Okay. Okay, good evening everybody. Welcome to today's AOAAM webinar on the impact of the illicit fentanyl use on opioid use disorder treatment by Dr. Andrew Woon. My name is Julie Kmic and I'll be your moderator for this session. This is the first of a six-hour webinar series on hot topics in the treatment of opioid use disorder and stimulant use disorders. I'd like to introduce Dr. Woon who is an assistant professor of psychiatry and behavioral sciences at the Johns Hopkins University. Dr. Woon earned his PhD at Penn State University in 2016 and an MBA from Johns Hopkins Carey School of Business in 2018. His research is focused on understanding the human experience of opioid use and opioid use disorder. The majority of his work has been in the human laboratory studies and clinical trials to identify risk factors for drug relapse and medication strategies to improve opioid use disorder treatment outcomes. His lab employs diverse methodological approaches to better understand opioid use and opioid use disorder including neuroimaging, ecological momentary assessments, wearable technologies, human laboratory studies, and survey research. Taken together, this research is aimed at improving treatment outcomes directly and evaluating and strategizing macro level changes to improve health care for substance use and related disorders. At this point, I'd like to turn it over to Dr. Woon. Thank you. Great. Thank you so much and thanks everybody for being here. This talk will be on the impact of illicit fentanyl on opioid use disorder treatment. This initiative was made possible by funding from the Substance Abuse and Mental Health Services Administration. I'd like to thank them. The views expressed in my presentation do not necessarily reflect the Department of Health and Human Services. Unfortunately, I'm not there yet in my career. Yep, so my name is Andrew Hoon. I work in the Behavioral Pharmacology Research Unit within the Department of Psychiatry and Behavioral Sciences within the Johns Hopkins University School of Medicine, so a lot of umbrellas there. The majority of my work is with human subjects in clinical trials and human laboratory studies, and then I also do some kind of macro level health services research. I don't have any financial conflicts of interest for this talk. I do receive research funding through my university from the National Institute on Drug Abuse, the National Heart, Lung, and Blood Institute, and Ashley Addiction Treatment, which is a nonprofit organization. I'd like to thank Dr. Kmick for inviting me to speak today. So for the next hour, we're going to be talking about fentanyl. We're going to review national trends in fentanyl use and opioid overdose mortality. We're going to understand the pharmacokinetics of fentanyl in persons with opioid use disorder. We'll actually look at it first in just acute dosing and then some evidence from folks with OUD or opioid use disorder. We're going to identify how fentanyl and its analogs might impact OUD treatment and discuss approaches to improve OUD treatment for persons who use fentanyl. And I'll put in an early plug for the seminar next week where we're going to go much more in depth into that last topic through case studies and some other clinical data. So fentanyl is a dangerous drug. I hardly need to say it, but in relation to other drugs that are commonly used on the street, fentanyl is widely recognized as the most dangerous. And here we see the toxicity of these different drugs. And toxicity here is defined as the median effective dose as a percent of the median lethal dose. And so we can see that fentanyl has higher toxicity even than heroin. And then the list, you know, the toxicity kind of drops off from there. So a very dangerous drug to be using. And it's increasingly used around across the United States, highly, highly problematic just from an overdose potential perspective. So the current opioid crisis, I would really call it a protracted crisis or a protracted emergency, began around the turn of the century. So around 1999 or the year 2000, we started to see this uptick in opioid overdose deaths. And in a 20 year span between 99 and 2019, nearly half a million persons in the United States died from an opioid overdose. It's just a staggering number. And I hate that I have to start off presentations with this kind of depressing statistic. But even this doesn't really capture the impact of opioid use disorder in the U.S., right? I mean, this doesn't capture the millions of people who have suffered with opioid use disorder and, you know, lost family relationships and jobs and housing. It doesn't reflect the families of these folks who have also suffered and entire communities, you know, that have been impacted by opioid use. And it hasn't just been a steady problem throughout. The type of opioids that have been used and the way that they're getting into the illicit drug supply has changed over time. And we could break that into kind of three distinct waves within the opioid crisis. The first wave starting around the end of the 90s, early 2000s, where there was just a general overprescription of opioid medications. There was this kind of idea in the 90s that pain was the fifth vital sign and that we weren't doing enough to treat pain. And I agree with the need to treat pain. But at the same time, there's been a lot of press coverage around, especially the use of OxyContin or Oxycodone during that time period. And so there's a kind of general overprescription of these medications. And then there's some very few physicians who were just bad actors who were setting up pain clinics. All you had to do is show up and say your back hurt and you would get a prescription for Oxycodone. And this proliferated greatly throughout the early 2000s and became a real health crisis. And right around the time where the DEA and FDA actually started to do something about this around 2009, 2010, they start to crack down on these pill mills and on this kind of overprescription in general. These people are getting booted off of their opioids that they've been on for a long time. And heroin comes back on the street and it's cheap. Around that time, you could buy heroin for $5 a bag and it was way cheaper than buying Oxycodone off the street. And so people switched from prescription opioids to heroin. And you see this sharp rise starting in 2010 of heroin overdose deaths. And that was already bad enough. Like at this point, this is around the time too that I started doing opioid research myself. The situation seemed really bad. I felt good about doing research in an area that needed change. But then around 2013, we see this sharp rise in fentanyl use across the United States. Heroin being laced with fentanyl, fentanyl being sold as its own product. And here the opioid overdose rate just skyrockets. And as you can see now, from where we started in the 90s compared to where we are today has been a really dramatic increase in the number of overdose deaths per year. It's not getting any better right now. The COVID-19 pandemic has made things worse actually. We expect these numbers to go up. They did go up in 2020. 