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It's been about 3 years since Joseph D'Orazio, MD, and his colleagues at Temple University Hospital in Philadelphia first noticed something different among injection drug users who came to the hospital.

Some patients who overdosed responded differently to the rescue agent naloxone (Narcan), and then there were the wounds -- severe wounds that required extensive treatment, and sometimes, amputation.

That wasn't something they'd seen before in the ongoing opioid crisis.

They learned that a veterinary sedative called xylazine was increasingly being added to fentanyl, the predominant opioid in the area, to boost its effects and extend its high.

"That's where we're feeling it the most, with these really severe wounds," D'Orazio told 麻豆传媒. "We've been doing a lot more amputations over the last couple of years for really bad necrotic wounds and dysfunctional limbs and infections that go all the way down to the bone."

Philadelphia has been flagged as the epicenter of the xylazine crisis, which is now prevalent throughout the northeast and has started to show up in cities across the U.S. The problem is popping up on regulators' radars. In the past few months, several federal agencies, , the (ONDCP), and the have released statements about the growing problem.

"Xylazine is making the opioid crisis worse," said Andrew Kolodny, MD, an expert in opioid policy and addiction medicine at Brandeis University in Waltham, Massachusetts. "It's hard to imagine anything could make the opioid crisis even worse. But this really is making it worse, both in increased mortality and in people becoming addicted to xylazine as well as opioids."

What Is Xylazine?

Xylazine was never intended for use in humans, according to Kelly Ramsey, MD, MPH, chief of medical services at the New York State Office of Addiction Services and Supports in Albany.

"It was actually studied by a pharmaceutical company in the 1960s as a potential medication for hypertension in humans, but because of the severe central nervous system sedation, it was deemed not appropriate for human use ... but it was approved by the FDA as a veterinary medication," Ramsey, a member of the American Society of Addiction Medicine board of directors who was speaking for herself, said in a phone interview. "It's used most typically as an anesthetic and a sedative for procedures for both large and small animals."

Xylazine is an alpha-2 agonist that would be most comparable to dexmedetomidine (Precedex), a sedative used in the intensive care unit, said Lewis Nelson, MD, a medical toxicologist and chair of emergency medicine at Rutgers New Jersey Medical School in New Brunswick. Another comparable medicine, he said, is clonidine (Catapres).

Xylazine is added to fentanyl to make its effects last longer, said Chelsea Shover, PhD, of the University of California Los Angeles, who co-authored on xylazine's spread across the U.S.

"Fentanyl is very strong, but it's also very short-acting," Shover told 麻豆传媒. "If someone has a fentanyl use disorder, they have to use frequently to stay well. That's difficult with illicit drugs. Lots of people in that situation don't have a lot of money ... so if something shows up on the market that can extend the high, there becomes a demand for that."

It's not clear exactly how xylazine found its way into the street drug market, but Shover notes that ethnographic studies first called attention to the problem in Puerto Rico in the mid-2000s.

"We have a significant Puerto Rican population here in Philadelphia," particularly in the Kensington neighborhood where xylazine use is prevalent, D'Orazio said. "But Philadelphia isn't the only place that has people who immigrated from Puerto Rico."

A senior Biden administration official told 麻豆传媒 that the earliest report of xylazine was "in the early 2000s. ... The rise in the U.S. where it was used as an adulterant of fentanyl started in the mid-20-teens, with a real increase in 2019."

A issued in December by the Drug Enforcement Administration (DEA) and the Department of Justice noted that according to findings from the DEA's lab system between 2020 and 2021, although the xylazine problem is most prominent in the Northeast, "each of the four regions [Northeast, South, Midwest, and West] has seen an increase in identifications of xylazine. The South has the largest increase, reporting a 193% increase in xylazine instances, followed by the West with an almost 112% increase."

What is clear is that the xylazine on the streets is not illicit. It's pharmaceutical-grade, and it's being diverted, doctors said.

"This isn't clandestine production of a drug," D'Orazio said. "This is a pharmaceutical. They're finding empty bottles of pharmaceutical-grade xylazine at packaging areas, where dealers are bagging [drugs]."

Narcan Still Works

One of the problems with xylazine is that it brings on profound sedation that "knocks you out for a long time," Shover said.

"If you're out in a public place, that leaves you vulnerable to physical or sexual assault or robbery," she said. "You're not aware of what's going on around you and you're not able to protect yourself."

Being passed out for hours could also lead to other conditions such as deep vein thrombosis or compartment syndrome, Ramsey said.

The opioid overdose reversal agent naloxone may appear to be ineffective in someone who has overdosed with both fentanyl and xylazine in their system, but it's actually not, several sources said.

When trying to reverse these patients with naloxone, "they've remained really sleepy and many have been deemed Narcan-resistant, but really it's just a polysubstance overdose since they're on a sedative also," D'Orazio said. "Xylazine doesn't reverse with Narcan so they remain sedate."

While xylazine doesn't cause respiratory depression, he said, it causes mental status depression, which can lead to a blunted response to the hypoxia that comes with an overdose.

"It's like you have an occluded airway," he said. "It's sort of the same as how a benzodiazepine overdose would look."

