Revisiting the Role of Ergots in the Treatment of Migraine and Headache

Eric P. Baron, DO; Stewart J. Tepper, MD

Disclosures

Headache. 2010;50(8):1353–1361 

In This Article

Historical Background

Saints Cosmas and Damian, the patron saints to physicians and surgeons, were twin brothers and early Christian Martyrs who died ca. 287 AD. In a tale set in 348 AD, a miracle takes place in which the twin brothers successfully transplant the ulcerated, gangrenous leg of a priest during a dream, and upon awakening, his leg is healed. This story was famous through the Middle Ages and has been the subject of renowned paintings. The story raises the possibility that the priest was one of the afflicted in an ergotism epidemic, common during these times.[1] The ergot mold grew on bread eaten by the masses, resulting in multiple forms of ergotism. There are references to ergots dating to 400 BC by the Parsees who described "grasses that cause pregnant women to drop the womb and die in childbirth," and to 600 BC where the Assyrians described the "noxious pustule in the ear of grain."[2] There is an extensive history of ergotism plagues throughout Europe and the world, the first of which was described in Germany in 857.[2]

Historical ergotism had 2 primary manifestations. The first was gangrene and was known as Holy Fire or St. Anthony's Fire, since those afflicted developed intense burning pain and gangrene of digits and limbs because of vasoconstriction. These vasoconstrictive effects were also to blame for many unexplained miscarriages. Saint Anthony had no direct connection to ergotism, but his name is associated with it because of the Antonite monks, who traveled across medieval Europe funding hospitals and were credited with many cures. They provided Saint Anthony's crushed bones sprinkled with holy water or wine, which was then drunk by the afflicted, presumably followed by a healing.[2]

A second cardinal manifestation of ergotism was tonic-clonic convulsions, often accompanied by mania and hallucinations. This syndrome was due to serotonergic effects by components of one of the ergots' diverse alkaloid components, lysergic acid. Lysergic acid is structurally related to the potent hallucinogen which modern chemists later discovered, lysergic acid diethylamide.[2]

As noted above, ergots are the alkaloid containing product of the fungus Claviceps purpurea, which grows on grain, especially rye. The fungal spores germinate into hyphal filaments, which grow deeply into the rye, forming a dense tissue that hardens into a purple curved spur or sclerotium. Indeed, the word "ergot" is derived from "argot," Old French for "cock's spur." The sclerotium is the main commercial source of ergot alkaloids.[2]

In 1596, a German physician, Wendelin Thesius, was one of the first to describe the causative role of ergot rye in ergotism,[2,3] but the role of the fungus was not fully recognized until 1630 by Tullier.[4] The therapeutic use of ergot was first documented in 1582 when A. Lonicer recommended giving the sclerotium to stimulate the uterus in prolonged labor.[2,3] This use of ergot was refined and frequently used over subsequent years.

In addition to these potent oxytocic effects, the ergots act as serotonin agonists, which also cause vasoconstrictive and central nervous system (CNS) effects. These vascular effects led to the discovery of ergot as treatments for headache and migraine.

The first known record of ergot in treating migraine appeared in Italian in 1862,[4,5] and the first record in the English language was in 1868 by Edward Woakes.[4] Subsequent research, writings and case reports by others such as A. Eulenburg, W.R. Gowers, and W. H. Thompson furthered the concept of ergot use in migraine, including injection by Oppenheim in 1911.[4]

All naturally occurring ergot alkaloids (ergolines) of therapeutic interest are derivatives of the tetracyclic compound lysergic acid.[2] The first pure alkaloid, E, was isolated by A. Stoll in 1918.[2–4] In 1925, Maier in Switzerland first used E in acute migraine treatment,[6] and Rothlin successfully treated 2 migraine patients by subcutaneous (SC) administration. In 1926, Maier successfully used E as a migraine preventive.[4] And in 1938, Graham and Wolff described decrease of temporal pulsations and headache after E administration, which inspired Wolff's vascular theory of migraine.[6]

Dihydroergotamine was introduced as an adrenolytic agent in 1943, and its potential for use in migraine became quickly evident.[6] E and DHE remained the only available acute specific antimigraine therapies until the development of sumatriptan by Pat Humphrey and his team in the 1980s, although some patients respond acutely to methysergide, methylergonovine, and other ergots as well.

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