Very good. Greetings, everyone. I'm Dr. Steve Wyatt, an addiction psychiatrist located in Asheville, North Carolina, and your moderator today. I welcome you to this Opioid Response Network-sponsored webinar. Today's webinar is a follow-up to a very interesting presentation by Drs. Marone and Nelson on the initiation of buprenorphine in the emergency department, a program that also had broad implications to the use of buprenorphine in other inpatient and outpatient settings. Dr. Perone is a professor in the Department of Emergency Medicine and the director of the Penn Center for Addiction Medicine and Policy. Dr. Perone has served on numerous regional and national task forces and advisory committees with the CDC and the FDA addressing judicious opioid use and has advocated for state and national level, at the state and national level, for harm reduction and ED treatment of opiate use disorders. She has won numerous awards for educational, education and mentorship of students, residents, and fellows, and is boarded in Emergency Medicine, Medical Toxicology, and Addiction Medicine. Dr. Lewis Nelson is a professor and is the professor and chair of the Department of Emergency Medicine and chief of the Division of Medical Toxicology at Rutgers New Jersey Medical School in Newark, New Jersey. He's also a senior consultant to the New Jersey Poison Information and Education System. He is board certified in Emergency Medicine, Medical Toxicology, and Addiction Medicine. Dr. Nelson is an editor of the Medical Toxicology textbook, Coltrane's Toxicology Emergencies, and on the editorial board of several peer-reviewed journals. He is on the board of the American Board of Emergency Medicine and several other academic organizations, and is past president of the American College of Medical Toxicology, and is a longstanding consultant of the CDC, DHS, and FDA. So I welcome you both. And I believe you're gonna be starting off with a few cases, and then following this, we'll have an opportunity to ask questions. So there were a few that came in over the week that they'll start with. So welcome. Great, thank you. Thank you. Jim, maybe I'll just run through the first few. I mean, we could just show funding, and I think there is a slide, if you can advance here. And then just, we have no disclosures. And we would like to thank Julie, because she really put a lot of time into helping us get this organized. So these were some of the questions that came up. Some we actually discussed towards the end of the last meeting, or the end of the last webinar. And then I know we got a couple, I got one more that came in today directly to me, which I'll raise. Jim, the first question, I think, is really directed at you. Yeah, so you can see that they were asking about how patients afford Belbuca. And I think we generally only give Belbuca in the emergency department. We don't actually prescribe it, because astutely, it is more expensive than sublingual. And it's also not actually indicated for opioid use disorder. So while we start people on it as the first small dose, we do that because we're not allowed to cut sublingual strips in the emergency department from our pharmacy rules. So that's how we were able to make the trade-off to giving the first dose, or giving doses in the hospital of Belbuca, but not actually writing prescriptions for it. It's a great question. Yeah, I think, I'm going to assume, Steve, that everybody on this webinar was on the previous one. I think, is that correct? So we won't have to describe the context of a question like that? That was the intent that everyone would have seen the seminar last week. Good, good. I did neglect to thank you for the introduction and to thank the organizations, the ORN, and the Osteopathic Society for inviting us to speak about this. I think we did last week, but I think we continue our thanks for the invitation. The next question you can see was, does weight have anything to do with precipitation? And I'll just take a quick crack at that and then, Jim, you can if you'd like as well. But I would say, I could see why somebody would think that because I spent a lot of time talking about how important adipose tissue is for storing fentanyl because it's a very lipophilic drug. So you would think that the more adipose tissue, which I assume we're correlating with weight here, which obviously is an imperfect relationship, how that would correlate with having excessive burden in the body of fentanyl. But I don't know that there's anything to suggest. And of course, the more fentanyl you have in your body, conceptually, the higher fentanyl blood levels would be, the higher fentanyl blood levels are at a sustained level over a sustained period of time, the worse your dependence would be. And the worse your dependence is, meaning physiological dependence, the more likely and the more severe you would precipitate when you got a drug like buprenorphine or naloxone or something like that. So that makes sense. I don't know that there's any data to support that. And I don't really know that there is a correlation between the amount of adipose tissue you have and the quantity, the concentration of fentanyl circulating at a steady state level in your blood. But it would make sense that if I was to take two otherwise equal, people who have equal use quantities of the drug, the person with more adipose tissue would have a total body burden of fentanyl that was higher than somebody with less. But I don't know if that translates into a blood level that would be any different. So the answer to your question for me is, I don't think so, but I don't know. I don't think there are any data to support that. I don't know, Jeanne Marie, if you had another thought on that. Yeah, I mean, I think it just is coming from the now frequently quoted Andrew Yoon study about the idea that fentanyl is stored in fat and leaches out of fat. So if you have more weight, that you would be holding onto more fentanyl. But as you said, it doesn't necessarily correlate with where that fentanyl goes from your fat to your blood. So as you know, there's also often few people who are, you know, many of our patients are quite on the lean side to begin with. So I haven't observed that just anecdotally either. Right, good. I think, Jeanne Marie, the third question we'll save because it's kind of the basis of one of the cases we're gonna talk about. Is that okay? Yeah, sounds good. The fourth question, if you want to take a crack at that first. I think the fourth question goes right into your first case, basically. Okay, so we'll just do that. I was asked a question, which I don't want to forget to cover, which was, you know, both, you noticed from introductions, both Jeanne Marie and I are emergency