All right. Well, we are right at 3.15. So buy a little bit of time. I'll catch all the stragglers coming in. But it's so nice to be here in Naples, Florida. Y'all look great. Great looking audience. It looks like some of you have been dressed up to be here, I would guess. Dress like this every day. But excellent. So I'm Dr. Jeremy Welloff. I'm assistant professor at University of Alberta. I'm adjunct assistant professor at Yale University. And also presenting with us is Dr. Julian Raffoul from Stanford University. Currently, CL fellow, addiction trained. I'll let you give all of your many, because you've had quite the career. And Dr. Emily Casey, pharmacist, University of Pennsylvania. And we're going to talk about injectable opioid agonist treatment, or IOT. If you're here to hear about sublocade, you're not in the right space. This is not sublocade. We are talking about what's commonly referred to in the literature as heroin-assisted treatment and its historical roots. We're talking about IV hydromorphone, IV diacetylmorphine, and those sort of things for treatment. And what we're able to do in some countries, but not able to do in this country for many, many reasons. But we're going to talk a little bit about how to get there in America. Often, I'm sure, you kind of see and hear news stories from how things are done in other countries. And you go, oh my gosh, I wish I had that, this maybe utopic vision of what it might look like to practice in those countries and do those sort of things. So we're going to kind of break some of those down, open those up so everybody can kind of get a better understanding of what we can do up in Canada and some of the strategies you can implement here. And we have no disclosures. So we're going to talk about international strategies for using IV and oral hydromorphone and diacetylmorphine. We're also going to talk a little bit about slow release oral morphine, which is another treatment we can use for opioid use disorder in Canada. We're going to talk about how we use some of these strategies during methadone inductions to get stabilization more quickly for our patients that are really difficult to stabilize, that we would like to maintain in treatment. And then we're going to talk about some of these regulatory policy issues that impact the use of these medications in the US and some of the next steps to getting there. So the missing link. So I joke. I was born and raised in Canada, and I spent the last 10 years in the US doing my medical training and fellowship training and more fellowship training. And I have finally just partially returned back to Canada to do IOT, and that's where my primary clinical work mostly is spent. And so I make the joke. I'm probably closer to the guy with the rake thing. Anyway, in terms of being this missing link and thinking about how can we bring these strategies to the USA, how can we here have more tools to treat our patients who are particularly hard to treat and particularly hard to stabilize? So my work is mostly with those in the downtown. 90-plus percent are homeless or housing-unstable and have been through a lot of different treatments and are very, very tricky to get into treatment. So that's the link. So slow-release oral morphine being an expression of one of those links and how we get there, and IOT being another one of those. So let's talk about other bridges and other links. Choluteca. This is the Choluteca Bridge in Honduras. And in 1998, the Honduran government said, let's spend a ton of money to build the new Choluteca Bridge over this important trade route and replace the old Choluteca Bridge that hasn't been there. Japanese country got the contract. It's one of the largest contracts they ever got in Central South America. And they decided, hey, we're going to build a bridge that's going to last forever and withstand the test of time. And unfortunately, 1998 was the same year that Hurricane Mitch came to town. And for those of you that don't know Hurricane Mitch, it was a big deal. I think it was like over 30,000 people died. There's like this quote from the Honduran government where they're like, hey, this set us back 50 years of economic development. It was a big hurricane. It was no slouch. And well, the bridge survived, which was great. Unfortunately, the entire river that the bridge was supposed to span moved over. So we're left with this. It was nicknamed the Bridge to Nowhere. May last forever, but again, may not be doing the job it's supposed to be doing. So looks great, Bridge to Nowhere. And so if you haven't put the analogy together, that is a story about systems. And building systems that are built to last forever, maybe over highly regulated, maybe very, very strict and strong for good reason. But when they are tested, when there's a change, when Hurricane Mitch comes around and the river moves, they're far less useful. And so this is within a system. You've seen this picture probably a million times. I do not have to tell you opioid epidemic is really bad, that stimulants and synthetic stimulants are this big rising part of drug poisoning, drug toxicity, and overdose events alongside fentanyl. You know that. And in terms of adaptability and rigidity of systems, it's been 10 years since we mark the beginning of wave three, or when fentanyl came in. And we really have a relatively unchanged regulatory framework. We have a slow uptake of tertiary prevention or harm reduction in this country. Supervised consumption sites are now starting to pop up a little bit. Continue to have inequitable access and low treatment rates. All of these questions pop up about how to do bupinductions the right way or different ways. And really, no or limited new drugs or treatments or adoptions of treatments that are already internationally used. But the bright side and politics aside, there's a general liberalization of OUD care. So COVID-19 brought about some expansion of take-home dosing for methadone, buprenorphine, the removal of X waiver, these sort of things. Kind of even the philosophy of take-home doses around buprenorphine and having to provide therapy alongside it, et cetera, has changed in the last 10 years or so. And then we have the first supervised consumption site in America opening up in 2021. So there's a general liberalization this way. And so we're talking about how the river has already moved. I'd say we're probably all right. It's moved again, probably. I think we're already way behind. These are the recommendations from CFSRE, who monitor novel psychoactive substances in the US. This is their most recent, sorry, it's not their most recent now, but this is a recent recommendation from quarter one of 2023. These are the benzos that are showing up and should be tested for by all of our labs. These are the opioids, right? We're starting to get talk about the nitazines, but there's others. These are the synthetic stimulants and the pentolones and eutolones, which we're not quite talking about yet on the main stage. And then these things that are unpronounceable, right? I mean, I think we're already behind and our clinical treatment guidelines are already, are certainly way behind, right? So the rivers move and it keeps moving. So, I don't know, do you guys feel like the current regulations around MOUD get in the way of getting your patients the most, the best possible care? Show of hands. A couple nods, yeah, okay. So we surveyed folks at ASAM a couple years ago, and yeah, I think that's the general sentiment. So about 89% say that, hey, fentanyl really changed the way I practice in the last five years. Again, about 86% said I prescribe medications for opioid use disorder differently because of this. When we asked them, hey, does it get in the way? Sorry, when we asked them if practice standards included other full opioid agonists, like slow release oral morphine and these options, about 84% say, yeah, I would, if practice standards included those, I would use them, most certainly. And then about 84% says, hey, these regulations get in the way of me providing the best available care. And about 30% or so are already using full opioid agonist off-label. So that was either during withdrawal or assisting in starting medications for opioid use disorder, right? So that includes things like using a fentanyl patch or using full opioid agonist in the hospital to stabilize someone before getting onto MOUD. So this is already, it pops up a little bit in the back of my mind, but it's not a big deal. It's already, it pops up a little bit in practice, or at least people admit it, right? Because it may or may not be legal. We'll talk about that. So this is the spectrum of care for OUD management in Canada. These are the, we commonly refer to these as the BC guidelines, where you have withdrawal management, of course, and then you have everything that's essentially available here in the middle. So bup and methadone here is your agonist treatments. We also have this category of expert-led approaches, which are generally earmarked for folks with additional specialist training. Depending on the province, there's different requirements. You may have to have a certification, et cetera, in order to prescribe them, or you're prescribing them in consultation with someone with those requirements. But those include slow-release oral morphine, and those include diacetylmorphine and hydromorphone given in a supervised setting, injection, pharmaceutical grade. Sometimes, or you may have seen this talked about as safe supply in the news, and that's where a lot of the hype and controversy is. But there are also programs that are not as liberal as what the news, what the news stories and the things you may see there. I'll keep that simple and political like that. And then, of course, across the entire spectrum in the Canadian setting, kind of tertiary prevention, commonly called harm reduction, is used across that. So supervised injection sites across Canada, I think there's about 42 or so or more now. And then naloxone has been available free from pharmacies since about 2016 or so. It's kind of like that infrastructure's been there and been hanging around for a while. So that's some of the treatment differences, some of the setting differences coming into this talk. So we know, and you probably have, patients who have come into your office and they're unstable, and they've been on Bupre a couple of times, and maybe methadone a couple of times, and you're trying to figure out the right thing for them, and it feels like they continue to fall through the cracks, or it's really hard to get them stable. And I'm gonna assume you all would like more options in order to stabilize them. But even for those that do get stable, we know that retention on MOUD is low-ish, right? 