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

NEUROLOGICAL REVIEW

SECTION EDITOR: DAVID E. PLEASURE, MD Mechanisms of Action of the 5-HT1B/1D Receptor Agonists

Stewart J. Tepper, MD; Alan M. Rapoport, MD; Fred D. Sheftell, MD

ecent 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 tri- geminocervicalR 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 mi-

graine. 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 trigemi-

nal 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. Arch Neurol. 2002;59:1084-1088

The pathophysiology of migraine is fairly Increased understanding of the patho- well understood, and evidence supports physiology of migraine has led to the de- contributory roles of both neural and vas- velopment of improved migraine treat- cular mechanisms. The manifestation of ments such as the 5-HT1B/1D receptor headache in migraineurs is probably as- agonists, collectively known as triptans. sociated with activation of the trigemino- The emergence of the triptans has revo- vascular system, followed by the release lutionalized the management of mi- of vasodilatory neuropeptides. Changes in graine by providing options for the highly circulating levels of the neurotransmitter selective stimulation of 5-HT1B/1D recep- serotonin (5-HT) are characteristic of mi- tors, while reducing or eliminating un- graine and may contribute to the patho- wanted activity at other receptor sub- genesis of the disorder. Recent progress in types, thus improving therapeutic understanding the pathophysiology of mi- tolerability. This article focuses on the graine includes the identification of the mechanisms of action of the triptans in re- physiologic roles of vasoactive neuropep- lation to current concepts of the patho- tides associated with migraine and the physiology of migraine and the clinical role characterization of 5-HT receptor sub- of these drugs in the management of pa- types. tients with migraine.

From the New England Center for Headache, Stamford, Conn (Drs Tepper, Rapoport, PATHOPHYSIOLOGY OF MIGRAINE 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 The manifestation of headache in mi- Medical College, Valhalla (Dr Sheftell). Drs Tepper, Rapoport, and Sheftell are consultants for GlaxoSmithKline, Merck, AstraZeneca, and Pharmacia; conduct graineurs has been attributed to activa- research for GlaxoSmithKline, Merck, AstraZeneca, Pharmacia, Allergan, Elan, and tion of the sensory trigeminovascular OrthoMcNeill; and are on the speakers bureau for GlaxoSmithKline, Merck, and system and the subsequent release of va- 1 AstraZeneca. Dr Rapoport is also a consultant for Abbott, Pfizer, Forest Laboratories, soactive neuropeptides. In the geneti- Elan, and Bristol-Myers Squibb. Dr Sheftell is also a consultant for Pfizer. cally susceptible patient, activation of the

