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Establishing a Standard of Speed for Assessing the Efficacy of the Serotonin1B/1D Agonists (Triptans)
Dawn A. Marcus, MD
Arch Neurol. 2001;58:1056-1058.
ABSTRACT
The current International Headache Society guidelines for migraine clinical
trials recommend assessment of pain relief at 2 hours as a primary end point.
Patients, however, express a clear preference for more rapid pain relief,
with most patients defining rapid relief as occurring within 30 minutes after
drug administration. Thus, consideration should be given to establishing clinical
trial end points that more accurately reflect the preferences of patients
with migraine. In this case, assessment of pain relief at 1 hour would be
an appropriate primary end point. Using speed of relief as a criterion for
migraine drug selection also is appropriate. The migraine-specific serotonin1B/1D agonists, or triptans, are able to meet this faster relief end
point and are preferred by patients.
INTRODUCTION
The serotonin1B/1D agonists, or triptans, have revolutionized
the care of patients with migraine by providing fast, effective treatment
with few adverse effects to add to the disability of migraine. Consequently,
expectations for both the degree and speed of relief have changed for researchers,
clinicians, and patients. Headache researchers have begun to use a variety
of primary end points to better describe the efficacy of various medications,
although controversy remains regarding which end point is the most valid.1 Our understanding of the typical course of migraine
and its associated disability suggests that aborting the headache in its early
stages is clinically the most beneficial approach to preventing long-lasting
episodes of pain and disability.
Clinical trial investigators have begun to report complete migraine
pain relief instead of the traditional standard of a 50% decrease in pain
severity. In addition, in clinical trials, the expected time to pain relief
has been decreased from 4 to 2 hours, with consideration for further reductions
to 1 hour. Ultimately, the best end point will be that which is most clinically
relevant. Researchers must begin to ask patients what features of medications
are most important to them.
EPIDEMIOLOGY
Migraine affects about 10% of the adult population and causes significant
disability and economic losses. Employed migraine patients report missing
an average of 2.2 days of work per month because of migraine.2
Six or more workdays are lost yearly by 56% of women and 38% of men with migraine.3 Fishman and Black4
estimated the annual indirect costs in 1990 for employed migraine patients
at $4827 for men and $6146 for women. Direct health care costs for migraine
constitute between 0.4% and 1.7% of total national health care spending.2 Effectively treating migraine, with an effort to decrease
migraine-associated disability, is therefore important for both the patient
and society.
PATIENT PRIORITIES IN MIGRAINE TREATMENT
Migraine typically begins with mild to moderate pain that increases
in severity over several hours to reach peak severity. The painful phase of
the migraine attack persists for 6 to 12 hours in most migraine patients.
This course suggests that an ideal migraine treatment would work rapidly,
while the headache is in its milder stages, before significant levels of disability
occur.
For those with migraine, the 2 most important features of migraine medications
are providing quick relief and effectively decreasing pain.5
Dahlof6 questioned migraine patients about
desired treatment characteristics and found that rapid headache relief was
ranked as very important by 69% of patients. Patient's perception of rapid
relief was 30 minutes for 84% and 1 hour for 16%. No patient considered relief
occurring more than 1 hour after treatment as rapid. Thirty-seven percent
rated ability to return to work quickly as very important. Patients expected
to be able to return to work within 1 hour after taking a migraine medication.
Similarly, in a study by Lipton and Stewart,7
the most common reasons migraine patients reported for dissatisfaction with
migraine medications were pain relief taking too long (87%), lack of complete
pain relief (84%), and inconsistent headache response (84%). These migraine
patients reported an expectation that rapid relief of headache should occur
within 30 minutes (71%) or 1 hour (21%).
EXPECTATIONS OF MIGRAINE RESPONSE IN CLINICAL TRIALS
The International Headache Society guidelines for evaluating migraine
therapy in clinical trials recommend evaluation of headache response 2 hours
after drug administration.8 The guidelines
further recommend using the number of attacks resolved within 2 hours as a
primary end point. Interestingly, the guidelines note that the expectation
of complete headache relief within 2 hours might be unrealistic; however,
this shorter time frame was chosen to allow patients to take rescue medications
after 2 hours. These views are in sharp contrast with the expectations expressed
by patients.
Davies et al9 reported on factors that
determined patient satisfaction with rizatriptan. Complete relief of pain
within 2 hours resulted in satisfaction for 97% of patients. Only 69% of patients
who achieved partial relief of headache, with a reduction of pain from severe
or moderate to mild, were satisfied. Patients are telling us that they want
rapid, complete relief of pain and they do not feel it is unrealistic to expect
relief within 2 hours after drug administration.
MIGRAINE-SPECIFIC ACUTE CARE TREATMENTS
Effective, migraine-specific acute care medications include ergotamines
and triptans. Patients prefer triptan medications to dihydroergotamine mesylate.
Comparisons between sumatriptan succinate and dihydroergotamine have shown
better relief of pain and associated migraine symptoms with sumatriptan.10 Differences between sumatriptan and dihydroergotamine
are apparent within 45 minutes after dosing.
