Yeah, and then we'll get started here. So good afternoon, everybody. Welcome to today's AOAAM webinar on the impact of illicit fentanyl use on opioid use disorder treatment by Dr. Andrew Hoon. My name is Julie Kmik, and I'll be your moderator for this session. This is the second of a six hour webinar series on hot topics in the treatment of opioid use disorder and stimulant use disorders. I'd like to introduce Dr. Hoon, who is an Assistant Professor of Psychiatry and Behavioral Sciences at the Johns Hopkins University. He earned his PhD at Penn State University in 2016 and an MBA from Johns Hopkins Carey School of Business in 2018. Dr. Hoon's research is focused on understanding the human experience of opioid use and opioid use disorder. The majority of his work has been done in human laboratory studies and clinical trials to identify risk factors for drug relapse and medication strategies to improve opioid use disorder treatment outcomes. His lab employs diverse methodological approaches to better understand opioid use and opioid use disorder, including neuroimaging, ecological momentary assessments, wearable technologies, human laboratory studies, and survey research. Taken together, this research is aimed at improving treatment outcomes directly and evaluating and strategizing macro level changes to improve healthcare for substance use and related disorders. So I'd like to turn it over now to Dr. Hoon. Thank you. Great, thanks so much. And thanks everybody for being here. I'd like to start off by thanking SAMHSA for funding this series of talks. The views expressed in my talk are not necessarily the views of the Department of Health and Human Services. I don't have any new disclosures since last week. I still receive funding from the NIH and Ashley Dixon Treatment, which is a nonprofit, but no direct financial conflicts of interest. Okay, so today we are going to be talking mostly about buprenorphine in the context of fentanyl. So we're gonna understand the scope of buprenorphine precipitated withdrawal, learn strategies for buprenorphine inductions from the case studies and discuss approaches to improve OUD treatment in general for individuals who use fentanyl. We'll talk a little bit about other treatment pathways besides buprenorphine as well. Okay, so if you remember from our talk last week, fentanyl is a very strong opioid agonist. It has high affinity for the mu opioid receptor and it likely desensitizes mu opioid receptors via the beta-arrestin pathway, intracellular pathway. And it also likely decreases mu receptor availability relative to other opioids, the majority of other opioids, at least, that you would see people using illicitly. So it causes a lot of issues. And when you add buprenorphine to the mix, and we also learned that this fentanyl can stick around for a long time, right, that it's highly lipophilic, that it likely has a biphasic clearance where a lot of the fentanyl is leaving the system immediately, but some is being stored in adipocytes, re-released out into the bloodstream. So it's hard to gauge how much fentanyl somebody has in their system if they're using it every day. It would depend on a lot of factors. It would depend how quickly they metabolized it, how well they stored it. And it makes the bupenductins really tricky. And why does buprenorphine cause precipitative withdrawal? Well, buprenorphine also has high affinity for the mu opioid receptor. It has higher affinity than fentanyl, higher affinity than most any opioid. And it's a partial agonist, but it's also a partial antagonist. And it's competitive. It will displace opioids that are on the receptor. So you couple this high affinity with its kind of decreased efficacy relative to other opioids. And when it kicks off these full mu opioid agonists like fentanyl, it's just replacing it with something that's very weak, and it can throw people into opioid withdrawal. And for those of you who have seen buprenorphine precipitated withdrawal firsthand, it is quite alarming. We're gonna go through some case studies, some experiences that we had in a clinical trial. But this is a big issue right now in addiction medicine. So how big is the problem? This is a survey study that we did about a year and a half ago. We surveyed about 1,700 individuals who were entering treatment for opioid use disorder across the United States. We were able to piggyback on another treatment outcome through a survey provider called TRAC9. They let us use their platform to ask some questions about fentanyl because this was such a big issue and there really wasn't any data out there on it. And so we were just asking basic questions about like, have you experienced withdrawal after taking buprenorphine, if you were using fentanyl, et cetera. So the patients who were in the study were at average of 30 years old, about 70% male and 80% white. So fairly standard. It definitely skews white in this study, but I guess that's something to consider with the results. About 70% of the patients reported either probably or definitely using fentanyl prior to opioid treatment. So prior to entering treatment, they said, yes, I have definitely or probably used