Good evening, everybody. Welcome to today's AOAAM webinar, Silazine, An Introduction to a New Drug, by Dr. Tony Paison. My name is Julie Kimmick and I'll be your moderator for this session. This is the fourth of a seven hour webinar series on hot topics in the treatment of opioid use disorder and stimulant use disorders. I'd like to introduce our speaker for today. Dr. Paison received his medical degree from the University of Toledo School of Medicine in 2001. He then completed his emergency medicine residency at the University of Pittsburgh Medical Center in 2004 and his medical toxicology fellowship at Banner Good Samaritan Medical Center in Phoenix, Arizona in 2006. Dr. Paison is currently a professor in the Department of Emergency Medicine, Division of Medical Toxicology at the University of Pittsburgh School of Medicine. He serves as Chief of the Division of Medical Toxicology and Director of the Medical Toxicology Fellowship at UPMC. He's also Assistant Medical Director of both the Pittsburgh and West Virginia Poison Centers. Yet most importantly, he's blessed with his amazing wife, Karen, and four wonderful children. So I'd like to welcome Dr. Paison. Thank you, Julie. Thank you for the nice welcome. I really appreciate it. It's a pleasure to be part of this. Pleasure to be introduced to do this. And I guess might as well get started with this interesting topic that I find very interesting, particularly as a toxicologist and someone who's really fond of pharmacology. In addition, Dr. Kimmick will sort of scan the chat and the Q&A. So if you have questions, please chime in. We may save questions for the end. We may interrupt and have questions throughout. So feel free to chime in and throw questions in the chat as we go and we can kind of field them as we see fit. Funding from this is from a generous grant from SAMHSA and both Dr. Kimmick and myself have no disclosures. So how did we get here? How did we get to where we are with xylosine, which is a very interesting topic for today. But as many of you know that unintentional injury deaths have been steadily decreasing over many years. We've done a great job of preventing accidental injury and death from motor vehicle crashes. But some would say now is a really good time to be a toxicologist because as you can see here, poisoning deaths have really ramped up since about the turn of the new millennia, if you will. And we have really seen a ramping up of poisoning unintentional deaths. And that's largely driven by the fentanyl opioid outbreak that we've been experiencing for now decades. So how does xylosine fit into that? And as many of you know, I mean, I'm sure many of you are kind of near and dear to xylosine with addiction and your practices and so forth. It's all over the news. If you don't know, if you haven't heard about xylosine, then maybe you're not watching the news media too much, but goes often by tranq or dope and a lot of sensational about the wounds it causes, about an animal tranquilizer mixed with fentanyl and drugs and so forth. So it's not new, it's been around. And certainly has lots of interesting headlines. So what is xylosine? It's quite an interesting drug, honestly. You know, the 1960s was a heyday of drug development, a lot of which never really came to fruition. Xylosine was one of those, it was manufactured by Bayer in 1962. You know, it's interesting going back in the 1960s, a lot of drugs were developed, including a lot of the synthetic cannabinoids that, as you know, are not FDA approved, but 1960s was an interesting time for drug development. But, you know, xylosine was marketed or sort of touted as an antihypertensive, analgesic, hypnotic, anesthetic, which is quite the battery of things it could do, right? And it was looked at as a non-opioid sedative analgesic, but it quickly didn't go very far as it really, with human trials, it was demonstrating an overabundance of hypotension, CNS depression that was seen as a adverse side effect. So it was never FDA approved for humans. Instead, it is used as, you know, an animal tranquilizer, as an animal sedative for cats, dogs, horses, and even deer. Deer, we'll come back to the deer issue here later, which is another interesting point. It always comes down to the pharmacology. You know, I find it interesting, you know, xylosine is in a class of drugs that are alpha-2 adrenergic agonists. And this is not a comprehensive list, but this is a list of a lot of the alpha-2 adrenergic agonists that are on the market today, either over the counter or prescription medicines. And you can see there's quite a wide variety of uses from clondidine, you know, really marketed as an antihypertensive, but we use it for opioid withdrawal, as you know. Dexmedetomidine, or Presidex, is a sedative. Oxymidazoline is the active ingredient in Afrin as a nasal decongestant. Tetrahydrozoline, Viazine, is an eye redness reducer. Tizanidine, or Xanaflex, is a muscle relaxer. And guanfacine, or Tenex, as an adjunct to ADHD meds to help, you know, with the overstimulation of ADHD meds. So it's interesting that such a wide variety of medications and their uses, and each of these drugs are all alpha-2 adrenergic agonists, but they have slightly different variations in terms of where they're most effective. And I want to bring your attention for a minute to the structure, which I don't want to bore you to death with this, but as a toxicologist, this is always the fun part, right? And I always tease the residents and med students that this is where you really kind of understand the pharmacology when you look at these structures. But, and you can see the obvious similarities between xylosine and clonidine there. And you can see, you know, subtle differences as well. But one difference I want to really point to, because this becomes a point of contention when you read the literature and you read what's out there in the news media as well, that clonidine, that top ring structure on clonidine is a five-membered ring. And that five-membered ring makes it an imidazoline. That's the imidazoline structure. Now, as you can see, xylosine is not, is not an imidazoline. It does not have that imidazoline structure. And we'll come back and talk about why this is of particular importance when we talk about how the drugs work pharmacologically. All of these drugs are alpha-2 adrenergic agonists, including xylosine, but xylosine is the only one on this list that's not an imidazoline. Again, now, I'll come back and talk about that a little bit later. And that little structure difference may offer some points of discussion. So what do alpha-2 adrenergic agonists do? Well, they're presynaptic receptors, and it basically is a feedback inhibition mechanism to