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

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


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.

Publication types

  • Randomized Controlled Trial

MeSH terms

  • Adult
  • Clopidogrel
  • Cross-Over Studies
  • Double-Blind Method
  • Drug Interactions / physiology
  • Drug Therapy, Combination
  • Female
  • Humans
  • Injections, Intravenous
  • Intestinal Absorption / drug effects
  • Intestinal Absorption / physiology*
  • Male
  • Morphine / administration & dosage*
  • Morphine / blood*
  • Ticlopidine / administration & dosage
  • Ticlopidine / analogs & derivatives*
  • Ticlopidine / blood
  • Treatment Outcome
  • Young Adult


  • Morphine
  • Clopidogrel
  • Ticlopidine

Associated data