Okay, sorry, my Zoom was acting up. So, good afternoon, everybody. Welcome to today's webinar, The Trials and Tribulations of ED Initiation of Buprenorphine in the Age of Fentanyl. My name is Julie Kmyk, and I'm going to be your moderator for this session. This webinar is by Drs. Jean-Marie Perron and Drs. Lewis Nelson, Dr. Lewis Nelson. This is the first of a six-hour webinar series on hot topics in the treatment of opioid use disorders and stimulant use disorders. Dr. Perron is a professor in the Department of Emergency Medicine at the University of Pennsylvania and Director of Addiction Medicine Initiatives for the ED. She has led numerous organ investigations in opioid stewardship, and has advocated at the state and national level for emergency treatment of opioid use disorder. Her work has been featured in prominent media, including the New York Times, USA Today, and NPR. She has served on the Philadelphia Mayor's Task Force, the PA State Opioid and PDMP Task Force, and the National Quality Forum, and advisory committees with the CDC and FDA to address judicious opioid prescribing. She has won numerous awards for education and mentorship, and has triple boarded in emergency medicine, medical toxicology, and addiction medicine. She was inducted into Penn Academy of Master Clinicians in the Department of Emergency Medicine and Director of the Division of Medical Toxicology at Rutgers New Jersey Medical School and University Hospital in New York, New Jersey. He was a member of the core expert group for the CDC opioid prescribing guidelines, and chair of the FDA Drug Safety and Risk Management Advisory Committee. He's participated in the development of several opioid stewardship programs at his institution and others. Dr. Nelson is a director of the American Board of Emergency Medicine and on the Executive Committee of Association of Academic Chairs in Emergency Medicine. So I'd like to welcome both Drs. Perone and Nelson. Thanks, Julie. I guess I'm gonna share the slides. As long as that works, we're ready to get started. All right, great. So hi, everyone. As Julie said, I'm Jean-Marie Perone, and I'm excited to be here with you today and with my colleague, Lewis Nelson. Neither of us have any disclosures, and this initiative is funded by SAMHSA. So today we're gonna talk a little bit about why and how we treat opioid use disorder in the emergency department, and we're gonna review some of the barriers that we've uncovered and mitigated, and then facilitators of making buprenorphine the default for patients with opioid use disorder when they're in the emergency department. Next slide, please. So why do we think that addiction treatment from the emergency department is a good idea? Really, it's really where the patients are. We have, as clinicians over the past 20 years, we saw the overdose crisis escalating really from the beginning. So we see patients in their essentially worst, most life-threatening moments post-overdose. We see patients who come to the emergency department seeking treatment for their opioid use, or more often these days for a complication of opioid use, such as endocarditis or really prominent wound infections, and we're always open 24-7. Next slide. So with that, there's really been a lot of evidence to support the fact that this is a life-threatening disease and when it manifests in the emergency department. So colleagues in Massachusetts actually studied the mortality of patients who presented after a non-fatal overdose and who came into the emergency department, and they looked at about 12,000 patients who had been reversed with naloxone and who arrived. They excluded the small group of patients who actually ultimately had a fatal overdose, and then including the patients who then were revived and treated in the emergency department. And what they found was that there was a 6% or almost 6% mortality due to a fatal overdose in the next year, of which about 2% of that happened in the first 30 days after their non-fatal opioid overdose, their index opioid overdose. So that's very disheartening to us. We do so many things for chest pain and stroke for albeit a much older population. We stop everything. We do stroke alerts and STEMI alerts to mitigate that. And here we have a disease that we do a lot less for, unfortunately, with a higher mortality and far more years of lives lost potentially. So that's why a lot of our work has been centered on the ED. Next slide, please. So, and then very importantly, colleagues at Yale started a study in 2012, which was published in 2015, where they engaged patients who came to the emergency department seeking treatment, and they randomized them into three groups. So these were patients with opioid use disorder who were either referred for treatment or had some motivational interviewing and a brief intervention, or they were started on buprenorphine that day and then referred for treatment. And what they found here is that they, at 30 days, the patients who were started on buprenorphine had double the rate of engagement at 30 days compared to the other two groups. So this study is really the evidence basis for why we aggressively think about starting buprenorphine in the emergency department. Next slide. So with the publication of that study, very many colleagues of ours who were probably doing opioid stewardship work, really working like Lewis and I had to try and get people to prescribe less opioids for pain and kind of reining in that element of the opioid crisis. And then many people around the country started their own emergency department buprenorphine programs. This was featured in the New York Times. This is a colleague of ours in Highland Hospital in San Francisco, where he treats patients in the emergency department. And many of us essentially just copied that model. Next slide. We needed some resources. We needed some support from our institutions. And this practice has grown over the past four or five years to the point that in 2021, the American College of Emergency Physicians published consensus recommendations that this should be the standard of care. Next slide. So when a patient comes to the emergency department, they should be offered buprenorphine and that providers should be prepared to write those prescriptions and administer this drug and create a warm handoff to follow up treatment. Next slide. So our first iteration of our program in our emergency department really looked like a few clinical champions, treating a few people here and there. And then gradually there was some momentum from the institution. There was a program in the state that was incentivizing hospitals to provide better treatment and more treatment. So we were able to capitalize on a small grant to allow all of our emergency physicians to take the original eight hour ex-waiver course. And so we were able to get about 90% of our clinicians ex-waivered over the course of six weeks using an incentive. And from then we started treating about 15 to 20% of patients who presented with opioid use disorder were going home with a prescription or getting buprenorphine in the emergency