prevent release of norepinephrine. And then there are postsynaptic alpha-2 adrenergic receptors that in the periphery largely live on your blood vessels that cause vasoconstriction. Centrally, alpha-2 adrenergic agonists are what we call generically sympatholytic. They cause sedation, bradycardia, hypotension, antigenosusception, or pain relief, or less sensation of pain. So essentially, sympatholytic, peripherally, vasoconstriction. And this is just a schematic of what these do from one of my favorite toxicology textbooks from Goldferring's Toxicologic Emergencies. And you can see here's an alpha-2 receptor there in the bottom left-hand corner. It postsynaptically, and you can see it cause CNS inhibition and peripheral vasoconstriction, and then presynaptically as well, inhibits exocytosis and inhibition. That's a feedback inhibitor for norepinephrine release. But here, I want to talk a little bit about imidazoline and alpha-2 adrenergic receptors, come back to that structure thing that I mentioned a few slides back. This is a nice slide produced from a publication from Dr. Lowery. I changed her slide just ever so slightly, so hopefully she's okay with that. But as you can see, I changed, you may be able to see the text difference, the font difference, imidazoline-1 binding site as opposed to imidazoline-1 receptor. This is a subtle but important thing to mention is that a lot of times you'll read, people will talk about the imidazoline receptor. Now, the problem with that is we really don't know a lot about imidazoline receptors, and I'll use that in air quotes because there is an international governing body, believe it or not, that sort of governs and decides what's a receptor and what's not a receptor. And imidazoline, quote, binding sites are not considered receptors. It's largely because there's just so much we don't know about imidazolines. We don't know much about the receptors or binding sites, so they're just considered binding sites right now. For example, there are three SO binding sites from imidazoline-1, 2, and 3, and imidazoline-1 binding sites all appear to be closely affiliated with the alpha-2 adenoreceptor. There's a theory that the imidazoline binding site is just an allosteric binding site on the alpha-2 adenoreceptor that causes a conformational change in alpha-2 receptors. It may not be truly its own receptor, but that's unclear. Now, we do have a better understanding of imidazoline-type-2 binding sites. They're really allosteric binding sites on MAOB. So there's a lot we don't understand, and the reason why I bring this up is because in the literature, people say, well, xylosine's not an imidazoline. You know, it doesn't bind imidazoline binding sites, so it can't cause hypertension and it can't cause bradycardia, but that's why I love Dr. Lowry's diagram here, and this clearly demonstrates that alpha-2 adenorhetic receptor binders, regardless of whether they're imidazoline or not, can cause hypotension bradycardia through kind of backdoor channels, through nucleus tractus solitarius or the medulla, and you can see what I like to call the sympatholytic pathway, you know, basically inhibition of sympathomimetic activity through those other tracts that cause hypotension bradycardia. So I just want to bring up this point because if you really dive deep into xylosine and what it can and cannot do, it's not an imidazoline and so forth, and honestly, it doesn't matter. It really does the same things as clonidine and all those other alpha-2 adenorhetic agonists that I mentioned. Okay, I'll start getting really dorky on you here. So clinically, most importantly, clinically, what does this really mean? And interestingly, when we look at alpha-2 adenorhetic agonists, you know, when you first take an alpha-2 adenorhetic agonist and we have a lot of experience with them, as I showed you, there's lots of them out there and that are available, and in my practice, we see a lot of kids who overdose on these, even the Vyzene, you know, there's a movie that a kid, you know, poisons another kid by putting Vyzene in his milk, and the kid, I think he poops his pants or something. So it's kind of a funny scene in a movie, but, you know, so Vyzene seems to be the drug that people put in other people's drink to see if they can make them poop, but obviously it doesn't. It just does these things. So not as funny in real life, but so when you take an alpha-2 adenorhetic agonist, Zylozine in particular, you first get hypertension because it causes alpha-2 agonism at the vasculature and causes peripheral squeeze. So you get hypertension and you get a reflex bradycardia because of the hypertension typically. Then as the drug moves from the periphery and migrates, diffuses into the central nervous system, you get hypotension from that sympatholytic pathway that I showed you earlier, and you get ongoing bradycardia, you get sedation, you get the muscle relaxation, you get pinpoint pupils, and even respiratory depression in severe doses. So first hypertension, reflex bradycardia, then you get hypotension, bradycardia, sedation, all those sympatholytic central nervous system effects. And for those who say, well, Zylozine's not an imidazoline, it can't cause hypotension or bradycardia. Well, we know clinically it does. We have lots of animal data. I don't wanna bore you to death with the animal data, but I wanna stick just purely to human data. And you can see the kind of overarching theme in Dr. Caprero's case series, looking at Zylozine overdoses is that bradycardia and hypotension and mental status changes are kind of the predominant theme. So we know clinically it does that. And that fits what we understand about alpha-2 adrenergic agonists. And we'll come back to the slide a little bit later and talk about this more. But one thing I just, I can't not bring attention to, because it's interesting enough to me, like I said before, the fact that Zylozine is used as a deer sedative, apparently it can also lead to patient toxicity when used on elk, if you eat elk meat sedated with Zylozine. I'm not sure the findings for hyperactivity, but that must have been an interesting case. So it always comes back to the pharmacology, like I said. Okay. What about the pharmacokinetics of this drug? Well, you know, we don't really know that much about the pharmacokinetics in humans, and we'll have to generalize from what we know in the animal models. But I kind of line these up. Since Zylozine and fentanyl are almost always associated with each other, I thought I'd put these side by side. Fentanyl, like Zylozine, can be administered IM or IV. You know, in the veterinary world, they'll use Zylozine IM or IV. Those ranges are not too dissimilar in terms of fentanyl