webinar on The Fourth Wave, Addressing the Intertwined Fentanyl and Stimulant Overdose Crisis by Drs. Daniel Siccarone and Steven Shoptop. My name is Julie Kmic and I'll be your moderator for this session. This is the fifth 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 our presenters for today. Dr. Siccarone is a professor of family community medicine at UCSF. His research is centered on the contextual issues of treatment and prevention of HIV, AIDS, and related diseases in socially marginalized populations. His research is in exploring the different medical consequences of use of various sources and forms of heroin. The US has recently entered a new heroin epidemic, this time fueled by the recent opioid pill epidemic. He's exploring the economic, anthropological, historical, clinical, and public health dimensions of the crisis. His work has been published in JAMA, New England Journal of Medicine, PLOS Medicine, and the Journal of AIDS, as well as other peer-reviewed journals. Dr. Siccarone is a medical educator and has largely worked towards improving social, behavioral, and prevention science content within the undergraduate medical school curriculum. He is responsible for designing extensive curricula, editing syllabi, recruiting faculty, and hosting sessions and direct teaching, as well as designing and leading assessment activities. Dr. Stephen Schapta is our other presenter, and he's a licensed psychologist and director of the Center for Behavioral and Addiction Medicine. Dr. Schapta is a professor in family medicine and psychiatry and behavioral sciences, and vice chair for research in family medicine at UCLA. From these contexts, Dr. Schapta conducts a portfolio of research that focuses on the medical treatment of addiction and of HIV prevention in the context of addiction. His research collaborations are with basic scientists and clinicians to study the ways that drugs of abuse, especially methamphetamine, affects biological processes relevant to HIV transmission. Dr. Schapta energetically maintains research, clinical, and policy efforts to bring novel and high-impact solutions to delivering culturally competent care for patients affected by addictions and HIV. In addition to his extensive research portfolio, he maintains a limited clinical psychology practice at UCLA, treating patients with severe substance use and mental health disorders. So I'd like to welcome both of our presenters today, and thank you for attending. Thank you, Julie. It is a distinct honor and pleasure to be here joining the American Osteopathic Academy of Addiction Medicine and the Opioid Response Network, both terrific groups, and I'm honored and privileged to be here. The way this is planned out is this is a two-week, two-part series I'm gonna present today. Some of our findings around fentanyl use and methamphetamine use in combined ways, and then Steve, Dr. Schapta, will be the leader of next week's presentation using a more case-based format. So with that, let me share my screen, and we will get started. All right, the title of today's talk is The Fourth Wave, Addressing the Intertwined Fentanyl and Stimulant Overdose Crisis. Here's a message about funding for this webinar. My disclosures, I'm on the Psychiatric Advisory Board for Solero Systems, working on an overdose treatment device that has no relevance to the content of today's presentation. And here are my objectives. Hopefully at the end, you'll recall the history and epidemiology of overdose due to the four waves, as I'll discuss, explain two polydrug use patterns involving synthetic opioids and methamphetamine, and propose three harm reduction measures to prevent overdose deaths due to synthetic opioids. My work comes out of a seven-year study which just ended, actually, called the Heroin in Transition Study. It's funded by NIH NIDA. It is a multi-methodological study spanning the disciplines of economics, epidemiology, anthropology, and clinical interpretations. On the quantitative side, we're looking at supply changes and how they relate to problems such as hospitalizations or deaths. But we're really keen on our ethnographic work where we kind of take a deep dive, we'll go down to the street level, understand the lived experience of users themselves, how they're perceiving fentanyl, how they're adapting to it. That's been one of the major goals of this project. And you'll see a lot of publicly available data in this presentation from the CDC and the USDA, among others. The flow for today, I'm gonna go through the epidemiology, the triple wave, actually, the fourth wave, get into what's going on with methamphetamine. And the current research is moving into the direction of a historic era of polysubstance use involving a very powerful opioid and a very powerful stimulant. And then we'll get into clinical and harm reduction responses to this historic era. So let's start with some history. All right, here we have over 100 years of U.S. mortality data. This is a rate. We see, of course, a big spike up 100 years ago, the so-called Spanish flu epidemic causing a spike in mortality. And then 100 years of progress, of declining death, rising life expectancy, as one would expect from public health and medical advances in this country. Unfortunately, we've been hit by another pandemic, this one also causing a spike in mortality. That, of course, is COVID-19. But the goal of today's talk is not to talk about COVID. We can, if there's some questions about how it's affected overdose, we can address those at the end. But it's to talk about the reversal of fortune, the rise in mortality in this country that began before the COVID pandemic and has continued through it. If COVID didn't happen, we would have had about five, maybe six year, steady increase in mortality in this country. And that is due to the drug overdose problem. The overdose problem in this historic form, the thing we're talking about in the last decade or so is due to opioids. It's coming three waves. The prescription pill overdose wave, that's the blue line there, expanding 20 years, steady rise. It is finally leveled off, but it has not really come down despite our efforts to control prescribing practices, to reform prescribing practices, I should say, but it has morphed. As we got control over, to