Headache Medicine Volume 10 Número 1 - 2019
Headache Medicine Volume 10 Número 1 - 2019
Editorial
► Tenth year of Headache Medicine Journal, 25 years
Original Article
► ID-Migraine is a sensitive tool for screening
migraine among patients with multiple sclerosis
► Aerobic exercise training for migraine prevention:
A trigger-based analysis
► Melatonin reverts CGRP expression induced by
capsaicin
Views and Reviews
►
thrombin and vitamin K inhibitors on migraine
treatment
► Cerebral energetic metabolism of individuals with
migraine through 31P-MRS: A systematic review
► Of the available triptans, which should be chosen
and how should they be used?
Case Report
► Cardiac cephalalgia: A deadly case report
► Coexistence of Sunct Syndrome and pituitary
tumor: A possible association to be recognized
Capav10n1.indd 1 22/10/19 18:13
i
Headache Medicine, v.10, n.1, 2019
EDITORIAL
Tenth year of Headache Medicine Journal, 25 years of Brazilian publications in the headache eld
Mario Fernando Prieto Peres; Marcelo Moraes Valença .................................................................................................................... 1
ORIGINAL ARTICLE
ID-Migraine is a sensitive tool for screening migraine among patients with multiple sclerosis
ID-Migraine é uma ferramenta sensível para identicação de enxaqueca em pacientes com esclerose múltipla
Marcos Vinícius de Queiroz; Washington Luiz G. Medeiros Jr; Audred C. Biondo Eboni; Eduardo A. Guimaraes
Nogueira; Marcus Vinicius M. Gonçalves; Nise Alessandra C. Sousa; Yara Dadalti Fragoso ..................................... 2-4
VIEWS AND REVIEWS
Systematic review of the benecial effects of thrombin and vitamin K inhibitors on migraine treatment
Revisão sistemática dos efeitos benécos dos inibidores de trombina e de vitamina K no tratamento da
enxaqueca
Eduardo de Almeida Guimaraes Nogueira; Angela dos Anjos Couto; Beatriz Moraes Grossi; Gabriela Dias Nunes;
Taliê Zanchetta B. Hanada; Yara Dadalti Fragoso ........................................................................................................................... 5-9
ORIGINAL ARTICLE
Aerobic exercise training for migraine prevention: A trigger-based analysis
Treinamento físico aeróbico na prevenção da migrânea: Uma análise de fatores desencadeantes
Arão Belitardo Oliveira; Diego Belandrino Swerts; Mario Fernando Prieto Peres ....................................................... 10-15
VIEWS AND REVIEWS
Cerebral energetic metabolism of individuals with migraine through 31P-MRS: A systematic review
Metabolismo energético cerebral de indivíduos com migrânea através da 31P-MRS: Uma revisão sistemática
Mírian Celly Medeiros Miranda David; Letycia dos Santos Neves; Carlúcia Ithamar Fernandes Franco; Rhowena
Jane Barbosa de Matos .......................................................................................................................................................................... 16-23
ORIGINAL ARTICLE
Melatonin reverts CGRP expression induced by capsaicin
Melatonina reverte a expressão de CGRP induzida pela capsaicina
Fabiano da Cunha Tanuri; Debora Amado; Eliangela de Lima; Iron Dangoni Filho;
Mario Fernando Prieto Peres ............................................................................................................................................................... 24-28
VIEWS AND REVIEWS
Of the available triptans, which should be chosen and how should they be used?
Dos triptanos disponíveis, quais devem ser escolhidos e como devem ser usados?
Marcelo Moraes Valença; Emanuela Paz Rosas; Raisa Ferreira Costa; Amanda Araújo da Silva; Maria Rosana de Souza
Ferreira; Rita Santana dos Reis; Marcelo Andrade Valença; Luciana Patrízia Alves de Andrade-Valença .................. 29-31
CASE REPORT
Cardiac cephalalgia: A deadly case report
Paulo Sergio Faro Santos; Matheus Kahakura Franco Pedro; Ana Carolina Andrade ................................................... 32-34
Coexistence of Sunct Syndrome and pituitary tumor: A possible association to be recognized
Coexistência entre Cefaleia do tipo SUNCT e tumor pituitário: Uma associação que deve ser reconhecida
Julia Vescovi Vieira; Amanda dos Santos Cintra; Ana Paula Alves Fonseca; Antônio José da Rocha; Renan
Barros Domingues ........................................................................................................................................................................................... 35
Headache Medicine
Scientic Publication of the Brazilian Headache Society
VOLUME 10 ∙ NUMBER 1 ∙ 2019
CONTENTS
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Headache Medicine, v.10, n.1, 2019
ii
Headache Medicine
Scientic Publication of the Brazilian Headache Society
Editores-chefes
Marcelo Moraes Valença
Universidade Federal de Pernambuco, Recife, PE, Brasil.
Mario Fernando Prieto Peres
Hospital Israelita Albert Einstein, IPq – HCFMUSP. São Paulo, SP, Brasil.
Editor Cientíco
Raimundo Pereira Silva-Néto
Universidade Federal do Piauí, Teresina, PI, Brasil.
Editor Emeritus
Wilson Luiz Sanvito
FCM Santa Casa de São Paulo, São Paulo, SP, Brasil.
Pesquisa Básica e Procedimentos
Élcio Juliato Piovesan
Universidade Federal do Paraná, Curitiba, PR, Brasil
Ensino, alunos e residentes
Yara Dadalti Fragoso – Santos, SP, Brasil.
Cefaleia na Mulher
Eliane Meire Melhado
Universidade de Catanduva, Catanduva, SP, Brasil.
Multiprossional
Juliane Prieto Peres Mercante
IPq – HCFMUSP, São Paulo, SP, Brasil.
Arão Belitardo de Oliveira
ABRACES – Associação Brasileira cefaleia em Salvas e
Enxaqueca, São Paulo, SP, Brasil
Debora Bevilaqu
a-Grossi
FMUSP – R
ibeirao Preto
Cefaleias Secundárias
Pedro Augusto Sampaio Rocha
Universidade Federal de Pernambuco, Recife, PE, Brasil.
Hipertensão e Hipotensão Liquórica
Ida Fortini
HC FMUSP, São Paulo, SP, Brasil.
Sandro Luís de Andrade Matas
UNIFESP, São Paulo, SP, Brasil
Cefaleias Trigêmino-Autonômicas
Maria Eduarda Nobre
Rio de Janeiro, RJ, Brasil
Cefaleia na Infância
Marco Antônio Arruda
Universidade Federal de São Paulo, SP, Brasil.
Dor orofacial
E
duardo Grossmann – Porto Alegre,
RS, Brasil.
Controvérsias e Expert Opinion
João José Freitas de Carvalho – Fortaleza, CE, Brasil.
Clinical Trials
Fabiola Dach
FMUSP, Ribeirão Preto, SP, Brasil
Teses
Fernando Kowacs, Porto Alegre, RS, Brasil
Imagens e Vídeos
Paulo Sérgio Faro Santos
INC, Curitiba, PR, Brasil
Advocacy
Elena Ruiz de La Torre
WHAM (World Headache Association for Migraine)
Madrid, Espanha
A revista Headache Medicine é uma publicação de propriedade da Sociedade Brasileira de Cefaleia, indexada no Latindex e no Index Scholar, publicada
pela Sociedade Brasileira de Cefaleia, www.sbcefaleia.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.headachemedicine.com.br - Distribuição gratuita para os membros
associados, bibliotecas regionais de Medicina e faculdades de Medicina do Brasil, e sociedades congêneres
Editores Associados
CONSELHO EDITORIAL
ISSN 2178-7468
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Headache Medicine, v.10, n.1, 2019
Headache Medicine
Scientic Publication of the Brazilian Headache Society
CONSELHO EDITORIAL
Rodrigo Noseda
Harvard Medical School, Boston, MA, EUA
Marlind Alan Stiles –
Jefferson Universtty, Philadelphia, PA, EUA
Charles Siow, Singapore
Maurice Borges Vincent, Indianapolis, IN, EUA
Michele Viana, Novara, Italia
Margarita Sanchez Del Rio, Madrid, Espanha
Sait Ashina,
Harvard Medical School, Boston, MA, EUA
Todd D Rozen,
Mayo Clinic, Jacksonville, FL, EUA
Elena Ruiz de la Torre, Espanha
Marco Lisicky, Cordoba, Argentina
Maria Teresa Goycochea, Buenos Aires, Argentina
Alex Espinoza Giacomozzi, Santiago, Chile
Joe Munoz Ceron, Bogota, Colombia
Faisal Amin, Copenhague, Dinamarca
Uwe Reuter, Berlin, Alemanha
Abouch Valenty Krymchantowski, Rio de Janeiro, RJ
Alan Chester Feitosa Jesus, Aracaju, SE
Ana Luisa Antonniazzi, Ribeirão Preto, SP
Carla da Cunha Jevoux, Rio de Janeiro, RJ
Carlos Alberto Bordini, Batatais, SP
Daniella de Araújo Oliveira, Recife, PE
Djacir D. P. Macedo, Natal, RN
Elder Machado Sarmento, Barra Mansa, RJ
Eliana Meire Melhado, Catanduva, SP
Fabíola Dach, Ribeirão Preto, SP
Fernando Kowacs, Porto Alegre, RS
Henrique Carneiro de Campos, Belo Horizonte, MG
Jano Alves de Sousa, Rio de Janeiro, RJ
João José de Freitas Carvalho, Fortaleza, CE
Luis Paulo Queiróz, Florianópolis, SC
Marcelo C. Ciciarelli, Ribeirão Preto, SP
José Geraldo Speziali, Ribeirão Preto, SP
Marcelo Rodrigues Masruha, Vitória, ES
Pedro Ferreira Moreira Filho, Rio de Janeiro, RJ
Pedro André Kowacs, Curitiba, PR
Mauro Eduardo Jurno, Barbacena, MG
Paulo Sergio Faro Santos, Curitiba, PR
Pedro Augusto Sampaio Rocha Filho, Recife, PE
Renata Silva Melo Fernandes, Recife, PE
Thais Rodrigues Villa, São Paulo, SP
Renan Domingues, Vitória, ES
Conselho Editorial Internacional
Conselho Editorial Nacional
A revista Headache Medicine é uma publicação de propriedade da Sociedade Brasileira de Cefaleia, indexada no Latindex e no Index Scholar, publicada
pela Sociedade Brasileira de Cefaleia, www.sbcefaleia.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.headachemedicine.com.br - Distribuição gratuita para os membros
associados, bibliotecas regionais de Medicina e faculdades de Medicina do Brasil, e sociedades congêneres
ISSN 2178-7468
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Headache Medicine, v.10, n.1, 2019
iv
Sociedade Brasileira de Cefaleia – SBCe
liada à International Headache Society – IHS
Av. Tenente José Eduardo n° 453, sala 203
27323-240 Barra Mansa - RJ - Brasil
Fone:+55 (24) 9 8847-9980 www.sbcefaleia.com.br
secretaria@sbcefaleia.com.br
Josiane Moreira da Silva - Secretária Executiva SBCe
DIRETORIA 2018/2021
DELEGADOS
Academia Brasileira de Neurologia (ABN)
Fernando Kowacs
José Geraldo Speziali
American Headache Society (AHS)
Marcelo Cedrinho Ciciarelli
Associación Latinoamericana de Cefaleias (ASOLAC)
Carlos Alberto Bordini
European Headache Federation (EHF)
Marco Antônio Arruda
International Headache Society (IHS)
Pedro André Kowacs
Sociedade Brasileira para o Estudo da Dor (SBED)
Eduardo Grossman - José G Speziali
Responsável pelo Site
Paulo Sérgio Faro Santos
Responsável pelas Mídias Sociais
Arão Belitardo Oliveira
Comissão de Ética
Elcio Juliato Piovesan - Jano Alves de Souza
José Geraldo Speziali - Mauro Eduardo Jurno
Registro de Cefaleia no Brasil
Fernando Kowacs - Mauro Eduardo Jurno
Vanise Grassi - Élder Machado Sarmento
Liselotte Menke Barea - Luis Paulo Queiroz
Marcelo Cedrinho Ciciarelli - Mario FP Peres
Pedro Augusto Sampaio Rocha-Filho
Políticas Públicas, Institucionais e Advocacy
Patricia Machado Peixoto
COMISSÕES
Prêmios
Carlos A Bordini - Djacir Dantas de Macedo
Jano Alves de Souza - Mauro Eduardo Jurno
Pedro F Moreira Filho - Raimundo P Silva-Néto
Atividades Físicas e Fisioterapia
Cláudia Baptista Tavares - Daniela A Oliveira
Debora Bevilaqua-Grossi
Cefaleia na Infância
Marco Antonio Arruda - Thais Rodrigues Villa
Cefaleia na mulher
Eliana Meire Melhado
Dor Orofacial
Ricardo Tanus Valle
Leigos
Celia A P Roesler - Henrique Carneiro de
Campos - João José Freitas de Carvalho
Paulo Sérgio Faro Santos
Alunos Residentes
Yara Dadalti Fragoso - Diego Belandrino Swerts
Izadora Karina da Silva - Marcos Ravi Cerqueira
Ferreira Figueiredo - Caroline Folchini
Saulo Emanuel Gomes Silva - Walkyria Will-
Patrick Emanuell - Eduardo Nogueira
Psicologia
Juliane Prieto Peres Mercante - Rebeca V. A.
Vieira - Rosemeire Rocha Fukue
Procedimentos Invasivos
Cláudio Manoel Brito
Élcio Juliato Piovesan
Presidente Elder Machado Sarmento
Secretário Mario Fernando Prieto Peres
Tesoureiro Pedro Augusto Sampaio Rocha Filho
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1
Headache Medicine, v.10, n.1, p.1, 2019
EDITORIAL
Tenth year of Headache Medicine Journal, 25 years of
Brazilian publications in the headache eld
It is surprising to look back and realize that Headache Medicine, the Journal of the Brazilian Headache Society,
is now in its tenth year. Not only that, but also the fact that the Brazilian Headache Society through our journals,
Headache Medicine, formerly known as “Migraneas & Cefaleias”, has been publishing scientic articles since 1994. This
attests to the Brazilian tradition in the eld.
Nonetheless, we now live in a new era of online journals, completely different submission processes, alternative
metrics to academic scientic citations, so it is high time to put our Journal and the supportive Brazilian Headache
Society in its deserved place among outstanding international journals in the eld of Neurology. It is time for us to
become truly International, to be part of all main indexation databases. We have grown up and are gradually moving
in this direction.
The editorial board has been renewed, with the exceptional cooperation of outstanding researchers from the
United States, Asia, Europa and Latin America.
Mario Peres has joined Marcelo Valença as joint editor-in-chief, and a new board of associate editors has been
selected to cover different areas in headache science, such as, Procedures, Women and headaches, Clinical trials,
Orofacial pain, Theses, Non-pharmacological treatments, Secondary headaches, Intracranial hypotension and
hypertension, Trigemino-autonomic cephalgias and Headaches in children.
A number of new sections have been introduced including controversies, expert opinions, images and video, and
advocacy. Professor Wilson Luiz Sanvito, our editor emeritus, will contribute with his thoughtful articles, and Professor
Silva-Neto, the scientic editor, the liaison member with the editorial board and the editors-in-chief. The contributions
of previous editors need to be duly recognized for, we would not be around today without their invaluable efforts.
We hope everyone contributing to Headache Medicine will never regret it. We trust that all the studies or articles
already published or due to appear in forthcoming editions will make us proud to be part of this dynamic scientic
community.
Our journal Headache Medicine and the Brazilian Headache Society have been recognized by the American
Headache Society and its outstanding journal Headache (The Journal of Head and Face Pain). A new supplement on
Brazilian Headache Medicine is on course to be launched soon, similar to previous ones in 2007 and 2015.
