LEADING ARTICLE
`
`Drugs 2005; 65 (18): 2557-2567
`0012-6667/05/0018-2557/$39.95/0
`
`© 2005 Adis Data Information BV. All rights reserved.
`
`Calcitonin Gene-Related Peptide
`Antagonists as Treatments of
`Migraine and Other
`Primary Headaches
`Peter J. Goadsby
`Headache Group, Institute of Neurology and The National Hospital for Neurology and
`Neurosurgery, London, UK
`
`Abstract
`
`Calcitonin gene-related peptide (CGRP) is a potent neuromodulator that is
`expressed in the trigeminovascular system and is released into the cranial circula-
`tion in various primary headaches. CGRP is released in migraine, cluster headache
`and paroxysmal hemicrania. The blockade of its release is associated with the
`successful treatment of acute migraine and cluster headache. CGRP receptor
`blockade has recently been shown to be an effective acute anti-migraine strategy
`and is non-vasoconstricting in terms of the mechanism of action. The prospect of a
`non-vasoconstricting therapy for acute migraine offers a real opportunity to
`patients, and perhaps more importantly, provides a therapeutic rationale to rein-
`force migraine as a neurological disorder.
`
`Migraine is a common[1] and often very disabling what is the site of action of acute anti-migraine
`disorder[2] that is increasingly recognised as a neuro- medications? These questions lead us to the next
`logical condition.[3] Although there is a range of
`issue, which is whether drug development can move
`therapies for the acute treatment and prevention of
`away from the vessel and, thus, jump an important
`migraine,[4] the serotonin 5-HT1B/1D receptor ago-
`safety hurdle. These questions are not trivial in their
`nists or ‘triptans’[5] stand out in terms of their
`scientific impact, are certainly of considerable im-
`clinical and neuroscientific impact. Their descrip-
`portance to patients, and may be answered by the
`tion as acute anti-migraine compounds,[6] and the
`use of calcitonin gene-related peptide (CGRP) an-
`subsequent validation of sumatriptan in this re-
`tagonists.
`gard,[7,8] launched a wave of development that
`This review discusses the case for a non-vascular
`changed the face of migraine in particular, and prob-
`treatment of migraine and primary headache, in the
`ably primary headache more generally.
`context of CGRP antagonists. The historical devel-
`The triptans are considered to be safe[9] and effec-
`opment of the CGRP receptor antagonist for the
`tive.[10,11] However, the triptan development pro-
`treatment of migraine can be traced from early
`gramme left two crucial questions unanswered for
`trigeminovascular studies. This leads to a discussion
`the next generation of acute attack treatments. First,
`of CGRP and the trigeminovascular system, illumi-
`are acute anti-migraine drugs necessarily vasocon-
`nated by the interactions of these with the triptans.
`stricting in their mechanism of action?[12] Secondly,
`Finally, the clinical arguments are formulated and
`
`1
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`EX2010
`Eli Lilly & Co. v. Teva Pharms. Int'l GMBH
`IPR2018-01427
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`2558
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`Goadsby
`
`the initial clinical trial data discussed, which suggest
`that CGRP receptor antagonists are indeed likely to
`be the next development in the treatment of acute
`migraine.
`
`1. Historical Perspective
`
`CGRP was first recognised as the product of
`alternative RNA processing of
`the calcitonin
`gene.[13] It was reported at a very early stage follow-
`ing its discovery that this product was expressed in
`the brain.[14] Some years before reports of the exis-
`tence of CGRP, cranial blood vessels were noted to
`contain substance P,[15] and because migraine was
`considered to be a vascular headache,[16] interest
`developed around this innervation. The study of the
`innervation of the cranial circulation was accelerat-
`ed by the fact that substance P was a vasodila-
`tor.[17,18] After its discovery, CGRP was quickly
`recognised to co-exist with substance P in the nerve
`fibres that innervate blood vessels.[19] However, just
`prior to the first description of CGRP, it had been
`shown that substance P played a crucial role in the
`trigeminal innervation of the meninges. Pial blood
`vessels were shown to be innervated by substance P-
`containing fibres from the trigeminal ganglion,[20,21]
`and stimulation of the pial blood vessels in vitro
`could induce the release of substance P.[22,23] Tracer
`studies showed that neurons innervating the middle
`meningeal vessel, a branch of the external carotid
`artery, were co-localised in the trigeminal ganglion
`with substance P-like immunoreactivity[24,25] and,
`similarly, that the cerebral vessel innervation could
`be traced to the trigeminal ganglion.[26] Moreover, it
`was clear that dura mater received an important
`substance P innervation.[23] Thus, substance P was
`considered first, so-to-speak, in terms of a potential
`role in migraine,[27] and in many ways this delayed
`the study of CGRP-related mechanisms in migraine.
