April/May/June 2012

Nº 2

VOLUME

Headache

Medicine

Headache

Medicine

ISSN 2178-7468

EDITORIAL

Warming-up for the XXVI Brazilian Headache Congress

Aquecendo os motores para o XXVI Congresso Brasileiro de Cefaleia

Fernando Kowacs & Marcelo Moraes Valença

NEUROART

“Next time you have a headache, remember - pain is an illusion…”

“Na próxima vez que tiver uma dor de cabeça, lembre-se - a dor é uma ilusão…”

Marcelo Moraes Valença, Luciana Patrízia A. Andrade-Valença, Maria Helena Costa

HISTORICAL PAPERS

Brazilian Headache Society: how it all began

Sociedade Brasileira de Cefaleia: como tudo começou

Raimundo Pereira da Silva-Néto

VIEWS AND REVIEWS

Melatonin in headache disorders

A melatonina nas cefaleias

Andre Leite Gonçalves, Reinaldo Teixeira Ribeiro, Mario F. P. Peres

Headache and pregnancy

Cefaleia e gravidez

Eliana Meire Melhado, Andressa Regina Galego

Trigeminal neuralgia and persistent idiopathic facial pain

A neuralgia do trigêmeo e a dor facial persistente idiopática

Mark Obermann, Dagny Holle, Zaza Katsarava

ORIGINAL ARTICLE

Allodynia is more frequent in the individuals with more intense attacks of

headache and in women

Alodinia é mais frequente nos indivíduos com crises mais intensas

de cefaleia e nas mulheres

Gêssyca Adryene de Menezes Silva, Simone de Siqueira Bringel, Hugo André de Lima Martins,

Rosana Christine Cavalcanti Ximenes, Marcelo Moraes Valença, Daniella Araújo de Oliveira

Headache Medicine, v. 3, n.2, p.49, Apr./May./Jun. 2012 49

CONTENTS

EDITORIAL

Warming-up for the XXVI Brazilian Headache Congress .......................................................................................... 52

Aquecendo os motores para o XXVI Congresso Brasileiro de Cefaleia

Fernando Kowacs & Marcelo Moraes Valença

NEUROART

"Next time you have a headache, remember – pain is an illusion…" ........................................................................ 53

"Na próxima vez que tiver uma dor de cabeça, lembre-se – a dor é uma ilusão…"

Marcelo Moraes Valença, Luciana Patrízia A. Andrade-Valença, Maria Helena Costa

HISTORICAL PAPER

Brazilian Headache Society: how it all began .......................................................................................................... 55

Sociedade Brasileira de Cefaleia: como tudo começou

Raimundo Pereira da Silva-Néto

VIEWS AND REVIEWS

Melatonin in headache disorders ............................................................................................................................ 61

A melatonina nas cefaleias

Andre Leite Gonçalves, Reinaldo Teixeira Ribeiro, Mario F. P. Peres

Headache and pregnancy ...................................................................................................................................... 70

Cefaleia e gravidez

Eliana Meire Melhado, Andressa Regina Galego

Trigeminal neuralgia and persistent idiopathic facial pain ........................................................................................ 76

A neuralgia do trigêmeo e a dor facial persistente idiopática

Mark Obermann, Dagny Holle, Zaza Katsarava

ORIGINAL ARTICLE

Allodynia is more frequent in the individuals with more intense attacks of headache and in women ........................... 88

Alodinia é mais frequente nos indivíduos com crises mais intensas de cefaleia e nas mulheres

Gêssyca Adryene de Menezes Silva, Simone de Siqueira Bringel, Hugo André de Lima Martins,

Rosana Christine Cavalcanti Ximenes, Marcelo Moraes Valença, Daniella Araújo de Oliveira

Scientific Publication of the Brazilian Headache Society

Volume 3 Number 2 April/May/June 2012

Headache Medicine

ISSN 2178-7468

50 Headache Medicine, v. 3, n.2, p.50-51, Apr./May./Jun. 2012

Headache Medicine

ISSN 2178-7468

Jornalista responsável: Ana Carneiro Cerqueira – Reg. 23751 DRT/RJ

A revista Headache Medicine é uma publicação de propriedade da Sociedade Brasileira de Cefaleia, indexada no Latindex e no Index Scholar, publicada

pela Trasso Comunicação Ltda., situada na cidade do Rio de Janeiro, na Av. N. Sra. de Copacabana, 1059 sala 1201- 22060-001 - Copacabana - Rio

de Janeiro-RJ - Tel.: (21) 2521-6905 - Email: trasso@trasso.com.br - site: www.trasso.com.br. Os manuscritos aceitos para publicação passam a pertencer

à Sociedade Brasileira de Cefaleia e não podem ser reproduzidos ou publicados, mesmo em parte, sem autorização da HM & SBCe. Os artigos e

correspondências deverão ser encaminhados para a HM através de submissão on-line, acesso pela página www.sbce.med.br - caso haja problemas no

encaminhamento, deverão ser contatados o webmaster, via site da SBCe, a Sra. Josefina Toledo, da Trasso Comunicação ou a Sra. Magda Santos, da

SBCe, ou os editores (mmvalenca@yahoo.com.br ou fernandokowacs@gmail.com). Tiragem: 1.000 exemplares. Distribuição gratuita para os membros

associados, bibliotecas regionais de Medicina e faculdades de Medicina do Brasil, e sociedades congêneres. Publicidade: Paulo Carneiro

Editors-in-ChiefEditors-in-Chief

Editors-in-Chief

Fernando Kowacs

Marcelo Moraes Valença

ast Editorsast Editors

ast Editors

-in--in-

-in-

ChiefChief

Chief

Edgard Raffaelli Júnior (1994-1995)

José Geraldo Speciali (1996-2002)

Carlos Alberto Bordini (1996-1997)

Abouch Valenty Krymchantowsky (2002-2004)

Pedro André Kowacs and Paulo H. Monzillo (2004-2007)

Editors EmeritiEditors Emeriti

Editors Emeriti

Eliova Zukerman, São Paulo, SP

Wilson Luiz Sanvito, São Paulo, SP

International Associate EditorsInternational Associate Editors

International Associate Editors

Cristana Peres Lago, Uruguai

Gregorio Zlotnik, Canadá

Isabel Luzeiro, Portugal

José Pereira Monteiro, Portugal

Kelvin Mok, Canadá

Marcelo Bigal, USA

Nelson Barrientos Uribe, Chile

Editorial BoardEditorial Board

Editorial Board

Abouch Valenty Krymchantowski, Rio de Janeiro, RJ

Alan Chester F. Jesus, Aracaju, SE

Ana Luisa Antonniazzi, Ribeirão Preto, SP

Ariovaldo A. Silva Junior, Belo Horizonte, MG

Carla da Cunha Jevoux, Rio de Janeiro, RJ

Carlos Alberto Bordini, Batatais, SP

Celia P. Roesler, São Paulo, SP

Claudia Tavares, Belo Horizonte, MG

Cláudio M. Brito, Barra Mansa, RJ

Daniella de Araújo Oliveira, Recife, PE

Deusvenir de Sousa Carvalho, São Paulo, SP

Djacir D. P. Macedo, Natal, RN

Domingos Sávio de Souza Vieira, Caruaru, PE

Élcio Juliato Piovesan, Curitiba, PR

Elder Machado Sarmento, Barra Mansa, RJ

Eliana Meire Melhado, Catanduva, SP

Fabíola Dach, Ribeirão Preto, SP

Fabíola Lys Medeiros, Recife, PE

Jano Alves de Sousa, Rio de Janeiro, RJ

João José F. Carvalho, Fortaleza, CE

Joaquim Costa Neto, Recife, PE

José Geraldo Speciali, Ribeirão Preto, SP

Luis Paulo Queiróz, Florianópolis, SC

Marcelo C. Ciciarelli, Ribeirão Preto, SP

Marcelo Rodrigues Masruha, Vitória, ES

Marcos A. Arruda, Ribeirão Preto, SP

Mario Fernando Prieto Peres, São Paulo, SP

Maurice Vincent, Rio de Janeiro, RJ

Pedro A. S. Rocha Filho, Recife, PE

Pedro Ferreira Moreira Filho, Rio de Janeiro, RJ

Pedro André Kowacs, Curitiba, PR

Raimundo Silva-Néto, Teresina, PI

Renan Domingues, Vitória, ES

Renata Silva Melo Fernandes, Recife, PE

Headache Medicine

Scientific Publication of the Brazilian Headache Society

Headache Medicine, v. 3, n.2, p.50-51, Apr./May./Jun. 2012 51

Sociedade Brasileira de Cefaleia – SBCe

filiada à International Headache Society – IHS

Av. Pres. Vargas, 2001 sl. 125- Jd. América - Ribeirão Preto/SP 14020-260 - Tel: + (16) 3289-3143

Secretária executiva: Sra. Magda Santos – www.SBCe.med.br - secretaria2@sbcefaleia.com

Presidente

Marcelo C. Ciciarelli

Secretário

Luiz Paulo Queiróz

Tesoureiro

Carlos Alberto Bordini

Departamento Científico

Mario Fernando Prieto Peres, Luis Paulo Queiróz,

Eliova Zukerman, Marcelo C. Ciciarelli,

Pedro André Kowacs, José Geraldo Speciali, Eliana Melhado

Editores de Headache Medicine

Fernando Kowacs & Marcelo Moraes Valença

ComitêsComitês

Comitês

Comitê de Dor Oro-Facial

Renata Campi

Diretoria Biênio 2010/2012Diretoria Biênio 2010/2012

Diretoria Biênio 2010/2012

Presidente

Elder Machado Sarmento

Vicepresidente

Mônica Diez

Secretário

Alex Espinosa

Prosecretário

Michel Volcy

Associación Latinoamericana de Cefalea – ASOLACAssociación Latinoamericana de Cefalea – ASOLAC

Associación Latinoamericana de Cefalea – ASOLAC

Diretoria Biênio 2010-2012Diretoria Biênio 2010-2012

Diretoria Biênio 2010-2012

Tesoureiro

Cláudio Manoel Brito

Protesoureiro

Natali Arce leal

Vogais

Maria Teresa Goicochea

Mário Oliva

Noemi Tirretti

Comitê de Cefaleia na Infância

Sandro Espósito

Comitê de Leigos

Célia Roesler, Ana Antoniazzi,

Marcelo C. Ciciarelli, Patrícia Peixoto e Claudia Tavares

Delegado junto à IHS

Mario Fernando Prieto Peres

Delegado junto à ASOLAC

Elder Machado Sarmento

Responsável pelo Portal SBCe

Mario Fernando Prieto Peres

Representante junto à SBED

José Geraldo Speciali

Presidente do XXVI Congresso Brasileiro de Cefaleias

Pedro Ferreira Moreira Filho

52 Headache Medicine, v.3, n.2, p.52, Apr./May./Jun. 2012

Aquecendo os motores para o XXVI Congresso Brasileiro

de Cefaleia

EDITORIAL

esta segunda edição de 2012 da Headache Medicine, o leitor encontrará um conjunto de

artigos que certamente proporcionará uma leitura agradável e proveitosa. Além do relato original

descrevendo um levantamento sobre cefaleia e alodinia em um grande grupo de indivíduos,

realizado pela equipe da Universidade Federal de Pernambuco, temos um artigo de pesquisa

histórica cujo tema é a fundação da nossa Sociedade Brasileira de Cefaleia, escrito pelo colega

