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.