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. The IHS considers that complete response is the standard to evaluate any new drug for the migraine attack. • Recurrence of headache. Percentage of patients whose headache reappear after an initial relief in the first 24 hours and induce a new triptan dose. • Consistency of Response (intrapatient consistency). Reproducible pain relief from attack to attack in two or three migraine attacks. • Ability to diminish accompanied symptoms. Nausea, vomiting, photophobia and phonophobia. • Reduction in clinical disability. Triptan ability to reduce functional impairment due to headache or associated symptoms

son, the RR of HR2h is 1.8 for Ibuprofen 400 mg and 1.5 for New marketed NSAIDs. Most of them are NSAIDs al- sodium naproxen 500-1.000 mg; and the PF2h is 2.1 for ibu- ready known, but with different routes of administration. profen and 2.2 for sodium naproxen. - Powdered formulation of diclofenac potassium for oral Safety. NSAIDs present a low ratio of AEs (RR: 1.2 for solution. A recent randomized clinical trial (RCT) [50] has sodium naproxen) [48], but they are responsible of the 21- shown a good efficacy of this formulation in moderate-to- 25% of all adverse effects (AEs) of the human general severe migraine attacks in 68 patients comparing to 47 pa- therapy because of their extended use. The gastric intoler- tients who had taken a placebo. The PF2h was 25% for this ance is the more frequent AE of NSAIDs. Other AEs are new formulation versus 10% for the placebo. dizziness, nausea, peptic ulcer, digestive haemorrhage, he- - Intranasal ketorolac tromethamine 200 L containing patotoxicity, tinnitus, alterations of platelet aggregation, 6% of lidocaine intranasal spray. A RCT [51] has analysed depression, nephropathy and high blood pressure. They are the efficacy of this new formulation of ketorolac in 68 pa- not indicated in patients with peptic ulcer, inflammatory or tients against 72 patients who had taken a placebo in moder- diverticular bowel disease, and in the third trimester of ate-to-severe migraine attacks. The PF2h was of 24% for the pregnancy. The hypersensitivity to NSAIDs is uncommon ketorolac versus 10% for the placebo. (0.5-1.9%) in the population [45]. Finally, a NSAIDs over- use presents a low risk of transformation from episodic - Intravenous ibuprofen (800 mg)is undoubtedly the more migraine to chronic migraine (Odds Ratio: 0.85) regarding expected new formulation of NSAIDS. At present, an ongo- other drugs as barbiturates, opiates, and ergot alkaloids ing RCT is analysing its efficacy against placebo in migraine [49]. attacks [52]. Migraine Attack Treatment Recent Patents on CNS Drug Discovery, 2014, Vol. 9, No. 1 29

- Etodolac is a new NSAID that has showed a good effi- frovatriptan (Table 6). They differ from sumatriptan with cacy against paracetamol in a RCT that included 229 patients respect to their pharmacological profiles: complete pain re- [53]. lief, speed of pain relief, rate of migraine recurrence, AEs, and relief of associated symptoms. A lot of RCTs and open - Intra-oral topical ketoprofen gel applied to a branch of the trigeminal nerve. At present, this formulation of ketopro- label trials were performed in the nineties to find out who was the best triptan. That period of time was popularly called fen is being analyzed in an ongoing RCT against placebo “the war of the triptans” because the competition between [54]. pharmaceutical enterprises was very hard. The result was ERGOT ALKALOIDS (Ergotamine and dihydroergo- logical: there is not a first-choice triptan for all the patients. tamine – DHE). Their use has been restricted because of The choice of the best triptan for a patient must be an indi- their AEs and their minor efficacy regarding the triptans [53- vidualized selection, as a tailor-made suit, regarding the 57]. There are several ergot alkaloids formulations: tablets, medical history of the patient and the evolution profile of the subcutaneous, intravenous, suppositories and sublingual migraine attack: onset, speed and lasting [20, 64]. formulations. At present, ergot alkaloids are only indicated Indication. The triptans are indicated in an early stage of in migraine sufferers who are taking them with good efficacy the moderate-to-severe migraine attack (recommendation from before the advent of triptans with less than two moder- ate-to-severe migraine attacks a month (recommendation grade A) and in the mild-to-moderate migraine with poor response to NSAIDs or combinations of analgesics [18, 19]. grade A for nasal DHE and grade B for intravenous and in- Another indication is the mild-to-moderate migraine attack if tramuscular DHE and ergotamine) [20]. the patient present contraindications, intolerance or hyper- - Oral inhaled DHE mesilate (MDHE). This new formu- sensitivity to NSAIDs. The triptans are effective in about lation of DHE has been recently commercialized in the U.S. 60% of non-responders patients to NSAIDs [65]. They are and has provoked a recovering of the interest for ergot alka- not indicated in patients with ischemic cardiac, cerebrovas- loids. A RCT [58, 59] has included 450 patients treated with cular, or peripheral vascular diseases and in pregnant women MDHE and 453 treated with a placebo. The PF2h was 28% (Table 7). Only nasal sumatriptan and nasal zolmitriptan are for MDHE versus 10% for the placebo without severe AEs approved for migraine attacks in children older than 12 years TRIPTANS. The triptans were the first drugs specifi- old in the world. Additionally, oral almotriptan is approved cally designed for the migraine attack therapy. The first in US in children older than 12 years, and oral rizatriptan is triptan, sumatriptan, was a revolution in the migraine attack also approved in US in children older than six years old. therapy when it was introduced in 1991 [60] and is still con- Mechanisms of action. The mechanism and site of action sidered the gold standard [61-63]. At present, there are six of triptans remain unknown. The triptans are receptors selec- more marketed triptans (in chronological order): zol- tive agonists of serotonin of the head (5-HT1B/1D), but mitriptan, naratriptan, rizatriptan, almotriptan, eletriptan, and these receptors are located throughout the body [66, 67].

Table 6. Marketed Triptans.

Tablets Oral Dispersable Nasal Spray Subcutaneous Injection Transdermal Patch

Sumatriptan Imitrex® 25, 50, 100 mg Imitrex® 5, 20 mg Imitrex® 6 mg Zelrix® Imigran® 50, 100 mg Imigran® 10, 20 mg Imigran® 6 mg Imigran Neo® 50, 100 Inhalated Sumavel DosePro® (nee- mg AVP- 825 (Optinose dle-free) 6 mg Sumatriptan)

Zolmitriptan Zomig® 2.5 mg, 5 mg Zomig® (Flas ZMT or Zomig® 5 mg ODF) 2.5, 5 mg

Rizatriptan Maxalt® 10 mg Maxal® t (Max o MLT) 5, 10 mg

Almotriptan Asert® 6.25, 12.5 mg Almogran® 6.5, 12.5 mg

Eletriptan Relpax® 20, 40, 80 mg Relert® 20, 40 mg

Naratriptan Amerge® 1, 2.5 mg Naramig® 2.5 mg

Frovatriptan Forvey® 2.5 mg Frova® 2.5 mg

30 Recent Patents on CNS Drug Discovery, 2014, Vol. 9, No. 1 Belvís et al.

Table 7. Contraindications of Triptans. geminovascular neurons [69]. Another possible mechanism is a modulation of nitric oxide pathways [70]. Pharmacokinetics. Sumatriptan shows some limitations: • Pregnancy low bioavailability, short plasmatic half-life, and low • Lactation liposolubility. The sumatriptan bioavailability is 14% for the • Ischemic stroke oral formulation, 16.5% for the nasal formulation, and 96% • Ischemic heart disease for subcutaneous injections [21, 56]. The second generation of triptans improved the pharmacokinetic properties of su- • Prinzmetal´s angina matriptan (Table 8). • Raynaud´s disease Naratriptan, eletriptan and frovatriptan have hepatic me- • Uncontrolled high blood pressure tabolism, through the cytochrome P-450 system, and there- • Severe liver or renal failure fore they can present interactions with oral contraceptives, • Familial hemiplegic migraine but they do not have a MAO metabolism. However, suma- triptan and rizatriptan are not affected by concurrent use of • Basilar migraine oral contraceptives or medications metabolised by the he- • Association to ergotic alkaloid drugs patic cytochrome P-450 system as macrolide antibiotics, • Association to monoamine oxidase inhibitors antifungal medications and certain antivirals. Doses of ri- • Association to selective serotonin reuptake inhibitors zatriptan must be also halved when is used with propranolol. Rizatriptan, eletriptan and zolmitriptan present active metabolites after the hepatic metabolism. Rizatriptan is the They also bind to other 5-HT receptor subtypes, including oral triptan that presents the fastest onset of efficacy (30 the 5-HT1A and 5-HT1F receptors. The vasoconstriction in minutes) and time to peak plasmatic levels (60 min), but also the human meningeal arteries induced by triptans is 10 times presents the shortest plasmatic half-life time (2-2.5 hours). more powerful than in the human coronary arteries [68] and For this reason, it shows the longest recurrence rate at 24 is very selective since vasoconstriction in the peripheral cir- hours (superior to placebo). On the other hand, frovatriptan culation is mediated by 5-HT2 receptors. Despite of this vas- presents the longest plasmatic half-life time (26 hours) and cular effect, other mechanisms of action of triptans have the lowest recurrence rate at 24 hours (7-25%). However, it been described in migraine: an inhibition of the release of presents the slowest onset of the efficacy, and the slowest vasoactive neuropeptides by trigeminal terminals that inner- time to peak plasmatic levels. vate the intracranial vessels and dura mater; and inhibition of nociceptive neurotransmission within the trigeminocervical Efficacy. Several parameters have been suggested to ana- complex, in the brainstem, and in the upper spinal cord. Re- lyse the efficacy of oral triptans in the migraine [71, 72] (Ta- cently, it has been suggested that sumatriptan blocks the no- ble 5). The majority of RCTs apply the parameter pain-free ciceptive transmission between peripheral and central tri- at two hours (PF2h) to evaluate the response of an oral

Table 8. Pharmacokinetics Properties of Oral Triptans.

Onset of Time to Pike Lipophilicity Bioavailability Elimination Elimination Maximum Efficacy levels (hours) (%) half-life (hours) Routes Daily Doses (minutes) (mg)

Sumatriptan 45-60 2-3 Low 14 2-2.5 Hepatic, MAO 200

Rizatriptan 30 1 Moderate 45 2-2.5 Hepatic, MAO, 30 renal

Zolmitriptan 45-60 1-1.5 Moderate 40-48 2.5-3 Hepatic (active 10 metabolite), MAO, CYP

Almotriptan 45-60 1.5-2.5 Unknown 80 3.5 Hepatic (active 25 metabolite), renal MAO, CYP

Eletriptan 60 1.3-2.8 High 50 4-5 Hepatic (active 80 metabolite) CYP

Naratriptan Up to 4 hours 2-3.5 High 63-73 5-6 Hepatic, CYP, 5 renal

Frovatriptan Up to 4 hours 2-4 Low 24-30 26 Hepatic, CYP 7.5

CYP = cytochrome hepatic system; MAO= monoamine oxidase A.

