- 46 Downloads
Sumatriptan is a potent and selective agonist at a vascular serotonin1 (5-hydroxytryptamine1; 5-HT1) receptor subtype (similar to 5-HT1D) and is used in acute treatment of migraine and cluster headache. Following administration of sumatriptan 100mg orally, relief of migraine headache (at 2 hours) was achieved in 50 to 67% of patients compared with 10 to 31% with placebo in controlled clinical trials. In a comparative study, oral administration of sumatriptan 100mg consistently achieved significantly greater response rates than a fixed combination of ergotamine 2mg plus caffeine 200mg during 3 consecutive migraine attacks (66 vs48% for first attack). Oral sumatriptan 100mg was also more effective than aspirin 900mg plus metoclopramide 10mg orally in a similar study. In the majority of controlled clinical trials, headache relief (at 1 hour after administration) was achieved in 70 to 80% of patients with migraine receiving sumatriptan 6mg subcutaneously compared with 18 to 26% of placebo recipients
Approximately 40% of patients who initially responded to oral or subcutaneous sumatriptan experienced recurrence of their headache, usually within 24 hours, but the majority of these patients responded well to a further dose of sumatriptan.
Patients with cluster headache were treated for acute attacks with sumatriptan 6mg subcutaneously or placebo in 2 crossover trials. Headache relief was achieved within 15 minutes in 74 and 75% of patients receiving sumatriptan in these studies compared with 26 and 35%, respectively, with placebo. Patients receiving sumatriptan 12mg had a similar response rate as those receiving 6mg, but the higher dose was associated with an increased incidence of adverse events.
Based on extensive safety data pooled from controlled clinical trials, sumatriptan is generally well tolerated and most adverse events are transient. The most frequently reported adverse events following oral administration include nausea, vomiting, malaise, fatigue and dizziness. Injection site reactions (minor pain and redness of brief duration) occur in approximately 40% of patients receiving subcutaneous sumatriptan, although the incidence appears to be markedly reduced when patients self-administer the drug with an auto-injector. Chest symptoms (mainly tightness and pressure) occur in 3 to 5% of sumatriptan recipients, but have not been associated with myocardial ischaemia except in a few isolated cases. Sumatriptan is contraindicated in patients with ischaemic heart disease, angina pectoris including Prinzmetal (variant) angina, previous myocardial infarction and uncontrolled hypertension, but is not contraindicated in patients with migraine and asthma. Data from long term studies in acute treatment of migraine and cluster headache suggest that sumatriptan remains effective and well tolerated over several months.
Thus, sumatriptan rapidly relieves migraine and cluster headache attacks in the majority of patients and is well tolerated. Although the extent of its use may be tempered by relatively high acquisition costs, sumatriptan is now firmly established as a significant enhancement to the treatment options available for these disabling diseases.
The pathogenesis of migraine, like the mechanism of action of sumatriptan, is not completely understood. However, migraine pain is thought to result from vasodilation of cerebral blood vessels, particularly those in the dura mater, and/or release of vasoactive neuropeptides from perivascular trigeminal axons in the dura mater following activation of the trigeminovascular system. Indirect evidence suggests that serotonin is implicated in the pathogenesis of migraine. A vascular 5-HT1 receptor subtype (similar to 5-HT1D) is found predominantly in cranial vasculature and mediates constriction of cephalic arteries and arteriovenous anastomoses. Autoradiographical studies demonstrated that 5-HT1D receptors are prevalent in the human brain and function as autoreceptors
Radioligand binding studies in animal brain tissue demonstrated that sumatriptan has high affinity and relative specificity for 5-HT1D receptors (along with some affinity for 5-HT1A receptors). Ergot alkaloids have strong affinity for 5-HT1D receptors, but also have a relatively high affinity for 5-HT1A, 5-HT1C, 5-HT2 α-adrenergic and dopamine2 receptors. Studies of animal and human isolated cerebral blood vessels indicate a vasoconstrictor effect of sumatriptan, thought to be mediated by vascular 5-HT1 receptors. Sumatriptan administration in humans was associated with increased blood flow velocity in large cerebral conductance vessels, probably due to sumatriptan-induced vasoconstriction. In animal isolated tissue studies, sumatriptan had essentially no activity at 5-HT1 receptors mediating vascular smooth muscle relaxation, but weak vasoconstrictor activity mediated by vascular 5-HT1 receptors was noted in human isolated coronary arteries. Sumatriptan also had no activity at 5-HT2 or 5-HT3 receptors in animal isolated tissue studies.
