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Oral Almotriptan vs Oral Sumatriptan in the Abortive Treatment of Migraine
A Double-blind, Randomized, Parallel-Group, Optimum-Dose Comparison
Egilius L. H. Spierings, MD, PhD;
Baltazar Gomez-Mancilla, MD, PhD;
Daniel E. Grosz, MD;
Clayton R. Rowland, PhD;
Fredrick S. Whaley, PhD;
Kathleen J. Jirgens
Arch Neurol. 2001;58:944-950.
ABSTRACT
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Background Almotriptan malate is a novel, selective serotonin1B/D agonist,
or triptan, developed for the abortive treatment of migraine. In double-blind,
placebo-controlled studies, it has been shown to be effective, well tolerated,
and safe.
Objective To compare the efficacy, tolerability, and safety of almotriptan with
that of the "standard triptan," sumatriptan succinate. The power calculation
of the study was based on 24-hour headache recurrence, an efficacy measure
in the abortive treatment of migraine, and on the occurrence of adverse events.
Subjects and Methods Subjects, aged between18 and 65 years, with migraine with or without
aura but otherwise healthy, were randomized to take orally either almotriptan
malate, 12.5 mg, or sumatriptan succinate, 50 mg. The medications were provided
in identical-looking capsules to ensure blinding and were taken for the treatment
of moderate or severe headache. Efficacy was determined in terms of (1) headache
relief—a decrease in pain intensity to mild or no pain; (2) headache
freedom—a decrease to no pain; (3) use of rescue medications, allowed
after 2 hours; and (4) headache recurrence—moderate or severe pain returning
within 24 hours after headache relief at 2 hours. Adverse events were collected
for 96 hours after treatment and for safety evaluation, vital signs, blood
tests, and electrocardiograms were performed at the screening and exit visits.
Results Seventy-five investigators enrolled 1255 subjects of whom 1173 were
treated (591 with almotriptan and 582 with sumatriptan). At 2 hours, almotriptan
treatment provided headache relief in 58.0% of the subjects and sumatriptan
treatment in 57.3%; headache freedom was provided by the medications in 17.9%
and 24.6%, respectively (P = .005). Rescue medications
were taken by 36.7% of the subjects in the almotriptan-treated group and by
33.2% in the sumatriptan-treated group; headaches returned to moderate or
severe intensity in 27.4% and 24.0%, respectively. Treatment-emergent adverse
events occurred in 15.2% of the subjects in the almotriptan-treated group
and in 19.4% in the sumatriptan-treated group (P
= .06); treatment-related adverse events occurred in 9.1% and 15.5% of the
subjects, respectively (P = .001), including chest
pain, which occurred in 0.3% and 2.2%, respectively (P
= .004).
Conclusions Almotriptan and sumatriptan are similarly effective in the abortive
treatment of moderate or severe migraine headache; they are also similarly
well tolerated and safe.
INTRODUCTION
ALMOTRIPTAN malate is a novel, selective serotonin1B/D agonist,
or triptan, developed for the abortive treatment of migraine.1
In double-blind, placebo-controlled studies, it has been shown to be effective,
well tolerated, and safe.2 It has a high bioavailability
of approximately 80%3 and has been shown to
provide consistent benefit across 3 attacks.4
On the basis of dose-range studies, its optimum oral dose has been determined
at 12.5 mg5; it has been studied in doses ranging
from 5 to 150 mg.6 The 12.5-mg dose is the
highest effective dose of the medication with placebo-level adverse events.7 Low occurrence of adverse event, is important in the
context of patient satisfaction and treatment compliance.
In this double-blind, randomized, parallel-group study, we compared
oral almotriptan malate, 12.5 mg, with oral sumatriptan succinate, the first
triptan on the market, in its optimum dose of 50 mg.8
Apart from the standard outcome measures related to efficacy, tolerability,
and safety, we also determined patient satisfaction as well as the effect
of treatment on quality of life and health economic outcomes. However, the
results of the latter aspects of the study will be published elsewhere.
