So, good morning again, everybody. It's great to be here with you all this morning. Thanks for joining us. My name is Chelsea Kimura. I serve on the indigenous communities response team as a technology transfer specialist. My colleague Emily Mossberg is on the call with us as well today. And before I introduce our presenter for today, I'd like to share just a little bit more about the opioid response network with you all. Can we go to the next slide, please? The opioid response network is funded by SAMHSA to provide free training and consultation to communities across the country. The ORN can assist with requests related to opioid and stimulant use prevention, treatment, recovery, and harm reduction. Next slide, please. And this is just notice that this presentation today is grant funded by SAMHSA. Next slide. The approach of the ORN is to build on existing efforts, enhance, refine, and fill in gaps when needed while avoiding duplication and not recreating the wheel. Next slide, please. The ORN has a pool of about 300 consultants that we use to help provide expertise to our requesters. And that is why we are here with you all today. Sydney did submit an ORN request to us and we've been working with her to get this free training set up for your team. So now it is with much gratitude that I introduce our ORN consultant, Dr. Melody Isgro. Dr. Isgro is board certified in both addiction medicine and emergency medicine. She completed addiction fellowships with the Addiction Institute of New York and the San Diego VA and UCSD health care systems. Currently, she works for a tribal health organization and runs the MAT program at their outpatient treatment center in Anchorage, Alaska. We will be taking questions in the chat today, so please do add your questions there and Dr. Isgro will make sure that she answers them at the end of the session today. And with that, I will turn it over to you, Dr. Isgro, for whenever you're ready. Great, thank you so much, Chelsea. Well, as Chelsea mentioned this morning, we are going to do a deep dive into looking at xylosine and hopefully get you some good information so that you can both educate your patients on this dangerous substance that has entered our drug supply and also be able to give good care with information that I provide. I have nothing to disclose and we'll dive right in. So the agenda today is really to start off talking about what xylosine is, where it came from, why and how it's being used in the current drug supply. Also, the fact that you can get both a dependence and an addiction to xylosine and with that comes certain withdrawal symptoms that you can also get, how those withdrawal symptoms can be treated. We'll talk a little bit about the unique wounds and also the wound care that we need to be aware of with xylosine use, and then we'll end with some harm reduction tips. And to start off, you can see that there's a bottle there of xylosine on the side. That is standard how it usually comes when it's ordered through veterinary medicine supplies. And we'll go over that a little bit later, but that's one example of how it can come when you order it. So first of all, what is xylosine? It is an alpha-2 receptor agonist, an alpha-2 agonist. What does this mean? Basically, it inhibits presynaptic norepinephrine release. It really decreases the sympathetic response in your body. So if you think of the sympathetic response as sort of your fight or flight response, what these receptor agonists do is that they sort of dampen that down. So clinically, what this looks like is people can get sedated. These are often why these alpha-2 agonists are used as a sedative type of medications. With enough of a dose, you can actually lose consciousness, develop amnesia. Certainly, they can provide muscle relaxation, analgesia, euphoria at high doses. And they also tend to lower your body temperature, blood pressure, heart rate, and respiratory rate. So again, dampening that sympathetic response. Now, we already use various alpha-2 agonists in medicine today, and these are used to treat hypertension, ADD, ADHD, both pain and anxiety disorders, and also symptoms of any type of sedative withdrawal, such as for opioids, benzos, or alcohol withdrawal. So some of the alpha-2 agonists that we use today include clonidine, which you may be aware of, both used as an antihypertensive and also used in opioid withdrawal, tizanidine, which is a really popular muscle relaxant, dexmedetomidine, which is used a lot in procedural sedation, especially for kids, and guanfacine, which again is another antihypertensive. So again, we do use alpha-2 agonists today, just not xylosine. So xylosine was first synthesized in 1962 by Bayer, but really, unlike some of the other alpha-2 agonists that we do use, xylosine had pretty severe CNS depressant effects, and really notably, quite a bit of hypotension. So therefore, the FDA decided that it was not safe for human use. But about a decade later, in 1972, the FDA did approve it for use in veterinary medicine. And that's with large animals like horses, cattle, and deer, where it can be used as an anesthetic, an analgesic, a sedative, and also a muscle relaxant. Lily comes as a liquid solution for injection. We saw that bottle on the previous slide. It can come in different strengths, like 20 milligrams per ml, 100 milligrams per ml, and 300 milligrams ml. And it can both come in that multi-dose vial that we saw in the previous picture, or also in single preloaded syringes that are usually gauged by the appropriate weight of the species that they're trying to use it for. But in humans, toxicity can occur at dosages anywhere between 40 milligrams and 2,400 milligrams. And so you can see that those are fairly, you know, at least it starts at a fairly low dosage, where it wouldn't take much xylosine to really have even a toxic effect in humans. Again, it's legitimately sold through various pharmaceutical distributors, and also internet sites that cater to veterinarians. The problem, though, is that really it can easily also be bought from all kinds of internet sites without any association to the veterinary profession or any need to prove the legitimacy of its use. And on the internet, you can buy it in that liquid form, but also in an already pre-made powder form as well. And this can be very cheap. So a kilo of xylosine powder purchased online can be anywhere between $6 to $20 per kilo. So again, can be bought very cheaply. And at this low price, it is very easy for drug traffickers to use it as an adulterant to kind of bulk up their dope product and increase their profits. So again, I talked about how it's typically, you know, sold as a liquid, but even the liquid solution can be salted or dried into a powder. So you can either buy the powder directly or then again change the liquid solution to that powder to then add to a powder drug supply. When it's added illicitly to, let's say, your heroin or these days more so your fentanyl, it can appear like normal. It can look just like the normal heroin or fentanyl can look like, but some people also say it changes it a little bit to more of a brownish color, a little bit more flakier, sometimes has a little bit of a different taste, you know, per users. However, most commonly in our drug supply, it is found in combination with either powder, heroin, or again, most commonly these days with fentanyl. Although sometimes you can find it mixed with stimulants as well. And the known routes of administration are pretty much all the ways that you would normally use the fentanyl products. So IV, IM, IN, inhaled and orally. Now the thing about xylosine, it has a very rapid onset, really within minutes. And this is what you want in something that, you know, if you're using it, for example, in sedating animals for procedures, you want it to kind of work very quickly. It reaches its full effect, though, in about 30 to 