fentanyl. And then about 42% of patients knew somebody who had experienced precipitated withdrawal after taking buprenorphine. And this is likely highly variable based on region. So, you know, this study was done across addiction. These are like residential addiction treatment centers. They probably tend to be a little bit more suburban or middle to upper class clientele. You know, in Baltimore City, everybody knows about buprenorphine precipitated withdrawal now, this is like very common. And it's a big problem because it turns people away from seeking treatment. So in this study, though, we asked people, we compared buprenorphine and methadone, and we asked them if they had experienced, after taking buprenorphine or methadone, if they experienced no withdrawal, mild, moderate, or severe withdrawal symptoms following their fentanyl use. And the participants who were using buprenorphine were more likely to endorse moderate and severe withdrawal, which can also be seen here. They also were more likely to experience that withdrawal if they were taking buprenorphine within the first 24 hours or 48 hours since their last fentanyl use. 72 hours wasn't significant, although some people did endorse it and I've witnessed it myself. So I think 72 hours is still a good cutoff. And then these are just the statistics for that last graph. So the people who used buprenorphine within 24 hours of using fentanyl were five times more likely to experience precipitated withdrawal. The people using within 48 hours were about three, three and a half times more likely to experience precipitated withdrawal. These were statistically significant. None of the methadone stuff was statistically significant. I didn't think it would be. We just had included that as like a comparator, so that we weren't only asking about one medication. 72 hours wasn't significant, but it was kind of approaching significance. And again, anecdotally, we've seen this. So why is this such a big problem? Buprenorphine is the most preferred medication for OUD right now. It's the medication that we've put the most effort into for expansion. It's available in addiction treatment facilities. It's available from your primary care physician if they are wavered. And it just seems to have, it doesn't have the regulatory burden of methadone per se, and it doesn't require detox and a period of abstinence like extended release naltrexone. All three of these options are good options. I'm not advocating for one over the other. I'm just saying that buprenorphine is our most preferred, our most widely used option, I should say. It's our most widely used option. And so anything that detracts from the use of buprenorphine or encourages people not to use it is a big problem because our infrastructure that we have been building for years now has been being built around buprenorphine. And we're seeing this when we talk to participants for our trials, if it's a bup trial, they're often nervous about whether or not we can safely transition them on. And I think we've gotten better at that, which I'll show you some results. And there's several reasons why the bup might be precipitating withdrawal. It could be, I definitely think the protracted renal clearance plays a large role in it. But also, there might be some action at the mu opioid receptor, like that there just aren't enough receptors available or that those receptors are desensitized and that bup just isn't doing enough when it gets on the receptor. So now I'm gonna talk about a case series. These were individuals who were entering a clinical trial, a randomized controlled trial that took place in a residential addiction treatment unit. These people who I'm gonna show tested positive for fentanyl at admission. They, not all of them knew that they would be positive for fentanyl. In fact, one of them was quite surprised. And basically what I'm just gonna show here is how different bup induction protocols might end up with different results. So we started with our standard protocol where we'd give somebody four milligrams of buprenorphine naloxone if they had cows of nine or greater. And then we wait about three hours and give them another four milligrams and then they're done for the day. So they get up to eight milligrams on day one. This is very standard. This works well with people who use heroin and oxycodone and any other opioid. You wouldn't do this with methadone, but any other opioid should be fine. And we had some challenges with it. So we revised our protocol after a couple of cases that I'm gonna show you. And we used a lower dose, two milligrams. We let their cows go at least to 13 before we started. And we waited at least 48 hours since their last opioid use before we started. And then we were pushing two milligrams every 90 minutes. That was the revised plan. And that worked for us because it was a residential study anyways. So we had people there. We knew that they didn't have access to illicit opioids while they were in our unit. And we can track their withdrawal very closely over time. I think making people wait so long becomes more of a challenge in outpatient therapy, but we'll talk about that more in