`From a physiological viewpoint, a key observa-
`tion that suggested the importance of CGRP over
`substance P was presented by Edvinsson and col-
`leagues at a Neural Regulation of the Cerebral Cir-
`culation meeting[28] and then subsequently more ful-
`ly in 1986.[29] The authors demonstrated that CGRP
`was involved in protective mechanisms in the cere-
`
`bral circulation. Given the background of the study
`of the trigeminovascular system in terms of crani-
`ovascular physiology,[30] it seemed appropriate to
`this author to study CGRP-related mechanisms in
`humans. Edvinsson agreed to collaborate on 21 June
`1985, the European mid-summer, and the studies
`were commenced shortly thereafter. The dissection
`of the pre-eminence of CGRP mechanisms dates
`from this time as we performed human studies to
`establish that the direction of the animal work was
`correct.[31] It soon became apparent that CGRP was
`a crucial link in the understanding of trigeminovas-
`cular activation in migraine,[32] and so the story now
`unfolds…
`
`2. Calcitonin Gene-Related
`Peptide (CGRP) and the
`Trigeminovascular System
`
`Given that the distribution of the pain in migraine
`is largely in the first (ophthalmic) division of the
`trigeminal nerve and the cutaneous distribution of
`the C2 sensory root, the anatomy and physiology of
`the trigeminovascular system is reviewed (see figure
`1). These data underpin and inform the discussion of
`CGRP in migraine.
`
`2.1 Anatomy
`
`Surrounding the large cerebral blood vessels, the
`pial blood vessels, the large venous sinuses and the
`dura mater is a plexus of largely unmyelinated fibres
`that arise from the ophthalmic division of the tri-
`geminal ganglion in the posterior fossa[24] and from
`the upper cervical dorsal roots.[33] This sensory in-
`nervation has recently been much better character-
`ised for both an external carotid branch vessel,[34]
`and for the superior sagittal sinus.[35] Trigeminal
`fibres innervating cerebral blood vessels arise from
`neurons in the trigeminal ganglion that contain sub-
`stance P and CGRP,[19] both of which can be re-
`leased when the trigeminal ganglion is stimulated
`either in humans or the cat,[36] presumably by anti-
`dromic activation. Trigeminal neurons innervating
`the dura mater preferentially contain CGRP over
`substance P,[37,38] and this seems likely to be re-
`flected in a preferential use of CGRP as a crucial
`
`© 2005 Adis Data Information BV. All rights reserved.
`
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`Calcitonin Gene-Related Peptide Antagonists for Migraine
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`Ventroposteromedial
`thalamus
`
`Dural
`vasculature
`
`Posterior hypothalamus
`
`Periaqueductal
`grey matter
`
`Locus
`coeruleus
`
`Trigeminal
`ganglion
`
`Cervical
`muscle
`and
`joints
`
`Cervical dorsal
`root ganglion
`
`Trigeminocervical
`complex
`
`Midline
`Fig. 1. Illustration of the trigeminovascular system, its projections and its modulatory inputs. Trigeminal neurons, whose cell bodies are
`found in the trigeminal ganglion, innervate pain-producing structures within the head that have calcitonin gene-related peptide (CGRP)
`receptors, and project to second-order neurons in the trigeminocervical complex. This complex receives input from cervical structures and
`projects to the contralateral ventroposteromedial thalamus. Trigeminocervical complex neurons are modulated by subcortical structures
`such as the locus coeruleus, periaqueductal grey matter and posterior hypothalamus. CGRP receptor antagonists could act at the sites
`marked by a star to inhibit CGRP actions peripherally or, probably more importantly, reduce nociceptive traffic through the trigeminocervical
`complex.
`
`transmitter in the trigeminocervical complex (see
`ous damage sufficient to produce dense anaesthesia
`section 2.3.2).
