Background: While understanding the pathophysiology of migraine has led to CGRP-based treatments, other potential targets have also been implicated in migraine. Objectives: To catalog new promising targets for the treatment of migraine. Methods: We completed a literature review focusing on 5HT1F, PACAP, melatonin, and orexins. Results: The 5HT1F receptor agonist lasmiditan, following two positive randomized placebo-controlled trials, was FDA-approved for the acute treatment of migraine. PACAP-38 has shown analogous evidence to what was obtained for CGRP with its localization in key structures, provocation tests, and positive studies when antagonizing its receptor in animal models, although a PAC-1 receptor monoclonal antibody study was negative. Melatonin has undergone several randomized controlled trials showing a positive trend. Filorexant is the only dual orexin receptor antagonist, which was tested in humans with negative results. Conclusions: Further and ongoing studies will determine the utility of these new therapies with lasmiditan and melatonin having demonstrated efficacy for the treatment of migraine.
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