Drug-to-drug interaction. New evidences on Morphine and delayed onset of action of antiplatelet agents.

A recently published article entitled  “Chest pain relief in patients with acute myocardial infarction” (European Heart Journal: Acute Cardiovascular Care April 22, 2015) address in a very well documentrd way the topic about drug-to-drug interactiono between morfine and antiplatelets agents in STEMI patients.

Guido Parodi, a lead interventional cardiologist in Cardiovascular and Thoracic Department of Careggi Hospital in Florence, (Italy) author of the article, highlights the fact that “despite the complete absence of rigorous studies designed to assess the impact of morphine administration in patients with AMI, clinical practice guidelines for the management of patients with STEMI strongly recommend the use of morphine for analgesia.”

As indicated in the article recent literature indicates an increased risk of mortality in STEMI patients treated with Morphine.

The analysis of CRUSADE registry in 2005 has shown how patients treated with morphine had a higher adjusted risk of death than patients not treated with morphine even after using a propensity score matching method. This is a non randomized trial and so influenced from potential bias, and the hypothesis that morphine was administered to higher-risk patients is also to be considered. But an additional potential explanation of morphine’s negative impact on AMI outcome may be related to drug-to-drug interactions.

Biologically a cause effect relation can be explained, because morphine inhibits gastric emptying, delaying absorption and so decreasing peak plasma levels of orally administered drugs in general and antiplatelet agents in this particular case.
This was very well demonstrated in a 2015 study from the same author “Morphine is associated with a delayed activity of oral antiplatelet agents in patients with ST elevation acute myocardial infarction undergoing primary PCI” (Parodi G, Bellandi B, Xanthopoulou I, et al. Circ Cardiovasc Interv Epub ahead of print January 2015) in whom the negative impact of morphine on platelet inhibition was not only limited to patients who vomited (patients with vomiting were excluded), but morphine-treated patients clearly showed higher residual platelet reactivity compared with patients who did not receive morphine.

In ATLANTIC Trial (Montalescot G, van ‘t Hof AW, Lapostolle F, et al.; ATLANTIC Investigators. Prehospital ticagrelor in ST-elevation myocardial infarction. New Engl J Med 2014; 371: 1016–1027), STEMI patients who did not receive morphine had a significant improvement in the ECG-based primary end point (ST-segment resolution), reflecting better myocardial reperfusion,with a significant “p” value for interaction between morphine use and time of ticagrelor administration. Professor Montalescot one of the lead authors of this Trial noted:“Co-administration of morphine in the ambulance may have delayed ticagrelor’s onset of action. To what extent this interaction may have affected our results remains unknown at this stage.”

So what to do with analgesia strategy in STEMI patients?

Given the key importance of platelet inhibition in patients treated by PPCI for STEMI and the absence of data that may support a potential clinical benefit of morphine in patients with acute myocardial infarction, more caution should be used regarding morphine administration in STEMI patients, and a restricted morphine use seems to be reasonably recommended.

Morphine administration has to be reserved, as suggested in the article, just for level of pain ≥ 7 on the base of a numerical rating scale (NRS) related value.

Courtesely from Dott. Guido Parodi

For lower chest pain intensity (NRS ≤ 7) alternative strategies has to be persecuted.
The author indicates paracetamol (1 g) or aspirin (≥300 mg) as alternative of choice to reduce chest pain as well demonstrated in letterature.
It has also to be considered how first line agents, currently indicated from STEMI guidelines, as Beta- blocker and Nitrates are able to reduce AMI-related chest pain until the definitive pain relief effect obtained with myocardial mechanical reperfusion.

Bottom Line

The first impact to reduce chest pain has to be reserved to Nitrates or B-blockers (where all contraindications are excluded).

After this NRS has to be evaluated and the use of Morphine is indicated only for values above 7. For lower values Paracetamol or Aspirin are the agents of choice.

References

• Parodi G. Chest pain relief in patients with acute myocardial infarction. Eur Heart J Acute Cardiovasc Care. 2015 Apr 22. pii: 2048872615584078. [Epub ahead of print] Review.PMID:25904757

• Meine TJ, Roe MT, Chen AY, et al. Association of intravenous morphine use and outcomes in acute coronary syndromes: Results from the CRUSADE Quality Improvement Initiative. Am Heart J 2005; 149: 1043–1049.

• Parodi G,Valenti R, Bellandi B, et al. Comparison of prasugrel and ticagrelor loading doses in ST-segment elevation
  myocardial infarction patients: RAPID (Rapid Activity of Platelet Inhibitor Drugs) primary PCI study. J Am Coll Cardiol 2013; 61: 1601–1606
• Parodi G, Bellandi B, Valenti R, et al. Comparison of double (360 mg) ticagrelor loading dose with standard (60 mg) prasugrel loading dose in STEMI patients: The Rapid Activity of Platelet Inhibitor Drugs (RAPID) primary PCI 2 study.
  Am Heart J 2014; 167: 909–914.
• Nimmo WS, Heading RC, Wilson J, et al. Inhibition of gastric emptying and drug absorption by narcotic analgesics. Br J Clin Pharmacol 1975; 2: 509–513.
• Parodi G, Xanthopoulou I, Bellandi B, et al. Ticagrelor crushed tablets administration in STEMI patients: The MOJITO study. J Am Coll Cardiol 2015; 65: 511–512.
• Montalescot G, van ‘t Hof AW, Lapostolle F, et al.; ATLANTIC Investigators. Prehospital ticagrelor in ST-elevation myocardial infarction. New Engl J Med 2014; 371: 1016–1027
• Duggan ST and Scott LJ. Intravenous paracetamol (acetaminophen). Drugs 2009; 69: 101–113.
• Zijlstra F, Ernst N, de Boer MJ, et al. Influence of prehospital administration of aspirin and heparin on initial patency of
  the infarct-related artery in patients with acute ST elevation myocardial infarction. J Am Coll Cardiol 2002; 39: 1733–1737
• Yusuf S, Sleigh P, Rossi P, et al. Reduction in infarct size and chest pain by early intravenous beta blockade in suspected
  acute myocardial infarction. Circulation 1983; 67: 132–141.
• Kim YI and Williams JF Jr. Large dose sublingual nitroglycerin in acute myocardial infarction: Relief of chest pain and reduction of Q wave evolution. Am J Cardiol 1982; 49: 842–848.

Tag:ACS, acute coronary syndrome, clopidogrel, STEMI, Ticagrelor