Abstract
Migraine chronification very frequently exposes patients to the inevitable risk of excessive symptomatic intake that, in turn, prompts development of medication overuse headache (MOH). The latter further compromises headache severity establishing a vicious cycle of symptomatic intake and relapsing head pain that critically worsens the overall clinical status of patients. A great deal of attention has been focused on MOH pathogenesis, and thanks to preclinical and clinical studies knowledge about this disorder is now remarkably advanced. Still, some open questions remain regarding issues related to the neurobiology and neurochemistry underpinning pain chronification in MOH patients, as well as the remedies capable of interrupting pronociceptive cephalic sensitization and drug overuse. Here, a critical reappraisal of these issues is provided in an attempt to gain deeper insight and promote debate on a pain disorder that still represents a conundrum in the field of nociception.