Ranging Efficacy and Safety of Subcutaneous Sumatriptan in the Acute Treatment of Migraine
Dose
Mathew, MD; James Dexter, MD; James Couch, MD, PhD; Walter Flamenbaum, MD; Jerome Goldstein, MD; Alan Rapoport, MD; Fred Sheftell, MD; Joel Saper, MD; Stephen Silberstein, MD; Seymour Solomon, MD; Kenneth Welch, MD; on behalf of the US Sumatriptan Research Group
Ninan T.
\s=b\ Sumatriptan,
a
specific serotonin1-like receptor agonist,
studied in the acute treatment of migraine. Two hundred forty-two adult migraineurs participated in a randomized, double-blind study in which one dose of I, 2, 3, 4, 6, or 8 mg of subcutaneous sumatriptan succinate was evaluated in sequential ascending fashion. At each dose level, a placebo group was included. Efficacy was defined as reduction of moderate or severe pain to mild or no pain, without the use of rescue medication. Headache relief rates showed an approximate dose-response relationship and at 1 hour were as follows: placebo, 24%; 1 mg, 43%; 2 mg, 57%; 3 mg, 57%; 4 mg, 50%; 6 mg, 73%; and 8 mg, 80%. Relief of nausea and improvement in clinical disability were also approximately dose related. Adverse events were dose related; the most common types were injection site reactions and tingling. The 6-mg dose was as effective as the 8-mg dose but was associated with fewer adverse effects and so is optimal. (Arch Neurol. 1992;49:1271-1276) was
of migraine but may be the result of vascular and/or neurologic dysfunction.1"6 The first The between demonstration of is uncertain
cause
a
relationship
serotonin
(5-HT) and migraine was an increased urinary excretion of the main serotonin metabolite, 5-hydroxyindoleacetic acid,
some patients with acute migraine.7 A fall in platelet 5-HT levels during migraines in response to 5-HTreleasing substance present in plasma was next reported.8 Attempts to use serotonin as a treatment for acute migraine were unsuccessful because of side effects, despite some documented improvement in migraine headache.9
Four major classes of serotonin receptors exist: 5-HT], 5-HT2, 5-HT3, and 5-HT4; the 5-HT] class has several
subtypes.1012 Selective agonists and antagonists have been identified for many receptor types.13 Sumatriptan, a struc¬ tural analogue of 5-HT (Fig 1), is a selective agonist at 5-HTr-like receptor, principally found in cranial blood vessels.14"17 The diverse effects of 5-HT are due to activation of the wide variety of 5-HT receptor subtypes.9,10 In anesthetized animals, sumatriptan selectively con¬ stricts the carotid arterial
circulation, but there is no effect cerebral blood flow or blood supply to other major or¬ gans.15 Sumatriptan has also been shown to inhibit protein extravasation and neurogenic inflammation in the dura mater associated with antidromic stimulation of the on
trigeminal nerve.18 Because of the high specificity for the 5-HTi-like recep¬ tor and animal pharmacology, sumatriptan succinate was evaluated for efficacy in migraine. The objectives of this study were to determine whether a dose-response rela¬ tionship for both efficacy and safety exists. Second, we sought to determine whether pharmacokinetic variables are linearly related to dose and response. Using precise pharmacokinetic and pharmacodynamic clinical data, we aimed to find the optimal dose of sumatriptan for the acute treatment of migraine.
in
Accepted
for publication June 9, 1992. From The Houston (Tex) Headache Clinic (Dr
Mathew); Department
of Neurology, University of Missouri, Columbia (Dr Dexter); Southern Illinois University, Springfield (Dr Couch); Health and Science Research, Englewood, NJ (Dr Flamenbaum); San Francisco (Calif) Headache Clinic (Dr Goldstein); New England Center for Headache, Stamford, Conn (Drs Rapoport and Sheftell); Michigan Headache & Neurological Institute, Ann Arbor (Dr Saper); Germantown Hospital and Medical Center, Philadelphia, Pa (Dr Silberstein); Montefiore Headache Center, Bronx, NY (Dr Solomon); and Department of Neurology, Henry Ford Hospital, Detroit, Mich (Dr Welch). Presented at the IV International Headache Congress, Sydney, Australia, October 18, 1989. Reprint requests to The Houston Headache Clinic, 1213 Hermann Dr, Houston, TX 77704 (Dr Mathew).
