1. Cod. MCI2891408 CLINICAL CASE Presented by: Carlo Lisotto Headache Centre Department of Neurosciences University of Padua, Italy Man with migraine headaches occurring only at weekends

2. Cod. MCI2891408 IDENTIFICATION 40-year-old man with migraine headaches occurring almost exclusively at weekends The attacks usually occur on Saturdays, less frequently on Sundays and not uncommonly on both days

3. Cod. MCI2891408 PAST CLINICAL HISTORY AND FAMILY HISTORY (I) He experienced headaches since the age of 25, when he started working as a lawyer He is a non-smoker, does not consume alcohol, drinks little caffeine, and exercises regularly Since their onset his headaches have occurred almost exclusively at weekends The frequency of the attacks was initially low, on average one attack every two months, but over time it has progressively increased During the past three years the patient has experienced headaches on at least three weekends out of four The headaches are already present on awakening in the morning, or come on by noon; they build in intensity, reaching maximum intensity in one to two hours The response to acute medications is poor and unsatisfactory if he is not able to abort an attack early

4. Cod. MCI2891408 PAST CLINICAL HISTORY AND FAMILY HISTORY (II) The attacks usually occur on Saturdays, less frequently on Sundays and not uncommonly on both days The headaches are severe in intensity and throbbing in nature They are unilaterally located, usually on the right They often begin in the side of the nose and extend from there to behind the eye. They sometimes begin in the back of the neck They are associated with photophobia and phonophobia, and especially with severe nausea, usually followed by vomiting Non-steroidal anti-inflammatory drugs, in particular ibuprofen, are partially effective, but their intake is associated with an unpleasant gastric burning sensation

5. Cod. MCI2891408 DIAGNOSTIC PROCEDURES (I) His general examination was normal: BP 130/90 mm/Hg, pulse rate 65 bpm Pupillary examination and fundoscopy were normal His neurological examination (cranial nerves, power, tone, sensory function, reflexes, gait and coordination) was also within normal limits His psychological profile was normal, and there was no indication of depression or anxiety Routine laboratory data were normal, except for mild hypercholesterolaemia A previous CT scan of the brain did not reveal any abnormality

6. Cod. MCI2891408 DIAGNOSTIC PROCEDURES (II) A headache diary, completed for a four-week period before the first consultation, confirmed the occurrence of migraine attacks only at weekends The headaches have onset on awakening in the morning, or during sleep, 30-60 minutes prior to the scheduled waking-up time The pain occasionally starts by noon, and quite rarely in the afternoon or in the evening The patient gave a total score of 65 on the six-item Headache Impact Test (HIT-6) (Fig. 1), which indicates a severe impact

7. Cod. MCI2891408 Figure 1: THE PATIENT’S HIT-6 COLUMN 2 (8 points each) Total Score COLUMN 1 (6 points each) 1 2 3 4 5 6 When you have headaches, how often is the pain severe ? How often do headaches limit your ability to do usual daily activities including household work, work, school, or social activities ? Never When you have a headache, how often do you wish you could lie down ? In the past 4 weeks, how often have you felt too tired to do work or daily activities because of your headaches ? In the past 4 weeks, how often have you felt fed up or irritated because of your headaches ? In the past 4 weeks, how often did headaches limit your ability to concentrate on work or daily activities ? RarelySometimesVery oftenAlways Never Rarely SometimesVery oftenAlways Sometimes Rarely Sometimes Always Very often Always Very oftenAlways COLUMN 3 (10 points each) COLUMN 4 (11 points each) COLUMN 5 (13 points each) X X X X X X 65 Kosinski M, et al. Qual Life Res 2003;12:963-974.

8. Cod. MCI2891408 DIAGNOSIS Migraine without aura, with predictable attacks (at weekends)

9. Cod. MCI2891408 TREATMENT Given the typical characteristics of this migraine, occurring at the weekend, frovatriptan 2.5 mg od was considered to be the first-line medication for this patient having the longest duration of action and the lowest relapse rate

10. Cod. MCI2891408 FOLLOW-UP VISIT Assessment after 4 months: -frovatriptan was consistently effective when taken acutely in the morning on the appearance of the first symptoms -in particular, he was satisfied with its reliability of efficacy, sustained duration of action and lack of side effects, and with the improvement in his quality of life -he reported a prolonged effect, with a low occurrence of relapses and few doses needed to treat long-lasting attacks, provided the medication was taken promptly on appearance of the premonitory signs of a migraine attack

11. Cod. MCI2891408 COMMENTS (I) The term weekend migraine (WM) is used to define a type of headache that occurs only or almost only at weekends. About 30% of migraineurs claim to experience attacks mainly at weekends 1,2 The question of whether days off represent a trigger for headache has been debated in recent years, with some studies showing a clear relationship 2,3 and other surveys failing to confirm this association 4-6 Moreover, the sleep-wake cycle is reportedly altered at weekends (people generally get up later and sleep longer than on working days) and this may be a trigger for WM 7 1. Torelli P, et al. Headache 1999;39:11-20; 2. Cugini P, et al.Chronobiol Int 1990;7:467-469; 3. Torelli P, et al. Headache 1999;39:398-408; 4. Wöber C, et al. Cephalalgia 2007;27:304-314; 5. Morrison DP. Cephalalgia 1990;10:189-193; 6. Alstadhaug KB, et al. Cephalalgia 2007;27:343-346; 7. Nattero G, et al. Headache 1989;29:93-99.