Data from animal studies suggest that sumatriptan blocks neurogenic plasma extravasation, presumably by stimulating a presynaptic 5-HT1D autoreceptor, thus preventing release of inflammatory mediators within the trigeminovascular system. In humans, elevation of plasma levels of a vasoactive neuropeptide (calcitonin gene-related peptide) detected during migraine headache was attenuated by sumatriptan.
Thus, sumatriptan is a potent and selective vascular 5-HT1 receptor agonist which mediates constriction of certain large cranial blood vessels and/or inhibits release of vasoactive neuropeptides from perivascular trigeminal axons in the dura mater during a migraine attack.
A mean plasma concentration (Cmax) of 72 μg/L was achieved after a median of 10 minutes following subcutaneaous administration of sumatriptan 6mg to healthy volunteers. Sumatriptan 100mg orally achieved a Cmax of 54 μg/L after a median of 1.5 hours; however, 80% of Cmax was achieved within 45 minutes of oral administration. Mean bioavailability of sumatriptan was 96% after subcutaneous administration and 14% after oral administration
Following parenteral administration of sumatriptan in humans, mean volume of distribution was calculated as 170L. In vitro plasma protein binding of sumatriptan ranged from 14 to 21%. Animal data indicate that sumatriptan poorly penetrates the blood-brain barrier.
Sumatriptan is extensively metabolised, primarily to an inactive indoleacetic acid analogue. Metabolites and unchanged drug are eliminated in the urine and faeces; urinary excretion is higher following subcutaneous than oral administration. Sumatriptan undergoes active renal tubular secretion, as indicated by a renal clearance rate of 15.6 L/h following oral administration, although renal clearance accounts for only 20% of total clearance. Mean elimination half-life is approximately 2 hours following single-dose administration of oral or subcutaneous sumatriptan. Co-administration of food or various antimigraine agents, or the presence of a migraine attack do not appear to significantly affect the pharmacokinetic profile of sumatriptan.
A number of large, double-blind clinical trials have demonstrated that sumatriptan is clearly superior to placebo in acute treatment of migraine headache. Sumatriptan 100mg administered orally achieved headache relief (i.e. reduction in headache severity) at 2 hours after administration in 50 to 67% of patients compared with 10 to 31% with placebo. Comparative studies showed that orally administered sumatriptan 100mg achieved significantly greater response rates than ergotamine 2mg plus caffeine 200mg orally for 3 consecutive migraine attacks (66 vs 48% for first attack), and response rates were higher with sumatriptan than aspirin 900mg plus metoclopramide 10mg orally. In the latter trial, statistically significant differences were noted for only the second and third attacks (56 vs 45% for first attack). In the majority of controlled studies, 70 to 80% of patients receiving sumatriptan 6mg subcutaneously experienced relief of migraine headache at 1 hour after administration compared with 18 to 26% of placebo recipients. Concurrent administration of oral dihydroergotamine as prophylactic antimigraine therapy did not appear to affect clinical response to acute treatment with subcutaneous sumatriptan. Subcutaneous administration of sumatriptan 6mg was also effective in relieving early morning migraine attacks and menstruation- associated migraine headaches, both of which are often resistant to antimigraine treatment
Patients receiving oral or subcutaneous sumatriptan in controlled clinical trials consistently required less rescue medication for unresolved symptoms than those receiving either placebo or comparator agents. Sumatriptan was also effective at relieving associated symptoms of migraine such as nausea, vomiting and photophobia/phonophobia. Sumatriptan was equally effective regardless of migraine type (with or without aura), or whether administered early (< 4 hours) or late (> 4 hours) after the onset of migraine symptoms. In clinical trials, approximately 40% of patients who initially responded to sumatriptan developed recurrence of their headache, but the majority of these patients responded to a further dose of sumatriptan.
Efficacy of subcutaneous sumatriptan 6mg in acute treatment of cluster headache was demonstrated in 2 crossover studies. Sumatriptan provided headache relief within 15 minutes of administration in 74 and 75% of patients in these trials compared with 26 and 35%, respectively, with placebo. In addition, the need for oxygen rescue therapy was reduced, functional disability was improved and the incidence of conjunctival injections was decreased with sumatriptan.