department and a warm handoff. And then gradually over time, we increased our efforts to make it easier for clinicians to do this. So we wanted to not be burdensome to our colleagues who are already super busy. So I'm gonna describe the process where we enhanced identification and made this process easier. So the first thing we did was we instituted universal screening with a single screening question. You can see it there. And we really had focus groups with our nurses, really having them advocate for, asking this in a very compassionate way and to not ask with judgment. And I've often, now there's a job in emergency medicine where you're actually the triage doctor. So I often overhear when I'm in triage, this being asked and they really do a really nice job. And they sort of say, we also have resources. So please, you can tell me. Next slide, please. So if a patient answers, yes, the protocol defaults so that a nurse automatically gets an order to measure a cow score. And with that, we now have a withdrawal assessment starting in triage. And then every couple of hours after that, that nursing alert helps expedite treatment. And it also provides a banner to the clinician that says this patient has opioid use disorder. Next slide. And it also produces this banner. And in the banner, next slide, we can click on an order set that brings up the order set for buprenorphine. And it also has clinical decision support in there so that if your cows, which has already been measured is greater than eight, we go ahead and start treatment. If it's greater than 13, we start more treatment. And if it's less than eight, we start a different pathway. So we have three different pathways based on the cows and all of this is automated so that the clinician, is not figuring out who to call. It also activates a call to our peer support people who if they are on site, they can come and see the patient as well. Next slide, please. So again, the order set has that decision support. And then we have a smart set at discharge that actually manages all of the referral information as well as harm reduction brochure that we can talk to our patients about in terms of safer use and then a naloxone prescription. Everyone gets not just a naloxone prescription but naloxone being dispensed to them. So a box of naloxone, the provider writes a prescription, the prescription goes into our sort of pharmacy in basket but the patient immediately just gets dispensed with naloxone so that they don't have to fill that prescription. Essentially we fill it for them. So trying to take away some of those barriers that we know exist for our patients. Next slide. So with that, we really doubled the rate of identification before we required either patients to disclose or someone to have some risk factors for opioid use disorder. Now we're really identifying more patients and about also doubling the rate of patients getting buprenorphine. So it's really been an effective strategy and offloads the burden from the clinicians and the nurses and allows us to engage more patients into treatment. But we have come across many barriers as I'm sure you guys have as well. Next slide. So as we grew our program, we have had more people describing precipitated withdrawal. So patients will come in and say they don't want buprenorphine because it doesn't work for fentanyl or every time I take that, it makes me sick or I can't take that, I'm allergic. And if you go back to the original studies when buprenorphine came out in 2002 or 2003 and became more commonly used, there's an article published in 2010 looking at outpatient inductions between 2005 and 2008 looking for complication rates. So in that study, they actually found a complication rate of about 17% and either patients got precipitated withdrawal or what they called protracted withdrawal. So it was just a chart review of 107 outpatient buprenorphine inductions. But clearly patients have been having trouble with buprenorphine since the beginning of its use. And they identified the risk factors of recent methadone use, co-use of benzodiazepines or too low of a starting dose or too low of a dose overall. So this is really, I think, important because I don't know that we know that all of this is related to fentanyl, but Dr. Nelson's gonna talk specifically about why is it some of these effects may be related to the change in drug supply. Next slide, please. So is it that we're seeing more withdrawal problems because we're just initiating more buprenorphine? This slide only goes through 2017, but you can see we have almost tripled our rate of initiation. And I would say that the graph probably looks like it's doubled again between 2017 and 2022 if we had more current data. But it could just be that background rate of 16% is what our patients are experiencing today just because there's more buprenorphine being given. We're really not sure. Next slide. All right. I'll turn it over to Louis. Yeah, I'm gonna jump in here. There was actually a question in the chat or in the Q&A that nobody can see, but the question is about, it's essentially is what about fentanyl? I think there's nobody on this call that doesn't know that heroin these days pretty much equals fentanyl. And this is just a figure that every month I get confiscated analyses or analyses of confiscated quote-unquote heroin samples sent to me. And you can see that this is from earlier this year. And essentially every confiscated heroin sample has fentanyl or some fentanyl derivative, and none have only heroin. About a third of them have heroin at all. So this is New Jersey, but it's pretty much the same across the entire state. There's no question. And I think there's no question that we're seeing one of two problems. Problem number one is gonna be the increases of fentanyl or the prevalence of fentanyl in our drug supply, or we're seeing problems with buprenorphine. And I think it's probably a little bit of both. And so I'm gonna try to do is run through a little bit of fentanyl pharmacology and a little bit later about buprenorphine pharmacology to sort of frame it from my perspective as a medical toxicologist and somebody who really thinks and is passionate about how substance use plays out in our community, not just the ED, but throughout all of what we do. Now, you know, Jimmie and I were involved in a study that was kind of cute. It looked at the increased incidence of mentions of precipitative withdrawal from buprenorphine over the past number of years. And you can see that if you look at the study that the incidence has gone up dramatically. Now, admittedly, it's unclear if it's just because we've been using more buprenorphine, but it does seem that proportionally the numbers have gone up. And it was a qualitative study in a sense because it was looking at Reddit discussions, but this is basically the sort of comments that you would see when you read the posts on Reddit. And there's just hundreds and pages of these types of comments. People who have deep concerns about the use of buprenorphine and I think as was mentioned perhaps earlier, there's sort of a shared mentality