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©2002 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/27/2021 trigeminovascular system can be initiated by a variety of layed, migraine-like headache several hours after dos- triggers, including stress, certain foods or drugs, odors, ing—a headache not seen when healthy control patients trauma, and changes in sleep habits. The release of va- are given nitroglycerin, which suggests an increased vul- soactive substances from trigeminal nerve terminals in nerability in migraineurs to one or more of the toxic ef- patients with migraine induces inflammatory reactions fects of nitric oxide, including enzyme inhibition and the in meningeal blood vessels, characterized by vasodila- formation of peroxynitrate with lipid peroxidation.9 tion, plasma protein extravasation, and activation of trigeminovascular afferents.2 Studies in animals support the 5-HT RECEPTORS observation that pain-producing intracranial extracerebral vessels in the dura mater (peripherally), not the brain, The role of 5-HT in migraine is supported by the obser- are responsible for the generation of headache in pa- vations that urinary and platelet 5-HT levels decrease, and tients with migraine.3 that circulating levels of 5-hydroxyindoleacetic acid (5- Vasoactive neuropeptides found within the trigemi- HIAA), the major metabolite of 5-HT, increase during mi- nal neurons that innervate intracranial blood vessels and graine.10 The ability of 5-HT–depleting and 5-HT– contribute to the manifestation of head pain in mi- releasing agents such as reserpine and fenfluramine to graineurs include calcitonin gene-related peptide (CGRP), induce migraine-like symptoms provides further evi- substance P, and neurokinin A. Calcitonin gene-related dence of the role of serotonin in the pathophysiology of peptide is the most potent vasodilator neurotransmitter migraine.11 Intravenous infusion of 5-HT aborts both re- mapped to the trigeminal system, and its action is endo- serpine-induced and spontaneous headache, but the clini- thelium independent.4 Substance P, a nondecapeptide in- cal use of 5-HT in migraine is precluded by significant volved in nociceptive transmission, has endothelium- untoward effects.11 dependent vasodilatory effects on the cerebrovascular The 5-HT receptors are highly heterogeneous, bed.5 Neurokinin A is a decapeptide with a profile of ac- broadly distributed, and classified into 7 different fami- tion and localization in the trigeminal system that is simi- lies on the basis of their amino acid sequences and other 12 lar to that of substance P but with less potent vasodila- properties. The 5-HT1 receptors are the largest subfam- tory effects and longer-lasting effects on blood vessel ily of 5-HT receptors and typically demonstrate a high 6 permeability. The critical neuropeptide in the genera- affinity for 5-HT. The 5-HT1 receptors are further sub- tion of migraine seems to be CGRP rather than sub- divided according to their physiologic functions, bind- stance P or neurokinin A. ing affinity, and other features. Neurogenic inflammation within the meninges has The cloning of 5-HT1 receptors and the develop- been suggested as a potential model to explain the source ment of 5-HT receptor agonists with specific affinity for of head pain in patients with migraine, but it has been un- 5-HT1 receptor subtypes provided evidence for substan- clear whether neurogenic inflammation occurs during an tial populations of 5-HT1B receptors on vascular endo- acute migraine attack. Studies in animals demonstrate in- thelium and human meningeal blood vessels.6 The mes- creased endothelial permeability and leakage of albumin senger RNA for the 5-HT1B receptor is abundantly into the dura and the retina after high-intensity electrical expressed on neuronal tissues and vascular smooth muscle stimulation of the trigeminal ganglion, but no increased cells, and evidence suggests that this receptor mediates 13 endothelial permeability or protein extravasation has been contraction of vascular smooth muscle. Both the 5-HT1B documented in human retinal or choroidal vessels dur- and 5-HT1D receptors have been localized in human tri- ing migraine attacks or the headache-free interval in mi- geminal ganglia and trigeminal nerves, but only 5-HT1D graineurs.7 These findings suggest that other fundamen- receptors have been detected in trigeminal nerves pro- tal processes, probably in the central nervous system, are jecting peripherally to the dural vasculature and cen- 6,13 key to the pathophysiology of a migraine attack. trally to the brainstem trigeminal nuclei. The 5-HT1D The autonomic nervous system may contribute to receptors are thus localized peripherally to inhibit acti- the pathophysiology of migraine. Hyperfunctioning of vated trigeminal nerves and prevent vasoactive neuro- both the sympathetic and parasympathetic nervous sys- peptide release, and centrally to interrupt pain signal trans- tems has been suspected in patients with migraine, based mission from the blood vessels to sensory neurons located on vasomotor reactions to temperature changes, cardio- in the brainstem.6 vascular responses, and other investigations. The nor- Local application of 5-HT1B/1D receptor agonists in- mal responses of cranial arteries during increased sym- hibits firing activity by second-order trigeminal neu- pathetic activity cast doubt on a major role of sympathetic rons, and this activity is shared by ergonovine, a non- 14 dysfunction in the pathophysiology of migraine, but mild specific 5-HT1 receptor agonist. These observations parasympathetic hypofunction with denervation hyper- support the presence of inhibitory receptors on these neu- sensitivity could be a contributing factor.8 rons that are capable of decreasing trigeminal neuronal The role of nitric oxide in the pathophysiology of mi- traffic and thus pain transmission in migraine and other graine and other vascular headaches is supported by the primary headaches. observations that both glyceryl trinitrate (a nitric oxide do- nor) and histamine (an activator of endothelial nitric ox- MECHANISMS OF ACTION OF THE 5-HT1B/1D ide formation) cause dose-dependent headaches with sev- RECEPTOR AGONISTS eral migrainous characteristics.9 Patients with migraine respond to nitric oxide delivered by nitroglycerin by de- Studies of the mechanisms of action of 5-HT1B/1D recep- veloping an early nonmigraine headache and then a de- tor agonists, or triptans, provide important insights into

