Abstract
Although ergot had been used in obstetrics for several centuries, it was proposed for the treatment of migraine only in the 19th century. The British ENT-surgeon Edward Woakes (1837-1912) recommended ergot as a vasoconstricting agent for migraine and other neurogenic conditions associated with vasodilatation in 1868. He subscribed to the theory of vasodilatation by sympathetic deficit, presented in the early 1850s by Brown-Séquard and Claude Bernard. Du Bois-Reymond proposed vasoconstriction by sympathetic overactivity as the cause of migraine in 1860; Brown-Séquard opposed this in favour of vasodilatation. Vasodilatation due to sympathetic deficit in migraine was again supported by Möllendorf, with clinical evidence, in 1867. Woakes' paper of 1868 introduced ergot as a vasoconstrictor for the same condition. Reception abroad was prompt. A German version appeared in 1869, and Eulenburg cited Woakes in his textbook of 1871. Eulenburg presented the use of ergot for migraine as a routine measure in the second edition of his textbook in 1878, and in a paper published in 1883. The method was internationally accepted, but it became really popular only after the isolation of pure ergotamine in 1918, resulting in the first reliable compounds with stable properties and predictable effects. Contrary to Woakes' theory, in the early 20th century ergot was used for migraine because of its well-documented adrenolytic properties, as migraine was by then again believed to be a sympathotonic and vasospastic condition.
How ergot entered the pharmacopoeias and became a reliable drug
A large number of papers and books have been written on ergot and ergotism. Although the focus of interest of this paper is on the use of ergot in migraine, the general history of ergot provides the historical background of this particular development. Ergot may have been mentioned for the first time in Europe by Adam Lonitzer (1528–1586) who called it Kornzapfen (corn cone). The term Mutterkorn (literally mother-corn, corn cone) was used later, derived from German folklore:
‘when the corn waved in the wind, the corn-mother was said to pass through the field; her children were the rye wolves and ergot was of her making’
writes George Barger in his monograph Ergot and ergotism, p. 6 (1).
Ergot is produced by the ‘mother-corn’, the fungus Claviceps purpurea which grows in ears of rye. Wheat was more prevalent than rye in many countries. Therefore ergot was not well known in England before the 19th century, although the term itself appeared for the first time in an English text in 1683. Ergot is probably derived from the French: Farmers in Sologne, south of Paris, first called it argot, a word for the spur of a rooster, which later became ergot. The fungus of rye has been called many names in various countries, and Bove collected them in a table in his book, Story of Ergot (2).
Epidemics of ergotism have been reported since many centuries. Two types of ergotism were described, a gangrenous and a convulsive type, and there were mixed forms. The gangrenous type was observed more frequently in France, the convulsive type in Germany. This difference has been attributed to regional diets and differences in vitamin supply. What may be the first recorded epidemic was observed in 857. A more precise description dates from 945, the so-called ignis plaga in Paris (called ‘fire plague’ from the intense burning pain of gangrenous ergotism). The first known epidemic of the convulsive type was recorded in 1085. Epidemics seem to have increased in the 17th century (1), along with the contemporary renaissance of epidemiology. Victims of ergotism often invoked saints to come to their aid, especially St. Anthony. Gangrenous ergotism was called ‘St. Anthony's fire'or ‘holy fire’ (ignis sacer). The link between bread from ergot-infected rye and ergotism was found in the 17th century (3), but the epidemics only began to recede in the early 19th (and late 18th) century when public authorities ordered the inspection of crops and the sieving of rye (4).
