Key result
IV morphine reduces ticagrelor exposure ~36% vs. placebo in acute MI.
Why the study?
Data indicate a drug-drug interaction between morphine and oral P2Y12 receptor inhibitors, prompting evaluation of infused morphine effects on ticagrelor pharmacokinetics and pharmacodynamics in acute myocardial infarction.
Does intravenous morphine reduce ticagrelor exposure and antiplatelet action in patients with acute myocardial infarction?
RCT (n=74)
Double-blind
1:1
No
Does intravenous morphine reduce ticagrelor exposure and antiplatelet action in patients with acute myocardial infarction?
Intravenous morphine significantly delays and attenuates the pharmacokinetic exposure and antiplatelet effect of ticagrelor in patients with acute myocardial infarction.
Answers are grounded in this paper and cite their sources.
Captured external expert commentary on this paper, strongest first. Original sources are linked where available.
“To our knowledge, the current trial is the first one to confirm the negative impact exerted by morphine on the pharmacokinetics and antiplatelet action of ticagrelor in [patients with acute MI] obtained in a randomized study. Although we did not investigate the underlying mechanism of our findings in detail, it seems likely that morphine impairs absorption of ticagrelor.”
“The most important take-away message from our study is that despite good pharmacologic data to suggest that morphine administration negatively impacts area-under-the-curve and time to maximal concentration of co-administered antiplatelet agents, this is yet to be convincingly demonstrated to impact clinical outcomes such as re-infarction, increased stent thrombosis, or death.”
“This work is interesting, but it doesn't resolve the concern, because the effect that they're seeing in the IMPRESSION trial is a pharmacological effect and might ultimately be translating into worse clinical outcomes, especially if you were able to evaluate more patients in a randomized trial.”
Caution advised with morphine during ticagrelor loading in AMI; confirms interaction yet leaves clinical outcomes unresolved.
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.
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Kubica et al. (2015) conducted an RCT in Acute myocardial infarction (n=74). Morphine vs. Placebo was evaluated on Area under the plasma concentration-time curve (AUC(0-12)) for ticagrelor during the first 12 hours (36% reduction, p=0.003). Intravenous morphine reduced total exposure to ticagrelor by 36% (AUC(0-12): 6307 vs. 9791 ng h/mL) compared to placebo in patients with acute myocardial infarction.
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