and Zylozine. So it's nearly a one-to-one ratio. Duration of action is very similar too, honestly, in terms of onset of action and duration of action. Peak effect, very similar. Half-life is maybe a little bit shorter with Zylozine. Distribution, yeah, in the ballpark of each other. But you kind of see the similarities in terms of the pharmacokinetic effects of these two drugs and how they interact with each other. And this will become more pertinent when we talk about how these drugs are used together, largely. And where did it come from? It's an interesting phenomenon that this, quote, animal tranquilizer has sort of pitted our opioid outbreaks and our fentanyl use and so forth. And it appears it largely has come from Puerto Rico, the cattle farming rural towns of Puerto Rico in the beginning of the 2000s. And interestingly, the Zylozine wasn't always mixed with heroin. It was often packaged with, but separately with heroin and cocaine, and then a third package of Zylozine, and users could kind of mix and match in terms of augmenting their heroin with their Zylozine and their cocaine to get the whatever clinical effects they were seeking. So it's interesting. It was initially started sort of on its own and then became part of the mixture concoction that fentanyl has become. And with Puerto Rican immigrants, it sort of migrated with them, and the use of this drug has migrated with them to New York and Philadelphia. And those areas have really become the sort of epicenter of Zylozine use. But I really don't have a great understanding for the context of the use, why it's diverted, why this was. I can only imagine, and this is just me, Tony talking, that with the cattle farming towns of Puerto Rico, it must've been available. Someone thought it was a great idea to try this drug, and it sort of became the pervasive drug used with the heroin and cocaine in sort of that speedball mixture. So it's just kind of an interesting way that this drug sort of got its start. And in additional studies from Reese in 2012, kind of really diving deep into the emerging use of Zylozine in Puerto Rico, and it was largely men, largely men in their mid-30s, largely in the rural areas. They were largely injecting it. And even back then, there's these wounds associated with it. I'll come back to those wounds. Zylozine and wounds seem to be somehow intertwined in an interesting way that I don't have a great explanation for you, but we clearly see these wounds associated with Zylozine use. And you say, like, why are these adulterated drugs? Why is fentanyl adulterated with Zylozine and so forth? Well, I mean, our drug supply has been adulterated for a number of reasons. Some basically to dilute the drug down, to make your supply somewhat more plentiful and you can sell more. Other ways, it's added to enhance or augment the effects of the primary drug. Sometimes there's some kind of accidental contamination. That's been a historical thing. We've seen lots of drugs with accidental contamination. And I went back and just kind of thought myself over my career, what have I witnessed in terms of adulterated drugs and our adulterated drug supply in Pittsburgh? You know, since the 80s, we've seen, quote, China white in our heroin supply, which was largely fentanyl. Levamisome cocaine, it's still kind of prevalent here in Western Pennsylvania. We've even seen diltiazem contaminated in our cocaine. That was a kind of confusing picture when you expect a hypertensive tachycardic agitated patient, but didn't have the hypertension or the tachycardia. Clenbuterol in cocaine or heroin. Brodificum, you know, the super warfarin's contaminated synthetic cannabinoids. So this is not a new phenomenon of, you know, adding something to the drug supply for a cacophony of reasons. And so it's not new. But, you know, xylosine, I think is a little bit different. It's a little bit unique because other than some of those other drugs and other adulterants that I've mentioned, xylosine is sticking around. You know, it's now been around for over a decade and it's clearly demonstrating a multi-year progression. And I'll show you some additional slides and is not really showing us any demonstrated signs of slowing. And it's following this progression of the new novel psychoactive substances that are really impossible to police and monitor and track. So I like to call these novel psychoactive substances sort of the new normal of drug use. You know, gone are the days of growing your poppy field in Central America or South America, extracting the opium and making heroin, right? Now it's basically chemically synthesized drugs of all types, largely from clandestine labs in China. And, you know, it's the Amazon, it's the Amazon of drug use, right? If it fits, it ships. And so this has become our new normal and does not appear that it's going away. It's so easy to chemically synthesize it in a small lab and ship it wherever you want to go. And xylosine is following that trend and ramping up. And when you look at, this is the DEA tox testing program of novel psychoactive substances. And largely the number of drugs, new novel psychoactive substances are largely opioids, you know, on this chart you can see. And xylosine is kind of following that trend in terms of contaminating our opioid supply. So it's largely the opioids that are becoming our more novel psychoactive substances that are more widely available. And like I said before, Philadelphia, New York has become really the epicenter of the xylosine epidemic. And largely probably came with Puerto Rican immigrants, this new drug and has been, you know, sort of perpetuated from there. And the number or percentage of heroin and or fentanyl unintentional overdose death involving xylosine have continued to increase over this past decade. And you can kind of clearly see that trend upward. I'll continue to show the rapid increase over the years. And it's interesting too, it's not just that it's this incidental thing in the drug supply, but people are talking about it, which I find interesting too. So there's discussions about it. So this is online mentions of xylosine through social media and really peaked in 2022. I wonder if it peaked and kind of piddled, petered down is because, you know, people kind of know about it now and there's maybe less chatter about it, but it was clearly ramping up in terms of what xylosine was out there in terms of, you know, people's interest in it and discussing, you know, what that means for their drug use. And even in Pennsylvania, you can see that the year progression with this heat map from 2018, the top left-hand corner, 2019, 2020, 2021. And you can see how, you know, the xylosine contributing to deaths have increased