Migraine is one of the worlds most common neurological disorders. Current acute migraine treatments have sub-optimal efficacy and new therapeutic options are needed. Approaches targeting calcitonin gene related peptide (CGRP) signaling are clinically effective but small molecule antagonists have not been advanced due to toxicity. In this study, we explored the axonal growth/specification collapsin response mediator protein 2 (CRMP2) as a novel druggable target for inhibiting CGRP release and for potential relevance for treatment of migraine pain and post-traumatic headache. CRMP2 has been demonstrated to regulate N-type voltage gated Ca2+ channel (CaV2.2) activity and Ca2+-dependent CGRP release in sensory neurons. The co-expression of CRMP2 with CaV2.2 and CGRP in trigeminal ganglia (TG) sensory neurons suggested the possibility of a novel approach to regulate CGRP release in the trigeminal system. Screening protocols surprisingly revealed that (S)-Lacosamide ((S)-LCM), an inactive analog of the clinically-approved small molecule anti-epileptic drug (R)-Lacosamide (Vimpat), inhibited CRMP2 phosphorylation by cyclin dependent kinase 5 (Cdk5) in rat TG slices and decreased depolarization-evoked Ca2+ influx in TG cells in culture. We found that oral or intraperitoneal (S)-LCM blocked capsaicin-evoked CGRP release from dural nerve terminals in the rat ex vivo cranial cup preparation and inhibited cephalic and extracephalic cutaneous allodynia (CA) induced in rats by activation of dural nociceptors with a cocktail of inflammatory mediators (IM). We also found that (S)-LCM inhibited nitric oxide (NO)-donor-induced allodynia in a rat model with triptan-induced latent sensitization, demonstrating its potential in mitigating migraine. These data are now in preparation for publication.