CLINICAL CASE Presented by: Carlo Lisotto Headache Centre Department of Neurosciences University of Padua, Italy Woman with long-lasting migraines and high rates of relapse

IDENTIFICATION 39-year old woman with episodic migraine without aura and infrequent migraine with aura She took several NSAIDs, without any benefit

PAST CLINICAL HISTORY AND FAMILY HISTORY She suffered from headaches since her late teens The headaches gradually increased in duration and intensity and currently occur 2-3 times a month, last 3 to 4 days, and are extremely severe The headaches reach peak intensity on average within 2-3 hours Premonitory symptoms consist in fatigue, yawning, stiff neck, concentration problems and irritability The headaches are frequently associated with pallor, nausea, phonophobia, photophobia, osmophobia and, sporadically, with vomiting Mental strain, anxiety, lack of sleep, missing meals, exertion and changes in weather make the headaches worse She reports 5 episodes of visual aura Her grandmother had migraine, which resolved a few years after her menopause

DIAGNOSTIC PROCEDURES Physical and neurological examinations with fundoscopy showed no abnormalities BP 120/80 mmHg Pericranial muscles were slightly stiff and tender, and their tenderness was increased by digital pressure No sign of temporomandibular dysfunction (TMD) MRI with angiography of the brain showed small foci of hyperintensity in the deep white matter of both hemispheres; these abnormalities were considered non-specific and clinically unremarkable (Fig.1) Tests for disorders of coagulation were normal MIDAS score of 22 indicates severe disability

Figure 1: THE PATIENT’S BRAIN MRI

DIAGNOSIS Migraine without aura + migraine with aura

PAST TREATMENT The patient had been treated unsuccessfully with NSAIDs and then given oral rizatriptan 10 mg with remarkable benefit Rizatriptan was selected because of its rapid onset of action, taking into consideration that the patient’s attacks reach peak intensity within 2-3 hours on average Rizatriptan 10 mg acted quickly in relieving the head pain and associated symptoms, thus rapidly restoring the patient’s functions She was almost constantly pain-free within 2 hours, but unfortunately the pain tended to recur, usually 6 hours after taking the first dose

TREATMENT In the light of the relapses, the patient was recommended treatment with frovatriptan 2.5 mg once per day. If migraine recurs after initial relief it may be taken a second dose at a 2-h interval and not within the same attack. The total daily dose should not exceed 5 mg per day

FOLLOW-UP VISIT Assessment after 6 months: -rizatriptan and frovatriptan were equally effective (pain free  2 hrs after the first dose) -headache recurrence was much less frequent after taking frovatriptan than after rizatriptan use -fewer frovatriptan doses were required to treat her prolonged attacks Consequently, the patient preferred frovatriptan: -favourable sustained effect with a lower rate of relapse -prevents the worsening of migraine attacks and reduces their severity

COMMENTS (I) White matter hyperintensities (brain MRI): -more prevalent in migraineurs than in the general population (12-47% of all patients) -more frequent in female patients and in migraineurs with aura -pathogenesis and clinical significance are still unclear Long-lasting untreated severe migraine attacks result in significant disability and compromised function in a substantial proportion of patients (Fig. 2) 1 1. Lipton RB, et al. Neurology 2007;68:

Figure 2: MIGRAINE-ASSOCIATED DISABILITY Patients (%) Function normally Severe impairment or bed rest Some impairment Lipton RB, et al. Neurology 2007;68:

COMMENTS (II) Migraine attacks Almost three quarters of women have headaches that last over 24 hours, whereas only 50% of men have such long- lasting attacks 1 The mean duration of women’s headaches was found to be 31 hours, while in men the mean duration was shorter, being 19 hours 2 In clinical practice there is a huge inter-individual variability of migraine attacks in terms of severity, duration, associated symptoms and time to peak intensity Usually attacks with a gradual-onset are long-lasting and are frequently associated with headache relapse 3 1. Kelman L. Headache 2006;46: ; 2. Pryse-Phillips W, et al. Headache 2006;46: ; 3. Lipton RB, et al. J Headache Pain 2004;5:

COMMENTS (III) Triptans Triptans with the shortest T max are believed to provide the fastest speed of action 1 Triptans with longer half-lives seem to provide the lowest rates of headache relapse, with there being a significant inverse correlation between half-life and recurrence rate (Fig. 3) 2 In clinical trials, responses to frovatriptan and rizatriptan were consistently similar in terms of pain-free at 2 hours rates, but frovatriptan was associated with a significantly lower incidence of recurrence (Fig. 4) 3,4 1 Johnston MM, Rapoport AM. Drugs 2010;70: ; 2.Géraud G, et al. Headache 2003; 43: ; 3. Tfelt-Hansen P, et al. Cephalalgia 2012;32:6-38; 4. Savi L, et al. J Headache Pain 2011;12:

Figure 3: INVERSE CORRELATION BETWEEN TRIPTANS HALF-LIVES AND RECURRENCE RATE Geraud G, Keywood C, Senard JM. Headache 2003; 43: Incidence of relapse (%) Half-life (hours) Frovatriptan Naratriptan Eletriptan Almotriptan Zolmitriptan Sumatriptan Rizatriptan

Figure 4: PERCENTAGE OF RELAPSES (IHS) IN THE ITT POPULATION (N=125) Savi L, et al. J Headache Pain 2011;12: Episodes (%)

COMMENTS (IV) Recurrence and frovatriptan Relapse is one of the two main reasons for patients’ dissatisfaction with migraine treatment, together with incomplete pain relief 1 The pivotal importance of this attribute was clearly pointed out by 86% of patients in a survey by Lipton et al. 2 Frovatriptan provided in this patient rapid efficacy comparable to that of rizatriptan Conversely, the relapse rate was significantly lower after taking frovatriptan and the patient expressed a clear preference for this triptan, based on this crucial effect 1. Malik SN, et al. Headache 2006;46: ; 2. Lipton RB, et al. Headache 2002;42(Suppl 1):S3-S9.

COMMENTS (V) In conclusion Frovatriptan seems to be unique in the triptan class, having the longest duration of action and the lowest recurrence rate Compared to the other triptans, frovatriptan offers the advantage of a lower risk of relapse and therefore a more sustained effect Frovatriptan represents a particularly favorable option for treating migraine attacks with a high rate of relapse