History of the Use of Ergotamine and Dihydroergotamine in Migraine From 1906 and Onward

Abstract

Dale showed in 1906 in a seminal work that ergot inhibits the pressor effect of adrenaline. Stoll at Sandoz isolated ergotamine from ergot in 1918. Based on the belief that migraine was due to increased sympathetic activity, ergotamine was first used in the acute treatment of migraine by Maier in Switzerland in 1925. In 1938 Graham and Wolff demonstrated the parallel decrease of temporal pulsations and headache after ergotamine i.v. This inspired the vascular theory of Wolff: an initial cerebral vasoconstriction followed by an extracranial vasodilation. Dihydroergotamine (DHE) was introduced as an adrenolytic agent in 1943. It is still in use parenterally and by the nasal route. Before the triptan era ergotamine and DHE had widespread use as the only specific antimigraine drugs. From 1950 the world literature on ergotamine was dominated by two adverse events: ergotamine overuse headache and the relatively rare overt ergotism. Recently, oral ergotamine, which has an oral bioavailability of < 1%, has been inferior to oral triptans in randomized clinical trials. A European Consensus in 2000 concluded that ergotamine is not a drug of first choice. In an American review of 2003 it was suggested that ergotamine may be considered in the treatment of selected patients with moderate to severe migraine.

Increased Brainstem Serotonergic Transporter Availability in Adult Migraineurs: an [18F]FP-CIT PET Imaging Pilot Study

“…More than two-thirds of migraineurs reported experiencing limitation in their activities of daily life [1,2]. The serotonergic hypothesis, which argues that serotonin plays an important role in the pathophysiology of the migraine, is widening its ground with a new finding that the brainstem has an integral function in the beginning and the control of migraine [1,3,4]. This hypothesis insists that the nociceptive trigeminovascular pathway be activated during the low serotonin concentration state [5][6][7].…”

Triptans and ergot alkaloids in the acute treatment of migraine: similarities and differences

“…Then subcutaneous sumatriptan 6 mg was introduced in 1991 [2,3], and subsequently sumatriptan tablets (50-100 mg) and six other triptans, naratriptan, zolmitriptan, rizatriptan, almotriptan, eletriptan and frovatriptan were introduced [3,4]. This introduction of triptans was a major breakthrough in migraine therapy.…”

“…The affinities of ergot alkaloids and triptans indicate, however, that they should have similar efficacy when used in equipotent doses. Thus, both groups of drugs have high affinities at 5-HT 1B and 5-HT 1D receptors [3,6]. In addition, some triptans have affinity for the 5-HT 1F receptor [3], and ergotamine has affinity for the 5-HT 2B receptor, the a 1 -and a 2 -aderenoceptors, and the dopamine D 2 receptor and DHE have affinity for the same four receptors plus the 5-HT 1A receptor [6].…”

“…Thus, both groups of drugs have high affinities at 5-HT 1B and 5-HT 1D receptors [3,6]. In addition, some triptans have affinity for the 5-HT 1F receptor [3], and ergotamine has affinity for the 5-HT 2B receptor, the a 1 -and a 2 -aderenoceptors, and the dopamine D 2 receptor and DHE have affinity for the same four receptors plus the 5-HT 1A receptor [6]. Triptans were developed as specific drugs for the 5-HT1B/1D receptors [3], and the effect of ergot alkaloids in migraine is also most likely mediated by these receptors [3,6].…”

“…In addition, some triptans have affinity for the 5-HT 1F receptor [3], and ergotamine has affinity for the 5-HT 2B receptor, the a 1 -and a 2 -aderenoceptors, and the dopamine D 2 receptor and DHE have affinity for the same four receptors plus the 5-HT 1A receptor [6]. Triptans were developed as specific drugs for the 5-HT1B/1D receptors [3], and the effect of ergot alkaloids in migraine is also most likely mediated by these receptors [3,6]. Compared with triptans, ergot alkaloids are 'relatively dirty drugs' and this lack of specificity probably explain the higher incidence of adverse events (AEs) with ergot alkaloids than with triptans, see below [3,6].…”