40 to 60% discontinue in their first year or have a return to use. 30 to 60% started on Bupre, are retained at the six-month mark. Some limit, some people just aren't at that stage of change, et cetera, there's all these reasons why people aren't there. But our current options sometimes don't get us where we wanna go. For those who use intravenously, it comes with, I don't have to tell you, it comes with significant risk, right? Really bad, premature death, overdose, non-fatal overdose, infections, violence, arrest, et cetera. And then folks discontinue for a variety of, discontinue their MOUD for a variety of reasons, right? Side effects, ineffective dosing, continued craving, stage of change, as I mentioned. So, I'm gonna tell the story of what we can do in Alberta, which is a province in Canada, of the Narcotic Transition Service, which is a slightly more conservative version of what you see on the news of safe supply, but it's our model for what to do with those folks who have severe OUD, have been unable to initiate or stabilize on bute, methadone, or slow-release oral morphine. They have to have at least a treatment failure of two of those, at least, where we have clinics built to give supervised IV and liquid hydromorphone. And it's established, and the understanding is that this is a transition, a temporary, this is a period of stabilization, and within the next two years or so, you're gonna be on bute, methadone, or slow-release oral morphine. Of course, that's the paper, that's what it says, and that's the hope, but some folks are not stable. So, there's some leeway there within that. And these are restricted to special clinics. I'll show you some pictures of what those clinics look like also. So, this is the clinic. This is the downstairs of our building. Connected to this is the pharmacy. And upstairs, we have social work, and everybody, and all the addiction psychiatrists, and all of the team up there. And this is where folks come in to get injectable treatment. It is not a supervised consumption site. This is prescribed treatment. It's not just harm reduction. As I showed you, it's the fourth-line evidence-based treatment, and the BC guidelines, they have to have these past attempts, and it's to mitigate a lot of those risks of injection drug use, and prescribed. So, pharmaceutical-grade stuff, not the risky stuff that you're seeing out on the streets. They come in for clinical visits. Like I said, the pharmacy is attached where the drugs are made up and put into the syringes. There's no take-home dosing. People come in for clinics, you can't take meds to go, and that sort of stuff. So, again, a little bit different than safe supply you hear on the news. It's supervised. They're usually coming in two to three times a day. And again, embedded team, connection to primary care. They can have nurse assist for IM administration, but they don't assist for IP. So, the person has to be fully able to do this treatment themselves. This is the upstairs. Again, we have the full spectrum of MOUD care, about 1,000 or so patients probably now, about 70 patients in the NTS program, in the injectable program. We call it high-intensity, low-volume. The high-intensity is that a lot of patients say it's like a full-time job, right? Like, this is how unstable folks are. We're right in the downtown, and people can come three times a day to do this. So, we're gonna talk a little bit about this later too, but injectable treatments are not new. I'm not giving you something brand new and fancy. It's been around for a long time. In the US and the UK, it was actually the standard of care in the early 1900s, and having these options. And the Rolston Report was a big one in 1926, but even before that, there was a bunch of international conglomeration discussion that led to the Harrison Narcotic Act and Prohibition in the early 1914 to 1920 that kind of set off, set some of this off. And heroin was the main treatment unsupervised until the 1960s in a lot of ways. This was one of the early ones. This was the Swiss National Study in the early 90s, and where kind of heroin-assisted treatment comes from, and the model of having a place where people can come in and get this treatment and engage with care, right? Another critical touchpoint to engage people and move on to care. Since then, there's been a bunch of trials. This is just the randomized control trials, but UK, Switzerland, Germany, Spain. There's a couple from Canada we'll talk a little bit more, and then Netherlands. They're not small trials, 50 to 250, which is like decent in what you see in a lot of the, unfortunately, in the addiction literature that we have. And pretty good follow-up, six to 12 months follow-up in most of these studies. This is a nice one. I'm not gonna go into all the details, but Heroin on Trial is the big systematic review here, which is a nice name to remember to go, and you can see all the studies in detail. But in summary, what we have, you don't have to look at the picture. Really what we have is, in comparison to methadone, supervised injectable heroin, you have improved treatment outcome in terms of greater reductions in illicit street use. You have greater retention in treatment. You have no difference in comparison to methadone in mortality. So it's as safe as methadone in many ways. And then, from a mortality standpoint, but it may be less safe than methadone overall, of course, people are injecting. There's other risks that we'll talk about here. And a lot of these trials are set up with people with similar criteria to the NTS clinic. They failed at least two medications. Some of the trials had these requirements where they had to have opioid use disorder for at least five years. Really kind of these folks that keep falling through the cracks and are just particularly hard to treat. These were the early Canadian studies. So this is NAOMI, which was the big one. It was a two-site RCT between Vancouver and Montreal. The 250 patients come from this one. So 111 on oral methadone versus 115 getting injectable heroin supervised. They did it in a hydromorphone group, a small one also, who were double-blinded. So these are high quality. These are not people just coming in and getting. These are real trials. I just want to set that in stone. So anyway, retention rates were high, I think upwards in the 80 plus percent. Street heroin and heroin reduced. People could not tell the difference between injectable heroin and injectable hydromorphone. They continued on. This is the Salome trial, looking at hydromorphone versus diacetylmorphine. This is the Crosstown Clinic where a lot of the BC work happens at. But again, illicit drug use decreased. Retention was about 80% for both arms, so that's heroin and diacetylmorphine, and hydromorphone, and IV hydromorphone, non-inferior to diacetylmorphine or heroin. As I mentioned, there are considerable risks. You do, someone's injecting high potency opioids. There's gonna be risks of respiratory depression. There are risks of cellulitis and abscesses. Seizures go up with opioids, with some of these opioids when you're prescribing them. So something to consider, something that maybe we're not thinking about too much with the current street supply, but is a real risk in the prescribing of these things. And so three non-fatal overdoses in the hydromorphone arm and 11 in the diacetylmorphine arm. And then this was, all of these were much higher than those on methadone or buprenorphine, as you would expect. So it does come with considerable risk versus our regular treatments available. This is some of the new stuff. These are what the guidelines look like. This is more just for completeness of these slides, but kind of the recommendations here. Concerns and challenges. So I think a lot of the talk we have around in the USA about supervised consumption sites is the honeypot effect. Who's gonna come here just to get drugs? What's gonna happen to crime and all of these things in my neighborhood? And it really never bore fruit in the Canadian setting. Even in the New York studies, you do the geospatial analyses around crime and other things, that hasn't been the case. It's also an amazingly expensive treatment. So the NTS program and the stuff we're doing in Alberta, we are often told by our administrators how expensive it is to run and how difficult. Because we are open, we're the only clinic, we're gonna be the only place, we're only a shop open in town past 7 p.m. You have to be there seven days a week and you're open early and you're open late. And so it's a lot of staff, plus pharmacy, plus nursing, et cetera. So I hope that's a good introduction to kind of what IOT is and what IOT isn't and what these programs mostly look like. This is just some of the team. So we have social work and we have a ton of peer supporters, which we're very lucky to have, and other therapists there. We have a street outreach team. Like I said, we're downtown, so we're kind of trying to bring people in and make those connections warm and very smooth. I had mentioned some of these. Most people have to have additional certification or specialty addiction training. The criteria I've mentioned. So again, they've failed other treatments. They have severe OUD, and they're generally currently injecting, or they're at high risk of returning to IV drug use. Of course, we've seen a shift away from IV use in recent years and towards smoking, fentanyl and stenozin, so we have that kind of flexibility within that. Cautions, of course, and relative contraindications, youth, older adults, pregnant women, these sort of things we're thinking about, of course. Folks that can't safely self-administer can't really be a part of the program because of that, can't really assist them in that part. And also, lots of big cautions about other sedating compounds, right? So those with benzodependence or alcohol use disorder, et cetera. And so we're watching out for those. Of course, they have to be able to provide consent, and they have to be able to self-administer. So I'm going to start just with a study, the story of patient J, and kind of how these generally work, and then we'll move on to what this could look like in America. So patient J came in 2019, homeless, unemployed, he was saying that drugs was a 24-hour job. He was using five points of fentanyl daily as a cultural point, so that's how it's talked about in Edmonton, Alberta, points is needles, so I was using five, yeah, five needles. And so he'd been injecting for the last five years, been to 10 residential treatments across seven different centers, so it wasn't just a bad