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Table 1. 
Antimigraine Mechanisms of the 5-HT1B/1D Receptor Agonists*
Antimigraine Mechanisms of the 5-HT1B/1D Receptor Agonists*6,15
Table 2. 
Comparison of Efficacy of Approved and Investigational Oral Triptans at Most Commonly Used Doses*
Comparison of Efficacy of Approved and Investigational Oral Triptans at Most Commonly Used Doses*34,28,30,40,41,31,39,32,35,37,29,36,42,27
1.
Hamel  E Current concepts of migraine pathophysiology. Can J Clin Pharmacol.1999;6(suppl A):9A-14A.
2.
Moskowitz  MA Neurogenic versus vascular mechanisms of sumatriptan and ergot alkaloids in migraine. Trends Pharmacol Sci.1992;12:307-311.
3.
Goadsby  PJ Mechanisms and management of headache. J R Coll Physicians Lond.1999;33:228-234.
4.
Hanko  JHardebo  JEKahrstrom  JOwman  CSundler  F Calcitonin gene-related peptide is present in mammalian cerebrovascular nerve fibres and dilates pial and peripheral arteries. Neurosci Lett.1985;57:91-95.
5.
Zawadzki  JVFurchgott  RFCherry  P The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by substance P. Fed Proc.1981;40:689.
6.
Hargreaves  RJShepheard  SL Pathophysiology of migraine: new insights. Can J Neurol Sci.1999;26(suppl 3):S12-S19.
7.
May  AShepheard  SLKnorr  M  et al Retinal plasma extravasation in animals but not in humans: implications for the pathophysiology of migraine. Brain.1998;121:1231-1237.
8.
Thomsen  LLOlesen  J The autonomic nervous system and the regulation of arterial tone in migraine. Clin Auton Res.1995;5:243-250.
9.
Olesen  JThomsen  LLIversen  H Nitric oxide is a key molecule in migraine and other vascular headaches. Trends Pharmacol Sci.1994;15:149-153.
10.
Johnson  KWPhebus  LACohen  ML Serotonin in migraine: theories, animal models and emerging therapies. Prog Drug Res.1998;51:219-244.
11.
Humphrey  PPFeniuk  WPerren  MJBeresford  IJMSkingle  MWhalley  ET Serotonin and migraine. Ann N Y Acad Sci.1990;600:587-598.
12.
Hamel  E The biology of serotonin receptors: focus on migraine pathophysiology and treatment. Can J Neurol Sci.1999;26(suppl 3):S2-S6.
13.
De Vries  PVillalon  CMSaxena  PR Pharmacological aspects of experimental headache models in relation to acute antimigraine therapy. Eur J Pharmacol.1999;375:61-74.
14.
Storer  RJGoadsby  PJ Microiontophoretic application of serotonin (5HT)1B/1D agonists inhibits trigeminal cell firing in the cat. Brain.1997;120:2171-2177.
15.
Goadsby  PJ Serotonin receptors and the acute attack of migraine. Clin Neurosci.1998;5:18-23.
16.
Pauwels  PJ Na(+)-dependent metabolic coupling upon 5-HT1B receptor activation by sumatriptan and related agonists. Receptors Channels.1998;5:367-373.
17.
Read  SJManning  PMcNeil  CJHunter  AJParsons  AA Effects of sumatriptan on nitric oxide and superoxide balance during glyceryl trinitrate infusion in the rat: implications for antimigraine mechanisms. Brain Res.1999;847:1-8.
18.
Stepien  AChalimoniuk  MStrosznajder  J Serotonin 5HT1B/1D receptor agonists abolish NMDA receptor-evoked enhancement of nitric oxide synthase activity and cGMP concentration in brain cortex slices. Cephalalgia.1999;19:859-865.
19.
Longmore  JRazzaque  ZShaw  D  et al Comparison of the vasoconstrictor effects of rizatriptan and sumatriptan in human isolated cranial arteries: immunohistological demonstration of the involvement of 5-HT1B-receptors. Br J Clin Pharmacol.1998;46:577-582.
20.
Longmore  JHargreaves  RJBoulanger  CM  et al Comparison of the vasoconstrictor properties of the 5-HT1D-receptor agonists rizatriptan (MK-462) and sumatriptan in human isolated coronary artery: outcome of two independent studies using different experimental protocols. Funct Neurol.1997;12:3-9.
21.
Maassen VanDenBrink  AReekers  MBax  WAFerrari  MDSaxena  PR Coronary side-effect potential of current and prospective antimigraine drugs. Circulation.1998;98:25-30.
22.
Williamson  DJShepheard  SLHill  RGHargreaves  RJ The novel antimigraine agent rizatriptan inhibits neurogenic dural vasodilation and extravasation. Eur J Pharmacol.1997;328:61-64.
23.
Durham  PLRusso  AF Regulation of calcitonin gene-related peptide secretion by a serotonergic antimigraine drug. J Neurosci.1999;19:3423-3429.
24.
