Okay. Good afternoon, everybody. Welcome to today's AOAAM webinar, ED Treatment of Opioid Use Disorder, Truth, Trends, and Treatments by Dr. Gail D'Onofrio. My name is Julie Kimmick and I'm your moderator for this session. I just wanted to mention I have no conflicts of interest to disclose. This is the fourth of our, or fifth of our spring webinar series on hot topics in the treatment of opioid use disorder and stimulant use disorders. I'd like to introduce our speaker. Dr. Gail D'Onofrio, MDMS, is the Albert E. Kent Professor of Emergency Medicine and Professor of Medicine and Public Health in the Schools of Medicine and Public Health at Yale University. She served as the inaugural chair of the Department of Emergency Medicine at the Yale School of Medicine from 2009 till 2022. Dr. D'Onofrio has extensive experience as a leader, researcher, mentor, and educator. She's internationally known for her work in alcohol and other substance use disorders, as well as her research on gender disparities in their treatment and outcomes of young individuals with acute STI elevation myocardial infarctions. As a physician scientist, she has continual NIH funding for over two decades, designing and conducting clinical trials that have changed clinical practice. Dr. D'Onofrio is the PI of the New England Consortium Node with Dr. Weiss at Harvard being the MPI for the NIDA Clinical Trials Network. She's PI of a NIDA-funded K-12 drug use, addiction, and HIV prevention training program with scholars in multiple disciplines. She's committed to preparing young faculty to become independent investigators, advancing the science of emergency medicine and addiction. So thank you so much for joining us and welcome to Dr. D'Onofrio. Okay, thank you very much. And we are going to share our screen here and get ready in one second. So good afternoon, everyone. And I am not sure since a lot of people will sign up of whether or not you are from the ED. Okay, there. Does everybody see it? All set? Perfect. All right, thanks. Okay, so I don't know exactly how many people are working in EDs and in which capacity, but that's what we're going to talk about this afternoon. If you have a like burning question that you don't understand something, Julie's going to help me and present that to me. We hopefully will have time at the end, but I don't want to go on if you are, if it's something that will, you know, really impeach your learning about something else. So we'll move forward in that vein. So I don't have any disclosures except my funding sources. Some of the things I talk about are medications that I try and those medications are given to NIDA and given to me, and I don't have anything to do with the companies. So just in general, what we know is that the problem is huge. And if you look, this is a national household drug and survey results. And as you know, they're always a year behind, but these are the most recent ones that we have. Almost 50 million people have a substance use disorder who are greater than or equal to 12 years of age. And you can see that 30 million have alcohol use disorder, 27 have drug use disorder, and 8 million have actually both. Almost 9 million report misuse of opiates, which are for non-medical use, and 6 million had an opiate use disorder. So when you think about it, there's not much else that has such an overwhelming amount that death happens very quickly. And these numbers, unfortunately, do not seem to ever be going down appreciably. These, again, are the latest ones that we have. There are about 108,000 reported deaths in 2022 that are overdose deaths, and around 82,000 of those are specifically from opioids. And we do know that these are primarily synthetic opiates and fentanyl. We also know that methamphetamine is rising, and we have many individuals who are using both fentanyl and methamphetamine, as well as other stimulants, which have been cocaine, which have continued to rise. And we're seeing less heroin and less other prescription drug uses, which really were the primary drugs of use when I first started studying opiate use disorder. We also know, unfortunately, that the death rates have really increased for those who are non-white. And originally, again, this was much more of a white disease. And unfortunately, this is something now where we're seeing that the rapid rise in patients who identify as Black, non-Hispanic, and American Indian, Alaskan Native. We also know that adolescent overdoses have increased. The overall number is not huge. They still keep going up. And those overdoses are many times not necessarily from opiate use disorder, but from just using anything that they take that could potentially have fentanyl in it. We also know that the treatment gap is huge. This was presented a while ago, and also more recent data from the National Survey on Health and Drugs, too, is maybe that MOUD has, and particularly we're interested in opiate agonists when I say that, which are buprenorphine and methadone. They have increased. Unfortunately, there are, whatever paper you read, somewhere around 13% to 18% of individuals that actually receive these medications, which is pretty abysmal, knowing that they can save a life. We know treatment works, so we don't have anybody who's telling us it just doesn't work. The science is really there. These are older, very well-done systematic reviews, which clearly show that methadone and buprenorphine in multiple trials will decrease opiate use and retain people in treatment, and it does not necessarily have to be associated with any psychosocial supports. Obviously, everyone thinks if you have them, it can only help, but we don't need them. We don't need any programs telling us that you can't show up or get your medicines if you don't show up and go to group, or you don't do this, or you don't do that, that medicines are really the most important thing. You can think about that as in diabetes, right? In diabetes, there are a lot of things, individuals, behavioral things that individuals could do. They can do a lot, some with diet. They can have more exercise, but no one would withhold their treatment of their insulin unless they promised they were going to go do these other things. We also know that not only will opiate agonists help us with treatment, what it really does is besides reducing their illicit use, there's less viral transmission of hepatitis, HIV, and other complications of injection drug use. There's decreased risk in any risky behaviors, and any reduced legal consequences can be reduced, and as a result of all of this, the individual has more time to develop sustainable relationships, gain employment, and deal with all the other medical issues that may have come as a result. This is the consensus study report from the National Academy of Medicine, came out in 2019, clearly showed all of what we just talked about, that medications that treat OED are effective and safe. Long-term retention is associated with better outcomes, of course. The lack of ability of behavioral intervention does not justify not giving them, and most people could benefit and do not receive it, and we