over this time period with this heat map. The gray counties from Pennsylvania, we didn't have any data on those. That doesn't mean there wasn't xylosine there, but we just don't have any data on them. And for those who may not know where Pittsburgh is, and Pittsburgh's in Allegheny County way here on the left-hand side of the state and the Western side, and Philadelphia is way down here in the corner. And, you know, I find it interesting too, when you look at some of those back years of xylosine, you know, Allegheny County was kind of protected for whatever reason, and a lot of the surrounding counties began to develop fine signs of xylosine before it hit Allegheny County. But anyway, you can kind of see the rapid progression over the years. And this is just, you know, numeric representation of number of overdose deaths where xylosine contributed to the death. You know, 2022 is actually an incomplete year. I don't have all the data from that, but you can see the rapid progression of that as well, or the number of counties where xylosine contributed to death in terms of how many locations where xylosine has been exposed. So it continues to rise. Like I said, there's no slowing of xylosine at this time. And I'll come to the regionality of xylosine and where it is. And this is a little bit of anecdote and more of a gestalt than a true hard number, but our Allegheny County medical examiner has about 25% positive xylosines in their fentanyl associated deaths. And we too, we're really fortunate that here at UPMC, we have amazing tox lab with, you know, the state-of-the-art technology. So we can get xylosine. We don't get quantitative levels, we can get qualitative levels, but we too are seeing about 25% xylosine with those who are using fentanyl. So it's here in Pittsburgh. We're not quite a little behind what's happened in Philly, but we definitely are seeing a lot of xylosine here in the Pittsburgh area. And even just as recently, this MMWR report has just been published, which is interesting looking at even outside of Pennsylvania where over this three-ish year timeframe that xylosine associated deaths have increased 276%. That's quite a phenomenal rise. And interestingly, that xylosine nationwide is only detected in less than 12% of all fentanyl deaths, but the range is from zero to 27%. So I guess in Pittsburgh, maybe we're on the higher end of the incidence of fentanyl. In other areas, there's no xylosine. And you can see from the map down here, the darker the color, the higher the incidence of xylosine. And you can see it's really concentrating in the Northeast and less so in other parts of the world. But xylosine as the cause of death is really variable. I mean, it's interesting to read this report because it's probably medical examiner or coroner dependent of how they list the xylosine as a cause of death or associated with death. And as you can imagine, that's a really difficult thing for a medical examiner. When you get an autopsy and you have a toxicology report after a post-mortem and you have all these drugs, you know, what contribution does the xylosine make to the death? And so it's reporting as a cause of death is really variable across counties and across states. But I wanna talk about that a little bit more because I've been fortunate to be involved with this Fentanylog study, which is really looking at fentanyl analog. So it's a very clever name. It's been led by Dr. Manini at Mount Sinai. And it's really looking at a prospective cohort of ED patients with suspected opioid overdoses. And so there's nine participating sites across the country. And we are still in the middle of our data collection phase. And not only do we get waste blood samples, from patients that we send off for novel psychoactive substances and xylosine testing and fentanyl and fentanyl analog testing, we also get some clinical information from the emergency medicine record too. And this has been a collaborative effort from grants from NIH and CDC, and really kind of overseen by the American College of Medical Toxicology. So these are the nine sites across the country. And it's a nice sort of representation of various areas from West Coast to East Coast, even the heart of the country in Denver. So it's interesting. American College of Medical Toxicology has this consortium called a Toxicology Investigators Consortium called TOXIC, which is a very clever name, right? It's hard to do toxicology research. RRBs don't let us poison patients to see what happens. So the best way to do it is to collaborate with others and kind of collate our data to see what meaningful information we can collaborate with and understand better. So these are nine of the many more sites in this toxicology consortium across the entire country with this Dr. Manini's study. And this data has been published at least in part preliminarily by Dr. Love, and basically data as of August, 2021, so two years ago, there was about 321 total opioid cases associated with this, and xylosine was present in 90 of 321, or by 28% of the opioid cases. But what I found most interesting about this, particularly when we go back and talk about xylosine-associated deaths, is that xylosine was associated with reduced odds of coma or cardiac arrest, which is kind of an interesting phenomenon. Again, I'm gonna dive in this a little bit more deeply here. But you can see here, this is additional data from the Fentanylog study. This is an additional to the Love data compiled since. So there's a few more. There's 761 fentanyl cases without xylosine and 226 cases of fentanyl with xylosine. And you can see not quite a p-value of less than 0.05, but there's certainly a trend to those with xylosine to require less intubation, you know, 67 or 8.8% versus 4.9%, and fewer requiring CPR, you know, 9.7% versus 4.4%. So is there a protective effect of having xylosine present in the drug supply, which is very intriguing and very interesting to me. Again, very preliminary. I don't know what to make of this, but this is just an interesting fact that has come out of this collaborative effort with Toxic and Dr. Menini and his Fentanylog study. One more slide from that. Again, this is unpublished preliminary data. You can see hospital admissions to the ICU, 11.5% of fentanyl with xylosine versus fentanyl without xylosine, 17.5%. So again, is there a protective effect with xylosine present in the drug supply? I don't know. I'm not encouraging xylosine use. We're just noticing these trends that there may be something to it, less respiratory depression, you know, maybe other things that offer benefit from that. And one more, not to beat this too much, but this was a really interesting study, Dr. Kinsinko, who looked at multi-drug