Symposium: Rapid Initiation of MOUD in Acute Care Settings: Findings from the SWIFT and ED-INNOVATION trials from the NIDA Clinical Trials Network (CTN)-Rapid Initiation of MOUD in Acute Care Settings: Findings from the SWIFT and ED-INNOVATION trials from the NIDA Clinical Trials Network (CTN)

Rapid Initiation of MOUD in Acute Care Settings: Findings from the SWIFT and ED-INNOVATION trials from the NIDA Clinical Trials Network (CTN)
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Video Transcription
So it is my pleasure to welcome the Symposia Group Rapid Initiation of MOUD in Acute Care  Setting, findings from the SWIFT and ADD Innovation Trials from the NIDA Clinical Trials Network chaired by Dr. Matisyamu Shulman.  Dr. Shulman is a clinical researcher focusing on opioid use disorder multi-site clinical trials.  He is a lead investigator on the Clinical Trials Network 0126 trial, a long-term follow-up registry trial to follow long-term recovery outcomes in individuals with OUD.  He is also a co-investigator on the lead team of Clinical Trials Network 100, optimizing  retention, duration, and discontinuation strategies for OUD pharmacotherapy, a two-phase multi-site  randomized control trial to test strategies to improve retention on buprenorphine and extended release naltrexone.  He is also a lead team member of the CTN097, surmounting withdrawal to initiate fast treatment  with naltrexone, which is a multi-site hybrid effectiveness implementation, stepped wedge  cluster randomized trial to foster widespread adoption of a rapid protocol for detoxification  and initiation of treatment with extended release naltrexone at inpatient and residential program.  With that, I'm going to hand it over to Dr. Shulman, who will introduce the rest of the panel and begin his presentation. Thank you. Thank you so much. Okay. Hello, everyone.  It's great to be here. We're really excited to present data from two Clinical Trials Networks, NIDA Clinical Trials Networks trials today.  Before I introduce the panel, I'd like to first thank AAAP for giving us the honor to kick everything off, get everyone hopefully excited about learning, and also just inviting  us to share our findings. Particular thanks to Katherine Cates-Wessel for finding Ned to make sure this really happened. Who laughed? I said it's good. Okay.  So, a little bit of an inside joke. And also, thank you so much to Tammy Borden for making sure that everything was smooth with the presentation.  And I think hopefully everything will be really smooth, so we'll see. If anything goes wrong, it's my fault, not hers. Okay.  So, with that, before I want to introduce everyone in the panel, I want to introduce my co-chair, Udi Gita. Udi is a project officer, a scientific officer at the NIDA CTN.  He's going to tell us a little about the CTN, but I just wanted to say CTN is really an amazing branch of NIDA in that it, sort of the explicit goal is to really get research  out of the ivory tower and into the real world. We're able to do trials with partners in the community, and we'll talk a little bit more about that.  And so, it's a really amazing scientific opportunity to really gather data in real world settings, and also to work very collaboratively with the representatives from NIDA.  I just wanted to actually quote something in honor of Udi. So, there's a new book by Michael Lewis out.  It's called The Fifth Risk, and it's an ode to the federal government, actually. It says how great the federal government is.  And so, he has a quote where he talks about someone from industry came to a federal organization, and they were sort of amazed at what they saw there. And I'll read the quote.  It says, this idea that the government is full of these bureaucrats who are overpaid and not doing anything, I'm sure that in the bowels of some of these places you could find  that, but the people I got to work with were so impressive. And I want to say, thank Udi for his help with the trial.  I mean, without Udi, we would not have been able to finish the trial on time. He really kept us disciplined, and it was really amazing to work with him. And Udi, take it away.  Thank you very much, Dr. Shulman, and thank you for inviting us for this symposium. And I would like to give a brief introduction about the NIDA Clinical Trials Network, and  the opinions are those of my own. So, the CTN was established to bridge the gap between research and practice, to improve  substance use disorder treatment, and through collaborative partnerships and cooperative  agreements of researchers, treatment providers, and community members, the CTN seeks to address  critical research questions with direct relevance to clinical practice and the needs of people with SUDs.  CTN research encompasses efficacy, effectiveness, implementation research, and is conducted primarily through multi-site clinical trials.  And over the past two decades, the CTN's research infrastructure and agenda have evolved  to reflect the changing landscape of SUD treatment community and transformation of healthcare systems, as well as emerging scientific advancements.  And the CTN currently is comprised of 16 nodes, a data and statistics center, and a clinical coordinating center.  Each node is primarily a performance site with numerous affiliated clinical research sites.  The objectives of the nodes include to develop and conduct clinical trials to evaluate SUD  prevention, treatment, recovery, and implementation interventions, as well as to engage and actively  involve community partners together, including people with lived experiences, to inform needs  and benefit the health of participants, and to ensure health equity and inclusion principles  as a fundamental aspect of research, to ensure that the CTN SUD research encompasses youth and individuals from NIH-designated U.S. health disparity populations, and to develop  collaborations with organizations where patients are located, such as pharmacy systems and community groups and settings, as well as other settings, and to generate evidence that  addresses sustainability and informs healthcare policy decisions and clinical practice guidelines  in healthcare settings, and importantly also to translate and disseminate research findings to the public, clinicians, and policymakers.  And examples of high-priority research topics are in the recent notice of funding opportunity that was published last month, and include but are not—they include but are not limited  to testing medications, therapeutics, neuromodulation approaches, behavioral strategies, and treatment  models to address substance use of substances with high or rising rates, including but not  limited to opioids, methamphetamine, cannabis, and cocaine, to test strategies for integrating  and the delivery of SUD prevention and treatment in specialty SUD care settings and general medical settings, including but not limited to primary care, emergency care, and pharmacy  settings, as well as strategies for linking patients in general medical settings to SUD specialty care settings or vice versa.  Importantly also to test interventions that address polysubstance use, which is becoming more common, co-occurring disorders, and social and environments determinants of health, and  other research priorities which could be found in our notice of funding opportunity announcement as well.  So I urge those who are interested to look at the various aspects of that notice of funding opportunity for more information, and thanks again for inviting me.  Okay, thanks, Udi, and you can see Udi is sort of selling the RFA. So we're going to move on to the rest of the panel. I'll introduce everyone.  We'll start at the, actually I'm going to go in the order that people are going to present.  So we're going to start out with a presentation about the CTN-97 trial, and that's going to be given by Dr. Adam Bazzaga. He's going to present.  He's the, so let me tell you a little about Adam. Adam is a very senior researcher, has recent expertise, although originally he started  out with general psychopharm for substance use disorders, but has recently been involved in development of medications for opioid use disorder.  In particular, he ran successful trials showing that we could start Vivitrol more quickly, and the CTN-97 trial was really a continuation of that work that he's done.  He's a full professor at Columbia and has been involved in research for, I think, more than 20 years. Second, we'll hear from Dr. Miranda Greiner, who's directly on my left.  She has just recently graduated from fellowship at Columbia and has started a job at NYU. She is, I'd say, a future star, a rising star in the world of research, and her research  interest is in implementation science, and she really was helping our trial work on bringing the goals that we had, which were to change the practice on units, as you'll hear, into  the real world. And finally, I want to thank Kate Hawk, who came from Yale, who we all met in person for  the first time today, but we've been collaborating for a long time over email. She is a little bit of an outsider here, so everyone should be very welcoming.  She's an emergency room physician and not a psychiatrist, but she's going to teach us about the ED innovation trial, which is another CTN trial, which is bringing buprenorphine  into the emergency room, and it's really a very exciting trial, and we thank her for coming and joining the AAAP community.  I'm going to speak briefly after Kate about fentanyl in the CTN-97 trial, and then we'll wrap up with Ned Nunes, who is probably most people here know him, but he's a very senior  researcher and mentor to many, including myself. In the research world, he's been involved in clinical trials research for over 30 years.  He's one of the lead investigators of the New York node of the CTN, and he's going to  help lead the discussion along with Mark Fishman, who leads, and I think Mark is also a really important representative.  He's an addiction psychiatrist, but he has an academic appointment, but I'd say, really, you represent the real world, I think, for me.  Mark runs treatment centers in Maryland, the Maryland Treatment Centers, they're called, right?  He's a researcher and a clinician and an administrator, and really will bring, I think, a perspective  of the difficulty of bringing and the opportunities of bringing research into real clinical settings. So I think that's everyone. I've introduced everyone.  I'm looking forward to the presentation, so we'll jump right into Dr. Buzaga's presentation.  These are some of our disclosures. And I think this is my presentation. Well, thank you for coming. Welcome everyone.  This is a wonderful day, wonderful place, and I cannot be more excited to meet everyone during these three days and speak about what has been happening in the real world over  the past year. What we have done is that we have designed this trial to see whether we can actually affect the change in the real world, right?  So this is a research study run on like a very rigorous research trial, but we at the same time wanted to learn whether those innovations can be implemented in clinical practice.  The title, the study was CT-97, and the acronym was SWIFT. And I briefly want to just describe the trial, tell you a little bit more about the procedure  for initiating extended release naltrexone, and then summarize my main finding. So as you know very well, extended release naltrexone has been approved for over 15 years  now and used in clinical practice, but it's used rarely, right? Many people who would like to offer extended release naltrexone as a relapse prevention  to patients with opioid use disorder talk about challenge of initiating treatment as being one of the main barriers.  Because the package insert will tell you that you have to do detox first, you have to then wait for seven, 10 days before you can safely give medication.  But what we have learned is that most patients cannot really wait that long, change their mind and either, you know, drop out of treatment or start other medications, but basically  give up on this idea. If you're going to hold the idea of waiting for medications too weak and you are an impulsive,  uncomfortable person with a lot going on in your life, you can imagine why most people give up on this idea.  So over the past 20 years, we have actually been running many iterations of this kind of rapid protocol, which was first started in Yale in the 80s by Herb Kleber, but we  have then adopted this to oral naltrexone and then when injectable naltrexone came, we've been trying to see how can we shorten the wait period to kind of minimum necessary  to allow patients to be more successful. And then we have done this controlled study when we randomized patients to either standard  protocol or this abbreviated version, which was about five, six days. And we have seen that in outpatient basis, we had 56% of patients completing the, receiving  the first injection in the standard versus, in the rapid versus 33 in the standard. And we wanted to see, because this was done in the research setting, we wanted to see  can this be also done in the community settings? The key features about this rapid induction is that we basically abbreviated the detox  portion, step down from full agonist, the buprenorphine to about one day, just one day of buprenorphine. Then you use adjunctive medications to alleviate any residual withdrawal.  And then you start naltrexone with very small doses, quickly escalating it, right? So we give buprenorphine as soon as the patient is ready, as soon as the patient has some  mild withdrawal, six, eight on cow scale. We give it a very low dose just to make sure that patient can tolerate it.  We know very well that lower doses are usually tolerated very well. Most clinicians learn to start with two or four and that we believe has been a problem.  So we start with one or even half. And if there is any residual withdrawal, we use adjunctive medications.  This protocol really relies on adjunctive medications, which are given as early as possible, even during the bup induction or even the washout before getting to buprenorphine.  