know that that care is inequitable. We know that we should be giving in all settings, including the justice settings, and confronting the major barriers to the use of OED is critical to addressing the opioid crisis, because without that, although honestly, you'll see as I go on, I become more militant as I get older, and I'm not so easy to just say, I hate the word barriers. I think it has to be done. As we talked about, I do a lot of work with cardiovascular, and particularly with women, and ST elevation MIs, and you don't with that disease, you can't say, I don't feel like treating it. I don't think I'll get the person to the cath lab. I don't think I'll send them home with the right medicines after they are discharged. You would be sued. I really feel like the biggest, most important problem that we have is that clinicians don't actually offer the most appropriate medicines. We also know that when we don't, what happens? The ED is the available place, 24-7-365, that we can do to combat this disease, and that's why I talk about it, and we are really there all the time, and that's really where most of these patients are, even more so now than previously, in that so many of our patients are unhoused, and this was not the case when I first, again, started studying obese disorder. There were maybe 10% of patients who were unhoused, and now it's 50 or 60% of the patients that we see, but true of all medical care, there is very little care for primary care options, and so that, as everything else, people are visiting the ED for all kinds of reasons, and as you can see here, quite a number are related to drug use. So what can we do? We're there for people who do overdose. We are there for people who are seeking treatment, and then we're there for anybody that we can, during the course of their visit, identify that they may have an obese disorder and ask a few questions. I really try to avoid ever using the word screening because when you use that, everyone gets really excited. The emergency department is supposed to screen for at least 100 things. The nurses get very annoyed because they think that it's their job to do it, and they don't have time either. They're stressed to the health, and so I say in this disease, don't worry about it. If you see someone who comes in asking you for help, if you see someone who comes in with an overdose, which is easy, if you see someone comes in an infection from an injection drug use or anything that's obvious, go to those patients and help those patients. That's the best we can do right now. I'm not asking you to have these screening questions that everybody gets and everybody will do it because honestly, they never come off well, and the nurse is so busy. You feel safe at home, don't you? You don't drink, do you? You don't use drugs, do you? That's how they come off, and they're never going to be that effective. So if you can just take those patients that are right in front of you and work with them, that would be a major step forward. We know what happens, and I'm forever indebted to Mark LaRochelle from Boston University, who's done multiple studies, but this particular one that he looked over a period of time of all the non-fatal overdoses that happened throughout Massachusetts from EDs, and he found that there were 1,700, 500 and something who came in by an ambulance, and then he looked 12 months later and found out that only 3 in 10 of those patients had received medications over that 12-month period since they came in from an overdose, a non-fatal overdose until 12 months later, and that almost five of those deaths occurred per 100 person years, which is like impossible. That's just about almost reaching what it is for a ST-elevation MI. He also showed in this same paper that if you did give methadone or buprenorphine, you had a significant reduction in mortality, and nothing changed if you gave naltrexone. So we do know that agonist treatment does work, and we only, we have to do is get people on it. The evidence is clear there in the emergency department. We published this in 2015. This was truly a study where we were, we did everything perfectly, so really it was much more than an effectiveness study. It really was amazing that we gave medicine out. We handed it to them. They all went to one doctor, so we would be really clear that it was the medication that helped, and we were surprised that the buprenorphine group was as good as it was that it, 30-day period, 80% of people followed up. The brief intervention, which I thought would be really almost just as good because that in itself is that we have these health promotion advocates here, and they get a brief intervention to motivate them to seek treatment, and they get a facilitated referral to somebody within the next day, and that was better than most people do today, but they didn't get the medicine, and referral was better the most because they wouldn't allow people just to get referral based on their insurance and preference. We did tell them where they could go, but those who got medication did very well, and they also had a significant reduction in their days of illicit opiate use, and also Dr. Bush did a cost-effectiveness analysis, and so really literally for every dollar willingness to pay, treatment was cost-effective, and so was a change in opiate-free days. So what do we do with all this research when we get it? So we learned that translating that into real practice is not really easy to do. In fact, it's really quite a nightmare. We had some extra help in that ASAP put out a consensus recommendation that a bunch of us were on a group that wrote this, and they have agreed that it is the evidence-based care and an expected care that people would administer and prescribe buprenorphine. So what do we do? We identify patients, we provide the treatment initiating, and we provide also overdose education and naloxone distribution. Obviously, the more you can hand it out in the state of Connecticut, we're very fortunate. We have money from the Department of Public Health, and we actually give people the Narcan, this nasal spray. Most of your states have gotten opiate withdrawal money. Hundreds of millions of dollars have been spent, so that's a lot of money that you should make sure that your state perhaps can help you in giving out this naloxone. And then we directly link patients to therapy, ongoing therapy, and we do it here. We're very lucky because I have places that people can go to six days a week. Sundays may be a little difficult, but they can go the following day. But this is why I always make sure that people go out with enough medication. And if you are at some place that doesn't have that direct access, you'll need to give the scripts longer than until you can get them in. I can tell you that there is not a place that people have called me about that I've looked that I can't find places. I'm sure there are probably some in rural areas, but now we're allowed to do telemedicine, so we can usually find some place to help people. I particularly like buprenorphine. We'll talk a little bit about methadone. Methadone is a wonderful