Silva-Néto - que vem tornando-se a referência para quem busca conhecer a história da cefaliatria

brasileira e seus fundadores. A sessão Neuroarte traz a visão de um artista de rua sobre a migrânea,

sendo muito interessante a concordância da imagem desenhada por ele com o quadro clínico

habitual da migrânea, em contraponto com a sua compreensão enviesada - ao nosso ver - sobre

a natureza do sintoma cefaleia. Os artigos de revisão nos permitem "absorver" o estado-da-arte

em três assuntos de grande importância: cefaleia e gravidez, cefaleia e melatonina e neuralgia do

trigêmeo & dor facial persistente idiopática. Os dois primeiros, escritos, respectivamente, por André

Gonçalves, Reinaldo Ribeiro e Mário Peres e por Eliana Melhado e Andressa Galego, mostram os

frutos do estudo aprofundado de alguns temas específicos por colegas da SBCe, compartilhados

com a comunidade cefaliátrica nesta publicação. O último é a benvinda contribuição de um dos

grupos de maior destaque da cefaliatria mundial, o grupo da Universidade de Duisburg-Essen,

que nos oferece uma revisão aprofundada, e ao mesmo tempo voltada para a prática clínica,

destes dois temas.

Não podemos deixar de citar a proximidade do XXVI Congresso Brasileiro de Cefaleia, que terá

lugar na fantástica cidade do Rio de Janeiro, em setembro próximo - acreditamos que esta edição da

Headache Medicine será um bom aperitivo para os tradicionais três dias de intensa aquisição de

conhecimento e troca de experiências que caracterizam os encontros anuais da nossa SBCe.

In this Headache Medicine 2012 second number, the reader will find a set of papers that will

certainly ensure a pleasant and fruitful reading. Besides an original work that describes headache

and allodynia association in a large group, made by Universidade Federal de Pernambuco team,

we have a historic research article, written by Silva-Néto - who is becoming the reference for those

who want to know the history of the Brazilian Headache Society and its founders. The Neuroart

section brings the point of view of a street artist on headache and the intriguing harmony between

his drawing and migraine usual clinical presentation, in opposition to his biased understanding -

in our view - about the nature of head pain. The review articles allow us to "absorb" the state-of-art

of three extremely important subjects: headache and pregnancy, headache and melatonin and

trigeminal neuralgia & persistent idiopathic facial pain. The two first, written respectively by André

Gonçalves, Reinaldo Ribeiro, Mário Peres and by Eliana Melhado and Andressa Galego, are

representative of the profound dedication to specific headache fields by some Brazilian Headache

Society members. The last one is a welcome contribution from the Duisburg-Essen University group,

one of the most prominent of world headache, which offers a review at the same time profound and

oriented to the clinical practice.

It is imperative to mention how close we are from the XXVI Brazilian Headache Congress,

which will take place in the wonderful city of Rio de Janeiro in September - we think that this edition

of Headache Medicine will be a good appetizer to the traditional three days of intense acquisition

of knowledge and experiences exchange that characterize SBCe annual meetings.

Fernando Kowacs & Marcelo Moraes Valença

Warming-up for the XXVI Brazilian Headache Congress

Headache Medicine, v.3, n.2, p.53-54, Apr./May/Jun. 2012 53

"Next time you have a headache, remember – pain

is an illusion…"

"Na próxima vez que tiver uma dor de cabeça, lembre-se – a dor é uma

ilusão…"

NEUROARTNEUROART

NEUROART

INTRODUÇÃO

During the 54

Annual Meeting of the American

Headache Society in Los Angeles we visited Santa Monica,

California on Sunday June 24, 2012. It was a beautiful

sunny day, with a happy crowd walking along the Third

Street Promenade. There were many musicians, dancers,

jugglers, among other artists entertaining the crowd. On

the sidewalk we met Sterling Simons, a young American

who was in the company of two friends offering his

drawing artistic expertise to the public. He could draw a

picture of anything of somebody's choice. Our request

was for him to draw whatever he could think of (or

interpret as) a "headache". He asked us to return in 30

minutes. Half an hour later he showed us the drawing of

a woman with migraine, which he entitled "The migraine"

(Figure 1). On the reverse side of the drawing Simons

wrote: "Next time you have a headache, remember -

pain is an illusion…" (Figure 2). Simons reported that he

had frequent headache attacks. We paid U$15.00 for

this precious work of art.

Trying to interpret the drawing, we think the artist,

whether consciously or not, represented the right part of

the woman's face somewhat blurred, as if a visual aura

were present. In addition, the hair covering the right eye

suggests the woman was suffering from some degree of

photophobia. The photophobia is also suggested by the

fact that both eyes are closed. It seems to represent a

severe attack, since she appears to express the facial

Figure 2. The reverse side of the drawing.

Marcelo Moraes Valença

, Luciana Patrízia A. Andrade-Valença

, Maria Helena Costa

Neurology and Neurosurgical Unit, Federal University of Pernambuco, Recife, PE, Brazil

Research Scholar in the International Institute at University of California at Los Angeles – UCLA, California, USA

Valença MM, Andrade-Valença LP, Costa MH. "Next time you have a headache, remember – pain is an

illusion…". Headache Medicine. 2012;3(2):53-4

Figure 1. Drawing: "The migraine".

54 Headache Medicine, v.3, n.2, p.53-54, Apr./May/Jun. 2012

VALENÇA MM, ANDRADE-VALENÇA LP, COSTA MH

mimicry of pain, reinforced by a clenched positioning of

the teeth, characteristic of a person suffering from pain.

Her hair is also uncombed, indicating an intense feeling

of sickness, common in migraineurs, and the characteristic

restful undisturbed behavior and less concern for personal

appearance during the period of suffering.

Thus, this is another example of neuroart, in which

neurological disorders depicted in a drawing may transmit

feelings of pain. Furthermore, the representation itself tells

us more about someone's (in this case, the artist's) particular

view on a specific subject which must be interpreted within

the context of a general (cultural?) understanding (in some

cases, misunderstanding) of a particular subject. In the

end, artistic representations influence the way the subject

itself is regarded, viewed, understood and interpreted.

Received: 6/25/2012

Accepted: 6/29/2012

Correspondence

Marcelo M. V Marcelo M. V

Marcelo M. V

alençaalença

alença

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

Headache Medicine, v.3, n.2, p.55-60, Apr./May/Jun. 2012 55

Sociedade Brasileira de Cefaleia: como tudo

começou

Brazilian Headache Society: how it all began

HISTORICAL PAPERHISTORICAL PAPER

HISTORICAL PAPER

Raimundo Pereira da Silva-Néto

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

Silva-Néto RP. [Brazilian Headache Society: how it all began].

Headache Medicine. 2012;3(2):55-60. Portuguese

RESUMORESUMO

RESUMO

A Sociedade Brasileira de Cefaleia (SBCe) foi fundada no dia 19

de maio de 1978 graças ao empenho de Edgard Raffaelli Júnior

(1930-2006). Ele foi o pioneiro no estudo da cefaleia na América

Latina e dedicou toda a sua vida a essa causa. Tudo começou

com 14 médicos e, hoje, a SBCe tem quase 400 membros

associados, distribuídos por todas as regiões do País. A partir de

1979, a SBCe passou a organizar uma reunião científica anual

(simpósio, curso ou congresso).

alavrasalavras

alavras

chave:chave:

chave: Cefaleia; Sociedade Brasileira de Cefaleia

ABSTRACTABSTRACT

ABSTRACT

The Brazilian Headache Society (BHS) was founded on May

19, 1978 thanks to the efforts of Edgard Raffaelli Jr. (1930-

2006). He pioneered the study of headache in Latin America

and he dedicated his life to this cause. It began with 14 doctors

and today, BHS has approximately 400 associate members

spread across all regions of the country. Since 1979, the BHS

organized an annual scientific meeting (symposium, conference

or course).

Keywords: Keywords:

Keywords: Headache; Brazilian Headache Society

A IDEALIZAÇÃO

A Sociedade Brasileira de Cefaleia (SBCe) foi fun-

dada no dia 19 de maio de 1978. No entanto, a sua

história é bem mais antiga e se confunde com a história

de Edgard Raffaelli Júnior (1930-2006), o pioneiro no

estudo da cefaleia na América Latina.

(1)

No ano de 1956, Raffaelli, aos 26 anos, ex-funcio-

nário do Citibank, era estudante do terceiro ano de

medicina. Naquele ano, procurou um neurologista, que

lhe disseram ser um dos melhores do país, para tratar

uma cefaleia diária que apresentava há mais de sete

anos. Após a consulta, saiu sem diagnóstico e sem trata-

mento, apenas orientado a procurar um psiquiatra.

Decepcionado, ele disse a si mesmo que, se os melhores

neurologistas do Brasil não conheciam cefaleia, ele iria

estudá-la.

(1,2)

Concluiu o curso de medicina em 1959 e, após três

anos, a residência médica em neurocirurgia. Em 1973,

ocorreu o seu doutoramento pela Faculdade de Medicina

da Universidade de São Paulo. Por conta própria,

dedicou-se ao estudo da cefaleia. Contudo, a partir de

1973, já não conseguia mais progredir nos estudos aqui

no Brasil. Desde então, começou a participar de todos

os congressos de cefaleia, na Europa e nos Estados

Unidos (em média, quatro ao ano), sem jamais encontrar

outro brasileiro (e isso continuou assim até 1983), e só

duas ou três vezes encontrando outro latino-americano,

o professor Gustavo Poch, catedrático de Neurologia na

Universidade Ramos Mejia, de Buenos Aires.

(1,2)

56 Headache Medicine, v.3, n.2, p.55-60, Apr./May/Jun. 2012

SILVA-NÉTO RP

Em 1975, fechou seu consultório na Avenida Pau-

lista para fundar, na Avenida Eusébio Matoso, a primeira

clínica de cefaleia da America Latina e que mantinha

ligações internacionais com o Migraine Trust of London

(Dra. Marcia Wilkinson), em Londres; Centro Cefalee di

Firenze (Prof. Federigo Sicuteri), em Florença; Centro

Cefalee di Torino (Prof. Giovani Nattero), em Turim;

Headache Clinic of the Faulkner Hospital (Dr. John

Graham), em Boston; Headache Clinic of Chicago (Dr.

