Sumatriptan nasal spray for the acute treatment of migraine

The introduction of the selective serotonin-1 (5HT₁) receptor agonist sumatriptan has expanded the range of therapeutic options for painful and often debilitating migraines. Both the subcutaneous and oral formulations of sumatriptan are effective in the treatment of headache and other migraine symptoms, including nausea, photophobia, and phonophobia.^1-6 Sumatriptan (6 mg) administered subcutaneously alleviated headache in over 80% of patients within 2 hours of dosing.^1-4 Sumatriptan (100 mg) administered orally alleviated headache in about 70% of patients within 4 hours of dosing.^5,6 Across studies,^1-6 placebo relief rates 2 hours and 4 hours postdose were about 30%.

For patients whose migraine-associated nausea and vomiting render the use of oral medication impractical or for patients who prefer not to use an injectable form of migraine drug, and intranasal form may provide a more attractive and useful treatment option. The results of early European studies⁷ evaluating sumatriptan nasal spray (1, 5, 10, 20, and 40 mg) suggest that the 10-, 20-, and 40-mg doses are each more effective than placebo at alleviating migraine headache and associated symptoms, but that the 40-mg dose does not confer additional therapeutic benefit relative to 10 mg or 20 mg. We report the first double-blind, parallel-group, single-attack studies in the United States to evaluate the efficacy and tolerability of sumatriptan nasal spray (20 mg or 10 mg) compared with placebo in the acute treatment of migraine.

Methods. Patients. Men or women (aged ≥18 and≤65 years) with a ≤1-year history of migraine with or without aura diagnosed according to International Headache Society criteria⁸ and eligible for the studies. Patients must have had one to six migraine attacks per month during the 2 months prior to screening. Patients with Raynaud's syndrome, Prinzmetal's angina, a history suggestive of cerebrovascular pathology, ischemic heart disease, or uncontrolled hypertension were excluded. Women of child-bearing potential not using adequate contraception, pregnant women, and breast-feeding women were excluded. All patients provided written, informed consent prior to participation in a study.

Procedures. Each patient administered sumatriptan nasal spray(10 mg or 20 mg) or placebo for one migraine attack in one of two double-blind, randomized, parallel-group studies. The same protocol, approved by an institutional review board for each of the 54 sites (27 sites per study), was followed in each study.

Screening procedures, conducted during a migraine-free period, included medical history and physical examinations (including vital sign assessments), 12-lead ECGs, and clinical laboratory tests (hematology, blood chemistry, and urinalysis). Patients meeting study eligibility criteria returned to the study site for a second visit, during which they were randomized to treatment(2:1:1 sumatriptan 20 mg:sumatriptan 10 mg:placebo), issued study medication, and instructed in the use of patient diaries. Patients were asked to use study medication to treat a single moderate or severe migraine attack at home during the next 8 weeks. The use of ergotamine-containing medications or subcutaneous sumatriptan was not permitted during the 24-hour period before of after study treatment. Patients were not permitted to take MAO inhibitors, serotonin reuptake inhibitors, or lithium during the study. Patients were instructed not to take rescue medication during the first 120 minutes after any study drug treatment.

Immediately before and 15, 30, 60, 90, and 120 minutes after dosing with study drug, patients rated headache severity (0 = no pain, 1 = mild pain, 2 = moderate pain, 3 = severe pain); the presence/absence of nausea, vomiting, phonophobia, and photophobia; and clinical disability (0 = able to work/function normally, 1 = working ability mildly impaired, 2 = working ability severely impaired, 3 = requires bed rest). Patients also recorded the time to meaningful relief of migraine (a subjective interpretation measured with a stopwatch started at dosing) through 120 minutes after dosing. Unlike headache relief, which was rated on a 4-point scale, meaningful relief was a subjective, non-scaled measurement determined by patients as the time when any combination of relief of headache and associated migraine symptoms became meaningful to them.

Patients who experienced headache relief (defined as a reduction of moderate or severe pain to mild or no pain) 120 minutes after dosing, who did not use rescue medication, and who experienced recurrence (a return or a significant worsening of their headache within the next 22 hours) were eligible to take a second (identical) dose of study drug. Patients taking the second dose rated headache severity 1 and 2 hours after this dose.