45 minutes. So it is definitely ramping up until that time. Now, this is the very opposite of fentanyl. So fentanyl, you're getting a full effect fairly quickly, but then after about 30 to 45 minutes, the fentanyl effect is going down. So as the fentanyl effect is going down, when these two are combined, that's when the xylosine effect is going up. And so, therefore, it sort of stretches out that sedation or that sort of euphoria that people get. And that's why they like it sometimes when it's combined. The effect of xylosine can actually last upwards of eight hours, depending on how it's taken and the way it's taken and how it's mixed. But it can have, again, a very long effect. So there's a lot of street names that you may have already heard of through the news or other places for this xylosine. It can be called Trank, Sleep Cut, Zombie Drug. Sometimes it's referred to as its brand name. So you can see on the right-hand side in that picture there, a bottle, a used bottle that says Anacid, which is the brand name. So sometimes it's referred to as Anacid. Rompun is another brand name. Cetazine, another brand name. It's also been referred to as a horse tranquilizer or Anastasia de Caballo, which is Spanish for horse tranquilizer, mostly because, again, that's how it's been used in the past. It's currently used in the veterinary system as a horse or other large animal sedative. Specifically, when it's combined with fentanyl, sometimes it's referred to as Trank Fent, Trank Dope, or Philly Dope. And Philly Dope because it references where it sort of got its foothold in the United States in Philadelphia. Now, federally, it's not currently listed as a controlled substance at all. If it was, then it would allow the DEA to more fully regulate it. But it's not currently, so the DEA doesn't really have a lot of authority to do anything regarding xylosine. But that's certainly being considered by the federal government at this time. There is some oversight under the Federal Food, Drug, and Cosmetic Act. That is where it resides right now. Having said that, several states have decided to, you know, that it's a very, you know, it's come up into the drug supply. They've decided to list it as a controlled substance on their own state-controlled websites. So, for example, Ohio has it listed as a Schedule 3. Pennsylvania has a Schedule 3. New York is in the process of scheduling it as a 3. West Virginia has it listed as a Schedule 4. And Florida just has it listed as on their scheduled controlled substance list. And regardless of that, right now, because it has been quite a problem in so many places, the federal and state public, you know, entities have put out many safety alerts to kind of alert their constituents about what it is and what the concerns are. So, for example, the Biden-Harris administration did designate fentanyl combined with xylosine as an emerging threat to the United States in April of this year. And what that did was it allowed there to be sort of an action response to be set up. And those things that included authorizing more testing, more data collection, more research into doing prevention, harm reduction, and treatment. Research into trying to have supply reduction. Research into possibly scheduling it. And then also, you know, just authorizing more research to be done in general. And then similarly, the states. Some states have put out some informational brochures for their constituents. This one came from the University of Pittsburgh where it talks about xylosine and just puts it in more layman's terms, what it is, what it does, how to prevent overdose. And then also talks about the wounds and also talks about self-care for wounds when they develop. So, again, both federal and state entities trying to get the word out to their constituents. Now, where did xylosine come from? Well, you know, again, it's been used legally for some time now, but really started to enter the human drug supply, we think, in Puerto Rico in the 2000s, in the early 2000s. In the beginning, what we've heard is that it was gifted with heroin. They were still, you know, selling the heroin, but they were just giving it for free, a little side packet of the xylosine for their users to try out and see if they liked it. And what they found is that, again, because people were finding that it extended that kind of high of the heroin at the time, that they liked it, there was increasing demand for it. So over time, it became an additive. And then, again, they found that they could bulk up and kind of spread out their product more. And so it became an adulterant as well. And for a few number of people, it also became a drug of abuse on its own. They would actually sell the xylosine by itself as well. And what they found that patients who, or users who tended to want the xylosine tended to be the higher risk injection behaviors, mostly because those had a quicker onset and a quicker offset, so they were finding more benefit from using the xylosine. It was the Puerto Rican public health department that first made the link between xylosine use and increasing overdose rates due to that respiratory depression of that combined xylosine and fentanyl use that we've all heard about now. And they also made that link between all these novel types of soft tissue infections that we've seen in both the news and in different storylines. Now, unfortunately, what happens in Puerto Rico, I didn't stay in Puerto Rico. In the 2010s, what happened is that there was a lot of migration over time of Puerto Ricans to inner city communities in Philadelphia. That's just where a lot of them had initially come. And then there would continue to be sort of people continue to come to that same area. And so this knowledge about this, you know, this very powerful adulterant and at that time enhancer of heroin back in Puerto Rico started to hit the streets and there started to create some demand for this to also be sold there in Philadelphia. So it actually turned up as early as 2006 in various overdose reports in Philadelphia. So again, starting to wreak its havoc as early as that time, but really didn't start to take a strong foothold until the mid 2010s. So, you know, almost a decade ago. And it started to become increasingly prevalent in Philadelphia as the hotspot, but then spreading out through that Rust Belt region. And then the last few years, really, as the opioid supply on the East Coast has changed, you know, over from heroin to pretty much fentanyl now, increasingly has become a mix of fentanyl and xylosine. And also, you know, we also know that cocaine is now changing over to Mexican meth that's now entering that area as well. So really the supply has changed from heroin, cocaine, really now to fentanyl, xylosine, and also meth. And drug testing in Philadelphia more recently has shown that in the local dope supply, what they're finding is about, you know, of the kind of chunk of powder or whatever you're getting there, it's about two to 10% fentanyl, about 30% xylosine, then a bunch of bulk additives and really no heroin at all. So really the drug supply chain has really changed there. And there's been some question about whether xylosine is being added in the fentanyl in Mexico before it comes over the border, or is it being added afterwards here? And what they have, they're not really sure, probably a bit of both. But one of the things they found is that when they look at drug dealers' homes or stash houses, they found these empty xylosine vials lying around. So they think that a good part of it is actually added after it already arrives here. I want to just shift for a minute and talk about U.S. overdoses in general over the past two decades. I think it's important to kind of see the overall picture. So if you remember back in the 2000s, you know, cocaine at that point in time was the leading drug that was associated with overdose deaths. I