My name is Alex Sedelnick, and I'm an addiction and consult psychiatrist at NYU Langone. And I'm very happy and grateful to be giving this talk today with Dr. Arshad and Dr. Accurso, who are also at NYU as well. So today we're going to be talking about buprenorphine microinduction. So hopefully we can give an overview of what the microinduction process is like and get some perspectives as well as some of the review literature for both inpatient and outpatient settings. So we all have no disclosures to make at this point. And in terms of objectives, so hopefully by the end of the talk, we can compare and contrast conventional and microinduction techniques, recognize opportunities and challenges of microinduction in the inpatient and outpatient settings, and finally gain confidence to implement buprenorphine microinduction within inpatient and outpatient settings. Okay, so in terms of the outline for the talk, so Dr. Arshad's going to start us off by giving a background in the pharmacology of buprenorphine microinduction. And I'll next talk about some inpatient experiences and also review the literature about buprenorphine microinduction. And then Dr. Accurso will next talk about outpatient microinduction. And then finally, hopefully we can have a large group discussion to hear about everybody's experiences with buprenorphine microinduction and to answer any questions or review cases that might be interesting to discuss. So let's start with some survey questions. So first question is about familiarity with microinductions. So how familiar are you? We're getting these Likert scale questions for the polls, so one is I've never heard of it before, and five is I'm already doing this in my practice already. OK, so it looks like the majority of people have heard of microinductions, but have never tried them. And there's a few people that have tried somewhat, and some people that are already doing it in their practices. So it's a nice bell curve of responses there. So I think with that, we'll go to the next question. So for those of you using microinductions in their practice, how successful have you found it to be? One being it never works, and five being it always works. Okay, so it looks like for most people, there's 60% of people works about half the time. And then there's about 32% of people, it seems like it works a little more than half the time, and about 5% of people that works every single time, which would be pretty, pretty great if it worked like it doesn't experience as well. But so by and large, it seems like, you know, it's, it's working for some folks, which is nice to see. Okay, now in turn, this is kind of gets at more of the indications for buprenorphine microinduction. And so the question is, for which of the following situations haunts you the most. So one is transitioning from methadone to buprenorphine. So this can be very challenging to do. Two is post operative pain management. So that can be people that have opioid use disorder or on medications for opioid use disorder like buprenorphine. C is induction of patients who are using fentanyl, and D, which is all these haunt me. Okay, so it looks like there's a good spread of responses here, looks like a third of people say these all haunt me, which I think is very fair. And then a third of patients say that switching from buprenorphine to fentanyl, a kidney industry product, is haunting, which I think we all have experienced in doing this and would definitely agree with that. Post-operative pain management can be very challenging, as we all know, and also transitioning from methadone, especially high doses, to buprenorphine. So I think that this kind of gets at some of the potential indications for microinduction, and so hopefully by the end of the talk we might be able to provide at least some ideas about how to manage these complex situations. I think I skipped over that. Okay, now we'll stop and we'll go to Dr. Arshad. Hi, my name is Arsalan Arshad. So I will be talking about the general overview of buprenorphine and the microinduction, as well as the pharmacology of it. So in traditional induction, you advise the patient to stop using the full opioid agonist, they experience the withdrawal, and then in essence you rescue them by giving them buprenorphine. An advantage of this is there's no further full opioid agonist that's needed, and a disadvantage is, and we've all probably seen it, is that it requires the patient to experience withdrawal, and that can be fairly discomforting to patients either in the hospital or in the outpatient setting. So what we'll be talking about is microdosing, and in essence you gradually escalate the buprenorphine dose over several days while the patient's still taking the full opioid agonist. Another name for this is called the Bernese method, and an advantage of this is you may avoid opioid withdrawal, and a disadvantage of this is it's still new, it's not that well studied, which is why we're talking about it now, and there are times though where the patient can still have withdrawal. So this just outlines what the steps are. You continue the full opioid agonist, you slowly introduce buprenorphine, and as the buprenorphine is increased, in theory the full agonist is slowly displaced, and eventually the buprenorphine saturates the mu receptors, and then when that happens you discontinue the full opioid agonist abruptly. So one of the reasons why we're talking about this, and a problem that we're increasingly seeing in the hospital setting, is the introduction of fentanyl into the drug supply, and with that we really do need to change how we induce suboxone. So with fentanyl, you can still have precipitated withdrawal with traditional induction in patients who are using fentanyl. This is even after they have moderate to severe withdrawal, and that can happen 24 to 48 hours after the last use, and the reason for this is it's very lipophilic, so there's an increased volume of systemic distribution and there's slow dissipation depending how much fat the person has. The clearance of fentanyl and the metabolite norefentanyl are pretty long as well too. It's found in the urine up to a week after discontinuation, and norefentanyl is found two weeks after. And this is just a graph that depicts that. This is from a study from urine samples in a 28-day residential facility, and the x-axis is days and the y-axis is the norefentanyl or fentanyl found in the urine. And the fentanyl clearance time is about 7.3 days here, norefentanyl is 13.3, as I mentioned earlier. So when we're talking about the receptors, so buprenorphine binds to all four opioid receptors, the mu, kappa, delta, and ORL1. And the benefit of buprenorphine, it has specific unique qualities. So the binding affinity of bup for the mu opioid receptor is 4.5.4 times greater than that of morphine and 6.2 times greater than that of fentanyl. And so while in the presence of full opioid agonists such as heroin or methadone, buprenorphine acts like an opioid antagonist, competitively binding to the mu opioid receptor. And this leads to the precipitated withdrawal when bup is introduced. Conversely, in the absence of the mu opioid receptor agonist, buprenorphine activates the receptor partially, and this alleviates the opioid withdrawal. So another clinical translation of this is that there is a ceiling effect when you're using buprenorphine for its mu opioid receptor-mediated actions, such as the euphoria, the physiologic dependence, and the respiratory depression as well. Bup is highly potent as well. The dose required to produce an effect of a given intensity, for instance, like analgesia, is lower than that required from a full opioid agonist, such as methadone or morphine. Bup is 20 to 50 times more potent than morphine. So when we're going down and talking more specifically about the ligand pathways, there's two competing pathways for full opioid agonists, as well as buprenorphine. There's the G-protein pathway and the beta-arrestin pathway. The G-protein pathway, there's an internalization of the ligands, adenylacyclase is inhibited, and then GABA interneurons hyperpolarize in the ventral tegmental area, and this subsequently causes increases in dopamine in the nucleus incumbens. And the effect of this is the therapeutic efficacy of the full opioid agonist or buprenorphine. The competing pathway is the beta-arrestin pathway, which has phosphorylation of specific amino acids, and this causes an internalization of the receptors and a down regulation of signaling down the line. And this causes the increased risk, misuse, dependence, and respiratory depression. So these two are often competing. Methadone activates both of them, which is why you have the therapeutic efficacy, as well as the misuse, dependence, and depression. Buprenorphine stimulates the G-protein pathway, but there's limited recruitment of the beta-arrestin pathway, so that's a benefit. So this just describes or shows the full mu-opioid receptor agonist and it binding to the mu-opioid receptor. And in theory, as you're putting in, as the person's being given buprenorphine, it displaces the full agonist, and eventually all of the receptors are saturated. Small doses of buprenorphine administered during the microinduction stay below the threshold to displace all of the full opioid agonists, enough to induce withdrawal. So that's one of the theories as to why you don't go into withdrawal when you slowly introduce buprenorphine. So what we really want to avoid is the opioid withdrawal. There are two theories as to what causes opiate withdrawal. It's believed that there's a sudden decrease in the opiate tone in key brain regions, including the mesolimbic area and the locus coeruleus, as well as the chronic neuroadaptations when you have prolonged opioid exposure, which causes changes in the receptor signaling, like the two ligand pathways I described. So then we get to a question. Having seen the pharmacology presentation, are we convinced that microinduction will work? All right, so there's a range. 