Progress in Neurobiology 62 (2000) 509±525 www.elsevier.com/locate/pneurobio

The pharmacology of headache

Peter J. Goadsby*

Institute of Neurology, The National Hospital for Neurology and Neurosurgery, Queen Square, London WC1N 3BG, UK Received 10 January 2000

Abstract

Headache is a common problem which besets most of us at some time or the other. The pharmacology of headache is complex in an overall sense but can be understood in terms of the anatomy and physiology of the pain-producing structures. Migraine can be used as a template to understand the activation of nociceptive systems in the head and thus their neurotransmitter mediation and modulation. In recent years, the role of serotonin (5-HT) in headache pharmacology has been unravelled in the context of both understanding its role in the nociceptive systems related to headache and by exploiting its 5- HT1 receptor subtypes in headache therapeutics. The pharmacology of the head pain systems, as they are known and as they might evolve, are explored in the context of both, the anatomy and physiology of trigeminovascular nociception and in the context of clinical questions, such as those of ecacy, headache recurrence and adverse events. 7 2000 Published by Elsevier Science Ltd.

Contents

1. Introduction ...... 510

2. Serotonin (5-HT) and headache ...... 510 2.1. Ecacy and 5-HT receptor activity...... 511

2.2. Molecular action of the 5-HT1B/1D agonists ...... 511

3. Pain expression in primary headache...... 512 3.1. Cranial vessels and the dura mater ...... 513 3.2. Peripheral terminals of the trigeminal nerve...... 513 3.2.1. Neurogenic Plasma Protein Extravasation (PPE) ...... 513 3.2.2. Intravital durally-evoked vasodilatation ...... 513 3.2.3. Inhibition of neuropeptide release...... 514 3.3. The trigeminal nucleus...... 515 3.3.1. Serotonin pharmacology ...... 515 3.3.2. Other receptor systems ...... 516

4. Speci®c pharmacological targets in primary headache...... 516 4.1. Inhibitors of neurogenic plasma protein extravasation ...... 516

4.2. 5HT1F receptor agonists...... 516 4.3. 5HT1D receptor...... 517

Abbreviations: 5-HT, serotonin. * Tel.: +44-(0)207-837-3611; fax: +44-(0)207-813-0349. E-mail address: [email protected] (P.J. Goadsby).

0301-0082/00/$ - see front matter 7 2000 Published by Elsevier Science Ltd. PII: S0301-0082(00)00010-1 510 P.J. Goadsby / Progress in Neurobiology 62 (2000) 509±525

5. Speci®c issues in headache pharmacology ...... 517 5.1. What makes an acute attack drug better? ...... 517 5.2. Headache recurrence ...... 517 5.2.1. Ergotamine Ð back to the future for an answer ...... 518 5.3. P-glycoprotein pump substrates Ð evidence for central action of triptans ...... 518 5.4. Side e€ects and the coronary issue ...... 519

Acknowledgements...... 519

References ...... 519

1. Introduction ally and then attempt to discuss the pain modulation systems (Table 1). Conveniently, this division includes Headache is perhaps among the commonest a‚ic- the essential therapeutic options of acute attack and tions of humans. Its classi®cation runs to 96 pages preventative management (Goadsby and Olesen, 1996). (Headache Classi®cation Committee of The Inter- Much of what has been studied has been speci®cally national Headache Society, 1988) and the number of directed at migraine therapeutics which provides the headache types keeps the most devoted, enthralled. best data and will be used as a template for under- However, the cranial nociceptive system for headache standing headache more broadly. Serotonin pharma- is relatively limited in terms of the structures that are cology will be outlined broadly ®rst, this is in some involved so that understanding basic headache phar- ways historical, although it is impossible to adequately macology is a reasonable goal. Headache is broadly consider the current state of headache pharmacology divided into primary or idiopathic headache, and sec- without some consideration of the role of serotonin (5- ondary or symptomatic headache. Symptomatic head- HT). aches rely upon entraining the nociceptive pathways that the primary headache syndromes also employ so that basic headache biology is best considered in terms of the primary headaches. The subject is dealt with 2. Serotonin (5-HT) and headache more fully in the clinical sense in recent monographs (Lance and Goadsby, 1998; Silberstein et al., 1998) Suggestions for the involvement of serotonin in and reviews (Ferrari, 1998; Goadsby, 1998a, 1998b). migraine date back to nearly 40 years and stem from Broadly, primary headache can be understood in certain seminal observations. The most convincing terms of the pain expression system, the trigeminovas- data demonstrated that: cular and cranial autonomic innervation, and pain . Urinary excretion of 5-hydroxyindoleacetic acid, the processing and modulation systems. The pain ex- main metabolite of serotonin, was increased in as- pression is shared, and to some extent this is why there sociation with migraine attacks (Curran et al., 1965; is so much phenotypic overlap in headache syndromes, Sicuteri et al., 1961); yet the central mechanisms, at least those that are cau- . Platelet 5-HT was found to drop rapidly during the sative, hold the individual keys to the syndromes. This onset of the migraine attack (Anthony et al., 1967); review will detail the pain expression systems generic- . Intravenous injection of 5-HT aborts either reser-

Table 1 An anatomical and physiological approach to headache

Pain expression systems (treating the acute attack) Pain response or modulation systems (preventing headache)