`did not flush when coagulated. These observations
`were quantified by Drummond and colleagues,[48]
`Stimulation of the cranial blood vessels, such as
`the superior sagittal sinus, is painful in humans[39,40] who recorded increases of 0.5–2.0°C in facial tem-
`and, remarkably, faradic stimulation is more con-
`perature in the distribution of the division coagu-
`sistently painful than mechanical stimulation.[16]
`lated.
`The human dural nerves that innervate the cranial
`In experimental animals, stimulation of the tri-
`blood vessels largely consist of small diameter mye-
`geminal ganglion, or discrete branches of it, produc-
`linated and unmyelinated fibres[41-43] that almost cer-
`es increases in skin temperature in the cutaneous
`tainly subserve a nociceptive function.
`distribution of the appropriate divisions of the tri-
`geminal sensory nerve.[49] Cranial blood flow is
`increased after trigeminal ganglion stimulation in
`the cat,[30] monkey[50] and in humans.[51] In the cat,
`the vasodilatory response appears to be 80% medi-
`ated by the facial (greater superficial petrosal
`[GSP]) nerve dilator pathway and 20% mediated by
`antidromic activation of the trigeminal system.[30]
`The facial/GSP response is mediated through the
`sphenopalatine (pterygopalatine in humans) and otic
`ganglia[52] and employs vasoactive intestinal peptide
`as one of its transmitters.[53] The cerebral vasodilator
`effects of trigeminal activation are largely seen in
`
`Studies of human trigeminovascular physiology
`provide some insight into what may occur when this
`nerve system is activated. Injection of ethanol into
`the trigeminal ganglion leads to facial flushing[44]
`and increased facial temperature[45] ipsilateral to the
`injections. Moreover, facial flushing after thermoco-
`agulation of
`the
`trigeminal ganglion for
`tic
`douloureux is limited to the distribution of the sen-
`sory division coagulated.[46] Onofrio[47] confirmed
`this observation and noted that divisions with previ-
`
`2.2 Physiology
`
`© 2005 Adis Data Information BV. All rights reserved.
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`Goadsby
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`tagonists have been studied for the prevention[67]
`frontal and parietal cortices,[54] and are somatotopi-
`and acute treatment[68-71] of migraine, and each one
`cally specific.[55] The vasodilator effects of trigemi-
`has failed to show an effect.[72] Moreover, the en-
`nal nerve activation are unaffected by cortical
`dothelin antagonist bosentan,[73] two specific PPE
`spreading depression, which, in contrast, blocks
`inhibitors, CP 122288[74,75] and GR 4991W93
`hypercapnic vasodilation.[56] Trigeminal ganglion-
`(4991w93),[76,77] and
`the neurosteroid ganax-
`ectomy reduces post-ischaemic cerebral vasodila-
`olone,[78] which are all effective PPE antagonists in
`tion,[57] and the trigeminovascular innervation seems
`animal experiments, have each subsequently failed
`to be involved in seizure-induced changes in the
`blood flow of the brain.[58] Thus, the trigeminovas-
`to show an effect in studies of acute migraine treat-
`cular system innervates the dura mater and pial ment. Taken together, it seems unlikely that sub-
`blood vessels, and probably has a physiological role,
`stance P-related mechanisms are important in mi-
`broadly speaking, as a neural protector system.
`graine and equally doubtful that CGRP blockade
`These observations in humans and animals suggest
`alone would block neurogenic PPE. It seems unlike-
`that any form of head pain may be accompanied by
`ly that a mechanism related to PPE is pivotal in
`trigeminovascular activation and, to a large extent, it migraine, and it is certainly probable that the effects
`is the degree of activation and the somatotopic na-
`of CGRP receptor antagonists in migraine are unre-
`ture of the trigeminovascular system that underlies
`lated to PPE.
`its involvement in migraine.
`
`2.2.1 CGRP Alone Does Not Mediate Plasma
`Protein Extravasation
`Stimulation of the trigeminal ganglion results in
`leakage of plasma proteins from the vascular space
`into the dura matter, a process termed neurogenic
`plasma protein extravasation (PPE).[59] Is this phe-
`nomenon relevant to migraine? First, considering
`CGRP, there is no direct evidence that CGRP alone
`will produce increased vascular permeability in the
`dura mater.[60] In a study in mice, CGRP was not
`active in the plasma extravasation assay[61] but was a
`potent vasodilator.[62] Consistent with this, and in
`contrast to mice who have a neurokinin-1 receptor
`knockout,[63] animals in which the α-CGRP gene is
`disrupted still have a plasma extravasation response
`to application of mustard oil to the ear, which in turn
`can be blocked by a neurokinin-1 receptor antago-
`nist.[64] Maltos and colleagues[65] applied substance
`P or CGRP to exposed dental pulp, after first drilling
`into the tooth and then inserting a probe through the
`cavity onto the pulp. Given the pre-stimulus of the
`drilling, CGRP by virtue of vasodilation, but not
`acting alone, may have promoted Evans Blue leak-
`age.
