Abstract
BackgroundMorphine decreases the concentrations and effects of clopidogrel, which could lead to treatment failure in myocardial infarction.ObjectivesTo clarify whether more potent P2Y12-inhibitors may provide an effective alternative, we examined drug–drug interactions between morphine and prasugrel.MethodsTwelve healthy volunteers received 60 mg prasugrel with placebo or 5 mg morphine intravenously in a randomized, double-blind, placebo-controlled, cross-over trial. Pharmacokinetics were determined by liquid chromatography tandem mass spectrometry, and prasugrel effects were measured by platelet function tests.ResultsMorphine neither diminished total drug exposure (AUC), which was the primary endpoint, nor significantly delayed drug absorption of prasugrel. However, morphine reduced maximal plasma concentrations (Cmax) of prasugrel active metabolite by 31 % (p = 0.019). Morphine slightly, but not significantly, delayed the onset of maximal inhibition of platelet plug formation under high shear rates (30 vs. 20 min). Whole blood aggregation was not influenced.ConclusionsAlthough morphine significantly decreases the maximal plasma concentrations of prasugrel active metabolite, it does not diminish its effects on platelets to a clinically relevant degree in healthy volunteers. However, it should be considered that the observed decrease in Cmax of prasugrel active metabolite caused by morphine co-administration may gain relevance in STEMI patients.Clinical Trial Registration: NCT01369186, EUDRA-CT#: 2010-023761-22.
Highlights
To clarify whether more potent P2Y12-inhibitors may provide an effective alternative, we examined drug–drug interactions between morphine and prasugrel
Pharmacokinetics were determined by liquid chromatography tandem mass spectrometry, and prasugrel effects were measured by platelet function tests
Conclusions morphine significantly decreases the maximal plasma concentrations of prasugrel active metabolite, it does not diminish its effects on platelets to a clinically relevant degree in healthy volunteers
Summary
As adenosine-50-diphosphate (ADP) is one of the primary mediators for platelet aggregation, the administration of P2Y12-inhibitors in combination with aspirin is a mainstay in the treatment of patients with acute coronary syndromes [12]. In contrast to the extensive evidence that ADP inhibitors are beneficial in patients suffering from myocardial infarction, such data from randomized controlled trials are lacking for morphine. The use of morphine is associated with higher mortality in patients with non-ST-segment elevation ACS [13]. While this is not a causal proof, there may be a biologically plausible cause–effect relationship: opiates inhibit gastric emptying which delays drug absorption and may decrease peak plasma levels of peroral drugs [14]. Morphine decreases the concentrations and effects of clopidogrel, which could lead to treatment failure in myocardial infarction
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