55% of people said that perhaps tell me more, which I think is pretty good. And 12% of people are ready to start it tomorrow. All right, so I will stop sharing. Talk about buprenorphine microinduction in the inpatient setting. So I'm an inpatient consult psychiatrist. So we have some experience in doing it in our hospital, but I'll leave it to Dr. Acroso to talk more about some of the outpatient implications and use in general. So let's start with the question. It's a really common case in the hospital setting. So there's a patient who's 35 years old and a history of opioid use disorder, injection drug use coming in with painful osteomyelitis. So kind of a serious infection, which is a complication of injection drug use. So he was stabilized on a combination of opiates, including methadone 50 milligrams with hydromorphone four milligrams every four hours as needed. And he'd like to be discharged on buprenorphine naloxone due to concern for a pickup schedule with methadone, which would be a common concern for many patients. And so would buprenorphine microinduction be feasible? So it's patients getting a fairly decent amount of methadone and hydromorphone. OK, so there's a combination of people, mostly in the range of maybe to absolutely well, with some degree of healthy skepticism, which I think makes a lot of sense. So this is a patient that we were able to do microinduction with. And so the person was converted to buprenorphine via a buccal formulation of buprenorphine. That was a protocol that we developed in NYU based on a case series or a case that was published at Yale and a couple of years ago, which we'll go in a bit later. And so over the course of about eight days, the person was converted from methadone and hydromorphone to buprenorphine. And with that regimen of eight milligrams three times a day, their pain seemed to be well-controlled. So in terms of buprenorphine microinductions, there's a basic principle that I think is important to recognize because there's a lot of different approaches that can be taken. So the basic principle is that buprenorphine started in small and incremental doses while the concurrent full agonist opiate is continued, which avoids the need for opiate withdrawal. And so in essence, it's kind of like instead of slamming on the brakes when you initiate buprenorphine and cause precipitated withdrawal, it's like a slow deceleration by kind of gradually pressing on the brake to decrease opiate receptor activation over time. And so there's no kind of singular approach. And that largely depends on a number of factors. And that can include the formulation of buprenorphine that's needed to get that really small doses, and also the duration of the microinduction. So some have been described about three days, some up to like 120 days. So there's a huge range. And the evidence currently right now is mostly based in case reports, case series, and also retrospective cohort studies. I might add that there's a randomized control trial that's being undertaken in Vancouver looking at it. So that becomes the first randomized control trial of this that's to be published. And so in terms of there's a nice review done in 2021 that was published. It looked at cases that were published up until about April of last year. And this included about 18 separate publications. And it gives us a sense about what is the microinduction landscape look like right now. And they described a total of about 63 patients that were successfully transitioned to buprenorphine through some type of microinduction process. So not necessarily one specific protocol or another. And the initial buprenorphine dose ranges were really small. So as you can see, it's about 0.2 milligrams of Suboxone or buprenorphine. It depends on which formulation they were using. And the average duration of the titration was about four to eight days. And most participants cross titrated to about eight to 16 milligrams per day. I'd also like to add that there's a large retrospective cohort study that was published this year, which added about 72 more cases to the existing literature. So it's over 130 cases that have been published so far. So it's still kind of in the early phases of discussion. But it seems like from the current evidence that there is some clinical benefit and it can be safe in certain populations. So what are the indications for a microinduction in a hospital setting? So this kind of gets at one of the poll questions we had earlier. So the first indication can be co-occurring pain. And this is kind of, in my experience, the most common reason why we choose to go this route. So in order to do a conventional induction, people would have to be off of opiates for a period of time. And if somebody has co-occurring acute pain, it can be really challenging to manage their pain with non-opiate alternatives. So for example, if this person had painful osteomyelitis or if they had recent cardiac surgery, it can be really challenging to go through opiate withdrawal. The next is opiate withdrawal intolerance. So in the hospital setting, we oftentimes see people that are acutely medically ill. So they might have severe heart failure. And if they go into opiate withdrawal, they could get really sick. And so there's a real risk that by going into opiate withdrawal by doing conventional induction, it can cause more medical consequences than you're hoping for. And the next indication would be transitioning from methadone to buprenorphine. And so normally, for switching from methadone to buprenorphine, as we all know, we have to decrease the dose to about 20 or 30 milligrams per day and then hold the methadone for a couple of days to induce opiate withdrawal. And that time can be really vulnerable for patients in terms of the risk of relapse. And so for patients that need to be switched to buprenorphine, this could be an alternative. The next indication is concern for opiate withdrawal. And I think this is more an indication on the outpatient side because it can be, if somebody is coming in in fentanyl withdrawal in the hospital setting, an eight-day long course of microinduction can be really hard for a patient to tolerate. That being said, if you'd stabilize somebody on methadone during fentanyl withdrawal, then you could use this as a way to switch them over to buprenorphine. And then lastly, more specific to the inpatient setting, the inability to continue methadone after hospitalization. So for many patients, enrolling in a methadone program can be very challenging. There can be a lot of barriers to enrollment, like the need for photo ID or need for proof of residence or even things like insurance. So if a person is stabilized on methadone in the hospital but can't be continued after discharge, this can be a way to maintain them on medication for opiate use disorder without that being methadone. And then finally, history of precipitated withdrawal. I think this is kind of another important indication that we oftentimes will see where patients have gone through this traumatic experience of precipitated opiate withdrawal with buprenorphine, and they're really reluctant to go through withdrawal and try it again. And so for some particular patients, undergoing a microinduction can be a little bit more reassuring. However, if you're telling somebody it's high precipitated withdrawal to take buprenorphine with their methadone, of course, it's gonna be pretty anxiety provoking for them. So let's see here. So I'll go through, now in terms of the types of buprenorphine that's used for the microinduction, the differences usually tend to vary on the formulation of buprenorphine that's used to get that really small dose of buprenorphine, that 0.2 milligrams or that 0.5 milligrams of buprenorphine. And so for, when thinking about how do we get those really small doses? Well, there's largely four different types of formulations that we can think about that have at least been published in the literature. So one is looking at suboxone films or buprenorphine naloxone. It can also include Zubsolve. And so the next formulation would be Elbaca, which is buccal buprenorphine, and it's approved for chronic pain and it comes in very, very small doses. So I think the lowest dose is 75 micrograms. And the next formulation is the buprenorphine transdermal patch or Butrans. And finally is Buprenex, which is the buprenorphine parenteral solution. And so I have a table here that's more of a summary of kind of the advantages and disadvantages of each approach and some of the other considerations. And I think this is more hopefully a resource for people to look back on when I go through too much of the specifics for each one. I think a few things would be helpful to highlight. So in terms of buprenorphine naloxone, I think for a lot of hospitals, it's very common to have it on formulary. So it doesn't necessarily require work to get it approved to be on formulary. People are usually familiar with it. It's already FDA approved for opioid use disorders. So that extra barrier is removed. When thinking about using other formulations of buprenorphine, they aren't necessarily approved for opioid use disorder. And some of the challenges, so there's some conflicting evidence, not so conflicting, but there's limited evidence about the stability of splitting buprenorphine naloxone films. So some hospitals are comfortable in terms of splitting films and others are not. I think it kind of depends on the institution. There's some evidence looking at cutting films in half, the two milligram films, that at that dose of one milligram per day, it's stable, although they didn't actually study the quartering of the film, so it could potentially be safe. It's kind of an open-ended question because the film wasn't necessarily designed to be split. In terms of Bellbacca, the buprenorphine buckle formulation, so it already comes in very, very small doses. So it doesn't really require the need to be split, which can be useful. However, it's not typically on hospital formularies, so it may require a process of applying for it to be added to the