Cranial vessels and dura mater Frontal cortex Trigeminal innervation Insula cortex peripheral terminals Cingulate cortex central terminals Thalamus Cranial parasympathetic innervationa Disease speci®c regions rostral brainstemb posterior hypothalamic grey matterc

a Activated particularly in trigeminal-autonomic syndromes, such as, cluster headache and paroxysmal hemicrania (Goadsby and Lipton, 1997). b Migraine. c Cluster headache. P.J. Goadsby / Progress in Neurobiology 62 (2000) 509±525 511

pine-induced or spontaneous headache (Kimball et 2.1. Ecacy and 5-HT receptor activity al., 1960; Lance et al., 1967). Although the Triptans have some variable 5HT These data suggested since 5-HT drops during 1A, 1E agonist actions (Table 3), it would seem that the migraine and when infused relieves attacks, that a suit- or 1F commonality of their action is at the 5HT1B/1D sites. It able serotonin receptor target might be identi®ed to is noteworthy that despite this clear pharmacology and retain the anti-migraine e€ects without the unwanted the known heritability of migraine (Honkasalo et al., e€ects of serotonin administration, such as, ¯ushing, 1995), each of the 5HT1B, 5HT1D (Marttila et al., nausea, faintness, hyperpnoea and paraesthesiae. 1999) and 5HT1F (vanDenBrink et al., 1998) sites have The classi®cation of the 5-HT receptors has received been excluded as being responsible for migraine and considerable attention in recent years driven in large the 5HT1B site from predicting sumatriptan responses measure by developments in molecular techniques and (Maassen vanDenBrink et al., 1998b). It may be of the therapeutic roles of speci®c drugs, such as, triptans research interest that some of the compounds, such as, sumatriptan, almotriptan (Bou et al., 1997) and frova- (5-HT1B/1D) and 5-HT3 anti-emetics. The current classi®cation (Hoyer et al., 1994) (Table 2) and the triptan (SB209509 or VML- 251) (Brown et al., 1996), alignment of the nomenclature with the molecular data have actions at the vasodilator 5HT7 receptor (Eglen (Hartig et al., 1996) have provided a robust system et al., 1997), but at the doses used clinically this action (Table 3). This alignment of the 5HT-1 subclass seems largely irrelevant. Relative speci®city of action distinguishes the Triptans from the ergots (Tfelt-Han- nomenclature with the known molecular biology has sen et al., 2000) (Table 4). It has been suggested that eliminated some unnecessary complications. The the 5HT receptor may play a role in migraine preven- 5HT , 5HT and 5HT receptors have been 2 1Da 1Db 1B tion (Fozard and Gray, 1989; Kalkman, 1994). reclassi®ed as 5HT1D and 5HT1B, respectively (Table 3). The human and rat receptors, previously 2.2. Molecular action of the 5-HT1B/1D agonists called 5HT1Db and 5HT1B, are now called h- or r- 5HT1B to indicated human or rat forms. The Triptans Activation of the 5-HT1 subclass of receptors leads in clinical development or use, viz., sumatriptan, almo- to a reduction in intracellular c-AMP (Pauwels et al., triptan, eletriptan, frovatriptan, naratriptan, rizatriptan 1997; Pauwels et al., 1998). Studying human 5-HT1B and zolmitriptan, share the pharmacology of being and 5-HT1D receptors in stably transfected C6 glioma

5HT1B/1D receptor agonists in this nomenclature. cells, John and collaborators established that sumatrip-

Table 2 Classi®cation of serotonin (5-HT) receptorsa

5HT receptor class Second messenger Antagonist Comments

1 q Adenylate cyclase Subclasses A, B, D, E, F

2 Q Phosphoinositide turnover Methysergide pizotifen Contraction of smooth muscle Central nervous system excitation

Subtypes: 2A,2B,2C

3K+ Ondansetron Membrane depolarisation Ca2+ Granisetron Na+

4 Q Adenylate cyclase GR113808 bGI smooth muscle relaxation Found in striato-nigral system

5 ± Subclasses A and B

6 Q Adenylate cyclase Ro04-6790 (Bentley et al., 1999) Found in limbic system Atypical anti-psychotics bind

7 Q Adenylate cyclase SB 258719 Splice variants (Jasper et al., 1997) Vasodilator Role in circadian rhythms

a Modi®ed from Hoyer et al. (1994). b GI, gastrointestinal. 512 P.J. Goadsby / Progress in Neurobiology 62 (2000) 509±525

Table 3 Classi®cation of serotonin (5-HT)-1 receptorsa

Subtype of 5HT1 receptor Agonist Antagonist Function

A 8-OH-DPATc WAY100165b Hypotension Dihydroergotamine Behavioural (satiety) Sumatriptan Eletriptan Frovatriptan Naratriptan

Rat B CP-93,129b Central autoreceptor (rat) Human B Dihydroergotamine SB 216641 Craniovascular receptor b (Previously 1Db) All Triptans GR127935

D Dihydroergotamine BRL 15572 Trigeminal neuronal receptor b (previously 1Da) All Triptans GR127935

E±±?

F Sumatriptan Eletriptan Frovatriptan ± Trigeminal neuronal receptor Naratriptan Zolmitriptan LY334370d

a Modi®ed from Hartig and colleagues (1996) and assigning activity only for pKi's of 7.0 or greater, see Table 4. b 8-OH-DPAT (8-hydroxy-2-(di-n-propylamino)tetralin), WAY100165, CP-93,129 and GR127935 are all compounds used in the laboratory for pharmacological purposes and have no current clinical indications. c Triptans: sumatriptan, almotriptan, eletriptan, frovatriptan, naratriptan, rizatriptan, zolmitriptan. d Dose-dependent anti-migraine e€ect; development stopped for animal toxicity (Goldstein et al., 1999c; Phebus et al., 1997).

tan binding produced hyperpolarisation by an and an IP3 receptor blocker, respectively, indicating + increased K current and this e€ect could be blocked that the 5HT1B/1D current was calcium dependent, by the 5-HT1B/1D antagonist (Le Grand et al., 1998) IK/Ca. GR127935 (Clitherow et al., 1994). Moreover, this increase in IK could be prevented by a calcium chela- tor, an endoplasmic reticulum Ca-ATPase inhibitor 3. Pain expression in primary headache

Table 4 Understanding the pharmacology of acute anti- Comparison of the pharmacology of dihydroergotamine and suma- migraine compounds is intimately linked to under- triptana standing the pain-producing innervation of the cranial circulation and the intracranial contents that is largely Dihydroergotamine Sumatriptan subserved by branches of the ophthalmic division of Serotonergic (5-HT) the trigeminal nerve (Pen®eld, 1932; Pen®eld and