PATIENTS AND METHODS
STUDY POPULATION
Men and women were eligible for the study if they were between 18 and
65 years, suffered from migraine with or without aura, as defined under codes
1.2 and 1.1, respectively, by the International Headache Society (IHS),9 and were otherwise healthy. They had to be of sound
mind; able to read and understand the informed consent form, written in English;
able to comply with the requirements of the study; and voluntarily consent
to it. They had to have had a history of migraine headaches for at least 6
months, with an onset before the age of 50 years, and no history of head or
neck trauma within the preceding 6 months. They also had to have had an average
of at least 2 moderate or severe migraine headaches per month during the preceding
3 months, with an interval of at least 24 hours between consecutive attacks.
The subjects could not suffer from migraine with prolonged aura (IHS
code 1.2.2), migrainous infarction (IHS code 1.6.2), hemiplegic (IHS code
1.2.3), or basilar migraine (IHS code 1.2.4). Subjects were allowed to have
other than migraine headaches, for example, tension or sinus headaches, but
had to be able to distinguish between them and their migraine headaches. Women
were required to be either menopausal or agree to avoid pregnancy and not
be nursing for the duration of the study. The nonmenopausal women had to have
used a reliable method of contraception for at least 2 months before enrolling
in the study. In addition, they had to have a negative result for a serum
pregnancy test at screening and at day 30 of the study, if applicable. Also
at screening, they were required to have a clinically acceptable physical
examination, blood tests, and electrocardiogram (ECG); the ECG was considered
clinically unacceptable if the corrected QT interval was longer than 450 milliseconds
for men or 470 milliseconds for women.
Exclusion criteria included the following: the subjects could not have
uncontrolled hypertension, defined as a diastolic blood pressure higher than
95 mm Hg or a systolic blood pressure higher than 160 mm Hg, or clinically
significant disease affecting any system but especially the cardiovascular
or gastrointestinal tract. They could not have (a history of) gastrointestinal
disease or surgery that would affect the absorption of medications taken orally
and had to be mentally stable, without significant psychiatric disease, or
have a history of substance abuse as defined by the Diagnostic
and Statistical Manual of Mental Disorders, Fourth Edition, within
the preceding year. They also could not be using opioids or tranquilizers
to the extent that, in the investigator's opinion, it would interfere with
the determination of the efficacy, tolerability, or safety of the study medications.
Preventive migraine treatment was allowed with the exclusion of monoamine
oxidase inhibitors, lithium carbonate, cyproheptadine hydrochloride, methysergide
maleate, ergotamine tartrate, and dihydroergotamine mesylate; taking of these
medications had to be discontinued at least 2 weeks before enrollment. Subjects
who were triptan naive were also excluded from the study, as well as those
with hypersensitivity to or contraindications for the use of triptans, in
particular sumatriptan, or ergots, that is, ergotamine and dihydroergotamine.
They also could not have had exposure to almotriptan or have participated
in an investigational drug or device study within 1 month before screening.
STUDY DESIGN
The subjects completed a screening visit, which included a headache
and medical history, physical examination, blood tests, and ECG, and returned
7 to 10 days later for the enrollment visit, if still eligible. They were
randomized per investigator and in blocks of 4 to take a single oral dose
of almotriptan malate, 12.5 mg, or sumatriptan succinate, 50 mg, provided
in identical-looking capsules to ensure blinding, for migraine headache with
pain of moderate or severe intensity. They were followed up by keeping a 48-hour
diary after taking the study medication and had to return for the exit visit
approximately 24 hours later for evaluation of adverse events. They had to
treat a migraine headache within 60 days of screening and the women who had
not treated a headache by day 30 had to have another serum pregnancy test.