formula, which can be kind of an intensive process. There's also limited published titration schedules or case reports describing its use. The Butrans transdermal patch is another formulation of buprenorphine that's kind of commonly used. And it's been probably described the most in terms of cases in literature. And, you know, it's fairly easy to initiate microinduction with the patch. So you basically place a patch on and you continue the induction over the course of the next seven days to four days. One thing that can be a barrier, at least in our hospital, was the cost of the Butrans patch itself, which is about $160 per initiation. And then finally, the buprenorphine, buprenex IV formulation is kind of the last formulation where you can get that really small dose of buprenorphine. And it allows for parenteral administration, which can be really useful for patients that are maybe reluctant to take it, or it's hard to get that frequent dosing that might be needed for maybe more of a rapid titration. Unfortunately, it's not common in a lot of hospital formularies, so it can be hard to have access to it. So I'll go through some of the- Alex, before you move on, can I chime in for a minute? Yeah, sure. Hi, so I made the interesting decision to open up the chat, and I'm watching the chat. I'm not sure if you see it in front of you, but there are some interesting questions that were posed during your presentation. Would you mind terribly if I air them? Yeah, sure. Sorry, I didn't realize there were questions here. Happy to- Yeah, it's kind of hard to present and monitor the chat at the same time. I definitely trust you guys to do that while I'm talking. But so one of the questions involved, there are two questions related to Belbuca. The first question was sort of why, and you addressed that, that it has to do with lower dosing. But the second, which we'll address a little bit later, but I thought you might want to touch on it now, is there are concerns from the audience about the legality of prescribing Belbuca in the outpatient setting for opioid use disorder. Do you want to maybe discuss that? Yeah, sure. That's a good question. So as you know, Belbuca is not approved for opioid use disorder. So to prescribe it for the indication wouldn't necessarily be legal in accordance with the data 2000 rule. So you couldn't actually prescribe buprenorphine Belbuca for opioid use disorder, for microinduction as an outpatient. So on the inpatient side, there's more flexibility in terms of prescribing opiates to help facilitate medical treatment. I think it's the DEA rule 1306. I think if I want to say it's like title 42 or title 56, I have to look at it for sure, but it gives, there's definitely a lead way in terms of using opiates to help facilitate medical treatment. So that's why, that's kind of how we're getting around that in the hospital setting. But that's a very good point. So if you want to use Butrans in the outpatient setting, it can be more challenging to justify that, if somebody's in pain maybe, but and also getting prior authorization can be challenging as well. And I think there's a question about having slides in the presentation. So we should definitely make sure those are available for download. Yeah, I also, I addressed that. We intended to share the slides to the extent that the AAP is okay with that, which I think they are. But I dropped my email address into the chat too. So feel free to reach out after the conference and if there's anything you'd like to add. Feel free to reach out after the conference and if there's anything you missed, we'll take care of you. Yeah. And I think in the outpatient setting, I don't want to get too much into it, but Dr. Kirsten will talk about how to navigate microinductions in that setting where the choices for the type of, or how to get those small doses are more limited. I'll kind of go on to our experience here with Bell Bucca at NYU. So we based our, we have a protocol here that was based on a case that was published in 2021 by Melissa Weimer, where she had a seven-day titration schedule using buccal buprenorphine, initially starting at 225 micrograms per day with a goal dose of eight milligrams. I think it was BID in the schedule for buprenorphine naloxone. And the person was admitted for pancreatitis, their buprenorphine was held and they were re-initiated on Suboxone gradually through this process. So we looked at this case series and the existing literature that was already around and we were thinking about how do we incorporate or how do we do microinductions in our hospital? And so I met with some of the stakeholders from pharmacy and from psychiatry, trying to figure out which formulation of buprenorphine would be most feasible for our hospital. And so we actually landed on buccal buprenorphine. And there's a few reasons for that, which I'm happy to get into later on, but kind of one was there was some cost considerations, kind of ease of changing dosing. And also we had piloted this earlier and it seemed to work out pretty well. So we came up with two different titration schedules and one being a long schedule, which is about an eight day titration schedule and then one being a short schedule, which is about four days. And so we had modified the Weimer case report, like they're scheduled by only having one formulation type of belbucca to kind of limit the need to purchase multiple dosages of buprenorphine. So I think she used like 75 and the 150 micrograms to get a certain dose. And so we just went with one dose and it seemed to be working pretty well. And so this is some of the initial data that we have from our experience so far in the past year. There's actually about 12 more cases that I wasn't able to add to the slide, but we've done about 14 cases over the past 12 months. And the range of methadone or sorry, opiate requirements is pretty broad, but at the highest I saw was about 60 of methadone, you know, eight milligrams of hydromorphone Q4 was another something that was common. So the most common indication for approaching people with a microinduction was for co-occurring pain. So it was about 50% of our cases where they weren't able to tolerate going into opiate withdrawal due to co-occurring pain. About 43%, so not a small amount, had anxiety around going into opiate withdrawal, which I think shouldn't be understated because I think in the hospital setting where people are very medically ill and there is risk of going into opiate withdrawal, just in general, that I think avoiding going to withdrawal can be really beneficial. So if somebody is in withdrawal, they might be more likely to leave the hospital against medical advice or prematurely, or even, you know, have symptoms of opiate use disorder. Like they might have somebody bring in opiates to use because they feel so sick and they're not feeling better right away. And then finally, the last one that we had one case where a person can be on methadone on discharge. So the completion rate was pretty high. So it was about 86% of our cases completed the microinduction process. So it was pretty good. One person discontinued buprenorphine due to concerns about adequate pain control with buprenorphine. And in one case, a patient was able to tolerate buprenorphine due to an adverse effect, which is specific to buprenorphine rather than the microinduction process. Only about 17% of cases actually had some adverse effect to buprenorphine microinduction where they had some mild opiate withdrawal symptoms. So for most patients, it was pretty well tolerated at the schedule. The average duration was about six days. So in the hospital setting, that's something definitely to consider that it can prolong length of stay. So if somebody needs to leave the hospital quickly, it can be challenging to initiate the process. If you don't have an outpatient provider like Dr. Recurso to help if they leave the hospital to continue the process. And about 75% of the patients completed in the hospital, whereas 25% were discharged to complete as an outpatient. Okay, so I'll talk about the next type of formulation of buprenorphine, which is buprenorphine naloxone. And there's a number of different case series describing the use of splitting of suboxone films to get that small dose of buprenorphine as an approach. And so there's one, this is a protocol that was published by Azar and it describes some of the schedule itself. They start at 0.5 milligrams of buprenorphine naloxone. So a quarter of a two milligram film. And we kind of talked about some of the concerns about splitting. There's concerns about, it's not recommended to split necessarily. There's concerns about stability, uniformity. However, there's many case series and case reports that people do that commonly, and it hasn't been a major issue. So the next formulation is buprenorphine IV. And there's been a few case reports that have been published. I think about three. This is a buprenorphine microinduction schedule that was by Thakkar et al published this year. There's a case series of two, case reports of two. And so with buprenorphine IV, you can see it start very, very small doses of what, about 0.5 micrograms. But I think the advantage of their protocol is that you can frequently dose. So if you want to do a more rapid titration schedule, it's easier to do. In terms of the transdermal patch of buprenorphine, this seems to have kind of the most evidence in terms of case reports and case series. So it's initially approved for chronic pain. And there's many different types of low doses that they have for the transdermal patch. The most commonly used dose is 20 micrograms. It can be more costly in general, and one benefit, it can actually decrease the need for frequent dosing. That's something that we've come across on our side with rapid titrations with the buccal buprenorphine. If you're dosing every six hours, it can be challenging for nursing staff. So if you look at the completion rate on the right side, you see the completion rates about 70% in the hospital, which is pretty good. And then