title: Morphine decreases ticagrelor concentrations but not its antiplatelet effects: a randomized trial in healthy volunteers.
abstract: BACKGROUND
  Our recent drug interaction trial with clopidogrel shows that morphine decreases the concentrations and pharmacodynamic effects of clopidogrel, which could lead to treatment failure in susceptible individuals. We hypothesized that the pharmacodynamic consequences of drug-drug interactions would be less between morphine and ticagrelor.
  
  
  METHODS
  Twenty-four healthy subjects received a loading dose of 180 mg ticagrelor together with placebo or 5 mg morphine intravenously in a randomized, double-blind, placebo-controlled, crossover trial. Pharmacokinetics were determined by liquid chromatography tandem mass spectrometry, and ticagrelor pharmacodynamic effects were measured by platelet function tests (whole blood platelet aggregation: multiplate, platelet plug formation: PFA-100, vasodilator-stimulated phosphoprotein (VASP) phosphorylation assay).
  
  
  RESULTS
  Concomitant i.v. injection of morphine slows drug resorption of ticagrelor and its active metabolite (P < 0·05) by 1 h and decreases plasma levels of ticagrelor and its active metabolite by 25-31% (P ≤ 0·03) and the drug exposure (area under the curve) by 22-23% (P ≤ 0·01). Importantly, however, the pharmacodynamic effects of ticagrelor on platelet aggregation in whole blood, platelet plug formation and VASP phosphorylation are not affected by morphine.
  
  
  CONCLUSIONS
  Morphine co-administration moderately decreases ticagrelor plasma concentrations but does not inhibit its pharmacodynamic effects in healthy volunteers within 6 h after drug administration. Limitations of our trial include the investigation in healthy volunteers under standardized conditions, which does not necessarily reflect a realistic emergency scenario.
authors.affiliation: Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria.
authors.forename: Eva-Luise
authors.initials: EL
authors.lastname: Hobl
authors.affiliation: Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria.
authors.forename: Birgit
authors.initials: B
authors.lastname: Reiter
authors.affiliation: Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria.
authors.forename: Christian
authors.initials: C
authors.lastname: Schoergenhofer
authors.affiliation: Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria.
authors.forename: Michael
authors.initials: M
authors.lastname: Schwameis
authors.affiliation: Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria.
authors.forename: Ulla
authors.initials: U
authors.lastname: Derhaschnig
authors.affiliation: Department of Cardiology and Internal Medicine, Collegium Medicum, Nicolaus Copernicus University, Bydgoszcz, Poland.
authors.forename: Jacek
authors.initials: J
authors.lastname: Kubica
authors.affiliation: Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria.
authors.forename: Thomas
authors.initials: T
authors.lastname: Stimpfl
authors.affiliation: Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria.
authors.forename: Bernd
authors.initials: B
authors.lastname: Jilma
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives* / Q000097:blood / Q000494:pharmacology; D000328:Adult; D000701:Analgesics, Opioid / Q000494:pharmacology*; D001792:Blood Platelets / Q000187:drug effects*; D015815:Cell Adhesion Molecules / Q000187:drug effects / Q000378:metabolism; D002853:Chromatography, Liquid; D018592:Cross-Over Studies; D004311:Double-Blind Method; D004347:Drug Interactions; D005260:Female; D064368:Healthy Volunteers; D006801:Humans; D008297:Male; D008840:Microfilament Proteins / Q000187:drug effects / Q000378:metabolism; D009020:Morphine / Q000494:pharmacology*; D010750:Phosphoproteins / Q000187:drug effects / Q000378:metabolism; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000097:blood / Q000494:pharmacology*; D010979:Platelet Function Tests; D053719:Tandem Mass Spectrometry; D000077486:Ticagrelor; D055815:Young Adult; D000098662:Vasodilator-Stimulated Phosphoprotein
chemical_list: D000701:Analgesics, Opioid; D015815:Cell Adhesion Molecules; D008840:Microfilament Proteins; D010750:Phosphoproteins; D010975:Platelet Aggregation Inhibitors; D000098662:Vasodilator-Stimulated Phosphoprotein; D009020:Morphine; D000077486:Ticagrelor; D000241:Adenosine
keywords: drug interaction; morphine; multiple electrode aggregometry; platelet function analyser; ticagrelor; vasodilator-stimulated phosphoprotein