remember that was a lot in the news back then. You know, around 2007, we started with really the increasing utilization of prescription opioids and, of course, the increasing number of overdose deaths from that, you know, usually talked about as the first wave of real opioid overdoses. And then after regulations changed to try to tighten down on prescription opioids in 2014 to 2015, it kind of shifted over to heroin. And then quickly after that, we started seeing these illicitly manufactured fentanyls as rising the drug supply causing the most overdose. I would say that right now, just in the last couple of years at least, we seem to have shifted to this culture of polysubstance use. You know, I think back in the day, I remember when it was just heroin, people came in just using heroin or just even using, you know, started having just be some fentanyl. But nowadays, it just seems like people are on multiple substances. And really, although, you know, fentanyl is pretty much always seen with xylosine, what they've also found in various overdose studies is that about 45 percent of time, at least on the East Coast, has been cocaine present. Benzodiazepines in about 28 percent, heroin 23 percent, and alcohol in 20 percent. So again, this more polysubstance use is what's really contributing to overdose deaths these days. And so I think that the term opioid crisis really isn't reflecting what's going on right now. It's really more a more overdose crisis that we're having for multiple substances, predominantly led by fentanyl and now increasingly also by the combination with xylosine. Okay, back to xylosine. So, you know, why is it being used? Well, we'll talk about it from several different viewpoints. From the user's viewpoint, we talked about how, you know, as heroin, it changed over from heroin use to fentanyl use because of the drug supply. That fentanyl was more potent, but also it's much more short-lived than heroin. It was quick on, but also quick off. And so because of that quick off, people had to dose more frequently to not go into withdrawal, which, of course, became more expensive when you have to keep buying it. Also very inconvenient to have to dose more frequently and then also increase their risk. And what users found was that, again, like in Puerto Rico, when the fentanyl was combined with xylosine, it tended to prolong that high, prolong that sedation, quote, give the fentanyl some legs. And so, you know, what you end up having is a real delay in that withdrawal, at least to the extent that people were still being sedated for a long time. And so users kind of got the sense that they were getting more bang for the buck. For a lot of people who use substances, they have a difficult time sleeping because most substance abuse do dysregulate sleep. And so, you know, because the xylosine was a sedative, it kind of knocked them out and they felt like they were getting no longer sleep. At least they weren't having to get up every few hours to use again with the fentanyl. And I think most importantly, we have to understand that most people don't even realize that the xylosine's in their drugs. So, you know, there's that too. And here's a quote from someone who has used both, you know, fentanyl and xylosine as well as other substances. They said, yeah, I like a good tranq fent bag. I like it because fentanyl is such a short-lived high. It's a good high, but it's so short that the knot is over real quick and you get sicker faster. See, the tranq, like, extends the high. It gives the dope more of a heroin effect. It's a good rush with a heroin-like effect. So, again, it's trying to, you know, for this user's perspective, it actually extends that fentanyl high a little bit longer like it used to be with the heroin. Now, from the seller's viewpoint, we talked about how there actually has been a demand for, you know, the xylosine or some type of adulterant to extend the length and the quality of the fentanyl high. What we know is that fentanyl is actually super potent, right? You only need a little tiny bit for it to cross over from giving you a high to being deadly. So they couldn't use a lot of fentanyl to bulk up the dope, you know, as a filler. They couldn't use the fentanyl itself. So xylosine fulfilled this need as well. It both extended the high but also could be used as a filler. We talked already about how xylosine is low-cost. And also because it's not a controlled substance right now, not regulated by the DEA, there's a lower risk of sort of law enforcement scrutiny, maybe a little bit easier for them to use it in general since it is still legal, at least in veterinary circles. And then certainly, again, its addition to the fentanyl can increase the profits, as we talked about, and also attract additional customers who didn't like the quick on-off of fentanyl by itself. So, again, people who, you know, were holdouts for heroin, now they can kind of get more of that heroin effect with the xylosine being added. I want to take a little sidebar here just to talk a little bit about another substance. So, again, once the drug supply more recently changed from heroin to fentanyl, again, we, you know, users were looking for adulterants that would extend that high. And methamphetamine, very similarly, in a different way, but similarly can make the high last longer, because methamphetamine has a longer half-life, and it can also stave off those opiate withdrawal symptoms from fentanyl as well. So another little sort of quote from someone who uses these substances, fentanyl is so short-lived that we gotta get high every six hours. But sometimes, let's say things were tough or whatever, if we were 10 hours in and you started getting sick, a nice shot of meth will hold you over another six hours as far as not being sick altogether. You just wouldn't be as sick. I mean, eventually it would turn against you, but it would keep you feeling better to get up and make a move to make money. So again, this idea that with the change to fentanyl, using different adulterants to make the high last longer, or at least the withdrawals not come on as soon, and so we see a lot of combination these days of fentanyl with meth as well. And we know that really the psychostimulant overdose deaths in the U.S. have significantly risen, at least in the last decade, and that really the overdose rates from psychostimulants have been quite high in the West, but really they're still low in the Northeast. But again, we know there's meth now expanding over, and I'm sure those overdose rates are gonna be as high as we have in the West here at some point in time. Okay, back to xylosine. Some people actually do try to avoid that fentanyl-xylosine mix out there because of a few things. Number one, some people really don't like that sensation of the mixture of the substances. So sometimes with xylosine, especially if you have a bit too much in the drug supply, you go out right away, you basically go to sleep and get sedated right away, and you actually never even feel the high from the fentanyl. So some people don't like that combination effect or they miss the high. Also, people have heard about xylosine. They're afraid of overdose, of becoming dependent or addicted to xylosine, and they don't wanna use it for that reason. They've heard of some of the skin wounds and they're scared of that, and rightfully so. And also they've heard that people can, because you're so sedated, people can injure themselves or sometimes get assaulted in that deep sedation. Another quote from someone who uses, but then other times they straight put bags out there that are just all tranq. You shoot it, you feel no rush, and you're just out. You're asleep for at least 40 minutes. You're sitting there one second talking, and then you're waking up two to three hours later in a weird position. So again, some people really don't wanna end up in that position