Send Orders for Reprints to [email protected] 26 Recent Patents on CNS Drug Discovery, 2014, 9, 26-40 Migraine Attack Treatment: A Tailor-made Suit, Not One Size Fits All Robert Belvís*, Natalia Mas and Azahara Aceituno Headache Unit. Department of Neurology, Quiron Dexeus University Hospital, Barcelona, Spain Received: October 28, 2013; Revised: January 11, 2014; Accepted: February 06, 2014 Abstract: About 15% of people in the world suffer migraine attacks. Migraine can induce a great impact in the quality of life, and the costs of medical care and loss of productivity can be also high. Non-steroidal anti-inflammatory drugs (NSAIDs) are the best treatment in mild-to-moderate migraine attacks and triptans are the first line option in the acute treatment of moderate-to-severe migraine attacks. At present, there are seven marketed triptans: sumatriptan, rizatriptan, zolmitriptan, eletriptan, naratriptan, almotriptan and frovatriptan. Obviously, every drug presents different pharmacoki- netic and pharmacodynamics properties and, moreover, some triptans have several formulations. The prescription of one of these seven triptans for a specified patient is based in the drug profile: efficacy, safety, pharmacokinetics and pharma- codynamics. Other data to take account in the final prescription are clinical characteristics of the migraine attack (speed of onset, intensity of pain, lasting of the attack) and patient characteristics as working habits, life style or medical history. It is therefore mandatory to perform an individualization of the treatment of migraine attack. In recent years, several new patents of drugs have been registered in the treatment of migraine attack, although most of these are already known drugs that only provide new routes of administration. We present an update on the treatment of the migraine attack Keywords: Analgesics, ergot alkaloids, migraine attack, NSAIDs, triptans. INTRODUCTION it has analysed the disability of 291 diseases and injuries using “Disability-adjusted life years (DALYs)” as unit of Migraine is a common and frequently disabling headache measure. As a consequence, the burden of migraine is enor- disorder characterized by recurrent episodic attacks of mod- mous. Migraine sufferers spend a total of 112 million days erate to severe headache alternatively accompanied by neu- bedridden and the annual cost of missed work or reduced rological, gastrointestinal and//or autonomic symptoms [1]. productivity is $5.6 to 17.2 billion in U.S. ($2,571 per person The third edition of the International Classification of Head- per year) [7, 10, 11, 16-19]. ache Disorders (ICHD-3) of the International Headache So- ciety (IHS) is the more accepted guideline of headache in the world [2]. It establishes three major forms of migraine: epi- TREATMENT OF THE MIGRAINE ATTACK sodic migraine without aura (Table 1), episodic migraine At present, two types of drugs have shown efficacy in the with aura (Table 2), and chronic migraine (Table 3). The migraine attack therapy: non-specific drugs (analgesics and aura consists of focal neurologic symptoms (usually visual non-steroidal anti-inflammatory agents – NSAIDS) and spe- symptoms) that precedes headache, and it appears in 15-25% cifics drugs (ergot alkaloids and triptans). We will apply in of migraine patients. The transformation from episodic mi- this paper the recommendations of the guidelines of the graine to chronic migraine happens in the 2-3% of migraine European Federation of Neurological Societies and the patients every year [3]. This is the more disabling form of guidelines of the American Academy of Neurology to ana- migraine lyse the efficacy and safety of drugs employed in migraine Migraine affects approximately 15% of people (18% of attack [20-22]. women and 6% of men) in western countries, and 20-40% of ANALGESICS: Some studies show efficacy of phena- patients experience an attack frequency of greater than one zone [23], dipyrone [24] and tolfenamic acid [25] in the per month. Moreover, migraine is severe or very severe in treatment of migraine attack (recommendation grade B) [21]. more than 80% of patients and persists for more than 24 Acetaminophen alone is not recommended for moderate-to- hours in more than 50% of patients [4-14]. For these reasons, severe migraine (recommendation grade B) [20], but it is the Global Burden of Diseases, Injuries, and Risk Factors indicated in mild migraine (recommendation grade A), pae- Study 2013 (GBD 2013) reported that migraine is the eighth diatric migraine and in pregnant women with migraine at- disease more disabling of the human pathology [15]. The tacks [21, 26]. However, analgesic combinations with aspi- GBD 2013 is a study of the World Health Organization and rin, caffeine, codeine, tramadol or butalbital can be also ef- fective [20, 21, 27-29]. *Address