2021 will also be a higher number. And so we really need to get a handle on this. One thing I'd like to note here is that the overdose deaths due to prescription opioids have not appreciably declined since 2010. They've kind of went up and down like a little bit, but we haven't even really gotten this under control, let alone the heroin and fentanyl problems. And so there's really is a macro level change needed to address this issue. This is a distribution of the highest overdose death rates by state in 2019. So as you can see in 2019, the Midwest is still being hit hard by the opioid crisis. Some Southern states, especially West Virginia, Kentucky, which are kind of considered the epicenter of the epidemic are still being hit quite hard. The Northeast is being hit hard and the Southwest is seeing an increase. I think since 2019, there's been an increase in fentanyl use in California. Just from what I talked to, I have some colleagues in San Francisco who just hadn't seen fentanyl at the same level that we've seen it on the East Coast, but now they're starting to. And actually I found this really interesting case study in Ohio. So this is a percent of all drug seizures that contain fentanyl and it goes from 2014 to 2021. So for methamphetamine, as you can see in 2014, practically none of the methamphetamine contained fentanyl. Now about 5% contains fentanyl. Now that's a huge number, but that's like a one in 20 chance if you're using methamphetamine that you're also going to get fentanyl in the same drug supply, which of course can lead to overdose death. Cocaine is much more. They're up to 15% now in 2021, under 1% in 2014. And then heroin. In 2014, only 3.5% of heroin drug seizures contained fentanyl. Now it's 81.5% across the state of Ohio. Now I can tell you in Baltimore where I work, I think that close to 100% of our opioid supply contains fentanyl. I think you're more likely to get fentanyl in Baltimore than you are heroin at this point. And there's a lot of other things being mixed into the drug supply too here locally where I am that is cause for concern. We're seeing benzodiazepines and barbiturates being mixed into the drug supply, different types of opioids. Sometimes we even see methadone mixed and people are testing positive for these things when they show up and they say they've never taken them. And I do wonder from a drug dealer perspective, what is the rationale for putting all this stuff into the opioid supply? Do they think they're creating a better high for their customers? Are they trying to create levels of physical dependence that grip people physically in a way that makes it nearly impossible to get off? I'm not sure, but what I am sure about is that this is not an East Coast problem. This is not a Midwest problem that I talked to colleagues from many parts around the country and everybody is seeing an increase in fentanyl use period. And because fentanyl is cheap and because it's so potent and it can be shipped in small amounts, I think the black economic, the black market economics are such that fentanyl is here to stay. So this is just an overview of fentanyl. It's a highly potent new opioid receptor agonist. It's approximately a hundred times more potent than morphine and 50 times more potent than heroin. It has a common metabolite nor fentanyl. So mostly if you're testing for fentanyl in the urine, what you're testing for is fentanyl and nor fentanyl. Primarily metabolized by CYP3A4. There are some other things going on there too, but we'll just focus on that. The duration of effect for an IV administration, single administration is about a half hour to an hour for analgesic effects. Intramuscular administration is a little bit longer. However, the respiratory depressant effects of fentanyl can persist longer than the analgesic effects and of the forogenic effects. So this becomes problematic as people think that they're coming down and it's time to get high again. They may still be experiencing respiratory depressant effects that you wouldn't want to compound by taking more. And this is one of the ways that fentanyl is a very deadly drug. At the receptor level, it acts on the mu opioid receptor. These are G-protein coupled receptors. That's a very classic receptor type that's found throughout the brain and throughout the body. In general, these receptors activate a G-protein cascade and can also activate other cascades. Fentanyl compared to some other opioids works, it increases beta-arrestin-2 signaling. This is associated with respiratory depression, as opposed to analgesia. It is a very strong analgesic, but also a very strong respiratory depressant. And so we can start to imagine that this is a biased compound that's biasing towards being more lethal. The other thing about beta-arrestin signaling is that as that increases, it inhibits the efficacy of morphine. So we've actually seen this play out and we have some clinical trials where we do a morphine maintenance phase. When people come in, they've been actively using, we maintain them on morphine for a brief period of time to equilibrate their physical dependence before putting them through a clinical trial protocol. And what we've found recently is that the morphine isn't working right. It's not suppressing withdrawal the same way that it used to when