1A +++ + McNaughton, 1940). The e€ect of anti-migraine drugs 1B +++ ++ upon the trigeminovascular system is the crucial link 1D +++ ++ 1E ++ 1F +++Table 5 2A/C + Current concepts of the pharmacology of acute anti-migraine drugs 3 Adrenergic Target Receptor a1a,b ++ a ++ 2a,b,c Large cranial vessels 5-HT1B b1,2,3 //+ Peripheral terminal of the trigeminal nerve Dopaminergic Inhibits plasma protein extravasation 5-HT1D/1F D 1,5 Blocks dural vasodilatation 5-HT1D D ++ 2,3,4 Inhibits release of trigeminal neuropeptides 5-HT1D Trigeminal nucleus inhibition 5-HT1B/1D a Based on direct comparative anity data (Goadsby and Har- 5-HT1F greaves, 2000). P.J. Goadsby / Progress in Neurobiology 62 (2000) 509±525 513 in understanding the clinical e€ects of these drugs and the anti-migraine action is unclear, although certainly has informed the whole range of headache problems the AVA shunt model has been extremely useful in (Table 5) (Goadsby, 1997a). terms of dissecting the pharmacology surrounding the Triptans' development. 3.1. Cranial vessels and the dura mater 3.2. Peripheral terminals of the trigeminal nerve The role and pharmacology of the large intracra- nial vessels and dura mater in headache, and The pathway from the pain-producing structures to speci®cally in migraine, has been de®ned by the the level of cortical processing has a peripheral (extra- search for compounds that would mimic the e€ects axial) component and a central dimension. The periph- of serotonin and ergotamine on the cranial circula- eral element, the trigeminal innervation of pain-produ- tion without systemic e€ects (Humphrey et al., cing, mainly vascular, structures (the trigeminovascular 1990). The role of serotonin is discussed explicitly system), has been studied in considerable detail in below. The development of sumatriptan was facili- recent years. The inhibition of trigeminal a€erents in tated by the selective distribution of the ultimate the periphery may be monitored in three ways: ®rst, target receptor in the carotid bed (Humphrey et al., an inhibition of neurogenic plasma protein extravasa- 1991) and in the saphenous vein (Bax et al., 1992), tion, second, by monitoring vessels in situ, and third, which has now been con®rmed anatomically using inhibition of neuropeptide release. highly selective 5HT1B and 5HT1D receptor anti- bodies, to be almost exclusively of the 5HT1B sub-type 3.2.1. Neurogenic Plasma Protein Extravasation (PPE) (Longmore et al., 1997b; Nilsson et al., 1999a). Seroto- Electrical stimulation of the trigeminal ganglion nin contracts large human carotid vessels in vivo results in leakage of plasma proteins (Markowitz et al., (Lance et al., 1967) and has potent actions in the 1987) from post-capillary venules (Dimitriadou et al., monkey cranial circulation (Spira et al., 1978). Suma- 1992). This plasma protein extravasation (PPE) results triptan, and its immediate predecessor AH25086B in a sterile in¯ammation in the dura mater that may (Doenicke et al., 1987), is a potent constrictor of large explain some symptoms, particularly exacerbation of cerebral vessels (Friberg et al., 1991; Perren et al., headache by movement (Burstein et al., 1998; Strass- 1991) and pial vessels (Connor et al., 1992). It has, man et al., 1996). PPE can be blocked by an array of however, no e€ects on resting cerebral blood ¯ow in agents including aspirin (Buzzi et al., 1989), indo- experimental animals (Goadsby and Edvinsson, 1993; methacin (Buzzi et al., 1989; Buzzi and Moskowitz, Humphrey et al., 1991) or in humans (Weiller et al., 1990), sumatriptan (Buzzi and Moskowitz, 1990), 1995). valproate (Lee et al., 1995) and neurosteroids (Limm-

The dog carotid vessel has been widely used to roth et al., 1996). This e€ect is mediated by the 5HT1B evaluate the cranial vasoconstrictor potency of the receptor in mice, since in genetically altered mice with

