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Morphine and clopidogrel don’t play well together in patients with certain high-risk heart conditions. A study in the Journal of The American College of Cardiology (JACC) found that this treatment combination was associated with a higher likelihood of ischemic events in patients with non-ST-segment elevation acute coronary syndrome (NSTEACS).

Clinical trials have yet to explore the safety risks of morphine as a pain manager for NSTEACS, although guidelines support its use for this purpose. Previous studies have shown that morphine can reduce the effects of oral adenosine diphosphate (ADP) receptor blockers or P2Y12 inhibitors such as clopping, ticlopidine, prasugrel, and ticagrelor, leading to a U.S. Food and Drug Administration label warning about morphine and other opioid drugs.

“It is concerning that morphine has been shown not only to delay the onset of action of clopidogrel but also to reduce clopidogrel active metabolite levels, suggesting that morphine may promote conversion of clopidogrel to its inactive metabolite,” Robert F. Storey, MD, DM and William A.E. Parker, MD wrote in a related editorial.

The clinical relevance of this interaction has been debated, however.

Other studies have produced mixed results over the link between morphine and myocardial infarction (MI).

“Our main goal was to analyze whether the well-established pharmacological interaction between clopidogrel and opioids could translate into any impact in clinical outcomes,” Remo Holanda M. Furtado, MD, PhD, the study’s lead author, told CLN Stat. Specifically, Furtado and colleagues looked at the association between morphine and higher risk of ischemic events in patients receiving clopidogrel for acute coronary syndrome.

Investigators recruited more than 5,400 NSTEACS patients from a clinical trial, comparing them against a control group of 3,462 patients who weren’t getting treated with clopidogrel. The study included several clinical endpoints: MI; composite of death, recurrent ischemia, or thrombotic bailout at 96 hours (four-way endpoint); and the composite of death or MI at 30 days.

Morphine use was associated with higher rates of ischemic events in patients pre-treated with clopidogrel, including the four-way endpoint at 96 hours. Higher rates of death or MI at 30 days also trended higher in these patients. “Those results were in accordance with the pharmacological interaction previously described, so we were not so surprised by that finding,” Furtado said. In comparison, patients not pre-treated with clopidogrel did not appear to experience harm from morphine.

Overall, the study underscores the link between pharmacological findings in prior studies with platelet aggregability and the clinical implications, Furtado said.

In light of these results, physicians should be aware of these interactions and try to avoid morphine with concomitant clopidogrel loading, he said. If morphine is judged to be mandatory, they should think about alternatives to overcome this interaction, such as parenteral or more potent oral ADP receptor blockers (cangrelor, prasugrel, or ticagrelor), directing patients to chew tablets to improve the drugs’ absorption, repeating clopidogrel loading in the cardiac catheterization lab or administering prokinetic drugs to improve clopidogrel absorption, he said.

This study’s results and others suggest that the further loading dose of clopidogrel should occur 6 to 8 hours after the last dose of opiate to optimize its therapeutic strength, Storey and Parker noted in their editorial. Another strategy would be to delay the administration of clopidogrel until the time of percutaneous coronary intervention, when morphine levels and their impact decline.