Morphine decreases clopidogrel concentrations and effects: a randomized,
double-blind, placebo-controlled trial.
Author(s): Hobl EL(1), Stimpfl T(2), Ebner J(2), Schoergenhofer C(1), Derhaschnig U(3),
Sunder-Plassmann R(2), Jilma-Stohlawetz P(2), Mannhalter C(2), Posch M(4), Jilma
B(5).
Affiliation(s): 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.
Publication date & source: 2014, J Am Coll Cardiol. , 63(7):630-5
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).
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