or have that feeling. Now, right now in our current drug supply, xylosine and fentanyl are very closely linked. And this is some data from Millennium Health, which is a very large drug testing entity that has offices and tests all across the United States. They released this data in September of 2023, so just a few months ago. And what they found is that of all the urines that were submitted for testing, with the xylosine positive specimens, 99% were combined with fentanyl, or at least they had fentanyl on board. So, again, you usually find xylosine connected with fentanyl. Only less than 1% people have had xylosine only in their urine with no opioids or no fentanyl. On the flip side, if you look at all the fentanyl positive specimens across the country, you'll see on average about 16% of those total specimens have also been found combined with xylosine. So 16% is the more average across the United States. But if we look at a geographical map, we'll see that although 16% is the average, definitely in some parts of the country, there is much more xylosine combined with fentanyl as opposed to other parts. So on the map on the left-hand side, the areas that are the darkest have the highest levels. So we can see the Mid-Atlantic having about a 40% positivity of xylosine in their fentanyl positive urine drug tests. And then it becomes lower as we go to the West with the Pacific only having about 4% at this time. And then if we look at the bar graph on the right-hand side, we can see, again, by states. You see Pennsylvania, again, leading the pack there, followed by North Carolina. And then if you look on the right-hand side of that graph, we can see Oregon right now at about 4.7% positivity of xylosine in their fentanyl in those who have a positive fentanyl in their urines. Alaska is trailing a little bit behind at 3.3% in my state. Now, remember what I talked about before, there's really kind of become a polysubstance use environment out there. And then also certainly that methamphetamines is also used a lot of times as either co-used with fentanyl, most often sometimes added as an adulterant. And so when we look at fentanyl positive specimens, both with and without xylosine, but we'll just focus on the fentanyl positive specimens with xylosine, which is the orange bar. You can see going from the right-hand side, upwards of almost 60% of the time, you can see methamphetamine also being co-used. Oftentimes there are also fentanyl analogs. We see marijuana in the 40 percentile range, followed by cocaine, benzos, GABA, heroin, alcohol, and prescription opioids. So again, there can be a whole lot of things combined in people's, combined both in the drug supply and that people are co-using together. And in fact, DEA put out a joint intelligence report last year, about a year ago, and what they said was xylosine is most frequently found in combination with two or more substances. So again, we see this polysubstance use. Now, both these graphs here are looking at drug seizures across the United States, mostly comparing the data we have here is from 2020, and then again in 2021. And so in that top chart up there, again, this looks at seizures of xylosine by region. And we can see that in general, if you look at the numbers between 2020 and 2021, the Northeast has the highest number of seizures of xylosine by region, which we know, again, it started up there in Philadelphia in that Rust Belt region. But you can see that even between 2020 and 2021, all the regions saw an increase. The South actually had the largest increase and they're really having a problem with xylosine right now. But the West, although lower in numbers, did still have a high percentage increase. And then certainly the lower chart there is the xylosine positive overdose deaths, which you'll see pretty much mirrors the upper chart as far as where it's been seized. Again, the Northeast still has the cumulative highest total at least between 2020 and 2021. But again, the South and also the West are certainly having significant high increases in overdose deaths as well. So, and I do want to say that going back to this previous slide, especially that lower one, lower chart there, that these deaths are probably underestimated, underreported, primarily because there wasn't always testing available, easily available at that point in time. And so, we really don't know the true number. That's just basically kind of a little bit of a snapshot. So, we don't know a lot about xylosine testing. Again, it's just more recently been developed, both point of care and also for more definitive testing. But we have heard that it's very difficult to detect, mostly because it has a very rapid elimination from the body. It may have a prolonged effect, but actually its half-life is only 23 to 50 minutes as far as the parent product is understanding. In animal models, the total drug can be eliminated even from a single dose over 10 to 15 hours. So, we're still not sure how many days it actually lasts in the urine for it to be picked up. There has been definitive testing with gas chromatography mass spectrometry or liquid chromatography mass spectrometry available for some time now through companies like Millennium or LabCorp. But point of care testing has more recently become available. Right now, it's being made by BTNX biotech company. You can see in the box in the right upper hand corner, the brand name is really Rapid Response. And you might be familiar with this already if you use point of care fentanyl testing from this company. It's the same company that makes it except usually the labels are blue with fentanyl. Now it's red for xylosine. But right now, unfortunately, there is a dearth of information on how accurate they are. Again, we really don't know how quickly they turn positive, how long they stay positive, et cetera. There's been some data that high concentrations of diphenhydramine or Benadryl, lidocaine, levamisole, MDMA, or meth may possibly produce a false positive result. So again, that could be a confounder when we're testing and need to be aware of that. Many state health departments have been able to get these point of care testing supplies and have been able to provide them for free to some of their constituents. But if not, I know mine right now is a website that you can get them and order them for free. That's certainly where we're currently getting ours from. You can also buy them online, a pack of 100, right now online costs about $175 or $1.75 per strip. I wanna talk a little bit about how we've found over time that ziazine can cause a dependence. People can get addicted to it, although the data is still somewhat limited. Mostly it's from, again, the data from Puerto Rico and early on from the East Coast. On the left-hand side, we have the known effects of ziazine that we already covered. These are mostly some of the effects that you can get from a lot of the alpha-2 agonists, but again, ziazine has more profound effects than the ones that we currently use. But on the right-hand side are some other user-reported effects of chronic ziazine use or addiction. People report that when they do use, oftentimes they get hypertension and tachycardia first, and then after a brief period of time goes on, they get the bradycardia and the hypotension, which is more common. People have complained about getting blurred vision with use, super dry mouth, weak reflexes, slurred speech incontinence, some degree of dysglycemia, either high or low blood sugar. And there's been some early reports that chronic use can lead to a pretty significant iron deficiency anemia. Not really sure exactly why that occurs, but apparently it can be pretty significant. People have reported dysrhythmias, and then of course, we've heard about the severe skin wounds. Again, some limited data, but what they think is with long-term use, there may be some marked cognitive decline, and