Guidelines for the prevention of migraine Dirk Deleu, MD, PhD, Yolande Hanssens, Pharm. ABSTRACT Treatment of migraine has traditionally been divided into managing acute attacks and prophylactic treatment. Treatment of acute migraine has been the subject of many research papers and review articles in recent literature partly at the cost of prophylactic treatment, which is the focus of this review. The objective of prophylactic therapy is to reduce frequency, duration and severity of attacks in addition to optimize the patient’s ability to function normally. Preventive therapy is usually undertaken in patients who have more than two migraine episodes per month or when less frequent have severely disabling headaches resistant to usual treatment. Beta-blocking drugs without intrinsic sympathomimetic activity (e.g. propranolol) are usually the first drugs of choice followed by tricyclic antidepressant agents (e.g. amitriptyline), non- steroidal anti-inflammatory drugs (e.g. naproxen), calcium antagonists (e.g. flunarizine) or valproate. The use of serotonin antagonists (e.g. methysergide) is limited because of their potential serious side effects. Migraine refractory to standard prophylactic therapy is very often the result of overuse of abortive antimigraine drugs. The choice of medication clearly depends on the patient’s profile (age, co-morbid medical conditions) and the contraindication and side effect profile of the drug. Keywords: Migraine, prophylaxis, beta-blocking drugs, tricyclic antidepressants, non-steroidal anti-inflammatory drugs, valproate, flunarizine, serotonin antagonists. Neurosciences 2000; Vol. 5 (1): 7-12 igraine is a chronic intermittent disorder disease has a substantial socio-economic impact on Mcharacterized by paroxysmal, moderate-to- both patient and society, resulting from limitations in severe attacks of unilateral, throbbing headache daily function, reduced quality of life and loss of exacerbated by physical activity and accompanied by productivity. Indirect costs, particularly loss of anorexia, nausea, vomiting, photophobia and productivity in the workplace, represent the largest phonophobia.1 It is ubiquitous with variable proportion of total costs of migraine. geographical prevalence. Prevalence rates range There is now substantial evidence that the from 1.5% in Hongkong2 to 14% in the Western pathophysiology of migraine is based on the world.3 The prevalence rate on the Arabian constriction of intracranial (pial and dural) blood Peninsula was reported 2.6%.4 Migraine is much vessels. The ophthalmic branch of the fifth cranial more common in females than in males; 11-18% and nerve transmits nociceptive information from the 3-8%.3 Furthermore, there is a clear racial difference intracranial structures to the trigeminal nucleus from in genetic vulnerability to migraine and the disorder where neurons project to the midbrain (lateral is known to be age (most common between 25-55 geniculate body, superior colliculus), cerebral cortex years) and income-dependent (affecting mostly lower (visual cortex) and retina. Depolarization of these socio-economic groups)3 Since migraine is a trigeminovascular neuron results in the release of common illness, which reduces health-related quality vasoactive neuropeptides (e.g. calcitonin gene- of life both during and between acute attacks, the related peptide (CGRP) from the dense trigeminal From the Departments of Clinical Pharmacology and Neurology, (Deleu), College of Medicine, Sultan Qaboos University, Muscat-123, Drug Information Services Hospital Pharmacy, (Hanssens) P.O. Box 38, Sultan Qaboos University, Al Khod, Muscat-123, Sultanate of Oman. Published with special permission from Saudi Medical Journal. Address correspondence and reprint request to: Dr. Dirk Deleu, Department of Clinical Pharmacology and Neurology, College of Medicine, P.O. Box 35, Sultan Qaboos University, Al-Khod, Muscat-123, Sultanate of Oman. Fax. 968 513519. E-Mail: [email protected] 7 Migraine prophylaxis ... Deleu & Hanssens perivascular network into the vessel wall. This, in its conditions such as tension headache and depression turn, results in neurogenic mediated vasodilation and or both. plasma protein extravasation.5 This inflammatory In the following paragraphs the pharmacological response is transmitted to adjacent tissues. characteristics of the agents used in the prophylactic Furthermore, this noxious response can be conveyed treatment of migraine in adults will be discussed. to the trigeminal nucleus caudalis and higher brain Our evaluation of the clinical efficacy of drugs is centers for the registration of pain. based on double blind, controlled clinical trials with Activation of presynaptic serotonin (5-HT1D) a significant number of patients (at least 50 patients