center, and he only stayed sober when he was in treatment, and he would return to use immediately, right? We all have patients like this, I assume, or many of us have patients like this. Eight unintentional overdoses in the last year. One very recent before presentation. He's had drug-related infections and ICU stays. He's had multiple attempts on buprenorphine. He was up to 24 milligrams at some point, right, give it the old college try, he actually got up to a treatment dose that was quite good, he'd been up to methadone 120, continued use all the way through with it, and then there was a couple trials of SROM also. So we did the things, right? We gave him, we gave it everything we had. Hep C history, five suicide attempts, hospitalizations for these, has concurrent meth use, so there is this history of drug-induced psychosis, and was still using when he initially engaged, no other sedative use. So this is an example of how we would start someone on IOP. So on the left here is someone who's not using fentanyl, so this one we don't look at anymore. And here's for what we would do with someone using fentanyl, right? So we have a three-day titration where they have, this is dose one, two, three during the day, and then there's additional PRN dosing we can provide alongside of it. So they come in, this is where they start, and then there's a PRN dose available three times a day. And then for a lot of folks, because we're not open 24 hours, you can do a long-acting opioid at night. And so we'll prescribe something like slow-release oral morphine in lots of folks to get that nighttime coverage. So they can come in, and then they get that dose of slow-release oral morphine probably before they go. Again, it's daily witness, and it's witness injection also, so again, these aren't take-home doses of those meds. And that would hopefully get coverage in the morning, et cetera. So you don't have to remember these numbers, but that's kind of what that would look like. And this is the faster schedule, two-day, two-day visit. This is an example for patient J here. Before he injects, there's all the protocols in place for a nursing assessment. Is he able to do this? Are there any other risks? Is he overly sedated? Is he slurring his speech? Does he smell like alcohol? These sort of things. What other testing do we need to do? So we have this pre-injection and post-injection assessment to maintain safety. So he started in August. By September, we got him to 150 hydromorphone IV TID, and using a little bit of slow-release oral morphine at night. He's still using fentanyl, but he's only down to one point a day, which is a huge win, right? Middle of September, continued, we got him at a higher dose, slightly higher of the slow-release oral morphine. He starts working. He's had a bunch of infections that have now since healed. He's not using fentanyl anymore. He's connected to social work for housing. He's getting that little bit of stability. He's still using his methamphetamines, but was started on a stimulant through the clinic, which again is also daily dispense, or daily witness dosing, we call it, where folks can just go to the pharmacy and the pharmacist witness, again, no take-home dosing, but you present every single day to get your doses. So he's stabilized, attended a rehab. He then, don't worry, it's not all shiny, he returns to use. I'm not going to give you a story like that shiny. He returns to use. He wants to come off his meds and taper off treatment. Actually, kind of quickly, he gets tapered off, returns to use within weeks, and destabilizes. Comes back to the clinic and is restarted, continuing to struggle with supplementing, so he's using on top, as we refer to it, and ongoing methamphetamine use and some psychoses intermittently and social instability. He's briefly lost a follow-up for a while. About a year or so later, he reconnects. He wants to just be started on SROM monotherapy. So we stabilize him on 1100 milligrams of slow-release oral morphine. And from there, about a year of being on slow-release oral morphine, we can do these really smooth transitions to buprenorphine. So because you're on a, I'll say, regular opioid, you can just do traditional bup inductions without having to think about low-dose, high-dose protocols and all this other fancy stuff. You stop the medication on one day, and 12 hours or so, you're doing your two milligram, two milligram, two milligram of bup, and they're back on it, just like the good old days. No, anyway. I wasn't practicing during heroin and stuff. Anyhow, so transitions from bup, gets on supplicate, and 2024 and follow-up is doing well a couple years later. So that's kind of an example of how this bears out. And the kind of really fun things, I'm going to say fun, it's recorded also, the fun things you can do and the utility of all of these other opioid medications to provide stability in various settings. So a couple other reasons people would be discontinued. Diversion we're not really, it's just kind of on here. People aren't taking stuff home, we're not too worried about diversion generally. And of course, if they're threatening and violent behaviors towards staff. We've had incidences where this has happened, or other funny behavior around the clinic and stuff like that. We do have, so in Edmonton, there's the Royal Alex Hospital, which is a very, very large trauma hospital. We have one of the very first supervised consumption sites inside of a hospital. So it also allows us to continue this within the community. So these folks get admitted, we can continue IOD, and we can continue these treatments and have these really smooth bridges along here. Hospitals are also a critical touchpoint, we all know this, this is where our folks go, this is where EMS brings them. And so we have those services there, and we have the bridge clinics to do that. I'm going to skip this case because I think you want to hear from, I think it's important you hear more from my American colleagues, and hear more about the practical realities of what this would take to get there in America, or what sort of trials we would need to do, and what sort of work would need to get done to make those next regulatory barriers. So this is a case of someone who, very similar story, but we're able to continue our IOD during her many, many hospital stays, and during her many, many medical sequelae that she faces, and bring her back and get the stability. So, I'm going to hand it off to Emily Casey from PEM. Hi, I'm Emily, I am a clinical pharmacist in pain management and addiction, and I work at University of Pennsylvania at our flagship hospital. I work with one of our psychiatrists, Sam Zweibel, and we kind of run like an ad hoc addiction service at PEM. We're starting a formal addiction service in January, but I'm going to tell you a little bit about what we've been doing in the meantime. So I'm going to go through all of our protocols that we have available at PEM right now, and tell you that this is all new within the last four years. We weren't doing any of this five years ago, and we hope to keep doing new things. So we have some survey questions first, about things we're going to talk about. If you could just raise your hand if the answer is yes. Who here has started a PCA, or a patient-controlled analgesia, for someone with OUD, for pain concerns or withdrawal? Two people, good, better. Who here has started methadone and buprenorphine at the same time? Any buprenorphine? Wonderful. More people than I thought. And who here has started oral or IV ketamine for someone in opioid withdrawal? No one. Okay, cool. We're going to talk about all of these things, and how we do them at PEM. Is it legal to do these things? The answer is yes. So this is one of the laws that we often cite to people that are really worried about doing these things, and we cite it in all of our papers so that everyone knows it's legal. So this CFR, essentially what it says, I wrote it down because I'm not a lawyer, clinicians may legally administer short-acting opioids to maintain or detoxify hospitalized patients as an adjunct to medical treatment. And so essentially, as long as folks are admitted to the hospital for a reason other than detox, you can give them short-acting opioids for pain or withdrawal, or whatever you want to give it to them for. There's also the three-day rule that I think has kind of picked up a lot of interest over the last few years. And so I think there's like two different ways to interpret it. How we use it at PEM, if our folks are discharged from the hospital, they can present to the ED for three days, and we will dispense methadone to them. I think some folks at probably more progressive institutions actually dispense methadone for three days. We would love to get there, but don't use it that way right now. So I'm going to talk a little bit about, this is kind of like bird's eye view of what we typically are doing at PEM. And again, this is in the inpatient setting. So all of our patients are admitted to the hospital for infections or whatever else they're coming in for, and then subsequently experiencing opioid withdrawal because they're in the hospital. So often, so we use filaggrinous opioids in everyone. Comfort is impossible without opioids, right? We're in Philadelphia. It was the center of the fentanyl crisis. We were one of the first drug supplies in the country to be 100% fentanyl, and now we're struggling with all of the contaminants in the drug supply, like xylosine and metatomidine and all of the other things. So actually, as I was looking over this presentation a couple of days ago, we had made this months ago, and I was looking at the doses I put in here, and I was like, wow, I wish we were still using these doses. What we're having to do today is use much higher doses than what's presented here, because the drug supply has really shifted over the last few months. But either way, this is still the basis of what we do. We stabilize them with short-acting opioids, usually in IV dilaudid when they come into the hospital, if they're anywhere from cows of 8 to 12 or above. And then we also give them a long-acting opioid, and we'll talk about why in a couple of slides, in addition to an oral short-acting opioid, and these things are usually scheduled around the clock. We think about this like IV short-acting opioid in the beginning as a load. You need to give patients a lot so they can get comfortable, and then you can stabilize them with long-acting and short-acting opioids. And so this is an example. If our patient has cows of 18 at 8 a.m., maybe you'll try IV hydromorphone 2 milligrams, and maybe their cows went down by 2, but like not