in some areas about the risks of starting buprenorphine and the concerns that people have as they are offered buprenorphine. And once you've had a bad experience, you're probably not gonna go back and take buprenorphine again, certainly not easily. So a big part of what we do is try to minimize that first experience, which many people have in the emergency department and make sure that they don't precipitate. Because if they do, whether it's because of the fentanyl they're using or the buprenorphine they're getting from us, that trauma that they have from precipitate withdrawal will persist with them and will probably prevent them from getting it again without a really good reason. Now, I'm gonna propose to you two things. One of them is fentanyl is a problem and I'm gonna go through why that is. The other problem that I'm proposing is that we use the wrong dose of buprenorphine. Everything that's been studied in buprenorphine before the recent era has been buprenorphine in heroin users. And everything we really think we understand about buprenorphine and its dosing involves heroin. Fentanyl is not heroin. And buprenorphine in people who use heroin is very different than buprenorphine in people who use fentanyl. The same could be said about naloxone. I mean, naloxone precipitate withdrawal used to be real with high doses and it was short-lived and people did fine. Now, even with low dose of naloxone, we're seeing full-blown precipitate withdrawal because the depth of dependence that we're seeing in people who use fentanyl is so much greater. So again, this is the facts I think everybody would more or less agree on with fentanyl. So full agonist, we'll talk a little about efficacy later. It's high potency, which is why we give microgram doses, not milligram doses, even when used therapeutically. It has a short half-life. I'm going to come back to that. It is highly lipophilic, which is one of the reasons it's so euphorigenic. It rapidly enters the brain and it's able to bind quickly and rise rapidly to the opioid receptors. And it has a medium affinity for the opioid receptor. I think everybody thinks it's a high affinity drug, but I think I'll show you some data later that it actually is not. Now, why the lipid solubility is so important is that with chronic heavy use, whether it's an ICU stand therapeutic fentanyl or a couple of days of use of fentanyl in the illicit drug supply, after a couple of days, fentanyl basically becomes methadone, right? Think about the short half-life. When we say it has a short half-life, what we mean is that its distribution and redistribution of half-lives are short, right? I give it to you in your vein or in your nose, it goes right into your brain, rapidly rises, and that's very brief. And then it rapidly redistributes out of your brain. So the effect is very brief. So when we think about the half-life, we think about how long does it cause you to be analgesic, sedate, euphoric, whatever it is. It's brief, right? I'm gonna show you some numbers in a little while. But when it leaves the brain, it doesn't leave the body. It goes into the fat, right? The octanol water coefficient, so to speak, the amount that partitions into fat versus into water is somewhere in the range of 700 to one. So it loves to go into fat, it's lipophilic. And then it leaches out of the fat really slowly and it goes out in the urine. So the elimination half-life, the time it takes that fentanyl to leave your body is measured in days, not in minutes, like the distribution and redistribution half-life. So just a quick look at what some of that looks like. So it rapidly leaves the brain, it rapidly gets into the brain in two minutes. It leaves the brain with a half-life of 12, but then it leaves the body over several hours. It's similar to methadone, which is also a fairly lipophilic drug, right? It gets into the brain slowly, which is why it's not nearly as euphorigenic. And then it leaves the body over a very long period of time. That's with a therapeutic single dose. Now, here's what we call the log P, right? Log, you remember, is measured on a tenfold scale. So each one point of log change is a tenfold difference in solubility, right? And what you'll see is that fentanyl is well more lipid soluble than, say, heroin, right? By the order of several hundred, or even a thousand fold, right, at each of those points in the log scale is a tenfold increase. So fentanyl is exceptionally lipophilic. And you can see the example I give you comparing morphine and heroin, just kind of drives home the importance of lipophilicity. If we tried to sell morphine on the street as a substance of use, nobody would buy it because it gets to the brain so slowly. But by giving it, by acetylating it and converting it into diacetylmorphine, we markedly increase, you can see, we double the lipid solubility. It's still well below that of fentanyl, of course, but we give much larger doses. And the drug becomes much more euphorigenic, much more rewarding. And if you look at the bottom diagram, this study, it's old, but it's an oldie but goodie. You can see that in a mouse, given in the mouse tail, the amount of drug uptaken by the brain in the first pass through the brain blood supply with morphine is essentially zero. With heroin, it's well more than half of it, right? And with fentanyl, it would be pretty much all of it, which is why a small dose of fentanyl so rapidly partitions into the brain and makes you so high. But we really have to think about context-sensitive half-life, right? So it's not just the single use. In our cases, it's actually long-term use that matters. Again, in a single use, the half-life of fentanyl elimination is over the better part of a day or two. But with long-term use, because of its high lipid solubility, its entry into the fat and slow leaching out, it gets eliminated with a half-life of days. And in this one study, which you might've even seen before in a previous lecture, you can see that that half-life, I'm sorry, that the fentanyl measurements in the urine specimens goes out well over a week. And the norfentanyl metabolite, even a couple of days longer than that. So yes, it's got a short half-life in concept, but with chronic or long-term use, the half-life prolongs markedly. Why is that important? Well, it's important because when you use heroin in a conventional way, or if you use fentanyl in a single dose or a few doses, it's up and down and up and down. We're talking about the blood level here. So when it's high, you're high. When it's low, you're in withdrawal or you're back to your baseline level of mental status. And you can do that for a while. But when you use methadone or an extenderized opioid or chronic use of fentanyl, because the half-life prolongs so long, the blood levels are maintained in an elevated, in an elevated state for a prolonged period of time. Now, the up and down, up and down, up and down means that your receptors never really get reset. Or if they get reset, it's to much less of an extent in terms of the development of tolerance or dependence, which is obviously linked to