Reports of Arrhythmias, Cardiac Arrests Linked to Nonprescription Opioids

Tighter regulations on prescription opioids in response to the opioid epidemic are increasingly pushing people to seek out easier-to-access alternatives to either manage withdrawal symptoms or get a euphoric high, and a new study suggests this shift may bring with it the risk of life-threatening arrhythmias.

Two of those alternatives—loperamide, an over-the-counter opioid used to treat diarrhea, and kratom, a widely available herbal substance containing the opioid mitragynine—were associated with disproportionate reports of ventricular arrhythmias and cardiac arrest in pharmacovigilance databases from the US and Canada between 2015 and 2021.

Loperamide also was tied to increased reporting of QTc prolongation/torsade de pointes, which could lead to sudden cardiac death, according to researchers led by Mori Krantz, MD, who conducted the study while working for Clario, a healthcare research technology company involved in clinical trials. He has since joined the US Food and Drug Administration as a medical officer in the Division of Cardiology and Nephrology, although when speaking with TCTMD, he said his opinions do not reflect the position of the agency.

Though loperamide, when taken at high doses, has been linked to dangerous arrhythmias before—with the FDA issuing a safety alert in 2016—these data newly call into question previous assertions that kratom may be relatively safe because it has not been associated with many reports of QTc prolongation. The FDA, however, has warned against its use.

“I think most of us in the author pool believe that this signal is very worrisome and . . . at least temporarily refutes some prior literature where people state that they think kratom may be a much-safer alternative to other opioids,” Krantz said. “We don’t believe that the scientific community, whether it’s addiction [medicine] or otherwise, has enough evidence to state that this drug is a safer alternative to other opioids, and we feel strongly that it needs to be studied from a cardiac perspective much more thoroughly.”

The findings were published online ahead of the June 13, 2023, issue of the Journal of the American College of Cardiology.

Nonprescription Opioid Alternatives

Starting in the mid- to late-1990s, multiple organizations began pushing for pain to be the so-called fifth vital sign, along with body temperature, pulse rate, blood pressure, and respiration rate. The ensuing years saw the aggressive marketing of prescription opioids, sparking the epidemic of opioid-related overdoses and deaths that continues to this day. Eventually, regulations around prescribing the medications tightened, forcing those who remained dependent on them to look for alternatives, either illicit options like heroin and fentanyl or legal options like nonprescription medications and herbal substances.

Loperamide was easy to obtain over the counter, and up until recent changes were made to packaging, could be purchased in bulk. More recently, kratom—which contains mitragynine, an herbal opioid with stimulant properties obtained from an evergreen tree in Southeast Asia—has become more popular. It is banned in many countries and in certain parts of the US but still remains widely available in places like gas stations, head shops, and vaping stores in the form of teas, powders, and capsules. “Both of those two would be drugs that are very cheap and very available that we are concerned about,” Krantz said.

The increasing popularity of kratom led the investigators to wonder whether it might carry a risk of arrhythmias similar to those seen previously with loperamide and methadone, an opioid used for the treatment of morphine or heroin addiction.

To look for a signal, they turned to three pharmacovigilance databases in North America: the FDA Adverse Event Reporting System (FAERS), the US Center for Food Safety and Applied Nutrition Adverse Event Reporting System (CAERS), and the Canada Vigilance Adverse Reaction (CVAR) database. Methadone was included in the study as a positive control, whereas buprenorphine and naltrexone were included as negative controls.

Within FAERS, the largest database, the researchers uncovered 1,163 reports of ventricular arrhythmia/cardiac arrest involving methadone, 1,008 involving loperamide, and 46 involving kratom (mitragynine) between 2015 and 2021.

When compared with other drugs, all three were associated with disproportionate numbers of reports, as indicated by the proportional reporting ratio (PRR):

• Mitragynine (PRR 8.9; 95% CI 6.7-11.7)
• Methadone (PRR 6.6; 95% CI 6.2-7.0)
• Loperamide (PRR 3.2; 95% CI 3.0-3.4)

Reports with mitragynine were most likely to be fatal (91%), followed by those involving methadone (73%) and loperamide (37%).

Only methadone and loperamide were associated with disproportionate reporting of QTc prolongation/torsade de pointes, with only two such reports involving mitragynine.

Similar signals were observed in the CVAR and CAERS databases.

Buprenorphine, naltrexone, and diphenoxylate (another antidiarrheal agent) were not associated with arrhythmic outcomes.

Scope of the Potential Problem Unknown

Because the databases used in this study reflect voluntary reporting of adverse events, the information cannot be used to establish incidence rates, “so you can’t tell from this data how big of a problem it is,” Krantz acknowledged. The signals detected in research like this spur additional studies to explore the possible associations between medications and adverse outcomes, he added.

Asked about potential mechanisms to explain how loperamide and kratom might increase the risk of life-threatening arrhythmias, Krantz said it’s easier to create a link for loperamide, whose molecular structure is similar to that of methadone. Both loperamide and methadone block a potassium ion channel, the human ether-a-go-go related gene (hERG) channel, which leads to QTc prolongation and increases risks of various arrhythmias.

The potential mechanism of harm for kratom is less clear, particularly because it includes not only mitragynine, but also dozens of other alkaloids, Krantz said, noting that there hasn’t been adequate research involving ECGs or evaluation of ion channels with the substance. These studies are now ongoing to better quantify the risk, and it’s possible kratom is increasing arrhythmias via other routes besides the hERG channel.

Without knowing the mechanism and magnitude of the potential risk with mitragynine, “it’s hard to know what to do” regarding kratom, Krantz said. “It’s not my place or certainly not the FDA’s place to suggest a ban at this stage, . . . but the manufacturing, standardization, and regulation process perhaps offers an opportunity to understand this medication better to sort of allow us to get these much-needed studies [done].”

As for loperamide, Krantz applauded the FDA’s efforts to push manufacturers to distribute the drug in blister packs with limited quantities rather than selling it in bottles of 200 or more pills, which reduces the likelihood that someone will ingest very large quantities. He likened the moves to efforts around tightening restrictions on products containing pseudoephedrine, which is used to illicitly manufacture methamphetamines.

“While that’s not a perfect analogy, it gives you an idea of how we can safeguard the public health through different techniques such as packaging,” Krantz said.

Still, the opioid epidemic has not waned, and in fact has increased in disenfranchised populations, who are increasingly turning to opioid alternatives like loperamide and kratom, he pointed out.

“This I think will probably remain a public health threat for the foreseeable future,” Krantz predicted. “It’s not something we should just ignore.”

In an accompanying editorial, Lee Eckhardt, MD, and Andrew Nickel, MD (both from the University of Wisconsin-Madison), say that despite the limitations of this analysis, it “clarifies that kratom may not be a ‘safe’ opioid.

“Significant gaps in knowledge of the proarrhythmic and pro-death effects remain,” they continue. “Ascription of the arrhythmia vulnerability as related to hERG blockade is clearly barking up the wrong (kratom) tree. We think that instead of touting the lack of QT prolongation from kratom as justification for its safety, efforts should be directed to increase access to safer alternatives (ie, buprenorphine) for opioid use disorder.”