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Triptan Efficacy and Time to Peak Blood Concentration (Tmax)*
Triptan Efficacy and Time to Peak Blood Concentration (Tmax)*
1.
Goadsby  PJ The scientific basis of medication choice in symptomatic migraine treatment. Can J Neurol Sci.1999;26(suppl 3):S20-S26.
2.
Osterhaus  JTGuterman  DIPlachetka  JR Healthcare resources and lost labor costs of migraine headache in the U.S. Pharmacol Econ.1992;2:67-76.
3.
Lipton  RBStewart  WFCelentano  DDReed  M Undiagnosed migraine: a comparison of symptom-based and self-reported physician diagnosis. Arch Intern Med.1992;152:1273-1278.
4.
Fishman  PBlack  L Indirect costs of migraine in a managed care population. Cephalalgia.1999;19:50-57.
5.
Silberstein  SD Migraine symptoms: results of a survey of self-reported migraineurs. Headache.1995;35:387-396.
6.
Dahlof  C How to assess patient preference of migraine treatments. Cephalagia.1999;19(suppl 24):2-5.
7.
Lipton  RBStewart  WF Acute migraine therapy: do doctors understand what patients with migraine want from therapy? Headache.1999;39(suppl 2):S20-S26.
8.
Tfelt-Hansen  PBousser  MGSolomon  S  et al Guidelines for controlled trials of drugs in migraine: first edition. Cephalalgia.1991;1:1-12.
9.
Davies  GMSantanello  NCKramer  MMatzura-Wolfe  D Determinants of patient satisfaction with migraine treatment [abstract]. Headache.1998;38:174.
10.
Boureau  FKappos  LSchoenen  JEsperancea  PAshford  E A clinical comparison of sumatriptan nasal spray and dihydroergotamine in the acute treatment of migraine. Int J Clin Pract.2000;54:281-286.
11.
Ahrens  SPFarmer  MVWilliams  DL  et al Efficacy and safety of rizatriptan wafer for the acute treatment of migraine. Cephalalgia.1999;19:525-530.
12.
Goadsby  PJFerrari  MDOlesen  J  et al Eletriptan in acute migraine: a double-blind, placebo-controlled comparison to sumatriptan. Neurology.2000;54:156-163.
13.
Klassen  AElkind  AAsgharnejad  MWebster  CLaurenza  A Naratriptan is effective and well tolerated in the acute treatment of migraine: results of a double-blind, placebo-controlled, parallel-group study. Headache.1997;37:640-645.
14.
Ryan  RKeywood  C Frovatriptan: review of efficacy in acute treatment of migraine [abstract]. Headache.2000;40:429.
15.
Spencer  CMGunasekara  NSHills  C Zolmitriptan: a review of its use in migraine. Drugs.1999;58:347-374.
16.
Spierings  ELGomez-Mancilla  BGrosz  DERowland  CRWhaley  FSJirgens  KJ Oral almotriptan vs sumatriptan in a double-blind, randomized, parallel-group study in migraine patients [abstract]. Headache.2000;40:433.
17.
McDaris  HLHutchison  J Frovatriptan: a review of overall clinical efficacy.  Poster presented at: Ninth Congress of International Headache Society; June 22-29, 1999; Barcelona, Spain.
18.
Kellstein  DELipton  RBGeetha  R  et al Evaluation of a novel solubilized formulation of ibuprofen in the treatment of migraine headache: a randomized, double-blind, placebo-controlled, dose-ranging study. Cephalalgia.2000;20:233-243.
19.
Pascual  JMunoz  RLeira  R Sumatriptan 50 mg vs zolmitriptan 2.5 mg: an open preference study in 100 migraine patients [abstract]. Headache.2000;40:423.
20.
Landy  SHMauskop  AHu  XHMarkson  LBerger  M Real world experience in migraine treatment with rizatriptan in patients previously treated by other oral triptans [abstract]. Headache.2000;40:415.
21.
Gerth  WCMannix  LKMcCarroll  KAVandormael  KZhang  QSantanello  NC Patient satisfaction with rizatriptan 10 mg vs. other triptans: head-to-head comparisons [abstract]. Headache.2000;40:408.
22.
Loder  EBoyle  DWang  L  et al Comparison of preference for Maxalt-MLT® 10 mg or Imitrex® 50 mg tablet for the acute treatment of migraine.  Poster presented at: 42nd Annual Scientific Meeting of the American Headache Society; June 23-25, 2000; Montreal, Quebec.
23.
Adelman  JULipton  RBFerrari  MDMcCarroll  KAVandormael  KLines  CR Comparison of rizatriptan vs. other triptans on a composite measure of efficacy at 2 hours: freedom from pain and associated symptoms [abstract]. Headache.2000;40:401.
Neurological Review
July 2001

Establishing a Standard of Speed for Assessing the Efficacy of the Serotonin1B/1D Agonists (Triptans)

Author Affiliations

From the Departments of Anesthesiology and Neurology and Multidisciplinary Headache Clinic, University of Pittsburgh Medical Center, Pittsburgh, Pa.

