Morphine drip delivers cardioprotection in acute myocardial infarction

Administering intravenous (IV) morphine prior to primary percutaneous coronary intervention (PCI) cuts myocardial and microvascular damage in patients with acute myocardial infarction (AMI), as shown in the MonAMI* trial.

On the other hand, the combined administration of morphine and metoclopramide does not provide the same benefit for infarct size or microvascular obstruction (MVO) compared with placebo.

The results, according to the investigators, seem confusing at first, given that morphine may slow intestinal absorption of oral platelet inhibitors and that distal embolization of thrombotic material is one mechanism of microvascular injury that might aggravate in case of delayed onset of effective platelet inhibition.

“However, MVO is a multifactorial process that includes ischemia‐reperfusion injury, tissue inflammation, and endothelial dysfunction in addition to distal embolization. Our results imply that thrombotic material is not the pivotal factor for microvascular injury or that the effect of P2Y₁₂ inhibitors is not sufficient to prevent distal embolization and MVO,” they pointed out. [Circ Res 2019;125:245-258]

MonAMI randomly assigned 138 AMI patients (ST-segment–elevation myocardial infarction [STEMI], n=94; non-STEMI, n=44) to receive ticagrelor 180 mg plus one of the following: (1) IV morphine 5 mg (morphine group), (2) IV morphine 5 mg and metoclopramide 10 mg (morphine+metoclopramide group), or (3) IV placebo (control group) prior to primary PCI.

The median age of the population was 64 years, and most of the patients were men and had a cardiovascular risk profile typical of patients with AMI. All patients received drug‐eluting stent implantation, preceded by a predilatation in 72 percent of cases. Thrombolysis in Myocardial Infarction (TIMI) flow grade 3 occurred in 91 percent of patients.

Results revealed a markedly smaller infarct size in the morphine-only than in the control group (percentage of left ventricular mass, 15.5 vs 17.9; p=0.047). Moreover, fewer patients who received morphine only developed MVO (28 percent vs 54 percent; p=0.022), and the extent of microvascular obstruction was smaller relative to the control group (percentage of left ventricular mass, 0 vs 0.74; p=0.037). [J Am Heart Assoc 2021;doi:10.1161/JAHA.120.018881]

In multivariable regression analysis, morphine administration was associated with a more than 60-percent reduction in the risk of incident MVO as compared with placebo (odds ratio, 0.37, 95 percent confidence interval, 0.14–0.93; p=0.035).

Meanwhile, neither infarct size (p=0.491) nor extent (p=0.753) or presence (p=0.914) of MVO differed between the morphine+metoclopramide and the control groups.

“Opioids have been associated with favourable cardioprotective effects on the myocardium, which might explain our findings… Enhanced endogenous release of opioids has been proposed as a key mechanism to confer protection against ischaemia‐reperfusion injury and translate conditioning stimuli from various organs to the heart,” the investigators said. [J Cardiovasc Pharmacol Ther 2017;22:112-121; JACC Cardiovasc Interv 2010;3:49-55; J Mol Cell Cardiol 2002;34:1317-1323] 

Concerning the lack of beneficial effects on myocardial and microvascular injury in the morphine+metoclopramide group, the investigators said that a potential drug interaction between intravenously administered morphine and metoclopramide seems unlikely but cannot be completely excluded. [Clin Exp Pharmacol Physiol 2007;34:106-112; Xenobiotica 2008;38:1365-1376] 

“Differences in baseline characteristics are the more likely explanation for our findings. Despite being a randomized trial, the morphine+metoclopramide arm … included a higher proportion of patients with STEMI and a more severely impaired TIMI flow pre‐PCI compared with the other study arms, albeit statistically not significant,” they pointed out.

In view of the study limitations—including the inability to assess differences in imaging parameters of myocardial injury, small sample size, and inclusion of both STEMI and non-STEMI patients—the results of MonAMI trial have to be considered as hypothesis generating and must be validated in future investigations, the investigators said.

*Impact of Morphine Treatment With and Without Metoclopramide Coadministration on Platelet Inhibition in Acute Myocardial Infarction