title: Morphine decreases clopidogrel concentrations and effects: a randomized, double-blind, placebo-controlled trial.
abstract: OBJECTIVE
  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).
authors: Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria.
authors: Eva-Luise
authors: EL
authors: Hobl
authors: Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria.
authors: Thomas
authors: T
authors: Stimpfl
authors: Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria.
authors: Josef
authors: J
authors: Ebner
authors: Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria.
authors: Christian
authors: C
authors: Schoergenhofer
authors: Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria; Department of Emergency Medicine, Blood Group, Medical University of Vienna, Vienna, Austria.
authors: Ulla
authors: U
authors: Derhaschnig
authors: Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria.
authors: Raute
authors: R
authors: Sunder-Plassmann
authors: Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria.
authors: Petra
authors: P
authors: Jilma-Stohlawetz
authors: Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria.
authors: Christine
authors: C
authors: Mannhalter
authors: Center for Medical Statistics, Informatics and Intelligent Systems, Medical University of Vienna, Vienna, Austria.
authors: Martin
authors: M
authors: Posch
authors: Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria. Electronic address: bernd.jilma@meduniwien.ac.at.
authors: Bernd
authors: B
authors: Jilma
mesh_terms: D000328:Adult; D000077144:Clopidogrel; D018592:Cross-Over Studies; D004311:Double-Blind Method; D004347:Drug Interactions / Q000502:physiology; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D007275:Injections, Intravenous; D007408:Intestinal Absorption / Q000187:drug effects / Q000502:physiology*; D008297:Male; D009020:Morphine / Q000008:administration & dosage* / Q000097:blood*; D013988:Ticlopidine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D009020:Morphine; D000077144:Clopidogrel; D013988:Ticlopidine
keywords: clopidogrel; drug interaction; morphine