Both natural and synthetic opioid drugs have been linked to poor cardiovascular outcomes and adverse events in both chronic and acute care settings, creating a global public health problem. Cardiovascular specialists should remain vigilant in their opioid prescribing practices to mitigate these results, according to a recent review published in the Journal of the American College of Cardiology.
The American College of Cardiology (ACC) issued a 2020 call to action addressing the current opioid epidemic, noting that neither cardiovascular medicine nor surgical care teams have been “untouched” by the opioid crisis: hospital admissions acute coronary syndrome (ACS) increased from 168 to 315 per 100,000 quarterly in 2015, while endocarditis incidents nearly doubled between 2010 and 2015.
The clinical focus of the opioid crisis was primarily on prescribing behavior in primary care, pain management and addiction medicine with the aim of reducing the risk of opioid overdose and subsequent respiratory depression. Cardiovascular specialists, however, are “increasingly affected” and there is evidence that opioid abuse can trigger cardiovascular events and life-threatening cardiac arrhythmias.
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Cardiovascular consequences
In a recent JACC review, researchers looked at the cardiovascular consequences of chronic opioid use, abuse, overdose, and withdrawal. The authors also reviewed the emerging evidence of the additional cardiac repolarization effects of synthetic opioid analogs.
The cardiac response to narcotic analgesics is primarily due to opioid receptor-mediated effects, which are primarily mediated by the mu-, kappa, delta, and nociception / orphanin FQ peptide receptors. Modulation of opioid receptors is “increasingly recognized” for its effects on the cardiovascular system. Endogenous opioid peptides – including endorphins, enkephalins, and dynorphins – are also present in the human heart. Opioid receptor functions modulate heart rate, inotropic state, vascular function, and cellular adaptation.
“The effects of opioid receptor agonism on the cardiovascular system are multifactorial and depend heavily on the circumstances of patient exposure,” the authors write. “Chronic opioid use, abuse, overdose, and withdrawal are all associated with unique complications, including vascular, valvular, and arrhythmic consequences.”
However, acute opioid receptor-mediated cardiovascular effects are known; these effects include hypotension, orthostasis, syncope, and bradycardia. Since opioids such as morphine – “ubiquitously used” in acute care – are associated with a higher risk of death, it is “prudent”, according to the authors, to delay opioid use in order to suppress chest pain.
Rare benefits with chronic use
Research into cardiovascular effects related to chronic opioid use is ongoing. Only one forensic study was published indicating a potential benefit: this study compared 98 people who had been on chronic opioid treatment with 97 who had died who were opioid-free. Severe coronary artery disease was less common in patients on chronic opioid therapy (adjusted odds ratio 0.43).
Risks of overdose, abuse, withdrawal and reversal
The association between cardiovascular effects and opioid overdose is more consistent and well documented. Noncardiogenic pulmonary edema following overdose has been documented, and both hypotension and bradycardia can be reversed by intravenous administration of naloxone. Opioid overdose has also been associated with ischemic events, heart failure, and arrhythmias.
Valvular endocarditis in drug users is one of the major consequences of opioid abuse. This condition is primarily due to particulate contamination, which leads to bloodborne bacterial and / or fungal infections. With the increase in intravenous heroin use and abuse, there has been a “dramatic” absolute increase in cardioembolic strokes due to endocarditis. Endocarditis in this population is also “strongly associated with” recurrent prosthetic valve infections – creating ethical and societal concerns and challenges for cardiovascular surgeons and other specialists.
The cardiovascular manifestations of opioid withdrawal are opposite to those of opioid intoxication or overdose: often include increased catecholaminergic tone and an abrupt increase in rate-pressure product and myocardial oxygen consumption. These effects can destabilize high-risk cardiovascular patients, particularly those with “poor” coronary perfusion due to profound epicardial coronary artery disease, severe stenotic valvular disease, and significant left ventricular systolic dysfunction.
Stress-induced cardiomyopathy is also seen during opioid withdrawal, as is acute pulmonary edema as a result of naloxone therapy.