Migraine Attack Treatment Recent Patents on CNS Drug Discovery, 2014, Vol. 9, No. 1 31 triptan. However, the complete response (the headache dis- sent the worse. The rest of triptans have similar complete appears at two hours and does not appear in the next 24 responses than the gold standard. hours) is the most desired parameter by patients. For this Routes of administration. Triptans are available in sev- reason, the IHS considers that complete response is the stan- eral formulations (Table 6): conventional tablets, fast- dard to evaluate any new drugs for the migraine attack [73, disintegrating/rapid-release tablets, oral disintegrating tab- 74]. lets, wafer formulations, subcutaneous injections, nasal The seven marketed triptans have shown relief and/or sprays, transdermal patches, lingual sprays, and supposito- absence of pain at two hours, and relief at one hour superior ries. to placebo in RCTs and in a meta-analysis of 53 RCTs [64, - Fast-disintegrating/rapid-release tablet formulation 75-88]. Moreover, the triptans considerably decrease the (FDT/RRT) of sumatriptan (50 and 100mg). This formula- need for rescue medications if the patients take them at the tion has showed similar efficacy parameters to its respective headache onset [89, 90], and are also effective for the mi- oral forms but a faster relief [94]. graine-associated symptoms, such as nausea, vomiting, pho- tophobia, and phonophobia. About 15-40% of the patients - Oral disintegrating tablet (ODTs) and wafer triptans. who take an oral triptan can need a second dose that it is They are the more popular formulations of triptans. About effective in most cases [91]. The recurrence of migraine 70% of patients prefer them to conventional tablets because seems to be less frequent after taking a triptan with a long they dissolved on the tongue in 30 seconds. However, the plasmatic half-life time as frovatriptan or naratriptan [92]. differences between these two forms regarding the speed of These are the results of efficacy studies regarding oral forms onset seem to be small [64]. There are two triptans marketed (Table 9) [64, 88]: with these forms: zolmitriptan ODTs and wafer rizatriptan. Both have shown a good tolerance and more efficacy than - Pain relief at half an hour: At present, sumatriptan (50 placebo and sumatriptan [95-100]. The two-hour therapeutic mg) and rizatriptan (10 mg) were the only triptans that gain with ODTs zolmitriptan 2.5 mg is 41% and with wafer showed better parameters than placebo. rizatriptan is 46%. A new oral formulation of zolmitriptan - Pain-free at two hours (PF2h): 1. Eletriptan (80mg), has been recently presented. It is the O.D.F zolmitriptan almotriptan (12.5 mg), and rizatriptan (10 mg) show this (Oral Dissolvable rapid-Films) and presents a similar bioe- parameter superior to the gold standard. 2. Sumatriptan (50 quivalence that the regular zolmitriptan tablet [101]. mg), zolmitriptan (2.5 and 5 mg), and eletriptan (40 mg) are - Subcutaneous injection. Sumatriptan presents an injec- similar to the gold standard. 3. The rest of triptans: Na- tion formulation of 6 mg. Its maximum dose is 12 mg. It is ratriptan (2.5mg), sumatriptan (25 mg), and eletriptan the faster triptan formulation (onset of efficacy in about 10 (20mg) show a PF2h inferior to the gold standard. minutes) and presents better efficacy than the oral suma- - Recurrence of headache at 24 hours: The best triptans triptan (100 mg) and the placebo [102, 103], but induces regarding this parameter seems to be eletriptan (40 and 80 more AEs than the oral forms. The subcutaneous sumatriptan mg) and naratriptan (2.5 mg). The worst are zolmitriptan (5 shows a PF2h in the 76-80% of the patients [104]. It has an mg) and rizatriptan (10 mg). The rest of triptans presents a intrapatient consistency in multiple attacks of 89% (two of similar risk of recurrences than the gold standard. Recur- three attacks) to 73% (three of three attacks). Its recurrence rence is possible in 34-38% of patients under oral suma- rate at 24 hours is 34-38%. Despite of its excellent efficacy, triptan treatment [93]. it is the more expensive triptan and requires auto-injections. However, a needle-free subcutaneous formulation of suma- - Complete response: Rizatriptan (10 mg), eletriptan (80 triptan injection is already marketed in the U.S. [105]. It is mg) and almotriptan (12.5 mg) have the best complete re- based on a revolutionary concept because the injector pulver- sponse and naratriptan (2.5 mg) and eletriptan (20 mg) pre-

Table 9. Parameters of Efficacy of Oral Triptans in Migraine Attack.

HR2h (%) FF2h (%) Two Hours Therapeutic gain (%) Recurrence Rate at 24 Hours (%)

Sumatriptan oral 50-61 30-32 29-36 29-34

Rizatriptan oral 70-77 40-44 27-40 28-47

Zolmitriptan 2.5 mg 64 33 34 13-39

Zolmitriptan 5 mg 65 38 37 24-32

Almotriptan 12.5 mg 57-65 20-25 26-32 18-27

Eletriptan 40 mg 65 29 22-41 19-23

Eletriptan 80 mg 65-80 37 30-53 21-33

Naratriptan 2.5 mg 45-52 21-27 21-22 17-28

Frovatriptan 2.5 mg 38-40 23-28 16-19 7-25

32 Recent Patents on CNS Drug Discovery, 2014, Vol. 9, No. 1 Belvís et al. izes sumatriptan through the epidermis using a nitrogen gas HR2h 3.5, PF2h 4.7 and sPF24h 6.5; for nasal formulation of pressure mechanism. The bioequivalence is the same regard- 10 mg was HR2h 5.5, PF2h 7.3; and for the subcutaneous ing subcutaneous sumatriptan injected with a regular needle formulation of 6 mg HR2h 2.1, PF2h 2.3, and sPF24h 6.1. in a study that included 109 patients. The patient satisfaction Safety. The triptans are safer than the other drugs used is very high among patients who had already received for the migraine [126]. triptans [106]. The percentage of patients with PF were 0.7% at 15 minutes, 14% at 30 minutes, 35% in a hour, 48% in 2 - Adverse effects (AEs). The AEs ratio of the sumatriptan hours (PF2h), and 65% in 24 hours in an open study that (100 mg), the gold standard, is 13-36% [126]. The safest included 90 patients [107]. In open studies [108, 109], 212 triptan seems to be almotriptan (12.5 mg) followed by na- patients have treated 669 attacks with a PF2h of 75%, and ratriptan (2.5 mg), and frovatriptan (2.5 mg) [127]. The ratio pain-free at 15 minutes of 33%; without AEs. This new nee- of AEs of the rest of triptans is similar to the gold standard. dle-free subcutaneous system could replace to the regular The more frequent AEs were feeling groggy/impaired con- subcutaneous administering in the next years. centration (5%), and somnolence/feeling tired (4%) if we ask an open question about AEs to the patients [128]. However, - Nasal spray. This formulation bypasses small bowel the percentage of AEs increases if we propose a list of AEs gastrointestinal tract absorption and is more rapidly effective to the patient: feeling groggy/impaired concentration (17%) than oral tablets. They are optimal in patients with severe and somnolence/feeling tired (6%). Other triptans AEs are vomiting. Moreover, the nasal route is more comfortable dizziness, paraesthesia, warm sensations, palpitations, facial than injections or suppositories. Sumatriptan nasal spray (5 flush, and neck, chest, and throat tightness. The tolerability mg, 10 mg and 20 mg) has the same efficacy than oral suma- of individual triptans cannot be predicted on the basis of triptan (50 mg and 100 mg). Patients also prefer zolmitriptan lipophilicity, bioavailability, absolute dose size, or any com- nasal spray over subcutaneous sumatriptan because it pre- bination of these variables [128]. Contraindications of sents a shorter speed of action and better efficacy [110-115]. triptans are listed in the Table 7. The headache response of nasal zolmitriptan is 70.2% at 2 hours, with a therapeutic gain of 40% and a PF2h of 35.9% Cardiovascular risk. The triptans are highly selective of [115]. Although nasal sprays are faster than oral formulation, cranial arteries, but a coronary effect is possible because they their efficacy is more transitory [103]. The nasal sprays are can also activate the [5-HT2A] receptor in peripheral arter- therefore an intermediate option between the oral triptans ies. This possibility is very low when the triptans are admin- and the subcutaneous sumatriptan. istered at the recommended doses. The incidence of cardiac arrhythmias, myocardial infarct, and stroke is about 1 in A new powder formulation of intranasal sumatriptan has 1.000.000 patients under triptan treatment, but prior contra- been recently marketed. It is delivered by a bi-directional indications to triptan treatment have been reported in many breath-actuated device and provides a better drug impregna- of these cases. In population based studies, the triptan users tion of the pharyngeal mucosa with a similar bioequivalence have not showed an increased risk of vascular events regard- to subcutaneous sumatriptan [116]. In a recent RCT [117], ing healthy people [129, 130]. Regarding cardiovascular 39 patients have taken sumatriptan 10 mg, 39 patients have death, nineteen patients died worldwide within 24 hours of taken sumatriptan 20 mg, and 39 patients have taken a pla- administration of sumatriptan in a five-year follow-up study. cebo with this new system and the PF2h was respectively: In this period of time more than 100 million of migraine pa- 84%, 80%, and 44%. tients received this triptan [131]. The chest pain may appear -Transdermal patch. A new iontophoretic transdermal in the 3-5% of patients taking triptans, but it is not associated patch of sumatriptan has been also marketed. It contains two with ECG changes. Alternative explanations to chest pain sumatriptan doses (for two attacks) and penetrates skin using other than ischemia are: oesophageal spasm, intercostal mus- an electric gradient system. A study has reported a good cle spasm, pulmonary vasoconstriction and anxiety [128, bioequivalence regarding subcutaneous sumatriptan [118]. A 132, 133]. Almotriptan (12.5 mg) presents the best profile of RCT [119, 120] has compared 226 patients treated with this thoracic adverse effects [117]. patch of sumatriptan versus 228 patients treated with a pla- Pregnancy. The migraine gradually improves in 55-90% cebo. The PF2h was respectively 18% for the patch and 9% of pregnant women (47% already in the first trimester). It for the placebo. On the other hand, an iontophoretic trans- even disappears in the 55-90% of women, remains indiffer- dermal almotriptan patch is also under investigation [121]. ent in the 5-30%, and gets worse only in the 4-8% [134-138]. - Lingual spray. A lingual spray of sumatriptan is under For this reason is very unusual they need triptans during investigation and it has showed a good bioequivalence re- pregnancy. At any rate, they are formally proscribed in preg- garding oral sumatriptan 50 mg [122]. nant women. A risk of premature delivery, a low weight new-born, and a major congenital malformations (MCM) - Suppositories. Sumatriptan (25 mg) also exists as sup- ratio in lower extremities has been reported [139-141], and positories and its efficacy is similar that oral sumatriptan (50 all the triptans receive the grade of recommendation C in the mg and 100 mg) [123, 124]. FDA guideline, and the grade U in the Teratogen Informa- A recent meta-analysis [125] has compared the efficacy tion System (TERIS). However the risk of MCM was in two of three routes of the administration of sumatriptan: oral (61 studies: 4.7% for sumatriptan [142], and 3.1% for rizatriptan RCTs with 37.250 patients), nasal (12 RCTs with 4.755 pa- [143]. Finally, a recent study that includes 1,535 pregnant tients), and subcutaneous (35 RCTs with 9.365 patients). The women who took triptans during the first trimester of preg- NTT for the oral formulation of 50 mg was HR2h 4.0, PF2h nancy reports a risk of general foetal malformations and 6.1, and sPF24h 9.5; for the oral formulation of 100 mg was MCM similar to pregnant women with migraine who do not Migraine Attack Treatment Recent Patents on CNS Drug Discovery, 2014, Vol. 9, No. 1 33 take triptans and to the healthy controls. The risk of any mal- • Change the route of administration: oral to nasal spray formation was around 5%, and of MCMs was 3% in the (only sumatriptan or zolmitriptan) or subcutaneous in- three groups. Only an increase of the risk of uterus atony and jections (sumatriptan). more blood loss during the delivery have been reported if the pregnant women take triptans during the second and the third Triptan Associations trimester [144-146]. Sumatriptan (85mg) combined with sodium naproxen Sumatriptan is the only triptan approved for women un- (500mg) is the best analysed combination and is the only der lactation and eletriptan 20 mg also seems secure. marketed in the U.S. Two RCTs and a pool data analyses Drug interactions. This is an infrequent problem. It is (2800 patients) [161-168] have shown a PF2h of 15% for forbidden to combining triptans with ergot alkaloids or naproxen, 9% for placebo, 25% for sumatriptan, and 34% for triptans with monoamine oxidase inhibitors because a sero- the combination. Another combination of NSAIDs plus tonin syndrome is possible, but exceptional. triptan under investigation is naratriptan plus naproxen [169]. Other drugs combined with triptans under investiga- Risk of developing a chronic migraine. A chronic daily tion are: acetaminophen [170], trimebutine [171, 172], ro- headache is possible due to triptan drug overuse but it hap- fecoxib [173, 174], metoclopramide [175], and diclofenac pen more frequently with other drugs of the migraine attack potassium [176]. (NSAIDs, opioids and ergot alkaloid) [147-149]. For this reason, the treatment with triptans must not exceed 10 days a Other triptans. The investigation and development of month [21]. other triptans, as alniditan [177, 178], avitriptan [179, 180], and donitriptan [181, 182] have been abandoned. If a triptan fails… We have not reached an agreement about the triptan non-responder patient definition (15-40% of Reality of the prescription of triptans twenty years after. patients under triptan therapy) [150]. There are several ex- The general satisfaction of patients about migraine attack planations to non-response, but the use of the medication late treatment is 84% for triptans and 37% for NSAIDs [183]. in a migraine attack is the more frequent scenario. Three The ergotamine and sumatriptan are the most preferred drugs reasons usually induce this delay: to wait a spontaneous worldwide in the attack of migraine [14]. However, 40% of resolution, to wait the climax of the pain, and to think that the U.S. emergency room doctors have never prescribed a taking triptans it is dangerous or addictive [151-153]. How- triptan in a migraine attack [184]; and only 36% of general ever, the treatment of migraine attack is a race against the practitioners and the 58% of neurologists usually prescribe neuronal sensitisation phenomenon in the brain. Therefore, triptans to treat migraine attacks in Spain [185]. On the other to wait decreases success chances of the treatment. In this hand, the WHO encourages therapeutic adherence, and it is way, the self-administration of the subcutaneous sumatriptan about 100% in the majority of RCTs, but is approximately presents a PF2h of 94% in the first hour of pain, but it de- 64% in headache units and 18% in general practitioner of- creases to 6% in the fourth hour [154, 155]. fices [186-193]. Therefore, there is much work for making.

