Neurol Sci DOI 10.1007/s10072-015-2217-y

BRIEF COMMUNICATION

Angiotensin II receptor blockers: a new possible treatment for chronic migraine? Caterina Disco1 • Ferdinando Maggioni1 • Giorgio Zanchin1

Received: 5 January 2015 / Accepted: 13 April 2015 Ó Springer-Verlag Italia 2015

Abstract The objective is to suggest a possible role of different angiotensin receptor blockers in the treatment of chronic migraine, especially in hypertensive subjects. Chronic migraine is a highly disabling disorder affecting between 1.4 and 2.2 % of the general population. Despite many pharmacological and non-pharmacological treatments proposed, the results are rather discouraging. Therefore, we believe that should be highlighted all the possible therapies that may lead to an improvement of the symptomatology. Particularly, data available on efficacy of ARBs in preventing chronic migraine are poor. Methods include case reports, literature review and discussion. We report three cases recently treated with angiotensin II receptor blockers that showed a significant improvement, never previously presented with more conventional treatments, including beta blockers. In all three cases, we obtained the reversibility from a chronic migraine to an episodic. Taking a cue from this observation, we consider desirable large controlled, randomized trials to assess the effectiveness of ARBs both in CM hypertensive patients and in patients who do not require anti-hypertensive therapy; furthermore are desirable comparative studies between the various ARB inhibitors to assay any intermolecular differences in efficacy. Keywords Therapy

Chronic migraine  Migraine  Sartans 

& Caterina Disco [email protected] 1

Department of Neurosciences, Headache Centre, University of Padua, Via Giustiniani, 5, 35128 Padua, Italy

Introduction Chronic migraine (CM) in the International headache classification beta version (ICHD-III) [1] is not considered a complication of migraine but a peculiar nosography entity characterized by headache attacks occurring more than 15 days/month, 8 of them with migrainous features. Although CM is less common than episodic migraine (EM), with a prevalence ranging between 3 and 5 % in the general adult population [2], it is very debilitating and limited the possibilities of its effective treatment. Angiotensin II receptor blockers (ARBs) are drugs modulating the renin–angiotensin system (RAS). ARBs action consists of blocking RAS by competing directly with angiotensin II type 1 (AT1) receptors [3, 4]. Among drugs administered for migraine prophylaxis, recently a role for ARBs has been proposed. However, data available on ARBs efficacy in migraine prophylaxis are poor, in particular on their use in CM treatment. We present three CM cases (ICHD-III) [1], noticeably improved by the administration of different ARBs.

Case reports Patient 1 A 70-year-old woman suffered from sporadic migraine without aura (MO) since childhood; at age of 20, MO had became chronic and disabling (VAS score 8/10, MIDAS score 47) with almost 20 headache days for month, resistant to non-steroidal anti-inflammatory drugs and triptans, responsive only to suppositories of an association of ergotamine tartrate 2 mg, caffeine 100 mg and aminophenazon 250 mg (15 doses/month). General and neurological

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examinations as well as brain magnetic resonance imaging (MRI) were unremarkable. No positive effect was obtained with the preventative drugs amitriptyline, flunarizine, propranolol and topiramate, in adequate dosage during periods of almost 3 months. In previous years, the patient took atenolol 50 mg/die for a mild essential hypertension. This anti-hypertensive therapy improved blood pressure but did not modify MO. In March 2012, because of an incomplete blood pressure control, association of valsartan 160 mg with hydrochlorothiazide 12.5 mg 1 tab/die was added. After about 15 days, the patient reported complete disappearance of MO attacks, documented by headache diary. One month later, the patient had to discontinue the valsartan/hydrochlorothiazide association because of an hypotensive effect. After a few days, migraine attacks recurred with the previous frequency and intensity. Two weeks later, she took again valsartan 160 mg without hydrochlorothiazide. A week after, she began to rapidly improve and in a few days she reached a 3 attack/month frequency, with considerable improvement of headache severity and disability (VAS score 6, MIDAS score 12) unchanged at 18-month follow-up. Patient 2 A 21-year-old man reported a history of sporadic MO dating back to age 13. Attacks became chronic when he was 18 years old, with more than 10 migrainous attacks/month of moderate–severe intensity (VAS score 7/10) and with a grade IV severe disability (MIDAS score 64). Moreover, since 2009, the patient was diagnosed with a mild hypertension, confirmed by a 24-h blood pressure monitoring, and a grade II obesity. Magnetic resonance imaging (MRI) gadolinium enhanced (GE), MR angiography, electrocardiography, transthoracic echocardiogram, supra-aortic and intracranial vessels echocolordoppler were unremarkable. A secondary hypertension screening resulted normal. Propranolol 40 mg/day had been administered as preventative migraine therapy for 3 months with improvement of blood pressure but without effectiveness on headache. Because of adverse events, propranolol was replaced with irbesartan 150 mg/die. About 1 month later, the headache diary documented a noticeable MO reduction to one attack every 2 months of mild intensity (VAS score 3–4/10) and with a minimal disability (MIDAS score 4), unchanged at a 1-year follow-up. Patient 3 A 42-year-old woman, was affected by MO since her childhood progressively worsened during years, becoming