Adverse events were defined as any untoward medical occurrence, drug-related or not, that worsened or occurred after study drug administration. Adverse events were recorded by the clinician, who queried patients about them during weekly telephone calls. Clinical laboratory tests and ECGs were repeated as clinically indicated during the follow-up clinic visit after the patient had treated a migraine.

Data analysis. The primary efficacy endpoint was headache relief, defined as a reduction in pain severity from moderate (2) or severe(3) to none (0) or mild (1) 120 minutes after the first administration of study drug. Headache relief 15, 30, 60, and 90 minutes postdose was also assessed. Other efficacy measures, statistically tested at 120 minutes postdose, included the percentages of patients pain-free; the percentages of patients with nausea, vomiting, photophobia, phonophobia, and no or mild clinical disability; the percentage of patients experiencing meaningful relief; and the median time to meaningful relief. Between-group differences in headache relief rates (no or mild pain); pain-free rates; clinical disability(normal or mildly impaired); presence/absence of nausea, vomiting, photophobia, and phonophobia; and percentage of patients with meaningful relief were tested using the van Elteren, Fisher's exact, and Cochran-Mantel-Haenszel tests.

The median time to meaningful relief among patients achieving meaningful relief was tabulated, but not statistically analyzed. Similarly, the percentage of patients taking a second dose of study medication to treat recurrence and the percentage of patients experiencing relief after the second dose of study medication were examined. However, no statistics were performed on these data because patients were not re-randomized to treatment for the second dose.

The primary safety measures were the incidence of adverse events and the results of clinical laboratory tests (which were performed only if clinically indicated). The numbers of patients per treatment group experiencing adverse events were tabulated.

Data from the two studies were not combined for statistical analysis of efficacy or safety data. All statistical tests were two-sided. The significance level for all statistical tests was prospectively set at α≤ 0.05.

The studies were powered to detect differences between doses of sumatriptan and placebo, but not to detect differences between doses of sumatriptan. Approximately 50 patients per treatment group were required for power 0.80 to detect differences between the placebo group and the sumatriptan groups assuming a dichotomous efficacy response variable with 65% success for active treatments and 35% for placebo. In order to compile a more complete safety profile for sumatriptan nasal spray, approximately 400 patients per study were to be enrolled using a 2:1:1 randomization scheme (20 mg:10 mg:placebo).

Results. Patient characteristics. Nine hundred twenty-six (926) patients enrolled in the studies, 845 of whom received study medication (409 in study 1 and 436 in study 2). Data from one patient (study 1) who withdrew and failed to return a diary card were not included in the efficacy analyses (n = 408 for study 1 and 436 for study 2); data from all 845 patients were included in the safety analyses.

Demographics and patient characteristics were similar between groups and between studies (table 1). The majority of patients were Caucasian, female, and aged approximately 40 years. Most patients suffered from migraine without aura. Twenty-seven percent (27%) of patients in study 1 and 30% of patients in study 2 took migraine prophylactic medications during the study period. The most frequently used prophylactic medications were propranolol (used by 5% of patients in study 1 and 9% in study 2), amitriptyline (used by 8% of patients in study 1 and 6% in study 2), and verapamil (used by 5% of patients in each study).

Headache relief. Predose headache severity was scored as moderate or severe (2 or 3) by all patients. Two hours after dosing, headache relief was experienced by 62 to 63% of patients in the sumatriptan 20-mg groups and 43 to 54% of patients in the sumatriptan 10-mg groups compared with 29 to 35% of placebo-treated patients (figure 1;p < 0.05 sumatriptan 10 mg or 20 mg versus placebo in study 1 and 20 mg versus placebo in study 2). Sumatriptan nasal spray 20 mg was more effective than placebo at relieving headache beginning 15 minutes postdose in study 2 and 60 minutes postdose in study 1 (p < 0.05; seefigure 1). Headache relief rates did not systematically vary according to sex or migraine type (with aura versus without aura). However, because of the small number of men and the small number of patients with migraine with aura in the studies, definitive conclusions cannot be drawn.

Two hours after dosing, 31 to 32% of patients in the sumatriptan 20-mg groups and 20 to 23% of patients in the sumatriptan 10-mg groups compared with 4 to 20% of placebo-treated patients reported complete headache relief(no pain; p < 0.05 sumatriptan 20 mg and 10 mg versus placebo for study 2).

