Summary
Synopsis
Sumatriptan is a selective agonist at serotonin 5-HTI-like receptors, including 5-HT1B/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.
Overview of Pharmacodynamic Properties
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-HT1B/1Dreceptor subtypes. It has a high affinity and relative specificity for the 5-HT1d receptor subtype and also shows some affinity for 5-HT1a and 5-HT1f 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 (Cmax) of 42 to 72 μg/L were achieved in a median or mean time (tmax) of 0.17 to 0.23 hours. Broadly similar Cmax 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 Cmax values after single intranasal doses of sumatriptan 5 to 20mg ranged from 4.7 to 14.4 μg/L (reached in a median tmax of 1 to 1.5 hours); after single rectal doses of 50 or 100mg, mean Cmax 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.
Therapeutic Efficacy
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 other migraine-associated symptoms (including nausea, photophobia and phonophobia) and in reducing clinical disability in patients with migraine. Headache recurred in 21 to 57% of patients with migraine treated with oral or subcutaneous sumatriptan, but most affected patients responded to a second dose of the drug.
In placebo-controlled trials, headache relief (beginning 10 minutes after drug administration) was experienced by 56 to 80% of patients 1 hour after receiving sumatriptan 6mg subcutaneously, compared with 6 to 32% of placebo recipients. Results of comparative trials show that subcutaneous sumatriptan 6mg was significantly more effective than patients’ usual antimigraine treatments; relief of headache 1 to 2 hours after administration was experienced by 63 to 82% of sumatriptan recipients, compared with 19 to 39% of patients who received their usual treatments.
Subcutaneous sumatriptan 6mg was more effective than subcutaneous dihydroergotamine mesylate 1mg in relieving migraine headache 1 and 2 hours after administration, but response rates were similar for both drugs 3 and 4 hours after administration. The headache recurrence rate was significantly lower in the dihydroergotamine mesylate recipients than in the sumatriptan group. Subcutaneous sumatriptan 6mg was consistently significantly more effective over a 24-hour period than intranasal dihydroergotamine mesylate lmg.
Relief of migraine headache 2 hours after treatment occurred in 50 to 69% of patients treated with oral sumatriptan 100mg, compared with 10 to 31% of placebo recipients. Oral sumatriptan 100mg showed efficacy similar to that of the 5-HT1b/1d receptor agonists naratriptan 2.5mg and rizatriptan 10, 20 or 40mg, administered orally, in terms of relieving headache, but the rate of headache recurrence was significantly lower in naratriptan-treated patients than in sumatriptan recipients. Response rates were similar in patients treated with either oral sumatriptan 100mg or oral lysine acetylsalicylate 1620mg (equivalent to 900mg aspirin) plus metoclopramide 10mg.
In placebo-controlled trials, intranasal sumatriptan 20mg (administered in 1 or both nostrils) produced relief of migraine headache in 62 to 78% of patients 2 hours after administration, whereas headache relief occurred in 29 to 42% of placebo recipients. Intranasal sumatriptan has a rapid onset of action, with headache relief beginning within 15 minutes of treatment.
Rectal sumatriptan, administered as either a 25 or 50mg single dose, was significantly more effective than placebo in relieving migraine headache and other migraine-associated symptoms in a recent trial.
Cluster headaches are also effectively treated with subcutaneous sumatriptan. In 2 trials, headache relief was reported by 74 and 75% of patients who received sumatriptan 6mg subcutaneously.
Pharmacoeconomic Considerations
Several pharmacoeconomic analyses, based on nonblind, sequential trials, showed that estimated gains in workplace productivity of 12.1 to 89.8 hours per patient per year were achieved with sumatriptan; these gains were greater than those achieved with other non-‘triptan’ antimigraine therapies. In a single costbenefit study, treatment of acute migraine with oral sumatriptan 50mg led to a net reduction in the cost of migraine to society of £125 per patient per year (1996 pounds), compared with customary treatment.
In sequential nonblind clinical trials and in a large nonblind multinational trial, patients with migraine experienced significant improvements from baseline in most overall health-related quality-of-life scores and in dimensional quality-of-life subscores during treatment with oral, subcutaneous or oral and subcutaneous sumatriptan.
Tolerability
Sumatriptan is generally well tolerated, whether given subcutaneously, orally, intranasally or rectally, with adverse effects being mild (though in rare circumstances intense) and transient.
Nausea, vomiting, malaise and fatigue are the most frequent events with oral sumatriptan. Minor injection site reactions, the most common reported event with subcutaneous sumatriptan, are experienced by 10 to 40% of recipients of this formulation. Serious adverse events have been reported in 0.14% of patients treated with oral or subcutaneous sumatriptan.
Chest tightness and pressure occur in 3 to 5% of recipients of subcutaneous or oral sumatriptan, but there is little evidence of an association between these symptoms and the development of myocardial ischaemia in previously healthy patients. In patients with underlying cardiovascular disease, sumatriptan has been associated, albeit rarely, with serious cardiovascular effects, including coronary vasospasm, myocardial infarction and unstable angina pectoris.
A taste disturbance (described as bitter/unpleasant at the back of the mouth) is the most frequent adverse event with intranasal sumatriptan. The tolerability profile of sumatriptan suppositories appears to be similar to that of placebo.
Dosage and Administration
The recommended dose of subcutaneous sumatriptan is 6mg, administered at the onset of the migraine headache. Patients who experience temporary or partial responses may receive a second dose of 6mg (administered at least 1 hour after the first dose) [maximum subcutaneous dosage: 12mg in 24 hours].
The optimal starting dose of oral sumatriptan is usually 50mg (although some patients may require a 100mg dose), administered as soon as possible after the onset of a migraine attack. Up to 2 additional doses may be taken during a 24-hour period (maximum oral dosage: 300mg in 24 hours). The recommended dose of intranasal sumatriptan is 20mg, administered at the onset of the migraine attack. Patients who experience a temporary response during a 24-hour period may receive 1 further 20mg dose (with a 2-hour interval between doses).
Second doses of sumatriptan are not recommended for the treatment of nonresponders within a given attack.
The dosage of subcutaneous sumatriptan recommended for the treatment of cluster headache is the same as that used to treat migraine.
Sumatriptan is contraindicated in the treatment of patients with a history of cardiovascular disease.
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Various sections of the manuscript reviewed by: F. Boureau, Hôpital Saint-Antoine, Paris, France; P. Cortelli, Clinica Neurologica, Università di Bologna, Bologna, Italy; S. Evers, Department of Neurology, University of Munster, Munster, Germany; J.P. Ottervanger, Department of Cardiology, Hospital ‘De Weezenlanden’, Groot Wezenland, Zwolle, The Netherlands; A. Panconesi, Institute of Internal Medicine IV, Headache Center, University of Florence, Florence, Italy; A.M. Rapoport, The New England Center for Headache, Stamford, Connecticut, USA.
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Perry, C.M., Markham, A. Sumatriptan. Drugs 55, 889–922 (1998). https://doi.org/10.2165/00003495-199855060-00020
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DOI: https://doi.org/10.2165/00003495-199855060-00020