Other explanations are inadequate dosing, variability in CURRENT & FUTURE DEVELOPMENTS individual response [156], an inadequate indication for the migraine attack characteristics, treat a tension-type headache The more promising drugs for migraine attack were the with triptans, the awakening migraine, and an inadequate calcitonin gene-related peptide (CGRP) antagonists called route of administration. gepants. The intravenous olcegepant [194] and the oral tel- cagepant showed better efficacy than placebo [195], and On the other hand, content of the stomach can influence similar that rizatriptan and zolmitriptan [196-199] without the absorption of triptans, and the gastric emptying can be AEs in the treatment of migraine attack. However, severe delayed because of the migraine attack [157, 158]. Thus, hepatic AEs were reported in a simultaneous RCT in daily some pharmacokinetics parameters can be different for the treatment with telcagepant as preventive drug for migraine. same triptan both during and outside the migraine attack For this reason, the telcagepant program was suspended sine [159, 160]. Moreover, some gender differences have been die. Another gepant, MK-3207, also presented hepatic AEs reported in the metabolism of triptans (i.e. zolmitriptan) [200]. Two other gepants are still under investigation: BI [160]. We propose several alternatives when a triptan fails: 44370 TA and BMS-927711 [201, 202]. • Insists in the early administration of the same triptan At present, several monoclonal antibodies (mAbs) selec- when the patient recognizes the first symptoms of mi- tive against the CGRP-receptor try to avoid the hepatic AEs graine onset. of the gepants. Experiences in animals with NOX-C89 [203, • Verify the IHS criteria of migraine. 204] and in-vitro with AA71 are promising [205]. ALD403 is the first mAb against CGRP-receptor that has started a • Change the triptan. phase-II RCT in humans. Other mAbs in less advanced • Think about a possible loss of the drug because of an stages of development are LBR-101, AMG 334 and early vomiting. LY2951742. If despite everything, the efficacy of the treatment is not Another interesting drug is lasmiditan (COL-144), a se- acceptable: lective agonist against the receptor 5-HT(1F) that has pre- • Take simultaneously a triptan plus a NSAIDS. sented a good efficacy and tolerance in two RCTs (intrave- nous and oral) [206, 207]. NXN-188 is a nitric oxide syn- • Increase the triptan dose if it is possible. thase (NOS) inhibitor under investigation in two RCTs [208- 34 Recent Patents on CNS Drug Discovery, 2014, Vol. 9, No. 1 Belvís et al.

210]. Other NOS inhibitors are GW-273629 [211] and efficacy in a concrete patient can become ineffective in other GW274150 [212]. period of his life, because the migraine characteristics can change during the life. For these reasons, an individualiza- Tonabersat is a multi-target drug in migraine that has tion of the indication is the best therapeutic strategy because shown a promising efficacy in the migraine prevention, but not in the migraine attack in two RCTs [213, 214]. every triptan shows singular, pharmacokinetics and pharma- codynamics, properties. Plochlrorperazine is a dopaminergic antagonist that has The Fig. (1) shows a proposal of a general strategy for shown excellent results in a RCT compared with the subcu- the selection of oral NSAID or triptan regarding the intensity taneous sumatriptan [215]. Other drugs are: SB-705498 of the pain, the onset and the lasting of the migraine attack. [216] (TRPV1 receptor antagonist), BGC20-1531 [217] (se- lective prostanoid EP4 receptor antagonist), BGG-492 [218, Aspirin, naproxen sodium, diclofenac, and ibuprofen are good options when the attacks present a mild-to-moderate 219] (glutamate receptor blocker), and NPS-1776 [220] intensity. (isovaleramide). Several inhaled drugs are also under inves- tigation: nitrous oxide [221], normobaric oxygen [222], If the attack presents a moderate-to-severe intensity, ri- nebulized lidocaine [223], dronabinol [224], and nasal car- zatriptan and zolmitriptan seem the better option when at- bon dioxide [225]. tacks are severe with rapid onset but short-lasting. On the other hand, frovatriptan and naratriptan are better in moder- CONCLUSIONS ates and long-lasting attacks and eletriptan in severe long- lasting attacks due to their long half-life. The zolmitriptan The best option to treat a migraine attack is the fast self- ODT and the wafer rizatriptan are indicated when vomiting administration of an oral NSAID when the attack begins is severe or when the patient needs a very rapid relief. Almo- with mild-to-moderate pain intensity and of an oral triptan, triptan and naratriptan are advised when the patient presents when it begins with moderate-to-severe pain intensity. A triptan AEs. The nasal sprays (zolmitriptan or sumatriptan) triptan can relief the pain of migraine in approximately 80% are indicated when an oral triptan fails, and the subcutaneous of patients after two hours if the patients take it fast, with a sumatriptan injection, when nasal form fails. lower headache recurrence. Sumatriptan was the first oral triptan and is yet the gold standard. Six more triptans are at However, several open problems persist regarding the present marketed. triptans: First, the triptans generally failed to achieve relief when the migraine has already occurred. Second, they are However, prescribe always the same triptan to all mi- not safe during pregnancy or in cardiologic patients. Finally, graine patients is not correct, because there is not a first uni- although most patients prefer triptans over the ergot alka- versal option. Furthermore, an individual triptan with good