Seymour Diamond), em Chicago; Headache Clinic of

Hospital Mount Sinai (Dr. David Coddon), em Nova

Iorque; Headache Clinic of Surrey County Hospital (Dr.

Desmond Carroll), na Inglaterra; Headache Clinic of

California (Dr. Lee Kudrow), na Califórnia; Grupo Austra-

liano, liderado pelo Dr. James Lance e o Grupo Escan-

dinavo (Noruega), liderado pelo Prof. Ottar Sjaastad.

(1,3)

Há alguns anos, Raffaelli procurava outro brasileiro

que se interessasse por cefaleia. Então, pediu a um amigo,

o ortopedista Júlio Casoy, médico do Laboratório Sandoz,

que o ajudasse. Com muita dificuldade, Casoy encontrou

dois neurologistas no Brasil que eram estudiosos em

cefaleia: Wilson Farias da Silva (1933-2008), em Recife,

e Gilberto Rebello de Mattos (1932-2011), em Salvador.

Em 1976, num encontro histórico, Edgard Raffaelli,

Wilson Farias, Gilberto Rebello de Mattos e Júlio Casoy

decidiram fundar uma sociedade.

(1,2)

OS FUNDADORES

Não foi uma tarefa fácil; somente no dia 19 de maio

de 1978, numa noite de sexta-feira, Raffaelli conseguiu

reunir, na sua clínica de cefaleia, situada à Avenida Eusébio

Matoso, 366, bairro Pinheiros, em São Paulo, um grupo

de 14 médicos (alguns pouco interessados em cefaleia)

para a fundação da Sociedade Brasileira de Cefaleia e

Enxaqueca (SBCe). O seu endereço tornou-se a sede

oficial da SBCe, conforme consta nos estatutos da

Sociedade. O Ce foi criado, por Raffaelli, para diferenciar

da SBC (Sociedade Brasileira de Cardiologia) e o adendo

"e Enxaqueca" foi para evitar que algum outro grupo

inventasse criar uma Sociedade Brasileira de Enxaqueca,

omitindo a cefaleia. Somente em 1992, não mais temendo

que se fundasse outra Sociedade no Brasil, mudou-se o

nome para Sociedade Brasileira de Cefaleia.

(1,2)

Foram esses os médicos que fundaram a SBCe

(Tabela 1): Edgard Raffaelli Júnior (Neurologista, São

Paulo), Wilson Farias da Silva (Neurologista, Recife),

Wilson Luiz Sanvito (Neurologista, São Paulo), Orlando

J. Martins (Neurologista, São Paulo), Roberto Melaragno

Filho (Neurologista, São Paulo), Nelson Augusto Pedral

Sampaio (Ginecologista, São Paulo), Reinaldo de Souza

Correa (Psiquiatra, São Paulo), Gilberto Rebello de Mattos

(Neurologista, Salvador), Luiz Márcio Itkis Hummel (Otorri-

nolaringologista, São Paulo), Osmar Trojan (Gineco-

logista, São Paulo), Julio Casoy (Ortopedista, São Paulo),

Ozir Scarante (Neurologista, São Paulo), José Ivan Cipoli

Ribeiro (Neurologista, Londrinas), Antônio Douglas

Menon (Otorrinolaringologista, São Paulo). Naquela

assembleia, além dos 14 médicos, havia uma mulher,

Paula Nohara, funcionária da clínica e que exerceu a

função de secretária da Sociedade até 1996. Portanto,

é importante reconhecer o seu silencioso trabalho de

apoio, companheirismo e luta incansável por uma causa

de valor imensurável em prol da cefaliatria brasileira.

(1-3)

Dos 14 fundadores, a maioria era conhecida por

Raffaelli de longa data. Por exemplo, em 1973, ele enca-

minhava os exames otoneurológicos ao Dr. Antônio

Douglas Menon, e os pacientes que necessitavam de ava-

liação psiquiátrica, ao Dr. Reinaldo de Souza Correa.

Por outro lado, atendia as pacientes migranosas enca-

minhadas pelo Dr. Osmar Trojan. Quando inaugurou a

sua Clínica de Cefaleia, criou o serviço de otoneurologia

e, por indicação do Dr. Antônio Menon, convidou para

trabalhar o Dr. Luiz Márcio Itkis Hummel. No período de

1970 a 1976, Raffaelli foi o chefe do serviço de Neuro-

logia e Neurocirurgia do Hospital e Maternidade Brasil,

Headache Medicine, v.3, n.2, p.55-60, Apr./May/Jun. 2012 57

SOCIEDADE BRASILEIRA DE CEFALEIA: COMO TUDO COMEÇOU

em Santo André, São Paulo. Lá, ele conheceu o Dr.

Orlando J. Martins, que sempre fez parte da clínica de

cefaleia, desde a sua fundação.

(3)

Era amigo do Dr. Nelson Augusto Pedral Sampaio

e, graças a essa amizade, conseguiu criar, em 1979, um

ambulatório de cefaleia na Clínica Ginecológica do

Hospital das Clínicas da Universidade de São Paulo

(HC-USP). Quanto aos doutores Wilson Luiz Sanvito e

Roberto Melaragno Filho, amigos de Raffaelli, foram

convidados, obviamente, por serem renomados neuro-

logistas e também demonstrarem interesse pela cefaleia.

No ano de 1976, no encontro de Salvador, conheceu

Wilson Farias da Silva e Gilberto Rebello de Mattos.

(3)

Roberto Melaragno Filho (1919-1998) formou-se na

Faculdade de Medicina, da Universidade de São Paulo

(USP), em 1942. Nos anos de 1947 e 1948, realizou

seus estudos em Neurologia como Assistente-Estrangeiro,

na Faculdade de Medicina de Paris, no serviço do

Professor Raymond Garcin. Foi professor livre-docente

da Faculdade de Medicina da USP.

(4)

Foi autor de vários livros, entre eles, destacam-se:

Afecções vasculares cerebrais (1959); Neuroimunologia

(1982); Esclerose Múltipla – manual para pacientes e

suas famílias (1992). Além disso, escreveu capítulos de

diversos livros didáticos de clínica médica e de neurologia,

assim como dezenas de trabalhos publicados em revistas

científicas. Faleceu no dia oito de fevereiro de 1998,

aos 79 anos.

(4)

Wilson Farias da Silva (1933-2008) formou-se pela

Faculdade de Medicina da Universidade do Recife (hoje,

Universidade Federal de Pernambuco), em 1957. Foi

professor titular de Neurologia e chefe do Departamento

de Neuropsiquiatria, da Universidade Federal de Pernam-

buco. Em 2006, recebeu o título de Professor Emérito

daquela instituição. Contribuiu na formação de inúmeras

gerações de neurologistas, tanto na graduação como

na pós-graduação. Faleceu, em Recife, no dia 24 de

outubro de 2008, aos 75 anos.

(5,6)

Na década de 1960, iniciou seus estudos em cefa-

leia e realizou as primeiras publicações sobre esse tema,

na América Latina. No entanto, o seu encantamento pelas

cefaleias veio, definitivamente, a partir de 1974.

(5)

1976, conheceu Edgard Raffaelli Júnior naquele encontro

histórico com Gilberto Rebello de Mattos e Júlio Casoy,

quando decidiram fundar a SBCe.

(5-7)

Ele, juntamente com Edgard Raffaelli Júnior, foi uma

das maiores autoridades brasileiras nos estudos e

pesquisas em cefaleias, com inúmeros artigos e livros

publicados. Finalmente, em 2000, a SBCe reconheceu

o seu mérito e criou o "Prêmio Wilson Farias da Silva",

um incentivo aos pesquisadores brasileiros no campo da

cefaleia.

(5,6)

Gilberto Rebello de Mattos (1932-2011) formou-se

pela Faculdade de Medicina da Universidade Federal

da Bahia (UFBA), em 1956. Fez residência médica em

Neurologia, na Santa Casa da Misericórdia, Rio de

Janeiro, de 1957 a 1959. Fez curso de Neuropediatria,

no HC-USP, em 1962. Foi professor adjunto de Clínica

Neurológica da Universidade Federal da Bahia e chefe

dos serviços de Neurologia e Eletroencefalografia do

Hospital Universitário Dr. Edgard Santos, em Salvador.

Em 1981, publicou o primeiro livro em língua portuguesa

sobre migrânea, intitulado Enxaqueca – o controle das

crise, com a colaboração de Wilson Farias da Silva.

(8)

Após a aposentadoria, como professor da UFBA, em

1988, foi morar em Sergipe, onde faleceu no dia dois

de abril de 2011, aos 79 anos.

(9)

Dos 14 membros fundadores, ainda vivos, apenas

dois participam, regularmente, das reuniões anuais da

SBCe: Wilson Luiz Sanvito e Orlando J. Martins. Segundo

Raffaelli, desses 14, sete compareceram apenas à reunião

de fundação da Sociedade, assinaram a ata, mas não

persistiram.

(1)

Wilson Luiz Sanvito formou-se pela Faculdade de

Medicina da Universidade Federal do Paraná, em 1958.

Iniciou o seu treinamento em Clínica Neurológica no

Serviço de Neurologia do Hospital das Clínicas de São

Paulo e complementou a sua formação de especialista

no Hospital da Salpétrière, na França. Lá, obteve o título

de Assistant Étranger da Faculdade de Mecidina de Paris.

Atualmente, é médico da Irmandade da Santa Casa de

Misericórdia de São Paulo e professor titular de Neuro-

logia da Faculdade de Ciências Médicas da Santa Casa

de São Paulo.

Publicou mais de uma centena de trabalhos científicos

em revistas nacionais e estrangeiras. É autor de sete livros

em neurociências e vários volumes de crônicas. São livros

de sua autoria: O mau gênio do cérebro: o impacto da

doença neurológica (A girafa, 2006); Esclerose Múltipla

no Brasil: aspectos clínicos e terapêuticos (Atheneu, 2005);

Doença de Parkinson: prática clinica e terapêutica (Atheneu,

2005); O mundo das minhas reflexões (Atheneu, 2005);

O Homen (Im) Perfeito (Atheneu, 2002); O Livro das

Cefaleias (Atheneu, 2001); O colecionador de idéias

(Atheneu, 1998); A arte de pensar & Outras artes (Lemos

Editorial, 1998).