tolerance. Because the receptors for part of their time are normal. They have nothing bound to them. They're not soaking in heroin all of that time. But with fentanyl, because the half-life is so long, the opioid receptors are continually soaking. So they undergo the desensitization that you expect from a receptor that's been chronically exposed to a stimulant or to an agonist, I should say. Stimulant's the wrong word, to an agonist. So they undergo that transition, which is what drives tolerance and drives dependence, which is why we know that from methadone, the withdrawal phenomenon is later and is longer and is worse, right? And the precipitate withdrawal from methadone is later, or is worse than it would be from, say, heroin. And that's basically just how it all looks. So going back to that original slide I presented to you, I wanna just correct a few things I said, right? It is indeed a full agonist and a high-policy drug, but it has a very long elimination half-life, right? And it is highly fulfilled. But the long elimination half-life means that because your receptors are continually stimulated by that agonist, they desensitize, right? The dependence and the tolerance becomes greater, which means that, and we'll talk about this when we get to the buprenorphine section, which means that induction, the initiation with buprenorphine or the response to naloxone, if you like that better, is markedly different than it ever was with fentanyl. It's this deep dependence that is part, at least a large part of what I think is what we're seeing and why we switch from the standard model of administration of buprenorphine to these alternative models that I'm gonna talk about in a little bit. Shumi, this is you. Sorry. Yeah, so back to what I was saying about adverse events and precipitated withdrawal. I mean, there's no doubt that this fentanyl has changed the landscape and increasingly creating this depth of dependence that people are maybe, if you will, more addicted than we've ever really seen before. But in addition, these adverse events that we're seeing with buprenorphine, maybe they're not all precipitated withdrawal. So we looked through a series of cases that were reported to me and others on our addiction community. Basically, people would call me and say, oh, I just had somebody precipitate or somebody just had precipitated withdrawal in the hospital or last night in the ER. And so we collated about 20 cases that had occurred over several months time and looked more in depth at what was happening, what was the adverse event look like? Was it really precipitated withdrawal? And we excluded a few cases because there wasn't enough data. But as you know, because we were doing these serial cow scores, we had a pretty good sense of the pre-cows and the post-cows. So our case definition of precipitated withdrawal was an increase in cows score after receiving buprenorphine. And that increase had to occur in the first one to two hours after the dose. Most of them were within the one hour after the dose, but some of that was tricky with chart review. And what we found, it was pretty much evenly split into three groups. The first group really had precipitated withdrawal and that's the data I'm showing you here. These are the doses that they got on the left-hand side and the range of hours that they had been abstinent from last use. And then their initial cow score followed by their increased cow score and then what happened to them. So that first group really had what we'd all call precipitated withdrawal. The second group had relatively low cow scores when they were treated, something in the range of two to seven. And they were probably treated too early, although they ultimately also had precipitated withdrawal. And then the third group were people who had elevated cows that didn't really get better after buprenorphine, perhaps because of too low of a dose. And those people we call protracted withdrawal. So I think that there are some pitfalls in who we're treating, at least in the emergency department. It's not infrequently that I get called about a patient who has a cows of 13 or 14 and I go and see them. And maybe in triage, they looked a little less comfortable, but by the time they're in a room and have been reassured that someone's gonna help them, they're much more comfortable and their cows is really more like a six or a seven. And those are big treatment division points in our branching point in the way we start people on buprenorphine. So I would caution that when we start people on bup, we should be using very objective signs of withdrawal, such as diaphoresis, dilated pupils, goose flesh, rather than restlessness or nausea. And the period of time that they've been abstinent from fentanyl can be quite variable. And I think for people that have very heavy use, treatment may really need to be started more gradually and after a longer period of abstinence than we know we were able to get away with in the era of fentanyl. Thanks. Next slide, please. Or I should say in the era of heroin. So moving forward, I think a lot of people on this call probably have familiarity and awareness of newer strategies that we're gonna talk about. The first one that we commonly do in the emergency department, and much has been published in small case series about microinduction. And essentially the idea along the management strategy is that rather than giving a little bit of buprenorphine, which has a partial agonist effect, but maybe also displaces the fentanyl, we're gonna start with a smaller dose that isn't gonna displace the fentanyl as abruptly and gradually replace the receptor with an agonist type effect. So these microinduction protocols, this one is from colleagues of ours in Rochester, where they started with 150 micrograms of buprenorphine sublingually, Q6 hours, and then ramped up to 450 and then to one. And you can see, and during that time, either if they're in the hospital, a full opioid agonist is tapered off, or if they're out in the community, they're tapering their own fentanyl use as their bup goes up. I can tell you that most of us actually just start at 450 now as we've gotten a little bit more comfortable. And I don't think that that essentially day of 150 is particularly necessary because I haven't seen anyone get sick from a dose of 450, which is probably about the equivalent of a little bit less than one milligram of buprenorphine. So we gradually replace the bup on the receptor. And what we'll do for those people who have cows of seven or less, or really for me, 12 or less, if I think they can tolerate, we give them a dose of this buccal buprenorphine, and then we write a prescription for a home induction. Next slide. But we feel it's really important to start something in the emergency department rather than just send them home with a script, because when somebody gets all the bandwidth and wherewithal and effort to come to the emergency department seeking treatment, we wanna validate and really let them know that today is the day, they've done something, they're moving on, they've really started it. And if we leave