Intensity Intensity

A B

Hours Hours

Intensity Intensity D C

Hours Hours

Fig. (1). A proposal of general Strategy about the Selection of an oral NSAID or a Triptan Regarding the Onset and the Lasting of Migraine Attack. First option: A. NSAIDs (mild-to-moderate intensity, fast onset, long lasting); B. Eletriptan (moderate-to-severe intensity, fast onset, long lasting); C. Rizatriptan or Zolmitriptan (moderate-to-severe intensity, fast onset, short lasting); and D. Frovatriptan or Naratriptan (mod- erate-to-severe intensity, slow onset, long lasting). Migraine Attack Treatment Recent Patents on CNS Drug Discovery, 2014, Vol. 9, No. 1 35 loids, the triptans are not considered as a first-option therapy Global Burden of Disease Study 2010. Lancet 2012; 380(9859): in developing countries because they are expensive. 2163-2196. [16] Hu XH, Markson LE, Lipton RB, Stewart WF, Berger ML. Burden New triptans and NSAIDs have not been marketed in the of migraine in the United States: Disability and economic costs. last years. However, a lot of new formulations from the al- Arch Intern Med 1999; 159: 813-8. [17] Auray JP. Socio-economic impact of migraine and headaches in ready marketed NSAIDs and triptans are appearing, using France. CNS Drugs 2006; 20: 37-46. new routes of administration. The efficacy/tolerance profile [18] Stewart WF, Wood GC, Razzaghi H, Reed ML, Lipton RB. Work of these new formulations seems at least equal to the gold impact of migraine headaches. J Occup Environ Med 2008; 50: standard. Despite the lack of new marketed NSAIDs and 736-45. triptans in the last years, the pharmaceutical industry is in- [19] Hawkins K, Wang S, Rupnow M. Direct cost burden among insured US employees with migraine. Headache 2008; 48: 553-63. vestigating new drugs to treat the migraine attack. After the [20] Practice parameter: Evidence-based guidelines for migraine “the war of the triptans” and of the “disaster of the gepants”, headache (an evidence-based review). Report of the Quality the new selective monoclonal antibodies against the CGRP Standards Subcommittee of the American Academy of Neurology. receptor are a ray of hope in the near future of migraine at- Neurol 2000; 55: 754-763. [21] Members of the task force: Evers S, Afra J, Frese A, Goadsby PJ, tack therapy. Linde M, May A, Sándor PS. EFNS guideline on the drug treatment of migraine - report of an EFNS task force. Eur J Neurol CONFLICT OF INTEREST 2006; 13: 560-572. [22] Belvís R, Pagonabarraga J, Kulisevsky J. Individual triptan Authors have no conflict of interest related to the rec- selection in migraine attack therapy. Recent Pat CNS Drug Discov ommendations given in this paper. 2009; 4(1): 70-81. [23] Göbel H, Heinze A, Niederberger U, Witt T, Zumbroich V. Efficacy of phenazone in the treatment of acute migraine attacks: A ACKNOWLEDGEMENTS double-blind, placebo-controlled, randomized study. Cephalalgia 2004; 24: 888-93. We thank Ramon Santaularia for the editing of this [24] Tulunay FC, Ergun H, Gulmez SE, Ozbenli T, Ozmenolu M, Boz manuscript. C, et al. The efficacy and safety of dipyrone (Novalgin) tablets in the treatment of acute migraine attacks: A double-blind, cross-over, randomized, placebocontrolled, multi-center study. Functional REFERENCES Neurol 2004; 19: 197-202. [1] Goadsby PT, Lipton RB, Ferrari MD. Migraine-current [25] Myllyla VV, Havanka H, Herrala L, Kangasniemi P, Rautakorpi understanding and treatment. New England J Med 2002; 346: 257- I, Turkka J, et al. Tolfenamic acid rapid release versus sumatriptan 70. in the acute treatment of migraine: Comparable effect in a double- [2] The InternationalClassification of Headache Disorders, 3rd edition blind, randomized, controlled, parallel-group study. Headache (beta version). Headache Classification Committee of the 1998; 38: 201-7. International Headache Society (IHS). Cephalalgia 2013; 33(9): [26] Lipton RB, Baggish JS, Stewart WF, Codispoti JR, Fu M. Efficacy 629-808. and safety of acetaminophen in the treatment of migraine: Results [3] Lipton RB. Tracing transformation: chronic migraine classification, of a randomized, double-blind, placebocontrolled, population-based progression, and epidemiology. Neurol 2009; 72 (5Suppl): s3-7. study. Arch Internal Med 2000; 160: 3486-92. [4] Stewart WF, Lipton RB, Celentano DD, Reed ML. Prevalence of [27] Lipton RB, Stewart WF, Ryan RE, Saper J, Silberstein S, Sheftell migraine headache in the United States. Relation to age, income, F. Efficacy and safety of acetaminophen, aspirin, and caffeine in race, and other sociodemographic factors. JAMA 1992; 267: 64-9. alleviating migraine headache pain- Three double-blind, [5] Rasmussen BK, Olesen J. Symptomatic and nonsymptomatic randomized, placebo-controlled trials. Arch of Neurol 1998; 55: headaches in a general population. Neurol 1992; 42: 1225-31. 210-7. [6] Lipton RB, Stewart WF, von Korff M. Burden of migraine: [28] Diener H, Pfaffenrath V, Pageler L. The fixed combination of Societal costs and therapeutic opportunities. Neurol 1997; 48(suppl acetylsalicylic acid, paracetamol and caffeine is more effective than 5): S4-9. single substances and dual combination for the treatment of [7] Fox AW, Davis RL. Migraine chronobiology. Headache 1998; 38: headache: A multicentre, randomized, double-blind, single-dose, 436-41. placebocontrolled parallel group study. Cephalalgia 2005; 25: 776- [8] Hamelsky SW, Stewart WF, Lipton RB. Epidemiology of migraine. 87. Curr Pain Headache Reports 2001; 5: 189-94. [29] Goldstein J, Silberstein SD, Saper JR, Ryan RE Jr, Lipton RB. [9] Lipton RB, Stewart WF, Diamond S, Diamond ML, Reed M. Acetaminophen, aspirin, and caffeine in combination versus Prevalence and burden of migraine in the United States: Data from ibuprofen for acute migraine: Results from a multicenter, the American Migraine Study II. Headache 2001; 41: 646-57. doubleblind, randomized, parallel-group, single-dose, placebo- [10] Lipton RB, Stewart WF, Scher AI. Epidemiology and economic controlled study. Headache 2006; 46: 444-53. impact of migraine. Curr Med Res Opin 2001(17 Suppl 1): S4-S12. [30] Chabriat H, Joire JE, Danchot J, Grippon P, Bousser MG. [11] MacGregor EA, Brandes J, Eikermann A. Migraine prevalence and Combined oral lysine acetylsalicylate and metoclopramide in the treatment patterns: The global migraine and zolmitriptan. acute treatment of migraine: A multicentre doubleblind Evaluation survey. Headache 2003; 43: 19-26. placebocontrolled study. Cephalalgia 1994; 14: 297-300. [12] Stovner LJ, Zwart JA, Hagen K, Terwindt GM, Pascual J. [31] Nebe J, Heier M, Diener HC. Low-dose ibuprofen in Epidemiology of headache in Europe. Eur J Neurol 2006; 13: 333- selfmedication of mild to moderate headache: A comparison with 45. acetylsalicylic acid and placebo. Cephalalgia 1995; 15: 531-5. [13] Steiner TJ, Birbeck GL, Jensen R, Katsarava Z, Martelletti P, [32] Tfelt-Hansen P, Henry P, Mulder LJ, Scheldewaert RG, Schoenen Stovner LJ. Lifting the burden: the first 7 years. J Headache Pain J, Chazot G. The effectiveness of combined oral lysine 2010; 11: 451-5. acetylsalicylate and metoclopramide compared with oral [14] Atlas of headache disorders and resources in the world 2011. A sumatriptan for migraine. Lancet 1995; 346: 923-6. collaborative project of World Health Organization and Lifting The [33] Diener HC, Bussone G, de Liano H, Eikermann A, Englert Burden. WHO Library Cataloguing-in-Publication Data. Trento, R, Floeter T, et al. Placebo-controlled comparison of effervescent Italy 2011. acetylsalicylic acid, sumatriptan and ibuprofen in the treatment of [15] Vos T, Flaxman AD, Naghavi M, Lozano R, Michaud C, Ezzati migraine attacks. Cephalalgia 2004; 24: 947-54. M, et al. Years lived with disability (YLDs) for 1160 sequelae of [34] Kirthi V, Derry S, Moore RA, McQuay HJ. Aspirin with or without 289 diseases and injuries 1990-2010: a systematic analysis for the an antiemetic for acute migraine headaches in adults. Cochrane 2010; (4): CD008041. 36 Recent Patents on CNS Drug Discovery, 2014, Vol. 9, No. 1 Belvís et al.

