Fifty years ago migraine was regarded as a vascular headache, the result of the pioneering work of Harold G Wolff and his colleagues in New York. Acute treatment relied on ergotamine and preventive therapy on "Bellergal", a mixture of ergotamine, phenobarbitone and belladonna alkaloids. Federigo Sicuteri in Florence started the serotonin story when he reported that an ergot derivative, methysergide, a so-called serotonin antagonist, was an effective prophylactic agent. Our laboratory in Sydney followed this lead, showing that serotonin was discharged from blood platelets at the onset of migraine headache and confirming an American report that the intravenous injection of serotonin eased the headache, at the expense of severe side effects. This work came to the attention of Patrick Humphrey of Glaxo Laboratories in the UK who devised an agent that had the desired action with minimal side-effects - sumatriptan.

Migraine aura was identified in the 1980s as a manifestation of Cortical Spreading Depression. Interest turned to the part played by the brain’s endogenous pain-control pathway. Recent PET studies have demonstrated the hypothalamus, PAG and locus ceruleus "lighting up" during migraine headache. Studies by Peter Goadsby, now in London, and the Sydney team have developed an animal model in which vascular dilatation is secondary to brain stem activation, providing a satisfactory dual neural-vascular hypothesis. Advances in prophylaxis include amitriptyline (1964), pizotifen (1967), MAO inhibitors (1969), beta blockers (1961), sodium valproate (1988) and topiramate (2005).