some degree, of the prescription side of things, we launched wave two of the opioid problem. And that is folks transitioning from dependency on opioid pills to heroin. And that's wave two there in the burgundy line, a rise since 2011 in mortality due to heroin. That has become flat more recently and maybe even declining. Unfortunately, that also begat and is intertwined with a third wave of overdose mortality. This due to synthetic opioids, including fentanyl, fentanyl analogs, and a small number of non-fentanyl synthetic opioids. This attack curve has not ended. It's only gotten worse. And unfortunately, we're now moving into a different class. This was predicted by some of us that throughout history, we undulate between opioid crises and sort of downer crises to upper crises. And now we have the uppers coming back. This is the mortality rate increasing due to cocaine in gold and psychostimulants in gray. And we'll talk more about this. But I'm calling it the fourth wave of the opioid overdose crisis because it is intertwined with the waves that came before. Or at least that's my thesis. To catch us up, that was the date up to 2017. I show that graph because it's colorful and it allows me to demonstrate the waves clearly. But let's catch up on the more recent data. This is CDC provisional overdose data. It's got us up to September. I think that October data might be out at this point as well. And what we see here is very unfortunate. That during COVID, the black line is all opioid overdoses rose dramatically. You can see that after January of 2020, we see further acceleration in deaths due to opioids. And this of course is driven by the second line there in gold, which is synthetic opioids. So let's focus on the third wave. Let's focus on fentanyl, and it should be fentanyls because it's a plurality of chemicals that are involved here. Where are these fentanyls coming from? The first thing we need to understand is that they're illicit products. This is not diverted pharmaceutical product. There's a small amount of diversion of pharmaceutical fentanyl. It is not what we're talking about in terms of this historic rise in overdose due to synthetic opioids. These illicitly manufactured fentanyls are coming from China and down to the United States in three routes. One is direct importation through the dark web. This is a small flow of drugs, but they tend to be of higher purity. The second and actually largest flow is through Mexico where the fentanyl is being mixed in or co-shipped with heroin. And we'll talk more about that. And the third, and this one is a rising phenomenon. It's not just the Canadian route, but it's also the Mexican route where fentanyl is being pressed into counterfeit pills and then shipped across the respective border into the United States. This data comes from this schematic, if you will, comes from the DEA as best they understand it. DEA is also telling me that more fentanyl is being manufactured in Mexico and the pill side of the problem has switched from what was probably as of 2016, largely Canadian export issue to more of a Mexico export issue. Where's the fentanyl going? This illicitly manufactured fentanyl is a regional phenomenon. It's expanding now, and we'll talk about that, but initially very strongly going, this is supply data going to the Midwest, sorry, the Northeast, that's in red and the Midwest in gold. Where is it landing? This is a map of mortality. The darker the state, the higher the mortality. We see that fentanyl, at least as of this snapshot, this is 2018 data, Northeast, the industrial Midwest down into Appalachia. Things we need, basic facts we need to understand in addition to the fact that this is illicitly manufactured product is that it's integrated into the heroin supply. When we do work in places where fentanyl is hit and we say, so, what do you call this? People always say, well, I call it fentanyl, but there's no good slang for it. Maybe now some people are calling it Fetty. That's sort of a little bit of a whisper of slang that's coming around from some parts, but for the bulk of the time that fentanyl has been in the United States, since about 2014, at least this wave of it, there hasn't been any lingo, and that the reason for that is because it was folded into the heroin and people were just buying heroin. And we wrote a number of papers, sort of thought papers on this, that basically said fentanyl was imposed upon the market. It's a market imposition as opposed to a demand-led phenomenon, right? If fentanyl was a light drug, if it was the new version of MDMA or some other kind of party drug, we would quickly have developed lingo. It would have been sold as is, and it would have been marketed, right? None of those things happened. It's folded into heroin, sold as kind of a substitute or an adulteration, a contaminant almost, of heroin. We recognize now that fentanyl is very strong. It's somewhere between 20 to 40 times as strong as heroin by weight, depends on whose data you're looking at. And that potency is a major part, obviously, an obvious risk factor for overdose. But it's not just potency. We also have to keep in mind that purity matters, that fentanyl analogs come in different potencies compared to the mother chemical. And so vicissitudes in potency, vicissitudes in purity are also very strong concerns in the overdose phenomenon in wave three. I've already talked about bullet number three. And we do have a prior example, and it's a contemporary example as well, and that is levamisole went from a sort of a minor, occasional adulterant of cocaine to fairly ubiquitous at this point. And there's a lot of concern about that. So here's the problem with the vicissitudes, the variation in fentanyl. There are now hundreds of fentanyl analogs out there. And the literature, the chemical theoretical literature supports this family containing at least 600 members. Now, are there 200 members of forms of fentanyls currently on American streets? No. The mother chemical fentanyl is the majority product, and there's about a dozen, maybe 15, 18 that are floating around in various forms. Some of the more common ones are listed here. We also get little spikes or little notices about other novel synthetics, like the U-series, U47700, U48800. They have very