Morphine interaction with prasugrel: a double-blind, cross-over trial in healthy volunteers

Clin Res Cardiol. 2016 Apr;105(4):349-55. doi: 10.1007/s00392-015-0927-z. Epub 2015 Oct 22.


Background: Morphine decreases the concentrations and effects of clopidogrel, which could lead to treatment failure in myocardial infarction.

Objectives: To clarify whether more potent P2Y12-inhibitors may provide an effective alternative, we examined drug-drug interactions between morphine and prasugrel.

Methods: Twelve healthy volunteers received 60 mg prasugrel with placebo or 5 mg morphine intravenously in a randomized, double-blind, placebo-controlled, cross-over trial. Pharmacokinetics were determined by liquid chromatography tandem mass spectrometry, and prasugrel effects were measured by platelet function tests.

Results: Morphine neither diminished total drug exposure (AUC), which was the primary endpoint, nor significantly delayed drug absorption of prasugrel. However, morphine reduced maximal plasma concentrations (C max) of prasugrel active metabolite by 31 % (p = 0.019). Morphine slightly, but not significantly, delayed the onset of maximal inhibition of platelet plug formation under high shear rates (30 vs. 20 min). Whole blood aggregation was not influenced.

Conclusions: Although morphine significantly decreases the maximal plasma concentrations of prasugrel active metabolite, it does not diminish its effects on platelets to a clinically relevant degree in healthy volunteers. However, it should be considered that the observed decrease in C max of prasugrel active metabolite caused by morphine co-administration may gain relevance in STEMI patients.

Clinical trial registration: NCT01369186, EUDRA-CT#: 2010-023761-22.

Keywords: Drug interactions; Morphine; Platelet function tests; Prasugrel; Vasodilator-stimulated phosphoprotein.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Analgesics, Opioid / administration & dosage*
  • Analgesics, Opioid / adverse effects
  • Austria
  • Biotransformation
  • Chromatography, Liquid
  • Cross-Over Studies
  • Double-Blind Method
  • Drug Interactions
  • Drug Monitoring / methods
  • Female
  • Healthy Volunteers
  • Humans
  • Male
  • Morphine / administration & dosage*
  • Morphine / adverse effects
  • Platelet Aggregation / drug effects*
  • Platelet Aggregation Inhibitors / administration & dosage
  • Platelet Aggregation Inhibitors / adverse effects
  • Platelet Aggregation Inhibitors / blood
  • Platelet Aggregation Inhibitors / pharmacokinetics*
  • Platelet Function Tests
  • Prasugrel Hydrochloride / administration & dosage
  • Prasugrel Hydrochloride / adverse effects
  • Prasugrel Hydrochloride / blood
  • Prasugrel Hydrochloride / pharmacokinetics*
  • Purinergic P2Y Receptor Antagonists / administration & dosage
  • Purinergic P2Y Receptor Antagonists / adverse effects
  • Purinergic P2Y Receptor Antagonists / blood
  • Purinergic P2Y Receptor Antagonists / pharmacokinetics*
  • Risk Assessment
  • Tandem Mass Spectrometry
  • Young Adult


  • Analgesics, Opioid
  • Platelet Aggregation Inhibitors
  • Purinergic P2Y Receptor Antagonists
  • Morphine
  • Prasugrel Hydrochloride

Associated data

  • EudraCT/2010-023761-22