PATIENTS AND METHODS
Population Two hundred forty-two healthy adult migraineurs were stud¬ ied at 10 centers in the United States between May 1988 and June 1989. Written informed consent was obtained after study proce¬ dures had been fully explained. Migraine (with or without aura) was diagnosed according to the criteria established by the Inter¬ national Headache Society.19 Exclusion criteria included partici¬ pation in any other clinical trial within the previous 2 weeks, acute illness immediately before treatment, history of angina, hepatic or renal impairment, uncontrolled hypertension, and pregnancy or breast-feeding. Use of analgesic or ergot-containing medication within the previous 24 hours (or 6 hours for simple analgesics) was prohibited. Migraine prophylaxis was allowed.
Study Design This was a randomized, double-blind, placebo-controlled trial. Each placebo-controlled arm of the study evaluated a different single dose of sumatriptan in ascending fashion: 1 mg followed by 2,3,4, 6, and 8 mg. At each study site, patients were randomized
Downloaded From: http://archneur.jamanetwork.com/ by a University of Pennsylvania User on 06/19/2015
Clinical Assessments Migraine symptoms were evaluated before treatment (base¬ line); at 10, 20, 30, 40, and 50 minutes; and 1, VA, 2, ZVi, 3, and
in blocks of
four, with three patients receiving sumatriptan and receiving placebo at each dose level. Each patient was treated once. Safety data for each block of four were evaluated before the patients proceeded to the next higher dose of sumatriptan. Thirty patients at each dose level received sumatriptan. Eleven patients received placebo at the 4- and 6-mg dose level, and 10 received placebo at each remaining dose level. Predose evaluations included physical examination, electrocardiography, clinical laboratory tests, vital signs, and migraine symptom assessments. Study medication was administered subcutaneously in the deltoid area. Patients remained in the clinic for
one
4 hours after the dose. Rescue medications,
4 hours after dose. Patients rated headache
by means of a fourpoint scale, where 0 indicated no pain; 1, mild pain; 2, moderate pain; and 3, severe pain. Clinical disability also was rated by pa¬ tients by means of a four-point scale, where 0 indicated able to work/function normally; 1, working ability mildly impaired; 2, working ability severely impaired; and 3, requiring bed rest. Ab¬ sence or presence of nausea, vomiting, and photophobia was noted at each time point.
excluding ergot-containing drugs, were investigator beginning 1 hour af¬
Safety Assessments Adverse events (AEs) and vital signs were assessed at the same time as migraine symptoms. Unresolved or new AEs developing after discharge were followed up the next day by telephone. All AEs beginning after dosing were recorded regardless of their re¬ lationship to the study medication. Serial electrocardiograms were recorded every 10 minutes for the first hour and 2 and 4 hours after dose. Samples for clinical laboratory tests were ob¬ tained before the dose and before discharge. Serum and urine pregnancy tests were performed in women before the dose, folîowed by a serum pregnancy test 7 days after the dose.
allowed at the discretion of the ter
dosing.
NH2
HO
5-Hydroxytryptamine (Serotonin)
Pharmacokinetic
N(CH,)2
CH,NHS02CH
Sumatriptan
Statistical
5-Methane Sulfonamide
1.—Chemical structures of serotonin
(5-hydroxytryptamine) and
statistically significant.
sumatriptan. Table
Analysis
We undertook nonparametric analyses of pain, clinical disabil¬ ity, nausea, photophobia, and vomiting. Scores were adjusted for use of rescue medications by carrying the last observation (before rescue) forward.20 Relief was prospectively defined as reduction in headache pain from severe or moderate (grade 3/2) to no or mild pain (grade 0/1) after dose without the use of rescue med¬ ication. Mantel-Haenszel and extended Mantel-Haenszel tests with two-sided values less than .05 were predetermined to be
3-[2-(Dimethylamino)ethyl]-N-Methyl-IH-lndoleFig
Sampling
Blood samples for determining sumatriptan serum concentra¬ tions were collected before the dose and 10, 20, and 30 minutes after the dose. Sumatriptan concentrations were determined by high-performance liquid chromatography with electrochemical detection, with a lower limit of quantitation of 1.0 ng/mL and a coefficient of variation of 13.2%.
