Challenging 50 Years of Pain Relief for Treating Heart Attacks

Researchers from the school’s Center for Cardiac Research and Education in Therapeutics (CCRET) have built a body of work that challenges more than 50 years of medical practice regarding the use of opioids to treat people experiencing myocardial ischemic pain — pain caused by a blockage of the blood supplying the heart.

A severe blockage can lead to a heart attack, heart failure, and abnormal heart rhythms.

Opioids are often used by doctors and paramedics to relieve pain with the long-held belief that they lead to better results. However, recent research has raised concerns about potential interactions between opioids and antiplatelet agents called oral P2Y.12 inhibitors, a cornerstone of therapy in heart attack management thanks to their anti-clotting actions that reduce the risk of death.

It is thought that opioids may work in two ways: first, by slowing the natural forward movement of the stomach, hindering stomach absorption of the inhibitors. This, in turn, is thought to contribute to a delay in the inhibitors’ anti-platelet activity.

dr. Himawan Fernando (picture right) is a cardiologist with PhDs from CCRET, Alfred Health and Baker Heart and Diabetes Institute, under the supervision of A/Prof Dion Stub of CCRET and Prof Karlheinz Peter at the Baker Institute. In a series of trials and other studies, they questioned 50 years of accepted practice and set out to look for alternative pain relievers to opioids.

In 2020, they and colleagues published a review in Pharmacology and Therapeutics examining both the mechanisms underlying drug interaction and promising alternative pain medications.

dr. Fernando says, “It was clear to us after that review that there were very plausible theories about the nature of drug interactions and a great need for clinical trials and other robust evaluations of alternative analgesics for use in this context.”

Together with cardiac researchers from Alfred Hospital, Monash University & Ambulance Victoria, they then led a secondary observational study investigating the association between reported pain levels and clinical biomarkers of myocardial injury (heart damage). They used a secondary analysis of the AVOID study for this. The AVOID study included 638 patients suspected of having a heart attack between 2011 and 2014, who were subsequently transferred to percutaneous coronary intervention (PCI) hospitals in Melbourne, Australia, and questioned the accepted role of oxygen therapy in AMI.

“Pain relief in these patients is entrenched in medical practice, not only for patient comfort, but also for the belief that pain reduction produces better outcomes. Therefore, ample doses of opioids are often used to achieve a pain-free status. Our Study however, showed a limited association between pain status and markers of cardiac damage, suggesting that more judicious use of opioids, with a focus on patient comfort, might be appropriate.”

From here, Dr. Fernando and A/Prof Stub evaluated the association between pre-hospital dose opioids and clinical outcomes for patients with acute coronary syndrome (ACS), a wide variety of heart conditions with blocked blood vessels to the heart.

To do this, they linked data housed in Ambulance Victoria and two clinical registries maintained by the Monash School of Public Health and Preventive Medicine – the Victorian Cardiac Outcomes Registry and Melbourne Interventional Group databases. More than 10,000 ACS patients were enrolled in the study, all of whom were transported by emergency services to the hospital where they underwent PCI from 2014 to 2018.

A/Prof Stub says: “We found no significant association between opioid use and the rate of serious heart disease in these patients up to 30 days after hospitalization. So while it appears that opioids have an interactive negative effect on P2Y12 inhibitors, the clinical results may not be seriously affected. But what this study did do is lend credibility to the fact that a really robust clinical trial is needed to compare opioids with alternatives.”

The LOCAL study is a study that fills this gap. The alternative the researchers chose was the local anesthetic lignocaine (lidocaine), which has systemic analgesic properties when administered intravenously.

A/Prof Stub says: “We already know that intravenous (IV) lignocaine is effective for ischemic limb pain, works quickly and is generally well tolerated, including in patients with coronary artery disease. It’s exciting to think that a readily available, affordable option may in fact be a superior candidate for what is in use.”

The LOCAL study, published in the European Heart Journal in late 2021, compared the effects of lignocaine and the opioid fentanyl on the bioavailability of the oral P2Y12 ticagrelor inhibitor and its antiplatelet effects in patients with suspected heart blocks (as indicated by undergoing coronary angiography or PCI). The study also evaluated the safety and efficacy of lignocaine compared to fentanyl as procedural analgesia in patients with unstable angina (UA) and a type of heart attack called non-ST elevation myocardial infarction (NSTEMI). NSTEMIs are often less damaging to the heart than their counterpart, STEMI.

They found that IV lignocaine avoided the biochemical effects of IV fentanyl, leading to greater bioavailability of ticagrelor and comparable levels of pain relief. Patients reported good satisfaction with both drugs. They further advised to reconsider routine pain relief during PCI, and if implemented, lignocaine is a beneficial alternative to fentanyl.

“These results indicate that lignocaine can be considered as a potential alternative to fentanyl in patients with UA and NSTEMI. They also warrant further research into lignocaine and other non-opioid agents for use in patients with acute ischemic chest pain, such as STEMI,” said A/Prof Stub.

This point may be alleviated in the second half of 2022, when the duo, together with Ambulance Victoria, hope to publish the results of a randomized clinical trial examining lignocaine versus fentanyl in a cohort of patients experiencing the more severe STEMI heart attacks.

dr. Fernando says: “Whatever these results reveal, it is becoming increasingly clear that safer alternatives to opioids need to be identified, and when that happens, it will revolutionize more than 50 years of medical practice around the world.”

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