`Secondly, PPE itself can be blocked by substance
`P and neurokinin-1 antagonists, such as vofopitant
`(GR 205171).[66] Several neurokinin-1 receptor an-
`
`2.3 Pharmacology
`
`The trigeminovascular system, the cell bodies of
`which are found in the trigeminal ganglion, projects
`to the periphery to modulate the dural vascula-
`ture[79,80] and to the trigeminocervical complex to
`activate second order trigeminal neurons.[81] The
`importance of CGRP in influencing both the periph-
`eral and central innervation of this system has been
`explored extensively in experimental animals.
`
`2.3.1 The Peripheral Trigeminovascular Interface:
`Intravital Microscopy of Dural Blood Vessels
`and CGRP
`Williamson et al.[79] demonstrated that electrical
`stimulation of the dura mater causes CGRP release
`from the pre-junctional nerve fibres innervating the
`dural blood vessels, resulting in reproducible vaso-
`dilation. Both CGRP- and electrically induced dila-
`tion of dural blood vessels can be blocked by the
`classic peptide CGRP
`receptor
`antagonist,
`CGRP8–37.[79] Neurokinin-1 receptors are not im-
`portant in mediating neurogenic dural vasodila-
`tion,[79] nor are adrenergic,[82] histaminergic[83] or
`cholinergic[84] mechanisms. However, there are im-
`portant receptor systems that interact with CGRP in
`the dural neurogenic vasodilator response that sug-
`gest that CGRP receptor antagonists will provide
`effective therapy for those with migraine, and that
`
`© 2005 Adis Data Information BV. All rights reserved.
`
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`Calcitonin Gene-Related Peptide Antagonists for Migraine
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`ies by an action not blocked by the CB1 receptor
`antagonist AM 251. However, the anandamide dural
`vasodilator effect was attenuated by the specific
`TRPV1 antagonist, capsazepine, and
`involved
`CGRP release,[101] just as the effect of capsaicin in
`the same model does.[102] Thus, the biology of
`anandamide receptors and their ability to influence
`the trigeminovascular system and interact with
`CGRP mechanisms offers an interesting area for
`further exploration.
`
`CGRP and Transient Receptor Potential (TRPV1)
`Bolus injections of capsaicin produce a reproduc-
`ible dural vessel dilation that has been measured in
`the rat using intravital microscopy. The capsaicin-
`induced dilation can be inhibited by the TRPV1
`antagonist capsazepine to a modest degree.[102] Cap-
`saicin-induced dilation is also inhibited by the
`CGRP receptor antagonist, CGRP8–37[102] and by
`trigeminal denervation.[103] While relatively few tri-
`geminal ganglion cells produce TRPV1 receptors,
`perhaps about 16%,[104] and its dural vascular effects
`seem small in comparison to, for example, CGRP,
`its interaction with CGRP-related mechanisms de-
`serves further exploration.
`
`they will offer even further avenues for development
`of medications for this indication. These are briefly
`covered in the following sections.
`
`CGRP, Triptans and Other Anti-Migraine Agents
`It has been shown that the triptans block
`neurogenic vasodilation in the dura mater.[85,86]
`Flunarizine, a clearly effective preventive agent for
`migraine,[87] does not alter neurogenic vasodila-
`tion.[88] On the other hand, topiramate, which is also
`certainly effective as a preventive agent in migraine
`therapy,[89] does attenuate neurogenic vasodila-
`tion.[90] More work is required to understand the
`importance of CGRP-related mechanisms and pre-
`ventive anti-migraine medications as a possible role
`for CGRP receptor antagonists in migraine preven-
`tion is considered.