We give them as standing doses rather than as needed. And we have found combination of clonidine and clonazepam and ondacetron to be highly,  highly effective, patient tolerated very well, and really like how they, you know, how the detox is going on for them. And then a day later, we initiate naltrexone.  Again, if you give a low enough dose, you don't precipitate withdrawal. It's a simple, you know, low agonist kind of replacement at the receptor site.  So if you give a half milligram or one milligram, no one really has much withdrawal, but at least they can have on the receptors.  The receptors undergo modification, and then you can very quickly escalate the dose. And there are studies from, again, from 80s from Yale showing that if you give just several  naloxone doses, people on day two can get naltrexone. It is just how the pharmacology work, that lower doses will help you tolerate higher  doses that otherwise would not be tolerated. We give them those naltrexone doses in divided doses two or three times a day, again, just  to make sure there is always a medication on the receptor. And then once you get six milligrams, it's probably equivalent of the blood level that you get from injection naltrexone.  So then we proceed to give injection naltrexone after tolerating six milligrams. And again, you can modify this protocol.  Some patients do much better, and they would like to get Vivitrol sooner. We can give it on day four. Some patients are more uncomfortable. We give them extra day or two.  It also depends when it falls during the weekday. So the protocol can be modified based on how patient tolerate it. So we had in this study two protocols, right?  So either standard protocol, which was five days, buprenorphine taper. And then you have about five, seven days of the washout.  And then you give challenge, either naloxone or naltrexone challenge. And then you administer injection.  Adjunctive medications are given, but they're given as needed, which is, I think, standard of care. This protocol takes about 12 to 14 days.  Versus the rapid procedures, as you see on day one, you give minimum tolerated dose. Six milligram is probably optimal.  You start adjunctive medication just to hit any residual withdrawal. And then after one day of kind of bup taper or washout, if you call it, we start naltrexone.  With oral doses, once the low doses are tolerated, very quickly escalate over the period of two, three days. And usually injection is given on day six.  So in this study, we wanted to study the effectiveness. We want to compare the two procedures.  But we're also interested in the implementation aspects, whether this can be done on the community-based treatment programs.  We had the effectiveness objective, which is we want to compare with the standard, make sure that it's no worse, non-inferior to the standard procedure.  And we also wanted to study barriers and facilitator to implementing this protocol. So the study was done within the CTN network at six sites spread throughout the country,  as you see. It included five steps. Each of them was 14 weeks. So we randomized one of the sites to initiate the RAPID protocol.  Those that were not randomized were still continuing with standard. So as you see, this is a step wedge design.  Every 14 weeks, a new site was starting the RAPID, shown here in blue. And the other sites were continuing with standard. So it was randomized.  But at the same time, it was an open label, right? Everybody knew what they were getting. This was the only protocol  available on the site. Obviously a lot of the sites had to be trained and prepared to do that. We took about six to eight weeks to kind of help them prepare  for when they start. They are ready to do that. As you see, we ran the study from spring of 21 to summer of 22. So this was a very trying time for everybody. It was  in the middle of pandemic. A lot of the units really struggled. And this was, I think, an added stress on testing the limits of the health care system. Whether  they can do that primary outcome was receiving the first injection. The secondary outcome was how long it took, how much craving, withdrawal, what what  are the safety outcomes and its significant side effects. And then we had also implementation outcome. We were able to recruit out of plant 450. We were  able to recruit 415 patients, which which was we're quite pleased during during COVID, when many of the sites were actually closed for some at some  point of time. As you see, half of the sites recruited more than planned, half less than planned, which is again the standard. But we got a sample from  all parts of the country, all different types of patients. Clearly patients on the West Coast and Texas look very different than patients on the East  Coast. We had on average 34 year olds, who 50% of whom were females. We're lucky that we had a site that was female on this site. So we got experience with  this population, 70% white, half of them had health insurance, third of them didn't have stable housing. Most of them, well half of them, have been in treatment  with medication before. Most of them had overdoses, on average four in their lifetime, and most of them tried detoxification, again four on average.  63% of those patients tested positive for fentanyl, quarter had methamphetamine or cocaine, about 40% had cannabis in their system. Most of them had  significant psychiatric symptoms on admission to the detox unit. Again, I didn't say that, but those community sites were inpatient sites. So either  inpatient hospital, residential site, or some kind of version of the outpatient, inpatient setting. Coming back, on admission most of them had a  clinical significant anxiety or depression scores. I think this represents the population, the six treatment. So when you look at the  primary outcome, where the people receive injection, again we were able to demonstrate that it's not only non-inferior, but actually was superior.  The odds ratio of receiving first dose of naltrexone, injection naltrexone, was 3.6 in rapid versus standard, which was highly, highly significant. And there was  no impact on the site, and no impact, well no impact on the step, and no interaction with any other demographic characteristics. So when you look at the  percentage that were successful on the top left, you see that in rapid about 63 percent of patients were able to receive the first dose versus 36 percent in the  standard. And if you look at the right, that's the outpatient trial that we had run about, I don't know, seven years beforehand. Before that we had 56 percent  versus 33. So again, it's not 90 percent. Clearly there is a room to improve, but we were able to replicate the study in the inpatient setting, either time where  fentanyl is predominant. When you actually look whether fentanyl had an impact, which everybody was concerned, we actually didn't know how this procedure  will work with the fentanyl, but there was no difference. Patients who were fentanyl positive were equally likely to be successful than patients who did not  have fentanyl in their system, about 60, you know, 65 percent of time. So we're, this was an interesting finding that fentanyl didn't really have much impact  on the success, and Mattis will tell you about what were the slight differences that we have seen in this population. When you look how long it took to get  injection in the standard procedures, it took on that average about 14 and a half days from the time of initiating treatment to getting injection, and it  took only seven days on average. With it, you know, as you see here, this is the range, seven to 25, so that the middle 50 percent of patients were getting plus  minus one day. And again, the hazard ratio was 25, so patients initiating rapid procedure are 25 times more likely to start injection naltrexone, which I  think is pretty convincing and pretty, I hope it's a convincing finding as to what should be the practice. Now, how do patients do? We were worried that if  you're gonna give them a lot of naltrexone very fast, they'll have more withdrawal, more craving, but when you actually look at that, so this is an  example for cow's withdrawal scores. As you see, the two procedures, blue and red, tracked from day one. You see slight increase when we're waiting for the  withdrawal to come before you give them buprenorphine, and then basically withdrawal remained low for a whole week and remained around six on average. So  again, most patients had mild, if any, withdrawal, which is probably, you know, right. And so the buprenorphine taper, you get about as much withdrawal as you  get when you start giving naltrexone. It's very, very comfortable procedure, no effect on craving or subjective or objective withdrawal. When you look at  the reason why people left, so again, a third of the patient may be more dropped out. When you look at the reasons left, if you, most patients, they just wanted to  go. As you know, the patient, some patients changed their mind, and for whatever reason, they leave the detox. Again, there was not so much difference  between the groups. Interestingly, 20% of patients in each group switched, stayed on buprenorphine, right? So they did not want to continue with induction, but  they were happy to stay on buprenorphine, which again, was highly kind of supported and encouraged. We definitely were very happy when patient left the  unit on end of the medication. The withdrawal symptoms were too uncomfortable. Yes, there were 12 patients who left because they were  uncomfortable in rapid, but again, small number of people. When you look at the safety events, so we were interested in the falls, acute changes in mental status,  acute medical complications likely resulting from withdrawal, acute psychiatric symptoms. We're tracking those between two groups. There was  really no difference in them between, during the induction phase. This is just the listing. We had three SAEs in rapid and standard. None of them are really  related to procedure, but when you look at the safety events, there was more safety events in the rapid. So five patients had vomiting, two had  precipitated withdrawal, one had worsening of asthma versus one had seizures, two precipitated withdrawal in the standard. So there is slight, slight  increase in the kind of medical events that happen in this rapid induction group. Again, non-significant between groups and very infrequent, 5% or less,  which I think most would be very happy. So let me just skip and give a chance to my colleagues to talk about this, but I think we still have a lot of work to do.  I think even if we can now offer this protocol to patients who want relapsed prevention with naltrexone, there is a lot of patients that leave  unit without being on medications. I think we have learned a lot about how to convince patients to leave the unit on medications. We developed tools that  Miranda will tell you about, and I think we can then learn from you about the questions you may have or lessons you've learned about implementing new  procedures. So let me stop here. I acknowledge Alkermes for donating Vivitrol samples for this study through NIDA and everybody else who worked on this study. Thank you.  All right. Thank you, Adam. And so very good to be here. Good to see some very familiar faces. I'm certainly not missing the giant rats or litter of New York  City right now. So just moving into the implementation of this study. So, all right, so we're going to be talking about some of the barriers that we encountered  during the study on the inpatient units. Now remember these units were across the United States, so different states, different implications in terms of  Medicaid, how that was impacting the unit. Also different in the sense that some of these units were community addiction treatment programs, and then there was  one unit in particular that was a hospital-based detox. So there were different barriers and facilitators across these units, but there were some  commonalities, things that we saw across these units. And I want to say that these barriers and facilitators, although unique to the rapid procedure for  Vivitrol induction, some of these are likely to be encountered for initiating other medications for opioid use disorder. So as Adam went over, this was  a type 1 hybrid effectiveness implementation study. So what that means is the effectiveness aim is still a primary aim, and then the implementation  aim is secondary, where it's more exploratory. We want to see what's happening on the ground, what are the barriers, what are the facilitators, and  then develop an implementation facilitation package around that. What are the strategies that we use to overcome those barriers? Now these  strategies, we use multiple strategies, and again, it was different across units, but there were some very common strategies used across all sites.  