The Chinese and the Arabs had used ergot in obstetrics long before the 16th century when it began to appear in European literature. Poudre obstétricale or pulvis ad partum, ‘powder for delivery’, containing ergot, was prescribed by physicians in the 18th century, and ergot for obstetrics was introduced in the USA by Stearns in 1808. In the 19th century chemists attempted to extract the active principle of ergot, and Bonjean prepared an aqueous extract in 1842 which he called ‘ergotine’. Ergotine was later injected subcutaneously. However, these preparations were not very reliable as their contents varied in quality and quantity, until Stoll isolated the alkaloid, ergotamine, in 1918. Stoll's crystallized substance provided constant reactions and predictable pharmacological effects. Meanwhile, Sir Henry Dale (1875–1968), a Nobel Prize winner in 1936, had discovered that the liquid extract of ergot blocked the effects of stimulation of the sympathetic nerves. This led to the discovery of the effects of histamine, noradrenaline (5) and acetylcholine (6, 7) and to Barger's and Dale's new concept of sympathomimetic activity.
Introduction of ergot for migraine: fallacies of secondary literature
For most of its history, ergot had been used in obstetrics. Its early use for migraine has not been correctly dated since the available work on the history of ergot carries a twentieth century bias. The descriptions of developments in the 19th century are diluted at least twice, summarized from authors who already relied on secondary literature, while original sources are harder to ascertain and to obtain. A typical example is the first chapter of Discoveries in pharmacology, ‘The versatile ergot of rye’ (8). Its information on the twentieth century is more reliable than that on the 19th:
‘Mentions of its use [of ergot in migraine] began to appear in the medical literature only towards the end of the last century, the first a hundred and one years ago (Eulenburg, 1883).’
On the contrary, we found that the use of ergot for headache was reported in 1862 in an Italian journal (9), and ergot for migraine was introduced in an original British paper in 1868 (10), with a German version in 1869 (11), which was cited by Eulenburg in 1871 (12).
Edward Woakes and his paper of 1868
Edward Woakes (1837–1912) was the son of a physician in Luton, Bedfordshire, England. He studied at the University of London and worked at St. Thomas' Hospital from 1854, as house surgeon. He obtained his membership of the Royal College of Surgeons in 1858. One year later he went to join his father in their general practice in Luton where he remained until 1876, when he returned to London to specialize in Otology, Rhinology and Laryngology. He joined the staff of Golden Square Hospital, and was appointed Senior Aural Surgeon at London Hospital where he taught otology. He wrote books and papers on deafness, nasal polyps with neuralgia, ethmoiditis, vertigo, and diphtheria. He acquired eponymous fame for his description of ‘necrosing ethmoiditis’, but its theoretical background was soon found to be untenable. However, in French rhinological literature the term ‘Maladie de Woakes’–‘Woakes’ disease' survived for a long time although he had not completely described this syndrome featuring nasal polyps, necrosis of the ethmoid, and disfiguring hyperplasia of the bony nasal pyramid. Ethmoidal necrosis was omitted in later descriptions (13).
Woakes' interest in headache derived from his observations of ‘neuralgia’ associated with nasal polyps; hence his paper of 1868 on ‘neuralgias’, migraine, and ergot (10); he also wrote on occipital headache in 1878 (14). Woakes' paper ‘On ergot of rye in the treatment of neuralgia’ was published in the British Medical Journal of 1868 (10). He had read it at the Annual Meeting of the British Medical Association in Oxford in August 1868. Woakes expounded his theory of neuralgia, reported the use of ergot in its treatment, and summarized five cases. He distinguished two types of neuralgia: traumatic and idiopathic. In both types the
… symptoms were shown to be manifestly due to the paralysing influence of the injury or shock upon the fibres of the sympathetic system of nerves accompanying the arteries in their distribution to the skin and to the sentient nerves … (10)
Woakes' use of the term ‘shock’ may derive from the work of Marshall Hall (1790–1857), who had explained ‘spinal shock’ in the 1840s:
‘… the reflex actions are not manifested immediately after an injury of the spinal marrow … the first influence of shock is to diminish the excito-motory power.’ (15)
Woakes used neuralgia associated with shingles as an example of his nontraumatic, hence ‘idiopathic’ type of neuralgia. He stated that both the neuralgic and eruptive phenomena of shingles were due to the usual reactions after nerve injury from any cause:
The sympathetic nerve-fibres accompanying, say, an intercostal artery, are lost in the direction of the skin, on the minute divisions of the artery supplying its ultimate structure. When these nerve-fibres are paralysed from any cause, their function of regulating the calibre of the vessels will be withdrawn. Passive congestion of these vessels, and consequent effusion of liquor sanguinis, are the physiological effects of this nerve-palsy (10).
