Abstract 10981: Morphine Decreases Clopidogrel Concentrations and Effects: a Randomized, Double Blind, Placebo-Controlled Trial
Background: Morphine is the recommended routine therapy of pain in patients suffering from myocardial infarction, for which clopidogrel has become a mainstay. We hypothesized that morphine lowers the plasma levels of clopidogrel active metabolite as well as clopidogrel effects by delaying gastric emptying.
Methods: 24 subjects received a loading dose of 600 mg clopidogrel together with placebo or 5 mg morphine intravenously. Pharmacokinetics of clopidogrel and its active metabolite were quantified by mass spectrometry. Clopidogrel effects were measured by the vasodilator-stimulated phosphoprotein (VASP) assay, whole blood aggregometry, and the platelet function analyzer. Subjects were genotyped for CYP2C9 and CYP2C19 polymorphisms.
Results: Morphine reduced maximal clopidogrel levels (p=0.02). Concentrations of the active metabolite were 2-4 fold higher after placebo as compared to morphine injection during the first 2h and peak concentrations occurred later after morphine (difference in AUC p=0.002). After morphine injection, subjects responded poorly in the VASP assay (PRI: 59% vs. 41%; p=0.02) Morphine delayed the onset of platelet aggregation by an average of 2h and up to 5h (p<0.001). Residual platelet function was higher 1-4h after morphine injection (median 17 AU vs. 3 AU at 2h; p<0.005), which led to treatment failure particularly in some intermediate or poor metabolizers. Morphine also delayed inhibition of platelet plug formation under high shear rates (p<0.001). Clopidogrel prolonged collagen adenosine diphosphate induced closure times (CADP-CT) in normal metabolizers from 110s to 162s (p<0.001), but failed to prolong CADP-CT in intermediate or poor metabolizers or when morphine was co-administered.
Conclusion: This trial identified a novel and clinically relevant drug-drug interaction: morphine slows resorption of clopidogrel, decreases levels of its active metabolite, and retards and diminishes clopidogrel effects, which can lead to treatment failure in susceptible individuals. These results provide a possible mechanism for the reported association of morphine use and poor clinical outcome in patients with myocardial infarction and should discourage concomitant administration of morphine and clopidogrel.
- © 2013 by American Heart Association, Inc.