Orlando J. Martins formou-se pela Escola Paulista

de Medicina da Universidade Federal de São Paulo

58 Headache Medicine, v.3, n.2, p.55-60, Apr./May/Jun. 2012

(Unifesp), em 1969. Fez residência médica em Neurologia

no Hospital do Servidor Público do Estado de São Paulo,

de 1970 a 1972. Recebeu os títulos de especialista em

Neurologia, concedido pela Associação Médica Brasileira,

em convênio com a Academia Brasileira de Neurologia,

em 1978, e de especialista em Eletroencefalografia, conce-

dido pela Associação Médica Brasileira e pela Sociedade

Brasileira de Eletrofisiologia Clínica, em 1978.

(10)

Ele participou de todos os congressos, simpósios,

encontros e cursos de atualização em cefaleia, organi-

zados pela SBCe, desde a sua fundação até 1998.

Dentre os grandes vultos da cefaliatria nacional,

deve-se lembrar o nome de Eliova Zurkerman que,

mesmo não tendo participado da fundação da SBCe,

tinha interesse em cefaleia há muito tempo. No ano da

fundação da SBCe, em 1978, ele inaugurou o Setor de

Investigação e Tratamento da Cefaleia, na Escola Paulista

de Medicina.

(2)

OS CONGRESSOS

Em 1979, a SBCe organizou o seu primeiro sim-

pósio, no Hospital do Servidor Público Estadual, em

São Paulo, com a presença de 126 participantes. Foram

convidados três professores estrangeiros: John Graham

(EUA), Federigo Sicuteri (Itália) e Gustavo Poch (Argen-

tina). A partir desse ano (Tabela 2), a SBCe passou a

organizar uma reunião anual (simpósio, curso ou con-

gresso).

(1,2)

Naquela época, não era fácil conseguir patrocínio

e, nos primeiros anos, Raffaelli pagava, às suas próprias

custas, todas as despesas. Teve que comprar um mimeó-

grafo usado para reproduzir os boletins da SBCe.

SILVA-NÉTO RP

Fotos do Primeiro

Simpósio

Brasileiro de

Cefaleia e

Enxaqueca (1979).

Headache Medicine, v.3, n.2, p.55-60, Apr./May/Jun. 2012 59

deve ao fato da SBCe ter sido fundada naquele estado.

No entanto, é bom lembrar que a primeira reunião feita

pelos neurologistas Edgard Raffaelli Júnior, Gilberto

Rebello de Mattos e Wilson Farias da Silva ocorreu no

Nordeste, na cidade de Salvador e, curiosamente, essa

região desponta em segundo lugar em número de

associados (Tabela 3).

A SBCe tem participação ativa, através de seus

membros, no Departamento Científico (DC) de Cefaleia

da Academia Brasileira de Cefaleia. Em 2007, esse

departamento criou o dia nacional da cefaleia, a exemplo

da Europa, que comemora o migraine day, no dia 12 de

setembro, e dos EUA, o headache day, no dia 10 de

novembro. No Brasil, foi escolhido o dia 19 de maio,

uma homenagem ao dia da fundação da SBCe.

AS DIRETORIAS

Raffaelli foi o comandante que determinou o plano

de voo da SBCe e, no período de 1978 a 1996, ele

esteve à frente da Sociedade, ora como presidente, ora

como secretário (quando o presidente era Sanvito ou

Wilson Farias). A partir de 1996, os presidentes da SBCe

(Tabela 4) foram, Carlos Alberto Bordini (1996 a 2000),

Pedro Moreira Ferreira Filho (2000 a 2004), Jano Alves

de Sousa (2004 a 2008), Carlos Alberto Bordini (2008

a 2010) e Marcelo Cedrinho Ciciarelli (a partir de

2010),

(1,2)

SOCIEDADE BRASILEIRA DE CEFALEIA: COMO TUDO COMEÇOU

Somente em 1994 veio a ser publicada a revista Migrâ-

neas & Cefaleias (criada e batizada com esse nome, por

Raffaelli) e que, no ano de 2010, passou a ser chamada

de Headache Medicine.

(2,3,11)

Em 1979, durante a realização do I Simpósio de

Cefaleia, em São Paulo, o artista plástico Francisco

Raffaelli, falecido em julho de 1997, criou a logo-

marca

(12)

da SBCe. Ele era irmão de Edgard Raffaelli

Júnior.

OS MEMBROS

Atualmente, a SBCe tem 383 membros associados

e distribuídos em 25 estados do Brasil e no Distrito

Federal. No estado de Alagoas tem apenas um membro.

Ainda não está presente nos estados do Amapá e

Roraima.

A maioria de seus membros se encontra na região

sudeste, principalmente no estado de São Paulo. Isto se

60 Headache Medicine, v.3, n.2, p.55-60, Apr./May/Jun. 2012

CONCLUSÃO

Seguramente, não existiria uma SBCe sem Edgard

Raffaelli Júnior, um homem que se aventurou a ser mal

falado numa época em que cefaleia não era bem vista

pela classe médica. Graças à sua seriedade e hones-

tidade, emprestando o seu nome à SBCe, a cefaliatria

brasileira tem, hoje, renome internacional.

REFERÊNCIAS

1. Silva-Néto RP. Quem foi Edgard Raffaelli Júnior. Migrâneas

Cefaleias 2006;9(4):152-8.

2. Maranhão Filho P. História das cefaleias. In: Speciali JG, Silva

WF. Cefaleias. São Paulo: Lemos Editorial, 2002, p. 15-33.

3. Nohara P. Depoimento [mensagem pessoal]. Mensagem

recebida por netoesperantina@terra.com.br em 30 nov. 2010.

4. Melo ACP, Spina-França A. In Memoriam: Roberto Melaragno

Filho. Arq Neuropsiquiatr 1998;56(2):328-9.

5. Valença MM, Costa Neto, J. Professor Wilson Farias - Um

baluarte da cefaliatria brasileira. Migrâneas Cefaleias

2007;10(3):88-93.

6. Bastos O, Costa Neto J. Necrológios: In Memoriam - Wilson

Farias da Silva. Neurobiologia 2009;72(1):149-52.

7. Silva-Néto RP. Cefaleia no Nordeste do Brasil e o idealismo de

José Martônio Ferreira de Almeida. Headache Medicine 2012

(trabalho aceito para publicação).

8. Mattos GR. Enxaqueca: o controle das crises. Salvador: Artes

Gráficas e Indústria Ltda., 1981, 71 p.

9. Dicionário Biográfico de Médicos de Sergipe. Disponível em:

<http://linux.alfamaweb.com.br/asm/dicionariomedico/

dicionario.php?id=31906> Acesso em: 29 dez. 2011.

10. Raffaelli Jr E, Silva Neto R, Roesler CP. Dor de cabeça: um guia

para entender as dores de cabeça e seus tratamentos. Rio de

Janeiro: Prestígio Editorial, 2005, 118 p.

11. Silva-Néto RP. A revista Migrâneas & Cefaleias - quinze anos de

história. Migrâneas Cefaleias 2009;12(2):44-9.

12. Silva-Néto RP. O uso de um diagrama craniano na localização

da dor. Hedache Medicine 2011;2(1):13-5.

Correspondência

aimundo Paimundo P

aimundo P

ereira da Silva-Nétoereira da Silva-Néto

ereira da Silva-Néto

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

Recebido: 19/12/2011

Aceito: 10/4/2012

SILVA-NÉTO RP

COMENTÁRIOS

Nosso colega e amigo de Teresina, Silva-Néto é um

historiador da Sociedade Brasileira de Cefaleia. Conviveu

com o Dr. Rafaelli alguns anos, tendo sido um dos seus

últimos estagiários. Contou-nos que durante esse contato

com nosso saudoso professor, este lhe confidenciou

inúmeros dados relativos à sociedade. Dr. Raffaelli ainda

relatou varias passagens importantes de sua vida. Em

algum dos nossos congressos conversei longamente com

Silva-Neto sobre sua missão de tornar públicas todas as

conversas que teve com nosso grande mestre, e vejo com

alegria e interesse os seus artigos publicados na revista

abordando a história da SBCe. Considero este artigo,

ora publicado, um marco, pois Silva-Néto descreve o

perfil de cada um dos precursores de nossa sociedade,

que se desenvolveu com o esforço e determinação dos

colegas citados nesse artigo, sob a batuta firme e impar-

cial do Dr. Raffaelli. Todos nós podemos avaliar como

foi difícil esse começo, com a cefaleia desacreditada como

problema maior de saúde. Silva-Néto nos dá uma ideia,

na medida certa, do quanto devemos para esses

pioneiros e apaixonadas pelo ensino das cefaleias. Os

congressos no exterior eram pagos do próprio bolso e

os congressos e simpósios brasileiros eram subsidiados

pelos seus organizadores. As listagens dos congressos e

das diretorias aqui colocadas foram possíveis por causa

da obstinação de Silva-Néto. Meu incentivo agora é que

Silva-Néto organize o Museu da Cefaleia e conclamo

todos os que possuem algo interessante e que retrate

uma parte importante da vida da SBCe e dos seus mem-

bros natos que entreguem esse material ao Silva-Néto a

fim de que ele os organize e os reúna em um local público

aberto à visitação dos interessados.

José Geraldo SpecialiJosé Geraldo Speciali

José Geraldo Speciali

Faculdade de Medicina de Ribeirão Preto, USP

Ribeirão Preto, SP, Brasil

Headache Medicine, v.3, n.2, p.61-69, Apr./May/Jun. 2012 61

Melatonin in headache disorders

A melatonina nas cefaleias

VIEW AND REVIEWVIEW AND REVIEW

VIEW AND REVIEW

Andre Leite Gonçalves, Reinaldo Teixeira Ribeiro, Mario F. P. Peres

Universidade Federal de São Paulo (UNIFESP), São Paulo, SP, Brazil; Hospital Israelita Albert Einstein,

Instituto de Ensino e Pesquisa (INCE), São Paulo, SP, Brazil

Gonçalves AL, Ribeiro RT, Peres MF. Melatonin in headache disorders. Headache Medicine. 2012;3(2):61-9

ABSTRACTABSTRACT

ABSTRACT

Melatonin have diverse physiological functions, including the

control of circadian rhythms, sleep regulation, enhancement

of immunological functioning, free radical scavenging and

antioxidant effects, inhibition of oncogenesis, mood regulation,

vasoregulation, regulation of seasonal reproductive activity

and analgesia. Melatonin also have several actions within

the central nervous system and in the pathophysiology of

headaches, which include an anti-inflammatory effect, toxic

free radical scavenging, reduction of proinflammatory cytokine

up-regulation, nitric oxide synthase activity and dopamine

release inhibition, membrane stabilization, GABA and opioid

analgesia potentiation, glutamate neurotoxicity protection,

neurovascular regulation, serotonin modulation, and the

similarity of chemical structure to that of indomethacin. A

relation with seasonal and circadian pattern has been observed

in cluster an hypnic headache. The literature of headache is

convergent in pointing to low levels of melatonin in patients

with migraine and cluster headache. Treatment of headache

disorders with melatonin and other chronobiotic agents is

promising. Some trials showed that melatonin was effective in

cluster headache and migraine prevention but future studies

are necessary for the better understanding of the role of

melatonin in headache disorders treatment.

