EDITORIAL.

Fernando Kowacs & Marcelo Moraes Valença

Functional Anatomy

Functional anatomy of headache: hypothalamus

Marcelo Moraes Valença, Luciana P. A. Andrade-Valença, Carolina Martins

VIEW AND REVIEW

Neuromodulators and its combinations for the preventive treatment of migraine

Abouch Valenty Krymchantowski, Carla da Cunha Jevoux

Pain and the endogenous antinociceptive neuronal system: physiologic role of oxytocin

Marcelo Moraes Valença, Luciana Patrízia A. Andrade-Valença, José Antunes-Rodrigues

Cronologia do tratamento medicamentoso da crise migranosa

Raimundo Pereira da Silva Néto

ORIGINAL

Hospital management of intractable headaches. The Instituto de Neurologia de

Curitiba approach

Adriel Rowe, Renato Iachinski, Vanessa Rizelio, Henry Koiti Sato, Maria Tereza de M. S. Nascimento,

Ricardo Krause Martinez de Souza, Pedro André Kowacs

Prevalence of headaches in individuals referred from primary care to secondary care

Joismar Manuel Rodrigues, Vanessa Vilela Caires, Kátia Beatriz C. Fontoura, Teresa Cristina Santos Silva,

Simone Fonseca Goulart, Cláudia Marcucci Rocha, Antônio Lúcio Teixeira,

Ariovaldo Alberto da Silva Junior

Síndrome musculoarticular superior

Miguel Angel Siderman

CASE REPORT

Exploding head syndrome – the early steps

Elcio Juliato Piovesan, Pedro André Kowacs, Helder Granhold Campos, Lucas Pires Augusto,

Lucas Coluni, Lineu Cesar Werneck

NEUROART

Neuroarte e cefaleia: os enigmas nos afrescos de Michelangelo

Marcelo Moraes Valença, Luciana P. A. Andrade-Valença

THESES

Chronic post-traumatic headache after mild brain injury (Abstract)

Hugo André de Lima Martins

Craniomandibular dysfunction, migraine and tensio-type headache: influence on quality of life

(Abstract)

Michelly Cauás de Queiroz Gatis

Oculo-nasal autonomic symptoms in migraine and cluster headache (Abstract)

Maria da Conceição Filgueira Sampaio

October/November/December 2011

Nº 4

VOLUME

Headache

Medicine

Headache

Medicine

ISSN 2178-7468

Headache Medicine, v. 2, n.4, p.161, Oct./Nov./Dec. 2011 161

CONTENTS

EDITORIAL ...................................................................................................................................................................... 164

Fernando Kowacs & Marcelo Moraes Valença

FUNCTIONAL ANATOMY

Functional anatomy of headache: hypothalamus ............................................................................................................ 165

Anatomia funcional da cefaleia: hipotálamo

Marcelo Moraes Valença, Luciana P. A. Andrade-Valença, Carolina Martins

VIEWS AND REVIEWS

Neuromodulators and its combinations for the preventive treatment of migraine .............................................................. 173

Neurotransmissores e suas combinações para o tratamento preventivo da migrânea

Abouch Valenty Krymchantowski, Carla da Cunha Jevoux

Pain and the endogenous antinociceptive neuronal system: physiologic role of oxytocin ................................................... 182

Dor e sistema neuronal antinociceptível endógeno: papel fisiológico da ocitocina

Marcelo Moraes Valença, Luciana Patrízia A. Andrade-Valença, José Antunes-Rodrigues

Cronologia do tratamento medicamentoso da crise migranosa ....................................................................................... 187

Chronology of drug treatment of migraine attack

Raimundo Pereira da Silva Néto

ORIGINAL ARTICLES

Hospital management of intractable headaches. The Instituto de Neurologia de Curitiba approach ................................. 194

Manejo hospitalar das dores de cabeça intratáveis. Abordagem do Instituto de Neurologia de Curitiba

Adriel Rowe, Renato Iachinski, Vanessa Rizelio, Henry Koiti Sato, Maria Tereza de Moraes Souza Nascimento,

Ricardo Krause Martinez de Souza, Pedro André Kowacs

Prevalence of headaches in individuals referred from primary care to secondary care ...................................................... 200

Prevalência de cefaleia em indivíduos encaminhados da atenção primária para a secundária

Joismar Manuel Rodrigues, Vanessa Vilela Caires, Kátia Beatriz Costa Fontoura, Teresa Cristina Santos Silva,

Simone Fonseca Goulart, Cláudia Marcucci Rocha, Antônio Lúcio Teixeira, Ariovaldo Alberto da Silva Junior

Síndrome musculoarticular superior ................................................................................................................................ 204

Superior articular muscle syndrome

Miguel Angel Siderman

CASE REPORT

Exploding head syndrome – the early steps ..................................................................................................................... 209

Síndrome da cabeça explodindo – os primeiros passos

Elcio Juliato Piovesan, Pedro André Kowacs, Helder Granhold Campos, Lucas Pires Augusto, Lucas Coluni, Lineu Cesar Werneck

NEUROART

Neuroarte e cefaleia: os enigmas nos afrescos de Michelangelo ...................................................................................... 212

Neuroart and headache: the enigmas in the Michelangelo's frescos

Marcelo Moraes Valença, Luciana P. A. Andrade-Valença

THESIS ABSTRACTS

Chronic post-traumatic headache after mild brain injury (Abstract) ................................................................................... 216

Cefaleia pós-traumática crônica após traumatismo cranioencefálico leve (Resumo)

Hugo André de Lima Martins

Craniomandibular dysfunction, migraine and tensio-type headache: influence on quality of life (Abstract) ........................ 217

Disfunção craniomandibular, migrânea e cefaleia do tipo tensional: influência na qualidade de vida (Resumo)

Michelly Cauás de Queiroz Gatis

Oculo-nasal autonomic symptoms in migraine and cluster headache (Abstract) ............................................................... 218

Sinais and sintomas autonônomicos óculo-nasais na migrânea e na cefaleia em salvas (Resumo)

Maria da Conceição Filgueira Sampaio

Scientific Publication of the Brazilian Headache Society

Headache Medicine is indexed in Latindex and Index Scholar.

Volume 2 Number 4 October/November/December 2011

Headache Medicine

ISSN 2178-7468

164 Headache Medicine, v. 2, n.4, p.164, Oct./Nov./Dec. 2011

EDITORIAL

t the end of the first year of publishing Headache Medicine, the new configuration

of Migrâneas & Cefaléias, we are pleased to report that our journal is now being indexed in

both Latindex and Index Scholar. The number of scientific submissions is growing and we

continue to receive strong support from the membership of the Brazilian Headache Society.

We hope you will enjoy this last edition of 2011 and assure you that we'll maintain our

best editorial efforts to further improve Headache Medicine.

In the current issue a broad range of subjects of our specialty are in focus. For example,

the second article of the series in the section Functional Anatomy deals with the hypothalamus

in a review of the role of the hypothalamus in the physiopathology of primary headaches,

including the use of hypothalamic deep brain stimulation as a form of treatment of refractory

cluster headache. Neuromodulators and their combinations for the preventive treatment of

migraine are explored by Krymchantowski and Jevoux. Pain and the endogenous

antinociceptive neuronal system, specifically commenting the physiologic role of oxytocin, is

another article of interest. As well, “Chronology of drug treatment of migraine attack”;

“Hospital management of intractable headaches”; “Prevalence of headaches in individuals

referred from primary care to secondary care”; “Superior articular muscle syndrome”; and

“Exploding head syndrome” are highlighted as important presentations of this edition. The

article “Neuroart and headache: the enigmas in Michelangelo's frescos” is the first of a new

section of the journal entitled Neuroart. Finally, three abstracts of Brazilian PhD theses are

published herein, e.g., (1) “Chronic post-traumatic headache after mild brain injury”; (2)

“Craniomandibular dysfunction: migraine and tension-type headache, influence on quality

of life”; and (3) “Oculo-nasal autonomic symptons in migraine and cluster headache”.

As is evident in this edition of Headache Medicine a variety of new subjects are presented

to expand the basis of your expertise in our field.

ernando Kernando K

ernando K

owacs & Marcelo Moraes Vowacs & Marcelo Moraes V

owacs & Marcelo Moraes V

alençaalença

alença

Editors

Headache Medicine is now indexed in Latindex and Index ScholarHeadache Medicine is now indexed in Latindex and Index Scholar

Headache Medicine is now indexed in Latindex and Index Scholar

Headache Medicine, v.2, n.4, p. 165-172, Oct/Nov/Dec. 2011 165

Functional anatomy of headache: hypothalamus

Anatomia funcional da cefaleia: hipotálamo

ABSTRACTABSTRACT

ABSTRACT

There is now compelling evidence that the hypothalamus exerts

a major role in the mechanism of headache triggering. Pain

and concomitant changes in the hormonal secretory pattern

occur during an attack of headache when hypothalamic

structures are involved. During spontaneous migraine or cluster

headache attacks activation of the hypothalamus is shown by

positron emission tomography. Over the past 10 years a

number of patients with refractory chronic cluster headache

have received neurostimulation of the posteroinferior

hypothalamus as a form of treatment. The clinical use of deep

brain stimulation (DBS) is based on the theory of posterior

hypothalamic nucleus dysfunction as the cause of cluster

headache attacks. In this article the authors review the

functional anatomy of the hypothalamic region and its

neighborhood, using silicone-injected cadaveric head and

MRI. In conclusion, a better understanding of the functional

anatomy of the hypothalamus and its neighborhood is

imperative for understanding the pathophysiology of several

of the primary headaches, particularly migraine and the

trigemino-autonomic headaches. Direct stimulation of the

posterior hypothalamic region using DBS devices is now the

"state of the art" form of treatment indicated for refractory chronic

cluster headache. The exact mechanism and the actual region

where the DBS may act are still unknown, and studies on the

functional anatomy of the hypothalamus are crucial to the

progress in this marvelous field of functional neurosurgery.

Keywords:Keywords:

Keywords: Anatomy; Hypothalamus; Cluster headache;

Migraine; DBS; MRI

FUNCTIONAL ANATOMYFUNCTIONAL ANATOMY

FUNCTIONAL ANATOMY

Marcelo Moraes Valença

, Luciana P. A. Andrade-Valença

, Carolina Martins

Neurology and Neurosurgery Unit, Universidade Federal de Pernambuco, Recife, PE, Brazil and

Hospital Esperança, Recife, PE, Brazil

Medical School of Pernambuco IMIP, Recife, PE, Brazil

Valença MM, Andrade-Valença LP, Martins C

Functional anatomy of headache: hypothalamus. Headache Medicine. 2011;2(4):165-72

RESUMORESUMO

RESUMO

Há agora evidência suficiente indicando exercer o hipotálamo

um importante papel no mecanismo de deflagração de uma

crise de cefaleia. Dor e alterações concomitantes no padrão

secretório hormonal ocorrem durante uma crise de cefaleia

quando o hipotálamo é envolvido. Ativação do hipotálamo

foi mostrada na tomografia por emissão de pósitrons durante

crises espontâneas de migrânea ou de cefaleia em salvas.

Durante a última década, um número de pacientes com

cefaleia em salvas crônica refratária recebeu neuroestimulação

no hipotálamo posterior como forma de tratamento. O uso

clínico de estimulação cerebral profunda foi baseado na teoria

de haver uma disfunção no núcleo hipotalâmico posterior

como causa das crises de salvas. Neste artigo, os autores

estão revisando a anatomia funcional da região hipotalâmica

e sua vizinhança, utilizando cabeça cadavérica injetada com

silicone e imagens de ressonância magnética. Concluindo,

um melhor entendimento da anatomia funcional do hipo-

tálamo e sua vizinhança é imperativo para compreender a

patofisiologia de várias das cefaleias primárias, em particular

da migrânea e das cefaleias trigêmino-autonômicas. Estimu-

lação direta da região hipotalâmica posterior é agora o "estado

da arte" no tratamento da cefaleia em salvas crônica refratária.

O mecanismo exato e a região onde a estimulação atuaria

ainda são desconhecidos; estudos no campo da anatomia

funcional do hipotálamo são críticos para que haja progresso

neste novo e encantador setor da neurocirurgia funcional.

alavrasalavras

alavras

chave:chave:

chave: Anatomia; Hipotálamo; Cefaleia em

salvas; Migrânea; Ressonância magnética; Estimulação

cerebral profunda

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Headache Medicine, v.2, n.4, p. 165-1

72, Oct/Nov/Dec. 2011

VALENÇA MM, ANDRADE-VALENÇA LP, MARTINS C

INTRODUCTION

There is now compelling evidence that the

hypothalamus exerts a major role in the mechanism of

headache triggering.

(1-11)

Pain and concomitant changes

in the hormonal secretory pattern occur during an attack

of headache when hypothalamic structures are involved.

(5)

For instance, the hypothalamus, especially in the posterior

region, is activated during attacks of trigeminal autonomic

headaches, such as cluster headache, paroxysmal

hemicrania and short-lasting unilateral neuralgiform

headache attacks with conjunctival injection and tearing

(SUNCT), while during migraine attacks the activation

occurs preponderantly in the brainstem (e.g., dorsal

pontine region), but hypothalamic activation also

occurs.

(1,2)

The hypothalamus and the adjacent brainstem form

a complex interconnected structure responsible for the

chronobiological features of some types of primary

headache, especially sleep-related attacks, a characteristic

feature of trigeminal autonomic headaches, hypnic

headache and migraine.

(12)

The hypothalamus, through hormonal and autonomic

regulation, controls a number of physiological functions,

such as blood pressure, fluid and electrolyte balance, body

temperature, and body weight, maintaining a fairly

constant value known as the "set point".

(13,14)

The hypothalamic nuclei constitute part of the

corticodiencephalic circuitry activating, controlling, and

integrating the peripheral autonomic mechanisms,

endocrine activity, and many somatic functions, e.g.,

regulation of water balance, body temperature, sleep,

food intake, and the development of secondary sexual

characteristics.

(7)

The hypothalamus is wired in the brainstem to the

periaqueductal gray substance, the locus coeruleus, and

the median raphe nuclei, all of which are involved in

autonomic, sleep, and in the descending control of pain

perception mechanisms. The hypothalamus also receives

input from different locations of the central nervous

system, obtaining information on the state of the body,

thereby initiating compensatory physiological changes.

(7)

These inputs come from: (1) nucleus of the solitary

tract, with information on blood pressure and gut

distension; (2) reticular formation, receiving information

on skin temperature; (3) retina and optic nerve, whose

fibers go directly to the suprachiasmatic nucleus and are

involved in the regulation of circadian rhythms; (4)

circumventricular organs, nuclei located along the

ventricles, which lack a blood-brain barrier, allowing them

to monitor substances in the blood (e.g., organum

vasculosum of the lamina terminalis, which is sensitive to

changes in osmolarity, and the area postrema, which is

sensitive to toxins in the blood and can induce vomiting);

and

(5)

the limbic and olfactory systems. Structures such as

the amygdala, the hippocampus, and the olfactory cortex,

all of which are connected with the hypothalamus, regulate

a broad range of psychological and physiological

functions, including anger, fear, reproduction, learning

and memory, drinking, eating, autonomic activity and

pain.

(7,13,14)

The hypothalamus is continually informed of the

physiological changes occurring in the organism, and

immediate adjustments take place to maintain homeostasis

by means of two major outputs: first, neural signals to the

autonomic nervous system; and second, endocrine signals

working through the hypothalamic-pituitary axis.

The lateral hypothalamus projects onto cells that

control the autonomic systems located in the medulla.

These include the parasympathetic vagal nuclei and a

group of cells that descend to the sympathetic system in

the spinal cord. Thus the physiological functions of heart

rate and force of contraction; constriction and dilation of

blood vessels; contraction and relaxation of smooth

muscles in various organs; visual accommodation and

pupil size; and secretions from exocrine and endocrine

glands (i.e., digestion, lacrimation, sweating) are all also

influenced by the hypothalamus.

(7)

The master coordinator of hormonal endocrine activity

in mammals is the hypothalamus. Large hypothalamic

neurons positioned around the third ventricle send their

axons directly to the neurohypophysis, where the nerve

terminals release oxytocin and vasopressin into the

bloodstream. Smaller neurons located all over the

hypothalamus send their axons to the median eminence

in the medial basal hypothalamus, where they discharge

releasing factors [corticotropin-releasing hormone (CRH),

gonadotropin-releasing hormone (GnRH), growth

hormone-releasing hormone (GHRH), thyrotropin-

releasing hormone (TRH)] and inhibiting factors

(dopamine, somatostatin) into the hypophyseal portal

capillary. This specialized system of vessels connects the

base of the hypothalamus with the anterior pituitary gland

in order to regulate the secretion of hormones such as

ACTH, TSH, LH, FSH, and GH. In contrast, inhibiting

factors, such as dopamine and somatostatin, cause a

strong inhibition of prolactin (PRL) and GH secretions,

respectively.

(7,13,14)

Headache Medicine, v.2, n.4, p. 165-172, Oct/Nov/Dec. 2011 167

FUNCTIONAL ANATOMY OF HEADACHE: HYPOTHALAMUS

The hormonal effects vary widely, including stimulation

or inhibition of growth; regulation of the metabolism;

preparation for a new activity (e.g. fighting, fleeing, or

mating); preparation for a new phase of life (e.g. puberty,

caring for offspring, menopause); controlling the

reproductive cycle; induction or suppression of apoptosis;

activation or inhibition of the immune system, among

others.

(7)

FUNCTIONAL ANATOMY

The hypothalamus (from the Greek hypo, meaning

"below" and thalamus, meaning "bed") is located at the

base of the brain, in the diencephalon, in an

anteroventral position in relation to the thalamus and

above the sella turcica and pituitary. The dimensions of

the hypothalamus are 1.5 cm in height, 1.5 cm in the

antero-posterior length and 1.3 cm in width. Its weight

varies from 2.5 to 5 g, considering a human brain of

1,200-1,300 g.

(13,14)

It also forms the roof, lateral walls and floor of the

third ventricle. The anatomical limits of the hypothalamus

are: anteriorly, the rostral border of the optic chiasm and

lamina terminalis; caudally, the posterior border of

mamillary nuclei; and rostrally and posteriorly, the

thalamus and the hypothalamic sulcus. The lateral

boundaries are less clear, varying with the level studied,

including the optic tract, internal capsule, pes pedunculi,

globus pallidus, ansa lenticularis and the subthalamic

region.

(13,14)

Because the boundaries between these areas

are disputable, in anatomy, it has been conventioned to

use a coronal plane at the level of mammillary bodies to

separate the hypothalamus, anteriorly, from the

subthalamic region, just behind.

(15)

The hypothalamic region includes the tuber

cinereum, the infundibulum, the optic chiasm,

mammillary bodies and the neurohypophysis. There are

two major tracts in the hypothalamus: (1) the

mamillothalamic tract (bundle of Vicq d'Azyr), which

emerges from the medial and lateral mamillary nuclei,

passing dorsally, and terminates at the anterior thalamic

nuclei. At the beginning, it forms a well-defined bundle

Figure 1. The hypothalamus and its neighborhood. Dissection of a silicone-injected cadaveric head has been performed at George Colter

International Microsurgical Lab - University of Florida, Gainesville. A sagittal cut through the head has been made and dissection with

preservation of the retrocomissural fornix has been undertaken. The path of the left column of fornix can be followed down to the mammillary

body. From the mammillary body, a fiber tract passes up along the lateral wall of the ventricle to the anterior nuclei of thalamus: the mammilothalamic

tract - involved in the circuitry of recent memory acquisition. The septum has been removed to expose the right lateral ventricle cavity. The

topographic limits of the hypothalamus are arbitrary. Anatomically, the hypothalamus is defined as the area including the lateral walls of the third

ventricle in front of a coronal plane passing posterior to the mammillary bodies. The anterior limit of this area is the anterior limit of the third

ventricle and is formed by the lamina terminalis. The hypothalamic sulcus can be seen as a groove on the lateral wall of the third ventricle,

between the foramen of Monro and the cerebral aqueduct. The hypothalamic sulcus is used as a landmark to divide the diencephalon. Posterior

to the sulcus is the pars dorsalis (dorsal thalamus and epithalamus), while anterior to the hypothalamic sulcus is the pars ventralis (hypothalamus

and subthalamus). Above the hypothalamic sulcus the walls of the third ventricle are united in 2/3 of the human brains by the interthalamic

adhesion, a portion of gray matter that signals the location of the medial nuclei of thalamus.