I think about 20% discontinued in the hospital. About 12% were scheduled to complete as an outpatient. So they were started on the microinduction in the hospital and then transitioned out. So it seems like that the completion rate in general is about 80% is what they were finding with their protocol. You can see that they have three different protocols, but the one I chose includes kind of the standard is what they were using, where they have a 20 microgram buprenorphine patch. They place it on day one, and then they start providing buprenorphine naloxone on day two with half of a two milligram film and they increase daily. So in terms of microinduction, there's a number of outstanding questions I think are really important to think about. So because this is such a new process, it's hard to, I think it's difficult for us to know what maximum morphine equivalence is it safely to perform a microinduction. So is it safe to perform on somebody that's on 280 methadone, or is it much better at people that are on lower morphine equivalence? And also in terms of, there's many different approaches that all follow this basic principle of low doses of buprenorphine increasing in a stepwise manner. And there's no comparisons about which protocol seems to be better tolerated by patients. And in terms of the optimal duration of titration, it's also another civic concern. So from the hospital setting, at least there's a pressure to not have people in the hospital for long periods of time. And some of these schedules can be, for long periods of time and some of these schedules can be eight days or six days, where if there's some way to increase the speed of the titration, it can reduce some of that length of stay, those considerations. And also there are differences in retention and treatment between protocols. So for people that are on the transdermal patches, is it better tolerated than somebody undergoing the sublingual buprenorphine naloxone microinduction. I think it's also an interesting new consideration for special populations like pregnancy, where generally we think about avoidance of opiate withdrawal and also for its use in patients that are using fentanyl. And then finally also for patient preferences, is something that people would prefer to be undergoing rather than having a conventional induction when you'd have to go into opiate withdrawal. So in conclusion, I think microinduction, at least in the hospital setting is a very clinically useful tool. And especially if we were trying to initiate this really effective medication, but have some of these challenges like co-occurring pain or people that are on methadone or can't tolerate going into opiate withdrawal. And it seems like there's multiple approaches that are feasible. So, and that's usually dependent on the formulation of buprenorphine that's used. And in terms of choosing between formulations, there's some considerations to take into account, like hospital policies about splitting suboxone films, the duration of the titration schedule, also cost is something that we kind of ran into as well. And each institution has its particular considerations and it's important to identify stakeholders in this process like pharmacy, nursing staff that have to cut the films and also us as addiction providers. And then finally, I think during this process, about 20% of patients that we did have, had some mild opioid withdrawal symptoms or had some anxiety about making this, undergoing this switch via microinduction where they've heard, they've experienced precipitated withdrawal. But by telling somebody to take buprenorphine while you're concurrently taking a full agonist opiate, you're not gonna go into withdrawal, it makes people really nervous. So I think it takes a lot of education and building that alliance with the people that are somewhat reluctant to this. And I think importantly, there needs to be larger studies completed to look at the different protocols and tolerability in some of these special populations that we've talked about before. So I think that's it from my side. I see some questions here. I'm happy to take a few minutes and to look at them here. Yeah, I was gonna suggest Alex, before I get to dive in, I think we owe it to this fine audience to address some of their questions. Agreed. Do you wanna skim the chat or do you want me to throw a few highlights at you, my friend? Do you wanna throw some highlights out at me? All right, I got a nice one here. Not going exactly in order, but trust me, I'll get to you. So one person is asking, how do you typically coordinate with the inpatient team? Meaning how do you coordinate anticipated length of stay with the choice of microinduction agent? And I'm gonna put my own spin on this question. In this climate that we now work in where there's a lot of pressure to get people out of the hospital, how does microinduction fit into that? Yeah, I think there's a few perspectives on it. It's a great question. My first kind of knee jerk reaction is that we have very effective medications for opioid use disorder that decrease mortality by about 50%. So incredibly effective treatment in general. And if this is some way that we can provide this lifesaving treatment, I think we can justify it. Of course, I don't wanna be naive and say that there's no pressure to discharge people as well. So what I'll do before I start the microinduction process is I'll have a conversation with teams about anticipated length of stay to see how long they'll be here for. And if they're here for at least three days, then I can initially give them this first few doses of buprenorphine or the buccal buprenorphine formulation, and they can follow up with an outpatient provider if I give them a schedule. So it's really important to have the outpatient follow-up. And I think from our hospital P&T committee, that was also an important piece for approving this protocol, that we had some assurance that this wouldn't be increase in length of stay across the board for a lot of people, because there is some outpatient follow-up. I think that the second piece to this too is that we do have a short titration schedule that we're trying to play around with a little bit more these days. And it's a three-day process. And our preliminary kind of experience of it is that for some people it works. I think there's definitely a higher risk of precipitated withdrawal, unfortunately. And so I think we're trying to find the sweet spot on how to manage that rapid schedule more safely, but it's definitely more challenging. Got it. And there's one other curve ball question for you, Alex. So here it goes. So have you done any micro dosing to sublingual buprenorphine and then transitioned to the long acting injectable buprenorphine, AKA sublocate in the inpatient setting? Or furthermore, have you done any where you were inpatient and you just got the long acting injectable buprenorphine into the patient before they marched out of the hospital? So I haven't done that. We don't have it. We don't sublocate it on our formulary yet. So it's really hard to do. We found a workaround to have it available if we want to prescribe it, but it takes a lot of coordination with the distributors and things like that. So we haven't actually had a case that's come up. I do think there is some, I think there's a couple of case reports, I think out of Vancouver, where they had described a case like that, where they had done a rapid microinduction with transition to the long acting buprenorphine formulation. And it seemed like it went well, but I can't remember the specifics of it. Okay. Yeah. All right. It's funny. Now that we like opened the chat, like it's starting to really heat up. So probably the best is we'll get through our deck and then we'll open the floor. In regards to that last question, we have at least one person in the audience who has some experience with the long acting injectable. All right. So I can't really help myself here. We've been sitting and listening for a little while. So I'm gonna suggest while I bring up my slides, anybody who feels comfortable doing this for just a minute, turn on your video camera, look around the audience, say hi to everybody. We're all here. We're having a nice time. And then I'll go ahead and get my screen up. Okay. So just say hi. So just a few disclaimers before I get started. This is my first AAAP conference. I'm a general internist. I'm ACM addiction medicine certified. I work in an outpatient clinic. About 50 or 60% of my patients are on buprenorphine. And I have a referring relationship with Alex. He'll treat patients in the hospital setting in Manhattan. And if they live in Brooklyn, they'll often end up in my family health center clinic, which is affiliated with NYU in Brooklyn. And as I go forward, I've got a few pearls from my practice, but one of the biggest ones is, listening to patients is actually extraordinarily helpful. I find that people who use opioids are often very knowledgeable about it. And so a lot of this information initially sort of came from patients. People have asked me, have you seen the Bernese method? Or what do you know about microinduction, doc? And so we take it from there. Let's go ahead and put the first polling question out. I have a 35 year old lady who I know well. She had been in my primary care clinic three years prior and tried buprenorphine therapy and really failed. She had very severe opioid use disorder and was never able to really induce on buprenorphine. She then went on methadone maintenance and I hadn't heard from her for about a year and a half. And then I found out she was getting discharged from her methadone maintenance program. So she was being administratively discharged for reasons that were not entirely her fault. And she comes to me saying, I wanna get back on buprenorphine. She had been going on a 30, 25, 20, 15, 10 milligram taper and was on 10 milligrams. And so she asked me, can I do buprenorphine? And my question is, do you think it will work in this case? So let's open the chat or open the poll. I'm