefer to

keep my headaches and remain thin or with my hair" are

common complaints brought to the health provider

prescribing full doses of these pharmacological

agents.

(68,69)

Clinical experience suggests that patients with good

therapeutic response but poor tolerability may often benefit

from combining medications at smaller doses.

(29,70)

Combining low doses of TPM and DVP may be of interest

also because of their sometimes opposite adverse events

profile (e.g. increase vs. decrease in weight). In addition,

thinking about the fundamentals, specifically regarding

TPM and DVP, one can speculate that a synergistic effect

occurs. Since Valproate increases GABA levels and

potentiates GABA-mediated responses possibly blocking

its degradation by GABA transaminase, and blocks low-

threshold T-type calcium ion channels,

(12,13,17)

whereas

TPM enhances GABA neurotransmission by facilitating

GABA

receptor action increasing the opening frequency

of the chloride ion channels in GABA

receptors, in

addition to the reduction of the L-type Ca channels

activity, it is reasonable to think that these combined

effects could result in better efficacy on migraine

prevention. Additionally, TPM negatively modulates the

excitatory neurotransmitter glutamate thru binding to the

non-NMDA kainate/AMPA receptors, thereby decreasing

the flow of sodium and calcium ions across the

postsynaptic membrane.

(20,24-26)

In fact, a recent open label trial with a small number

of patients suggested that TPM and DVP, combined in

smaller doses than usually used, was an interesting option

for patients that benefited from therapeutic doses of these

medications but would be otherwise discontinued due to

tolerability issues.

(31)

Another possible approach is the combination of

the modulatory effects of a gabapentinoid, which acts

on alfa-2-delta subunit of voltage-gated ion calcium

channels, modulating their currents and increasing the

rate of GABA synthesis in the brain in addition to alter

N-methyl-D-aspartate (NMDA) receptor-mediated

responses, with TPM, which aims its action also on

calcium channels and glutamatergic system, but in

different receptors.

(12,26,32,33)

Finally, perhaps the potential advantages of obtaining

a modulatory effect of TPM on Kainate/AMPA receptors

with the modulation on NMDA receptors promoted by

memantine also in the excitatory glutamatergic system may

represent an interesting option.

(70)

Although these combinations or any other involving

two neuromodulators have never been tested in

randomized controlled trials, one might speculate on

whether this could be useful for those patients failing the

adequate trials of individual options of this class for

migraine prevention, especially if they needed higher doses

for obtaining efficacy.

Although not every neuromodulator can be combined

with each other due to metabolism interactions and

inductions mediated by inhibition of different types of CYP

enzymes, most of the more recent members of

neuromodulators could be considered as ad on

therapies, for patients not responding or doing so, but

with tolerability issues, when using full doses of a specific

agent (Table 2).

Until it cannot be proved by the rigors of large

controlled studies, the option of combining neuro-

modulators, even in smaller doses, may only be

speculated.

Five-year viewFive-year view

Five-year view

There have been exciting developments in

understanding the molecular biology and involved

mechanisms of migraine in the past years. Since migraine

may involve an unbalance between the excitatory

glutamatergic and inhibitory gabaergic systems as well

as a calcium "channelopathy" directly affecting the

regulation of neurotransmitter release, drugs aiming at

stabilizing the neurochemical synchronization of central

circuits, probably involved in migraine, through actions

on various mechanisms, may, indeed represent powerful

components of the migraine treatment arsenal. However,

as presented, a ceiling effect of 50-60% headache

frequency reduction is the only achieved outcome for most

patients. Additionally, tolerability issues may limit treatment

success due to the impossibility of using full-dose schemes.

Trials on combination therapies for migraine are just

beginning, mostly due to previous lack of funding interest.

Although nothing has been proved yet, especially for the

prevention of migraine, the next few years may represent

a changing paradigm, reasoned by the better outcome

figures obtained with combination of drugs for migraine

acute attacks. The expectations for more efficacious and

Headache Medicine, v.2, n.4, p.173-181, Oct/Nov/Dec. 2011 179

better tolerated migraine preventive treatments are

anxiously expected. Until then, exciting results on

combining available drugs may fulfill the upcoming

horizon for relieving the burden of migraine.

Key issuesKey issues

Key issues

– Migraine is a genetically inherited disease, which

involves a brain hiper excitable state

– Neurotransmitter dysfunction, probably related to

a calcium channelopathy, is also involved in migraine

– The neurotransmitter dysfunction probably results

in a state of central dysnociception and/or dysmodulation

– Neuromodulators are effective migraine

preventive pharmacological agents through the decreasing

of neuronal excitability

– Some neuromodulators are proven effective.

Others may be used, but further evidence of their efficacy

is still lacking

– The combination of two neuromodulators may

useful for some patients who don't tolerate full doses of

individual drugs or need better efficacy outcomes

– The future of migraine preventive treatment may

involve two or more drugs aiming at different mechanisms

of action and/or brain circuits

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Correspondence

Abouch VAbouch V

Abouch V

alenty Krymchantowski, MDalenty Krymchantowski, MD

alenty Krymchantowski, MD

Headache Center of Rio

Rua Siqueira Campos 43/1002 – Copacabana

22031-070 – Rio de Janeiro, RJ, Brazil

Phone: 55-21-22551055

abouchkrym@uol.com.br

www.dordecabeca.com.br

Received: 10/12/2011

Accepted: 10/23/2011

NEUROMODULATORS AND ITS COMBINATIONS FOR THE PREVENTIVE TREATMENT OF MIGRAINE