curious names, chemical names. Isotonitazid is now a current one that's out there, and it's cousins as well. The one that we're really worried about is the fentanyls that end in NIL, carfentanil, alfentanil, sufentanil. These are super potent. Carfentanil is 10,000 times as potent as morphine by volume or by weight. And everywhere that carfentanil goes, you immediately see a wave of mortality. And it has come in waves, because I think what happens is the supply realizes that it's an unreasonably strong chemical to be out there to pulse it back, because it's killing off too many customers. So you can see the bottom graph is darkly shaded in all states, except for a couple. The point I wanna make with this slide is that COVID is making things worse, but the drug supply is also making things worse. We have here a map showing a rise in overdose based on the last 12 months. So this would be January, 2020 to January, 2021, impacting all states in the country. And I just showed you that fentanyl was a regional problem, right? So how do we explain the rise in mortality? Well, fentanyl is spreading westward, right? It's hard for me to put that in a single graph other than this one, but if I were to show you a graph, let's just say of California, we would see a similar attack curve that we saw from 2014 to 2017 for fentanyl in the Northeast. We'd see that in California beginning around 2018. So other states, Washington State, New Mexico, Colorado, reporting the same, right? What's also happening is that methamphetamine is moving out of its traditional zone, which is sort of west of the Mississippi River. Methamphetamine is also going to the Southeast United States, and there's even reports, and I wrote one with Dr. Sarah Wakeman in Boston, showing methamphetamine is showing up in the Northeast now. So multiple trends, all to the negative. Let's talk about methamphetamine, and let's talk about why I believe that it's intertwining with fentanyl. It's what's causing the fourth wave. You've seen this graph already. That's opioid overdose deaths rising. That's fentanyl deaths rising. And here we have the psychostimulants in gray and cocaine just below that rising. The CDC does its best job interpreting local coroner and medical examiner reports to determine what class to put in. There's gonna be overlap in this reporting data in terms of if it's a co-occurring death, how do they classify it? They may have classified it as both. But other data show that cocaine, for example, mortality rate has tripled in the last 20 years. Psychostimulant data of mortality, 18-fold increase over the last almost 20 years. The question that becomes why, because we don't think of cocaine and methamphetamine as particularly mortality-dangerous drugs, right? Yes, of course, a weakened heart or a weakened cerebral vascular system can lead to a death from acute methamphetamine toxicity, but it's not the same as strong opioids, heroin, fentanyl, and the like, in terms of causing the level of risk for acute overdose and death. So some of this mortality rise has to be explained, right? So typical for someone who studies drug policy, I'm gonna break it down between supply and demand. Are there changes in the drug itself? Has methamphetamine become, is it being produced more? The answer is yes. I've cut out some of the slides to keep this presentation within a reasonable time frame, but I'm going to say yes to a lot of these. Have there been changes in production? Yes, there's changes in the version and in the way the methamphetamine is being produced that are making it more dangerous, and we can talk about that if you all are interested in. Is methamphetamine of high purity and potency? Yes, increasingly more pure, increasingly more potent, potency measured by the de-isomer, the dextro-isomer of methamphetamine. Current wholesale and retail samples of methamphetamine show purities in excess of 95% and 95% de-isomer, which is of historically high quality. But the thing I want to focus on on the supply side is, is the meth, or for that matter the cocaine, contaminated with fentanyl, right? Can we see some of the co-occurring deaths being explained by contamination? I'm going to show you some data on that. And then on the demand side, is there intentional co-use of stimulants and of powerful opioids that might be leading to some of the stimulant-related mortality? So just to break these down a little bit further, by unintentional co-use, I mean a contamination phenomenon. For example, we know that heroin is adulterated or contaminated by fentanyl. And the Levamisol example I already gave you. The point is that the person who's using this drug is unaware. They didn't choose this. Whereas intentional co-use, we think that poly-drug use is always the norm. But I would argue, and I think I just mentioned this to Steve the other day, Dr. Schachtel, that, you know, I think we're entering, in addition to this normal baseline, we're going into a historic era of poly-use and consequences. But the person who's using is making choices here about what to combine. So let's look at the contamination question first. And for this, our study team has been privileged, and also through hard work, through multiple FOIA requests, to obtain drug seizure data from the state of Ohio. We chose Ohio for a couple reasons. One, because it has relatively lenient FOIA laws, and secondly, because it's been a central state in understanding the ebbs and flows of fentanyl. It's been a particularly hard-impacted state. This is a very robust data set. We have over 300, at this point, over 300,000 drug samples over, I think we're up to 12 or maybe 13 years at this point, and we have most of the counties of Ohio. Just to cut to the results section, this is a paper in progress. We have not published these other than presenting them in presentations results. So this is a fraction of cocaine samples. Again, this very large database, large period of time, most counties in Ohio. Look at this line here for cocaine and heroin, right? So at a peak around 2017, about 8% of cocaine had some measurable heroin in it, and that's declined recently. And here's the fentanyl curve, starting from nothing to about 11% of cocaine samples registering something for fentanyl. Going on to meth, we see a much