Headache - Well Care Pharmacy

Treatment of Acute Migraine With
Subcutaneous Sumatriptan
Roger K. Cady, MD; Jeanette K. Wendt, MD; John R. Kirchner, MD;
John F. Rothrock, MD; Harold Skaggs, Jr, MD
Joseph D. Sargent, MD;
Sumatriptan succinate, a 5-HT1D receptor agonist, constricts human cranial
arteries. Two parallel-group trials for treatment of acute migraines were conducted in the United States. Adult patients were randomized and given either 6 mg of
sumatriptan succinate subcutaneously (n 734) or placebo (n 370). At 1 hour,
sumatriptan was significantly more effective than placebo in reducing moderate
or severe headache pain to mild or no pain (70% vs 22%), in completely relieving
headaches (49% vs 9%), and in improving clinical disability (76% vs 34%).
Sumatriptan also reduced nausea and photophobia significantly better than
placebo. Patients with residual migraines received another injection; those who
had originally received sumatriptan received either a second active injection
(n 187) or placebo (n 178), while those who had received placebo received a
second placebo injection (n 335). Statistical evidence for benefit of second
sumatriptan injection is absent. Adverse events associated with sumatriptan
were tingling, dizziness, warm-hot sensations, and injection-site reactions. Sumatriptan is effective and well tolerated in patients with acute migraine.
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(JAMA. 1991;265:2831-2835)
EIGHT million Americans have mi¬
Sufferers often experience
two or more incapacitating attacks ev¬
ery month, causing considerable disrup¬
tion to both work and leisure time.2"4 ßBlockers, calcium channel antagonists,
and antidepressant drugs are some¬
times used for prophylaxis. Current
therapies for acute migraine include er¬
got derivatives, analgesics, and antiemetics. The effectiveness of existing
rescue treatments for migraines is in¬
consistent, and the side effects of the
treatments may be intolerable.
The pathogenesis of migraine is not
well understood. Dilation of cranial
blood vessels is thought to play an im¬
portant role.5,6 Serotonin (5-HT) is a po¬
tent vasoconstrictor and is effective in
treating migraines, but its unpleasant
side effects prevent its routine use.7"9
The brain has three classes of 5-HT
receptors: 5-HT„ 5-HT2, and 5-HT3. The
5-HT\ class is further subdivided; stimu¬
lation of the 5-HT1D receptors causes
graines.1
From the
Shealy Institute for Comprehensive Health
Care, Springfield, Mo (Dr Cady); Department of Neurology, Health Science Center, University of Arizona, Tucson (Dr Wendt); the Migraine Treatment Clinic, Omaha,
Neb (Dr Kirchner); Headache and Internal Medicine
Research Center, Menninger, Topeka, Kan (Dr Sargent); Department of Neurology, University of California
at San
Diego Medical Center (Dr Rothrock); Neurology
Section, Center for Clinical Research, Austin, Tex (Dr
Skaggs); on behalf of the US Sumatriptan Research
Group.
Dr Cady owns stock in Glaxo Pharmaceuticals Inc.
Reprint requests to Shealy Institute for Comprehensive Health Care, 1328 E Evergreen St, Springfield, MO
65803 (Dr Cady).
vasoconstriction, specifically in the cra¬
nial blood vessels in a variety of animal
species, including man.10"12 Sumatriptan
succinate is a specific 5-HT1D agonist.13
In animals, sumatriptan also blocks
plasma extravasation, which may be
part of the migraine pathogenesis.14
Sumatriptan has been studied in
small, controlled clinical trials by the
subcutaneous, intravenous, and oral
routes.15"19 We
now
report the results of
identical, large-scale, multicenter
(61 total sites), randomized, doubleblind, placebo-controlled studies that
show the efficacy and tolerability of su¬
matriptan in the treatment of patients
two
with acute migraines.
METHODS
Otherwise healthy adults were eligi¬
ble for enrollment in these studies be¬
tween May and November 1989. Mi¬
graines were diagnosed using a 1-year
history ofclassic migraine (with aura) or
common migraine (without aura) and
the criteria established by the Interna¬
tional Headache Society.20 Written, in¬
formed consent
was
obtained from all
patients. The protocol and consent form
were approved by an institutional re¬
view board for each clinic.