not actually sure if we can see the poll. So if anybody can see the poll, let me know what it looks like, because I can't see it. So it does look like we've got some responses in. So 2% said definitely not, 4% landed on 2, 17% said maybe, 28% fell between 3 and 5, and 49% said absolutely it will. Got it. Well, so in this particular situation, I was trying to figure out how we might microdose our patient onto the buprenorphine. So I went hunting around for microdosing protocols, and I found one from Rondawa et al. It was just a short letter, but they wrote that they were having success getting patients who were on full-dose opioids onto buprenorphine by commingling the following regimen with the full opioid. So I've just got it displayed right here. I'll let everybody absorb it. So you take a half a milligram of buprenorphine. They use buprenorphine naloxone, and then they do that twice a day on day two. They take one milligram twice a day on day three. Day four, two milligrams twice a day. Day five, three milligrams twice a day. Day six, four milligrams twice a day. And day seven, 12 milligrams twice a day, and stop their opioids. But the challenge that I had while sitting in clinic was, how can we organize this patient for this? This is a pretty challenging regimen. And so I was really thinking about this, and we had an idea, and I'm not sure if I'm the first person to have this idea, but I was the first person around here to have this idea. So we asked ourselves, can we starter pack this? Can we make a buprenorphine starter pack to get our patient onto the micro-induction regimen? And so I'm not affiliated with any of the brands on this slide, but these are four well-known dose pack series. And I'm just going to let everybody study them, see if you recognize them. You'll recognize the one in the upper left as the Varenicline starter pack for folks who are trying to quit smoking. So the Chantix starter pack. I'll go to the right-hand side because I'm an internist. The one on the right is azithromycin, the so-called Z-pack. Take two tablets the first day, and then one tablet a day for five days. And then a steroid dose pack called the Meddrol dose pack, which is methylprednisolone with a built-in taper. So you could see the patient encounters six tablets the first day, then five, four, three, two, one. And because this is a psychiatry conference, I wanted to include the Lamictal starter pack for lamotrigine. And I gather there's also a few different lamotrigine starter packs, depending on whether patients are on valproic acid at the time of the lamotrigine induction or not. So starter packs exist. And the question was, could we make one for buprenorphine? And the answer is we could. So we contacted a local community pharmacy. And I went over to the pharmacy myself after work one day, and I showed them the article. And they showed me this blister pack. And they say, yeah, we use this for geriatric patients and people who ask us to put all of their meds for the day. And I said, oh, well, this might be just right. And so we asked the pharmacy. And the pharmacy experimented cutting the buprenorphine monoproduct two milligram tablet. And what they found is they could successfully take a buprenorphine two milligram tablet, and they could cut it into four pieces. And they could pack this dose pack with the regimen shown on the slide 36 here. So this regimen becomes reflected in this dose pack. And generally speaking, the pill didn't shatter too bad. So then the question was how to order it. So we all probably have different EMRs. I'm on an EMR called Epic. I suspect I'm not the only one on this call who's on Epic. But we were able to code in a buprenorphine two milligram monoproduct order. So this, quote, Subutex two milligram tablet. And we use the miscellaneous texting as written here. And it fits. And so we're able to send that to the pharmacy. And I have this programmed as a favorite. So in the current state, I'm able to order a buprenorphine microinduction starter pack from the pharmacy with one click. But the key is they have to go to the one community pharmacy with whom I have this relationship. So outcomes. So this 35-year-old lady who was admittedly on a pretty low dose of methadone, but who is also, she's morbidly obese. She had a lot of lipid tissue. And so I was worried about methadone lingering around. But she reported that she had complete success using the dose pack and marching on to buprenorphine. And I'm happy to report that she's been stable on buprenorphine with me for one year. So I'm debating now whether to go here now or later. I'm seeing conversation on the chat about whether we should be using the buprenorphine monoproduct or the buprenorphine naloxone combination product. And to be specific, there are buprenorphine naloxone tablets and films with two milligrams of buprenorphine and 0.5 milligrams of naloxone. So my thought on this, when I was doing this, there were two schools of thought on whether to use the monoproduct. One school of thought was people have had success using the BUP now suboxone combination product. So maybe we should use that. And furthermore, there's pretty good data to suggest that if people take the product as prescribed, naloxone should not affect anything. And in fact, any precipitated withdrawal would be from the buprenorphine, not the naloxone. So that's argument one. On the flip side, I have, you know, in my panel of about 100 patients, I have about 5%, maybe five patients, three patients who I trust, who I don't think are using or diverting medication, who say, when I take the naloxone-containing product, I don't feel well, my stomach is upset or I feel like the product doesn't last longer. And I just feel better on the buprenorphine monoproduct. And so my logic on using the buprenorphine monoproduct in the dose pack was, if there is even a chance that we're gonna bungle the induction because somebody has naloxone intolerance, that's a real problem. So while I'm not certain that the buprenorphine monoproduct is essential, that is what I've decided to use. And I think it's gone okay. But I do not know for sure if the naloxone product would work as well. I'll pause for a second to see if either Alex or Arslan wanna chime in on that idea. All right. I'll defer back to you. Sorry, go ahead, Alex. I'll defer back to you on that. All right, there's a pretty good idea going here. Let me stop my share for a second or pause the share. Oh, I've never paused the share. I don't know what's gonna happen, but I'm gonna pause the share. I'm gonna stop the share. Because there was a suggestion from David Hathaway, which I think is pretty funny, which is like, well, we've got everybody here. So I'm gonna put up a voting question, okay? And we're gonna get everybody's opinion on this. So there are seven big screens of people. Let's see how it goes. The question to everybody is, if you think that we should definitely use the buprenorphine monoproduct, aka Subutex, thumbs up this. On the flip side, if you think that the BUP now, Suboxone 2 milligram will work just fine, thumbs down this. And if you abstain or you don't care, thumb in the middle. So yeah, and you gotta keep your thumbs because I'm looking through. I'm getting a fair amount of pro-Suboxone combination product thumbs downs. I'm getting a few buprenorphine monoproduct thumbs ups. I'm getting a fair number of, yeah, it looks like for whatever reason we can't respond, but that's okay. Oh, geez, I have no way to tally. Well, I'm gonna make the inference. And Alex, I defer to you on this. I think that was about 50-50. I think maybe there were a few more saying Suboxone BUP now, I think that BUP now won the vote slightly. Although I still stick by my word, but we'll leave it to everybody else. Let me share my screen again. And let me minimize everybody. So the outcome here was a 35-year-old with a successful induction. So my next patient who we tried this on was a 60-year-old male wanting methadone to buprenorphine. He was on 30 milligrams of methadone. And I called his program and they were okay with us trying this. So he attempted the induction and he just failed. He returned right back to methadone. I called the methadone program back two months later after I hadn't heard from him. I was like, is he okay? And the methadone program said, well, we don't have the release form, so we can't tell you. And I was like, but I'm worried. And they were like, well, we can't tell you, but you don't have to worry about it. So he just went back to methadone. So I have another patient, the third patient we tried this buprenorphine starter pack with. It was a 60-year-old man with prior kratom addiction who had been induced very stably on 12 milligrams of buprenorphine. But six months after he was induced, he went in for very painful shoulder surgery. And he had the painful shoulder surgery and he definitely had to do physical therapy to loosen up that joint after the surgery. So he required full-dose oxycodone. So he was put on oxycodone and I saw him in clinic that week after he got out of the hospital. And we talked about how best to get him on. And so on week one, we gave him the... On week one, he was on full opioids. From week one to two, he had the starter pack of buprenorphine and was maintained on full-dose opioids, oxycodone, 10 milligrams, six times a day. His outcome, he managed the overlap very well. He experienced no physical withdrawal. He went to physical therapy. And on day 14, he was completely back on buprenorphine. Outcome three, so then the fourth patient I'll tell you about was a 60-year-old man. I knew him well. He had been stable on buprenorphine. He had relapsed on street product. And he came in, he said, doc, I don't know why, but I'm having a hard time getting back on the buprenorphine. I'm doing the same thing I've always done. So I prescribed him the buprenorphine starter pack and then he disappeared. And for a little while, I didn't know what happened to him. The epilogue to that story is this man came back into practice and he reported