Novel Optimization of Multi-Mechanistic Approaches for the Acute Treatment of a Migraine Attack: A Review.

OBJECTIVE:To highlight key factors required to optimize multi-mechanistic approaches with oral combination treatments for the acute management of a migraine attack. BACKGROUND:Given the complex multi-factorial nature of migraine, combining treatments with different mechanisms of action should improve outcomes compared to monotherapies, but this has not been demonstrated with all treatment combinations. METHODS:For this narrative review, we searched PubMed using combinations of these terms: migraine, acute treatment, combination therapy, fixed-dose combination therapy, multi-mechanistic treatment, pharmacokinetics, and pharmacodynamics. All articles considered relevant were included. RESULTS:None of the existing migraine acute treatments as monotherapy effectively treat the key pathophysiological processes of migraine completely. Many patients do not achieve 2-h pain freedom, which is key to avoiding migraine recurrence, medication overuse leading to chronification, and migraine-related disability. The development of combination approaches has led to only two combinations with demonstrated superiority over their individual components: aspirin/acetaminophen/caffeine and sumatriptan/naproxen sodium. The latter is the most effective proven combination treatment because it targets peripheral activation of central pain pathways during the early migraine stages and central sensitization that develops later, independent of peripheral input. Other triptan/nonsteroidal anti-inflammatory drug combinations with higher efficacy as monotherapies could be more effective than sumatriptan/naproxen sodium, particularly if their pharmacokinetic profiles align with the vasoactive mediators of peripheral and central sensitization that they target. CONCLUSIONS:Combination treatments with different mechanisms of action targeting key distinct pathophysiological processes of migraine may be more effective than monotherapies, particularly if their pharmacokinetic profiles are optimized to target those processes at the right time. Further research in this area is warranted.