Clinical Correspondence Persistent Headache in Patients With Multiple Sclerosis Starting Treatment With Fingolimod Yara Dadalti Fragoso, MD, MSc, PhD; Tarso Adoni, MD, PhD; Sidney Gomes, MD, PhD; Marcus Vinicius Magno Goncalves, MD; Andre Palma da Cunha Matta, MD, PhD; Maria Fernanda Mendes, MD, PhD; Fabio Siquineli, MD It is difficult to think of a medication that does not have “headache” as a potential adverse event listed by the manufacturer. However, this symptom is not described in detail by the pharmaceutical companies, and no considerations are made regarding the acceptable duration of this side effect or how to manage it, should it occur. This letter concerns 12 potential cases of headache associated with use of fingolimod, a new and very efficient drug for treating multiple sclerosis (MS). Upon starting with fingolimod, these patients presented persistent head- ache that resembled new daily persistent headache (NDPH) but were, in fact, attributable to a new substance. 1 Fingolimod is an orally bioavailable compound that antagonizes the sphingosine 1-phosphate (SP1) receptor. In vivo, fingolimod is phosphorylated to fingolimod-phosphate, which resembles naturally occurring S1P. Through binding to SP1 sites in lym- phocytes, fingolimod prevents these cells from leaving the lymph nodes. 2 The first dose of fingolimod may be associated with bradycardia, fatigue, gastrointestinal disturbance, headache, and upper respiratory tract infection. 3 Other adverse events in patients using fingolimod that are more serious but rare include atrioventricular block, herpetic viral infections, and macular edema. 3 Although headache is described as a potential side effect of fingolimod and many other drugs for the treatment of MS, the present cases caught our attention because of the characteristics that these patients presented. These patients comprised 8 males and 3 females, of mean age 33.5 years (range 23 to 46 years), who are undergoing treatment for MS. Fingolimod was prescribed due to suboptimal response to other drugs. One patient had a previous history of episodic migraine. They were not using any drugs other than immunomodulatory treatments for MS. In all patients, their headache started within the first week of use of fingolimod and persisted for at least 3 months. In all cases, the pain was bilateral, non-pulsatile, of moderate intensity, and persistent From the MS Reference Center, Universidade Metropolitana de Santos, SP, Brazil (Y.D. Fragoso); MS Reference Center, Hospital Sirio-Libanes, Sao Paulo, SP, Brazil (T. Adoni); Department of Neurology, Hospital Beneficencia Portuguesa de Sao Paulo, Sao Paulo, SP, Brazil (S. Gomes); MS Unit, Centro Hospitalar Unimed, Joinville, SC, Brazil (M.V.M. Goncalves); Department of Neurology, Hospital Universitario Antônio Pedro, Universidade Federal Fluminense, Niterói, RJ, Brazil (A.P.C. Matta); Department of Neurology, Medical School, Irmandade de Misericordia da Santa Casa de Sao Paulo, Sao Paulo, SP, Brazil (M.F. Mendes); Department of Neurology, Universidade Regional de Blumenau, Blumenau, SC, Brazil (F. Siquineli). Address all correspondence to Y.D. Fragoso, Rua da Constituicao 374, Santos, SP CEP 11015-470, Brazil. Accepted for publication December 16, 2014. Conflict of Interest: The authors have no conflicts of interest to declare. ISSN 0017-8748 doi: 10.1111/head.12526 Published by Wiley Periodicals, Inc. Headache © 2015 American Headache Society 578