This concept was based on an important discovery made by Brown-Séquard, Bernard and Waller nearly 20 years earlier. In 1852 the French physiologist Claude Bernard (1813–1878) found that section of the cervical sympathetic resulted in increased blood flow with elevated temperature in the face, and constriction of the pupil (16). At first Bernard did not understand these phenomena, as the sympathetic system was thought to be the origin of animal warmth, the ‘chaleur animale’; he expected a lowering of facial temperature, and was surprised when it was rising. In the same year the physician and physiologist Charles-Edouard Brown-Séquard (1817–1894) galvanized—or rather, faradized, using the induction coil invented by Du Bois Reymond—the cervical sympathetic, and found constriction of the blood vessels in the ear, and decreasing temperature of the facial skin. Unlike Bernard, he interpreted the effects of both section and stimulation correctly. Claude Bernard did not acknowledge Brown-Séquard's priority in this respect; he began to use the term vasomotricity only many years later, in 1862 (17–19).
Woakes went on to explain that the exudation of watery fluid from the dilated arteries caused both the elevation of the cuticle and the mechanical stimulation of sensory fibres resulting in pain:
These vasi (sic) nervorum will therefore acknowledge the same impressions, and manifest the same behaviour under them … there will ensue, synchronously with the corresponding skin-phenomena, a state of dilatation of these vessels, and exudation from them of watery elements between the fibrillae of the nerve; … a mechanical stretching and compression of its constituent sensory fibres ensue, resulting, as might be expected, in the acute pain so characteristic of neuralgia (10).
It is most important to ‘restore the tone of the vessels’, which will result in the disappearance of the exudate ‘from its disturbing … the fibrillae of the sentient nerves’. Woakes assumed vasodilatation as the effect of sympathetic paralysis, and he needed a vasoconstricting substance to counter it. He mentioned belladonna as the best among the usual drugs, but he recommended to add ergot of rye to the list. He based this claim on the effect of ergot on uterine blood vessels, and ‘its power of controlling the haemorrhage in a case of haemoptysis’.
He summarized five cases of ‘neuralgia’, where ergot had been successfully applied, with his diagnoses: I. shingles, II. sciatica, III. and V. tic douloureux, and IV. hemicrania. In two other cases of sciatica, ergot failed to provide relief.
These cases need some comments.
• Case I. ‘Shingles’ can be diagnosed retrospectively from the typical rash under the right breast extending to the back, and the very severe pain in the same region. This was a 22-year-old-woman, who also had unspecified headache for six weeks. Spontaneous remission of zoster neuralgia is common at this age. On the other hand, ergot has been widely used in this condition during most of the 20th century, although without controlled evidence.
• Case II. ‘Sciatica’ since four months, suggestive of irritation of S 1, cured within two days. Contrary to Woakes' theory, we would rather attribute this anecdotic cure to the sympatholytic effect of ergot.
• Case III. ‘Tic douloureux’. A 21-year-old-woman was cured of ‘very severe tic of the left side of the face, affecting especially the inferior dental nerve, and extending downwards to the shoulder. She had some dyspepsia …’ This acute disorder lasted two days. Again, the pain is not specified. It was one acute episode of facial pain not confined to trigeminal branches, in a very young woman, certainly not what we would call tic douloureux, or idiopathic trigeminal neuralgia. To judge from its duration, unilaterality, accompanying dyspepsia, and the spreading of the pain to the shoulder, it may have been an atypically localized migraine with atypical odontalgia.