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©2002 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/27/2021 the pathophysiology of migraine. The triptans have at least The normalization of vessel diameter in cerebral ar- 3 distinct modes of action, all of which may be additive teries in migraineurs can be achieved without frank va- in their antimigraine effects (Table 1).6,15 These effects soconstriction through inhibition of CGRP release, and include vasoconstriction of painfully distended intracra- this mechanism may contribute to the relief of head- nial extracerebral vessels by a direct effect on vascular ache in patients treated with triptans. Studies in anes- smooth muscle, inhibition of the release of vasoactive neu- thetized rats demonstrate that rizatriptan has no direct ropeptides by trigeminal terminals innervating the in- vasoconstrictor effects, and blocks electrically stimu- tracranial vessels and dura mater, and inhibition of no- lated dural vasodilation and plasma protein extravasa- ciceptive neurotransmission within the trigeminocervical tion by inhibiting the release of CGRP via activation of complex in the brainstem and upper spinal cord.15 Other prejunctional receptors located on trigeminal sensory possible antimigraine effects of the triptans include modu- nerve terminals.22 Sumatriptan inhibits potassium- lation of nitric oxide–dependent signal transduction path- stimulated CGRP secretion from cultured trigeminal neu- ways, nitric oxide scavenging in the brain, and sodium- rons in a dose-dependent manner and may also inhibit dependent cell metabolic activity.16-18 the release of substance P.23 These observations support Sumatriptan and rizatriptan have been shown to act the concept that sumatriptan and other triptans may block selectively to cause vasoconstriction in isolated human a deleterious feedback loop in migraine whereby neuro- middle meningeal arteries and are 10 times more potent genic inflammatory agents sensitize the trigeminal gan- in these arteries than in human coronary arteries.19 The glia neurons to sustain elevated levels of CGRP. maximal response evoked by both agents is less than that The dilation of meningeal blood vessels may evoke of 5-HT.20 These observations and those of Maassen a sensitization of central trigeminal neurons that may un- VanDenBrink et al21 suggest that therapeutic plasma con- derlie the symptoms of headache and allodynia in mi- centrations of the triptans do not reach levels likely to graineurs.24 The inhibition of evoked trigeminal nucleus cause myocardial ischemia in patients with normal coro- firing by 5-HT, and the blockade of this activity by a nary circulation. However, given that there are some 5-HT1B/1D agonist with central nervous system penetra- 5-HT1B receptors in coronary arteries, triptans are con- tion suggest that triptans inhibit trigeminal activity cen- traindicated in patients with cerebrovascular or cardio- trally.25 Rizatriptan has been shown to have central tri- vascular disease. geminal antinociceptive activity in addition to peripheral vasoconstriction and inhibitory effects on the trigemi- novasculature,26 and these effects may be mediated by the Table 1. Antimigraine Mechanisms 5-HT1D receptor. of the 5-HT1B/1D Receptor Agonists* CLINICAL EFFICACY OF THE 5-HT1B/1D Location Mechanism of Action RECEPTOR AGONISTS Vascular Selective constriction of pain-producing intracranial extracerebral blood vessels The 5-HT1B/1D receptor agonists are remarkably effective Neurogenic Reduction of trigeminal sensory nerve activation and in the treatment of migraine pain (Table 2),27-43 con- inhibition of vasoactive neuropeptide release siderably decreasing the need for rescue medications. The Central Inhibition of neurotransmitter release from activated trigeminal nerves in the brainstem and upper triptans are also effective for migraine-associated symp- cervical spinal column toms, such as nausea, vomiting, photophobia, andphonophobia. A primary shortcoming of most trip- *Data from Hargreaves and Shepheard6 and Goadsby.15 tans is headache recurrence.