In general, triptans as a group are very effective in relieving both
the pain and disability associated with migraine. The onset of relief also
is faster and associated with fewer adverse effects compared with symptomatic
treatment, such as that with opioids and antiemetics. The rapid onset of action
of the triptans might be related to the rapid time to peak blood concentration
(Tmax) seen with most drugs in this class11, 12, 13, 14, 15, 16, 17
(Table 1). Analgesics, in comparison,
have a longer Tmax of 2 to 5 hours.
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Triptan Efficacy and Time to Peak Blood Concentration (Tmax)*
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Considerable data are available describing the efficacy of each triptan
compared with placebo and compared with other triptans. Results of some of
these trials are summarized in Table 1.11, 12, 13, 14, 15, 16, 17
Of note, different end points have been used in these studies, and not all
of the studies evaluated patients for complete pain relief. In addition, improvement
in functional disability is recorded differently in different studies. The
data in Table 1 reflect the percentage
of patients who reported relief of migraine-related disability within 1 and
2 hours after dosing with a triptan. In most studies, relief of functional
disability is considered to be a partial improvement to milder levels of disability.
The rizatriptan studies, however, used an end point of complete relief of
all disability. This end point addresses patient requests for complete relief.
Other studies report the average number of hours during which the patient
experienced disability; these data are not presented in Table 1 because patients prefer medications that provide relief
within 1 to 2 hours after dosing.
Differences among triptans can be seen most clearly when evaluating
patients who achieve complete pain relief. This end point also separates triptan
response from response to nonspecific symptomatic treatment. For example,
a recent controlled study evaluated the efficacy of ibuprofen in treating
nondisabling migraine in known analgesic responders.18
Relief with ibuprofen, 400 mg, exceeded that obtained with placebo. Improvement
to mild or no headache occurred within 30 minutes in 15% of the ibuprofen
group and in 12% of the placebo group, within 1 hour in 45% of the ibuprofen
group and 25% of the placebo group, and within 2 hours in 72% of the ibuprofen
group and 50% of the placebo group. Complete relief, however, was seen in
no patients in either group at 30 minutes; in 5% and 2% of the ibuprofen and
placebo groups, respectively, at 1 hour; and in only 28% and 12%, respectively,
at 2 hours. The median time to complete pain relief with ibuprofen was nearly
5 hours.
COMPARISON AMONG TRIPTANS
Although each of the triptans is highly effective, patients do report
preferences for individual drugs in this class. A comparative trial between
sumatriptan and zolmitriptan showed that patients were more likely to prefer
zolmitriptan.19 Zolmitriptan was preferred
by 44% of the patients, sumatriptan by 29%, and 27% had no preference. The
main reason patients preferred zolmitriptan, cited by 73% of patients preferring
this drug, was speed of onset of effect.
Migraine patients who have used several triptans are most likely to
prefer rizatriptan.20 Gerth et al21
reported data collected from several trials in which patients were treated
with 2 different migraine drugs and asked about their oral medication preference.
Patient satisfaction was significantly greater with rizatriptan than with
sumatriptan (P<.05), zolmitriptan (P = .05), or naratriptan hydrochloride (P
= .001). The faster time to headache relief, reported as important by most
patients, may account for this preference for rizatriptan. Similar findings
were reported by Loder et al22 in a study assessing
patient preference for rizatriptan or sumatriptan. Among the 374 patients
who expressed a preference, 57% preferred rizatriptan and 43% preferred sumatriptan
(P<.001). The principal reason patients preferred
one drug over the other was speed of relief.
In a study by Adelman et al,23 patients
were more likely to achieve complete symptom relief within 2 hours after dosing
with rizatriptan, 10 mg (complete relief in 31% of patients), than with sumatriptan
succinate, 100 mg (22%), zolmitriptan, 2.5 mg (24%), or naratriptan hydrochloride,
2.5 mg (11%).
RECOMMENDATIONS FOR NEW STANDARDS OF ASSESSING OUTCOME
Both patient and physician expectations for migraine headache relief
have changed considerably with the advent of migraine-specific drugs. Although
research studies continue to evaluate partial relief 2 or 4 hours after treatment,
patients are clearly requesting more rapid relief of symptoms, complete pain
relief, and ability to return quickly to work. Rapid relief for patients means
relief within 1 hour, suggesting that the 1-hour period is a clinically important
end point. Research end points should reflect those factors that are clinically
relevant for patients, because patient satisfaction is the ultimate goal for
every treating physician.
AUTHOR INFORMATION
Accepted for publication February 15, 2001.
From the Departments of Anesthesiology and Neurology and Multidisciplinary
Headache Clinic, University of Pittsburgh Medical Center, Pittsburgh, Pa.
Corresponding author: Dawn A. Marcus, MD, Pain Evaluation and Treatment
Institute, 4601 Baum Blvd, Pittsburgh, PA 15213 (e-mail: dawnpainmd{at}yahoo.com).
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SECTION EDITOR: DAVID E. PLEASURE, MD
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