that that cognitive decline, unfortunately, may be irreversible. Now, for those people who unfortunately have either purposely or inadvertently had chronic use, we know that once they develop a dependence, there can be withdrawal symptoms that occur. It's not really well-defined at this point, and it's not a specific syndrome. Longer term, we've seen people who have chronically on clonidine for their blood pressure or dexmedetomidine. For various reasons, they have had withdrawal symptoms like rebound hypertension, tachycardia, diaphoresis, anxiety, and agitation. So some of the xylosine withdrawal symptoms might be similar to those similar alpha-2 agonists. But again, as far as withdrawal symptoms, users also report this profound dysphoria, insomnia, jitteriness or restlessness, chills, these kind of weird physical symptoms like head zaps, maybe some tingling and tactile sensations on the scalp and neck, hallucinations, various palpitations or a chest discomfort, and even a few cases of seizures. And you can see that some of these withdrawal symptoms are very similar to opioids and other type of, again, sedatives, so they do overlap. People have also reported that withdrawal symptoms of xylosine can be just as or even more severe than from heroin or methadone. So it can be, again, very severe at times. What about the treatment? Well, we're still figuring this out is the bottom line. What we do know is that you need to manage xylosine withdrawal symptoms simultaneously with opioid withdrawal. Just treating for opioid withdrawal and someone who has had xylosine on board or is dependent on xylosine won't cover it. You'll still need to add other medications to kind of help with some of the more xylosine-specific symptoms. In general, one of the ideas that's come up is to treat, since xylosine is a sedative, treat it similar to other sedative withdrawals such as benzo or alcohol withdrawal, which we will usually treat with benzos, phenobarbital, gabapentin, and sometimes using antipsychotics as adjuncts if people need that to calm down. Another theory is to kind of replace, when you're in xylosine withdrawal, to replace it with other alpha-2 agonists such as clonidine, dexmedetomidine, or tizanidine. And then always the idea is to add other symptomatic management with adjunctive medications like your Tylenol, NSAIDs, and again, other meds that might be used for any other withdrawal symptom. And there's been some case reports of, again, treating severe xylosine withdrawal mostly as an inpatient. So here's one quote from a case report in 2022. Her xylosine withdrawal was managed with a combination of dexmedetomidine infusion, phenobarbital, and tizanidine, later transitioned to clonidine. By hospital day four, she was no longer experiencing withdrawal symptoms and was ultimately discharged on buprenorphine, and the buprenorphine is probably for her, or for her, you know, concomitant obesity disorder, but buprenorphine, clonidine, and gabapentin on day 19 of admission. So again, one example of what medications have been used when people are treated for their xylosine withdrawal. Let's move on to the xylosine wounds. Again, I'm sure that you all have heard about this. Maybe some of you have seen some of these. You know, they were really first reported, again, in the Puerto Rican public health literature, mostly in people who injected the xylosine chronically. What they did note is that these xylosine wounds can look very different than other wounds from people who inject other drugs. So, you know, when people who inject other drugs, not xylosine, oftentimes people get more of a local cellulitis. Sometimes they could get an abscess. Sometimes they can get some, you know, red streaking coming off the wound, some lymphangitis from the wound. Obviously there's other more systemic things that can happen, but, you know, locally, usually that's what the wound looks like. But these wounds that they were seeing with xylosine were quite different. One of the things they found was that the risk of developing these wounds occurred irrespective of the route of administration. So not just from injection, but it could be from, you know, snorting, smoking, you know, orally, whatever not, you'd still get these wounds. And that was definitely something different. So again, the wounds would show up either at the site of the injection or away from it or with no injection. And they found that most commonly these wounds tended to occur on the extremities, usually on the forearms or the lower legs. And we'll talk about why this occurs in a minute, but basically it's because those places also have probably the poorest perfusion being further away from the central circulation. And what they also found was that the wounds tend to be quicker to appear and worse at the site of a missed vein injection. So again, you're trying to inject into a vein, you missed the vein, you're actually injecting the xylosine, fentanyl or xylosine heroin combination directly, you know, into the soft tissue. And that would be definitely a higher risk factor to develop a wound right there and become worse. The pathophysiology of why these wounds occur is not super well understood. One idea is that xylosine also has some partial alpha-1 agonist activity. And what this alpha-1 agonist activity does, it does cause some peripheral basal constriction or, you know, just poor circulation basically. So there's poor skin perfusion and poor oxygenation in the peripheral vasculature. And this sort of sets up for all kinds of wounds to form and also have poor healing long-term. So another theory is that it may be because of the chemical interaction or the dual presence of both xylosine and opioids. So when they were looking at studies from Puerto Rico, sometimes with just xylosine alone, people would still develop wounds, but not as quickly or as severe as people who again had this use of both the xylosine and fentanyl combo products. So there may be something to do with that interaction of those two medications or drugs that caused some kind of worsening of this problem of the wounds developing. Lesions are definitely more likely to result from more chronic or long-term either exposure or use. What we know is that from a single exposure in animal studies, the xylosine tends to be more concentrated in the organs and not necessarily in the blood or the soft tissue, but certainly with systemic use or with chronic use, there can be a systemic accumulation of the xylosine in the tissues. And then certainly if people are injecting, there can be localized direct exposure that starts to accumulate. We still have a lot of unknowns though about these wounds. It's still unclear about the length of time between the actual exposure and when the wound starts to occur, why the lesions can look different sometimes from person to person, and also all the factors that contribute to its progression or severity. We do know that places where there is some other initial trauma tends to be where the wounds start to occur and also accelerate in getting worse. So for example, if people have been skin picking maybe from co-occurring meth use or they have excoriations from who knows bed bugs or other bites from being outdoors or bed sores already, then those can be places where the wounds would go ahead and start. Wounds can also be worsened by repeated injections into or near the wound. You might ask, gosh, why is anybody repetitively injecting into a wound? Well, first of all, that may be where the only source where they can still find access to a vein that's usable. Also, we know that in the middle of the sort of the wound progression, there's a point where the wound can get very painful when it's kind of open and goopy and the wound can be so painful that people actually are injecting again, the fentanyl and xylosine mixture into the wound to help decrease the pain locally. So, you