Triptans. The ED50 for carotid constriction in the dog no 5HT1B receptors sumatriptan is ine€ective in block- in mg/kg for sumatriptan is 39 (Feniuk et al., 1989), ing PPE (Yu et al., 1996). while in comparison it is 010 for almotriptan in the With respect to the Triptans, the ED50 in mg/kg for cat (Bou et al., 1997), 12 for eletriptan (Gupta et al., inhibition of PPE in the rat is 4 for sumatriptan (Buzzi 1996), 19 for naratriptan (Connor et al., 1997), 30 for and Moskowitz, 1990), 200 for almotriptan (Bou et al., rizatriptan (Williamson et al., 1997c), 10 for zolmitrip- 1997), 100 for eletriptan (Gupta et al., 1996), which tan (Martin et al., 1997) and 0.38 for frovatriptan was a dose for inhibition rather than an ED50, 4 for (SB209509, VML-251) (Parsons et al., 1996). On this naratriptan (Connor et al., 1997), 30 for rizatriptan basis, there is little to choose between the compounds (Williamson et al., 1997c), 10 for zolmitriptan (Martin in terms of cranial vasoconstrictor potency, save frova- et al., 1997), and is unknown for frovatriptan triptan, which is much more potent, and this may con- (SB209509, VML-251). There is a range of potency fer some formulation advantages. However, these that does not directly predict clinical ecacy and other di€erences can largely be overcome by careful choice issues which are addressed below. of clinical doses. It has been suggested that an important aspect of 3.2.2. Intravital durally-evoked vasodilatation the e€ect of 5HT1B/1D agonists is through an e€ect on Activation of dural a€erents can produce two re- arteriovenous shunts (Saxena, 1991). It is certainly well sponses, plasma extravasation and dural vasomotor documented that this class of drugs closes such shunts change. The latter has been speci®cally examined as an (de Vries et al., 1997; Den Boer et al., 1992; Villalon et attempt to study pre-junctional trigeminal terminals. al., 1992), and it is primarily through this mechanism Brie¯y, the model involves local electrical stimulation that cranial ¯ow is redistributed after their adminis- of the dura mater through a thin bone window. tration. The extent to which this change contributes to Vessels, branches of the middle meningeal artery, are 514 P.J. Goadsby / Progress in Neurobiology 62 (2000) 509±525 observed with a video microscropy-image measurement (Goadsby and Sercombe, 1996). The parasympathetic device to dynamically record vessel calibre. Measure- system is vasodilator, arises from the pterygopalatine ments of calibre can thus be made continuously, as the (sphenopalatine), optic and internal carotid mini- dural nerves are activated, and various substances ganglia, and is marked by vasoactive intestinal poly- administered. It has been shown that sumatriptan and peptide (VIP) and other substances (Goadsby and rizatriptan, both potent 5-HT1B/1D agonists (Goadsby, Edvinsson, 1997). The trigeminovascular system is 1998a) and e€ective acute anti-migraine compounds both sensory and vasodilator, arises from the trigem- (Ferrari and The Subcutaneous Sumatriptan Inter- inal ganglion, and is marked by substance P (SP), cal- national Study Group, Ferrari, 1991; Tfelt-Hansen et citonin gene-related peptide (CGRP) and neurokinin A al., 1998), are inhibitors of neurogenic dura vasodilata- (NKA). The distribution of the neuropeptides is sum- tion (Williamson et al., 1997b, 1997c). marised in Table 6. Moreover, in the same setting neurokinin-1, sub- stance P, mechanisms do not play a role in vasodilata- 3.2.3.1. Calcitonin gene-related peptide. Stimulation of tion, rather, calcitonin gene-related peptide (CGRP) is the trigeminal ganglion in cats and humans results in the main vasodilator transmitter (Williamson et al., the release of both SP and CGRP (Goadsby et al., 1997a). By studying both trigeminal neurons and using 1988). This e€ect is blocked by dihydroergotamine, intravital microscopy together, it has been shown that sumatriptan (Goadsby and Edvinsson, 1993), avitrip- CGRP-induced vasodilatation can lead to activation of tan (Knight et al., 1997) and zolmitriptan (Goadsby trigeminal neurons (Cumberbatch et al., 1999), o€ering and Edvinsson, 1994b) but not by CP122,288 (Gupta some insight into possible mechanisms of sensitisation et al., 1995), a conformationally restricted analogue of of dural nociceptors during migraine. sumatriptan (Knight et al., 1997), or 4991w93 (Giles et al., 1999), a conformationally restricted analogue of 3.2.3. Inhibition of neuropeptide release zolmitriptan (Knight et al., 1999). In this setting, Trigeminovascular activation is marked by release of CGRP release seems a good predictor of clinical out- neuropeptides (Edvinsson and Goadsby, 1998). The come possibly because it re¯ects trigeminal activity cranial circulation is innervated by three extrinsic (to directly. Stimulation of the superior sagittal sinus the brain) systems which are: the sympathetic, para- results in release of CGRP in the rat, which is attenu- sympathetic and trigeminal systems. The sympathetic ated by sumatriptan (Buzzi et al., 1991) and CGRP nerves are vasoconstrictor, arise from the superior cer- and VIP in the cat (Zagami et al., 1990). In humans vical ganglion and are marked by neuropeptide Y during migraine, CGRP is released instead of SP (Gal-

Table 6 Extrinsic innervation of the cerebral circulation

Ganglia E€ect of stimulation on CBF Transmitters

Sympathetic Superior cervical Noradrenaline Neuropeptide Y (NPY)

Parasympathetic Sphenopalatine Acetylcholine Otic + VIPa ICb miniganglia PHI (M)c PACAPd Helodermin Helospectin I and II Nitric oxide (NO)

Trigeminal Trigeminal + Substance P CGRPe Neurokinin-A (NKA) Amylin Cholecystokinin-8 PACAP NO

