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

• Published in: Journal of the American College of Cardiology Vol. 63; no. 7; pp. 630 - 635
• Main Authors: HOBL, Eva-Luise, STIMPFL, Thomas, EBNER, Josef, SCHOERGENHOFER, Christian, DERHASCHNIG, Ulla, SUNDER-PLASSMANN, Raute, JILMA-STOHLAWETZ, Petra, MANNHALTER, Christine, POSCH, Martin, JILMA, Bernd
• Format: Journal Article
• Language: English
• Published: New York, NY Elsevier 25.02.2014; Elsevier Limited
• Subjects: Acute coronary syndromes; Adenosine; Adult; Aspirin; Biological and medical sciences; Blood platelets; Cardiology; Cardiology. Vascular system; Clinical trials; Clopidogrel; Collagen; Cross-Over Studies; Double-Blind Method; Drug dosages; Drug Interactions - physiology; Drug therapy; Drug Therapy, Combination; Female; Heart; Humans; Injection; Injections, Intravenous; Intestinal Absorption - drug effects; Intestinal Absorption - physiology; Liquid chromatography; Male; Mass spectroscopy; Medical sciences; Metabolism; Metabolites; Morphine; Morphine - administration & dosage; Morphine - blood; Myocardial infarction; Pain; Pharmacokinetics; Phosphorylation; Plasma levels; Platelet aggregation; Ticlopidine - administration & dosage; Ticlopidine - analogs & derivatives; Ticlopidine - blood; Treatment Outcome; Variables; Young Adult; Austria; Opiates; Morphine; Cardiovascular disease; Concentration; Narcotic analgesic; Randomized controlled trial; Antiplatelet agent; Randomization; Decrease; Antithrombotic agent; Double blind study; Clopidogrel; Clinical trial; Circulatory system; Thienopyridine derivative; Cardiology; clopidogrel; drug interaction; morphine
• ISSN: 0735-1097; 1558-3597; 1558-3597
• DOI: 10.1016/j.jacc.2013.10.068

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