Metoclopramide May Mute Morphine’s Hampering of Ticagrelor Efficacy

Metoclopramide, a drug typically used to prevent and treat nausea and vomiting, may prove useful for overcoming morphine’s blunting effect on ticagrelor, according to findings from a single-center study of patients with unstable angina.

Specifically, the medication appears to shorten the time required to reach low platelet reactivity, investigators led by Joanna Sikora, PhD, and Piotr Niezgoda, MD (both from Nicolaus Copernicus University, Bydgoszcz, Poland), suggest.

J. William McEvoy, MBBCh (National University of Ireland, University Hospital Galway),commenting on the new results for TCTMD via email, described the morphine-P2Y12 inhibitor interaction as a “significant concern.”

“Multiple mechanistic randomized trials show a delay in P2Y12 absorption and antiplatelet effect with opiates. This is true for morphine, but our group has also shown similar findings with fentanyl in the PACIFY trial. Morphine has also been associated with adverse clinical outcomes in observational studies of ACS patients,” he said. “What we need now is randomized trials powered for clinical outcomes.”

However, McEvoy cautioned that the current study, published online recently in Thrombosis and Haemostasis, isn’t enough to sway practice. “The trial was too small and the effect of metoclopramide too modest to translate anything into clinical practice at present,” he noted.

As of now, both McEvoy and the researchers say, there are few strategies to address the “morphine effect” on P2Y12 inhibitors like ticagrelor, prasugrel, and clopidogrel.

One method is to employ the drug only in "cases where pain is a problem—this makes sense as many get prophylactic opiates in the cath lab,” McEvoy suggested, adding, “For me, the take home is to try to limit, where possible, the dose of opiates to as low as reasonably achievable (the ALARA concept) in patients being loaded with oral P2Y12 inhibitors for imminent PCI.”

Ticagrelor Hits Faster With Metoclopramide

The researchers enrolled 32 patients with unstable angina who had received a 300-mg loading dose of aspirin as well as 180 mg of crushed ticagrelor administered orally and 5 mg IV morphine, with half of the individuals randomized to receive 10 mg IV metoclopramide.

There were no serious events during the study. Among those not taking metoclopramide, nausea was reported by two patients, excessive sweating by one patient, and feeling nonspecifically unwell by one patient; there also was one mild episode of bradycardia. No adverse events were seen among patients in the metoclopramide arm.

“Of note, mean platelet activity in the time range between 0 and 60 minutes was noticeably higher in the metoclopramide-naive group,” the investigators say, adding, however, that at 30 minutes the portion of patients with high on-treatment platelet reactivity was smaller in the metoclopramide versus control groups (P = 0.0325).

Unfortunately, this opiate interaction with platelet inhibitors is not on many cardiologists’ radar and doubters will say we need prospective trials powered for clinical events before changing practice. J. William McEvoy

Additionally, the mean plasma concentration of ticagrelor was significantly higher among metoclopramide-treated patients than among controls at 15, 30, 45, and 60 minutes. Maximum plasma concentration was reached faster with metoclopramide than without (123 vs 168 min; P = 0.015).

Sikora, Niezgoda, and colleagues note that it’s unclear how all this applies to STEMI patients, who weren’t enrolled in their study. Indeed, for this subgroup, the potential of metoclopramide to cause cardiac arrhythmias is an issue, McEvoy told TCTMD.

Beyond following ALARA when it comes to morphine and fentanyl, one idea being “floated is to consider IV P2Y12 inhibitors that would not be affected by opiates—though expense has been a limitation there and I’m not sure that’s needed as most patients catch up even with opiates,” McEvoy said. Another being explored is oral naloxone, which, like metoclopramide, can mute the effect of opiates on GI motility.

The level of attention paid to the drug-drug interaction varies by region, McEvoy observed. “In Europe, opiates are less frequently given, so many feel this is less of an issue there. In contrast, we know that morphine is given to around a third of ACS patients in the US and almost all are getting fentanyl in the cath lab. Unfortunately, this opiate interaction with platelet inhibitors is not on many cardiologists’ radar and doubters will say we need prospective trials powered for clinical events before changing practice.”