to me, doc, this actually helped me, but I still had withdrawal. So he went to an inpatient withdrawal management facility, then went upstate. And three weeks off of fentanyl, he started on buprenorphine, got on it, came back, and then he was on the buprenorphine. He did okay. Then a few months later, he was back on street product and asked me for the buprenorphine starter pack again and was able to induce on it again. So this is something it seems like he taught himself to use the starter pack. So I know these cases look a little disjointed. And what I will say is with this buprenorphine starter pack is only about eight or nine months old. So I have a summary slide showing more or less everything that happened to it. Let me go ahead and try to make that as big as possible. I'm hoping folks can see this okay. So we've now done this about 20 times and you can see that it works great some of the time. It works so, so yellow some of the time and it fails or we don't know what happens some of the time. So, I'm happy to linger on this slide a little bit, but I think the moral of this slide is simply the colors. So, like for instance, we had like a 47 year old lady who was on buprenorphine before previously that was on street product and used this. She said, I can't get back on now because fentanyl is in my drug product. And I said, do you want to try the drug? And I said, do you want to try the dose pack? And she said, yes. And she got back on buprenorphine with it and she liked it. She said, I would do it again. I had a 34 year old lady with polysubstance use and she was able to get back on. But then I have other people like patient, if we look at patient 11, this is a 42 year old man who had been on the 60 milligrams. This is who we had spoken about before and he's sort of on and off trying to use the buprenorphine starter pack as often as he can. I had a 47 year old lady who tried the starter pack, had withdrawal, went away to Hawaii, induced in Hawaii and is now okay using very low doses of buprenorphine. We recently had a 69 year old lady who I say it's in progress who tried the starter pack this past weekend. This is a lady with cerebral palsy and 30 years of iatrogenic opioids, just like on chronic opioid therapy for non-cancer pain. And she's pretty fragile. And so we were worried about precipitated withdrawal, but we were also worried about just traditional induction. So we gave her the starter pack. She took the first two doses and she had withdrawal. She called me over the weekend. She said, what should I do? And I said, well, at this point, since you're experiencing precipitated withdrawal, we were trying to use the starter pack to keep you off of it, but we're just going to go ahead and say, break open the pack and get yourself on the buprenorphine. And she did it. And she actually said within a few hours, she felt a lot better. So there are many questions that we had before the chat. And I'm going to tell you those questions in a minute, but I've been talking at you for a while. So I thought maybe Alex and Ari, you think we could take a moment for questions from the chat, which I haven't read yet? Yeah, I think so. There's a couple of questions that I saw that were more targeted to the outpatient setting. So there's a question from Claudia Rodriguez who says in the outpatient setting and someone who uses fentanyl, do you recommend that they continue using while doing the microinduction? Given that we don't have the option of continuing the prescription for opioid agonists, or using Bell Buck or Butrans? So that's a great question. And I have a slide on that coming up, but it's an interesting thing because I do say, as you're ramping up on the starter pack, you're probably still going to need to use some bags of whatever you're using. And I get two different answers. When I say that. So one answer I get from the patient is, okay, I'll keep using the bags and I'll do what you say. But the other answer I get from patients sometimes is, Doc, I'm in your office because I never want to buy a bag of heroin fentanyl again. And so now you're telling me I'm supposed to go buy a week of bags? So I say, well, I guess we'll try the traditional induction with you. But you have to explain, at this point, yeah. Now, I think in a system that had different legal structure, the logical pharmacologic way to get somebody who's using street product onto buprenorphine probably would be to do one week of a dilaudid or hydromorphone prescription concurrent with the buprenorphine induction. That makes pharmacologic sense. Unfortunately, in our country, I would argue that it doesn't make legal sense at this time. Yet. So I think that's all I'll say about that. So yeah, I guess the short answer to the question is, I say, yeah, you may have to buy a few bags, but try to use fewer and fewer bags every day as you feel the buprenorphine kicking in. And what you'll probably find if the buprenorphine is working is that you're going to feel the bags less and less. And on day seven, you're going to walk off your bags. Alex, were there any other questions that you think we should take? There is. I think it's a lot of questions around how to this difficulty initiating buprenorphine off of fentanyl. I think it'd be good to hear kind of more generally be in discussion about that. There was one specific question about a case from Dr. Weiss who says in the outpatient setting, she had a patient who she transitioned from looks like opiates for pain to buprenorphine through the use of a Butrans patch, Belbucca and decreasing opiate agonists rather than stopping abruptly. Says it worked. And was this rational? So in other words, sorry, the buprenorphine patch was effective. It sounded like it was a combination of the Butrans patch with Belbucca and full agonist opiates. The main issue or question was that it was done over weeks rather than days. She was on one strength of patch for a week. Then we went out for a week. So it was a very gradual process as opposed to this more long-term process. Now, I have some wisdom to share here. You know, I've talked to a lot of different providers who do buprenorphine work. And I find that different people have different levels of comfort with the letter of the law, the spirit of the law, and the ends justifying the means. So for instance, I have a few times written Belbucca for a patient and said, I don't know, do you have some chronic pain? Yeah, where's your pain? Your back hurts? Okay. So for that week, they received a prescription for Belbucca for pain. And then I followed that up the next week with the full dose buprenorphine. Now there's probably somebody on the call who might report me to the DEA. So I hope that's okay. I hope most people realize that the reason we were doing that was with the patient's best interest and beneficence in mind. But there are some people who really do want to follow the law to the letter. And I think there are other people who realize that there's a real gray area about addiction with chronic pain. And opioid dependence can occur when somebody has chronic pain. There is a disease entity called complex persistent opioid dependence, which is not addiction, but still it can be treated with buprenorphine. And let me see here. Oh, there is a point coming in on the chat, at least privately to me, that it may be easier for me to treat pain as an internist than it is for some people who are psychiatrists on the call. And I think that's a very reasonable point. There was a question about the legality of buprenorphine monoproduct for addiction. I may be wrong about this, but we definitely have some patients with opioid dependence who are on buprenorphine monoproduct. We usually have to submit a prior authorization documenting intolerance to the buprenorphine naloxone combination product in order to get them to pay for it. But I do not think that there's a problem prescribing buprenorphine in the two and eight milligram monoproduct doses for addiction. And clearly in patients who are pregnant, that is still considered to be the preferred therapy. Alex, Arslan, I'll see. Let's see if there's one or two more questions for the chat now, and then I'll dive in on the slides. There's an interesting question that's asking about if you have, if there's a sense of macroinductions or the traditional induction compared to microinduction and fentanyl users and how that works. I love the term macroinduction. I've never heard that before. If not, I mean, we could make the argument that we should just refer to the traditional induction as macroinduction from now on. It makes me think about economics, macroeconomics and microeconomics. I don't know. Um, but, uh, I, all kidding aside, I think my, um, my gut feeling working in the outpatient clinic is that most people who've never tried buprenorphine should probably try traditional induction, even though fentanyl is still in the drug product with a fair amount of anticipatory guidance. And the one thing that I think has changed markedly as a result of fentanyl in the drug product is I used to tell people, go ahead and advance your dose pretty quickly. Like if you're sick, you know, go ahead and you need to take four milligrams, maybe a half a strip, um, or a whole strip on that first day and see if you feel okay. What I try telling people now is for your test dose, take a tiny little piece of that first film and just make sure that you don't get sick taking that tiny little first piece in an hour or two later, take another tiny little sliver of that film. And if you're feeling okay, go ahead and escalate your dose. So it's sort of a pseudo microinduction. But so, yeah, I, I would submit to everybody that I, the minority of my inductions are microinductions. The majority are macroinductions or traditional inductions. Um, okay. So I'm going to move on, uh, with the presentation. Uh, Alex, folks can still see my screen, right? Um, oh, wait, I'm sorry. You know, this is like somebody's raising their hand. I, I don't know if we can recognize David Hathaway or not. I'm willing to