that great. Then you can try 4 milligrams at 9 a.m. You know they handled the 2 milligrams, right, and things didn't get much better for them. They're not having any adverse effects. So it's perfectly safe to increase that dose by 50 to 100%. That's like how we learn about opioids and pain management in palliative care, and you can apply that to folks with addiction as well. 9.30, cows are like a little bit better, 14, but not great. Totally safe to increase that opioid dose by 50% again, right? So you can give them 6 milligrams IV dilaudid, and then at 10 a.m., we finally get them to a cows of 10 after they've gotten all of this opioid, 12 milligrams of IV dilaudid. And then at that point, you can probably get them on oral because they're probably not throwing up anymore. So this is kind of our pathway. I'll go through and show you like screenshots, too, of our pathways at Penn. They're all called Penn pathways that we have available for all of our hospitals. Basically we are always recommending starting a long-acting opioid, a scheduled short-acting opioid, using our non-opioid adjuvants, which I'll go through. And then our goal always is to transition solely, only to methadone or buprenorphine, of course. Does this happen in everyone? No. But this helps us get there. I'll go through this dosing more in a minute. So this is kind of, this is a graph that we always show in our presentations when we're talking about why we use these medications. We think about it like, our folks that are using illicit opioids, right, fentanyl, whatever it is, have like extremely, extremely, extremely high opioid tolerance. I don't have to tell you guys that. And so we need to treat their withdrawal before we're going to be able to treat any pain at all. And so we think about treating their withdrawal with a long-acting opioid. And we think like probably 75% of the time that long-acting opioid, once we get it to the best dose, is treating that withdrawal. But that's not treating pain, right? The patients are here for terrible xylosine wounds. Maybe they're getting debridements. Maybe they have endocarditis and they're getting sternotomy. They need short-acting opioids on top of that to treat the pain. The long-acting opioid's not touching their pain at all. It's just touching their withdrawal. And so the short-acting opioids are there to treat pain. And sometimes when the long-acting opioid isn't at its peak effect, also treating a little bit of withdrawal. But the goal is to stabilize, quote-unquote, with a long-acting opioid. We try to use methadone as frequently as possible. Methadone, even if it's for acute periods of time, right? We're not like... When our patients are in the ED and in terrible withdrawal, we're not talking to them about what medication they want to be on long-term. Like they're not in a place to talk about that, right? Like they're uncomfortable. That's not what they want to talk about. They're probably not making the best decision for themselves in that moment anyway. And so usually what we try to do is get them on methadone for those first few days, and we tell them, like, you don't need to be on it forever. This is for acute use. And we can transition you to whatever you want, whether it's a different opioid, suboxone, nothing at all later. But methadone's going to work way better than oxy ER or morphine ER because of that NMDA antagonism. It's decreasing their opioid tolerance. It's decreasing the opioid-induced hyperalgesia that they all have because they're all using fentanyl. So, point being, we use methadone in almost everyone as long as they don't have any contraindications. This is our short-acting opioid guideline. So this is... You can see the little stickers, like, from our Penn Pathways. This is a pathway available to all of our clinicians at all of our Penn hospitals. And so these doses we have determined to be, like, completely 100% safe for people who are not experts in this field to use and prescribe or order in the hospital. So these doses are pretty low in our standards when we're talking about, like, the addiction team. But they're safe for general practitioners to use, and so we recommend starting everyone as long as they're using fentanyl on oxy 20 Q4 hours standing or oral dilaudid 8 milligrams Q4 hours standing. And then we recommend increasing that dose, oxy by 10 or oral dilaudid by 4 every 4 hours if their cows are greater than 6, so until their cows are less than 6. I will tell you that most of our folks wind up on, like, day 1 on methadone 40 to 60 and oxy 30 to 40 Q4, along with all of our other non-opioids that I'll tell you about. We often destabilize them to have to use IV opioids. And so on the bottom we have folks can give IV dilaudid 2 milligrams every 4 hours as needed for pain on top of these orals. Or they can consider starting a PCA, which I'll talk about how to do. We often use PCAs in our patients because lately we've been seeing, like, extreme uncontrollable nausea and vomiting when our folks come in, like, completely unable to take oral medications at all. And oftentimes we're sending these patients to the floor where our nurses cannot administer opioids or any medication more frequently than every 3 hours. And IV dilaudid has a peak of, like, 15 minutes. So waiting 3 hours in between doses is not going to cut it. So we have to order a PCA. It's the only way to get our patients' doses any sooner than every 3 hours if they're on the floor. And even in the ICU, we can really only give doses, like, every hour. Our nurses have other patients. So we use PCAs. And I will tell you that PCAs are significantly safer from my perspective as a pharmacist than scheduled oral opioids. And that's because if there's no basal rate, if there's a basal rate, the safety goes out the window. But our Penn Pathway recommends a dilaudid PCA with no basal, a 1.5 milligram demand dose every 10 to 15 minutes, a loading dose of 2 milligrams or maybe more if you're already past that, and no 4-hour lockout. This is, like, a property that some PCAs have and some don't. But PCAs are safer than scheduled oral opioids because that peak of the IV dilaudid is, like, less than 15 minutes. It's probably, like, 7 minutes. And they can't get another dose until 10 or 15 minutes. So if your patient is awake, alert at that 15 minutes, it's safe for them to get another dose. The highest risk of all of the adverse effects of opioids that we're afraid of, sedation, respiratory depression, is at the peak. And so if we've passed that peak and our patients are awake and in pain and in withdrawal, it's totally safe for them to get another dose. Opioid overdose is, like, a continuum, right? You don't just, like, get an opioid and then stop breathing. You, like, get a little bit sleepy and then maybe you fall asleep and then eventually you stop breathing. So it's safe to use a PCA because if you get a dose that's too high for you, you'll become really sleepy. And then you're asleep, you're not going to get another dose for the next hour because you can't push the button when you're asleep. This is safer than nurse-administered, either IV or oral standing opioids because what the nurse is doing is going in every two hours, three hours, four hours, waking the patient up and saying, like, how are you feeling? And even if they were asleep, they wake up and they're like, oh, you know what? Like, now that you asked me, I actually, like, really don't feel good. My pain's a 10 out of 10. So even though they were just sleeping, the nurse is still going to give them that dose. And, like, nothing against nurses. My husband's a nurse. This is just how they do their job. So PCAs are much safer because it's the patient administering themselves the dose and they're not, like, being woken up and giving it by the nurse. So this is our guideline. We use this pretty frequently. If we're worried that... I think there's, like, a lot of worry around PCA in people with opioid use disorder because, like, of course people with addiction, like, want more. That's how addiction works. So sometimes if we're worried that the dose is a little bit too high or patients are using doses when they don't necessarily need them, we'll increase that lockout interval. And so maybe you don't get a dose every 15 minutes, but you have the availability to get a dose every 30 minutes or 60 minutes. And that's how we kind of, like, mitigate those things when we're not sure if they really need a PCA, but we're putting them on one anyway. There's so many different things you can do with a PCA. We use hydromorphone. There's morphine. There's fentanyl. There's actually methadone PCAs. We try not to use a basal rate, especially if we're using another long-acting opioid. So if you're using oxy-ER or methadone, we try not to put them on a basal rate, because you can consider the basal rate as a long-acting opioid, and you don't want your folks on two long-acting opioids. That's when we run into trouble, because they last so long. And that's where all the risks come in. So we try to avoid basal rates, and just crank that full list of stuff if we need to. And then, like we said, we can change the lockout interval pretty easily. We know this is safe, because we've looked into it, and we've published on it. So I think this paper was published maybe three years ago. And before that at Penn, trying to get anyone to give a patient with addiction or opioid use disorder an opioid was like pulling teeth. But we had a couple of people to do it ourselves, and Sam Zweibel convinced enough people to do it that we were able to publish on it. And so essentially, we gave, this was three, four years ago, when we were only using short-acting opioids. We weren't using the combination of long and short-acting. And so essentially, the short-acting opioid dosing was guided by an expert pharmacist, which is my boss, who used to do my job. And she gave everyone oral oxy or dilaudid, those doses that we were talking about in the beginning, the oxy 20q4, the oral dilaudid q8, and escalated the doses every four to 12 hours as needed for the first one to three days that folks were in the hospital. Patients who didn't respond to this approach were offered PCAs with IV dilaudid. But essentially, what the paper showed and what the study showed was that our patient-directed discharge rates fell significantly from 69% to 44%. Our length of stay increased from three days to five days, so folks were more comfortable and able to stay for their treatment. Our MOUD on discharge increased significantly from 33% to 65%. And way more people were discharged with naloxone. There were no evidence, no instances of iatrogenic overdose, so our patients weren't