Sumatriptan

Summary

Synopsis

Sumatriptan is a potent and selective agonist at a vascular serotonin₁ (5-hydroxytryptamine₁; 5-HT₁) receptor subtype (similar to 5-HT_1D) 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.

Pharmacodynamic Properties

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-HT_1D) is found predominantly in cranial vasculature and mediates constriction of cephalic arteries and arteriovenous anastomoses. Autoradiographical studies demonstrated that 5-HT_1D 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-HT_1D receptors (along with some affinity for 5-HT_1A receptors). Ergot alkaloids have strong affinity for 5-HT_1D receptors, but also have a relatively high affinity for 5-HT_1A, 5-HT_1C, 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-HT_1D 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.

Pharmacokinetic Properties

A mean plasma concentration (C_max) 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 C_max of 54 μg/L after a median of 1.5 hours; however, 80% of C_max 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.

Therapeutic Efficacy

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.

Tolerability

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