Chapter 2: The 5-HT1B and 5-HT1D Agonists in Acute Migraine Therapy PDF

Handbook of Clinical Neurology, Vol. 199 (3rd series) Migraine Management J.W. Swanson and M. Matharu, Editors https://doi.org/10.1016/B978-0-12-823357-3.00008-2 Copyright © 2024 Elsevier B.V. All rights reserved, including those for text and data mining, AI training, and similar technologies....

Handbook of Clinical Neurology, Vol. 199 (3rd series) Migraine Management J.W. Swanson and M. Matharu, Editors https://doi.org/10.1016/B978-0-12-823357-3.00008-2 Copyright © 2024 Elsevier B.V. All rights reserved, including those for text and data mining, AI training, and similar technologies. Chapter 2 The 5-HT1B and 5-HT1D agonists in acute migraine therapy: Ergotamine, dihydroergotamine, and the triptans MARK WHEALY1 AND WERNER J. BECKER2* 1 Department of Neurology, Mayo Clinic, Rochester, MN, United States 2 Department of Clinical Neurosciences, Cumming School of Medicine, University of Calgary, and Hotchkiss Brain Institute, Calgary, AB, Canada Abstract The advent of the triptans revolutionized acute migraine treatment. The older migraine-specific drugs, the ergot alkaloids (ergotamine and dihydroergotamine), also relieve migraine attacks through agonism at the 5-HT1B and 5-HT1D receptors, but the triptans have much greater specificity for these receptors. Unlike the ergot alkaloids, the triptans do not activate many other receptor types, and therefore are much better tolerated. This reduction in side effects greatly enhanced their clinical utility as it allowed a far greater proportion of patients to take a full therapeutic dose. As a result, the clinical use of ergotamine is minimal today, although dihydroergotamine still has a significant clinical role. There is extensive evidence that the seven triptans available today, sumatriptan, zolmitriptan, rizatriptan, eletriptan, naratriptan, almotriptan, and frovatriptan, are effective in the acute treatment of migraine. Available formulations include oral tablets, orally dissolving tablets, subcutaneous injections, nasal sprays, and in some countries, rectal sup- positories. For optimal benefit, therapy needs to be individualized for a given patient both regarding the triptan chosen and the formulation. This chapter discusses the ergot alkaloids and the triptans, including mechanism of action, evidence for efficacy, clinical use, and adverse effects. INTRODUCTION receptor agonist. The gepants are antagonists at the cal- citonin gene-related peptide (CGRP) receptor. Ergotamine and the triptans are acute migraine medica- Although nonspecific acute migraine therapies in- tions which specifically target mechanisms now known cluding the NSAIDs, acetaminophen, and antiemetics to be involved in the generation of a migraine attack. This like metoclopramide still play an important role in the contrasts with the nonsteroidal anti-inflammatory drugs treatment of migraine attacks, this chapter focuses on (NSAIDs) and other analgesics which affect general pain ergotamine, DHE, and the triptans. It reviews the mech- mechanisms and are used to treat a variety of pain anism of action, evidence for use, clinical use, and side disorders. effects of these 5-HT1B and 5-HT1D receptors agonists. Today the migraine-specific medications include not only ergotamine, dihydroergotamine (DHE), and the Acute therapy in relation triptans, but also the gepants and ditans. Ergotamine, to preventive therapy DHE, and the triptans exert their therapeutic effects in migraine primarily through agonism at the 5-HT1B and Acute therapy is used to eliminate a current attack of 5-HT1D receptors. Lasmiditan, a ditan, is a 5-hT1F migraine, while the goal of preventive therapy is to *Correspondence to: Werner Becker, Department of Clinical Neurosciences, Cumming School of Medicine, University of Calgary, and Hotchkiss Brain Institute, Calgary, AB, Canada. Tel: +1-587-229-6363, E-mail: [email protected] 18 M. WHEALY AND W.J. BECKER reduce the frequency of migraine attacks. For many of ergotamine would “stop the headache of the moment,” patients, acute and preventive therapy should both be but tended to foster development of the next headache used. Acute therapies should be made available to any- (Graham, 1955). one with migraine, while preventive therapy is usually Since the advent of the triptans in the 1990s, ergota- reserved for patients with relatively frequent episodes mine is infrequently used. It acts upon a wide spectrum of migraine. of receptors, and as a result it causes far more side effects than the much more specific