The subjects were allowed rescue medications, excluding a triptan or
ergot, 2 hours after taking the study medication if the migraine pain had
not decreased to mild or none. They were allowed to take the second dose of
the study medication if, after relief at 2 hours as specified above, the pain
returned at moderate or severe intensity within 24 hours of treatment. They
were requested to record the appropriate information in the diary at baseline
and at 0.5, 1, 2, 4, 24, and 48 hours after taking the first dose of study
medication.
SAFETY ASSESSMENT
At the exit visit, the subjects were asked about any health problems
they had experienced since taking the study medication, which were recorded
whether or not they were considered by the investigator to be related to the
study. However, migraine-related symptoms, that is, headache, nausea, vomiting,
photophobia, and phonophobia, were not recorded as health problems and, therefore,
not as adverse events unless they were worse than usual. An adverse event
was considered serious if it (1) was fatal or life-threatening, that is, resulted
in an immediate risk of death; (2) was permanently or substantially disabling;
(3) resulted in or required intervention to prevent permanent impairment or
damage to the body; (4) required hospitalization or a prolonged hospitalization;
or (5) was a congenital abnormality or birth defect. The adverse events were
classified as mild when they did not interfere with normal functioning, moderate
when they interfered somewhat with normal functioning, or severe when they
interfered significantly with normal functioning.
EFFICACY ASSESSMENT
Subjects assessed the intensity of migraine pain at baseline as moderate
or severe and at 0.5, 1, 2, 4, 24, and 48 hours after taking the study medication
as none, mild, moderate, or severe. In doing so, they were asked to use the
following guideline: mild pain allows normal functioning; moderate pain inhibits
but does not prohibit normal functioning and does not require bed rest; severe
pain prohibits normal functioning or requires bed rest. Headache relief was
defined as a decrease in pain intensity from moderate or severe at baseline
to mild or no pain at the time of postbaseline assessment; those subjects
who achieved this degree of headache relief at 2 hours were considered responders.
Headache freedom was defined as a decrease in pain intensity from moderate
or severe at baseline to no pain at the time of postbaseline assessment. Rescue
medications were allowed 2 hours after taking the first dose of the study
medication and was defined as any medication taken for pain relief. Recurrence
was defined as an increase in pain intensity to moderate or severe within
24 hours after taking the first dose of the study medication, after relief
to mild or no pain at 2 hours.
The primary efficacy determination was headache relief at 2 hours after
taking the first dose of study medication; headache freedom was also assessed.
In addition, efficacy of the study medication for headache relief and headache
freedom was determined at 0.5 and 1 hour after taking the first dose of the
study medication and recurrence at 24 hours. The degree to which the migraine-associated
symptoms, that is, nausea, vomiting, photophobia, and phonophobia, troubled
the subjects was recorded at baseline and at 0.5, 1, and 2 hours only, in
terms of not having the symptom at all or being not, slightly, moderately,
very, or extremely bothered by it.
STATISTICAL ANALYSIS
Efficacy data were analyzed using an intent-to-treat approach in which
all randomized subjects were included who experienced moderate or severe migraine
headache, took at least 1 dose of study medication, and had at least 1 postbaseline
efficacy assessment. Carrying the last recorded observation forward whenever
this was possible was used to impute missing data, and a difference with a P value of .05 was considered statistically significant.
The proportion of subjects in each of the 2 treatment groups experiencing
headache relief or headache freedom at 0.5, 1, and 2 hours were compared using
the  2 or Fisher exact test. We also compared the proportion
of those subjects experiencing recurrence of moderate or severe pain within
24 hours and the proportion using rescue medications. Analyses adjusting for
baseline pain intensity were performed using the Cochran-Mantel-Haenszel test;
subgroup analyses were performed by sex as well.
Safety data were also analyzed using an intent-to-treat approach in
which all randomized subjects were included who experienced moderate or severe
migraine headache and took at least 1 dose of the study medication. The primary
safety end point was that of treatment-emergent adverse events, which includes
all adverse events whether or not they were considered to be related to the
study medications. The adverse events were tabulated by body system and by
disorder within each body system. They were compared between the treatment
groups by body system and by selected disorders, using the 2
or Fisher exact test.