Today I'm going to be focusing in on the qualitative data analysis around this. We did collect some quantitative data around the implementation of this  intervention. For the qualitative data, what we did is we interviewed staff at each site about their experience implementing the rapid procedure, and  then throughout the trial, we collected implementation process data. Now what that means is every meeting, we had a lot of meetings, and all of the trainings  that we did prior to implementing the rapid procedure with these sites, we collected data. And so we were collecting data on barriers, on facilitators, on  other things that were happening with the implementation. And in particular, we were capturing specific implementation strategies. So I want to emphasize with  implementation science, it's a new and developing field, and it's exciting, and that we have tools and methodology to really capture what's happening on  the ground with implementation, which we need. You know, we need to be able to standardize the implementation strategies so that we can continue to test them. So  that's what we did. In this study, we used various implementation frameworks and models to standardize our collection of the data, and we use that in analyses. And  we're still, these analyses are ongoing, so some of the findings that we're going to be going over today, they're preliminary. Now one of the most common  barriers that we saw across the unit, and this isn't too surprising with any shift in clinical practice, you're changing the culture, changing the clinical practice  on the unit. These were inpatient detoxification units, and I say detoxification units because that historically is the culture. Patients  were being tapered off opioids in the past, prior to medications for opioid use disorder, and some of these units hadn't fully shifted to this mindset of  initiation of medication for opioid use disorder prior to discharge and stabilization. And so that was a big barrier. We're talking about getting  patients on to Vivitrol in a rapid procedure, a medically complex rapid procedure to some degree, and also shifting the culture. So we used various  implementation strategies to target this. First, we did a lot of training, clinical coaching guidance, and then the administration and clinical leadership  at the sites were heavily involved. They were doing a lot on the ground to change practice and to create buy-in on their units so that staff are on board  with making these changes, not just for the rapid procedure for Vivitrol, but for initiating all medications for opioid use disorder for every patient with  opioid use disorder that was admitted. So Dr. Adambasaga created this shared decision-making tool around medications for opioid use disorder. So we changed  the practice by having patients have these discussions early on in admission, whereas prior to this, a lot of times patients were talking about initiating  MOUD maybe on day two or day three of admission. Now again, rapid procedure for Vivitrol induction, we've got to speed things along. We need to get patients on,  you know, on a plan earlier on, and so we did that. Patients that were not interested in Vivitrol, we encouraged methadone or buprenorphine initiation. So  we implemented this tool. Another strategy that we did was, you know, it was really not our doing, but the peers that underwent the rapid procedure for  Vivitrol induction shared their positive experience, really helped to create buy-in. So it was at all levels. Staff were getting buy-in from their own  leadership and clinicians helping with that. We were doing our bit on external facilitation and providing support, and then patients themselves were sharing  their positive experience. Now this is the tool. It's not the full tool, but you get an idea of what this shared decision-making tool looks like. It goes  over all three medications for opioid use disorder, methadone, buprenorphine, and Vivitrol, and then it talked about myths, some misinformation, talked about  frequently asked questions that patients might have and how they might navigate initiating MOUD. And then along with that, this tool is available on this  website. We started development of a website in partnership with ATTC, or Addiction Technology Transfer Centers, and the idea was we not only wanted to  house all of the information for rapid initiation of Vivitrol, we want to have resources available for initiating buprenorphine and methadone as well. But  if you go to this website, it's active. You can find all of the training, all of the implementation strategies, common implementation strategies rather, that we  use for this study. And then we're still building when it comes to buprenorphine initiation guidance in the fentanyl era and then methadone. Another common  barrier was just buy into this clinical practice like we talked about. The rapid procedure did require more medical monitoring than the standard induction  procedure that you would do for Vivitrol. There was more frequent medication administration. We were monitoring opioid withdrawal more  frequently because that was the dosing of low dose naltrexone was contingent on opioid withdrawal symptoms. And then monitoring vitals more frequently, falls  precautions. So as you can imagine, going on to these units during the pandemic, talking to nursing staff and other staff and saying, hey we got this really great  rapid induction procedure for a Vivitrol initiation, but it's going to require a little bit more work and a little bit more monitoring, wasn't always well  received. So we had to do a lot to get buy-in. And this was also during the pandemic with staffing shortages. So a lot of staff turnover, a lot of new  facilitation of buy-in. So it was ongoing. So we did a lot of implementation strategies around this. You know, I think a common favorite was just having food  on the ground, staff luncheons. People loved that. The other thing is we we spent a lot of time creating training tools and didactics. I think we had a  drop box of far too many materials. And at the end of the day, the team said, you know what we really found helpful is just train the trainer strategy. It's  what we do in medicine day to day. You see, you know, you see one, do one, teach one. That's how people were learning. The didactics, all of the preparation prior  to implementation might have been helpful, but most staff shared that that's where they were learning. That was the key thing that helped them. And less  is more when it comes to paperwork. I think it's all of you might guess, that's not a surprising finding. And in terms of videos and training. We also  provided clinical coaching as external facilitators. I think one thing that is unique about this study is we we had, you know, we had some expert addiction  psychiatrists on our team guiding the implementation of this. So we were very involved in that sense. And then each site had their own implementation team  on the ground that was providing coaching.  And then I talked about this briefly with another another barrier that we saw was staffing. And we we expected this to be related to the pandemic. But what  we learned is that there were some staffing shortages across these community addiction treatment programs even prior to the pandemic. Funding's  limited. There's high staff turnover rates. And so when the pandemic hit and we were working with these units, it was that much more challenging. We did a  number of things to navigate that. Some of the administration at these sites were really great about shifting work effort and responsibilities for some of  their staff so that they could implement the rapid procedure and take on this new task. Another thing that we did was task shifting. So I talked about how we  wanted to change the clinical practice of having discussions around MOUD early on, getting patients on treatment prior to discharge. What was challenging is  that there wasn't necessarily a clinician readily available early on in admission. So we had social workers helping with that. The research staff did  step in and have a lot of discussions around MOUD. And that's one piece of this that challenges the sustainability of the implementation. But ideally, you'd  have a peer or someone else who could step in and fill that role. And then we really helped to facilitate communication across the the  teams, the interdisciplinary teams, and talk with administration. If we saw something that was something that was lagging in the implementation, you know,  we talked to them, have discussions, and I would say generally the administration of these sites, COOs, CEOs, they were involved and they were really doing what  they could to help support their staff and that that helped a lot I think. And then just some other things that we saw that were helpful that weren't  necessarily implementation strategies but facilitators or things that helped with the implementation of this new clinical intervention was most sites  that were doing very well had had solid engagement from administration and a lead clinician on their team. I talked about the peers. Peers on the unit would  complete their inpatient, what we would call previously detox, or their inpatient stabilization period and they would stay on for rehab on that same unit. So they  would be interacting with some of the new patients that came on to the other in the inpatient unit for stabilization and they shared their positive  experience with the rapid procedure, being comfortable throughout, and then positive experience being on Vivitrol and not experiencing cravings. Another  thing was the, I talked about this, the clinical champion on the ground using train-the-trainer strategies. That was essential. We absolutely needed a  clinical champion to help pioneer this new intervention. And then I think generally the units, a lot of the sites that we worked with, had previous  experience in research, implementing new interventions, and changing practices, but those that had more experience did tend to do better. And just to summarize, you  know, as I started out we need more research around this. We need solid implementation research that's using methodology to test implementation  strategies so that we can see how we can increase uptake of medications for opioid use disorder. You know, this pandemic continues, pandemic and epidemic  for opioid use disorder, and we need to be making changes. And the way that we have to do that is we have to standardize how we're looking at  implementation strategies and narrow in on what is really helping to increase uptake and adoption. And with that I'm going to go to the next presenter.  Hi, thanks for having me. It's an honor to be here. I'm certainly the odd person out as the emergency clinician. Before we get started I want to get a sense of how  many people are in communities where your emergency department is doing anything with buprenorphine. If you just raise your hands. Oh my gosh, I wish I had  a camera. We've spent a lot of time in this work and so it's actually, this is something that it's really exciting to see that it is happening. Obviously  that's room for improvement. So the things that I'm going to talk about here today are the ED innovation trial, which is another one of the clinical trials  network trials, and then a little bit of our, some data around precipitated withdrawal for some of the participants in our study. I am here  presenting on behalf of Gail D'Onofrio, who was really the lead for this study, but was unable to be here today, and Dave Filene, who's also co-lead. So  disclosures, I have research funding, no pharmaceutical or other obligations. I spent a lot of time talking about buprenorphine, so I just  want to be very clear, I have no conflicts of interest there. The medication for the injectable formulation that we're going to talk  about for this study was donated from Braeburn to NIDA for the conduct of the study, but that's it. So today we're going to talk about the rationale and  strategies used to initiate buprenorphine in the emergency department. It's wonderful, it sounds like you guys are all very familiar with that. We're going to talk a  little bit about the rationale behind ED innovation, which is an ongoing  randomized clinical trial looking at a seven-day injectable formulation of buprenorphine and comparing that to sublingual treatment initiation with a  primary outcome of linkage to treatment in seven days. We're going to talk a little bit about how the seven-day injectable formulation is different  from sublingual and sort of the implications for that in the emergency department and in our clinical trial, and then we're going to talk a little bit  about precipitated withdrawal that we've seen in participants in the study. So we certainly know, this audience is very  aware, that treatment for opioid use disorder works. We also know that there is a huge treatment gap among people who have untreated opioid use  disorder and access to treatment. So, you know, I'm sure many of you are like, well, it sounds like you understand why we're focusing on the ED because it's  happening in our communities, but really this came about because, you know, the ED is certainly someplace that we see an awful lot of untreated substance use  disorder, and it is a place where we see lots of people who come in either post overdose, they come in with infection, they come in because they have a cough,  they come in because they don't have a warm place to go at night. I mean, it's, you know, the gamut is wide, and there are about 130 million ED visits in  the country, and so the idea is if we can capture and harness some of those folks and help really put people into a, it's really to put people into the pipeline  to treatment, you know, that's really the goal that underlines all of this work that we're doing. So, this is a study that is probably familiar to many of you.  