The potential for cardiovascular events resulting from acute reversal of opioid intoxication is of regulatory interest. A recent study of alvimopan – a peripheral µ-opioid receptor antagonist – was conducted on 805 patients who were randomly assigned 2: 1 to receive the drug versus placebo. 11 ischemic events were observed in the treatment group compared to no events in the placebo group, resulting in a boxed warning. However, sufficiently powered randomized trials are still needed to evaluate cardiac events associated with other opioid antagonists.
Alarming statistics
According to the U.S. Centers for Disease Control and Prevention (CDC), nearly 500,000 people died from illicit opioid use between 1999 and 2018. Americans filled nearly 250 million opioid prescriptions in 2014; This most widely prescribed class of drugs was responsible for nearly 29,000 unintentional deaths, or about 79 deaths per day. The number of prescription opioid-related deaths declined in 2018 but was still above 15,000, suggesting an area where public health remains a priority.
Arrhythmia Risks of Opioids
Opioid mortality is due to respiratory depression due to overdose. More recently, however, the association between arrhythmia and mortality has been recognized. A study of 857,283 US veterans who used opioids found that veterans who took chronic opioids had a significant increase in atrial fibrillation (odds ratio 1.34). Although the authors hypothesize that opioid-associated hypoventilation and central sleep apnea with nocturnal hypoxia may be responsible for this association, the effect of opioids and atrial arrhythmias on the risk of sudden death has not yet been described.
Ventricular arrhythmias associated with opioid use were “more comprehensively assessed”, according to researchers, with oxycodone and prolonged-release methadone being “disproportionately” involved in opioid-associated mortality. Since the death rate from methadone is relative to prescription volume, it is an order of magnitude higher when compared to the oxycodone death rate.
In 2006, the US Food and Drug Administration (FDA) required a boxed warning label to help reduce methadone-associated arrhythmias. A guideline committee at the US Center for Substance Abuse Treatment recommended QTc interval screening for methadone treatment, although a Cochrane review concluded that QTc prolongation was not a safety risk because the available evidence “did not support the EKG -Screening reduced mortality for QTc-prolonging drugs. ”
Opioid derivatives such as levacetylmethadol, buprenorphine, propoxyphene, loperamide, and dextromethorphan can also have proarrhythmic potential mediated in a manner similar to methadone.
Future trends
There are many gaps in understanding for future research. Genetic and metabolic factors are an important area for future research and will enable clinicians to offer tailored, individualized therapy.
The immediate contexts in which sudden death occurs also require additional understanding. Future outcome studies are also needed to clarify the routine use of potent opioids in cardiac catheterization laboratories in the United States as part of periprocedural sedation. European standards forego the use of opioids such as morphine and fentanyl due to delayed absorption in the stomach and decreased effects of oral P2Y12 antiplatelet agents such as clopidogrel, ticagrelor and prasugrel.
“Given the body of the evidence, we claim that opioids play a very limited role in cardiovascular practice: only in acute post-operative pain,” the authors write. “Although natural opioids cause respiratory depression, synthetic opioids show additional influences on conduction, repolarization and the risk of arrhythmias in susceptible people.”
“Cardiovascular complications from opioids are a major public health concern around the world,” they added. “Cardiovascular specialists should be careful about the amount prescribed for post-operative patients and avoid chronic prescribing. This cautious approach is supported by recent data that 1 in 10 cardiac surgery patients> 3 months after surgery had potentially habitual opioid use. “
“While the primary strategy for reducing the effects of opioids on mortality is vigilant prescribing, there remains an unmet need to promptly detect cardiovascular events in the event of overdose, prevent endocarditis, and stratify the risk of arrhythmias in susceptible patients on chronic opioid therapy,” concluded they .
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Krantz MJ, Palmer RB, Haigney MCP. Cardiovascular Complications of Opioid Use: JACC State of the Art. J. Am. Coll. Cardiol. 2021; 77 (2): 205-223. doi: 10.1016 / j.jacc.2020.11.002
This article originally appeared on Clinical Pain Advisor
