A look at the interaction between opioids and oral P2Y12 inhibitors
Are opioids blocking platelet inhibition?
Click Here to Manage Email Alerts
A recently recognized drug-drug interaction between opioids and P2Y12 inhibitors may have clinical implications for patients with ACS.
Dual antiplatelet therapy with aspirin and a P2Y12 inhibitor is the standard of care for initial treatment in patients with ACS to reduce the risk for subsequent CV events. The current ACS guideline and the Focused Update of the DAPT guideline recommends ticagrelor (Brilinta, AstraZeneca), clopidogrel or prasugrel (Effient, Daiichi Sankyo/Eli Lilly) as P2Y12 inhibitor options for patients undergoing PCI for rapid antiplatelet activity. In the acute phase of ACS treatment as well as during PCI, opioid agonists are commonly used in patients with ACS to provide analgesia and sedation. The ACS guidelines recommend use of morphine as the opioid.
The mechanism of the drug-drug interaction between opioids and P2Y12 inhibitors is not completely understood, but it is well known that opioids decrease gastrointestinal motility and delay gastric emptying, which contributes to delays in absorption and action of oral medications, including P2Y12 inhibitors (Figure). If opioids delay the absorption of P2Y12 inhibitors, they could diminish the antiplatelet effects that patients with ACS need.
Several nonrandomized, retrospective trials have attempted to address the clinical effect of this drug-drug interaction with mixed results. Trip J. Meine, MD, and colleagues evaluated patients with non-STEMI and concluded that morphine associated with significantly higher mortality. Mickael Bonin, MD, and colleagues evaluated patients with STEMI and concluded that morphine did not associate with a significant increase in major CV events. In 2018, the FDA required manufacturers of all three oral P2Y12 inhibitors to add a warning to the product labels stating that coadministration of an opioid agonist delays and reduces the P2Y12 inhibitor concentration. This warning further advises the consideration of a parenteral antiplatelet agent in patients with ACS who require the use of an opioid agonist. Randomized clinical trials have assessed the effect of opioids on all three oral P2Y12 inhibitors.
A look at the data: Ticagrelor
The IMPRESSION trial was a randomized, double-blind comparison of 5 mg IV morphine with placebo in 70 patients with STEMI or non-STEMI also receiving a 180 mg loading dose of ticagrelor. The primary outcome was active drug exposure within the first 12 hours after ticagrelor administration. Ticagrelor area under the curve was 36% lower in patients who also received morphine (P = .003), and there was a 2-hour delay in peak concentrations (4 hours vs. 2 hours; P = .006). Differences in total ticagrelor exposure were more pronounced within the first 6 hours with a 55% reduction in AUC for those treated with morphine (P = .002). Antiplatelet activity, measured using a variety of tests, was diminished in the morphine group for up to 3 hours post-loading dose, with more patients exhibiting high platelet reactivity compared with those who did not receive morphine. None of the patients experienced death, MI, stroke or TIMI major bleeding.
The PACIFY trial evaluated fentanyl, a shorter-acting opioid, to assess if it had the same effect on ticagrelor concentrations as morphine. This randomized trial included 70 patients undergoing elective PCI. Ticagrelor concentrations were lower in the fentanyl-treated patients at 0.5, 1 and 2 hours and were 41% lower 24 hours after receiving a loading dose of ticagrelor. Platelet reactivity, measured by the VerifyNow system (Instrumentation Laboratory), was significantly lower and the number of patients defined as having high platelet reactivity was higher at 2 hours post-loading dose in the fentanyl group. Platelet reactivity was not significantly different at 0.5, 1, 4 or 24 hours post-loading dose; however, the study was not powered to detect a difference in this outcome.
Both the IMPRESSION and PACIFY trials produced similar results with lower ticagrelor concentrations, a delay in peak effect and reduced antiplatelet activity when administered with an opioid agonist.
A look at the data: Clopidogrel
A randomized, double-blind, placebo-controlled, crossover study with 24 healthy volunteers evaluated the drug concentration and antiplatelet effects of a 600 mg loading dose of clopidogrel with morphine 5 mg IV or placebo. Clopidogrel plasma concentrations at 24 hours were decreased by 34% in patients receiving morphine (P = .001). From an antiplatelet perspective, morphine administration resulted in a more than twofold delay in the time required for maximal platelet inhibition (3 hours vs. 1.25 hours; P < .001) as measured by phosphorylation of vasodilator-stimulated phosphoprotein. While this trial did not include patients with ACS, the results were similar when compared with the aforementioned trials evaluating ticagrelor in the ACS population.