physicians, and a lot of this talk is based on how we practice in our ED. I mean, as Jeanne Marie said, she'll give the bucca as a dose in the ED, but not send people home. So the question was, how does this translate into outpatient settings or telehealth, for example? And the answer is, it may not, depending on the setting you work in. I think that microdosing could certainly, and that Jeanne Marie is gonna speak more about, could probably translate nicely if you're willing to, you know, take the time to explain to somebody how to do a microdosing protocol. Most of our practices, if it's not in the ED, it's in the inpatient setting, and it's easy to do because you can, you know, just write an order, and the nurses will dose the patient properly. For macrodosing, which is what I'm gonna spend more time talking about, it is a little tricky. And you'll see that, you know, while it's a pretty good way to approach a rapid conversion from an opioid, a phlegonist opioid to buprenorphine, it is not without risk. I mean, microdosing tends to be fairly risk-free. Macrodosing does carry small risk of precipitation, which can be somewhat severe, but it can be from, you know, regular dose initiation as well. It's particularly a problem when you do it from, you know, a standstill, from where the cows have zero, one, or two. It's a little less risky, obviously, if you're gonna macrodose with the cows at 15 or 20. The one thing I would say is that when it's been done and the person does precipitate and you're concerned in an outpatient setting, there is an ED available. And if you felt uncomfortable managing the patient by giving high-dose bup, you would be able to send them, I presume, if you're nearby, to an ED or at least a higher acuity setting than an outpatient clinic that you'd be in. So I think that would probably be my answer. Gina, I don't know if you had any other thoughts on that. I can definitely mention how we do things on telehealth, because we do operate a big telehealth program. And it has been a great adjunct to prevent people who are falling out of care from, you know, they miss their second appointment and then all of a sudden they have to start all over again. But if you can get them a prescription via telehealth, it's really patient-centered and, you know, less stigmatizing and seems like, you know, a really conducive environment to prevent gaps in care. So I will talk about that. And we've had no problem doing microdosing over the phone that way. Can I get started on this case, Louis? Yeah, you ready? So this is a case that I'm gonna talk about. This is a 46-year-old woman who's on methadone, 120 milligrams a day for OUD, not for pain. And she's hospitalized for pneumonia. On admission, she's got a QTC that's very long and everybody's uncomfortable with it. We don't really know what her baseline is. We didn't put on any antibiotics that would cause the QT to prolong. And it is the admission cardiogram. So presumably this is her baseline that she walks around with. Her labs are otherwise normal. She's admitted to a monitored bed and her methadone is reduced to 90 with the presumption that this is a dose-related or dose-dependent QTC prolongation, which often they are, especially at high-dose methadone, but some people just prolong even with low-dose methadone. But even after their dose reduction, her QT stays long, prolonged, too long for most of us to be comfortable with saying that there's nothing to do about it. So the decision is made at the time to switch to buprenorphine. Next slide, please. So speaking of starting from a standing start, she had a CAUS of zero and she was going to be discharged that day. So we didn't really have time to let her develop opioid withdrawal. I wasn't ready to precipitate withdrawal intentionally to start her on buprenorphine. And she was leaving and I didn't really feel like she was going to be capable of a microdosing protocol as an outpatient. Her last dose was 24 hours ago. So the decision was made to initiate a macrodosing protocol. I'm happy to entertain questions as they come. I think we both are in the Q&A or the chat. And if people want to raise them there, it might just be easiest than waiting for the end. What I put on the right, I showed this or something very similar last time, just to show you why I think macrodosing makes a lot of sense. So if you look at the KI or the affinity of the drug for the receptor, you'll see that the higher the number, the lower the affinity, right? This is a concentration of which you get 50% of the effect. So the higher the concentration, you get 50% of the effect, the lower the affinity is for the receptor. So you can see that buprenorphine has got a much higher affinity than methadone does. And it does for pretty much all of the opioids that we think about. So next slide. We gave her, yeah, next step, thank you. We gave her 16 milligrams of sublingual buprenorphine and her cows never budged. I mean, it stayed at zero the entire time. So this is somebody who I would call a clear success. I mean, this is somebody who, despite being on a reasonably high dose of methadone with a 16 milligram buprenorphine dose, it was able to displace enough of the methadone. And I presume some of that methadone was gone. So we know that after 24 hours, you pretty much have a half-life worth in most people of methadone eliminated, but still her cows at the time was zero. We did give her a little bit more buprenorphine prior to discharge. The question that could be asked is why? And it's the one for the road concept. We knew that she probably would continue to eliminate methadone and she might need a little bit more buprenorphine. We felt that since her cows didn't budge, she was probably pretty safe to give an additional dose to she's not gonna, from that point, you're not going to go into a worse withdrawal in our experiences. So we went ahead and did that. And she did remarkably well. Next slide. Again, any questions, please raise them as we go. Just to remind everybody what we do here, because I think this is a concept that is foreign to many people with macrodosing, but the idea is that, and in part methadone is reminiscent of heroin and not of fentanyl, right? Because methadone and heroin have fairly low affinities and the depth of dependence that people have on the drug and the effects that people develop on them tend to be fairly manageable, unlike what we see with fentanyl. So by giving her a low dose, but not a microdose, you actually have a higher risk of displacing the wrong amount, or you could say just the right amount of drug to cause withdrawal, to which you would then give more buprenorphine. So macrodosing basically takes out the need to risk precipitate withdrawal, then to give