Woakes described the fourth case as follows
Case IV. Hemicrania. John Gray, aged about 35, has been repeatedly under treatment for that form of neuralgia known as brow ague. His attacks have been cured alike by quinine and sesquioxide of iron. Sometimes they are very severe, and the treatment long continued. He was last seen in May 1868, when he had a very sharp attack of neuralgia of the right temple. He was ordered to take, every four hours, an ounce of a mixture of two drachms of liquid extract of ergot in six ounces of infusion of ergot. After taking this for two or three days, he was cured more satisfactorily and quickly than in his former attacks (10).
Again, no details are given on the character of the pain, or accompanying symptoms but the pattern of periodically recurring episodes of hemicranial pain requiring forceful medical treatment is suggestive of migraine. When this was written, the term brow ague was used for hemicrania lasting from six to 24 hours (20). The episodes described here must have been protracted as ergot shortened the duration to only two or three days.
Case V. ‘Tic douloureux’. ‘Miss E., aged 22, was seen on June 2nd, 1868. She had tick in the left temple for two weeks, very severe at times. … The neuralgia was relieved immediately after commencing this [ergot] treatment, and entirely left her after using it two or three days.’ Again, an episode of unspecified hemicranial headache, probably not trigeminal neuralgia, more likely a primary headache, probably migraine, was immediately terminated by ergot.
Woakes' paper ends in a plea for trials on greater numbers of patients, and for a new classification of these pain syndromes permitting more precise indications.
… but it is hoped that the very favourable result which the examples now reported indicate to have accrued from its use may gain for the drug a more extended trial in neurotic affections; and that, shortly, sufficient data may be collected to enable one to decide with some degree of precision the class of cases in which to expect from it the marked benefit it is evidently capable of effecting in many forms of the disease (10).
Fortunately, Woakes did not know that his hope for a useful classification would have to wait another 120 years until 1988. ‘Neurotic affections’, in the medical language of the time, included trigeminal and postherpetic neuralgia as well as the primary headaches, without any psychological connotation.
International reception of Woakes' innovation
A German version of Woakes' 1868 innovation appeared in Schmidt's yearbooks of medicine in 1869 (11). A French monograph on ergot of 1870 did not yet include its use in migraine (although mentioning an indication for paralysis) (21). But Eulenburg cited Woakes' recommendation of ergot for migraine in his textbook of functional neurological diseases of 1871 (12). In the second edition of this textbook of 1878, he already proposed ergot among the routine treatments of migraine, along with diet, amyl nitrate, and the electrotherapies (22). In 1883, Eulenburg recommended subcutaneous injections of ergotinin generally for attacks of vasoparalytic character including palpitations in hyperthyroidism, panic attacks in depression, paralytic incontinence, and migraine. His paper of 1887 summarized his views on ergot in migraine (23). In 1886–7, Thomas' prize-winning French monograph on migraine confirmed Eulenburg's indication ‘for the neuro-paralytic forms’, mentioning another German author, Vogt, who had proposed ergot therapy for the same in 1872 (24). Observers of European medicine in the United States followed Eulenburg and Woakes in 1872 (25), and a Swedish case of ‘angio-paralytic migraine’ was published in Swedish in 1875 (26), and in English in the Lancet in 1878 (27). Successive British monographs reflect this development: Wright's Headaches (1856) does not mention ergot treatment (20), whereas its direct successor, W.H. Day's Headaches (1878) has it (28):
‘Ergot is a remedy highly spoken of by some authorities, but I have not employed it with so many more remedies at hand’[such as quicksilver chloride, aconite, arsenic, bromides, strychnine, etc.].