people were coming in who primarily used heroin. So we're seeing this play out in real life. What beta-arrestin also does is it desensitizes the mu-opioid receptors in general, so they're not as sensitive to the effects of agonists. And it also promotes endocytosis of these receptors so that there are fewer opioid receptors available. And we'll come back to this topic when we're talking about treatment, why some of the treatments might not be working the same way they used to. In part, it could be because, A, the receptors that are there just aren't as sensitive to the medications that we're using, and, B, that there are straight up fewer opioid receptors available, which causes, which increases tolerance and has implications for withdrawal and for kind of post-withdrawal, or what might be termed as protracted abstinence syndrome. But it's not just the mu-opioid system that gets affected by opioids, right? There's this kind of classic dopaminergic reward system in the brain that's common to all substances of abuse, and this primarily consists of dopamine neurons in the ventral tegmental area of the brain that project to the nucleus accumbens, and this is your primary reward signaling. This signals natural rewards like food, water, sex, things that are, you know, biologically that we are motivated to engage in, and drugs of abuse hijack this system. And opioids in particular, actually, there are opioid receptors directly in the nucleus accumbens, so opioids can signal reward independent of dopamine, but they also promote dopamine signaling, and in the case of fentanyl, over time, it actually shifts the amount of the opioid signaling. So in an acute administration, you would get increased dopaminergic signaling, particularly increased availability of these D2 receptors, but with chronic use and tolerance, you start to see these kind of shifting set points, and you get a decreased reward response, you get kind of diminishing effects, and then when you take the opioid away, you really get into a bad state where there's a lot of, this kind of translates into not just talking about the acute withdrawal syndrome, but feelings of depression and anxiety that might persist for weeks or months after people are finally able to stop using. So some key points from this. Chronic fentanyl use down-regulates mu-opioid receptor availability. It desensitizes available mu-opioid receptors. It can also reduce the efficacy of morphine through beta-arrestin signaling. It decreases dopamine signaling in the brain reward system, and increases the risk of respiratory depression and opioid overdose fatalities. Fentanyl has some structural characteristics that are different than other opioids. So fentanyl is a fully synthetic opioid, not like morphine and heroin, which are derived from the poppy. So it has a different, even though it interacts in the same receptor system, it has a different structure, and it has a long carbon chain that makes it highly lipophilic. So in this figure, we're looking at the neurovascular unit, the blood-brain barrier, and on the left-hand side is the lumen, or the inside of the neurovasculature, and on the right-hand side is the cytosol of the endothelial cells that kind of create this blood-brain barrier and decide basically what gets into the brain and what doesn't. And so most things like morphine and heroin readily pass into the brain. Fentanyl passes into the brain very quickly, and it can be passive because it's so lipophilic. There's also a possibility that there's another transporter that aids in its transport across the blood-brain barrier. This affects a couple of things. One, how high it gets you. Basically, the quicker a drug hits the brain, the more high you will feel from that drug. This is why people change the route of administration, and there's been several studies across classes of drugs that demonstrate this, that the euphorogenic effects are largely in part to the molecule and how quick it can hit the neural reward system. And so fentanyl acts very quickly. But it also is passing easily across these endothelial cells and that has some implications for how it gets distributed in the body. So if we think about the kind of basics of pharmacokinetics, we think about absorption, how does the drug get into the body in the first place? Distribution, what type of tissues can it be distributed to? Metabolism, how is it broken down and what are its metabolites and are they active? And then finally, excretion from the body. And there's increasing evidence that chronic fentanyl use results in a biphasic elimination pattern. And there may be some evidence that even a single dose of fentanyl has a sort of biphasic pattern. Let's see, the chat is filling up. I'm going to go through this stuff at the end unless the moderator interrupts me. Yeah, just keep going, the chat's doing okay. Okay, great. So, oops. So again, fentanyl is broken down primarily through CYP3A4. Norefentanyl is its primary metabolite. It says here that it's inactive and everything I've read says it's inactive, but I've never actually seen the study that shows that norefentanyl doesn't act at the mu opioid receptor. So to me, this is a bit of a question mark. I'm not entirely sure if norefentanyl is inactive. I think it probably is, but if it is active, I don't think it does very much. But that's the metabolite. And then of course there are fentanyl analogs like remifentanyl, alfentanyl, and they often have different metabolic pathways and they have different metabolites. So you can start to imagine if you're trying to, you know, in your practice, figure out what somebody is using, norefentanyl is not like the universal metabolite for alfentanyl analogs. You would actually need a panel test of the kind of different, more common analogs to determine if somebody had used something, fentanyl for sure, but then if, you know, if they're using any of the other metabolites, and these become very tricky as we are going to learn in a minute. So this is some basic pharmacokinetic information on fentanyl and a few of its metabolites. There is a transdermal patch that some might be familiar with. This is for like chronic severe pain, chronic severe pain. It has a terminal half-life