more and to just start with a higher dose. And this schematic, which is not an evidence-based schematic, it's a representative diagram. By starting with that 16 milligram dose, most people do fine, at least most people with heroin and most people with methadone. The risk of precipitation is indeed higher with fentanyl, but I've seen numerous cases where we've done it in people on fentanyl, who use fentanyl and they've done fairly well. I do not tend to do it from a standing start, accounts of zero in people who use fentanyl. I do tend to wait till we see withdrawal, but rather than start with the two or four milligram dose, we start with a 16 milligram dose and it really quells the withdrawal very quickly and allows us to discharge them right away on a 16 or sometimes even a 24 milligram dose of buprenorphine. Next slide. So again, this is the concept of what's happening. You would say that we are basically giving people enough buprenorphine to displace the methadone or whatever the opioid that they're taking is. Next slide. But with the 16 milligram, can you advance please? Yeah, so you can see by giving such a high dose, we're able to cover all of the receptors. And then by giving that excessive dose of 16, we're able to actually provide additional agonism to the opioid receptor. And if you remember the diagram I showed, that receptor pharmacokinetics are really on-off phenomenon, where the receptor is on most of the time, not all of the time, but by providing more partial agonist, you're able to really saturate the receptor completely and you're able to overcome any of the potential for precipitated withdrawal. Next slide. There's a question with fentanyl. I'm sorry. I was gonna get to the question, I'm driving around. So Dr. Weiterman, with fentanyl, I've not found the cows helpful. So the macro would be okay and not the timing? You want me to answer that? Yeah, I think that the cows, I mean, this is a conversation, it's hard to have in a Q&A, but I'm not sure the cows is not helpful. It may not be as helpful as it has been for heroin. It depends on how you're looking. If you're looking at it as a communication tool to say what degree of withdrawal somebody's in, it works. You can say the same about the CEWA or a lot of other scoring systems we use. It doesn't necessarily help to predict how severe withdrawal is going to be or how they're gonna do when they get buprenorphine. But I think that macro dosing as a concept is probably okay to do early, but with fentanyl, just because I found that there's, and I'll talk about it in case two, there does seem to be a somewhat greater risk of precipitation. I do like to wait until people have some cows. And this is a good example of why that is. And this patient in case two, you'll see, it's a middle-aged man who's got a long history of heroin use. Obviously heroin nowadays in probably all of the country is primarily fentanyl. He'd been on buprenorphine several times with easy inductions and he had good treatment success. Obviously he's fallen off a few times in order to need to get started back up again. He's not really in withdrawal. I mean, his cows is two, he's got some anxiety, probably a lot of anticipatory issues related to impending withdrawal, but he is really insistent on starting buprenorphine before he leaves the ED. And we had a nice sort of conversation, level setting, expectation management, shared decision-making, and I gave him both the micro and macro dosing option. And he seemed having been on this before to be able to understand the micro dosing protocol, but he was insistent, next slide. And I felt I had no problem doing it in starting a macro dosing protocol. So remember he started out at two and after the first 16, he went up to 12, his cows. And then we gave him an additional eight milligrams. So now he'd gotten 24 milligrams and his cows went up a little bit more to 16, but he felt like pushing through. We gave him an additional eight milligrams and as up to 32, and you see that the trajectory now is going in the right direction. So he's down to a cows of six and one more click, if you don't mind, we gave him another eight milligrams, brought him up to 40 milligrams and his cows was essentially zeros. You could say one or two or put something low enough to be helpful. So again, back to Dr. Weidman's question as a metric to measure and communicate, I think the cow still does help in these folks who use fentanyl. But this is just an example of a case that, you know, in a clinic setting, you might be, you know, you need to have a bit of an iron stomach to do something like this, because it's hard to precipitate people. In the ED, not that I like to do this, but at least we have the ED. You know, we have monitors, we have equipment, we have other drugs to use, and it's just a much more comfortable place to see a patient who precipitates this hard. But ultimately, by increasing the dose. Now, I have gone up to 64 milligrams in some people. I usually try not to go past 40, but that's the general approach that we've taken. Next slide. And then the third case, if there's any questions, I'll wait for a second in the Q&A or chat. I don't see anything. Yeah, I don't see anything. Okay. So the third case, it's off the beaten path from what we've talked about already, but I think it really illustrates nicely just another concept about buprenorphine. And now, I've seen several of these cases. I know, Jean-Marie, when we've talked about this, you've seen these cases too. And I bet you some of the folks out there have seen this, but this is a person who... Okay, just quickly back. 32 is the ceiling dose for buprenorphine. I don't know where that comes from. I've heard that too. I think that, you know, just like we say, the dose of an opioid for analgesia is whatever the dose takes to make the pain go away, which is a dangerous concept, by the way, but it's something we've all learned. I think with buprenorphine, there's no rule that says you can't give as much as you want. There are reports in the literature of people giving 128 milligrams. I mean, I... Whoops. If you don't mind, go back. Yeah. I think that there's definitely no rule that says the stomach... That says the stomach. I read your quote. That says there's a ceiling. So I think that contemplating macro in the office, but not yet. Yeah, I would agree. I mean, I think it's a bit tricky depending on, you know, where you are when you're doing this. Perhaps if you're in a higher-end clinic environment, you might feel comfortable doing it. But in the ED, I think most of us have grown... Not most. Some of us have grown more comfortable doing this. But thank you for the questions, Bob, and saying that both of you. A 32-year-old man inadvertently receives an