it to them to start a prescription that they're already afraid of, I think we're really missing an opportunity. So the idea here is give them a dose, tell them it's a really small dose, they're not gonna get sick from it, but if they do get a little bit sick, you're right there to help them. And I haven't seen anyone get sick from these lower doses. And then we prescribe. We had a protocol where we were starting with two milligram strips and cutting them in four pieces, which is probably the right pharmacologic dose. But honestly, it's quite difficult to find pharmacies that carry the two milligrams. And then because we need 41 of them to do a seven-day prescription, we get a lot of pushback from pharmacies. So we're really back to just prescribing eight milligrams and having them cut it into eight pieces and essentially start their own microinduction taking tiny pieces at a time. Next slide, please. Again, so this is really what we're doing is, that's what I said we started doing, but we start with this lower dose. And again, we continue it in this manner, but we're now just prescribing the eight milligram films because of the challenges in getting the twos. And then the nice part is they don't need 43 or 41 strips because once they get to day three, they're actually on a therapeutic dose and they don't need to take two milligram strips on each side of their mouth to get to 16 per day. So it's less cumbersome for the patient and for the pharmacist. Next slide, please. Other colleagues have suggested, I'm really intrigued by the idea of starting with just a transdermal buprenorphine patch. And this is something that people can do in the hospital while they're cross-tapering a full agonist opioid is just essentially put on a transdermal buprenorphine patch and on day three, depending on which protocol you're following and while you're weaning the opioid, you can stop the full agonist and then start with full doses of buprenorphine. Next slide. I really like this protocol on this slide where they really just spell it out. They put the patch on. Before they put the patch on, they slowly taper the full agonist opioid, either in the hospital or outpatient. And then on day two, they can just start with a test dose of two milligrams and then go up from there. And so this is, I think, one that's probably much better tolerated by the patient and much more easy to follow, especially for people who are unhoused or don't have phones and don't have a lot of support. However, the transdermal buprenorphine, it doesn't have an indication for opioid use disorder. So you can get some pushback. That's why I like the idea of actually just putting one patch on a patient in the ED and then discharging them with the microinduction strategy that we talked about. Next slide, please. So we've gained a bit of experience with this product, XR buprenorphine or CAM2038. This is the one week, seven day duration, subcutaneous injection that's being involved in an emergency department clinical trial, originally at about 30 sites around the country. And my hospital is one of the sites. So, so far we've given it to about 88 patients at my site and at about 1100 patients around the country. And the rate of precipitated withdrawal has been extraordinarily low. In fact, one day we had a couple who came in for treatment and they both had similar use. They were both thin, albeit one was a woman and one was a man. But the woman was randomized to sublingual and the man was randomized to the XR buprenorphine. So we literally had our own little, you know, end of two trial. Unfortunately, she developed horrendous precipitated withdrawal after getting eight milligrams of the cows of 13. Terrible, what I call grade four precipitated withdrawal. She was agitated. She was fecally incontinent many, many, many times. She, you know, really looked terrible with the cows in the high twenties. And despite the fact that we gave her multiple other doses of buprenorphine, she had a lot of vomiting. She wasn't able to tolerate the doses. In the future, since we ultimately got IV access in her, I would have potentially given her IV buprenorphine rather than repeating doses of sublingual that she vomited. And you couldn't really tell, you know, how much she was absorbing. But anyway, so I do think that this product works pretty well. It's really not available yet, but we've been able to also give it to people with low cows. So people with the cows of one to eight, you know, in one arm of the trial. So overall, it seems to be working with a pretty low rate of precipitated withdrawal. And the idea is that it would mitigate diversion concerns so that emergency departments could stop this, initiate people without too much concern, and then hand them off sometime, you know, between day three and seven for a follow-up care plan. Next slide, please. So this is a little bit about the kinetics of the sublingual versus the XR. So if you see there, I guess the bar further to the left is the sublingual pharmacokinetics. So sublingual peaks within the first hour, you see getting up to a buprenorphine concentration of five or so, and that might be what makes people so sick, and then gradually tapers over 24 hours. The XR bup rises much more slowly over four to eight hours, and then just reaches this plateau that continues for a week. So it's a little more gentle. It might be like a rapid microdosing protocol, but it's something that we're really seeing people tolerate very well. Next slide, please. I think that's you, Luke. Yeah, so this is great. So I'm gonna kind of pick up where Jimmie left off. So microdosing, as you can see, sort of allows you to creep up slowly with the buprenorphine blood concentration and sort of minimally displace the agonist opioid off the receptor or replace it if the patient's already in withdrawal. And that works great. So Jimmie and I both work as inpatient consultants and in the emergency department, very different clinical scenarios. In the inpatient service, you can do microdosing. In the outpatient world, you can do microdosing if you have the right patient population. In the ED, A, I don't have the patients to do microdosing, and B, my patients probably don't really, they're not really capable of doing it on average. It's just a different population you see in an outpatient clinic and that you see in the hospital. In the hospital, the doses are given by the nurse, the patient can be monitored. In the outpatient world, in order to do this, you really need to have a home and maybe some family support and some shelter and some good, some food and all the other things you need in order to be compliant with this. And most people make it to the ED in need of this, don't have a lot of those things. Not all of them, obviously, we all work in different places. I tend to, I work in an urban setting, I don't have a lot of resources and my patients don't either. So we've really gotten used to macrodosing. As I said earlier, and I know this is a very controversial thing to say, I think that the worst dose of buprenorphine you can give is the standard dose that's recommended