[35] Johnson ES, Ratcliffe DM, Wilkinson M. Naproxen sodium in the sumatriptan in the acute treatment of migraine.Eur Neurol 1991; treatment of migraine. Cephalalgia 1985; 5: 5-10. 31: 314-22. [36] Treves TA, Streiffler M, Korczyn AD. Naproxen sodium versus [56] Christie S, Gobel H, Mateos V, Allen C, Vrijens F, Shivaprakash ergotamine tartrate in the treatment of acute migraine attacks. M, Rizatriptan-Ergotamine/Caffeine Preference Study Group. Headache 1992; 32: 280-2. Crossover comparison of efficacy and preference for rizatriptan 10 [37] Suthisisang CC, Poolsup N, Suksomboon N, Lertpipopmetha mg versus ergotamine/caffeine in migraine. Eur Neurol 2003; 49: V, Tepwitukgid B. Meta-analysis of the efficacy and safety of 20-9. naproxen sodium in the acute treatment of migraine.Headache. [57] Diener HC, Jansen JP, Reches A, Pascual J, Pitei D, Steiner TJ, 2010; 50(5): 808-18 Eletriptan and Cafergot Comparative Study Group. Efficacy, [38] Karachalios GN, Fotiadou A, Chrisikos N, Karabetsos tolerability and safety of oral eletriptan and ergotamine plus A, Kehagioglou K. Treatment of acute migraine attack with caffeine (Cafergot) in the acute treatment of migraine: A Diclofenac sodium: A double-blind study. Headache 1992; 32: 98- multicentre, randomized, double-blind, placebo-controlled 100. comparison. Eur Neurol 2002; 47: 99-107. [39] Dahlöf C, Björkman R. Diclofenac-K (50 and 100 mg) and placebo [58] Aurora SK, Rozen TD, Kori SH, Shrewsbury SB. A randomized, in the acute treatment of migraine. Cephalalgia 1993; 13: 117-23. double blind, placebo-controlled study of MAP0004 in adult [40] The Diclofenac-K/Sumatriptan Migraine Study Group. Acute patients with migraine. Headache 2009; 49(6): 826-37. treatment of migraine attacks: Efficacy and safety of a nonsteroidal [59] Aurora SK, Silberstein SD, Kori SH, Tepper SJ, Borland antiinflammatory drug, diclofenac potassium, in comparison to oral SW, Wang M, et al. MAP0004, orally inhaled DHE: A sumatriptan and placebo. Cephalalgia 1999; 9: 232-40. randomized, controlled study in the acute treatment of migraine. [41] Derry S, Rabbie R, Moore RA. Diclofenac with or without an Headache 2011; 51(4): 507-17. antiemetic for acute migraine headaches in adults. Cochrane [60] Humphrey PP, Feniuk W, Perren MJ, Beresford IJ, Skingle Database Syst Rev 2012; 2: CD008783. M, Whalley ET. Serotonin and migraine. Ann NY Acad Sci 1990; [42] Havanka-Kanniainen H. Treatment of acute migraine attack: 600: 587-98. Ibuprofen and placebo compared. Headache 1989; 29: 507-9. [61] Pfaffenrath V, Cunin G, Sjonell G, Prendergast S. Efficacy and [43] Kloster R, Nestvold K, Vilming ST. A double-blind study of safety of sumatriptan tablets (25 mg, 50 mg, and 100 mg) in the ibuprofen versus placebo in the treatment of acute migraine attacks. acute treatment of migraine: Defining the optimum doses of oral Cephalalgia 1992; 12: 169-71. sumatriptan. Headache 1998; 38: 184-90. [44] Suthisisang C, Poolsup N, Kittikulsuth W, Pudchakan [62] McCrory DC, Gray RN. Oral sumatriptan for acute migraine. P, Wiwatpanich P. Efficacy of low-dose ibuprofen in acute Cochrane Database Syst Rev 2003; 3: CD002915. migraine treatment: Systematic review and meta-analysis. Ann [63] Winner P, Landy S, Richardson M, Ames M. Early intervention in Pharmacother 2007; 41: 1782-91. migraine with sumatriptan tablets 50 mg versus 100 mg: A pooled [45] Rabbie R, Derry S, Moore RA, McQuay HJ. Ibuprofen with or analysis of data from six clinical trials. Clin Ther 2005; 27: 85- without an antiemetic for acute migraine headaches in adults. 1794. Cochrane 2010; (10): CD008039. [64] Pascual J, Mateos V, Roig C, Sanchez-Del-Rio M, Jiménez D. [46] Allais G, De Lorenzo C, Airola G, Peano S, Benedetto C. Marketed oral triptans in the acute treatment of migraine: A Dexketoprofen trometamol in the treatment of acute migraine systematic review on efficacy and tolerability. Headache 2007; 47: attack. Minerva Med 2000; 91: 153-9. 1152-68. [47] Meredith JT, Wait S, Brewer KL. A prospective double-blind study [65] Diamond M, Hettiarachchi J, Hilliard B, Sands G, Nett R. of nasal sumatriptan versus IV ketorolac in migraine. Am J Emerg Effectiveness of eletriptan in acute migraine: Primary care for Med 2003; 21: 173-5. excedrin nonresponders. Headache 2004; 44: 209-16. [48] Sanchez-Borges M, Caballero-Fonseca F, Capriles-Hulett A, [66] Potrebic S, Ahn AH, Skinner K, Fields HL, Basbaum AI. González-Aveledo L. Hypersensitivity reactions to nonsteroidal Peptidergic nociceptors of both trigeminal and dorsal root ganglia anti-inflammatory drugs: An Update. Pharm 2010; 3(1): 10-8. express serotonin 1D receptors: Implications for the [49] Bigal ME, Serrano D, Buse D, Scher A, Stewart WF, Lipton RB. selectiveantimigraine action of triptans. J Neurosci 2003; 23: Acute migraine medications and evolution from episodic to chronic 10988-97. migraine: a longitudinal population-based study.Headache 2008; [67] Wotherspoon G, Priestley JV. Expression of the 5-HT1B receptor 48(8): 1157-68. by subtypes of rat trigeminal ganglion cells. Neurosci 2000; 95: [50] Lipton RB, Grosberg B, Singer RP, Pearlman SH, Sorrentino 465-71. JV, Quiring JN, et al. Efficacy and tolerability of a new powdered [68] Asghar MS, Hansen AE, Amin FM, van der Geest RJ, Koning formulation of diclofenac potassium for oral solution for the acute Pv, Larsson HB, et al. Evidence for a vascular factor in migraine. treatment of migraine: results from the International Migraine Pain Ann Neurol 2011; 69: 635-45. Assessment Clinical Trial (IMPACT). Cephalalgia 2010; 30(11): [69] Levy D, Jakubowski M, Burstein R. Disruption of communication 1336-45 between peripheral and central trigeminovascular neurons mediates [51] Pfaffenrath V, Fenzl E, Bregman D, Färkkila M. Intranasal the action of 5HT1B/1D receptor agonists. Proc Natl Acad Sci ketorolac tromethamine (SPRIX(R)) containing 6% of lidocaine USA 2004; 101:4274-9. (ROX-828) for acute treatment of migraine: safety and efficacy [70] Tepper SJ, Rapoport AM, Sheftell FD. Mechanisms of action of the data from a phase II clinical trial. Cephalalgia 2012; 32(10): 766- 5-HT1B/1D receptor agonists. Arch Neurol 2002; 59: 1084-8. 77. [71] Ferrari MD, Goadsby PJ, Roon KI, Lipton RB. Triptans (serotonin, [52] A Double-blind, Placebo-controlled Pilot Study to Collect and 5-HT1B/1D agonists) in migraine: Detailed results and methods of Evaluate Data on the Use of Intravenous Ibuprofen in the a meta-analysis of 53 trials. Cephalalgia 2002; 22: 633-58. Treatment of an Acute Migraine Attack. In: ClinicalTrials.Gov. A [72] Gladstone JP, Dodick DW. Acute migraine: Which Triptan? service of the U.S. National Institutes of Health[online].Available Practical Neurol 2004; 4: 6-19. at: http://clinicaltrials.gov/. Accessed October 11, 2013. [73] Tfelt-Hansen P, Block G, Dahlöf C, Diener HC, Ferrari [53] Oztürk V, Erta M, Baykan B, Sirin H, Ozge A; The Mig-Etol MD, Goadsby PJ, et al. International headache society clinical Study Group. Efficacy and safety of 400 and 800 mg etodolac vs. trials subcommittee. Guidelines for controlled trials of drugs in 1,000 mg paracetamol in acute treatment of migraine: A migraine: Second edition. Cephalalgia 2000; 20: 765-86. Randomized, Double-blind, Crossover, Multicenter, Phase III [74] Davies GM, Santanello N, Lipton R. Determinants of patient Clinical Trial. PainPract. 2012. satisfaction with migraine therapy. Cephalalgia 2000; 20: 554-60. [54] A Randomized Double Blind, Placebo Controlled Phase III Trial to [75] Mathew NT. Naratriptan: A review. Expert Opin Investig Drugs Determine the Efficacy and Safety of Topical Intra-oral Ketoprofen 1999; 8: 687-95. for the Treatment of Acute Migraine. In: ClinicalTrials.Gov. A [76] Spencer CM, Gunasekara NS, Hills C. Zolmitriptan: A review of service of the U.S. National Institutes of Health[online].Available its use in migraine. Drugs 1999; 58: 347-74. at: http://clinicaltrials.gov/. Accessed October 11, 2013. [77] Oldman AD, Smith LA, McQuay HJ, Moore RA. Rizatriptan for [55] The Multinational Oral Sumatriptan and Cafergot Comparative acute migraine. Cochrane Database Syst Rev 2001; 3: CD003221. Study Group. A randomized, doubleblind comparison of [78] Smith LA, Oldman AD, McQuay HJ, Moore RA. Eletriptan for acute migraine. Cochrane Database Syst Rev 2001; 3: CD003224. Migraine Attack Treatment Recent Patents on CNS Drug Discovery, 2014, Vol. 9, No. 1 37