He quotes Bucknill, Tuke and Browne from Psychological Medicine (1874, p. 745):
‘I have found it almost uniformly efficacious in reducing excitement, in shortening attacks, in widening the intervals between them, and occasionally in altogether preventing the recurrence, and in averting that perilous exhaustion by which excitement is so often succeeded.’ (28), p. 85
In the chapter on headaches of advanced life, Day declares: ‘Ergot of rye is a useful remedy, and has been given with benefit in these cases.’ However, he finds large doses ‘not advisable’ …‘Judging from the headache it sometimes induces when used in menorrhagia, smaller doses are preferable …’. Among his catalogue of mixtures Day has two formulae for ergot mixtures, with and without chloroform. Day's book was a bestseller with at least three editions in the United States and Britain from 1877 to 1880.
The international reception of Woakes' paper began immediately, and spread continuously within the next 19 years. Ergot treatment was soon taken for granted, and its initiator, Woakes, was not cited in later years except in Thomas' French overview of 1887 and Flatau's German monograph of 1912 (24, 29).
Theoretical and practical environment
The theory of vasodilatation by failure of sympathetic nerves had been proposed by Brown-Séquard and Bernard in the 1850 s, and Du Bois-Reymond's theory of migraine as a result of vasoconstriction by increased sympathetic activity was confronted by Brown-Séquard's concept of vasodilatation by sympathetic paralysis (18, 30). But Brown-Séquard was cited in 1870 as recommending ergot for paralysis, not for migraine (21). In 1867, one year before Woakes' ergot treatment for migraine against vasodilatation by sympathetic deficit, Möllendorff reported clinical evidence of vasodilatation in migraine, including hyperemic fundi carefully observed during the attack with Helmholtz' ophthalmoscope (31). (Möllendorff's paper is usually misrepresented as an early description of cluster headache).
International background: German and British interactions
A direct influence of Möllendorff on Woakes may be inferred, as cooperation of German and British medical publishing was surprisingly close. Romberg's German textbook of neurological diseases of 1846 (32), defining migraine as neuralgia of the brain, classed among the ‘neuroses’ (without today's psychological connotation) appeared in English in 1853. What may well be the first English headache monograph, Weatherhead's A Treatise of Headaches of 1835, came out in German after one year (33), and a German version of Woakes' paper of 1868 was published after one year, in 1869. Only two years later Eulenburg cited Woakes in his German textbook of 1871 (12), where he began to combine the vasospastic with the vasodilatory theory of migraine, and again two years later Latham proposed a similar combination of sympathetic overactivity followed by sympathetic failure, resulting in vasoconstriction followed by vasodilatation (34). He cited Du Bois-Reymond, Möllendorff, Romberg and Brown-Séquard. Finally, Latham described a human model, having used digitalis on himself to induce visual aura by vasoconstriction, and recommended guarana, not ergot. On the other hand Liveing (35) considered migraine a ‘nerve storm’, akin to epilepsy, and his concept, later elaborated in a book, was shared by Hughlings Jackson (36) and later, by Gowers (37). They rejected vasomotor theories of migraine, and the rationale of ergot treatment.
Conclusion
In the 19th century ergot seemed just one among a multitude of remedies for migraine (28), from Weatherhead's mild rules for a balanced way of life (33), to a veritable Borgia pharmacopoeia, where none of the strongest poisons was lacking, from potassium cyanide through hyosciamine and strychnine to aconite, arsenic, atropine, digitalis, hemlock, chloroform, nicotine, the opiates, hashish, quinine, phosphates and the quicksilver compounds (20, 28, 29, 33). Ergot had the advantage of a specific theory justifying its use, and this may explain its prompt and continuous reception. When Stoll's isolation of ergotamine in 1918 provided a new and more reliable form of ergot, Rothlin and Maier proposed it for migraine as a sympatholytic agent, contrary to its 19th century vasoconstrictor role (38, 39). Later pharmacological research again reversed this view despite the experimental evidence documented by Rothlin, and supported by Maier. The conflicting theories of the actions of ergot and its derivatives were finally integrated into a common context in the second half of the twentieth century by the discovery of the contradictory effects of different 5HT receptors where ergot alkaloids act as both agonists and antagonists.