CATR: Give us an overview of xylazine.
Dr. D’Orazio: Xylazine is a central alpha-2 adrenergic agonist first reported in the illicit drug supply in the 1990s in Puerto Rico. It made its way to the mainland US in 2006, and since 2016 it has become increasingly prevalent in the opioid supply. Philadelphia is where it is most prevalent—now detected in over 90% of the bags taken off the streets (www.tinyurl.com/4hxue8nf). 

CATR: Is xylazine being sold on its own?
Dr. D’Orazio: We’re primarily seeing it with fentanyl. Clinicians in this area may know of a few patients using just xylazine, but that’s rare. In fact, most people are trying to avoid it. They’re looking for opioids but can’t find a supply without xylazine in it.

CATR: If people are trying to avoid it, why is xylazine being introduced into the drug supply at all?
Dr. D’Orazio: We can only speculate about that. But our patients tell us that using opioids with xylazine keeps them sedated longer—even after the opioid effects have worn off. People report using a bag and then waking up many hours later already in opioid withdrawal. Over time, repeated exposure creates a xylazine dependence. So really, people become dependent on two drugs—opioids and xylazine. 

CATR: What are the other effects of xylazine?
Dr. D’Orazio: Clinically, it presents as a sedative hypnotic. As an alpha-2 agonist, it activates a negative feedback loop that prevents outflow of catecholamines. Catecholamines promote alertness, so blocking that outflow produces the opposite effect: sedation. But there is some confusion and misinformation that I think comes from people extrapolating from familiar alpha-2 agonists like clonidine and dexmedetomidine. These drugs are imidazolines, but xylazine is a pure alpha-2 agonist. We don’t really see the bradycardia and hypotension with xylazine like we see with the imidazolines. 

CATR: Can you talk about the association of xylazine exposure with peripheral wounds? 
Dr. D’Orazio: Certainly. Injection drug use has always been associated with wounds, but xylazine wounds are something completely different. These are not wounds that develop simply from an infection at a break in the skin. Many of the patients who present with wounds are engaging with injection drug use, but not all of them. The wounds themselves mostly occur on extensor surfaces of the forearms and legs at sites where people are injecting, though not exclusively. 

CATR: What do we understand about the formation of these wounds?
Dr. D’Orazio: We don’t have many data, but there are ideas (D’Orazio J et al, Annals of Int Med 2023;176(10):1370–1376). Some have postulated that xylazine has direct cytotoxic effects that interrupt the integrity of tissues, leading to wounds. Others have pointed to the vasoconstrictive effects of xylazine. This, coupled with mechanical compression in people who are unconscious for long periods of time, could result in local hypoxia–related injury. There may even be other compounds that go along with xylazine, ones that we haven’t identified yet contribute to wounds. One interesting observation is that the wounds don’t occur in areas of the body that are hard to reach. So we think there’s something happening locally that might promote wound formation. But overall, we don’t have a full understanding of the pathophysiology.

CATR: There are reports that wounds don’t always form at the site of injection but instead can form in other areas of the body.
Dr. D’Orazio: I think that’s still up for debate. Anecdotally, I’ve had patients tell me they don’t inject at a site where a wound developed. But I would say most develop at or near an injection site. It can be confusing because I think some wounds are misidentified—not every wound is due to xylazine. Often a wound from a simple ruptured abscess is misattributed as a xylazine-associated wound. It can be difficult to tell the difference between the two without the relevant history. 

CATR: What are xylazine wounds like?
Dr. D’Orazio: One distinguishing feature is their necrotic nature. They sometimes start as a small lesion that will continue to grow, particularly if someone continues to inject in that area. And even if they start small, they can become quite severe and expansive, encompassing an entire forearm, for example. Not only do the wounds spread laterally across the skin surface, but they go deep as well. There can be tendon involvement, sometimes leading to the loss of a tendon and a completely dysfunctional hand. The infection can go to the bone and cause osteomyelitis.

CATR: What’s your clinical approach to the treatment of xylazine wounds?
Dr. D’Orazio: Very little research has been done about how to treat these wounds specifically. So, we have to generalize our approach from general principles of wound management. First is removal of the cause of the wound. We’ve found that this doesn’t necessarily mean the total removal of drug exposure, though that would be ideal. In fact, the worst thing we see is patients injecting into wounds. From a harm reduction standpoint, we sometimes advise patients to snort or smoke rather than inject if abstinence is not possible. If the patient is not ready to do that, we recommend that they rotate injection sites.

CATR: Is it common to inject into wounds? Why would a patient do that?
Dr. D’Orazio: It’s more common than you might think, and something we should advise patients to avoid. Finding veins to inject into can be challenging as substance use disorder (SUD) progresses. Wound beds are highly vascularized, so a wound can serve as a second-best site for injection. And if the wound is through the dermal layer, injections would be rather painless. And patients may also want to prevent further wound development, so their logic goes, “I already have a wound here. If I inject someplace else, then I’ll just create a second wound.”

CATR: What are other important treatment considerations?
Dr. D’Orazio: Next comes conservative wound care management. Keep it clean with soap and water, something mild. Silver sulfadiazine is a great topical antimicrobial that can be applied on top of a cleaned wound. If that isn’t available, patients could use a petroleum-based antimicrobial ointment, like over-the-counter triple antibiotic. Even something as simple as Vaseline can be used to hold in moisture, preventing scabbing over, which harbors bacteria. And then we recommend keeping it covered with a nonadherent dressing. Using something like gauze can be counterproductive because the dressing can adhere to the wound as it dries out. Removing the dressing will then be super painful, can cause tissue damage, and will discourage the patient from keeping up with wound care. So it’s very important to use nonadherent dressings, like Vaseline gauze, Adaptic, or Xeroform. Once that’s on top of the wound, patients can use an ACE wrap or Cobans to keep the dressing in place.

