Clopidogrel Interaction With Morphine in ACS Linked to More Ischemic Events

Giving morphine and clopidogrel simultaneously to patients who present with non-ST-segment elevation acute coronary syndromes is associated with an increased risk of ischemic events in the first few days after PCI, new research confirms.

The analysis, drawn from data collected for the randomized EARLY ACS trial, supports prior mechanistic and observational studies suggesting that morphine blunts the antiplatelet effects of oral adenosine diphosphate (ADP) receptor blockers. Remo Furtado, MD, PhD (Brigham and Women’s Hospital, Boston, MA), and co-authors, writing in an early online publication in the Journal of the American College of Cardiology, say their paper could be used to bolster drug warnings and guideline recommendations.

“I consider this kind of study hypothesis-generating,” senior investigator Robert Giugliano, MD (Brigham and Women’s Hospital), told TCTMD. “The findings are supportive of the warnings of a potential interaction, but it really says to researchers in the field: look, we really need to study this better and sort it out. And it should also raise the attention of clinicians to avoid giving morphine and clopidogrel at the same time, now that we have so many other potential options.” 

Morphine and other intravenous opioids for pain have been recommended for use during ACS for the better part of a century, but concerns about an interaction with oral ADP receptor blockers related to delayed absorption prompted the US Food and Drug Administration to update labels in 2018 warning about simultaneous use of the agents. Retrospective and mechanistic trials that have attempted to clarify these drug-drug interactions have been inconsistent, such that “the clinical relevance of those pharmacological findings is still a matter of debate,” Furtado et al write.

EARLY ACS Insights

For the current analysis, investigators reviewed 30-day outcomes among 5,438 NSTE ACS patients treated with upstream clopidogrel in the EARLY ACS trial, comparing patients who were given morphine simultaneously (11.3%) with those who were not (88.7%). Negative controls were the 3,462 patients not given upstream clopidogrel (prior to angiography), also stratified by morphine administration.

In the first 96 hours, morphine use at the time of upstream clopidogrel was associated with increased rates of a four-way composite of death, MI, recurrent ischemia, or thrombotic bailout. Death/MI was significantly higher at 48 hours (adjusted HR 1.54; 95% CI 1.07-2.23), and that appeared to have been driven by higher rates of periprocedural MI. A nonsignificant trend towards more death/MI was seen at 30 days. There was no signal of increased bleeding associated with morphine use within the first few days postprocedure.

Outcomes at 30 Days

By contrast, in patients not treated with upstream clopidogrel, there was no association between early morphine use and either the four-way endpoint or death/MI at 30 days and no sign of other serious adverse events—an analysis that helps confirm that patients given morphine were not simply a sicker group, Giugliano explained.

Possible Solutions

Speaking with TCTMD, Giugliano pointed out that the EARLY ACS trial is more than 10 years old and newer antiplatelet agents are now widely in use, but said its design allowed for a “unique opportunity” to look at the timing of clopidogrel in relation to morphine administration.

Whether switching to more potent oral antiplatelet agents—ticagrelor and prasugrel—would resolve the morphine problem is unclear. Mechanistic studies with these new more potent agents, noted Giugliano, also suggest an interaction with morphine, but again this has not been prospectively studied. Cangrelor, which is an intravenous antiplatelet, might be a reasonable work-around, since it’s not absorbed through the gastrointestinal system. “When you have a patient with a lot of pain and morphine is an important therapy, perhaps the solution there is to give cangrelor rather than clopidogrel,” he said.

I hope that these EARLY ACS results will give the interventional field a ‘kick in the rear end’ and that the field will now begin to accept that this is an important issue that justifies more study. John William McEvoy

Other potential options, said Giugliano, include crushing clopidogrel to aid absorption or trying other analgesics that may not interact in the same way, although he acknowledged that other analgesics have not been widely studied in this context.

In an accompanying editorial, Robert Storey, MD, DM, and William Parker, MD (both from University of Sheffield, England), point out that clinical guidelines already recommend the use of ticagrelor or prasugrel in preference to clopidogrel in patients without an indication for oral anticoagulation. “These are clearly more reliable options in morphine-treated ACS patients, accepting the need to still consider the potential delay in their onset of action,” they say. If clopidogrel is used, one work-around supported by the current analysis as well as prior pharmacodynamic studies would be to give another loading dose 6 to 8 hours after the last dose of opiate. Cangrelor, they add, may not fully protect patients since the commonly used 2-hour infusion may not “cover the entire window of delayed absorption.”

Reconsidering Opioids?

Just how often an analgesic is needed should also be considered, Giugliano noted. EARLY ACS was an international study and morphine use was highly variable in different regions around the globe. As such, another potential solution would be to have “a little higher threshold” for using morphine, rather than having it be default use, he said.

This has long been the position of John William McEvoy, MB BCh (National University of Ireland, Galway), who led the PACIFY study investigating fentanyl’s effects on P2Y12 absorption, delayed platelet inhibition, and myocardial injury. Commenting on the EARLY ACS analysis for TCTMD, McEvoy called the paper “interesting and timely” given the focus on opioid prescribing in the US and worldwide.

According to McEvoy, he and his co-investigators faced an uphill battling finding a publisher for PACIFY: US reviewers had a hard time believing that an interaction between opioids and oral antiplatelets was possible, while European reviewers were not interested because “few if any European patients in the cath lab get opioids, even for ACS,” he said in an email. “This transatlantic divide should generate serious questions as to why opiates are so ubiquitous in US cath labs. . . . I hope that these EARLY-ACS results will give the interventional field a ‘kick in the rear end’ and that the field will now begin to accept that this is an important issue that justifies more study.”

Just what such a study could look like is not a simple question. “You could use a different type of analgesic than morphine, you could crush clopidogrel instead of swallowing the pill whole, you could test a different oral antiplatelet and crush ticagrelor, for example, you could use cangrelor, and you could see which of these different strategies would make a difference,” Giugliano mused. “The obvious randomized trial, which is that half the patients get morphine and half don’t—that would be tough and I’d have ethical concerns about withholding analgesics. I think you'd need some other way to manage the patients’ pain.” 

McEvoy, likewise, stressed the need for an outcomes trial but acknowledged: “The feasibility and logistic of this will be very challenging.”