altrexone from a friend to treat his opioid withdrawal. And when you read the prescription bottle, it's kind of confusing, right? It says every day for opioid withdrawal, right? And it makes it sound like you should take it when you have opioid withdrawal. And it's just, it's odd wording from the pharmacy. So moments after taking the medication, not hard to imagine, because this drug is very well-absorbed in the GI tract, and it has very good clearance on first pass. So it clears the liver very well on first pass. It does not get eliminated on first pass to the liver, unlike naloxone, which is absorbed well, but instantaneously eliminated by the liver, which is why naloxone is not available, bioavailable from an oral dosing, but naltrexone is. So you can see that he develops quite an impressive degree of presbytery. Drills cows to 30. He's got hypertension, tachycardia. He's vomiting and he just looks miserable. Next slide. So just to point out again, that buprenorphine has a much higher affinity, a threefold higher affinity or so than naltrexone. So there's no reason to think that naltrexone would not be displaced by buprenorphine. We have seen this several times. Now in the old days, so to speak, quote unquote, many people in this situation would try to dose with high dose, full agonist opioids and try to compete at the new opioid receptor and eliminate withdrawal that way. That is almost never successful. And you can see why you'd have to give fairly high doses of most of the conventional opioids to compete successfully with naltrexone. But buprenorphine does a very nice job. And I'll just point you to a paper we looked at a few years ago. We did a literature review of all of the cases that we could find about precipitation by naltrexone. And the winner in that review really was buprenorphine in terms of how well it functioned. All of the people that tried to use fentanyl infusions and things like that, they just never really worked very well. So if you ever run into this situation, it's just something to put in your back pocket is another trick that you can use to treat naltrexone precipitated withdrawal. Next slide. Yeah, there is a quick, another question in the chat. So after doing the macro dosing, what dose do you send them home with? I would say that I almost always send people home on 16. And often what they'll do when they come back to our clinic is we'll put them on ATID, so wind up on 24. But I usually just use ABID. And it was the macro dosing just to get you over the hump. Right, it's not necessarily the dose you have to be on in perpetuity, but it's just to get you. I mean, you know, whether you pull it in deuce or initiate onto buprenorphine, you got to get them on. So just like with macro dosing, you don't leave them on 0.5 for the rest of their trajectory. You don't leave people on 40 either, you put them on 16. Thank you. Next slide. And just to remind everybody, I showed this last time, but it's the same idea that some people, and I know some of the folks that have been mentioned on this call, including Andrew Herring and Mark Greenwald have published some literature, as has Rachel Horose down in Camden and some others, to give people naloxone intentionally to cause opioid withdrawal, and then to treat that with buprenorphine. Now, in my mind, that makes some sense. And you can argue there is some literature that suggests that naloxone can change the opioid receptor in some way to make it more amenable to buprenorphine. But I would argue that macro dosing makes more sense. Sometimes people do precipitate. In this model, everybody precipitates, and then you rescue them. In my model, macro dosing model using buprenorphine naloxone, most people don't precipitate, but some do. So this, and I wrote an editorial about one of these papers once, and I kind of said it seemed like a bit cruel and unusual to do this to somebody, because you're causing precipitated withdrawal, which is miserable, and then trying to treat them. And there's just no reason in my mind to do that. So I would just think through if you're trying, I'm not suggesting this is a bad pharmacological idea. I just think from a medical perspective, you're probably better off not intentionally causing precipitated withdrawal if you can avoid it. That's all. Next slide. There's a question to comment on BID or TID or once-daily dosing of buprenorphine. I'll let you answer that too, but I got to tell you, I'm a BID person, but I work with a group of really knowledgeable and seasoned addiction physicians, some of whom believe TID is the way to go. When I started doing this, I used Q-Day. I was a big 16-a-day person once a day. And I sort of felt the goal is to just take a medication once a day. And they've convinced me, or at least they've tried to convince me, that by having somebody do things several times a day, you give them something to sort of look forward to, something to engage with, and there's better psychological connections to it. That is probably an art and not a science explanation for it. So I now use pretty much BID and I split the baby, so to speak. I don't do Q-Day and I don't do TID, but many of our patients wind up on TID. Do you have a little bit? Yeah, I've heard some nice analogies about why to break it up. And part of it is that locus of control, they can decide when they're going to take the subsequent doses. But also, analogous to nicotine patches, you can stop somebody by smoking by pharmacologically, replacing the act of getting nicotine into your body, but you're not replacing the habit of smoking. And so in some ways, redosing is reinforcing the idea that you have some ability to get your next dose in or have something else that you're doing that's sort of more active to control your symptoms and your cravings. Yeah, yeah, I think that's true. And I bet there's a lot of people on the phone with a psychiatry background who'd have a lot to say about what's the best approach to that. I can say it in the chat. Yeah, please do, it's a great conversation. And to Dr. Easley, I don't know that we would address that right now. I think we've run out of time, but it's a great question about Ibogaine, but certainly not necessarily directly related to this. All right, I think those were Louis's three cases, but feel free to throw more questions in the chat. I was going to share a couple of my experiences. This was a 50-year-old female who had a long time history of first intranasal oxycodone use that progressed to intranasal fentanyl use that had progressed to IV fentanyl use more recently. And of course, as is the case when we're talking to patients, there are days when they use a lot more, maybe they have a little bit more resources that day, and then days when they're using