overdoses. So those of you who are familiar, NMS is a reference lab in Philadelphia. They're probably arguably, I don't know this for sure, but probably the largest clinical reference lab in the country, I can only imagine. They do a lot of forensic work, a lot of clinical work. And basically they looked at hundreds of thousands of multi-drug overdoses and looked at what drug results they got. And really of the thousands of cases that had xylosine, you know, 3,077 cases had xylosine in them, only really two fatalities associated with isolated xylosine. And you can see one was a 50-year-old man found with a bottle of xylosine in a needle. So it's pretty clear that there was an intent there. And the drug concentration of xylosine on the postmortem was 9,000, it's pretty sky high. And another 38-year-old who worked at a racetrack, presumably had access to xylosine, again, had a really high postmortem xylosine concentration. While the other 3,000 some cases had xylosine concentrations not anywhere near those high levels. So very few isolated xylosine cases, xylosine is almost always mixed with other drugs and maybe it offers some other benefits when it is mixed with these other drugs. One more case, this is from that Caprero case series that I showed earlier. There was a severe intoxication with xylosine in a 16-year-old horse breeder, bradycardic, not so hypotensive, but bradycardic, pinpoint pupils, apneic breathing, given naloxone with no benefits and extubated after 14 hours with no ill effects. And it estimated that he ingested quite a fair dose, 4.3 grams of xylosine. And this is, again, I showed you this slide earlier. This is a compilation of other cases from the Caprero paper, looking at presumed xylosine doses, really only one death from that big series, but from this small case series. And most of them had very, very similar clinical effects. So switching gears a little bit, we've talked enough about the basic pharmacology of xylosine, but certainly xylosine and wounds have been an issue, have been a clear association from way back in early 2000, when xylosine was first discovered as use in Puerto Rico. We continue to see this, that picture on the left is from a paper in a Journal of Addiction Medicine, and the arm on the right is a patient of mine that I had just a few days ago. And they do have a very characteristic wound, sort of that got scooped out, a lot of granulation tissue and fibrinous material and often gets super infected and so forth. So the very characteristic wounds of xylosine, I mean, it's very noticeable when they come in with this. And I was a little bit of a, I'll be honest, I was a little bit naysayer about the wounds associated with xylosine at first, but now I'm a bit of a believer because I do have that characteristic appearance because our IV drug, patients with IV drug use have a long history of skin wounds from a multitude of reasons, right? It may be from increased injection frequency, it may be vasculitis from repetitively attacking a vessel, direct tissue damage from whatever diluents or additives are in with drugs, skin picking from anxiety, pressure necrosis from passing out on your limbs, they may be infectious, maybe poor wound healing, decreased skin perfusion. I mean, there's lots of reasons why xylosine may cause wounds. I don't claim to understand exactly why these wounds and why they are the way they are, but there's definitely, there's undoubtedly in my mind, there's some association with these wounds and it's not from the injection site. You know, you'll see these wounds in someone's leg where they don't inject, where there's not track marks. You can see on this lady's arm, which I find interesting, you can kind of see closer to the hand, kind of the beginning of the track mark and how it tracks up and she has additional track marks up here. And you can see it's not really where she was necessarily injecting. And there's other patients, again, will have wounds that are completely remote from the area of injection, which again, really is quite interesting in my mind. So what do we do about xylosine? Like what's the treatment? When you have someone with xylosine, basically give naloxone. Yeah, I did tell you earlier, it probably doesn't do anything, right? But unfortunately, I think what happens is people would know that xylosine is not likely affected by naloxone. So then the push becomes off. Why give it then? Well, why give it is because vast majority of these cases, xylosine is mixed with an opioid. And maybe, as suggested earlier, xylosine has some kind of protective effect against death, ICU admission, and so forth. So maybe give the naloxone to reverse the deadly opioid effects when necessary. And it may address the deadly part of a polysubstance ingestion or polysubstance use. So still give naloxone. It's interesting how knowing xylosine is out there, some people are advocating, why bother giving naloxone? But give the naloxone. And one little tidbit that I like to teach our residents and so forth is, the breathing, sleeping patient is the most pleasant patient to take care of, right? So the idea of naloxone is not necessary to awaken the patient. You give a large dose of naloxone to particularly someone who's very dependent on opioids, you can then push them into precipitated opioid withdrawal, which is another issue. They're agitated, they're delirious, they're vomiting on you. And then what do you do to sedate them back down again, right? You're just giving them more sedatives to combat what you did to precipitate withdrawal. So the idea with naloxone is really just to keep them breathing and keep them safe. So in my mind, the indication for naloxone is apnea or hypoxia, sat less than 90, hypercarbia and PCU two greater than 50. And obviously IV is the easiest way to give it because it's easiest to titrate. And I certainly have given big dose of naloxone when someone comes in basically blue and not breathing and then you have to deal with precipitated withdrawal, but it is what it is. So when you can, we will often dilute the 0.4 milligram naloxone vials into a 10 cc syringe of saline, 90 cc of that with one cc of the 0.4 milligrams naloxone and give one cc at a time, which is essentially 0.04 milligrams every few minutes until a patient is adequately breathing and oxygenating. If they're apneic, you may wanna give a slightly bigger dose. And certainly in cardiac arrest, you're probably gonna push a bigger dose because at that point you really have not much to lose, right? So the intent is not necessarily to awaken the patient, but just keep them breathing, prevent the precipitated withdrawal, which again will be another issue that you'd have to deal with otherwise. So despite knowing