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chronic with a frequency of [10 attack/month, of severe intensity (VAS score 8/10). Previous prophylaxis treatments with flunarizina, verapamil, amitriptyline, topiramate, pizotifen and valproate have been ineffective. In 2008, the patient reported further worsening of migraine with [15 attack/month (MIDAS score 60). Electroencephalogram and cerebral MRI-GE were unremarkable. In 2013, a mild essential hypertension was diagnosed and she was prescribed olmesartan 10 mg/die resulting in a marked improvement in the frequency of attacks (2–3 attacks/month) and the reduction of disability, although no difference was reported on headache severity (MIDAS score 18); in addition, the frequency and severity of headache were unchanged at 1-year follow-up.

Discussion These cases show that valsartan, irbesartan and olmesartan have been effective in reducing attacks in CM. In the last years, efficacy of angiotensin-converting enzyme inhibitors and ARBs as preventative migraine treatment has been documented. A placebo-controlled trial on candesartan 16 mg administration on 60 patients with EM (attacks frequency 2–6/month), showed an improvement of primary outcomes (number of headache days, migraine days and migraine hours compared with placebo), and a 32–46 % of responders with at least of 50 % reduction on at least 1 of the efficacy outcomes [4]. Candesartan effect size in migraine prophylaxis was found similar to propranolol in a randomized, triple-blind, double cross-over study on 72 adult patients with both episodic and chronic migraine [5]. On the other hand, a placebo-controlled trial performed on telmisartan did not show a similar effect [6]. Olmesartan 10–40 mg also has been tested in an open label study on 24 hypertensive patients (22 with MO) and was found effective with 82.5 % average reduction of migraine attacks frequency and a 45 % average reduction in the severity of headache pain [7]. However, the mechanisms of action of ARBs in migraine prevention are poorly understood. It has been suggested that hypertension may induce chronification of migraine, probably by enhancing endothelial disfunction on the vascular wall [8]. Although preventive effect of ARBs administration may be mediated by anti-hypertensive action, we reported two cases in which optimal blood pressure control with other anti-hypertensive therapies did not result in an improvement of migraine. Therefore, ARBs neuromodulatory effect could be hypothesized to explain as migraine preventative therapy: AT1 receptors placed in caudal ventrolateral medulla seem to have a pain modulatory role as supported by experimental hyperalgesia induced by

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intrathecal administration of angiotensin II, significantly attenuated by local administration of losartan [9]. On the other hand, ARBs effects on attenuating inflammatory and oxidative stress and on the regulation of the nitric-oxide synthase isoenzymes in the brain have been suggested [10]. Based on these data, RAS may be involved in CM, playing a role both in the endothelial dysfunction and through a neuromodulatory action.

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Conclusions 6.

Our limited case series suggests a possible effectiveness of ARBs in CM therapy; moreover, a role of hypertension in migraine chronification has been suggested as well the involvement of RAS system in migraine pathogenesis: these elements could induce to collect more consistent data by performing a retrospective cohort study of migrainous patients followed by hypertension centers. Conflict of interest The principal author also declares that there is no conflict of interest. Compliance with ethical standards The principal author takes full responsibility for the data presented in this study, analysis of the data, conclusions, and conduct of the research.Patient consent was obtained for the publication of case reports and data have been omitted which could lead to a recognition of the patients.

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References 1. Headache Classification Committee of the International Headache Society (IHS) (2013) The International Classification of

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Angiotensin II receptor blockers: a new possible treatment for chronic migraine?

The objective is to suggest a possible role of different angiotensin receptor blockers in the treatment of chronic migraine, especially in hypertensiv...
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