Headache-type adverse effects of NO donors: vasodilation and beyond

Although nitrate therapy, used in the treatment of cardiovascular disorders, is frequently associated with side-effects, mainly headaches, the summaries of product characteristics of nitrate-containing medicines do not report detailed description of headaches and even do not highlight the possibility of nitrate-induced migraine. Two different types of nitrate-induced headaches have been described: (i) immediate headaches that develop within the first hour of the application, are mild or medium severity without characteristic symptoms for migraine, and ease spontaneously; and (ii) delayed, moderate or severe migraine-type headaches (occurring mainly in subjects with personal or family history of migraine), that develop 3-6 h after the intake of nitrates, with debilitating, long-lasting symptoms including nausea, vomiting, photo- and/or phono-phobia. These two types of headaches are remarkably different, not only in their timing and symptoms, but also in the persons who are at risk. Recent studies provide evidence that the two headache types are caused by different mechanisms: immediate headaches are connected to vasodilation caused by nitric oxide (NO) release, while migraines are triggered by other actions such as the release of calcitonin gene-related peptide or glutamate, or changes in ion channel function mediated by cyclic guanosine monophosphate or S-nitrosylation. Migraines usually need anti-attack medication, such as triptans, but these drugs are contraindicated in most medical conditions that are treated using nitrates. In conclusion, these data recommend the correction of summaries of nitrate product characteristics, and also suggest a need to develop new types of anti-migraine drugs, effective in migraine attacks, that could be used in patients with risk for angina pectoris.