J Neurol (1991) 238:$66-$69
Journal of
Neurology © Springer-Verlag 1991
Subcutaneous sumatriptan in the acute treatment of migraine F.-B. M. Ensink, for the Sumatriptan International Study Group Zentrum Anaesthesiologie, Rettungs- und Intensivmedizin, Universit~it G6ttingen, Robert-Koch-Strasse 40, W-3400 G6ttingen, FRG
Summary. Two double-blind, randomized, placebo-controlled multicentre studies were carried out to assess the efficacy and tolerability of subcutaneous (s. c.) injections of 1-3 mg and 1-8 mg sumatriptan, respectively, in the acute treatment of migraine. Data are presented from a total of 519 patients. In both studies, the primary endpoint of efficacy was a reduction in headache severity from severe or moderate to mild or no headache. All doses of sumatriptan were significantly more effective than placebo in relieving symptoms, and the response appeared to be dose-related; an effective response to treatment was achieved within 30 min in 73% of patients treated with 6mg sumatriptan and 80% of patients treated with 8 mg sumatriptan s. c., compared with 22% for placebo. Sumatriptan was well tolerated and the majority of adverse events were mild and transient. The most frequent complaint was irritation and pain at the site of injection. No changes in laboratory values were noted and E C G readings were unaltered by treatment. On the basis of these results, the 6 mg subcutaneous dose has been selected for further evaluation in large-scale studies.
Key words: Sumatriptan - Subcutaneous administration Acute therapy - Migraine
Introduction Migraine is a common neurological disorder characterized by recurring headache attacks. The headache pain is usually unilateral and sometimes preceded by visual and/ or sensory disturbances in an aura. The majority of patients, however, do not experience an aura and in a small percentage of cases the headache may be bilateral. The condition is disabling to the patient and, therefore, prophylactic treatment is recommended for those experiencing frequent attacks [9]. Early studies on the subcutaneous use of sumatriptan, a 5-hydroxytryptamine (5-HT)l-like receptor agonist, indicated that it is effective in the treatment of acute migraine attacks [1, 2, 8]. Pharmacokinetic evaluation in healthy subjects showed that the drug is absorbed
quickly and efficiently [4]. This is associated with a rapid attack-aborting effect in migraine sufferers; in early open studies using 1-4 mg sumatriptan s.c., a high proportion of patients was found to gain complete recovery from their symptoms within 20-60 min of treatment [2,
8]. This paper reports two international multicentre studies carried out to evaluate further the efficacy and tolerabitity of subcutaneous sumatriptan in the acute treatment of migraine with or without aura. Both studies were placebo-controlled and investigated a range of single therapeutic doses: 1-3 mg and 1-8 mg respectively.
Patients and methods Two multicentre studies were carried out: one in Europe (The Netherlands, France, Switzerland and West Germany), the Middle East (Israel) and Canada (Study 1); and the other in the United States of America (Study 2). Both studies followed a double-blind, placebo-controlled, parallel-group design. In Study 1, patients were randomized to receive s. c. placebo, or 1, 2 or 3 mg sumatriptan. In Study 2 the same dose range was studied initially, but the range was later extended to include 4mg, 6mg and 8 mg. All patients who entered the study had at least a 12month history of migraine attacks with aura (classical migraine) or without aura (common migraine) in accordance with the International Headache Society classification [5]. They were between 18 and 60 years of age and suffered at least one and not more than six migraine attacks per month of moderate to severe intensity. The exclusion criteria comprised pregnancy or lactation, opiate/ergotamine abuse, ischaemic heart disease, hypertension and/or other serious illness. Analgesics and opiate/ergotamine were not allowed to be taken within 6 and 24 h of study treatment, respectively. Informed consent was obtained from all patients prior to their entry into the study. At the first sign of an attack, patients were asked to report to the clinic to receive a single subcutaneous injection of the trial medication. Headache severity was
$67 100
assessed 30 minutes, 1 h and 2 h after the injection, using a four-point scale:
( n = 277)
80
0, 1, 2, 3,
no pain mild pain moderate pain severe pain
If headache had not improved to grade 0 or 1 at 30 min in Study 1, a 3 mg open dose of sumatriptan was permitted, with other rescue medication from 60 min. In Study 2, rescue medication (not sumatriptan) was available from 60 min onwards. Overall functional disability was also assessed using a four-point scale: 0, 1, 2, 3,
able to work/function normally mildly impaired severely impaired required bedrest
Adverse events were monitored throughout the study. Baseline blood tests for general biochemistry and haematology were performed on arrival at the clinic and were repeated after 2 h. Pulse, blood pressure and E C G were recorded at baseline and every 10 min throughout the first 30 min and then again at 1 and 2 h. Statistics
Pairwise comparisons between treatments employed the Mantel-Haenszel chi-square test at the 5% significance level.