Cumberbatch  MJWilliamson  DJMason  GSHill  RGHargreaves  RJ Dural vasodilation causes a sensitization of rat caudal trigeminal neurones in vivo that is blocked by a 5-HT1B/1D agonist. Br J Pharmacol.1999;126:1478-1486.
25.
Goadsby  PJHoskin  KL Serotonin inhibits trigeminal nucleus activity evoked by craniovascular stimulation through a 5HT1B/1D receptor: a central action in migraine? Ann Neurol.1998;43:711-718.
26.
Cumberbatch  MJHill  RGHargreaves  RJ Rizatriptan has central antinociceptive effects against durally evoked responses. Eur J Pharmacol.1997;328:37-40.
27.
Not Available Axert tablets.  In: Medical Economics Inc, eds. Physicians' Desk Reference. Montvale, NJ: Medical Economics Co Inc; 2000:1148-1151.
28.
Pharmacia Corp Axert tablets prescribing information.  Available at: http://www.axert.com. Accessed July 13, 2001.
29.
Bomhof  MPaz  JLegg  NAllen  CVandormael  KPatel  Kand the Rizatriptan-Naratriptan Study Group Comparison of rizatriptan 10 mg vs naratriptan 2.4 mg in migraine. Eur Neurol.1999;42:173-179.
30.
Deleu  DHanssens  Y Current and emerging second-generation triptans in acute migraine therapy: a comparative review. J Clin Pharmacol.2000;40:687-700.
31.
Dooley  MFaulds  D Rizatriptan: a review of its efficacy in the management of migraine. Drugs.1999;58:699-723.
32.
Dulli  DA Naratriptan: an alternative for migraine. Ann Pharmacother.1999;33:704-711.
33.
Goadsby  PJFerrari  MDOlesen  J  et al Eletriptan in acute migraine: a double-blind, placebo-controlled comparison to sumatriptan. Neurology.2000;54:156-163.
34.
Not Available Imitrex tablets.  In: Medical Economics Company Inc, eds. Physicians' Desk Reference. Montvale, NJ: Medical Economics Co Inc; 2000:1204-1208.
35.
Klassen  AElking  DAsgharnejad  MWebster  CLaurenza  Afor the Naratriptan S2WA3001 Study Group 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.
36.
Kramer  MSMatzura-Wolfe  DPolis  A  et al A placebo-controlled crossover study of rizatriptan in the treatment of multiple migraine attacks. Neurology.1998;51:773-781.
37.
Mathew  NTAsgharnejad  MPeykamian  MLaurenza  Afor the Naratriptan S2WA3003 Study Group Naratriptan is effective and well tolerated in the acute treatment of migraine: results of a double-blind, placebo-controlled, crossover study. Neurology.1997;49:1485-1490.
38.
Not Available Maxalt tablets.  In: Medical Economics Company Inc, eds. Physicians' Desk Reference. Montvale, NJ: Medical Economics Co Inc; 2000:1822-1826.
39.
Perry  CMMarkham  A Sumatriptan: an updated review of its use in migraine. Drugs.1998;55:889-922.
40.
Pfaffenrath  VCunin  GSjonell  GPrendergast  S Efficacy and safety of sumatriptan tablets (25 mg, 50 mg, and 100 mg) in the acute treatment of migraine: defining the optimum doses of oral sumatriptan. Headache.1998;38:184-190.
41.
Spencer  CMGunasekara  NSHills  C Zolmitriptan: a review of its use in migraine. Drugs.1999;58:347-374.
42.
Spierings  ELHGomez-Mancilla  BGrosz  DERowland  CRWhaley  FSJirgens  KJ Oral almotriptan vs oral sumatriptan in the abortive treatment of migraine. Arch Neurol.2001;58:944-950.
43.
Not Available Zomig tablets.  In: Medical Economics Company Inc, eds. Physicians' Desk Reference. Montvale, NJ: Medical Economics Co Inc; 2000:5878-5900.
44.
Fox  AW Comparative tolerability of oral 5-HT1B/1D agonists. Headache.2000;40:521-527.
45.
Diener  HCKaube  HLimmroth  V Antimigraine drugs. J Neurol.1999;246:515-519.
46.
Tepper  SJDonnan  GADowson  AJBomhof  MAMElkind  AMeloche  J A long-term study to maximize migraine relief with Zomig. Curr Med Res Opin.1999;15:254-271.
47.
Tfelt-Hansen  PRyan  RE Oral therapy for migraine: comparisons between rizatriptan and sumatriptan: a review of four randomized, double-blind clinical trials. Neurology.2000;55(suppl 2):S19-S24.
48.
Pascual  JFalk  RMPiessens  F  et al Consistent efficacy and tolerability of almotriptan in the acute treatment of multiple migraine attacks: results of a large, randomized, double-blind, placebo-controlled study. Cephalalgia.2000;20:588-596.
49.
Tepper  SJ Frovatriptan: widening therapeutic options in acute migraine.  Paper presented at: International Headache Congress Satellite Symposium; June 24, 1999; Barcelona, Spain.
50.
Deleu  DHanssens  Y Profiles of 5-HT1B/1D agonists in acute migraine with special reference to second generation agents. Acta Neurol Belg.1999;99:85-95.
Neurological Review
July 2002