less or they can't get as much. So there's sometimes really a lot of range of when people are using. A lot of times when we can, we tell people to titrate their use down to a low use day before initiation. So in this case, the patient came in with this history. They came in in the morning, their last use was 8.30 PM the night prior. And so eventually when we started her treatment, she was about 15 hours post last use. As I mentioned, we're doing this clinical trial with XR buprenorphine. And so we actually randomized people to either getting sublingual buprenorphine with a protocol based on cow score, or get one injection of the XR buprenorphine, which is a once weekly subcutaneous dose. So in this case, she was randomized to the eight milligrams of sublingual for cows of 13, and her partner was randomized to the injection of the XR bup. He actually just did fantastically well. He tolerated four hours of observation and all of his mild withdrawal symptoms resolved. Unfortunately for her, about 10 minutes into her sublingual, she began to get really sick. She visibly started sweating. She vomited, she ran to the bathroom. She wanted to leave, but she was really actually too kind of ill to leave. And I think she knew that. She, you know, we could sort of redirect her and say, we're gonna give you more buprenorphine. You know, that's gonna make you feel better. Stay with us. So we tried that. We gave her another 16. Unfortunately, she vomited that. And each time, you know, we do this in the emergency department, but much like a clinic, you still have to wait for a nurse to be available and an order to be written and a drug to be getting out of, you know, from the pharmacy. So none of this is particularly quick and it's kind of agonizing to watch, but she had multiple episodes of diarrhea. We were ultimately able to get her a room. For those of you who practice emergency medicine, it wouldn't be foreign to know that we do most of these initiations in the hallway and patients do great, but unfortunately she was just doing really poorly. So we were able to get her into a room. We gave her some lorazepam, which seemed to help a little bit and got her nausea down enough to tolerate another dose of buprenorphine. But she remained quite ill for six to eight hours. So her cows got down to, you know, 17 or 15 at best at the end of about six to eight hours and her partner was being discharged. And so the two of them went home to kind of ride it out. She was better the next day, but she was no longer interested in buprenorphine. So that is, you know, one of the big casualties of somebody who has an adverse event. So things that we learned. Ancillary medications for withdrawal and comfort. Usually buprenorphine is good enough, but in these cases we do add, you know, medicines for nausea. I have on dancetron there, but if you have IV access, I really like droperidol or Phenergan, something that's sedating because you really just wanna quiet these people down. Ideally place an IV if somebody gets sick so that you can more rapidly titrate their medication, including the use of IV buprenorphine, which I would definitely have on standby. You know, somebody who's already nauseous is already having a problem with the taste, isn't gonna want something else that's nauseating in their mouth. We've had more success with much larger doses, like Louis just presented. 40 milligrams ultimately will reverse a precipitated withdrawal episode. Benzos, at least two milligrams, either PO or IM is a reasonable dose of lorazepam to quiet things down. And just know that this is gonna take a few hours, but it does resolve ultimately with time and support. So just a few words about XR buprenorphine. It goes with the investigational drug named CAM2038. It's available in several formulations, both a seven-day and 28-day subcutaneous injection. It's extraordinarily well-tolerated. You can give it in the abdomen or the thigh or the buttocks. And it's just, you know, compared to what I hear about sublocate from patients who have had both is that this seems like a breeze. It's really much less of an injection, much, much, much less discomfort. And then the initiation with it is people are now giving it to people with cows of one to eight, or basically anything greater than one. And people are doing tremendously well. So it's really comes down to that agonism antagonist. Maybe when you're not in withdrawal, you know, you have a little bit more agonism on board. And so you're really just treating, you know, getting more agonist in terms of buprenorphine, but also a little bit of displacement of fentanyl, but there's more agonism around. I can't explain it, but it seems like it might actually be easier to treat people who don't have a lot of withdrawal with this method. It is available in Europe and its US approval has been held up on manufacturing issues. So it's been approved by the FDA, but their site where they were going to manufacture it has not been approved. And then just a little bit, I really like this pharmacokinetic slide. The dashed or grayish line is the buprenorphine concentrations after a dose of subliminal bup 16 milligrams. So you can see your plasma concentration rises very quickly in the first hour and then starts to fall. And it could be that quick, you know, on that is causing people to have more symptoms depending on the timing of their withdrawal. Conversely, you can see this gradual uprise of the bup concentration after the XR formulation, which is rapidly reaches steady state, but does so without having that big spike in serum levels. So just a second case of bup precipitated withdrawal. This happened about two or three weeks ago. I think three weeks ago, actually. This was a 35 year old female who had a really successful period of recovery on suboxone up until May of 22, but had recently had a reoccurrence of use. We had actually treated her partner a few days before with XR bup and he had done beautifully, didn't have any withdrawal symptoms. So she came in seeking the same thing. Unfortunately, she was randomized to the sublingual and with her initial cows at 13, she got eight milligrams. She was 12 hours from her last use. So I just copied the nursing notes out of the chart. And this is really just what happened. To receive the eight milligrams, her cows went from 13 to 22. So she was very uncomfortable. Within about 10 minutes, she was given additional 16 milligrams of bupnorphine all at one time. And we do use bupnorphine without naloxone for rescue. We could just be using bupnorphine for everything, but we do actually stipulate. It seems to be a little more patient accepting. She was still in discomfort after the 16. We gave her a little bit of lorazepam, a little bit of other