Table 2. Comparison of Efficacy of Approved and Investigational Oral Triptans at Most Commonly Used Doses*

Sumatriptan Zolmitriptan Naratriptan Rizatriptan Almotriptan Frovatriptan Eletriptan 50 mg 2.5 mg 2.5 mg 10 mg 12.5 mg 2.5 mg† 80 mg† Headache 50-61 (Medical 62-65 (Medical NA§ 67-77 (Medical 57-65 (Pharmacia 38-40 (Deleu 65-80 (Deleu and response at 2 Economics Inc34) Economics Economics Corp28) and Hanssens30) hours‡ Inc34) Inc34) Hanssens30) Complete relief 30-32 (Pfaffenrath 22-39 (Spencer NA¶ 40-44 (Dooley and 18 (Spierings NA 37 (Goodsby et al) of pain at 2 h࿣ et al40) et al41) Faulds31) et al) Headache 29-34 (Perry and 13-39 (Spencer 27-45 (Dulli32; 28-47 (Bomhof 18-27 (Deleu and 9-14 (Deleu and 21-33 (Deleu and recurrence at Markham39; et al41) Klassen et al35; et al29; Kramer Hanssens30; Hanssens30) Hanssens30) 24 h Pfaffenrath et al40) Mathew et al37) et al36) Spierings et al42)

*All data are presented as percentage of patients (reference). NA indicates unavailable data. †Not yet approved for use in the United States. ‡Response is defined as a decrease in pain from moderate or severe to mild or none. §Headache response to naratriptan was reported at 4 hours, not 2 hours. Sixty percent to 66% of patients taking 2.5 mg of naratriptan reported headache response at 4 hours.27 ࿣Defined as a decrease in pain from moderate or severe to none (ie, pain free). ¶Complete pain relief with naratriptan was reported at 4 hours, not 2 hours. Thirty-three percent of patients taking 2.4 mg of naratriptan reported being pain free at 4 hours.32