Mechanisms of Action of the 5-HT1B/1D Receptor Agonists

Author Affiliations

From the New England Center for Headache, Stamford, Conn (Drs Tepper, Rapoport, and Sheftell); the Department of Neurology, Yale University School of Medicine, New Haven, Conn (Drs Tepper and Rapoport); and the Department of Psychiatry, New York Medical College, Valhalla (Dr Sheftell). Drs Tepper, Rapoport, and Sheftell are consultants for GlaxoSmithKline, Merck, AstraZeneca, and Pharmacia; conduct research for GlaxoSmithKline, Merck, AstraZeneca, Pharmacia, Allergan, Elan, and OrthoMcNeill; and are on the speakers bureau for GlaxoSmithKline, Merck, and AstraZeneca. Dr Rapoport is also a consultant for Abbott, Pfizer, Forest Laboratories, Elan, and Bristol-Myers Squibb. Dr Sheftell is also a consultant for Pfizer.

 

DAVID E.PLEASUREMD

Arch Neurol. 2002;59(7):1084-1088. doi:10.1001/archneur.59.7.1084
Abstract

Recent studies of the pathophysiology of migraine provide evidence that the headache phase is associated with multiple physiologic actions. These actions include the release of vasoactive neuropeptides by the trigeminovascular system, vasodilation of intracranial extracerebral vessels, and increased nociceptive neurotransmission within the central trigeminocervical complex. The 5-HT1B/1D receptor agonists, collectively known as triptans, are a major advance in the treatment of migraine. The beneficial effects of the triptans in patients with migraine are related to their multiple mechanisms of action at sites implicated in the pathophysiology of migraine. These mechanisms are mediated by 5-HT1B/1D receptors and include vasoconstriction of painfully dilated cerebral blood vessels, inhibition of the release of vasoactive neuropeptides by trigeminal nerves, and inhibition of nociceptive neurotransmission. The high affinity of the triptans for 5-HT1B/1D receptors and their favorable pharmacologic properties contribute to the beneficial effects of these drugs, including rapid onset of action, effective relief of headache and associated symptoms, and low incidence of adverse effects.

The pathophysiology of migraine is fairly well understood, and evidence supports contributory roles of both neural and vascular mechanisms. The manifestation of headache in migraineurs is probably associated with activation of the trigeminovascular system, followed by the release of vasodilatory neuropeptides. Changes in circulating levels of the neurotransmitter serotonin (5-HT) are characteristic of migraine and may contribute to the pathogenesis of the disorder. Recent progress in understanding the pathophysiology of migraine includes the identification of the physiologic roles of vasoactive neuropeptides associated with migraine and the characterization of 5-HT receptor subtypes.