medication if people need it, but it also requires people to go there a lot of times, and it's not a great medicine for people who are pregnant if you can avoid it. Because again, it is more difficult for the baby abstinence-wise at delivery for people who are on methadone than buprenorphine. We will not transfer people or transition people once they're on something because we're too worried about precipitative withdrawal. So once people started, they're pretty much on that pathway, and it may be really hard for a new mother to get places to get her methadone. So in that case, I'm pretty bullish about trying to use buprenorphine if you can. If not, there are other lots of reasons that people can do one or the other, but people can be sent to their treatment programs and be assessed in terms of what would be the best for the patient if they can afford it. For example, if they don't have insurance or if for any reason they're in a state that does not have Medicaid expansion. So we know that there are these issues related to adoption and patient success, and even though we know buprenorphine is great, it's not widespread. And these are both on the part of the clinician as well as on the patient, and that's reticent. And you could say any clinician now, whether it's outpatient, because I talk to a lot of outpatient clinicians as well, they're reticent to prescribe. There's a lack of prompt access perhaps to community providers for treatment programs, and they really are worried about precipitative withdrawal, and I'm going to go into that in quite a bit, that we've had quite success all over the country initiating buprenorphine, regardless if they're on fentanyl. And of course, there are a lot of patient logistical problems about insurance, whether they need preauthorization, whether they have transportation, even many pharmacies are not stocking buprenorphine. And patients present without the necessary withdrawal symptoms, so we can give them induction on their own, but it would be really, not everyone will do that, so it'd be really helpful if we could start initiating treatment immediately. And there's treatment ambivalence on part of the patient too, and so there's some conversations we can have to help that. But imagine there was a solution to overcome many of these barriers. And that is the seven-day injectable buprenorphine preparation. So I'm going to talk a little bit about this. This is a medication that we've been studying as part of something called CTN, the Clinical Child Network, 0099. It's called the ED Innovation, and we've been studying this for years now. We have over 1,900 patients who are enrolled in this study in over 31 sites throughout the country. These individuals we're getting, we are comparing XR bup, this XR bup of seven-day injectable versus the sublingual preparation. And the primary outcome is engagement and treatment at seven days, but, and I don't have the, we're just coming to the end, I don't have the answer to that, but I do have the answers and a lot of our things that, things I can tell you about XR bup in our experiences. So we studied this in an IND preparation protocol called CAM2038. It is now available, and it's called Bruxadi. Bruxadi comes in a seven-day and a 30-day injectable, and I have only used the seven-day injectable. And the really advantage of the seven-day injectable of CAM is that if you look over here in the plasma concentration levels, it really takes about four hours before you get up here to about 1.6, but eight nanograms per milliliter, and then it rapidly, and then it rises, and then it, obviously, it goes on and lasts for seven days. That's very different than sublingual because sublingual has a rapid rise in the blood plasma, so that very quickly you will get this lot in the bloodstream, and then it kind of self-deprecates over 24 hours. So if people are going to have a problem with it, you're going to have a problem with it really, literally around 30, 45 minutes afterwards, where people who are taking the injectable with that slow rise really don't have a problem. And if they do, it'll be around, it will be somewhere within the first four hours, but we'll show you that we've had very little. And I think that's because it's very variable for individuals, how this works and why some people do really well right away, or some people do well in a few hours. But in any event, it's the slow rise that makes it so easily to be administrated in the ED. Once you do that 30 day, it'll be just like supplicate, it's a rapid rise because you want it to be the person's on it. You want to make sure you get the medication in quickly. This is the large trial that I was telling you about. We have a little over 1900 now they're enrolled in all different areas of the U.S. and all different types of really drugs that are being used in those particular areas. And what we did was we took initially a small group of people in four sites that were very experienced emergency physicians and actually were all boarded in addiction as well. And those sites we took was Yale New Haven Hospital with Dr. Hawk here. We took Dr. Jean Marie Brown from University of Pennsylvania. And we took Dr. Samuels, who was at the time Elizabeth Samuels in Rhode Island. She's now moved to UCLA. And we took our friends here, Dr. Herring and Eric Anderson, who are out in Alameda. And then we had some expert consultants that most of you probably know Dr. Sharon Walsh and Dr. Michelle Laffle, who did the first phase two and three trials with CAM as our expert consultants. We took these sites and we tried to see whether or not we could administer the seven day injectable in patients who had low CALS scores. And so we did this under, again, under IND, we did it with a hundred patients and we looked to see if they would have an increase in five or more points in their CALS scores, or if they were to transition to a moderate CALS withdrawal, meaning 13 or more. And we looked at how many of those would precipitate people within an hour at the time. We only knew the aboriginal data that from sublingual, that would be within an hour, but we kept people, it was a very robust study that kept people for four hours and loss of observation. And then individuals giving phones and we had communication with them in terms of what they're craving and what their use of not prescribed medications were every single day. And then we brought them back at seven days. So they were pretty well tied into the group and the intervention for them as is in the entire study is that we gave the 24 milligrams of CAM or Bruxade, which is equivalent to six milligrams daily. As I said, we looked at them for four hours and they went all went on to care and a specific area of care so we could follow them really quickly. So something to know just about Bruxade, it's a very tiny syringe. It's only a half an inch long and it's a 23 gauge, which is very, very tiny. It's only one millimeter of solution. So again, it's a very small solution. We give it in certain areas. It should not be given in the arm for the first like three or four times because there's decreased