1.—Consistency of Demographic Characteristics
Between
Sumatriptan and
Placebo Treatment
Croups
Sumatriptan Succinate, mg t
2
3
4
6
8
(n=30)
(n=30)
(n=30)
(n=30)
(n=30)
(n=30)
37±9.9 18-56
37.4±8.2 20-54
36.9±9.7 20-58
39.8±9.3 19-60
35.7±8.9
89
20 80
10 90
10 90
10 90
20 80
13 87
53 47 73 94
50 50 80 80
57 43 70 97
53 47 73 93
47 53 70 90
53 47 63 83
43 57 67 97
18 27 55
27 37 33
30 33 37
23 23 53
30 30 40
30 20 50
23 17 60
Placebo (n=62)
Age,
y Mean±SD
Range Sex, % of patients M F
Clinical symptoms present before treatment, % of patients Headache severity Moderate Severe Nausea
Photophobia disability, % of patients Mildly impaired (grade 1) Severely impaired (grade 2) Requiring bed rest (grade 3)
40.2 + 8.3
21-58 11
39.2±11 20-58
21-52
Clinical
Downloaded From: http://archneur.jamanetwork.com/ by a University of Pennsylvania User on 06/19/2015
100-
Placebo
12
3
4
6
Dose of
Sumatriptan Succinate, mg Fig 2.—Headache relief (defined as the percentage of patients with mild ¡solid bars] or no [open bars] pain) at 1 hour. There is an approximate dose-response relationship. Significant differences between placebo and sumatriptan succinate were seen at all closes (P
Dose
Mathew, MD; James Dexter, MD; James Couch, MD, PhD; Walter Flamenbaum, MD; Jerome Goldstein, MD; Alan Rapoport, MD; Fred Sheftell, MD; Joel Saper, MD; Stephen Silberstein, MD; Seymour Solomon, MD; Kenneth Welch, MD; on behalf of the US Sumatriptan Research Group
Ninan T.
\s=b\ Sumatriptan,
a
specific serotonin1-like receptor agonist,
studied in the acute treatment of migraine. Two hundred forty-two adult migraineurs participated in a randomized, double-blind study in which one dose of I, 2, 3, 4, 6, or 8 mg of subcutaneous sumatriptan succinate was evaluated in sequential ascending fashion. At each dose level, a placebo group was included. Efficacy was defined as reduction of moderate or severe pain to mild or no pain, without the use of rescue medication. Headache relief rates showed an approximate dose-response relationship and at 1 hour were as follows: placebo, 24%; 1 mg, 43%; 2 mg, 57%; 3 mg, 57%; 4 mg, 50%; 6 mg, 73%; and 8 mg, 80%. Relief of nausea and improvement in clinical disability were also approximately dose related. Adverse events were dose related; the most common types were injection site reactions and tingling. The 6-mg dose was as effective as the 8-mg dose but was associated with fewer adverse effects and so is optimal. (Arch Neurol. 1992;49:1271-1276) was
of migraine but may be the result of vascular and/or neurologic dysfunction.1"6 The first The between demonstration of is uncertain
cause
a
relationship
serotonin
(5-HT) and migraine was an increased urinary excretion of the main serotonin metabolite, 5-hydroxyindoleacetic acid,
some patients with acute migraine.7 A fall in platelet 5-HT levels during migraines in response to 5-HTreleasing substance present in plasma was next reported.8 Attempts to use serotonin as a treatment for acute migraine were unsuccessful because of side effects, despite some documented improvement in migraine headache.9
Four major classes of serotonin receptors exist: 5-HT], 5-HT2, 5-HT3, and 5-HT4; the 5-HT] class has several
subtypes.1012 Selective agonists and antagonists have been identified for many receptor types.13 Sumatriptan, a struc¬ tural analogue of 5-HT (Fig 1), is a selective agonist at 5-HTr-like receptor, principally found in cranial blood vessels.14"17 The diverse effects of 5-HT are due to activation of the wide variety of 5-HT receptor subtypes.9,10 In anesthetized animals, sumatriptan selectively con¬ stricts the carotid arterial
circulation, but there is no effect cerebral blood flow or blood supply to other major or¬ gans.15 Sumatriptan has also been shown to inhibit protein extravasation and neurogenic inflammation in the dura mater associated with antidromic stimulation of the on