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©2002 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/27/2021 Significant differences in safety among the triptans multiple attacks, with 2 of 3 attacks relieved in 75% of have not been demonstrated, although the clinically used patients treated with 12.5 mg of almotriptan.48 doses of naratriptan and almotriptan yield few adverse Frovatriptan has one of the highest affinities for the effects, producing a tolerability similar to that seen with 5-HT1B receptor and a long elimination half-life (as long placebo. Typical adverse effects of the triptans are fa- as 25 hours).30 Frovatriptan seems to have a slower on- tigue, dizziness, paresthesias, warm sensations, and neck, set of action than most other triptans. About one third chest, and throat tightness. The tolerability of indi- of patients in open-label extension studies longer than 1 vidual triptans is relative and cannot be predicted on the year reported pain relief in less than 2 hours after dos- basis of lipophilicity, bioavailability, absolute dose size, ing, with headache recurrence rates of less than 10%.49 44 or any combination of these variables. Because all trip- Eletriptan has affinity for 5-HT1B/1D receptors that is 50 tans are 5-HT1B/1D agonists in the low nanomolar range, 4 to 8 times higher than that of sumatriptan. Eletriptan differences in their adverse effects profiles are unlikely is a substrate for P-glycoprotein, an important efflux trans- 44 to be mediated through 5-HT1B/1D receptors. porter at the blood-brain barrier. This finding suggests that The first triptan to be developed and approved for eletriptan has the potential for increased central nervous clinical use in patients with migraine was sumatriptan, system concentrations and drug-drug interactions when which is available in injectable, intranasal, and oral for- coadministered with medications that are substrates or in- mulations. The limitations of sumatriptan include low hibitors of P-glycoprotein. In addition, eletriptan is me- bioavailability, short plasma half-life, and low liposolu- tabolized by the cytochrome P 4503A4 system, and dose bility. These and other drawbacks prompted the devel- reduction may be mandated in the prescribing informa- opment of triptans with improved pharmacokinetic tion when eletriptan is administered with medications that properties. also are degraded by cytochrome P 4503A4, such as mac- Zolmitriptan has a significantly higher oral bioavail- rolide antibiotics and antifungal medications. ability than sumatriptan (40% vs 14%).45 Zolmitriptan has efficacy similar to that of sumatriptan for the relief CONCLUSIONS of a single migraine attack, and a high consistency of response in open-label extension studies longer than 1 year, Triptans are a major clinical advance in the treatment of with 95% of attacks aborted by 4 hours with 1 to 2 doses migraine. The clinical efficacy of these drugs in mi- of 2.5 mg or 5 mg.46 Zolmitriptan is generally well tol- graine is related in part to their multiple mechanisms of erated, with mild, brief adverse effects typical of all trip- action at vascular, neural, and central physiologic sites tans. implicated in the pathophysiology of migraine. In com- Naratriptan, compared with sumatriptan, has greater bination with their highly selective affinity for 5-HT1B/1D bioavailability (about 60%); a longer elimination half- receptors, the triptans have favorable pharmacologic prop- life (5.0-5.5 hours); better lipophilicity, and thus, better erties, characterized by high oral bioavailability, rapid on- central nervous system penetration; and less reversibil- set of action, and low incidence of adverse effects. These ity in 5-HT receptor binding.32 Comparative trials have features underlie the beneficial effects of the triptans in shown that 2.5 mg of naratriptan is less effective than 100 patients with migraine, including rapid relief of head- mg of sumatriptan in terms of the likelihood of achiev- ache and associated symptoms and improvements in pro- ing headache relief, but has almost no adverse effects.45 ductivity and health-related quality of life. Future stud- Naratriptan has a lower headache recurrence rate than ies may identify additional mechanisms of action of the sumatriptan and rizatriptan when directly compared, but triptans and the optimal role of these agents in the man- the time to recurrence is not longer with naratriptan.29 agement of patients with migraine. Rizatriptan has a rapid onset of action, high bioavailability, and a favorable adverse effects profile. In di- Accepted for publication October 8, 2001. rect comparisons of oral sumatriptan and rizatriptan in Author contributions: Study concept and design (Drs patients with migraine, 10 mg of rizatriptan had a slightly Tepper, Rapoport, and Sheftell); acquisition of data (Drs Tep- quicker time to headache relief in hazards ratio analysis per, Rapoport, and Sheftell); analysis and interpretation of against both the 50-mg and 100-mg doses of sumatrip- data (Drs Tepper, Rapoport, and Sheftell); drafting of the tan and better effects on several other secondary mea- manuscript (Drs Tepper, Rapoport, and Sheftell); critical sures of efficacy, including reduction of functional dis- revision of the manuscript for important intellectual con- ability and the proportion of patients who were pain free tent (Drs Tepper, Rapoport, and Sheftell); statistical exper- at 2 hours.47 As with sumatriptan, rizatriptan is not af- tise (Drs Tepper, Rapoport, and Sheftell). fected by concurrent use of oral contraceptives or medi- Corresponding author and reprints: Stewart J. Tepper, cations metabolized by the hepatic cytochrome P 4503A4 MD, the New England Center for Headache, 778 Long Ridge system. Doses of rizatriptan must be halved when ad- Rd, Stamford, CT 06902-1251 (e-mail: [email protected]). ministered concomitantly with propranolol, but not with other ␤-blockers. REFERENCES Almotriptan is structurally related to sumatriptan, but its potency at the 5-HT1D receptor is lower than that 1. Hamel E. Current concepts of migraine pathophysiology. Can J Clin Pharmacol. 1999;6(suppl A):9A-14A. of sumatriptan, though its potency at the 5-HT1B recep- 30 2. Moskowitz MA. Neurogenic versus vascular mechanisms of sumatriptan and er- tor is similar to that of sumatriptan and rizatriptan. Re- got alkaloids in migraine. Trends Pharmacol Sci. 1992;12:307-311. sults from a randomized, double-blind, placebo- 3. Goadsby PJ. Mechanisms and management of headache. J R Coll Physicians controlled trial indicate that almotriptan is effective across Lond. 1999;33:228-234.

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