A.: Artery, Ant.: Anterior, I. A.: Interthalamic Adhesion, C.: Corpus, Car.: Carotid, Cav.: Cavernous, Cer.: Cerebral, Chor.: Choroid, Com.: Commissure,,

C.N.: Cranial Nerve, For.: Foramen, Int.: Internal, Lam.: Lamina, Lat.: Lateral, Pit.: Pituitary, Segm.: Segment, V.: Vein, Venous, Vent.: Ventricle.

168

Headache Medicine, v.2, n.4, p. 165-1

72, Oct/Nov/Dec. 2011

Figure 2. The sella turcica, infundibular stalk and optic quiasm.

Dissection of a silicone-injected cadaveric head has been performed

at George Colter International Microsurgical Lab - University of Florida,

Gainesville. A – Superior panel, anterior view of the optic quiasm and

infundibular stalk. B – Inferior panel, superior view of the sella turcica,

optic nerve, infundibular stalk, and neighborhood. This region is very

sensitive to stimuli that are painful, such as unruptured cerebral

aneurysms, pituitary adenomas, etc.

VALENÇA MM, ANDRADE-VALENÇA LP, MARTINS C

known as the principal mamillary bundle (fasciculus

mamillaris princeps). This bundle passes dorsally for a

short distance before dividing into two components: the

mamillothalamic tract (the larger) and the

mamillotegmental tract (the smaller); and (2) the

postcommissural fornix. The postcommissural fornix

extends from the fornical column, continues behind the

anterior commissure to reach the mamillary body. The

fornix group fibers connect the hippocampus to the

mammillary body. It is divided into fimbriae, crura,

commissure, body and columns. The columns, at the level

of the anterior commissure, divide into pre- and

postcommisural fibers. The former projects fibers to the

septal, lateral preoptic, diagonal and anterior

hypothalamic nuclei.

(13,14)

The Figures 1 and 2 show the

anatomy of the hypothalamic region and its

neighborhood, using silicone-injected cadaveric head.

Using the MRI scan in a sagittal view we can delineate

the hypothalamus using "imaginary lines" described by

Saleem et al.

(16)

The anterior boundary of the

hypothalamus, a "line" that extends from the anterior

commissure to the optic chiasm, corresponds to the lamina

terminalis. The posterior boundary, would extend from

the mamillary bodies to the posterior commissure (it is

imprecise because the hypothalamus blends into the

mesencephalic tegmentum) (Figures 3 and 4).

Superiorly the hypothalamic sulcus separates the

hypothalamus from the thalamus. The hypothalamic sulcus

extends from the interventricular foramen to the cranial

opening of the aqueduct. This sulcus is the remnant in the

adult of the sulcus limitans of the early development of

the neural tube. The sulcus limitans divides the neural tube

into a ventral lamina or basal plate – which will eventually

originate the motor nuclei of spinal cord and brainstem –

and a dorsal lamina or alar plate, that will differentiate

into input receiving structures.

(15)

Another practical way to

limit the hypothalamus from the thalamus in radiological

images is to draw a line between the anterior commissure

and the posterior commissure.

(16)

Inferiorly, the hypothalamus presents the tuber cinereum.

This is a tubular structure composed of gray matter and lies

between the two mamillary bodies (posteriorly) and the

optic chiasm (anteriorly). The lateral boundary of the

hypothalamus is, in its superior part, the medial thalamus.

The median eminence or infundibulum is a small

prominence in the tuber cinereum, formed by third ventricle

floor that continues downward to form the infundibular

stalk. The infundibular stalk is connected to the posterior

lobe of the pituitary gland (Figures 3 and 4).

(13,14,16)

Figure 2 A. Superior panel.

Figure 2 B. Inferior panel.

Headache Medicine, v.2, n.4, p. 165-172, Oct/Nov/Dec. 2011 169

FUNCTIONAL ANATOMY OF HEADACHE: HYPOTHALAMUS

Figure 3. A – MRI scan (T1-weighted sagittal cut, 54-year-old woman)

showing the hypothalamic region (dashed line), based on Saleem

and colleagues.

B – MRI scan showing the different areas visualized

in the hypothalamic region. AC, anterior commissure; LT, lamina

terminalis; OQ, optic quiasm; IS, infundibular stalk; PG, pituitary gland;

TC, tuber cinereum; MB, mamillary body; HS, hypothalamic sulcus;

red line, postcommissural fornix; blue line, mamillothalamic tract.

The high-signal-intensity area in the posterior part of the sella turcica

is the posterior pituitary gland.

Cell proliferation in the posterior lobe and sprouting

of hypothalamic nerve fibers in humans result in closure

of infundibular recess – the path between the third ventricle

and the posterior lobe of the gland – kept naturally

opened in other mammals (e.g. cat). In conditions of high

ventricular pressure (e.g. hydrocephalus), the infundibular

recess can become patent. In this situation, the reddish

rue of the gland can be seen from inside the ventricle and

might be a cause of disorientation during endoscopic

ventriculostomies.

(17,18)

Several nuclei and fiber tracts are arranged

symmetrically in the hypothalami, into the floor and lower

medial surface of the third ventricle. To better identify the

Figure 4. MRI scan (T1-weighted coronal plane, 17-year-old girl four

years after surgical removal of a craniopharyngioma) showing the

different positions of the hypothalamic nuclei, based on Saleem and

colleagues.

AC, anterior commissure; LPO, lateral preoptic nucleus;

SC, suprachiasmatic nucleus; SO, supraoptic nucleus; MPO, medial

preoptic nucleus.

intrahypothalamic structures two imaginary axes are

used, the medial-lateral and the rostral-caudal axes. The

lateral and medial areas of the hypothalamus are

separated by the medial-lateral axis. The rostral-caudal

axis subdivides the hypothalamus into three regions:

anterior, tuberal, and posterior.

(16)

In the proximity of the hypothalamus there are the

optic nerves that ascend from the skull base toward the

chiasm at an angle of approximately 45 degrees with

the nasotuberculum line; the intracranial segment of the

optic nerve is 17 ± 2.4 mm in length, and the optic chiasm

sits about 10.7 ± 2.4 mm above the dorsum of the sella

turcica.

(19)

ROLE OF THE HYPOTHALAMUS ON THE

HEADACHE PATHOPHYSIOLOGY

rigeminal autonomic headachesrigeminal autonomic headaches

rigeminal autonomic headaches

The clinical manifestation of hemicrania continua

overlaps with that of other trigeminal autonomic headaches

and migraine, and activations observed in the hypothalamus

and dorsal rostral pons, respectively, appear to play an

important pathophysiological role.

(1,2,20-23)

Functional brain

imaging has demonstrated significant activation of the

ipsilateral dorsal rostral pons in association with the

headache attacks of hemicrania continua.

(20,21)

There was

also a significant activation of the contralateral posterior

hypothalamus and ipsilateral ventrolateral midbrain, which

extended over the red nucleus, the substantia nigra and

the pontomedullary junction. The distinction between two

170

Headache Medicine, v.2, n.4, p. 165-1

72, Oct/Nov/Dec. 2011

headache subtypes is that the ipsilateral hypothalamus

mediates cluster headache, while the contralateral

hypothalamus mediates hemicrania continua.

Proton MR spectroscopy of subjects with cluster

headache showed a reduction in the NAA marker of

neuronal integrity.

(10,11)

These results were confirmed by

Wang et al.,

(11)

who also found a decrease in the Cho/Cr

metabolite ratio, both during and between episodes. This

suggests that both neuronal dysfunction and changes in

the membrane lipids occur in the hypothalamus in cluster

headache patients.

During the last decade more than 50 patients with

refractory chronic cluster headache received neuro-

stimulation of the posteroinferior hypothalamus as a form

of treatment.

(24)

Clinical use of deep brain stimulation (DBS)

was based on the theory of posterior hypothalamic nucleus

dysfunction as the cause of cluster headache

attacks.

(1,2,10,11,20-22)

In a recent publication Seijo and colleagues

(24)

implanted five patients with a tetrapolar electrode (always

ipsilateral to the pain side) into the hypothalamus, using

the stereotaxic coordinates of 4 mm lateral to the third

ventricle wall, 2 mm behind the midintercommissural

point and 5 mm under the intercommissural line. An

improvement of the headache was obtained in all

patients. The authors postulated that the stimulated brain

area included a lateral hypothalamic area (LHA) and

the fasciculi mammillotegmentalis (FMTG), mammillo-

thalamicus (FMTH) and medialis telencephali (FMTL) or

medial forebrain bundle.

(24)

As a result of stimulation (target of a brain volume of

approximately 3 mm in radius) persistent myosis and

euphoria/well-being feeling were observed in 3 subjects.

Occasional dizziness (n=3), blurring vision/diplopia

(n=2), concentration difficulties (n=1), cervical dystonia

(n=1), generalized headache (n=1) and increase in

appetite (n=1) were symptoms transiently induced.

(24)

The "calming effect" was observed in three subjects.

(24)

In this regard, Sano and coworkers

(25)

reported their

experience with hypothalamic stimulation and lesion in

order to treat 51 patients with aggressive behavior. An

increase in blood pressure, tachycardia, and maximal

pupillary dilatation were provoked after stimulation in the

posteromedial hypothalamus (more than 1 mm and less

than 5 mm lateral to the lateral wall of the third ventricle),

a triangular area (ergotropic triangle) formed by the

midpoint of the intercommissural line, the rostral end of

the aqueduct, and the anterior border of the mammillary

body. Sano et al.

(25)

reported that sympathetic or

parasympathetic responses would depend on the region

of hypothalamic stimulation: an internal area of 0-1 mm

that has parasympathetic responses; a medial area of

1-5 mm that has sympathetic responses; a lateral area

of >5 mm, parasympathetic responses; and 3 mm under

the midintercommissural point and 5 mm from the lateral

wall of the third ventricle, parasympathetic responses.

Electrical stimulation of this ergotropic triangle

resulted in desynchronization of the electro-

encephalogram (EEG) with hippocampal theta waves,

or diffuse irregular delta waves of high voltage,

demonstrating that the hypothalamus may regulate the

cerebral cortex as well.

(25)

Interestingly, in the series of patients of Seijo and

colleagues

(24)

two typical cluster headache attacks were

triggered on the contralateral side after the performance

of the procedure in a 48-year-old woman. This is an

unquestionable indication that abnormalities in the

hypothalamus can induce cluster headache. Another

interesting fact was that all individuals were painfree up

to 2 weeks after the implantation of the DBS in the absence

of electrical stimulation. Probably related to a local

microlesion or a neuronal shock.

(24)

In another series, Fontaine and colleagues

(26)

studied

10 patients with refractory chronic cluster headache who

were implanted with DBS electrodes located in the

posterior and ventral wall of the third ventricle (theoretical

target 2 mm lateral to the midline, 3 mm posterior and

5 mm below the mid-commissural point). All of electrodes

were posterior to the mamillary body and the mamillo-

thalamic tract, at the diencephalo-mesencephalic junction

tract (retro-mamillary posterior hypothalamus?). In the 5

responder patients the electrodes were in the proximity

of the following structures: grey mesencephalic substance

(5/5), red nucleus (4/5, superficial; 3/5 core), fascicle

retroflexus (4/5), fascicle longitudinal dorsal (3/5), nucleus

of ansa lenticularis (3/5), fascicle longitudinal medial

(1/5) and the thalamus superficial medial (1/5), suggesting

a participation of some of these anatomical structures.

They admitted two possibilities to explain the pain relief

effect: a direct stimulation on a local cluster headache

generator, or through activation of an anti-nocioceptive

systems. Since there is a latent period after the onset of

DBS, neuroplastic mechanisms seem to play a role.

MigraineMigraine

Migraine

A disruption in the normal function of the hypothalamus

is implicated in the genesis of some prodromal symptoms

VALENÇA MM, ANDRADE-VALENÇA LP, MARTINS C

Headache Medicine, v.2, n.4, p. 165-172, Oct/Nov/Dec. 2011 171

and signs of migraine, such as mood changes, drowsiness,

thirst, craving for food, and yawning.

(7)

Some of the migraine prodromal symptoms are

controlled by the limbic system.

(27)

In a study involving 97

patients, premonitory symptoms predicted migraine attacks

in 72%.

(28)

The most common premonitory symptoms were

feeling tired and weary, observed in 72% of attacks with

warning features, followed by difficulty in concentrating

(51%) and a stiff neck (50%). These signs and symptoms

may occur over several hours, or for even as long as 2

days, before the onset of pain.

During spontaneous migraine attacks activation of

the hypothalamus is shown by positron emission

tomography scanning.

(3)

During the headache Denuelle

and coworkers

(3)

reported significant activations in the

hypothalamus, midbrain and pons that persists after

headache relief by sumatriptan treatment. A theory

explaining the relationship between the hypothalamus and

migraine attacks is that the joint effect of several migraine

triggers may cause temporary hypothalamic dysfunction

and this will result in a migraine attack.

(4)

Furthermore, some of the hypothalamic peptides

appear to be involved in the physiopathology of

migraine.

(7)

Acute migraine headache attack can be

relieved by intravenous oxytocin administration.

(29)

addition, a lactational headache was attributed to

oxytocin surges in association with the milk-ejection

reflex.

(30)

A case of a woman suffering from brief attacks

of headache that happened on every occasion of

nursing was reported.

(30)

On the other hand, another

case was described when the apparent headache trigger

was breast overfulness, and not the oxytocin surge.

(31)

In this case the headaches were alleviated by putting

the baby to the breast by the activation of the milk-

ejection reflex.

(31)

Another indication that the hypothalamus is involved

during a migraine attack is the report of 6 subjects with

a history of increased urinary frequency during migraine

episodes.

(32)

An evident diuresis and natriuresis occurred

within 12 hours of the onset of the headache, associated

with a significant decrease in urinary arginine

vasopressin.

Intracranial lesions in the hypothalamic region and

its neighborhood (e.g. cerebral aneurysm and pituitary

adenomas)

(33,34)

may trigger headache with similar

features to those encountered in primary headaches.

Figure 5 shows an MRI scan of a man with a recent

history of headache caused by a hypothalamic cystic

tumor.

CONCLUSION

In conclusion, a more thorough understanding of the

functional anatomy of the hypothalamus and its

neighborhood is imperative for understanding the

physiopathology of several of the primary headaches,

particularly migraine and the trigemino-autonomic

headaches. Direct stimulation of the posterior

hypothalamic region, using DBS devices, is now the "state

of the art" form of treatment indicated for refractory chronic

cluster headache. The exact mechanism and the actual

region where the DBS may act are still unknown, and

studies on the functional anatomy of the hypothalamus

are crucial to the progress in this marvelous field of

functional neurosurgery.

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VALENÇA MM, ANDRADE-VALENÇA LP, MARTINS C

Correspondence

Marcelo M. VMarcelo M. V

Marcelo M. V

alença, MDalença, MD

alença, MD

Neurology and Neurosurgery Unit,

Department of Neuropsychiatry

Universisdade Federal de Pernambuco

50670-420 – Recife, PE, Brazil

mmvalenca@yahoo.com.br

Received: 11/23/2011

Accepted: 12/20/2011

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1634-41.

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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

NEUROMODULATORS AND ITS COMBINATIONS FOR THE PREVENTIVE TREATMENT OF MIGRAINE

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

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

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

182

eadache Medicine, v.2, n.4, p.182-186, Oct/ Nov/Dec. 2011

Pain and the endogenous antinociceptive

neuronal system: physiologic role of oxytocin

Dor e sistema neuronal antinociceptível endógeno: papel fisiológico

da ocitocina

ABSTRACTABSTRACT

ABSTRACT

The unpleasant pain sensation is a sub-modality of somatic

sensation that exerts fundamental warning and protective

functions. Pain is the more frequent complain in a neurological

outpatient clinic. In a series of 200 consecutive patients in a

neurological outpatient clinic, 51% of them complained of

some type of pain, the more frequents were headache and

carpal tunnel syndrome. The role of oxytocin in pain regulation

was reviewed. It seems that oxytocin may play a major role in

the mechanism of pain regulation, particularly through the

endogenous antinociceptive neuronal system.

eywords: eywords:

eywords: Pain; Headache; Oxytocin; Carpal tunnel syndrome

RESUMORESUMO

RESUMO

A sensação desagradável de dor é uma modalidade sensitivo-

somática que serve como alarme e exerce funções de proteção.

A dor foi a queixa mais frequente em um ambulatório neuro-

lógico. Em uma série de 200 pacientes consecutivos em um

ambulatório de neurologia, 51% deles se queixaram de algum

tipo de dor, mais frequentemente cefaleia e síndrome do túnel

do carpo. O papel da ocitocina na regulação da dor foi

revisado. Parece que a oxitocina pode desempenhar uma

função importante no mecanismo de regulação da dor,

particularmente através do sistema neuronal antinociceptivo.

alavrasalavras

alavras

chave:chave:

chave: Dor; Cefaleia; Ocitocina; Síndrome do

túnel do carpo

VIEW AND REVIEWVIEW AND REVIEW

VIEW AND REVIEW

Marcelo Moraes Valença

, Luciana Patrízia A. Andrade-Valença

1,2

, José Antunes-Rodrigues

Neurology and Neurosurgery Unit, Department of Neuropsychiatry, CCS,

Universidade Federal de Pernambuco, Recife, PE, Brazil

Division of Neurology, Universidade de Pernambuco, Recife, Brazil

Department of Physiology, School of Medicine of Ribeirão Preto, Universidade de São Paulo,

Ribeirão Preto, SP, Brazil

Valença MM, Andrade-Valença LP, Antunes-Rodrigues J

Pain and the endogenous antinociceptive neuronal system: physiologic role of oxytocin.

Headache Medicine. 2011;2(4):182-6

INTRODUCTION

The unpleasant pain sensation (pricking, aching,

burning, stinging, or soreness) is a sub-modality of somatic

sensation that exerts fundamental warning and protective

functions.

Under physiologic conditions, pain sensation are

mediated by two primary afferent neurons: 1) the small-

diameter nonmyelinated C-fibers and 2) thinly myelinated

Aδ-fibers, both referred to as nociceptors. Nociceptors

respond to mechanical, thermal, and chemical forms of

energy. Polymodal nociceptors are activated by thermal,

chemical and high-intensity mechanical stimuli. The Aδ

fibers are glutamatergic neurons that transmitter the fast

sharp pain (5-30 m/s). The C-fibers transmitter the slow

dull pain. Substance P is released from C fibers, and may

enhance and prolong the actions of glutamate.

(1)

In human, rapid immersion of a finger in a hot water

bath (57° C) causes at onset a stinging pain after a time

interval of 0.84 s on average. This is followed by a second

wave of a burning pain after 2.1 s. The latency between

the two forms of pain waves decrease as the stimulus moves

up the limbs toward the trunk, and at the trunk level it is

not feasible to obtain a double pain sequence. This double

pain experience is triggered by fast rising stimulus (electric

Headache Medicine, v.2, n.4, p.182-186, Oct/ Nov/Dec. 2011 183

shock, pinprick, or heating pulse). Interestingly, opioid

substances appear to affect the second pain component

more than the first one.