a Vasoactive intestinal polypeptide. b Internal carotid. c Peptide histidine isoleucine (methionine). d Pituitary adenlyate cyclase activating polypeptide. e Calcitonin gene-related peptide. P.J. Goadsby / Progress in Neurobiology 62 (2000) 509±525 515 lai et al., 1995; Goadsby and Edvinsson, 1993; trigeminocervical complex. It has also been shown that Goadsby et al., 1990); similarly, in cluster headache metabolic activity arising from stimulation of a clearly CGRP and VIP instead of SP release is seen (Fanciul- ophthalmic nerve (trigeminal) innervated structure, su- lacci et al., 1995; Goadsby and Edvinsson, 1994a) and perior sagittal sinus (Goadsby and Zagami, 1991), and similarly in chronic paroxysmal hemicrania (Goadsby the greater occipital nerve, a branch of C2 (Goadsby et and Edvinsson, 1996). al., 1997), has a considerable degree of overlap in the trigeminocervical complex. This overlap explains the 3.2.3.2. Substance P. In humans, thermocoagulation clinical fact that primary headache often ignores per- (Onofrio, 1975; Sweet and Wepsic, 1974) or injection ipheral cutaneous innervation patterns. These neurons of alcohol (Oka, 1950) into the trigeminal ganglion then form a target for headache pharmacology. (VG) is accompanied by ¯ushing of the skin in the dis- tribution of the appropriate division or divisions of the 3.3.1. Serotonin pharmacology nerve. Consistent with this ¯ush, increases in skin tem- The trigeminocervical complex has receptors that perature and capillary pulsation have been observed bind ‰3H]-dihydroergotamine (Goadsby and Gundlach, after thermocoagulation of the VG in humans for tic 1991). Speci®c binding of ‰3H]-sumatriptan in cat douloureux (Drummond et al., 1983). Cutaneous ¯ush- (Mills and Martin, 1995), guinea pig (Waeber and ing and pain can be associated with local release of Moskowitz, 1995) and humans (Pascual et al., 1996) calcitonin gene-related peptide (CGRP) in patients and of ‰3H]-zolmitriptan in the cat (Goadsby and with facial pain (Goadsby et al., 1992). Stimulation of Knight, 1997) has been demonstrated in the trigemino- the trigeminal ganglion in humans causes release of cervical complex and provides a locus of action for substance P, and calcitonin gene-related peptide levels 5HT1B/1D agonists. These cells can be inhibited by are increased in the ipsilateral external jugular vein if anti-migraine drugs, such as, dihydroergotamine (Hos- the patient ¯ushes (Goadsby et al., 1988). However, as kin et al., 1996a), eletriptan (Goadsby and Hoskin, observed above, substance P is not released in any 1999), naratriptan (Cumberbatch et al., 1998a; Knight detectable level in acute migraine (Goadsby et al., and Goadsby, 1997), rizatriptan (Cumberbatch et al., 1990). These clinical observations are consistent with 1997) and zolmitriptan (Goadsby and Hoskin, 1996). the lack of e€ect of substance P, neurokinin-1 antag- Sumatriptan does not inhibit the activity of these cells onists in acute migraine (Connor et al., 1998; Diener, unless the blood±brain barrier is disrupted (Kaube et 1996; Goldstein et al., 1997; Norman et al., 1998) and al., 1993a; Shepheard et al., 1995), an observation in its preventative management (Goldstein et al., broadly consistent with the lack of ecacy of subcu- 1999b). taneous sumatriptan given during the migraine aura Thus, neuropeptide release is a robust method of (Bates et al., 1994). Given the long-standing interest in detecting trigeminovascular activation in vivo, which serotonin in migraine (as discussed above), it is of can be applied to humans. The ®nding of VIP release some importance that intravenous 5-HT can block tri- implicates activity of parasympathetic nerves which geminal cell ®ring, just as those compounds syn- supports our basic observation of the presence of a thesised to mimic its actions, at doses comparable with functional trigeminal-autonomic loop (Goadsby and those used in humans (Goadsby and Hoskin, 1998). Duckworth, 1987) within the brain stem. Such a loop For both, serotonin (Goadsby and Hoskin, 1998) and would explain the very marked autonomic symptoma- the 5HT1B/1D agonist naratriptan (Knight and tology that accompanies certain primary headaches, Goadsby, 1997), the inhibition of trigeminal activity is such as, cluster headache and paroxysmal hemicranias blocked by the speci®c 5-HT1B/1D antagonist (Goadsby and Lipton, 1997) and is certainly seen in GR127935 (Clitherow et al., 1994). Data concerning some patients with migraine (Goadsby et al., 1990). the e€ect of 5-HT1A agonists suggests that they play no role in inhibiting trigeminocervical transmission 3.3. The trigeminal nucleus (Cumberbatch et al., 1998b). Considering that all these physiological studies have Electrical (Kaube et al., 1993b) or mechanical (Hos- employed intravenous administration of compounds, it kin et al., 1996b; Kaube et al., 1992) stimulation of the has been essential to question whether the e€ect of sagittal sinus or dural vessels (Davis and Dostrovsky, 5HT1B/1D agonists may be at some other site than the 1986) in the cat; and electrical stimulation of the sinus trigeminocervical complex. Microiontophoretic appli-

(Goadsby and Hoskin, 1997), or middle meningeal cation of 5HT1B/1D agonists, sumatriptan and zolmi- artery in the monkey (Hoskin et al., 1999) or cat triptan, as well as an ergot derivative on clearly (Davis and Dostrovsky, 1988; Hoskin et al., 1999) de®ned trigeminovascular nociceptive neurones results results in the activation of a group of cells in the the in reversible inhibition of ®ring (Storer and Goadsby, trigeminal nucleus caudalis and the super®cial laminae 1997). Using this method, no non-5-HT1B/1D agonist of the dorsal horn of the C1 and C2 spinal cord, the activity of the PPE inhibitor 4991w93 (Earl et al., 516 P.J. Goadsby / Progress in Neurobiology 62 (2000) 509±525

1999) could be detected in the trigeminal nucleus blocked neurogenic plasma protein extravasation (Storer et al., 1999). In humans, zolmitriptan can inhi- (PPE) by a prejunctional mechanism since it did not bit the auditory evoked potential (Proletti-Cecchini et prevent PPE induced by the exogenous substance P al., 1997), which has a degree of serotonergic in¯uence (Buzzi and Moskowitz, 1990). This observation and (Wang et al., 1996). There seems little doubt that the general thinking on the mechanism of action of suma- more lipophilic brain penetrant Triptans can e€ect triptan (Humphrey and Goadsby, 1994) lead to the CNS structures, and the trigeminocervical complex is pursuit of purely neural means of blocking PPE. One an ideal target for drug action currently proven for the such molecule CP122,288, a conformationally 5HT1B/1D receptor class agonists. restricted sumatriptan analogue, was 1000 times more potent than sumatriptan in blocking PPE and there- 3.3.2. Other receptor systems fore active at doses without vascular e€ects (Gupta et The trigeminal nucleus has a rich pharmacology al., 1995; Lee and Moskowitz, 1993). This compound which has begun to be explored. Glutamate is a major was studied in a double-blind placebo-controlled study source of excitatory transmission within the central and was ine€ective in acute migraine (Roon et al., nervous system (Seeburg, 1993). N-Methyl-D-aspartate 1997). A second speci®c PPE inhibitor, 4991w93, a (NMDA), a-amino-3-hydroxy-5-methylisoxazole-4-pro- conformationally restricted analogue of zolmitriptan, prionic acid (AMPA), kainate and metabotropic gluta- which is also a highly potent blocker at doses without mate receptors have been identi®ed in the super®cial vascular e€ects (Giles et al., 1999), is also clinically laminae of the trigeminal nucleus caudalis of the rat inactive in acute migraine (Earl et al., 1999). (Greene-Tallaksen et al., 1993). Furthermore, the pio- Similarly, both bosentan, an endothelin antagonist neering studies of Hill and Salt (Hill and Salt, 1982; (Brandli et al., 1996), and substance P, neurokinin-1 Salt and Hill, 1982) showed that iontophoretically (Lee et al., 1994), antagonists are highly e€ective anti- applied L-glutamate excited neurons in the trigeminal PPE agents but are also ine€ective in acute migraine nucleus caudalis. It has been shown that NMDA and studies (Goldstein et al., 1997; May et al., 1996). AMPA antagonists can inhibit trigeminal ®ring (Storer Neither substance P antagonists nor CP122,288 are and Goadsby, 1999), Fos expression (Classey et al., e€ective at the central trigeminal synapse described 1999) and local spinal cord blood ¯ow (Goadsby and above (Goadsby and Hoskin, 1999; Goadsby et al., Classey, 1999) due to stimulation of the superior sagit- 1998). In a study examining retinal extravasation tal sinus in the cat. Similarly, Fos expression in the tri- which can be measured in rat retina and blocked by geminal nucleus after administration of capsaicin can sumatriptan, no extravasation was seen in human ret- again be inhibited by NMDA (Mitsikostas et al., 1998) ina during acute migraine or cluster headache (May et or AMPA blockade (Mitsikostas et al., 1999b). Gluta- al., 1998). This human study has important impli- mate receptor blockade (Nicolodi and Sicuteri, 1996) cations. PPE involves at least albumin extravasation or NMDA receptor modulation, such as glycine site since 125I-albumin is used for its detection, and PPE is modulation (Carignani et al., 1998; Marret et al., 1999; seen in the retina of the rat behaving just as it does in Miyazaki et al., 1999; Nankai et al., 1998), form an the dura mater. Similarly, ¯uroscein is bound to albu- obvious target for acute intervention if adverse event min and thus leakage on ¯uroscein angiography would can be contained. be expected if the human retina had the same patho- physiological processes during migraine and cluster headache, as are seen in the rat when the trigeminal 4. Speci®c pharmacological targets in primary headache ganglion is stimulated. No changes are seen on ¯uros- cein angiography so that certainly the processes are The success of the triptan development programmes di€erent and the di€erence requires explanation. have led to demands for further innovative therapies.