correspondence to this author at the Department of Neurology. NSAIDs: Aspirin [30-33], naproxen sodium [35-37], Quiron Dexeus University Hospital. Address: C/ Sabino Arana nº5-19, cp diclofenac [38-41], and ibuprofen [42-45] are indicated in 08028, Barcelona; Spain; Tel: 34 93 253 09 10; mild-to-moderate migraine attack treatment (recommenda- E-mail: [email protected] 2212-3954/14 $100 00+ 00 © 2014 Bentham Science Publishers Migraine Attack Treatment Recent Patents on CNS Drug Discovery, 2014, Vol. 9, No. 1 27 Table 1. Diagnostic Criteria of Migraine Without Aura. The International Classification of Headache Disorders, 3rd edition. A. At least five attacks fulfilling criteria B–D B. Headache attacks lasting 4-72 hours (untreated or unsuccessfully treated). C. Headache has at least two of the following four characteristics: 1. Unilateral location 2. Pulsating quality 3. Moderate or severe pain intensity 4. Aggravation by or causing avoidance of routine physical activity (e.g. walking or climbing stairs) D. During headache at least one of the following: 1. Nausea and/or vomiting 2. Photophobia and photophobia E. Not better accounted for by another ICHD-3 diagnosis. Table 2. Diagnostic Criteria of Migraine With Aura. The International Classification of Headache Disorders, 3rd edition. A. At least two attacks fulfilling criteria B and C B. One or more of the following fully reversible aura symptoms: 1. visual 2. sensory 3. speech and/or language 4. motor 5. brainstem 6. retinal C. At least two of the following four characteristics: 1. at least one aura symptom spreads gradually over 5 minutes, and/or two or more symptoms occur in succession 2. each individual aura symptom lasts 5-60 minutes 3. at least one aura symptom is unilateral. 4. the aura is accompanied, or followed within 60 minutes, by headache D. Not better accounted for by another ICHD-3 diagnosis, and transient ischemic attack has been excluded. Table 3. Diagnostic Criteria of Chronic Migraine.The International Classification of Headache Disorders, 3rd edition. A. Headache (tension-type-like and/or migraine-like) on >15 days per month for >3 months and fulfilling criteria B and C B. Occurring in a patient who has had at least five attacks fulfilling criteria B-D for 1.1 Migraine without aura and/or criteria B and C for 1.2 Migraine with aura C. On >8 days per month for >3 months, fulfilling any of the following: 1. criteria C and D for 1.1 Migraine without aura 2. criteria B and C for 1.2 Migraine with aura 3. believed by the patient to be migraine at onset and relieved by a triptan or ergot derivative D. Not better accounted for by another ICHD-3 diagnosis. tion grade A) [20, 21]. Other NSAIDS as flurbiprofen, (PF2h), and sustained pain-free (sPF) (Table 5). The ana- dexketoprofen trometamol [46], and intramuscular ketorolac lysed doses of ibuprofen are 200 mg and 400 mg. We have [47] are also useful (recommendation grade B). no data of the efficacy of the dose of 600 mg. On the other hand, soluble formulations of ibuprofen seem to be faster Efficacy. Table 4 shows the results of several meta- than oral formulations in achieve pain relief. Sodium analyses of the efficacy of NSAIDs. The analysed variables naproxen is not in the Table 4 because its studies analysed are: number of patients-to-treated (NTT) to achieve head- the risk relative (RR), not the NTT. In an indirect compari- ache-relief at two hours (HR2h), pain-free at two hours 28 Recent Patents on CNS Drug Discovery, 2014, Vol. 9, No. 1 Belvís et al. Table 4. Efficacy of NSAIDS in Migraine Attack. NTT Aspirin 1000 mg Aspirin 1000 Ibuprofen 200 mg Ibuprofen 400 mg Potassium diclofenac mg+metoclopramide 50-100 mg Clinical trials 15 9 5 Patients 4.222 4.374 1.356 HR2h 4.9 3.3 6.3 3.2 8.9 PF2h 8.1 8.8 9.7 7.2 6.2 sPF24h 6.6 6.2 / 4.0 9.5 Table 5. Efficacy Parameters to Evaluate Triptan in Migraine Attack. • Headache scale: absence, mild, moderate or severe. • Headache response is defined as a decrease in headache intensity from moderate to severe or to mild to none at previously established times (i.e. 2 hours). • Headache-relief at two hours (HR2h). Percentage of patients whose headache intensity decreases within two hours. • Pain-free outcome (moderate-severe to none) at also established times (i.e. 2 hours). • Pain-free at two hours (PF2h). Percentage of patients whose headache disappears within two hours. The majority of RCTs apply PF2h to evaluate the response of an oral triptan as primary endpoint • Two hours therapeutic gain. Difference between the PF2h of the triptan and the PF2h of the placebo. • Sustained pain-free (sPF). Percentage of patients pain-free at two hours with no relapse for the next 48 hours • Complete Response. Headache disappears at two hours and does not appear in the next 24 hours. The patient does not need a rescue triptan.