lower fraction, right? Only about three, maybe three and a half percent of methamphetamine samples have fentanyl in it. What we don't have here is we don't have purity measurements. So I can't tell you whether a positive for fentanyl is even clinically relevant to the person. I can just tell you that we see increasing rates over time, and we have a robust data set that's giving us at least some point estimate, 11% cross-contamination cocaine, 3% for methamphetamine. I also can't answer whether this is accidental or purposeful. There's some scare stories out there in the media saying that, oh, they're just trying to hook stimulant users on fentanyl, get everyone on fentanyl. I discount those. I think when I talk to low-level dealers, they say there's a lot of messiness going on, right? And there has been something around dealing that has shifted it from a highly professional to a bit more sloppy. And I'll just leave it at that, that there's some signals that the cutting tables have become a bit less professional in recent years. I also think there's a lot of co-dealing going on, meaning that, you know, in the past, if you wanted stimulants or you wanted heroin, you go to different neighborhoods or different blocks in the same neighborhood. It seems to be a lot of the same dealers have both products. And I'll show you some qualitative data on that. And that, of course, is also going to lead to some degree of contamination, accidental contamination. Let's get into the intentional co-use. And for this, well, we'll start off by trying to define some terms, right? Historically, cocaine and heroin was called a speedball. In fact, it's still called a speedball in most parts of the country. People like the term. There's not a lot of disagreement about the term. But they also like the combination. This is historically, traditionally a well-liked combo, particularly for somebody who's been using heroin for, oh, let's say about five years. And the romance has worn off. They're using heroin just to stay well now, to avoid withdrawal symptoms. The addition of cocaine makes the heroin fun again, at least temporarily. It gives it a little bit, if you have the extra money, you want to put cocaine in there, it gives the heroin a little bit of a boost, all right? It's very well-liked across time and geography. Now, the goofball is not that. The goofball is not traditional. It's unusual historically. It is not well-liked. It's physiologically challenging. So the fact that it's happening, whether it's happening in my mind from a patient that I've worked with, or from my street-based research where I've heard that's happening, or from the data that shows that 50 percent of methamphetamine deaths have co-occurring fentanyl, it just puts a light bulb in my head that says, oh, this is something that has to be explored. And I believe this point so much that I wrote my current grant on it, right? My current five-year grant is to explore the goofball and a few other things, not just the goofball. Here we have, sorry, I should have showed this picture a minute ago, a person who's holding two capsules of East Coast heroin and two vials with the gold tops of cocaine, and he's about to prepare a traditional speedball. So for questions that involve new drug phenomena, I go to my ethnographic team and say, let's go explore the goofball. Where did we go? We went to West Virginia. We went there a couple of times, a couple of towns in southern West Virginia or southwestern West Virginia, Charleston and Huntington, for example. And as I mentioned earlier, our aims for the ethnographic work are to understand the lived experience from the experts themselves, people who know these drugs intimately. We're trying to build explanatory models, not to be conclusive with our findings. If you want to know more about our methods, I've got a TEDx talk for you to look at and a wonderful chapter that Jason Fessel led from 2020 on our rapid assessment methods. Here are some snapshots from West Virginia, a lovely place to visit, lovely people. Here's my warning. I've got some photos coming up that might be a bit triggering for some people, so be careful. How do we do our work? Briefly, we spend a lot of time with people. We hang out parks, alleyways, apartments, cars. We're interested in their lived experience. We're interested in drugs, the drug preparation process. Because we're talking about new drugs, whether it's fentanyl or this combination, the goofball combination, we're interested in what the drug looks like, what it smells like, what it acts like, how it looks in powder form, how it looks in solution. And here's just a couple of snapshots. This paper is also being worked on. We're calling it the goofball paper. I don't know what we'll call it when it actually goes out, what the title will be. But just some snapshots from this work, this two years worth of work. One is the obvious. Methamphetamine is back. It's big time. It's popular. The supply has changed. It's less about local forms of methamphetamine. For example, in West Virginia, they call it shake and bake. And now more about an imported product, which people recognize is of high quality. And also, it's coming in at a cheap price point. Believe it or not, it's beating out the local production in terms of bang for the buck, if you will. And that's what it looks like. It kind of looks like crushed up rock salt. Now, this is Julie. She's in her 50s. She's been injecting for only about five years, but is suffering from scoliosis-induced pain. She talks about ice as a popular alternative to heroin. And for her, there was a pain management and a market-based rationale. She says, if I can get heroin, that's all I want for the pain. Now, if I don't, sorry, I have to move my visuals out of the way. Here we go. Now, if I don't have the money or I can't get heroin, I'll get ice, because it's so much easier. It's cheaper. It kind of takes my mind off it, and I can move. And even if I'm feeling the pain, it gives me the energy that I can at least get something accomplished. So it's meth as a purposeful drug, as an enabling drug, but also, interestingly, that it's cheaper and can control pain. Just fascinating stuff. Getting to a polysubstance idea, people are telling us that dealers were selling multiple