Increased understanding of the pathophysiology of migraine has led to the development of improved migraine treatments such as the 5-HT1B/1D receptor agonists, collectively known as triptans. The emergence of the triptans has revolutionalized the management of migraine by providing options for the highly selective stimulation of 5-HT1B/1D receptors, while reducing or eliminating unwanted activity at other receptor subtypes, thus improving therapeutic tolerability. This article focuses on the mechanisms of action of the triptans in relation to current concepts of the pathophysiology of migraine and the clinical role of these drugs in the management of patients with migraine.

PATHOPHYSIOLOGY OF MIGRAINE

The manifestation of headache in migraineurs has been attributed to activation of the sensory trigeminovascular system and the subsequent release of vasoactive neuropeptides.1 In the genetically susceptible patient, activation of the trigeminovascular system can be initiated by a variety of triggers, including stress, certain foods or drugs, odors, trauma, and changes in sleep habits. The release of vasoactive substances from trigeminal nerve terminals in patients with migraine induces inflammatory reactions in meningeal blood vessels, characterized by vasodilation, plasma protein extravasation, and activation of trigeminovascular afferents.2 Studies in animals support the observation that pain-producing intracranial extracerebral vessels in the dura mater (peripherally), not the brain, are responsible for the generation of headache in patients with migraine.3

Vasoactive neuropeptides found within the trigeminal neurons that innervate intracranial blood vessels and contribute to the manifestation of head pain in migraineurs include calcitonin gene-related peptide (CGRP), substance P, and neurokinin A. Calcitonin gene-related peptide is the most potent vasodilator neurotransmitter mapped to the trigeminal system, and its action is endothelium independent.4 Substance P, a nondecapeptide involved in nociceptive transmission, has endothelium-dependent vasodilatory effects on the cerebrovascular bed.5 Neurokinin A is a decapeptide with a profile of action and localization in the trigeminal system that is similar to that of substance P but with less potent vasodilatory effects and longer-lasting effects on blood vessel permeability.6 The critical neuropeptide in the generation of migraine seems to be CGRP rather than substance P or neurokinin A.

Neurogenic inflammation within the meninges has been suggested as a potential model to explain the source of head pain in patients with migraine, but it has been unclear whether neurogenic inflammation occurs during an acute migraine attack. Studies in animals demonstrate increased endothelial permeability and leakage of albumin into the dura and the retina after high-intensity electrical stimulation of the trigeminal ganglion, but no increased endothelial permeability or protein extravasation has been documented in human retinal or choroidal vessels during migraine attacks or the headache-free interval in migraineurs.7 These findings suggest that other fundamental processes, probably in the central nervous system, are key to the pathophysiology of a migraine attack.

The autonomic nervous system may contribute to the pathophysiology of migraine. Hyperfunctioning of both the sympathetic and parasympathetic nervous systems has been suspected in patients with migraine, based on vasomotor reactions to temperature changes, cardiovascular responses, and other investigations. The normal responses of cranial arteries during increased sympathetic activity cast doubt on a major role of sympathetic dysfunction in the pathophysiology of migraine, but mild parasympathetic hypofunction with denervation hypersensitivity could be a contributing factor.8

The role of nitric oxide in the pathophysiology of migraine and other vascular headaches is supported by the observations that both glyceryl trinitrate (a nitric oxide donor) and histamine (an activator of endothelial nitric oxide formation) cause dose-dependent headaches with several migrainous characteristics.9 Patients with migraine respond to nitric oxide delivered by nitroglycerin by developing an early nonmigraine headache and then a delayed, migraine-like headache several hours after dosing—a headache not seen when healthy control patients are given nitroglycerin, which suggests an increased vulnerability in migraineurs to one or more of the toxic effects of nitric oxide, including enzyme inhibition and the formation of peroxynitrate with lipid peroxidation.9

5-HT RECEPTORS

The role of 5-HT in migraine is supported by the observations that urinary and platelet 5-HT levels decrease, and that circulating levels of 5-hydroxyindoleacetic acid (5-HIAA), the major metabolite of 5-HT, increase during migraine.10 The ability of 5-HT–depleting and 5-HT–releasing agents such as reserpine and fenfluramine to induce migraine-like symptoms provides further evidence of the role of serotonin in the pathophysiology of migraine.11 Intravenous infusion of 5-HT aborts both reserpine-induced and spontaneous headache, but the clinical use of 5-HT in migraine is precluded by significant untoward effects.11

The 5-HT receptors are highly heterogeneous, broadly distributed, and classified into 7 different families on the basis of their amino acid sequences and other properties.12 The 5-HT1 receptors are the largest subfamily of 5-HT receptors and typically demonstrate a high affinity for 5-HT. The 5-HT1 receptors are further subdivided according to their physiologic functions, binding affinity, and other features.