meds, some quantadine. And then since she was still uncomfortable, we gave her another 16 milligrams of bupnorphine. And you can see there from the nurse's note, her cows was eight and then back down to zero by the time she was discharged. So again, it still takes about four hours, but early bupnorphine and big dose is really helpful. And she is still engaged in treatment. So this is somebody who's gotten back and stayed on bupnorphine despite having a bout of precipitated withdrawal. Jimmy, there's a question that says, I think the question is, is the IV dose to bupnorphine equal to the PO dose? I think it's actually slightly different. I wanna say, I know we were looking at this for Elbuca. The IV dose that we have is 0.3 milligrams. Yeah, I was gonna say 300 micrograms. Yeah, so comparable to the Elbuca, which is also about 20% more than sublingual. So I would encourage you to look that up, but yeah, it's close to the, it's the doses are actually smaller. Yeah, you know, the Buprenex, which was just the brand of what the IV used to be, was used for pain. And, you know, in people who were not opioid dependent, 0.3 is a fine pain dose IV. I don't know that you could use it equivalently. I mean, in a microdosing fashion, it would work well, but I don't know that you could use it in a macro dosing way. I mean, you'd have to give lots and lots and lots of doses to get it to work. It's pharmacogenetics are different though, because it's obviously 100% bioavailable and the levels rise very rapidly because you're giving it IV. It doesn't require absorption over time, but there are a few people that have used it, but I still don't think most of us use it a lot. I mean, maybe in the situation you described, but in general, it's not widely used for this or for pain for that matter. It should be probably. Great. So this is another story of a, this is a man who had also had a history of sustained recovery, but recently had a reoccurrence of use. And he came in really just complaining of shortness of breath and was having a COPD exacerbation. He's somebody who we only discovered his opioid use because he answered the single screener question that we have in triage. So there is some value to screening when you get a chance to uncover somebody that you can help who otherwise may not have been as treatment seeking. So initially we thought he was gonna be discharged. So we had started him on buprenorphine with the microdosing. So we didn't wanna risk getting him sick. He was already having some respiratory issues. So we started him on the Belbuca 450 micrograms and up titrated him to a therapeutic dose. So when you have the time, you can do it for 50 Q6 and then go to a one milligram Q6 or two milligrams Q6 and then to a therapeutic dose on the third day. So this is the schedule that we use, but essentially this was written initially to start with 150. We don't think that people really need the 150. We found that people who don't have withdrawal still can tolerate the 450 micrograms of Belbuca. You could also, that's about the equivalent of one milligram of buprenorphine. So if somebody was doing a home induction, we usually start them at 0.5 to one Q6 hours. But in this case, he was in the hospital, was supervised, he got these doses and was able to get to a therapeutic dose of buprenorphine while in the hospital. So that was a big success. I don't know if you've experienced this, but he was in the hospital for three days. And on the fourth day, we finally gotten him on a therapeutic dose of buprenorphine but there was nobody to prescribe buprenorphine on the hospital service. So we have this problem quite commonly. We have all of our emergency physicians. It's actually a requirement that you be X-wavered. It's a credentialing requirement when you get onboarded as our faculty. And many of our hospital's colleagues do have it as well. But unfortunately on this day, it was just, there was not somebody. And we see this a lot, this gap in care potentially. So this is why we've started a buprenorphine telehealth line. And we do this by, we've partnered with our city of Philadelphia Department of Public Health who's funding our substance use navigators. But the first call goes to a substance use navigator and they can talk the patient through what resources they might be looking for. And if it is somebody who would be a good person to get started on buprenorphine, we go right to our virtual urgent care in our health system. And an advanced practice provider who's been trained in buprenorphine actually orders that first prescription. He prescribes it to a pharmacy. And if the patient needs other resources, we can lift them to the pharmacy to pick it up. So we really feel that this is the wave of the future in bridging primary care, outpatient, inpatient. We see people who are leaving incarceration, people who are leaving rehabs and have a follow-up appointment in 10 days and their prescription is for five days of buprenorphine. So it really fills these potentially dangerous gaps that occur in treatment. So this is our standard protocol. As I mentioned, when we're doing this over the phone or discharging a patient from the emergency department, we either tell them to, you know, for over the phone, tell them to cut a two milligram strip into four pieces or an eight milligram strip into eight pieces and just take a tiny piece. And they can do that every four to six hours depending on how they're feeling and what their level of anxiety about precipitative withdrawal is, or if they've had good or bad experiences in the past. And then we continue to up titrate that up for seven days to get them on a therapeutic dose. This strategy now gets them on a therapeutic dose by day three or four, which seems to be a better strategy because patients really can't tolerate, can't really follow these instructions when they're more detailed than that. So that was our last slide. I don't know if there have been additional questions, but we're happy to chat further or answer any other questions. There were no other questions in the chat or the Q&A, but obviously, Stephen, I think you said you might have something or did anything come through? So that's all great information. I did see some discussion around whether it's BID dosing, TID dosing or once a day, and there's pluses and minuses, I think, to all of them. I wondered, one, how, because a lot of people around the country have problems with the pharmacies. And so when you're writing your micro dosing, Dr. Perrone, what prescription do you actually send to the pharmacy? Because this has also been an issue about sending the patient home with one prescription and then writing a different prescription for the pharmacy. So what's your- Yeah, that's a great