POWER CALCULATION
The power of the study was calculated on the basis of the 24-hour headache
recurrence and occurrence of adverse events. On the basis of prior studies,
it was assumed that the 24-hour headache recurrence would be 25% for almotriptan
malate, 12.5 mg, and 35% for sumatriptan succinate, 50 mg. With the use of
a 2-sided test and  of .05, a sample of 329 responders in each group
was calculated to provide a power (1 - ß) of 0.80, to detect this
difference as statistically significant. It was projected that 70% of the
enrolled subjects would, in fact, take study medication within the 60 days
allotted and that 70% of them would respond to it, in terms of headache relief
at 2 hours. Therefore, 660 subjects were thought to be required in each of
the 2 treatment groups to obtain 329 responders in each, making a total of
1320 for the whole study. Of the 1320 subjects, 924 would then be evaluable
for efficacy analysis because they took the study medication within the allotted
time. Information about adverse events gathered from previous studies suggested
overall rates of 11% for almotriptan malate, 12.5 mg, and 20% for sumatriptan
succinate, 50 mg. The power (1 - ß) to detect this difference as
statistically significant given a total sample size of 924, that is, 462 per
treatment arm, was more than 0.95.
RESULTS
DEMOGRAPHIC CHARACTERISTICS
Seventy-five investigators (see the acknowledgment section at the end
of the article) enrolled a total of 1255 subjects, 632 in the almotriptan-treated
group and 623 in the sumatriptan-treated group (Figure 1). There were 1173 subjects who treated moderate or severe
migraine headache with the study medication, 591 in the almotriptan-treated
group and 582 in the sumatriptan-treated group. Because at least 1 postbaseline
efficacy assessment was available per subject who treated moderate or severe
migraine headache, these groups were identical to the intent-to-treat populations.
One subject in the sumatriptan-treated group had a postbaseline efficacy assessment
but did not record pain intensity at 0.5, 1, or 2 hours. This subject was
included in the intent-to-treat population but was excluded from the headache
relief, headache freedom, and headache recurrence analyses.
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Figure 1. Flowchart of the study. Almotriptan
given as almotriptan malate; sumatriptan succinate.
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Of the 591 subjects who took almotriptan, 65 (11.0%) were men and 526
(89.0%) were women; exactly the same sex distribution was seen in the 582
subjects who took sumatriptan (64 [10.9%] were men and 518 [89%] were women).
Their mean (±SD) ages were 41.2 ± 10.1 years and 40.3 ±
10.1 years, respectively. Of those in the almotriptan-treated group, 94.9%
were white, 3.9% black, and 1.2% other; these numbers were 94.7%, 4.0%, and
1.4%, respectively, for the sumatriptan-treated group. The only statistically
significant difference between the 2 groups in terms of demographics was body
weight: the subjects in the almotriptan-treated group had a mean weight of
74.5 kg and those in the sumatriptan-treated group, 72.3 kg (P = .003).
BASELINE MIGRAINE CHARACTERISTICS
The baseline migraine characteristics, that is, pain, nausea, vomiting,
photophobia, and phonophobia, for the 2 treatment groups are listed separately
in Table 1. In both treatment
groups, the baseline pain intensity was severe in approximately 33% of the
subjects, with a slightly lower proportion of men in comparison to women having
severe pain. The occurrence of migraine-associated symptoms in both treatment
groups was in agreement with what is generally seen in clinical studies. In Table 1, subjects who did not have the
symptom or were not bothered by it were classified as not having the symptom;
they were classified as having the symptom if they were slightly, moderately,
very, or extremely bothered by it.