do that. Hi. Hi. I just wanted to mention that, uh, macro dosing is a separate thing than regular initiation. I think there's a case now of it where they use really high dosing. Um, so it is distinct actually from the standard traditional initiation method. I'm going to try to see if I can put the case in the chat. Yeah, no. So this is being recorded. So strike my last comment. Let us not equate macro induction to traditional induction. Thanks for that, David. Uh, yeah, I'd be curious to see that reference. I've never seen that. Um, okay. So let me show you the questions that we thought exist, and then we'll look into the many more that will probably come out of the chat. So some outstanding questions. Uh, so this one addresses an initial question, um, which is, is micro dosing a good name for this process or should we call it microinduction or low dose ramp? And I used to call this micro dosing that delighted me to no end. I thought it was a nice way of describing this, uh, process, but I now recognize that there are two problems with this and I am trying to train myself not to use the word micro dosing at all. And the reason the first one is micro dosing has a homeopathic overtones. So, um, some people say like I'm micro dosing on vitamin B or I'm micro dosing on St. John's word or something like that. And that involves taking like very, very low doses of something that are, that are sub therapeutic and probably like sub physiologic. Um, so nobody here is, is, uh, implying that we're, that we're really taking a millionth of a dose. Um, and so, so, you know, from that sense and also from a true chemistry sense, micro meaning a million, like we're not, we're not getting a millionth of a dose. But I think the second reason, which is also labeled number one, uh, is that micro dosing can, um, has overtones in, uh, psychedelic compounds. So, um, I'm not sure how many people on this book are well versed in psychedelic compounds, or maybe have read Michael Pollan's recent book on this, how to change your mind. It was a good read. It's thought provoking. I'm not sure how many people on this call believe that psychedelic compounds, such as LSD and psilocybin should be scheduled one, or whether they should perhaps be, uh, scheduled down so that we could see if they're useful in clinical practice. But what I will say is taking a tiny quantity of LSD and seeing how that makes, um, you know, how that makes the user feel that is called micro dosing. And so if we as addiction clinicians use the word micro dosing, we could very well confuse people who then go looking for information online and find out information about micro dosing of psychedelics. That's going to muddy our water. So, uh, I'll take a moment to get feedback both from the co-panelists and also from the chat. Um, but I'm hoping that we agree by consensus on this call that the term micro dosing should probably be avoided. I would, I would agree with that. I've been making a conscious effort to use the word micro induction in my practice. I agree. I think micro dosing is confusing. I think there's a lot of push to, you know, for low dose buprenorphine inductions is kind of an alternate term, that can be less confusing to patients. Um, but I think, I think clinically you could probably use either one, but I think there should be some kind of consensus about what the terms are going to be. Yeah. I, you know, people are putting in a lot of support on the, on the chat here, gradual induction, micro induction. Um, I will open the floor for anybody on this fairly large call who believes that micro dosing is a good name for what we're doing. I see no hands raised. Somebody's noping this on the chat and I think that's right. Uh, this is enjoyable. Uh, I, I'm not hearing a lot of support for the term micro, micro dosing. So I, I, I submit to most people on the call, uh, that we should not use it. I fear micro induction may be sort of here to stay. It kind of got here first, although I'm hearing some really nice ideas coming out of this chat. Um, cross titration, bupaginous cross titration seems very nice. Um, let's see. Very low dose induction, withdrawal, sparing induction or initiation. Hmm. The only thing is I would not want to promise withdrawal sparing in any name because I, I, you know, although there may be a placebo effect there if we say that, but I, I, I have encountered precipitated withdrawal with people who are doing everything, you know, according to the dose pack. So, um, so as we move on, uh, you know, another question is, does this allow transition? This does buprenorphine microinduction or, um, bupaginous cross titration. Uh, does this allow transition for patients from methadone to buprenorphine? This was the unicorn for a long time. I've been telling patients it's easy to go from buprenorphine to methadone. It's not so easy to come back from methadone to buprenorphine, but maybe now we can. So the question in the inpatient and in the outpatient, having seen this talk, we think the answer to this is as follows inpatient with a lot of support and with Dr. Sedelnik watching, uh, yeah, outpatient with my dose pack and an occasional phone call, but not that many phone calls from me. Um, not as good, but maybe we just haven't figured out the right way yet. Um, I'll, I'll, I'll pause here, Alex, or, uh, Ari, you guys want to chime in on this slide? I, I think we could probably keep going. We have a few more minutes left in the talk, about 10 minutes. So we could probably, so let me speed up a little bit. So just some insights that I've gotten, uh, it is hugely important to get to know our local pharmacy. This, this project wouldn't have been possible unless like I had made connections with a local community pharmacy. I'd highly recommend if you're practicing somewhere in this country, and you haven't made a good connection with a local pharmacy where you have the cell phone of the pharmacist and they have your cell phone number, you may be missing out. Um, we find that the dose pack does help people organize, but that precipitated withdrawal still happens. That patients do not always stop the opioid on day eight, the same way with the Vereniclein starter pack. Sometimes people don't stop smoking, even though the starter pack tells them to, well, even though our starter pack tells people to stop using fentanyl bags, sometimes they don't. Uh, coordination with methadone maintenance programs has been a challenge, uh, for me, uh, as we already described, some patients don't necessarily want to buy any more bags, but I find that positive framing and anticipatory guidance really helps. I say, look, you're trying to get on buprenorphine. It's going to be a bit of a roller coaster, but you'll get through it. And, uh, and that sometimes helps people. Um, are there implications for perioperative management? I think there are, because the pendulum is swinging on this. The pendulum swung towards keeping people on their buprenorphine during surgery. And I think that's generally a good thing, but now there's a fear about stopping the buprenorphine. But if people can be, uh, uptight, if they can be micro-induced on buprenorphine while they're on their full opioid agonist, this may provide a way that we can be more confident with our buprenorphine maintained patients when they go into surgery. Uh, and then the legal and practical issues we've already discussed, but technically speaking, we should not be prescribing Belbuquem Butrans for, for the treatment of opioid use disorder with their, their treatments for pain. And when we do do that, we have to be sort of mindful about how we code it. Um, I do find that the buprenorphine, uh, dose protocol that I have, um, will waste a very small amount of buprenorphine. So you're like, well, where do I put that? It's a controlled substance. So I say, just tuck any extra buprenorphine from a misplaced cut into the last day of the well. And then we still don't know the optimal duration. The current dose pack that we have is a seven day duration, but maybe it should be shorter, three days, maybe it should be longer. And maybe we should be starting with a lower dose than 0.5 milligrams. Although cutting that tablet would be hard. We touched on the idea already of monoproduct versus combination product, and I'm going to say that we don't know. So let me stop sharing my screen, turn it over to, uh, Alex, and we'll see what we can accomplish in the remaining time. Thanks for your talk, Dr. Caruso. Um, and thanks for the audience for this lovely discussion. It seems like there's a lot of questions and, uh, lots of fodder for discussion. Uh, so I'll try to get to some of these questions. Um, we probably won't be able to get to all of them, but, uh, we'll see what we can do. So, uh, the first question I see, um, is from Ian King. Can any of the panelists comment on the use of cadian as a bridge between methadone, uh, particularly high doses and suboxone? So cadian, uh, is the, the long-acting morphine, but it's once a day. And I think it's approved in Canada, at least, uh, it probably went around for the treatment of opioid use disorder. Um, so I, I mean, the hospital setting, you know, sometimes we'll, there'll be instances where, you know, we'll need to, uh, stop somebody's methadone kind of emergently and need a bridge of some type of opiate to reduce the, or to stabilize opiate withdrawal. Um, and so you can use any type of, uh, opiate, but oftentimes it can be challenging to find the right dose given how the, uh, you know, the conversion ratios of methadone changes with the dose. So using a long-acting morphine, um, I think I, it could be used, uh, if the person's withdrawal is stabilized, um, but it's hard to predict how much morphine will require. So I think what's worked well, at least in the inpatient setting is using, if methadone truly needs to be stopped emergently and person needs to be converted to buprenorphine or some other agent is to try to bridge them with some short-acting opiate. Um, that can be something like hydromorphone or oxycodone, uh, hopefully