12. Cod. MCI2891408 COMMENTS (II) In an observational study of 3,301 patients it was found that more than 5% of all migraineurs have their attacks mostly at weekends 1 WM seems to affect men more than women; in one survey 2, males accounted for the majority of the 200 patients with WM (102 cases, 51.0%) The attacks were found to be severe in intensity and disabling in most cases, responding only to triptans in over 55% of the subjects Because of the severely reduced functioning at weekends, resulting from these attacks, the patient misses many leisure and social activities, and feels deeply frustrated 1.Evers S, et al. Eur Neurol Rev 2013;8:149-152; 2. Kelman L. Pain Headache 2006;46:942-953.

13. Cod. MCI2891408 COMMENTS (III) Although WM has been a poorly investigated condition and specific evidence of drug efficacy for treatment of this condition is lacking, there is no reason to doubt that current medications for migraine treatment can also be effective in this type of headache Limited evidence is available on the efficacy of anti-migraine drugs in patients whose attacks occur mostly at weekends Selective serotonin 5-HT 1B/1D receptor agonists (the triptans) have been shown to be effective acute migraine drugs, and are currently recommended, by the EFNS Guidelines 1, as first-line treatments for moderate-to-severe migraine, and for mild-to-moderate migraine attacks which have not responded to adequate doses of simple analgesics 1. Evers S, et al. Eur J Neurol 2009;16:968-981.

14. Cod. MCI2891408 COMMENTS (IV) Since WM attacks usually last a long time, up to two days, the triptans with a long half-life are the most suitable medications The ideal drug for the present patient is a compound with some prerequisite pharmacokinetic properties, in particular a long-lasting effect. Frovatriptan, having the longest duration of action (26 hours) (Table 2) and the lowest risk of relapses, could be considered a first-line medication for patients affected by WM since it is likely to provide a more sustained effect Due to the consistent predictability of his attacks, the present patient was instructed to take frovatriptan as soon as possible, during the migraine premonitory phase 1. Evers S, et al. Eur J Neurol 2009;16:968-981.

15. Cod. MCI2891408 Table 2: HALF-LIVES OF THE DIFFERENT TRIPTANS Johnston MM, et al. Drugs 2010; 70:1505-1518. TriptanRoute and dose (mg)Half-life (hours) SumatriptanSC 62 SumatrriptanPO 502 Sumatriptan1002 SumatriptanNS 202 Zolmitriptan2.53 Zolmitriptan52.71 ZolmitriptanODT 2.52.5-3 ZolmitriptanNS 52.82 Rizatriptan102 RizatriptanODT 102 Naratriptan2.55-6.3 Almotriptan12.53.2-3.7 Eletriptan403.6 Eletriptan405.5 Frovatriptan2.526 NS=nasal spray; ODT=orally disintegrating tablet; PO=oral tablet; SC=subcutaneous injection

16. Cod. MCI2891408 COMMENTS (V) A retrospective analysis of three randomised, double-blind, crossover studies comparing frovatriptan vs other second- generation triptans was carried out 1 Of the 346 intention-to-treat population patients, 188 (54%) had WM and were included in the analysis. A total of 569 attacks occurred during weekends and 1,281 on workdays The proportion of pain-free episodes at two hours did not significantly differ between weekend and workday attacks for frovatriptan (26% vs 27%) or for comparators (34% vs 32%) Conversely (Fig. 2) the relapse rate within 48 hours for weekend attacks compared to workday attacks was significantly lower with frovatriptan (17% vs 30%, p<0.05), but not with comparators (weekends 34% vs workdays 40%, p=NS) 1. Lisotto C, et al. Brain Disord Ther 2014;3:3. http://dx.doi.org/10.4172/2168-975X.1000128.

17. Cod. MCI2891408 Figure 2: RELAPSE RATES WITHIN 48 HOURS Modified from: Lisotto C, et al. Brain Disord Ther 2014;3:3. http://dx.doi.org/10.4172/2168-975X.1000128.

18. Cod. MCI2891408 COMMENTS (VI) 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 seems to offer the advantage of a lower risk of relapse and therefore a more sustained effect