know, that's ostensibly making the wound overall probably get worse, but in temporarily, at least it can help dull the pain and that's why some people are injecting into the wounds. Oftentimes these wounds are not initially infected, but they can get colonized and also can get co-infected with typically a normal skin bacteria, including strep, staph and MRSA. The wounds often are described as scabby. They can look punched out. They can certainly become necrotic. And again, they're very slow healing. Unfortunately, there's been higher amputation rates than in those who inject drugs that don't contain xylosine because of many different factors, but or healing like we talked about. Unfortunately, due to a lot of different psychosocial factors, a lot of people often present latent progression, which again, you know, doesn't help with wound healing either. Another factor that we've seen more recently is that patients who do present to hospitals saying, gosh, I need this terrible wound, you know, treated, please help me. And they get admitted oftentimes because the providers there either aren't aware that the wounds are being caused by xylosine or aren't aware that the patient's going through xylosine withdrawal. They end up getting inadequately treated for their xylosine withdrawal and the patients end up leaving against medical advice because they're so uncomfortable. So again, something to be aware of that we need to treat both the xylosine and opioid withdrawal symptoms when they're admitted. Talk a little bit about the wound progression. Usually they start as small spots that are kind of dark, and then they certainly progress to a larger, darker area with typically an odd border. Then they develop these sort of reddish purple blisters on top of them. And then once that blister opens up, then they can have an area of central necrosis. Can start looking like these sort of punched out lesions all over the place that sometimes end up coalescing to a single, much larger wound. Oftentimes they can look like very granular and have this sort of heterogeneous appearance of areas where the skin is still intact, and also these areas where the lesions are punched out. They're not typically pussy or purulent, and oftentimes they don't require any antibiotics unless they actually are, frankly, infected. And unfortunately, again, they can progress to underlying tissue and muscle, and sometimes bone. So I'm gonna present some slides now about what these wounds can look like. So if you don't wanna look at these images, please look away, and I'll let you know when we're through with them. So this example is some of the early stages of the wound. On the left-hand side, you can see maybe on the right side of the foot there, on the outside of the foot at least, there's some more smaller lesions. You can see maybe centrally on the foot, there's now these larger, darker areas with that irregular border that they talked about. At the top of that left-hand slide, maybe at the ankle area, you can see that maybe there's a blister starting to form up there. And then you can see about four or five days later how the surface of those wounds have, a surface of those wounds has kind of eroded off. The blisters have popped, and now you have some of these sort of eroded, punched-out lesions all over. Another example here on the left-hand side, picture where you have multiple lesions usually from someone injecting somewhere in that limb, where you can get multiple of these punched-out lesions in one limb or one area. On the right-hand picture, you can see how they are starting to coalesce and become a larger wound. And these are some examples of more progressive wounds. You can see on the middle picture there, the wound is a bit more goopy and a bit more moist and open. This is typically the stage that they say is the most painful. Again, that's the stage where you have to worry about people injecting into the wound to try to get some pain relief. So if someone in that stage, make sure they get some other methods of pain management to help so that they won't feel like they want to inject into the wound to help decrease the pain. You can see in the right-hand side, it's more of a dried out, sort of probably the next stage in the progression of these wounds. And then in the first two slides, you can also see some sort of necrotic, that blackish tissue on the periphery of the wounds that's starting to develop. So another slide here where you can see that there's some various stages of wounds. You can see on this person's hands, they're starting to get some early lesions that we saw maybe in the first picture, right? Some of these dark, irregular areas there, but on the lower legs, you can see that the wounds have been more in the advanced state where they certainly coalesced into these large areas. And there's certainly some of that blackish, necrotic skin there as well. And here, sort of probably one of the more advanced pictures where they have quite a bit of that necrotic dead tissue present, and definitely will need to breathe at this stage. Okay, end of those slides. So if you were looking away, it's okay and safe to look back now. Really the key point here is that early intervention with any of these xylosine wounds is really key. Simple wound care can actually make a big difference down the line to try to avoid these things progressing. Really the biggest thing you wanna do in the beginning is to prevent secondary trauma and prevent it from getting infected. Both of those things would make it obviously get worse. You wanna tell a patient to try to let the limb cool down. Try to encourage them to not inject both into or even around the wound. And really you wanna avoid that whole limb. You wanna, if they are gonna continue to inject, ask them to rotate to a different limb, to again, try to minimize the trauma to the currently infected limb. And certainly if there's any types of cuts, wounds, or other injection sites anywhere on their body, they wanna do all they can to keep those areas clean and covered so those don't progress into these xylosine wounds. Xylosine wound care is really actually more or less like any other wound care. These are just basic principles of wound care, but we'll go through them. So starting on the left-hand side, you wanna make sure that the patient sanitizes their hands using soap and water or hand sanitizer or even gloves if available. They wanna gently wash their wounds with soap and water or a wound cleanser, or if they can afford to buy some saline over the counter, they can kind of use that to clean out the wounds. Tell them not to use any alcohol or hydrogen peroxide that can make the wound healing actually more prolonged or worse. They wanna coat the surrounding healthy skin with a nice ointment like A and D to try to help that to not get macerated in case there is any drainage from this wound. Then they wanna cover the complete open area of the wound with a nonstick gauze or xeroform usually coated with some type of antibiotic ointment to try to, again, prevent any kind of infection. Then on top of that xeroform, you're gonna put some type of absorbent dressing on top to collect any kind of moisture and pull it away from the wound if there is any kind of drainage. They wanna wrap the whole extremity with a wrap like coban or ace bandage to keep everything on. And then you wanna have the patient ideally change these dressings daily and I'll hopefully send them out with enough supplies to do so until the next scene and tell them that if the wound worsens at all or they start seeing that blackish color or necrosis that they really need to be seen by a medical professional at that time or a wound care specialist. So again, to kind of put this more in pictorial form, you can see on the left-hand side there at the very bottom, that kind of a reddish area would be the open wound. Right on top of