(2,3)

On the other hand, the first

pain is differentially blocked by compression-ischemia.

(1)

FREQUENCY OF PAIN COMPLAINS IN

CLINICAL PRACTICES

Pain is the more frequent complain in a neurological

outpatient clinic. Table 1 illustrates the principal diagnoses

identified in a series of 200 consecutive patients in a

neurological outpatient clinic of one of the authors (MMV,

Hospital Santa Helena, 1993).

the latency, although it reduced the analgesia induced by

OT (1 mg kg

-1

On the contrary, Xu and Wiesenfeld

(8)

interpreted the

increase in the latency response in the hot-plate test in rats

as a result of sedative and vasoconstrictive effects of OT,

rather that an analgesic phenomenon. Additionally, they

also reported that OT-ANT (1 mg/kg, i.p.) did not influence

response latency to heat pain sensitivity in rats.

Yang

(9)

investigated the actions of OT on the analgesia

in both rat and human being. In humans, acute and

chronic low back pain causes significant change of OT

concentration within CSF and plasma. Oxytocin

administration alleviated low back pain. In rats, OT had

a dose-related analgesic effect. The use of the OT-ANT

[d(CH2)5, Tyr(Me)2, Orn8]-vasotocin and naloxone both

reversed the analgesia induced by OT. Oxytocin also

increased the levels of endogenous opioide peptides

(EOP) (endorphin, encephalin, and dynorphin) in the

spinal cord, whereas OT-ANT caused a decline.

As clinical use, OT, vasopressin and somatostatin were

injected into the cerebral ventricle of a ill cancer patient a

diffuse mesothelioma suffering intractable continuous and

incapacitating thoracic pain. Oxytocin induced a strong

analgesia (by 88%) lasting 77 minutes. Somatostatin-14

reduced pain by 90% for 48 min and arginine vasopressin

reduced pain by 95% for 75 min.

(10)

Furthermore, acupuncture caused changes in OT

content in many regions of rat brain, suggesting that OT

might modulate acupuncture-induced analgesia.

(11)

Liu

(12)

studied the effects of intracerebroventricular (icv)

injections of OT, naloxone, or CCK-8 on electro-

acupuncture (EA) analgesia in rats. They concluded that

the role of OT in EA was not entirely dependent upon the

EOP.

Song and coworkers

(13)

studied the possible

involvement of EOP on OT analgesic actions, by using

icv injection of anti-opioid peptide sera in rats which OT

induced an increase of EA analgesia. Injection of anti-

beta-endorphin serum alone attenuated EA analgesia.

Although, the same antiserum treatment, prior to

intraventricular injection of OT, could not block the

enhancement of EA analgesia by OT. The antidynorphin

A1-13 serum alone could also reduce the EA analgesia

and when the antiserum was given prior to injection of OT

a potentiation of the EA analgesia induced by OT was

found. No effect was observed with the administration of

either anti-methionine enkephalin serum or the anti-leucine

enkephalin. They concluded that the enhancement of EA

analgesia by OT does not depend upon the brain EOP.

OXYTOCIN

In 1982, Berkowitz and Sherman

(4)

reported that

peripheral injection of oxytocin (OT) does not have any

analgesic effects. On the other hand, Caldwell et al.

(5)

demonstrated that intracisternal injection of OT in mice

induced analgesia. Kordower and Bodnar

(6)

showed in

rats that injection of OT into the lateral ventricle also

caused analgesia. Besides, OT levels in plasma and

cerebrospinal fluid (CSF) increased after 30-min exposition

to different non-noxious sensory stimulation, which were

concomitant with the development of analgesia.

(7)

The OT

antagonist 1-deamino-2-D-Tyr-(OEt)-4-Thr-8-Orn-

oxytocin (1 mg kg

-1

) reversed the prolongation of the

latency observed in the TFT after exposition to such stimuli.

The OT-ANT treatment by itself did not change significantly

PAIN AND THE ENDOGENOUS ANTINOCICEPTIVE NEURONAL SYSTEM: PHYSIOLOGIC ROLE OF OXYTOCIN

184

Headache Medicine, v.2, n.4, p.182-186, Oct/ Nov/Dec. 2011

VALENÇA MM, ANDRADE-VALENÇA LP, ANTUNES-RODRIGUES J

In a review Richard and colleagues

(14)

concluded that

"in no case does OT-induced analgesia appear to be

opiate dependent". Interestingly, they also described that

fragment of the OT molecule, oxytocin-,

(7-9)

can under

certain circumstances act as an opioid antagonist.

Urnäs-Moberg and coworkers

(15)

postulated that low

doses of ethanol could cause anti-nociceptive effects via

an oxytocinergic mechanism. Administration of ethanol

also stimulated the elevation in plasma OT levels and the

use of OT-ANT reduced the increased pain threshold

produced by ethanol. However, Urnäs-Moberg and

colleagues

(15)

made a statement that "opioid mechanisms

do not seem to be involved in the oxytocin induced effects

on pain threshold, since the effects are not blocked by

naloxone (Lundeberg, personal communication)." The

results of the mentioned experiment was not published

neither the doses or the study design, as far as we know.

Looking back the results published by Urnäs-Moberg and

colleagues,

(16)

the latency in the tail flick test in the presence

of OT-ANT was higher with OT, suggesting some degree

of analgesia exerted by OT throw some other receptor

subtype not blocked by the OT-ANT used.

Lundeberg and colleagues

(17)

suggested a central

action of OT since after intrathecal injection of this

neuropeptide (1 µg kg

-1

) induced a delay in the reaction

time in the paw pressure test.

Parturition and vaginal dilatation both cause

enhancement in plasma OT concentration and increase

of the pain threshold, and since during the labour is of

paramount importance the action of OT over the uterus,

provoking increment in muscle contraction, an event which

would trigger pain sensation, it would be logical that the

same peptide would exert a dual physiological function:

analgesia and uterus contraction during labor.

(18)

Under physiologic conditions OT is released from

nerve terminals of the neurophypophisis and median

eminence into the blood, into the cerebrospinal fluid (CSF)

or into specific regions of the CNS. The half-life of plasma

OT is 1-2 min. At CSF OT is present with concentrations

raging from 10 to 50 fmol/ml, which half-life is 28 min.

At a physiologic level the OT present in the sytemic blood

does not penetrete into the CSF or into the brain. The OT

perikarya are presented largely in the magnocellular nuclei,

although fibers are widely distributed in CNS (dorso medial

hypothalamic nucleus, thalamic nuclei, limbic system,

mesencefalic central nucleus, substancia nigra, locus

coeruleus, raphe nucleus, nucleus of the solitary tract, dorsal

motor nucleus of the vagus nerve, and at the spinal cord

ending particularly in layers I, II, and X of the gray matter).

In guinea pigs only 2%-3% of the ip administrated

OT were detected in brain. Hence, the necessity of high

doses of OT, if injected systemically, to induce analgesia,

in the case of considering a central site of action.

(19)

It was

reported that the neurohypophyseal hormones or their

fragments are transported under normal conditions from

blood to brain.

Lesions of the PVN had no effect on nociception. In

the spinal cord the OT fibers may originate from PVN

and C-fibers of the dorsal root ganglia.

Modification of the response latencies to the jump

test (hot plate) and TFT at different temperatures were

encountered with OT anti-serum icv injections: no

changes at high temperatures, decrease in the latencies

at moderate temperature, and increase the latencies at

low temperature (analgesia). Similar results were

observed with other antisera, such as against

vasopressin, met-enkephalin, and beta-endorphin.

Naloxone does not cause pain, but may enhance the

perception of pain.

(20)

Thermal nociceptores are activated by extreme

temperatures (>45º C or <5º C). The mechano- and

heat-responsive C-fibers present heat thresholds raging

from 40º and 50º C in the glabrous and hairy skin of

mammals.

In human heat pain thresholds range from

41º to 49º C.

(21)

In addition, chronic treatment with OT had no effect

on analgesia.

(22)

Analgesia may be caused by different type of stress,

(23)

in some of them the analgesia is mediated by EOP,

(24)

other are unaffected by previous opioid receptor blockade

or through a nonopioid mechanism.

Recent evidence from our Laboratory suggests that

OT leads to an analgesic state, an effect that was

abolished with the blockade of opioid receptor by

naloxone, in mice. This indicated that OT might cause

analgesia throw the involvement of EOP.

(25)

Administration of OT (icv) or antioxytocin serum in

rats modified the pain threshold to electroacupuncture

analgesia, evaluated by potassium iontophoresis induced

tail flick. The OT when injected icv elevated both the pain

threshold and electroacupuncture analgesia. On contrary,

the antiserum reduced the analgesia induced by

electroacupuncture.

(26)

The concentration of OT in CSF of dog with spinal

cord compression was higher than what found in control

dogs, suggesting that during painful conditions OT is

released into CSF or other CNS sites to attenuate the animal

unpleasant, hurtful situation.

(27)

Headache Medicine, v.2, n.4, p.182-186, Oct/ Nov/Dec. 2011 185

In humans, intrathecal injection of oxytocin is effective

in treating low back pain for up to 5 hours.

(28)

Interestedly,

it was described an enhanced hind paw withdrawal latency

in response to nociceptive heat after OT subcutaneous

administration in rat, an effect also found in the untreated

cage mates of an OT-treated animal. This analgesic action

of OT was canceled in OT-ANT-injected cage mates.

Suggesting that cage mates develop anti-nociception

mediated via olfactory tract, which is induced throw, an

oxytocinergic mechanism.

(29)

HEADACHE AND OXYTOCIN

Phillips and colleagues

(30)

reported that acute

migraine headache attack can be relieved by intravenous

oxytocin. On the other hand, a few authors reported that

there is a lactational headache in the literature attributed

to OT surges in association with the milk-ejection

reflex.

(31,32)

A case of a 26-year-old woman suffering from

brief attacks of headache that happened on every

occasion of nursing was reported by Askmark and

Lundberg.

(32)

However, a case was described when the

apparent headache trigger was breast overfulness, and

not the oxytocin surge, occurring when the infant was

sleeping through the night or after a missed, delayed, or

partial feed. In this case, interestingly, the headaches were

alleviated by putting the baby to the breast (activation of

the milk-ejection reflex).

(33)

CONCLUSION

In conclusion, pain is a frequent complain observed

in a neurological outpatient clinic. In this report, 51% of

the patients complained of some type of pain, the more

frequents were headache and carpal tunnel syndrome.

Oxytocin plays a major role in the mechanism of pain

regulation, particularly through the endogenous

antinociceptive neuronal system.

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analgesia]. Zhen Ci Yan Jiu. 1992;17(2):136-8

13. Song CY, Liu WY, Gu XY, Lin BC. Effect of anti-opioid peptide

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14. Richard P, Moos F, Freund-Mercier MJ. Central effects of oxytocin.

Phisiol Rev. 1991;71(2):331-70.

15. Uvnäs-Moberg K, Lundeberg T, Bruzelius G, Alster P. Low doses

of ethanol may induce anti-nociceptive effects via an oxytocinergic

mechanism. Acta Physiol Scand. 1993;149(1):117-8.

16. Uvnäs-Moberg K, Bruzelius G, Alster P, Bileviciute I, Lunderberg

T. Oxytocin increases and a specific oxytocin antagonist

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17. Lundeberg T, Meister B, Björkstrand E, Uvnäs-Moberg K.

Oxytocin reverses galanin-induced hyperalgesia in rats. Brain

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27. Brown DC, Perkowski S. Oxytocin content of the cerebrospinal

fluid of dogs and its relationship to pain induced by spinal cord

compression. Vet Surg. 1998;27(6):607-11.

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in low back pain involving the endogenous opiate peptide system.

Spine (Phila Pa 1976). 1994;19(8):867-71.

29. Agren G, Uvnas-Moberg K, Lundeberg T.Olfactory cues from an

oxytocin-injected male rat can induce anti-nociception in its

cagemates. Neuroreport. 1997;8(14):3073-6.

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migraine headache with intravenous oxytocin: report of two

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32. Askmark H, Lundberg PO. Lactation headache - a new form of

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Correspondence

Marcelo M. VMarcelo M. V

Marcelo M. V

alença, MDalença, MD

alença, MD

Neurology and Neurosurgery Unit,

Department of Neuropsychiatry,

Universidade Federal de Pernambuco – Cidade Universitária

50670-420 – Recife, PE, Brazil.

Phone: +55 81 99229394; +55 81 34263501;

Fax: +55 81 21268539

mmvalenca@yahoo.com.br

Received: 5/9/2011

Accepted: 4/12/2011

VALENÇA MM, ANDRADE-VALENÇA LP, ANTUNES-RODRIGUES J

Headache Medicine, v.2, n.4, p.187-193, Oct/ Nov/Dec. 2011 187

Cronologia do tratamento medicamentoso da

crise migranosa

Chronology of drug treatment of migraine attack

RESUMORESUMO

RESUMO

No passado, a migrânea era tratada apenas durante as crises

com o conhecimento e a cultura de cada civilização. Nesse

ínterim, o uso das ervas medicinais contribuiu para o surgi-

mento das primeiras medicações analgésicas, apesar de sua

não especificidade para cefaleia, como o ácido acetilsalicílico

e a dipirona. Durante o século XX, foram sintetizados os demais

anti-inflamatórios não esteroides e os primeiros medicamentos

específicos para a migrânea: a ergotamina e os triptanos. O

desenvolvimento dos triptanos é considerado o maior avanço

no tratamento da crise migranosa nos últimos 50 anos.

alavrasalavras

alavras

chave:chave:

chave: Migrânea; Cefaleia; Tratamento medica-

mentoso

ABSTRACTABSTRACT

ABSTRACT

In the past, migraine was treated only during attacks with the

knowledge and culture of each civilization. In the meantime,

the use of medicinal herbs has contributed to the emergence

of the first analgesic drugs, despite their non-specificity for

headaches, such as acetylsalicylic acid and dipyrone. During

the twentieth century, other nonsteroidal anti-inflammatory drugs

and the first specific drugs for migraine were synthesized:

ergotamine and triptans. The development of triptans is

considered the greatest advance in the treatment of migraine

attacks in the past 50 years.

Keywords: Keywords:

Keywords: Migraine; Headache; Drug treatment

VIEW AND REVIEWVIEW AND REVIEW

VIEW AND REVIEW

Raimundo Pereira da Silva Néto

Neurologista e Membro da Sociedade Brasileira de Cefaleia

Centro de Neurologia e Cefaleia do Piauí – Teresina,PI, Brasil

Silva Néto RP. Cronologia do tratamento medicamentoso da crise migranosa.

Headache Medicine. 2011;2(4):187-93

O SURGIMENTO DOS ANALGÉSICOS E

ANTI-INFLAMATÓRIOS

A partir do século XIX surgiram as primeiras subs-

tâncias químicas no combate à dor em geral, sendo utili-

zadas de forma rotineira no tratamento da crise migra-

nosa apesar de suas inespecificidades.

Em 1826, dois químicos italianos, Brugnatelli e

Fontana, identificaram os compostos ativos da casca do

salgueiro (Salix alba), tais como a salicina. Esta substância

agia como anti-inflamatório e analgésico e era metabo-

lizada em ácido salicílico, mas causava irritação no

estômago.

Finalmente, em 1829, o farmacêutico francês Henri

Leroux isolou, pela primeira vez, a salicilina. Mais tarde,

o químico italiano Raffaele Piria, em 1838, converteu-a,

por hidrólise e oxidação, em ácido salicílico.

(1)

Devido à persistência da irritação gástrica causada

pela droga, o químico alemão Felix Hoffmann (1868-

1946) sintetizou, em 1887, o ácido acetilsalicílico, numa

forma estável que permitia o seu uso como fármaco.

(2)

No entanto, esse produto somente foi colocado à venda

no dia 10 de outubro de 1903 pela empresa Bayer, com

o nome de Aspirina©. Inicialmente, era vendida em pó,

mas doze anos mais tarde ela ganhou a versão em com-

primidos.

Nos anos de 1886 e 1887, foram desenvolvidas

duas substâncias antipiréticas e analgésicas, a acetanilida

e fenacetina, respectivamente. Em 1893, o químico norte-

americano Harmon Northrop Morse (1848-1920)

188

Headache Medicine, v.2, n.4, p.187-193, Oct/ Nov/Dec. 20

SILVA NÉTO RP

sintetizou o paracetamol, também com notáveis proprie-

dades antipiréticas e analgésicas. Tanto a acetanilida

como a fenacetina e o paracetamol pareciam ter exata-

mente o mesmo efeito sobre o organismo.

Em 1895, foi constatada a presença de paracetamol

em pacientes que haviam ingerido fenacetina; em 1889,

em pacientes que haviam ingerido a acetanilida.

Somente em 1948, os bioquímicos Julius Axelrod (1912-

2004), nascido em Nova York, filho de judeus imigrantes

da Polônia, e Bernard Brodie (1907-1989), nascido em

Liverpool, no Reino Unido, constataram que o parace-

tamol era o maior metabólito da fenacetina e da

acetanilida.

(3)

Hoje, sabe-se que o paracetamol ou acetamino-

feno é um fármaco com propriedades analgésicas, mas

sem propriedades anti-inflamatórias clinicamente signi-

ficativas e que atua por inibição da síntese das pros-

taglandinas. Esta substância também apresenta efeitos

antipiréticos.

A partir de 1955, o paracetamol foi comercializado

nos EUA com o nome de Tylenol© e, no ano seguinte,

na Inglaterra. Seu uso é extremamente popular, puro ou

combinado com outros fármacos.

Em 1883, o químico alemão Ludwig Knorr (1859-

1921) tentava sintetizar um antitérmico substituto da

quinina, um produto de custo excessivamente alto e de

eficácia relativa. Acidentalmente, obteve a antipirina,

derivada da pirazolona. Posteriormente, em 1897,

utilizando-se a antipirina, foi sintetizada a aminopirina,

outro analgésico derivado pirazolônico. Somente em

1889, as propriedades analgésicas da antipirina e da

aminopirina foram constatadas.

Em 1913, a empresa alemã Hoechst AG (hoje

Sanofi-Aventis) desenvolveu a melubrina, o primeiro

composto injetável da família pirazolona. Finalmente, em

1920, esta mesma empresa sintetizou o mais importante

derivado pirazolônico, a dipirona, também chamada de

metamizol ou metilmelubrina, composta de uma asso-

ciação de melubrina (50%) e aminopirina (50%). No

Brasil, a sua comercialização se iniciou em 1922, com o

nome de Novalgina©, sendo o principal analgésico

utilizado nas unidades de emergência para combater a

crise migranosa.

(4)

Em 1949, foi desenvolvido o primeiro anti-inflama-

tório não salicilato, a fenilbutazona, utilizada no trata-

mento da artrite reumatoide e doenças relacionadas.

(1)

Em 1963, surgiu outro anti-inflamatório não salici-

lato, a indometacina, um derivado do ácido indolacético,

sintetizada por Shen e colaboradores no laboratório

Merck Sharp. Difere, ligeiramente, dos outros anti-inflama-

tórios não esteroides nas suas indicações e efeitos tóxi-

cos.

(1)

A partir dos anos de 1960, novos fármacos passa-

ram a ser sintetizados, hoje denominados de anti-infla-

matórios não esteroides tradicionais, como: naproxeno,

cetoprofeno, ibuprofeno, piroxicam, tenoxicam, meloxi-

cam e diclofenaco.