under close monitoring to make sure that a person's being, you know, dosed effectively and, um, and not in, not sedated or in withdrawal, which can be really hard to manage, especially with methadone. You know, if, as the methadone gets metabolized, the withdrawal can can change over time. So it can be, can be challenging. So a case like that makes me think that microinduction could be, could have a role potentially. So if you do like more of a rapid microinduction in a person that methadone is discontinued, you have a shorter window where you can stabilize a person's opiate withdrawal. Uh, so instead of waiting a couple of weeks, you might be able to wait like three or four days if you do rapid titration. Yeah, I've, I've been using, um, MS content a lot more frequently these days. They extended release morphine, um, to bridge people. Um, and it increases the chance that people stay in the hospital as well till, um, rather than leaving because they're going into withdrawal when you have to abruptly discontinue methadone, um, for a QTC or whatever reason. Um, but depending how long they've been on, uh, the methadone, uh, it, you really need to talk to the primary team about how long they expect the hospitalization to be. Um, in the few cases I've like transitioned higher doses of methadone to, uh, to suboxone and buprenorphine, um, has been when like they've been in rehab as well till, um, so they're in the hospital for like a month or so. But I've been using it more. Yeah. You know, I think we all have to be a little bit careful about how we, um, prescribe pain medications in the outpatient setting. Um, you know, I, I think certainly pharmacologically there's no reason to believe the Canadian wouldn't work. Um, I think pharmacologically if you are going to do, it's probably better to do multiple short acting, um, pain, uh, medications per day, but just for a very short period of time. Um, I also, I'm looking through the, uh, chat here and there's, there's a very good point. I think from, uh, Claire Twerk writes and she may not be the first, I think she is, she's saying the word induction sounds scary. Um, and maybe initiation might be a better, uh, more patient centered way of, uh, describing this. Uh, and then, and some others on the chat seem to agree. Um, and I had never really thought of that. I always thought of induction as being sort of a harmless drug, but maybe it sounds scientific and electricity related and scary. So maybe initiation might be a better term. Okay. It looks like there's another question from a Jessica Arbogast about, uh, what about the transition from injectable naltrexone to buprenorphine? Well, I think I'll, I'll take this one. I mean, I guess there's a question of whether that, that's the patient's desire inpatient or outpatient. Um, maybe I'll go first, Alex. I figure that it's, it's probably, um, it, it's probably an outpatient question. So, so briefly, I, I, I think opinions about, uh, injectable naltrexone and buprenorphine, um, are, are so, so briefly, I, I, I think opinions about, uh, injectable naltrexone, i.e. Vivitrol probably vary on this call. I think there are some people who really like it. I think there are some people who are growing increasingly wary of it. Um, my impression is that once you're on Vivitrol, it performs reasonably well, but getting onto it has been a challenge for people. Um, I think there's also some thoughts that, um, Vivitrol, the, the survivorship of opioid use disorder patients who are on long-term Vivitrol may not be as good as those who are on opioid agonist therapy with buprenorphine or methadone. So with that as a caveat, I'll say that if a patient comes to me and is like, I really want to get on Vivitrol, we could try it. Um, and, uh, I, I, like I had a patient who had taken buprenorphine low dose, like two milligrams, two or three days prior. And he just said like, and then he had dipped in dad with opioids the day before. And he walked into my office and said, just give me the Vivitrol. Like I'm fully prepared to get into, you know, to go into withdrawal. And I don't think I'm going to go into withdrawal because I think all of the full opioids out of my system. And so we gave him the, uh, naltrexone, you know, documenting that that's what he wanted. And he went into withdrawal. Um, but he's like, I called him the next day. He's like, I'm okay. That hurt. Um, but you know, he appreciated that we worked with him. Um, I I'm not certain that there, um, great methods of getting people onto the, um, naltrexone product. I'll, I'll yield to the inpatient. Uh, if you guys have any ideas, I have to say, we don't, we don't really convert people to naltrexone often the hospital setting. It's just really challenging to do. Um, if somebody is acutely ill and plus the length of stay is usually an issue. So if the wait, you know, 14 days to initiate buprenorphine or naltrexone, it can be challenging, but, um, there are, you know, some titration schedules where you do low dose naltrexone that we haven't done in our hospital, but it could be a consideration. Yeah, I would echo that. Um, I don't think we've done that at Bellevue, but reasonable consideration. Yeah. Yeah. I think it's one, one last question. I think it's a interesting question in general, but so Bruce Ferris asked, I routinely ask patients to cut off the film to get to the tolerated dose for tapers and inductions. Is that okay? Generally, I'm confused now. Um, and I think I, in some ways it kind of echoed that confusion, but it, you know, I think it's a, it's a really important question because I think a lot of the outpatient inductions were really limited to splitting films. Uh, cause we can't really prescribe, um, you know, the lower dose formulations. So, I mean, I, from what I can gather when we were doing some chart review for the hospital setting about splitting, um, it seems like there's an absence of evidence that says that there's stability in terms of cutting the films. Um, and to what dose is not sure, like how stable the films are or how much buprenorphine you're actually getting in each dose. So it was kind of the hangup for our hospital in particular, uh, which prevented us from wanting to go the route of splitting the films. Um, that being said, there, there, I pasted a study in the chat about, uh, there, there was one study looking at cutting the two milligram films in half, which showed some stability and that was okay to use essentially. Um, but I think in general, if you, if we think about how effective buprenorphine is, you know, it's so, uh, important in reduction of mortality and treating this lethal disease that if we're getting hung up about like stability of films, uh, rather than thinking about the bigger picture of getting somebody on a stable dose of lifestyle medication, I think it's, uh, we can kind of be looking at the wrong way. Um, however, I think it's a big, it's an important question. Like, are there other ways that we can get these small doses of buprenorphine in an outpatient setting or somehow study them to see if they're, uh, stable, but, um, it'd be interesting to hear your thoughts too, Anthony, about it and also the audience too. I'm really enjoying the chat, Alex. Like there's a lot of stuff coming out of the chat. I want, one of which is, I think we should all walk away from this meeting among other things, trying not to use the word micro dosing. And now I am even going to try not to use the word induction. Somebody points out in pregnancy that could get quite confusing. If you say you're inducing a patient, that might mean that you're inducing labor. So, um, fair, fair points. Well, well done. Um, in terms of splitting films, I will say that reports from my patients, I think that the behavior of splitting films is quite common. Actually, most people, many people who are on buprenorphine split the films. I encourage this. I think people can stretch their product out that way. They can sometimes, many patients achieve the dose of 12 milligrams by taking one and a half, eight milligram doses per day. And I have one delightful story I'd like to share. Um, uh, just from a page, but Alex, how much more time do we have? Um, I think we're a little bit over Samantha. All right. So I'll tell the, I'll tell the story this way. I had a patient I hadn't seen for two years. He came in and said he was dividing a film into 16ths. He was splitting a two milligram film in half and then slicing it eight times and taking a 16th of a two milligram. And he said, you know, doc, I'm really having a hard time getting off that 16th of a butte. And we looked up the receptor occupancy and there's a graph, which hopefully somebody can dig it up while we're on the, on the call, but, um, there's the receptor occupancy, like fully 20 or 30% of his opioid receptors are occupied at a one 16th of a two dose. So, um, you know, pharmacologically he was, you know, reporting, he was clinically reporting what pharmacologically made a lot of sense. And this is why precip precipitated withdrawal can occur even with tiny doses, quote unquote 0.5 milligrams of buprenorphine is still quite a bit, uh, in terms of percentage of receptor occupancy. Yeah. And just to comment on that, right. The, um, at two milligrams of, uh, buprenorphine, uh, there is, uh, about a reduction in for about, for the mu opioid receptor, 40%. Uh, and at 16, it's 80%. And at 32, it's 84% just to, uh, put some numbers to that. Okay. So I think we're a little bit over on time, but I, uh, I really appreciate everybody coming to our talk and for the lively discussion. Uh, and hopefully we'll, we'll hear more about microinduction in the future. And it seems like, uh, it's definitely an interesting tool for, uh, for very challenging situations in the hospital and also the outpatient side. Um, so thanks again, everybody for coming.

microinduction

low-dose ramp

buprenorphine

opioids

dose pack

transitioning patients

gradual increase

methadone programs

research

perioperative management

formulations

individualized approaches

pharmacies