Pooled data from controlled studies of patients receiving sumatriptan for acute treatment of migraine indicate that sumatriptan is generally well tolerated. The most frequently reported adverse events with oral sumatriptan include nausea, vomiting, malaise, fatigue, dizziness and vertigo, which usually occur within 60 minutes of administration and are short-lived. Subcutaneous administration of sumatriptan produces minor injection site reactions in approximately 40% of patients. These are also transient and appear to be less likely when the drug is self-administered using an auto-injector. The overall incidence of serious adverse events thought to be associated with sumatriptan is 0.14%. Chest tightness and pressure occurs in 3 to 5% of patients with migraine receiving sumatriptan, but has only been associated with myocardial ischaemia in a few isolated cases. Sumatriptan is contraindicated in patients with ischaemic heart disease, angina pectoris including Prinzmetal (variant) angina, previous myocardial infarction and uncontrolled hypertension. Patients with migraine and asthma are not at increased risk of adverse events with sumatriptan, and the drug is not contraindicated in asthmatic patients. The incidence and pattern of adverse events associated with sumatriptan use does not appear to be altered by long term administration of the drug
Dosage and Administration
The recommended dose of oral sumatriptan is 100mg at the onset of migraine symptoms. If headache recurs after initial relief of symptoms, up to 2 additional 100mg doses may be taken during a 24-hour period. The maximum oral dosage is 300mg in 24 hours. The recommended dose for subcutaneous sumatriptan is 6mg at the onset of migraine or cluster headache. If symptoms recur, a second 6mg dose may be administered at least 1 hour after the first dose. The maximum subcutaneous dosage is 12mg in 24 hours
KeywordsMigraine Sumatriptan Cluster Headache Migraine Attack Migraine Headache
Unable to display preview. Download preview PDF.
- Anderson BA for the Clinical Trial Study Group. Optimising the dosage regimen for oral sumatriptan — clinical results. Abstract. 9th Migraine Trust International Symposium. London. September 7–10, 1992Google Scholar
- Anon. Sumatriptan prescribing information. Canada, 1992bGoogle Scholar
- Anon. Sumatriptan product monograph, UK, 1992aGoogle Scholar
- Ashford EA for the Clinical Trial Study Group. Optimising the dosage regimen for oral sumatriptan — methodology and patients. Abstract. 9th Migraine Trust International Symposium, London, September 7–10, 1992Google Scholar
- Ashford EA, Arnold WSG. Intensive ECG surveillance after treatment with sumatriptan. XVth World Congress of Neurology, Vancouver, September 5–10, 1993Google Scholar
- Ashford EA, Lloyd DK, Pilgrim AJ, Ferrari MD for the Study Group. Delayed treatment with sumatriptan does not increase the incidence of headache recurrence. Abstract. Cephalalgia 13 (Suppl. 13): 159, 1993aGoogle Scholar
- Ashford EA, Lloyd DK, Pilgrim AJ, Ferrari MD for the Study Group. Sumatriptan in the treatment of recurrent non-headache symptoms associated with migraine. Abstract. Cephalalgia 13 (Suppl 13): 158, 1996Google Scholar
- Bates D for the Study Group. Treatment with subcutaneous sumatriptan during the migraine aura. Abstract. Cephalalgia 13 (Suppl 13): 188, 1993Google Scholar
- Blakeborough P, Fowler PA, Ashford EA. The use of sumatriptan in patients taking migraine prophylactic agents. Abstract. Cephalalgia 13 (Suppl 13): 163, 1993Google Scholar
- Buzzi MG, Dimitriadou V, Theoharides TC, Moskowitz MA. 5-Hydroxytryptamine receptor agonists for the abortive treatment of vascular headaches block mast cell, endothelial and platelet activation within the rat dura mater after trigeminal stimulation. Brain Research 583: 137–149, 1992PubMedCrossRefGoogle Scholar
- Cutler NR, Hussey EK, Sramek JJ, Clements BD, Paulsgrove LA, et al. Oral sumatriptan in pharmacokinetics in the migrainous state. Cephalalgia 11: 222–223, 1991Google Scholar