of 20 to 27 hours after patch removal. That's due in part because the fentanyl patch creates a depot of the drug on the skin, or in the skin that, so even when you take the patch off, you are still getting fentanyl in your system for several hours after it's removed. IV fentanyl has a terminal half-life of two to four hours. Different studies show kind of wildly different terminal half-lives for fentanyl, but this is kind of how we think about it, right? I mean, fentanyl, it was designed as a analgesic for acute severe pain, mostly for anesthesia purposes or like in a hospital setting. And so these different studies have been done with that in mind. They aren't necessarily looking at what happens when you take fentanyl every day for months and years, which is what we're seeing now, and how does that change things? And we're gonna talk about that in a little bit too. And then there's some of the different fentanyl analogs. These are common. Remy fentanyl is extremely short-acting, three to 10 minute half-life. These are, it's potency compared to fentanyl and compared to morphine. What I wanna point out is that the different analogs have wildly different potencies, up to 10,000 times as potent as morphine. The CAR fentanyl, which my understanding is that it's relatively easy to make and it's, you know, has been introduced into the US drug supply. I don't, it's not ubiquitous, but it's in there here and there. It's extremely potent. I mean, I can't imagine having somebody who isn't a trained professional working with this compound and that being sold on the street. And it's very, very dangerous. So like I mentioned, these previous pharmacokinetic studies of fentanyl they generally rely on a single dose administration to determine the PK or perhaps a few doses over a relatively short period of time. And they only go out, even the fentanyl patch information, they almost never report longer than a day, sometimes up to three days to determine that half-life. But, you know, especially for the fentanyl patch, like we don't know how long that actually takes to fully clear out of your system. And you get these wide ranges of potential half-lives from one and a half to seven hours for the IV, one and a half to six hours for intranasal. And it's just not totally clear how the fentanyl behaves in different situations, in different people. There is some evidence of this biphasic clearance that I was talking about where I think, what's happening is that fentanyl use, so if you were to use fentanyl or have it administered, that there's like an initial clearance that occurs that some of that fentanyl is soaked up into adipocytes or fat cells and is compartmentalized there and then re-released into the body. So while you get this like initial dip and when you're trying to determine your half-life that then there's can actually be a protracted clearance after that. And in this study on the left-hand side, they were showing morphine versus fentanyl and a couple of different fentanyl analogs with the percent time into the system, systemic circulation via the spinal cord and how it would pass between the spinal cord and the epithelial, I'm sorry, the epidural fat. So in this, the, the dotted line is how quickly it goes into the systemic circulation and the straight line is how quickly it gets soaked up into endothelial cells. And so as you can see, fentanyl compared to all these other drugs is primarily being compartmentalized in endothelial cells. And then here on the right-hand side, it shows the transfer rate for drug movement into epidural fat, which is too small to be calculated for morphine. It's 15 times greater for fentanyl than it is compared to another lipophilic analog, which is sufentanil. So highly lipophilic, definitely not just something that's going into the circulation, being metabolized and being excreted. And so this information coupled with some of our experiences in recent clinical trials where we were kind of battling against this buprenorphine precipitative withdrawal problem, which I'm sure a lot of you are very interested in, caused us to really question how long it might take to clear fentanyl from the system. And so we did a small pilot study in a 28 day residential treatment facility. This is just a study with 12 individuals who came in testing positive for fentanyl. We had them give a urine sample upon admission, and then every three days after that, until they either tested negative for fentanyl or they left the facility. And so the, interestingly, the mean time for fentanyl clearance in this study was about two weeks. And the range of time was three days to 26 days. So we had one person who just never tested negative and left treatment. And I actually think this average time is probably an underestimation because not everybody in this study was a daily fentanyl user. Some people had maybe gotten something that was laced here and there, but weren't using every day, like the good folks at Baltimore, who I think are exposed to this on a daily basis. So this is definitely something that we're interested in following up on, but it has several implications, right? Like, and it explains a lot about the buprenorphine precipitated withdrawal problem. Like just because somebody is in enough withdrawal to meet the criteria for a standard bup induction doesn't mean in the case of fentanyl that it's all cleared out of their system or that enough of it is cleared out that the bup isn't gonna come through and kick off the fentanyl from the receptor and throw you into this kind of wild precipitated withdrawal state. And so that was one really important implication from this study. Another important implication is legal, right? So people are being drug tested by the courts and they could have quit using weeks before. And if they're getting fully quantitative testing, they can still test positive for a long period of time. And so I've actually been contacted by lawyers because of this paper, who were interested in showing that the client indeed hadn't been using heroin or fentanyl. There's a bunch of fentanyl analogs out there and it's hard to keep track of them all. They generally fall into three categories based on what part of the fentanyl the parent