that, you're gonna put that xeroform or non-adhesive dressing with maybe some antibacterial ointment on it. The second sort of in this picture, a kind of brownish layer is that absorbent layer. And then on the outside, the white would be the outside dressing to keep everything intact and protect the wound. So these wounds can take months or even years to heal. And unfortunately, some of them may not even heal without a higher level of medical care, especially if they're deep or especially if there's a lot of a necrotic tissue. The wounds again, at one stage, usually in the middle, can get pretty goopy, yellow, red, and swollen. Again, this one tends to be when it's most painful. So make sure that you're again, addressing pain management needs at that time. And then you wanna tell people about the warning signs for really any wound that doesn't heal from any cause. Usually these are wounds that won't stop bleeding, any signs of a systemic infection like sepsis, if the wound is getting worse, if now they're having a difficult time moving their limb, there's new pain or numbness. Obviously, if there's chunks of skin falling off or you can see any of the underlying structures like bones or tendons. If that wound does start to get that necrotic black dead tissue, then it probably should be seen by a medical professional to determine what to happen next, maybe best by even a wound care specialist. And there's various different ways that they have gotten rid of that necrotic tissue. Some of it is doing what we just talked about, that wet to dry dressing, but there's also various autolytic, biologic, chemical, mechanical, and physical means of also getting rid of that necrotic tissue. And again, at this point, like other slow and chronically persistent wounds, they are looking at hyperbaric oxygen therapy as a possible way to help these things heal up faster. But again, that would still need to be probably determined by a wound care specialist if the wound is at that point where it's needed to be trialed. Okay, another warning here, a couple more possibly disturbing images. So look away if you care not to see them. So this is a example of a person who did have quite a bit of a surgical debridement here. You can see in the upper part of the picture here that you can see all the underlying tissue with the overlying skin tissue mostly being already removed. And here they're putting on that first layer or xerofoam dressing onto the wound. And we know that wound care can work and wounds do heal. This is an example here where someone had those xylosine wound on the left-hand side. You can see this person had a pretty advanced case with sort of that heterogeneous patchwork appearance with some necrotic tissue. But over time, you can see with good wound care, it did end up healing, albeit with what looks like a fair amount of scarring, but still it did fully heal up at the end. Okay, end of those slides. So you can look back now if you were looking away. I wanna spend the last part of this talk talking really about harm reduction and what to do, especially with acute intoxication and overdose. So if there's an overdose and you're suspecting that it's probably a good chance that it's due to opioids like fentanyl, but it certainly could be involving xylosine as well. If it's suspected that it is due to xylosine, the first thing is to make sure that everyone is aware, first responders, your patients, any bystanders, that there's no risk to first responders from xylosine exposure. So if someone were to come across a packet of something and then it contains xylosine, at this point in time, we don't know of any known risk to anyone who's trying to help somebody in an overdose situation. Also, the wounds are not contagious by themselves at all. Of course, we should use personal protective equipment whenever available, like always. Of course, you're gonna call. Of course, you're gonna start basic life support. As soon as you see someone, we're not gonna go over that. Of course, call 911 like you normally would. You wanna make sure that the person's airway is open and then if they're not breathing or not breathing well to provide rescue breathing. And then as soon as it's available, administer naloxone. Now, naloxone does not reverse xylosine. It doesn't have any effect on the xylosine at all, but it will reverse any opioid, the fentanyl, heroin, or whatever other opioid that might be on board. And the patient probably won't wake up if there's xylosine on board. They'll be in that deep sedative state for probably some time, but it may reverse the opioid enough where they actually start breathing on their own. And that's really the biggest goal here in overdose is that they start breathing on their own. Once they do start breathing on their own, put them in the recovery position. And then again, you wanna do supportive management until the sedation resolves. A lot of times these patients will, again, hopefully get naloxone in the field and then they'll be transported to the ER or hospitalized. We wanna just make sure that once they're hospitalized, they get continuously monitored as far as their oxygenation and supplies supplemental oxygen if they become hypoxic. Remember, some of these people may need blood pressure support because the xylosine may be making them hypotensive and there's different medications that you can give for that. And another thing to make sure that staff are aware, if you're just monitoring someone wherever, even if it's at home by other people, that the person needs to be repositioned every couple hours, rolled to the other side, or gently massaged so that they don't develop bed sores, rhabdomyolysis, which is sort of muscle breakdown, or neuropathy from being in one position too long, like you can be with the prolonged sedation from some xylosine. And again, if they are hospitalized, remind providers to treat both for opioid and xylosine withdrawal symptoms so that patients can get adequately comfortable. There are no currently recommended reversal agents for xylosine that are approved for human use. There are things that are used in veterinary medicine. Again, these xylosines are used to, again, sedate these large animals. And then, of course, you want to kind of wake them up pretty quickly so they can be moved or back on their way. So in veterinary medicine, there is something called atipamazole, which is an alpha-2 antagonist, the opposite of the agonist, right? The antagonist that is used. This was actually approved for human use to be used when patients got approved alpha-2 agonists, and we wanted to reverse that. So it was approved for human use up until 2017, but they just found that there was too many unwanted side effects. People were getting nauseated, getting really restless after use. Blood pressures kind of spiked up at the levels where this medication was needed to reverse sedation. So it was discontinued for human use. There have been some recent studies where it's been utilized in a much lower dose. So hopefully avoiding some of those bad side effects along with caffeine as sort of an antidote for reversal when dexmedetomidine, an approved alpha-2 agonist, is being used in pediatric sedation. So some early studies that have shown that maybe it can be used in low doses, but whether that's going to be applicable to xylosine or not, we're not sure. Some other agents under consideration to be used as reversal agents for xylosine are yohimbine, which is another alpha-2 antagonist, atropine, and tolazoline, mostly to kind of reverse some of the side effects. There is some concern, though. All of these studies that have been done as far as reversals agents for alpha-2 agonists, these have been done in patients who've just had it for one-time use, right? In animals that just got it for one-time use for their procedure and humans that were on other alpha-2 agonists for one-time use for