more prone to overdose, no instances of adverse effects like increased sedation or anything like that. So essentially, folks were more comfortable, able to stay for longer when they're able to stay for longer. We got them on methadone or buprenorphine. And it didn't hurt them. These are some of the non-opioids that we use. This is another screenshot from our Penn Pathways that this also links to an order set. So it's really easy for all of our hospitals to order if you work in a hospital system that's like huge, like Penn. This is all I can recommend doing, like more than anything else, making things so easier for your colleagues to order. We always recommend discussing with symptoms that patients their most common symptoms, right? Like some people have really bad nausea and vomiting. Some people have really bad restlessness. And so what medications can you schedule that aren't opioids to help specifically with those symptoms? So these are all the meds, typical, typical, like, withdrawal medications, right? Like you guys are all familiar with this. What we have found most helpful recently is using combinations of opioids with ketamine, phenobarbital, and or olanzapine. Not all together always, but something is in the drug supply lately that's making folks like incredibly restless, incredibly irritable, and have really bad nausea and vomiting. And so sometimes you guys might disagree with this approach since you're a psychiatrist. But sometimes we'll give folks in the beginning like a pretty large dose of olanzapine or another antipsychotic, like Caldol or Doperdol, to keep that nausea and vomiting at bay. That's been working pretty well lately. And then we're able to actually get them to take oral medications. And then we can go back to all of our opioids. We use ketamine pretty frequently. We just started doing this maybe about two years ago. Ketamine is also incredibly helpful, because similar to methadone, it's an NMDA receptor antagonist, right? Only it's a much stronger NMDA receptor antagonist. And so what that means is it's like resetting the opioid receptors, quote unquote. No one's 100% sure about how that works, but we say it. We know it helps significantly with pain. I'm sure you're all more familiar with it than I am that it helps significantly with mood, as well. And it really helps reduce opioid tolerance. So maybe we need to use less opioids if we're using ketamine in combination with this. And we actually know this is true, because at Penn, we give ketamine to most of our patients. And at one of the other hospitals in the city, they don't use ketamine at all. And they use much, much, much, much higher opioid doses than we do, which who knows which approach is the correct approach. But we think that this is very, very beneficial. And so essentially, ketamine decreases opioid tolerance and is making your opioids more effective. You can use lower doses of opioids, and ketamine's kind of boosting them up. And also providing a different route of analgesia, right? Not just an opioid. Our patients are so opioid tolerant, have opioid-induced hyperalgesia. Our opioids that we're giving them aren't really working for pain a lot of time, and ketamine tends to really help with pain for them. There are some cases out there. There's a really great group on the West Coast, Hutch and Grande, who have published on using ketamine during buprenorphine low-dose inductions, actually in the outpatient setting. And there's a bunch of cases about using ketamine for cases of precipitated withdrawal, like in the ED. And so in these cases, they just use ketamine, like no opioids at all. And it treats precipitated or just regular withdrawal actually really well. And so there might be room for that as well. Right now, we use it in combination with opioids, I think because the doses we're using are pretty low, because ketamine can be one of those very scary drugs. We have restrictions at our hospital that we can only use IV ketamine in the ICUs, and so we had to get creative, and we just made oral ketamine. I think there's a lot of thoughts about oral ketamine. There's ways to make it in a trochee or a powder and put that in capsules. At our hospital, we just take the IV ketamine and put it in oral syringes, and people swallow it, and that's our oral ketamine. It has extensive first pass, so it's maybe like, it's like, has very, very low oral bioavailability, so the folks aren't getting ketamine necessarily, but they're getting nor-ketamine, because it's extensively metabolized to this, which actually is more potent than ketamine itself, so we can probably use lower doses. We use, actually, incredibly low doses. We start at 1.5 mix per Kg per day divided in Q6 hours, so most patients get 20, 30, 40 milligrams every six hours, which, compared to an IV dose, is probably like 0.1 to 0.2 mix per Kg IV. It's not a lot. Our IV infusions, if patients are in the ICU and we're using them, we try not to do boluses, because that's where you run into trouble, right? If we go back to think about our PK and our pharmacology, the peak is where you're getting adverse effects, so we should probably try not to boluse and just keep people on a low-dose infusion, but this has been incredibly effective, especially lately when our patients are coming in with really bad nausea, vomiting, restlessness. This is just an excerpt of what we do for our buprenorphine New Starts. I'm sure you guys have all seen this in your practice or in other lectures. We do a low-dose induction on pretty much everyone, because everyone in Philadelphia and the world is using fentanyl and are actively using, right? They're sometimes using in the hospital or just before they came in, so we do a low-dose induction for everyone. We also do a low-dose induction for people who are in the ICU, and then after they came in, so we do a low-dose induction for everyone. Right now, we start a buprenorphine either 150 or 300 micrograms and split it either Q3 or Q4 hours for day one, and then move right on to Suboxone 2 milligrams and then Suboxone 4 milligrams on day two or day three. It's a little bit of a prolonged buprenorphine low-dose induction. One of our other hospitals has a shorter induction where they do it over like 48 hours, or they do 150 for two doses, 300 for two doses, two milligrams for two doses instead of doing this full day thing. This, I think, allows us to taper our full agonist a little bit easier. Essentially, if someone's on methadone 60 and Oxy 30 and they want to start Suboxone low-dose induction, I will leave them on the methadone and the Oxy for the first day of the Suboxone induction. They stay on the bup 300, Q4, and just get used to it for one day. We actually usually leave them on it throughout day two as well where they get Suboxone 2 milligrams, Q6, and then once we're getting to this day three where they're actually getting 16 milligrams of Suboxone on that day, we start to decrease the full agonist. You can taper it really, really rapidly. It doesn't need to be this crazy cross taper. On day three or day four, we decrease that full agonist, so the methadone or the Oxy by 50% and then we stop it a day or two later. And patients seem to tolerate this really, really well. We used to do, we were afraid to do low-dose inductions when folks were on methadone. We just weren't, we thought the withdrawal was going to be much worse and people are going to have really bad precipitated withdrawal, but out of necessity, we just started doing it. And people actually tend to tolerate low-dose inductions when they're on methadone way better than they do with just short-acting agonists. I think it gives them some level of stability in the background because the methadone is long-acting. So that's just an excerpt of our low-dose induction and then this is our methadone dosing and initiation. This may look high or low to you depending on where you practice, but essentially this is our quote-unquote rapid methadone initiation that anyone in the hospital can use. You do not need to consult psych or addiction medicine or anyone to start these doses. So you can essentially give someone 40 milligrams on day one, 50 milligrams on day two, and 60 milligrams on day three with this little split dosing without consulting psych or addiction. Once you get to day three, if you want to keep going up, which you should if you're in Philadelphia, consult psych or addiction and we'll help you increase it. So this is what our general hospitalists can do. Oftentimes if we're involved on day one, we'll put people on 60 milligrams on day one. This is like a small case for you to kind of like show you how this might be done. This is a real case that we had a couple months ago. So a 34-year-old female who was admitted for treatment of lower extremity wounds. This is something that we see super commonly, right? Like really bad dialyzine wounds in the hospital requiring debridement. Uses 14 bags of fentanyl a day. Long-term MOUD goal is suboxone. So when she comes into the hospital, her cows are 16. We give her 40 milligrams of methadone and 10 milligrams of IV dilaudid in three hours. She's feeling a little bit better. Her cows are 11. Oral intake is still limited by nausea and vomiting. So we have to start a PCA at the doses that we talked about before, right? No basal 1.5 milligram demand. And eventually when she's feeling more comfortable, and able to take oral, we continue that methadone as the long-acting and also start her on buprenorphine. So day two, when she's more comfortable, we give her another 40 milligrams of methadone, start her on that buprenorphine, 300 micrograms, and leave the PCA on so she can get doses when she's feeling pain or withdrawal. That's the short-acting opioid, right? Day three, let her get 40 milligrams of methadone again, move on to the two-milligram step of the buprenorphine low-dose induction, and leave the PCA exactly the same. Usually for days one, two of the bup low-dose inductions, we're leaving all of the opioids the same. Then day three, when we're getting to this 16 milligrams of suboxone, we don't give her a dose of methadone, and we keep the PCA on, but we increase that lockout interval to 60 minutes as a way to taper off the PCA. So now she can only get one dose every 60 minutes. Day five, she's on 24 milligrams of bup, eight milligrams three times a day, and we stop the PCA altogether. Usually at this point, we'll transition over to PRN opioids if there's still pain, if they're going to need it, or if they're going to need additional debridements. But this is an example of, we do this pretty frequently. This is a very typical case where we leave someone on a PCA while we're doing the low-dose