triptans (Dahlof and Maassen Acute medication overuse Van Den Brink, 2012). Ironically, although their effects on migraine were discovered by accident, the ergot alkaloids Medication overuse headache is a common problem, relieve migraine in the same way as the triptans; they are particularly in patients with high-frequency episodic agonists at the 5-HT1B and 5-HT1D receptors. Because of migraine and chronic migraine and can adversely affect this mode of action, ergotamine is considered the first the overall treatment of migraine. Both ergotamine and migraine-specific drug, despite its effects on many other the triptans, if taken on 10 days a month or more, can receptor types. put patients with migraine at risk for medication overuse headache (Headache Classification Committee of the Mechanism of action International Headache Society (IHS), 2018). It is impor- tant to educate patients about the possibility of medica- The ergots treat migraine mainly through agonism of tion overuse headache and provide specific guidelines the 5-HT1B and 5-HT1D receptors, with activity at the regarding frequency of use of triptans and ergotamine. 5-HT1F receptor playing a lesser role. The ergots also A gradual increase in headache frequency, coupled with demonstrate agonism at the 1A, 2A, 2C, 3, and 4 sub- an increasing frequency of acute medication use, should types of the 5-HT receptors and act on adrenergic and alert both the physician and the patient to the possibility dopaminergic receptors (Fig. 2.1). It is unclear if ergota- of medication overuse headache. mine effects on other 5-HT, adrenergic or dopaminergic receptors provide any additional benefit in migraine, but ERGOTAMINE there may be some benefit as patients who do not respond to triptans may respond well to the ergots (Tfelt-Hansen Historical overview et al., 2000; Tfelt-Hansen and Koehler, 2008; Baron and Ergotamine is a good example of how poisonous sub- Tepper, 2010; Silberstein et al., 2020). In addition there is stances may become effective therapeutic agents if the some evidence that ergotamine and DHE activate novel, dose is carefully regulated. For centuries ergot poisoning uncharacterized receptors (De Vries et al., 1998; Tfelt- from rye contaminated with the ergot fungus, Claviceps Hansen et al., 2000). All together these actions result purpurea, caused epidemics of gangrene. Ergot extracts in inhibition of trigeminal peptide release, interference were being used for migraine treatment by the 1870s, but with central trigeminal nucleus caudalis nociceptive it was not until 1918 that the ergot alkaloid ergotamine transduction and processing, reduction in neurogenic was isolated, and a more reliable formulation be- inflammation/plasma protein extravasation, reduction came available (Silberstein and McCrory, 2003; Tfelt- of central nociceptive signaling to the thalamus and Hansen and Koehler, 2008). For many decades thereafter reduction in the activity of other ascending pathways ergotamine was a mainstay of acute migraine therapy. In to the cortex.(Markowitz et al., 1988; Saito et al., his classic monograph, “Treatment of Migraine” in 1955, 1988; Baron and Tepper, 2010) John R. Graham devoted most of his 40 pages on acute migraine treatment to ergotamine (Graham, 1955). Over Formulations three decades later, Neil Raskin in his book “Headache” Ergotamine has been available as oral tablets, sublingual did the same (Raskin, 1988). tablets, and rectal suppositories, often in combination But even early pioneers like Graham recognized two with caffeine, although other combinations are available. major liabilities of ergotamine. He pointed out that that It has also been available as an inhaled product in an oral although he considered it an effective drug, patients aerosol device containing a fine particle suspension. showed great variability in how well they tolerated it. Whereas one patient might do well, “another may man- Evidence for efficacy ifest so many of the transitory unpleasant side effects (such as nausea, vomiting, muscle cramps and prostra- Lennox reported his experience with ergotamine and tion) that the cure becomes worse than the disease.” ergonovine in the acute treatment of migraine in 1938 He also noted the ability of ergotamine to cause medica- (Lennox, 1938). Since then there have been many ran- tion overuse headache and commented that frequent use domized trials which showed conflicting results with  THE 5-HT1B AND 5-HT1D AGONISTS IN ACUTE MIGRAINE THERAPY 19 Fig. 2.1. The receptor profile of the triptans vs the ergot