- Ebihara A, Ohashi K, Fujimura A, Kumagai Y, Nakashima H, et al. Phase I study of sumatriptan tablet (the 1st report) — single- and multiple-oral dose study in Japanese subjects. In Japanese. Rinsho Iyaku 9: 757–765, 1993bGoogle Scholar
- Ebihara A, Ohashi K, Fujimura A, Kumagai Y, Ohira H, et al. Phase I Study of sumatriptan injection (the 2nd report) — sing1e- and multiple-subcutaneous dose study in Japanese healthy subjects. In Japanese. Rinsho Iyaku 9: 767–776, 1993aGoogle Scholar
- Ekbom K for the Study Group. Long-term acute treatment of cluster headache attacks with sumatriptan — an interim review. Abstract. Cephalalgia 13 (Suppl. 13): 36, 1993Google Scholar
- Ekbom K. Subcutaneous sumatriptan in acute cluster headache. Headache Quarterly 3: 260, 1992Google Scholar
- Ensink F-B for the Clinical Trial Study Group. Using subcutaneous and oral sumatriptan in a flexible regimen. Abstract. 9th Migraine Trust International Symposium, London, September 7–10, 1992Google Scholar
- Ferrari MD. Subcutaneous sumatriptan in the acute treatment of migraine. Abstract. XVth World Congress of Neurology, Vancouver, September 5–10, 1993Google Scholar
- Fowler PA, Lacey LF. The effect of food on the pharmacokinetic profile of sumatriptan. Abstract. XVth World Congress of Neurology, Vancouver, September 5–10, 1993Google Scholar
- Goadsby PJ, Edvinsson L. Sumatriptan reverses the changes in calcitonin gene-related peptide seen in the headache phase of migraine. Cephalalgia 11 (Suppl. 11): 3–4, 1991Google Scholar
- Göbel H, Krapat S, Ensink FB, Soyka D. Exteroceptive suppression of temporalis muscle activity is activated by application of sumatriptan during migraine attack but not in migraine interval. Cephalalgia 13 (Suppl. 13): 146, 1993Google Scholar
- Gross M. Sumatriptan use with a novel cartridge system self-injector. Abstract. 9th Migraine Trust International Symposium, London, September 8, 1992Google Scholar
- Gross MLP, O’Caliaghan J, Hallett K for the Study Group. Longterm efficacy of subcutaneous sumatriptan using a novel self injector. Abstract. Canadian Journal of Neurosciences 20 (Suppl. 4): S37, 1993Google Scholar
- Headache Classification Committee of the International Headache Society. Classification and diagnostic criteria for headache disorders, cranial neuralgias and facial pain. Cephalalgia 8 (Suppl. 7): 1–96, 1988Google Scholar
- Hulme A, Dalton DW. The efficacy of subcutaneous sumatriptan in the treatment of headache recurrence. Abstract. Cephalalgia 13 (Suppl 13): 157, 1993Google Scholar
- Humphrey PPA, Appedy E, Feniuk W, Perren MJ. A rational approach to identifying a fundamentally new drug for the treatment of migraine. In: Saxena et al. (Eds) Cardiovascular pharmacology of 5-hydroxytryptamine, prospective therapeutic applications, pp. 417–428, Kluwer Academic Publishers, Dordrecht, 1990Google Scholar
- Krabbe AA. Early clinical experience with subcutaneous GR 43175 in acute cluster headache attacks. Abstract. Proceedings of the Fourth International Headache Congress, Sydney, October 14–18, 1989Google Scholar
- Kumagaya Y, Ohhashi K, Fujimura A. Phase I clinical study of antimigraine drug, sumatriptan (SN-308): single and repeated subcutaneous administration. In Japanese. Rinsho Yakusi 23: 177–178, 1992Google Scholar
- Lacey LF, Fowler PA. The clinical pharmacology of sumatriptan, Abstract. cephalalgia 13 (Suppl. 13): 156, 1993Google Scholar
- Middlefell VC, Price TL. The carotid arterial vasoconstrictor action of sumatriptan in the anaesthetised rabbit. Abstract no. 260. FASEB Journal 7: A46, 1993Google Scholar
- Journal of Pharmacology 227: 99–102, 1992Google Scholar
- Monstad L Pre-emptive oral treatment with sumatriptan during a cluster headache period. Abstract. Cephalalgia 13 (Suppl. 13): 35, 1993Google Scholar
- Mushet GR, Clements B. Efficacy of subcutaneous sumatriptan administered by a novel autoinjector device. Abstract No. II. Headache 32: 255, 1992Google Scholar
