What's Best for Treating Patients Who Are on Xylazine or 'Tranq'?

This discussion was recorded on December 12, 2022. This transcript has been edited for clarity.

Robert D. Glatter, MD: Welcome. I'm Dr Robert Glatter, medical advisor for Medscape Emergency Medicine. Joining me today to discuss the growing epidemic and abuse of the sedative xylazine (street name, Tranq), along with its unique skin findings, is Dr Joseph D'Orazio, an associate professor of emergency medicine at Temple University and director of the Division of Medical Toxicology and Addiction Medicine.

Welcome, Dr D'Orazio.

Joseph L. D'Orazio, MD: Thanks for having me.

Glatter: It's very important that we discuss a growing trend that's been noted, especially in Philadelphia — and you're quite aware of this — of the drug xylazine. I want to ask you, how did it come to be a drug of abuse?

D'Orazio: Well, it started mostly in Puerto Rico in the 2000s. That's our first knowledge of this drug being used recreationally. It made it to Philadelphia in as early as 2006. It's typically consumed with opioids together as a unit, like fentanyl and xylazine together. In Puerto Rico, we have some knowledge that it was used the same way, and then sometimes, people were using that drug primarily.

Glatter: What is the mechanism of action of the drug itself and what's the reason it's being cut with fentanyl and heroin? It's gotten into the United States supply pretty rapidly.

D'Orazio: Xylazine is a sedative. In all intents and purposes, it's an anesthetic. Veterinarians have used this drug for a long time to do procedures on cats, dogs, or larger animals. They've used that drug to sedate the animal for a procedure. It acts in similar ways in humans. It's a sedative that looks like a benzodiazepine to the outsider, but it works at a very different receptor. It doesn't work at the benzodiazepine receptor like other sedatives do.

This works at the central alpha 2–agonist receptor. There are other medications that are similar to this drug (eg, clonidine or dexmedetomidine) that work at the same receptor. This is a veterinary drug, and we don't have much experience in humans. This is not a drug that is produced clandestinely like fentanyl. This is a product that is coming directly from veterinary supply into our opioid supply.

Glatter: What are the signs and symptoms we see clinically of a xylazine-involved overdose?

D'Orazio: Sedation is the major thing that we are seeing. On the low end, someone who has used xylazine can be sleepy and then on the high end, they are unconscious. We are not seeing respiratory depression with this drug. Because this drug is commonly used with an opioid, it's not uncommon to have respiratory depression from the opioid that the person is using.

Glatter: Naloxone is given for any suspected opioid overdose, but in truth, it's not going to make any difference in the outcome. Do you still recommend that it be given?

D'Orazio: Absolutely. Just remember that these drugs are used in unison. We're not really seeing people who are using xylazine alone. It's always with an opioid. If you encounter somebody with an opioid overdose, giving naloxone to restore respiratory function is the most important part of all of that.

The major point here that I want to bring up is that we're so used to giving naloxone to patients who have an opioid overdose to restore their breathing, and with that, they wake up and talk to you. We're seeing a lot of sedation even after giving naloxone. It's important to titrate the naloxone to respiratory depression and hypoxia, and ensure that you restore that respiratory function, but be aware that they may not wake up and communicate with you initially, so giving supportive care in that scenario rather than giving more naloxone is the answer.

Glatter: Given that the drug obviously produces heavy sedation, is there any reversal agent that has been entertained or looked at? In the animal literature, I'm aware of a few of them, but can they be given to humans?

D'Orazio: There is no medication that is approved for xylazine reversal. There are certainly drugs out there that people have thought about or, I'm sure, have brought up. One is yohimbine. We've talked about that with clonidine reversal, but that is not recommended. Atipamezole is another drug in the veterinary literature that is used for reversal in animals, but it is not a drug used in humans, so it is not recommended.

