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With rising reports of the veterinary sedative xylazine -- also known as "tranq" -- being mixed in with illicit fentanyl, physicians should be aware that the clinical endpoint for "reversing" an overdose should be that the person is breathing, experts said during a CDC call for clinicians.

"The idea that people have to wake up to be successful is a bit of a misunderstanding," Lewis Nelson, MD, chair of emergency medicine at Rutgers New Jersey Medical School in Newark, said during a CDC Clinician Outreach and Communication Activity (COCA) call on Thursday hosted by the agency's National Center for Injury Prevention and Control (NCIPC).

"We don't really need people to wake up. We need them to breathe," he said. "If they have a combination overdose, it may be the xylazine that's causing sedation. But if they're breathing, they're going to do fine."

It's possible to administer too much of the opioid overdose reversal agent naloxone (Narcan) to these patients, leading to opioid withdrawal, Nelson noted.

"It's better than dying, but most of these people don't die," he said. "If we're concerned about somebody not waking up because we're looking at wakefulness as an endpoint, instead of breathing, it can lead to adverse outcomes."

In a similar vein, there's not really a need to administer a xylazine reversal agent. One does exist, in veterinary medicine at least: atipamezole. It is not approved for use in humans, he said, and "there's probably not a need to invest a lot of resources in development of this drug for humans."

Yohimbine -- a botanical extract of the bark of a west African evergreen tree historically used to enhance sexual performance -- is also a xylazine reversal agent, but again, one that is not needed, he added.

There is "rarely" such a thing as a naloxone-resistant overdose, as naloxone is "very good at reversing fentanyl," Nelson said. "Remember, we're really not treating xylazine here, we're treating the opioid."

While fentanyl may be a potent opioid agonist, it's not really potency that matters in reversing an overdose -- it's affinity, Nelson explained, noting that naloxone has a much higher affinity for opioid receptors than fentanyl or other fentanyl analogs.

"Naloxone should have no problem reversing fentanyl or its analogs," he said. "It will not reverse xylazine, which is why patients may appear to be naloxone-resistant."

But as long as they are breathing, they will be fine, since they are likely just experiencing the sedative effects of the xylazine, he reiterated.

Though data on xylazine's respiratory depressant effects in humans are sparse, Nelson noted three case reports in the literature of people attempting to use xylazine for self-harm. All show survival and "the sum of this really suggests xylazine probably doesn't have tremendous respiratory depressant effects in humans."

Josh Schier, MD, MPH, a captain in the U.S. Public Health Service and a senior medical officer in CDC's NCIPC, reviewed the current data on xylazine epidemiology in the U.S., pointing to a in CDC's Morbidity & Mortality Weekly Report showing a 276% increase in fentanyl-involved deaths where xylazine was detected from 2019 to 2022.

That said, recent data from the National Forensic Laboratory Information System reported in September 2023 showed an apparent downturn in xylazine reports, and data from the Maryland Rapid Analysis of Drugs program also showed a recent reporting drop in xylazine in all samples tested.

Schier noted that there are many caveats, including possible reporting delays or transient drop-offs, that may account for these recent trends. "Only time will tell," he said.

Rachel Wightman, MD, of the Alpert Medical School at Brown University in Providence, Rhode Island, who is also a consultant medical director at the Rhode Island Department of Health, discussed strategies for managing xylazine-laced fentanyl in the community, including surveillance testing, public education campaigns, and harm reduction initiatives.

Xylazine is an alpha-2 adrenergic receptor agonist that was originally developed in the 1960s as an antihypertensive but was quickly shelved because of its strong sedative effects. Its use in the illicit drug supply was first reported in drug samples from Puerto Rico in the early 2000s, Schier said. It's unclear why it's been increasingly added to fentanyl but it could have a synergistic psychoactive effect or it could prolong the short-acting effects of illicitly manufactured fentanyl, he noted.

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