absorption in the arm, but it can be given in the thigh and the abdomen or the glute, upper gluteal area, which is personally where I like to inject it. It's, again, it's small. The only issue is obviously you do not rub it once you give it because it becomes a little gel that dissolves. And sure. We did have one question. The prescribing information talks about giving a four milliliter. Did you guys give that four milligram sublingual first? No, thank you for asking that question. We did not. The whole purpose of this, if I did format, first of all, I hate four milligrams. It's like the worst thing you can possibly do is give someone that small. It's not enough to really get on the receptor. So I try to avoid for as much as I can. And if I did give four, it's like that, remember that rapid rise. So I'm going to put people in precipitator withdrawal that I know. So I would not do that with people who have low Cal scores. These are people with scores, less than eight, zero to seven. So no, we, and we did not do the lead in. And so we have a lot of data on this now, and it's sitting with the FDA. I believe that the government gave all of our data to the FDA and hopefully they'll take that off of the pamphlet, but I would never give a lead in or you ruin the whole purpose of using XR view of this formulation of XR view, but thank you for asking that. Yep. Thank you. So I'm going to go this quick. It's not published yet. So it will be hopefully shortly, but in any event, all we had was we had seven people who went into precipitator withdrawal out of a hundred and only two of them were between four and seven. And that was like 3%. So I'm going to go by that pretty quickly, but we did have, we didn't have as many people that were in zero to three. We tried to recruit more people and we did have a much more significant rate of, I think I just told you that right there, which was 14%. So we really decided that we would not, we would not encourage people to use it in the zero to three group. There are caveats to that. And I can tell you this because we wrote this paper on our experience with seven day injectable in annals of emergency medicine that came out in 2023. If someone came in and they hadn't used for days and they were withdraw, they might not be withdrawing at that point, but they were craving and they wanted to start on medicine. Then we would, I'd do it in a, in without any issues, but I wouldn't do it in any other respect. In this trial, people really had to not use within the six hours before they came to the emergency department. And we did not put people in who were in withdrawal. Not that you couldn't, I mean, that were overdosed, not that you can't, but because we were so careful with this and this was had never been done before. We didn't want any complicating issues. We do in our main trial have people who are entered, who come in after overdose, but in this trial we did not. And as a result of this trial, we did expand our eligibility to four accounts of four or greater. So we've been doing that with quite success in our main trial. We only have five people in the entire trial so far of like half of that 1900. So I mean, I don't know, 850 or more have gotten XR bupe and we've only had five individuals who had precipitated withdrawal. And we found out that a lot of people really liked it. The nurses liked it, the doctor, you know, the patients like it, the treating physicians who liked it. And people were pretty engaged. We've always had one or two people who were right. Oh, it hurt, whatever. But overwhelmingly the responses are positive. And in terms of precipitated withdrawal, we did publish this as part of that large trial when we had our first 1200 patients. And in that trial, we had less than 1% who had precipitated withdrawal. And that was with cows greater than or equal to four. And so it is, I can just give you a, you know, a spoiler alert. And as I said, in the 1900, we've had only five that are with XR bupe, I think at this particular time. And I can't remember exactly how many in the other group, I think the total is 13. It's still less than 1%. And these are the places during that paper, where the black dots are where we're enrolling. And then the stars are the precipitated withdrawal. And you can see that the red stars were sublingual precipitated withdrawal, and the blue stars were the location of the XR bupe. And the only thing I can tell you is that they pretty much occurred most places, you know, I can't tell you anywhere, it's in parts of the country. So I don't know what to make about it. And if I told you now of the 13 or so patients, we have a be very similar, it's scattered all over, there's nothing specific about it. And if you look at these patients, and we did in great detail, there is absolutely nothing that can tell you about them. It is true that all of the patients and including the ones that we, you know, of the 100 that we did, and we said we had seven people with precipitated withdrawal, those individuals were all positive for fentanyl, but 70% of our population was positive for fentanyl. So a small, so we always say, okay, go ahead and give the bupe, keep calm. And if you do precipitated withdrawal, stay calm and push the ketamine. So we are going to show share with you, this is something that's really mostly like this on the California bridge and Dr. Herring and us here at Yale have really agree on almost all of this, that if someone goes in precipitated withdrawal, that the most important thing is to give more bupe. All right. So in general, that would be about 16 more milligrams. We also like to give a little bit of lorazepam, as you know, you don't like to mix these medications, but we always give a little bit because it takes the anxiety and the worry away from patients. And often if people are just worsening and not in precipitated withdrawal, if you give them a little bit more bupe or you give them a little tad of lorazepam, they tend to do totally fine and settle down. But these are people here who have gone into rapid withdrawal and you know it when you see it. So we give a bunch of bupe. If we give more bupe of 16 as it work is law and hopefully we can encourage the patient to take it because sometimes they don't want to take it. If we give a bunch more bupe and nothing is still, people are really sick. We give a little lorazepam. We can give any of these adjunctive medications. And if they're still not feeling well, we do go ahead and give them ketamine. And generally it's around 20 milligrams or 0.3 per kilo. You give that slowly over 15 minutes or so and generally that settles people down. You can repeat the ketamine, but be careful, it does have some stacking events. So all of these individuals are monitored in the ED setting. If all fails, you may give a little bit of fentanyl to take the edge off. But in general, our patients have done well and two of them got admitted. There was no reason to get admitted, but I think in most situations we all would send these home. We keep them in the ED. As I said, many of these individuals are homeless, so there was no way we would send them