Results In both studies, an effective response to treatment was defined as a reduction in headache severity from moderate or severe (grade 3 or 2, respectively) to mild or none (grade 1 or 0, respectively). No significant differences were detected in the severity of headache between the groups before treatment in either study. Study 1
A planned interim analysis of 277 patients showed that all three subcutaneous doses of sumatriptan were significantly superior to placebo in relieving migraine headache (Fig. 1). In the placebo group, an effective response at 30min was recorded in 17/66 (26%) patients, compared with 33/69 (48%) in the l mg sumatriptan treatment group (P < 0.008), 38/71 (54%) in the 2mg sumatriptan group (P = 0.001), and 42/71 (59%) in the 3 m g sumatriptan group (P < 0.001). No significant differences were observed between the three sumatriptan treatment groups, although a dose-related trend was evident (Fig. 1). A second injection at 30min was required by 50/66 (76%) patients in the placebo group, 40/69 (58%) patients in the l m g sumatriptan group, 33/71 (46%) in the 2 m g group, and 30/71 (42%) patients in the 3 m g treatment group. All three doses of sumatriptan were well tolerated. Discomfort at the site of subcutaneous injection, which
60
(n= 71) p
Journal of
Neurology © Springer-Verlag 1991
Subcutaneous sumatriptan in the acute treatment of migraine F.-B. M. Ensink, for the Sumatriptan International Study Group Zentrum Anaesthesiologie, Rettungs- und Intensivmedizin, Universit~it G6ttingen, Robert-Koch-Strasse 40, W-3400 G6ttingen, FRG
Summary. Two double-blind, randomized, placebo-controlled multicentre studies were carried out to assess the efficacy and tolerability of subcutaneous (s. c.) injections of 1-3 mg and 1-8 mg sumatriptan, respectively, in the acute treatment of migraine. Data are presented from a total of 519 patients. In both studies, the primary endpoint of efficacy was a reduction in headache severity from severe or moderate to mild or no headache. All doses of sumatriptan were significantly more effective than placebo in relieving symptoms, and the response appeared to be dose-related; an effective response to treatment was achieved within 30 min in 73% of patients treated with 6mg sumatriptan and 80% of patients treated with 8 mg sumatriptan s. c., compared with 22% for placebo. Sumatriptan was well tolerated and the majority of adverse events were mild and transient. The most frequent complaint was irritation and pain at the site of injection. No changes in laboratory values were noted and E C G readings were unaltered by treatment. On the basis of these results, the 6 mg subcutaneous dose has been selected for further evaluation in large-scale studies.