kinds of drugs, which to me is new information. Elizabeth, in her 30s, injecting only for one year, reported being able to buy multiple drugs from her dealer, suggesting that heroin has been slotted into existing drug distribution networks. She says, now, it's like, you know, I called the drug dealer to get crack, and they got heroin, too. You know, really, all the ones I deal with. They got ice. They got crack. They got heroin. You know, it's like, you know, everyone has it. It's like it's right around. It's on every block. So ubiquity in the drug supply. I also want to point out that even though people are in their 30s, 50s, 40s, 50s, we're seeing new people entering the scene, which is, you know, quite disturbing. Here's an alleyway in South Charleston. Spent a fair amount of time there. And the goofball is back, right? They just don't call it a goofball. They call it a speedball. It's like, wait a second. If cocaine and heroin is a speedball, what do you call the meth and heroin speedball? They said, yeah, we just call it a meth speedball or a speedball. Cocaine is not very common in Southern West Virginia. So I think that partly explains why they use the term speedball. Those who like it say it's a fantastic field. And those who don't say they feel the physiological fight between the up forces and the down forces. And for some of those people, what they'll do is they'll split it up. They'll use the drugs purposely, different parts of the day, or they'll wait a little bit of time in their combinations. I'll show you that in a minute. In fact, here it is. There's a variety of speedball from people who don't use it to people who only use it when it's free, to people casual, maybe their buddy's using it, but it's not really important to them. Those who are using it regularly, either in combination or separate. I use meth to get up. I use heroin in the latter part of the day. And every time I say heroin here, it should really be in quotes like it is in the first line, meaning heroin plus or minus fentanyl of some degree. Because most of the heroin here has fentanyl in it. And then that last bullet point, some people are using meth regularly to actually control their heroin or fentanyl habit, if you will. Here's the gentleman from earlier who's in the crushed rock salt in his cooker. In this case, a plastic cooker, because nothing has to be heated up here. And he's mixed in a shot of heroin, and he's drawing back up a combined methamphetamine heroin slash fentanyl goofball. Rebecca says, who's in her 30s, and again, a new fairly new injector, says she prefers methamphetamine to heroin, but also like to do both of them. She says, but I mean, I prefer meth. I like heroin and stuff like that. But it's not my choice preference. But I do it every now and then. And actually, mixing it with meth is the better buzz, believe it or not. So question, how do you decide on a given day? Well, it's just what we feel like. I mean, like, well, how sick are we for heroin? How bad is the dope sickness? If the dope sickness is not bad, we'll choose meth, because then you can fend off the dope sickness even more by being high on meth, and you won't feel it. Right confounds a little bit of our understanding of opioid use disorder, opioid dependency, right, by saying meth is an adaptive drug to some degree. But still, fascinating anecdotes here. One of my favorite, personally favorite photos. This is a full moon of Friday the 13th in West Virginia. But in summary of this data, I didn't present this, but supply is up, purity is up, price is down. Contamination is happening. Unfortunately, we don't know purity levels. So we don't know to what degree it's physiologically meaningful, nor whether it's accidental or purposeful. This idea of cross-contamination is not necessarily new. That's why I showed the heroin data showing that prior to fentanyl, heroin was also being contaminated to some degree. But it's more impactful in the fentanyl era, because fentanyl is a stronger drug. I do think that co-use and co-dealing are also implicated in this contamination problem. In terms of co-use, the speedball is back, the goofball is back. Robust supply, cheap price is driving, but so are adaptive responses. People are substituting heroin and fentanyl for meth to try to reduce fentanyl exposure. Is it working? Doesn't seem to be working, at least not when we look at the mortality data, which shows that it's going up. But we should focus on the fact that fentanyl is the deadly element, and we have some responses to that. We have more responses to fentanyl than we do for methamphetamine. So where do we go from here? Some railroad tracks in Huntington. America's awash in pills and powders, solutions, combinations. We're a crisis, we need a crisis response. So the first thing is we don't panic. When we panic, when we have a sort of a moral panic, it only leads to politicians making statements, media leading fear-based responses. It doesn't lead to our best public health and medical responses because it adds to stigma, and stigma remains our biggest enemy. Stigma is what keeps people out of our clinics. Stigma keeps them using. We need to de-stigmatize drug use in any and every way possible in order to invite people to come forward and ask for help or be helped. The rise in stimulants shows a failure, a basic failure of public policy that we seem to focus on the drug at the moment. You know, oh, it's crack problem, oh, it's a fentanyl problem, right? We need to think of the drug problem in America and not on single classes of drugs. We need a comprehensive solution, and I talk with Congress about this, I talk with Dr. Gupta, our current director of ONDCP. He understands this, right? People are starting to get it. It's not just, oh, I'm in the supply-side camp, oh, I'm in the demand-side camp, right? We need a comprehensive solution that intertwines and funds, well, supply reduction supply reduction and demand reduction and harm reduction. The national drug policy that just came out from the White House and from ONDCP for 2022 has pillars for all of these, including harm reduction for the first time ever. We'll talk a bit about harm reduction, but before we get there, let's talk a little bit about demand reduction. We have treatments for overuse