Characteristics of Patients With Inadequate Responses to Acute Triptan Treatment

Characteristics of Patients With Inadequate Responses to Acute Triptan Treatment for Menstrual Migraine John Tobin,1 Bob Shaw,1 Steve Pawsey,1 John C. Campbell,2 Jan Lewis Brandes,3 E. Anne MacGregor4 Poster #S08 1 Vernalis Development Ltd, Winnersh, UK; 2Endo Pharmaceuticals Inc., Chadds Ford, PA, USA; 3Nashville Neuroscience Group, PC, Nashville, TN, USA; 4 The City of London Migraine Clinic, London, UK Introduction Approximately 50% of women with migraine experience menstrual migraines (MM),1-3 recently defined as those migraines starting on day –2 to +3 relative to the onset of menstruation.4 MM attacks have been reported as more severe, longer lasting, and more resistant to treatment than other migraines.5,6 In multiple studies, acute treatment with triptans provided significant pain relief at 2 hours, but ≤30% of patients experience sustained pain-free responses lasting at least 2–24 hours.7,8 Patients with an inadequate response to acute triptan treatment of MM attacks may be appropriate candidates for shortterm preventive treatment with frovatriptan, which has been shown to be efficacious in the prevention of MM when taken during the perimenstrual period (PMP).9,10 Additional information on the clinical characteristics of patients with difficult-to-treat (DTT) MM attacks may help facilitate a proper diagnosis and treatment of MM. Inclusion Criteria Women aged ≥15 years (in the United States, France, Sweden, and Finland) or aged ≥18 years (in Canada, Norway, Germany, Italy, and the United Kingdom) with MM attacks occurring during the PMP from day –2 to day +3 relative to the onset of menses (day +1) Women with DTT MM, defined as a history of inadequate response to current/previous triptan therapy over a minimum of two PMPs and previous exposure to nontriptan treatment ▪ An inadequate response included lack of efficacy or tolerability, recurrence within 48 hours, need for rescue medication, exceeding the recommended triptan dose, or partial response. At least two MM attacks in the past three menstrual cycles Predictable menses and a stable contraceptive regimen in women using hormonal contraception Table 1. Patient Demographics of the Safety Population Safety Population (n=416) Figure 2. Incidence and Severity of MM, MM-Associated Symptoms, and Functional Impairment during the Placebo Run-in Period 100 None Mild Table 3. Reasons for Failure of Prior Triptan Therapy Reason for Failure, n (%) Lack of efficacy Lack of tolerability Exceeded maximum dose Rescue used Recurrence (<48 h) Partial response Almotriptan 36 (46) 5 (6) 1 (1) 24 (30) 50 (63) 42 (53) Eletriptan 33 (33) 15 (15) 5 (5) 36 (36) 55 (55) 65 (65) Frovatriptan 13 (30) 0 1 (2) 17 (39) 20 (45) 31 (70) Naratriptan 36 (47) 7 (9) 4 (5) 20 (26) 44 (58) 47 (62) Rizatriptan 62 (41) 10 (7) 3 (2) 53 (35) 91 (61) 89 (59) Sumatriptan 102 (47) 41 (19) 17 (8) 63 (29) 117 (54) 126 (58) Zolmitriptan 69 (47) 18 (12) 8 (5) 44 (30) 77 (52) 82 (56) Percentage of Total Patients Mean age, y (SD) Range Age group, n (%), y <18 18–45 >45 Race/ethnicity, n (%) White Black Hispanic Asian Other Height (cm), mean (SD) Range Weight (kg), mean (SD) Range SD=standard deviation. 38.1 (7.6) 16–58 2 (1) 346 (83) 68 (16) 393 (94) 13 (3) 5 (1) 2 (0) 3 (1) 165.3 (6.7) 140–185 67.7 (14.7) 42–158 75 Moderate Severe Missing data 50 25 0 M M Exclusion Criteria Pregnant or lactating women Women with >3 intercurrent (non-MM) migraines or >15 headache days per month History of myocardial infarction, heart disease, coronary vasospasm, peripheral vascular disease, uncontrolled hypertension, or cerebrovascular disease o ho ph op no ot o Ph Ph a bi a bi us Na ea l ng na t iti tio en om n c ir m V Fu pa Im Figure 3. Number of Patients Who Tried Different Previous Triptans as Treatment for Migraines 250 Number of Patients Who Tried Each Triptan Conclusions Some women with MM are difficult to treat using acute triptan therapy, having had inadequate responses to prior therapy with one or more triptans. ▪ Many of these patients use multiple medications for acute or preventive migraine treatments, yet the majority (80%) report moderate or severe MM attacks of long (>3 d) duration. ▪ Many of the difficult-to-treat patients also experience moderate or severe functional impairment. Multiple factors may contribute to an inadequate response to acute triptan treatment; the most frequently cited are a partial response, headache recurrence, and/or a lack of efficacy. Women with predictable, moderate to severe disabling MM attacks who do not respond adequately to acute triptan treatment may be appropriate candidates for short-term preventive treatment. MM=menstrual migraine. 