Despite advances in medical and interventional management of acute myocardial infarction, treatment of the associated chest pain has remained relatively unchanged since opioids were first utilized in the 1930's. This dominance can be partially attributed to initial studies suggesting hemodynamic benefits with opioid treatment. However, delayed gastrointestinal absorption of P2Y inhibitors due to opioids and the consequent impairment in antiplatelet activity of this established therapy is cause for concern. Coupled with the lack of randomized clinical trial evidence to support widespread opioid use, there is now an opportunity to re-evaluate our approach to analgesia in myocardial infarction. This review characterizes the mechanism of the opioid-P2Y inhibitor interaction, strategies aimed at mitigating the interaction and appraises promising alternative agents to opioid therapy in patients with myocardial infarction.12