For bystanders who administer naloxone, that means if breathing returns but patients aren't awake, they should be placed on their side in the recovery position.

In hospitals, physicians will do some airway maneuvers for these patients, such as putting their head to the bed at 30 degrees, keeping their airways open, and monitoring oxygen levels via a pulse oximeter.

Only rarely do these cases require intubation and ventilation, D'Orazio said.

He also noted that xylazine has a withdrawal profile that's different from other sedatives, like alcohol or benzodiazepines. Instead of primary effects such as increased heart rate, sweating, confusion, or seizures, xylazine withdrawal "has primarily been anxiety-associated. People are very restless and uncomfortable. They feel dysphoric, and it's quite difficult to manage," D'Orazio said.

"Just recognizing that there is a xylazine withdrawal syndrome is number one," he added.

While an optimal treatment strategy for xylazine withdrawal remains to be developed, he said, he usually recommends using benzodiazepines for detoxification.

'The Wounds Are Much More Severe'

D'Orazio said the wounds he and his colleagues are seeing with xylazine use are different from anything they've witnessed with injection drug use in the past.

"There's always been the risk of an abscess or cellulitis that leads to a wound that takes some time to heal, but this is very different," he told 麻豆传媒. "With xylazine, the wounds are much more severe, much deeper, and much harder to manage."

He said his hospital has done more amputations over the last couple of years, as not all injuries can be managed with wound care therapy.

There are no data on what percentage of those who use fentanyl adulterated with xylazine develop these severe wounds, but D'Orazio said that "most patients have at least some wounds to some degree. It may not be so severe that they need to be hospitalized, but they've got some degree of wounds."

However, clinicians don't see such wounds with people who smoke or use fentanyl intranasally, he said, so it's not clear exactly why xylazine seems to cause these wounds.

"There's a lot of speculation that it's cytotoxic," D'Orazio said, noting that more research is needed, as only animal studies exist. Indeed, there are some reports that repeated use in animals causes lesions, "so it was typically recommended that if you had to sedate that animal multiple times, don't use xylazine in a chronic fashion," he said.

Nelson noted, however, that there's a lot of xylazine in the drug supply in New Jersey, but that state hasn't seen as much of a problem with severe wounds. Philadelphia may have a larger proportion of injection drug users, he said.

It's possible that xylazine may cause wounds via its activity as a vasoconstrictor, reducing blood flow to the area, Nelson said.

Fears of unmanageable withdrawal could also play a role in wound development, D'Orazio said. Since withdrawal is harder to treat, people worry they'll get sick, and avoid coming to the hospital, he said. Wounds may be more severe because of that delay, he noted.

One of the downstream effects of wounds is that people can't get into inpatient rehabilitation programs, as many don't take complex medical cases, D'Orazio said. Wounds also prevent people from getting into sober living facilities for the same reason, he said.

"It has really cut off people who are looking to achieve recovery," he said.

Better Tracking Needed

It's hard to tell exactly how widespread xylazine use is in the U.S., since there's no national tracking of the compound. The DEA report notes that "a comprehensive count of xylazine-positive overdose deaths in the United States is not currently possible, as not all jurisdictions routinely conduct testing for xylazine in postmortem toxicology. Testing procedures can vary even within the same state. In addition, it is not currently included with the CDC's reporting of national statistics on fatal overdoses. As a result, it is very likely the prevalence of xylazine is widely underestimated."

"It's not part of drug use surveys," Shover said. "It's not a variable you can pull from publicly available data, like you can for, say, cocaine or heroin."

The CDC did not return a 麻豆传媒 request for comment regarding xylazine monitoring. However, the agency has published two studies on xylazine in its journal Morbidity and Mortality Weekly Report in recent years.

In 2021, from the State Unintentional Drug Overdose Reporting System in 38 states and Washington, D.C. Of 45,676 overdose deaths in 2019, 1.8% were xylazine-positive and 1.2% were xylazine-involved. The authors concluded that xylazine detection in overdose deaths is likely under-reported.

, researchers reported that Cook County, Illinois, saw a total of 210 xylazine-associated deaths from January 2017 to October 2021, with the numbers rising throughout the study period. As with the other study, fentanyl was present in the vast majority of xylazine-involved deaths, the team found.

Ramsey said more than 90% of fentanyl samples in Philadelphia in 2021 were found to contain xylazine. Nelson said the figure stood at 30% in New Jersey a year ago, and has likely grown since. New York City recently announced that nearly 20% of opioid-involved overdose deaths also involved xylazine.

"It's difficult to get even just like, within the last couple months, a picture of what's happening with xylazine in the U.S.," Shover said.

The ONDCP discussed xylazine last month at a meeting of its evolving and emerging threats committee. "It is critical to continually assess changes in the illicit drug market to guide our approach to new threats like Xylazine," ONDCP director Rahul Gupta, MD, said in a statement emailed to 麻豆传媒. "This includes evaluating existing data on trends and emerging patterns of use, listening to people and experts on the ground, utilizing the Emerging Threats process outlined by Congress in the SUPPORT Act, and ensuring that our response is protecting the people of the United States."

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