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Table 1. Baseline Migraine Characteristics of Each Treatment Group
by Sex*
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EFFICACY
The efficacy of the study medications for headache relief and headache
freedom, as defined earlier, for the first 2 hours of the study are shown
in Figure 2. Almotriptan provided
headache relief at 2 hours in 58.0% of the subjects, compared with 57.3% for
sumatriptan; for headache freedom at 2 hours, the percentages were 17.9% and
24.6%, respectively. The differences between the 2 study medications at 0.5,
1, and 2 hours were not statistically significant, except for headache freedom
at 2 hours in favor of sumatriptan (P = .005). Adjusting
for baseline pain intensity did not alter the results and neither did the
determination of efficacy for moderate and severe pain separately and for
men and women separately.
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Figure 2. A, Graph shows the percentage
of subjects who experienced headache relief during the 2 hours after taking
1 of the 2 study medications. Subjects were given oral doses of either 12.5
mg of almotriptan malate (n = 591) or 50 mg of sumatriptan succinate (n =
581). Headache relief was defined as a decrease in pain intensity from moderate
or severe at baseline to mild or no pain. B, Graph shows the percentage of
subjects who experienced headache freedom at 2 hours after taking 1 of the
2 study medications. Headache freedom was defined as a decrease in pain intensity
from moderate or severe at baseline to no pain.
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The results of the study with regard to the migraine-associated symptoms—nausea,
vomiting, photophobia, and phonophobia—are shown separately for the
almotriptan-treated and sumatriptan-treated groups (Figure 3). If a subject was slightly, moderately, very, or extremely
bothered by an associated symptom, that subject was classified as having the
particular symptom, as opposed to not having it or not being bothered by it.
The differences between the 2 medications in reducing the migraine-associated
symptoms were not statistically significant.
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Figure 3. A, Effect of oral almotriptan
malate, 12.5 mg, on migraine-associated symptoms in the abortive treatment
of moderate or severe migraine headache at 2 hours compared with baseline.
Graph shows the percentage of subjects who experienced migraine-associated
symptoms at baseline (n = 591) and 2 hours after taking almotriptan (n = 586).
B, Effect of oral sumatriptan succinate, 50 mg, on migraine-associated symptoms
in the headache treatment of moderate or severe migraine headache at 2 hours
compared with baseline. Graph shows the percentage of subjects who experienced
migraine-associated symptoms at baseline (n = 581) and 2 hours after taking
sumatriptan (n = 570).
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Rescue medications were taken by 36.7% of the subjects in the almotriptan-treated
group and by 33.2% in the sumatriptan-treated group. Of the 343 responders
in the almotriptan-treated group, 27.4% experienced recurrence of moderate
or severe migraine headache within 24 hours, as compared with 24.0% of the
333 responders in the sumatriptan-treated group. The differences were not
statistically significant and adjusting for baseline pain intensity did not
affect these results. No statistically significant differences were noted
between the 2 treatment groups for recurrence, when determined for moderate
and severe pain separately and for men and women separately.
TOLERABILITY AND SAFETY
The frequency of occurrence of treatment-emergent and treatment-related
adverse events for the 2 groups is shown separately in Figure 4. There were no serious adverse events in either group and
no subject discontinued treatment prematurely because of adverse events. The
difference between the 2 groups for treatment-emergent adverse events was
almost statistically significant (P = .06); the difference
for the treatment-related adverse events was statistically significant in
favor of almotriptan (P = .001).
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Figure 4. Treatment-emergent and treatment-related
adverse events in subjects treated orally with either 12.5 mg of almotriptan
malate (n = 591) or 50 mg of sumatriptan succinate (n = 582) for moderate
or severe migraine headache.
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Table 2 lists the treatment-emergent
adverse events that occurred in at least 1% of the subjects in either treatment
group. The most common adverse events were nausea, dizziness, and somnolence;
the difference between the 2 groups for chest pain was statistically significant
for the almotriptan-treated group (P = .004).