induction, mostly because they had really bad nausea and vomiting in the beginning. You could easily transition them to short-acting oral opioids instead of the PCA. But I think a part of the PCA that our patients really like is the control, not having to ask the nurse. They feel a lot of stigma. They don't want to ask the nurse for doses. We hear that a lot, and so the PCA gives them back some control, and why not let them have that? This is for our next presenter. We're going to talk about what we do in other parts of the US. Thank you. Thank you, guys. My name is Dr. Julian Raffoul. I'm the CL psychiatry fellow at Stanford, working with Dr. Jose Maldonado, who's wonderful at putting together protocols. I did my general psychiatry and addiction psychiatry fellowship at Vanderbilt. Worked with Dave Markovits and Chris Kass, and what I'm about to discuss is what I learned with them, and future protocols to be written, hopefully, will be done at Stanford. This is basically just an overview of what we all probably know, standard induction of buprenorphine, microinduction protocols, macroinduction, then delayed induction, how we conceptualize it at Vanderbilt. It kind of, for me, all started because when I would see patients who came in with opioid use disorder that were pregnant, it made me very uncomfortable. I had many long nights where I would be freaking out. I'm getting called by the OB triage. I need to come help manage these patients, and I didn't know what to do, so I dove into the addiction fellowship, wanting to be comfortable with taking care of these patients. We know that opioid use disorder is serious. Opioid withdrawal can be uncomfortable for patients, let alone a newer resident or an intern taking care of them because people can die, and imagine with a baby inside somebody, it's gonna make people even more uncomfortable. And to skip through some of the facts, there's a lot of risk factors for OUD and pregnancy. There's a lot of adverse childhood experiences. There could be childhood sexual abuse, problematic relationships. I pulled some of this data from our reproductive psychiatry lectures at Stanford. Ultimately, we want to have comprehensive treatment for these patients. There's methadone, bup, naltrexone. There's some pregnancy unique considerations, different induction protocols. Induction protocols in pregnancy with patients that are using fentanyl can be very tricky. The patients can come in, they're feeling very sick, and they wanna leave the hospital before we even initiate any of this care. What do you do in that situation? Do you try to play tug-of-war, et cetera? So that's ultimately how I'm gonna color this first case. I saw a 29-year-old female. She was pregnant at 24 weeks. Lots of OUD history. There's also stimulant use, many psychiatric admissions in the past, suicide attempts, housing instability. There's infectious issues related to injection use. She had stopped and started buprenorphine and methadone multiple times, but never been able to sustain herself on MOUD. So already walking into a scenario like, what do I do? And my thought always went to, why can't we give her some medication, aka some opiates, to calm her down, to help with the withdrawal, because after multiple conversations, that's what she tells us she's gonna do. I'm gonna leave the hospital and go use again. I don't want her to do that. What if she overshoots and dies, and then there's a baby involved? So that kind of gets my antennae up. So when she came into the hospital, and this was the scenario that we're in, we have developed a guideline of what we should do for these patients. She admitted ongoing fentanyl use. She was going through severe withdrawal, a lot of autonomic symptoms. What do we do? So we stabilized her on a hydromorphone IV, four milligrams, every four hours until her CalScore come down. She was admitted to the OB triage unit. She probably got around three to four doses. I don't have the heart data because I'm just trying to color the case so you guys can get an impression. We gave Dilaudid for her to relax, to feel stable, for us to kind of contain the situation, and then be able to talk to her and figure out what is driving other than just use. You can get a good psychosocial history, you can build a treatment alliance, you tell them we're gonna take care of you, et cetera. There's no fear on my part because we're actually engaging in conversation. To me, once we get to the point where the patient's relaxed, they're not going through withdrawal, then I can actually be a psychiatrist instead of being like a pharmacologist, essentially just dispensing medicine. She ended up staying throughout her treatment course without issue. We ended up starting her on buprenorphine. She was titrated to 16 milligrams. It was about a one-week hospitalization. She didn't leave AMA and go use. To me, it was like a very satisfying experience. And we have a clinic at Vanderbilt called the Firefly Clinic. It's basically maternal opioid use disorder run by OB-GYN docs. And she ends up seeing psychiatry there. There's a separate psychiatrist at the way the clinic is structured. OUD with the OB-GYN, psychiatry with the psychiatrist. If there's an addiction psychiatrist there, they could do it all, but you still need an OB-GYN doc to help with the pregnancy issues. That's one scenario that used to make me very uncomfortable. Here's another scenario that made me very, very uncomfortable. 25-year-old guy, again, OUD, polysubstance use would use anything that would help him not feel, shut down his feelings. He said he was using five grams of fentanyl. I don't know how much that is. If he was using five grams, he'd be dead. So he's using a lot. He didn't know how much to tell me. We couldn't conceptualize what's going on. He injects. Listening to Jeremy, maybe he's using five points like in the Canadian system. I don't know, but he's uninsured. This is all in Tennessee, a Medicaid non-expansion state. He has a family history of substance use. He was able to hold down a job in construction, but this opioid use disorder was taking over his life. I think he was ultimately doing pills, but he tries to get heroin, but who gets pure heroin? He's getting fentanyl, lost his job. Very angry, very agitated, and causing a ruckus in our psychiatric assessment service where he's walking in for care, refusing care, refusing this and that. It's a problem. And then as a resident on call, you come into this situation. No prior psychiatric issues. This is like first touch coming to the psych hospital before he would present to the ED. He had a Cal score of in the 20s. We started him on a dilaudid bridge, quote unquote. And this is controversial in the atmosphere that we are practicing. We haven't written this up because we didn't want to be known as the dilaudid hospital, right? That's a great question. Maybe my colleagues and I will answer at the end, but this to me felt like this is what we were doing for the pregnant patients. I was like, why not try it on somebody who's not pregnant, just to see. Kind of like maybe culturally, this is how we're doing it, right? I don't have a good answer for that question specifically, but this is what we're doing. We gave also like PRNs. I'm gonna walk through some of the detail of our protocol there in a second. Started on the hydromorphone. Had the same outcome ultimately. Stabilized that day, but was admitted to the psych hospital, our dual diagnosis unit, where we were able to again engage and figure out what's really, what is he really trying to self-medicate outside of him having OUD? What is he actually doing? Ultimately, we convinced him that after three to five days in the psych hospital, that maybe he should do residential treatment. But the way I induced buprenorphine or Suboxone for him, I didn't like do the standard induction. I didn't tickle him with a microinduction. I asked my attending, can we kind of go in hard and do a macroinduction? So I gave him eight milligrams every two hours for four hours and he calmed down and he felt much better. He told me this is the best he's ever felt in his life. Again, a patient exaggerates a lot of his emotion. His affect is very heightened, but my attending was like, why don't we do 16 milligrams times two, right? Like this is kind of like, well, we're supposed to do two milligrams and weight and do a test dose and this and that, but we're like, you know, let's just kind of dive into this patient. The patient was willing. We went all the way up to 32 milligrams. Again, feeling great. Talked about other issues. But when we sent him to the residential treatment center, well, that's where we're starting to get pushback. You're not gonna be able to send him anywhere in Tennessee. He's above 16, sometimes 12. And a lot of times it would really upset me when I'm talking to medical quote unquote medical directors at these residential treatment centers because they would say we are opioid free here and Suboxone is an opioid. I have a conversation with you on the phone I get angry I put my mouth on the phone I'm like this is medication I'm not like giving him you know drugs off the street so it was very upsetting and that's what Jeremy will wrap up a conversation about but the protocols that we're using the left side standard protocol wait for a moderate withdrawal take two to four milligrams get up to eight to twelve and it's like you know it's calm and careful and it works for some patients right microinduction if we don't know where they are when they're withdrawal we're just gonna tickle them a little bit and it works and we get them up and they're fine macroinduction was what I was doing I was like let's just go hard go fast and see what happens you know I've listened to many lectures by Dr. Greenwald Mark Greenwald about buprenorphine I'm like I feel comfortable my attending felt comfortable so we did it and it worked nobody died I wasn't expecting anybody to die I feel like Suboxone is safe to use and I was gonna you know even go higher but I didn't want to go overboard so macroinduction but the delayed induction to me is very interesting conceptually because I am giving my patient opioid but I'm not giving them methadone I'm not a methadone clinic I'm inpatient setting I'm getting them high quote-unquote but I'm not getting them high I'm helping prevent withdrawal that's how I look at it so as a doctor I'm thinking I'm saving my patient from the awful symptoms of opioid withdrawal and I really honestly doesn't matter what opiate I give them I'll give them whatever I give them I just I want to treat the withdrawal so they calm down and don't leave you know before medically advised and then get