disorder. We need to use them, and there's been campaigns to roll out, increase the number of buprenorphine, wavered prescribers. For that matter, let's deregulate buprenorphine and not make it such a special and such a cloistered medication. There's other things that fit under demand reduction that we're going to have to face if we want to face this historic crisis of overdose, and that is what's going on with our communities. Drugs fall into the cracks of communities. Drugs are often self-medication, both on a personal level and also metaphorically on a community level. We need to think about ACEs, Adverse Childhood Experiences, and work on those so that we prevent the drug use that's going to happen from them 15, 25 years down the road. We need healing in our communities, both social, economic, and spiritual. I believe this strongly. Maybe it's because of my bias because I work in some of these places in the ethnographic work, and I see the decay. I see the fragmentation. And combining supply reduction, demand reduction leads us to the notion of public health, public safety partnerships. Can we work together to address overdose? Do we have a North Star that says lives matter and we want to save people's lives? And then, of course, there's harm reduction. So, treatment. We have medications for opiate use disorder. They're highly effective. They work. We've added one recently, Naltrexone XR. Methadone is one that has the most history and literature behind it. Buprenorphine has the most effectiveness, if you will, at the population level because you can have more providers for it. Methadone is limited. Naltrexone, the new player on the block, has some evidence base for it and some limitations as well. MOUD is effective. It is not just substituting one drug for another. That's what the naysayers are going to say. It's a stabilization. It leads to improvement in neurological function, right? It leads to retention and treatment. Number one marker for somebody doing well in clinical care across any illicit drug category is can we retain them in treatment, right? Because we need time. The person needs time. The provider needs time. The family needs time. Retention and treatment. We also know that MOUD reduces harms, and these are important, both in terms of lives and morbidity and mortality, but also in terms of costs, also in terms of societal costs, of medical economic costs, right? These drugs reduce illicit use by decreasing craving. They reduce all-cause mortality, not just overdose, but including overdose. Hepatitis C and HIV transmission goes down. Criminal activity and other social nuisance issues go down when these are well implemented. In the limited time I have remaining, I just want to talk a little bit about treating people that have opioid use disorder that involves fentanyl and some of the challenges that are going on. Most take-home messages, most are doing fine. Clinicians are a little frustrated. I talked to folks on the East Coast, Midwest, West Coast. The West Coast people are a little behind the curve because fentanyl is kind of new, and they're a little bit more anxious right now. The East Coast people say, oh, we got this. Yeah, it's frustrating, it's challenging, but we got this, right? So I'm talking to the FDA, saying, can we have a national conference where we get East Coast and West Coast folks to kind of talk to each other and, you know, come up with a plan on getting people onto buprenorphine now in this age of fentanyl? So what are the challenges, right? The challenge is mainly that, and this is a bit of a secret, and I'm going to let you all in on, right? We think of fentanyl as a short-acting drug, right? In the hands of an anesthesia person who is in a surgical setting, I like fentanyl because it's short-acting. It's powerful, it gets the job done, and it's short-acting, meaning that if there's anything that doesn't look good about the clinical situation, I can pull it back, right? And it'll wear off quickly, you know, it's got a half-life of an hour, right? But that is not what we're seeing on the streets, and that is not what we're seeing in people who are trying to treat people who are fentanyl exposed. What we're seeing is that fentanyl starts acting like a long-acting drug, right? There's a little bit of physiological evidence for this, that there's reduced renal clearance, that people chronically exposed to fentanyl have a clearance, a half-life, I think that's half-life there, of 7.3 days, right? And so now imagine that you're trying to get someone off of this highly potent drug, which now has a long half-life, onto buprenorphine. You have to get them through that withdrawal period, right? And if you do it too soon, whether it's, you know, naltrexone, the full block, or buprenorphine, which is, you know, the partial agonist, which can act as a blocker, if you push the bup too quickly or too much, you'll induce precipitative withdrawal, right? Great way to lose a patient, and not necessarily through death, but through, bye, I'm out of here, I didn't like that at all, right? Precipitative withdrawal is not fun. And before I move on to the slide, the other thing that's leading to fentanyl acting or maybe the mechanism, there's a question mark there, it's a lipophilic drug. It's a highly lipophilic drug, which is why it's so potent, right? It's going past the blood-brain barrier, saturating the neurons, and so it may also be being stored in fat tissue, but that's a question mark after that. So how are we dealing with this problem? Fentanyl is a long-acting drug, you know, among people who are chronically exposed. Buprenorphine, we know it works for heroin, but now we have some challenges in terms of how to get someone on it when they're fentanyl exposed. One option is to go slow, right? We need to wait longer for people to fully experience withdrawal symptoms. We have to wait for a higher CalScore. People are waiting up to four days, sorry, up to two days, 48 hours to initiate, which is hard. It's hard on the patient. It's hard on the clinical care system. It's hard on the family, right? So it requires counseling. It's going to require adjunctive medications, comfort medications. And you also can start with lower doses, right? When you do say, person's suffering