`
`CGRP and Nitric Oxide
`Nitric oxide (NO) donors can induce migraine[91]
`and cluster headache.[92] NO donor-induced dural
`vasodilation can be antagonised by sumatriptan.[88]
`Dural vasodilation caused by CGRP infusion can be
`inhibited by inhibitors of endothelial NO synthase
`(NOS),[93] while neurogenic dural vasodilation can
`be inhibited by neural (n)NOS inhibitors.[93] These
`data, taken together with clinical data suggesting
`that NOS inhibition is useful in the treatment of
`migraine, further point to the likely utility of CGRP
`receptor antagonists in migraine[94] and to an impor-
`tant interaction between CGRP and NO in primary
`headache.
`
`2.3.2 CGRP Receptor Antagonists Block
`Trigeminovascular Transmission
`Olcegepant (BIBN 4096BS) is a potent, highly
`specific non-peptide CGRP receptor antagonist
`that
`is devoid of vasoconstrictive actions
`in
`humans.[105-107] Local microiontophoresis of olcege-
`pant inhibits trigeminocervical neurons in vivo.[108]
`These data complement studies that demonstrate
`CGRP and Cannabinoids
`that triptans[109] and ergot alkaloids[110] can inhibit
`Anandamide (AEA; arachidonylethanolamide) is
`second-order
`trigeminal neurons when
`ion-
`believed to be the endogenous ligand to the cannabi-
`noid CB1 and CB2 receptors.[95-98] Using the model
`tophoresed into the trigeminocervical complex.
`of intravital microscopy, it has been shown that Moreover, electrophysiological or Fos protein stud-
`anandamide is able to attenuate both neurogenic
`ies using the model of superior sagittal sinus stimu-
`dural vasodilation and CGRP- and NO-induced du-
`lation, which excites by consecutive depolarisation
`ral vessel dilation.[99] Anandamide is structurally
`of trigeminal afferents,[111] or local dural stimula-
`tion,[112] show that aspirin (acetylsalicylic acid),[113]
`related to capsaicin and olvanil (N-vanillyl-9-
`dihydroergotamine mesilate[114] and triptans[115-121]
`oleamide), and both are transient receptor potential
`(TRPV1) agonists,[100] having both an amide group
`inhibit trigeminovascular transmission. Remarka-
`and an aliphatic side chain. Using the intravital dural
`bly, GR 4991W93, which is a potent inhibitor of
`neurogenic PPE in the dura mater[76] but is ineffec-
`microscopy model,
`it has been shown
`that
`tive in the treatment of acute migraine,[77] is also
`anandamide can dose-dependently dilate dural arter-
`
`© 2005 Adis Data Information BV. All rights reserved.
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`2562
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`Goadsby
`
`release in both settings, with subsequent improve-
`ineffective in inhibiting trigeminocervical complex
`activity unless the dose is increased to levels at ment in headache.[126,136]
`which it has 5-HT1B/1D receptor agonist proper-
`ties.[122] Taken together, these data again suggest
`that CGRP receptor antagonists will be effective
`anti-migraine treatments. A plausible site of action
`for these compounds, as for the triptans,[115] is the
`trigeminocervical complex, where interruption of
`afferent nociceptive traffic may allow the regularly
`over-tasked brainstem systems to normalise and
`thus terminate the migraine attack.
`
`3.3 Cluster Headache and
`Paroxysmal Hemicrania
`
`Cluster headache and paroxysmal hemicrania are
`classified as trigeminal autonomic cephalalgias
`(TACs) in the current edition of the International
`Headache Society diagnostic criteria.[137] CGRP is
`elevated in spontaneous cluster headache[138] and in
`attacks.[139] Sumatriptan
`nitroglycerin-triggered
`reverses this elevation as it controls the acute at-
`tack.[138] Similarly, paroxysmal hemicrania is asso-
`ciated with elevations in CGRP that are reversed by
`indometacin.[140] Importantly, CGRP is not elevated
`in chronic tension-type headache,[141] so the findings
`in migraine and the TACs do seem specific and,
`consistent with this, since sumatriptan does not help
`tension-type headache.[142]
`
`4. Effect of Blockade of CGRP Release,
`or of CGRP Receptor Antagonists
`in Migraine
`
`3. CGRP Release in Disease and
`its Models
`
`3.1 Models of Trigeminovascular Activation
`
`Triptans inhibit CGRP release in the superior
`sagittal sinus of the rat[123] and in the spinal cord of
`the cat.[124] Triptans also inhibit release of CGRP
`into the cranial circulation of experimental animals
`when such release is evoked by trigeminal ganglion
`activation.[125,126] Similarly, stimulation of the supe-
`rior sagittal sinus in the cat leads to cranial release of
`CGRP,[127] which can be blocked by triptans but not
`by specific inhibitors of neurogenic dural PPE, such
`as CP 122288[128] and GR 4991W93.[129] Interest-
`ingly, triptans also influence the CGRP promot-
`er,[130] and regulate CGRP secretion from neurons in
`culture.[131] All of these data would predict that a
`CGRP receptor antagonist would also have anti-
`migraine effects without the need for vascular ac-
`tions.
