Lack of association between CGRP-related gene polymorphisms and medication overuse headache in migraine patients

We investigated whether calcitonin gene-related peptide (CGRP)-related gene polymorphisms are involved in the aggravation of migraines due to medication overuse. In total, 47 migraine patients (6 males and 41 females; 36.4 ± 10.3 years) and 22 medication overuse headache (MOH) patients (1 male and 21 females; 39.6 ± 9.9 years) who had migraine participated in this study. Calcitonin gene-related polypeptide-alpha (CALCA, α-CGRP, Insertion/Deletion rs1553005, rs145837941) and CGRP receptor (receptor activity-modifying protein 1: RAMP1, rs3754701, rs7590387) were analyzed by polymerase chain reaction (PCR) and PCR-restriction fragment length polymorphism (PCR-RFLP) methods. No significant differences were observed in the genotype distributions of CALCA and RAMP1 between migraine patients and MOH patients. The results of this study showed no association between CGRP-related gene polymorphisms and the complication of MOH in migraine patients. Introduction Migraine patients are particularly prone to developing medication overuse headache (MOH) [1-3]. Moreover, it has been shown that 56.8% of migraine sufferers use over-the-counter medicine alone [4]. Although MOH is known to be caused by triptan, ergotamine, opioid, and/or analgesic overuse in patients with headache [1], 85.1% of MOH patients overuse combination analgesics according to research by Imai et al. [2]. Most patients return to an episodic migraine pattern following drug withdrawal. However, the complication of MOH markedly decreases the quality of life of these patients [1]. In addition, the incidence of comorbidity with depression is higher in MOH patients than in migraine patients [3,5]. Therefore, the aggravation of migraines due to medication overuse needs to be prevented. Calcitonin gene-related polypeptide-alpha (CALCA, α-CGRP) is a potent vasodilator and one of the mediators of neurogenic inflammation. Plasma levels of calcitonin gene-related peptide (CGRP), later called α-CGRP, are elevated in migraine patients [6,7], and an infusion of CGRP can trigger a migraine attack [8]. In addition, CGRP antagonists have good efficacy in the treatment of acute migraine attacks [9, 10]. Thus, CGRP is a key molecule in migraine pathogenesis. Interestingly, in MOH model animals, triptan increased CGRP levels [11]. In addition, exposure to μ opioids such as morphine also increased CGRP in cultured dorsal root ganglion cells [12,13]. Therefore, increasing CGRP through medication overuse seems to aggravate migraines.. On the other hand, Menson et al. [14] showed no significant association between the intronic 16 bp deletion in the CALCA gene and migraine. Sutherland et al. [15] also reported that CALCA polymorphisms (rs3781719, rs145837941) and CGRP receptor (receptor activity-modifying protein 1: RAMP1, rs3754701, rs7590387) are not involved in the pathogenesis of migraine. However, to the best of our knowledge, there have been no studies on the relationship between CGRP-related gene polymorphisms and MOH. In present study, we focused on CGRP-related gene polymorphisms such as CALCA and RAMP1 and investigated the relationship between CGRP-related gene polymorphisms and the complication of MOH in migraine patients. Methods Subjects We enrolled 47 migraine patients [6 males and 41 females: 5 with migraines with aura (MA), 36 with migraines without aura (MO), 6 with both MA and MO at different times; 36.4 ± 10.3 years of age] and 22 MOH patients who had migraine (1 male and 21 females: 1 with MA and 21 with MO; 39.6 ± 9.9 years of age) who were seen in an outpatient clinic of the Department of Neurology, Showa University Correspondence to: Masakazu Ishii, Ph.D, Department of Pharmacology, Toxicology and Therapeutics, Division of Physiology and Pathology, Showa University School of Pharmacy, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan; Tel: +81-3-3784-8041; Fax: +81-3-3786-0481; E-mail: [email protected]