1,2
A virtual
section has been added to the Headache Journal website on Brazilian headache medicine since 2012.
3
Also, Toolboxes,
translated to Brazilian Portuguese,
4
can be found on this website, a section dedicated to patient education on a specic
topic, a clear indication of the prestige in which our society is held. This indicates that our work and prestige as
headache specialists have been recognized, as have our efforts in contributing to the progress of Headache Medicine
worldwide.
Mario Fernando Prieto Peres
Marcelo Moraes Valença
Editors-in-Chief, Headache Medicine
REFERENCES
1. Valença MM. The Brazilian contribution to the diagnosis and treatment of headache disorders. Headache. 2015 Feb;55 Suppl 1:1-3.
2. Valença MM, da Silva AA, Bordini CA. Headache research and medical practice in Brazil: an historical overview. Headache. 2015
Feb;55 Suppl 1:4-31.
3. https://headachejournal.onlinelibrary.wiley.com/doi/toc/10.1111/(ISSN)1526-4610.cefaliatria_no_brasil
4. https://headachejournal.onlinelibrary.wiley.com/page/journal/15264610/homepage/material_educativo_sobre_cefaleia__dor_
de_cabea_.htm
Creative Commons (CC BY) Attribution 4.0 International.
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2
Headache Medicine, v.10, n.1, p.2-4, 2019
ABSTRACT
RESUMO
Descritores: Enxaqueca; Migrânea; Cefaleia; Esclerose Múltipla; Interferona
ORIGINAL ARTICLE
ID-Migraine is a sensitive tool for screening migraine
among patients with multiple sclerosis
ID-Migraine é uma ferramenta sensível para identicação de
enxaqueca em pacientes com esclerose múltipla
Marcos Vinícius de Queiroz
1
Washington Luiz G. Medeiros Jr
2
Audred C. Biondo Eboni
2
Eduardo A. Guimaraes Nogueira
1
Marcus Vinicius M. Gonçalves
2
Nise Alessandra C. Sousa
3
Yara Dadalti Fragoso
1
1
Department of Neurology and Programa
de Pós-Graduação em Saúde e Ambiente,
Universidade Metropolitana de Santos, Santos,
SP, Brazil
2
Department of Neurology, Universidade da
Região de Joinville, Joinville, SC, Brazil
3
Department of Neurology, University Hospital
Getulio Vargas, Manaus, AM, Brazil
*Correspondence
Yara Dadalti Fragoso
E-mail: yara@bsnet.com.br
Received: November 24, 2018.
Accepted: January 13, 2019.
Creative Commons (CC BY) Attribution 4.0
International.
Introduction: Migraine and multiple sclerosis (MS) have been described as
comorbidities. While other types of headaches can be seen in patients with
MS, it is migraine that usually adds to the burden of patients suffering from an
already disabling and chronic neurological disease. Migraine is more prevalent
in patients with MS than in the general population, and can be worsened by
certain treatments that are used to control MS. ID-migraine is a tool to screen
migraine in a population. It consists of only three self-reported questions, and
shows good sensitivity, specicity and reliability. The aim of the present study
was to assess the role of ID-migraine as a potential tool for screening migraine
in patients with MS. Method: Patients diagnosed with MS for at least one
year were invited to answer ID-migraine. Demographic data and information
on MS therapy were obtained at the same time. Results: Sixty-two patients
participated in the study. There were 16 men and 46 women, of average age
35 years. Migraine was identied in 51.5% of them and 18% reported having
the characteristics of chronic migraine. ID-migraine showed 93% sensitivity
and specicity for migraine in this population. The medication most frequently
associated with worsening of previous migraine was interferon beta 1-a (27.4%
of the cases). Conclusion: ID-migraine was shown to be a potential tool for
identifying migraine in patients with MS. However, the high prevalence of
migraine in this population may have constituted a selection bias, since most
patients without headache may not have felt inclined to participate in this
voluntary investigation. The results from this pilot study will be expanded and
investigated in more detail in a large national study.
Keywords: Migraine; Headache; Multiple Sclerosis; Interferon.
Introdução: Enxaqueca e esclerose múltipla (EM) têm sido descritas como
comorbidades. Enquanto outros tipos de cefaleia podem ser vistos em pacientes
com EM, é a enxaqueca que geralmente completa a incapacidade de um paciente
que já sofre de uma doença neurológica crônica e incapacitante. Enxaqueca é
mais prevalente em pacientes com EM do que na população geral e pode piorar
quando certos tratamentos são utilizados para o controle da EM. ID-Migraine
é uma ferramenta utilizada para avaliar enxaqueca em populações. Consiste em
apenas três questões auto relatadas, mostrando boa sensibilidade, especicidade
e conabilidade. O propósito do presente estudo foi avaliar o papel de ID-Migraine
como potencial ferramenta para determinação de casos de enxaqueca em
pacientes com EM. Método: Pacientes diagnosticados com EM por pelo menos um
ano foram convidados a responder ID-Migraine. Dados demográcos e informações
sobre tratamento da EM foram obtidos na mesma ocasião. Resultados: Sessenta
e dois pacientes participaram deste estudo. Foram 16 homens e 46 mulheres, com
média de idade de 35 anos. Enxaqueca foi identicada em 51,5% deles, sendo que
18% relataram características de enxaqueca crônica. ID-Migraine mostrou 93%
sensibilidade e especicidade para esta população enxaquecosa. A medicação
mais frequentemente associada com piora de enxaqueca previamente existente
foi a interferona beta 1-a (27,4% dos casos). Conclusão: ID-Migraine mostrou-se
uma opção para identicação de casos de enxaqueca em pacientes com EM. No
entanto, a alta prevalência de enxaqueca na população estudada pode reetir um
viés de seleção, uma vez que muitos pacientes sem cefaleia podem não ter se
sentido dispostos a participar da investigação. Os resultados deste estudo piloto
serão expandidos e investigados com maiores detalhes em um amplo estudo
nacional.
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Migraine and MS
Queiroz MV, et al.
3
Headache Medicine, v.10, n.1, p.2-4, 2019
INTRODUCTION
Patients with multiple sclerosis (MS) are consistently
reported as having higher prevalence of headaches,
particularly migraine
1
. The reason for this nding is yet
to be claried, but the predominance of inammatory
cytokines and adverse events from medications
rate highly among the potential causes of increased
prevalence of headache among MS cases
2
. In addition,
demyelinating lesions in and around the periaqueductal
grey area may be associated to (often-intractable)
headaches in patients with MS
3,4
. Adverse events
relating to MS therapy may also account for the onset or
worsening of migraine
5,6
.
ID-Migraine is a simple three-item questionnaire
that is used for screening migraine cases in primary care.
However, it has only rarely been used in MS clinics
7
. It has
been validated in several languages, including Brazilian
Portuguese
8
. Only one previous study investigated the
potential use of ID-Migraine among patients with MS
9
.
In this previous Italian study, ID-Migraine showed high
sensitivity (91%) and specicity (94%) for identifying
migraine in 144 patients with MS. The present investigation
was a pilot study with the aim of expanding these data,
through including a population of Brazilian patients with
MS in which ID-migraine was used.
METHOD
This was a cross-sectional study carried out in three
university MS centers. Patients with MS attending regular
consultations at these centers were invited to reply to an
online questionnaire that sought ID-migraine responses.
Cases of episodic and chronic migraine were diagnosed
in accordance with thecriteria of the International
Headache Society (ICDH-3)
10
.Details of these patients’
MS therapy were recorded. All information was obtained
online without identication of patients.No healthcare
professional had any inuence on the responses that
patients gave. Only patients with at least one year of
conrmed diagnoses of MS were included in the study.
The results are presented mainly in a descriptive manner.
RESULTS
Sixty-two patients entered this pilot study. The
group consisted of 16 men and 46 women, of average
age 35 years. All of them had had a diagnosis of MS for
at least one year. Migraine was identied in 51.5% of these
patients. Among these individuals, 69% reported having
aura occasionally, but most attacks were migraine without
aura. Eighteen percent of the patients with migraine
fullled the diagnostic criteria of chronic migraine.
ID-Migraine identied 10 men and 20 women as
migraineurs in this study. Using the ICDH-3 criteria,
eight men and 20 women had all the necessary items
for diagnosing migraine.Thus, ID-Migraine presented 93%
specicity. The questionnaire showed 100% sensitivity,
since no cases of migraine were identied using the
ICDH-3 criteria and not through ID-Migraine.
Thirty-one patients in this study reported having had
migraine episodes before they received the diagnosis
of MS, while only one person started having migraine
after being diagnosed with MS. Onset or worsening
of migraine due to MS therapy was observed in 20
patients (62.5%). Interferon beta 1-a led to worsening of
migraine in 27.4% of the patients, irrespectively of the
mode of administration of this drug (subcutaneously or
intramuscularly).
DISCUSSION
This pilot study showed that ID-Migraine is a sensitive
and specic tool for screening migraine in populations of
patients with MS. If we apply this questionnaire in our
MS centers, we may be able to identify a large group of
patients in need of special attention to their headache.
MS clinics tend to concentrate efforts on maintaining
good neurological function, appropriate mobility,
visual ability, adequate coordination and sphincter
function, cognition, control of neuropathic pain (such as
trigeminal neuralgia), but without any specic programs
for attending to primary headaches. Since migraine can
negatively inuence patients’ quality of life, mood, sleep
and cognition
11
, it is important to address migraine in
patients with MS.
The very high prevalence of migraine in this
population (51.5%) may have been biased by the online
tool that was used for screening. It is plausible that only
individuals who suffer from headache might feel inclined
to reply to an online survey on headache. However, other
studies have reported migraine in 50% of patients with
MS
2,4
and the results obtained here may just reect
the same prevalence in Brazilian patients. In fact, the
only other previous study using ID-Migraine to screen
patients with MS showed that 53.5% of the patients had
a diagnosis of migraine.
Interferon beta 1-a was associated with worsening
of migraine in these patients. This nding has been
systematically reported by other authors
5,6,12
and often
directs neurologists caring for patients with MS not
to prescribe interferon beta 1-a whenever there is a
concomitant history of migraine. More recently, other
drugs have been described as headache triggers
13
, but
the population of this pilot study did not allow for further
assessments.
CONCLUSION
ID-migraine was a sensitive tool for identifying
migraine in patients with MS and its use can be
implemented in MS units. As previously described by
several groups, interferon beta may worsen migraine
symptoms.
REFERENCES
1. La Mantia L, Prone V. Headache in multiple sclerosis and
autoimmune disorders. Neurol Sci. 2015;36Suppl 1:75-8. doi:
10.1007/s10072-015-2146-9.
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Migraine and MS
Queiroz MV, et al.
Headache Medicine, v.10, n.1, p.2-4, 2019
4
2. Putzki N, Katsarava Z. Headache in multiple sclerosis. Curr
Pain Headache Rep. 2010;14(4):316-20. doi: 10.1007/s11916-
010-0126-6.
3. Fragoso YD, Brooks JB. Two cases of lesions in brainstem
in multiple sclerosis and refractory migraine. Headache.
2007;47(6):852-4.
4. Gee JR, Chang J, Dublin AB, Vijayan N. The association of
brainstem lesions with migraine-like headache: an imaging
study of multiple sclerosis. Headache. 2005;45(6):670-7.
5. Villani V, Prosperini L, De Giglio L, Pozzilli C, Salvetti M,
Sette G. The impact of interferon beta and natalizumab
on comorbid migraine in multiple sclerosis. Headache.
2012;52(7):1130-5. doi: 10.1111/j.1526-4610.2012.02146.x.
6. Patti F, Nicoletti A, Pappalardo A, Castiglione A, Lo Fermo
S, Messina S, D’Amico E, Cimino V, Zappia M. Frequency and
severity of headache is worsened by interferon-beta therapy
in patients with multiple sclerosis. ActaNeurol Scand.
2012;125(2):91-5. doi: 10.1111/j.1600-0404.2011.01532.x.
7. Lipton RB, Dodick D, Sadovsky R, Kolodner K, Endicott J,
Hettiarachchi J, Harrison W; IDMigraine validation study. A
self-administered screener for migraine in primary care: The
IDMigraine validation study. Neurology. 2003;61(3):375-82.
8. Mattos ACMT, Souza JA, Moreira PF Filho, Jurno ME,
Velarde LGC. ID-Migraine™ questionnaire and accurate
diagnosis of migraine. ArqNeuropsiquiatr. 2017;75(7):446-
450. doi: 10.1590/0004-282X20170069.
9. Villani V, Prosperini L, Pozzilli C, Salvetti M, Ciuffoli A,
Sette G. The use of ID migraine™ questionnaire in patients
with multiple sclerosis. Neurol Sci. 2011;32(2):269-73. doi:
10.1007/s10072-010-0443-x.
10. Headache Classication Committee of the International
Headache Society (IHS) The international classication of
headache disorders, 3rd edition (beta version) Cephalalgia.
2013;33(9):629–808. doi:10.1177/0333102413485658
11. Saylor D, Steiner TJ. The global burden of headache. Semin
Neurol. 2018;38(2):182-190. doi: 10.1055/s-0038-1646946.
12. Pöllmann W, Erasmus LP, Feneberg W, Then Bergh F,
Straube A. Interferon beta but not glatiramer acetate
therapy aggravates headaches in MS. Neurology.
2002;59(4):636-9.
13. Fragoso YD, Adoni T, Gomes S, Goncalves MV, Matta AP,
Mendes MF, Siquineli F. Persistent headache in patients
with multiple sclerosis starting treatment with ngolimod.
Headache. 2015;55(4):578-9. doi: 10.1111/head.12526.
10(1).indb 4 21/10/2019 19:33:56
5
Headache Medicine, v.10, n.1, p.5-9, 2019
ABSTRACT
RESUMO
Descritores: Enxaqueca; Migrânea; Warfarina; Acenocoumarol; Vitamina K;
Trombina
VIEWS AND REVIEWS
Systematic review of the benecial effects of thrombin
and vitamin K inhibitors on migraine treatment
Revisão sistemática dos efeitos benécos dos inibidores de
trombina e de vitamina K no tratamento da enxaqueca
Eduardo de Almeida Guimaraes
Nogueira
1
Angela dos Anjos Couto
2
Beatriz Moraes Grossi
2
Gabriela Dias Nunes
2
Taliê Zanchetta B. Hanada
2
Yara Dadalti Fragoso
1
1
MS & Headache Research, Santos, SP, Brazil
2
Department of Neurology, Medical School,
UNIMES. Medical students, Universidade
Metropolitana de Santos, Santos, SP
*Correspondence
Yara Dadalti Fragoso
E-mail: yara@bsnet.com.br
Received: November 24, 2018.
Accepted: January 30, 2019.
Creative Commons (CC BY) Attribution 4.0
International.
Background: Prophylactic migraine therapy includes beta-blockers,
anticonvulsants, tricyclic antidepressants and calcium channel modulators.
These drugs have been serendipitously identied as agents capable of
migraine control. In order to reduce drug intake, interactions and potential
adverse events, patients who have high blood pressure and migraine are
often prescribed beta-blockers or calcium channel antagonists. Patients with
epilepsy and migraine can use anticonvulsants, those with depression and
migraine can be treat with antidepressants, and those with heart arrhythmia
or recurrent vertigo and concomitant migraine can benet from use of calcium
channel antagonists. The benecial effects of vitamin K or thrombin inhibitors
on migraine attacks were rst described decades ago, and there may be a place
for these drugs in migraine prophylaxis. Objective: To investigate the potential
benecial effects of this class of anticoagulants regarding prevention of
migraine attacks. Method: Systematic review of the literature including papers
with patients’ results. Results: A search of the literature yielded 16 papers with
data on patients using inhibitors of vitamin K or thrombin for thromboembolic
conditions. Articles typically reported on single cases or small case series. In all
but one of these reports, the effect of the drug was remarkable in decreasing
migraine severity. Conclusion: Although the level of recommendation is low
due to the lack of proper clinical trials, vitamin K or thrombin inhibitors may be
useful for migraine management in patients who also require anticoagulation.