This is driven by two issues, ®rst, not all patients 4.2. 5HT1F receptor agonists respond to triptans for reasons far from clear (Visser et al., 1996a), and second, perceived cardiovascular It has been suggested that the 5HT1F receptor risks (Ottervanger et al., 1997b) have encouraged (Adham et al., 1993) may be a possible target for an development of non-vascular acute anti-migraine anti-migraine drug (Branchek and Archa, 1997). The drugs. The issue of cardiovascular safety is moot and potent speci®c 5HT1F agonist LY334,370 has been is addressed explicitly below. developed (Phebus et al., 1997) and shown to block PPE (Johnson et al., 1997), consistent with early mol- 4.1. Inhibitors of neurogenic plasma protein ecular studies (Wainscott et al., 1998). Activation of 5- extravasation HT1F receptors does not seem to have vascular e€ects (Cohen and Schenck, 1999; Razzaque et al., 1999). It was shown very clearly in the rat that sumatriptan LY334,370 has recently been reported to be e€ective P.J. Goadsby / Progress in Neurobiology 62 (2000) 509±525 517 in acute migraine, albeit at doses with some central 5. Speci®c issues in headache pharmacology nervous system side e€ects (Goldstein et al., 1999c). No cardiovascular problems were seen in these studies 5.1. What makes an acute attack drug better? (Goldstein et al., 1999a), but unfortunately, develop- ment has stopped because of a toxicity problem in the It seems almost provocative to ask the question as it dog. Although these studies are of enormous interest, begs an answer that some drugs work better than they do not contribute to the PPE issue since there are others. While there are now a number of direct com-

5HT1F receptors in the trigeminal nucleus (Castro et parisons between the triptans and di€erences emerge al., 1997; Fugelli et al., 1997; Pascual et al., 1996; (Bomhof et al., 1999; Diener et al., 1999; Goldstein et Waeber and Moskowitz, 1995) and trigeminal ganglion al., 1998b; Tfelt-Hansen et al., 1998), it is possible to understand properties of individual drugs that can (Bouchelet et al., 1996). Moreover, 5-HT1F agonism is inhibitory in the trigeminal nucleus in rat (Mitsikostas answer this question. A comparison of the response et al., 1999a). Anti-migraine drugs not potent at the rates of sumatriptan for subcutaneous, intranasal and oral formulations, as they have been summarised 5HT1F receptor, such as rizatriptan, are e€ective anti- PPE agents (Williamson et al., 1997c) and are clinically (Dahlof, 1999; Tfelt-Hansen, 1998), demonstrates that e€ective. Yet, it must be borne in mind that sumatrip- the tablets work less e€ectively than the nasal spray tan and a number of other Triptans, notably eletriptan, which is in turn less e€ective than the injection. Given naratriptan and zolmitriptan, are also agonists at the that the drug is the same with identical receptor a- nity and physico-chemical properties, the di€erence 5HT1F site, while alniditan, which is certainly active in migraine (Goldstein et al., 1996) and PPE (Limmroth can be only a few. Given time, the area-under-the- et al., 1997), but is no longer being clinically devel- curve can be comparable but what is never the same is the T , the time to reach maximal plasma concen- oped, is relatively inactive at the 5HT receptor max 1F tration. Similarly, comparing ecacy rates for nara- (Leysen et al., 1996). On pre-clinical grounds, the triptan by oral administration (Goadsby, 1997b; 5-HT1F receptor seems to represent a second target Gunasekara and Wiseman, 1997; Klassen et al., 1997; which does not displace what can be concluded about Mathew et al., 1997) and injection (Dahlof et al., the 5HT receptors but provides another useful 1B/1D 1998b), there is stark di€erence between the oral re- treatment option. sponse rates and the much superior injectable response

