JACC Review Highlights Cardiovascular Outcomes Associated With Acute and Chronic Opioid Use

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This review explores the cardiovascular consequences of opioids and the contributions of off-target electrophysiologic properties to mortality, and provides practical safety recommendations.

Both natural and synthetic opioid agents have been associated with poor cardiovascular outcomes and adverse events in both chronic and acute care settings, creating a worldwide public health issue. Cardiovascular specialists should remain vigilant in their opioid prescribing practices in order to mitigate these outcomes, according to a state-of-the-art review published in the Journal of the American College of Cardiology.

The American College of Cardiology (ACC) issued a Call to Action in 2020 addressing the current opioid epidemic, noting that neither cardiovascular medicine nor surgery care teams were “not untouched” by the opioid crisis: Hospital admissions for 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 has primarily been on prescriber behavior in primary care, pain management, and addiction medicine settings, with the goal of reducing the risk of opioid overdose and subsequent ventilatory depression. Cardiovascular specialists, however, are “increasingly affected” and evidence shows that cardiovascular events and life-threatening arrhythmias can be triggered by opioid abuse.

Cardiovascular Consequences

In a JACC state-of-the-art review, researchers reviewed the cardiovascular consequences of chronic opioid use, misuse, overdose, and withdrawal. Authors also reviewed the emerging evidence for the ancillary cardiac repolarization effects of synthetic opioid analogues.

Cardiac responses to narcotic analgesics is primarily due to on-target opioid receptor-mediated effects, primarily through the mu, kappa, delta, and nociception/orphanin FQ peptide receptors. Opioid-receptor modulation is “increasingly recognized” for its impact 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 adaption.

“Effects of opioid receptor agonism on the cardiovascular system are multifactorial and highly dependent on the circumstances of patient exposure,” the authors wrote. “Chronic opioid use, misuse, overdose, and withdrawal are each associated with unique complications including vascular, valvular, and arrhythmic sequelae.”

Acute opioid receptor-mediated cardiovascular effects, however, are well-known; these effects include hypotension, orthostasis, syncope, and bradycardia. Because opioids like morphine — “ubiquitously used” in acute care settings — are associated with a higher risk of death, it’s “prudent,” per the authors to delay opioid use for the purpose of suppressing chest pain.

Benefits Rare With Chronic Use

Investigations into the cardiovascular effects associated with chronic opioid use are ongoing. Only 1 forensic study has been published that indicates a potential benefit: In that study, 98 decedents on chronic opioid treatment were matched with 97 decedents who were opioid-free. In those on chronic opioid treatment, severe coronary artery disease was found less often (adjusted odds ratio, 0.43).

Risks of Overdose, Misuse, Withdrawal, and Reversal

The connection between cardiovascular effects and opioid overdose are more consistent and well-documented. Noncardiogenic pulmonary edema subsequent to overdose has been documented, and both hypotension and bradycardia can be reversed by administration of intravenous naloxone. Opioid overdose has also been associated with ischemic events, heart failure, and arrhythmias.

Valvular endocarditis in injection drug users is one of the most important sequelae of opioid misuse. Primarily, this condition is due to particulate contamination, leading to blood-borne bacterial and/or fungal infections. With intravenous heroin use and abuse on the rise, there has been a “dramatic” absolute increase in cardioembolic stroke resulting from endocarditis. Endocarditis in this population is also “strongly associated with” repeated prosthetic valve infections — leading to ethical and societal concerns and challenges for cardiovascular surgeons and other specialists.

Cardiovascular manifestations of opioid withdrawal are opposite those of opioid intoxication or overdose: frequently, include increased catecholaminergic tone and abrupt increases in rate-pressure product and myocardial oxygen consumption. These effects can destabilize high-risk cardiovascular patients, especially those with “tenuous” coronary arterial perfusion due to high-grade epicardial coronary artery disease, severely stenotic valvular heart disease, and significant left ventricular systolic dysfunction.

Stress-induced cardiomyopathy is also seen during opioid withdrawal, as well as acute pulmonary edema secondary to naloxone therapy.