naloxone doesn't help xylosine, likely give the naloxone anyway. And interestingly as well, there's a withdrawal with xylosine. You know, there is this tachyphylaxis with afronasal spray, with clonidine, with a lot of these other alpha-2 adenergatic agonists. So there's no surprise that there's a xylosine withdrawal. And we're just beginning to recognize that as well here in Pittsburgh and Western Pennsylvania. And interestingly, largely the withdrawal is anxiety and restless and hypertension, dysphoria. It's a bit different than the opioid withdrawal, which certainly those symptoms could be associated with opioid withdrawal, but we're not seeing the GI symptoms, the pylor erection, the yawning with it. But there definitely is a withdrawal syndrome separate from the opioid withdrawal symptoms. But what to do about it, right? So, you know, we'll treat what at first seems like your garden variety opioid withdrawal on our toxicology patients and our addiction medicine patients with typical buprenorphine or methadone dosing. And they do get better because it treats half of the withdrawals, treating the opioid withdrawal, but it really doesn't seem to adequately treat the xylosine withdrawal. And so you're gonna have to give some kind of other adjunct for the most part. And mechanistically, knowing now what the pharmacology of xylosine is, I like to stick to the drugs that will probably most likely work, like other alpha-2 adrenergic agonists, like clonidine, dexamethamidine, tizanidine. Those, I think, make the most sense in terms of treating withdrawal. We'll often do scheduled doses of clonidine or continue to use as-needed doses of clonidine based on an opioid withdrawal scale of some sort, whatever your favorite one is. We use the cows. So I think that's probably the best way to go, but certainly people will use benzos, people have used antipsychotics, ketamine, dopamine agonists in terms of ropinarol. So there's lots of different ways to go about this, but we typically have gone with clonidine. Obviously, dexamethamidine would only really effectively be used in the ICU, but certainly for very sick patients, that could be the case. In this case I'm referencing was a case example of xylosine withdrawal in Philadelphia. And this lady who had quite, it's quite a great story about, she was, you know, an extreme level of withdrawal and managing her withdrawal was quite a challenge. And that withdrawal with xylosine could continue to offer us great challenges because I always tell people, I think, you know, one of the greatest services we do in toxin with our addiction inpatients is treat their opioid withdrawal symptoms because it helps with compliance, it helps with them manage the other issues and keep them in the hospital to treat their infections or whatever led to their primary admission. And if we're not addressing the xylosine withdrawal in parallel with the opioid withdrawal, I think you're gonna have a lot of patients leaving against medical advice, leaving before their treatment is completed and then, you know, leads to other downstream issues. So I think addressing xylosine withdrawal if xylosine is present in your area is really critically important to helping our patients and helping them manage them and keep them safe. Also, maybe prevention, right? Here at the University of Pittsburgh we have xylosine test kits. I don't know the intent people have if they prefer xylosine mixed in with their opioids or not. I'm sure there's a subset of people who don't, especially when they know there's wounds associated with it or it could be another bad withdrawal associated with it as well. But if people don't want xylosine mixed with their drugs, you know, there are test kits available and we do provide those regularly here in the Pittsburgh area for people to test for xylosine. Knowing that, 25% of the drug supply seems to have xylosine in it. So, but again, it's still unclear to me if people seek xylosine out intentionally or not. The last but not least, the take-home points, right? It appears xylosine is here to stay. You know, it's unlike other additives, other substance that have been mixed with our drug supply. It's clearly ramping up. We have not seen the peak as far as I'm aware. It's an alpha-2 adrenergic agonist, which is very unique and different. It causes very opioid-like effects, interestingly, in a non-opioid way, coma, pimple, pupils, hypotension, sedation. It is associated with wounds. I think we'll discover there's some separate mechanism, a direct mechanism from the xylosine, not from needle sticks, that causes these wounds on these patients. It's clear there's some interesting association. And basically, I would continue to encourage people to treat the overdose victim no different than we have in the past with naloxone and all our supportive care measures, even though we know xylosine may be a contributing factor. And in the end, maybe we'll find that xylosine is actually helping patients in terms of leading to less issues with ICU admissions and respiratory depression and so forth. And really important, too, is recognizing if xylosine is in your area that there is a separate withdrawal, and it's a little bit more nebulous. It's a little bit more insidious. You'll treat the opiate withdrawal with your typical agents, buprenorphine, methadone, whatever your preferred agents are, but they're better, but not completely. They're still acting as if they're in an opioid withdrawal in a restless, kind of dysphoric way. And that should kind of maybe trigger in your mind that maybe there is a xylosine withdrawal component, and continuing with withdrawal management with clonidine or other alpha-2 adrenergic agonists may be the best choice. I try to avoid benzos personally, particularly when they're anxious. It may offer other benefits to the patient that you wouldn't otherwise want to see. So I would often stick with alpha-2 adrenergic agonists in terms of the mechanism seems to make the most sense. So that's what we got. I had to pull a little plug from Mr. Yuck in the Pittsburgh Poison Center. They're at the end. Hopefully that was enlightening and helpful, Dr. Kimmick. And I don't know if there's any questions along the way. I wasn't screening the chat anywhere. We do have time for questions and we have a couple in the chat box. So the first one I'm gonna go through is a question about the wounds. Is bruising and the other skin patterns of darker bruising throughout the body normal or a sign of xylosine use? I know those prototypical pictures I showed you here that this, in my mind, is very prototypical xylosine exposure. I had a trauma patient a week or so ago, came in as an MDC and they were disrobing her. She had the