A look at the data: Prasugrel
In a study that evaluated patients with STEMI undergoing primary PCI, Guido Parodi, MD, PhD, and colleagues studied the effect that morphine administration had on platelet reactivity. Platelet reactivity was assessed by VerifyNow at 1, 2, and 4 hours after ticagrelor 180 mg (n = 134), ticagrelor 360 mg (n = 71) or prasugrel 60 mg (n = 95). There were significantly more patients with high residual platelet reactivity (PRU 208) at 1 hour (79.1% vs. 59.7%), 2 hours (52.8% vs. 29.2%) and 4 hours (24.3% vs. 9.5%) among those who received morphine compared with no morphine. This study demonstrated decreased antiplatelet activity among those receiving morphine. However, there were no differences in clinical outcomes (death, reinfarction, stroke, TIMI major and minor bleeding) between the two groups, as the study was underpowered to detect such differences.
Where do we go from here?
Providers need to be aware of the potential clinical consequences of this drug-drug interaction and avoid co-administration whenever possible. Several alternatives to coadministration of opioids and P2Y12 inhibitors have been proposed, but none of them have been evaluated in a clinical trial. Some of the suggested alternatives proposed include the use of an IV P2Y12 inhibitor such as cangrelor (Kengreal, Chiesi USA) to avoid the gastrointestinal route of absorption, concomitant administration of a glycoprotein IIb/IIIa inhibitor during PCI to target another route of platelet aggregation, administration of a prokinetic agent with opioids to promote gastrointestinal motility and administration of crushed oral P2Y12 inhibitor loading doses for faster absorption. Another example would be avoiding the routine use of planned fentanyl during PCI procedures.
The available data demonstrate a reduction in drug concentration and the antiplatelet effects of oral P2Y12 inhibitors when given in conjunction with opioid agonists. The negative effects on drug concentration and platelet inhibition appear to be present across various oral P2Y12 inhibitors and opioid agonists. Registry data and post hoc analyses of clinical trials have produced mixed results on clinical consequences. This drug-drug interaction warrants further investigation with prospective trials evaluating the effect on clinical outcomes for patients with ACS and/or undergoing PCI. In the meantime, clinicians should practice prudence when considering opioids in patients who are P2Y12 naive.
- References:
- Amsterdam EA, et al. J Am Coll Cardiol. 2014;doi:10.1016/j.jacc.2014.09.017.
- Bonin M, et al. J Am Heart Assoc. 2018;doi:10.1161/JAHA.117.006833.
- Hobl EL, et al. J Am Coll Cardiol. 2014;doi:10.1016/j.jacc.2013.10.068.
- Ibrahim K, et al. Thromb Haemost. 2018;doi:10.1055/s-0038-1666862.
- Koh JQS, et al. Heart Lung Circ. 2018;doi:10.1016/j.hcl.2018.12.015.
- Kubica J, et al. Int J Cardiol. 2016;doi:10.1016/j.ijcard.2016.04.077.
- Levine GN, et al. Circulation. 2016; doi:10.1161/CIR.0000000000000404.
- Meine TJ, et al. Am Heart J. 2005;doi:10.1016/j.ahj.2005.02.010.
- O’Gara PT, et al. Circulation. 2013;doi:10.1161/CIR.0b013e3182742cf6.
- Parodi G, et al. Circ Cardiovasc Interv. 2015;doi:10.1161/CIRCINTERVENTIONS.114.001593.
- For more information:
- Kathryn O. Jones, PharmD, BCPS, is assistant professor of clinical pharmacy practice at Union University College of Pharmacy in Jackson, Tennessee.
- Dylan S. Wilson, PharmD, BCPS, is pharmacy clinical specialist in cardiology at Jackson-Madison County General Hospital in Jackson, Tennessee.
- Sarah A. Spinler, PharmD, FCCP, FAHA, FASHP, AACC, BCPS (AQ Cardiology), is the Cardiology Today Pharmacology Consult column editor. She is professor and chair of the department of pharmacy practice, School of Pharmacy and Pharmaceutical Sciences, Binghamton University. She can be reached at sspinler@binghamton.edu.
Disclosures: The authors report no relevant financial disclosures.