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Table 2. Treatment-Emergent Adverse Events per Body System and per
Treatment Group, Occurring in at Least 1% of the Subjects*
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Finally, with regard to safety, the treatment-emergent adverse events
that involve the cardiovascular system are summarized in Table 3. The occurrence of these adverse events was very low in
both treatment groups. Also, there were no changes observed in the vital signs,
blood test results, and ECGs as recorded at screening and at the exit visits,
approximately 96 hours after taking the study medication.
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Table 3. Treatment-Emergent Adverse Events Related to the Cardiovascular
System per Treatment Group*
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ADJUSTMENTS FOR MULTIPLE COMPARISONS
As mentioned, the difference between the almotriptan-treated and sumatriptan-treated
groups for chest pain was statistically significant (P
= .004). However, there were 18 other treatment-emergent adverse events that
were reported by enough subjects to make it possible for the events to be
statistically significantly different between the 2 treatment groups, but
none of them were. Nevertheless, if there was, indeed, no difference between
the 2 groups for treatment-emergent adverse events, the probability of at
least 1 of the 19 comparisons emerging as statistically significant may be
much greater than .05. To adjust the chest pain–related P value for the other 18 treatment-emergent adverse events, a bootstrap
resampling simulation approach was used.10
Unlike the Bonferroni correction for multiple comparisons, this approach considers
the correlation between the comparisons. In 2548 of the 100 000 simulated
sets performed on the 1173 treated subjects, the P
value for at least 1 of the 19 comparisons was less than .004. This makes
the adjusted P value for the chest pain comparison
between the 2 treatment groups .03, that is, it remains statistically significant
even after the adjustment.
A similar simulation approach was used to adjust the P value of the almotriptan-sumatriptan comparison for headache freedom
at 2 hours, to account for the 5 other comparisons related to headache relief
and headache freedom at 0.5, 1, and 2 hours. The adjusted P value was .03, which means that after the adjustment, the comparison
between the 2 treatment groups for headache freedom at 2 hours also remained
statistically significant.
COMMENT
In this double-blind, randomized, parallel-group study comparing almotriptan
malate, 12.5 mg, with sumatriptan succinate, 50 mg, both administered orally,
the 2 medications were found to be similarly effective in providing relief
of migraine headache. Sumatriptan has been available for a decade and has
become the standard in abortive migraine treatment, prompting the comparison
with almotriptan. It has an extensive efficacy, tolerability, and safety record
and, therefore, lends itself well as a comparator for a novel medication in
the same class. Its optimum oral dose has been determined at 50 mg,8 which is the lowest dose with maximum therapeutic
benefit and the highest effective dose with placebo-level adverse events.7 In this study, it was compared with the optimum oral
dose of almotriptan, which has been determined to be 12.5 mg and is the highest
effective dose of the medication with placebo-level adverse events.5 With regard to almotriptan, prior studies have also
shown a particularly good duration of action of the medication, resulting
in a relatively low 24-hour headache recurrence of approximately 25%.
A total of 1173 subjects were treated in the study with no significant
differences between the 2 treatment groups for sex, age, race, and baseline
migraine characteristics. There was a statistically significant difference
between the 2 treatment groups for body weight, with the subjects in the almotriptan-treated
group on average being heavier than the subjects in the sumatriptan-treated
group. They also experienced nausea at baseline more frequently than those
in the sumatriptan-treated group did but the difference was just above the
level of statistical significance. Despite these differences to the disadvantage
of almotriptan, the 2 medications proved similarly effective as determined
by headache relief at 0.5, 1, and 2 hours after treatment and headache freedom
at 0.5 and 1 hour.