eywords: eywords:

eywords: Melatonin; Pineal gland; Migraine; Pathophysiology;

Treatment

RESUMORESUMO

RESUMO

A melatonina tem diversas funções fisiológicas, incluindo o

controle de ritmos circadianos, regulação do sono, melhoria

do funcionamento imunológico, varredura de radicais livres

e efeitos antioxidantes, inibição da oncogênese, regulação

do humor, vasoregulação, regulamentação da atividade

reprodutiva sazonal e analgesia. A melatonina também tem

várias ações dentro do sistema nervoso central e na fisio-

patologia das cefaleias, as quais incluem um efeito anti-infla-

matório e de limpeza de radicais livres tóxicos, a redução de

citocinas pró-inflamatórias, da inibição da atividade da óxido

nítrico sintase e da produção de dopamina, a estabilização

das membranas, potencialização da analgesia GABA e de

opioides, proteção contra a neurotoxicidade do glutamato,

regulação neurovascular, modulação da serotonina, além

de possuir estrutura química similar à da indometacina. Uma

relação com padrão sazonal e circadiano tem sido observada

na cefaleia em salvas e hipnica. A literatura de dor de cabeça

e melatonina é convergente em apontar a presença de baixos

níveis deste hormônio em pacientes com enxaqueca e cefaleia

em salvas. O tratamento das cefaleias com melatonina e

outros agentes cronobióticos é promissor. Alguns estudos

mostraram que a melatonina foi eficaz na cefaleia em salvas

e na prevenção da enxaqueca, porém futuros estudos são

necessários para comprovar seu beneficio no tratamento das

cefaleias.

alavrasalavras

alavras

chave:chave:

chave: Melatonina; Glândula Pineal; Enxaqueca;

Fisiopatologia; Tratamento

INTRODUÇÃO

Melatonin (5-methoxy-N-acetyltryptamine) was

discovered by Aaron Lerner in 1958. Melatonin synthesis

has been described in numerous peripheral organs, such

as the retina,

(1)

bone marrow,

(2)

skin,

(3)

platelets,

(4)

lymphocytes,

(5)

testis,

(6)

and in the gastrointestinal tract.

(7,8)

In these tissues melatonin seems to plays either an autocrine

or a paracrine role. Data on messenger RNA expression

62 Headache Medicine, v.3, n.2, p.61-69, Apr./May/Jun. 2012

GONÇALVES AL, RIBEIRO RT, PERES MF

of two key enzymes responsible for melatonin synthesis,

arylalkyamine-N-acetyltransferase and hydoxyindole-O-

methyltransferase, suggest that even more peripheral

organs may be able to produce this hormone.

(9)

Physiology of melatoninPhysiology of melatonin

Physiology of melatonin

The pineal gland is highly vascular and consists of two

types of cells: neuroglial cell and pinealocytes, which

predominate and produce indolamines (melatonin) and

peptides (such as arginine vasotocin). In the biosynthesis of

melatonin, tryptophan is converted by tryptophan hydroxylase

to 5-hydroxytryptophan, which is decarboxylated to serotonin.

Melatonin is produced after serotonin is catalyzed by two

enzymes (arylalkylamine N-acetyltransferase and

hydroxyindole-O-methyltransferase).

(10,11)

The production

and secretion of melatonin are mediated largely by

postganglionic retinal nerve fibers that pass through the

retinohypothalamic tract to the suprachiasmatic nucleus,

then to the superior cervical ganglion, and finally to the

pineal gland. This neuronal system is activated by darkness

and suppressed by light. The activation of alpha-1 and

beta-1-adrenergic receptors in the pineal gland raises

cyclic AMP and calcium concentrations and activates

arylalkylamine N-acetyltransferase, initiating the synthesis

and release of melatonin. The daily rhythm of melatonin

secretion is also controlled by an endogenous, free-

running pacemaker located in the suprachiasmatic

nucleus. Melatonin is able to enter every cell of the body

and readily crosses the blood-brain barrier and the

placenta. Melatonin is enzymatically degraded in the

liver by hydroxylation (to 6-hydroxymelatonin) and, after

conjugation with sulfuric or glucuronic acid and is finally

excreted in the urine as 6-sulphatoxymelatonin (aMT6s).

Analysis of urine by the ELISA method is used as a

measure of melatonin secretion, since it closely parallels

with the profile of plasma nocturnal melatonin

concentrations.

(12)

There is some evidence suggesting that

a seasonal variation exists in the synthesis of melatonin

in humans, the levels possibly being higher in winter than

in summer.

(13)

Melatonin is a potent antioxidant, which can exert its

action in directly or indirectly. In addition to its direct free

radical scavenging action, melatonin has been reported

to increase the activity of some important antioxidant

enzymes at molecular level, including superoxide

dismutase and glutathione peroxidase.

(14)

Also melatonin

decreases the activity of nitric oxide synthase, a pro-

oxidative enzime.

(15)

In fact melatonin can also scavenge

hydroxy radical, peroxil radical, peroxinitrite anion, and

singlet oxigen protecting cell membrane, proteins in the

cytosol and DNA in the nucleus.

PharmacologyPharmacology

Pharmacology

The half-life of melatonin in the serum is between 30

and 57 minutes.

(16)

Intravenously administered melatonin

is rapidly distributed and eliminated.

(17)

In normal subjects,

80 mg of melatonin orally administered promote serum

melatonin concentrations that were 350 to 10,000 times

higher than the usual nighttime peak, 60 to 150 minutes

later, and these values remained stable for 90 minutes.

(18)

Lower oral doses (1 to 5 mg), result in serum melatonin

concentrations that are 10 to 100 times higher than the

usual nighttime peak, within one hour after ingestion,

followed by a decline to base-line values in four to eight

hours. Very low oral doses (0.1 to 0.3 mg) given in the

daytime result in peak serum concentrations that are within

the normal nighttime range.

(19)

otential use of melatonin in analgesia:otential use of melatonin in analgesia:

otential use of melatonin in analgesia:

mechanisms of actionmechanisms of action

mechanisms of action

Melatonin has been shown to exert antinociceptive

and antiallodynic actions in a variety of experimental

models in animals.

(20)

Induction of pain involves the release

of several pro-inflammatory mediators like cytokines and

the activation of a number of neurotransmitter receptor

sites present in both the spinal cord and brain. The

mechanisms that melatonin may act in pain are control

the release of pro-inflammatory mediators; inhibit the

activation of receptors involved in pain perception present

at spinal cord; inhibit receptor activation in brain regions

involved in pain perception and promote sleep that can

be extremely effective for controlling/inhibiting pain

perception.

The available evidence demonstrates that melatonin

seems to have a action in the opioid system and a

modulatory effect on the circadian rhythm of nociception.

Yousaf, in a review

(21)

of the use of melatonin in peri-

operative setting, reports anxiolytic and analgesic

properties. Melatonin premedication is effective in

ameliorating perioperative anxiety in adults. Compared

with midazolam, melatonin has similar anxiolytic efficacy

but less psychomotor impairment and fewer side effects.

The elderly population has been shown to be refractory

to the hypnotic and anxiolytic effects of melatonin.

(22)

The

clinical impact of melatonin on pain need to more studied

and the evidence regarding its potential analgesic effects

in the perioperative setting is inconsistent and limited.

Melatonin premedication was associated with an analgesic

Headache Medicine, v.3, n.2, p.61-69, Apr./May/Jun. 2012 63

MELATONIN IN HEADACHE DISORDERS

effect in the studies with pain as a primary outcome,

whereas the lack of analgesic effect was observed in

studies with pain as a secondary outcome.

(23-25)

It seems

that high doses of melatonin are required to produce major

analgesic effects.

(20)

The antinociceptive and antiallodynic

properties of melatonin have a perspective in future studies

in patients that suffer from pain due to inflammation,

occurring during headache, cancer patients, neuropathic

pain and fibromyalgia. It may be useful in patients with

comorbidities like anxiety that is frequently associated with

headache disorders.

is known to be important in the pathophysiology of

migraine. Finally, melatonin inhibits the synthesis of

prostaglandin E

, which has been identified as one of

many substances that can lead to sterile perivascular

inflammation (neurogenic inflammation) that activates the

trigeminovascular nociceptive afferents.

otential therapeutic use of melatonin inotential therapeutic use of melatonin in

otential therapeutic use of melatonin in

headache disordersheadache disorders

headache disorders

Melatonin has been implicated in the treatment of

different types of headaches (Table 2).

MELATONIN AND HEADACHES

Melatonin indeed demonstrates several actions within

the central nervous system (SNC), which may account for

its putative analgesic role in headache.

(26)

(Table 1).

First, melatonin potentiates the inhibitory action of

GABA on SNC and several GABAergic drugs have been

used successfully in the prophylaxis of migraine, such as

topiramate, divalproex and gabapentin.Thus, reduced

concentrations of melatonin might lower the activation

threshold of pain circuits normally inhibited by GABAergic

transmission. Second, because melatonin modulates the

entry of calcium into cells, a reduction in melatonin might

alter the tone or vasoreactivity of cerebral blood vessels.

Furthermore, melatonin receptors have been identified on

cerebral arteries and melatonin has also been shown to

modulate 5-HT2 receptors on cerebral arteries.

Antagonism at this 5-HT receptor is exploited by drugs

used to prevent migraine and CH. Additionally, a

melatonin-driven modulation of 5HT2 receptors was

suggested, similar to drugs used for migraine prophylaxis,

such as flunarizine, methysergide and beta-blockers.

(27)

Melatonin modulates different serotonin receptors which

MIGRAINE

The literature of headache and melatonin is

convergent point to low levels of this hormone in patients

with migraine,

(28-29)

menstrual migraine,

(30-31)

chronic

migraine

(32)

and cluster headache.

(33-38)

Claustrat et al.

(28)

were the first to demonstrate lower

plasma melatonin levels in samples from migraine patients

compared with controls. Migraine patients without

depression had lower levels than controls, but migraineurs

with superimposed depression exhibited the greatest

melatonin deficiency. Murialdo et al.

(31)

also found nocturnal

urinary melatonin to be significantly decreased throughout

the ovarian cycle of migraine patients without aura

compared with controls. Melatonin excretion was further

decreased when patients suffered a migraine attack.

Brun et al.