prototypical wounds like that on her legs. I said, I was probably xylosine. And sure enough, she was someone who had opioid use disorder. So this characteristic look is very typical of xylosine. It seems to be very characteristic of that, if that answers that question. Okay. I had a question. What does tuzanidine do for withdrawal? Does it have an advantage over cyclobenzaprine? Their center is currently using cyclobenzaprine, it sounds like, for opioid withdrawal. Yeah, I mean, that's a really good question. And the short answer is, I don't know. Me, as a toxicologist, knowing that xylosine is an alpha-2 agonist, I personally would prefer sticking with other alpha-2 agonists because it's hitting the right receptor, it's agonizing in the right way. If you're finding success with cyclobenzaprine, by all means, go for it. You know, it's sort of like alcohol withdrawal. I'm kind of fickle about alcohol withdrawal. Alcohol is an NMDA receptor antagonist and a GABA agonist. So I like to stick with drugs that work on those receptors in that fashion. But if you're finding success with cyclobenzaprine, go at it. But we've been dabbling with clonidine in our really sick ICU patients with dexmedetomidine. There's a question about how much xylosine, the frequency, duration, and dose, does it take to create the lesions? Man, I wish I knew. I really wish I knew. I have no idea. And I don't know that that's knowable at the moment. I think it's just, it's hard to know that. If it's regularity of use, a concentration that's required, and so forth. You know, Sandra's follow-up question there, are the wounds from basal constriction? Maybe it might be. I think there's lots of theories about that it could be. I don't have a great pathophysiologic reason to explain those, but it could be basal constriction, so. Okay. How well is xylosine detected in blood? I understand that xylosine is better detected in the urine. Has the technology improved in detecting xylosine in human body? Yeah, I mean, you can detect it either location. We find urine is easier because it's less preparation, and drugs tend to concentrate in the urine. So we, here in Pittsburgh, do most of our testing in the urine. I know a lot of the reference labs do it on blood. We just find it much easier, because there's really, with our technology, the LC-MS machine, basically our pathologist says, dilute and shoot. You know, he dilutes the urine and shoots it in the machine. It's really like no preparation. Blood requires a little preparation before you can stick it in the machine. So it's really easy. But with current technology, it's easy to detect it. It's just a matter of having the right technology to do it. A question came in early, pretty much at the beginning of the talk, and it said, I'm starting to get a sense that there may be a behavioral or possibly physical dependence on xylosine. Your thoughts? I think you did answer largely throughout the presentation. Yeah. Do you have any other thoughts or not? Yeah, I think, definitely. I think there is for sure. And I don't know, what I don't know is, are people seeking out xylosine knowingly, or are they being exposed to it, not recognizing that they're exposed to it? But there definitely is a withdrawal. And so I presume there's definitely at least a physiological dependence, if not a psychological dependence on it too. Somebody wanted a reminder on the symptoms of withdrawal from xylosine. Yeah, I can go back. I had, I forget where it was now, but basically anxiety. Yeah, here we go. Anxiety, restlessness. You know, opioid withdrawal kind of has very similar symptoms in addition to the GI effects. What I've seen regularly is just really anxious, really restless, you know, often tearful. That seems to be the driving factor with withdrawal from xylosine. What are your thoughts on a three to four week tizanidine or clonidine taper? That may not be a bad choice. I don't know. I haven't in my mind come up with a great treatment plan, but I think longer the better, honestly, because, you know, there is a tachyphylaxis to these alpha-2 adrenergic agonists like clonidine. And I think a slow, slow taper is probably the best way to go. So I think a few weeks, you know, whatever you think the compliance would be is probably the best way to go. Another question about wounds, if they could appear after the first dose. I think you covered that that we don't really know, but there's also another question here. Might they be immune-mediated? Again, I wish I knew. I don't know. There may be some other association with them that we don't quite know. Okay. Is there a recommendation on treatment for xylosine withdrawal in an OTP, so an opioid treatment program? What is the presentation we would use for distinguishing between opioid withdrawal versus xylosine withdrawal when treating new patients in an OTP or with MAT to determine an effective blockade dose with methadone? That's a good question. I normally, most of my addiction is on the inpatient side. And so I often start thinking xylosine when they're on your typical full dose of buprenorphine or a decent dose of methadone, and they're still really restless. Restless and anxious beyond expectations. Because, you know, traditionally, you know, you get somebody on full, you know, 16 milligrams of buprenorphine, patients are really comfortable. They're really grateful. Like, oh, thank you, doc. I feel so much better. You know, the patient who's not better and really anxiety, restlessness is sort of driving their symptoms is when I start thinking xylosine. And the question was, so what would be a good, yeah, so that's usually, you know, what I kind of use to start considering xylosine. And then what would be a good dose? That I still don't know. I think right now, probably the best way is like an as-needed PRN dosing of clonidine or tizanidine or whatever you feel comfortable. Cyclobenzapine, apparently, for one person. Like a PRN dosing with some restrictions. Like what we do with the cows. I mean, you know, back in the day, we would give people these package of hydroxyzine and clonidine and Zofran and so forth to go home with. I think there may be more benefit to using, going back to that model of, you know, 0.1 milligrams of clonidine PRN as needed based on a cow score and let them do, let them kind of self-administer from your clinic. That might be the best way to go. Right, I do work in an OTP and I've had this problem come up with some patients and I did treat them with some clonidine in addition to increasing their methadone dose because to stop using xylosine, they're also stopping their fentanyl use typically. And they'll have both the opioid withdrawal as well as the xylosine withdrawal and want to get