(1)

Em meados de 1975, o químico norte-americano

George Moore, nascido em Boston (1941), juntamente

com seus colaboradores nos Laboratórios Riker, desen-

volveu a nimesulida. Esta droga foi, primeiramente,

autorizada e vendida na Itália em 1985.

(5,6)

O mecanismo de ação de todos esses medicamentos

permaneceu desconhecido por bastante tempo, apesar

do primeiro anti-inflamatório não esteroide, o ácido

acetilsalicílico, ter sido criado no século XIX. Contudo,

somente em 1971, o farmacologista inglês Sir John Vane

(1927-2004) sugeriu que esses medicamentos agiam no

sistema nervoso central e periférico inibindo a atividade

da cicloxigenase (COX), uma enzima responsável pela

síntese de substâncias envolvidas na inflamação, tais como

as prostaglandinas.

(1,7)

Em 1990, a partir dos estudos de

Sir John Vane, foi demonstrada a existência da ciclooxi-

genase 1 (COX-1) e da ciclooxigenase 2 (COX-2).

(1)

Em 1999, foram desenvolvidos os anti-inflamatórios

do grupo dos coxibs, inibidores seletivos da COX-2, e

foram lançados em vários países, inclusive no Brasil.

Progressivamente, surgiram vários questionamentos

sobre a segurança desses coxibs, especialmente com

relação à toxicidade cardiovascular. Por isso, foram

retirados do mercado brasileiro: o rofecoxib (Vioxx©),

em setembro de 2004; o valdecoxib (Bextra©), em abril

de 2005 e o lumiracoxib (Prexige©), em outubro de

2008. Ainda restam o celecoxib (Celebra©) e o etoricoxib

(Arcoxia©), mas vendidos somente com a retenção da

receita médica, de acordo com Resolução nº 79, de 5

de novembro de 2008, da Portaria nº 344/98 da

Agência Nacional de Vigilância Sanitária (Anvisa).

Na Tabela 1, mostra-se a classificação tradicional,

baseada na estrutura química, de alguns anti-inflama-

tórios convencionais de uso corrente.

(7)

O USO DE NEUROLÉPTICOS E

CORTICOIDES

Em 1977, o neurologista italiano Federigo Sicuteri

(1920-2003) foi o primeiro a propor a associação entre

dopamina e migrânea.

(8)

A partir da segunda metade

Headache Medicine, v.2, n.4, p.187-193, Oct/ Nov/Dec. 2011 189

CRONOLOGIA DO TRATAMENTO MEDICAMENTOSO DA CRISE MIGRANOSA

dos anos de 1990, Stephen Peroutka e colaboradores

avaliaram o comportamento dos receptores deste neuro-

transmissor em migranosos.

(9)

Devido ao antagonismo em receptores dopaminér-

gicos, começou-se a estudar os neurolépticos no trata-

mento agudo da migrânea, especialmente a clorpro-

mazina e o haloperidol.

Em 1950, o químico francês Paul Charpentier sinte-

tizou a clorpromazina, uma substância antipsicótica da

classe das fenotiazinas, usada pela primeira vez em 1952

em pacientes esquizofrênicos. Ela atua inibindo os recep-

tores pós-sinápticos dopaminérgicos mesolímbicos no

cérebro e tem como efeito adverso o bloqueio de recep-

tores alfa-1 adrenérgico.

Em 1958, o médico belga Paul Jansen (1926-2003)

sintetizou o haloperidol, um fármaco da classe das butiro-

fenonas que possui potente ação antiemética com fraco

poder sedativo no bloqueio de receptores alfa-adrenér-

gicos. Além do efeito em receptores dopaminérgicos,

também é antagonista de receptores serotoninérgicos.

(10)

Em 1982, Iverson, pela primeira vez, observou a

resposta terapêutica da clorpromazina parenteral no

tratamento da migrânea.

(11)

A partir daí, inúmeros

trabalhos foram realizados utilizando-se a clorpromazina

ou o haloperidol.

(12-15)

Atualmente, o uso de neurolépticos no tratamento

agudo da migrânea vem mostrando resultados anima-

dores.

(16,17)

Em 1999, Bigal et al.

(4)

comprovaram que a

clorpromazina parenteral é tão eficaz quanto a dipirona,

isoladamente ou associada a anti-inflamatórios. No

Brasil, o maior entusiasta no uso de neurolépticos para

tratamento de cefaleia na emergência é o neurologista

Paulo Hélio Monzillo, de São Paulo.

Em 1935, o bioquímico americano Edward Calvin

Kendall (1886-1972) descobriu, isolou e sintetizou

parcialmente a cortisona, a partir do córtex das glân-

dulas suprarrenais. Posteriormente, em 1949, o também

americano Philip Showalter Hench (1896-1965) e seus

colaboradores, da Clínica Mayo, nos EUA, constataram

que esta substância provocava uma melhoria acentuada

190

Headache Medicine, v.2, n.4, p.187-193, Oct/ Nov/Dec. 20

sobre a artrite reumatoide. Mais adiante, comprovaram

que sua ação combatia apenas a inflamação provo-

cada por essa enfermidade. A descoberta foi o ponto

de partida para o desenvolvimento de uma família de

drogas anti-inflamatórias de vasto emprego, os corti-

coides.

Corticoides ou corticosteroides é o nome dado a

um grupo de hormônios esteroides produzidos pelas

glândulas suprarrenais ou de seus derivados sintéticos.

São divididos em duas categorias: glicocorticoides e

mineralocorticoides. Os primeiros, representados pelo

cortisol, controlam o metabolismo dos carboidratos,

gorduras e proteínas e são anti-inflamatórios, enquanto

os segundos, representados pela aldosterona, controlam

os níveis de eletrólitos e água, principalmente por promo-

verem a retenção de sódio no rim.

O uso de dexametasona, via intravenosa, no trata-

mento da cefaleia é conhecido há muito tempo, embora

na literatura médica existam poucos estudos duplo-cegos

e randomizados, o que a torna uma substância de

evidência classe III. Habitualmente, ela é prescrita para

o tratamento do estado migranoso, em associação com

a dipirona.

(17,18)

ERGOTAMINA, O PRIMEIRO MEDICAMENTO

ESPECÍFICO

É importante ressaltar que, na metade do século XVII,

o britânico Thomas Willis (1621-1675) descobriu que a

migrânea tem aspectos hereditários e sofre influência da

alimentação e do meio ambiente, além de ser causada

pela vasodilatação.

(19-21)

A explicação de Willis não curou ninguém, mas

levou à descoberta de substâncias como o ergot, alca-

loide extraído de um fungo que ataca o centeio, deno-

minado de esporão de centeio (Claviceps purpurea). O

uso do ergot foi registrado em 1833 e, mais tarde, no

século XX, daria origem à ergotamina, o primeiro medi-

camento específico para a crise migranosa.

Em 1878 e 1894, Eulenberg, na Alemanha e

Thomson, nos EUA, respectivamente, passaram a usar

extratos fluidos de esporão de centeio no tratamento das

crises de migrânea.

(22)

Em 1918, o químico suíço Arthur Stoll (1887-1971),

durante seus trabalhos nos laboratórios Sandoz, isolou,

pela primeira vez, a partir do ergot, a ergotamina. Em

1925, o também suíço Ernst Rothlin (1988 -1972) utilizou

a ergotamina subcutânea para uma crise de migrânea.

No entanto, somente em 1926 o tartarato de ergotamina

foi utilizado por Maier no tratamento das crises de

migrânea.

(22,23)

Somente em 1938, os neurologistas americanos

Harold George Wolf (1898-1962) e John Ruskin Graham

(1909-1980) publicaram artigo comprovando a ação

do tartarato de ergotamina na contração dos vasos

sanguíneos dilatados durante a crise de migrânea. A partir

daí, iniciou-se, definitivamente, a pesquisa moderna sobre

essa doença.

(22)

Em 1943, Arthur Stoll e outro químico suíço, Albert

Hoffman (1906-2008), obtiveram, pela hidrogenação

parcial do ácido lisérgico, a dihidroergotamina, uma

substância menos tóxica que o tartarato de ergotamina.

(23)

No ano de 1945, a dihidroergotamina foi indicada para

o tratamento das crises de migrânea, pelos neurologistas

americanos Horton (o mesmo que descreveu a cefaleia

de Horton, em 1939), Peters e Blumenthal, da Clínica

Mayo.

A ERA DOS TRIPTANOS

Desde o isolamento da ergotamina, em 1918, e a

síntese da dihidroergotamina, em 1943, não existia outra

droga específica no tratamento da crise migranosa.

Finalmente, em 1972, o farmacologista inglês Patrick

Humphrey (1946) iniciou sua pesquisa no laboratório

Glaxo com a missão de encontrar uma droga agonista

dos receptores serotoninérgicos, com mais especificidade

e menos efeitos adversos do que a ergotamina.

(24)

Em 1980, após alguns insucessos, finalmente ele

sintetizou o composto AH25086, obtido por modificação

da estrutura da serotonina, posteriormente denominado

sumatriptano.

(24)

O sumatriptano, um indol derivado do grupo dos

triptanos, age como agonista dos receptores seroto-

ninérgicos tipo 5-HT1B/1D, que levam à redução da

vasodilatação meníngea, diminuição da liberação de

neuropeptídeos e redução da transmissão sináptica nas

terminações trigeminais.

A eficácia do sumatriptano no tratamento agudo da

migrânea foi comprovada em vários estudos clínicos

duplo-cego, primeiramente, publicados em 1989.

(25)

Contudo, para aumentar mais ainda esta eficácia e evitar

a cefaleia rebote, deve-se associá-lo com algum anti-

inflamatório não esteroide.

(26)

Em 1991, o sumatriptano tornou-se disponível para

uso clínico, inicialmente na Holanda e, finalmente, em

1993, chegou aos EUA e ao Brasil.

(23,24,27)

Posteriormente,

outros triptanos foram desenvolvidos e vendidos, inclusive

SILVA NÉTO RP

Headache Medicine, v.2, n.4, p.187-193, Oct/ Nov/Dec. 2011 191

no Brasil, entre 1998 e 1999, dentre eles, zolmitriptano,

naratriptano e rizatriptano.

(23)

Além desses, existem tripta-

nos que ainda não estão disponíveis no Brasil, como

eletriptano, almotriptano, frovatriptano e avitriptano.

Hoje, não resta nenhuma dúvida que o desenvol-

vimento e o uso dos agonistas de receptores 5HT1B/1D

foi o avanço isolado de maior impacto no tratamento

das crises agudas de migrânea nos últimos 50 anos.

(27)

RECOMENDAÇÕES DA SOCIEDADE

BRASILEIRA DE CEFALEIA

Em 2000, a Sociedade Brasileira de Cefaleia (SBCe)

designou um Comitê Ad Hoc para estabelecer um con-

senso para o tratamento das crises de migrânea, visando

elaborar recomendações para a difusão entre os

profissionais da área médica. Esse Comitê procurou res-

paldo em evidências da literatura médica mundial e na

experiência pessoal dos relatores.

(28)

Nesse consenso, o tratamento a ser utilizado leva

em consideração a eficácia e os efeitos adversos à

terapêutica prévia e as contraindicações, assim como a

intensidade e frequência das crises, a presença de sinto-

mas e sinais associados e o tempo necessário para que

o medicamento atinja a sua eficácia máxima.

(28)

No tratamento das crises de intensidade leve preco-

nizam-se os anti-inflamatórios não esteroides, associ-

ados ou não a antieméticos, enquanto que nas crises

moderadas, além dessas medicações, é também reco-

mendado o uso dos triptanos. Para as crises de forte

intensidade, acrescentam-se os neurolépticos (clorpro-

mazina e haloperidol) e corticoesteroide (dexame-

tasona).

(28)

A associação da medicação analgésica com antie-

méticos pode aumentar a eficácia do primeiro, além de

diminuir a morbidade causada pelas náuseas e vômitos.

(4)

Pelo fato da migrânea possuir vários mecanismos neuro-

transmissoriais, outras combinações de analgésicos são,

rotineiramente, utilizadas para se obterem efeitos adicio-

nais. Comumente, é vista a associação de anti-infla-

matórios não esteroides, analgésicos comuns (não

opiáceos) ou dihidroergotamina com outras drogas,

como a cafeína, mucato de isometepteno, antieméticos,

ou até mesmo relaxantes musculares.

No Brasil, a maioria das unidades de emergência

não dispõe de medicações específicas para a crise migra-

nosa, como os triptanos ou a ergotamina. Na maioria

das vezes, a droga de eleição é a dipirona ou os demais

anti-inflamatórios não esteroides.

(4,29)

Todas as drogas, aqui apresentadas, têm indicação

no principal sintoma da crise migranosa, a cefaleia.

Ocasionalmente, a aura é o único sintoma da crise e,

muitas vezes, sem resposta terapêutica.

Vale ressaltar que, por definição, a aura da migrânea

deve durar menos de uma hora, o que dificulta a compa-

ração do efeito das drogas sobre a mesma, já que há

tendência espontânea ao desaparecimento desse sinto-

ma. No entanto, Bigal et al. verificaram a evolução da

aura em pacientes submetidos a placebo e a três drogas

diferentes: dipirona, clorpromazina e sulfato de magnésio

e concluíram que, após 30 minutos, o sulfato de mag-

nésio foi o mais eficaz.

(30)

Outros tratamentos não farmacológicos, tais como

acupuntura, técnicas de relaxamento, biofeedback e

psicoterapia, além da homeopatia têm sido considerados,

entretanto não há evidências da eficácia destas medi-

das.

Destes, apenas a acupuntura parece exercer algum

efeito benéfico, mas carecendo de mais estudos.

(31)

NOVAS DROGAS PARA A CRISE

MIGRANOSA

Baseado nos mecanismos fisiopatológicos da migrâ-

nea, algumas drogas estão em desenvolvimento (estudos

fase inicial III) e parecem promissoras, como os bloque-

adores dos receptores de CGRP, os inibidores da síntese

de óxido nítrico e os agonistas seletivos dos receptores

5HT1D e 5HT1F.

Bloqueador dos receptores de CGRPBloqueador dos receptores de CGRP

Bloqueador dos receptores de CGRP

O peptídeo relacionado ao gene da calcitonina

(CGRP), neuropeptídeo liberado de neurônios sensitivos

do nervo trigêmeo, é um potente vasodilatador. O seu

papel na fisiopatologia da migrânea foi sugerido em

1990, quando se observou um aumento de CGRP em

amostra de sangue da veia jugular durante ataques de

cefaleia. Também foi demonstrado que a sua infusão

pode induzir uma crise migranosa.

(32)

A partir desse conhecimento, a procura por um

antagonista de receptores de CGRP tornou-se uma meta

importante para novos tratamentos da migrânea. Em

2004, o médico pesquisador Tony W. Ho, diretor sênior

de neurociências do Laboratório de Pesquisa Merck, na

Pensilvânia, desenvolveu o olcagepant, mas tinha que

ser administrado por via intravenosa. Posteriormente,

foram realizados estudos com a administração oral

telcagepant.

(33)

CRONOLOGIA DO TRATAMENTO MEDICAMENTOSO DA CRISE MIGRANOSA

192

Headache Medicine, v.2, n.4, p.187-193, Oct/ Nov/Dec. 20

O telcagepant, também conhecido como MK-0974,

é um antagonista, ou seja, bloqueador dos receptores

de CGRP e, após a síntese dos triptanos, ele é o primeiro

medicamento desenvolvido, primariamente, para o trata-

mento da crise migranosa.

(32)

Em estudos clínicos, foi

demonstrado que a sua eficácia antimigranosa é similar

à dos triptanos, mas com a vantagem de não estar asso-

ciado aos efeitos adversos cardiovasculares que, em raros

casos, os triptanos podem gerar.

(34)

Ainda não está

disponível no Brasil.

Inibidores da síntese de óxido nítricoInibidores da síntese de óxido nítrico

Inibidores da síntese de óxido nítrico

O óxido nítrico (NO), também conhecido por monó-

xido de nitrogênio e monóxido de azoto, é um mensa-

geiro molecular envolvido em várias funções biológicas,

incluindo a neurotransmissão. Ele é sintetizado pelas célu-

las endoteliais, macrófagos e certo grupo de neurônios

do cérebro.

É bem conhecida a sua participação na fisiopato-

logia da migrânea, onde o uso de inibidores de NO

pode abortar uma crise migranosa. Por outro lado, a

administração intravenosa de nitratos pode desencadear

cefaleia, mas com mais frequência em pacientes com

migrânea.

(32)

Apesar do importante papel do NO na migrânea,

surpreendentemente, poucas pesquisas terapêuticas têm

sido realizadas. Contudo, é digno de nota o estudo

duplo-cego feito por Lassen et al. (1998), onde um grupo

de 15 pacientes recebeu infusão de um inibidor da sinte-

tase de óxido nítrico (resposta de 67%), em comparação

com um grupo semelhante que recebeu placebo (resposta

de 14%).

(35)

Agonistas seletivos dos receptores 5HT1D eAgonistas seletivos dos receptores 5HT1D e

Agonistas seletivos dos receptores 5HT1D e

5HT1F5HT1F

5HT1F

Sabe-se que os triptanos, ao agirem em receptores

serotoninérgicos 5-HT1B e 5-HT1D, causam, respectiva-

mente, vasoconstricção e redução da inflamação neuro-

gênica.

Recentemente, os receptores 5HT1D e 5HT1F foram

testados em pacientes com migrânea, através de ensaios

randomizados, controlados e duplo-cegos. O agonista

seletivo do receptor 5-HT1D, PNU-142633, impede o

extravasamento de plasma induzido pela estimulação do

gânglio trigeminal. Por outro lado, o agonista seletivo

do receptor 5-HT1F, LY334370, bloqueia a inflamação

neurogênica ou a informação nociceptiva no núcleo

caudal do trigêmeo. Na dose testada, este útimo parece

não ter efeito vasoconstrictor e pode, portanto, ser usado

com segurança em pacientes com doenças vasculares.

(39)

CONCLUSÃO

Para o tratamento da crise migranosa, é necessário

um maior esforço para o desenvolvimento de novos

medicamentos e melhoria dos já existentes, para que se

possa reduzir, substancialmente, o grande impacto

negativo que a migrânea causa na sociedade, como o

absenteísmo e a perda de produtividade.

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Correspondência

aimundo Paimundo P

aimundo P

ereira da Silva Néto, MDereira da Silva Néto, MD

ereira da Silva Néto, MD

Centro de Neurologia e Cefaleia do Piauí

Rua São Pedro, 2071 – Centro

Ed. Raimundo Martins, Salas 303/304

64001-260 – Teresina, PI, Brasil

Tel./fax: + 55 86 3221.9000

neurocefaleia@terra.com.br

CRONOLOGIA DO TRATAMENTO MEDICAMENTOSO DA CRISE MIGRANOSA

Received: 8/28/2011

Accepted: 11/2/2011

194 Headache Medicine, v.2, n.4, p.194-199, Oct/ Nov/Dec. 2011

Hospital management of intractable headaches.

The Instituto de Neurologia de Curitiba approach

Manejo hospitalar das dores de cabeça intratáveis. Abordagem do

Instituto de Neurologia de Curitiba

ABSTRACTABSTRACT

ABSTRACT

Intractable headaches, also called refractory headaches, are

usually unresponsive to standard therapies and comprise

clinical conditions that represent a clinical management

problem regarding therapy. Thereby, many approaches to

manage "intractable headaches" have been proposed;

meanwhile many aspects remain unclear and open to debate.

Accordingly, these patients often require special care and

customized management, such as inpatient treatment.

Hospitalization aims to enhance management of the patients

as a whole and thus improve their quality of life. This paper

summarizes the Instituto de Neurologia de Curitiba (INC)

approach, which comprises withdrawal of the overused

medication, management of abstinence symptoms,

management of rebound headache, introduction of effective

prophylactic therapy, general counseling and education of

the patient, and other aspects of management. The inpatient

approach used at the INC is presented and a small sample of

patients treated according to this approach is described and

discussed.