The potential for cardiovascular events resulting from acute reversal of opioid intoxication is of regulatory interest. A recent trial of alvimopan — a peripheral µ-opioid receptor antagonist — was conducted in 805 patients who were randomly assigned 2:1 to receive the drug vs placebo. In the treatment group, 11 ischemic events were seen compared with no events in the placebo group, resulting in a boxed warning label. However, adequately powered randomized trials are still needed to evaluate cardiac events associated with other opioid antagonists.

Alarming Statistics

According to data from the US Centers for Disease Control and Prevention (CDC), nearly 500,000 people died from illegal opioid use between 1999 and 2018. Americans filled nearly 250 million opioid prescriptions in 2014; this most frequently prescribed medication class was responsible for nearly 29,000 unintentional deaths, or roughly 79 deaths per day. Prescription opioid-related deaths decreased in 2018, but were still in excess of 15,000, indicating an area for ongoing public health prioritization.

Arrhythmia Risks of Opioids

Opioid mortality is attributable to ventilatory depression due to overdose. More recently, though, the relationship between arrhythmia and mortality has been recognized. A study of 857,283 US veterans who used opioids found that there was a significant increase in atrial fibrillation in veterans who received chronic opioids (odds ratio, 1.34). Although the authors hypothesize that opioid-associated hypoventilation and central sleep apnea with nocturnal hypoxia might account for this association, the effect of opioids and atrial arrhythmia on sudden death risk has not yet been described.

Ventricular arrythmias associated with opioid use have been “more comprehensively assessed,” according to researchers, with extended-release oxycodone and methadone “disproportionately implicated” in opioid-associated mortality. Because the death rate from methadone is relative to prescription volume, it is an order of magnitude higher compared with the oxycodone death rate.

In 2006, a boxed warning label was mandated by the US Food and Drug Administration (FDA) in an effort to reduce methadone-associated arrhythmia. A US Center for Substance Abuse Treatment guideline committee recommended QTc interval screening in methadone treatment, although a Cochrane review concluded that QTc prolongation is not a safety concern, because available evidence “did not demonstrate that ECG screening reduced mortality for any QTc-prolonging medication.”

Opioid derivatives such as levacetylmethadol, buprenorphine, propoxyphene, loperamide, and dextromethorphan may also have proarrhythmic potential mediated in a similar fashion to methadone.

In terms of future research, gaps in understanding are many. Genetic and metabolic factors are an important area for future research, and will allow clinicians to provide tailored, individualized therapy.

The proximate contexts in which sudden death occur also require additional understanding. Future outcomes studies are also needed to clarify the routine use of potent opioids in cardiac catheterization laboratories in the US as part of periprocedural sedation. European standards forgo the use of opioids such as morphine and fentanyl due to a delay in gastric absorption and reduced effects of oral P2Y12 platelet inhibitors like clopidogrel, ticagrelor, and prasugrel.

“Given the totality of evidence, we contend that opioids have a very limited role in cardiovascular practice: solely in post-procedure acute pain,” the authors wrote. “Although natural opioids cause ventilatory depression, synthetic opioids exhibit additional influences on conduction, repolarization, and arrhythmia risk in susceptible individuals.”

“Cardiovascular complications of opioids are a major public health concern worldwide,” they added. “Cardiovascular specialists should be prudent regarding the quantity prescribed for post-procedure patients and should avoid chronic prescribing. This cautious approach is supported by recent data that 1 in 10 cardiac surgery patients exhibited potentially habitual opioid use at >3 months postoperatively.”

“The most important strategy for reducing the impact of opioids on mortality is vigilant prescribing practices, yet there remains an unmet need to promptly identify cardiovascular events in overdose, prevent endocarditis, and stratify arrhythmia risk among vulnerable patients on chronic opioid therapy,” they concluded.


Krantz MJ, Palmer RB, Haigney MCP. Cardiovascular complications of opioid use: JACC state-of-the-art review. J Am Coll Cardiol. 2021;77(2):205-223. doi: 10.1016/j.jacc.2020.11.002