The cloning of 5-HT1 receptors and the development of 5-HT receptor agonists with specific affinity for 5-HT1 receptor subtypes provided evidence for substantial populations of 5-HT1B receptors on vascular endothelium and human meningeal blood vessels.6 The messenger RNA for the 5-HT1B receptor is abundantly expressed on neuronal tissues and vascular smooth muscle cells, and evidence suggests that this receptor mediates contraction of vascular smooth muscle.13 Both the 5-HT1B and 5-HT1D receptors have been localized in human trigeminal ganglia and trigeminal nerves, but only 5-HT1D receptors have been detected in trigeminal nerves projecting peripherally to the dural vasculature and centrally to the brainstem trigeminal nuclei.6,13 The 5-HT1D receptors are thus localized peripherally to inhibit activated trigeminal nerves and prevent vasoactive neuropeptide release, and centrally to interrupt pain signal transmission from the blood vessels to sensory neurons located in the brainstem.6

Local application of 5-HT1B/1D receptor agonists inhibits firing activity by second-order trigeminal neurons, and this activity is shared by ergonovine, a nonspecific 5-HT1 receptor agonist.14 These observations support the presence of inhibitory receptors on these neurons that are capable of decreasing trigeminal neuronal traffic and thus pain transmission in migraine and other primary headaches.

MECHANISMS OF ACTION OF THE 5-HT1B/1D RECEPTOR AGONISTS

Studies of the mechanisms of action of 5-HT1B/1D receptor agonists, or triptans, provide important insights into the pathophysiology of migraine. The triptans have at least 3 distinct modes of action, all of which may be additive in their antimigraine effects (Table 1).6,15 These effects include vasoconstriction of painfully distended intracranial extracerebral vessels by a direct effect on vascular smooth muscle, inhibition of the release of vasoactive neuropeptides by trigeminal terminals innervating the intracranial vessels and dura mater, and inhibition of nociceptive neurotransmission within the trigeminocervical complex in the brainstem and upper spinal cord.15 Other possible antimigraine effects of the triptans include modulation of nitric oxide–dependent signal transduction pathways, nitric oxide scavenging in the brain, and sodium-dependent cell metabolic activity.1618

Sumatriptan and rizatriptan have been shown to act selectively to cause vasoconstriction in isolated human middle meningeal arteries and are 10 times more potent in these arteries than in human coronary arteries.19 The maximal response evoked by both agents is less than that of 5-HT.20 These observations and those of Maassen VanDenBrink et al21 suggest that therapeutic plasma concentrations of the triptans do not reach levels likely to cause myocardial ischemia in patients with normal coronary circulation. However, given that there are some 5-HT1B receptors in coronary arteries, triptans are contraindicated in patients with cerebrovascular or cardiovascular disease.

The normalization of vessel diameter in cerebral arteries in migraineurs can be achieved without frank vasoconstriction through inhibition of CGRP release, and this mechanism may contribute to the relief of headache in patients treated with triptans. Studies in anesthetized rats demonstrate that rizatriptan has no direct vasoconstrictor effects, and blocks electrically stimulated dural vasodilation and plasma protein extravasation by inhibiting the release of CGRP via activation of prejunctional receptors located on trigeminal sensory nerve terminals.22 Sumatriptan inhibits potassium-stimulated CGRP secretion from cultured trigeminal neurons in a dose-dependent manner and may also inhibit the release of substance P.23 These observations support the concept that sumatriptan and other triptans may block a deleterious feedback loop in migraine whereby neurogenic inflammatory agents sensitize the trigeminal ganglia neurons to sustain elevated levels of CGRP.

