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Eur Heart J. 2016 Jan 14;37(3):245-52. doi: 10.1093/eurheartj/ehv547. Epub 2015 Oct 21.

Morphine delays and attenuates ticagrelor exposure and action in patients with myocardial infarction: the randomized, double-blind, placebo-controlled IMPRESSION trial.

Author information

1
Department of Cardiology and Internal Medicine, Collegium Medicum, Nicolaus Copernicus University, Bydgoszcz, Poland.
2
Department of Principles of Clinical Medicine, Collegium Medicum, Nicolaus Copernicus University, 9 Skłodowskiej-Curie Street, Bydgoszcz 85-094, Poland piotr.adamski@wp.eu.
3
Department of Principles of Clinical Medicine, Collegium Medicum, Nicolaus Copernicus University, 9 Skłodowskiej-Curie Street, Bydgoszcz 85-094, Poland.
4
Department of Pharmacology and Therapy, Collegium Medicum, Nicolaus Copernicus University, Bydgoszcz, Poland.
5
Department of Medicinal Chemistry, Collegium Medicum, Nicolaus Copernicus University, Bydgoszcz, Poland.
6
Department of Pathophysiology, Collegium Medicum, Nicolaus Copernicus University, Bydgoszcz, Poland.
7
Department of Theoretical Foundations of Biomedical Science and Medical Informatics, Collegium Medicum, Nicolaus Copernicus University, Bydgoszcz, Poland.
8
Department of Cardiology and Internal Medicine, Collegium Medicum, Nicolaus Copernicus University, Bydgoszcz, Poland Department of Internal Medicine, Division of Cardiology, Pulmonology and Vascular Medicine, Heinrich-Heine-University, Düsseldorf, Germany.
9
Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria.
10
Department of Cardiology, Medical University of Vienna, Vienna, Austria.

Abstract

AIMS:

The currently available data indicate a drug-drug interaction between morphine and oral P2Y12 receptor inhibitors, when administered together. The aim of this trial was to assess the influence of infused morphine on pharmacokinetics and pharmacodynamics of ticagrelor and its active metabolite (AR-C124910XX) in patients with acute myocardial infarction.

METHODS AND RESULTS:

In a single-centre, randomized, double-blind trial, patients were assigned in a 1:1 ratio to receive intravenously either morphine (5 mg) or placebo, followed by a 180 mg loading dose of ticagrelor. Pharmacokinetics was determined with liquid chromatography tandem mass spectrometry and ticagrelor antiplatelet effects were measured with up to three different platelet function tests: vasodilator-stimulated phosphoprotein phosphorylation assay, multiple electrode aggregometry and VerifyNow. The pharmacokinetic and pharmacodynamic assessment was performed in 70 patients (35 in each study group). Morphine lowered the total exposure to ticagrelor and its active metabolite by 36% (AUC(0-12): 6307 vs. 9791 ng h/mL; P = 0.003), and 37% (AUC(0-12): 1503 vs. 2388 ng h/mL; P = 0.008), respectively, with a concomitant delay in maximal plasma concentration of ticagrelor (4 vs. 2 h; P = 0.004). Multiple regression analysis showed that lower AUC(0-12) values for ticagrelor were independently associated with the administration of morphine (P = 0.004) and the presence of ST-segment elevation myocardial infarction (P = 0.014). All three methods of platelet reactivity assessment showed a stronger antiplatelet effect in the placebo group and a greater prevalence of high platelet reactivity in patients receiving morphine.

CONCLUSIONS:

Morphine delays and attenuates ticagrelor exposure and action in patients with myocardial infarction. ClinicalTrials.gov Identifier: NCT02217878.

KEYWORDS:

Morphine; Myocardial infarction; Pharmacodynamics; Pharmacokinetics; Ticagrelor

PMID:
26491112
PMCID:
PMC4712351
DOI:
10.1093/eurheartj/ehv547
[Indexed for MEDLINE]
Free PMC Article

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