For these individuals, use of this class of anticoagulants could avoid adding
extra drugs for migraine management.
Keywords: Vitamin K, Migraine, Treatment
Introdução: O tratamento prolático da enxaqueca inclui betabloqueadores,
anticonvulsivantes, antidepressivos tricíclicos e modulares dos canais de cálcio.
Estas drogas foram identicadas de forma casual como agentes capazes de
controlar enxaqueca. Os efeitos benécos dos inibidores da vitamina K ou da
trombina na prevenção de crises de enxaqueca foi inicialmente descrito há
muitas décadas, podendo haver lugar para estas medicações na prolaxia. O
objetivo desta revisão foi a investigação dos potenciais efeitos benécos desta
classe de anticoagulantes como preventivos de crises de enxaqueca. Método:
Revisão sistemática da literatura usando como termos de busca “heparin” OR
“warfarin” OR “coumarol” OR “thrombin” AND “migraine” nas seguintes bases
de dados: Medline, PubMed, LILACS, SciELO e Google Scholar. Resultados: A
busca sistemática resultou em 16 artigos com dados sobre pacientes que usavam
inibidores da vitamina K ou da trombina para condições tromboembólicas.
Os artigos relataram casos isolados ou pequenas séries de casos. Em todos,
exceto um artigo, o efeito destas drogas foi ótimo na redução da gravidade
da enxaqueca. Conclusão: Embora o nível de recomendação seja baixo pela
falta de estudos clínicos apropriados, inibidores da vitamina K ou da trombina
podem ser úteis no controle da enxaqueca de pacientes que necessitam
anticoagulação. Para estas pessoas, o uso desta classe de anticoagulantes
poderia evitar a adição de drogas extras para o controle da enxaqueca.
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Vitamin K inhibitors in migraine treatment
Nogueira EAG, et al.
Headache Medicine, v.10, n.1, p.5-9, 2019
6
INTRODUCTION
Migraine is a common neurological disorder
characterized by episodic attacks and by a chronic
phase, both of which can be disabling.
1
In addition to
cortical, thalamic and hypothalamic dysfunction, the
cascade of reactions led by the trigeminovascular
system requires adequate management and therapeutic
interventions.
1
In subjects who do not tolerate or do not
respond well to acute treatments, continuous use of a
prophylactic drug is the best option. Interestingly, these
prophylactic agents have mostly been identied by
chance: while undergoing treatment for another disease
with a certain drug, patients reported reduced numbers
and lower intensity of migraine attacks. Beta-blockers,
anticonvulsants, tricyclic antidepressants and calcium
channel modulators have all been identied as potential
prophylactic therapies for migraine. These are now
approved and recommended for migraine prevention,
with evidence supporting their use.
2
It is only logical that patients who can benet from
the same drug to treat two diseases should receive
this drug when they have no contraindication for this
minimalistic approach. Therefore, patients who have
high blood pressure and migraine can benet from
beta-blockers or calcium channel antagonists, and those
with epilepsy and migraine can use anticonvulsants.
Likewise, individuals with depression and migraine can
be treat with antidepressants, while subjects with heart
arrhythmia or recurrent vertigo and concomitant migraine
can benet from use of calcium channel antagonists.
Following the same line of thought, migraineurs
requiring anticoagulation can benet from vitamin K or
thrombin inhibitors, according to the theory and results
presented in papers published over the last 55 years.
Following an initial investigation on the potential role
of basophil granulocytes in migraine.
3
heparin became
a matter of interest in the physiopathology of migraine
attacks. Thonnard-Neumann published a series of papers
discussing the potential role of heparin in migraine
4, 5
after
an initial case-control open trial.
6
Other papers followed
but the subject is yet far from clear. The objective of the
present review was to assess the potential benecial
effects of this class of anticoagulants on prevention of
migraine attacks.
METHOD
This study was a systematic review and did not
require approval from an Ethics Committee, since the
authors only accessed published data. The present review
followed the guidelines of the
Preferred Reporting Items
for Systematic Review and Meta-Analysis
(PRISMA)
protocol.
7
The search terms were “heparin” OR “warfarin”
OR “coumarol” OR “thrombin” AND “migraine” in
the following databases: Medline, PubMed, LILACS,
SciELO and Google Scholar. The term “headache” as
an alternative to “migraine” generated thousands of
unrelated papers and was, therefore, not used in the
search. The search was not limited by date and only
papers presenting data on patients were selected. Only
articles that used the English language in title, key words
and abstract were included. Abstracts from conferences
and journal editorials were not included in this review.
References from selected articles were further used in
the search for other potential papers.
The authors individually searched for papers
following the set criteria for inclusion and exclusion
and, after two meetings, decided which articles should
be included. The results from this systematic review are
presented essentially in descriptive form with no meta-
analyses or statistical assessment of the results.
RESULTS
The initial search generated 163 papers. After reading
the titles of these papers and their abstracts, 16 articles
were selected for this review. One article, published in
1974
8
had no authors listed and no abstract. It could not
be retrieved and was, therefore, excluded, despite its
potential interesting title. One case report from Sweden
9
was also excluded, although it had been identied as a
reference to other authors. This paper is in Swedish and
the search in the original journal rendered no results for
that particular article.
There were 11 case reports from eight different
countries (UK,
10
, Holland,
11, 12
Brazil,
13
South Africa,
14
Italy,
15-17
Taiwan,
18
Canada,
19
USA
20
), one retrospective cohort from
Holland,
21
one prospective cohort (from USA),
22
one open
crossover trial from Holland,
23
two case control studies
(USA,
4
Spain,
24
). Data were typically obtained from
isolated cases or small series of patients. The results from
15 studies suggested that heparin, warfarin and coumarin
derivatives can be very effective in reducing the intensity
and/or frequency of migraine attacks. One of the studies
did not obtain the same good result when comparing
acenocoumarol to propranolol in migraine prophylaxis.
23
An International Normalized Ratio (INR) of around 2.5
was sufcient to induce improvement in migraine, thus
indicating that full anticoagulation is not necessary to
alleviate the headache. A summary of the papers with
data on patients is presented in Table 1.
DISCUSSION
Serendipitous discoveries have been a characteristic
of many drugs used in migraine prophylaxis. The present
review showed that potent anticoagulants that are vitamin
K inhibitors have shown remarkable benecial effects in
migraineurs. All studies have the same conclusion and it
would be of great interest to prospectively study large
cohorts of patients (who happen to have migraine) and
need to be treated with vitamin K inhibitors.
Thrombin is a serine protease involved in a cascade
of coagulation and inammation via the proteinase-
activated receptors (PARs).
25
Pro-inammatory
mediators are released through activation of PAR1, while
the activation of PAR2 induces the release of substance
P and calcitonin-gene-related peptide (CGRP).
26-28
The
aberrant activity of serine proteases, including thrombin,
can be identied in many neurological conditions,
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Nogueira EAG, et al.
7
Headache Medicine, v.10, n.1, p.5-9, 2019
Author Year Ref Country Method Result
Thonnard-
Neumann
1973 4 USA
Case-control (n=20 migraine;
21 control)
5,000 U of heparin intravenously leading to a
substantial reduction in severity and frequency of
migraine attacks in 16 out of 20 migraine patients.
Suresh et al 1994 10 UK Case report (n=1)
6mg/day warfarin prescribed to a 71 year-
old woman (DVT) led to migraine control.
Withdrawal resulted in migraine returning to
basaline pattern. Patient was treated blindly
with warfarin-placebo and only warfarin
improved her headache attacks
van
Puijenbroek
1996 11 Holland Case report (n=1)
3-4mg/day acenocoumarol led to a dramatic
reduction of migraine attacks in a 68 year-old
woman. Migraines returned after drug was
withdrawn and was well controlled again after
re-starting acenocoumarol
Fragoso 1997 13 Brazil Case report (n=2)
Two patients with remarkable improvement
on the intensity and frequency of their
migraine attacks after taking 5mg/day of
warfarin (INR kept at 2.5).
Morales-
Asin et al
2000 24 Spain
Case-control (66 migraine; 100
non-migraine headache)
Remarkable improvement on migraine during
the use of acenocoumarol. More severe
migraine had better response to this treatment
Rahimtoola
et al
2001 21 Holland
Retrospective analyses (n=32
warfarin; n=60 aspirin)
Coumarin treatment was clearly associated with
a reduction of migraine attacks and severity in
comparison with low-dose aspirin treatment
Wammes-
van der
Heijden et al
2004 12 Holland Case report (n=4)
Patients with migraine and thromboembolic
predisposition improved of their headache
during acenocoumarol therapy
Wammes-
van der
Heijden et al
2005 23 Holland
Open crossover study using
propranolol or acenocoumarol
(n=12)
No beneficial effect of propranolol or
acenocoumarol could be established after 12 weeks
Asherson
et al
2007 14 South Africa Case report (n=1)
Patient with anti-phospholipid syndrome
undergoing therapy with warfarin had
dramatic improvement in migraine
Maggioni
et al
2012 15 Italy Case report (n=1)
Complete remission of migraine in a woman
undergoing warfarin therapy. Migraines
returned after drug was withdrawn and was
well controlled again after re-starting warfarin
Russo et al 2013 16 Italy Case report (n=1)
Patient undergoing therapy with warfarin
had total remission of migraine pain but
remained with aura
Mohanty
et al
2015 22 USA
Prospective (n=40 migraine;
n=85 control)
Migraine symptoms substantially decreased in
38 patients using warfarin
Kung et al 2015 18 Taiwan Case report (n=1)
Dabigratan 110mg twice a day controlled
migraine-like visual aura without headache
Maggioni
et al
2015
17 Italy Case report (n=1)
Complete remission of migraine with aura on
warfarin. Return of symptoms within 3 weeks of
switching to apixaban. Resolution of symptoms
once again when warfarin was reintroduced
Nilsson et al 2017 19 Canada Case report (n=1)
Complete remission of migraine with aura on
warfarin. Return of symptoms within 3 weeks of
switching to apixaban. Resolution of symptoms
once again when warfarin was reintroduced
Beh 2018 20 USA Case report (n=1)
Patient with vestibular migraine who
improved when warfarin was associated to
his previous topiramate therapy
Table 1. Summarized results from articles reported on migraine patients using vitamin K or thrombin inhibitors.
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Headache Medicine, v.10, n.1, p.5-9, 2019
8
including hemorrhagic, hypoxic, oncogenic, traumatic
and infectious injuries.
29
Expressed in astrocytes,
microglia and neurons, PAR1 has been described as a
well-positioned receptor to play a central role mediating
the complex inammatory cascades within the central
nervous system,
29,30
It is, therefore, perfectly plausible
that thrombin might be involved in the inammatory
trigeminovascular cascade of events in migraine.
This review is not without limitations. The results
are essentially based on case reports with the bias of
publication of positive results. There may be migraineurs
with no benet at all from these drugs whose cases
are never going to be reported. Even the larger series
of patients and the prospective cohort identied by the
reviewers typically reported on insufcient numbers
of cases assessed in open studies. At present, it is only
possible to give a low (Code C) or very low (Code
D) recommendation for this therapy as a migraine
prophylactic alternative. As a reminder, Code C means
that there are only a few studies with severe limitations,
while Code D, in essence, denotes a recommendation
from experts.
31
In order to improve the personal and societal
impact of migraine, patients need to receive appropriate
treatments and continuity of care.
32
Adherence to therapy
is of essence and the fewer the numbers of drugs and
daily doses a patient has to use, the higher the chances
are that he/she will follow medical recommendations.
33,34
Patients who suffer from migraine and require
anticoagulant therapy for any other reason might achieve
improvement of their migraine through use of vitamin
K and thrombin inhibitors, even when the target INR is
relatively low. However, this recommendation is limited
by the low level of evidence presented by the data in
the medical literature. Prospective observational cohorts
among patients who suffer from migraine and receive
anticoagulant therapy for any other disease could be the
next step in this investigation.
CONCLUSION
The present systematic review showed that vitamin
K or thrombin inhibitors have a potential benecial
effect regarding prevention of migraine attacks. Careful
interpretation of the results is recommended since most
published data come from small series or single cases.
Role of authors:
Eduardo de Almeida Guimaraes Nogueira – recently
graduated medical doctor, coordinated the study and
prepared the nal table of results.
Angela dos Anjos Couto - medical student in training
for systematic reviews, had an active participation in the
literature search and selection of papers
Beatriz Moraes Grossi - medical student in training
for systematic reviews, had an active participation in the
literature search and selection of papers
Gabriela Dias Nunes - medical student in training
for systematic reviews, had an active participation in the
literature search and selection of papers
Taliê Zanchetta B. Hanada - medical student in
training for systematic reviews, had an active participation
in the literature search and selection of papers
Yara Dadalti Fragoso - designed and supervised the
study, wrote the nal paper and is ultimately responsible
for data collection and analyses.
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10
ABSTRACT
RESUMO
Descritores: Atividade Física, Exercício Físico, Migrânea, Fatores
Desencadeantes, Estresse.
ORIGINAL ARTICLE
Aerobic exercise training for migraine prevention: A
trigger-based analysis
Treinamento físico aeróbico na prevenção da migrânea: Uma
análise de fatores desencadeantes
Arão Belitardo Oliveira
1,2
*
Diego Belandrino Swerts
3
Mario Fernando Prieto Peres
1,3
1
Universidade de São Paulo, Instituto de
Psiquiatria, Hospital das Clínicas da Faculdade
de Medicina, 785, Rua Dr. Ovídio Pires de
Campos, CEP: 05403-903, São Paulo - SP,
Brazil.
2
Universidade Federal de São Paulo,
Departamento de Neurologia e Neurocirurgia,
669, Pedro de Toledo, CEP 04039-032 São
Paulo, Brazil.
3
Hospital Israelita Albert Einstein, Brain
Institute, 627/701, Avenida Albert Einstein, CEP
05652-900, São Paulo, Brazil.
*Correspondence
Arão Belitardo Oliveira
E-mail: araoliva@gmail.com; aboliveira@
unifesp.br
Received: February 15, 2019.
Accepted: February 25, 2019.
Creative Commons (CC BY) Attribution 4.0
International.
Background: Although aerobic exercise has been recommended for migraine
management, no study has yet explored the effects of regular aerobic exercise
on migraine triggers prole. Objective: To evaluate the effects of a 12-week
aerobic exercise intervention on migraine triggers prole. Methods: We
conducted a secondary, post hoc analysis of a randomized, controlled clinical
trial. Triggers were recorded in a paper-based headache diary with a formal list
including 8 common migraine triggers. Results: Twenty-ve patients concluded
the protocol and were analysed (exercise: n = 12; waitlist: n = 13). In the whole
cohort, the most common triggers were stress/irritability (60 %), sleep
deprivation (60 %), fasting (28 %), and foods (28 %). Most patients (52 %) had ≥
3 triggers. The exercise group showed a higher baseline proportion of patients
with ≥ 3 triggers (69 %) compared to waitlist group (25 %) (p = 0.041). After
intervention period, there was no difference in the proportion of patients with ≥
3 triggers between waitlist (16.6 %) and exercise (30 %) groups (p = 0.502). The
exercise group showed greater numeric reductions (from group’s sum) than
waitlist group for triggers stress/irritability (-14 vs -9), fatigue (-12 vs -6), and
menstruation (-9 vs -5). This seemed to reect the reduced number of attacks
in the exercise group [mean (CI95 %): -2.5 (-3.7, -1), p = 0.002] vs waitlist [0.9
(2.4, -0.8), p = 0.341]. Conclusion: Tracking migraine triggers during exercise
interventions may help to unravel specic clinical effects of regular exercise.
Trial registration: #NCT01972607.
Keywords: Physical Activity, Exercise, Stress, Treatment, Triggers.