trigeminal nerve.18 Because of the high specificity for the 5-HTi-like recep¬ tor and animal pharmacology, sumatriptan succinate was evaluated for efficacy in migraine. The objectives of this study were to determine whether a dose-response rela¬ tionship for both efficacy and safety exists. Second, we sought to determine whether pharmacokinetic variables are linearly related to dose and response. Using precise pharmacokinetic and pharmacodynamic clinical data, we aimed to find the optimal dose of sumatriptan for the acute treatment of migraine.
in
Accepted
for publication June 9, 1992. From The Houston (Tex) Headache Clinic (Dr
Mathew); Department
of Neurology, University of Missouri, Columbia (Dr Dexter); Southern Illinois University, Springfield (Dr Couch); Health and Science Research, Englewood, NJ (Dr Flamenbaum); San Francisco (Calif) Headache Clinic (Dr Goldstein); New England Center for Headache, Stamford, Conn (Drs Rapoport and Sheftell); Michigan Headache & Neurological Institute, Ann Arbor (Dr Saper); Germantown Hospital and Medical Center, Philadelphia, Pa (Dr Silberstein); Montefiore Headache Center, Bronx, NY (Dr Solomon); and Department of Neurology, Henry Ford Hospital, Detroit, Mich (Dr Welch). Presented at the IV International Headache Congress, Sydney, Australia, October 18, 1989. Reprint requests to The Houston Headache Clinic, 1213 Hermann Dr, Houston, TX 77704 (Dr Mathew).
PATIENTS AND METHODS
Population Two hundred forty-two healthy adult migraineurs were stud¬ ied at 10 centers in the United States between May 1988 and June 1989. Written informed consent was obtained after study proce¬ dures had been fully explained. Migraine (with or without aura) was diagnosed according to the criteria established by the Inter¬ national Headache Society.19 Exclusion criteria included partici¬ pation in any other clinical trial within the previous 2 weeks, acute illness immediately before treatment, history of angina, hepatic or renal impairment, uncontrolled hypertension, and pregnancy or breast-feeding. Use of analgesic or ergot-containing medication within the previous 24 hours (or 6 hours for simple analgesics) was prohibited. Migraine prophylaxis was allowed.
Study Design This was a randomized, double-blind, placebo-controlled trial. Each placebo-controlled arm of the study evaluated a different single dose of sumatriptan in ascending fashion: 1 mg followed by 2,3,4, 6, and 8 mg. At each study site, patients were randomized
Downloaded From: http://archneur.jamanetwork.com/ by a University of Pennsylvania User on 06/19/2015
Clinical Assessments Migraine symptoms were evaluated before treatment (base¬ line); at 10, 20, 30, 40, and 50 minutes; and 1, VA, 2, ZVi, 3, and
in blocks of
four, with three patients receiving sumatriptan and receiving placebo at each dose level. Each patient was treated once. Safety data for each block of four were evaluated before the patients proceeded to the next higher dose of sumatriptan. Thirty patients at each dose level received sumatriptan. Eleven patients received placebo at the 4- and 6-mg dose level, and 10 received placebo at each remaining dose level. Predose evaluations included physical examination, electrocardiography, clinical laboratory tests, vital signs, and migraine symptom assessments. Study medication was administered subcutaneously in the deltoid area. Patients remained in the clinic for
one
4 hours after the dose. Rescue medications,
4 hours after dose. Patients rated headache
by means of a fourpoint scale, where 0 indicated no pain; 1, mild pain; 2, moderate pain; and 3, severe pain. Clinical disability also was rated by pa¬ tients by means of a four-point scale, where 0 indicated able to work/function normally; 1, working ability mildly impaired; 2, working ability severely impaired; and 3, requiring bed rest. Ab¬ sence or presence of nausea, vomiting, and photophobia was noted at each time point.