receptors identified on trigeminal perivascular per study arm), unless otherwise stated. Finally, neurons inhibits both the releases of these prophylactic agents are at most 60% better than proinflammatory mediators and neurogenic placebo and less than 10% of patients will become 8 inflammation. While 5-HT1B receptor activation, completely free of headache. Therefore, it needs to expressed on vascular smooth muscle cells, mediate be considered whether this 30-60% reduction in vasoconstriction.6 headache frequency or severity will provide Non-pharmacological measures. Rational meaningful improvement in the patient’s quality of prophylactic management of migraine necessitates life. the accurate identification and elimination of Table 1 gives an overview of all drugs, which are potential trigger factors (e.g. stress, emotions, and have been used, either successfully or non- fatigue, certain foods and beverages, hormonal successfully, in migraine prophylaxis. No single factors and drugs e.g. oral contraceptives, prophylactic drug is superior when potential side vasodilators). Consequently, regular sleep and effects are also considered. Finally, it is important to meals, and relaxation techniques for coping with recognize that migraine refractory to standard family-or-work-related stress and emotional prophylactic therapy is very often the result of problems may constitute part of the non- overuse of abortive antimigraine drugs. Gradual pharmacological prophylactic management. withdrawal from any overused drug followed by Pharmacological measures. The objective in prophylactic therapy is cornerstones of the treatment prophylactic treatment of migraine is to reduce the of analgesic rebound headache. frequency, severity and duration of attacks whilst Beta-blocking drugs. The mechanism by which keeping side effects to a minimum. Prophylactic b-blocking drugs prevent migraine is unclear. Most treatment is particularly recommended for patients likely their effect can be explained by an interaction with more than two migraine attacks per month or if between the adrenergic and serotoninergic systems in the response to treatment of the acute attack is the central nervous system, or by a direct 5-HT2 disappointing. Patients with infrequent migraine antagonistic effect.6 attacks are unlikely to sufficiently benefit to justify b-Blocking drugs without intrinsic the inconvenience and side effects of prophylactic sympathomimetic activity are the only class of b– agents and, last but not least, the cost of the blockers with proven effect in migraine prophylaxis. tretment.7 Other considerations include severity or The beneficial effect is usually seen within 4 weeks, disability from pain or associated symptoms. but seems to increase with time. This class of agents Most prophylactic therapy needs to be given on a is particularly useful in patients whose attacks are daily basis for months or years. However, periodical triggered by stress. Propranolol has been the most therapy can be considered in e.g. exercise-triggered extensively studied and has proved to be effective in migraine attacks. Similarly, menses-related migraine 19 of 21 controlled trials.9 The standard dose long- can be effectively managed with prophylactic acting formulation of propranolol (Inderal-LA‚® 160 therapy starting one week before the menstrual mg o.d.) is more effective in reducing the frequency period is due. When prophylactic medication is of migraine attacks compared to the lower dose long- indicated, it is advised to begin with a low dosage acting formulation (Half-Inderal LA‚® 80 mg bid).10 and titrate gradually upward until the agent is given Bisoprolol11 metoprolol12 and timolol13 are useful at full therapeutic dosage or the migraine attacks are alternatives, resulting in 22-49% reduction in the properly controlled. Treatment should be given for 3 number of migraine attacks. Propranolol is highly months before reassessment, and continued for 6 liposoluble, which explains the higher rate of central months or longer if beneficial. If attack frequency nervous system side effects compared to metoprolol and severity have been reduced to such a level that and timolol. Furthermore, because of lack of preventive medication is not longer indicated (e.g. selectivity, it causes b2-induced bronchoconstriction. less than two attacks per month without significant The choice of b-blocking drug might, therefore be clinical disability) prophylactic therapy can be dictated by its side effects. None of the b-blockers is gradually withdrawn. Although monotherapy is safe during pregnancy. preferable because it improves compliance, Other b-blocking drugs, like atenolol and nadolol, combination of propranolol and amitriptyline is have also been evaluated for their prophylactic