[79] Dowson AJ, Charlesworth B. Review of zolmitriptan and its systematic review based on number needed to treat. Cephalalgia clinical applications in migraine. Expert Opin Pharmacother 2002; 1998; 18: 532-8. 3: 993-1005. [104] The Subcutaneous Sumatriptan International Study Group. [80] Keam SJ, Goa KL, Figgitt DP. Almotriptan: A review of its use in Treatment of migraine attacks with sumatriptan. New England J migraine. Drugs 2002; 62: 387-414. Med 1991; 325: 316-21. [81] Pascual J. A review of rizatriptan, a quick and consistent 5- [105] Brandes JL, Cady RK, Freitag FG, Smith TR, Chandler P, Fox HT1B/1D agonist for the acute treatment of migraine. Expert Opin AW, et al. Needle-free subcutaneous sumatriptan (Sumavel Pharmacother 2004; 5: 669-77. DosePro): bioequivalence and ease of use. Headache 2009; 49(10): [82] Ashcroft DM, Millson D. Naratriptan for the treatment of acute 1435-44. migraine: Meta-analysis of randomised controlled trials. [106] Cady RK, Aurora SK, Brandes JL, Rothrock JF, Myers JA, Fox Pharmacoepidemiol Drug Saf 2004; 13: 73-82. AW, et al. Satisfaction with and confidence in needle-free [83] Poolsup N, Leelasangaluk V, Jittangtrong J, Rithlamlert C, subcutaneous sumatriptan in patients currently treated with triptans. Ratanapantamanee N, Khanthong M. Efficacy and tolerability of Headache 2011; 51(8): 1202-11 frovatriptan in acute migraine treatment: Systematic review of [107] Rothrock JF, Cady RK, Aurora SK, Brandes JL, Myers JA, Fox randomized controlled trials. J Clin Pharm Ther 2005; 30: 521-32. AW, et al. Needle-free subcutaneous sumatriptan for triptan users [84] McCormack PL, Keating GM. Eletriptan: A review of its use in the requiring a change in migraine therapy: efficacy and impact on acute treatment of migraine. Drugs 2006; 66: 1129-49. patient-rated functionality, satisfaction, and confidence. Curr Med [85] Markus F, Mikko K. Frovatriptan review. Expert Opin Res Opin 2011; 27(11): 2185-91. Pharmacother 2007; 8: 3029-33. [108] Brandes JL, Rothrock JF, Cady RK, Aurora SK, Myers JA, Fox [86] Chen LC, Ashcroft DM. Meta-analysis examining the efficacy and AW, et al. Multiple-attack efficacy and tolerability sumavel- safety of almotriptan in the acute treatment of migraine. Headache doseproTM (needle-free subcutaneous sumatriptan) among current 2007; 47: 1169-77. triptan users. Presented at the 15th Congress of the International [87] Chen LC, Ashcroft DM. Meta-analysis of the efficacy and safety of Headache Society: June 23-26 2011; Berlin. zolmitriptan in the acute treatment of migraine. Headache 2008; 48: [109] Rothrock JF, Cady RK, Aurora SK, Brandes JL, Myers JA, Fox 236-47. AW, et al. Current triptan users requiring a change in migraine [88] Ferrari MD, Roon KI, Lipton RB, Goadsby PJ. Oral triptans therapy demonstrated improved treatment satisfaction and (serotonin 5-HT(1B/1D) agonists) in acute migraine treatment: A confidence after trying sumavel-doseproTM (needle-free meta-analysis of 53 trials. Lancet 2001; 358: 1668-75. subcutaneous sumatriptan). Presented at the 15Th Congress of the [89] Bates D, Ashford E, Dawson R, Ensink FB, Gilhus NE, Olesen J, et International Headache Society: June 23-26 2011; Berlin. al. Subcutaneous Sumatriptan during the migraine aura. Neurol [110] Charlesworth BR, Dowson AJ, Purdy A, Becker WJ, Boes-Hansen 1994; 44: 1587-92. S, Färkkilä M. Speed of onset and efficacy of zolmitriptan nasal [90] Olesen J, Diener HC, Schoenen J, Hettiarachchi J. No effect of spray in the acute treatment of migraine: A randomised, eletriptan administration during the aura phase of migraine. Eur J doubleblind, placebo-controlled, dose-ranging study versus Neurol 2004; 11: 671-7. Zolmitriptan tablet. CNS Drugs 2003; 17: 653-67. [91] Ferrari MD, James MH, Bates D, Pilgrim A, Ashford E, Anderson [111] Dodick D, Brandes J, Elkind A, Mathew N, Rodichok L. Speed of BA, et al. Oral sumatriptan: Effect of a second dose, and incidence onset, efficacy and tolerability of zolmitriptan nasal spray in the and treatment of headache recurrences. Cephalalgia 1994; 14: 330- acute treatment of migraine: A randomised, double-blind, 8. placebocontrolled study. CNS Drugs 2005; 19: 125-36. [92] Geraud G, Keywood C, Senard JM. Migraine headache recurrence: [112] Pascual J, Navarro A, Caminero AB, Jurado C, Díaz-Insa S, Huerta Relationship to clinical, pharmacological, and pharmacokinetic M. Symptomatic treatment of migraine with zolmitriptan: properties of triptans. Headache 2003; 43: 376-88. Experience with 82 patients. Neurologia 2006; 21: 188-91. [93] Tepper SJ, Rapoport AM. The triptans: A summary. CNS Drugs [113] Goadsby PJ, Yates R. Zolmitriptan intranasal: A review of the 1999; 12: 403-17. pharmacokinetics and clinical efficacy. Headache 2006; 46: 138- [94] Sheftell FD, Dahlöf CG, Brandes JL, Agosti R, Jones MW, Barrett 49. PS. Two replicate randomized, double-blind, placebo-controlled [114] Bellavance A, Belsey J. Triptan preference in acute migraine trials of the time to onset of pain relief in the acute treatment of management: A retrospective review of patient records from a migraine with a fast-disintegrating/rapid-release formulation of Canadian clinic population. Headache Care 2006; 3: 39-43. sumatriptan tablets. Clin Ther 2005; 27: 407-417. [115] Dowson AJ, Boes-Hansen S, Farkkila AM. Zolmitriptan nasal [95] Loder E, Brandes JL, Silberstein S, Skobieranda F, Bohidar N, spray is fast-acting and highly effective in the acute treatment of Wang L, et al. Rizatriptan Protocol 060 Study Group. Preference migraine. Eur J Neurol 2000 7(Suppl 3): 82. comparison of rizatriptan ODT 10-mg and sumatriptan 50-mg [116] Luthringer R, Djupesland PG, Sheldrake CD, Flint A, Boeijinga P, tablet in migraine. Headache 2001; 41: 745-53. Danjou P, et al. Rapid absorption of sumatriptan powder and [96] Cady R, Crawford G, Ahrens S, Hairwassers D, Getson A, Visser effects on glyceryl trinitrate model of headache following WH, et al. Rizatriptan-RPD Study Group.Long-term efficacy and intranasal delivery using a novel bi-directional device. J Pharm tolerability of rizatriptan wafers in migraine. Med Gen Med 2001; Pharmacol 2009; 61(9): 1219-28. 3: 1. [117] Djupesland PG, Docekal P; Czech Migraine Investigators Group. [97] Dowson AJ, MacGregor EA, Purdy RA, Becker WJ, Green J, Levy Intranasal sumatriptan powder delivered by a novel breath-actuated SL. Zolmitriptan orally disintegrating tablet is effective in the acute bi-directional device for the acute treatment of migraine: A treatment of migraine. Cephalalgia 2002; 22: 101-6. randomised, placebo-controlled study. Cephalalgia 2010; 30(8): [98] Dowson AJ, Charlesworth BR. Patients with migraine prefer 933-42. zolmitriptan orally disintegrating tablet to sumatriptan conventional [118] Pierce M, Marbury T, O'Neill C, Siegel S, Du W, Sebree T. Zelrix: oral tablet. Int J Clin Pract 2003; 57: 573-6. a novel transdermal formulation of sumatriptan. Headache 2009; [99] Spierings EL, Rapoport AM, Dodick DW, Charlesworth B. Acute 49(6): 817-25. treatment of migraine with zolmitriptan 5 mg orally disintegrating [119] Schulman E, O´Neill C, Pierce M, Griesser J, angelov A.S. tablet. CNS Drugs 2004; 18: 1133-41. Efficacy of Zelrix, a novel iontophoretic transdermal sumatriptan [100] Allen C. Rizatriptan: Clinical update. In: Humphrey P, Ferrari M, patch, in the treatment of acute migraine in patients with nausea. Olesen J, editors. The triptans: Novel drugs for migraine. New Presented at the 62nd Annual Meeting of the American Academy York: Oxford University Press, 2001; 199-205. of Neurology; April 10-17, 2010; Toronto. [101] PrasannaD, Manoranjan S. Formulation and evaluation of fast [120] Smith T, Pierce M, Griesser J. An open-label study to evaluate the dissolving films of zolmitriptan. Int Res J Pharm 2012; 3(5): 373-6. long-term safety of zelrixTM, a sumatriptan iontophoretic patch for [102] Visser WH, Ferrari MD, Bayliss EM, Ludlow S, Pilgrim AJ. the treatment of acute migraine. Presented at the 15Th Congress of Treatment of migraine attacks with subcutaneous sumatriptan: the International Headache Society: June 23-26, 2011; Berlin. First placebo-controlled study. The Subcutaneous Sumatriptan- [121] Calatayud-Pascual MA, Balaguer-Fernández C, Serna-Jiménez CE, International Study Group. Cephalalgia 1992; 12: 308-13. Del Rio-Sancho S, Femenía-Font A, Merino V, et al. Effect of [103] Tfelt-Hansen P. Efficacy and adverse events of subcutaneous, oral, iontophoresis on in vitro transdermal absorption of almotriptan. Int and intranasal sumatriptan used for migraine treatment: A J Pharm 2011; 416(1): 189-94. 38 Recent Patents on CNS Drug Discovery, 2014, Vol. 9, No. 1 Belvís et al.