This was published in JAMA in 2015, and it was a randomized clinical trial that was done in the Yale Emergency Department among patients with untreated  opioid use disorder, and folks were randomized to either receiving treatment referral, a brief intervention, and a facilitated referral to outpatient  treatment, or to starting buprenorphine in the emergency department and receiving an outpatient referral to linked treatment. And so, primary outcome for  this study was treatment engagement at 30 days, and as you can see by this red bar here, these are folks who received buprenorphine, were randomized to the  buprenorphine arm, were more than twice as likely to be engaged in treatment at 30 days compared to those who received referral or brief intervention. And so,  really the idea is if we can get people, you know, started on medication and get them into treatment, you know, are they dumping them, are we dumping them more  effectively into the pipeline? We also looked at past seven-day opioid use, and there was a decrease in those that were started on buprenorphine also. But really,  this study provided the foundation for a lot of work that was done through the Clinical Trials Network, for whom we've been really grateful around how we  really think about initiating practice change amongst emergency clinicians. One thing I do want to point out about this trial that was not necessarily, is  not necessarily well known, so we started with, participants were started with cows of 12 or more, received 8 milligrams of sublingual buprenorphine  in the emergency department. So that's sort of the dose that we've been using all along in the ED. And about half of those folks that were randomized to the  buprenorphine arm did not have a cows of 12, and so they went home with unobserved treatment initiation. And so when we talked to emergency clinicians  about, you know, they're worried or scared about prescribing this medication, this is, you know, something that was actually baked into the initial  randomized control trial, although people don't necessarily focus on that. So following this study through the Clinical Trials Network, we did, and I'm  so thrilled to be following somebody who's talked a lot about implementation facilitation, because we did really two implementation trials, and  I'm not going to get into the details about, but one focused on sort of urban academic emergency departments, and one focused on community and critical access  and low resource EDs, where we know most of the people who access emergency care get care. It's not necessarily in sort of your urban academic centers. And so we  did lots and lots of IF, we did lots and lots of focus groups, and the things that we really took out of it is there are certainly barriers to implementation, and  all of them are really, you know, they are able to be overcome. Obviously the X waiver is gone, but that was a big barrier for a lot of  emerged clinicians to do the training, to follow the path, and so that was definitely an identified barrier. Sort of lack of experience in treating opioid  disorder with buprenorphine. Many clinicians did not get this training, you know, in medical schools, certainly not in residency, and so there's a lot of  education that needed to happen, and still needs to happen, amongst emergency clinicians. But, you know, to be honest, these are folks who do work with a lot  of medications that, you know, have a lot of complicated medications. This is, and buprenorphine really is a medicine that  is very, the pharmacology is very easily learnable to folks who were interested in learning. You know, ability to link to treatment. We certainly hear  about, you know, one of the biggest barriers that we hear from EDs is they don't know where to send people. From going into these communities and  meeting with these folks, we've often found that there actually are treatment clinicians. There are programs, there are, you know, primary care centers, there are  residency programs, there are addiction psychiatrists, but it's just often that the emergency department doesn't actually know about that, or know them,  and so it's really trying to get people to force them into sort of going out in the community to really better evaluate their treatment resources. And then,  obviously, stigma and sort of a misunderstanding is just, it's a huge, huge thing. And so, you know, out of, I think the thing that we learned from  doing, like, honestly probably about a hundred focus groups, I would never do that many again, but it was really, like, make it easy, make it easy, and change the  culture. Like, those are really the two things. And so you make it easy by having a protocol, you can integrate it into your electronic medical record, you know,  and then, you know, just set it as the expectation for your ED. And so those are really the two things that we, that at least I think about when I'm  talking to EDs. And then the other thing that came out of this was ACEP consensus recommendations. So ACEP is the American College of Emergency Physicians, which is  our professional society, and in doing these focus groups, there was a sort of a clinician up in rural New Hampshire who was like, I don't care about Yale, I don't  care about JAMA, I care about what my professional society says. You know, and if they tell me that I need to do this, then I'll do this. And so that was a  product that sort of came, I mean, it started at a clinical trials network and it sort of came back around to ACEP, and we said, look, we really need to have, you  know, consensus recommendations that say this is sort of the expectation for our professional society. And so they were published a little over a year ago in  the Annals of Emergency Medicine. So if you have ED clinicians who say, this is not my job, our professional society actually says that it is, which is  helpful. So, I mean, lots of different strategies. So I'm going to talk a little bit about, these are different strategies that we use for buprenorphine  initiation in the emergency department. It is a little bit different because they are right in front of us, and we clearly have different resources than  you may have as, you know, an outpatient treatment clinic, or even on the floor of a hospital, or in other settings. So we certainly, we have ED, standard ED dosing,  which as I mentioned before, was sort of starting with eight milligrams. There's high dose, which was really led by a group out of California, and really  developed by California Bridge. And the high dose is really between 16 and 32, sort of depending on your dose, but it's really starting with a much higher dose.  There's low dose, which I'm not really going to talk a lot about. There are certainly some EDs that are doing it. I think it's most helpful when you have  people that are coming into the hospital on agonist and cross-tapering. It's not something that there's been a lot of uptake amongst emergency  physicians because, you know, in part because people are, you know, on a very low dose. You know, if you send them out with a plan of continuing to use, like  there's just a lot of complications around it. So it's not something that we have a ton of experience with. And then the injectable formulations, which is  sort of a really new and interesting development in the last, I don't know, five years, a couple years. So rationale for high dose, I probably don't, probably  self-evident, but I mean the idea is to rapidly titrate people to therapeutic levels, to really treat minimized craving and withdrawal as soon as possible,  rather than sort of doing it over a longer period of time. There are studies that were done from, you know, a couple decades ago that show that, you  know, actually if you do high dose, like 24 milligrams, you can actually suppress craving and withdrawal for up to 72 hours. And so that provided some  rationale around the idea of, you know, when you see somebody in the emergency department, you give them a dose, you write them a prescription, you know, there  are a million things that can go wrong between leaving the emergency department and picking up your medication in the pharmacy. And whether it's not having an  ID, or whether it's insurance, or whether it's cash, or a ride, or the prescription got messed up, or the X waiver number was not on there correctly, or  they're out of stock. And so the idea was that if you can get enough medicine to cover people for a couple of days, they stand a better chance of  actually being able to successfully link to treatment after on. So that's sort of the rationale. Injectable formulations, I'm sure many of you are  very, very familiar with. Sublocade was FDA approved several years ago, is a 30 day injection, is supposed to be sort of after a 7 day sublingual lead-in. And  then there's another formulation, CAM2038, which was just recently FDA approved, comes in a 7 and a 30 day version. And that is the 7 day  version is what we elected to use for our ED clinical trial, with a rationale that, you know, we can get people therapeutic, you know, work on getting them  treatment with a week. And actually I'm going to show you, yeah, it's the next slide. And the pharmacokinetics are actually very, very favorable for  being able to initiate people with lower withdrawal scores. So if you look at this, I don't have a pointer, but if you can see that big sort of bump up  front, that's the plasma pharmacokinetics of sublingual buprenorphine. So you see people get sort of rapid increase with 16 milligrams, whereas with the  one-week CAM2038 injection, it's actually a pretty slow gradual uptake. And so we actually did, I'm not going to talk about it today, but actually did  some studies with about, I think we actually wound up enrolling about a hundred individuals across five EDs in the U.S. looking at this particular  formulation with people with cows of less than eight. And based on the first, I think, I want to say 50 of the protocol, we actually changed our protocol and  used this formulation with cows of four or more. And people do very, very well. So that is, you know, one of the benefits for this. This sort of slow gradual  uptake, the pharmacokinetics are different for the 30-day formulation. So I don't want you to leave here and say, oh, we can do four or more with, you know,  sublucate or 30-day. I can't tell you anything about that. But for the seven-day injectable formulation, we've had a lot of luck. So this is, so jumping  into the actual clinical trial, so it's the ED innovation trial. It's CTN-99 being led by Gail D'Onofrio, who's an emergency physician out of Yale, and  David Filene, who is an internal medicine addiction physician also out of Yale. And so the goal of the study was to compare the effectiveness of injectable  buprenorphine at sublingual induction in approximately 2,000 patients with untreated opioid use disorder in the ED with a primary outcome, primary outcome  of formal addiction treatment in seven days. And so from this slide here, you can see, you know, we tried to, we used EDs really across the U.S. There definitely  is a little bit of a, more people in the Northeast were interested in participating in this clinical trial than other places. But we tried to get a  smattering of academic and community and a wide geographic distribution. This is the team. It is huge. This is actually only a very small part of it. I like  Matt's point earlier about really expressing gratitude to the PO. Kristen Huntley is the NIDA Clinical Trials Network PO for this, who has  been really, really an integral partner in all this. And the sort of five of us up top, our lead co-investigators for the study, is myself and Jean-Marie Perrone,  who's an emergency physician and toxicologist at Penn. Andrew Herring, who's an emergency physician here in California and one of the PIs of  California Bridge. Ethan Cohen, who is at NY, in New York. And Ryan McCormick, who's at Bellevue. And so, huge team in making this all work. So, so the way that,  I just want to take you through a little bit of how it worked. And of course, I neglected to mention, so we started this, our very first enrollment was in June of  2020. So EDs were very much doing a lot of other things. And so we had a, had a lot of sort of competing challenges around getting the study up and  running. So we started initially with 28 sites and 27 institutions. And this was actually done as an implementation study in the sense that these were EDs that  were not routinely prescribing buprenorphine in the ED. And so we had, actually wound up having, having successful implementation in at least  25 of the EDs that actually moved on to the RCT part of the trial. And then we pulled in a couple of EDs that already very much had programs going, including  Highland and Alameda and our program at Yale. And so over the course of the year, of the, since June of 2020, we've had some variations. We brought in an  additional institution and institutions that, you know, were having challenges around recruitment or other things have dropped off. And so right now  we have 18 sites and 17 institutions. So we are still, we are getting very, very close, but still not there. Obviously COVID very much slowed down our ability  to recruit and enroll patients. But we have, as of last week, have 1,755 patients enrolled. So just under 250 to go. So we're hoping to be done with  recruitment by April. And so one of the things, so obviously I can't tell you anything about our primary outcome data. I can tell you 50% of these folks got  injectable versus sublingual. And so we, so we have a lot of experience and there are a lot of EDs around this country that have experience using the injectable.  It was not FDA approved at the time that we started the study, so it's been, was done under an IND. I just figured I'd mention that. But so we definitely have a  lot of experience using injectable buprenorphine, but I can't tell you anything about sort of primary outcomes. What I can tell you about is we, you know,  there's obviously been a lot of attention and interest around precipitated withdrawal and concern around precipitated withdrawal. And so  that is one of the things that we're, you know, we're monitoring very closely and keeping track of as one of our secondary outcomes for the study. And so, you know,  when we set up the protocol, we, you know, define precipitated withdrawal as this one hour, this sort of rapid increase in withdrawal symptoms one hour after bup  administration, and it's sort of based on the Rosado paper. And then, you know, again, the assessment was based on sort of rapid onset of withdrawal symptoms,  similar to when sort of a someone receives naloxone or Narcan. And so one of the things that I want to say about precipitated withdrawal is we, we knew, I  guess we didn't have a sense of quite how interested people would be in this when we sort of made this protocol four or five years ago. But we knew that we  were not going to, we couldn't be the ones that would say this is, is not precipitated withdrawal. And so we have consultants that are out of Kentucky,  Michelle Lafawal and Sharon Walsh, who any, any, any case in which there was sort of any question of precipitated withdrawal, we would have sort of these  case presentations where they would go through all of the details and it would be presented to experts and they would adjudicate, you know, whether this was  precipitated withdrawal versus, you know, what we call for lack of a better word, kind of a rocky course. There are definitely people who, you know, maybe  don't feel great or they feel a little worse or it takes them a while to feel better. But, you know, there's not necessarily, you know, precipitated  withdrawal where you have sort of this big increase in withdrawal symptoms, and I already said that part. So we actually published our outcomes from their first 1,200 people,  and this was in JAMA open last May. We actually had a very, very low rate of precipitated withdrawal. So out of the 1,200 potential participants that were enrolled, we had nine  that had precipitated withdrawal. It was just sort of a rate of less than 1%. And so, you know, in the context in an era where people are talking  about how challenging precipitated withdrawal is, you know, we just want to make sure that, you know, this is sort of prospective data that we're looking  at very carefully, and we want to make sure that people in EDs and other places are, you know, not afraid to offer this life-saving medication,  as I think that's part of why we were talking about this so much. So if you look sort of back at this chart, the black dots are the location of enrolling sites,  and the red and blue stars are locations of precipitated withdrawal. So as you can see, there's not really a geographic distribution. Clearly, there is with drug use.  