Morphine’s Worrisome Effects on Ticagrelor Affirmed in Pharmacokinetic Study

The problematic interaction between morphine and oral antiplatelet drugs in acute MI patients is a little bit clearer following results from a small study demonstrating that morphine both lowers total exposure to ticagrelor and delays its absorption.

Findings from the single-center, double-blind IMPRESSION trial are the first to demonstrate a pharmacokinetic effect of morphine on the antiplatelet action of ticagrelor in a randomized, placebo-controlled study, researchers led by Jacek Kubica MD, and Piotr  Adamski, MD, of Nicolaus Copernicus University (Bydgoszcz, Poland), note.

“The results of the IMPRESSION study show that in patients with myocardial infarction, morphine not only doubles the time from the loading dose to maximal concentration of ticagrelor … but also leads to a reduction of ticagrelor maximal concentration, its total exposure, and total exposure to its active metabolite by approximately one third,” Adamski told TCTMD. “We expect that higher on-treatment platelet reactivity observed in the morphine vs placebo arm of our study is a direct result of lower concentrations of ticagrelor and its active metabolite.”

Crucially, he added, “all of this occurs during the most acute phase of myocardial infarction exposing the patients to a potential threat of thrombotic complications.”

IMPRESSION was published online October 21, 2015, in the European Heart Journal.

Less Exposure to Ticagrelor, Its Metabolite

Earlier studies have documented a pharmacodynamic effect of morphine on other oral P2Y12 receptor inhibitors. Parodi et al, for example, showed using platelet function assays that onset of action with both clopidogrel and prasugrel was delayed in STEMI patients also treated with morphine. Other registries and trials have showed, albeit in post-hoc analyses, that adverse clinical outcomes are higher among morphine-treated acute MI patients, while successful coronary reperfusion is reduced.

In the current study, investigators randomized 70 patients to receive 5 mg morphine or placebo, with both followed by 180 mg ticagrelor. Liquid chromatography tandem mass spectrometry was used to measure pharmacokinetics, while as many as 3 different platelet function tests were used to assess the antiplatelet effects of ticagrelor.

In the morphine-treated patients, total ticagrelor exposure and exposure to its active metabolite (AR-C124910XX) were reduced by 36% and 37%, respectively (P = .003 and .008). Additionally, time to maximal plasma concentration was doubled in the morphine group at 4 hours vs 2 hours (P = .004). All 3 platelet function tests showed a stronger antiplatelet effect among patients given the placebo and a higher prevalence of high platelet reactivity in the morphine-treated patients.

Commenting on the study for TCTMD, Dominick Angiolillo, MD, University of Florida College of Medicine-Jacksonville, pointed out that the pharmacokinetic information is a key piece of the puzzle because it specifically documents the circulating levels of ticagrelor and its metabolite.

This analysis, he said, “adds to prior studies supporting that this interaction is real. But then it leads to the question, what are we doing in clinical practice?

Morphine Use a ‘Double-Edged Sword’

“On the one hand, particularly in patients with AMI, we have guidelines that indicate we should be using morphine to alleviate pain. One may also ask whether it would be unethical to withhold it,” Angiolillo continued. “At the same time, we are identifying a problem: [morphine] is interfering with the effects of a medication that is key for taking care of these patients. It’s a double-edged sword.”

Indeed, an accompanying editorial points out that morphine may have physiological benefits not yet considered in this setting. “Apart from the pain relief, morphine administration is associated with decreased sympathetic activity which may have beneficial effects,” write Dan Atar, MD, and Stefan Agewall, MD, both of Oslo University Hospital Ullevål.

Adamski stressed that IMPRESSION is underpowered to address clinical outcomes but that its findings nevertheless “warrant prompt investigation in clinically powered randomized trials in the myocardial infarction setting.” While the case against concomitant morphine use in the acute MI setting is building, he said, “its routine avoidance cannot be recommended until such trials are completed.”

Both Adamski and Angiolillo suggested similar ideas for overcoming the problem. Intravenous drugs, either glycoprotein IIb/IIIa receptor inhibitors or the recently approved IV P2Y12 receptor inhibitor cangrelor, are an option. Other strategies include crushing the ticagrelor tablets, using a prokinetic agent like metoclopramide to hasten gastrointestinal absorption of ticagrelor, or replacing morphine with the short-acting analgesic alfetanil.

Pointing out that morphine appears to interact with all oral P2Y12 inhibitors, Angiolillo predicted cangrelor will be different because it is not dependent on gastrointestinal absorption, though this remains to be proven in ongoing studies. Regardless, interventional cardiologists should have this issue on their radar, he said “I do believe that as they become more aware, they will likely become more concerned. ... When you look at the data, it’s very convincing of a drug-drug interaction—it’s limited in time, within the first few hours, but those first few hours post-MI are very important, so having more reliable antiplatelet coverage would be very useful.”

Sources: 
1. Kubica J, Adamski P, Ostrowska M, et al. Morphine delays and attenuates ticagrelor exposure and action in patients with myocardial infarction: the randomized, double-blind, placebo-controlled IMPRESSION trial. Eur Heart J. 2015;Epub ahead of print.
2. Atar D, Agewal S. Morphine in myocardial infarction: balancing on the tight rope. Eur Heart J. 2015;Epub ahead of print.

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