Patient-defined meaningful relief. Onset of patient-defined meaningful relief occurred by 120 minutes post-dose in 50 to 59% of patients in the sumatriptan 20-mg groups and 38 to 51% of patients in the sumatriptan 10-mg groups compared with 21 to 31% of placebo-treated patients (p< 0.05 sumatriptan 10 mg and 20 mg versus placebo in both studies). In study 1, the median time to meaningful relief among patients achieving meaningful relief in the sumatriptan 20-mg group (n = 120) was 69 minutes, in the sumatriptan 10-mg group (n = 54) was 64 minutes, and in the placebo group (n = 31) was 69 minutes. In study 2, the median time to meaningful relief among patients achieving meaningful relief in the sumatriptan 20-mg group (n = 125) was 51 minutes, in the sumatriptan 10-mg group (n = 41) was 58 minutes, and in the placebo group (n = 23) was 84 minutes.

Clinical disability. Predose clinical disability scores were 2(severely impaired) or 3 (requiring bed rest) for 37 to 50% of patients in each treatment group in both studies. Two hours after dosing, clinical disability scores were reported as 0 (normal) or 1 (mild impairment) in 72 to 74% of patients in the sumatriptan 20-mg groups and 56 to 68% of patients in the sumatriptan 10-mg groups compared with 47 to 58% of placebo-treated patients (p < 0.05 sumatriptan 20 mg versus placebo for both studies; figure 2).

Other migraine symptoms. The percentage of patients with predose nausea, vomiting, photophobia, and phonophobia was similar between groups in each study (see table 1). Two hours after dosing in both studies, sumatriptan nasal spray 20 mg compared with placebo reduced the incidence of nausea, photophobia, and phonophobia (p< 0.05; see table 1); sumatriptan nasal spray 10 mg compared with placebo reduced the incidence of nausea (p < 0.05; see table 1). The infrequent occurrence of vomiting in these studies precluded meaningful statistical comparisons.

Relief of recurrent headache. The percentages of patients who achieved headache relief 120 minutes postdose and used a second dose of study drug to treat a mild, moderate, or seven recurrent headache within the next 22 hours were 32% in the sumatriptan 20-mg groups, 43 to 46% in the sumatriptan 10-mg groups, and 34 to 55% of patients receiving placebo. Although patients were not re-randomized for the second dose, summary statistics were calculated: Relief of mild, moderate, or severe recurrent headache 120 minutes after the second dose of study drug occurred in 63% to 88% of patients in the sumatriptan 20-mg groups, 62% to 65% of patients in the sumatriptan 10-mg groups, and 39% to 58% of placebo-treated patients (seetable 1).

Safety evaluations. Adverse events reported in more than two patients in any treatment group after one dose of study medication are listed in table 2 according to the dose taken prior to the onset of the event. The most frequently reported adverse event was taste disturbance (bad, bitter, or unpleasant taste), reported by more patients in the sumatriptan groups than in the placebo groups. With the exception of taste disturbance, the adverse event profile of both doses of sumatriptan nasal spray was similar to that of placebo. The incidence of chest symptoms with active treatment was similar to the incidence with placebo. Chest tightness, pressure, or heaviness was reported after a single dose by one placebo patient, one sumatriptan 10 mg patient, and one sumatriptan 20 mg patient in study 1; no patient in study 2 reported chest tightness, pressure, or heaviness. Administration of a second dose of sumatriptan nasal spray did not appear to confer an increased risk of adverse events relative to a single administration. No serious adverse events were reported in either of the studies.

No clinically meaningful post-treatment changes in clinical laboratory evaluations were observed in either of the studies.

Discussion. The results of these two double-blind studies demonstrate that sumatriptan nasal spray is an efficacious, well-tolerated treatment for migraine. In each study, approximately two-thirds of patients treated with sumatriptan nasal spray 20 mg experienced headache relief at 2 hours postdose. Onset of relief occurred as early as 15 minutes with the 20-mg dose (study 2). Similarly, nausea, photophobia, and phonophobia were alleviated in the majority of patients 2 hours after dosing with sumatriptan nasal spray 20 mg. Although this study was not designed or powered to detect differences between doses of sumatriptan, data for many of the efficacy variables, including headache severity and clinical disability, demonstrate dose-related trends in which the 20-mg dose is associated with higher efficacy rates. In addition, although the 10-mg dose was significantly more effective than placebo at relieving headache, it did not differ from placebo in ameliorating photophobia, phonophobia, or nausea (with the exception of nausea in study 2). The dose-related trends in efficacy data were similar across studies.