question. We've had that definite barrier. The first thing is we can prescribe the two milligram strips to our hospital pharmacy and they've stocked it. And we have a dot phrase in the notes to pharmacy that explains exactly what I mentioned there. When we prescribe to other pharmacies, we actually have a big problem and that's why we've just gone to eight milligram strips. And the substance use navigators tell the patients in great detail over the phone how to do it. And we just prescribe eight BID to the pharmacy because we really can't navigate that in instructions. We have enough difficulty e-prescribing that and having the patient pick it up and having, we're trying to get, we pay the pharmacy over the phone with a credit card that we have. And that also raises issues. So the more scrutiny we have, the more less productive it is. So we've resorted to just using the eights and having people cut them up on their own. And it seems to be working. We have about 50% retention in treatment from the telehealth line. So people do seem to tolerate it. Well, the Care Connect looks like a really great program. I wonder too, and both of you are doing work with the FDA, if there's been any discussion about the potential for us being able to use like B-TransPatch over the, for patients with OED or is there any further discussion of widening the scope of buprenorphine availability for these patients? It's a really good question. Louis is really the FDA expert in terms of what it would take to get a new indication for the B-TransPatch. It is the easiest and most patient-centered version of uptitration, but I don't know what it would take. Maybe Louis, you can answer that. I don't have a real answer. I can tell you what I believe. Drugs carry specific indications and particularly when it's this negotiated agreement between the DEA and the FDA about what drugs can be used. Because remember the whole data waiver and you go back to the Harrison Narcotic Act and all of these rules that are in place and the Methadone Act in the 70s, these all very much limit the ability of the FDA to independently make decisions. So a lot of the literature is really written about, and the data is really about the sublingual buprenorphine. I mean, technically, even the idea of buprenorphine is not legally allowed to be used to treat, you can use it to treat opioid withdrawal, but you're not really allowed to use it to just use sustained treatment for people with OUD, just like you're not allowed to use Butrans technically to do any of that because it does not carry that indication. And as everybody on the call probably knows, there are very few buprenorphine preparations that actually carry the label indication for OUD. Now in the hospital for short-term use, three-day rule, a lot of these other things we get around it, but to use Butrans technically, which is a pain, which carries a pain indication for this, it's really sort of skirting the law, which is something I always remind people. I don't imagine they're gonna come breaking down our doors to do anything about it, but it's not technically legal. In the hospital, you're probably much safer because you're administering it to the patient, you're not prescribing it to the patient, right? And you could probably use that wiggle room around it, but I always get a little concerned when people prescribe these things off-label because this is an area where, yes, we could use anything off-label we want, but there's specific legislation around treatment of patients with opioid use disorder with opioids, and this is an opioid, that make it a little bit complicated. So I don't anticipate anything rapidly changing, to be honest, and so what it took even to get rid of the educational component of the waiver, I mean, it took a federal interaction, or intervention to get that done. Thank you, and I think it would be great. And this idea that there was, there's discussion of kind of redoing the whole data, the data 2000 law, and obviously throwing out the waiver, but would that involve some of this too? I think it would be interesting to see. Yeah, well, it's a great area for adequacy for all of the various organizations that are involved. The osteopathic group, ASAM, ORN, whomever else gets involved, ASAP. I mean, there's a lot of groups that could push for this but that's what got the change to the waiver. I mean, it was just a lot of advocacy for it. Yeah. In the, well, I guess the other piece of that is the idea that the FDA really has only approved buprenorphine, suboxone type products up to 32 milligrams. So, are people potentially getting in trouble even there if they are prescribing 40 milligrams a day? I think that's a question. That was a question earlier. And again, it's the same sort of answer. There's no law that says you can't do it, but going outside the labeled indication is going outside the labeled indication. You just gotta be careful. There's doses, there's indications, and there's just, anytime you do any of these things with our patient population, you always, I think treading on canise a little bit. Yeah. So the other thing that actually was brought up in the annals paper and has been of discussion, and that is the idea of microdosing on an outpatient basis and suggesting to patients that they continue to use fentanyl until they obviously get up to the place where it's being blocked and they just stop, can be a risk and are we, the idea that there is the potential for overdose during that period of time, any thoughts on that and alternatives of things that could be done as opposed to suggesting to patients that they would continue their illicit use of opioids? Yeah, I think we debate this all the time. I mean, for patients coming into the emergency department, any bupe is still better than no bupe. And the alternative is methadone, which we really can't get people onto methadone. So somebody who's having a treatable moment and wanting to get started, if it's, I'm too afraid of precipitated withdrawal, I don't wanna be on bupe, the alternative is unfortunately just full use of fentanyl, they're not gonna get anything. So I think that's the way I frame it. I wouldn't want to encourage people, but I think I highlight the fact that they're getting started on a treatment that will ultimately help them help reduce their overdose risk and probably even just a few doses of buprenorphine reduce their overdose risk. I've learned from my harm reduction study coordinator that when somebody comes in looking for treatment, that if they can actually do something that they said they were gonna do that day, that it's so reinforcing to the concept of starting the journey, that I think is really what's convinced us that everyone should get a dose of low dose