History and results of physical exami¬
nation, 12-lead electrocardiogram, and
routine clinical laboratory tests were
recorded at patient screening. Patients
with hepatic or renal impairment, histo-
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ry of ischémie heart
disease, Raynaud's
syndrome, uncontrolled hy¬
pertension, those who had previously
been treated with sumatriptan, and
those who were pregnant, were using
inadequate contraception, or were lactating were excluded.
disease
or
STUDY DESIGN-PROTOCOL
Patients presenting to the clinic with
acute migraines gave information on
headaches, concomitant symptoms, and
clinical disability. Headaches were ver¬
bally rated by patients using a scale
from 0 through 3, where 0 indicated no
pain; 1, mild pain; 2, moderate pain; and
3, severe pain. Patients had to have
moderate (grade 2) or severe (grade 3)
headaches in order to be treated. Use of
opioids or ergotamine within 24 hours or
simple analgesics within 6 hours of
study-drug administration disqualified
the patient. Long-term prophylactic
medications for migraine were not rea¬
sons for disqualification.
Qualified patients (n=1104) were
randomly assigned to 6 mg plus 6 mg of
sumatriptan succinate, 6 mg of suma¬
triptan succinate plus placebo, or place¬
bo plus placebo, according to a random¬
ization schedule generated prior to the
trial and administered based on the
chronological order that patients pre¬
sented for treatment (Fig 1). Each dose
was administered as a 0.5-mL subcuta¬
neous injection over the deltoid muscle
of the left or right arm. Absence of pain
(grade 0) 1 hour after the first injection
disqualified the patient from receiving
the second injection. The second dose
was given to evaluate whether remedication would provide additional efficacy
if the first dose was not effective or if
partial relief was achieved. Rescue
therapy was administered at the discre¬
tion of the investigator if migraine per¬
sisted 1 hour after the second dose. Pa¬
tients could use their usual rescue
medications, such as aspirin, acetamin¬
ophen, meperidine hydrochloride, and
promethazine hydrochloride, but ex¬
cluding ergotamines.
Efficacy Measurements
Severity of headaches was rated by
patients at 10, 20, 30, 40, 50, 60, 90, and
120 minutes after each dose. Pain relief
prospectively defined as reduction
of moderate or severe headache pain
(grade 2 or 3) to mild or no headache pain
(grade 1 or 0). Mean pain scores and
summed pain intensity differences
scores are also reported.21,22 Patients
who received rescue medication were
defined as treatment failures.
Clinical disability and presence or ab¬
sence of nausea, vomiting, and photo¬
phobia were assessed on the same
schedule as headaches. Clinical disabil¬
ity was rated by patients using the fol¬
lowing scale: 0 indicated the ability to
work and function normally; 1, working
ability mildly impaired; 2, working abili¬
ty severely impaired; and 3, bed rest
required. After discharge and for 48
hours after receiving treatment, pa¬
tients kept a diary of headaches and of
use of rescue medications.
was
Safety Assessments
Physical examinations and routine
clinical laboratory tests were per¬
formed before treatment and prior to
discharge. Vital signs (heart rate and
blood pressure) were measured every
30 minutes after each dose until dis¬
charge from the clinic. Adverse events
were recorded throughout the in-clinic
treatment period and in the diary
Double-blind
2:1 Randomization
(n=1104)
(n=370)
Nonparametric analyses of pain, clin¬
ical disability, nausea, vomiting, and
photophobia were used. The last effica¬
cy score prior to rescue medication was
carried forward to subsequent time
points. The P values were computed for
each time point using Mantel-Haenszel
and extended Mantel-Haenszel tests.
All tests were two-sided, with P<.05
prospectively defined as statistically
significant. There was no adjustment of
P values to account for multiplicity of
testing; reported P values were usually
far smaller than those defining statisti¬
cal significance.