The question I want to bring up is whether we need a reversal agent for this when supportive care is usually enough, especially in controlled, monitored settings. I would bring up the same care for how we manage patients with clonidine overdose. Naloxone has controversial use in that care. It's mostly supportive care [that is needed] to manage this, and this is what we need to do with xylazine overdose.

Glatter: I want to switch gears a little bit and talk about the skin ulcers and skin findings that have been described. Does xylazine cause these ulcers and abscesses, and in some cases, tissue necrosis, or is this more of an association? Has that been studied at this point?

D'Orazio: We don't have any studies looking directly at this, certainly not in the human literature. There are some data from animal and veterinary literature that say it does cause some skin necrosis. I think we're still trying to figure that information out. There are necrotic wounds that have been associated with its use rather than skin infection and abscess.

Certainly, that is a problem with injection drug use in general, but there's been a major increase in the skin necrosis associated with xylazine. We've got to think that there is some association with this drug. I'm not quite sure the underlying pathophysiology of why it's causing skin necrosis, but it may also have to do with a little bit of the behavior involved with using this drug too.

Glatter: I had been reading that if you smoke, snort, or swallow the drug, the incidence of these skin findings is independent of the mode of how you use the drug. Any insight on that?

D'Orazio: Most of the patients that we encounter with skin necrosis is due to injection drug use. We're seeing less patients who are snorting or smoking fentanyl and xylazine. We also hear many reports of, "I inject in one area, and I developed a wound in a separate area that I never inject in." I think that's a corollary of what you're describing, that it's not necessarily just a local effect of where that drug was injected. We have concern about that also.

If it was a systemic effect, you would think that you would develop skin ulcerations, necrotic wounds all over your body in a uniform pattern that may be symmetrical. What we mostly see are wounds on extensor surfaces, on forearms and lower extremities. I'm not quite sure I understand the underlying cause of that, but it's certainly not a wholly systemic effect.

Glatter: We're seeing amputations arising from use of xylazine. Given that peripheral vasoconstriction is one of the mechanisms of the alpha 2–adrenergic agonist, would that be some of the explanation related to the amputations?

D'Orazio: I don't think it can wholly explain the reason why people are developing these wounds. We see people with proximal wounds that develop and not necessarily in the hand or the foot. That's where you'd expect if it was just due to vasoconstriction. There's also a component of infection that develops. After you've developed this necrotic, chronic wound, oftentimes it gets infected and that's the secondary hit that leads to patients with a necrotic limb that requires amputation.

We see all sorts of injuries, infections, and wounds. Sometimes we see patients who have necrotic fingers, but that doesn't necessarily directly correlate to xylazine use. Sometimes that's like an injection into the artery (eg, radial artery), and then you lose three fingers. You may have a wound on the dorsum of your hand that develops and causes deep infection that requires a hand amputation. We're also seeing forearm or lower extremity wounds that's more proximal that develop and become so severe you lose function distally, and then that requires an amputation when it's severe.

Glatter: Is it causing any organ ischemia, splenic infarcts, or mesenteric ischemia? Any issues in that capacity? Are you aware of that?

D'Orazio: No, we haven't seen anything like that. We do see patients who come in after significant hypoxic injury from opioid overdose that's associated (eg, toxic brain injury, cardiomyopathy, acute lung injury, acute kidney injury). I would assume that's more related to the opioid overdose rather than xylazine use.

Glatter: There's no current way to test for xylazine that I'm aware of. Is there anything in the pipeline or anything on the horizon that you've seen?

D'Orazio: There certainly is a way to test for xylazine. I can't say it's effective for bedside management. They're mostly through forensic labs, and they're sent out to a lab that's typically doing more higher-end techniques that'll take sometimes days. It doesn't really help you at the bedside.

There is talk about a point-of-care test coming out in the very near future. Hopefully, that's going to be available to us as an immunoassay, as a point-of-care test for harm reduction for the community of people who are injecting drugs.