Key words: Sumatriptan - Subcutaneous administration Acute therapy - Migraine
Introduction Migraine is a common neurological disorder characterized by recurring headache attacks. The headache pain is usually unilateral and sometimes preceded by visual and/ or sensory disturbances in an aura. The majority of patients, however, do not experience an aura and in a small percentage of cases the headache may be bilateral. The condition is disabling to the patient and, therefore, prophylactic treatment is recommended for those experiencing frequent attacks [9]. Early studies on the subcutaneous use of sumatriptan, a 5-hydroxytryptamine (5-HT)l-like receptor agonist, indicated that it is effective in the treatment of acute migraine attacks [1, 2, 8]. Pharmacokinetic evaluation in healthy subjects showed that the drug is absorbed
quickly and efficiently [4]. This is associated with a rapid attack-aborting effect in migraine sufferers; in early open studies using 1-4 mg sumatriptan s.c., a high proportion of patients was found to gain complete recovery from their symptoms within 20-60 min of treatment [2,
8]. This paper reports two international multicentre studies carried out to evaluate further the efficacy and tolerabitity of subcutaneous sumatriptan in the acute treatment of migraine with or without aura. Both studies were placebo-controlled and investigated a range of single therapeutic doses: 1-3 mg and 1-8 mg respectively.
Patients and methods Two multicentre studies were carried out: one in Europe (The Netherlands, France, Switzerland and West Germany), the Middle East (Israel) and Canada (Study 1); and the other in the United States of America (Study 2). Both studies followed a double-blind, placebo-controlled, parallel-group design. In Study 1, patients were randomized to receive s. c. placebo, or 1, 2 or 3 mg sumatriptan. In Study 2 the same dose range was studied initially, but the range was later extended to include 4mg, 6mg and 8 mg. All patients who entered the study had at least a 12month history of migraine attacks with aura (classical migraine) or without aura (common migraine) in accordance with the International Headache Society classification [5]. They were between 18 and 60 years of age and suffered at least one and not more than six migraine attacks per month of moderate to severe intensity. The exclusion criteria comprised pregnancy or lactation, opiate/ergotamine abuse, ischaemic heart disease, hypertension and/or other serious illness. Analgesics and opiate/ergotamine were not allowed to be taken within 6 and 24 h of study treatment, respectively. Informed consent was obtained from all patients prior to their entry into the study. At the first sign of an attack, patients were asked to report to the clinic to receive a single subcutaneous injection of the trial medication. Headache severity was
$67 100
assessed 30 minutes, 1 h and 2 h after the injection, using a four-point scale:
( n = 277)
80
0, 1, 2, 3,
no pain mild pain moderate pain severe pain
If headache had not improved to grade 0 or 1 at 30 min in Study 1, a 3 mg open dose of sumatriptan was permitted, with other rescue medication from 60 min. In Study 2, rescue medication (not sumatriptan) was available from 60 min onwards. Overall functional disability was also assessed using a four-point scale: 0, 1, 2, 3,
able to work/function normally mildly impaired severely impaired required bedrest
Adverse events were monitored throughout the study. Baseline blood tests for general biochemistry and haematology were performed on arrival at the clinic and were repeated after 2 h. Pulse, blood pressure and E C G were recorded at baseline and every 10 min throughout the first 30 min and then again at 1 and 2 h. Statistics
Pairwise comparisons between treatments employed the Mantel-Haenszel chi-square test at the 5% significance level.
Results In both studies, an effective response to treatment was defined as a reduction in headache severity from moderate or severe (grade 3 or 2, respectively) to mild or none (grade 1 or 0, respectively). No significant differences were detected in the severity of headache between the groups before treatment in either study. Study 1
A planned interim analysis of 277 patients showed that all three subcutaneous doses of sumatriptan were significantly superior to placebo in relieving migraine headache (Fig. 1). In the placebo group, an effective response at 30min was recorded in 17/66 (26%) patients, compared with 33/69 (48%) in the l mg sumatriptan treatment group (P < 0.008), 38/71 (54%) in the 2mg sumatriptan group (P = 0.001), and 42/71 (59%) in the 3 m g sumatriptan group (P < 0.001). No significant differences were observed between the three sumatriptan treatment groups, although a dose-related trend was evident (Fig. 1). A second injection at 30min was required by 50/66 (76%) patients in the placebo group, 40/69 (58%) patients in the l m g sumatriptan group, 33/71 (46%) in the 2 m g group, and 30/71 (42%) patients in the 3 m g treatment group. All three doses of sumatriptan were well tolerated. Discomfort at the site of subcutaneous injection, which
60
(n= 71) p