(n=734)
Yes
Yes
Allocation
per Initial
None
(n=35)
Randomization
None
Placebo
I
(n=364)
(n=335)
6 mg of Sumatriptan
Succinate
(n=187)
Placebo
(n=178)
Fig 1 .—Randomization and disposition of study subjects in large-scale, double-blind studies of subcutane¬
sumatriptan succinate in acute migraines. Subjects who were not pain free at 1 hour received a second
dose of placebo or sumatriptan according to the initial randomization.
ous
Table 1—Consistency of Demographic Characteristics Between Placebo and
Treatment Groups in Each Clinical Trial
Sumatriptan Succinate
Study 2
Study 1
period.
Statistical Analysis
6 mg of Sumatriptan
Succinate
Placebo
6 mg of Sumatriptan
Succinate (n=384)
(n 190)
39.8 ±9.6
Characteristics
Age, y*
Sex
M
Clinical
Placebo
6 mg of Sumatriptan
Placebo
Succinate (n=350)
(n 180)
39.6 ±9.7
40 ±9.8
37.7 ±10
88
86
89
92
46
49
49
84
48
79
85
93
94
=
=
12
symptoms present at pretreatment
Headache severity
Moderate (grade 2)
Severe (grade 3)
Nausea
Photophobia
Vomiting
Clinical disability
Mildly impaired (grade 1 )
Severely impaired (grade 2)
Requires bed rest (grade 3)
51
83
93
12
19
32
46
42
18
19
37
31
50
*Age is shown as mean ± SEM; other data are percent of patient population.
RESULTS
Demographic characteristics and
baseline migraine symptoms were com¬
parable between the two studies and
among all sites and treatment groups
(Table 1). Therefore, the combined re¬
sults from all patients and both studies
are presented herein.
Migraine Relief: First Dose
Sumatriptan provided rapid relief of
migraine pain. It was significantly more
effective than placebo in treating head¬
ache pain at every point from 10 minutes
to 1 hour after treatment (P<.001) (Fig
2). At 1 hour, 515 (70%) of 734 patients
who had received a single dose of suma¬
triptan reported mild pain (grade 1) or
no pain (grade 0) compared with 81
(22%) of 370 patients who had received
placebo (P<.001). Of these, 356 (49%) of
734 patients who had received suma¬
triptan were completely pain free
(grade 0) compared with 35 (9%) of 370
patients who had received placebo
(P<.001). Of the 356 patients who were
pain free at 1 hour, 351 (99%) were still
pain free at 2 hours.
Mean pain scores for patients receiv-
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ing sumatriptan at 10 minutes were sig¬
nificantly lower than those for patients
receiving placebo and remained lower
throughout the entire observation peri¬
od (at 1 hour they were 0.91 vs 2.09;
P<.001). The summed pain intensity
differences scores at 1 hour were signifi¬
cantly higher in patients receiving su¬
matriptan compared with placebo
(P<.001).
Migraine Relief: Second Dose
Of the 734 patients who initially
re¬
ceived sumatriptan, 178 received a sec-
Table 2. —Patients Using Rescue Medications in
Placebo and Sumatriptan Succinate Treatment
Groups*
Treatment
Groups,
No.
_(%)_
Sumatriptan
Succinate
Placebo
(n 370)
145
734)
(20)t
218
(59)
306
389
445
483
(42)t
(53)t
(61 )t
(66)t
296
313
324
329
(80)
(85)
(88)
(89)
_(n
In clinic only
Time after treatment, h
8
16
24
48
=
=
*Data are combined for two identical trials. Number
of patients receiving rescue medication was cumulative
throughout the 48-hour period.
tSumatriptan succinate was significantly better than
placebo (P<.001).
sumatriptan administration, fewer pa¬
reported nausea or light intoler¬
ance compared with patients receiving
placebo. At 1 hour, 43% of sumatriptantreated patients had photophobia com¬
pared with 76% of placebo-treated pa¬
tients (P<.001). Twenty-seven percent
of patients receiving sumatriptan had
nausea at 1 hour compared with 51% of
patients receiving placebo (P<.001)
(Fig 3). Beginning 20 minutes after
treatment, more sumatriptan-treated
patients reported normal or slightly im¬
paired working ability than did placebotreated patients (P<.001).
tients
Fig 2. Headache relief was defined as the percentage of patients with mild or no pain from 10 to 60 minutes
after the first dose of sumatriptan succinate (n 734) or placebo (n 370) in trials of subcutaneous
sumatriptan for acute migraine. All patients had moderate or severe migraines at baseline. There was a
significant difference (P<.001) between the sumatriptan and placebo groups for both mild and no pain at
every point in time.