The results of these studies are consistent with data from two European dose-ranging studies⁷ in which sumatriptan nasal spray(1, 5, 10, 20, or 40 mg) was administered as a single dose via one nostril or a divided dose via both nostrils. Headache relief rates 120 minutes after the 20-mg dose were 78% in the one-nostril study and 74% in the two-nostril study. Across the two studies, the 20-mg dose was most consistently effective at alleviating clinical disability and associated migraine symptoms, although the 10-, 20- and 40-mg doses were each often statistically superior to placebo. The reason for the slightly higher efficacy rates for the 20-mg dose in the European studies (conducted in France, Germany, Norway, Finland, Sweden, and Ireland) compared with the US studies described here is unknown. The placebo response rates in the European study were also slightly higher(35% and 42%) 120 minutes after dosing than in the present study. Possibly, cultural differences in perception and reporting of symptoms contribute to these discrepancies.

The maximal efficacy rates in this study are consistent with those reported in studies with oral sumatriptan; the 4-hour efficacy rates for oral sumatriptan^6,9-12 are similar to the 2-hour efficacy rate with sumatriptan nasal spray in the present studies. For example, Nappi et al⁹ reported that oral sumatriptan 100 mg relieved headache by 2 hours postdose in 51% of patients given one dose and by 4 hours postdose in 71% of patients given one or two doses. In another study,¹⁰ headache relief 4 hours after the first dose was experienced by 71% of patients treated with 100 mg oral sumatriptan compared with 38% of patients treated with placebo. By comparison, subcutaneous sumatriptan, which may be associated with slightly higher maximal efficacy rates than oral sumatriptan, produces headache relief in more than 80% of patients within 2 hours of dosing.^1,2

In the present studies, a second dose of study drug was used within 24 hours of initial dosing to treat recurrence in about one-third of patients in the 20-mg groups. This finding is consistent with data obtained with the oral and subcutaneous formulations of sumatriptan, which are associated with recurrence rates ranging from 34 to 43%.^1,2,13 Headache recurrence has also been reported to occur with other migraine medications.^14,15 Because recurrence is defined inconsistently across sumatriptan studies, as well as across studies involving other migraine medications, it is difficult to compare recurrence rates across studies and drugs. The mechanism of recurrence has not been determined, although it may be related to the relatively short half-lives of antimigraine drugs relative to the usual 4- to 72-hour duration⁸ of a migraine attack.

The treatment of recurrence with a second nasal spray appeared to be effective in alleviating recurrent headache in the present studies, although the number of patients taking a second nasal spray for headache recurrence was small. These data are consistent with studies showing that the oral form of sumatriptan is effective in the treatment of recurrence. Cady et al.¹³ reported the oral sumatriptan (100 mg) relieved moderate or severe headache recurring after treatment with subcutaneous sumatriptan in up to 81% of patients compared with 27% of placebo-treated patients.

The safety profile of sumatriptan nasal spray, like its efficacy profile, was favorable and consistent with the safety profile of sumatriptan tablets.^5,6 With the exception of taste disturbance, which was reported more frequently in the sumatriptan groups compared with placebo, the pattern and incidence of adverse events were similar between active and placebo treatments. Administration of a second dose of sumatriptan nasal spray was not associated with an increased frequency of adverse events and thus does not appear to confer an increased risk of adverse events relative to a single administration.

In summary, sumatriptan nasal spray (20 mg, 10 mg) was effective and well-tolerated in the acute treatment of migraine in two multicenter studies. The intranasal form of sumatriptan may be particularly well suited for patients who desire a rapid onset of relief but prefer not to use an injectable form of medication or for patients whose migraine-associated vomiting renders the use of an oral medication impractical. The intranasal form of sumatriptan may prove to be especially convenient to administer at home, at work, and while traveling.