History of methysergide in migraine.

Harold Wolff's theory of vasodilation in migraine is well-known. Less known is his search for a perivascular factor that would damage local tissues and increase pain sensitivity during migraine attacks. Serotonin was found to be among the candidate agents to be included. In the same period, serotonin was isolated (1948) and, because of its actions, an anti-serotonin drug was needed. Methysergide was synthesized from lysergic acid (LSD) by adding a methyl group and a butanolamid group. This resulted in a compound with selectivity and high potency as a serotonin (5-HT) inhibitor. Based on the possible involvement of serotonin in migraine attacks, it was introduced in 1959 by Sicuteri as a preventive drug for migraine. The clinical effect was often excellent, but 5 years later it was found to cause retroperitoneal fibrosis after chronic intake. Consequently, the use of the drug in migraine declined considerably, but it was still used as a 5-HT antagonist in experimental studies. In 1974 Saxena showed that methysergide had a selective vasoconstrictor effect in the carotid bed and in 1984 he found an atypical receptor. This finding provided an incentive for the development of sumatriptan. Bredberg et al. showed that methysergide is probably a prodrug for its active metabolite methylergometrine. Whereas methysergide is 'a clean drug', methylergometrine is 'a relatively dirty drug' with additional dopaminergic activity. The mechanism for the preventive effect of methysergide (methylergometrine) in migraine remains elusive. We describe the rise, fall and subsequent use as a third-choice drug of the first effective migraine prophylactic, methysergide.