[122] Dilone E, Bergstrom D, Cabana B, Nedumpara M, Fox AW; [146] Nezvalová-Henriksen K, Spigset O, Nordeng H. Triptan exposure Sumatriptan Lingual Spray Study Group. Sumatriptan Lingual during pregnancy and the risk of major congenital malformations Spray Study Group. Rapid oral transmucosal absorption of and adverse pregnancy outcomes: results from the Norwegian sumatriptan, and pharmacodynamics in acute migraine. Headache Mother and Child Cohort Study. Headache 2010; 50(4): 563-75. 2009; 49(10): 1445-53. [147] Evers S, Gralow I, Bauer B, Suhr B, Buchheister A, Husstedt IW, [123] Tepper SJ, Cochran A, Hobbs S, Woessner M. Sumatriptan et al. Sumatriptan and ergotamine overuse and drug-induced suppositories for the acute treatment of migraine.Int J Clin Pract headache: A clinicoepidmiologic study. Clinical Neuropharmacol 1998; 52: 31-5. 1999; 22: 201-6. [124] Bertin L, Brion N, Färkkilä M, Göbel H, Wessely P. A dose [148] Limmroth V, Kazarawa S, Fritsche G, Diener HC. Headache after defining study of sumatriptan suppositories in the acute treatment frequent use of new serotonin agonists zolmitriptan and naratriptan. of migraine. Int J Clin Pract 1999; 53: 593-8. Lancet 1999; 353: 78. [125] Derry CJ, Derry S, Moore RA. Sumatriptan (subcutaneous route of [149] Katsarava Z, Fritsche G, Muessig M, Diener HC, Limmroth V. administration) for acute migraine attacks in adults. Cochrane Clinical features of withdrawal headache following overuse of Database Syst Rev 2012; 2: CD009665. triptans and other headache drugs. Neurol 2001; 57: 1694-8. [126] Feleppa M, Apice G, D'Alessio A, Fucci S, Bigal ME. Tolerability [150] Viana M, Genazzani AA, Terrazzino S, Nappi G, Goadsby PJ. of acute migraine medications: influence of methods of assessment Triptan nonresponders: do they exist and who are they? and relationship with headache attributes. Cephalalgia 2008; Cephalalgia 2013; 33(11): 891-6 28(10): 1012-6. [151] Gallagher RM, Kunkel R. Migraine medication attributes important [127] Jamieson DG.The safety of triptans in the treatment of patients for patient compliance: concerns about side effects may delay with migraine. Am J Med 2002; 112: 135-40. treatment.Headache 2003; 43(1): 36-43. [128] Fox AW. Comparative tolerability of oral 5-HT1B/1D agonists. [152] Brandes JL. Treatment approaches to maximizing therapeutic Headache 2000; 40: 521-7. response in migraine. Neurol 2003; 61: S21-26. [129] Hall G, Brown M, Mo J, MacRae KD. Triptans in migraine: The [153] Foley KA, Cady R, Martin V, Adelman J, Diamond M, Bell CF, et risks of stroke, cardiovascular disease, and death in practice. al. Treating early versus treating mild: timing of migraine Neurol 2004; 62: 563-8. prescription medications among patients with diagnosed migraine. [130] Velentgas P, Cole JA, Mo J, Sikes CR, Walker AM. Severe Headache 2005; 45(5): 538-45. vascular events in migraine patients. Headache 2004; 44: 642-51. [154] Burstein R, Yarnitsky D, Goor-Aryeh I, Ransil BJ, Bajwa ZH. An [131] Dahlöf CG, Mathew N. Cardiovascular safety of 5HT1B/1D association between migraine and cutaneous allodynia. Ann Neurol agonists is there a cause for concern? Cephalalgia 1998; 18: 539- 2000; 47(5): 614-24 45. [155] Cady RK, Lipton RB, Hall C, Stewart WF, O'Quinn S, Gutterman [132] Visser WH, Jaspers NM, de Vriend RH, Ferrari MD. Chest D. Treatment of mild headache in disabled migraine sufferers: symptoms after sumatriptan: A two-year clinical practice review in results of the spectrum study. Headache.2000; 40(10): 792-7. 735 consecutive migraine patients. Cephalalgia 1996; 16: 554-9. [156] Dodik DW. Triptan Nonresponder Studies: Implications for clinical [133] Tfelt-Hansen P. Efficacy and adverse events of subcutaneous, oral, practice. Headache 2005; 45: 156-62 and intranasal sumatriptan used for migraine treatment: A [157] Thomsen LL, Dixon R, Lassen LH, Gibbens M, Langemark M, systematic review based on number needed to treat. Cephalalgia Bendtsen L, et al. 311C90 (zolmitriptan), a novel centrally and 1998; 18: 532-8. peripheral acting oral 5-hydroxytryptamine-1D agonist: A [134] Granella F, Sances G, Zanferrari C, Costa A, Martignoni E, comparison of its absorption during a migraine attack and in a Manzoni GC. Migraine without aura and reproductive life events: a migrainefree period. Cephalalgia 1996; 16: 270-5. clinical epidemiological study in 1300 women. Headache1993; [158] Tfelt-Hansen P, Edvinsson L. Pharmacokinetic and 33(7): 385-9. pharmacodynamic variability as possible causes for different drug [135] Sances G, Granella F, Nappi RE, Fignon A, Ghiotto N, Polatti F, et responses in migraine. A comment. Cephalalgia 2007; 27: 1091-3. al. Course of migraine during pregnancy and postpartum: a [159] Lacey LF, Hussey EK, Fowler PA. Single dose pharmacokinetics prospective study. Cephalalgia 2003; 23(3): 197-205. of sumatriptan in healthy volunteers. Eur J Clin Pharmacol 1995; [136] Lance JW, Anthony M. Some clinical aspects of migraine. A 47: 543-8. prospective survey of 500 patients. Arch Neurol 1966; 15(4): 356- [160] Seaber E, On N, Dixon RM, Gibbens M, Leavens WJ, Liptrot J, et 61. al. The absolute bioavailability and metabolic disposition of the [137] Somerville BW. A study of migraine in pregnancy. Neurol 1972; novel antimigraine compound zolmitriptan (311C90). Br J Clin 22(8): 824-8. Pharmacol 1997; 43: 579-87. [138] Marcus DA, Scharff L, Turk D. Longitudinal prospective study of [161] Brandes JL, Kudrow D, Stark SR, Frishberg BM, Alexander WJ, headache during pregnancy and postpartum. Headache.1999; 39(9): Zhang Y, et al. Sumatriptan-naproxen for acute treatment of 625-632. migraine. JAMA 2007; 297: 1443-54. [139] Olesen C, Steffensen FH, Sorensen HT, Nielsen GL, Olsen J. [162] Winner P, Cady RK, Ruoff GE, Frishberg BM, Alexander WJ, Pregnancy outcome following prescription for sumatriptan. Zhang Y, et al. Twelve-month tolerability and safety of Headache 2000; 40: 20-4. sumatriptan-naproxen sodium for the treatment of acute migraine. [140] Källén B, Lygner PE. Delivery outcome in women who used drugs Mayo Clin Proc 2007; 82: 61-8. for migraine during pregnancy with special reference to [163] Smith T, Blumenthal H, Diamond M, Mauskop A, Ames sumatriptan. Headache 2001; 41: 351-6. M, McDonald S, et al. Sumatriptan/Naproxen sodium for migraine: [141] Bánhidy F, Acs N, Horváth-Puhó E, Czeizel AE. Maternal severe Efficacy, health related quality of life, and satisfaction outcomes. migraine and risk of congenital limb deficiencies. Birth Defects Headache 2007; 47: 683-92. Res A Clin Mol Teratol 2006; 76(8): 592-601. [164] Krymchantowski AV, Jevoux CDA.The experience of combining [142] Cunnington M, Ephross S, Churchill P. The safety of sumatriptan agents, specially triptans and non steroidal anti-inflammatory and naratriptan in pregnancy: what have we learned? Headache drugs, for the acute treatment of migraine - a review. Recent 2009; 49(10): 1414-22. Patents CNS Drug Discov 2007; 2: 141-4. [143] Fiore M, Shields KE, Santanello N, Goldberg MR. Exposure to [165] Silberstein SD, Mannix LK, Goldstein J, Couch JR, Byrd SC, rizatriptan during pregnancy: post-marketing experience up to 30 Ames MH, et al. Multimechanistic (sumatriptan-naproxen) early June 2004. Cephalalgia. 2005; 25(9): 685-8. intervention for the acute treatment of migraine. Neurol 2008; 71: [144] Reiff-Eldridge R, Heffner CR, Ephross SA, Tennis PS, White AD, 114-21. Andrews EB. Monitoring pregnancy outcomes after prenatal drug [166] Landy S, White J, Lener SE, McDonald SA. Fixed-dose exposure through prospective pregnancy registries: a sumatriptan/naproxen sodium compared with each monotherapy pharmaceutical company commitment. Am J Obstet Gynecol 2000; utilizing the novel composite endpoint of sustained pain-free/no 182: 159-63. adverse events. Ther Adv Neurol Disord 2009; 2(3): 135-41. [145] Fox AW, Chambers CD, Anderson PO, Diamond ML, Spierings [167] Landy S, DeRossett SE, Rapoport A, Rothrock J, Ames MH, EL. Evidence-based assessment of pregnancy outcome after McDonald SA, et al. Two double-blind, multicenter, randomized, sumatriptan exposure. Headache 2002; 42(1): 8-15. placebo-controlled, single-dose studies of sumatriptan/naproxen Migraine Attack Treatment Recent Patents on CNS Drug Discovery, 2014, Vol. 9, No. 1 39