And this particular graph here includes the nine cases that we talked about in that paper that were up through October of last year, and then we've had five additional cases  in the past year as we enrolled the additional 500 people. So we're still right around under that rate of about 1%. So participant characteristics, there was no clear cause.  There's no one thing that we could point out and say this is it. So, you know, unfortunately, we wish that there was, but there's really, you know, lots and lots of substance,  co-occurring substance use. This is sort of the individual chart by chart of each participant who was classified as having precipitated withdrawal.  As you can see, a mix of sort of races and ages, genders. Last use is something that people would probably be particularly interested in.  You know, all these folks were, you know, some were 8, some were 16, a couple were more than 24, both smoking, snorting, and injection use.  You know, not a clear pattern as to where or why. What I can say is that we, none of these patients had to be admitted to the hospital.  So this is something that can be very easily, well, okay, never mind, not very easily. But this is something that can be managed,  can be effectively managed in the emergency department. And so I'll go through some of the lessons learned and a protocol that we've done.  But all of these folks, if you look at the length of stay on the right, you know, there are a couple of folks who were put in ED OBS or observation, but nobody was  in the ED or nobody was sort of within the healthcare system for more than 24 hours. So even when this does happen, you know,  if you treat it effectively and jump on it, it is, you know, something that's very doable. So I already said that part. So this is, I don't want to imply at all that this is easy.  It is something that, you know, even we spend a lot of time in this space and a lot of time thinking about it and talking about all the cases.  You know, it is, you know, it is a stressful thing for the patient. It's a stressful thing for the clinician. You know, it's definitely something that we certainly recognize.  But really it is one of the things that we want to make sure doesn't deter people from offering or taking this life-saving medication. So lessons learned.  So definitely more buprenorphine. Before I enroll, whether the trial or not, before I give anyone buprenorphine, I say, you know,  there is a small chance this may make you feel worse. The answer is going to be more of this medicine. So don't look at me, you know, I just want to tell you that up front.  And they're like, that sounds weird. Okay. But, you know, if you don't tell them ahead of time, they are going to look at you and say that's what made me feel  that I don't want more. So we, lots of buprenorphine. And we don't wait a lot. So if people are looking really uncomfortable, if they, you know, the idea is just,  you can just give them additional buprenorphine. Obviously also ancillary medications. They were used throughout the study both sort of during and after enrollment.  You know, you can certainly consider IV fluids. Lorazepam, you know, is often one of the things we do. Ketamine, we actually do use quite a bit in the emergency department.  It is, we can use it IV and ED, and so we often do. We do this sort of the, just the sub-dissociative dose of 0.3 mg per kg. It winds up being about 15 or 20 milligrams IV  in a bag over 10 minutes. If you push it, they get more dissociative. So it's better to do it over 10 minutes. But in general, you know,  and I think the science behind this is still not terribly, this is a little bit of a mystery. I think it probably has something to do with just sort  of engaging a different set of receptors. And, but by and large, people do very well with it. And then obviously, like, you know, in a noisy ED  in the hallway where there's yelling and screaming, that's like, when people don't feel good, they're not going to feel good there. So try to tuck them in a room.  This is an algorithm. I put the California Bridge logo there. I don't actually know that it's on their website yet. But we had a lot of internal discussions around sort  of developing a protocol for this. And Andrew Herring was the one who took the initiative to actually put it into a nice pathway.  So I put their logo there just so they would get credit for, they've done a lot of really amazing work. And so, you know, there's a lot of variability  in how people use this, but additional, you know, in general, 16 of bupe, you know, and you can do some oral lorazepam, do a couple of rounds of bupe.  And then, you know, additional adjuncts as needed. So this is not, this is just sort of what we learned, our best guess. This is definitely not a protocol  that I would say we have tested or is evidence-based. But that is, people always want to know what we do. And so we wanted to put it in a way that was accessible to folks.  So that's it. I'm going to stop there and look forward to hearing your questions. Thank you. All right. Thanks. So that was a setup for my presentation,  which is also going to be about precipitate withdrawal. But, you know, it's, we've been talking for a while. I wanted to maybe hear from all of you.  So I want to just ask everyone for a raise of hands. Since fentanyl has infiltrated the drug supply in the United States, how many people feel that the way we start people  on buprenorphine needs to change in the room? Okay. How many people feel that they're not sure or they just didn't raise their hand because they're just starting out?  And how many people say no? No, that's okay. We need to, we need to allow for dissenting opinion. So we have at least someone who says  that maybe we don't have to change things so much, which is okay, right? But for the people who think things need to change, so I've heard a lot of things and I think  that we're starting to actually get some data and some real evidence. But I've heard some people are arguing that we shouldn't put anyone onto buprenorphine directly.  We should start everyone on a full agonist like methadone and then do a cross titration. How many people agree with that approach? Anyone here agree with that? Anyone doing that?  Impractical, agreed. I think it sounds a little crazy, but that's, I'm sorry we're being recorded, but that's what some people are arguing. And again, we don't have data,  so I guess we should be no judgment. All right. Another option is starting with a very low dose of buprenorphine to start. How many people are saying we should use half a milligram  of buprenorphine to start? Anyone do that? So some people. All right. How many people are just going hard and saying we should go high fast? A little bit like the ED.  Okay. So that's a little bit more people. Okay. Other approaches? Oh, the other one, how many people are using a lot of adjunctive medications beforehand and waiting longer?  So we have, okay. So we have a few people with that approach. Okay. So I think, I hope, we were trying to look at some of these questions using the data from the CTN-97 trial,  which I'll remind you is the trial that Adam spoke about at the beginning of the lecture, which was a trial about starting people on Vivitrol and Exxon and Altrexone,  but the first part of the procedure in every case and every person who entered the trial was to start them on buprenorphine. So we tried to look at the data retrospectively  to get some answers. So I think people know fentanyl is in the drug supply. There are reports out there about people having trouble getting on to buprenorphine, a lot of fear.  And then there was also reports, which we just heard the paper, that it's not as bad as people think. So just a quick background on the pharmacology for people,  most people are probably aware, but this is very high potency either medication or illicit drug. Fentanyl is also more lipophilic, so it's absorbed in the fat and probably  for that reason takes longer to clear. So the mean clearance for fentanyl is seven days and the breakdown product is almost two weeks.  So it might take a lot longer to get the medication or the illicit drug out of people's systems. So in our trial we had 415 people, as Adam mentioned before.  These were in community-based sites. People were coming into treatment with active drug use seeking treatment for their withdrawal usually, sometimes hoping to get  on to medications for opioid use disorder, sometimes not. And we tried to put everyone who entered the trial on to buprenorphine. Now just a note, and you might say when you talk  about this question, a lot of these questions of how often people get more withdrawal when they start buprenorphine depends on a lot of other clinical factors.  So in this trial we gave guidance, we didn't require because this was a real-world implementation trial. So we just guided the sites and told them we think this is a  good idea, but we're not going to force you to do anything. And that was to wait longer if someone was fentanyl positive and also start with lower doses.  So we agreed to start with the low-dose buprenorphine to start, and then you could go higher if people still had withdrawal or got worse.  So in the end we were able to do an analysis on 218 participants. So these 218 participants in the trial, all of them had received at least one dose of buprenorphine.  So we could ask the question, did they get worse or better when they received the buprenorphine? Two, they had cows from before the buprenorphine  and within the 24 hours before the buprenorphine and the 24 hours after the buprenorphine. And three, they had a urine toxicology so we could say does this person likely  to have been using fentanyl before the trial or not? So those were the requirements. And so we had the 218 participants. Of those 218 participants, a little bit more  than half had fentanyl positive when they got that trial-delivered urine toxicology. Here's a quick demographics table just to give an idea  of whether the fentanyl group differed in any way. So with regards to age, the fentanyl group was exactly the same basically. There was a difference in terms of sex.  So there were more fentanyl positive, the fentanyl positive was more male and the fentanyl negative group was more mostly female.  And that's probably because the site that was all women in the trial was in a place where fentanyl only started being found in the drug supply towards the end of the trial.  So that's the explanation for that. And with regards to the other demographics that were close to the same but probably mostly driven by site-level differences.  Okay, so how do we determine our outcome in the trial, in the secondary analysis? So what we did was we broke down this question of change in cows  into three categories just to make things simple in terms of thinking about things clinically. We took anyone who had less than a five-point increase,  a five-point or less increase in cows as low or no precipitated withdrawal or increase in withdrawal or if they had an improvement. So we put those people in one category.  We had a category of people that were five to ten that were considered to have mild withdrawal but not necessarily something we had to really worry about.  And then people who had more than a ten-point increase in cows, those are the people that we treated as though they had a real significant withdrawal. So we had a couple aims.  The first thing we wanted to do in the analysis was to look at what factors were associated with changes in the way people reacted to the buprenorphine.  Did people fall into the first, second, or third category depending on different demographics and different clinical factors including fentanyl?  And so we put those into univariate models and then into multivariable models and we looked at whether the change in cows was associated with any of these predictors.  So before I tell you what we found, I'll just give you some of the background just to give you a little bit of information so you can think how you can think about things.  So first of all, people that were fentanyl negative had slightly higher first dose of buprenorphine in the trial. So as I said, we guided sites to give a lower dose  of buprenorphine so that makes sense. The total dose after the first dose of buprenorphine within the first 24 hours was about the same. So fentanyl positive, fentanyl negative,  the sites were what they would do is they would give, most sites would give a little bit of buprenorphine and a little bit more and a little bit more.  People ended up getting about the same amount of buprenorphine regardless of which group they were in fentanyl positive or negative. And the group that was fentanyl positive,  people were waiting a little bit longer than the group that was fentanyl negative to give buprenorphine. So it was 52 hours from the last use, self-reported use,  this is self-report, in the fentanyl positive group whereas the buprenorphine was given about at 45 hours on average in the fentanyl negative group. This is the clonidine dosing.  I would just say, and benzodiazepine dosing, I would say that clonidine and benzodiazepine were about the same across both groups. Okay, so this is the outcome.  