The dilation of meningeal blood vessels may evoke a sensitization of central trigeminal neurons that may underlie the symptoms of headache and allodynia in migraineurs.24 The inhibition of evoked trigeminal nucleus firing by 5-HT, and the blockade of this activity by a 5-HT1B/1D agonist with central nervous system penetration suggest that triptans inhibit trigeminal activity centrally.25 Rizatriptan has been shown to have central trigeminal antinociceptive activity in addition to peripheral vasoconstriction and inhibitory effects on the trigeminovasculature,26 and these effects may be mediated by the 5-HT1D receptor.

CLINICAL EFFICACY OF THE 5-HT1B/1D RECEPTOR AGONISTS

The 5-HT1B/1D receptor agonists are remarkably effective in the treatment of migraine pain (Table 2),2743 considerably decreasing the need for rescue medications. The triptans are also effective for migraine-associated symptoms, such as nausea, vomiting, photophobia, andphonophobia. A primary shortcoming of most triptans is headache recurrence.

Significant differences in safety among the triptans have not been demonstrated, although the clinically used doses of naratriptan and almotriptan yield few adverse effects, producing a tolerability similar to that seen with placebo. Typical adverse effects of the triptans are fatigue, dizziness, paresthesias, warm sensations, and neck, chest, and throat tightness. The tolerability of individual triptans is relative and cannot be predicted on the basis of lipophilicity, bioavailability, absolute dose size, or any combination of these variables.44 Because all triptans are 5-HT1B/1D agonists in the low nanomolar range, differences in their adverse effects profiles are unlikely to be mediated through 5-HT1B/1D receptors.44

The first triptan to be developed and approved for clinical use in patients with migraine was sumatriptan, which is available in injectable, intranasal, and oral formulations. The limitations of sumatriptan include low bioavailability, short plasma half-life, and low liposolubility. These and other drawbacks prompted the development of triptans with improved pharmacokinetic properties.

Zolmitriptan has a significantly higher oral bioavailability than sumatriptan (40% vs 14%).45 Zolmitriptan has efficacy similar to that of sumatriptan for the relief of a single migraine attack, and a high consistency of response in open-label extension studies longer than 1 year, with 95% of attacks aborted by 4 hours with 1 to 2 doses of 2.5 mg or 5 mg.46 Zolmitriptan is generally well tolerated, with mild, brief adverse effects typical of all triptans.

Naratriptan, compared with sumatriptan, has greater bioavailability (about 60%); a longer elimination half-life (5.0-5.5 hours); better lipophilicity, and thus, better central nervous system penetration; and less reversibility in 5-HT receptor binding.32 Comparative trials have shown that 2.5 mg of naratriptan is less effective than 100 mg of sumatriptan in terms of the likelihood of achieving headache relief, but has almost no adverse effects.45 Naratriptan has a lower headache recurrence rate than sumatriptan and rizatriptan when directly compared, but the time to recurrence is not longer with naratriptan.29

Rizatriptan has a rapid onset of action, high bioavailability, and a favorable adverse effects profile. In direct comparisons of oral sumatriptan and rizatriptan in patients with migraine, 10 mg of rizatriptan had a slightly quicker time to headache relief in hazards ratio analysis against both the 50-mg and 100-mg doses of sumatriptan and better effects on several other secondary measures of efficacy, including reduction of functional disability and the proportion of patients who were pain free at 2 hours.47 As with sumatriptan, rizatriptan is not affected by concurrent use of oral contraceptives or medications metabolized by the hepatic cytochrome P 450 3A4 system. Doses of rizatriptan must be halved when administered concomitantly with propranolol, but not with other β-blockers.

Almotriptan is structurally related to sumatriptan, but its potency at the 5-HT1D receptor is lower than that of sumatriptan, though its potency at the 5-HT1B receptor is similar to that of sumatriptan and rizatriptan.30 Results from a randomized, double-blind, placebo-controlled trial indicate that almotriptan is effective across multiple attacks, with 2 of 3 attacks relieved in 75% of patients treated with 12.5 mg of almotriptan.48

Frovatriptan has one of the highest affinities for the 5-HT1B receptor and a long elimination half-life (as long as 25 hours).30 Frovatriptan seems to have a slower onset of action than most other triptans. About one third of patients in open-label extension studies longer than 1 year reported pain relief in less than 2 hours after dosing, with headache recurrence rates of less than 10%.49

Eletriptan has affinity for 5-HT1B/1D receptors that is 4 to 8 times higher than that of sumatriptan.50 Eletriptan is a substrate for P-glycoprotein, an important efflux transporter at the blood-brain barrier. This finding suggests that eletriptan has the potential for increased central nervous system concentrations and drug-drug interactions when coadministered with medications that are substrates or inhibitors of P-glycoprotein. In addition, eletriptan is metabolized by the cytochrome P 450 3A4 system, and dose reduction may be mandated in the prescribing information when eletriptan is administered with medications that also are degraded by cytochrome P 450 3A4, such as macrolide antibiotics and antifungal medications.