=
=
—
100
Rescue Medication
During the clinic period, 20% of suma¬
triptan-treated patients received res¬
cue medication compared with 59% of
placebo-treated patients (P<.001) (Ta¬
ble 2). However, within 24 hours, 61% of
sumatriptan-treated patients and 88%
of placebo-treated patients took rescue
medication (P<.001). Throughout the
diary period,
tients took
more
rescue
placebo-treated pa¬
medications (Table
2).
10 20 30 40 50 60
10 20 30 40 50 60
10 20 30 40 50 60
Minutes After First Dose
Fig 3.—Effects of sumatriptan succinate on symptoms associated with acute migraines. The data shown are
the percentage of patients who received sumatriptan (n 734) compared with placebo (n 370) and who
had nausea (left panel), photophobia (center panel), and improvement in clinical disability (right panel) at the
times shown. Sumatriptan was significantly more effective than placebo where indicated by single asterisks
(P<.001) or double asterisks (P<.03). Hatched bars indicate placebo; solid bars, 6 mg of sumatriptan
=
=
succinate.
ond dose of placebo, and 187 received a
second dose of 6 mg of sumatriptan suc¬
cinate. There was no statistical evi¬
dence for differences in pain variables or
associated symptoms between one and
two doses of sumatriptan (P>.15 for
comparison of 6 mg plus 6 mg of suma¬
triptan succinate vs 6 mg of sumatriptan
succinate plus placebo). A comparison
at 2 hours of sumatriptan-treated pa¬
tients (one or two active doses) with
placebo-treated patients, prior to any
rescue medication, revealed that 81% of
those receiving sumatriptan had mi¬
graine pain relief compared with 34% of
those receiving placebo (P<.001).
Associated Migraine Symptoms:
First Dose
Most patients reported nausea and
photophobia at presentation for treat¬
ment
(Table 1). Within 20 minutes of
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Duration of Complete Migraine
Pain Relief
Of the 734 sumatriptan-treated pa¬
tients, 69% (511/734) were pain free at
discharge compared with 22% (80/370)
of placebo-treated patients (P<.001).
Of the sumatriptan-treated patients,
250 (34%) of 734 remained completely
pain free for 24 hours compared with 40
(11%) of 370 of placebo-treated patients.
Note that these results are in spite of
the greater use of rescue medication by
placebo- than sumatriptan-treated
patients.
Safety Results
Vital sign measurements and clinical
laboratory test results were similar be¬
fore and after treatment for all groups.
Seven patients (six sumatriptan-treat¬
ed and one placebo-treated) withdrew
from the study before receiving a sec¬
ond dose because of adverse events.
One hundred ninety-seven placebotreated patients (53%) experienced 462
adverse events (1.25 adverse events per
patient) compared with 622 sumatrip¬
tan-treated patients (85%) who experi¬
enced 2275 adverse events (3.1 adverse
events per patient). Significantly fewer
placebo-treated patients had adverse
events that were considered by the in¬
vestigator to be drug related (156 [79%]
of 197 placebo-treated patients com¬
pared with 600 [96%] of 622 sumatrip¬
tan-treated patients [P<.001]). Ad¬
verse events were described as severe
in 34 (17%) of 197 placebo-treated pa¬
tients and in 122 (20%) of 622 sumatrip¬
tan-treated patients.
Table 3 shows the
adverse
incidence of 1%
occurring
or more in the sumatriptan-treated pa¬
tients. Most adverse events began with¬
in minutes of the injection and lasted
less than 1 hour.
events
at
specific
an
COMMENT
Sumatriptan rapidly reduces the se¬
verity and duration of acute migraine.