The extent to which rescue medications were taken, allowed 2 hours after
treatment, was the same in the almotriptan-treated and sumatriptan-treated
groups, that is, approximately 35%. The same was true for the 24-hour headache
recurrence, which was approximately 25% in both treatment groups. For adverse
events, nothing serious was encountered in the study and no subjects discontinued
treatment prematurely because of them. The occurrence of treatment-emergent
adverse events was the same in both groups (15%-20%). However, treatment-related
adverse events occurred more than one third less often in the almotriptan-treated
group than in the sumatriptan-treated group, a difference that was statistically
significant. In addition, chest pain reported by the subjects after taking
study medication was only a fraction in the almotriptan-treated group of what
it was in the sumatriptan-treated group.
The triptans, a pharmacological group to which both almotriptan and
sumatriptan belong, are potent arterial vasoconstrictors. They exert their
vasoconstrictor effect through stimulation of the serotonin1B receptor
for which they have a high selectivity. The serotonin1B receptor
is present particularly on the cranial, including the extracranial,11 arteries and to a much lesser extent on those in
the coronary circulation, where the serotonin2A receptor predominates.
As a result, the vasoconstriction exerted by the triptans on the coronary
arteries is only about one fourth of that exerted on the cranial arteries
and, in clinically relevant concentrations, is close to negligent.12 Nevertheless, coronary vasoconstriction is a concern
with the triptans, which is also the reason that uncontrolled hypertension
and coronary artery disease are considered contraindications for their use.
Chest pain can be a manifestation of coronary vasoconstriction; however,
it was also found to occur with a compound that is devoid of vasoconstrictor
activity but shares with the triptans high affinity for the neuronal serotonin1D receptor.13 As stated earlier, the
occurrence of chest pain was only a fraction in the almotriptan-treated group
of what it was in the sumatriptan-treated group, emphasizing the better tolerability
of almotriptan. As the relationship of chest pain to coronary vasoconstriction
is far from clear, extrapolation to safety is, therefore, unwarranted. However,
no safety issues emerged in the study in which almost 1200 subjects were treated,
half with almotriptan and half with sumatriptan, and were followed up for
up to 96 hours after treatment, with the inclusion of vitals signs and ECGs.
AUTHOR INFORMATION
Accepted for publication December 11, 2000.
Presented as an abstract at the 52nd Annual Meeting of the American
Academy of Neurology, San Diego, Calif, May 3, 2000 (Neurology. 2000;54[suppl 3]:A206), and the 42nd Annual Meeting of the American
Headache Society, Montreal, Quebec, June 24, 2000 (Headache. 2000;40:433).
We thank the following investigators and their coordinators for conducting
the study, which was paid for by Pharmacia, Kalamazoo. Jeffrey Adelglass,
MD, Dallas, Tex; Jeffrey T. Apter, MD, Princeton, NJ; Sue Barcellos, MD, Iowa
City, Iowa; Joan Ryder Benz, MD, PhD, Cedar Rapids, Iowa; Robert J. Bielski,
MD, Okemos, Mich; John A. Brose, DO, Athens, Ohio; Malcolm D. Brown, Montgomery,
Ala; Roger Cady, MD, Springfield, Mo; Harry Collins, MD, South Plainfield,
NJ; Bruce Corser, MD, Cincinnati, Ohio; Meera Dewan, MD, Omaha, Neb; William
T. Dickey, MD, Irving, Tex; Eugene A. DuBoff, MD, Denver, Colo; Michael T.
Edmond, MD, Austin, Tex; Victor A. Elinoff, MD, Endwell, NY; Arthur H. Elkind,
MD, Mount Vernon, NY; John Ervin, MD, Kansas City, Mo; James M. Ferguson,
MD, Salt Lake City, Utah; Charles M. Fogarty, MD, Spartanburg, SC; David B.