of two or four milligrams, right? I think if you give very low doses like Jimri described, whether it's transdermal or sublingual or however, and you creep up on the full agonist with the dose of buprenorphine, you will not precipitate withdrawal and it's absolutely safe. There was a comment in the Q&A that said it's safe and Jimri presents some nice data that says it's safe and she's seen it with the XR prep that she's administering and I am. Giving it in a macrodose model, which I'm gonna describe is definitely not as safe as giving in a microdose model. However, it's pretty good and I'll give you some of the data we have and it's very fast, right? And when I say macro, I mean really 16, it might be eight plus eight on top of each other, but it's really 16 in the first couple of, maybe in the first hour or maybe two, right? And the reason I'm describing, you'll see in the middle, has to do with displacement of agonist opioid leading to withdrawal and inadequate agonist. If you can get enough agonism from the buprenorphine after you've displaced the full agonist, you can make the patient happy. And again, at low levels, this isn't a problem because you never displaced enough to be problematic. It's this mid-range dose that seems to be a problem. And again, buprenorphine grew up in an age of heroin and it was not a problem, but in the age of fentanyl, because of deep dependence and all of the other wraparound that goes along with fentanyl, it isn't the same drug anymore, or at least the way we use it isn't the same. We recognize that all the opioids we talk about are full agonists. Their efficacy is 100%. And we recognize that naloxone has an efficacy of zero. It's an antagonist. Buprenorphine, as everybody on the call knows, is a partial agonist. So it binds to the receptor, and it only partially stimulates, partially agonizes. That's part of the problem, right? That can be overcome to some extent, as I'm going to describe, with dose, by increasing the dose. And to some large extent, you can maximize the partial agonism to attempt to approximate a full agonist. The other issue that's really important, and I alluded to it earlier, is affinity. It's how tightly, so to speak, some drug binds to the opioid receptor. And we use the word tightly because it's easy to understand. And I'm going to describe in the next slide that tightly doesn't actually mean tightly. But what I want you to see here is these are the KIs, right? That's essentially the binding. How many nanomoles of a drug does it take to have a 50% occupancy of that receptor? The lower the number, the higher the affinity, because it means a lower concentration. And you'll see that buprenorphine is by far the highest affinity and agonist that we have. Now, it is a partial agonist once it binds, but it binds really tightly, right? The naloxone is interesting, because somebody put a question in the chat about whether we should be giving the combination prep or the bup-only prep. In theory, because the affinity of buprenorphine is five-fold that of naloxone, if you give them simultaneous, the buprenorphine should win. And that's sort of why I'm not really concerned about the naloxone-containing preparation. It's a smidgen more expensive. It's probably not necessary. I know a lot of people believe they feel ill when they get it. There's no pharmacological reason to think that's true. But I am not going to argue with them, not here anyway. But what you see is that fentanyl has a fairly low affinity compared to buprenorphine. But methadone's affinity is even lower. It's half or even a third that of fentanyl's, right? Which is why it's not fair, even though methadone's long-acting and produces deep dependence, it's not fair to compare the ability to initiate somebody on buprenorphine between methadone and fentanyl. It's really not bound very tightly. When I say bound very tightly, and I told you it doesn't mean what you think it means, it really means receptor occupancy. So if you think about it, and you learned this in medical school or whatever school you learned pharmacology in, drugs don't really bind and stick to a receptor. They're constantly on and off that receptor. So affinity really has to do with how much of a given time period is that drug bound to that receptor? So the higher the affinity, the longer that drug is bound before it unbinds, right? Activation, of course, is efficacy, and that's whether it's a full agonist or a partial agonist. But you can adjust occupancy by giving a greater dose. And I'll show you in a slide coming up, the more of a drug you give, the more likely it is to be bound to that receptor at any given time, right? But buprenorphine's got very high affinity. So it's able to, so to speak, knock any other drug off of that receptor. The lower the affinity of the agonist, the better able buprenorphine is to knock it off and occupy that receptor preferentially. So here's just an example of something we've done in my institution when we've taken patients who've had long QT syndromes primarily from methadone and converted them using macro dosing over to buprenorphine. And you can see that we've taken several people with cows of zero or two or five, very, very low cows. We gave them 16, and that was it. They were done. A single dose of that high affinity partial agonist replacing a low affinity full agonist, but in high dose. And we've essentially instantly converted them. And some people that already had withdrawal in progress, like we usually would wait for in people that get buprenorphine, it's taken a single dose. Now you can see there were a few people who didn't get better, right? Even with fairly high dose buprenorphine. And this is what I said, it's not as perfect a treatment or it's not as perfect in terms of its ability to precipitate withdrawal or not treat withdrawal as micro dosing might be. But you really do have to ask how it is that, you know, we managed to get people that are using methadone buprenorphine all the time. And how is it that you get up to 40 milligrams dose and they haven't gotten better? Is there something else going on? Well, this is a critically ill patient who was also on continuous fentanyl, as was this person. So they're not really the standard methadone users who you're converting for QT or converting because they want to switch from methadone to buprenorphine. But we have really nice experience with methadone, right? Here think about the baseline. You have a certain amount of your receptors occupied by an agonist, in this case fentanyl, and you go into withdrawal when that fentanyl level falls and you have open receptors. And it makes sense why if you give somebody a dose, it's going to help, and it probably is going to help a little bit more when you give a little bit more buprenorphine, right? So because buprenorphine is partial agonist, not full agonist, sometimes it takes a little bit more than you think it would take to get the effect. But this is pretty classic. They're in withdrawal, you give them buprenorphine and they get better, right? I think everybody can follow that one pretty easily. However, if