CONCLUSIONS

Triptans are a major clinical advance in the treatment of migraine. The clinical efficacy of these drugs in migraine is related in part to their multiple mechanisms of action at vascular, neural, and central physiologic sites implicated in the pathophysiology of migraine. In combination with their highly selective affinity for 5-HT1B/1D receptors, the triptans have favorable pharmacologic properties, characterized by high oral bioavailability, rapid onset of action, and low incidence of adverse effects. These features underlie the beneficial effects of the triptans in patients with migraine, including rapid relief of headache and associated symptoms and improvements in productivity and health-related quality of life. Future studies may identify additional mechanisms of action of the triptans and the optimal role of these agents in the management of patients with migraine.

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Article Information

Accepted for publication October 8, 2001.

Author contributions: Study concept and design (Drs Tepper, Rapoport, and Sheftell); acquisition of data (Drs Tepper, Rapoport, and Sheftell); analysis and interpretation of data (Drs Tepper, Rapoport, and Sheftell); drafting of the manuscript (Drs Tepper, Rapoport, and Sheftell); critical revision of the manuscript for important intellectual content (Drs Tepper, Rapoport, and Sheftell); statistical expertise (Drs Tepper, Rapoport, and Sheftell).

Corresponding author and reprints: Stewart J. Tepper, MD, the New England Center for Headache, 778 Long Ridge Rd, Stamford, CT 06902-1251 (e-mail: SJTepper@aol.com).

References
1.
Hamel  E Current concepts of migraine pathophysiology. Can J Clin Pharmacol.1999;6(suppl A):9A-14A.
2.
Moskowitz  MA Neurogenic versus vascular mechanisms of sumatriptan and ergot alkaloids in migraine. Trends Pharmacol Sci.1992;12:307-311.
3.
Goadsby  PJ Mechanisms and management of headache. J R Coll Physicians Lond.1999;33:228-234.
4.
Hanko  JHardebo  JEKahrstrom  JOwman  CSundler  F Calcitonin gene-related peptide is present in mammalian cerebrovascular nerve fibres and dilates pial and peripheral arteries. Neurosci Lett.1985;57:91-95.
5.
Zawadzki  JVFurchgott  RFCherry  P The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by substance P. Fed Proc.1981;40:689.
6.
Hargreaves  RJShepheard  SL Pathophysiology of migraine: new insights. Can J Neurol Sci.1999;26(suppl 3):S12-S19.
7.
May  AShepheard  SLKnorr  M  et al Retinal plasma extravasation in animals but not in humans: implications for the pathophysiology of migraine. Brain.1998;121:1231-1237.
8.
Thomsen  LLOlesen  J The autonomic nervous system and the regulation of arterial tone in migraine. Clin Auton Res.1995;5:243-250.
9.
Olesen  JThomsen  LLIversen  H Nitric oxide is a key molecule in migraine and other vascular headaches. Trends Pharmacol Sci.1994;15:149-153.
10.
Johnson  KWPhebus  LACohen  ML Serotonin in migraine: theories, animal models and emerging therapies. Prog Drug Res.1998;51:219-244.
11.
Humphrey  PPFeniuk  WPerren  MJBeresford  IJMSkingle  MWhalley  ET Serotonin and migraine. Ann N Y Acad Sci.1990;600:587-598.
12.
Hamel  E The biology of serotonin receptors: focus on migraine pathophysiology and treatment. Can J Neurol Sci.1999;26(suppl 3):S2-S6.
13.
De Vries  PVillalon  CMSaxena  PR Pharmacological aspects of experimental headache models in relation to acute antimigraine therapy. Eur J Pharmacol.1999;375:61-74.
14.
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