(30)

studied urinary melatonin in women with

migraine without aura attacks associated with menses and

controls. Melatonin levels throughout the cycle were

significantly lower in the migraine patients than in controls.

In the control group, melatonin excretion increased

significantly from the follicular to the luteal phase, whereas

no difference was observed in the migraine group.

64 Headache Medicine, v.3, n.2, p.61-69, Apr./May/Jun. 2012

Peres et al.

(32)

studied plasma melatonin nocturnal

profile in chronic migraine patients and controls. Lowered

melatonin levels in patients with insomnia were observed

compared with those without insomnia, and a phase delay

in the melatonin peak in patients versus controls.

Masruha et al.

(39)

were the first to demonstrate

reduction in melatonin levels during attacks in episodic

and chronic migraine. The study assessed 6-sulpha-

toxymelatonin (aMT6s) levels in a large consecutive series

of patients with migraine, comparing with controls. A total

of 220 subjects were evaluated (146 had migraine and

74 were control subjects). aMT6s urinary samples were

measured with quantitative ELISA technique. Among

patients with migraine, 53% presented pain on the day of

the urine samples collection. Their urinary aMT6s

concentration was significantly lower than in the urine of

patients without pain. There was no significant difference

in the aMT6s concentration of patients with migraine

without pain on the day of their urine samples collection.

AMT6s levels were even lower in patients with chronic

migraine and in the presence of a migraine attack. It was

also observed that the higher is the frequency of migraine

attacks, lower levels of aMT6s. These are also strongly

correlated, inversely, with levels of depression, anxiety,

fatigue, diagnosis of excessive daytime sleepiness and

the number of points of fibromyalgia.

(40)

CHRONIC MIGRAINE

The role of the hypothalamus in the pathophysiology

of chronic migraine (CM) was first studied by Peres el al.

(32)

in a experiment to explore the hypothalamic-tubero-

infundibular system (prolactin, growth hormone), the

hypothalamic hypophyseal-adrenal axis (cortisol), and

pineal gland function (melatonin) in CM. A total of 338

blood samples (13/patient) from 17 patients with CM

and nine (age and sex matched) healthy volunteers were

taken. Melatonin, prolactin, growth hormone, and cortisol

concentrations were determined every hour for 12 hours.

The study showed an abnormal pattern of hypothalamic

hormonal secretion in CM. Forty-seven per cent of patients

with CM had a significant phase delay in the melatonin

peak, and half had insomnia. Melatonin concentrations,

peak secretion, and AUCs were significantly lower in

patients with CM who had insomnia than in controls and

patients with CM without insomnia. In conclusion, they

found a decreased nocturnal prolactin peak, a increased

cortisol concentrations, a delayed nocturnal melatonin

peak in patients with CM, and lower melatonin

concentrations in patients with CM with insomnia. It

supports the report of Nagtegaal et al.

(41)

that showed a

phase delay in the nocturnal melatonin peak in patients

with delayed sleep phase syndrome and associated

headaches. They had a great improvement of both

symptoms after treatment with 5 mg melatonin.

reatment of migrainereatment of migraine

reatment of migraine

Claustrat et al.

(29)

reported six patients with status

migranous which were treated with infusion of 20 mg of

melatonin. Four patients have a headache relief in the

morning after night melatonin infusion and the other two

patients reported an improvement after the third night of

infusion, and three patients reported a decrease in intensity

during the migraine attacks.

Nagtegaal et al.

(41)

reported the case of a 54-year-

old man who suffered from disabling migraine attacks

without aura, twice a week. After starting melatonin

treatment, only three migraine attacks were reported in

12 months.

In an open study carried out by Peres et al.

(42)

the use

of 3 mg of melatonin was effective in the preventive

treatment of migraine. Of the 34 patients who were

evaluated, 78.1% showed clinical response, defined as a

reduction greater than 50% of the frequency of attacks.

The complete response, i.e. a reduction of 100% of

seizures, was observed in 25% of patients. The frequency

of headache, duration, intensity and analgesic

consumption decreased significantly (p <0.001) in the

first month of treatment in relation to the baseline period.

Miano et al.

(43)

designed a 3-month open label trial

of melatonin prophylaxis in children with primary headache.

After a one month baseline period patients received

preventive therapy with melatonin (3 mg) administered

orally at bedtime for three months without receiving

preventive drugs. A total of 22 children were enrolled and

13 subjects had migraine without aura, one male had

migraine with aura. On assessment at the completion of

the trial, 14 of the 21 subjects reported that the headache

attacks had decreased by more than 50% with respect to

baseline, and 4 reported having no headache attacks. In

7 of the 21 children the frequency of headache attacks

remained unchanged from baseline (three with migraine

without aura and four with chronic tension-type headache).

None of the patients reported an increased number of

attacks during the trial. One subject dropped out because

of excessive daytime sleepiness.

Side effects have been reported in association with

the ingestion of melatonin but are not serious. Physiologic

GONÇALVES AL, RIBEIRO RT, PERES MF

Headache Medicine, v.3, n.2, p.61-69, Apr./May/Jun. 2012 65

effects of the hormone (hypothermia, increased sleepiness,

decreased alertness, and possibly reproductive effects),

that are dose-dependent, have not yet been properly

evaluated in individuals that use large doses of melatonin

for prolonged periods of time.

TENSION-TYPE HEADACHE

In 1998, Nagtegaal et al.

(41)

reported three women

(aged 14, 14, and 23) suffering from chronic tension-type

headache (CTTH) in a total of 30 patients with delayed

sleep phase syndrome which were treat with 5 mg

melatonin. After treatment with melatonin their headache

disappeared within two weeks.

In a trial of melatonin prophylaxis in children, Miano

et al.

(43)

treated eight patients with CTTH in total of 22

children with primary headache. After a one month baseline

period without receiving preventive drugs, all children

received a 3-month course of melatonin (3 mg)

administered orally, at bedtime. The study lasted four

months: during the first month (baseline period) patients

received no preventive therapy for recurrent headache and

for the next three months received therapy with pure

melatonin (3 mg) administered orally at bedtime. From

the total of eight patients four are males. Headache attacks

had decreased, by more than 50%, in four patients, and

none reported a complete remission of headache.

CLUSTER HEADACHE

The circadian rhythmicity of CH has oriented the

studies toward the hypothalamus. The suprachiasmatic

nucleus (SCN) is the main control center of the biological

clock, which receives retinal information on luminosity and

projects it to the pineal gland where melatonin needs to

be produced in a circadian rhythm to act satisfactorily.

(44)

During the symptomatic phase of CH, the melatonin

production is reduced until its nocturnal peak

disappears,

(35)

thus altering biological rhythms and

decreasing its additional analgesic effect related to

gabaergic reinforcement,

(33)

calcium modulation

(26)

and

prostaglandin synthesis inhibition.

(45)

In 1984, Chazot et al.

(35)

detected a decrease in

nocturnal melatonin secretion and abolished melatonin

rhythm in CH patients. Waldenlind et al.

(37)

also showed

lowered nocturnal melatonin levels during cluster periods

than remissions and found that women had higher

melatonin levels than men throughout the year.

(36)

Smokers

had lower levels than non-smoking cluster headache

patients. Leone et al.

(34)

observed melatonin and cortisol

peaks significantly correlated in controls but not in cluster

headache patients, indicating a chronobiological disorder

in these patients. Blau and Engel

(46)

observed that 75 of

200 CH patients have a increase in body temperature

from exercise, and hot bath or elevated environmental

temperature may trigger cluster headache attacks. This

finding can be explained by a decrease in melatonin

secretion caused by temperature increase.

(47)

Melatonin has been implicated in the treatment of

cluster headache. There is one study Class II RCT on

melatonin for cluster prevention.

(33)

This is a double-blind,

placebo-controlled, parallel-group trial. The RCT (20

people; 18 with episodic cluster headache; two with chronic

cluster headache) compared oral melatonin 10 mg daily

versus placebo for two weeks. In comparison to the run-in

period, there was a reduction in daily headache frequency

in the melatonin group (p < 0.03), but not the placebo

group. Two patients with chronic cluster headache did not

respond to melatonin therapy. Adverse events were not

reported.

Peres and Rozen

(48)

described two chronic CH patients

who responded to melatonin (9 mg at bedtime). Melatonin

prevented nocturnal cluster attacks and also daytime attacks.

Nagtegaal et al.

(41)

reported one patient with delayed sleep

phase syndrome in association with episodic CH in whom

both disorders improved after melatonin treatment. There

are a few trials to evaluate melatonin in prevention of CH

and it was considered Level C for the prevention of CH.

(49)

INDOMETHACIN-RESPONSIVE HEADACHE

SYNDROMES

Melatonin has a chemical structure similar to that of

indomethacin and thi fact has led researchers to use

melatonin in the treatment of indomethacin-responsive

headache.

Primary stabbing headachePrimary stabbing headache

Primary stabbing headache

Rozen

(50)

reported three patients with primary stabbing

headache (PSH) with a positive response to indomethacin

that were administered melatonin to assess its effectiveness.

The three patients were given different dosages of

melatonin (3, 9 and 12 mg, respectively). All the patients

became asymptomatic and remained so throughout a 2-

to 4-month follow-up. Melatonin appears to be an

effective alternative treatment for PSH. Melatonin has a

clearly more favorable side-effect profile than

indomethacin. Rozen recommended to start with a bedtime

MELATONIN IN HEADACHE DISORDERS

66 Headache Medicine, v.3, n.2, p.61-69, Apr./May/Jun. 2012

dose of 3 mg and then to increase the dose by 3 mg

every four nights until pain relief is obtained, setting 24 mg

as the upper dose limit. However, in most cases, no

treatment is necessary given that PSH has a natural course

of spontaneous fluctuations, with only 14% of patients

experiencing persistent symptoms.

(51)

Hypnic headacheHypnic headache

Hypnic headache

Hypnic headache (HH) or primary sleep-related

headache is a rare primary headache disorder that mainly

affects elderly people. It was first described by Raskin, in

1988,

(52)

and 174 cases have been reported in the literature

so far.

(27)

The exact pathophysiological mechanisms of

HH have not yet been elucidated. It has been postulated

that HH may be the result of a chronobiological disorder,

serotonin, and melatonin dysregulation or a disturbance

of rapid eye movement (REM) sleep. In most of the patients

with HH who had polysomnographic studies, attacks were

associated with REM sleep,

(53-57)

however, non-REM related

HHs have also been reported.

Many patients reported a good response to

indomethacin, but some could not tolerate it. Caffeine

and melatonin treatments did not yield robust evidence to

recommend their use as single preventive agents.

Nevertheless, their association with lithium or indomethacin

seems to produce an additional therapeutic efficacy.