Keywords:Keywords:

Keywords: Intractable headaches; Refractory headaches;

Inpatient treatment.

ORIGINAL ARTICLEORIGINAL ARTICLE

ORIGINAL ARTICLE

RESUMORESUMO

RESUMO

As dores de cabeça intratáveis, também chamadas de

"cefaleias refratárias", geralmente não respondem aos trata-

mentos habituais e compreendem diversas clínicas as quais

representam um problema de manejo terapêutico. Muitos

esquemas para abordar as "dores de cabeça intratáveis" têm

sido propostos, porém diversos aspectos referentes ao seu

manejo permanecem obscuros e abertos ao debate. Frequen-

temente, estes pacientes necessitam de cuidados especiais e

personalizados de tratamento, tais como o manejo hospitalar.

A hospitalização visa propiciar o manejo destes pacientes de

uma forma abrangente, e, assim, melhorar sua qualidade de

vida. Este artigo resume a abordagem do Instituto de Neuro-

logia de Curitiba (INC), a qual compreende a retirada da

medicação em demasia, o manejo de sintomas de abstinência,

o tratamento da dor de cabeça rebote, a introdução de terapia

profilática eficaz, o aconselhamento geral e a educação do

paciente, assim como outros aspectos envolvidos. A abor-

dagem de internação usada no INC é apresentada e uma

pequena casuística de pacientes tratados de acordo com esta

abordagem é descrita e discutida.

alavrasalavras

alavras

chave:chave:

chave: Dores de cabeça intratáveis; Dores de

cabeça refratárias; Tratamento hospitalar.

Rowe A, Iachinski R, Rizelio V, Sato HK, Nascimento MT, Souza RK, Kowacs PA

Hospital management of intractable headaches. The Instituto de Neurologia de Curitiba approach.

Headache Medicine. 2011;2(4):194-9

Adriel Rowe

, Renato Iachinski

, Vanessa Rizelio

, Henry Koiti Sato

, Maria Tereza de Moraes Souza Nascimento

Ricardo Krause Martinez de Souza

, Pedro André Kowacs

Fundação Universidade Regional de Blumenau, PR

Serviço de Neurologia do Instituto de Neurologia de Curitiba, PR

Headache Medicine, v.2, n.4, p.194-199, Oct/ Nov/Dec. 2011 195

INTRODUCTION

Intractable headaches

(1-3)

(also called "refractory

headaches") represent a clinical management problem

regarding therapy. The problem stems from its definition:

previous treatments in adequate doses have failed to control

the symptoms. Table 1 summarizes a proposed classification

for refractoriness of a headache to prophylactic therapy.

Most patients presenting "intractable headaches" have

probable chronic migraine and probable headache

secondary to the overuse of excessive symptomatic

medication. There are several approaches to managing

"intractable headaches", some of them not tested with

adequate methods. In this paper, the inpatient approach

used at the Instituto de Neurologia de Curitiba (INC) for

treating chronic headaches intractable to prophylactic

therapy is presented and a small sample of patients treated

according to this approach is described and discussed.

TRANSITIONAL THERAPY

Withdrawal of the medication overusedWithdrawal of the medication overused

Withdrawal of the medication overused

Medication previously overused is withdrawn

abruptly

(4-7)

and is never administered again during

hospitalization.

Management of the abstinence symptomsManagement of the abstinence symptoms

Management of the abstinence symptoms

Abstinence symptoms are managed accordingly to

their occurrence. Nausea is managed either with

metoclopramide or with bromopride. Previously to their

prescription, the staff performs a detailed anamnesis

directed towards detecting previous adverse events to

these compounds such as somnolence, akathisia and/

or other extrapyramidal reactions.

(8)

If some of these

symptoms are detected, preference is given for

domperidone, trimebutine, ondasentron or similar

drugs.

(9)

Insomnia is usually managed with a

benzodiazepine such as midazolam. Anxiety might be

treated with other benzodiazepines such as alprazolam,

cloxazolam, and bromazepam. Risperidone or

quetiapine might be prescribed instead, in case of

extreme anxiety or in case bipolar disorder is associated

or suspected.

(10,11)

A sensitive point is hydration.

(4)

It is

important to remind that these patients may present with

vomiting, become drowsy and lessen their water intake.

In this setting, if drugs that may lead to hypotension such

as chlorpromazine are needed, vigorous hydration with

saline is desired, unless in the case of a clear

contraindication such as heart failure or uncontrolled

hypertension.

Management of rebound headacheManagement of rebound headache

Management of rebound headache

Although rebound headache is considered to be an

abstinence symptom, it will be considered separately due

to its complexity. The first step used in the INC is to place

the patient on an intravenous NSAID, usually ketoprofen

100 mg t.i.d.

(12)

– an approach avoided if the overused

medication was ketoprofen or another NSAID. Besides

ketoprofen, intravenous chlorpromazine is given,

(4,13)

except for patients bearing a low systolic blood pressure

or bringing a history of intolerance to chlorpromazine or

to other dopamine receptor antagonist. Chlorpromazine

may be given at doses ranging from 0.2 mg/kg up to

0.7 mg/kg.

(13)

Although some authors advocate it to be

given in bolus, we prefer to dilute it in 100 ml of saline

THE INC APPROACH

The INC approach combines several lines of therapy,

to know: a) withdrawal of the overused medication, b)

management of the abstinence symptoms, c) management

of rebound headache, d) introduction of effective

prophylactic therapy, e) general counseling and education

of the patient, d) other aspects of management. All these

aspects of management are not new and will be discussed

below. Although the items a, b and c are usually coined

as "bridge therapy", we prefer the expression "transitional

therapy", akin to its use for the treatment of cluster

headache.

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196

Headache Medicine, v.2, n.4, p.19

4-199, Oct/ Nov/Dec. 2011

ROWE A, IACHINSKI R, RIZELIO V, SATO HK, NASCIMENTO MT, SOUZA RK, ET AL

and infuse it in about 30-60 minutes. We start with a fixed

dose of 25 mg + 100 ml of saline, stopping infusion

whenever headache is controlled. The dose is gradually

increased if this does not happen. It is important to

remember that adverse effects like nasal congestion, mild

akathisia and severe hypotension may occur.

(13)

While

nasal congestion and mild akathisia may be cumbersome,

orthostatic hypotension may be severe, thus both the nursing

staff and the patient must be warned that he should avoid

standing and walking unattended. As reported by Monzillo

et al., haloperidol may be given as well.

(14)

Metamizole

(dipyrone) is not used frequently at the INC emergency

room, but 1 gram intravenously is reported to be

effective.

(15)

Metamizole potential to cause hypotension

must be also kept in mind, and respective care should be

taken. Until the year of 2010 we used intravenous

dihydroergotamine (DHE),

(4)

except for those patients

overusing ergots or with cardiovascular disorders or risk

factors. About 30 minutes prior to the administration of

DHE, we used to prescribe an intravenous antiemetic. DHE

was given in the dose of 0.5 mg diluted in 50 ml of isotonic

saline, given in 30 minutes or until the resolution of pain.

Unfortunately, the lack of registration on the local

regulatory board (ANVISA) halted the administration of

DHE. Resort to the use of propofol is our last therapeutic

frontier.

(16)

Propofol is quite easy to administer, but great

attention must be paid in case of previous administration

of chlorpromazine or another sedating drug. Before starting

propofol infusion, even the most experienced physician

should take care to have the resuscitating material close

by.

(16)

Administration should start with a bolus injection of

3 mg, followed by sequential injections of 2 mg, always

letting the patient to regain consciousness before the

administration of the next dose. If there is any improvement,

doses are given repeatedly up to a total dose of 300 mg.

However, if the patient headache fails to improve in the first

three doses, the procedure is stopped.

(16)

Several trials have

failed to show steroids as an effective transitional therapy

or in solving rebound headache.

(6,17)

However, in selected

cases especially those in which other approaches have

failed, the administration of steroids should be considered

as an option.

(5,6)

Responders must be warned about the

dangers of prolonged use of steroids, since steroid

dependence may occur.

Introduction of effective prophylactic therapyIntroduction of effective prophylactic therapy

Introduction of effective prophylactic therapy

Patients that seek for hospital management of their

chronic and refractory headaches usually have been

submitted previously to several prophylactic therapies.

That is why a detailed past medication history is a key

point in choosing the prophylactic drug to be introduced.

Not only the kind of medication previously used, but also

its dosage, efficacy and tolerability must be surveyed to

draw a clear picture of the patient's background. The

prophylactic drug usually introduced is methysergide, a

drug with a strong effect on 5HT2A, 5HT2B and 5HT2C

receptors.

(18)

Methysergide has a clear-cut advantage of

an early prophylactic effect, and has also been strongly

recommended in the literature for the treatment of resistant

cases of migraine with a high attack frequency.

(18)

But it

is never enough to remind that, as methysergide has some

vasoconstrictive effect, the prescriber must exert great

caution – or even avoid – recommending other vaso-

constrictive drugs such as ergotics or triptans. Another

key point is that methysergide prescription should follow

the rule "start low, go slow", usually beginning at 1 mg

at bedtime and increasing the dose at 1 mg a day until

1 mg tid or 2 mg bid. Among other traditional migraine

prophylactic drugs, one most formally tested for chronic

migraine is topiramate. However, topiramate prophylactic

effect may take longer to ensue.

(5,19,20)

Valproate is

another useful prophylactic drug, especially for patients

with concomitant bipolar disorder, in whom the daily

dose must be raised above the usual 1 g/day.

(21)

As beta-

blockers, amitriptyline is a useful migraine prophylactic

drug

(22)

and was also shown to be effective for chronic

tension-type headache.

(23)

Patients responding to

intravenous chlorpromazine may be switched to oral

chlorpromazine. Chlorpromazine may be useful in

anxious patients, in those presenting with manic

symptoms or with a family history of psychiatric

disorders.

(13)

Most chronic headache patients have used

several prophylactic drugs and associations of them.

Choice of the prophylactics to be introduced during

hospitalization and at the time of hospital discharge

involve several, factors, such as efficacy, tolerability,

previous response, and the combination of different

mechanisms of action.

(24)

General counseling and education of the patientGeneral counseling and education of the patient

General counseling and education of the patient

Further than just giving medicines to the refractory

headache patient, the hospitalization is an excellent

opportunity for counseling the patient against medication

overuse behavior and to detect and treat anticipatory

anxiety.

(25)

Patients are advised for aerobic physical

activity.

(25-27)

Patients are also advised to promote changes

Headache Medicine, v.2, n.4, p.194-199, Oct/ Nov/Dec. 2011 197

in their lifestyle, if deemed necessary, and taught to have

realistic expectations regarding their headache control,

which may not be absolute.

Other aspects of managementOther aspects of management

Other aspects of management

Other therapeutic approaches can be undertaken

according to the patients needs. Rheumatologic,

psychiatric or psychological consultations are asked for

when needed.

(25,28)

If deemed appropriate, biofeedback

sessions are prescribed.

(25,29,30)

SERIES PRESENTATION

We retrospectively gathered data from the INC

hospital files dated from 2006 to 2007. Nineteen records

were retrieved. Of these, 18 were female and one male.

Fifteen suffered from chronic migraine or probable chronic

migraine – since associated medication-overuse headache

was not ruled out –, one from post craniotomy headache

and one from sustained hydrocephalus-related headache.

Most patients had associated probable medication-

overuse headache and all had a class II or a class III

intractability to prophylactic therapy.

(3,31)

Regarding

comorbidities and associated conditions, one suffered from

somatoform disorder, two from major depression, four

from bipolar mood disorder and two from generalized

anxiety, as diagnosed either by the consulting psychiatrist

or by the neurologist in charge based in the DSM-IV

criteria. Most of the patients were using multiple

prophylactic drugs. As an example, 17 of the patients

were using two or more preventive drugs. Intravenous

dihydroergotamine was given for 17 of the 19 patients,

usually in a tid. dose regimen or as needed, for periods

ranging from one to 12 days. Thirteen of the patients

responded completely to dihydroergotamine, one had a

partial response and three did not respond at all. Four

patients needed intravenous propofol, and all of them

were responders. Methysergide was given for eight of the

19 patients.

HOSPITAL MANAGEMENT OF INTRACTABLE HEADACHES. THE INSTITUTO DE NEUROLOGIA DE CURITIBA APPROACH

198

Headache Medicine, v.2, n.4, p.194-199, Oct/ Nov/Dec. 2011

ROWE A, IACHINSKI R, RIZELIO V, SATO HK, NASCIMENTO MT, SOUZA RK, ET AL

DISCUSSION

Hospitalization aims to control or to reduce the

intractable headache, to restore functionality to the patients

by reducing the incapacity, and to treat the associated

comorbidities, thus improving the patients' quality of life.

While abrupt withdrawal of the medication overused is

perhaps the greater unanimity in the management of

refractory chronic headaches associated with medication

overuse, all the other aspects are open to challenge and

debate. Aspects regarding management of analgesics

abstinence symptoms and rebound headache, transitional

(bridge) therapy, timing and type of prophylaxis are all

less clear and amenable to be challenged.

(32)

The

aggressive analgesic/antimigraine approach that we have

described probably would not be enough without the

concomitant changes in prophylactic therapy. Even the

issue of hospitalization is not a consensus.

(25)

Although it is

still possible in Brazil, in many countries it has been

substituted by day-hospital approaches, because of lack

of acceptance by the insurers. From the scientific

standpoint, hospitalization is not associated with better

outcomes in the management of chronic headaches

regarding withdrawal of the overused drug or adherence

to prophylactic therapy.

(32)

As advantages we list a better

monitoring of the drug withdrawal at its first days, earlier

rescue therapy for rebound headache and optimal facilities

for continuous medication and/or procedures needing to

be monitored.

(32)

Besides, taking the patient away from its

environment is an excellent opportunity for reviewing all

the aspects exposed above, and it allows a comprehensive

approach. Since patients to be hospitalized usually belong

to a more complex group of patients, they frequently have

associated fibromyalgia, psychiatric symptoms and/or

sleep disorders.

(25)

As posed before, psychiatric

consultation, or rheumatologic consultation as well, may

enhance patient care as a whole. Saper et al

(28)

and Freitag

et al

(25)

also share this view in favor of using hospitalization

to treat these patients. As there are no rules that fit all

patients, each patient must be individually evaluated and

his/her physician must weight the decision about how and

where to treat him/her. Although the series presented in

this paper is merely illustrative and did not aimed to justify

the approach, it gives an idea of the profile of the patients

that were submitted to this approach at our neurology

service. Based in the arguments above-mentioned, the

INC staff feels quite well acquainted in using the inpatient

approach for treating complex chronic headache and/or

intractable headache patients. However, unexpected

pitfalls may impair the INC's approach such as the recent

repetitive shortages on the supply of methysergide and

the comments about the supplier's discontinuation of the

sale of this prophylactic medication.

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Rua Jeremias Maciel Perretto, 300

81210-310 – Curitiba, PR, Brazil

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Received: 9/ 8/ 2011

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Prevalence of headaches in individuals referred

from primary care to secondary care

Prevalência de cefaleia em indivíduos encaminhados da atenção

primária para a secundária

ABSTRACTABSTRACT

ABSTRACT

Background:Background:

Background: Improve the quality of public health is a growing

necessity today. Identifying reasons for medical referral (from

general to specialized care) is a prelude for developing

educational initiatives that have this goal.

Objective:Objective:

Objective: To

estimate the prevalence of headaches as a cause of referral

from the primary to the secondary level of public medical care.

Methods: Methods:

Methods: First-time referrals from four primary care units to

neurology care were assessed.

Results:Results:

Results: Sample consisted of

587 individuals referred to neurology consultation. Headache

was the cause of referral in 31.2% of the individuals; 79.2%

of the headache cases were in women. Rates for other diseases

were lower and are presented for benchmarking.

Conclusion:Conclusion:

Conclusion:

Headache represented an important cause of demand for

neurological care. Education initiatives on principles of

headache management are necessary and may translate into

decreased referral rates to neurologists.

Keywords: Keywords:

Keywords: Headache; Primary health care; Secondary health

care

RESUMORESUMO

RESUMO

Introdução:Introdução:

Introdução: Melhorar a qualidade da saúde pública é uma

necessidade crescente nos dias atuais. Identificar os motivos

de encaminhamento médico (da atenção generalista para a

especializada) é um prelúdio para o desenvolvimento de ini-

ciativas educacionais que tenham este objetivo.

Objetivo:Objetivo:

Objetivo:

Estimar a prevalência de cefaleias como causa de encami-

nhamento do nível primário para o secundário, de assistên-

cia médica, na saúde pública.

Métodos:Métodos:

Métodos: Num primeiro mo-

ORIGINAL ARTICLEORIGINAL ARTICLE

ORIGINAL ARTICLE

Joismar Manuel Rodrigues

, Vanessa Vilela Caires

, Kátia Beatriz Costa Fontoura

Teresa Cristina Santos Silva

, Simone Fonseca Goulart

, Cláudia Marcucci Rocha

, Antônio Lúcio Teixeira

Ariovaldo Alberto da Silva Junior

Universidade José do Rosário Vellano – Unifenas, Belo Horizonte, MG, Brazil

Faculdade de Ciências Médicas, Belo Horizonte, MG, Brazil

Rodrigues JM, Caires VV, Fontoura KB, Silva TC, Goulart SF, Rocha CM, Teixeira AL, Silva Junior AA

Prevalence of headaches in individuals referred from primary care to

secondary care. Headache Medicine. 2011;2(4):200-3

mento, os encaminhamentos de quatro unidades de atenção

primária para a atenção neurológica foram avaliados.

Re-Re-

Re-

sultados:sultados:

sultados: A amostra consistiu em 587 indivíduos referen-

ciados para consulta em neurologia. Cefaleia respondeu por

31,2%; 79,2% dos casos de cefaleia foram em mulheres. As

porcentagens de outros motivos de atendimento foram mais

baixas e são apresentadas para comparação.

Conclusão:Conclusão:

Conclusão:

Iniciativas educacionais voltadas para o manejo das cefaleias

são necessárias e podem resultar na diminuição das taxas de

encaminhamento para neurologistas.

alavrasalavras

alavras

chave:chave:

chave: Dor; Cefaleia; Ocitocina; Síndrome do

túnel do carpo

INTRODUCTION

The Brazilian Public Health System (PHS) provides

universal medical access to the population. It is structured

in three levels of care. The primary care consists of basic

health units (BHUs), being the typical "entry door" into the

system.

(1)

It accounts for the preventive care, as well as for

treatment (by family physicians or general practitioners).

An important component of the primary care in the PHS is

the family heath program (FHP), which mainly focuses on

preventive and educational health strategies. A recent study

demonstrated that 85% of the families seeking medical

care in the PHS do it so trough the FHP,

(2)

which is largely

Headache Medicine, v.2, n.4, p.200-203, Oct/ Nov/Dec. 2011 201

responsible for referrals to the secondary level of care.

The secondary care consists of specialty clinics, and patients

are to be referred by the primary care doctors into this

level.

(2)

The tertiary care consists of subspecialty and high

complexity hospitals. It has been suggested that a

considerable proportion of referrals to the secondary

neurological care is due to headaches.

(3)

The Brazilian PHS follows the structural

recommendations of the World Health Organization

(WHO) to the BRIC countries (Brazil, Russia India and

China).

(4,5)

The system seems to be effective in providing

primary care,

(6)

and important successes are reported in

the control of diabetes and hypertension.

(7,8)

Nonetheless,

headaches have not deserved specific recommendations

from a public health perspective.