enough, withdrawal score is high enough, it's still going to tease it into their body. And the dosing recommendations are there. This is the go slow camp. And this is a camp because there's another camp that I'm going to talk about. Bottom line to this slide is some folks won't do well with Buprenorphine, with Suboxone, brand name, and we have to consider the other two medications. Oh, I don't have the other slide. So before I move on, I'll tell you that there's two other camps. I don't know why I left the slide out. There's two other camps. One camp is the micro dosing approach where we'll start really early. We won't wait the 48 hours. We'll use even lower doses, microgram doses instead of milligram doses and tease the Buprenorphine in, right? And there's evidence for this and there's proponents of it. And then there's the newest camp led by Andrew Herring over at Highland Hospital in Oakland, California, who says, go big, go fast, right? Other side of the coin, where he has a nice case series at this point, a robust case series showing that high doses of Buprenorphine up to 16 milligrams in the first day, right? Now it's an ER setting. He gets to monitor people. If people do have problems with precipitated withdrawal, he's got IV Ketamine he can use. So it's setting dependent, but it is a model out there with some evidence base. And these three camps are just going to have to talk with each other and help us with prescribing guidelines moving into our fentanyl future. Moving on to psychostimulants, and I'll end shortly. Clearly, there's renewed interest in medications for psychostimulant use disorder. Why? Because we don't have them. We don't have FDA approved ones. And so FDA is very keen on this now. Dr. Choptar and colleagues wrote a wonderful New England Journal of Medicine paper saying, hey, we got one, you know, not FDA approved yet, but their combination of extended release naltrexone dosed every three weeks instead of every four weeks. And on the higher end of the dose spectrum of bupropion, 450 milligrams shows significant reduction in methamphetamine use. So this is a pathway that needs another trial or two, needs to be followed. It's the largest clinical trial ever. I think there's still a few questions that Dr. Choptar and others would like to ask, but this is one recommendation. There's some evidence for mirtazapine as well as pharmacotherapy, but these are currently off-label uses. There's behavioral treatments for stimulant use disorder listed here. The number one is on top. I should have bolded it. Contingency management, right? Contingency management has good evidence base. It's stymied by the fact of who's going to pay for the incentives that are used within it. And we're still arguing and working on that issue. I know state, local, regional, national governments are keen on this and are trying to work out some of the barriers to the payments. Some resources for continued learning, particularly around stimulant treatments. Let's talk about harm reduction. If my thesis is correct, that a lot of methamphetamine deaths are being driven by fentanyl exposure. And then, of course, we have the people in the heroin camp who are being exposed to fentanyl and the consequences. There are things that harm reduction offers. Basic things, overdose prevention, that's providing naloxone in one of its many forms to peers to use on each other. And there's also hepatitis C and HIV prevention, that is provision of sterile syringes through syringe exchange programs. But some of the avant-garde stuff is in the world of surveillance. If the world really is becoming more complex, in terms of drug supply and contaminations and accidental or purposeful commingling of drugs, then the ideas of drug checking and the ideas of drug market surveillance come to the fore. I've given you two references down at the bottom, one of which is my own. We use the Ohio Crime Lab data to show that if you understand the vicissitudes of fentanyl as well, you can actually predict overdoses with about a week lag. And so, something to consider. I love seeing naloxone in all of its forms. This is the auto-injector, but there's many forms out there. I love seeing them when I'm out in the fields, knowing that people are protected. When talking about drug checking, I like to call it testing the lettuce, right? If we had a poisoned food supply, we would go and investigate it. In this case, if people are concerned about the drug they're about to consume, they can test it for fentanyl. So, this is a $1 fentanyl test strip that somebody has inserted into a solution. The solution already looks suspect because it's a clear solution as opposed to a typical heroin solution, which would be brown. This is a clear solution suggesting that it's synthetic opioid. And I don't recall what this particular test, actually, I do recall this test strip was positive in this case. The pink lighter is reminding me. We also, a couple of places, have rolled out spectrometry. These are portable spectrometers that cost $10,000 to $20,000. But places like Chicago are using them in their harm reduction programs so that people can bring in a sample and know all the substances that are in there across multiple categories. So, if information is power, then these folks are leading it. San Francisco just rolled out a project like this as well. There's another one in North Carolina. On the behavioral side of things, harm reduction has suggestions, right? This stems in some small or large part from the research that my team and I have done collecting stories about organic adaptive strategies to fentanyl. And what we heard is people said, oh, you know, I'm concerned about fentanyl. So, what I do is I put a little bit in my nose first. I toot it. And they call it toot his taste. I toot a little bit first, and then I can decide, oh, that tastes kind of synthetically. That feels kind of strong. I don't need to inject it. I'm good just by using my nose. Other people say, well, I like to inject, but I just do a partial shot or I do a diluted shot. I can always do more later. I could do it 20 minutes later, an hour later. So, they break up their shots. So, there's the go slow approach. There's the partial injection approach. And then there's the toot his taste approach. And we wrote all these up in a paper highlighted right there at the bottom. You see two examples here of a very concentrated and enlarged shot and more diluted and small shot on the right. Go slow, stay in control is the idea. And people resonate with this. Not everyone. Some people are more chaotic or don't resonate with the notion of staying in control. But, you know, there's people who do. Be more powerful. Be more power. I think they meant to say be more powerful. Be more power. It's a wonderful harm reduction group in Baltimore. They say go slow fence moles here. 20 seconds to save a life. Meaning, inject slowly. 