`
`3.2 Migraine
`
`Triptans are effective,[11] well tolerated[9] treat-
`ments for acute migraine. Successful treatment of
`acute migraine[126] or cluster headache[138,139] with
`sumatriptan is associated with normalisation of cra-
`nial CGRP levels. Ergotamine is a somewhat less
`effective treatment for acute migraine,[143] and in-
`hibits CGRP release in experimental animals[144] as
`well as inhibiting the activation of trigeminocervical
`neurons.[114] Clearly, blockade of the release and
`action of CGRP both inhibits trigeminovascular no-
`ciceptive transmission in the trigeminocervical com-
`plex and CGRP release in experimental animals and
`humans. In a randomised, double-blind, multicentre
`Stimulation of the trigeminal ganglion in the cat
`clinical trial of olcegepant,[145] a total of 126 patients
`and humans results in elevations in CGRP and sub-
`stance P levels in the cranial circulation.[36] Howev- were treated with one of the following: placebo or
`er, during acute attacks of migraine, CGRP is elevat-
`olcegepant 0.25, 0.5, 1.0, 2.5, 5.0 or 10.0mg given
`ed but substance P is not.[132,133] Similarly, nitroglyc-
`intravenously over 10 minutes. A group sequential
`erin-induced migraine, which has no important
`adaptive treatment assignment design was used to
`clinical differences to so-called spontaneous at- minimise the number of patients. The 2.5mg dose
`tacks,[91,134] is also associated with increased levels was selected and was associated with a response rate
`of CGRP in the plasma.[135] Sumatriptan, a triptan
`of 65.6% versus 26.8% for placebo (p = 0.001).
`that is clearly effective in migraine,[10] blocks CGRP
`Significant superiority over placebo was also ob-
`
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`served for most secondary parameters: freedom
`from pain at 2 hours; sustained response over 24
`hours; headache recurrence; nausea; photophobia;
`phonophobia; improvement in functional capacity;
`and time to meaningful relief. An effect was appar-
`ent after 30 minutes and increased over the next few
`hours. The overall adverse event rate was 25% fol-
`lowing treatment with olcegepant 2.5mg and 20%
`for all active doses versus 12.2% for placebo. The
`most frequent adverse effect was paraesthesias.
`There were no serious adverse events.[145]
`
`5. Conclusion
`
`From the results discussed in section 4 it seems
`clear that olcegepant is an effective treatment for
`acute migraine. The rationale for the development of
`CGRP receptor antagonists is firmly based on the
`interaction between basic science and clinical prac-
`tice, and represents a classic case of translational
`medicine at work. However, many questions re-
`main, such as whether CGRP receptor antagonists
`will be effective in preventive use or short-term
`prophylaxis, whether they will be useful in medica-
`tion overuse headache, whether they will be useful
`in cluster headache, and how useful they can be in
`migraine. One hypothesis for their action would be
`an entirely neural one, in that the major effect in-
`volves the blockade of nociceptive traffic in the
`trigeminocervical complex. Such a neural action,
`and the lack of a vasoconstrictor effect, would pro-
`vide major advantages in practice, eliminating con-
`cerns regarding unwanted vascular effects in pa-
`tients. The future for these medications looks bright
`and, therefore, the future for patients with migraine
`or other primary headaches looks even brighter.
`
`Acknowledgements
`
`The work of the author has been supported by the
`Wellcome Trust. The author has advised or collaborated with
`the manufacturers of the triptans and Boehringer-Ingelheim.