compound is being altered. These are common fentanyl analogs in the drug supply. And depending, we now do fully quantitative urine testing for all of our studies because I'm just incredibly interested in this topic. And so some of these are now being done standard if you do a fentanyl panel with like Quest Diagnostics or different lab, LabCorp or whatever, we have a different one that we use. But you can actually get some semi-quantitative results on some of these because they don't, like I mentioned before, they don't necessarily have a common metabolite in norfentanyl, but it's pretty common to see acetyl fentanyl, acrofentanyl, butyrophentanyl. Carfentanyl hasn't been common in the Baltimore area since I've been doing this, but I know that it's around different parts of the US. And so these are some of the things that you might expect to see. Big question though is, so we've shown this kind of PK information even with the common analogs that are used medically, but a lot of these are just like stuff that doesn't get used in medical. And it's like, what do these different analogs do, right? So this is a study that was done by Neil Varshnia. He was a postdoc in my lab. This is something that he did as part of his dissertation research before he came to us, where he was looking at different fentanyl analogs and what the respiratory depressant effects of those analogs were in mice, or I'm sorry, in rats. And these are a lot of like, Neil had this whole line of research where he was looking at the pharmacokinetics of different fentanyl analogs. And some of these are kind of like, I would say kind of exotic fentanyl analogs are not super common. The point of this slide is not to go through the study per se, but the point is to show the wide variation in what they do. So in the black dot lines, the filled dots, he would pre-treat with naloxone just to show that naloxone would, mostly protect against the respiratory depressant effects of these different analogs. In the white circles, this is without naloxone pre-treatment and it's showing the percent decrease in respiration. And as you can see, different analogs have different respiratory depressant effects. That's the whole point of this slide. It's just different. If you're taking fentanyl versus acetyl fentanyl versus acro fentanyl, if you have some combination of those things in your drug supply, you can just expect a different risk for mortality and respiratory depressant. They also have different euphorogenic effects. So this is a separate set of analogs. Here, he actually tested it against morphine on the upper left, fentanyl on the middle upper panel, and then some different fentanyl analogs. Some of these you might be familiar with, most of them you're probably not, but that's okay. Because all I want to show here is that for different types of dosing. So the clear lines here are cumulative dosing. The black dots are single ascending doses done on different days. And the clear dots are showing analgesic effects. The black dots are showing straight up locomotor effects, which is kind of like a crude measure of drug effects, maybe euphorogenic effects. It's kind of just a crude measure of how the drug is subjectively affecting somebody. So some of these analogs, fentanyl itself, are highly analgesic, some are not. Some produce greater locomotion effects. Some produce no locomotor effects. They're all dead. Once you change the structure of fentanyl and you have these different analogs, they're just different. And it's so risky when people are using these on the street. And it's kind of turned into this like fentanyl analog whack-a-mole, especially for places like the DEA or the World Health Organization where they're trying to schedule these medications to make it illegal to transport them, et cetera, et cetera. As soon as they give a handle on one set of analogs, another set of analogs shows up. They can broadly be classified as structural classes, but there's 121 known fentanyl analogs out there, and the number keeps going up. So the analog problem is another biggie, right? The fentanyl in itself, though, I mean, that's the primary synthetic opioid that's being used. Fentanyl is the primary one. But then these different analogs are popping up. We're not sure about the risk of them all. We're not sure about the risk of mixing those with other opioids, with other non-opioid illicit Medicaid drugs. This is a big, complicated problem. And so it makes us think as we shift into a discussion about treatment, how does fentanyl affect drug use behaviors in general? And also, how does the proliferation of fentanyl affect opioid use disorder treatment? Namely, I'm gonna be talking about buprenorphine treatment, methadone, medical supervised withdrawal treatment, and extended release of naltrexone. So first, we'll talk about the behavioral economics of fentanyl use. So this is a study that we did in 69 individuals who currently use opioids. And this is kind of like a behavioral economics task, basically people are asked hypothetical questions about their drug use, how much drug they would use if it costs a penny, if it costs a dollar, $5, $10, to kind of see how much they value different drugs. And then we would frame these questions by prompts. So we would say, well, what if your drug contained impurities that were inactive, like baking soda, would that affect how much you would use or how much you would purchase? What if they had impurities like fentanyl that could have drug effect? How would that affect how much you would buy? And then, so we didn't just do it by the impurity questions, though we also did it by known overdoses from a batch of drugs. So this was the really novel aspect of the study is that we would hit them with this proposition, like, you know, 100 people have used opioids from this batch and zero died. How much would you purchase? Five people died. How much would you purchase? 