rate; and the di€erence between the Tmax is greater for naratriptan. This principle extends to even non-speci®c therapies, such as aspirin, where again the intravenous 4.3. 5HT1D receptor formulation (Diener and ASASUMAMIG Study Group, Diener, 1999) with its very rapid Tmax seems to be superior to oral aspirin (Tfelt-Hansen et al., 1995) Similar to the 5HT1F agonists, 5HT1D agonists were in the treatment of acute migraine. shown to be potent inhibitors of PPE (Waeber et al., 1997) and to have no vascular e€ects. Speci®c potent 5.2. Headache recurrence 5HT1D agonists have been developed by taking advan- tage of similarities between human and non-human Headache recurrence is the phenomenon of an acute primate 5HT1B and 5HT1D receptors (Pregenzer et al., migraine treatment improving, probably strictly abol- 1997). One compound has gone forward into clinical ishing pain and then the pain worsening signi®cantly studies, PNU 142633, and was ine€ective (McCall, per- within 24 h of that improvement. Not all recurrence sonal communication), although it was a relatively data have been collected in the same way but the over- weak agonist when compared to sumatriptan in in all concept is of getting distinctly better and then vitro studies (Pregenzer et al., 1999). This compound worse. This author takes the view that recurrence was developed in gorilla receptors and it must, there- might be simpler to study if it necessarily implied fore, be asked as to whether this was the correct com- headache resolution, and the adoption of the headache pound to test the 5-HT1D hypothesis. It is perhaps free endpoint, as currently suggested by the Inter- more remarkable that there were no complaints of national Headache Society Clinical Trials Committee adverse events of a cardiovascular nature in the pla- (International Headache Society Committee on Clini- cebo group, with cardiovascular adverse events, includ- cal Trials in Migraine, 1991), would make the process ing chest pain, in the PNU 142633, treated group. It being examined more homogenous and perhaps easier would be very important to show conclusively that to study. However, to be practical if patients say that some part of triptan chest symptoms are non-vascular, their headache gets better and then gets worse, what- as these data suggest. A further study with a more ever they mean, they may well be describing recur- potent agonist would clarify this situation enormously. rence, and the gap between understanding and 518 P.J. Goadsby / Progress in Neurobiology 62 (2000) 509±525 characterising recurrence is probably broader than we BMS181885 have shown that the compound has a currently imagine. The mild to moderate transition long duration of action in vivo constricting vessels and remains a problem when it comes to understanding the a Ko€ that is 50 times slower than dihydroergotamine nature of headache recurrence. As it stands, headache and 70 times slower than sumatriptan, yet its rate of recurrence can be seen with all acute attack medi- headache recurrence is identical to sumatriptan in cations that have been studied properly. It is not a clinical studies. Triptan only phenomenon but was recognised as suma- A plausible explanation for dihydroergotamine or triptan ushered in a new era of controlled clinical trials indeed for naratriptan would be that the combination in migraine. What is its pharmacology? of the pharmacology and their actions at central recep- Sumatriptan has a short half life of 2 h (Fowler et tors might contribute to a reduction of headache recur- al., 1991) which has been considered responsible for rence by in¯uencing central brain stem areas (Goadsby headache recurrence. Recurrence rates for sumatriptan et al., 1991), which are within the regions active in across studies are between 30 and 40% (Visser et al., migraine (Weiller et al., 1995) on PET studies. This 1996c, 1996g). Similar rates are seen with rizatriptan view is supported by the outcome across the eletriptan (Gijsman et al., 1997; Goldstein et al., 1998b; Teall et trials with a high early ecacy and relatively less al., 1998; Tfelt-Hansen et al., 1998; Visser et al., 1996e, recurrence than sumatriptan in a more lipophilic drug 1996f) and zolmitriptan (Dahlof et al., 1998a; Rapo- (Pitman, 1999). A reasonable hypothesis might be that port et al., 1997; Solomon et al., 1997; Visser et al., recurrence is due to an ongoing central nervous system 1996d). Naratriptan had a consistently low rate of process which re-activates and thus, the crucial combi- recurrence across the clinical studies (Goadsby, 1997b), nation in a Triptan will be of appropriate pharma- and a signi®cantly lower rate of recurrence when tested cology and good brain penetration. against sumatriptan in a double-blind crossover study in a group of patients in whom recurrence was com- mon (Gobel et al., 1997). These data ®t the t1=2 hy- pothesis but not all data do. 5.3. P-glycoprotein pump substrates Ð evidence for Frovatriptan (SB209509, VML-251) has as its major central action of triptans reported advantage lower headache recurrence ranging from 8 to 10%, however, in the same study, placebo The dose of 80 mg required to obtain clinical e€ects recurrence was 18% (Goldstein et al., 1998a; Ryan with eletriptan superior to sumatriptan (Goadsby et and Keywood, 1997) and thus half what is seen in al., 2000) seems high given that eletriptan has better most large clinical studies. Frovatriptan (SB209509, bioavailability at 50% (Morgan et al., 1997) compared VML-251) has the longest half life of any of the Trip- to that of sumatriptan at 14% (Fowler et al., 1991), tans, in development or use, at 25 h but the recurrence and sumatriptan has pKi's at the 5HT1B and 5HT1D data are unconvincing against placebo and cannot be receptors of 7.9 and 7.9, respectively, compared to 8.0 sustained without a sumatriptan comparative arm. and 8.9, respectively, for eletriptan. Given the superior Alniditan had a similar initial highly promising low bioavailability and comparable receptor anity, the recurrence rate in its phase II development programme dose might suggest perhaps another receptor or site is (Goldstein et al., 1996), along with a much longer half involved. However, eletriptan is the most lipophilic of life (Goldstein et al., 1996), but has been abandoned the triptans, either during the development or after its because this advantage was not sustained in phase III. completion (Rance et al., 1997), and as it happens, is a Given these results the drug t1=2 life hypothesis cannot substrate for P-glycoprotein (Pgp) (Hargreaves, per- be sustained. sonal communication), a membrane glycoprotein that is an ATP-dependent active e‚ux pump which leads 5.2.1. Ergotamine Ð back to the future for an answer to lower intracellular accumulation of its substrates Dihydroergotamine (DHE) has a long elimination (Gottesman and Pastan, 1993). Pgp is localised in the half life but a short redistribution that sees its plasma luminal membrane of the brain capillary endothelium, level drop 50% within 2 h. It is absolutely clear from and contributes to the function of the blood±brain the studies of both the nasal and injectable forms of barrier (Cordon-Cardo et al., 1989; Tatsuta et al., DHE that it has a lower recurrence rate than suma- 1992). The gene that codes for Pgp in humans is called triptan (Massiou, 1996; Touchon et al., 1996; Winner MDR1 and in rodents mdr1a and mdr1b (Gros et al., et al., 1996). Martin et al. (1995) speculated on the 1986). Knock-out mice have been developed that are basis of experimental work and theoretical consider- mdr1a (/) (Schinkel et al., 1994). Since eletriptan is ations that the low recurrence rate of dihydroergota- a Pgp substrate, higher doses are required than would mine may be related to a slow dissociation from the be predicted from bioavailability or anity data and, receptor or from its local environment. Yocca et al. moreover, suggest that a crucial aspect of its action (1997) in studying the pre-clinical e€ects of must be within the central nervous system. P.J. Goadsby / Progress in Neurobiology 62 (2000) 509±525 519