Pain scores analyzed by four methods
(mean pain score, percentage of pa¬
tients achieving a 0 or 1 pain score, per¬
centage of patients who were pain free,
and summed pain intensity differences
scores) consistently showed sumatrip¬
tan to be more effective than placebo in
relieving moderate or severe mi¬
graines. Sumatriptan also produced sig¬
nificant improvement in clinical disabil¬
ity scores, nausea, and photophobia. A
second injection at 1 hour was not asso¬
ciated with significantly more relief of
migraine or associated symptoms. A
secondary measure of sumatriptan's ef¬
ficacy was the comparison of rescue
medication use between treatment
groups. Overall, 88% of placebo-treated
patients received rescue medication
within 24 hours compared with 61% of
sumatriptan-treated patients. This in¬
dicates both the need to evaluate the
duration of action of a single dose and to
define a multiple-dose regimen. Howev¬
er, rescue medications were taken at
the patient's discretion. It was not un¬
common for patients to self-medicate
with rescue medication in anticipation
of the return of headache or associated
symptoms, in spite of being pain free.
Significantly more adverse events oc¬
curred following treatment with suma¬
triptan than placebo. Concern whether
this unblinds the trial must be consid¬
ered. Since patients were treated only
once, which limited their exposure to
study medication, and since adverse
events and efficacy parameters were re¬
ported by the patient, it is unlikely that
Table 3.—Percent of Adverse Events by Body System
Controlled Clinical Trials of Sumatriptan Succinate*
Category Reported by
6 mg of
Placebo
Cardiovascular
Pulsating sensation
Flushing
Hypertension
Ear, nose, and throat
Throat symptoms
Disease: nasal cavity and/or sinuses
Disturbance of hearing
Sumatriptan
Succinate
(n=370)
(n 547)
0.3
2.4
0.8
0.7
6.6
0.7
0.5
3.3
0.5
0.9
=
at Least 1% of Patients in
6 mg
Succinate
(n 187)
=
0.5
8.0
1.6
1.6
Eye
Visual disturbance(s)
Gastrointestinal
Nausea and/or vomiting
Abdominal discomfort
Injection-site reactions
Miscellaneous
Pressure sensation
Feeling of heaviness
Chest symptoms
Jaw symptoms
Mouth and teeth
Disorder of mouth and/or tongue
Musculoskeletal
Weakness
Neck pain and/or stiffness
Feeling of tightness
6 mg of
+
Sumatriptan
1.6
12.4
1.3
58.7
20.3
0.8
23.8
1.6
7.1
7.5
1.1
62.6
7.3
5.3
5.5
1.6
5.3
4.6
Myalgia
1.8
4.3
5.9
1.6
Muscle
1.1
0.5
0.5
6.8
4.0
9.1
Drowsiness-sedation
2.2
2.7
Dizziness-vertigo
Malaise-fatigue
Feeling strange
4.3
Disturbance of taste
Burning sensation
Prickling sensation
Numbness
3.0
0.3
Tingling
cramp(s)
Neurological
Anxiety
Migraine
Cold sensation
Warm-hot sensation
Headache
Tight feeling in head
Hot and cold sensations
4.8
0.5
0.3
5.1
0.8
0.3
3.2
0.5
1.1
2.2
2.7
0.9
10.2
2.1
3.0
0.5
3.5
13.5
9.6
10.8
0.3
0.3
2.0
12.8
2.7
2.2
1.6
0.8
0.7
2.1
Respiratory
Dyspnea
Skin
0.5
Erythema
Sweating
*Treatment groups are amalgamated into three groups; all placebo-treated patients, those receiving
of 6 mg of sumatriptan succinate, and those receiving 6 mg + 6 mg of sumatriptan succinate.
patients introduced bias into the study
results.
In contrast to other migraine trials,
the rigorous International Headache
Society entry criteria were used to es¬
tablish the diagnosis of migraine. A sim¬
ple four-point pain scale has practical
advantages, and the data, which were
analyzed by four different methods,
yielded consistent results. Reproducibility between both studies and among
all sites and all four analyses validates
this technique.
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4.8
11.8
a
total dose
Most currently available rescue mi¬
graine therapies fail to provide consis¬
tent pain relief and are associated with
potentially intolerable side effects. Sim¬
ple analgesics are frequently used to
treat migraines, often with metoclopramide hydrochloride because of gastric
stasis or vomiting during the attack.23"26
Metoclopramide can cause acute dystonic reactions, particularly in young
adults.27 Naproxen and anthranilic acid
are more
effective than placebo in re¬
but the adverse ef-
ducing migraines,
fects of these nonsteroidal anti-inflam¬
matory drugs are well known.28"32
Parenteral narcotics are frequently
used in emergency departments, but
these may exacerbate the nausea and
vomiting seen with migraine and can
obscure neurological differential diag¬
noses. Narcotics also have abuse poten¬
tial and usually require that the patient
remain under observation by the clini¬
cian after administration of the drug.
