Sumatriptan

Abstract

Sumatriptan is a selective agonist at serotonin 5-HT_I-like receptors, including 5-HT_1B/1D subtypes. It is an effective treatment for acute migraine attacks and the injectable form has also shown efficacy in the treatment of cluster headaches. In placebo-controlled clinical trials, sumatriptan, administered subcutaneously, orally, intranasally or rectally was significantly more effective than placebo in relieving migraine headache and in producing resolution or reduction of other symptoms associated with migraine, including nausea, photophobia and phonophobia. Improvements in clinical disability were also significantly greater after sumatriptan than after placebo. Headache recurred in 21 to 57% of patients who received oral or subcutaneous sumatriptan, but most patients responded to a second dose of the drug. Results of comparative trials showed that subcutaneous sumatriptan 6mg was significantly more effective than either patients’ usual antimigraine treatments or intranasal dihydroergotamine mesylate 1mg in relieving migraine headache. Subcutaneous sumatriptan 6mg and subcutaneous dihydroergotamine mesylate lmg provided similarly effective migraine relief, but the headache recurrence rate was significantly higher after sumatriptan than after this formulation of dihydroergotamine mesylate. Response rates achieved after oral sumatriptan were similar to those reported after treatment with oral naratriptan, rizatriptan or lysine acetylsalicylate plus metoclopramide. Treatment of acute migraine attacks with oral or subcutaneous sumatriptan leads to less loss of workplace productivity than other antimigraine therapies. Several pharmacoeconomic analyses showed that gains in workplace productivity in sumatriptan recipients ranged from 12.1 to 89.8 hours per patient per year. Significant improvements from baseline in overall health-related qualityof-life scores were also experienced by sumatriptan recipients. Sumatriptan is generally well tolerated. Nausea, vomiting, malaise and fatigue are the most common adverse events with oral sumatriptan. Injection site reactions occur in 10 to 40% of patients receiving the drug subcutaneously. A bitter taste at the back of the mouth occurs frequently after intranasal administration. Serious adverse events occur in about 0.14% of patients with migraine treated with sumatriptan. As the drug is associated with the rare development of cardiovascular effects, it is contraindicated in patients with a history of cardiovascular disease. Conclusions. Despite its relatively high acquisition cost, reductions in lost workplace productivity experienced by patients treated with sumatriptan may result in savings in the overall cost of migraine to society. Thus, sumatriptan is a usefulfirst- or second-line treatment option for patients with moderate or severe migraine. Although the mechanisms involved in the pathogenesis of migraine are not yet completely understood, the disease is widely believed to be both vascular and neurogenic in origin. Serotonin 5-HT₁-like receptors located in the cranial vasculature and nervous tissue appear to play a critical role in the pathogenesis of the disorder. Sumatriptan is an agonist at 5-HT_1B/1Dreceptor subtypes. It has a high affinity and relative specificity for the 5-HT_1d receptor subtype and also shows some affinity for 5-HT_1a and 5-HT_1f receptor subtypes. The drug has no appreciable activity at 5-HT₂ or 5-HT₃ receptor subtypes or at muscarinic, dopamine D₁, D₂, benzodiazepine or α₁-, α₂ - or β-adrenoceptors. Sumatriptan causes vasoconstriction of large cerebral blood vessels. Increased blood flow velocity in these vessels occurs in sumatriptan-treated patients between and during migraine attacks. Contraction of human isolated epicardial coronary arteries by sumatriptan is probably mediated via the drug’s activity at 5-HT₁-like receptors. Sumatriptan inhibits the release of calcitonin gene-related peptide (CGRP) and blocks neurogenic protein extravasation within the trigemino-vascular system. Increased plasma CGRP levels in patients with migraine were attenuated by sumatriptan. Pharmacokinetic Properties The bioavailability of sumatriptan after subcutaneous administration is high (96%), but its oral bioavailability is only 14%. After administration of subcutaneous doses of 3 or 6mg to healthy volunteers and patients with migraine, maximum plasma concentrations (C_max) of 42 to 72 μg/L were achieved in a median or mean time (t_max) of 0.17 to 0.23 hours. Broadly similar C_max values (54 to 95 μg/L) were reported 1.25 to 2.29 hours after administration of oral doses of 100 to 200mg. Absorption of oral sumatriptan is unaltered either by administration with food or by delayed gastric emptying. Mean C_max values after single intranasal doses of sumatriptan 5 to 20mg ranged from 4.7 to 14.4 μg/L (reached in a median t_max of 1 to 1.5 hours); after single rectal doses of 50 or 100mg, mean C_max values of 50.1 and 94.8 μg/L were attained in a mean tmax of 2.5 hours. The volume of distribution of sumatriptan (after single subcutaneous doses of 6mg) is 170 to 203L, suggesting that the drug is widely distributed in body tissues. Plasma protein binding of sumatriptan is low (14 to 21%). After absorption, sumatriptan is extensively metabolised to an inactive indoleacetic acid analogue, which is excreted predominantly in the urine. A small amount of the active drug is excreted via the renal and faecal routes. The therapeutic efficacy of sumatriptan is well established. Results of clinical trials have shown that sumatriptan, administered subcutaneously, orally or intranasally, is significantly more effective than placebo in relieving headache, in producing resolution or reduction of...