you give them a partial agonist and display some of the full agonist, they're going to develop withdrawal, right? That makes sense, right? The more partial agonism you give them, the better you're going to be able to do withdrawal. So rather than giving them a low dose of buprenorphine, give them a somewhat higher dose of buprenorphine, right? And it works because you're able to utilize a higher dose of a partial agonist to approximate what a full agonist would have been done. Now, what we really see when we're giving macro dosing is just massive overwhelming of the opioid receptors. To maximize that off time on the receptor, to put another buprenorphine molecule on there, and you can conceptualize it that way, I think it really helps to understand why macro dosing works so well, right? You're basically giving an overwhelming amount of a partial agonist. Think just mathematically. If you can maximize the partial agonist by giving an increased dose, you can approximate full agonism. It's an imperfect model, undoubtedly, but empirically, when we do it in the emergency department, we have very good results. I've done it on a number of people who use fentanyl with cow scores of zero, right? I prefer to wait until they're in withdrawal, of course, because it's a little bit more predictable because you have some open receptors before you give it, but we've done it even with cow scores of zero. It is much more risky, unquestionably, but the risk of precipitatory withdrawal is still measured well into the low single digits. We're not talking about 50 or 80 percent precipitation. We're talking about a few percent here or there. Here's our guideline from our hospital. I'll just show you how we do it. If you come in and they're in withdrawal and the cow score is low, you can go this way and that's just standard management for the most part. If they come in with their cow score is low or they don't have objective signs of withdrawal, we won't give bup unless we, the MedTOX, which is also the addiction service, gets involved. In those patients, we will give them either a micro dosing model, like Jim has already talked about, or a macro dosing model where we'll start with the 16 milligram dose or sometimes 32, but usually 16 plus 8 plus 8. In almost all cases, 16 is enough. Occasionally, we go to 24 and sometimes we have to go to 32. I've had only one patient in my experience who has a response to 32 and you always wonder if you're really looking at the right thing. Given the amount of sort of psychological overlay, now it's hard in Jean-Marie's case to explain the diarrhea and all that other stuff as a psychological overlay. When people are just telling you they don't feel right and they're feeling anxious and they're feeling jittery, I don't know how much of that is anticipatory anxiety and sort of what you expect to happen from the drug or how much of it's truly physiologic. Clearly diarrhea is something you can't fake, but anxiety is something you can, and I don't mean to use the word fake in a pejorative way, but it may not necessarily be precipitated withdrawal. In another nice utilization that I think is worth thinking about, our colleagues down in Camden, New Jersey, which is in the southern half of New Jersey, I'm in the northern half, have a protocol you might have heard about where people who get naloxone by EMS, sometimes in order to initiate buprenorphine, but if they get naloxone to awaken them from their opiate overdose and they develop severe withdrawal, will be given a high dose of buprenorphine. They'll be given 16 plus 8, just like I talked about, which will not only reverse the naloxone precipitated withdrawal, but it will put them back into a state of normalcy. They won't wind up with precipitated withdrawal from that buprenorphine they just got. They'll wind up being normal, which kind of is interesting, because you would think that if they got the naloxone and precipitated, the buprenorphine, once naloxone wears off in an hour, would leave them in a state of buprenorphine precipitated withdrawal. But it doesn't, for exactly the same reasons I'm talking about, because the buprenorphine at that dose is able to displace enough and agonize enough to make you normal, right? And that's the model they use. If you want to read a little bit more about this, and I'm not going to spend a lot of time on this figure, but just this week, a paper that Jean-Marie and I were involved with, which is a true tour de force in neuropharmacology, if you like this stuff, was posted on the Addison Emergency Medicine website, written with Mark Greenwalt, who's a basic science researcher, Andrew Herring, whose image you saw in the Highland Hospital New York Times article, and Poyya Azar, who's an addiction specialist, I believe is an addiction psychiatrist up in Canada. But what it really does is it tries to model very nicely for you this balance that I'm trying to refer to a little bit about agonism versus antagonism, withdrawal versus intoxication, and tries to show you how these various models of macro and micro dosing work based on the agonist antagonist ratio, which is this ALE that you'll talk about. I'm not going to spend time talking about this, it would take a little bit too long, but I really, if you like this stuff, if you find it interesting, I really do refer you to the paper to try to read it. If you precipitate, and I know we all see this happen, and I imagine that most of you would agree that if you see precipitated withdrawal in your clinic or in your setting, the first line of defense is to give more, or offense, I guess, is to give more buprenorphine. Again, preferably without naloxone, there's just no reason to give naloxone, but you give another eight. And often we'll give even more, we'll give 16, I've gone up to as high as 64 milligrams with success. Sometimes it doesn't work, you want to take the anxiety away from the patient, give them a little lorazepam, midazolam, diazepam, whatever benzodiazepine you like. Many of us just use lorazepam because it's easy and it can give an IM. Often we'll give an antiemetic because they're vomiting a lot, and we tend to use the antiemetics that are a little bit sedating. There's nothing wrong with indanatron or metoclopramide, but promethazine or droperidol seem to work really well, because they take away some of that anxiety as well. Of course, there's reassurance and de-escalation and all of the other things we do to try to make patients more comfortable with what's going on, and again, other symptoms you can see here, the management of things like diarrhea and sympathomimetic signs, which is not usually a big problem, but sometimes you have to incline it in to try to take away some of the tachycardia or hypertension the patient's facing. So to summarize, and if we have a minute, we can try to address a few of the questions if you have, are adverse reactions to buprenorphine clearly occur? There are less common with the microdosing. I think they're most common with standard dosing, and they're mid-range common with the macrodosing model. Not all adverse reactions that you