excluding ergot-containing drugs, were investigator beginning 1 hour af¬
Safety Assessments Adverse events (AEs) and vital signs were assessed at the same time as migraine symptoms. Unresolved or new AEs developing after discharge were followed up the next day by telephone. All AEs beginning after dosing were recorded regardless of their re¬ lationship to the study medication. Serial electrocardiograms were recorded every 10 minutes for the first hour and 2 and 4 hours after dose. Samples for clinical laboratory tests were ob¬ tained before the dose and before discharge. Serum and urine pregnancy tests were performed in women before the dose, folîowed by a serum pregnancy test 7 days after the dose.
allowed at the discretion of the ter
dosing.
NH2
HO
5-Hydroxytryptamine (Serotonin)
Pharmacokinetic
N(CH,)2
CH,NHS02CH
Sumatriptan
Statistical
5-Methane Sulfonamide
1.—Chemical structures of serotonin
(5-hydroxytryptamine) and
statistically significant.
sumatriptan. Table
Analysis
We undertook nonparametric analyses of pain, clinical disabil¬ ity, nausea, photophobia, and vomiting. Scores were adjusted for use of rescue medications by carrying the last observation (before rescue) forward.20 Relief was prospectively defined as reduction in headache pain from severe or moderate (grade 3/2) to no or mild pain (grade 0/1) after dose without the use of rescue med¬ ication. Mantel-Haenszel and extended Mantel-Haenszel tests with two-sided values less than .05 were predetermined to be
3-[2-(Dimethylamino)ethyl]-N-Methyl-IH-lndoleFig
Sampling
Blood samples for determining sumatriptan serum concentra¬ tions were collected before the dose and 10, 20, and 30 minutes after the dose. Sumatriptan concentrations were determined by high-performance liquid chromatography with electrochemical detection, with a lower limit of quantitation of 1.0 ng/mL and a coefficient of variation of 13.2%.
1.—Consistency of Demographic Characteristics
Between
Sumatriptan and
Placebo Treatment
Croups
Sumatriptan Succinate, mg t
2
3
4
6
8
(n=30)
(n=30)
(n=30)
(n=30)
(n=30)
(n=30)
37±9.9 18-56
37.4±8.2 20-54
36.9±9.7 20-58
39.8±9.3 19-60
35.7±8.9
89
20 80
10 90
10 90
10 90
20 80
13 87
53 47 73 94
50 50 80 80
57 43 70 97
53 47 73 93
47 53 70 90
53 47 63 83
43 57 67 97
18 27 55
27 37 33
30 33 37
23 23 53
30 30 40
30 20 50
23 17 60
Placebo (n=62)
Age,
y Mean±SD
Range Sex, % of patients M F
Clinical symptoms present before treatment, % of patients Headache severity Moderate Severe Nausea
Photophobia disability, % of patients Mildly impaired (grade 1) Severely impaired (grade 2) Requiring bed rest (grade 3)
40.2 + 8.3
21-58 11
39.2±11 20-58
21-52
Clinical
Downloaded From: http://archneur.jamanetwork.com/ by a University of Pennsylvania User on 06/19/2015
100-
Placebo
12
3
4
6
Dose of
Sumatriptan Succinate, mg Fig 2.—Headache relief (defined as the percentage of patients with mild ¡solid bars] or no [open bars] pain) at 1 hour. There is an approximate dose-response relationship. Significant differences between placebo and sumatriptan succinate were seen at all closes (P