bupe, just to say, here you are, you started, you're doing something, it's a step in the right direction, even if it's a baby step. Yeah, very good. Yeah, I agree. So having been involved in some clinical trials of buprenorphine back in the 90s, I do wonder a little bit about ED docs that would give very high doses in the emergency department and then do ultimately to have a warm handoff, no question is the best, but patients potentially would be covered for, if you gave 40 milligrams or 48 milligrams in the emergency department, they potentially be covered for at least 36 hours. Is that true with fentanyl also, or what's your thought on that? In order to get them to someplace where there's gonna be follow-up. I don't see why that wouldn't be the same. I mean, it's the buprenorphine, not the agonist, it's relevant. But that's the same thing that we ask when we say we give somebody naloxone and they wake up, how long do you have to watch them for? And does it matter whether they've taken heroin, fentanyl or methadone? Everyone says, oh, if it's methadone, you have to watch them a lot longer. But that's not true. Right. Because it's the duration of the naloxone that matters, not the duration of the agonist that they're taking. Right. Because once the naloxone is gone, and so it's the same issue here. I mean, you're protected against overdose in concept for as long as the buprenorphine is bound to the opioid receptor, not based on what agonist you're taking. Right. Right. Does that make sense? So I don't think it should really matter. I just wondered about the potential competition with the fentanyl that's still in the system, potentially, you know, and the fat. There's so many unknowns. Right. And they'll never be a good study. Right. There's just, there's too many variables here. Right. About the quality of the drug. People think how often they take it, their adipose quality. I mean, there's just so many variables that we're not going to really know. And so much of what we do is going to be by just feeling away in the dark and trying to figure it out. And it's going to be individualized treatment for the most part. I mean, that's what we started talking about at the beginning. I mean, it just will never be a cookie cutter way to doing this like there is with some other treatments that we have. Yeah. That idea that there's, that potentially an outpatient basis, that there would be a very low dose given to the patient on day one. They come back day two and get micro dosing. That's being done around the country in places. It kind of makes sense with what one of the protocols that you described, Dr. Lewis. I just wonder if you have thoughts on that. About outpatient micro dosing? Well, it would be giving a low dose day one and then macro dose day two as opposed to micro dosing. My concern about the, when you say low dose, do you mean low dose is two milligrams or 0.5 milligrams? Or how am I always have with these low doses? Go ahead. When the guidelines were put together, you know, around 2000, 2002, when buprenorphine really first came into existence, the only drug in the street was heroin. So I think a two milligram dose of buprenorphine is probably enough to displace enough heroin to cover adequately many of the receptors. The depth of dependence from heroin, as bad as it is, is much less than you see with fentanyl. So my concern is that that two or four milligram dose that we would give somebody in 2005, now and have some success, nowadays further enhances precipitated withdrawal, or further enhances withdrawal by precipitating. Even with a low to moderate cow score, I think we'll still see people precipitate. It's because they're not really equivalent dependences, physiological dependences, right? In one case, it's shallow relative to the other case where it's deep. So I think that by starting with that two or four milligram dose, it's probably the wrongest option, honestly, in my experience that we have. You should do micro or you should do macro. If you wanna be perfectly safe, I think macro is definite, I'm sorry, micro is definitely safer. You won't precipitate, right? And if you're willing to roll the dice a little bit, and I can't even give you a percentage of precipitation risk. It's 2% or 3% or half a percent or 5%. I don't know. We do it enough to say it's certainly in the single digits or lower. It's not something to say, but when I talked to Dr. Perrone about this, she'll tell me that every one of her patients that they tried on have severe withdrawal. And she only lives 90 miles away from me. I think we share a drug supply, right? Between Newark and Philadelphia. Yeah, and I always tell her it's the mindset of what they expect. Cause she'll tell me her patients, oh, I don't want that stuff, it's gonna make me precipitate. And if I say, don't, you might precipitate, they go, what's that? Right, so a lot of this is just anticipatory. I don't know, Jim, if you agree with that, but that's my experience. Until somebody has diarrhea and they're incontinent. You know, yeah, there's some anxiety, precipitated withdrawal, and then there's like grade four precipitated withdrawal, like the naltrexone patients. And that's an ugly thing to experience for the caregiver and the patient, for sure. Yeah, I agree. It's true. So we do see it. And I agree, we do see precipitated withdrawal with buprenorphine. I gave you that, my second case. It's just, I don't think it's all that common, but in all fairness, we only have QA type data on this. We don't have deep dives, we don't have randomized trials. You know, we just have observational stuff for the most part. Right. All right. I think we're right at 559. And I know Judy put some, the next webinar information in the chat. So thank you very much. This has been a fascinating discussion and some good cases. And I'm sure everyone's really appreciated it. If there are other questions that do come in, I'd like to think we could send them on to you and maybe be able to answer for folks. But I appreciate very much you taking the time to be with us today. Absolutely. Yes, hopefully people copy down our email addresses in the last slide that we presented. So feel free to email either of us. Great. I think the take home really is individualized care and really working with patients and talking to them and getting a sense of what's going on and then using a lot of this science, as much science as we have to really make the decision. So thank you very much. And thank you for having us. It's been a pleasure. Thank you. Appreciate it. Great opportunity.

buprenorphine initiation

opioid use disorder

dosing strategies

telehealth program

individualized care

withdrawal symptoms

patient preferences

precipitated withdrawal

overdose risk