Lithium indirectly increases the level of melatonin

(58-60)

and

may thus affect the pathophysiology of HH.

Domitrz describes a case of HH, which were effectively

treated with flunarizine and melatonin (3 mg) in a 45-

year-old woman.

(61)

Dodick

(54)

describe a 68-year-old woman presented

with a 6-year history of nocturnal headaches that awaken

her from sleep. Treatment with melatonin (3 mg) at bedtime

was begun, and headache severity decreased from

moderate to mild and duration decreased to 15 to 20

minutes. The dose was increased to 6 mg, which rendered

her headache-free over a 4-month period.

Ghiotto et al.

(62)

report two cases of HH that improve

after treatment with melatonin.

Melatonin seems to be effective in a daily dose 3-5 mg

and in association with caffeine or another drug for

prophylaxis of HH. Melatonin was effective in four of 174

cases, in a recent review; thus, more studies are necessary

to evaluate your efficacy in HH.

(27,63)

Hemicrania continuaHemicrania continua

Hemicrania continua

In a few reports melatonin was shown to be effective

for HC. Spears

(64)

reported a case of hemicrania continua

in which attacks were successfully eliminated while taking

melatonin (7 mg) at bedtime after the patient was no

longer able to tolerate indomethacin due to gastrointestinal

side effects. Rozen

(65)

also reported an improvement in

the hemicrania continua after treatment with melatonin.

HEADACHES AND PINEAL CYSTS

Pineal cysts are benign lesions found in up to 2.6%

of adults. Asymptomatic pineal cysts are usually an

incidental neuroimaging finding.

Peres et al. described five cases of primary headaches

associated with pineal cysts and suggested that pineal

cysts could be related to headache disorders not because

of compression but abnormal secretion of the pineal

hormone melatonin.

(66)

Seifert et al. studied 51 pineal cysts

patients compared with 51 controls. Pineal cyst patients

had 2-fold more headaches than controls (51% vs

25%).The most common diagnosis in pineal cysts patients

was migraine in 26%, including 14% with migraine with

aura. One patient had hemicrania continua. The authors

suggest pineal cysts may be related to headaches,

particularly migraine. Interestingly, cyst diameter was not

different in patients with headache as compared with those

without headache. This finding supports the idea of Peres

et al.

(66)

that melatonin dysfunction may be the main

mechanism related to the headache. Melatonin has been

linked extensively to headache disorders with experimental

and clinical evidence.

(33,39,42,67,68)

Unfortunately, to date,

no measures of melatonin secretion have been performed

in pineal cysts patients. Small, asymptomatic pineal cysts

require no therapy. If they become symptomatic from

hydrocephalus, surgical options can be considered. The

patient with a headache disorder and a pineal cyst may

be treated preventively with melatonin starting with 3 mg

at bedtime and increasing to 15 mg.

(67)

MELATONIN, HEADACHE AND MEDICINAL

PLANTS

Melatonin have been found in several plants of

medicinal value in species like feverfew (Tanacetum

parthenium), St John's wort (Hypericum perforatum) and

huang-qin (Scutellaria baicalensis).

(69-71)

Feverfew has been

used in migraine treatment but sufficient scientific evidence

of efficacy has not been established to date.

(72,73)

Angelicae

Dahurica combined with Scutellaria baicalensis has been

widely used as herb-pairs in traditional Chinese medicine

to treat migraine headache. The interplay between

GONÇALVES AL, RIBEIRO RT, PERES MF

Headache Medicine, v.3, n.2, p.61-69, Apr./May/Jun. 2012 67

melatonin and these other reportedly potent compounds

may be a promising field of future research.

Melatonin agonistsMelatonin agonists

Melatonin agonists

Melatonin and melatoninergic agonists may also be

important in migraine comorbidity.

(67)

Insomnia in

headache patients is the most likely associated condition

in migraine to respond to melatonin therapy. Ramelteon

(Rozeren®), a selective melatonin 1 or 2 receptor agonist

can also be used for treatment of insomnia in migraine

patients and have a profile with few side effects comparing

with hypnotics drugs.

Agomelatine is a novel antidepressant and a

melatonin agonist, a MT1 and MT2 receptor-site. It has

been approved for major depression in Brazil.

Although no controlled studies with large samples

have been published, two randomized clinical trials

controlled with placebo for migraine prevention are

registered in clinicaltrials.org, one with melatonin and other

with ramelteon.

In Brazil there is no approval of Brazilian Health

Survillance Agency (ANVISA) for the use of melatonin as

a vitamin, as is in the United States and most of developed

countries, we totally agree with that. Brazilian law enables

public advertisement when a compound is registered as

a vitamin and this is not desirable for melatonin with the

current health assistance access for the general population.

In contrast, melatonin as a natural substance found in the

human body cannot be applied for a patent, it is cheap,

therefore no pharmaceutical company has financial

interest in the application of melatonin as a medication.

Important to notice that melatonin is not a banned drug,

and not prohibited in Brazil, it is only not registered as a

vitamin or a medication, as many other compounds,

including vitamins and not yet approved medication for

oncology treatments, the patient has the right to take it

and receive the best treatment option, and the physician

has the right to prescribe the best treatment option for his

or her patient. We hope in the near future melatonin could

be better delivered to patients with the regulatory issues

resolved.

CONCLUSION

Melatonin plays a significant role in the patho-

physiology of headaches. Melatonin can also be a good

option in the treatment of primary headaches, not only

those with nocturnal occurrence but also migraine and

other headaches. In the presence of insomnia or circadian

rhythm disturbance melatonin may also be helpful.

However more randomized clinical trials should be done

in order to give more evidence for melatonin prescription

in our current practice (see take home messages).

MELATONIN IN HEADACHE DISORDERS

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MELATONIN IN HEADACHE DISORDERS

Correspondence

André Leite GonçalvesAndré Leite Gonçalves

André Leite Gonçalves

Rua Itália, 438

13070-292 – Campinas, SP, Brazil

goncalvesnp@yahoo.com.br

Reveived: 5/10/2012

Accepted: 7/5/2012

70 Headache Medicine, v.3, n.2, p.70-75, Apr./May/Jun. 2012

Headache and pregnancy

Cefaleia e gravidez

VIEW AND REVIEWVIEW AND REVIEW

VIEW AND REVIEW

ABSTRACTABSTRACT

ABSTRACT

Headache in pregnancy is a peculiarity of woman life phase.

Correct diagnosis in pregnancy is the best thing for a

management gold standard. Some secondary headaches that

mimic migraine may begin during pregnancy, and can be

caused by vasculitis, brain tumor, pituitary tumor, arteriovenous

malformation, sinus disease, idiopathic intracranial

hypertension, subarachnoid hemorrhage, stroke, cerebral

venous thrombosis, pre-eclampsia and eclampsia. These

headaches must be correctly diagnosed. At the conclusion, if

a pregnant patient presents primary headache, it will be

necessary to treat her. The classic teratogenic risk occurs from

the 29

day to the 70

day of gestation. Women with severe

headache during this period should be treated because nausea

and vomiting in association with pain can be teratogenic to

the fetus. Non-pharmacological techniques are effective for

acute and preventive treatment and should be applied. If drugs

are necessary, will be choose minimal doses and medications

that causes fewer problems in pregnancy. Management of

pregnant women with migraine should be done with caution,

keeping in mind the low level of scientific evidences.

ey words: ey words:

ey words: Pregnancy; Headache; Migraine; Treatment.

RESUMORESUMO

RESUMO

Cefaleia na gestação é uma peculiaridade de uma fase da

vida da mulher. O diagnóstico correto da cefaleia na gravidez

é a chave para um tratamento de excelência. Algumas cefaleias

secundárias que mimetizam migrânea podem se iniciar durante

a gestação, e podem ser causadas por vasculites, tumor

cerebral, tumor hipofisário, malformação arteriovenosa,

sinusopatias, hipertensão intracraniana idiopática, hemorragia

subaracnóidea, acidente vascular encefálico, trombose venosa

cerebral, pré-eclâmpsia e eclâmpsia. Tais cefaleias devem ser

diagnosticadas corretamente. Ao se concluir que a paciente

grávida apresenta cefaleia primária, é necessário tratá-la. O

risco teratogênico clássico das drogas ocorre a partir do 29º

até o 70º dia a partir do 1º dia da última menstruação da

mulher. Mulheres com cefaleia intensa nesse período devem

ser tratadas, pois náuseas e vômitos em associação com dor

podem ser teratogênicos ao feto. Técnicas não farmacólogicas

são efetivas para tratamento agudo e preventivo e devem ser

empregadas. Se drogas forem necessárias, escolher as

menores doses e que causem menos problemas na gravidez.

O tratamento da gestante com enxaqueca deve ser realizado

com muita cautela, tendo-se em mente que o nível de evidência

é baixo.

alavrasalavras

alavras

chave:chave:

chave: Cefaleia; Gravidez; Enxaqueca; Tratamento

INTRODUCTION

Pregnancy is a peculiar woman life phase, considered

optional. It usually occurs during woman´s professional

highest peak. Headache in pregnancy is a woman's

particularity, and like other disturbances in this phase, must

be seen with caution. Its progress must be followed and

its treatment must be carefully addressed.

(1)

Correct diagnosisCorrect diagnosis

Correct diagnosis

The diagnosis of a headache disorder must be correct

for a suitable management. In pregnant and lactating

woman this is done through the Classification of the

International Headache Society (2004).

(2)

On the anamnesis of a pregnant woman with

headache, it´s important to always ask her if she had

headaches before pregnancy, or if the headaches started

during pregnancy, or if she had a prior headache and

there were changes in the headache characteristics during

the pregnancy.

Eliana Meire Melhado, Andressa Regina Galego

Faculdade de Medicina de Catanduva das Faculdades Integradas Padre Albino (FIPA), Catanduva, SP, Brazil

Melhado EM, Galego AR. Headache and pregnancy. Headache Medicine. 2012;3(2):70-5

Headache Medicine, v.3, n.2, p.70-75, Apr./May/Jun. 2012 71

It is always necessary to distinguish between pre-

existing headaches and those initiated during pregnancy

because there may be three possibilities: (1) monitoring

the behavior of an existing headache prior to pregnancy,

during pregnancy; (2) appearance of a new headache

during pregnancy; and (3) the woman had presented a

headache before getting pregnant and then develops a

new one during pregnancy.

SECONDARY HEADACHES

Migraine-like headache that began during pregnancy

may be secondary to vasculitis, brain tumor, chorio-

carcinoma, pituitary tumor, arteriovenous malformation

(AVM), sinus disease, idiopathic intracranial hypertension,

subarachnoid hemorrhage, stroke, cerebral venous

thrombosis, pre-eclampsia and eclampsia.