 

DAVID E.PLEASUREMD

Arch Neurol. 2001;58(7):1056-1058. doi:10.1001/archneur.58.7.1056
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.

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 class1117 (Table 1). Analgesics, in comparison, have a longer Tmax of 2 to 5 hours.

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 1.1117 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.

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Article Information

Accepted for publication February 15, 2001.

Corresponding author: Dawn A. Marcus, MD, Pain Evaluation and Treatment Institute, 4601 Baum Blvd, Pittsburgh, PA 15213 (e-mail: dawnpainmd@yahoo.com).

References
1.
Goadsby  PJ The scientific basis of medication choice in symptomatic migraine treatment. Can J Neurol Sci.1999;26(suppl 3):S20-S26.
2.
Osterhaus  JTGuterman  DIPlachetka  JR Healthcare resources and lost labor costs of migraine headache in the U.S. Pharmacol Econ.1992;2:67-76.
3.
Lipton  RBStewart  WFCelentano  DDReed  M Undiagnosed migraine: a comparison of symptom-based and self-reported physician diagnosis. Arch Intern Med.1992;152:1273-1278.
4.
Fishman  PBlack  L Indirect costs of migraine in a managed care population. Cephalalgia.1999;19:50-57.
5.
Silberstein  SD Migraine symptoms: results of a survey of self-reported migraineurs. Headache.1995;35:387-396.
6.
Dahlof  C How to assess patient preference of migraine treatments. Cephalagia.1999;19(suppl 24):2-5.
7.
Lipton  RBStewart  WF Acute migraine therapy: do doctors understand what patients with migraine want from therapy? Headache.1999;39(suppl 2):S20-S26.
8.
Tfelt-Hansen  PBousser  MGSolomon  S  et al Guidelines for controlled trials of drugs in migraine: first edition. Cephalalgia.1991;1:1-12.
9.
Davies  GMSantanello  NCKramer  MMatzura-Wolfe  D Determinants of patient satisfaction with migraine treatment [abstract]. Headache.1998;38:174.
10.
Boureau  FKappos  LSchoenen  JEsperancea  PAshford  E A clinical comparison of sumatriptan nasal spray and dihydroergotamine in the acute treatment of migraine. Int J Clin Pract.2000;54:281-286.
11.
Ahrens  SPFarmer  MVWilliams  DL  et al Efficacy and safety of rizatriptan wafer for the acute treatment of migraine. Cephalalgia.1999;19:525-530.
12.
Goadsby  PJFerrari  MDOlesen  J  et al Eletriptan in acute migraine: a double-blind, placebo-controlled comparison to sumatriptan. Neurology.2000;54:156-163.
13.
Klassen  AElkind  AAsgharnejad  MWebster  CLaurenza  A Naratriptan is effective and well tolerated in the acute treatment of migraine: results of a double-blind, placebo-controlled, parallel-group study. Headache.1997;37:640-645.
14.
Ryan  RKeywood  C Frovatriptan: review of efficacy in acute treatment of migraine [abstract]. Headache.2000;40:429.
15.
Spencer  CMGunasekara  NSHills  C Zolmitriptan: a review of its use in migraine. Drugs.1999;58:347-374.
16.
Spierings  ELGomez-Mancilla  BGrosz  DERowland  CRWhaley  FSJirgens  KJ Oral almotriptan vs sumatriptan in a double-blind, randomized, parallel-group study in migraine patients [abstract]. Headache.2000;40:433.
17.
McDaris  HLHutchison  J Frovatriptan: a review of overall clinical efficacy.  Poster presented at: Ninth Congress of International Headache Society; June 22-29, 1999; Barcelona, Spain.
18.
Kellstein  DELipton  RBGeetha  R  et al Evaluation of a novel solubilized formulation of ibuprofen in the treatment of migraine headache: a randomized, double-blind, placebo-controlled, dose-ranging study. Cephalalgia.2000;20:233-243.
19.
Pascual  JMunoz  RLeira  R Sumatriptan 50 mg vs zolmitriptan 2.5 mg: an open preference study in 100 migraine patients [abstract]. Headache.2000;40:423.
20.
Landy  SHMauskop  AHu  XHMarkson  LBerger  M Real world experience in migraine treatment with rizatriptan in patients previously treated by other oral triptans [abstract]. Headache.2000;40:415.
21.
Gerth  WCMannix  LKMcCarroll  KAVandormael  KZhang  QSantanello  NC Patient satisfaction with rizatriptan 10 mg vs. other triptans: head-to-head comparisons [abstract]. Headache.2000;40:408.
22.
Loder  EBoyle  DWang  L  et al Comparison of preference for Maxalt-MLT® 10 mg or Imitrex® 50 mg tablet for the acute treatment of migraine.  Poster presented at: 42nd Annual Scientific Meeting of the American Headache Society; June 23-25, 2000; Montreal, Quebec.
23.
Adelman  JULipton  RBFerrari  MDMcCarroll  KAVandormael  KLines  CR Comparison of rizatriptan vs. other triptans on a composite measure of efficacy at 2 hours: freedom from pain and associated symptoms [abstract]. Headache.2000;40:401.
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