Glatter: According to a recent article, in 2021, up to 90% of fentanyl and heroin samples were contaminated with xylazine, making this really problematic. If you had a test strip similar to a fentanyl test strip, it would be very helpful for anyone who is injecting or using fentanyl or heroin.

D'Orazio: I think in communities where they're rarely encountering xylazine, it would be helpful to steer away from it. Certainly, in my community in Philadelphia, where all the bags of opioids contain fentanyl, fentanyl testing really isn't so helpful anymore because all the bags have fentanyl in it.

We're at that stage where almost all the bags have xylazine in it, so it's not really so helpful. Communities that are seeing it here and there can test for it, and then you can have an informed decision whether you're going to use that dose.

Glatter: The half-life, I believe, is about 25-50 minutes, so testing could be problematic.

I wanted to move into to the issue of withdrawal from xylazine for frequent users. That's been written about as well. Have you experienced that clinically, in terms of taking care of patients, seeing this type of withdrawal?

D'Orazio: Yeah, we see that often. There really isn't much information. You certainly can't find it in a textbook. We have some corollaries to help us define it when we're looking at clonidine and dexmedetomidine. We do see a significant portion of that. It's unlike benzodiazepines, where we don't see a lot of tachycardia, hypertension, diaphoresis, and seizures that you would expect from other sedative hypnotics or even alcohol.

It does cause a significant anxiety reaction with dysphoria and restlessness. It's difficult because those are two symptoms that overlap with opioid withdrawal. What we have seen is that even if the opioid withdrawals are managed well, the patients are left with this restlessness, anxiety, and dysphoria and it can be very difficult.

Many patients will report that, and many providers don't know about xylazine withdrawal, and so it gets undertreated. That has led to patients avoiding hospitals and inpatient drug rehabs because of their fear of xylazine withdrawal.

Glatter: It's an important point you raise that it should be on all clinicians' radar, especially when a patient comes in with hypotension, bradycardia, or cardiac conduction disturbances. At least consider this as an adulterant in someone who presents with an opioid overdose.

D'Orazio: There's really no drug that has been identified as the standard drug to use in this scenario. Giving back medication that works at that receptor would make sense. What we're seeing is that xylazine is used in a degree of magnitude higher than any of our other alpha 2–centrally acting agonists.

Providing too much clonidine can cause some bradycardia and hypotension. We're never able to give enough of our pharmaceutical drugs that work at that receptor to suffice the dependance or the withdrawal, so we need to use other medications. We have relied on using supportive care medications like benzodiazepines to manage most of the xylazine withdrawal.

Glatter: Would you be able to give us a few pearls to take away in terms of xylazine management and give clinicians an overall picture of what they should really be focusing on?

D'Orazio: If you are encountering a patient who is using fentanyl and xylazine or is suspected to be using xylazine with their fentanyl, remember to expect that providing naloxone may restore respiratory function, but may not necessarily restore their mental status. Providing more naloxone may not necessarily reverse that because naloxone doesn't work at the alpha 2–agonist receptor.

We see many wounds, so we need to ensure that we're addressing wounds. It's also important to consider withdrawal for the inpatient side, so we should be providing benzodiazepines as supportive care to manage xylazine withdrawal.

Glatter: I appreciate your time. This is very helpful for clinicians at the bedside, especially in the emergency department. Thank you again.

D'Orazio: Thanks for having me.

Robert D. Glatter, MD, is assistant professor of emergency medicine at Lenox Hill Hospital in New York City and at Zucker School of Medicine at Hofstra/Northwell in Hempstead, New York. He is an editorial advisor and hosts the Hot Topics in EM series on Medscape. He is also a medical contributor for Forbes.

Joseph L. D'Orazio, MD, is an associate professor of clinical emergency medicine at the Lewis Katz School of Medicine at Temple University in Philadelphia, Pennsylvania. He recently appeared on ABC News and NBC News to provide his perspective on xylazine, which is also known as "Tranq."

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