(9)

As a consequence,

unnecessary referrals to the secondary care may exist.

(10-

12)

The problem is further amplified by the recognized

difficulties in establishing a headache diagnosis at the

primary care level.

(13,14)

In the present study was assessed the prevalence of

headaches among patients referred from the primary care

system to a secondary neurology program.

METHODS

This study was conducted at subdistrict north of Belo

Horizonte, the capital of Minas Gerais state, Brazil.

Through the FHP, this subdistrict attends 193,764

inhabitants. It is structured into 19 primary care centers

and one secondary unit as main referral.

Patients should first be attended by general

practitioners. Patients in need of neurological care are

referred to secondary care units. Accordingly, in this study

we assessed reasons for referral from four primary care

units that can only refer patients to a secondary care

center.

The study was conducted from January of 2007 to

September of 2009. For referred patients we collected

demographic variables (gender, age) and reasons for

referral as follows: headache, epilepsy, fainting,

Alzheimer's disease, dementia or other memory problems,

Parkinson's disease and tremors, strokes, and other cau-

ses. We restricted our analyses to adults (17 or older).

Extracted data were entered into Epiinfo (version

3.5.1) and description of results was performed.

The study was approved by the Ethics Committee of

the University of José do Rosário Vellano (CEP/Unifenas)

and the Ethics Committee on Public Health Research, Belo

Horizonte (CEP/SMSA/BH).

RESULTS

Of 587 referrals, 183 were secondary to headaches.

Accordingly, headaches responded by 31.2% of the

referrals. Of headache patients, 79.2% were women with

a mean age of 40 years (SD= 2).

Other causes of referrals are described in Table 1.

The second most common cause of referral was epilepsy

and related syndromes (14.9%) followed by fainting (5.6%)

and Alzheimer's disease and memory problems (5.3%).

With regard to median age stratified by category the

average age was 38.5 years in epilepsy followed by 53

years for fainting and 72 years for Parkinson's disease.

This information can be seen in Table 2.

PREVALENCE OF HEADACHES IN INDIVIDUALS REFERRED FROM PRIMARY CARE TO SECONDARY CARE

202

Headache Medicine, v.2, n.4, p.200-203, Oct/ Nov/Dec. 2011

RODRIGUES JM, CAIRES VV, FONTOURA KB, SILVA TC, GOULART SF, ROCHA CM, ET AL

DISCUSSION

Headache was the main cause of referrals for

neurological care. With regard to age, headache and

epilepsy were the most frequent among young adults and

Alzheimer's disease and Parkinson's disease affected more

the elderly.

These results come at little surprise, since findings are

supported by the literature which suggests that headache

responds for around one third of referrals to neurological

care.

(3)

The relative frequency of referrals due to headaches

is particularly expressive when contrasted to other reasons.

For instance, epilepsy responded to less than half of the

headache referrals. Parkinson's disease responded by only

3.7%.

The expressive frequency of referrals due to

headaches has several potential explanations. First, the

prevalence of headaches in the population is far higher

than the prevalence of other neurological disorders.

However, since headaches are diagnosed based on

clinical grounds and are benign in most cases, this fact

alone unlikely explains the high proportion of referrals.

According to Galdino et al.,

(14)

the lack of dissemination

of diagnostic criteria for headaches among primary care

doctors is associated with reduced comfort in assigning

headache diagnoses and may explain the referrals.

(15)

Indeed, according to Vincent and Carvalho,

(16)

only

44.9% of the migraine cases seen by primary care doctor

in Brazil received a proper diagnosis.

Our study has clear limitations. The most important is

the lack of specific headache diagnoses, since we relied

on information obtained from the referral letters. Second,

our data may not be generalizable to other regions. We

aim to repeat this study after these educational initiatives

are conducted, in order to test the hypothesis that referral

rates will be reduced.

Accordingly, we demonstrated that high proportion

referrals to neurological cares are due to headaches in

the PHS. This may reflects the high prevalence of

headaches in the population, but also the ineffectiveness

of the primary care system in dealing with headaches.

Educational initiatives are to be created and tested in order

to change this paradigm.

REFERENCES

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os modelos de assistência à saúde no âmbito da reforma sa-

nitária brasileira. Revista Médica de Minas Gerais. 2003;

13(4):251-9.

2. Giovanella L, de Mendonça MH, de Almeida PF, Escorel S, Senna

M de C, Fausto MC, et al. Family health: limits and possibilities

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Portuguese]

3. Ferri-de Barros JE, Nitrini R. [Which patients does the neurologist

assist? Basis for a curriculum in neurology]. Arq Neuropsiquiatr.

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4. Steiner TJ. Lifting the burden: The global campaign to reduce

the burden of headache worldwide. J Headache Pain.

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5. Martelletti P, Haimanot RT, Láinez MJ, Rapoport AM, Ravishankar

K, Sakai F, et al. The Global Campaign (GC) to Reduce the

Burden of Headache Worldwide. The International Team for

Specialist Education (ITSE). J Headache Pain. 2005;6(4):261-3.

6. Escorel S, Giovanella L, Magalhães de Mendonça MH, de Castro

Maia Senna M. The Family Health Program and the construction

of a new model for primary care in Brazil. Rev Panam Salud

Publica. 2007;21(2-3):164-76. [Article in Portuguese].

7. de Paiva DC, Bersusa AA, Escuder MM. Healthcare assessment

for patients with diabetes and/or hypertension under the Family

Health Program in Francisco Morato, São Paulo, Brazil. Cad

Saude Publica. 2006;22(2):377-85.

8. Carvalho BG, Souza RKT, Soares DA, Yagi MCN. Diseases of the

circulatory system before and after the Family Health Program,

Londrina, Paraná. Arq Bras Cardiol. 2009;93(6):597-601, 645-

50. [Article in English, Portuguese].

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Correspondence

Ariovaldo Alberto da Silva JuniorAriovaldo Alberto da Silva Junior

Ariovaldo Alberto da Silva Junior

, MD, MD

, MD

Rua Bernardo Guimarães, 2154, apto. 501 – Lourdes

Belo Horizonte, MG., Brazil

juniorariovaldo@uol.com.br

9. Junior AS, Krymchantowski A, Moreira P, Vasconcelos L, Gomez

R, Teixeira A. Prevalence of headache in the entire population of

a small city in Brazil. Headache. 2009;49(6):895-9

10. Kowacs PA, Twardowschy CA, Piovesan EJ, Dal-Prá Ducci R,

Cirino RH, Hamdar F, et al. General practice physician knowledge

about headache: evaluation of the municipal continual medical

education program. Arq Neuropsiquiatr. 2009;67(3A):595-9.

11. Bigal ME, Bordini CA, Speciali JG. Etiology and distribution of

headaches in two Brazilian primary care units. Headache. 2000;

40(3):241-7.

12. Bigal ME, Bigal JO, Bordini CA, Speciali JG. Prevalence and

costs of headaches for the public health system in a town in the

interior of the state of São Paulo. Arq Neuropsiquiatr. 2001;

59(3A): 504-11.

13. Gantenbein AR, Sándor PS. Physiological parameters as

biomarkers of migraine. Headache. 2006;46(7):1069-74.

14. Galdino GS, Paz e Albuquerque TI, Medeiros JLA. Primary

headaches: a diagnostic approach by non-neurologist doctors.

Arq Neuropsiquiatr. 2007;65(3A):681-4. [Article in Portuguese].

15. Khu JV, Siow HC, HO KH. Headache diagnosis, management

and morbidity in the Singapore primary care setting: findings

from a general practice survey. Singapore Med J. 2008;49

(10):774-9.

16. Vincent MB, Carvalho JJ. Primary headache care delivery by

nonspecialists in Brazil. Brazilian Headache Care Cooperative

Group. Cephalalgia. 1999;19(5):520-4.

Received: 1/30/2011

Accepted: 11/25/2011

PREVALENCE OF HEADACHES IN INDIVIDUALS REFERRED FROM PRIMARY CARE TO SECONDARY CARE

204

eadache Medicine, v.2, n.4, p.204-208, Oct/ Nov/Dec. 2011

Síndrome musculoarticular superior

Superior articular muscle syndrome

RESUMORESUMO

RESUMO

Uma alta porcentagem de pessoas de todas as idades sofre

de tonturas, dores de cabeça e sintomatologias na região

cervical, cintura escapular, braços e mãos. A medicina diag-

nostica esses sintomas como doenças crônicas e se limita a

combater a sintomatologia com analgésicos, anti-inflamatórios

e relaxantes musculares, que o paciente passa a consumir

regularmente durante anos. Interpretamos que todas essas

regiões pertencem a um mesmo sistema, que chamamos de

musculoarticular superior (MAS). A mandíbula é o centro

fisiológico do mesmo. Assim o certificam as funções nas quais

participa (fonação, deglutição e mastigação), a amplitude

de movimentos que realiza, e a grande quantidade de mús-

culos que nela se inserem. As posições excêntricas tanto para

as funções como em repouso modificam a sincronização do

sistema, determinando a aparição de sintomatologia em uma

ou várias regiões que compõem o sistema. Este conjunto de

sintomas associados a uma mesma causa caracteriza a

síndrome. As conclusões do trabalho clínico aqui apresentado

mostram os sintomas relacionados e as porcentagens de

prevalência dos mesmos.

alavrasalavras

alavras

chave:chave:

chave: Mandíbula; Dor; Cefaleia

ABSTRACTABSTRACT

ABSTRACT

A high percentage of people of every age sufer, sickness,

headache and symptomatology in the neck, waist, arms and

hands. The Medical Institution diagnoses these symptoms as

chronic sickness, and it limits to fight the symptomatology

with analgesic, anti-inflamatorys and muscular relaxings who

the patient consume-regularly during years. We interpret of

all these regions belong to a same system, that we call Upper

Articulated Muscle (UAM ). Jaw is the phisiological centre of

itself. This certify the functions which take part phonation,

swallowing and mastication, the movement that it executes,

and a large number of muscles which inserts in it. The eccentric

positions in the functions and in the rest modify the

sincronization´s system determining the symptomatology

ORIGINAL ARTICLEORIGINAL ARTICLE

ORIGINAL ARTICLE

Miguel Angel Siderman

Cirurgião dentista. RS, Brasil

Siderman MA. Síndrome musculoarticular superior. Headache Medicine. 2011;2(4):204-8

INTRODUCTION

A relação entre distúrbios têmporo-mandibulares e

distúrbios da região cervical tem sido motivo de nume-

rosos trabalhos de investigação. Alguns citam a co-

existência,

(1-5)

outros mostram como disfunções na região

cervical podem desencadear dores na região da cabe-

ça,

(6-13)

as contraturas suboccipitais podem ser acom-

panhadas de dores irradiadas em direção à região

frontal e lateral da cabeça,

(14-18)

e, por último, encon-

tramos autores que relatam que pacientes portadores

de distúrbios têmporo-mandibulares (DTM) se queixa-

vam de dor no pescoço.

(4,5,8,19)

Embora esses estudos mostrem evidências de que

os distúrbios DTM e os distúrbios cervicais se apresentem

associados, não concluem definindo as causas ou meca-

nismos que os provocam.

Na prática é possível identificar uma alta porcen-

tagem de pacientes afetados por dores de cabeça e

sintomatologia cervical, que consultam diferentes tipos

de especialistas na busca de soluções que não aparecem,

condenados a conviver com diagnósticos de supostas

doenças crônicas (enxaquecas, bico de papagaio,

hérnias), e a ingerir medicamentos permanentemente, na

busca do alívio à dor.

appearance in one or several regions which compose the

system. All these associated symptoms in a same cause

characterize the syndrome.The conclusion of this clinical job

here presented show the related symptons and the percentages

of protrude of themselves.

eywords: eywords:

eywords: Jaw; Pain; Headache

Headache Medicine, v.2, n.4, p.204-208, Oct/ Nov/Dec. 2011 205

As publicações que tratam do tema mencionam a

existência de um sistema crânio-cérvico-facial (cabeça e

pescoço), o que consideramos um erro. Analisando a

região encontramos músculos importantes que têm

inserção em: escápula, esterno, clavícula e costelas, isso

significa que devemos incorporar a cintura escapular ao

sistema.

Do ponto de vista neurológico, se analisamos a

inervação que transita pela coluna cervical e as regiões

que são inervadas podemos incluir também os membros

superiores ao sistema (Figura1).

O homem moderno, por diversos motivos, costuma

apresentar hipofunção (não desenvolve os maxilares,

dando como consequência apinhamento dental), fluo-

ração das águas, uso de restaurações metálicas e de

porcelana, não conta com o elemento fusível, achando

interferências que levam a mandíbula a posições excên-

tricas, geralmente em direção à frente e a um lado, obri-

gando a musculatura de todo o sistema a compensar

essa situação.

A musculatura cervical posterior, que se encarrega

do equilíbrio ântero-posterior da cabeça, se contrai para

compensar o peso da mandíbula e de toda a massa

muscular que acompanha as posições excêntricas (Figura

2). Aparecem assim as contraturas cervicais e a sinto-

matologia ocasionada por essa situação.

Dessa maneira podemos associar sintomatologia de

cabeça, pescoço, cintura escapular e membros superiores

a uma única causa, posição excêntrica da mandíbula,

definindo assim o que chamamos de Síndrome Musculo-

articular Superior.

Definimos também a posição fisiológica harmônica

da mandíbula como aquela em que toda a musculatura

do sistema se encontra equilibrada, sem contraturas

compensatórias.

É importante definir a existência da síndrome, já que

isto nos permite tratar pacientes com afecções crônicas

cervicais, ou em membros superiores, através do reposi-

cionamento da mandíbula.

Figura 1. Inervação de braços e mãos que provêm de espaços cervicais

C5, C6, C7, C8.

Definimos assim o que chamamos de Sistema

Musculoarticular Superior, composto por cabeça,

pescoço, cintura escapular e membros superiores.

A importância deste conceito radica em que a

sintomatologia relacionada com estas estruturas pode

responder a uma única causa que afete todo o sistema,

caracterizando assim a presença de uma síndrome.

A importância da mandíbula dentro desse sistema é

evidente, basta analisar a grande quantidade de mús-

culos e ligamentos que nela se inserem, e seu desem-

penho funcional na mastigação, fonação e deglutição,

graças à grande amplitude de movimentos que pode

realizar.

Qualquer interferência que guie a mandíbula a

posições excêntricas tem que ser compensada pela

musculatura de todo o sistema.

Para que a mandíbula atue livre de interferências, a

natureza criou um elemento fusível, o dente, que se

desgasta, e é assim em várias espécies animais.

Figura 2. Musculatura que intervém no equilíbrio ântero-posterior da

cabeça, e sistema muscular que se associa à parte inferior da

mandíbula.

SÍNDROME MUSCULOARTICULAR SUPERIOR

206

Headache Medicine, v.2, n.4, p.204-208, Oct/ Nov/Dec. 2011

SIDERMAN MA

APLICAÇÃO CLÍNICA DA SÍNDROME

Começamos elaborando um protocolo de anamnese

e exame clínico, onde incluímos cabeça, ouvidos,

pescoço, cintura escapular e membros superiores.

A anamnese está baseada na descrição da sinto-

matologia da cabeça, ouvidos, cérvico-escapular, braços,

mãos e equilíbrio.

O exame clínico consta de palpação dos músculos

masseteiros, temporais, pterigoideos, suboccipitais,

trapézios, escalenos e esternocleidomastoidio. Também

palpação na região de ATM, análise de trajetória e

capacidade de abertura.

Este protocolo nos permite obter, em poucos minutos,

uma visão global do sistema MAS.

Na boca analisamos o espaço interoclusal livre,

auxiliados com laminilhas de Long.

Completamos, em alguns casos, com estudo em

articulador semiajustável, com modelo inferior com dentes

posteriores troquelados individualmente, o que nos

permitiu analisar as interferências, uma a uma.

As correções foram realizadas com ajustes, exo-

dontias, ortodontia e prótese.

Foram utilizadas placas interoclusais, em alguns

casos, só para aliviar sintomatologia aguda, na primeira

parte do tratamento.

Aconselhamos os pacientes a suprimir o uso de

medicamentos na medida em que o tratamento avança.

Considerávamos os casos concluídos quando

cessava a sintomatologia em períodos sempre superiores

a um mês. Também realizamos controles à distância,

contando com pacientes que já superam um ano de

tratamento.

Durante 18 meses tratamos 29 pacientes (Tabela 1)

Headache Medicine, v.2, n.4, p.204-208, Oct/ Nov/Dec. 2011 207

sempre obtendo êxito. No fim do tratamento, realizamos

entrevistas filmadas, onde cada um relata sua história

clínica completa, descrevendo sintomatologia, exames,

profissionais consultados e tratamentos realizados,

durante os anos de convalescimento.

Com base nas anamnese e nas entrevistas, elabo-

ramos um quadro de sintomatologia, no qual apa-

recem as porcentagens de prevalência de cada

sintoma.

ANÁLISE DOS RESULTADOS

O exame do quadro de resultados nos leva às

seguintes conclusões;

1) A sintomatologia cervical, associada aos braços

e mãos, junto com dores de cabeça, estava presente em

90% dos pacientes tratados. Ressaltamos que desapa-

receram depois do tratamento dental. O que comprova

a existência da síndrome de MAS.

2) O cansaço, manifestado por 82,75% dos paci-

entes, vem como consequência da atividade muscular

forçada.

3) Zumbidos e equilíbrio, com 62% com sintomas

frequentes, e devemos incluí-los na anamnese.

4) Apesar das desarmonias oclusais, presentes em

todos os casos, só 48% tiveram manifestações de ATM e

28% com bruxismo.

5) O resto da sintomatologia só apareceu em casos

com dores agudas, ou contraturas musculares crônicas,

com limitação de movimentos.

DISCUSSÃO

O homem moderno padece frequentemente de

sintomatologias crônicas nas regiões da cabeça, pescoço,

cintura escapular e braços.

Temos assim dores na região da cabeça, às que a

medicina chama enxaquecas ou migrânias. Dores

cervicais, justificadas pela presença de hérnias ou bico

de papagaio (deformação das vértebras, causada por

compressão). Zumbido nos ouvidos; tonturas e dese-

quilíbrios, diagnosticados como labirintite. Adorme-

cimento ou diminuição de mobilidade nos braços e mãos,

diagnosticados como contraturas tencionais, ou lesão por

esforço repetitivo – LER.

O certo é que as pessoas passam a conviver com

afecções consideradas crônicas e tratadas com anal-

gésicos, anti-inflamatórios e relaxantes musculares, para

aliviar os sintomas que elas provocam.

A especialização da medicina leva a que o otorrino

trate o zumbido, o traumatologista o pescoço, o neuro-

logista as dores de cabeça e as tonturas e o dentista os

dentes e a ATM.

O diagnóstico obtido através da análise de estruturas

ósseas e articulares, exame passivo (radiográfico), nos

leva a diagnosticar lesões que consideramos irreversíveis

e a pensar que são crônicas.

A medicina esqueceu o músculo, que é quem deter-

mina onde cada estrutura vai se posicionar, e do conceito

da sincronização muscular, onde toda a musculatura

trabalha associada.

O médico examina radiografias de coluna e não

palpa a musculatura, que é a que posiciona a vértebra,

e, portanto, não consegue interpretar a causa que pro-

vocou a lesão, geralmente associada a uma contratura

muscular.

A importância de poder observar o paciente de

forma global e funcional nos ajudará a resolver muitas

das afecções que se consideram crônicas. Prova do que

estou afirmando é que cresce cada vez mais a aplicação

da fisioterapia, como terapia alternativa.

O conceito fisiológico de sistema musculoarticular

superior nos leva a compreender a importância de esta-

belecer equilíbrio e harmonia para os músculos que o

compõem.

