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A peripheral opioid receptor antagonist failed to counteract the morphine-induced delay in ticagrelor (Brilinta) absorption among patients with stable coronary artery disease (CAD), according to a small randomized trial.

Ticagrelor recipients showed only modest changes in the plasma levels of the P2Y12 receptor inhibitor when treated with IV methylnaltrexone (Relistor) versus placebo:

• Maximum plasma concentration of ticagrelor (C_max): 951 vs 688 ng/mL (38% higher)
• Area under the plasma concentration vs time curve from time 0 to last measured (AUC_0-t): 2,952 vs 2,276 ng-hr/mL (30% higher)
• Time to C_max: 4.0 hours for both
• P2Y12 reaction units similar between groups at each time point
• No difference in platelet reactivity on VASP and LTA
• High on-treatment platelet reactivity similarly likely between study arms

Similar findings were noted when a major metabolite of ticagrelor was analyzed, reported by Dominick Angiolillo, MD, PhD, of the University of Florida College of Medicine, Jacksonville, and colleagues in .

"Although our study showed increased exposure to ticagrelor and its active metabolite (i.e. higher AUC_0-tlast and C_max) in patients receiving methylnaltrexone, it failed to show any modulating effects of methylnaltrexone on speed of absorption and on the [pharmacodynamic] profiles of ticagrelor in patients receiving morphine," they concluded.

Used as first-line strategy for pain relief in settings such as acute coronary syndrome (ACS), morphine has the downside of inhibiting gastric emptying and oral-cecal transit time. It's subjectively experienced as constipation, but it also has the effect of delaying onset of action for oral P2Y12 receptor inhibitors such as ticagrelor.

"The lack of adequate antiplatelet protection when morphine is being used in such high-risk patients raises concerns for the risk of thrombotic complications and underscores the need to define strategies that can enhance absorption of oral P2Y12 inhibitors," the investigators noted.

So far, a high loading dose has not been effective, whereas crushed tablets have been shown to accelerate these drugs' onset of action. IV metoclopramide along with crushed ticagrelor has also been associated with higher drug levels and lower platelet reactivity during the first hour after drug administration.

"Overall, these observations underscore the need to identify alternative strategies to accelerate the onset of effects of oral P2Y12 inhibitors in patients undergoing [primary] PCI," the authors said.

"Until then, intravenous antiplatelet therapies including cangrelor [Kengreal] and glycoprotein IIb/IIIa inhibitors represent the most attractive treatment options to bridge the gap in platelet inhibition induced by oral P2Y12 inhibitors occurring in morphine-treated patients undergoing PCI."

Angiolillo's group conducted the randomized, double-blind study in 30 stable CAD patients who were taking aspirin. Groups crossed over after 7 days of washout.

Notably, these were patients who were not undergoing elective percutaneous coronary intervention (PCI).

Administration of the assigned treatment (IV methylnaltrexone or placebo) was immediately followed by IV morphine, then a loading dose of ticagrelor 15 minutes later. Blood samples were taken at baseline and serially up to 6 hours after ticagrelor loading dose.

Limitations of the trial include its small sample and exclusion of ACS patients. Investigators acknowledged that they were also unsure if it would have been better to delay morphine administration after methylnaltrexone.

It was "astonishing" that methylnaltrexone neither improved platelet aggregation nor plasma concentrations of ticagrelor in the study, commented Christian Schoergenhofer, MD, PhD, and Bernd Jilma, MD, both of the Medical University of Vienna, Austria, in an .

This is now the second trial in which methylnaltrexone failed in this setting, the pair wrote. "Thus, to optimize current ACS treatment alternative strategies for analgesia or other ways to overcome the inhibitory effects of morphine on the gastrointestinal system are required."

Besides crushing ticagrelor tablets and IV cangrelor, Schoergenhofer and Jilma also suggested abciximab infusion as a possible option in some patients.