Embora o exercício aeróbico seja recomendado no tratamento da migrânea,
nenhum estudo seu efeito no padrão de fatores desencadeantes das crises,
os chamados “gatilhos”. O objetivo desse estudo foi avaliar se um programa
de exercícios aeróbicos de 12 semanas afeta o perl de gatilhos reportados
pelos pacientes. Foi realizada uma análise secundária post hoc de um estudo
controlado e randomizado. Os gatilhos foram registrados em diário da dor
impresso contendo uma lista de 8 gatilhos frequentemente reportados na
literatura. Vinte e cinco participantes concluíram o protocolo e foram analizados.
Na amostra total, os gatilhos mais comuns foram estresse/irritabilidade (60
%), privação do sono (60 %), jejum (28 %) e alimentos (28 %). A maioria dos
pacientes (52 %) reportaram ≥ 3 gatilhos. O grupo exercício mostrou maior
proporção de pacientes com ≥ 3 gatilhos (69 %) no período pré intervenção em
comparação com o grupo controle (25 %) (p = 0.041). Após intervenção, essa
diferença não foi observada (exercício = 30 % vs controle = 16.6, p = 502). O
grupo exercício mostrou maior redução numérica (dados de soma dos gatilhos
por grupo) em comparação com o grupo controle para os gatilhos estresse/
irritabilidade (-14 vs -9), fadiga (-12 vs -6) e menstruação (-9 vs -5). Esse efeito
reetiu redução no número dos ataques no grupo exercício [média (IC 95 %):
-2.5 (-3.7, -1), p = 0.002] vs grupo controle [0.9 (2.4, -0.8), p = 0.341]. O registro
no padrão de gatilhos durante intervenções com exercícios pode auxiliar no
rastreio de efeitos clínicos especícos ainda não estudados. Registro do estudo
clínico: NCT01972607.
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11
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INTRODUCTION
Growing body of evidence has strengthened the
therapeutic benets of regular physical activity for the
management of migraine
1
. In particular, aerobic exercise
performed at moderate intensity and practiced 3 times
per week is accounted for reducing around 30-40 % the
number of migraine attacks/days with migraine2–4),
with therapeutic effects comparable to preventive
medication
5,6
. Other health outcomes such as perceived
stress, mood, and well-being may also improve by
adopting aerobic exercise as an adjunct treatment for
migraine
2,7,8
. However, there are still other unexplored
effects of aerobic exercise on clinical aspects of migraine,
such as the triggers prole of patients.
Many patients perceive a myriad of internal or
external stimuli as precipitants of migraine attacks, the
so-called triggers
9–13
. A recent meta-analysis showed
that nearly 90% of headache patients report at least one
consistent trigger
9
. The most common triggers reported
by patients include stress, sleep deprivation, fasting,
certain foods, menstruation, to name a few
9
. While
physical exercise is also considered a trigger by around
20-40 % of patients
14,15
, many evidences from clinical and
epidemiological studies strengthen the recommendation
of regular aerobic exercise, and the current understanding
is that the protective effect outweighs possible harmful
triggered during exercise
1,16
. In fact, exercise imposes a
challenge to homeostasis at molecular and physiological
levels in several neurobehavioral and physiological
processes, it could interact with mechanisms thought
to be involved in migraine triggers, such as sleep, stress
response, hydration, hypoglycaemia, and so forth to
either worse/precipitate the attacks or prevent them
1,17
.
In this sense, exploring the patient´s trigger pattern
while engaging in an exercise training program may
have clinical and behavioural implications, and even
affect exercise prescription recommendation for this
population. Therefore, it is necessary to understand
better the relationship between aerobic exercise and
migraine under the perspective of triggers factors. To
our knowledge, no study has yet evaluated the response
of regular aerobic exercise on the triggers’ prole of
migraine patients. Thus, the scope of this study was to
evaluate the trigger prole of a migraine patient cohort
following a 12-week aerobic exercise program. Because
there is inter-person variability for triggers, we did not
set any a priori hypothesis. We rather conducted an
exploratory data analysis, then provided contextual
interpretation based on current literature.
METHODS
Study Design
This study consists of a secondary, post hoc, per-
protocol analysis of an open-label, randomized controlled
clinical trial aiming to assess clinical outcomes in migraine
patients following a 12-week aerobic exercise program
2
.
We retrospectively analysed the triggers recorded in the
headache diary of patients.
The study protocol was approved by the Research
Ethics Committee of the Sao Paulo Federal University,
and have therefore been performed in accordance with
the ethical standards laid down in the 1964 Declaration of
Helsinki and its later amendments. All participants gave
their informed consent prior to their inclusion in the study.
The trial has been registered in the National Institute of
Health (www.ClinicalTrials.gov) under #NCT01972607.
The study complies with the CONSORT’s Statement on
data reporting for non-pharmacological trials
18
.
Participants
Participants were recruited and screened in the
Neurology Department of the Sao Paulo Federal
University. The inclusion criteria were: subjects of both
sexes, between 18 and 65 years, physically inactive
the previous 12 months (dened as ≤ 1 day/week of
leisure-time physical activity). Exclusion criteria were:
patients taking any prescribed medication or dietary
supplements; practicing mind-body activities (e.g., yoga,
tai chi, etc.); pregnancy; clinical history of cardiovascular,
pulmonary, metabolic, rheumatic, musculoskeletal,
psychiatric, or other neurological disease. All participants
had a neurological and cardiological examination before
inclusion in study.
Migraine Triggers Assessment
Clinical data were retrieved from paper-based
headache diary. Besides the data on migraine frequency,
the diary had a formal list including eight common
migraine triggers: “stress/irritability”, “sleep deprivation”,
“oversleep”, “fasting”, “foods”, “odours”, “photic stimuli”,
“alcohol”, and “other” for non-listed factors. If there were
no identiable triggers, patients were instructed to let
the option for description blank.
Statistical Analyses
Descriptive statistics and comparison between
groups for participants’ characteristics were calculated
by independent t-test (normal distribution assumed).
Within-group differences for migraine frequency
(continuous variable) pre-post intervention were
computed by paired t-test. These data are shown as
mean and 95 % condence interval. For triggers/clinical
variables analyses, the pre- and post-intervention periods
were set as the 4 weeks prior the 12-week intervention
period and the last 4 weeks of this intervention period,
respectively.
Descriptive statistics for trigger prole are expressed
as either group or whole cohort percentage, or group’s
sum. Comparisons in the proportion of triggers/patient
pre and post intervention were calculated by two-sided
Exact Fisher’s test. Data were computed in the SPSS
software (IBM, Version 19.0, Chicago, IL). A p value < 0.05
was considered statistically signicant.
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12
RESULTS
Twenty-ve participants were per-protocol analysed.
Table 1 shows participants clinical and anthropometrical
characteristics. In the whole cohort, 92 % of patients (23
out of 25 patients) reported at least one trigger during
the intervention period. The most common triggers
were stress/irritability (15/25 patients, or 60%), sleep
deprivation (15/25 patients, or 60%), fasting (7/25 patients,
or 28 %), food (7/25 patients, or 28 %), and odours (5/25
patients, or 20%). The groups’ trigger prole are shown
in the Figure 1. Most patients (13/25, or 52%) ascribed ≥ 3
triggers to their attacks in the baseline period.
The exercise group showed a higher baseline
proportion of patients with ≥ 3 triggers (69 %)
compared to waitlist group (25 %) (p = 0.041)
(Figure 2). After intervention period, the exercise
group showed reduced migraine attack frequency
compared to waitlist group [mean (CI 95 %): exercise
= -2.5 (-3.7, -1), p = 0.002 vs waitlist = 0.9 (2.4, -0.8), p =
0.341], while there was no difference in the proportion
of patients with ≥ 3 triggers between waitlist (16.6 %)
and exercise (30 %) groups (p = 0.502) (Figure 2). The
exercise group showed greater numeric reductions
(i.e., “Δ” values computed from group’s sum) than
waitlist group for the triggers stress/irritability (-14
vs -9), fatigue (-12 vs -6), and menstruation (-9 vs -5)
(Figure 3).
Figure 4 illustrates the ow of migraine triggers for
each group across time from baseline to post intervention
period. Triggers that were not reported by patients in
any period of intervention were designated “no trigger”.
DISCUSSION
To our knowledge, this is the rst study to evaluate
the triggers prole of migraine patients following exercise
training. In this secondary analysis, we tracked back the
triggers’ prole of a migraine patient cohort enrolled in
a randomized control trial testing the efcacy of aerobic
exercise training for migraine prevention. We intended to
identify possible changes in the pattern of trigger prole
following the aerobic exercise training protocol.
Variables Waitlist Exercise
Age (years) 34.2±9.0 37.4±13.8
Body Mass (kg) 69.6±18.9 72.9±15.7
Height (m) 1.63±0.1 1.64±0.05
BMI (kg/m
2
) 25.9±6.03 27.0±4.5
Sex:
Male, n(%) 3(25) 2(15.4)
Female, n(%) 9(75) 11(84.6)
Time living with migraine (yrs.) 15.6±8.5 18.2±13.3
Days w/ Migraine (n/month) 7.6±.4 8.9±3.6
Attacks Frequency (n/month) 5.1±2.5 6.3±3
Table 1. Participants’ characteristics. Data expressed as
mean ± standard deviation, or group’ percentage.
Figure 1. Trigger prole observed in waitlist and exercise groups.
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Figure 2. Triggger prole before and after exercice.
Figure 3. Change in common migraine triggers after intervention period.
We conrmed previous studies showing a high
percentage of patients reporting at least one trigger
(over 90 %)
9
, as well as we replicated the data showing
perceive stress, sleep deprivation, and fasting (skipping
meals) as the most common triggers
9–13
. We found that
the higher proportion of patients with ≥ 3 triggers in the
exercise group compared to waitlist group at baseline
equalized the waitlist group after intervention period
(Figure 2), probably reecting the reduction in the
number of migraine attacks across time with exercise
training. This also seemed to be the case regarding
the greater numeric reduction for most triggers in the
exercise group (Figure 3). Moreover, this larger numeric
reduction for some triggers in the exercise group could
be due to a greater sample size in this group.
While regular aerobic exercise may reduce migraine
frequency
1,3
, between 1/4 and 1/3 of migraine patients
report physical exercise as a consistent trigger
14,15
.
Surprisingly, there was no reported physical exercise-
triggered attack in this study. Some explanations to this
nding may be the fact that all participants were willing to
participate in an exercise program, the exercise intensity
was gradually increased up to the level prescribed
(moderate intensity around 70% of the age-predicted
maximum heart rate) based on cardiorespiratory
parameters, and all exercise sessions were supervised.
It is relevant to understand the relation of triggers
with physical exercise, since there is no specic exercise
prescription recommendation for migraine patients with
regard to their personal trigger prole, or whether or not
the surge of new popular exercise modalities could be
deleterious for the migraine patient. For example, new
popular exercise modalities that rapidly gain adepts
worldwide such as high intensity interval training
19
or training in a fasted state
20
, can be challenging for a
migraine patient and is impractical to be recommended.
On the other hand, in face of positive metabolic and
cardiovascular benet of these exercise modalities,
one could question whether a progressive introduction
of such exercise types would benet clinical aspects
of migraine, including the trigger pattern. Such trigger
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Headache Medicine, v.10, n.1, p.10-15, 2019
14
Figure 4. Flow of migraine triggers for each group
across time from baseline to post intervention period.
analysis, in clinical practice, could help patients to detect
either positive or potentially harmful effects of regular
physical activity interacting with subjective triggers. In
the future, further studies could establish specic exercise
prescription recommendations for this population.
Although the data here do not allow us to draw
conclusion for specic effects of exercise training on
the pattern of migraine triggers, regular aerobic exercise
training mediates several neurdocrine, neuroimmune,
and neuromodulatory processes, which could be
accounted for the greater reduction in triggers such as
stress/irritability, sleep deprivation, menstruation, neck
pain, and fatigue in the intervention group. For example,
regular exercise is thought to promote anti-inammatory
effects
21
, regulate the hypothalamic-pituitary-adrenal
axis mediating habituation of stress response
22–24
, which
are akin with the recent evidence of exercise-mediate
anxiolysis and lower pro-inammatory cytokines in
migraine women
7
. Also, aerobic exercise may improve
sleep quality, and therefore could prevent sleep
deprivation-triggered attacks, by changing melatonin
production
25,26
, which in its turn represent a endogenous
molecule thought to play a role in the pathomechanisms
of migraine disorders
27
. A recent study showed that
aerobic exercise helped to reduce neck pain in a particular
subpopulation of patients presenting with both migraine
and tension-type headaches
28
. Less attacks due to
fatigue could reect improvement in oxidative energy
metabolism following exercise training through changes
in mitochondrial function, which has been also linked to
migraine pathophysiology
29,30
.
There was a large difference in non-identiable
triggers between groups (20 attacks). It is likely that
interference from attention and care delivered by
researchers to the exercise group during the exercise
sessions may have rendered participants more aware of
their triggers by speaking with researchers about their
personal clinical features.
Limitations and Strengths
There are limitations in this study, which hamper one
to generalise our ndings. The study is comprised of a
small sample of patients interested in adopting aerobic
exercise training as a non-pharmacological approach to
manage their migraine. This constitute selection bias and,
thus, this sample do not represent the general migraine
population. Furthermore, this is a secondary, per-protocol
analysis, which means that the analyses were designed
after randomization. The strengths of this study lie on
the trigger data collected through paper-based diary
throughout the study period, and a supervised exercise
program design.
Taking into account multiple neurophysiological
and biochemical processes affected by physical exercise,
and possible relation to migraine triggers mechanisms,
further studies are needed to elucidate particular
clinical responses of aerobic exercise training in a more
representative sample.
CONCLUSIONS
The preventive effect of regular aerobic exercise
may reect on the triggers pattern of patients. Mostly by
reducing the number of triggers, and the more frequent
ones. Tracking the patient triggers prole during exercise
training interventions may unravel specic clinical data,
and further advance the understanding of the relationship
between exercise and migraine. The implications on
exercise prescription should be further explored in the
future.
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15
Headache Medicine, v.10, n.1, p.10-15, 2019
Acknowledgements: The authors are grateful to
the whole staff of the Centre for Studies on Exercise
Psychobiology and to all patients.
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ABSTRACT
RESUMO
Descritores: Enxaqueca; Espectroscopia de Ressonância Magnética de Fósforo;
31
P-MRS; Metabolismo da Energia Cerebral; Disfunção Mitocondrial.
VIEWS AND REVIEWS
Cerebral energetic metabolism of individuals with migraine
through
31
P-MRS: A systematic review
Metabolismo energético cerebral de indivíduos com migrânea através
da
31
P-MRS: Uma revisão sistemática
Mírian Celly Medeiros Miranda David
1
*
Letycia dos Santos Neves
2
Carlúcia Ithamar Fernandes Franco
3
Rhowena Jane Barbosa de Matos
4
1
Master student in Neuropsychiatry and
Behavioral Sciences of the Universidade
Federal de Pernambuco (UFPE).
2
Nutrition Student at Academic Center of
Vitoria, Federal University of Pernambuco
(UFPE).
3
Ph.D. Professor at Physiotherapy Department
of the State University of Paraíba (UEPB).
4
Ph.D. Professor of the Physical Education
Nucleus of the Academic Center of Vitoria,
Federal University of Pernambuco (UFPE).
*Correspondence
Mírian Celly Medeiros Miranda David
E-mail: miriancelly@hotmail.com
Received: February 20, 2019.
Accepted: February 26, 2019.