So I just want to give you, I'll give you the highlights here. So the main takeaway is that people that were fentanyl negative, when they got buprenorphine,  on average people got slightly better. They felt better after they got their first dose of buprenorphine which is what we hope and all sort  of expected and learned when we learned about buprenorphine that when you give buprenorphine to someone withdrawal at the right time, they get better.  With the fentanyl positive group, so if you just looked overall on average, there was a slight increase in withdrawal but it was relatively small.  And then if you break that down into the categories, so the real difference was driven by that five to nine category. So people that were getting some withdrawal,  they were getting a little bit worse but they weren't getting severely worse. In the fentanyl positive group, 21% of people ended up in that category whereas  in the fentanyl negative group, only 3%. Now with regards to the real significant withdrawal, the increase in 10%, sorry, 10 points on the cows, those are pretty rare events.  Only 6% in the fentanyl positive and 4% in the fentanyl negative. That wasn't significant and, you know, I think the takeaway from that is that this didn't happen very often.  It happened more frequently than it did in the emergency room and we can have a discussion about why we found a slightly different data than the ED.  But I think in the ED, it seems to me that there was a much more robust plan. There was a lot more of sort of aggressive management  of the patients whereas in the emergency, on the units and Mark can correct me, there's probably a little bit less clinical observation.  People are given medication but there aren't, there isn't a physician standing by waiting if someone's not feeling well, let's jump in and give them something right away.  That would be, that's one hypothesis of why we found slightly more withdrawal. But again, nothing that I would say we should stop using  buprenorphine in people that are using fentanyl. Okay, so the last point I want to make before we open things up for discussion is about interaction.  So we had this question, we had all these options of how to approach people who are fentanyl positive. Should we treat them differently?  Should we do something differently clinically? So we didn't test that in a prospective way but we said is there any interaction between some of the clinical decisions we made  with withdrawal and fentanyl status? That's how, the way an interaction works is that you look at three different things and you look whether two of those things are interacting  with each other to affect the outcome, the third thing. So we looked at whether shorter time between the time when people told us they used opioids last  and got buprenorphine, did that make a difference depending whether people were fentanyl positive or negative? We looked at dose and we looked at adjunctive medications.  So the takeaway is that everything was not, there was no interaction except for time. So we were able to find that with regards to fentanyl positive individuals,  people that got buprenorphine a little bit earlier ended up having more withdrawal. So you can see the slope on this line is going down.  So that's as time passes, there's less likely increase in withdrawal whereas if you go earlier and it's a time, you go earlier with less hours  from the last opioid use you have more likelihood of a higher increase in cows. And then this is the group of participants that were fentanyl negative.  So people that were fentanyl negative, the units knew how long to wait or they were waiting the correct amount of time. So it made no difference whether they waited longer  or less time, the withdrawal was about the same. So that's the conclusion of my presentation. I'd say the takeaways are more people  who are fentanyl positive experienced a mild increase in cows. If only you could. What was that? What was that? Oh, you're hungry?  Sorry. There's more significant, the more significant and concerning withdrawal really was not very common on even on sort of real world clinical settings  where there was not a lot of clinical oversight. Waiting longer to start inductions may be all that's really necessary in people that are fentanyl positive,  although I would say this is preliminary data, this is secondary analysis and say take all this with a grain of salt and we really need prospective trials on this.  And it sounds like the ED is going to be doing some prospective trials on high dose versus low dose, so keep an eye out for that.  And more aggressive adjunctive medication may be helpful. Okay, so that concludes the didactic portion of our presentation. We really want to hear from all of you.  We're going to try to end in a, we're going to try to take as much time as we can for discussion. So I'm going to invite our discussants,  our two individuals designated to lead the discussion up to talk, Mark and Ned. Sure. Well, let me just say a few words. Yeah, that was great.  Before we take questions, I'll just say a few words about implementation. What a rich set of data and so interesting. Thank you guys. I wanted to step back for a second  and just reiterate why we do this kind of work and why it's so important. You heard that somewhere around only 20% of patients  with OUD get on to MOUD and that's across levels of care and across settings and obviously, that's not good enough. We think about our aspirational cascade of care,  we'll never get it to 100% but we sure would like it to be 90% with the definitive MOUD treatments we have. And so it's so vital to think about settings,  whether it's in inpatient specialty care detox units, rehabs, or whether it's ED or whether it's outpatient clinics, how we're going to do better  and how we're going to broaden our repertoire of tools. Eventually, what we aspire to is being able to customize them. There's not going to be one method that's  going to be necessarily better in a horse race or the definitive method. We eventually aspire to have treatment matching. We're not there yet, but obviously that's  why it's so important to do the work. Miranda talked about implementation. I was privileged to lead one of the sites where this was done in Maryland in a medium-sized public sector  multi-site addiction community specialty treatment program. And in one of the sites is a busy rehab withdrawal management detox center. We see 1,000 patients a year, and people  are churning through.  Lots of challenges to doing new work, lots of challenges to trying to figure out how to improve things. And just a few words, ditto what Miranda said,  but I think in terms of trying to do implementation in this very interesting setting where you're both doing research and doing community treatment and it's the perfect place to try  to learn about implementation, I would say that the biggest beginning factor is to create excitement and to reinforce therapeutic optimism, to try to give people tools.  Everybody wants to do well. Everybody wants to relieve suffering. Everybody wants better outcomes for patients. So how do you get them revved up to try new stuff  and feel like they can be successful? And so that's about creating the excitement, creating a pathway, getting them to be willing to try things,  feeling like there's no wrong answer to try. You can't fail. We can always back you up. We have a famous professor from Columbia who can teach us a method.  I was on the ground kind of leading rounds and talking to the providers and coaching. And that kind of individual case by case coaching, talking about patients,  talking about the pros and cons, what went right, what went wrong, getting people's back, and creating clinical championship at all levels. And you mentioned that, Miranda.  It's about the medical practitioners as leaders, but it's about the nurses. It's about the counselors. It's about the peers. It's about the techs.  Everybody's got to kind of feel like this is for the cause. And a lot of lessons learned. One of the most important ones was to do a better job about treating withdrawal  aggressively, because I think that historically, we've probably undertreated withdrawal. And of course, when you're in a busy setting,  you want to protocolize things, but you can't always. But the protocols need to be more robust. So converting from PRN adjunctive medicines to standing regimens of medicines,  using sympatholytics like clonidine and using them aggressively. Yes, sometimes people will get hypotensive. Sometimes people will get bradycardia.  But for the most part, you can push it more than you have. That was very welcomed by the staff, by the team. The idea of reducing burden when you implement research  in a clinical setting. You don't want to create a lot of extra work for a busy clinical team. Right in the Monsters, Inc. movie  where the supervisor says, you forgot to do your paperwork. That's not a winning strategy. Let the research team do that.  The clinicians shouldn't have to be doing scales and the like. They should be treating patients and feeling satisfied about it.  Another thing is that we did use lots of adjunctive medicines, including benzodiazepines. And in a kind of traditional conservative setting in community addiction treatment,  that's a little scary to culture for people. You're going to give them what? And so getting people over the hump about you can use benzos, you can use them safely.  We're not going to get people dependent and addicted. We're going to use them briefly. You can manage it. Look how much it really relieves suffering and helps people.  And a few days of some clonazepam or lorazepam or whatever it is you used will not be a gross violation of clinical ethics. Then it's been very interesting after the study  to see about persistent uptake into usual care. You know, after the research goes away, what can we learn? How do we continue in a kind of sustainable way?  And I've been very pleased that the team has continued to use the rapid initiation method. As I was looking at some of our data and talking to the practitioners,  I would say that about half or 60% of the cases now are still getting the rapid protocol, maybe a little less than half still getting the standard protocol.  And it's interesting to think about why that is. One of the reasons I think that is important is that in a trial, these were patients  who came in enrolling as participants in a trial with the express stated interest of seeking treatment with extended release naltrexone.  And I think that's, in a busy real-world clinical setting, maybe not the rule. That's more the exception. The rule is patients come in bewildered and chaotic  and in distress and in withdrawal and homeless and seven kinds of different crisis. And they don't know what they want. And we are trying to persuade them that standard of care  is to be on MOUD, any MOUD you pick, just be on an MOUD. And they don't know what they want. And they're not educated. And they think things like medicines,  that's not real recovery at all. They've heard it's bad. And so you can't necessarily know what their path is on day one. So thinking about how those pathways differentiate  over hours, but more like days, and then making decisions as quickly as you can. But you can't be too quick with them, because that sometimes pushes them away.  So the rapid protocol for somebody who's committed early on, but lots of people aren't sure. And if you are wondering whether this is a person who would better end up or decide  to end up on buprenorphine, maybe you don't want to spare buprenorphine. Maybe you want to have buprenorphine be their stabilization medicine for longer,  because you're moving towards a persistent maintenance on buprenorphine. So it's very interesting. When I asked the medical team how they make this decision in the 50-50, 60-40,  one of the things you learn is that we talk about precipitated withdrawal. There's probably increased attribution of salience to negative outcomes.  Although most people don't have precipitated withdrawal. It's an infrequent event, as you said. Few people do, and some people have more symptoms.  And that's, I think, reinforcing to us as clinicians, we don't want to hurt people. We put a lot of salience on the bad experiences we have. So they're a little conservative.  So if somebody has been using an awful lot of fentanyl, if somebody is wary of precipitated withdrawal and has poor distress tolerance, that's  a person maybe that they will lean on for standard protocol. And people who have more distress tolerance are people that they will push to rapid protocol.  Those that have a history of leaving earlier, because they're known frequent relapsers, people that are at risk of AMA, those might be people.  But it's just interesting to see and very, very gratifying to see that the practice has been sustainable as a nice byproduct of doing this work in a community treatment program.  Ned, anything you wanted to add? So two different settings where five, 10 years ago in the past, the standard of care was not to initiate medication treatment for opiate use  disorder, the emergency departments and the inpatient treatment programs. And so now we have all this rich data on how to initiate. One of things that struck me, I think,  what you said, Miranda, that the coaching was a lot more valuable than the didactics. And that's very consistent with literature for decades  about how do you get physicians and other clinicians to change their behavior. It's about supervision and coaching and having clinicians try the treatment  and then get feedback on what happened and get coaching from experts. So I think that's a key point, really, in terms of implementation.  Then the second thing is just reflecting on the patients. There's a bias among a lot of patients and stigma among patients about medication.  So I'd be interested in hearing more about that. To what extent is that a barrier to implementation? And then my third point is I was really  interested in Kate pointing out that the American College of Emergency Physicians has made this standard of care. And that's terrific.  And I'm wondering, what organization in our world could we write a guideline for to make this standard of care? Would it be the American Hospital Association?  