alkaloids. Common antimigraine receptor activities are seen at 5-HT1B, 5-HT1D, and 5-HT1F receptors. Off target activity at other monoamine receptors is responsible for many of the unwanted effects of the ergots. + indicates relative affinity at the various receptor subtypes. Figure used with permission Hargreaves R (2007). New migraine and pain research. Headache 47: S26–43. regards to the efficacy of ergotamine tartrate or its (Waters, 1970; Cortelli et al., 1996; Sharma et al., 2002). combinations. In 10 trials ergotamine was compared with Ergotamine 1 mg was superior to aspirin (500mg) in two placebo (Ostfeld, 1961; Ryan, 1970; Waters, 1970; comparative trials (Hakkarainen et al., 1978, 1980). It Hakkarainen et al., 1979; Kinnunen et al., 1988; was inferior to an isometheptene compound in one trial Sargent et al., 1988; Friedman et al., 1989; Cortelli (Yuill et al., 1972) and superior in another (General et al., 1996; Diener et al., 2002; Sharma et al., 2002). Practitioner Research Group, 1971). The following were While in the other 12 trials ergotamine was used as the found to be comparable to ergotamine: ergostine (Ryan, standard comparative drug without placebo control 1970), tolfenamic acid (Hakkarainen et al., 1979), (General Practitioner Research Group, 1971; Yuill dextropropoxyphene (combination) (Hakkarainen et al., et al., 1972; Hakkarainen et al., 1978; Hakkarainen 1978, 1980), naproxen sodium (Pradalier et al., 1985; et al., 1980; Pradalier et al., 1985; The Multinational Sargent et al., 1988; Treves et al., 1992), and pirprofen Oral Sumatriptan and Cafergot Comparative Study (Kinnunen et al., 1988). Group, 1991; Treves et al., 1992; Le Jeunne et al., Sumatriptan (The Multinational Oral Sumatriptan and 1999; Christie et al., 2003; Stepien and Kozubski, Cafergot Comparative Study Group, 1991), calcium car- 2004; Lainez et al., 2007; Miljkovic et al., 2018). basalate with metoclopramide (Le Jeunne et al., 1999), Initial doses of ergotamine varied between 1 and 5 mg, eletriptan (Diener et al., 2002), almotriptan (Lainez and many trials allowed repeated intake of test drugs. et al., 2007), rizatriptan (Christie et al., 2003), buccal Efficacy endpoints were not all validated and varied prochlorperazine (Sharma et al., 2002), and lysine acetyl- considerably, from benefit based on clinical interview salicylic acid with metoclopramide (Stepien and Kozubski, (Waters, 1970) to changes on a verbal headache 2004) have been shown to be superior to ergotamine (with scale (Yuill et al., 1972; Friedman et al., 1989; or without caffeine). However, in one trial that did not The Multinational Oral Sumatriptan and Cafergot report the doses of the drugs used, it was stated that a five Comparative Study Group, 1991; Cortelli et al., 1996). drug ergotamine compound was superior to sumatriptan Methodological flaws in these trials included lack of (Miljkovic et al., 2018), but the data for 2 h pain freedom clearly stated inclusion criteria, absence of reporting were no different when only considering the first dose of baseline criteria and randomization procedures, unusual study medication. design of some of the crossover trials with variable num- These studies do suggest some benefit from oral bers of attacks per patient, claims of superiority without ergotamine; however, it is not known what the best dose appropriate statistics, and absence of delineation of the is, and the benefit of ergotamine has not been sufficiently medication doses used. quantified. The benefits of oral ergotamine are likely Ergotamine (1–5 mg) was superior to placebo for reduced significantly by the poor oral bioavailability some parameters in seven trials (Ostfeld, 1961; Ryan, (Sanders et al., 1986). 1970; Hakkarainen et al., 1979; Kinnunen et al., 1988; Ergotamine rectal suppositories have only been Sargent et al., 1988; Friedman et al., 1989; Diener studied in two clinical trials. One trial, only accessible et al., 2002) and no better than placebo in three trials on the pharmaceutical company’s website, compared 20 M. WHEALY AND W.J. BECKER ergotamine suppositories (2 mg ergotamine/200 mg headache recurrence with ergotamine is not fully known caffeine) with sumatriptan suppositories (25 mg) in a and is not thought to be related simply to half-life (see cross-over design (No authors listed, 1995). Ergotamine Table 2.1). Several properties of ergotamine including suppositories were superior to sumatriptan suppositories several active metabolites with half-lives up to 21 h, pro- in the primary endpoint of headache relief (moderate to longed