Creative Commons (CC BY) Attribution
4.0 International.
Introduction: Migraine has a neurological origin and is characterized by failure
of central modulation leading to neuronal hyperexcitability. Among the factors
related to such excitability is the mitochondrial dysfunction that has been
considered since the 1980s. Objective: To investigate changes in the cerebral
energetic metabolism of individuals with migraine through phosphorus
magnetic resonance spectroscopy (
31
P-MRS). Methods: It was searched articles
on Pubmed, Web of Science and Science Direct betweenof June, 2018 and
February, 2019. There was no restriction regarding the year of publication and
language. The combination of the descriptors used for this systematic review
was: Migraine AND Magnetic resonance spectroscopy [MESH]. The inclusion
criteria chosen were: original articles using
31
P-MRS in individuals diagnosed
with migraine (with and/or without aura); studies with adults between 18 and
60 years of age diagnosed with episodic or chronic migraine; with control
group of individuals without migraine and without pathologies or conditions
that would interfere in the results. Excluded were articles: incomplete or
unpublished; animal studies; and research protocol articles. Results: Of the
319 articles found, nine were selected. The sample totaled 216 individuals with
migraine (53.7% without aura) and 233 healthy individuals in the control group.
It was veried a reduction of phosphocreatine, phosphorylation potential,
Mg
2+
and ATP, whereas it was observed increase of inorganic phosphate and
ADP. Conclusion: There are alterations in cerebral energetic metabolism in
individuals with migraine, revealing mitochondrial dysfunction. However, it is
needed more studies with higher quality and analysis of the relationships with
the socio-demographic and clinical variables.
Keywords: Migraine; Phosphorus Magnetic Resonance Spectroscopy;
31
P-MRS;
Brain Energy Metabolism; Mitochondrial Dysfunction.
Introdução: A migrânea tem origem neurológica e é caracterizada por falha
na modulação central, levando à hiperexcitabilidade neuronal. Entre os fatores
relacionados a essa excitabilidade está a disfunção mitocondrial considerada
desde os anos 80. Objetivo: Investigar alterações no metabolismo energético
cerebral de indivíduos com enxaqueca por espectroscopia de ressonância
magnética com fósforo (
31
P-MRS). Métodos: Foram pesquisados artigos no
Pubmed, Web of Science e Science Direct entre junho de 2018 e fevereiro de
2019. Não houve restrição quanto ao ano de publicação e idioma. A combinação
dos descritores utilizados para esta revisão sistemática foi: Migraine AND
Magnetic resonance spectroscopy [MESH]. Os critérios de inclusão escolhidos
foram: artigos originais utilizando
31
P-MRS em indivíduos com diagnóstico
de migrânea (com e/ou sem aura); estudos com adultos entre 18 e 60 anos
diagnosticados com enxaqueca episódica ou crônica; com grupo controle de
indivíduos sem migrânea e sem patologias ou condições que interferissem
nos resultados. Foram excluídos os artigos: incompletos ou inéditos; estudos
em animais; e artigos de protocolo de pesquisa. Resultados: Dos 319 artigos
encontrados, nove foram selecionados. A amostra totalizou 216 indivíduos
com migrânea (cerca de 53,7% sem aura) e 233 indivíduos saudáveis no grupo
controle. Vericou-se uma redução de fosfocreatina, potencial de fosforilação,
Mg
2+
e ATP, enquanto se observou um aumento de fosfato inorgânico e
ADP. Conclusão: Existem alterações no metabolismo energético cerebral
em indivíduos com migrânea, revelando disfunção mitocondrial. Porém, são
necessários mais estudos com maior qualidade e análise das relações com as
variáveis sociodemográcas e clínicas.
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Cerebral energetic metabolism in migraine
David MCMM, et al.
17
Headache Medicine, v.10, n.1, p.16-23, 2019
INTRODUCTION
According to the World Health Organization (WHO),
1
50 to 75% of individuals between 18 and 65 years old
presented at least one headache crisis per year in the
world, 30% of them with reports of migraine attacks. Still
according to the WHO, 1.7% to 4% of adults in the world
population present chronic headache (≥ 15 days/month).
1
Migraine has a neurological origin and is
characterized by a failure in central modulation that
leads to neuronal hyperexcitability,
2
it has moderate to
severe pain intensity, usually with pulsatile character,
presenting predominantly in hemicranial form, with a
duration of 4 to 72 hours.
3
The relationship between migraine and mitochondrial
dysfunction has been considered since the 1980s
.
4
Changes in mitochondrial functionality would lead to
high intracellular Ca
2+
penetration, phosphorylation
deciency, and excessive free radical production causing
energy failure in neurons and astrocytes, triggering,
among other factors, the Cortical Spreading Depression
involved with migraine.
5
In addition, mitochondrial impairments are
presented in muscle biopsy of individuals with
migraine, as well as, therapeutic strategies focused
on the improvement of mitochondrial metabolism are
effective in the treatment of migraine, such as riboavin,
coenzyme Q10, magnesium, etc.
5
In this context, phosphorus magnetic resonance
spectroscopy (
31
P-MRS) is a non invasive technique
used to investigate cerebral energetic metabolism in
vivo6 Mitochondrial functionality is veried through
the intracellular levels of adenosine diphosphate (ADP),
phosphocreatine (PCr), inorganic phosphate (Pi),
phosphorylation potential (PP), pH and Mg
2+
factors that
are indispensable for creatine kinase balance.
7,8
Despite this context, there is still no consensus
of the possible mechanisms related to changes in the
energy metabolism of individuals with migraine, such as
whether this relationship actually exists at the brain level,
whether mitochondrial dysfunction would be related to
the onset of migraine or it would be the consequence.
Thus, this systematic review aimed to investigate
changes in cerebral energetic metabolism of
individuals with migraine through
31
P-MRS, with the
hypothesis that individuals with migraine would have
altered rates of ADP, PCr, Pi and Mg
2+
when compared
with a control group, suggesting dysfunction in
mitochondrial activity.
METHODS
The study is a Systematic Review developed between
June, 2018 and February, 2019, registered in PROSPERO
as CRD42018112763. The review was carried out to answer
the reasearch guiding question: Are there changes in
cerebral energy metabolism in individuals with migraine?
In order to answer this question, the acronym PICOS was
used to guide the review (P: Individuals with Migraine, I:
31
P-MRS, C: individuals without migraine, O: Alterations in
cerebral energy metabolism, S: Transversal studies).
Searches were performed on Pubmed and
ScienceDirect by combining the descriptors: Migraine
AND Magnetic Resonance Spectroscopy [MESH]. It
was selected articles without restriction of year of
publication and language. The search and selection of
articles according to the eligibility criteria was described
in the owchart based on the Preferred Reporting Items
for Systematic Reviews and Meta-Analyzes (PRISMA)9
model (Figure 1).
Figure 1. Flowchart of articles selection. Source: Research Data.
The inclusion criteria chosen were: original articles
using phosphorus magnetic resonance spectroscopy
(
31
P-MRS) in individuals diagnosed with migraine (with and/
or without aura); studies with adults between 18 and 60
years of age diagnosed with episodic or chronic migraine;
with control group of individuals without migraine and
without pathologies or conditions that would interfere
in the results. Excluded were articles: incomplete or
unpublished; animal studies; and research protocol articles.
The search and selection of the articles according
to the eligibility criteria was done independently by
two evaluators (MD and LN), in case of disagreement,
they discussed and entered into a consensus. When
the disagreement between the two initial evaluators
remained, the third evaluator (RM) decided whether or
not to include the article in question. At the end of the
selection, the eligibility of the studies included in the
reference list of the selected articles was veried. The
owchart used, which presents in detail the selection
process, follows the model PRISMA
34
(Figure 1).
The selected articles were evaluated according to the
Strengthening the Reporting of Observational Studies
in Epidemiology Statement - STROBE Statement
10
by
the evaluators (MD and LN) independently. There was
agreement of 43.6% among the evaluators in the title and
abstract reading stage. In the article reading phase, there
10(1).indb 17 21/10/2019 19:33:59
Cerebral energetic metabolism in migraine
David MCMM, et al.
Headache Medicine, v.10, n.1, p.16-23, 2019
18
was an initial agreement of 61.5% and, after discussion,
the decision resulted in 9 articles.
The selected studies presented different methods
and variables, making it impossible to carry out
quantitative analyzes of the studies. Therefore, results
such as age, gender, diagnosis, medication, pain
intensity, frequency of attacks, imaging techniques and
main results were extracted and expressed in tables for
qualitative data analysis.
RESULTS
The search culminated in 319 articles, among which
nine studies were selected according to the eligibility
criteria of the review. The selected studies presented
moderate quality in the writing of the article according
to STROBE reaching the average score of 14.6 (66.4%),
with a mean of 64,1% of agreement (Table 1).
Regarding the characterization of the subjects,
the sample totaled 216 individuals with migraine
and 233 healthy individuals in the control group.
Among the individuals with migraine, it was observed
predominance of female (about 78.2%), adults in middle
age, diagnosis of migraine without aura (about 53.7%)
and no medication at the time of the imaging (Table 2).
The studies used devices with varied magnetic
eld strength, between 1.5 and 3T (Table 3). There were
prevalence of individuals in the interictal period (88.5%),
and the occipital area was chosen in the majority of
studies for
31
P-MRS analysis,
8,10-15
although it was not the
only region.
Regarding the results obtained through
31
P-MRS,
there was a reduction of PCr,
10,11,16
Phosphorylation
potential,
8,16
Mg
2+
,
8,11-13
and ATP,
8,12
whereas there was
an increase in Fi
8,16
and ADP
8,16
. In addition, there was a
reduction in Pcr/Pi and Pcr/TP (TP: total phosphorus)
in the ictal phase; on the other hand, in the ictal and
interictal phase there was an increase in Pi/TP
14
and ↑pMg
at ictal stage,
17
suggesting mitochondrial dysfunction.
Other studies did not nd statistical diferences in terms
of PCr/Pi, PCr/ATP, Pi/ATP and pH.
18,15
DISCUSSION
The ndings of the review support the initial
hypothesis that suggests the existence of a dysfunction
in cerebral energetic metabolism of individuals with
migraine. The reduced energy potential observed in
individuals with migraine was assumed to result from
reduced mitochondrial reserve, which is a biochemical
substrate for susceptibility to migraine attacks.
11
At rest, ATP is the result of the balance between its
use and synthesis. ATP is almost exclusively the product
of mitochondrial oxidative phosphorylation, requiring
glucose and oxygen as a supply. Changes in PCr leads
to an imbalance between the synthesis and delivery of
ATP, since ADP is refosphorylated by the creatine kinase
reaction, converting PCr to creatine.
16
On the other hand,
Mg
2+
is important because it binds to ATP so that the ATP
can be active, necessitating ideal levels of Mg
2+
,
16
which
has not been seen in individuals with migraine.
Mitochondrial dysfunctions and disturbances in
magnesium metabolism at the cerebral and systemic
level would lead to a neuronal hyperexcitability already
observed in individuals with migraine.
11
Magnesium is
an important component in the human metabolism, it
is an essential cofactor for more than 300 biochemical
reactions.
19
These reactions include cellular energy
production and storage stabilization of mitochondrial
membranes
20-22
The Mg
2+
has membrane stabilizing properties and is
fundamental in the function of several ATPases, especially
in the Na
+
/K
+
ATPase that controls the Na
+
pump. Neuronal
hyperexcitability would be a result of the reduction of
Mg
2+
levels that would justify the appearance of Cortical
Spreading Depression and the increased sensitivity to the
factors that trigger migraine. In addition, Mg
2+
regulates
brain excitation and/or inhibition by potentiating the
gamma-aminobutyric acid (GABA) receptors, thus the
reduction of Mg
2+
would lead to hyperexcitability by
reducing the inhibitory function of GABA.
23,24
The reduction of free Mg
2+
induces the increase of
ADP, essential in the regulation of mitochondrial ATP
production. High levels of ADP, in turn, induce high rates
of oxidation in an attempt to return to homeostasis.
12
Despite the repercussion of Mg
2+
, Lodi et al.,
12
based
on their ndings, argue that therapies that increase the
efciency of the production of Mitochondrial ATP would
be more advantageous than treatments based on the
administration of magnesium.
Because of the importance of Mg
2+
for energy
production, it may have a special role in the pathogenesis
of migraine. Nevertheless, it is seen that Mg
2+
medication
is useful in some cases of migraine
25-29
The predominance of the adoption of the occipital
region for analysis through
31
P-MRS would be in the
fact that it has regional cerebral metabolic oxygen rate
higher when compared to other cortical areas. Likewise,
the regional cerebral metabolic glucose rate is higher in
the occipital white matter and visual cortex than in other
areas, and the latter one remains without metabolic
changes with age.
30,31
The reason to some studies not verify alterations
on cerebral energetic metabolism could be the brain
region choosen to investigate. Changes in energy
metabolism in migraineurs have been shown in muscle
and platelets
6,32-34
defending a generalized character
of energetic metabolism alteration in individuals with
migraine that would unlikely exclude the brain.
Some studies found relations between energy
metabolism in complicated types of migraine, such
as prolonged aura, stroke migraine or hemiplegic
migraine
6,11,12,18,34,35
Therefore, rather than inuencing the
susceptibility to developing a migraine attack, changes
in energy metabolism would determine the clinical
characteristics of an attack.
18
Probably because of that,
some treatments with magnesium do not show good
results in the relieving migraine attacks.
36-38
Another assumption is that the energetic metabolism
alterations veried in some individuals diagnosed with
typical or classical migraine could be signals to a possible
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David MCMM, et al.
19
Headache Medicine, v.10, n.1, p.16-23, 2019
Authors
(year)
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 Total
Percentage
of
Agreement
(%)
Montagna et
al. (1994)
10
N/Y N/N N/Y Y/N N/Y N/Y Y/Y Y/N Y/N N/N N/N N/N Y/Y Y/Y Y/N Y/Y N/N Y/Y N/N Y/Y N/Y N/N 10/11 59.1
Reyngoudt et
al. (2011)
7
Y/Y Y/Y Y/ Y Y/Y N/Y N/Y Y/Y Y/N N/N N/N Y/Y Y/Y Y/Y Y/Y Y/Y N/Y N/N Y/Y N/N Y/Y Y/Y Y/Y 15/17 81.8
Boska et al.
(2002)
11
Y/Y Y/Y Y/ Y Y/Y Y/Y N/Y N/Y Y/ N N/Y N/N Y/Y Y/Y Y/ N Y/Y Y/Y Y/Y Y/Y Y/Y N/N Y/ Y Y/N N/N 16/16 72.7
Lodi et al.
(2000)
12
Y/Y Y/Y Y/ Y Y/Y N/Y N/Y Y/Y Y/N Y/Y N/N Y/Y Y/Y Y/Y Y/Y Y/Y Y/Y Y/Y Y/Y N/N Y/Y Y/ N Y/Y 18/18 81.8
Ramadan et
al. (1989)
13
N/Y Y/Y Y/Y Y/Y N/Y N/Y Y/ Y Y/N N/N N/N Y/N Y/N Y/Y Y/Y Y/Y N/Y Y/N Y/Y N/Y Y/ Y Y/ Y Y/N 15/15 54.5
Welch et al.
(1989)
14
N/Y Y/Y N/Y Y/Y N/Y N/N N/Y Y/Y N/N N/N Y/Y Y/N Y/ Y Y/Y Y/N N/Y Y/N Y/ Y Y/N Y/N Y/N Y/N 14/13 45.4
Halvorson et
al., (1992)
Y/Y Y/Y N/Y Y/Y N/N N/N Y/Y Y/N Y/N N/N N/Y Y/Y N/N N/N Y/Y Y/Y N/N Y/ Y N/N Y/Y Y/ N N/N 12/11 77.3
Schulz et al.,
2007
Y/Y Y/Y Y/ Y Y/N N/Y Y/Y Y/N Y/N Y/N N/Y Y/Y Y/Y N/Y Y/Y Y/Y Y/Y Y/ N Y/Y Y/N Y/ N Y/N Y/ Y 19/15 50.0
Welch et al.