200 150 100 50 0 n n n an an an an ta ta ta pt pt pt pt ip rip rip tr i tr i tr i tr i itr at ot ra va m iza Ele l m m o R Na Al Fr Su Zo Objective To identify the clinical characteristics and primary reasons for previous inadequate response to acute triptan treatment in women with DTT MM 83% (346/416) also experienced intercurrent migraines; the mean was 1.8 attacks per month. The majority of migraineurs (288/416; 69%) did not report aura. Before the study, many patients were taking one or more acute or prophylactic medications for migraine. All patients had received previous triptan treatment. In addition, patients were taking analgesics (212/416; 51%), opioids (92/416; 22%), antidepressants (26/416; 6%), ergot alkaloids (21/416; 5%), beta-blocking agents (16/416; 4%), muscle relaxants (17/416; 4%), and other antimigraine preparations (5/416; 1%) but were still experiencing MM. During the single-blind run-in phase, during which patients received placebo, 80% of patients experienced moderate or severe MM attacks (Figure 2). Moderate or severe MM-associated symptoms were reported by many patients during the single-blind run-in phase, including phonophobia (40%), photophobia (41%), nausea (36%), and vomiting (10%; Figure 2). Moderate to severe functional impairment in everyday tasks was experienced by 61% of patients (Figure 2). Methods Study Design Double-blind, placebo-controlled, parallel-group, phase IIIb study at 55 sites in Europe and North America. The study consisted of three phases: a single-blind run-in phase, a double-blind phase, and an open-label extension (Figure 1). Patients were randomized to one of three treatment groups: placebo, frovatriptan once daily, or frovatriptan twice daily. Additional frovatriptan was available for the acute treatment of breakthrough MM as well as for non-MM attacks. Assessments Migraine history was recorded for each patient at screening, and migraine characteristics were recorded during baseline when patients received single-blinded treatment with placebo during the PMP. Previous experience with triptans was recorded for each patient, including the reasons for the inadequate response to triptan therapy. ▪ More than one reason could be listed for each triptan. Table 2. Migraine History of Safety Population Characteristic Mean duration patients had MM, y (SD) Range Safety Population (n=416) 11.5 (8.9) 1–40 2.9 (0.4) Mean number of menstrual cycles in previous 3 months with MM attacks, n (SD) Mean average length of MM, d (median) Start of MM attack in relation to onset of menses, n (%) Day –2 –1 +1 +2 +3 Patient has intercurrent migraines, n (%) Yes No Mean number of intercurrent attacks, n (SD) Range Category of migraine With and without aura Without aura With aura MM=menstrual migraine; SD=standard deviation. Over the previous 12 months, patients had an inadequate response to an average of two triptans per patient, and on average, two reasons were given for poor response to each triptan. The most common reasons cited for the inadequate response were partial response (range, 53%–70%), migraine recurrence within 48 hours (range, 45%–63%), lack of efficacy (range, 30%–47%), and use of rescue medication (range, 26%–39%; Table 3). Intolerance to frovatriptan was an exclusion criterion. Lack of tolerability to other triptans was cited by 6%–19% of patients at baseline. ▪ References Dzoljic E, et al. Headache. 2002;42(3):185-193. Granella F, et al. Cephalalgia. 2000;20(8):701-707. Granella F, et al. Headache. 1993;33(7):385-389. Headache Classification Committee of the International Headache Society. Cephalalgia. 2004;24(suppl 1):9-160. 5. Couturier EGM, et al. Cephalalgia. 2003;23(4):302-308. 6. Granella F, et al. Cephalalgia. 2004;24(9):707-716. 7. Allais G, et al. Neurol Sci. 2006;27(suppl 2):S193-197. 8. Nett R, et al. Obstet Gynecol. 2003;102(4):835-842. 9. Silberstein SD, et al. Neurology. 2004;63(2):261-269. 10. Brandes JL, et al. Prevention of difficult-to-treat menstrual migraine using a 6-day regimen of frovatriptan: a second double-blind, randomized, placebocontrolled trial. Presented at: 49th Annual Scientific Meeting of the American Headache Society; June 7-10, 2007; Chicago, IL. 3.2 (3.0) Results Patient Demographics Overall, 416 patients participated in the study and provided safety data. The mean (standard deviation [SD]) age of patients was 38.1 (7.6) years, with most patients (83%) between the ages of 18–45 years (Table 1). Most patients (94%) were white (Table 1), with a mean ± SD history of MM of 11.5±8.9 years (Table 2). The mean number of menstrual cycles in the previous 3 months with MM attacks was 2.9. The mean average length of MM was 3.2 days (Table 2). 85% of migraineurs (353/416) experienced their MM attack starting on day –2 (40%), day –1 (24%), or day +1 (21%). Figure 1. Study Design RUN-IN Single-blind No MM Repeat RUN-IN No MM 1. 2. 3. 4. Single PMP Patient excluded 166 (40) 98 (24) 89 (21) 44 (11) 19 (5) 346 (83) 70 (17) 1.8 (0.8) 0–3 103 (25) 288 (69) 25 (6) MM Double-blind phase Triptan Responsiveness Patients had tried a variety of different triptans for the acute treatment of their migraines, including almotriptan (n=79), eletriptan (n=101), frovatriptan (n=44), naratriptan (n=76), rizatriptan (n=150), sumatriptan (n=218), and zolmitriptan (n=147; Figure 3). 3 PMPs Placebo, n=161 FRV QD, n=152 (5.0 mg QD on day 1; 2.5 mg QD on days 2–6) FRV BID, n=103 (5.0 mg BID on day 1; 2.5 mg BID on days 2–6) ▪ However, during short-term preventive treatment with frovatriptan, only 5% of patients withdrew from the study because of adverse events. This percentage compares favorably with tolerability to patients’ previous acute triptan treatment, despite the higher exposure to frovatriptan during a 6-day treatment period. This research was supported by Vernalis Development Ltd.,Winnersh, UK, and Endo Pharmaceuticals Inc., Chadds Ford, PA, USA 49th Annual Scientific Meeting of the American Headache Society June 7–10, 2007 Chicago, IL This information concerns a use that has not been approved by the US Food and Drug Administration. Open-label extension phase 3 PMPs FRV BID, n=309 (5.0 mg BID on day 1; 2.5 mg BID on days 2–6) BID=twice daily; FRV=frovatriptan; MM=menstrual migraine; PMP=perimenstrual period; QD=once daily.