see from bup are precipitated withdrawal, as we've sort of commented on both of us. The CAO scores can be misleading. We really do like to look for objective findings, right? I mean, this is like sepsis or anything else. You know, if you're not looking at the right disease, you apply a scoring system to it, you can certainly find that disease in that person, because so many of these metrics that make up these scoring systems are protean. You know, it's anxiety, it's tachycardia, you know, it's all these things that you'll find in so many other clinical syndromes. Even a low-dose of bup initiated in the ED can get people started on their road to recovery. I think this is really important. So this is why so many people who we see in the ED, we drop the ball when they leave without any sort of motivational interviewing, without any sort of referral for treatment, and especially without any buprenorphine. And it's why we, Jean Marie, I, Andrew, Harry, and the other people you've seen, have spent so much time trying to get emergency departments to initiate buprenorphine while the patient's there. Because if you don't get it started there, it's a long shot that they're going to wind up back in the clinic, like Gail D'Onofrio's study showed. So we want to capture them while they're in our emergency department. Reassure patients, acknowledge, all that stuff. I think, and you know, Jean Marie and I discuss this a lot, despite the fact that she only lives 90 miles away from me, and we probably share a drug supply on the Northeast Corridor, I'm in Newark and she's in Philly. We have very different experiences with buprenorphine. And I tend to believe a lot of it is the preconception that buprenorphine is going to precipitate withdrawal in the Philadelphia mentality. But in the Newark mentality, I've never heard that. People don't say that. So I think you have to really prep people. And again, this is a little bit of setting expectations. And let them know that even if it does happen, we can treat it. Jean Marie, do you have any comments? I know I ran through the summary, but I don't want to- No, that's great. There's a couple of questions in the chat, and we love the questions and the engagement. So next week, we're going to talk about question and answer and some cases that we have. A couple of people, just to touch on some of it, there was a question about macrodosing, which I think we covered. Some people asked about how patients afford Belbuca. I don't really prescribe Belbuca or the transdermal patch because it's not indicated for OUD and also because my patients couldn't afford it, and it's not on the Medicaid formulary without OUD. So we don't come across that, but we are dispensing one or two doses. Not dispensing for them to go home with, but giving them in the emergency department. And then there's another question about- XRB. XRB, which we can talk a little bit more next week. I use quite a bit of sublucate, sub-Q, and we stabilize on transmucosal first. Is this delivery available or is it still being considered? So XRB has been approved by the FDA, but the company that manufactures it has not met whatever manufacturing standards are required, so they've been having trouble with production. So we've been running our study as an investigational drug, but it is actually fully approved. It just is not available yet. So I suspect that it's going to come out certainly in the next 12 months, but possibly in the wintertime. That's what they said last year, and then they had this manufacturing problem. And some other specific questions I think that would be a little hard to tackle in these last few minutes. So we could do it on our next session, if that's what you want to do. Yeah, yeah. So Julie or Judy put in the chat where to post questions that we can talk about next time, and we will address them in the week that intervenes, as well as that the slides are available on the website. So feel free to review them, come up with new questions this week, and we'd love to talk to you all next week and have a little bit more of a conversation. Maybe in the intervening week, you can try some macro dosing or other strategies. I've been a little chicken about macro dosing. I've done it a few times and it's been successful. I consider macro more 16 than 8, because I've definitely had precipitate withdrawal with 8. And so I think 8 and 8 is not the same as 16, just in my experience. Yeah. Julie actually asked a question before we started about, do you really, should you have an ED nearby if you're in a macro dosing outpatient setting? Is that what you asked, if I remember something along those lines? Yeah, basically, if you would feel as comfortable if you were in an outpatient setting, if you weren't in the ED, would you do the same thing? You know, I always try to remind people that opiate withdrawal is not alcohol withdrawal. You know, and if you precipitate, it's not a life-threatening event in general, certainly not with buprenorphine. I mean, naloxone precipitate withdrawal I find to be much more dangerous than buprenorphine precipitate withdrawal. You know, even the severe withdrawal of buprenorphine patients, you don't see pulmonary edema, you don't see strokes, you know, you don't see the things you see sometimes when people get big dose naloxone and precipitate really hard. That being said, obviously most outpatient clinics aren't really set up for people having diarrhea and vomiting and a lot of those things. So you might want to have some sort of ability to get people to an acute care setting. And that's always a good idea, but anybody can get to an ED. I mean, most of us work and live in places where an ED is within reasonable distance away. Right. I think I was asking too, just because that would be something that I think would be very helpful because we do have patients that have had precipitated withdrawal and it's just really hard for them to get on the buprenorphine because they're very timid about it. After having that experience and offering them a higher, you know, the macro dosing would be helpful to get them on the medication. And I'd like to do that, but I only seen the publications in the emergency, you know, that come from an emergency department setting. That's just because, as I said earlier, we have no patients for anything. Yeah, I think that's true. Yeah. Well, thank you all. We look forward to next week and we hope we can hear some more questions in the week and we'll work together to try and come up with some scenarios that make sense. Yep. That sounds great. So if you guys have any questions for Drs. Perone or Nelson that weren't answered today, do go to the AOA education page and enter your questions under the discussion tab and the slides are available there for you to review. And we look forward to meeting with you again next week. Thank you so much for a great presentation and I'll talk to you guys later. Great. Thank you, Julie. Thanks for having us. Bye.

buprenorphine

opioid use disorder

emergency department

treatment

challenges

strategies

mortality rates

engagement in treatment

adverse events