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J Am Coll Cardiol. 2014 Feb 25;63(7):630-635. doi: 10.1016/j.jacc.2013.10.068. Epub 2013 Dec 4.

Morphine decreases clopidogrel concentrations and effects: a randomized, double-blind, placebo-controlled trial.

Author information

1
Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria.
2
Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria.
3
Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria; Department of Emergency Medicine, Blood Group, Medical University of Vienna, Vienna, Austria.
4
Center for Medical Statistics, Informatics and Intelligent Systems, Medical University of Vienna, Vienna, Austria.
5
Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria. Electronic address: bernd.jilma@meduniwien.ac.at.

Erratum in

Abstract

OBJECTIVES:

This study sought to examine the possible drug-drug interactions between clopidogrel and morphine.

BACKGROUND:

Because morphine-the recommended treatment for pain of myocardial infarction-is associated with poor clinical outcome, we hypothesized that morphine lowers the plasma levels of clopidogrel active metabolite as well as its effects on platelets.

METHODS:

Twenty-four healthy subjects received a loading dose of 600 mg clopidogrel together with placebo or 5 mg morphine intravenously in a randomized, double-blind, placebo-controlled, cross-over trial. Pharmacokinetics was determined by liquid chromatography tandem mass spectrometry, and clopidogrel effects were measured by platelet function tests.

RESULTS:

Morphine injection delayed clopidogrel absorption (p = 0.025) and reduced the area under the curve levels of its active metabolite by 34% (p = 0.001). Morphine delayed the maximal inhibition of platelet aggregation on average by 2 h (n = 24; p < 0.001). Residual platelet aggregation was higher 1 to 4 h after morphine injection (n = 24; p < 0.005). Furthermore, morphine delayed the inhibition of platelet plug formation under high shear rates (P2Y-Innovance; n = 21; p < 0.004) and abolished the 3-fold prolongation in collagen adenosine diphosphate-induced closure times seen in extensive and rapid metabolizers (n = 16; p = 0.001).

CONCLUSIONS:

Morphine delays clopidogrel absorption, decreases plasma levels of clopidogrel active metabolite, and retards and diminishes its effects, which can lead to treatment failure in susceptible individuals. (Drug/Drug Interactions of Aspirin and P2Y12-inhibitors; NCT01369186).

KEYWORDS:

clopidogrel; drug interaction; morphine

PMID:
24315907
DOI:
10.1016/j.jacc.2013.10.068
[Indexed for MEDLINE]
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