receptor binding of ergotamine and possible tissue severe headache relieved to mild or no headache) with a storage of ergotamine with a second peak plasma level response rate of 73% vs 63%, respectively. There was 24–48h after dosing are thought to contribute. The patient less use of rescue treatment at 2 to 24 h with ergotamine. should take ergotamine as early as possible in the migraine However, subjects preferred sumatriptan because ergot- attack, and the dose should be one that provides relief amine caused more side effects. In another study, an without undue side effects. This dose is usually between ergotamine suppository (2 mg) was no better than pla- 0.5 and 2 mg, and it was considered useful to test the tol- cebo, while a ketoprofen suppository (100 mg) was supe- erability of a patient for ergotamine between attacks by rior to placebo (Kangasniemi and Kaaja, 1992). taking gradually increasing dosages. Once the tolerated Inhaled ergotamine (maximum dosage 1.8 mg) was dose is established, the patient should take the entire dose found to be superior to sublingual ergotamine (maximum early in the attack rather than taking repeated doses over dosage 2 mg) which was no better than sublingual or time. Because of poor oral absorption, the rectal or inhaled placebo in one trial (Crooks et al., 1964). inhalational route is preferred if available and acceptable to the patient. Maximum frequency of use should be 6 Side effects and contraindications doses per month to avoid medication overuse headache (Tfelt-Hansen et al., 2000). Side effects of ergotamine are many and include nausea/ vomiting, abdominal pain, acroparethesia, swollen fin- gers, leg cramps, diarrhea, tremor, syncope, globus sensation (parenteral use), and in patients with ischemic DIHYDROERGOTAMINE heart disease: angina and myocardial infarction (Tfelt- Historical overview Hansen and Saxena, 2006). Chronic daily intake can lead to ergotamine overuse headache, ergotamine withdrawal Dihydroergotamine (DHE) is a semisynthetic deriva- headache, intermittent claudication, acrocyanosis, con- tive of ergotamine in which a single bond replaces the stant nausea, acroparethesia, anorectal ulcers (esp. with double bond at the 9–10 position of the ergoline ring. suppository use), ischemic neuropathy, dorsal column It was synthesized in 1943, first used in 1945 for treat- lesion, fibrotic disorders (may involve pleura, pericar- ment of migraine (Horton and Blumenthal, 1945), and dium, and retroperitoneum), or overt ergotism (Tfelt- approved for clinical use in the United States in 1946 Hansen and Saxena, 2006). (Silberstein et al., 2020). Raskin explored its use in Contraindications include coronary, cerebral or intractable headache in 1986 (Raskin, 1986). Even peripheral vascular disease, renal failure, hepatic failure, though clinical use of ergotamine has largely disap- pregnancy, breastfeeding, sepsis, shock, uncontrolled peared, because DHE causes less nausea and less arte- hypertension, hemiplegic migraine, migraine with brain- rial vasoconstriction than ergotamine, there is still stem aura, migraine with prolonged aura, use of a triptan significant interest in its use. within 24 h, and concomitant use of triacetyloleandomy- cin or erythromycin (Tfelt-Hansen and Saxena, 2006). Caution should be used with concomitant use of Mechanism of action methysergide. Like ergotamine, DHE relieves migraine headache Clinical use through activation of the 5-HT1B and 5-HT1D receptors, but like ergotamine, it also acts upon many other receptor Ergotamine has very limited utility in today’s treatment types and therefore generally has more side effects than of migraine due to availability of agents with superior the more specific triptans (Fig. 2.1). efficacy and tolerability. While some patients, including some who do not respond well to the triptans, do well on ergotamine, many have difficulty taking a therapeutic Formulations dose because of side effects. A European consensus publication in 2000 suggested DHE is available in intravenous (IV), intramuscular that ergotamine may have some utility in patients with (IM)/subcutaneous (SC), and intranasal (IN) formula- very long migraine attacks or frequent headache recur- tions. There are some new intranasal delivery systems rence after taking other medications. The reason for less in development for DHE.  THE 5-HT1B AND 5-HT1D AGONISTS IN ACUTE MIGRAINE THERAPY 21 Table 2.1 Pharmacokinetic properties of ergots and triptans.a Drug Tmax (min) Bioavailability (%) T1/2 (h) Active metabolites Ergotamine 2 mg oral 69