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For years, public health guidance about opioid overdoses has been relatively simple: Administer naloxone, then call 911.

But the days of simply spraying naloxone into an overdose victim’s nose, then watching that person resume breathing and wake up within minutes, are over.


The culprit is xylazine, the powerful sedative rapidly spreading throughout the U.S. illicit opioid supply. Xylazine, commonly known as “tranq,” is not an opioid, meaning that its effects can’t be reversed with naloxone, an overdose medication that specifically targets the brain’s opioid receptors.

As xylazine grows more common, harm-reduction groups across the country have reported that overdoses are becoming far more difficult to reverse. People experiencing overdoses from a combination of opioids and xylazine, they say, are requiring far more time and care before they regain consciousness — if they wake up at all.

“Six years ago, when you would hit somebody with naloxone, they would be very responsive,” said Sarah Laurel, the executive director of Savage Sisters, a Philadelphia nonprofit that provides resources and care to people who use drugs. But more recently, she said, “I started noticing that my friends, when we would hit them with Narcan, they weren’t responsive. Their color was not returning, and they weren’t beginning to breathe on their own.”


When responding to an overdose in the xylazine era, Laurel said, the new priority is simple: oxygen. Emergency responders and harm-reduction workers are increasingly using whatever tools and techniques they have available to make sure oxygen is reaching overdose victims’ brains, including mouth-to-mouth breathing and oxygen masks.

Amid the fast-changing landscape, doctors, first responders, public health officials, and nonprofits have scrambled to formalize their new overdose-response protocols. At the same time, they have worked to draw up new instructions for bystanders who encounter an overdose in progress. They are, in essence: Administer naloxone, call 911, and then immediately start “rescue breathing” to ensure the overdose victim doesn’t die or experience hypoxic brain injury before emergency responders arrive.

Recent guidance from the Philadelphia Department of Public Health encourages overdose responders to provide supplemental oxygen and employ “airway management” techniques — essentially, manipulating the head, neck, and body to ensure breathing isn’t blocked.

Savage Sisters workers now carry tools to track and improve overdose victims’ blood-oxygen levels, like pulse oximeters and oxygen tanks, and other organizations have followed suit. In New York City, the harm-reduction group OnPoint NYC has also incorporated a new emphasis on oxygen into the overdose-reversal training it offers laypeople, said Kailin See, the nonprofit’s senior director of programs.

“We train hundreds, many, many people, every year, and they leave that training crystal clear that naloxone is a tool that they’re going to use, but the No. 1 priority is getting oxygen to the brain,” she said. “I feel that we’re dispatching really well-trained citizen responders into New York.”

It is not lost on some harm-reduction leaders, however, that for potential bystanders, the act of reversing an overdose requires more effort than ever. Instead of merely administering a nasal mist or using a mechanized injector pen and calling 911, overdose responses may now require mouth-to-mouth breathing for up to 15 minutes, if not longer, before an ambulance arrives.

But none of those factors should be relevant when a human life is on the line, Laurel argued. If the prospect of administering rescue breathing to a stranger seems intimidating, she said, there are ways of avoiding direct mouth-to-mouth contact — like using hands, a T-shirt, or even “the bottom of a Dunkin’ Donuts cup” as a barrier.

The other critical component is patience, Laurel said. While naloxone acts quickly, it can take as long as 20 minutes even in typical cases for a victim of a xylazine-involved overdose to regain consciousness.

In many cases, she added, overdose responders focus first on vital signs like blood-oxygen saturation, knowing full well that the individual they’re helping won’t wake up immediately.

“We had a girl on our storefront who was there for five hours, and we eventually had to call an ambulance because she just kept going in and out of it,” Laurel said. “I would say an overdose reversal used to take three or five minutes, and now it’s triple that time frame. Just to make sure they’re OK, and stable enough, even if they aren’t conscious.”

But awareness remains an issue not only for potential bystanders and first responders, but also, in some cases, for people who use drugs and those recovering from an overdose.

“With the patients I’ve been seeing and asking about it, sometimes they know, and they’ll say, yeah, maybe [xylazine] could be in there,” said Jennifer Love, a New York-based emergency physician and research fellow at the Icahn School of Medicine at Mount Sinai. “And sometimes patients look at me like they aren’t totally familiar with xylazine, so then I try to do a lot of education at the bedside to let them know that this is a growing problem in the New York area.”

More education is needed among doctors, too, Love said — not just about how to reverse xylazine overdoses, but about spotting and treating many of the substance’s other harmful effects, like hard-to-treat skin wounds.

“For us as emergency medicine doctors, I think there’s a need for increased education around xylazine,” she said. If a patient who appears to be having an opioid overdose doesn’t respond to naloxone as expected, she added, “We need to consider that maybe there’s an additional adulterant like xylazine … watching them for longer, making sure that their vital signs are stable, continuing to do all of the really important harm-reduction work that we do in the emergency department.”

Most overdoses, however, are not treated in hospitals, but where they occur. Some emergency responders have embraced the new overdose-reversal strategies, See and Laurel said. But some emergency responders and bystanders, perhaps unaware of xylazine and its effects, still respond with large, repeated doses of naloxone and little else.

Administering too much naloxone, itself, can be dangerous. While reversing overdoses in progress is always the immediate priority, naloxone works by attaching itself to the brain’s opioid receptors. As a result, people who are revived from an opioid overdose often wake up experiencing painful withdrawal symptoms. The larger the naloxone dose, the worse the withdrawal.

Xylazine, which is already highly common in the Northeast and is spreading across the entire country, has only made things worse. The timing of its disruption to the drug supply and overdose-response protocols is especially unfortunate given the federal government’s recent emphasis on increasing naloxone access.

The Food and Drug Administration approved Narcan, a common formulation of nasal naloxone, for over-the-counter use earlier this year, making it the first naloxone product available without a prescription. And amid concerns about the medication’s accessibility, the White House gathered pharmaceutical manufacturers in Washington on Tuesday for a roundtable that Rahul Gupta, President Biden’s drug czar, said was aimed at discussing naloxone prices.

While naloxone is a valuable tool, See, the OnPoint NYC programs director, said that xylazine’s presence and the newfound focus on oxygen represents something of a full-circle moment for overdose response.

While the FDA first approved an injectable form of naloxone in 1971, the first nasal spray product, Narcan, only became available in 2015. As a result, public health messaging only began to target lay responders within the last decade. Even many harm-reduction groups and first responders trained to administer naloxone via intramuscular or intravenous injection did not have the medication.

“For many, many years, naloxone was not available, and lay responders — and many times drug users themselves, or EMS — were responding without naloxone,” she said. “The tool that they were using, predominantly, was oxygen. We sometimes forget that piece of the overdose story: That there was a time when naloxone wasn’t available, but it was still possible to survive an overdose.”

It is only in the last decade, she said, that the focus shifted to naloxone.

“Oxygen was really forgotten in that strategy,” she said, “and really de-emphasized in a way that now, we’re playing catch-up.”

STAT’s coverage of chronic health issues is supported by a grant from Bloomberg Philanthropies. Our financial supporters are not involved in any decisions about our journalism.

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