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Background  The treatment of migraine is impeded by several difficulties, among which insufficient headache relief, side effects, and risk for developing medication overuse headache (MOH). Thus, new acutely acting antimigraine drugs are currently being developed, among which the small molecule CGRP receptor antagonists, gepants, and the 5-HT 1F  receptor agonist lasmiditan. Whether treatment with these drugs carries the same risk for developing MOH is currently unknown.    Main body  Pathophysiological studies on MOH in animal models have suggested that decreased 5-hydroxytryptamine (5-HT, serotonin) levels, increased calcitonin-gene related peptide (CGRP) expression and changes in 5-HT receptor expression (lower 5-HT 1B/D  and higher 5-HT 2A  expression) may be involved in MOH. The decreased 5-HT may increase cortical spreading depression frequency and induce central sensitization in the cerebral cortex and caudal nucleus of the trigeminal tract. Additionally, low concentrations of 5-HT, a feature often observed in MOH patients, could increase CGRP expression. This provides a possible link between the pathways of 5-HT and CGRP, targets of lasmiditan and gepants, respectively. Since lasmiditan is a 5-HT 1F  receptor agonist and gepants are CGRP receptor antagonists, they could have different risks for developing MOH because of the different (over) compensation mechanisms following prolonged agonist versus antagonist treatment.    Conclusion  The acute treatment of migraine will certainly improve with the advent of two novel classes of drugs, i.e., the 5-HT 1F  receptor agonists (lasmiditan) and the small molecule CGRP receptor antagonists (gepants). Data on the effects of 5-HT 1F  receptor agonism in relation to MOH, as well as the effects of chronic CGRP receptor blockade, are awaited with interest.

The need for new acutely acting antimigraine drugs: moving safely outside acute medication overuse