(1988)
Y/Y Y/Y N/Y Y/N N/N N/N Y/Y Y/N Y/N N/N Y/N Y/ N N/Y Y/Y Y/ N Y/Y Y/N Y/ Y N/Y Y/Y Y/Y Y/Y 16/12
54.5
Table 1. Evaluation of the selected articles in accordance with the STROBE Statement.
Source: Research Data. 1: Title and abstract; 2: Background/rationale; 3: Objectives; 4: Study design; 5: Setting; 6: Participants; 7: Variables; 8: Data sources/ measurement; 9: Bias; 10:
Study size; 11: Quantitative variables; 12: Statistical methods; 13: Participants; 14: Descriptive data; 15: Outcome data; 16: Main results; 17: Other analyses; 18: Key results; 19: Limitations;
20: Interpretation; 21: Generalisability. 22: Funding; Y= Yes; N= No
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Cerebral energetic metabolism in migraine
David MCMM, et al.
Headache Medicine, v.10, n.1, p.16-23, 2019
20
Table 2. Characteristics of the individuals in the selected studies.
Source: Research Data. 1: Title and abstract; 2: Background/rationale; 3: Objectives; 4: Study design; 5: Setting; 6: Participants; 7:
Variables; 8: Data sources/ measurement; 9: Bias; 10: Study size; 11: Quantitative variables; 12: Statistical methods; 13: Participants;
14: Descriptive data; 15: Outcome data; 16: Main results; 17: Other analyses; 18: Key results; 19: Limitations; 20: Interpretation; 21:
Generalisability. 22: Funding; Y= Yes; N= No
Authors
(year)
Subjects Sex Age
Migraine
Type
Migraine
Duration
Pain
Intensity
Attacks
Frequency
Medication
Montagna
et al. (1994)
9
40
(E:22;
C:18)w
E: 19F;
C: 19F.
E: 34.0 ±
10.0;
C: 34.0 ±
18.0
MwoA (22)
19.0 ± 10.0
anos
X
3.6 ± 1.8
attacks/
month
Without medication
Reyngoudt
et al. (2011)
7
45
(E: 19;
C:26)
E: 18F;
C: 15F
E:32.3 ± 12.1;
C: 27.6 ±
10.9
MwoA (19) X X X
Without
prophylactic
medication
Boska et al.
(2002)*
11
78
(E: 38;
C: 40)
E: 32F;
C: 27F
E: MWA
(40.9 ± 8.4),
MwoA (35.7
± 9.5); C:
37.5 ± 11.3.
MWA (19),
MwoA (19)
X X X Without medication
Lodi et al.
(2000)*
12
94
(E:58;
C: 36)
E: 40F;
C: ?
E: MWA
(23.0 ± 2.0),
MwoA (32.0
± 2.0); C:
36.0 ± 3.0.
MWA (37),
MwoA (21)
MWA: 11.0
± 2.0 anos;
MwoA: 18.0
± 2.0 anos.
X X Without medication
Ramadan et
al. (1989)
13
44
(E: 19;
C: 25)
E: 17F;
C: 15F
E: MWA
(37.1 ± 13.2)
MwoA (34.3
± 9.7); C:
43.4 ± 18.2
MWA (8),
MwoA (11)
X X X
Individuals did not
use analgesics 4
hours before the
imaging. Some
used prophylactic
medication.
Welch et al.
(1989)
14
47
(E: 20;
C: 27)
E: 18F;
C: 17F
E: MWA
(37.1 ± 13.2)
MwoA (37.2
± 12.0); C:
45.1 ± 17.6.
MWA (8),
MwoA (12)
X X X
Individuals did not
use analgesics 4
hours before the
imaging. Some
used prophylactic
medication.
Halvorson
et al.,
(1992)*
28
(E: 10;
C: 18)
X X X X X X X
Schulz et al.,
(2007)*
26
(E: 10;
C: 16)
E: 7F;
C: 8F
E: 42.7 ±
13.7;
C: 39.0 ±
15.0
MWA (10)
≤1h (6);
>1h≤24h
(2);
>24h
≤7days(1);
>7h (1)**
X
≥1 attacks/
month (3);
<1 attacks/
month (7)
X
Welch et al.
(1988)
47
(E: 20;
C: 27)
E: 18F;
C: 17F
E: MWA
(37.1 ± 13.2)
MwoA (37.2
± 12.0); C:
45.1 ± 17.6.
MWA (8),
MwoA (12)
X X X
Individuals did not
use analgesics 4
hours before the
imaging. Some
used prophylactic
medication.
progression to a complicated migraine. Knowing the
suscetibility to future migraine stroke episode or a
progression to a prolonged aura crisis or another type
of complicated migraine would help to plan a more
specic treatment for each situation. In this way, with
more studies at the eld, the
31
-RMS could became a
search tool to determine individuals at risk to develop a
complicated migraine.
This review presented some limitations, such as
the necessity to consider subgroups of interest in
the articles with various subgroups of complicated
migraine. In some articles, it was not possible to nd
all the information that was intended (age, gender,
medication, duration, frequency neither intensity
of pain). Furthermore, it was not possible to apply
a specic tool of assessment risk of bias neither to
develop a meta-analysis due to the variability of the
results.
Despit
e the similarities of the conclusions obtained
with the selected articles, it is necessary to carry out more
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David MCMM, et al.
21
Headache Medicine, v.10, n.1, p.16-23, 2019
Authors (year)
Ictal/interictal
condition
31
P-MRS
Instrument
Region Results Conclusions
Montagna et al.
(1994)
9
Interictal 1.5T, Signa Occipital lobes
↓PCr; ↑Pi; ↑ADP; ↑V/
Vmáx; ↓PP
Presence of unstable metabolic
status in brain cells, indicating a
defect in the energy metabolism
of individuals with migraine
without aura.
Reyngoudt et al.
(2011)
7
Interictal 3T, Siemes
Medial occipital
lobe
↓PCr; ↑Pi; ↓ATP;
↑ADP; ↓PP; ↓Mg
2+
Disturb in the energetic
metabolism of individuals with
migraine. The reduction of ATP
indicates a possible participation
of mitochondria in the
pathophysiology of migraine.
Boska et al.
(2002)*
11
Interictal
3T, Magnex-
SMIS
Calcarine cortex,
temporal gyri,
occipital gyri, frontal
gyri, frontal forceps,
genu of corpus
callosum, occipital
cortex
MwoA: ↑PDE in most
brain regions, ↑Mg
2+
in posterior brain
regions.
No substantial alteration of
energy metabolism, but the
disturbances in Mg
2+
homeostasis
may contribute to brain
hyperexcitability
MWA: ↓PCr in
anterior brain
regions, ↓ Mg
2+
in posterior brain
regions, but no
consistent changes
in PME,
PDE, Pi, or pH.
Lodi et al.
(2000)*
12
Interictal 1.5T, Signa Occipital lobes
↓Cytosolic free
Mg
2+
, ↓free energy
released by the
reaction of ATP
hydrolysis.
There is mitochondrial
dysfunction in individuals
with migraine secondary to
bioenergetics décit.
Ramadan et al.
(1989)
13
Ictal (10);
Interictal (9)
1.89T, Bruker
Frontal,
frontotemporal,
parieto-occipital,
occipital cortex
↓Mg
2+
, especially
between controls
and migraineurs
measured during an
attack. No changes
in pH.
Low brain Mg
2+
is important in
migraine pathofhysiology.
Welch et al.
(1989)
14
Ictal (11);
Interictal (9)
1.89T, Bruker
Frontal,
frontotemporal,
parieto-occipital,
occipital cortex
Ictal: ↓PCr/Pi; ↓PCr/
TP; ↑Pi/TP
Energy phosphate metabolism is
altered during a migraine attack.
Interictal: ↑Pi/TP
Halvorson et al.,
(1992)
Ictal (10);
Interictal (10)
1.89T, Bruker/
Oxford
Research
X
Increased variability
of pMg among
migraineurs. ↑pMg
at ictal stage.
Increased variability of pMg
concrntration. The difference
between the means of ictal and
interictal period was statistically
signicant.
Schulz et al.,
(2007)*
Interictal 2T, Bruker
Level of the basal
ganglia (white and
grey matter)
Non-signicant
differences
between control
and migraine with
non-motor aura
in terms of PCr/Pi
, PCr/ATP, Pi/ATP
and pH
Energy metabolism alterations
may not initiate a migraine attack
but may be involved you the
clinical manifestation of aura.
Welch et al.
(1988)
Ictal (11);
Interictal (9)
1.89T, Bruker
Frontal,
frontotemporal,
parieto-occipital,
occipital cortex
Non-signicant
pH differences
between control
and migraine at ictal
neither interictal
phases.
The pain of migraine is unlikely
to be caused by cerebral
vasodilatation induced by
prodromal ischemic brain
acidosis neither other pH
alterations.
Table 3. Characteristics of selected studies.
Source: Research Data. PCr: Phosphocreatine; Fi: Inorganic phosphate; ADP: Adenosine diphosphate; V/Vmáx: Rate of ATP
synthesis; PP: Phosphorylation potential; ATP: Adenosine triphosphate; MwoA: Migraine without aura; MWA: Migraine with aura; PDE:
phosphodiester concentration, PME: phosphomonoester concentration; TP: total phosphorus. *Only the group with migraine (with
and/or without aura) and the control group was considered
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David MCMM, et al.
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22
studies in the area with higher quality and control of the
intervening variables like the medication, not only during
the imaging, but also in the routine of the individuals.
Likewise, it is important to carry out analyzes regarding
the relations of
31
P-MRS results with sociodemographic
and clinical variables such as differences between sexes
and age; duration of migraine history, pain intensity,
frequency of attacks and medication.
In addition, there has been a dearth of recent studies,
which are important, given socioeconomic and cultural
differences throughout the years, so that nowadays
greater knowledge of the disease, modication of the
eating and physical habits prole and greater exposure
to medicines may change the results.
From the results veried in the selected studies,
there are alterations in cerebral energetic metabolism
in individuals with migraine, revealing the importance of
considering mitochondrial dysfunction as a component
in the pathophysiology of this disease. More studies
in the area with higher quality, control of intervening
variables and analysis of the relationships with the
socio-demographic and clinical variables of the affected
individuals are necessary.
CONFLICT OF INTEREST AND FINANCIAL
SUPPORT
There was no conict of interest or funding for this
review.
FUNDING
This research received no specic grant from any
funding agency in the public, commercial, or not-for-
prot sectors.
ARTICLE HIGHLIGHTS
• There are alterations in cerebral energetic
metabolism in individuals with migraine;
• A mitochondrial dysfunction should be considered
as a component in the pathophysiology of
migraine;
• Energetic metabolism alterations veried
in some individuals diagnosed with typical
or classical migraine could be signals to
a possible progression to a complicated
migraine in the future.
• Treatments acting on energetic metabolism, such
as magnesium, coenzyme Q10 or riboavine
might be benecial in the migraine prophylaxis.
• More studies in the area with higher quality,
control of intervening variables and analysis of
the relationships with the socio-demographic
and clinical variables of the affected individuals
are necessary.
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ABSTRACT
RESUMO
Descritores: Melatonina, CGRP, Modelo Animal.
ORIGINAL ARTICLE
Melatonin reverts CGRP expression induced by capsaicin
Melatonina reverte a expressão de CGRP induzida pela
capsaicina
Fabiano da Cunha Tanuri
1
Debora Amado
1
Eliangela de Lima
1
Iron Dangoni Filho
2
Mario Fernando Prieto Peres
2,3
1
Departamento de Neurologia/Neurocirurgia,
Universidade Federal de São Paulo, Escola
Paulista de Medicina, São Paulo, Brazil
2
Hospital Israelita Albert Einstein, São Paulo,
Brazil
3
Instituto de Psiquiatria, Faculdade de
Medicina da Universidade de São Paulo
*Correspondence
Mario Fernando Prieto Peres
E-mail: marioperes@usp.br
Received: January 20, 2019.
Accepted: January 31, 2019.
Creative Commons (CC BY) Attribution 4.0
International.
Introduction: CGRP, a neuropeptide synthetized and released in the central
nervous system and potent vasodilator, has been implicated in migraine
physiopathology. Because of that, there are CGRP targeted therapies that
decrease CGRP levels. Melatonin, a pineal gland secretion, has already proved
its analgesic effect. We aimed to study CGRP expression in an animal model
comparing capsaicin, CGRP and melatonin. Methods: We used in our study
male animal rats and separated them into groups based in the kind of received
solution (control group, capsaicin only and melatonin plus capsaicin). It was
prepared brain stem slices and measured the CGRP levels in the trigemino
nucleus caudalis (TNC). Results: Capsaicin group (N = 5) presented low intensity
of GCRP expression and animals that received capsaicin plus melatonin (N =
5) showed high intensity of CGRP expression compared to capsaicin group.
Conclusion: Melatonin decreases CGRP in an experimental model in rats
induced by capsaicin, reducing its inammatory action in cerebral vessels.
Keywords: Melatonin, CGRP, Animal Model.
Introdução: CGRP, um peptídeo produzido e liberado no sistema nervoso
central e potente vasodilatador, tem sido implicado na siopatologia da
Migrânea. Devido a isso, tem surgido diversas terapias direcionadas ao CGRP
que reduzem seus níveis. A melatonina, substância produzida pela glândula
pineal, já possui seu efeito analgésico comprovado. Nós objetivamos estudar
a expressão do CGRP em um modelo animal comparando capsaicina, CGRP e
melatonina. Métodos: Foi utilizado em nosso estudo ratos machos adultos e
estes foram separados em grupos baseados na solução que recebiam (grupo
controle, apenas capsaicina e melatonina mais capsaicina). Foram preparadas
fatias dos cérebros dos animais e então medidos os níveis de CGRP no núcleo
caudal trigeminal. Resultados: Grupo da Capsaicina (N = 5) apresentou baixa
intensidade da expressão de CGRP, enquanto aqueles animais que receberam
capsaicina mais melatonina (N = 5) mostraram altos níveis de expressão de
CGRP quando comparados ao grupo do CGRP. Conclusão: No nosso estudo
experimental com ratos induzidos por capsaicina notou-se que a melatonina
reduz os níveis de CGRP, diminuindo a ação inamatória nos vasos cerebrais.
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Tanuri FC, et al.
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Headache Medicine, v.10, n.1, p.24-28, 2019
INTRODUCTION
CGRP (Calcitonin Gene-Related Protein) is a
37-amino acid neuropeptide that belongs to a family
of structurally related peptides (e.g. calcitonin, amylin,
adrenomodulin). This neuropeptide is synthesized and
released from sensory nerves in the central nervous
system and gastrointestinal system, where it acts as a
potent vasodilator
1,2
.
It has been implicated in the mechanisms of
migraine, acting along trigeminovascular pathways as a
vasodilator and nociceptive initiator
3
.
CGRP targeted therapies have been studied for both
acute (gepants) and preventive (anti-CGRP monoclonal
antibodies) treatment
4
.
Decrease CGRP levels contribute to migraine
treatment. Other strategies may also improve migraine
control by reducing CGRP levels, such as the use triptans,
coenzyme Q10, serotonin reuptake inhibitors, exercise,
acupuncture and some kinds of food, such as grape
pomace, cocoa and ginger extracts
4-9
.
Melatonin is the primary secretory product of the
pineal gland, an indoleamine derivate of the essential
amino acid tryptophan
9
. It has been extensively linked
to migraine pathophysiology, due to its capacity of
membrane stabilization, anti-inammatory properties,
modulation of serotonin, inhibition of dopamine release,
gamma amino butyric acid (GAMA) and glutamate
neurotransmission, scavenging toxic free radicals
and cerebrovascular regulation
10,11
. Besides, melatonin
plays important roles in antinociceptive mechanisms.
It has been reported that patients suffer less pain and
prolonged latencies thresholds during nighttime. These
observations were attributed to high melatonin levels
through night and its analgesic effect
12
.