10 people, 20 people, to see how much they might discount the drug by a function of how likely they were to overdose from it. And then on the right, this just shows the demographics from the study. So it was close to 50% male. The average age was 32, about 80% white. The mean dependence score was 8.3. That would be about moderate opioid use disorder. And there was a range of scores. So of the people in this study, many, 62%, had a history of opioid overdose. And those people had experienced on average about three and a half overdoses. An average of two where they maintained consciousness, an average of two where they lost consciousness. And these are the different substances they used during the overdoses, with heroin being the most common, fentanyl at the bottom here being the second most common, and then alcohol and so on and so forth. So these were identified as opioid overdoses. And it's noteworthy that people don't always know that there's fentanyl in their opioid supply. So this number could be higher. It could be higher in different regions of the country too. So one thing that I've seen discussed quite a bit among the research world is, do people actually like fentanyl? Are they, you know, there's this, I think misnomer that people are actually seeking out fentanyl. If they're seeking out more dangerous, versions of opioids because it gets them higher, this isn't what we found in this study. So here, this is the opioid demand for heroin on the top line versus fentanyl on the bottom line. As you can see quite clearly, people in this study greatly preferred heroin over fentanyl. So I don't think, and this jives with what I hear from participants who come through our studies and I talk to them about their drug use. They mostly are not liking the fact that they are using fentanyl every day. They hate it. The physical dependence is worse. They don't get high off it anymore. The window between them getting high and them overdosing is becomes more and more narrow over time and they just in general seem displeased. I think 10 years ago when fentanyl was more of a novelty you know people were attracted to it a little bit more it was like a change up in if you were using opioids that you know some people would say oh well this will get me really high and it's short it's like I heard one participant say it was like the crack of opioids but that wasn't their experience anymore now they use it every day it's it feels more like a maintenance drug to them. So the different purity questions in this study did not affect people's drug use behaviors which is actually pretty interesting so here when we gave them purity prompts about drug effects about inner impurities or about active impurities like fentanyl it didn't actually change how much they would use at all so this was a kind of a null finding which I thought was kind of interesting but what's more interesting is that when you start to talk to them about the risk of opioid overdose this does shift how much they might purchase and use. So there was a clear what I call death discounting in this study that as the overdose likelihood increased that people were less and less likely to use again interesting that these first couple of dots don't actually change so this is like on the far left is you know a zero percent chance of overdose a one percent chance of five percent chance you have to go over five percent before people started shifting their behavior which is kind of scary I mean if you think about that like a five percent chance of overdose that's a pretty high chance so I think there's still some things to be sorted out here and helping people understand the risks that they're taking but the death discounting was more effective than the purity discounting even though these two things were correlated which is shown on the far right in the middle panel here you can see clearly that people were less likely to use when they were prompted by discussions about drug overdose death and I think this is important to clinicians as you're talking to people who are using opioids every day that you know talking about oh geez you don't know what's in the drug that conversation on its own might not really shift drug use behavior but when you start talking to them about the risk of opioid overdose death and framing in that way as a future consequence of their use then perhaps this will start to shift some risky behaviors and then this is just we asked some questions too about different harm reduction strategies I'm not a real harm reduction isn't like the the crux of my research so this was kind of an interesting sidebar to me the most common harm reduction technique that people were interested in was carrying naloxone and there's a big push for this across the U.S. to get more naloxone out there people were you know about half were interested in safe injection sites and needle programs actually a pretty high percentage were interested in heroin maintenance and prescription opioid maintenance again that's not my I don't do that research myself there has been some some things done in Canada where these services are available and you know you can look those up this and I wanted to mention too this study was done by another postdoc in our group Sean Dolan he did a really excellent job with this study so the big takeaways here are that persons who use opioids do not necessarily prefer fentanyl over other opioids and that discussing the risk of overdose death might in fact reduce risky behaviors in this population and that there is a place and for harm reduction services and folks with OUD and that in fact they would be willing to use those services okay so buprenorphine precipitated withdrawal this is such a big problem and I'm interested to hear what other people have think and have experienced with this there's a lot of ideas flying around so this is just an over like a broad overview of what happens so at a mu opioid receptor buprenorphine which is a partial agonist partial antagonist has a very high affinity for the mu opioid receptor it can come through and actually kick the other opioids off the receptor and what it replaces it with is something that's much weaker and then further these other opioids got booted off the receptor start to be metabolized there's less other opioids circulating in the system and all of a sudden your mu opioid receptor system went from like you know heavily being agonized to if you know only partially being agonized maybe partially being antagonized and it throws you into this intense withdrawal