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


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.
Department of Cardiology and Internal Medicine, Collegium Medicum, Nicolaus Copernicus University, Bydgoszcz, Poland.
Jacek
J
Kubica
Department of Principles of Clinical Medicine, Collegium Medicum, Nicolaus Copernicus University, 9 Skłodowskiej-Curie Street, Bydgoszcz 85-094, Poland piotr.adamski@wp.eu.
Piotr
P
Adamski
Department of Principles of Clinical Medicine, Collegium Medicum, Nicolaus Copernicus University, 9 Skłodowskiej-Curie Street, Bydgoszcz 85-094, Poland.
Małgorzata
M
Ostrowska
Department of Pharmacology and Therapy, Collegium Medicum, Nicolaus Copernicus University, Bydgoszcz, Poland.
Joanna
J
Sikora
Department of Cardiology and Internal Medicine, Collegium Medicum, Nicolaus Copernicus University, Bydgoszcz, Poland.
Julia Maria
JM
Kubica
Department of Medicinal Chemistry, Collegium Medicum, Nicolaus Copernicus University, Bydgoszcz, Poland.
Wiktor Dariusz
WD
Sroka
Department of Pathophysiology, Collegium Medicum, Nicolaus Copernicus University, Bydgoszcz, Poland.
Katarzyna
K
Stankowska
Department of Theoretical Foundations of Biomedical Science and Medical Informatics, Collegium Medicum, Nicolaus Copernicus University, Bydgoszcz, Poland.
Katarzyna
K
Buszko
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.
Eliano Pio
EP
Navarese
Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria.
Bernd
B
Jilma
Department of Cardiology, Medical University of Vienna, Vienna, Austria.
Jolanta Maria
JM
Siller-Matula
Department of Medicinal Chemistry, Collegium Medicum, Nicolaus Copernicus University, Bydgoszcz, Poland.
Michał Piotr
MP
Marszałł
Department of Pathophysiology, Collegium Medicum, Nicolaus Copernicus University, Bydgoszcz, Poland.
Danuta
D
Rość
Department of Principles of Clinical Medicine, Collegium Medicum, Nicolaus Copernicus University, 9 Skłodowskiej-Curie Street, Bydgoszcz 85-094, Poland.
Marek
M
Koziński
D000241:Adenosine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D000284:Administration, Oral; D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000494:pharmacology*; D019540:Area Under Curve; D004311:Double-Blind Method; D004347:Drug Interactions; D005260:Female; D006801:Humans; D007275:Injections, Intravenous; D008297:Male; D008875:Middle Aged; D009020:Morphine / Q000008:administration & dosage / Q000494:pharmacology*; D009203:Myocardial Infarction / Q000188:drug therapy*; D062645:Percutaneous Coronary Intervention; D010975:Platelet Aggregation Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology; D010979:Platelet Function Tests; D058921:Purinergic P2Y Receptor Antagonists / Q000493:pharmacokinetics* / Q000494:pharmacology; D000077486:Ticagrelor
C561701:AR C124910XX; D000701:Analgesics, Opioid; D010975:Platelet Aggregation Inhibitors; D058921:Purinergic P2Y Receptor Antagonists; D009020:Morphine; D000077486:Ticagrelor; D000241:Adenosine
Morphine; Myocardial infarction; Pharmacodynamics; Pharmacokinetics; Ticagrelor