- Nappi G, Sicuteri F, Byrne M, Roncolato M, Zerbini O. Film-coated oral sumatriptan compared with placebo in the acute treatment of migraine. Journal of Neurology, in press, 1994Google Scholar
- Ottervanger JP, Stricker BHC, Van Witsen TB, Valkenburg HA. A postmarketing study of adverse reactions to sumatriptan. Post-Marketing Surveillance 7: 241–242, 1993aGoogle Scholar
- Perren MJ, Feniuk W, Humphrey PPA. Vascular 5-HT1-like receptors that mediate contraction of the dog isolated saphenous vein and carotid arterial vasoconstriction in anaesthetized dogs are not of the 5-HT1A or 5-HT1D subtype. British Journal of Pharmacology 102: 191–197, 1991PubMedCrossRefGoogle Scholar
- Pilgrim AJ. The methods used in clinical trials of sumatriptan in migraine. Abstract 25. Headache 33: 280, 1993aGoogle Scholar
- Pilgrim al. Long-term tolerability and safety of sumatriptan during a 2-year period. XVth World Congress of Neurology, Vancouver, September 5–10, 1993bGoogle Scholar
- Russell M, Holm-Thomsen O. The diagnosis of migraine in primary care: implications and experience with sumatriptan. Abstract. 9th Migraine Trust International Symposium, London, September 8, 1992Google Scholar
- Sargent JD. Oral sumatriptan in the acute treatment of migraine: the US experience. Abstract. Proceedings of the Fifth International Headache Congress, Washington, 1 Jul 1991Google Scholar
- Stewart W, Lipton R, Celentano D, Reed M. The epidemiology of severe migraine headaches from a national survey; implications of projections to the US population. Cephalalgia 11 (Suppl. 11): 87–88, 1991Google Scholar
- Tazaki Y, Sakai F, Tashiro K, Hirai S, Gotoh F, et al. Clinical evaluation of SN-308 (sumatriptan) tablet in migraine — early phase II study. In Japanese. Rinsho Iyaku 9: 777–794, 1993aGoogle Scholar
- Tazaki Y, Sakai F, Tashiro K, Hirai S, Gotoh F, et al. Clinical evaluation of SN-308 (sumatriptan) tablet on migraine — dose finding study by double-blind cross-over method. In Japanese. Rinsho Iyaku 9: 1539–1566, 1993bGoogle Scholar
- Tazaki Y, Sakai F, Tashiro K, Hirai S, Gotoh F, et al. Clinical evaluation of SN-308 (sumatriptan) tablet on migraine — double-blind parallel-group study. In Japanese. Rinsho Iyaku 9: 2147–2165, 1993cGoogle Scholar
- Tazaki Y, Sakai F, Tashiro K, Hirai S, Gotoh F, et al. Clinical evaluation of SN-308 (sumatriptan) injection on migraine — multicenter open trial. In Japanese. Rinsho Iyaku 9: 1897–1909, 1993eGoogle Scholar
- Tazaki Y, Sakai F, Tashiro K, Hirai S, Maruyama S, et al. Study on clinical usefulness of SN-308 (sumatriptan) subcutaneous injection in cluster headache — dose-finding study by envelope method. In Japanese. Rinsho Iyaku 9: 1095–1106, 1993fGoogle Scholar
- Tazaki Y, Sakai F, Tashiro K, Hirai S, Gotoh F, et al. Clinical evaluation of SN-308 (sumatriptan) subcutaneous injection on cluster headache — multicenter open trial. In Japanese. Rinsho Iyaku 9: 1911–1923, 1993gGoogle Scholar
- Tazaki Y, Sakai F, Tashiro K, Hirai S, Maruyama S, et al. Study on clinical usefulness of SN-308 (sumatriptan) subcutaneous injection in migraine — dose finding study by envelope method. In Japanese. Rinsho Iyaku 9: 1077–1093, 1993dGoogle Scholar
- Thomson AN, Arthur GP, Bergin PS, Pollock M, Parkin PJ, et al. Subcutaneous sumatriptan in acute treatment of migraine: a multicentre New Zealand trial. New Zealand Medical Journal 106: 171–173, 1993Google Scholar
- Totaro R, De Matteis G, Marini C, Prencipe M. Effect of sumatriptan on cerebral blood flow velocity measured by transcranial Doppler. Abstract. Stroke 24: 516, 1993Google Scholar
- Visser WH for the Study Group. Does a combined regimen of subcutaneous followed by oral sumatriptan prevent headache recurrence? Abstract. Cephalalgia 13 (Suppl. 13): 189, 1993Google Scholar
- Wells NEJ. The epidemiology and socio-economic impact of migraine. Abstract. 7th World Congress on Pain Congress Abstracts, p 287, IASP Publications, Seattle, 1993Google Scholar