syndrome and if anybody's seen this firsthand I mean there's great you know there's different levels of precipitated withdrawal but at the high level like seeing somebody go through a very severe precipitated withdrawal is alarming they are in a lot of pain it is a very difficult situation and with buprenorphine being you know probably our number one medication strategy to combat the opioid crisis the fact that so many people are struggling to get people who are using fentanyl onto buprenorphine is a major problem a major problem because we've put a ton of effort and research into getting people into the development of buprenorphine in and of itself and a lot of effort has gone into expanding buprenorphine availability getting more people on as a kind of pathway to long-term recovery whether they stay on extended maintenance or not that just it's a good treatment for opioid withdrawal if you want to use a buprenorphine taper highly effective drug but so many people across the country are are getting are really struggling with this so I'm going to go through one more brief study and then we'll stop there and we'll talk more about the buprenorphine precipitated withdrawal next week but here I just wanted to show you know how this is affecting people across the country so this is a different survey study that we did of people who were entering opioid use disorder treatment across the country we were able to survey 1600 people across 49 different addiction treatment centers we asked them about their withdrawal symptoms when taking buprenorphine only people who used opioids were allowed into the study in general the patients were about 30 years of age 70 percent male 80 percent white about 70 percent reported that they had probably or definitely used fentanyl prior to their treatment and about 42 percent knew someone who used fentanyl experienced precipitated withdrawal I would say this is much higher in Baltimore everybody I talk to now knows about precipitating withdrawal from buprenorphine but you know here we're capturing people across different but you know here we're capturing people across different geographic regions so here we ask people following their last following fentanyl use have you experienced withdrawal symptoms when taking buprenorphine or methadone and we don't expect methadone to produce opioid precipitated withdrawal at all this is kind of like a control condition and you know some people did endorse that they experienced some kind of moderate or severe withdrawal when taking methadone I suspect is that those are people who took a very low dose and it just didn't do enough to stop them from going into withdrawal but people were much more likely to report severe withdrawal with the buprenorphine and here we show when they were more likely to experience the withdrawal relative to their last fentanyl use so a very high percentage or a higher percentage of people within 24 hours so definitely need to wait longer than a day 48 hours still a high higher percent of people experiencing precipitated withdrawal 72 hours even you're seeing some precipitated withdrawal and on the right panel here we're just showing that again that people were more likely these are people who had used both methadone and buprenorphine after fentanyl and again that these people were much more likely to report withdrawal from buprenorphine and this is just showing the odds ratios for the bup versus the methadone none of the methadone stuff was significant so even though there was a little bit higher percentage at the 24-hour market didn't act wasn't actually statistically significant was significant for bup in 24 and 48 hours within using close to being significant within 72 hours as well and in my experience many people need to wait at least 72 hours before trying a buprenorphine induction although there's some different strategies here that we're going to go over next week and so at this point it's 5 50 I do want to be able to field some questions so I'm going to save the rest of the slides for next week and let's do this I'll switch to my uh my thank you slide so I'd like to thank everybody for attending I'd like to thank my collaborators Kelly Dunn and Eric Strain who are mentors to me Neil, Shawn, Jennifer and Elizabeth who are all postdocs who have worked with me and then Cecilia and Greg who are other collaborators with the lab and again I'll plug the webinar for next week where we're going to go through case studies and go much deeper into the clinical implications of fentanyl use and with that I thank you and I'm happy to answer questions okay thank you so much Dr. Hu that was very interesting research that you were able to go over and we do have some questions here somebody was asking when you were talking about fentanyl just being in the drug supply somebody had commented that it's in their state it's in marijuana and just wondering about putting it in other drugs too you know it seems to be in cocaine as well as heroin supply yeah yeah so we're seeing a lot of that I mean um you know we have like I've even had people test positive for fentanyl at treatment intake and all they used was prescription opioid you know it's like it gets pressed into pills that look like oxycodone or even that look like xanax or something like that yeah it's it's really becoming ubiquitous um well you know one thing I'll mention is that there are fentanyl test strips that are I think available definitely some stuff that's being developed that is just like a harm reduction service that you know people who are out there using it would be a good idea to test their drugs to make sure there's not fentanyl in it right um and then somebody was wondering what proportion of fentanyl overdose deaths are due to accidental fentanyl intake versus intentional has that been researched I don't know you stumped me on that one you did have a slide where the people who had experienced an overdose in that one study there were uh it was asking about intentional overdoses on that one slide I do remember down towards the end you in one of your studies that you did with your postdoc oh one yeah yeah that one um number of intentional yeah I don't think that was framed the same way I think we were