home at night. We would keep them there. Within 12 hours, they do better and then they can leave. And still to this day, all of us, all of these investigators and people around the country do the same thing. We keep people there. If patients are nervous about using buprenorphine, the one thing I think in the decision-making process is that we say, this can happen, but in our experience, it's very small, but it can happen. But what we do promise them is that we stay with them and I don't leave them and the ED will not abandon them. They will stay there until they feel better. And so this is what we do. I guess I should just stop there for a second because that's really important. If, Julie, there were any other major questions? Let me just see. There was a couple of questions just about, you didn't administer unless not using for six hours. Is this for fentanyl as well, because fat-soluble versus water-soluble and so it stays there? It's anything. We just ask them what they use. We wouldn't, in this study, we didn't put them in unless they didn't use for six hours. Okay. Okay. In the zero to three group, that's in the zero to three group. If in the regular trial, what I would also say, and just using that is, I think what happens with individuals, clinicians, is that because people who use drugs now and use lots of drugs and there's xylosine in it and all other kinds of things, people get very anxious. And so they'll tell you all the subjective forms of the Cal score. Oh, I feel terrible. Oh, this, oh, that, but you look at them, their eyes are not dilated. They're not tachycardic. They have no pyloreaction. They're not really moving around. And you look at them and there's no objective signs. To me, that's not withdrawal. So when we're looking at a four even, they must have one objectable sign of withdrawal. And I think that's where people got screwed up. I think you've got to see some evidence of objective withdrawal and whatever that is, if it's yawning, if it's pupils that are dilated, if it's moving around, something that you see that's objectable in those, at that four level, that's fine. But you have to be sure people are withdrawing and they're not just telling you, oh yeah, I have terrible, I have terrible diarrhea, I have terrible vomiting, I have terrible this and that. But they're standing you, they've been in the ED for 45 minutes as they get in the process and they haven't been to the bathroom and they haven't vomited. So you really want to see some level of any kind of withdrawal before you move forward. And that's true just without being kind of a research protocol or anything. When I'm looking at anyone and I put a lot of people on sublingual and it's really, I just want to see some level of withdrawal before we start. And if they're going to do it at home or on their own, we're very careful that they understand that before they start initiating the view. Looking at imagining other things that we can do is high dosing. And we did publish this one article. This is a retrospective review. That's all it is, is a retrospective review. It's now seen as like the thing, but there was nothing published on this. So as part of one of my other trials, we had money. And so we looked to Dr. Herring's and Oakland and his setting, and he had been doing a lot of it. So we did a very robust retrospective review at looking at all the patients who received more than 12 milligrams at a time. And this is at a really at a time in life when it was published in 21, but this is a time in life when we were looking back that nobody was giving high dose and except some of us. And we, we had nothing to go by. We're just giving it. If someone looked at some of my patients and said, what did you do? You just gave 32 milligrams when people are still saying to give four. So we did this retrospective review at this one site, and we did have a lot of patients. There were 391 with 579 encounters. And during that time, there was no cases of respiratory depression or sedation. And there were five cases of precipitate withdrawal, none of which were related to the dose. So and we had, as you can see here, we really had no decrease in respiratory rate, no decrease in oxygenation. And when you look here in this outcome, you'll see that we put people in two to six, so less than eight was primarily the amount that people give. And then we gave 10 to 12 because people were giving 12. And then we went over 16, 20 to 24 and more than 28. Okay. So there were 138 people who got 28 or more. And then you can see what everybody else got. And the length of stay was very interesting. The length of stay was less as you went up on the amount and more down here in the two to six or eight. And the kind of thing I think that when we looked back on this is that this is a group of individual, this whole, mostly given by appearance, by the way, but this protocol, they're very comfortable with giving lots of bup. So if they gave a small amount of bup, it was because they were concerned, either person had really bad COPD or something else that worried them. So that's probably why they ended up staying longer than these individuals who they didn't think there would be anything wrong and they just go ahead and give it. There was no real difference in hospitalization, no real difference in return visits or returning to the ED. So, and precipitative withdrawal, as you see, there was no difference. In fact, four of these people were at a level of eight and none of them between 10 and 24 and one of them in this very high group. So it really makes no sense. So that's the only study that has actually been done. And it is retrospective in a large group of people. And we're just about to embark in a large study of really looking at the eight milligrams versus 24 milligrams of buprenorphine. And this will be done in four sites, four health systems and five EDs around the country. We're just about to start that. And it's a dummy, dummy blind study, which is complicated. So what it'll mean is that people will get three pills, every one. They look exactly like each other with the exact signatures on them and the exact, as taste as much as possible, they're kind of minty taste. And they will be given the equivalent of eight. This is RxO who's doing this because they're the only ones who can produce a placebo pill. So they have a little bit different dosing, but it's the equivalent of eight and the equivalent of 24 of high dose induction. And so we'll see what happens in terms of their treatment in 10 days, but we're really following them very carefully over this 10 days. They're all getting phones and they will answer a lot of simple questions each day in terms of what's their withdrawal and kind of like a scale and what is their craving and did they use any other opioid. So putting this all together and trying to get people to do it, how do you do it in ED? And this is one of my favorite diagrams here, but I think you should be more explicit here in step two, because I keep telling people to do it and then nothing seems to get done. So we know that we need to do a lot of different things, finding to