Franck, MD, Portland, Ore; Benjamin Frishberg, MD, Oceanside, Calif; Martin
Gabica, MD, Boise, Idaho ; W. Thomas Garland, MD, Lawrenceville, NJ; Norman
A. Garrison, MD, Montgomery; Craig Garver, MD, Wenatchee, Wash; Jerome Goldstein,
MD, San Francisco, Calif ; David R. Greeley, MD, Spokane, Wash; Peter M. Green,
MD, Kalamazoo; Daniel E. Grosz, MD, Northridge, Calif; John Grubbs, MD, Paducah,
Ky; James T. Hartford, MD, Cincinnati; Alan R. Hirsch, MD, Chicago, Ill; Raymond
E. Jackson, MD, Southfield, Mich; Boris Kerzner, MD, Baltimore, Md; Jack A.
Klapper, MD, Denver; Thomas C. Klein, MD, Wichita, Kan; John J. Lary, Jr,
MD, Huntsville, Ala; Gary Lee, MD, Kaysville, Utah; Mark T. Leibowitz, MD,
Beverly Hills, Calif; Robert S. Lipetz, DO, Spring Valley, Calif; Alexander
J. Lockfeld, MD, Eugene, Ore; Frank P. Maggiacomo, DO, Cranston, RI; Ninan
T. Mathew, MD, Houston, Tex; William J. McEntee, MD, Sarasota, Fla; John S.
Meyer, MD, Houston; David J. Morin, MD, Bristol, Tenn; William S. Mullican,
MD, Evansville, Ind; Robert B. Nett, MD, San Antonio, Tex; Thomas O'Barr,
Jr, MD, Marietta, Ga; John E. Pappas, MD, Lexington, Ky; Andres Patron, DO,
Hollywood, Fla; William M. Patterson, DO, Birmingham, Ala; J. Steven Poceta,
MD, La Jolla, Calif; Anthony D. Puopolo, MD, Milford, Mass; Marc Raphaelson,
MD, Frederick, Md; Jeffrey Reich, MD, New York, NY; Robert A. Riesenberg,
MD, Decatur, Ga; Mouin Sabbagh, MD, Lake Jackson, Tex; Lawrence G. Seiden,
MD, Catonsville, Md; Ram K. Shrivastava, MD, New York; Richard P. Singer,
MD, Pembroke Pines, Fla; Timothy R. Smith, MD, St Louis, Mo; Malcolm J. Sperling,
MD, Fountain Valley, Calif; Egilius L. H. Spierings, MD, PhD, Wellesley Hills,
Mass; Randall Stoltz, MD, Evansville; Herman C. Sullivan, MD, Grand Rapids,
Mich; Jerry W. Swanson, MD, Rochester, Minn; Frederick Taylor, MD, Minneapolis,
Minn; Stewart J. Tepper, MD, Seattle, Wash; Jerry Tindel, MD, Austin; Phillip
D. Toth, MD, Indianapolis, Ind; Bret J. Warner, MD, Ninety Six, SC; Alberto
Yataco, MD, Towson, Md; Kelly Yoxall, MD, Kansas City.
The Lewin Group (Meryl I. Brod, PhD, and Shoshana S. Colman, PhD), San
Francisco, Calif, critically reviewed the manuscript. Maria K. B. Spierings,
MA, provided editorial assistance. The study could not have been realized
without the willing participation of the migraineurs, to whom we express our
gratitude.
From the Department of Neurology, Brigham and Women's Hospital and
Harvard Medical School, Boston, Mass (Dr Spierings); Departments of Central
Nervous System Development (Dr Gomez-Mancilla), Health Economics (Dr Rowland
and Ms Jirgens), and Biostatistics and Data Management (Dr Whaley), Pharmacia,
Kalamazoo, Mich; and the Pharmacology Research Institute, Northridge, Calif
(Dr Grosz). Dr Spierings received honoraria (advisory board, speakers bureau)
and grants from Pharmacia (almotriptan) and GlaxoSmithKline (sumatriptan);
Drs Gomez-Mancilla, Rowland, and Whaley as well as Ms Jirgens are employees
of Pharmacia.
Corresponding author: Egilius L. H. Spierings, MD, PhD, 25 Walnut
St, Suite 102, Wellesley Hills, MA 02481-2106 (e-mail: Spierings{at}MediaOne.net).
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