20 seconds is a very long time to inject IV bolus, but it'll give people useful information and the chance to stop the injection if the shot feels too strong. I like this campaign. With that, I'll end with some acknowledgments. There's my lovely ethnographic team for the West Virginia study. Thank the folks in West Virginia, of course, and my funder. And you all for your kind attention this evening. Thank you so much. Thank you so much, Dr. Ciccarone. We do have some questions. And I'll start from the beginning. I didn't leave a lot of time for questions, but there'll be more time for questions next week. Yes. So, yeah, we'll have about five minutes and then we'll be wrapping up here. So, the first question was, do people always mix their own speed balls or can they buy it pre-mixed? It's a good question. I have not heard of a pre-mixed speedball, except through that contamination arena. Are supply reduction efforts ever effective in reducing use and overdose rates? Good question. If you talk to people who get large amounts of funding to do supply reduction efforts, they say, of course, we're effective. The academic data is not as supportive. There's evidence that local, if you understand your local scene of dealers and their hierarchies, local efforts can have impact. Now, of course, that's going to push racial and discriminatory buttons as well. So, there's, you know, we have a little bit of a policy problem there. But interdiction, the large scale, you know, trying to stop drugs at the border, trying to make the drugs more expensive because we're grabbing a bunch of them out of the market, that's been a failure. I mean, there's very little data to support that we've done anything at the transnational level that's impacted drug supply in America. Of course, multiple categories, drugs have become cheaper and more pure and more potent over the last 30 years. Okay. Another question here was, does buprenorphine have any effect on straight meth overdose? And I'm assuming that's methamphetamine, not methadone. Oh, I'm going to turf that to Steve next week. I want to hear Dr. Sopto's question, answer to that question. So, whoever you are, I'm hoping you're attending next week as well and ask that question again. It's a good one. I like that question. Do you see a decrease in the cost of naltrexone XR? Oh, that's a really, that's a good question too. I don't track it, but one of the major problems is that it is quite expensive. And a bit of a problem to say that, oh, our evidence base is hinging on this very expensive drug. I was just debating this morning with a group of clinicians, we're trying to write national guidelines on treatment of stimulant use disorder about whether we could replicate the Trivedi study by using oral daily naltrexone, just because it's so much cheaper. But the answer to that, Steve's shaking his head, no. And the answer to that to me is unknown. And Steve's just going, no. So, ask that question again next week too. As far as, you kind of covered this about doses, but do you have any recommendations on methadone dose or buprenorphine dose? Do you need a higher dose of methadone to stabilize with the fentanyl in the supply chain now? I mean, the easy answer, the straight up academic clinical answer is you use what you need to use, right? And you dose appropriately and gather enough experience. And if you don't have enough experience, find someone who is experienced about escalating the dose to levels that are appropriate. We think that buprenorphine has a ceiling effect. And therefore, and it's debated, you know, it might have a ceiling effect for treatment of one condition and not for another condition. So, we have to have respect for, you know, the limits of buprenorphine. So, you know, if buprenorphine at 16 or 24 milligrams isn't working, I would start thinking about an adjunct to it or switching over to methadone. Assuming that something's going in the right direction, you know, the person has some degree of decreased craving, some degree of functional improvement, it's just not good enough. I also think, I like buprenorphine so much that I spend a lot of time, my team and I, clinical team and I spend a lot of time coaching patients to get them to respect the drug, use it well, not expect heaven and earth from it because there's nothing that we've created in the pharmacopedia that solves things quickly, but to not throw it away too quickly, you know, hang with that 16 milligram dose, hang with that 24 milligram dose, and work on other things because, you know, tincture of time is also a very important element in what we're doing. Okay, well, thank you so much for those responses. It looks like it's six o'clock and I wanted to make sure to be mindful of our time. So, I just want to reassure people that did ask questions that we will have those, copy those into next week, and then there's also the opportunity to go on our website, the AOAM Learning Management System website under education.aoam.org. You can enter your questions there for next week, and then next week, Dr. Shakta is going to be talking, doing a case-based presentation, as Dr. Ciccheroni had mentioned in the beginning, and you can enter questions for either in the education page box for that week. And so, please join us again next week on May 11th at five o'clock, and I'd like to thank you all for attending. I'd like to thank both Dr. Ciccheroni and Dr. Shakta for this presentation, and I look forward to seeing you both next week. Thank you.

webinar

fentanyl

stimulant overdose crisis

fourth wave

opioid overdose crisis

methamphetamine

heroin

harm reduction measures

overdose prevention

fentanyl contamination