Would it be, should it be AAAP, or who? Because I think that just makes a hell of a lot of sense, that when the professional organization says, this is now standard of care, then  that would make a big difference. And that might be reflected in local leadership, as well. I know, as I've made it my mission to try to get this to do better in my institution,  I'm a broken record. And when I talk about cases anywhere across our system, uh-oh, here comes Dr. Fishman again. He's going to ask me why this patient wasn't on MOUD.  And that becomes the expected ritual of debriefing cases. And I think it does gradually change the standard of care in the culture. Yeah. Yeah. OK. Nice group of people.  So open for questions. Why don't we, oh, everybody's on this side. Terrific. Mike Dawes, Boston Medical Center, VA Boston.  In line with this presentation, we put an eight-hour seminar series for all of our prescribers at VA Boston in September to address  all aspects of MOUD access, implementation, high dose, low dose, everything. And so it's more related to the question of coaching. And we're in that phase right now  of feeling out with faculty their comfort levels. So they got the basic ideas. They got the algorithms. They're using the information we shared with them for on call,  for when they're working in the emergency room with residents, but not changing their practice. And I asked a few questions, a few of the faculty why.  And the responses I'm getting back is we're scared to death about folks that are coming in on high dose benzos and opiates. And we don't know what's on board.  So we send them to our inpatient unit for detox. And I said, well, OK. So the question to the panel is, how have you addressed that in these trials?  And how are you addressing it subsequently in terms of patients who are using benzodiazepines more than safe levels, and also opiate use disorders in terms of induction,  whether they're on fentanyl or not, but most likely fentanyl. So it's the benzodiazepines that's scaring a lot of the clinicians. That's what it seems to be, yeah.  Kate's going to take that. So I'm happy to start and then hand off. Can you hear me? OK. Yeah, sort of. All right, I'll just get closer.  So I mean, I think from the emergency standpoint, down, up. Button. Button. Button, OK. From the emergency standpoint, I think  what we tend to think about is that these are people that are coming to us sort of in their natural state of their receptors being occupied  with what they're occupied by on a usual, on a regular basis. So if there are folks who are prescribed high dose benzos. They're not prescribed. It's off the streets.  Yes, or if they take them, that is honestly not a part that necessarily affects one way or the other our willingness to start buprenorphine.  We certainly know that the risks of being on buprenorphine are far lower than fentanyl with or without the co-occurring benzo use. I think the other thing that you had mentioned  was coaching. So I do want to say, so I didn't really talk about that here, but one of the most important things, at least we've found in ED practice, is if there is the see one,  do one, teach one is a real, real thing. And so we've definitely had people who can sit through all of these talks and lectures, but before they have someone who is in front of them  and is clearly an opioid withdrawal, there is no question about what the diagnosis or the history or anything. They often just want to be, this is the case. Should I do this?  And you just say, you just need somebody there to say yes. And so that has been something that has been really, really effective in a lot of EDs and so there are a lot of clinicians  who around the country are just like, have their colleagues just give me a call and I'll talk you through it. Or this is actually part of why I'm at this meeting.  It's wonderful to have experts outside of the ED. They can call and ask their other folks and they just want a little bit of reassurance before they do it.  I don't know if there are others. Do you want to say anything? I think that the setting, the controlled settings like ED and inpatient unit, I think are clearly  better for those patients that are unstable and we don't know what's going on with them. So whenever you're in doubt, you should have them admitted  and observe them and treat what you see. But we should be also doing this on outpatient basis because we don't have a luxury of admitting people.  And the question is, for me at this stage, how can we adopt those protocols to be done on outpatient basis because that's where the need is.  And we're hoping that we can continue this work. And there is some preliminary data we can send and share. And I'm just curious, Mike. Are your clinicians seeing bad outcomes  that are attributable to the benzos or is it more that's what the packet insert says? It's a broad spectrum of responses. It depends on which staff person you're talking with.  I would say overall, the fear is driving the action and behavior of the prescribers. The cow scores and stuff don't always support that it's actually precipitative withdrawal.  It's more anxiety generated by the prescriber than it is the patient. That's a good point. And I just want to add, I think, the other thing is it's  really important for all of us clinicians to start getting more comfortable with prescribing benzos because, as I think most of us have seen,  there's a rising prevalence of comorbid stimulant and opioid use disorders. And so we might stabilize the opioid withdrawal, but we also have to stabilize the stimulant withdrawal.  And I think in that sense, benzodiazepines can be helpful. So that comfort with combo dosing of buprenorphine and benzodiazepines, we've got to find a good balance of that  because I think it's going to help keep patients in treatment overall. Thank you. Why don't we switch sides? Yeah. OK. Thank you.  Jonathan Ridfoe, University of Colorado CEDAR program. A couple of related questions. One, that quit opioids for good handout doesn't mention extended release buprenorphine.  I hope you'll add that to it, or I don't know if you have plans to add that to it. Then I wondered what data there is on the effectiveness of different medication  strategies for fentanyl users. My predilection is to get them to extended release buprenorphine. And I'd be interested in how that compares to extended release naltrexone.  I think there are some reasons to expect it may be superior because you can get to higher levels of buprenorphine with extended release over time than sublingual.  And I also wonder about the capacity of fentanyl to override naltrexone, particularly towards the end of the dosage period. I mean, clearly there is no data on that.  The most effective medication is the one the patient takes. I think it's important with every patient to figure out the one that they are most likely going  to be adherent to. Naltrexone is a much more effective blocker than buprenorphine in terms of blocking fentanyl, but patients may not take it as readily.  So you have to weigh all these factors. And I think we need to be focusing on that right now because we don't have evidence to say that this is better than the other.  I don't think we'll ever have, to be honest. OK, thank you. There are at least two, maybe three large trials of sublingual versus injection buprenorphine that are running now.  So in a year or two, in a few years, there will be an answer, some data on your question about which is more effective. And one could look at subgroups like fentanyl. Thank you.  Oh, I just want to say, in regards to the shared decision-making guide, a lot of the units didn't have access to the extended release buprenorphine.  But we did actually partner with AAAP and PCSS on a separate project alongside this. And I think they might have it at the AAAP exhibit somewhere.  They have pronounce of an updated shared decision-making guide for medications for opioid use disorder that lists the extended release.  Oh, I'm glad to hear that because that is our, in my program, that's our recommended treatment. And we have it available on the day of discharge.  For various reasons, we can't give it while patient's in residential treatment. But when they're discharged, they can get it as an outpatient. Thank you. Yes.  I'm Ritu Bhatnagar from Madison, Wisconsin. And the question I had is more of a logistical one. You're talking about fentanyl testing, fentanyl positive tests for people.  And I'm just wondering how you were able to do that because the strips are not CLIA waived. And so in our systems, they are not allowed to use it as a point of care.  So it's a send-out, which is a couple-day return. So in these instances where it'd be really critical to know in the moment, I'm just curious  if you can speak to how you did that in the research. Right. So I think what we have shown is that it doesn't really matter. The fentanyl makes really not that much of an impact.  So you should treat everybody as if, I think, be cautious and assume that they have fentanyl. But I think there is a lot that you can learn by the history.  So if the people are taking, obviously, powder, prescribed pills, all of this is assumed to have fentanyl. And unless someone shows you the prescription,  you can look up PDMP and you know they've been in a prescription. Everything else is fentanyl. Heroin is really very, very low prevalent. So I think it is important issue,  but I don't think it's that relevant for clinical care. But I think there is one fentanyl CLIA wave right now, but I may be wishful thinking.  You can send the urine out too, right, for? For to the lab and you get 24 hours. But it's expensive. It's not necessary. Expensive and a slower turnaround, like you're saying.  So I think as Adam and all of us have been seeing with the rising prevalence of fentanyl, just treating as though they're likely fentanyl positive.  But you will see more CLIA wave products as they're coming out now. Yeah, we were able to do it in the research study, obviously, because it's a research study, so.  Yeah, no, that was my question. Also, from the coaching perspective, I've been part of Project ECHOES in our area that are specific to addiction treatment.  And that has been really helpful to get, and I love the idea of getting an ED-specific ECHOES started potentially for coaching. So, yeah, great ideas.  I think there's the potential for the psychiatrist to step outside of the outpatient zone is really powerful here, and the collaboration potential is great. So thank you very much.  I'm just gonna take a second. We'll alternate sides. Oh, sorry, I just wanted to, just in line for the ED coaching. So there are multiple ED-specific coaching things  that are out there. Arianna Sampson with Bridge is currently doing a lot of coaching for EDs who are interested. And then also on the ASEP EQUAL,  so there's an emergency quality network, which is an online learning collaborative where people can get a lot of resources, and it's, go to the ASEP EQUAL website  or send your ED folks there, at least for ED-specific coaching.  Sorry. Yes.  Thank you, wonderful presentation. I'm Dave Cundiff from Milwaukee, Washington. First time at AAAP, old public health physician, pretty new addiction physician,  and a lot of you all are my mentors, teachers, and heroes.  Dr. Nunes, thanks for asking the question,  where do AAAP have leverage? I'd ask you to remember two things. First, AAAP has leverage of its own. It has its own credibility to inject. And second off, all of you in this room,  by your memberships in the American Medical Association, have earned AAAP a seat in the AMA House of Delegates, where Alona Balasanova from Nebraska,  in my opinion, represents us very well.  Do not underestimate the power of medical expertise exerted through our AMA. Do not hesitate to use that, and please claim that by continuing to promote  AMA membership among AAAP members. That being said, what I'm gonna say next, I'm not speaking for anybody but myself.  Dr. Bisaga and Dr. Greiner, you've done a wonderful job of giving us new ways of thinking about naltrexone initiation.  And that would have really gone a long way to solve the problems I had with naltrexone initiation  in 2021, because I and the staff who work with me didn't know enough.  You're adding one more tool to a rich toolbox. My problem is not that patients can't endure the transition in my residential setting to naltrexone.  My problem is not that I run out of time. My problem is that I can no longer in 2023 get injected naltrexone for my patients, because Alkermes has raised the price  to about $1,800 a month. The insurance companies have done what they had to and have, as usual, overdone it, and I don't have the staff to fight the prior authorization.  In the real world of 2023, it's not what we don't know. It's greed that hurts our patients. Thank you.  I wasn't aware that they jacked the price up. I mean, the price was already a problem, but yeah. Yeah, and I'll just briefly add, you know,  some of the data that we have around implementation captures that. I think the challenges in accessing Vivitrol through the standard procedure,  getting prior authorizations on some of these inpatient units was something they need to do for usual practice. So that can take three to four days.  And then I think also one of our sites in particular, they're very dependent on the state opioid block grants funding their treatment. And that's an annual sum, a lump sum.  So if they run out of money with providing more Vivitrol than buprenorphine, which are fewer patients, just by the math of it all, then they can't provide further treatment  or they have to change the scale of how they might bill for that. So it's a very critical issue and we're gonna have some data on that.  And I think we have to make a point to capture those data in all of our trials moving forward and do cost analyses. And I think we'll see the same barriers  for the two formulations of extended release buprenorphine too, with all of these novel products, these price points are very much a barrier for patients.  