be perfect, but just make sure you don't need to have the perfect being the enemy of the good. So ideally it's really, you have to have someone to send them to. So you've got to find someone who's willing to do it and talk it up. We do need those partnerships and it is helpful if you can get some performance monitoring and feedback, especially in emergency medicine, we get feedback constantly every single day as a dashboard, every day you work, like how many patients you admit, how long did it take you to make this decision? How many tests did you do? You know, every single day I get the fact that I work. So it wouldn't be unusual to put in there, you know, if someone had it anywhere near them, OUD, did you actually give medication or did you just say that person really did not want or declined or whatever? And feedback is great. So we always have our navigators, which are health promotion advocates here is if they find a patient at 30 days where they always call them and ask them and just in our regular life, if they've done well, they try to go back to the individual who started them on the medication or the nurse and say, remember the patient you started, I just want you to know I talked to them and they're doing very well. So anytime you can give that feedback back to people, it's important because emergency physicians only see the bad things, right? We only see people who come back. And we'll talk to you about the IT infrastructure because that's something we really studied and we have really made a lot of strengths on that. And we have protocols, et cetera. So this is what we do. We identify people, whatever it is they come in with, simple, simple, simple. We then assess their opiate use disorder and their amount because you wanna make sure they have opiate use disorder. I rarely go through, I think once in my life, I went through the DSM criteria, but they're there and I'll show you where they are. And you wanna make sure they're in some degree of withdrawal and you wanna know if they're pregnant, not because you're not gonna give the medicines, but because they can move up on the line very carefully, very quickly to a lot of things. And some individuals don't know they're pregnant. And so they have few choices if they wanna continue with pregnancy or terminate the pregnancy. So I think it's really important that people know they're pregnant, women know they're pregnant. And then we treat and then we discharge with naloxone information and somewhere to go. So we make it as easy as possible to do this by implementing processes and EHR pathways. So I'm gonna show you that pupe initiation is free. You can get it on your phone. We're just about to put out another rendition of that soon, but you can get this one free. And the nice thing about that, I'll show you later, is it tells you everything that you can do. We did this paper, which looked at clearly all decision support. This unfortunately happened right before lockdown, but we developed this clinical support system and sent it out to a bunch of different departments, 18 EDs that were all clustered over five health systems in five states. And we were looking at the rate of initiation of buprenorphine administration and EDs. And then we were also looking at other things about how many physicians used it. And unfortunately we didn't find a rate change particularly, and that's just the way that randomization came out in that one place people were doing it really well. But we did find something that was important to us. And that was that it was initiated by many more physicians in the intervention arm that had the clinical decision part than in those who did not, right? And I can tell you that in real life, we've had this embedded in our EHR for before this trial started because we were testing it here. And one of my operational people called me one day and said, how many milligrams am I supposed to give out? And I said, you've done this a zillion times. I know you haven't seen it. He goes, okay. I said, well, why do you call me? He goes, Epic's down. So he clearly had done it before. He just couldn't remember. So I know for a fact that people use it all the time. And this was another paper that just recently came out that long ago. And what all this kind of shows is kind of like very difficult. I know a way of doing this, this kind of exposures, but what it does show you, and you just have to really look at those green lines is that one, somebody does it and somebody else sees that you do it and you do this over a period of time, everyone starts to do it. So it really is see one, do one and teach one. So this is our generally our protocol that if people are, if you're just doing sublingual now and you don't have XR bupe is if they're zero to seven, we give them what we call, used to call home induction, but no one seems to have a home anymore. So induction on their own unobserved induction. And then if they are eight or more, we'll give them at least eight to start with. And somewhere we could give them eight to 16, depending on what people do. We watch them and we give them more why they're here so that they always feel better. And then we prescribe 16 milligrams a day and then we get them someplace as soon as we can and give as much out as we are to get it. So, we generally don't give less than five to seven days of it and may actually give more. We are fortunate again, to have that money from the States and SAMHSA. So we give people five days of take homes. If they're not in a study, they can get five days to go home. What's really exciting is that it is now embedded in Epic. So, if you go into Epic, all Epic, anybody who has Epic, if you had an upgrade since, I don't know, months ago, six months ago, you have this available to you. You may need to turn it on. And so it may take your IT people time to turn this on and to make it yours because you want to be a specific, but it is available to everyone. So, if you go down the neck and LX zone pathway, it will give you some stuff to do and you just check and press a button and stuff comes out. If you want to begin their OUD evaluation, you just press a button that you do that. And then outcomes, these things, just like the BuPAP. The BuPAP, if you just go on your phone and download it on your phone, you can have this all the time and you can go in the patient with your phone, which I might not be able to do here with your computer, but you can begin the assessment. It has the OUD assessment there where you ask them the questions. It will score it for you. It'll also tell you, it will give you the Cal scores. And again, you can go through the whole thing yourself and score it. And you can do the same thing along with the app on your phone. And then it also has this areas. So on the phone or here is readiness for treatment. These are some questions that you can ask people to help motivate them on a scale of one to 10, one being very not ready at all, and 10 being totally ready. How do you feel about starting treatment with BuP today? They pick a number. This is like what we do for everything. So if they pick a five, you go, ah, it's