5.4. Side e€ects and the coronary issue behaviour induced by the selective 5-HT6 receptor antagonist, Ro 04-6790, in rats. Br. J. Pharmacol. 126, 1537±1542. The preferential action of triptans, 5HT ago- Rizatriptan±Naratriptan Study Group, Bomhof, M., Paz, J., Legg, 1B/1D N., Allen, C., Vandormael, K., Patel, K., 1999. Comparison of nists, in the cranial circulation is a direct consequence rizatriptan 10 mg vs. naratriptan 2.5 mg in migraine. Eur. of their potency and the relative lack of 5HT1B/1D Neurol. 42, 173±179. receptors in other vascular beds, particularly the cor- Bou, J., Domenech, T., Gras, J., Beleta, J., Llenas, J., Fernandez, onary circulation (Longmore et al., 1997a; Maassen A.G., Palacios, J.M., 1997. Pharmacological pro®le of almotrip- vanDenBrink et al., 1998a; Nilsson et al., 1999b). It tan, a novel antimigraine agent. Cephalalgia. 17, 421±422. Bouchelet, I., Cohen, Z., Case, B., Hamel, E., 1996. Di€erential ex- may be of interest that some of the compounds, such pression of sumatriptan-sensitive 5-hydroxytryptamine receptors as, sumatriptan, almotriptan (Bou et al., 1997) and in human trigeminal ganglia and cerebral blood vessels. frovatriptan (SB209509 or VML-251)(Brown et al., Molecular Pharmacology 50, 219±223.

1996), have actions at the vasodilator 5HT7 receptor Branchek, T., Archa, J.E., 1997. Recent advances in migraine (Eglen et al., 1997) but are unlikely to be of practical therapy. In: Robertson, D.W. (Ed.), Central Nervous System importance at the doses used in clinical studies. There Disease. Academic Press, San Diego, pp. 1±10 (Annual Reports in Medicinal Chemistry). has been considerable discussion of the cardiovascular Brandli, P., Lo‚er, B.-M., Breu, V., Osterwalder, R., Maire, J.-P., risks associated with triptan use (Ottervanger et al., Clozel, M., 1996. Role of endothelin in mediating neurogenic 1998, 1997a, 1997b; Visser et al., 1996b) and yet we plasma extravasation in rat dura mater. Pain 64, 315±322. are no closer to understanding the basis of the symp- Brown, A.M., Parsons, A.A., Raval, P., Porter, R., Tilford, N.S., toms. It has been suggested that some of the chest Gager, T.L., et al., 1996. SB209509 (VML251), a potent constric- pain may be oesophageal in origin (Foster et al., 1999; tor of rabbit basilar artery with high anity and selectivity for human 5-HT1D receptors. Br. J. Pharmacol. 119, 110P. Houghton et al., 1994) and the results of the 5HT1D Burstein, R., Yamamura, H., Malick, A., Strassman, A.M., 1998. agonist study (see above) certainly suggest that the Chemical stimulation of the intracranial dura induces enhanced question needs re-thinking. However, it seems beyond responses to facial stimulation in brain stem trigeminal neurons. J. Neurophysiol. 79, 964±982. doubt that there are 5HT1B receptors on human coron- ary arteries and that all triptans are 5HT agonists Buzzi, M.G., Moskowitz, M.A., 1990. The antimigraine drug suma- 1B triptan (GR43175) selectively blocks neurogenic plasma extrava- such that all have the potential to do harm and the sation from blood vessels in dura mater. Br. J. Pharmacol. 99, sensible contraindications for the use of sumatriptan, 202±206. uncontrolled hypertension, myocardial infarction, Buzzi, M.G., Moskowitz, M.A., Shimizu, T., Heath, H.H., 1991. stroke and ischemic heart disease, must apply to the Dihydroergotamine and sumatriptan attenuate levels of CGRP in whole triptan class. plasma in rat superior sagittal sinus during electrical stimulation of the trigeminal ganglion. Neuropharmacol. 30, 1193±1200. Buzzi, M.G., Sakas, D.E., Moskowitz, M.A., 1989. Indomethacin and acetylsalicylic acid block neurogenic plasma protein extrava- Acknowledgements sation in rat dura mater. Eur. J. Pharmacol. 165, 251±258. Carignani, C., Ugolini, A., Pinnola, V., Belardetti, F., Trist, D.G., Corsi, M., 1998. NMDA receptor subunit characterization of the The work of the author reported herein has been glycine antagonist GV196771A and its action on the spinal cord supported by the Wellcome Trust and the Migraine wind-up. Naunyn-Schmiedeberg's Archives of Pharmacology 358 Trust. PJG is a Wellcome Senior Research Fellow. (1S1), 1119. Castro, M.E., Pascual, J., Romon, T., Arco, Cd., Olmo, Ed., Pazos, A., 1997. Di€erential distribution of ‰3H]sumatriptan binding sites

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