`
`References
`1. Lipton RB, Stewart WF, Diamond S, et al. Prevalence and
`burden of migraine in the United States: data from the Ameri-
`can Migraine Study II. Headache 2001; 41: 646-57
`
`2. Menken M, Munsat TL, Toole JF. The global burden of disease
`study: implications for neurology. Arch Neurol 2000; 57:
`418-20
`3. Goadsby PJ, Lipton RB, Ferrari MD. Migraine: current under-
`standing and treatment. N Engl J Med 2002; 346: 257-70
`4. Lance JW, Goadsby PJ. Mechanism and management of head-
`ache. 7th ed. New York: Elsevier, 2005
`5. Goadsby PJ. The pharmacology of headache. Prog Neurobiol
`2000; 62: 509-25
`6. Doenicke A, Siegel E, Hadoke M, et al. Initial clinical study of
`AH25086B (5-HT1-like agonist) in the acute treatment of
`migraine. Cephalalgia 1987; 7: 437-8
`7. Doenicke A, Brand J, Perrin VL. Possible benefit of GR43175, a
`novel 5-HT1-like receptor agonist, for the acute treatment of
`severe migraine. Lancet 1988; I: 1309-11
`8. Ferrari MD, The Subcutaneous Sumatriptan International Study
`Group. Treatment of migraine attacks with sumatriptan.
`N Engl J Med 1991; 325: 316-21
`9. Dodick D, Lipton RB, Martin V, et al. Consensus statement:
`cardiovascular safety profile of triptans (5-HT1B/1D agonists)
`in the acute treatment of migraine. Headache 2004; 44: 414-25
`10. Ferrari MD, Roon KI, Lipton RB, et al. Oral triptans (serotonin,
`5-HT1B/1D agonists) in acute migraine treatment: a meta-
`analysis of 53 trials. Lancet 2001; 358: 1668-75
`11. Ferrari MD, Goadsby PJ, Roon KI, et al. Triptans (serotonin,
`5-HT1B/1D agonists) in migraine: detailed results and methods
`of a meta-analysis of 53 trials. Cephalalgia 2002; 22: 633-58
`12. Humphrey PPA, Goadsby PJ. Controversies in headache: the
`mode of action of sumatriptan is vascular? A debate.
`Cephalalgia 1994; 14: 401-10
`13. Amara SG, Jonas V, Rosenfeld MG, et al. Alternative RNA
`processing in calcitonin gene expression generates mRNAs
`encoding different polypeptide products. Nature 1982; 298:
`240-4
`14. Amara SG, Arriza JL, Leff SE, et al. Expression in brain of a
`messenger RNA encoding a novel neuropeptide homologous
`to calcitonin gene-related peptide. Science 1985; 229: 1094-7
`15. Chan-Palay V, Edvinsson L. Innervation of cerebral blood ves-
`sels by norepinephrine indolamine substance P and neuroten-
`sin fibres and the leptomeningeal indolamine axons: their roles
`in vasomotor activity and local alterations of brain blood
`composition. In: Owman C, editor. Neurogenic control of the
`brain circulation. Sydney: Pergamon Press, 1977: 39-53
`16. Wolff HG. Headache and other head pain. 1st ed. New York:
`Oxford University Press, 1948
`17. Edvinsson L, McCulloch J, Uddman R. Substance P: immu-
`nohistochemical localization and effect upon cat pial arteries in
`vitro and in situ. J Physiol 1981; 318: 251-8
`18. Uddman R, Edvinsson L, Owman C, et al. Perivascular sub-
`stance P: occurrence and distribution in mammalian pial ves-
`sels. J Cereb Blood Flow Metab 1981; 1: 227-32
`19. Uddman R, Edvinsson L, Ekman R, et al. Innervation of the
`feline cerebral vasculature by nerve fibers containing calci-
`tonin gene-related peptide: trigeminal origin and co-existence
`with substance P. Neurosci Lett 1985; 62: 131-6
`20. Liu-Chen LY, Han DH, Moskowitz MA. Pia arachnoid contains
`substance P originating from trigeminal neurons. Neuro-
`science 1983; 9: 803-8
`21. Liu-Chen LY, Mayberg MR, Moskowitz MA. Immunohisto-
`chemical evidence for a substance P-containing trigeminovas-
`cular pathway to pial arteries in cats. Brain Res 1983; 268:
`162-6
`
`© 2005 Adis Data Information BV. All rights reserved.