sodium in the acute treatment of migraine: Function, productivity, [189] Rains JC, Penzien DB, Lipchik GL. Behavioral facilitation of and satisfaction outcomes. Med Gen Med 2007; 9: 53. medical treatment for headache--part II: Theoretical models and [168] Mathew NT, Landy S, Stark S, Tietjen GE, Derosier FJ, White J, et behavioral strategies for improving adherence. Headache 2006; al. Fixed-dosesumatriptan and naproxen in poorresponders to 46(9): 1395-403. triptans with a shorthalf-life. Headache 2009; 49(7): 971-82. [190] Linde M, Jonsson P, Hedenrud T. Influence of disease features on [169] Efficacy and Safety of a Fixed-dose Combination of Naratriptan adherence to prophylactic migraine medication. Acta Neurol Scand and Naproxen in Acute Treatment of Migraine. In: Clinical Trials. 2008; 118(6): 367-72. Gov. A service of the U.S. National Institutes of [191] Hedenrud T, Jonsson P, Linde M. Beliefs about medicines and Health[online].Available at: http://clinicaltrials.gov/. Accessed adherence among Swedish migraineurs. Ann Pharmacother 2008; October 11, 2013. 42(1): 39-45. [170] Freitag F, Diamond M, Diamond S, Janssen I, Rodgers A, [192] Evans RW, Linde M. Expert opinion: adherence to prophylactic Skobieranda F. Efficacy and tolerability of coadministration of migraine medication. Headache 2009; 49(7): 1054-8. rizatriptan and acetaminophen vs rizatriptan or acetaminophenalone [193] Lafata JE, Tunceli O, Cerghet M, Sharma KP, Lipton RB. The use for acute migraine treatment. Headache 2008; 48: 921-30. of migraine preventive medications among patients with and [171] Krymchantowski AV, Filho PF, Bigal ME. Rizatriptan vs without migraine headaches.Cephalalgia 2010; 30(1): 97-104. rizatriptan plus trimebutine for the acute treatment of migraine: A [194] Olesen J, Diener HC, Husstedt IW, Goadsby PJ, Hall D, Meier U, double-blind, randomized, cross-over, placebo-controlled study. et al. BIBN 4096 BS Clinical Proof of Concept Study Group. Cephalalgia 2006; 26: 871-4. Calcitonin gene-related peptide receptor antagonist BIBN 4096 BS [172] Krymchantowski, A.V. Pharmaceutical combinations for the for the acute treatment of migraine. N Engl J Med 2004; 350(11): treatment of head-aches and migraine attacks as well as blisters and 1104-10. packs that contain them. US20080081798A1 (2008). [195] Ho TW, Mannix LK, Fan X, Assaid C, Furtek C, Jones CJ, et al. [173] Krymchantowski AV, Bigal ME. Rizatriptan versus rizatriptan plus MK-0974 Protocol 004 Study Group. Randomized controlled trial rofecoxib versus rizatriptan plus tolfenamic acid in the acute of an oral CGRP receptor antagonist, MK-0974, in acute treatment treatment of migraine. BMC Neurol 2004; 4: 10. of migraine. Neurol 2008; 70(16): 1304-12. [174] Krymchantowski AV, Barbosa JS. Rizatriptan combined with [196] Ho TW, Ferrari MD, Dodick DW, Galet V, Kost J, Fan X, et al. rofecoxib vs rizatriptan for the acute treatment of migraine: An Efficacy and tolerability of MK-0974 (telcagepant), a new oral open label pilot study. Cephalalgia 2002; 22: 309-12. antagonist of calcitonin gene-related peptide receptor, compared [175] Schulman EA, Dermott KF. Sumatriptan plus metoclopramide in with zolmitriptan for acute migraine: a randomised, placebo- triptan-nonresponsive migraineurs. Headache 2003; 43: 729-33. controlled, paralleltreatment trial. Lancet 2008; 372(9656): 2115- [176] Maichle, W.R., Whatley, C.L., Reiner, G., Reiner, A. Fixed 23. combination dosage forms for the treatment of migraine. [197] Connor KM, Shapiro RE, Diener HC, Lucas S, Kost J, Fan X, et al. WO2007127207A2 (2007). Randomized, controlled trial of telcagepant for the acute treatment [177] Goldstein J, Dahlöf CG, Diener HC, Olesen J, Schellens R, Senard of migraine. Neurol 2009; 73(12): 970-7. JM, et al. Alniditan in the acute treatment of migraine attacks: A [198] Ho AP, Dahlöf CG, Silberstein SD, Saper JR, Ashina M, Kost subcutaneous dose-finding study. Subcutaneous Alniditan Study JT, et al. Randomized, controlled trial of telcagepant over four Group. Cephalalgia 1996; 16: 497-502 migraine attacks. Cephalalgia 2010; 30(12): 1443-57. [178] Diener HC, Tfelt-Hansen P, de Beukelaar F, Ferrari MD, Olesen J, [199] Tfelt-Hansen P. Is the dose-response of telcegepant well Dahlöf C, et al. The efficacy and safety of sc alniditan vs sc characterized? Presented at the 15Th Congress of the International sumatriptan in the acute treatment of migraine: A randomized, Headache Society: June 23-26, 2011; Berlin. double-blind, placebocontrolled trial. Cephalalgia 2005; 21: 672-9. [200] Hewitt DJ, Aurora SK, Dodick DW, Goadsby PJ, Ge YJ, Bachman [179] Knight YE, Edvinsson L, Goadsby PJ. Blockade of calcitonin R, et al. Randomized controlled trial of the CGRP receptor generelated peptide release after superior sagittal sinus stimulation antagonist MK-3207 in the acute treatment of migraine. in cat: A comparison of avitriptan and CP122, 288. Neuropeptides Cephalalgia 2011; 31(6): 712-22. 1999; 33: 41-6. [201] Diener HC, Barbanti P, Dahlöf C, Reuter U, Habeck J, Podhorna J. [180] Sharma A, Jusko WJ, Fulmor IE, Norton J, Uderman HD, Salazar BI 44370 TA, an oral CGRP antagonist for the treatment of acute DE. Pharmacokinetics and pharmacodynamics of avitriptan during migraine attacks: results from a phase II study. Cephalalgia 2011; intravenous administration in healthy subjects. J Clin Pharmacol 31(5): 573-84. 1999; 39: 685-94. [202] Tong G, Savant I, Jariwala N, Burt D, Zheng, N, Buzescu A, et al. [181] Muñoz-Islas E, Gupta S, Jiménez-Mena LR, Lozano-Cuenca Phase I single and multiple dose study to evaluate the safety, J, Sánchez-López A, Centurión D, et al. Donitriptan, but not tolerability, and pharmacokinetics of BMS-927711 in healthy sumatriptan, inhibits capsaicin-induced canine external carotid subjects. Presented at the 3rd European Headache and Migraine vasodilatation via 5-HT1B rather than 5-HT1D receptors. Br J Trust International Congress of the Migraine Trust and European Pharmacol 2006; 149: 82-91. Headache Federation; Setember 20-23, 2012; London. [182] Létienne R, Blanchet JC, Sole E, John GW, Le Grand B. [203] Bowler KE, Worsley MA, Broad L, Sher E, Benschop R, Johnson Donitriptan decreases jugular venous oxygen saturation in rats in K, et al. Evidence for anti-inflammatory and putative analgesic the absence of cranial vasoconstriction: An overlooked mechanism effects of a monoclonal antibody to calcitonin gene-related peptide. of antimigraine action? J Pharmacol Exp Ther 2005; 315: 849-57. Neurosci 2012; S0306-4522(12): 1045-7. [183] Lantéri-Minet M, Massiou H, Romatet S, Barba A, Lucas C, Allaf [204] Juhl L, Edvinsson L, Olesen J, Jansen-Olesen I. Effect of two novel B. An instrument to assess patient perceptions of satisfaction with CGRP-binding compounds in a closed cranial window rat model. acute migraine treatment (EXPERT Study). Headache 2011; 51(4): Eur J Pharmacol 2007; 567(1-2): 117-24. 590-601. [205] Shi L, Rao S, Sun H, Wild K, Xu C. In vitro characterization of [184] Nijjar SS, Pink L, Gordon AS. Examination of migraine AA71, a potent and selective human monoclonal antibody against management in emergency departments. Pain Res Manag 2001; CGRP receptor. Presented at the 3rd European Headache and 16(3): 183-6. Migraine Trust International Congress of the Migraine Trust and [185] Mateos V, Diaz-Insa SI, Morera J, et al. Action plan against European Headache Federation; Setember 20-23, 2012; London. migraine (PALM). Migraine management in neurology clinics in [206] Ferrari MD, Färkkilä M, Reuter U, Pilgrim A, Davis C, Krauss M, Spain. Neurologia 2007; 3 (4): 7-14. et al. European COL-144 Investigators.Acute treatment of migraine [186] Steiner TJ, Catarci T, Hering R, Whitmarsh T, Couturier EG. If with the selective 5-HT1F receptor agonist lasmiditan – A migraine prophylaxis does not work, think about compliance. randomised proof-of-concept trial. Cephalalgia 2010; 30(10): 1170- Cephalalgia 1994; 14(6): 463-4. 8. [187] Mulleners WM, Whitmarsh TE, Steiner TJ. Noncompliance may [207] Färkkilä M, Diener HC, Géraud G, Láinez M, Schoenen J, Harner render migraine prophylaxis useless, but once-daily regimens are N, et al. COL MIG-202 Study Group. Efficacy and tolerability of better. Cephalalgia 1998; 18(1): 52-6. lasmiditan, an oral 5-HT (1F) receptor agonist, for the acute [188] Rahimtoola H, Buurma H, Tijssen CC, Leufkens HG, Egberts AC. treatment of migraine: a phase 2 randomised, placebo-controlled, Migraine prophylactic medication usage patterns in The parallel-group, dose-ranging study. Lancet Neurol 2012; 11(5): Netherlands. Cephalalgia 2003; 23(4): 293-301. 405-13. 40 Recent Patents on CNS Drug Discovery, 2014, Vol. 9, No. 1 Belvís et al.

[208] Medve RA, Lategan TW. A phase 2 multicenter, randomized, [217] Efficacy and safety of BGG492 in the treatment of migraine. In: double-blind, parallelgroup, placebo-controlled study of NXN-188 http://clinicaltrials.gov/. A service of the U.S. National Institutes of dihydrochloride in acute migraine without aura. Presented at the Health[online].Available at: http://clinicaltrials.gov/. Accessed 2rd European Headache and Migraine Trust International Congress October 11, 2013. of the Migraine Trust and European Headache Federation; October [218] A randomized, double blind, placebo controlled study to assess 28-31 2010; Nice. efficacy, safety and tolerability of BGG492 in migraine prevention. [209] Hougaard A, Hauge AW, Guo S, Olesen J. NXN-188 during the In: ClinicalTrials.Gov. A service of the U.S. National Institutes of aura phase of migraine with aura: a randomized, double-blind, Health[online].Available at: http://clinicaltrials.gov/. Accessed placebo-controlled cross-over study. Presented at the 15Th Congress October 11, 2013. of the International Headache Society: June 23-26, 2011; Berlin. [219] Double-blind, placebo-controlled study of BGC20-1531 in [210] Study of NXN 188 for the treatment of migraine with aura. In: migraine. In: http://clinicaltrials.gov/. A service of the U.S. ClinicalTrials.Gov. A service of the U.S. National Institutes of National Institutes of Health[online].Avalaible at: Health [online]. Available at: http://clinicaltrials.gov/. Accessed http://clinicaltrials.gov/. Accessed October 11, 2013. October 11, 2013. [220] Safety and efficacy of NPS 1776 in the acute treatment of migraine [211] Van der Schueren BJ, Lunnon MW, Laurijssens BE, Guillard F, headaches. In: http://clinicaltrials.gov/. A service of the U.S. Palmer J, Van Hecken A, et al. Does the unfavorable National Institutes of Health[online]. Avalaible at: pharmacokinetic and pharmacodynamic profile of the iNOS http://clinicaltrials.gov/. Accessed October 11, 2013. inhibitor GW273629 lead to inefficacy in acute migraine? J Clin [221] Nitrous oxide for acute migraine pain in the emergency room (ED). Pharmacol 2009; 49(3): 281-90. In: ClinicalTrials.Gov. A service of the U.S. National Institutes of [212] Adaptive design trial of GW274150 in the treatment of acute Health[online]. Available at: http://clinicaltrials.gov/. Accessed migraine. In: ClinicalTrials.Gov. A service of the U.S. National October 11, 2013. Institutes of Health[online].Avalaible at: http://clinicaltrials.gov/. [222] Normobaric oxygen (NBO) therapy in acute migraine. In: Accesed October 11, 2013. ClinicalTrials.Gov. A service of the U.S. National Institutes of [213] Silberstein SD, Schoenen J, Göbel H, Diener HC, Elkind AH, Health[online].Available at: http://clinicaltrials.gov/. Accessed Klapper JA, et al. Tonabersat, a gap-junction modulator: efficacy October 11, 2013. and safety in two randomized, placebo-controlled, dose-ranging [223] A double blind randomized controlled of placebo and nebulized studies of acute migraine. Cephalalgia 2009; 29 Suppl 2: 17-27. lidocaine for migraine headache. In: ClinicalTrials.Gov. A service [214] Dahlöf CG, Hauge AW, Olesen J. Efficacy and safety of of the U.S. National Institutes of Health[online]. Available at: tonabersat, a gap-junction modulator, in the acute treatment of http://clinicaltrials.gov/. Accessed October 11, 2013. migraine: a double-blind, parallel-group, randomized study. [224] Study to evaluate the efficacy and safety of dronabinol metered Cephalalgia 2009; 29 Suppl 2: 7-16. dose inhaler (MDI) in acute treatment of migraine headache. In: [215] Kostic MA, Gutiérrez FJ, Rieg TS, Moore TS, Gendron RT. A ClinicalTrials.Gov. A service of the U.S. National Institutes of prospective, randomized trial of intravenous prochlorperazine Health[online].Available at: http://clinicaltrials.gov/. Accessed versus subcutaneous sumatriptan in acute migraine therapy in the October 11, 2013. emergency department. Ann Emerg Med 2010; 56(1): 1-6. [225] The effect of nasal carbon dioxide in the treatment of moderate to [216] Lambert GA, Davis JB, Appleby JM, Chizh BA, Hoskin KL, severe migraine. In: ClinicalTrials.Gov. A service of the U.S. Zagami AS. The effects of the TRPV1 receptor antagonist SB- National Institutes of Health[online]. Available at: 705498 on trigeminovascular sensitisation and neurotransmission. http://clinicaltrials. gov/. Accessed October 11, 2013. Naunyn Schmiedebergs Arch Pharmacol 2009; 380(4): 311-25.