Melatonin has been studied as a prophylaxis
headache treatment in cluster headache and migraine,
but its underlying mechanisms has yet to be determined
11
.
We aimed to study the pattern of CGRP expression in an
experimental model of headache, comparing capsaicin,
melatonin and CGRP levels.
METHODS
Animals
The ethical committee of the Universidade Federal
de São Paulo (UNIFESP) approved all experimental
protocols. All efforts were made to minimize animal
suffering following the proposal of International Ethical
Guideline for Biomedical Research
13
. Wistar adult
male rats (250–300 g) housed under environmentally
controlled conditions in a 12 hours light/dark cicle and
granted free access to food and water were used. These
animals were separated into four groups.
Groups
VEI (n = 5): animals that received vehicle solution
only; CAP (n = 5): animals that received capsaicin solution
(200 nM) only; and CAP + MEL (n = 5) animals that
received capsaicin solution (200 nM) and intraperitoneal
melatonin (Sigma, 10 mg/kg) 20 min after capsaicin
injection.
Drugs
Capsaicin solution was prepared with 3.05 mg
capsaicin (Merck) per 1 ml of vehicle (saline–ethanol–
Tween 80, 8:1:1) and diluted 1:50 (200 nM) with saline.
Vehicle was diluted 1:50 in saline.
Surgical procedures
Capsaicin stimulation
For this procedure, all rats were anesthetized with
pentobarbital (40 mg/kg i.p.) and a surgical opening
was made in the region between the scalp and C1 (rst
cervical vertebra). An amount of 10 ml of capsaicin
solution (see ‘‘Drugs’’) was injected into the cisterna
magna (over 15 min) using a Hamilton syringe with the
aid of a stereotaxic frame
14
. To avoid capsaicin outow,
the needle was only removed 10 min after injection.
Perfusion and immuno-histochemistry
The rats were anesthetized with pentobarbital
overdose (120 mg/kg) after two hours infusion,
followed by perfusion via the ascending aorta with 0.1
M phosphate saline buffer (PBS, 200 ml, pH 7.4) and
4% paraformaldehyde (200 ml) in 0.1 M phosphate
buffer (PB, pH 7.4). Brain stem with attached cervical
cord was stored overnight in the same xative and then
placed in a cryoprotectant (30% sucrose in 0.1 M PB,
pH 7.4). Coronal serial sections (40 ml) were prepared
on a cryostat microtome at -20ºC and collected in PBS
with sodium azide (0.1%) to Nissl staining and immuno-
histochemistry. Sections were rinsed three times 5 min
in PBS, pre-treated with 0.3% H2O2 in PBS for 15 min,
rinsed three times 5 min in PBS and pre-incubated in
10% bovine serum albumin (Calbiochem) and 2% normal
serum (Vector) in PBS for 2 hours at room temperature.
Sections were incubated for 48 hours at 4ºC in PBS
solution containing 2% BSA, 2% normal serum and 0.3%
Triton X-100 in PBS. Following three washes in PBS, the
sections were incubated in a PBS solution contained
biotinylated rabbit IgG (1:200) (Vector) for 2 h at room
temperature. Sections were rinsed three times 5 min in
PBS and incubated with the avidin–biotin–peroxidase
complex (Vector) in PBS for 1 h and 30 min at room
temperature. Sections were rinsed twice 5 min in PBS
and 5 min in Tris–HCl (pH 7.6) and revealed with 0.06%
3,30-diaminobenzidine tetrahydrochloride (Sigma)
and with 0.002% H2O2. Sections were then mounted
in slides and dehydrated through alcohol to xylene and
coverslipped with Entellan (Merck).
Nissl staining
Brain stem slices (40 ml) were hydrated in alcohol
solutions of decreased concentration followed by
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Tanuri FC, et al.
Headache Medicine, v.10, n.1, p.24-28, 2019
26
staining in 0.5% cresyl Violet acetate (Sigma) diluted
in 0.1 M acetate buffer pH 4.0. Slices were dehydrated,
coverslipped and analyzed by light microscopy optic
Zeiss Axiolab.
Quantications
The CGRP expression sections in TNC layer I/II were
counted at 0 to - 1 mm caudal to obex. Representative
images of the brainstem slices were digitalized using the
Image 1.61 system. The images were transformed into
black and White. The image analysis were performed
in the anterior region of the TNC, which presented the
same area analyzed in all the cuts. It was quantied the
optic density from the negative obteined of the images,
through the grayscale analysis of the Image Tool program
in “pixels” unit. The white color “pixels” were quantied
and the results were expressed as mean ± standard
deviation.
Statistical analysis
Data were analyzed using one-way analyses of
variance (ANOVA) followed by Tukey’s Q test. A value of
p < 0.05 was accepted as signicant.
RESULTS
The studied groups presented difference in the
CGRP expression analyzed through the densitometry.
Control group that received vehicle into the cisterna
magna showed high intensity of CGRP expression
(VEI: 733,95 ± 144,08) in TNC (layer I/II). In contrast,
we observed that animals submitted to trigeminal
stimulation of intracisternal capsaicin presented low
intensity of CGRP expression (CAP: 295,1 ± 49,93). This
number is signicantly different when we compare
CAP x VEI (p < 0.001). On the other hand, animals
that received intraperitoneal melatonin 20 min before
the capsaicin stimulation presented high intensity of
CGRP expression (CAP + MEL: 584,02 ± 133,59) when
compared to animals that received capsaicin only (p <
0.05) and similar to VEI group.
The results of immunohistochemical and
quantication through CGRP expression optic density
were observable in gures 1, 2 and 3.
DISCUSSION
We found in this experimental study direct relation of
the levels of Melatonin and Capsaicin in rats model, which
were exposed to capsaicin and melatonin injection. After
that, it was measured the CGRP density and it showed
decrease of its density when associated to capsaicin.
However, when we measure melatonin and capsaicin
both together, its levels increase and almost normalize.
A similar study, has already evidenced data about the
relation of melatonin and pineal gland in neurovascular
headaches’ pathophysiology
15
.
Melatonin reverts CGRP alteration induced by
capsaicin due to the inhibition of CGRP-induced increase
Figure 1. Photomicrographs of CGRP expression in TNC
(layer I/II). A: Tissue from animal that received vehicle.
B: Tissue from capsaicin-injected animal. C: Tissue from
animal that received capsaicin and melatonin. Detail
shows the area used to quantify by optic density. x200,
scale bar 55 µc.
Figure 2. Photomicrographs of CGRP expression in TNC
(layer I/II). A: Tissue from animal that received vehicle.
B: Tissue from capsaicin-injected animal. C: Tissue from
animal that received capsaicin and melatonin. Detail
shows the area used to quantify by optic density. x200,
scale bar 55 µc. A’, B’ and C’ represents the negative of
the cut images used for quantication by density optic.
in adenylate cyclase. It has already been proposed that
CGRP and melatonin may share an active role in the
maintenance of arterial tone in cerebral vasculature.
Several studies have demonstrated that melatonin
causes constriction of rat cerebral arteries
16-18
.
We hypothesized melatonin could revert capsaicin
effect owing to its ability of avoiding capsaicin. These
data are in accordance with previous studies showing
melatonin is able to produce a signicant inhibition
against the neurogenic pain caused by capsaicin. It has
been reported the melatonin antinociceptive effect by
central administration of it, showing its high lipid solubility,
capacity to penetrate the blood-brain-barrier and
produce a signicant inhibition against the neurogenic
pain by activating supraspinal sites. In another study, it
was presented that melatonin has the ability of avoid
capsaicin effect of initiation and limit the development of
“central sensibilization”
19
.
Clinical implications
It is an exciting moment to migraine specialists
and patients. There is one approved CGRP receptor
antagonist and some others being studied. Thus, some
doubts about it and its interaction to other established
drugs will need to be answered in the next years.
Melatonin has been showed as a potential candidate
for migraine treatment, including a Brazilian study that
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Tanuri FC, et al.
27
Headache Medicine, v.10, n.1, p.24-28, 2019
Figure 3. Quantication of CGRP expression through
optic density in rats that received: VEI – vehicle (n = 5);
CAP – rats that received capsaicin (n = 5); CAP + MEL –
rats that received capsaicin and melatonin (n = 5). Rats
were killed 60 min after injection. Cells were counted in
40 µm sections sampled in the TNC layers I and II at 0
to – 1 mm caudal to the obex (3 secctions). *p < 0.05
compared with capsaicin-treated animals; **p <0.001
compared with vehicle only.
found signicant headache response with melatonin as a
migraine prevention
20
.
Our study brings new questions and challenges
to headache societies: may migraine patients taking
melatonin still respond to CGRP antagonists? Is the
decrease of CGRP the real explanation for melatonin
improvement in headache disorders? Or do these drugs
have synergistic effect?
Melatonin has been associated to CGRP decreased in
patients with pure menstrual migraine
21
. It was investigated
the melatonin capability of reduce inammation through
decreasing CGRP and inducible nitric oxide synthase.
At the beginning of the 2000s, it was proposed that
melatonin could inhibit CGRP vasodilatation effect and
increases cAMP in rats’ arteries
22
.
LIMITATIONS
CGRP should be measured in other brain structures
besides trigeminal nucleus caudalis, such as trigeminal
ganglion, cerebral ventricles, meningeal afferents and
even medullary components of the TNC, as well as
structures outside the central nervous system (CNS), like
skin
23
, gastrointestinal tract, lymphocytes
24
and thymus
25
.
CONCLUSION
Melatonin decreases CGRP in an experimental model
in rats induced by capsaicin, reducing its inammatory
action in cerebral vessels.
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synthesis by human lymphocytes and its physiological
signicance: possible role as intracrine, autocrine, and/or
paracrine substance. FASEB J, 18:537–539.
25. Naranjo MC, Guerrero JM, Rubio A, Lardone PJ, Carrillo-
Vico A, Carrascosca-salmoral MP, et al (2007) Melatonin
biosynthesis in the thymus of humans and rats. Cell Mol.
Life Sci, 64:781–790.
10(1).indb 28 21/10/2019 19:34:02
29
Headache Medicine, v.10, n.1, p.29-31, 2019
ABSTRACT
VIEW AND REVIEW
Of the available triptans, which should be chosen and how
should they be used?
Dos triptanos disponíveis, quais devem ser escolhidos e como
devem ser usados?
Marcelo Moraes Valença
1
Emanuela Paz Rosas
1
Raisa Ferreira Costa
1
Amanda Araújo da Silva
1
Maria Rosana de Souza Ferreira
1
Rita Santana dos Reis
1
Marcelo Andrade Valença
1
Luciana Patrízia Alves de Andrade-
Valença
1
1
Neurology and Neurosurgery Unit, Federal
University of Pernambuco, Recife, Brazil.
*Correspondence
Marcelo M. Valença
E-mail: mmvalenca@yahoo.com.br
Received: October 2, 2018.
Accepted: December 12, 2018
Creative Commons (CC BY) Attribution
4.0 International.
There is a plethora of articles dealing with the use of triptans to treat migraine,
but so far no unanimity exists regarding the optimal form of using this group
of drugs in a patient with recurrent attacks of migraine. Although all of them
may exert their pharmacological effects through a known specic mechanism
of action, i.e. agonist effects on serotonin 5-HT (1B/1D) receptors, distinct
differences exist. The author comment a few facts on the prescription of
triptans and possible adverse effects, depending on the clinical scenario. Thus,
even though an enormous amount of information has accumulated over the last
few decades on triptans, several questions remain to be answered, and research
priorities need to be addressed.
Keywords: Triptans, Adverse Effect, Migraine, Prescription.
RESUMO
Descritores: Triptanos, Efeito Adverso, Enxaqueca, Prescrição.
Há uma innidade de artigos que tratam do uso de triptanos no tratamento
da enxaqueca, mas até agora não existe unanimidade em relação à forma
ideal de usar esse grupo de medicamentos em um paciente com ataques
recorrentes de enxaqueca. Embora todos eles possam exercer seus efeitos
farmacológicos através de um mecanismo de ação especíco conhecido, isto é,
efeitos agonistas nos receptores da serotonina 5-HT (1B/1D), existem diferenças
distintas. Os autores comentam alguns fatos sobre a prescrição de triptanos
e possíveis efeitos adversos, dependendo do cenário clínico. Assim, embora
uma quantidade enorme de informações tenha se acumulado nas últimas
décadas sobre triptanos, várias questões ainda precisam ser respondidas e as
prioridades de pesquisa precisam ser abordadas.
10(1).indb 29 21/10/2019 19:34:02
Triptans, which should be chosen?
Valença, MM
Headache Medicine, v.10, n.1, p.29-31, 2019
30
There is a plethora of articles dealing with the use
of triptans to treat migraine, but so far no unanimity
exists regarding the optimal form of using this group
of drugs in a patient with recurrent attacks of migraine.
Although all of them may exert their pharmacological
effects through a known specic mechanism of action,
i.e. agonist effects on serotonin 5-HT (1B/1D) receptors,
distinct differences exist.
Rapoport and coworkers
1
suggested a few strategies
to be adopted when choosing a triptan. They pointed
out that some patients prefer a form of treatment that
works quickly, some consider as satisfactory treatment
triptans that provide complete relief of the pain, while
others expect consistent effects as the most important
result of triptan treatment. In addition, adverse effects
are not tolerated by some migraineurs.
1,2
Almas and coleagues
3
reported that eletriptan
provides consistent migraine relief with an 80-mg
dose. Some of these individuals reported failure with a
lower dose of 40 mg. This is of major importance since
the failure of triptan treatment may be caused by the
use of subtherapeutic doses. However, 80 mg is the
maximum daily dose allowed and a subsequent intake of
eleptriptan must be avoided to prevent serious adverse
effects. Nevertheless, only 18.6% and 8% of the patients
achieved pain-free status at 2 hours or 24 hours sustained
headache response, respectively, on all three sequential
treated attacks.
3
Although this is an excellent clinical
outcome in terms of current treatment of migraine
attacks, it is far from the ideal goal of a foreseeable 100%
effective antimigrainous drug.
Seven triptans are currently being used in clinical
practice (almotriptan, eletriptan, frovatriptan, naratriptan,
rizatriptan, sumatriptan and zolmitriptan)
1, 2
. The relevant
literature is controversial regarding the most successful
triptan in the treatment of migraine attacks. A number
of specic advantages are claimed for some of them as
compared with the others. Thus, among the available
triptans, which one should be chosen to treat a given
patient is still a moot point. In part, this is also due to
the different ways in which triptans are tested for their
efcacy and possible adverse effects.
Different study end-points are evaluated during
trials using triptans.
4
Even though an attempt is always
made to attenuate bias during clinical trials, it is virtually
impossible to eliminate completely. The ‘negative result’
bias and the supposed inuence of pharmaceutical
companies over the publication of favorable results of a
given drug produced by them must be considered when
interpreting study outcomes.
Huge amounts of money have been spent by
pharmaceutical companies to develop new drugs,
and the companies’ efforts in this regard should be
recognized. As a result, we have acquired a very high
level of understanding of the mechanisms of action of
triptans and their possible clinical applications.
Regarding the clinical use of triptans for migraine
attacks, a long-action triptan is the ideal treatment
for patients with crises of headache lasting over six
hours. Among the triptans naratriptan (5-6 hours) and
frovatriptan (26 hours) present a relatively long half-life,
and should therefore be remembered when prescribing
for such patients.
2
If a short-action triptan is to be used,
the physician may recommend an abortive dose of the
triptan in addition to a complementary “prophylactic”
dose a few hours later, and before the expected
recurrence of the headache, in order to maintain the
patient free of headache, bearing in mind the maximum
safety dose of the drug that one may use daily. This form
of treating (abortive/preventive) is not usual in clinical
practice. Some authors use the combination of a triptan
and NSAIDs to treat such migraine attacks.