How much does a Brixotic shot cost? Anybody know? Probably 1500, probably the same. The price points are all similar, all similar. And it's not the individuals, it's the system  that we all tolerate. Yeah, yeah, yeah. Thank you, thank you for making that point. Yes. David Lodge, Chicago. Follow-up, a couple of questions regarding the fentanyl testing.  I'm just curious with the testing that you used, how comprehensive it is to detect the different high-potency analogs? And if it's not, what implications would that have  for the study results?  And then also just to say, I think the way I interpreted your answers before, there really is not a compelling reason to do fentanyl testing before treatment  in general clinical practice at this point in time.  But to point out that sometimes that feels a little bit awkward when you're used to relying on that  to make the diagnosis, and sometimes people are taking fentanyl, but you can't pick up that or anything else with the testing that you have,  and that sometimes that just feels a little bit awkward. Thank you.  Yeah, as I mentioned, this trial wasn't designed to look at whether fentanyl is associated with increased withdrawal or not.  That being said, I think it's clear that we didn't have the sort of catastrophic outcomes that people had talked to us about, and I think the same in the emergency room.  Fentanyl is sort of very prevalent in the system, and we can assume most people are, if they're using street drugs,  probably have some fentanyl on board. So I think I would say, again, as I said before, you could take the specific results with a grain of salt, but the general message is  it's not as bad as people were saying it originally. That's our message. Yeah, and I stand by that. I think we all stand by that. One thing I will add about the ED, no, sorry.  One thing I'll add about the ED study is so we often don't check a urine toxicology at all, clinically, before starting buprenorphine. It really is based on patient history,  and so from that standpoint, obviously I recognize sort of in the outpatient treatment setting there are other sort of standards and things that are needed,  but we rely on history from the patient and sort of what we see in front of us. As far as the fentanyl testing that is available,  you're right, it actually is missing a ton of analogs and xylosine and all sorts of other contaminants.  As part of ED innovation, we're actually collecting urine samples from everyone who we've enrolled, and they're actually being sent off for additional analog testing,  and we're starting to get some of that back, but that's something that takes six to eight months, so it's clinically not really useful, but we will definitely have more information  about sort of contaminants and other fentanyl analogs that are from patients that were in the study. And I'll add with the CT in 97 data, although we didn't see a lot of cases  of precipitate withdrawal in those analyses, we did have a longer timeframe, you know, around two days before patients were receiving buprenorphine.  They were often getting injunctive medications, and the buprenorphine dose that we started with tended to be lower. So I think keep that in mind,  and when you see the final publication, you'll be able to tease out some of those data and better understand the protocol.  Yes, thank you. Hi, I'm Mike Susco, psychiatrist in Canandaigua, New York, a suburb of Rochester, New York. I'm gonna ask a therapeutic question.  How to get around the benzodiazepine quandary. I got a call just before leaving that one of my patients was on one milligram of Klonopin, and she fell.  Completely unrelated to anything.  So how do you get around that? How do you get around that? Let me give a context of what I'm up against. A very strong university program who likes to do very little,  like do as least as possible as not to harm. I was brought up that most malpractice suits are based on negligence, what you didn't do. So there's a lot of let's not do anything.  We hear a lot of that. I really like the panel, it's very diverse. I like the words you use, detoxification unit, right, stabilization unit.  That's gonna sound and feel so much better before you go to that place, because if you think of withdrawing, you're in hell, right? So if we say stabilization, oh, that's good.  Implementation, that's even better. I think, I'm sorry, I forgot your name, Doctor, right there. Mark. Use the word, patients don't know what they need.  Sometimes I'm accused of giving patients whatever they want. No, if I can gel what you need and what you want, we're together on this thing. That's very important words.  Also, words mean a lot. Whenever a medication has a nickname, it's abusable. So we hear benzos, we hear subs, we hear Gabby's,  we hear Zanny bars, it goes on and on and on and on and on. So I'm up against a real push. Doctor Susco, what are you doing? Well, I say I'm saving lives, right?  Just the other gentleman just said. That's really this business, because we're in a life-threatening condition. So it goes on and on with this thing.  So how do you defend, argue for, against rational benzodiazepine use? And if you look at any of the chemical dependency literature, it always says, always defer to a psychiatrist  who's familiar with benzodiazepines. I grew up with benzodiazepines. I grew up with the Valium epidemic in the 1970s and 80s. So I kind of know what I'm talking about,  but I'm really against a real groundswell of never use a benzodiazepine. In fact, a patient went to a program and they said, well, we can't treat you because you're taking Xanax.  You're drunk all the time.  The patient said, what are you talking about? So that's what I'm up against. So how do you fight against this? This really is a question for the whole panel,  any one of you out there. Well, I think it's partly showing people that you can use them short-term safely. Now, you gave an example of a safety, a bad outcome with a fall,  but that's also about doing individual assessment, what's a fall risk assessment, and maybe backing off on doses if you can see the warning signs. If the names are scary,  there's a whole range of these gabapentinoids that also can be used. Now, gabapentin itself has got a bad name. In some quarters, pregabalin is a useful agent.  Most people, at least on the street, haven't heard of it yet. So you can get some progress there and get lots of efficacy about managing withdrawal.  But I think that the issue is thinking about safety in short-term settings, customizing, as you would with any medicine. Clonidine can easily cause people to fall,  so you gotta be careful about monitoring blood pressure. But I think with a little attention, it can be done safely.  Others?  Yes, next question. Hi, Chris Cast with Vanderbilt. Very excited to hear all the information presented. And I think thinking about particularly the precipitated withdrawal risk  and the data that was presented, because I think I've been concerned about, with the early ED-based studies, kind of the duration of observation  often being very short with the length of stay and the high-dose inductions and also the low rates being reported.  And I liked seeing the data that shows dose as well as time since last use, because I think those are two very important variables that are often not known  in the emergency department setting. But one of the things that I worry about in interpreting this is, do we consider precipitated withdrawal and never a vent?  Because 5% rate is similar to the seizure rate in alcohol withdrawal if we don't treat anybody. And we don't consider that an outcome that's acceptable. And I know a lot of patients  who have experienced precipitated withdrawal who will flee treatment, who will attempt to go find their dealer, use a lot to try to overcome their withdrawal, leave the hospital.  And I think we have to ask ourselves, to what degree do we protect against precipitated withdrawal, particularly in vulnerable patients? I think we have seen pregnant patients  being particularly vulnerable for reasons I don't think we fully understand. I think the biology here is complicated and there's a lot of individual variability  in the likelihood of experiencing precipitated withdrawal. And the other pieces of how adequate is the sublingual absorption? Are patients being coached well  in how they're taking their first doses? What's the actual blood level they're getting to? Seems like at two milligrams, nobody's getting precipitated withdrawal,  but when we hit four is where patients are starting to. And I think thinking about those particular details will help us really know what is the absolute rate  and which of these protocols in particular settings  and in which populations are we going to be able to do this safely and how could we make this a never event? And I think that's one of the questions I want to ask  is do we think precipitated withdrawal is something we should be guarding against or is there an acceptable rate of this in our clinical practice?  You want me to answer that? You want to start? So I can start. One of the things that I didn't say that I probably should have was so for folks that got the injection in our study,  they were observed for at least two hours after in the emergency department. And then they did sort of daily surveys and a seven day follow up. So we do feel like we captured events  that might have happened after they left. And we haven't unblinded and looked at all of the outcome follow up, but we looked very closely  at all of our precipitated withdrawal cases. And we think that the follow up rate amongst those patients actually was higher than people who did not have precipitated withdrawal.  And that could be from a variety of things. One, I went through this awful thing and I don't want to go through it before. Or two, that they actually did get a lot of,  a lot of handholding and care during this episode where they felt like their concerns were listened to and they were treated. But it's something to certainly be concerned about.  And I never want to say I don't believe you when people tell you that that's their experience. But one of the things that we often talk through is what else is going on, what else.  And we didn't even get into this at all today, but I think xylosine is I think complicating things a lot. Sort of what is actually opioid withdrawal  versus xylosine withdrawal or benzo withdrawal that you're not really capturing over the first, in the first couple hours. So I'll stop there. And Kate, what do you do in the ED if,  I mean in the rare case of really bad precipitated withdrawal and you mentioned ketamine. So 16 milligrams of bupe. I mean it depends on the individual. It depends on how they look.  Whatever adjuncts match whatever symptoms they're having. If it is a lot of nausea, if it's GI.  More bupe, without a doubt. Either eight or 16. And then a half an hour or bupe.  And the razopam is often in there in the first one to two hours. And then at sort of the one hour mark, if they're still uncomfortable,  between one to two hours ketamine is really my go-to. And people do very well with it usually. Probably a little scary, right?  Well I'm worried about precipitated withdrawal. I don't want anybody to have to go through that. And I think we know, thinking about pharmacology, I think we know how to avoid it.  The problem is that we have very limited number of doses and we have to fit our protocols into this fixed dose, this two milligrams, whatever, increments. And that's a lot.  That by itself poses a risk. And unfortunately we don't have easily available lower doses. Buprenorphine is a very potent agent. Remember before the Suboxone came on the market,  it was available in .3 milligram doses, which is quite an effective analgesic dose and also subjective effects. And I think that kind of limits us in a way.  And we are in this quandary because people are trying to figure out how to cut into the smallest possible pieces, which is clearly crazy.  We think about thousands of patients having to do that. So I would say, but we have to work with what we have. So I think we have adjunctive medications to give it before,  just to ease patients' fear about precipitated. Often expectation makes it much worse. So I would definitely give patients Medicaid. Pre-treatment is the key. We've seen it here.  And then start with the low dose. Patient feels better. Clinician feels better. And then you give a higher dose. And probably after that two milligram threshold  of my before, you can then go up as far as you want. There will be no precipitated. So I think we are learning how to go around, but I wish we could put Bupatch on everybody  who comes to the unit, and there will not be any issue with precipitated. If you put a Bupatch on patient, I don't think there is an issue with precipitated withdrawal.  You can probably give even Vivitrol, you know, like the next day. It is just the limits of what we have to work with that causes this problem.  Do you think, Adam, we can make a commercial case for a half milligram commercial dose? I think we, yeah, we did try to make it.  You remember there is an Orexo one milligram equivalent commercially available. That's the lowest dose. I think that may be still too much.  Well, the Belbuca is out, right? So, but, you know, the reason really, one milligram, 0.1 or 0.3 commercially available, which I think will solve this problem,  but that's at least my take. Yeah, and I'll just add, I think it's definitely variable in setting, right? That's what we're hearing in some of the presentation from today.  And then what medications are being used, time to last use, I think is really key in trying to capture that in future research always, even if it's, you know,  patients are coming in, they're uncomfortable. It may not be the most reliable, but usually they know. I mean, if they're feeling uncomfortable, they know when they last use.  And then I think, yeah, we gotta wrap up soon.  Yeah, I will say clinically, I do use the protocol that we use for buprenorphine induction, and I use caution in patients, because you just don't know.  And if they're medically sick, you wanna be that much more cautious.
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