Dihydroergotamine for migraine: Evidence for multiple modes of action: The single molecule ‘combination’ product—A narrative review

Abstract

Background Here, we review studies conducted in the last 25 years that attempted to increase our understanding of the various receptors that play a role in the pathogenesis and treatment of migraine. Several of these studies evaluated the effects of dihydroergotamine (DHE), and we attempt to examine clinical evidence and plasma DHE levels, effects that likely relate to receptor class activation. Methods From a review of these studies, there is evidence about the potential role of the serotonergic 5-HT 1A receptor, alpha-receptors, and dopaminergic receptors in the pathogenesis of migraine. Interactions with these receptors likely contribute to the effectiveness of DHE at concentrations achieved clinically. Also included is a discussion of the observable clinical correlates of multiple mechanisms of action. The impact of 5-HT 1B and 5-HT 1D stimulation is easily documented by the efficacy of triptans. For dopaminergic stimulation, the clinical correlate (nausea) is well supported. In the case of alpha-adrenergic effects, there is considerable preclinical evidence, but the clinical evidence is more subtle. Conclusion Overall, DHE is a nonspecific, broadly acting drug, with activity at multiple receptors that contribute to migraine pathogenesis and likely have a role in migraine resolution. This broader activity may contribute to DHE's utility in treating migraines that have not responded to other drugs with a singular mechanism of action. An understanding of the pharmacological profile of DHE and how drug effects, including adverse events, will vary based on plasma concentrations may be important to clinicians as they contemplate therapeutic options for patients with difficult to treat migraines.