Sumatriptan: Pharmacological Basis and Clinical Results

Carl G. H. Dahlöf

Disclosures

Curr Med Res Opin. 2001;17(1s) 

In This Article

First Selective Migraine Pharmacotherapy

The discovery of the sumatriptan molecule in 1984 was the culmination of a search for a serotonergic agent with selective vasoconstrictor activity at the cranial blood vessels, the putative source of migraine pain[1]. The importance of serotonin in migraine had been suggested by the observations that platelet serotonin levels fall by as much as 40% at the onset of migraine; administration of reserpine, which causes serotonin to leak from synaptic vesicles, precipitates migraine headache; intravenous serotonin abolishes migraine pain; and non-selective serotonin agonists such as dihydroergotamine and ergotamine are often effective at alleviating migraine[2]. While agents such as dihydroergotamine and ergotamine are effective in migraine, their non-selective action results in treatment- limiting side-effects[3]. The poor side-effect profiles and the equivocal efficacy of migraine medications of the pre-sumatriptan era motivated the effort to develop a new, selective migraine therapy. The identification of 5-HT1B receptors located predominantly at the cranial vasculature and not plentiful in other parts of the body paved the way for the discovery of sumatriptan. Structurally related to serotonin, sumatriptan is selective for cranial vascular 5-HT1B receptors over other types of serotonin receptors[4].

Sumatriptan stimulation of the 5-HT1B receptor on cranial vascular smooth muscle is hypothesized to cause vasoconstriction that counteracts the paininducing vasodilation that may be responsible for headache[5]. Sumatriptan is also hypothesized to stimulate a 5-HT1 receptor (5-HT1D) on pain fibres innervating the cranial vasculature to block the release from the fibres of vasoactive peptides that cause neurogenic inflammation. Recent data show that sumatriptan also acts at another serotonin receptor subtype, the 5-HT1F receptor[6], which may be important in mediating transmission of cranial pain information in the trigeminal nucleus caudalis[7]. The clinical significance of sumatriptan's activity at 5-HT1F receptors remains to be elucidated.

The high degree of selectivity of sumatriptan for 5-HT1B receptors of the carotid circulation distinguishes it from other agents such as ergotamine and dihydroergotamine, which had been widely used before the introduction of sumatriptan in many countries. Unlike sumatriptan, ergotamines stimulate several other receptors involved in the regulation of diverse physiological and behavioural functions[8]. Ergotamines bind to beta-receptors as well as alpha1- and alpha2-adrenergic receptors, and potently affect 5-HT1C and 5-HT2 receptors as well as dopamine-1 and dopamine- 2 receptors. Activity at several of these receptor types causes untoward side-effects[3].

Sumatriptan's activity at the hypothesized source of migraine pain also distinguishes it from nonserotonergic agents such as simple analgesics and non-steroidal anti-inflammatory drugs (NSAIDs). These agents non-specifically influence inflammatory processes throughout the body, whereas sumatriptan selectively targets inflammatory processes important in producing pain-inducing cranial vasodilation[9].

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