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Morphine was not a good addition to clopidogrel (Plavix) in patients getting invasive management for non-ST-segment elevation acute coronary syndromes (NSTEACS), investigators found.

Rates of ischemic events -- death, myocardial infarction (MI), recurrent ischemia, or thrombotic bailout -- within 96 hours were greater with concomitant morphine use to alleviate chest pain in these patients (10.7% vs 8.5% without morphine, adjusted OR 1.40, 95% CI 1.04-1.87), reported Robert Giugliano, MD, SM, of Brigham and Women's Hospital in Boston, and colleagues.

Similarly, the composite endpoint of death or MI at 30 days was higher when morphine was given around the time of clopidogrel pre-treatment (12.3% vs 10.4%, adjusted OR 1.29, 95% CI 0.98-1.70), a finding that was driven by events in the first 48 hours (adjusted HR 1.54, 95% CI 1.07-2.23), according to the study in the .

NSTEACS patients not treated with clopidogrel, on the other hand, did not show an association between morphine and either endpoint.

"Based on our results, it seems reasonable that a higher risk of ischemic events with morphine restricted to patients treated with concomitant clopidogrel is most likely explained by a clinical interaction between these drugs, which is highly consistent with the pharmacological studies," Giugliano's team concluded.

This is possible because P2Y12 inhibitors like clopidogrel are absorbed entirely by the intestines, noted Robert Storey, MD, DM, and William Parker, MD, both of the University of Sheffield and the South Yorkshire Cardiothoracic Centre in England, writing in an .

"The clinical implications of this fact are slowly becoming more apparent in view of the fact that opiates, such as morphine, delay gastric emptying into the small intestine and may thus trap oral drugs within the stomach for many hours, sometimes until the opiate effect has worn off and gastrointestinal motility recovers," Storey and Parker explained.

This can be "catastrophic," they added, when an oral P2Y12 inhibitor is intended to prevent acute stent thrombosis.

"Although [the researchers] did not adjudicate stent thrombosis cases, the observed increase in periprocedural MI when clopidogrel and morphine appeared to have been administered concurrently before the procedure indeed points to higher rates of stent thrombosis with this strategy," the editorialists stated.

Study authors had used data from the EARLY ACS (Acute Coronary Syndrome) trial, which assessed early vs delayed provisional use of intravenous eptifibatide (Integrilin) in NSTEACS patients planned for coronary angiography and/or percutaneous coronary intervention or coronary artery bypass grafting surgery.

The present post-hoc analysis included 5,438 high-risk individuals pre-treated with clopidogrel within 24 hours before randomization, of whom 11.3% had also been administered morphine before randomization. Serving as negative controls were 3,462 people not pre-treated with clopidogrel.

Baseline imbalances between groups included the morphine group being more likely to have a history of previous heart failure or MI. The investigators said they attempted to adjust for these differences in two different ways: inverse probability of treatment weighting and logistic regression.

Nevertheless, the observational nature of the study cannot establish a causal relationship between morphine use and ischemic events, Giugliano and colleagues said, adding that the exact time of morphine administration had not been recorded in EARLY ACS.

Additionally, they said, the findings cannot be extrapolated to other P2Y12 inhibitors that may have faster onset of action and higher levels of platelet inhibition.

"Clinicians should take note of these findings when using clopidogrel in the management of ACS as part of a dual oral antiplatelet strategy," Storey and Parker urged.

They added: "When clopidogrel is used concurrently with morphine or another opiate, the results of the present analysis and prior pharmacodynamic studies suggest that a further loading dose of clopidogrel should be considered at 6 to 8 hours after the last dose of opiate to optimize the chances of achieving therapeutic levels of platelet P2Y12 inhibition."

Alternatives to clopidogrel in antithrombotic pre-treatment with morphine may include tirofiban (Aggrastat), cangrelor (Kengreal), selatogrel, and enoxaparin (Lovenox), the editorialists noted.

In 2018, the FDA updated the labels of the P2Y12 inhibitors clopidogrel, prasugrel (Effient), and ticagrelor (Brilinta) to include a and other opioids.

"Ultimately, this issue would be best evaluated by a randomized clinical outcomes trial," Giugliano and colleagues suggested.