really high again on their own I'd rather I want to be the one who manages the situation so I'm putting exactly what we do what I've done at Vanderbilt and I have one of my colleagues in the back who's the current addiction fellow there can say if this has been updated since I've left six months ago but you know you do the nursing assessments q4 vitals cows you get verbal consent all of that is good okay the delayed induction that the lot of bridge typically offered to this is literally verbatim what we have in our in our epic pregnant women reporting regular exposure to fentanyl leading up to presentation or patients reporting prior history of precipitated withdrawal during buprenorphine initiation officially but for me it's like patient going bananas telling me they're using opioids fentanyl essentially and they're gonna leave before medically advised and use okay let's do it so the goal of the delayed induction provide 12 to 24 hours of relief of the withdrawal symptoms using hydromorphone 4 milligram PO q4 hours scheduled hold for sedation or hydromorphone with hydromorphone 2 milligram PO q4 as needed for pain okay so there is there are you know bumpers on how we're giving it we're not just like giving it until they look better right we're still measuring and then before we do the induction we do wait 12 hours because we stop the clock and I know when he he or she last used and then after hydromorphone is held for 12 hours patient is ready for phase one induction or the test dose we should give them a little tickle of buprenorphine but then the other patient I showed I just I didn't tickle him I just gave it to him eight milligrams let's just do it so that's the part where it's not officially protocolized but we we tried it and then you know they have the standard induction two milligrams sublingual q2 our max of 12 buprenorphine without naloxone but now we have shown that suboxone is fine with pregnant patients and then you titrate up to 40 ID etc etc the thing that I wanted to highlight is on the bottom the symptomatic PRNs that we've had you know Clonidine, Zofran, Hydroxyzine, Trazodone, blah blah blah like all of this would work in an ideal setting with my patient who maybe if I had OUD I'd go let's try conservative I'm a reasonable person but give me OUD I'm probably gonna be the biggest jerk in the world because I'll have this knowledge in my head and I said I want to get high because of XYZ let alone a patient who's not gonna sit there and play around with the symptomatic PRNs I've never given symptomatic PRNs to a patient and they were like doc I love Trazodone I love Seroquel man give me some Requip for my restless legs I want to go home on these medicines and I want to follow up tomorrow and I'm gonna do better in life right they never do that I've never seen the symptomatic PRNs work as well as Dilaudid or hydromorphone worked to help them stay in the hospital and get the treatment they need and but why ultimately do I feel kind of uncomfortable talking even right now I feel like maybe I shouldn't be talking about this in public I'm being recorded people know that I'm kind of like the Dilaudid dude you know but it works and that's how we started talking together as a team and wanting to give this talk to not be afraid to give medication for opioid use disorder sorry before we wrap up we just wanted to quickly address the Dilaudid question the reason you'll see Dilaudid used in like most people's protocols is hydromorphone has a really strong affinity for the mu receptor so like significantly stronger than morphine or oxycodone and that's just like one part that makes a potency of an opioid but is important and when our folks are using fentanyl because fentanyl also has a really strong affinity for the mu receptor so Dilaudid is just like able to compete better with the fentanyl so we are yeah we're running out of time I'm gonna go quick and then we want to take your questions if you have detailed questions about doses and specific protocols I'm gonna ask you just to come up and talk about them if you have a little bit more conceptual or other issues like that but we're happy to talk so you're probably like your IOT thing is really great but that's never gonna fly in America it's never gonna fly in my hospital it's never gonna work I'm just gonna very quickly tell you that it wasn't always this way in America there's a time when IOT again was the standard of treatment coming out of the Civil War in the 1860s when we had this huge rate in opium and opiate use in veterans post-Civil War it was the standard this is when heroin is invented and first synthesized in 1898 heroin comes from hero it isn't talked about enough but I'm gonna guess that that's targeted marketing I think that's just very good pharmaceutical business but this is regular the hypodermic syringe and that sort of use was regular you could buy them in your sales in the calendars and you could order these things and it was the standard there plenty of ambulatory clinics doing this in the USA and this happened into the 1910 and then with the passing of the Harrison Narcotics Act of 1914 and then the Volstead Act which now is that which established the Bureau of Prohibition which is the early versions of essentially the DEA closed forced closure of all of these clinics by 1923 these are letters written by physicians to JAMA about the Harrison Narcotic Act hundred years ago calling it ironic calling saying this is overstepping into the practice of medicine if government can do this it's going to control all of medicine and these sort of arguments also massive confusion about the laws and around opioid prescribing these could have been written almost these could have been written today right okay can I prescribe methadone in the hospital yes or no can I prescribe buprenorphine by telemedicine yes or no right this is still similar ripples of these of this confusion 25,000 physicians were indicted post post Volstead Act and in this period of prohibition the DEA came after doctors and pharmacists who were treating folks during this time it took another 40 to 50 years for the next major advancement in opioid use disorder care come into place methadone was the next treatment that's how long it took to recover to start to recover from the wakes and ripple from some of them from some of the regulations that were put into place these are articles from around that time again could have been written today when a lot of these narcotic clinics were closed and kind of what to do with these folks what to do with these opium habituated patients and what are we going to do can I prescribe can I not prescribe now Harrison Narcotic Act Volstead Act became the Controlled Substances Act in the 1970s and have all tied together still exists today you should all be familiar with that one of course I don't need to go into that one methadone also so 1960s 1970s built around a the OTPs as we all know are really kind of built around fear of diversion right initial was called the No Diversion Control Act this level of regulatory barriers still cause at least one state to not have an OTP and we won't mention which Wyoming that is and these tensions between law enforcement and treatment providers just to this day so in saying that I bring up methadone as a good example because probably many of your hospitals will not let you start methadone in the hospital and this is a misinterpretation of CFR sorry 21 CFR 13 so these continue these continue to get in the way of best practice care for our patients so I'm going to skip this for for the sake of questions and more time but the FDA is was founded essentially by Harvey Wiley and you don't recognize you may not recognize Harvey Wiley but he was a guy him and his team of mostly young men and started a team called the poison squad and they were concerned about manufacturers tampering products so honey diluted with glucose olive oil made with actually cotton seed soothing syrups with morphine all these sort of things he was interested in he was interested in adulterants and in the manufactured food supply him and his group the poison squad would actually go around city to city and test these things and they test things on themselves and they do that sort of stuff there's a great documentary on them he fought to have the FDA created to to create the pure food and drug act to control regulate this unregulated supply this is the documentary and so just a small reminder that the FDA is founded on these principles of the way to control an unpredictable and toxic supply is to provide a safe and regulated supply and that's also early 1900s American history philosophically ideologically kind of aligned with how these treatments should probably have always left or should continue in the future so I'm gonna leave it here and then time for questions how would we do this well methadone when it was started it started as an investigational new drug any sort of application there is a history of using international data to support regulatory approval so some examples being a camper state which a lot of the evidence was based off European trials before the American trials were done in that time it got approval in this country I think this perfect for CTN study an international USA study on how to do this what would implementation look like probably limited to OTPs we can do this stuff in hospital already but how would you place these people how would you build these clinics well the OTP system I would argue is already the infrastructure for it it's already very highly regulated and structured that would be a nice place for enhanced or advanced addiction treatment but of course hospitals with more flexibility so with that I hope that the few things you pull away is that we should use the tools that we have to simplify treatment to keep people in treatment and to get people the treatment we know that works really well right buprenorphine methadone some of the probably some of the better medicines in the practice of medicine right in terms of production and mortality and the being the numbers need to treat is what they are so that's what we're talking about time of getting people stable and keeping them alive so we can use buprenorphine and use our use our fancy medication and then yeah thanks and with that we'll take questions and we'll be around the whole conference yeah I do not see I have not seen any study about that only report about that and if it's death because of opiate withdrawal what's the cause of death yeah I I'm not sure so there is a there is a case report of death by opioid withdrawal but I don't think that that's that case report is what's the cause of death yeah one case