great. You're five. You're a five. That means you're 50% ready to go. Why didn't you choose a lower number? Now you could ask them why not to choose a higher number, but quite simply, you're wasting your time. They're just going to tell you why they like to do it. So if you ask them why pick a lower number, you can see how somebody will look at you, which is done many times. Like, why did I say that to her? I should have just picked a one, but they come out right away. I've done this in studies with thousands of patients, and you'll be so surprised at what they say to you that they'll come out right away and tell you, well, I just had a baby or I lost my home. I lost my job, or they'll come out with a million things. And all you're doing is kind of reiterating back that that seems really difficult. And if they pick a one, we ask them some very specific questions, and that's also on here. Like, what would have to happen for you to want to make a change? And you can understand if I said that, or what would happen to happen and make a change? You'd have to kill somebody yourself. It wouldn't be very good. But if I just ask, what kind of would have to happen for you to want to think about a change? They'll come and say something very readily, and then you can build off that. And all of this takes about two or three minutes max to do this. You're not gonna talk someone into anything. You're just kind of bringing some information out from them that will be most helpful for them to begin. This is our guideline for treatment on their own. We have it in English and Spanish, and you can always go on our websites and pull it down. We have them start with eight milligrams. If they don't feel better, they take more. Heavy users can take more. I always tell people we can take more if you need it. And then the next day you take 16. We want to make sure that they are feeling sick. And so we go over that really carefully, that they really need to have these objective signs before they start. And this is the app. So you can see it, it has three frames on it. Basically, it's gonna tell you about whether or not they have an opioid disorder. If you know that they do, you just say yes. If you wanna go in here and ask all the questions you can, this is a scale. They'll tell you where they are, how ready are they to wanna make a change. And you can go with that. If you don't, you can press on it. It'll give you some questions to kind of motivate them. Now, severe withdrawal that they're in. If you don't know that, you can click on it. It'll give you the CALS score. So it's really quick. We are upgrading it now to give more bup than just eight if you need it. So it's gonna have a little bit more nuance to it. And we're gonna be able to say, be sure that there's an objective sign of withdrawal here to make it a little bit more up to date. And that's, I think, the same thing. Also, you can go on the NIDA website as well as on our website. And we have many videos that we've done kind of motivating people to change. These are real doctors here who are doing it. And then the patients are actually the Yale School of Drama. And so we have multiple different things here about an overdose or someone seeking treatment or harm reduction. We have an adolescent which does take a longer time and you can go on those and you can, they're good for training too if you bring on people who are helping you. And I also wanna make sure you know about the California BridgeWidth site that has just about everything that you could also want on it. And so in the end, we know the extent of the problem, treatment works, the ED is a great option to combat this crisis. We know that there are huge consequences of inaction and that there is great evidence-based treatments as in bupren methadone that we can actually give in the ED. And we do do in the ED. We learned how to break down the barriers and increase success. And we are investigating different strategies, surveillance techniques. And right now we are also talking about pre-hospital which there are several places who are doing a great job with that. So at the end of the day, I do not believe it's a choice. I think it is malpractice if it's not offered and we'll never rest until we see something like this that was actually in the California Bridge Hospital's right at triage that if you need help, please tell us we're here. And we have the opportunity to embrace these treatments, engage all of the emergency clinicians and our partners out of the ED as well so that we can maybe change this trajectory. And there are the websites there and I will stop sharing and see if anybody has any questions. Okay, thank you so much. We do have quite a few questions that came in and I'll get right to those. One question was, do you use 72-hour methadone dispensing in the ED? We do, we can. We don't really generally need to do that because where I am, we have the availability to do next day dosing. So I don't think I've ever had to do that. So I will start in the ED if I need to. The problem I have with that is I'm committing them to that and I can never, with methadone it's very difficult so we're never gonna get them to a place where they're not gonna use, right? Sort of like low dose bup. So they're gonna go out and use on it. So it's not my ideal thing, but there are some reasons people will only think about doing that. So we will, the regs have changed for that. So now you can at least use 50 and not start lower. People that are using large amount of doses, I would never start lower than that. And I actually start higher if they're coming into the hospital for some reason. Remember there are stacking issues with methadone. So that's why they do it gently, but I think all the old protocols are literally back from the heroin days and they're really not very helpful. So we need to like study those better, but I have administered it, but I really, we can do the three day, but I don't because I can send somebody somewhere. Okay. Can you talk about macro dosing versus micro dosing, do you have a preference? I have a great preference and I'm gonna tell you why I hate micro dosing for one reason, unless they're coming into the hospital, we do micro dose people in our hospital because when you micro dose people, what you do is you transition them, you give them a prescribed opiate and then you're micro dosing them to get on for some reason, for whatever reason. And you can do that in the hospital because I can give them hydromorphone and I can give them what, or Percocet or whatever. But you can't do that when you discharge people. So basically you're telling them to go out in the street and use, and I would just never do that. I don't think it's right. And I don't think the evidence is anywhere near close that it works. Many people, once they get to the part where they're actually using the right amount, then if they're gonna precipitate, they precipitate. But we've had such great success. I give out bubo all the time. I talk to people on the phone all over who are concerned, not just in the state of Connecticut that people will call me and we do bupe. And