them on a stable dose of methadone. But also be careful just because of the additive effects with the clonidine and hypotension with the methadone. So I did allow, you know, for them to take a PRN probably every four to six hours is what I did in that case. Yeah, it's tricky. I mean, Julie's concerns are my concerns too. I think it's, we're still navigating uncharted territories right now. So it's interesting times for sure. Hmm. I have a patient who states months after xylosine use that new wounds are appearing. Is this true or more likely to be recent use? Again, not quite understanding the pathophysiology of the wounds. I don't know, like if it's an autoimmune issue as someone else has alluded to, that may stick with somebody. So again, I of course don't have a great answer to that question. Okay. Any go-to recommendations for xylosine wound management? So when you saw that patient yesterday or... Yeah, I mean, it's basically just typical wound management. Like a lot of them need debridement, you know, the wet to dry dressings. You know, my lady's arm looked a bit infected too. They don't, it's not typically infected but they can get infected. So they may need antibiotics. But I think, you know, the wet to dry dressings, wound debridement is probably a good starting point. And then, you know, preventing infection and keeping them dry and clean would be critically important too. Are there any things that you see that patients might be doing at home for wound care on their own that are bad to do or that would maybe make it worse? I think a lot of them pick at their wounds. Honestly, Julie, it's, which obviously is not good because it's not often hygienic. You can do it with, you know, sterile gauze, wet, you put it on, wet, wrap it, and then a day later you peel it off. That peeling off of the dried gauze helps debride it. That's probably the best way to go about it. Okay, another question here. I work with neonates who are opioid exposed and in the past year or more, we're having more difficulty treating those needing treatment. We use morphine and sometimes clonidine in addition, unable to eat, sleep, console methadone. Our umbilical top screens do not include xylosine. I understand the USTDL, the bat drug testing laboratory, will begin testing the cord for this. Are you identifying neonates that you suspect are affected by xylosine and why do you suspect? You know, we have a whole separate group that takes care of neonatal abstinence syndrome at our women's hospital. I unfortunately don't have any experience there, but you bring up a good point that certainly if our parents and mothers are exposed to xylosine, certainly the children are too. So I think your approach is probably a good one. Just a comment that somebody was using xylosine to help with sleep. Let's see here. Indications to order xylosine in emergency room settings since this is not part test or? Yeah, I don't know there's a great, I mean, we do a lot in our tox land to get comprehensive drug testing on patients for surveillance and to really kind of tease out what they've overdosed on. There may not be a great indication to do it other than for surveillance, because I'm not sure it will really change what you do other than maybe be more aggressive with their withdrawal management. I do see one about using lofexidine. Could you use this for withdrawal? The newer med that was used, the other alpha? No, I have not tried using those two, but again, I think those would be very pertinent drugs to use for withdrawal, absolutely. Yeah, I think the reason it's not on our formulary is just the cost. Yeah, they're expensive. So let's see. Somebody asked if you did xylosine levels, but I believe you said you do qualitative testing. Yeah, just qualitative. I heard that using Porter-SAV on wounds has been helpful with the healing process was a comment from somebody. I don't know if you had some experience with that. No, I think that's probably not a bad approach either. Okay, then how high a dose of clonidine would you start to taper? I kind of do like Dr. Timmick had mentioned in terms of like 0.1 milligrams Q4 to Q6. I find, I mean, I have the benefit of doing inpatient, so it's a little bit different too. And I know Dr. Timmick does outpatient work, but so typically if I'm worried that I'm not gonna get a big enough dose, maybe I'll try 0.1 milligrams every eight hours with a PRN on top. I think it's hard to know because it's probably largely dependent upon how much they're using. I think the patient, what's the word I'm looking for? Tailored dosing is probably the best and a PRN based on a cow is probably the best. And then once you figure out what dose they're requiring, then you can start tapering it from there over a several week time period. Right, and I think I have the advantage too that I can see people on a daily basis in our outpatient withdrawal management clinic. So that's sometimes what I've been doing with these folks too. And so I can adjust and talk to them about their response. Another question about blood pressure parameters to hold the quantity and what do you suggest for that? Yeah, I mean, presuming they're not hypertensive, I try to make sure they keep their blood pressure greater than 110, 105 or so. Certainly if they're symptomatic, they need to hold back. We have somebody in the audience here who said that they're pretty aggressive at Jefferson and city center. We have been going up to 0.3 TID with 0.1 PRN Q3 hours as BP will allow. Yeah, I have colleagues as well who they feel like you need to go bigger doses. So absolutely, I don't think you're wrong in terms of starting high. Some of my colleagues like to go big or go home. They joke that, you know, as toxicologists we treat toxicology with toxic doses of other drugs, so. Okay, well, it is actually after the six o'clock hour. I thank you for staying on. Thank you so much for this very informative lecture. I think, you know, this is great information since xylosine is spreading across the country. So thank you so much for agreeing to do this webinar. So next week, our webinar is going to be on Brixadi or the buprenorphine extended release, the new medication for the treatment of opioid use disorder that was recently approved by the FDA. So to get your CME credits today, go to the AOA education page where you registered to claim those credits. And then don't forget to join us next Wednesday, September 13th at five o'clock Eastern time. And we'll have Dr. Antoine DeWahy speaking on the Brixadi for treatment of opioid use disorder. Thank you so much. Bye-bye. Thank you.

webinar

Silazine

pharmacology

opioid use disorder

alpha-2 adrenergic agonist

sedation

wounds

naloxone

withdrawal syndrome

research