report was because all these years we have been dealing with opiate over hundred years I think maybe your question I think maybe I'm gonna guess that maybe the part of your question is what's the point of treating withdrawal it's aggressively it's extremely painful you should die but you never die that's what it is with opiate withdrawal nobody has ever died of opiate withdrawal yes if you have drank alcohol with it maybe because of alcohol part that you have died if you have benzo with it maybe because of benzo part you have died from pure opiate opiate you don't die withdrawal I haven't seen any report the people say there is a case report what's the pathology yeah thanks yeah yeah I have a question also yeah I've I've sort of conceptualized opioid withdrawal when people aren't in withdrawal they don't want to use opioids when they're in withdrawal they feel like they're gonna die they use opioids and then they die so it is indirectly the opioid withdrawal that causes death and I've had way more people that I would consider died of opioid withdrawal than alcohol withdrawal in my career as an addiction psychiatrist so I do think we need to reconceptualize that especially in emergency room settings I think if we viewed it as a life-threatening situation I think some of these strategies that you're presenting today would be more acceptable yeah by some of our emergency room colleagues especially I mean it has higher mortality rates than am I so yeah my question is on the case that you prevented are presented the gentleman who came in cows of 21 why not just do a macro induction at that time I mean I know you did it the next day so I'm just trying I'm not yes curious how you conceptualize yeah when they do the bridge when just on the heels of what we were just saying for patients that are agitated aggressive threatening to leave before medically advised that's where it becomes you know like a secret that we're doing this the goal is to get the patient engaged in care to trust their doctor to take care of what they're going through it's a great option maybe in the moment you know I decided why don't we just give him something to relax him I didn't want to give him benzos I have in my mind I want to prove this concept works so probably the academic thinking drove more than like the clinical necessity but as long as the patient recovers does well is initiated in care I always felt like my main goal is their provider as their physician is to get them to the next level of care that they need by any means necessary and that's very aggressive but why not you know the other important point and what we do in clinical practice and can do outpatient in in Canada is we're stabilizing on these opioids and then we can do any sort of induction that we want so we'll stabilize someone on slow release oral morphine maintain them and then we can just do a traditional induction so it kind of gives you that flexibility and give you maybe a little bit of that time and the stability for engagement so that's that's one example or if someone's on methadone and they want to switch on to buprenorphine product or something like that we'll switch them onto slow release oral morphine there's a conversion so you just do it the same day and then as we stop the slow release oral morphine we make that switch so that's kind of the the other angle for and if the flexibility given to us with a full life full of good eggnog to launch that treatment so great talks very kind of innovative and I think many of us have learned something new today so I appreciate one comment on the withdrawal management and kind of you downplay the role of adjunctive medication but don't forget you can always give enough benzos to put someone to sleep and I think they're pretty comfortable I think we're clearly under using benzos and under using clonapine I would rather you know just keep it as an option but a quick question is whether IV methadone whether you've seen any revival and always been used in UK and in doctor's offices and I'm wondering how do you conceptualize why not to give something once a day why do you have to have patients come three times a day that makes completely no sense especially that you still have I think pretty low coverage of the buprenorphine you know in the field so absolutely great question the the problems lie I actually got this question yesterday I took someone to the clinic and they're like why don't you use a long-acting opioid why are you having them come so often most of that's regulatory and other issues of course so it hasn't been studied in the outpatient setting as well or at least on RCT so we have approvals for to do IV hydromorphone IV diacetylmorphine we can also do fentanyl no one has had the courage to do fentanyl but that's but but I would love to do a long-acting alongside it I think you have something well the methadone you talked about methadone IV right so can you say more yeah we use methadone IV in the hospital pretty frequently especially unlike our folks that can't take oral because they're vomiting so bad we usually do split dose methadone so like for those of you that don't know the ratio of IV to oral methadone is like one to two so if you give 10 milligrams of IV methadone you're giving like 20 to you so we'll usually split it and do like 10 milligrams IV every eight hours and we split it because the there's an excipient in IV methadone that actually like also prolongs QT so like the risk is just so much greater that's why we always like split it Q8 instead of giving like one big dose in the beginning of the day I think it means the recordings done oh we're still going okay I'm from Vancouver I'm wondering why you guys were giving the hydromorphone only every four hours instead of like every hour especially IV because like you said like peaks in six minutes plateaus for about an hour or two why are we not trying to so that you can catch up right and then you're catching up on those plateaus and the peaks and then you're getting ahead of the withdrawal instead of it lasting like three four hours and like are you guys titrating your dosages based on people's reported use like why start at two or four like when you could go to like 16 IV and like don't get someone comfortable in an hour if you know they can tolerate it that's a great question it could be something for us to consider I think the four Q4 was the PO dose and it was kind of a conservative way to approach it but that this is all new right so we could try maybe a different approach and stacking the doses the way you're saying yeah like I'm wondering is there like a regulatory restriction for you guys because like in Vancouver like we're doing a Q1H Q30 minutes sometimes right away when people are uncomfortable yeah it could it could be I don't have the direct answer it is regulatory or institutional or restricted in the hospital yeah yeah it's a great suggestion yeah for us like in the ED will often do like every 30 minutes or every hour because they kind of have the staffing to like be able to do it like the nurse is available and not seeing six other patients on the floor there's like restrictions around how frequently we can give medications because the nurses have so many patients they like can't go back into the room that frequently so that's why on the floor we only do like Q3 or Q4 hours but in the ED like to stabilize someone we're often doing like 6 8 12 like every 30 to 60 minutes because of like exactly like you said that's just how it like pharmacologically makes sense have used outside before coming to you so you can avoid overdose how do you determine that he see you he says i just did one bag he's doing 20 bags already because he knows if he tells you that you give him more medicine yeah how do you determine that you're not going to cause overdose that i'm not going to cause the overdose that's right how do you determine that how do you go with milligram and whatever how do you determine that what um so fentanyl is like so much more potent than any of the medications that we have in the hospital um so even if we're even if someone like the protocols that i showed like the oxy 20 the hydromorphone two milligrams those are based off calculations to give folks back 20 percent of the total opioid they were using based off someone using two bags of fentanyl we know that folks only need 20 percent of their opioid requirement back to prevent florid opioid withdrawal and so that's what our doses are based on and it's based off using one to two bags of fentanyl i'm just hoping there's an objective way to determine how much opiate is in the body because patient report is very flexible if they think you're going to give them opiate they say if they know that what's going to interact with what is in their body they tell you they use little if they feel like you're not the other way they give you more because yeah i hear what you're saying you know what i mean yeah and like of course people with addiction are gonna want more right um i can tell you in four years of doing this we've never overdosed anyone um even if we've given 10 12 16 milligrams of ivy dilaudid what people are taking on the street is incredibly potent compared to the medications that we have in the hospital there's no way to measure opioid in the body you can get a uds and you can measure fentanyl and nor fentanyl levels and that'll tell you how frequently someone uses or how recently um but usually you can tell based on like their objective withdrawal symptoms like how severe things are we're not giving people 10 milligrams of ivy dilaudid if they're sleeping we're giving them if they're vomiting and clearly really really bad withdrawal is any way to determine anything with blood level i'm trying to see if there's any any tools to be objective no like there are there are tools to determine like fentanyl blood levels but they take like days to come back yeah there's nothing in the acute setting that'd be possible it's like a billion dollar idea thank you guys for coming oh go ahead sorry i i know um we talked about fentanyl you know the potency and the tolerance is probably longer than other opiate um i'm just wondering as have you guys tried anything for like restart after misdose for people on methadone restarting after restarting methadone after misdose oh absolutely yeah there's tons of published protocols we can i can show you them and we can talk about them absolutely yeah thanks

injectable opioid agonist treatment

IOT

opioid use disorder

Canada

US

IV hydromorphone

diacetylmorphine

regulatory hurdles

heroin-assisted treatment

treatment retention

withdrawal management

patient stabilization

Harrison Narcotics Act