asking this more in a way of like um these these instances of like deaths of despair basically where people are kind of trying to um take too much um but not necessarily that they knew or didn't know that there was fentanyl oh yeah I see okay yeah um do you happen to know the proportion of opioid users who specifically seek out fentanyl no I don't think it's very high anymore though like I don't know I just can talk you know this anecdotal um that and the people that I talk to who enter into a clinical trial with us so I'm not you know they know I'm not their long-term treatment provider I'm not even a provider myself you know I'm a scientist but I'll often talk to them about their drug use and um specifically about fentanyl and most people who are using it every day hate it they hate that they have to keep using it um people preferred when there was heroin on the street um you know which is a funny thing for me to even say like that we're um we wish we could dial it back to heroin and the fentanyl stuff is just so bad I mean it's the overdose risk is worse the way that it interferes with treatment is worse um it's harder to get off okay um now a question about urine toxicology so the fentanyl analogs are they picked up in toxicology tests as fentanyl or are some of them not picked up at all I don't believe some of them are picked up as fentanyl so you have to read the label of your test if it's a dipstick right most dipsticks are testing for nor fentanyl and uh as we went over a lot of these analogs don't actually have a nor fentanyl metabolite no if there's cross reactivity or something I don't know um but we actually um we started doing fully quant testing for the fentanyl so we always send it to the lab and um so they'll give us a you know a concentration number for that and then a um a semi-quantitative uh number for several of the analogs um I actually don't know there probably is there's got to be a dipstick with the analogs with some of the more common ones um but again you know different analogs pop up they might may or may not show up on the test strip um there are some questions about higher dosages but I think next week when you talk about clinical scenarios you're probably going to be addressing that in terms of using higher dosages of buprenorphine yeah yep that is definitely one of the things we're going to talk about so there yeah um I mean just to give you a preview though there is I mean there's different strategies right for getting people on to buprenorphine in the first place one thing that we've used is this low dose approach which is sometimes termed microdosing or I don't know the azor method or the bernie's method or something um it's basically just using lower doses than normal um to get the buprenorphine into the system without creating a shock the drawback is that people have to be stuck in this kind of moderate withdrawal state for quite a while um and there is a high dose approach I just haven't seen enough I've talked to other I've talked to clinicians who have said oh yeah I just gave somebody like 24 milligrams off the bat and they and there was no precipitated withdrawal and it worked and I'm just until I see it like in a study I would just be really nervous about doing that but maybe other people here have experience with that as well um I've just you know having uh sat through many precipitated withdrawal uh sessions I am would be rather shy about attempting that approach um based on your research would you recommend buprenorphine dosing for persons who have used fentanyl after 72 hours or still use the cow scale to determine the timeline I think you have to do both um I mean there is there's a lot of variability in the way that people express withdrawal in the first place so we're typically we we want people up around like a cows of 13 or 14 before we start buprenorphine dosing if if they've if they test positive for fentanyl um but if it's been 72 hours and they're not there yet it could be that they just don't have the same level of physical dependence as some other people and uh you can try I mean we'll go into this more next week but like I'm becoming a really big fan of this low-dose approach at least like try like one milligram um and see what that does because if you precipitate any withdrawal with that small amount it'll be like a really kind of mild very mild precipitated withdrawal and then you'll know that you need to to take it slow with that person and if you don't then you can kind of feel better about going forward um let's see here yeah can you comment on xylosine being found in the supply another substance that you've been seeing in dea reports no I can write that down though I can ask I can ask one of my former postdocs about that and then um somebody would like to know has anyone created a user-friendly test for fentanyl that patients could use to screen their drugs so just like you were talking about these fentanyl test strips um yeah I just don't know if they're commercially available so that's another thing I can look up and speak to next week yeah there's some harm reduction programs will have fentanyl test strips available and yeah like I know I work with a group that does um they'll test your drug for you but it's not as convenient for some people I think it's just not actually practical for a lot of people okay so it is now six o'clock uh we will record any of these uh the rest of these questions that are in the q a box for next week and we're going to have case presentations next week from Dr. Hoon and also continue on with this question and answer session so if you do have any questions for him that they can answer today or you think of some in the next couple of days please go to the AOA education page and enter your discussion or your questions in the discussion board so I'd like to thank you all for attending today I'd like to thank Dr. Hoon for this very informative webinar and I look forward to seeing you all again next week great thank you bye

illicit fentanyl use

opioid use disorder treatment

drug supply

behavioral economics

risk of overdose death

buprenorphine precipitated withdrawal

withdrawal symptoms

fentanyl analogs

harm reduction services

opioid overdose deaths