Morphine Decreases Clopidogrel Concentrations and Effects: A Randomized, Double Blind, Placebo-Controlled Trial

Study Questions:

Is there a possible drug-drug interaction between clopidogrel and morphine?


The authors performed a healthy volunteer crossover study to assess the impact of morphine administration on the antiplatelet effect of clopidogrel. Twenty-four healthy subjects received a loading dose of 600 mg clopidogrel in addition to placebo or 5 mg morphine intravenously in a randomized, double-blind, cross-over trial. Pharmacokinetics were determined by liquid chromatography tandem mass spectrometry. In addition, antiplatelet effects were measured by platelet function tests.


Morphine was associated with delayed clopidogrel absorption (p = 0.025), and a 52% smaller area under the curve of active metabolite of clopidogrel (p = 0.001). Administration of morphine was associated with a delay in the maximal inhibition of platelet aggregation by 2 hours (n = 24; p < 0.001). Residual platelet aggregation was higher 1-4 hours after morphine injection (n = 24; p < 0.005). Randomization to morphine was associated with delayed inhibition of platelet plug formation under high shear rates (P2Y-Innovance; n = 21; p < 0.004).


The authors concluded that use of morphine was associated with delayed absorption of clopidogrel and decreased platelet inhibition.


The clinical implications of this study probably extend beyond clopidogrel. A recent study has demonstrated delay in onset of platelet inhibition with prasugrel and ticagrelor in patients undergoing primary percutaneous coronary intervention, and this effect was more pronounced in patients who had been administered morphine (Parodi G, et al. Comparison of prasugrel and ticagrelor loading doses in ST-segment elevation myocardial infarction patients: RAPID [Rapid Activity of Platelet Inhibitor Drugs] primary PCI study. J Am Coll Cardiol 2013;61:1601-6.) Physicians need to be cognizant of the delay in platelet inhibition with P2Y12 antagonists in patients who have received opiates, and consider additional measures in the appropriate setting.

Keywords: Drug Interactions, Chromatography, Liquid, Platelet Aggregation Inhibitors, Platelet Function Tests, Tandem Mass Spectrometry, Morphine

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