The efcacy of a specic triptan does not always
correlate with the patient’s preferred treatment. The
choice of a triptan by the physician will depend upon his
or her previous experience, the brand name, marketing
pressure, the usual features of the migraine attacks,
drug availability, cost, possible adverse side effects, the
patient’s risk of concomitant atheromatosis, vasospasm
susceptibility, or a previous failure or side effect with a
particular triptan reported by the patient.
The consensus is that triptan treatment in migraineurs
does not increase the risk of stroke, cardiovascular death,
or ischemic heart disease.
5
The contraindications for the
use of triptans are still poorly dened. There is general
agreement that triptans should not be used by patients
with a previous stroke or cardiovascular events. However,
we should be concerned when dealing with patients
with more than two of the following risk factors for
atheromatous disease: age >55 years, smoking, arterial
hypertension, dyslipidemia, diabetes mellitus or a familial
history of myocardial infarction at a young age. Migraine
with aura by itself seems to be a risk factor for ischemic
cardiovascular disease in women, and the widespread
use of hormonal contraception further enhances this risk.
Considering the potential vasoconstriction of the
coronary artery elicited by triptans as in vitro studies have
shown, the number of cardiovascular adverse events
reported is surprisingly low.
5
I wonder whether this is
a consequence of the characteristic behavior of the
migraineurs in avoiding intense physical activities or to
the attempt to remain at rest during a migraine attack.
Considering the abovementioned risk factors, we still
do not know if there is a signicant risk of symptomatic
vasoconstriction if we treat an athlete performing a
sporting activity with triptan. This scenario must be
relatively frequent since the current recommendation is
an early treatment of a migraine attack when the pain is
still mild.
6, 7
In this line of thinking, should one be afraid of
an ischemic event if during an exercise a person presents
“triptan sensations” (i.e
. chest, jaw or arm discomfort)?
8
This question remains to be answered.
As future research priorities we should address the
following questions: Why do some patients not respond
to triptan? What are the clinical and demographic
characteristics of patients who respond, compared to
nonresponders
9
? By answering this, we can, therefore,
identify those less likely to respond to triptan before
prescribing this particular pharmacological agent. Could
rest or sleep in a dark room potentiate the action of a
triptan compared to subjects that continue their daily
activities? Do some environmental conditions (light/
10(1).indb 30 21/10/2019 19:34:02
Triptans, which should be chosen?
Valença, MM
31
Headache Medicine, v.10, n.1, p.29-31, 2019
darkness, noise, weather), physiological events or mental
states (sleep, anxiety, stress, fear, hunger) inuence the
action of the drug on the specic migraine attack treated
with triptan? It seems that this may be so, which would
account for the absence of consistency observed with
the use of triptans used at the same dose at different
times and by the same individual.
Could variables such as age and gender inuence
the response to triptans? Why do some patients respond
to a specic triptan after reporting a failure of response
to a different triptan? Pharmacogenetics may explain
this at some future date.
One topic to be discussed is the use of triptans
by sexually active women during their fertile period.
Although triptans should be avoided during pregnancy,
women may use this drug in the rst month before
realizing that they are pregnant. Does this increase
the chance of a possible teratogenic effect of the drug
compared to other classes of analgesics? Evidence has
suggested that the use of triptans during pregnancy
is associated with atonic uterus and blood loss during
labor, but the risk of major birth defects is comparable to
that of the general population.
10
Another important issue is whether the physician
should explain the contraindications of triptans to the
patient. Some may argue that this is not necessary for
young patients with no cardiovascular risks. However, it
is not uncommon for patients to recommend a painkiller
to colleagues and family members, so they need to be
made aware that triptans may have serious adverse
effects when taken inappropriately. Furthermore, a
patient may use triptans for decades without returning
to the prescribing physician and his or her safety prole
may change with age. This is another point to be borne in
mind, considering the importance of patient education.
Thus, despite the fact that an enormous amount of
information has accumulated over the last few decades
on triptans, several questions still remain to be answered
and research priorities need to be addressed.
REFERENCES
1. Rapoport AM, Tepper SJ, Sheftell FD, Kung E, Bigal
ME.Which triptan for which patient? Neurol Sci. 2006
May;27 Suppl 2:S123-9.
2. Johnston MM, Rapoport AM.Triptans for the management
of migraine.Drugs. 2010 Aug 20;70(12):1505-18.
3. Almas M, Tepper SJ, Landy S, Schweizer E, Ramos E.
Consistency of eletriptan in treating migraine: Results
of a randomized, within-patient multiple-dose study.
Cephalalgia. 2014 Feb;34(2):126-35.
4. Silberstein S, Newman L, Marmura M, Nahas S, Farr
S. Efcacy Endpoints in Migraine Clinical Trials: The
Importance of Assessing Freedom from Pain. Curr Med Res
Opin. 2013 Mar 20. [Epub ahead of print]
5. Hall GC, Brown MM, Mo J, MacRae KD.Triptans in migraine:
the risks of stroke, cardiovascular disease, and death in
practice. Neurology. 2004;62(4):563-8.
6. Dodick DW. Applying the benets of the AwM study in the
clinic. Cephalalgia. 2008 Sep;28 Suppl 2:42-9.
7. Goadsby PJ. The ‘Act when Mild’ (AwM) study: a step
forward in our understanding of early treatment in acute
migraine. Cephalalgia. 2008 Sep;28 Suppl 2:36-41.
8. Stillman MJ, Tepper S, Tepper DE, Cho L. QT prolongation,
Torsade de Pointes, myocardial ischemia from coronary
vasospasm, and headache medications. Part 1: review of
serotonergic cardiac adverse events with a triptan case.
Headache. 2013;53(1):208-16. Epub 2012 Dec 6.
9. Viana M, Genazzani AA, Terrazzino S, Nappi G, Goadsby PJ.
Triptan nonresponders: Do they exist and who are they?
Cephalalgia. 2013 Apr 5. [Epub ahead of print]
10. Nezvalová-Henriksen K, Spigset O, Nordeng H. Triptan
exposure during pregnancy and the risk of major
congenital malformations and adverse pregnancy
outcomes: results from the Norwegian Mother and Child
Cohort Study. Headache. 2010 Apr;50(4):563-75.
10(1).indb 31 21/10/2019 19:34:02
Headache Medicine, v.10, n.1, p.32-34, 2019
32
ABSTRACT
CASE REPORT
Cardiac cephalalgia: A deadly case report
Paulo Sergio Faro Santos
1
Matheus Kahakura Franco Pedro
2
Ana Carolina Andrade
3
1
Neurologist, Head of Headache and Orofacial
Pain Division, Department of Neurology,
Neurological Institute of Curitiba, Curitiba, PR,
Brazil.
2
Neurologist, Department of Neurology,
Neurological Institute of Curitiba, Curitiba, PR,
Brazil.
3
Resident, Department of Neurology,
Neurological Institute of Curitiba, Curitiba, PR,
Brazil.
*Correspondence
Paulo Faro
E-mail: dr.paulo.faro@gmail.com
Received: December 22, 2018.
Accepted: January 13, 2019.
Creative Commons (CC BY) Attribution 4.0
International.
Cardiac cephalalgia is a nosologic entity that has only been acknowledged by
the turn of the century, and is, consequently, often underdiagnosed, even by
experienced neurologists. Unlike most headaches, however, failing to provide a
proper and timely diagnosis can have deadly consequences. Report of a case
of cardiac headache attended at the emergency department and literature
review. This entity was rst described in 1997; no studies have yet determined
its prevalence, with the literature relying on case reports. The pathophysiology
remains a mystery, with three main hypothesis: spinal convergence of cardiac
visceral afferent nerves with somatic afferent nerves from the head, increase
of intracranial pressure from decrease in cerebral venous return originated
from the reduced cardiac output, and release of inammatory markers during
cardiac ischaemia, such as bradykinin, serotonin and histamin, causing vascular
changes. Distinguishing this pathology from others, especially migraine, with
which it shares many traits, is of paramount importance: vasoconstrictor drugs
such as triptans are absolutely contraindicated, and the outcome can be
dramatic. This case illustrates the need to promptly recognize this rare entity
since failure to diagnose it can have devastating consequences.
Keywords: Cardiac Cephalalgia; Myocardial Ischemia; Cardiac Arrest.
10(1).indb 32 21/10/2019 19:34:02
Cardiac cephalalgia
Santos PSF, et al.
33
Headache Medicine, v.10, n.1, p.32-34, 2019
INTRODUCTION
Cardiac cephalalgia is a nosologic entity that has
only been acknowledged by the turn of the century,
and is, consequently, often underdiagnosed, even by
experienced neurologists. Unlike most headaches,
however, failing to provide a proper and timely diagnosis
can have deadly consequences
1
.
CASE REPORT
We aim to report he case of ES, a 62 years
old Caucasian male with no previous history of
headache who went to the ER due to a aching,
holocranial, and intense headache lasting over
two weeks, with few moments of respite in the
meantime, with nausea and emesis but no photo/
phonophobia. He developed angina pectoris at the
exact same time, and was subjected to a series of
cardiac exams in the weeks before the pain, which
appeared normal. His comorbities included having
been subjected to a kidney transplantation in 2004,
being still in dialysis, cardiac pacemaker in 2012, as
well as diabetes, heart failure and hypertension. His
admission laboratory workup showed creatinine of
9.16, troponine of 1,95 and CK-MB of 24.24; six hours
later, the exams showed an increase to 1.85 and
26.83, respectively. His EKG showed no ST-segment
elevation.
The hypothesis of cardiac cephalalgia
was raised and his care was transferred to the
cardiology department. He was admitted to the
Coronary Unit, received ASA and clopidogrel and
the patient underwent a percutaneous intervention,
which subsequently demonstrated critical lesions in
anterior descending and right coronaries as well as
thrombus in circumflex artery. After an emergency
coronary artery bypass, he developed hyperkalemia
and went into cardiac arrest, with unsuccessful
reanimation attempts. He fulfilled criteria for cardiac
cephalalgia, as the headache developed in close
temporal relation to the ischaemia and had both
moderate to severe intensity, nausea and absence
of photophobia (Table 1).
DISCUSSION
This entity was first described in 1997
2
; no
studies have yet determined its prevalence,
with the literature relying on case reports
3
.
The pathophysiology remains a mystery, with
three main hypothesis: spinal convergence of
cardiac visceral afferent nerves with somatic
afferent nerves from the head, increase of
intracranial pressure from decrease in cerebral
venous return originated from the reduced cardiac
output, and release of inflammatory markers during
cardiac ischaemia, such as bradykinin, serotonin and
histamin, causing vascular changes
4
. Distinguishing
this pathology from others, especially migraine,
with which it shares many traits, is of paramount
importance: vasoconstrictor drugs such as triptans
are absolutely contraindicated, and the outcome
can be dramatic. In a review of seven cases, three
had triple arterial lesion as well, but in all cases the
patient survived
4
.
CONCLUSION
This case illustrates the need to promptly recognize
this rare entity since failure to diagnose it can have
devastating consequences.
International Headache Classication - 3
rd
edition Part two - secondary headaches
A. Any headache fullling criterion C.
B. Acute myocardial ischaemia has been demonstrated.
C. Evidence of causation demonstrated by at least two of the following:
1. headache has developed in temporal relation to onset of acute myocardial ischaemia.
2. either or both of the following:
a) headache has signicantly worsened in parallel with worsening of the myocardial ischaemia.
b) headache has signicantly improved or resolved in parallel with improvement in or resolution of the myocardial ischaemia.
3. headache has at least two of the following four characteristics:
a) moderate to severe intensity.
b) accompanied by nausea.
c) not accompanied by phototophia or phonophobia.
d) aggravated by exertion.
4. headache is relieved by nitroglycerine or derivatives of it.
D. Not better accounted for by another ICHD-3 diagnosis.
Table 1. Diagnostic criteria for Cardiac Cephalalgia.
10(1).indb 33 21/10/2019 19:34:02
Cardiac cephalalgia
Santos PSF, et al.
Headache Medicine, v.10, n.1, p.32-34, 2019
34
REFERENCES
1. Headache Classication Committee of the International
Headache Society (IHS). The international classication of
headache disorders, 3rd edition (beta version). Cephalalgia.
2013; 33(9): 629-808.
2. Lipton RB, Lowenkopf T, Bajwa ZH, et al. Cardiac
cephalgia: a treatable form of exertional headache.
Neurology. 1997;49:813–6.
3. Wei JH, Wang HF. Cardiac cephalalgia: case reports and
review. Cephalalgia. 2008;28:892–6.
4. Torres-Yaghi Y, Salerian J, Dougherty C. Cardiac cephalalgia.
Curr Pain Headache Rep (2015) 19:14.
10(1).indb 34 21/10/2019 19:34:02
35
Headache Medicine, v.10, n.1, p.35, 2019
CASE REPORT
Coexistence of Sunct Syndrome and pituitary tumor: A
possible association to be recognized
Coexistência entre Cefaleia do tipo SUNCT e tumor pituitário:
Uma associação que deve ser reconhecida
Julia Vescovi Vieira
1
Amanda dos Santos Cintra
1
Ana Paula Alves Fonseca
2
Antônio José da Rocha
2
Renan Barros Domingues
1
1
Department of Neurology, Irmandade Santa
Casa de Misericórdia de São Paulo, São Paulo,
Brazil.
2
Department of Neuroradiology, Irmandade
Santa Casa de Misericórdia de São Paulo, São
Paulo, Brazil.
*Correspondence
Julia Vescovi Vieira
E-mail: jvescovivieira@gmail.com
Received: January 31, 2019.
Accepted:
February 15, 2019.
Creative Commons (CC BY) Attribution 4.0
International.
A 46-year-old woman reported headache with migraine without
aura and SUNCT symptoms. A previous diagnosis of pituitary
macroadenoma was confirmed with MR and an increased prolactin.
Cabergoline was started with improvement of symptoms. An imaging
follow-up showed a reduction of the macroadenoma (Figure 1).
Pituitary adenoma is a intracranial tumor that has been reported
in about 8% of patients with SUNCT. Dural stretch and hormonal
dysfunction are possible mechanisms for this association. The fact
that tumor and SUNCT were ipsilateral and that headache improved
after cabergoline may suggest an association between these
entities, supporting MR investigation when this type of headache is
diagnosed.
REFERENCES
1. Levy M, Matharu M, Meeran K, Powell M. The clinical characteristics of
headache in patients with pituitary tumours. Brain. 2005;128(8):1921–30.
2. Chitsantikul P, Becker WJ. SUNCT, SUNA and pituitary tumors: Clinical
characteristics and treatment. Cephalalgia. 2013;33(3):160–70.
3. Pareja J, Caminero A, Sjaastad O. SUNCT syndrome: diagnosis and
treatment. Headache. 2003;43(306).
Figure 1. Pituitary MRI, coronal post-gadolinium T1-weighted sequence (a)
demonstrate a rounded region of delayed enhancement in the left pituitary compared
to the rest of the gland, compatible with adenoma. (b) Imaging follow-up showed a
signicant reduction of the lesion.
10(1).indb 35 21/10/2019 19:34:03
Headache Medicine Volume 10 Número 1 - 2019
Headache Medicine Volume 10 Número 1 - 2019
Editorial
► Tenth year of Headache Medicine Journal, 25 years
Original Article
► ID-Migraine is a sensitive tool for screening
migraine among patients with multiple sclerosis
► Aerobic exercise training for migraine prevention:
A trigger-based analysis
► Melatonin reverts CGRP expression induced by
capsaicin
Views and Reviews
►
thrombin and vitamin K inhibitors on migraine
treatment
► Cerebral energetic metabolism of individuals with
migraine through 31P-MRS: A systematic review
► Of the available triptans, which should be chosen
and how should they be used?
Case Report
► Cardiac cephalalgia: A deadly case report
► Coexistence of Sunct Syndrome and pituitary
tumor: A possible association to be recognized
Capav10n1.indd 1 22/10/19 18:13