A mandíbula é o centro ósseo móvel que comanda

as funções mais importantes do sistema, fonação, mas-

tigação e deglutição. Além do mais, sua posição em

repouso exige a coordenação de todo o sistema muscular

superior de cabeça e pescoço. Cabe ao odontólogo

interpretar qual é a posição funcionalmente correta, que

não provoque desarmonias nas estruturas que o

compõem.

O dente funciona como fusível do sistema, já que se

desgasta. Foi assim no homem primitivo e é assim em

outras espécies. Substituir essa estrutura dental por

elementos mais duros e resistentes é um erro filosófico

que temos cometido na profissão.

Devemos analisar um pouco mais nossos princípios

reabilitadores. Não é possível que, ao terminar nossos

tratamentos, fiquemos satisfeitos por termos conseguido

lindos sorrisos fotográficos, mas condenados a usar uma

placa interoclusal noturna.

Interpretar a natureza e cuidar da qualidade de vida

de nossos pacientes é sem duvida o nosso objetivo. Está

em nossas mãos a solução de muitas das afecções

crônicas de cabeça, pescoço e braços. Devemos divulgar

estes conhecimentos para que a medicina os possa

SÍNDROME MUSCULOARTICULAR SUPERIOR

208

Headache Medicine, v.2, n.4, p.204-208, Oct/ Nov/Dec. 2011

Correspondência

Miguel Angel Siderman, MDMiguel Angel Siderman, MD

Miguel Angel Siderman, MD

miguel.siderman@hotmail.com

Recebido: 11 /27/2010

Aceito: 10/13/2011

diagnosticar como sintomas curáveis, e não como

doenças crônicas.

CONCLUSÃO

A definição de sistema musculoarticular superior

(MAS) e a influência que as posições excêntricas da

mandíbula exercem neste ficam claramente registradas

no trabalho apresentado neste artigo. Pacientes com

sintomas dolorosos crônicos em cabeça, pescoço, cintura

escapular e braços relataram o desaparecimento de suas

afecções depois de serem submetidos ao tratamento

odontológico de reposição mandibular.

Definimos então como síndrome musculoarticular

superior – SMAS, provocados por uma única causa, a

posição excêntrica da mandíbula.

É importante interpretar como a natureza resolve

nossas necessidades funcionais, estática (equilíbrio) e

dinâmica (fonação, deglutição e mastigação) para poder

tratar as patologias musculares crônicas.

REFERÊNCIAS

1. Gelb H, Tarte J. A two-year clinical dental evaluation of 200

cases of chronic headache: the craniocervical-mandibular

syndrome. J Am Dent Assoc. 1975;91(6):1230-6.

2. Rieder CE, Martinoff JT, Wilcox SA. The prevalence of mandibular

dysfunction Part I: sex and age distribution of related signs and

symptoms. J Prosthet Dent. 1983;50(1):81-8.

3. Clark GT, Green EM, Dornan MR, Flack VF. Craniocervical

dysfunction levels in a patient sample from a temporomandibular

disorders, joint clinic. J Am Dent Assoc. 1987;115(2):251-6.

4. Cacchiotti DA, Plesh O, Bianchi P, McNeill C. Signs and symptoms

in samples with and without temporomandibular disorders. J

Craniomandib Disord. 1991;5(3):167-72.

5. De Laat A, Meuleman H, Sterns A. Relation between functional

Limitations of the cervical spine and temporomandibular

disorders (Abstract). Journal of Orofacial Pain. 1993;1: 109

6. Curtis AW. Myofascial pain-dysfunction syndrome. The role of

non masticatory muscles in 91 patients. Otolaryngol Head Neck

Surg. 1980;88(4):361-7

7. Sjaastad O, Saunte C, Hovidahl, Breivik H, Gronbaek E.

“Cervicogenic” headache. An hypothesis. Cephalalgia. 1983;

3(4):249-56.

8. Alanen PJ, Kirverskari PK. Occupational cervicobrachial disorder

and Temporomandibular joint dysfunction. Cranio. 1984 Dec-

1985 Feb;3(1):69-72.

9. Friedman MH, Weisberg J. Temporomandibular joint disorders,

diagnosis and treatment. Chicago. Quintessence Publishing Co.,

1985.

10. Bärtschi-Rochaix W. () Headache of cervical origin. In: Vinken PJ,

Bruyn GW eds. Handbook of Clinical Neurology, Vol 5.

Amsterdam. North Holland Publ Co. 1986;192-203.

11. Bogduk N, Marsland A. On the concept of third occipital

headache. J Neurol Neurosurg Psychiatry. 1986;49(7):775-

80.

12. Pfaffenrath V., Dandekar R, Pöllmann W. Cervicogenic headache-

the clinical picture, radiological findings and hypotheses on its

pathophysiology. Headache. 1987;27(9):495-9

13. Kirveskari P, Alanem P, Karskela V, Kaitaniemi P, Holtari M,

Virtanen T, et al. Association of functional state of stomatognathic

system with mobility of cervical spine and neck muscle tenderness.

Acta Odontol Scand. 1988 ;46(5):281-6.

14. Ehni G, Benner B. Occipital neuralgia and the Cl 2 arthrosis

syndrome. J Neurosurg. 1984;61(5):961-5.

15. Simons DG, Travell JG. Myofascial pain syndromes. In: Wall PD

& Melzack R (eds). Textbook of Pain, 2nd ed. Churchill Livingstone,

London, 1989, pp 368-385.

16. Aprill C, Dwyer A, Bogduk N. Cervical zygapophyseal joint pain

patterns. II: A clinical evaluation. Spine (Phila Pa 1976). 1990;

15(6):458-61.

17. Star MJ, Curd JG, Thorne RP. Atlantoaxial lateral mass

osteoarthritis. A frequently overlooked cause of severe

occipitocervical pain. Spine (Phila Pa 1976). 1992;17(6 Suppl):

S71-6.

18. Dreyfuss P, Michaelsen M, Fletcher D. Atlanto-occipital and lateral

adanto-axial joint pain patterns. Spine (Phila Pa 1976). 1994;

19(10):1125-31.

19. De Leeuw JRJ. Psychosocial aspects and symptom characteristics

of craniomandibular dysfunction. PhD dissertation, Utrecht

University, The Netherlands, 1993.

SIDERMAN MA

Headache Medicine, v.2, n.4, p.209-211, Oct/ Nov/Dec. 2011 209

Exploding head syndrome – the early steps

Síndrome da cabeça explodindo – os primeiros passos

ABSTRACTABSTRACT

ABSTRACT

Exploding head syndrome is a rare entity associated with

migraine that occurs during sleep onset. A male migraine

with aura patient presented with episodes of abrupt awakening

following perceptions of sounds resembling a speeding up

motorcycle engine interspersed with bursts of exhaust explosions

like noises, accompanied by an exploding sensation in the

head. The patient presented in the evolution of self-limited

period of headache chronicity. This syndrome has been

associated with an atypical form of acoustic aura that often

leads to migraine chronification.

Keywords: Keywords:

Keywords: Acoustic aura; Exploding head syndrome;

Migraine.

RESUMORESUMO

RESUMO

A síndrome da cabeça explodindo é uma entidade rara

associada com a migrânea que ocorre durante o início do

sono. Um paciente do sexo masculino com migrânea com

aura apresenta episódios de despertar súbito após perceber

um som como uma motocicleta acelerando intercalada com

estouros de um escapamento. O paciente evoluiu com período

autolimitado de cronificação da cefaleia. Esta síndrome tem

sido relacionada a uma forma atípica de aura acústica e

aparenta intima relação com cronificação da migrânea.

alavrasalavras

alavras

chave:chave:

chave: Aura acústica; Migrânea; Síndrome da

cabeça explodindo.

CASE REPORTCASE REPORT

CASE REPORT

Elcio Juliato Piovesan

1,2

, Pedro André Kowacs

, Helder Granhold Campos

, Lucas Pires Augusto

Lucas Coluni

, Lineu Cesar Werneck

1,2

Neurology Service, Internal Medicine Department, Hospital de Clínicas da

Universidade Federal do Paraná (UFPR), PR, Brazil

Experimental Laboratory, Health Sciences Sector (LESCS), Universidade Federal do Paraná (UFPR), PR, Brazil

Faculdade de Medicina, Universidade Federal do Paraná, PR, Brazil. Sponsored by a grant from Conselho

Nacional de Desenvolvimento Científico e Tecnológico (CNPq)

Piovesan EJ, Kowacs PA, Campos HG, Augusto LP, Coluni L, Werneck LC

Exploding head syndrome – the early steps. Headache Medicine. 2011;2(4):209-11

INTRODUCTION

Exploding head syndrome (EHS) is a rare

phenomenon characterized by a painless loud noise at

the onset of sleep.

(1)

Armstrong-Jones described it for the

first time in 1920 and referred to it as "snapping of the

brain".

(2)

Pearce coined the name "exploding head

syndrome in 1989.

(3)

This is a rare benign sleep-wake

transition disorder of unknown aetiology.

(4)

The attacks are

characterized by a sudden "bomb-like explosion" or

"shotgun" noise felt in the head and in 10-20% of patients

there is also a sensation of "flashing lights".

(4)

The attacks

are not painful but are unpleasant.

(4,5)

This phenomenon

occurs in relaxed wakefulness or at the transition from

wakefulness to sleep.

(5)

The sensation lasts for a few seconds

only and disappears completely when awake, although it

may recur on further attempts to fall asleep.

(6)

The onset is

usually over the age of 50 years old and there is a slight

female preponderance.

(3)

The attacks occur with variable

frequency (from seven in one night to one in a few weeks

or months).

(6)

Symptoms such as nausea and vomiting did

not occur.

(6)

The vast majority of patients with EHS are

migraine with aura patients. Reports of patients with EHS

preceding the onset of migraine attacks suggest that EHS

can be considered as a form of migraine aura.

(7)

Here we present a new EHS case and compare it

characteristics to those of the cases described in the

literature.

210

Headache Medicine, v.2, n.4, p.209-211, Oct/ Nov/Dec. 20

PIOVESAN EJ, KOWACS PA, CAMPOS HG, AUGUSTO LP, COLUNI L, WERNECK LC

CASE REPORT

A 45-year-old man with a five years history of episodic

migraine with fortification spectra aura described a

peculiar sensation in the head, occurring once a year,

similar to the noise of an exploding bomb only at night

while going off to sleep. The "explosion" would wake him

up and disappear completely at the moment he woke

up. This would make him wake up extremely scared and

tachycardic. Regarding the last episode, the patient

described a sound like the one of a motorcycle being

accelerated followed by exhausting pipe bursts. Three of

these sequences of sounds were perceived until the patient

was awake (Figure). The patient observed a close

relationship to anxiety. After EHS episodes, the patient

reported migraine exacerbation, lasting 45 days. The

headache has been well described as migraine:

alternating unilateral, throbbing, disabling and associated

to nausea, phonophobia and photophobia, besides

important and persistent visual phenomena. General

physical examination was normal, as it was the

neurological examination, including mental status, cranial

nerves, muscle strength, muscle tone, stretch and superficial

reflexes, cerebellar function, gait and sensory testing.

Impedance and audiometry tests were normal, as well as

magnetic resonance imaging and magnetic resonance

angiography of the brain.

after an exhaustive literature review, only a few cases seem

to have been shared in almost 100 years of its initial

description.

The population affected by this syndrome is usually

also stricken by migraine with aura. From the standpoint

of pathophysiology, this syndrome cannot be confused

with nocturnal epilepsy since tests such EEG and

polysomnography (PSG) during EHS attacks do not

suggest this etiology.

(8,9)

On video PSG and multiple sleep

latencies test (MSLT), EHS attacks showed at the transition

from wakefulness to sleep (non-rapid eye movement

(NREM) sleep stage 1, NREM1) and from NREM2.

(4)

EHS

occurs at any age but usually occurs after age 50. A

gradual increase of stage 1 sleep occurs with brain

aging.

(6,12)

The basis for EHS is thought to be a delay in

the reduction of activity in selected areas of the brainstem

reticular formation as the patient passes from wakefulness

to sleep.

(6,13)

Many speculations had been done, especially after

the use of drugs that were able to control symptoms in

isolated cases. The existence of a transient calcium channel

dysfunction was hypothesized as a cause, since the

nifedipine,

(10)

flunarazine,

(6)

and topiramate (P type calcium

channel)

(1)

produced improvement of the symptoms. Other

drugs have shown satisfactory results, as clonazepam(

11)

and clomipramine.

(9-13)

The EHS attacks occur in relaxed wakefulness or at

the transition from wakefulness to sleep.

(4,5)

A very interesting

way patients, such as our, have reported that the onset the

EHS is directly associated with a worsening of migraine

taking some clinical aspects of chronicity.

(4)

Recent work

has suggested that EHS is considered an atypical acoustic

aura.

(4,7)

Two hypotheses suggest a momentary disinhibition

of the cochlea or its central connexions in the temporal

lobes,

(3)

sudden involuntary movement of the tympanum

or the tensor tympani,

(3)

rupture of the labyrinthine

membrane or a springing open of the Eustachian tubes.

(3,14)

Our case suggests a central origin since the sounds are

not only more elaborate single explosion.

In summary the exploding head syndrome is extremely

rare, occurs in patients with migraine, seems to be

associated with a clinical worsening of migraine and is

considered a form of acoustic migraine aura.

REFERENCES

1. Palikh GM, Vaughn BV. Topiramate responsive exploding head

syndrome. J Clin Sleep Med. 2010;6(4):382-3.

Figure – Sounds described by the patient

DISCUSSION

In this syndrome, the sudden start of the symptoms

resembles thunderclap headache. As the patient is not yet

dreaming, these sounds occur in a context totally unknown

to the patient. Maybe this is why patients wake up very

scared, looking for the source of the noise. This is a rare

disorder and our experience is limited to one case. Even

Headache Medicine, v.2, n.4, p.209-211, Oct/ Nov/Dec. 2011 211

2. Armstrong-Jones R. Snapping of the brain. The Lancet.

1920;196:720.

3. Pearce JM. Clinical features of the exploding head syndrome. J

Neurol Neurosurg Psychiatry. 1989;52(7):907-10.

4. Kallweit U, Khatami R, Bassetti CL. Exploding head syndrome -

More than "snapping of the brain"?. Sleep Med. 2008;9(5):589.

5. Green MW. The exploding head syndrome. Curr Pain Headache

Rep. 2001;5(3):279-80.

6. Chakravarty A. Exploding head syndrome: report of two new

cases. Cephalalgia. 2008;28(4):399-400.

7. Evans RW. Exploding head syndrome followed by sleep paralysis:

a rare migraine aura. Headache. 2006;46(4):682-3.

8. Bhatt M, Quinto C, Sachdeo R, Chokoverty S. Exploding head

syndrome misdiagnosed as nocturnal seizures. Neurology.

2000;54(Suppl3):A403.

9. Sachs C, Svanborg E. The exploding head syndrome:

polysomnographic recordings and therapeutic suggestions.

Sleep. 1991;14(3):263-6.

10. Jacome DE. Exploding head syndrome and idiopathic stabbing

headache relieved by nifedipine. Cephalalgia. 2001;21(5):

617-8.

11. Salih F, Kleingebiel R, Zschenderlein R, Grosse P. Acoustic sleep

starts with sleep onset insomnia related to a brainstem lesion.

Neurology. 2008;70(20):1935-6.

12. Fry JM. Sleep disorders. Med Clin North Am 1987;71(1):95-

110.

13. Landtblom AM, Fridriksson S, Boivie J, Hillman J, Johansson

G, Johansson I. Sudden onset headache: a prospective study

of features, incidence and causes. Cephalalgia. 2002;

22(5):354-60.

14. Gordon AG. Exploding head (letter). Lancet. 1988;ii:625-6.

Correspondence

Elcio Juliato Piovesan, MDElcio Juliato Piovesan, MD

Elcio Juliato Piovesan, MD

Rua General Carneiro, 1103/102

80060-150 – Curitiba, PR, Brasil

piovesan1@hotmail.com

Received: 9/6/2011

Accepted: 10/25/2011

EXPLODING HEAD SYNDROME – THE EARLY STEPS

212

eadache Medicine, v.2, n.4, p.212-215, Oct/ Nov/Dec. 2011

Neuroarte e cefaleia: os enigmas nos afrescos

de Michelangelo

Neuroart and headache: the enigmas in the Michelangelo's frescos

RESUMORESUMO

RESUMO

Neuroarte é uma disciplina das Neurociências onde arte e

ciências/medicina se misturam. Grandes nomes como Leo-

nardo da Vinci, Michelangelo, Vesalius usaram da arte da

ilustração para documentar a anatomia humana. Neste arti-

go comentamos sobre estruturas anatômicas ocultas nos

afrescos de Michelangelo encontrados na Capela Sistina.

Também mostramos imagens de dois homens com expressão

de dor unilateral e agitação, sugerindo cefaleia em salvas.

alavrasalavras

alavras

chave:chave:

chave: Michelangelo; Cefaleia; Arte; Neuroarte;

Capela Sistina; Cefaleia em salvas

ABSTRACTABSTRACT

ABSTRACT

Neuroart is a discipline of Neurosciences where there is an

interrelationship between art and sciences. Great names such

as Leonardo da Vinci, Michelangelo, Vesalius used the art of

illustration to document the human anatomy. In the present

article we are commenting about hidden anatomical structures

found in Michelangelo's frescos of the Sistine Chapel. We

also showed the imagem of two men, expressing unilateral

pain and agitation.

Keywords: Keywords:

Keywords: Michelangelo; Headache; Art; Neuroart; Sistine

Chapel; Cluster headache

NEUROARTNEUROART

NEUROART

Marcelo Moraes Valença, Luciana P. A. Andrade-Valença

Unidade Funcional de Neurologia e Neurocirurgia, Departamento de Neuropsiquiatria, Universidade Federal

de Pernambuco, Cidade Universitária, Recife, PE, Brazil

Valença MM, Andrade-Valença LPA. Neuroarte e cefaleia: os enigmas nos afrescos de Michelangelo.

Headache Medicine. 2011;2(4):212-5

INTRODUÇÃO

Um dos grandes incentivadores da Neuroarte no

Brasil é o nosso amigo neurocientista Norberto Garcia

Cairasco,

(1)

do Departamento de Fisiologia da Faculda-

de de Medicina de Ribeirão Preto-USP. Nas capas dos

exemplares das teses apresentadas por seus alunos são

mostradas criações artísticas que valorizam o conteúdo

de novos conhecimentos escritos e divulgados pelo dou-

torando ou mestrando no momento da defesa.

GÊNIOS DAS ARTES VISUAIS DA

RENASCENÇA

Gênios das artes visuais da Renascença como

Michelangelo (Michelagnolo) Buonarroti (1475-1564),

Raphael Sanzio (1483-1520) e Leonardo da Vinci (1452-

1519), bem como da Medicina [e.g. Vesalius (1514-

1564) e Albinus (1697-1770)], deixaram registrados

belos exemplos da Neuroarte.

Michelangelo pintou o afresco A Criação de Adão

(280 cm x 570 cm, Figura 1), por volta de 1511, expos-

to no teto da Capela Sistina no Vaticano, que representa

a criação de Adão por Deus. Estudiosos

(2)

acreditam que

a imagem pintada apresenta similaridades anatômicas

com o encéfalo, podendo ser visualizados na posição

lateral o lobo frontal, nervo ótico, glândula pituitária,

tronco cerebral e o cerebelo.