`
`Drugs 2005; 65 (18)
`
`7
`
`

`

`2564
`
`Goadsby
`
`22. Moskowitz MA, Brody M, Liu-Chen LY. In vitro release of
`immunoreactive substance P from putative afferent nerve end-
`ings in bovine pia arachnoid. Neuroscience 1983; 9: 809-14
`23. Edvinsson L, Rosendahl-Helgesen S, Uddman R. Substance P:
`localization, concentration and release in cerebral arteries,
`choroid plexus and dura mater. Cell Tissue Res 1983; 234: 1-7
`24. Liu-Chen L-Y, Gillespie SA, Norregaard TV, et al. Co-localiza-
`tion of retrogradely transported wheat germ agglutinin and the
`putative neurotransmitter substance P within trigeminal gan-
`glion cells projecting to cat middle cerebral. J Comp Neurol
`1984; 225: 187-92
`25. Uddman R, Hara H, Edvinsson L. Neuronal pathways to the rat
`middle meningeal artery revealed by retrograde tracing and
`immunocytochemistry. J Auton Nerv Syst 1989; 26: 69-75
`26. Edvinsson L, Hara H, Uddman R. Retrograde tracing of nerve
`fibers to the middle cerebral artery with true blue: co-localiza-
`tion with different peptides. J Cereb Blood Flow Metab 1989;
`9: 212-8
`27. Moskowitz MA, Reinhard JF, Romero J, et al. Neurotransmit-
`ters and the fifth cranial nerve: is there a relation to the
`headache phase of migraine? Lancet 1979; II: 883-4
`28. Edvinsson L, McCulloch J, Kingman TA, et al. On the function-
`al role of the trigemino-cerebrovascular system in the regula-
`tion of cerebral circulation. In: Owman C, Hardebo JE, editors.
`Neural regulation of the cerebral circulation. Stockholm: El-
`sevier Science Publishers BV, 1986: 407-18
`29. McCulloch J, Uddman R, Kingman TA, et al. Calcitonin gene-
`related peptide: functional role in cerebrovascular regulation.
`Proc Natl Acad Sci U S A 1986; 83: 1-5
`30. Lambert GA, Bogduk N, Goadsby PJ, et al. Decreased carotid
`arterial resistance in cats in response to trigeminal stimulation.
`J Neurosurg 1984; 61: 307-15
`31. Goadsby PJ, Edvinsson L, Ekman R. Vasoactive peptides in the
`trigeminovascular system of man. Proceedings of the 10th
`International Congress of Pharmacology. Copenhagen: El-
`sevier Science Publishers, 1987: O319
`32. Goadsby PJ, Edvinsson L, Ekman R. Extracerebral levels of
`circulating vasoactive peptides during migraine headache.
`Cephalalgia 1989; 9 Suppl. 10: 292-3
`33. Arbab MA-R, Wiklund L, Svendgaard NA. Origin and distribu-
`tion of cerebral vascular innervation from superior cervical,
`trigeminal and spinal ganglia investigated with retrograde and
`anterograde WGA-HRP tracing in the rat. Neuroscience 1986;
`19: 695-708
`34. Liu Y, Zhang M, Broman J, et al. Central projections of sensory
`innervation of the rat superficial temporal artery. Brain Res
`2003; 966: 126-33
`35. Liu Y, Broman J, Edvinsson L. Central projections of sensory
`innervation of the rat superior sagittal sinus. Neuroscience
`2004; 129: 431-7
`36. Goadsby PJ, Edvinsson L, Ekman R. Release of vasoactive
`peptides in the extracerebral circulation of man and the cat
`during activation of the trigeminovascular system. Ann Neurol
`1988; 23: 193-6
`37. O’Connor TP, van der Kooy D. Enrichment of a vasoactive
`neuropeptide (calcitonin gene related peptide) in trigeminal
`sensory projection to the intracranial arteries. J Neurosci 1988;
`8: 2468-76
`38. O’Connor TP, van der Kooy D. Pattern of intracranial and
`extracranial projections of trigeminal ganglion cells. J Neuros-
`ci 1986; 6: 2200-7
`
`39. Feindel W, Penfield W, McNaughton F. The tentorial nerves
`and localization of intracranial pain in man. Neurology 1960;
`10: 555-63
`40. Ray BS, Wolff HG. Experimental studies on headache: pain
`sensitive structures of the head and their significance in head-
`ache. Arch Surg 1940; 41: 813-56
`41. Penfield W, McNaughton FL. Dural headache and the innerva-
`tion of the dura mater. Arch Neurol Psychiatry 1940; 44: 43-75
`42. McNaught