(3,4)

Some comments about specific secondary headaches:

1. The diagnosis of sinusitis is often overstated,

chronic sinus does not cause headache;

(3,4)

2. Only 48% of brain tumor patients develop

headache during pregnancy. Pregnancy does not increase

the risk of brain tumor;

3. Pregnant women have 13 times the risk of having

a stroke. One of the most common stroke during

pregnancy is cerebral venous thrombosis. Most cases

present neurological deficits, but the superior sagittal sinus

thrombosis may present with progressive headache,

without neurological signs or symptoms;

4. Subarachnoid hemorrhage explains 50% of

intracranial bleeding during pregnancy. Subarachnoid

hemorrhage may mimic eclampsia. Most cases of

intracranial hemorrhage, especially in the eclampsia

group, result from hypertension. Illicit substances (alcohol

and cocaine) is a cause of subarachnoid and intracerebral

hemorrhage during pregnancy;

(3)

5. Differential diagnosis of thunderclap headaches

of sudden onset includes reversible cerebral vaso-

constriction syndrome, subarachnoid hemorrhage by

aneurysm, cerebral venous thrombosis, dissection of the

carotid or vertebral artery, intraparenchymal hemorrhage

and pituitary apoplexy. Neuroimaging is required in such

cases. Reversible cerebral vasoconstriction syndrome

encompasses a diverse group of conditions, including

hypertensive encephalopathy and vasculopathy

associated with pregnancy and the postpartum period

(postpartum angiopathy). Reversible cerebral vaso-

constriction syndrome is characterized by sudden onset of

a severe headache that subsides within a few days to weeks

and resolves in most patients, approximately 12 weeks

after the presentation. A similar syndrome can be seen

with pre-eclampsia and eclampsia occurring before birth

or postpartum. A diagnosis of reversible cerebral vaso-

constriction syndrome requires the exclusion of other causes

of headache accompanied by tomography or magnetic

resonance imaging and magnetic angiography

resonance to evaluate arterial and venous vasoconstriction

or cerebral edema, and exclude cerebral venous

thrombosis. Cerebrospinal fluid obtained via lumbar

puncture can eliminate vasculitis or infection.

(5)

Symptomatic headaches require neuroimaging or

lumbar puncture to diagnose. The guidelines for neuro-

imaging in patients who are or may be pregnant are:

1. Determinate the necessity and the potential risks

of the procedure.

2. If possible, perform the examination during the

first 10 days postmenses, or if the patient is pregnant,

delay the examination until the third trimester or preferably

postpartum.

3. Pick the procedure with the highest accuracy

balanced by the lowest radiation.

4. Use MRI if possible.

5. Avoid direct exposure to the abdomen and pelvis;

6. Avoid contrast agents.

7. Do not avoid radiologic testing purely for the sake

of the pregnancy.

8. If significant exposure in incurred by a pregnant

patient, consult a radiation biologist.

9. Consent forms are neither required nor

recommended.

(4)

Head CT is relatively safe during pregnancy and is

the study of choice for head trauma and possible non-

traumatic subarachnoid, subdural or intraparenchymal

haemorrhage.

MRI is preferable for all other non-traumatic or non-

haemorrhagic craniospinal pathologies. The potential

risks of MRI in pregnancy are still controversial. First use

angiography to evaluate suspected vascular pathology,

but, when necessary, angiography is reasonably safe in

pregnant patient.

(4)

A CT scan exposes the mother to a radiation of

<0.01 Gray (Gy), while the threshold of fetal damage

with ionizing radiation directly into the maternal pelvis is

>0.1 to 0.2 Gy. To maintain the safety margin, the

National Council for Radiation Protection and

Measurements grouped the acceptable limits of radiation

in all scan sat 0.05 Gy. MRI does not show the same

level of risk associated with ionizing radiation.

72 Headache Medicine, v.3, n.2, p.70-75, Apr./May/Jun. 2012

Gadolinium-based contrast agents have been

associated with the development of nephrogenic systemic

sclerosis . This condition is rare and has been reported

to occur in patients with compromised renal function.

Gadolinium can cross the placenta into the fetal

circulation and, subsequently, is excreted into the amniotic

fluid, where the agent can remain for an extended period

of time. No prospective studies with large numbers of

patients have evaluated the risk of teratogenic or

mutagenic effects.

The American College of Radiology Guidelines

Document for Safe MR Practices recommends that

pregnant patient should only receive gadolinium-contrast

agents after careful consideration of the risk-benefit ratio.

Iodinated CT contrast agent has been associated with

contrast-induced nephropathy in as many as 21% of

patients who had a baseline glomerular filtration rate of

<50 ml/min/1.73 m

. Nephropathy induced by iodinated

CT contrast agent is usually reversible, but the condition

can be associated with nonrenal complications that can

prolong hospital stays and increase in-hospital mortality.

Free iodide in the contrast medium given to the mother

has the potential to depress fetal and neo natal thyroid

function. Neonatal thyroid function should, therefore, be

checked after delivery in such patients. The risk associated

with absorption of contrast medium during lactation is small

and can be considered insufficient to warrant stopping of

breastfeeding. The neonatal thyroid should be checked

after labor in such patients.

(5-10)

Potential indications for computed tomography or MRI

in headache investigation during pregnancy are the same

as an average patient with suspected secondary headache

(Table 1).

MEDICATIONS ON PREGNANCY AND FETUS

If the conclusion is that the pregnant patient presents

primary headache, it will be necessary to treat headaches

during pregnancy. Then, there will be a concern with

regarding the treatment.

ManagementManagement

Management

Treatment of pregnant women is a part of medicine

based in low scientific quality of evidence. The experience

in treating these women comes from case-control studies

and and populational retrospectives.

Tables with drugs risks in pregnancy risk of learning

disabilities are deficient, and 40% of the drugs do not

have a listed category. The decision about what to use

during pregnancy should be made case by case, using

incomplete information.

It must always be applied in migraineurs pregnant

women non-pharmacological treatment which is free from

risk to fetus and mother.

(1,11)

The classic teratogenic risk occurs from the 29

day

to the 70

day of gestation (after the first day of the

woman's last menstruation). Women with severe headache

during this period should be treated because nausea and

vomiting resulting due to pain may be teratogenic to the

fetus.

(12)

The evaluation of the first trimester is therefore a

serious methodological error, only the second and third

months represent the critical period of most major

congenital abnormalities (CAs). On the other hand, we

know that the critical period of some CAs exceeds the end

of third month, e.g., the critical period of posterior cleft

palate and hypospadias covers the 12

-14

and 14

weeks of gestation, while the critical period of

undescended testis and patent ductus arteriosus is 7 to 9

months and 9 to 10 months, respectively. Thus, the optimal

approach is to consider the specific critical period of each

CA separately.

(12)

The FDA (Food and Drug Administration) lists five

categories of labeling for drug use in pregnancy. These

categories provide therapeutic guidance, weighting the

risks as well as the benefits of the drug. An alternate

rating system is TERIS (an automated teratogen

information resource wherein ratings for each drug or

agent are based on a consensus of expert opinion and

MELHADO EM, GALEGO AR

Headache Medicine, v.3, n.2, p.70-75, Apr./May/Jun. 2012 73

the literature) which was designed to measure the

teratogenic risk to the fetus from drug exposure (Tables

2 and, 3).

Table 4 presents some drugs and their risk categories

(FDA and TERIS)

(3-5,12-16)

Magnesium, riboflavin, pyridoxine hydro-Magnesium, riboflavin, pyridoxine hydro-

Magnesium, riboflavin, pyridoxine hydro-

chloridechloride

chloride – there is no evidence of risk of multiple

congenital anomalies associated with periconceptional use

of vitamin supplementation.

(17)

Symptomatic treatment of migraineurSymptomatic treatment of migraineur

Symptomatic treatment of migraineur

pregnant womenpregnant women

pregnant women

Measures that can be used taken symptomatic therapy

in migraine of pregnant women are:

– Hydration.

– NSAIDs (ibuprofen, naproxen, can close the fetal

ductus arteriosus), corticosteroids (useful, occasional).

– Aspirin (low dose).

– Common analgesics (acetaminophen).

– Narcotic analgesics.

– Chlorpromazine, promethazine, metoclopramide;

– Triptans (naratriptan and sumatriptan) (no evidence

of abnormality, can be used if other drugs do not solve,

to avoid during the 2

and 3

months).

– Pyridoxine (for nausea – not teratogenic).

What not to use in pregnant women withWhat not to use in pregnant women with

What not to use in pregnant women with

headacheheadache

headache

Natural or herbal therapy (because they are less

studied); feverfew (by presenting possible teratogenicity);

ergotamine, dihydroergotamine (are contraindicated for

showing an association with increased risk of neural tube

defects and a higher proportion of premature births,

neonatal lower weight birth and low gestational age;

(18)

benzodiazepines and barbiturates (for cleft palate

occurrence and heart and urogenital defects), valproate

and divalproex

(1)

(for neural tube defects such as bifid

spina and myelomeningocele, cardiac abnormalities, such

as levocardia, aortic stenosis, patent ductus arteriosus,

tetralogy of Fallot, partial right bundle branch block,

ventricular septal defect, and various facial defects);

Receptor inhibitors of the angiotensin converting enzyme

(ACE) (association with fetal kidney problems).

(1)

CONCLUSIONS

It is recommend that women at childbearing age take

vitamin supplement with 0.4 g of folic acid to reduce risk

of neural tube defect. If pregnancy is desired by the

migraineurs, discontinuation of medications must be made

before conception. If the woman becomes pregnant during

treatment, the conduct will depend of the used medication.

Non-pharmacological techniques are effective for

acute and preventive treatment.

Preventive or prophylactic treatmentPreventive or prophylactic treatment

Preventive or prophylactic treatment

Classes of drugs that can be used like prophylactic

on pregnant woman migraine:

Beta-blockersBeta-blockers

Beta-blockers

– Propranolol – adverse events: delay uterine growth,

hypoglycemia, bradycardia and breathless;

– Atenolol – adverse events: lower weight at birth;

– Metoprolol -adverse effects: growth delay;

– Labetalol

(11)

Corticosteroids Corticosteroids

Corticosteroids – helpful for occasional use in a

regimen of short prophylaxis helps in the maturation of

fetal lungs.

(15)

Prednisone and prednisolonePrednisone and prednisolone

Prednisone and prednisolone – no risk, they must

have preference over dexamethasone, as the latter crosses

the placental barrier.

Serotonin reuptake inhibitors (SSRIs)Serotonin reuptake inhibitors (SSRIs)

Serotonin reuptake inhibitors (SSRIs) – fluoxetine

and sertraline are useful in migraine and comorbid

conditions such as anxiety or depression.

HEADACHE AND PREGNANCY