Curiosamente o manto de Deus tem a forma de úte-

ro, e a charpe verde representaria o cordão umbilical

Headache Medicine, v.2, n.4, p.212-215, Oct/ Nov/Dec. 2011 213

ou, segundo outros, as artérias vertebral e basilar. Toda-

via a nossa interpretação é diferente: o manto de Deus

representa a aracnoide, membrana semitransparente

que envolve todo o neuroeixo, e a charpe representa o

sifão carotídeo que continua com as artérias cerebral

média e cerebral anterior. Ainda vizualizamos os forames

de Monro e de Magendie, a cisterna quadrigêmea, e,

no corpo de Deus, o aqueduto de Sylvius, os III e IV

ventrículos cerebrais. Tentem identificar a artéria comu-

nicante anterior, as artérias vertebrais, glândula pituitária,

o nervo/quiasma óptico... entre outras estruturas cerebrais

(Figura 1).

Será que Michelangelo intuitivamente também ten-

tou representar uma "sinapse" ao desenhar a mão direita

de Deus em direção à mão esquerda de Adão? Obser-

vem que há um mínimo espaço entre os dois dedos no

intúito de vincular a imagem com transferência de infor-

mação (Figura 1).

Ainda no teto da Capela Sistina podemos encontrar

a representação do tronco cerebral no pescoço de Deus

no afresco A Separação entre a Luz e as Trevas (Figura

2).

(3)

TENTOU MICHELANGELO PINTAR UMA

PESSOA COM CEFALEIA EM SALVAS?

No afresco O Juízo Final (Figura 3A), entre as inú-

meras imagens de pessoas pintadas por Michelangelo

encontra-se uma mulher, identificada como Santa Mô-

nica, com exoftalmia,

(4)

sugerindo oftalmopatia associ-

ada com doença tireoidiana, doença descrita só em

1835 por Graves. Duas outras imagens parecem re-

presentar homens com cefaleia, ambas sugerindo agi-

tação e dor unilateral (Figura 3B e 3C). Estaria

Michelangelo representando pessoas com cefaleia em

salvas?

Figura 1. Afresco “A Criação de Adão” (1511), por Michelangelo. Ver o desenho do III ventrículo no abdome e do IV ventrículo do lado esquerdo

do joelho direito. Seria esta imagem atrás de Adão a representação de uma mama, símbolo de nascimento e criação?

Figura 2. Cabeça de Deus no afresco “A Separação entre a Luz e as

Trevas”, por Michelangelo. Ver o desenho do tronco cerebral no

pescoço de Deus

NEUROARTE E CEFALEIA: OS ENIGMAS NOS AFRESCOS DE MICHELANGELO

214

Headache Medicine, v.2, n.4, p.21

2-215, Oct/ Nov/Dec. 2011

VALENÇA MM, ANDRADE-VALENÇA LPA

A CARICATURA DA DOR DE CABEÇA

Neuroarte inclui trabalhos de artistas, que, de uma

forma ou de outra, estejam vinculados com as neuro-

ciências, na pintura, literatura, música, teatro etc. Abai-

xo estamos mostrando a arte por pintura com o dedo

sobre um prato executada pelo artista mineiro Vagner

Bispo, quando foi solicitado na ocasião do XXV Con-

gresso Brasileiro de Cefaleia, para pintar o que ele acre-

ditava ser uma "dor de cabeça".

Sentado na rua 25 de março, na cidade de São

Paulo, ele riu sem acreditar no que havia sido pedido,

e cerca de 20 minutos depois podíamos ver a face de

dor representada como uma "caricatura" de uma pes-

soa com cefaleia, onde a língua representava "o grito

de dor". O artista Vagner não era um sofredor de

cefaleia, mas sua tia, falou ele, "corria doida quando

sua cabeça doía".

Um cefaliatra poderia identificar pistas de aura

visual (escótomas cintilantes no quadrante superior

esquerdo, turvação visual no quadrante superior

direito e espectro de fortificação no brinco) e sinais

autonômicos como hiperemia conjuntival, além de

expressão de intensa dor, próprios de uma crise de

enxaqueca.

Figura 3. Afresco “A Separação entre a Luz e as Trevas”, por Michelangelo (1537-1541)

Figura 4. Dor de Cabeça, por Vagner Bispo (2011)

Headache Medicine, v.2, n.4, p.212-215, Oct/ Nov/Dec. 2011 215

Correspondence

Marcelo M. V Marcelo M. V

Marcelo M. V

alença, MDalença, MD

alença, MD

Neurology and Neurosurgery Unit, Department of

Neuropsychiatry, Universidade Federal de Pernambuco

Cidade Universitária

50670-420 – Recife, PE, Brazil.

Phone: +55 81 99229394; +55 81 34263501;

Fax: +55 81 21268539

mmvalenca@yahoo.com.br

REFERÊNCIAS

1. http://www.cerebromente.org.br/n10/opiniao/cairasco/art.html

2. Meshberger FL. An interpretation of Michelangelo's Creation of

Adam based on neuroanatomy. JAMA. 1990; 264(14):1837-

41. Comment in: JAMA. 1991;265(9):1111.

3. Suk I, Tamargo RJ. Concealed neuroanatomy in Michelangelo's

Separation of Light From Darkness in the Sistine Chapel.

Neurosurgery. 2010 May;66(5):851-61; discussion 860-1.

Comment in: Neurosurgery. 2011;68(6):E1774-5.

Neurosurgery. 2011;69(2):E503; author reply E503-5.

4. Pozzilli P. Blessed with exophthalmos in Michelangelo's Last

Judgment. QJM. 2003;96(9):688-90.

Recebido: 11/28/2011

Aceito: 12/12/2011

NEUROARTE E CEFALEIA: OS ENIGMAS NOS AFRESCOS DE MICHELANGELO

216 Headache Medicine, v.2, n.4, p.216, Oct./Nov./Dec. 2011

Chronic post-traumatic headache after mild brain injury

(Abstract)

Cefaleia pós-traumática crônica após traumatismo cranioencefálico leve (Resumo)

Introduction:Introduction:

Introduction: Post-traumatic headache (PTH) is the most

common symptom found in the post-traumatic syndrome, it

starts within seven days after the trauma, the acute form of it

lasts until three months and the chronic form persists after this

period. The evaluation of patients with PTH remains a great

challenge to clinicians due to the lack of objective findings,

so there is always controversy if the symptoms are real,

psychogenic or "produced". Due to the similarity of the clinical

expression of chronic PTH (cPTH) with practically all forms of

primary headache, it was the objective of this study to determine

the occurrence of events that frequently arise in patients of

these groups: depression, anxiety, poor quality of life and

cutaneous allodynia (CA).

Methodology: Methodology:

Methodology: The subjects were divided in three

groups: (a) one group without headache (CONTROL, n=25),

in the 14-84 age group, mean of 35 years old (b) chronic

post-traumatic headache (cPTH, n=19), in the 11-70 age

group, mean of 34 years old and (c) migraine (MIGRAINE,

n=29), in the 13-59 age group, mean of 36 years old, with

no significant statistical difference among the groups when

related to age. The patients were assessed in relation to the

present symptoms of anxiety and depression by the Beck's

Anxiety Inventory (BAI) and Beck's Depression Inventory (BDI),

respectively. The Quality of Life Inventory was also applied,

analyzing the four functional quadrants (affection, social, health

and professional). In the quantitative evaluation of CA the

esthesiometer of Semmens-Weinstein was used for the thresholds

of pressure, and glass test tubes for the evaluation of thermal

sensitivity. In relation to the qualitative evaluation of CA, it

was used a simplified questionnaire.

Results:Results:

Results: The majority of patients with cPTH showed similar

headache symptoms to the migraine ones. The PTH was

associated to the anxiety and depression levels, which are

similar to the group with migraine and superior to the control

group (p<0.001). The quality of life of the patients with PTH

was similar to the migraine and inferior to the control group

Hugo André de Lima Martins

Universidade Federal de Pernambuco. Pós-graduação em Neuropsiquiatria e Ciências do Comportamento

(área de concentração: Neurologia). PhD Thesis. 2010. Orientador: Marcelo Moraes Valença

Martins HAL. Chronic post-traumatic headache after mild brain injury (Abstract).

Headache Medicine. 2011;2(4): 216

Correspondence

Hugo André de Lima MartinsHugo André de Lima Martins

Hugo André de Lima Martins

hugomt2001@yahoo.com.br

THESISTHESIS

THESIS

in all quadrants, (p<0.05). The thresholds of thermal and

mechanical sensitivity were inferior in the cPTH in relation to

the control group, (p<0.05). Patients with PTH showed a larger

quantity of cephalic allodynic symptoms and extra-cephalic

in relation to the control group in the evaluation by a simplified

questionnaire, (p<0.05).

Conclusion:Conclusion:

Conclusion: The cPTH presents similar clinical

characteristics to migraine. Patients with cPTH present high

levels of symptoms of anxiety and depression and reduced

level of life quality. The patients with cPTH showed reduced

thresholds of thermal and mechanical sensitivity and larger

quantity of allodynic symptoms in relation to the control group

and similar to the migraine group.

Headache Medicine, v.2, n.4, p.217, Oct./Nov./Dec. 2011 217

Introduction:Introduction:

Introduction: Craniomandibular dysfunction (CMD) is

a collective term for the clinical problems involving the muscles

of mastication, the temporomandibular joint (TMJ) and

associated structures. Headache is a symptom that appears

frequently associated with CMD due to the damage that

headache and (CMD) can cause the quality of life, this research

aims to determine the prevalence and correlation of these

nosologic entities for which in turn can contribute to the

prevention and treatment for possible improvement of the

individual.

Objective:Objective:

Objective: We examine the prevalence of CMD and

primary headaches (migraine and tension-type headache),

as well as, to quantify the influence on quality of life of military

and civilian employees of the Naval Hospital in Recife.

Methods:Methods:

Methods: Cross-sectional study analysis was made of

a population of 128 civilian and military personnel on active

duty in both genders. The age ranged from 19 to 72 years,

with an average of 33 years old. The officials were from the

Naval Hospital in Recife, Pernambuco, crowded in 2009, who

voluntarily answered the questionnaire divided into three

phases: the first on the anamnestic index of Fonseca to DCM,

the second according to the criteria of the International

Headache Society and the third assessment of quality of life

with the WHOQOL-brief. Participants were informed about

the nature of research and acceptance for the purpose of

ethics, informed consent was signed with the approval of the

Ethics in Human Research of the Center for Health Sciences,

Federal University of Pernambuco record No. 383/08.

Results:Results:

Results: Of 128 patients, 53 (41.4%) were aged under

29. The males accounted for 74 (57.8%) subjects and 54

(42.2%) were females. DCM was diagnosed in 38% of the

individuals (mild 31%, moderate 6%, severe 2%) and

headache in 20%. 16% of the subjects had the combination

of headache and DCM. Individuals with headache had more

DCM than the ones without headache [14/19 (74%) vs. 21/

79 (27%), p=0.0003 in the Fisher's exact test. For the areas

of quality of life (WHOQOL-brief) according to the presence

of DTM, individuals without DTM showed better results in the

four major domains are assessed: physical [72±13(SD) vs.

Correspondence

Michelly Cauás de Queiroz GatisMichelly Cauás de Queiroz Gatis

Michelly Cauás de Queiroz Gatis

michellycauas@yahoo.com.br

Craniomandibular dysfunction, migraine and tensio-type

headache: influence on quality of life (Abstract)

Disfunção craniomandibular, migrânea e cefaleia do tipo tensional: influência na

qualidade de vida (Resumo)

Michelly Cauás de Queiroz Gatis

Universidade Federal de Pernambuco. Pós-graduação em Neuropsiquiatria e Ciências do Comportamento

(área de concentração: Neurociências. PhD Thesis. 2010. Orientador: Marcelo Moraes Valença

Cauás M. Craniomandibular dysfunction, migraine and tensio-type headache: influence on quality of life

(Abstract). Headache Medicine. 2011;2(4): 217

78±10, p<0.05], psychological (71±13 vs. 79±10,

p<0.05), social relationships (75±15 vs. 82±15, p<0.05)

and environment (62±13 vs. 68±13, p<0.05. Presence of

headache in this study has no impact on the quality of life of

the individual.

Conclusion:Conclusion:

Conclusion: Association of headache and CMD are

common and constitute a public health problem of enormous

proportions, with an impact on quality of life of the sufferer.

Thus, required a multidisciplinary approach involving

professionals in medicine, dentistry and health support.

THESIS

218 Headache Medicine, v.2, n.4, p. 218, Oct./Nov./Dec. 2011

Oculo-nasal autonomic symptoms in migraine and cluster

headache (Abstract)

Sinais and sintomas autonônomicos óculo-nasais na migrânea e na cefaleia em

salvas (Resumo)

Maria da Conceição Filgueira Sampaio

Universidade Federal de Pernambuco. Pós-graduação em Neuropsiquiatria e Ciências do Comportamento

(área de concentração: Neurociências). PhD Thesis. 2010.

Orientadores: Marcelo Moraes Valença/Wilson Farias da Silva

Sampaio MCF. Oculo-nasal autonomic symptoms in migraine and cluster headache (Abstract).

Headache Medicine. 2011; 2(4):218

Migraine is a primary, incapacitating headache.

Autonomic symptoms may occur during migraine crises, but

are rarely mentioned in the literature. The aim of this study

was to determine the frequency of autonomic symptoms during

migraine crises. A series of case studies were used, data were

collected from both the private patient records and from the

headache clinic of the Clinical Hospital (HC) of the Federal

University of Pernambuco (UFPE) from July 2005 to July 2008.

Patients who had headaches specifically diagnosed as

migraine, with or without aura, were selected, in accordance

with criteria established by the International Headache Society.

The research was approved by the Ethics Committee of CCS-

UFPE and the results analyzed with SPSS 15.0. Six-hundred-

eight patients were selected, 266 (39.8%) of whom showed

autonomic symptoms as part of clinical signs of migraine crisis.

Of those, 125 had conjunctive hyperemia (102 women and

23 men), 110 had tearing (93 women and 17 men), 70 had

eyelid edema (63 women and 8 men), 21 had runny nose (18

women and 3 men), and 33 had nasal obstruction (25 women

and 8 men). With respect to the laterality of the pain, 309

(46.3%) were unilateral, 160 (24.0%) bilateral and 45 (6.7%)

unibilateral. 87 (13.0%) had unilateral and/or bilateral pain,

8 (1.2%) had unilateral and/or unibilateral, and 1 (0.2%)

had unilateral and/or bilateral and /or unibilateral. Aura were

found in 126 (18.9%) of the 667 examined. The most frequent

triggering factor was stress (emotional), 263 (47.5%) out of

554. 165 (29.8%) were triggered by sleep disturbance, 56

(10.1%) by fasting, 13 (2.3%) by strong smells, 15 (2.7%) by

eating chocolate, 9 (1.6%) by drinking an alcoholic beverage,

1 (0.2%) by physical effort, 9 (1.6%) from eating fried foods,

23 (4.2%) could not specify what the trigger was, and 114

(17.1%) did not supply this information. 405 (60.7%) of the

667 had a family history of migraines. The results of this

research indicate that although autonomic symptoms are

usually found in cases of unilateral pain, they may also be

found in patients with bilateral pain. As to autonomic symptoms

in the case of unilateral pain, eye disturbances (tearing,

conjunctive hyperemia and eyelid edema) were more common

than nasal (runny nose, nasal obstruction). No statistically

Correspondence

Maria da Conceição Filgueira SampaioMaria da Conceição Filgueira Sampaio

Maria da Conceição Filgueira Sampaio

concei2000@uol.com.br

significant relation was found between autonomic symptoms

and unilateral pain, nor was autonomic symptoms related to

the severity of the headaches. Aura, gender, triggering factors

and family history did not show any relationship to the

appearance of autonomic symptoms.

THESIS

219 Headache Medicine, v. 2, n.4, p.219, Oct./Nov/Dec. 2011

INFORMATION FOR AUTHORS

Headache Medicine is the official scientific journal of the Brazilian

Headache Society (SBCe) and of the Latin American Headache

Association (ASOLAC). It is published quarterly for the purpose of

recording and disseminating scientific production and contributions

from the scientific community in the field of Headache. Submitted

papers considered by the editors to be suitable for publication in the

journal will be evaluated by at least two reviewers and then accepted

or rejected according to the peer review system.

General RemarksGeneral Remarks

General Remarks

Manuscripts written in English are preferred, but those written in

Portuguese and Spanish are also accepted. The full title must be

written both in English and in Portuguese and the running title is

limited to a maximum of 50 characters. It is obligatory to list the

institution in which the work was carried out as well as the authors'

full names without abbreviations and their present position and

institution. Additionally, information about any possible conflict of

interest must be disclosed. The full address of the corresponding

author must include telephone numbers and e-mail. The manuscript

should be send as a Word file (double spacing, Arial or Times New

Roman, font 12) and must include abstracts in English and in

Portuguese, both of up to 250 words and three to five descriptors

(keywords and descritores).

ReferencesReferences

References

Headache Medicine adopts the International Committee of Medical

Journal Editors (ICMJE) Uniform Requirements for Manuscripts

(URM), available at http://www.icmje.org/manuscript_1prepare.html.

The references must be numbered as they appear on the text.

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Illustrations and Pictures

CMYK pattern should be used for illustrations and pictures and the

minimum resolution is 300 dpi. Only TIFF, JPG or CDR formats will

be accepted. Figures should not be included within the text, but sent

as individual files.

ables: ables:

ables: Tables should be consecutively numbered

using Arabic numerals and cited in the text in numerical order.

TheThe

The

tables should be as DOC files, instead of image files.tables should be as DOC files, instead of image files.

tables should be as DOC files, instead of image files.

Authors:Authors:

Authors: ll designated authors should qualify for authorship by

sufficiently participating in the work in order to accept responsible

for its contents. Authorship includes substantial contributions in: (a)

conception and design, analysis and interpretation of data; (b) drafting

or critical review of the intellectual content; (c) approval of the final

version. Further information on the criteria of authorship credits can

be obtained at www.icmje.org/ethical_1author.html. Participation

in the acquisition of funds, compilation of data and general

supervision of the research team does not justify authorship. The

number of authors should follow the guidelines of the NML/NIH/

Index Medicus which, depending on the type of contribution, may be

increased at the discretion of the editors.

Original ArticleOriginal Article

Original Article

Maximum of 4000 words, including references. Title in English

and in Portuguese and running title up to 50 characters. Abstract in

English and Portuguese or English and Spanish (up to 250 words

each). Tables, illustrations and photographs: up to 7. References:

up to 30. The text should be divided in sections: Introduction,

Methods, Results and Discussion.

View and Review ArticleView and Review Article

View and Review Article

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and Portuguese or English and Spanish (up to 250 words each).

Tables, Illustrations and Photographs: up to 7. References: up to

100. Title in English and Portuguese and running title up to 50

characters. A Review Article should include a synthesis and critical

analysis of a relevant area and not only a chronological description

of publications. It should be written by a researcher who has significant

contributions in the specific area of Headache Medicine.

Clinical CorrespondenceClinical Correspondence

Clinical Correspondence

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up to five. Abstract in English and Portuguese or English and Spanish:

maximum of 250 words each. Tables, Illustrations and Photographs:

up to 2. References: up to 20. Title in English and in Portuguese.

Apart from the general remarks, it must have at least one of the

following characteristics: (a) be of special interest to the scientific

community; (b) be a rare case which is particularly useful to

demonstrate disease mechanisms or diagnostic issues; (c) presents

a new diagnostic method or treatment modality. The text should be

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authors: up to four. References: up to seven. Title in English and in

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Thesis Abstract

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keywords). One author and one mentor.

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Corresponding Address

Marcelo M. V

alença (mmvalenca@yahoo.com.br)

Fernando Kowacs (fkowacs@yahoo.com)

Editors-in-chief

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