Medication overuse headache (MOH) insidiously evolves from episodic migraine or tension-type headache because of overconsumption of analgesics, ergotamine or triptans. It affects 1-2% of the general population, but 15-20% of patients attending specialized headache centers. The precise neurobiologic mechanisms underlying this complication of episodic headaches are not well understood. Abnormalities of central monoaminergic systems have been suggested and substance dependence is more frequent in personal and family histories of affected subjects. In a recent FDG-PET study of 16 migraineurs with MOH before and after analgesics withdrawal we found a persistent hypometabolism of the medial orbitofrontal cortex, comparable to the one described after withdrawal in substance abuse. The orbitofrontal cortex plays a pivotal role in drive, decision-making and drug dependence. We postulate that its hypoactivity predisposes certain migraineurs to MOH and to relapse after withdrawal. There is no unique management strategy for these patients, but medication withdrawal is a prerequisite for the effectiveness of preventive treatments and headache improvement.