their procedure. We really don't know about when someone's dependent from chronic xylosine use. If you use one of these reversal agents, there's maybe even a more significant and possibly dangerous spike in blood pressure that might occur. So again, still being looked at, still being studied. We'll have to see what pans out. Now, harm reduction when people are more chronically using it, either intentionally or unintentionally from being in the drug supply. As we mentioned before, if testing is available, I think that's the first place to start, really, to find out, again, if the patient is, that's what they're using or that's what they're being exposed to. So if it's available, try to offer these test strips to your patients so they can test their own drug supply. If patients are knowingly using, again, it is prevalent in the drug supply, maybe suggesting that they use other routes other than injecting. Again, they may still develop wounds. We're not saying they're not gonna develop wounds, but they may not be, as we talked about, as severe or progress as much if they are using xylosine and other methods, but that's not super clearly been proven either. It's reasonable to assume, though, that, again, limiting direct injection into the skin or soft tissue is probably going to at least help to not develop these nasty wounds as much. So again, having them use it by other routes, but if they're still having them specifically not use it sub-Q or muscling it, where it's just, again, a direct injection into the soft tissue, if they are injecting into a vein, one of the strategies is after they inject to have them pause for a minute to let the blood circulation sort of clear it from the vein before they remove the needle so that there's no residual xylosine sort of left at the end of the syringe or else leaking out of the vein into the soft tissue. And if they are choosing to sniff or snort, recommend that they flush their nasal passages maybe with a little bit of sterile water or saline afterwards so that opioid-xylosine combination is not just lying on top of their skin kind of possibly causing some negative effect. You want to tell people that if they are using xylosine products or might be to be in a very comfortable position when they use so that when they go out, they're not on any type of wrinkles or protrusions that might be causing pressure sores or that their joints are in some weird position where they may be more likely to develop clots or neuropathy. Also make sure that because they might be out for quite some time that they're not exposed to extreme heat or cold. I know up here in Alaska, at least we have unfortunately people dying every year from hypothermia because they've been out in the prolonged cold and some type of sedated state. You want to make sure they're also in a safe location because of that deep sedation, it does increase the likelihood that they can get injured or victimized. There've been some reports where people are sometimes purposely given xylosine just so that they will go out and that they will be victimized, that's unfortunate. So just letting people know that they need to be safely located. And then if they are chronically purposely using or it's very prevalent in the drug supply, consider recommending that patients get on a diet that's high in iron or get on some type of iron supplementation because again of these reports that the chronic xylosine use does cause this pretty significant iron deficient anemia. And then again, make sure that they're carrying naloxone so any kind of overdose data can be used and having them not use alone so that there's someone there to administer the naloxone if needed. And of course, you want to remind people of safer injection techniques. We're not going to go through this whole thing, but if you look at the picture on the right hand side, you can see there that the arms tend to be the safest areas with exception of the palm and the inner side of the wrist. But again, advising people on safe injection techniques. So hopefully they can limit the risk that they're having of developing sores and wounds from xylosine. All right, last slide, the takeaways from today's talk. What I want to say, number one, is that we really, you know, it's been very prevalent on the East Coast, but really it's coming our way on the West Coast. Really, we need to expect to see increasing levels of xylosine in the local drug supply over time. And that's been increasing in the last couple of years. You want to alert your substance using patients to the presence of xylosine, even in the low amounts that it is on the West Coast right now, and also its effects so they can prepare accordingly. Certainly if the xylosine test strips are available in your area where you have them, consider using them to test people's urine to see if that's in your drug supply. Well, we know it's in the drug supply, but if it's in your local area, or if it's specifically in your patient's urine, and then offering those strips for your patients to be able to test their own drug supply if possible. You want to monitor all of your patients for any new or concerning wounds. Now we know what they look like and how they can progress, and then certainly initiate good wound care immediately as soon as you see any kind of developing wound. And again, everyone should have a Naloxone kit and everyone should use as safely as possible. And that is the end of the presentation. Thank you so much for your patience. I know that was a lot of information. I hope that you've gotten some good data to both, again, spread that information to your patients and also to help you as you help to treat these patients. Thank you so much, Dr. Isgro. We can go ahead and take any questions you all might have. Feel free to either raise your hand and I can unmute you and you can ask questions or you can add them to the chat now. And this is a little list of instructions on how to get a certificate for this training. I will also send this out to Sydney so that she can send this on to you all. You will create a PCSS account online if you don't already have one. It is a free training system. And then once you're in there, you'll follow these instructions to download your certificate. If you do have a moment, go ahead and complete this evaluation for us, please. You can just scan the QR code here. And do we have any questions for Dr. Isgro? Coming in, but if there are any, please feel free to forward them on to Sydney and she can send them on to us as well. And we can answer them via email if anything pops into your head after the session today. And with that, I think we are concluded. So I will go ahead and send these slides out to Sydney so that you can have the QR code as well as the certificate information. But thank you all so much for joining us today. And thank you, Dr. Isgro, for such a great presentation. Thanks, everybody. Thank you. You're welcome. Have a great day. You as well. Um, Chelsea, are you still on? I think she might have logged off. Okay. So Sydney, I wanted to ask, are you guys, and just since I think we're, I think we're off now. Are you guys seeing a lot of, have you seen xylosine, do you know of? We are still learning about it. I don't think we have personally seen any here. Maybe more in the Portland area than out here on the reservation, but I just wanted to be proactive and so that way we're more aware of it if it does come this way. Yeah, yeah. I think, I think it will be coming eventually. It definitely is super high on the east coast, so I think it's coming this way, but hopefully it'll take its sweet time and hopefully not as, not as much, but. I agree. It is scary stuff. Okay. I appreciate you and thank you. Okay, sure. No problem. Take care. Bye.

xylozine

alpha-2 agonist

drug supply

fentanyl

overdoses

dependence

addiction

xylazine

illicit drug supply

harm reduction strategies