CATR: And when should we refer patients to a specialist who can treat these wounds?
Dr. D’Orazio: It’s an important question, but not one with a straightforward answer. Before answering the question of when to refer patients, we need to step back and ask whom we should be referring them to. Xylazine wounds are a relatively new phenomenon. It’s not clear who “owns” treatment of xylazine wounds. Dermatology? Plastic surgery? Vascular surgery? Even if we manage to refer these patients to a specialist, patients often feel stigmatized in these settings. Many won’t engage. So I am a strong advocate for co-locating addiction treatment and wound care whenever possible. And conservative wound care management is often sufficient. Cleaning the wound with soap and water, putting on ointment, applying a dressing, and not injecting into it is all the body needs to heal. Over and over, we’ve seen patients with severe wounds down to the bone who are able to close those wounds with just conservative management. It may take three to six months, but it doesn’t require anything groundbreaking or aggressive.

CATR: Are there signs to be wary of that indicate conservative management is insufficient?
Dr. D’Orazio: Referral to an emergency room is only necessary if there is concern for a deep space infection such as necrotizing fasciitis or a deep abscess. This will present as a rapid increase in pain or swelling. Signs of sepsis are also concerning because it indicates that an infection might no longer be localized to the wound but instead is becoming systemic. Presence of tachycardia, hypotension, or fever should point you in that direction and lead to an emergency department referral. I should say, though, that most of the wounds I see aren’t infected. A border of erythema is common and not concerning. Superficial bacterial growth, called slough, is common as well and not something that needs emergency treatment. Again, simple wound care with the steps I already outlined is sufficient in most cases. Implementing these practices in typical outpatient spaces where we treat SUD can do immense good.

CATR: What advice or education do you give patients regarding xylazine wounds? 
Dr. D’Orazio: Cessation of injection into the wound is number one. We discuss harm reduction strategies of switching the route of administration away from injection. We talk about rotating injection sites. We review basic wound care. And we talk to them about engaging with recovery. Ultimately, the best outcomes are going to be when these patients can be put on a medication for opioid use disorder (MOUD).

CATR: How does the presence of xylazine affect the process of starting MOUD?
Dr. D’Orazio: Remember, xylazine isn’t an opioid, so its presence shouldn’t increase the risk of precipitating opioid withdrawal with a dose of buprenorphine. On the other hand, it can be harder to get patients comfortable early in the induction process. 

CATR: And that’s because patients experience xylazine withdrawal? 
Dr. D’Orazio: That is the thought, yes, though we don’t have good evidence here. Our patients describe what appears to be more intense anxiety, restlessness, and dysphoria. But, of course, these are symptoms associated with opioid withdrawal as well. Could these symptoms be due to high doses of fentanyl or to a separate opioid withdrawal process? We don’t know for sure. But, at least in our experience, it can be more difficult to get patients comfortable when xylazine is in the picture. 

CATR: Does giving clonidine help?
Dr. D’Orazio: That approach makes sense on a receptor level, but practically, the level of alpha-2 agonism that patients are exposing themselves to with xylazine is usually much higher than anything we could approach with typical clonidine doses. We run the risk of bradycardia and hypotension with clonidine before achieving any meaningful clinical effect. So, our ­approach has been to also target other receptor systems, hopefully ones that the patient has not developed as much tolerance to. Gabapentin is another medication we use as a standard. In the hospital, benzodiazepines can be useful as an adjunct to withdrawal management, though there does appear to be some level of cross-tolerance, and we find that these patients require quite high doses. 

CATR: And otherwise, the approach to buprenorphine induction or starting methadone is the same? 
Dr. D’Orazio: Yes. I am a proponent of low-dose buprenorphine induction, which is just better tolerated than the traditional approach in the era of fentanyl. My own observation is that it works better with the population that I am treating here in Philadelphia. But there is a lot of heterogeneity. A bag of “dope” in Philadelphia is going to be different than Boston, Chicago, or San Francisco, and that is going to affect what induction approaches work best. That’s why I’m an advocate for local toxicosurveillance.

CATR: What do we know about the geographic distribution of xylazine? 
Dr. D’Orazio: It has been detected in most places in the US, though the prevalence is not well known and almost certainly varies widely by location. Philadelphia is the leading edge. Fortunately, we have access to one of the few labs that can test for xylazine and its metabolite, and here in Camden we are seeing >94% xylazine positivity in our patients who are positive for fentanyl. Interestingly, like fentanyl, xylazine has a short half-life, but it can remain positive in people who are exposed regularly. So, most of our patients who are positive for fentanyl are also positive for xylazine, if their last use was weeks ago.

CATR: What is your approach to drug testing with xylazine test strips?
Dr. D’Orazio: It can be an effective strategy, but it depends on the local prevalence. Remember, strips only tell you if the drug is present; they don’t give any information about the quantity of the drug. So, in a community where nearly all opioids contain xylazine, the strips aren’t very useful. However, if the prevalence is lower, then someone can test their supply, see if xylazine is present, and choose to discard the drug if it’s present. 

CATR: And finally, how can clinicians stay up to date?
Dr. D’Orazio: Unfortunately, we don’t have a good up-to-date database for toxicosurveillance. Many communities have local surveillance organizations or public health departments that issue reports, so I encourage people to look into what is available. I follow reports from the Center for Forensic Science Research and Education (www.cfsre.org), which provides really good information. We need to realize that the drug supply is always changing, so our information will always be out of date to some extent. I see a lot of static protocols. Instead, we need to listen to our patients, remain flexible, and adapt our practice to what they are experiencing. 

CATR: Thank you for your time, Dr. D’Orazio.