I literally in my entire life have precipitated withdrawal three times. Two times, by the way, were in that ancillary trial for the zero to three. That's why I'm like, I'm done with that zero to three because we were doing it very strict unless it was a very specific reason. Like I said, people hadn't used it, but we had a protocol, I followed it. And one patient was a person using a lot of fentanyl who would not go on methadone, who tried bupe, had a lot of difficulty of bupe. And our inpatient addiction service said, he'll come to see you and he'll try the high dose. And he was not ready to start. And he kind of talked me into it because he said, and he'd had two aortic valve surgeries, so it was a mess. And he said, if you don't do this now, I'm walking out of here and that's the end. So I said, okay, but I don't think you're really ready for this. And of course he precipitated, he went into the worst precipitated withdrawal. And I think I like stayed with him for three days, came back, in 12 hours, he was fine. In the long range, we did not, he did not survive his disease, but he did for a couple of months. We got him okay. We got him on sublocate for a couple of months, but he succumbed a few months later. But in my, of all the people I've ever given bupe or worked with people giving bupe in my life, that's the only times I have precipitated withdrawal. Okay. We do have a question going back to the pharmacology when you were talking about the Brixotic weekly versus the monthly, the more rapid, it's gonna be more like sublingual if you just monthly. The monthly dose is just like sublocate. It's very fast acting. You want it to be that way, right? Because you're starting it after being on bupe. I know that there are some people who have started it without bupe inductions first. I've not done that. You probably can, but it is a very specific patient that you'd wanna do that on because it is a rapid rise. There, I don't use them, but the people who are using them, the advantage of Brixotic in some ways are that it's a very small amount of fluid. So it's less painful. And there are a wide variety of dosing strategies that there aren't with sublocate, but I don't do it myself. So I have no real experience other than what people tell me. If you were not in an ED setting, if you're in an outpatient drug and alcohol program, would you feel comfortable using the Brixotic for the first induction based on- Yes, absolutely. I really have no problem with that at all. I mean, you can always send this when there is something happens, but I really think no. Objective evidence of withdrawal and use it. But I don't have a problem with starting people on Bupa outpatient and people keep sending me. I said, I can tell right away where someone could start. And I really think the disconnect is that people are not withdrawing at all. They're very anxious. I facetiously say to my friends who are outpatient, give everybody a little bit of Ativan, let them sit there for half an hour and then see if they're withdrawing. But I really kind of mean that in some ways, that you have to make sure they're withdrawing. And then I think the other thing is if they don't feel better, if they say to you, I generally always usually start with aid. If you start with 16, it makes people nauseous sometime. I mean, why do all this? I start with the aid. If they don't feel better, if they've said, oh my goodness, I'm feeling a little worse or I don't feel better, I give them more. So we kind of like prevent this. It doesn't mean you won't cause some worsening in a few points of cows, but you can easily work through that by medicines that you would have there. You don't need a whole lot of IV medicines. You could give, I don't know, a little clonidine or a little Tylenol or, you know, they may get nauseous if you get a bunch of bupes. So any anti-nausea medicines, but other than that, people do really well with it. We did have somebody ask about if you can't tolerate, if the patient can't tolerate any symptoms of withdrawal, what would you recommend at that point? I'm like, they can't even hang on. I would tell you that's not true because they are withdrawing all the time. Individuals are in a constant state of withdrawal because they can't always get their drugs. So they are always in a little degree of withdrawal. So it's not that they, I just, again, it's talking with the patient. That's not a realistic phenomenon. We're here to work together to make it as less painful for you as possible. And in that case, I'd give them a little Ativan and then I'd start. But I think it's like, it's just talking with the person because they're, everyone is constantly in some degree of withdrawal. They fall asleep. They can't get to their medication or whatever. And so what we're trying to do is make it as less painful for them as possible and do that kind of together. And less than 1% of the time things will get twisted but we'll be there to help them. We had some people comment that they've checked into the app. They're going to be using it. Somebody did ask, is extended release buprenorphine on the buprenorphine initiation app? No, no. The only thing that is there is our traditional pathway. That was eight milligrams starting, whatever. Brixadi is, you know, just now becoming available. And I can tell you that we got it through our PNT committee and in Atlanta, Grady did, Hennepin did, University of Pennsylvania did in their EDs. We have not, we have not used it because I have to go through with them now that I train everybody. Remember this, all that we did was through me and two other investigators. So I have to go through a lot of training and I will most likely say that they need to call one of us when they first use it so we can go through it with them to do it. So I think it needs to be gradually put out there but it's happening and I'm very excited about it. Well, it is 6.02 and I want to be respectful of your time. We did still have some questions. So sorry, we couldn't get to those to anybody who asked them but thank you so much. You gave us so much information and thank you for sharing your research and your experience with us. It's been really invaluable. So thank you again for being here with us today. I'd like to remind everybody that next week is our last one, our last webinar and it's going to be Dr. Tumadur Koha speaking on opioid prescribing by dentists and oral maxillofacial surgeons. So- And one other thing you can tell people they can email me if they have this persistent question. It's my name, gail.denofrio, no apostrophe at yale.edu and I will try to get back to you. Yeah, and we can put that on maybe on your slide too. Okay. And the handouts are available on our website. So do go in and complete your evaluation so you can get your continuing ed credits and we will hopefully see you all next week. Thank you so much.

Dr. Gail D'Onofrio

webinar

emergency department treatment

opioid use disorder

buprenorphine initiation

evidence-based treatments

extended release buprenorphine

motivational interviewing techniques

clinical decision support tools

patient outcomes