Sumatriptan treats headache- and mi¬
graine-associated
nausea,
suggesting
that concomitant analgesic and antiemetic drugs may be unnecessary.
Ergotamine has been used extensive¬
ly for many years, although few place¬
bo-controlled studies have demon¬
strated its superiority to placebo.33 Dihydroergotamine mesylate given intra¬
venously with prochlorperazine edisylate or metoclopramide aborts severe or
intractable migraines, although there is
a high rate of side effects.34,35 The side
effects of ergotamines include nausea
and vomiting, tiredness, tingling, chest
pain, light-headedness, rebound head-
aches, and peripheral vasoconstriction.
In addition, the nonselective vasocon-
strictive actions may cause both coro¬
nary and peripheral artery spasms, pos¬
sibly leading to gangrene, angina, and
acute myocardial infarction.S6J1
The structure of sumatriptan is simi¬
lar to serotonin, but it is different from
the ergot alkaloids. These trials pro¬
vided no evidence that sumatriptan has
the same serious adverse events as ergotamine. This may be due to the selec¬
tive pharmacological properties of su¬
matriptan compared with ergotamines.
We conclude that sumatriptan is an
effective treatment for patients with
acute migraine. A significant reduction
in headaches, clinical disability, nausea,
and photophobia occurs within minutes
of a subcutaneous injection, with lasting
effects for up to 24 hours.
This study was supported by a grant from Glaxo
Pharmaceuticals Inc.
We wish to acknowledge the other members of
the US Sumatriptan Research Group who contrib¬
uted to the conception, conduct, analysis of data,
and
writing
following:
of the
manuscript, including the
Clinical Investigators.—C. Camak Baker, MD;
William Bauer, MD; Barry Baumel, MD; Harvey
Blumenthal, MD; Richard B. Brobyn, MD; Walter
Brown, MD; Gregory Collins, MD; James Couch,
MD, PhD; Roger Curran, MD; James Dexter, MD;
Seymour Diamond, MD; Kathleen Digre, MD; Ar¬
thur Elkind, MD; Walter Flamenbaum, MD; James
H. Francis, MD; Daniel Freking, MD; Srini Govindan, MD; Randall Hawkins, MD; Robert L. Hazelrigg, MD; David Hubbard, MD; R. Terry Jackson,
MD; Gary Jay, MD; Jack Klapper, MD; Jennifer S.
Kriegler, MD; Benjamin Levy, MD; Jonathan
Licht, MD; Ralph J. Luciani, DO; Herbert Markley, MD; Charlotte McCutchen, MD; John Stirling
Meyer, MD; David Miller, DO; Ken Moore, MD;
Richard Moyer, MD; Philip O'Carroll, MD; Richard
Pantera, MD; Kenneth Peters, MD; John Porter,
MD; Somayaji Ramamurthy, MD; Alan Rapoport,
MD; George Rederich, MD; Barna Richards, MD;
Carl H. Sadowsky, MD; Richard P. Singer, MD;
Glen Solomon, MD; Seymour Solomon, MD; Wil¬
liam Speed, MD; Egilius Spierings, MD; Stuart
Stark, MD; Andrew Thieneman, MD; Michael M.
Tuchman, MD; Gary Tunell, MD; Scott Tyler, MD;
Eric Wall, MD; and Dewey Ziegler, MD.
Glaxo Research Group.—Margaret Asby; Mi¬
chael Busch, PhD; Bill Clements, MS; Carolyn Dav¬
enport; Randy Davis; Sandra DeBussey; Anthony
Fox, MD, PhD; Donna Gutterman, PharmD; Bar¬
bara Kirkhart; Lois Paulsgrove; Sally Schnitz; Rob¬
in Waymer; Chris Webster; and Mark Zimmerman,
PhD.
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