a bit. So this study did offer some standard PRN medications. This is all over the counter stuff. It helps somewhat with withdrawal symptoms, but it's certainly not gonna pull somebody out of precipitated withdrawal. It's kind of meant more as like comfort meds, in case people need it during the study. Okay, so patient number one was an older adult, a Caucasian man. His BMI would be overweight. He didn't strike me as somebody who was particularly, you know, wasn't obese, but was slightly overweight. In the past 30 days, he had used four to five capsules per day intranasally. And he had used opioids about 24 hours prior to us dosing him with buprenorphine. He had been using for a fairly long time, about five years, no clinically significant issues. The second participant was a middle-aged woman. She was in the category of obese. She used two to three capsules of heroin or fentanyl per day. She had a high blood pressure, two to three capsules of heroin or fentanyl per day. IV, she did not know that, that her drug supply contained fentanyl in it. Actually, she was quite surprised at some of the stuff she tested positive for at treatment admission. She had used opioids 20 hours before we started the buprenorphine induction. And a little bit less, you know, she had been using for about three years and she had some other medical issues, chronic pain and mood disorders. The third participant was a younger man who would have been considered overweight. I only mentioned the BMI category because of the, the protracted renal clearance and our kind of hypothesis that adipocytes are storing the fentanyl. I think this becomes interesting, although I haven't seen it necessarily be, haven't seen it be statistically significant in any of the stuff I've done with these data yet. We have a question about capsules of heroin or fentanyl. We talk about bags or bundles. It's all the same. They actually call them pills in Baltimore. They come in like a little plastic pill, but different places they come in a bag or whatever. It's a single unit of heroin or fentanyl. Okay, and then the final person was a 26 to 40 year old Caucasian man, normal BMI, used one capsule of fentanyl per day, had been using for four years. And so this is what their withdrawal looked like following buprenorphine. So this will be, this is the first participant. If you remember, he was kind of a heavier user. And so he came in, we tracked his Cal score. Once he hit a nine, we used two milligrams or four milligrams of buprenorphine. And about 45 minutes later, his withdrawal started to increase kind of dramatically. Not terrible, but certainly was in some discomfort. We didn't take any other cows. We didn't record any other cows. In this meantime, he did get a second dose of buprenorphine about three, three and a half hours later. And his last Cal score was a 19. So he probably went up into the around 20, maybe early 20 range for Cal scores. He was a really nice gentleman, was a real trooper through the whole thing. And he mentally knew how to navigate the situation. And so he was, he ended up being a successful participant. I should also note that on the left y-axis is the Cal scores. The right y-axis is their total buprenorphine dose. And that's like this gray shaded area. So here is the four milligram mark. Here is the eight milligram mark. And so I'm just showing cumulative dosing over there. And then the little arrows are where on the timeline they took the buprenorphine. So the second participant followed a similar trajectory. Her cows actually got up to about an 11. We used a four milligram dose and almost within, I don't know, 10 minutes, 15 minutes, her cows, her withdrawal score spiked. And it was really quite wild. We had her on cows of 36 for well over an hour. I don't know how to describe what a cows of 36 looks like. You're basically just maxing out every symptom on the opioid withdrawal scale. And so this was an incredibly difficult situation for this participant. It was way unexpected on our end. And she was also a very nice person. She didn't complete the entire study, but this was just really, this was really bad. And after this, we just didn't know about it, about how prevalent the precipitated withdrawal was and about all the issues with fentanyl. And so after this is when we kind of went back to the drawing board and said, we gotta change what we're doing here. We can't have this again. So she did end up taking another dose of buprenorphine and her cows got kind of under control. And it's like at a 19 here. This is a big gap. So here it just jumps from 20 to 30. Oops. Yeah, but so these first participants, one and two, were people who precipitated withdrawal. Then we revised our protocol to what I showed you before, where we wait at least 48 hours since their last opioid use. And we want them to go deeper into withdrawal naturally before we introduce buprenorphine. So we wanted them to get to at least a cows of 13 before we would try two milligrams of buprenorphine. And so that's what we did here. This person, number three, they were sitting around 12 for a little while. They jumped up. We introduced two milligrams of buprenorphine. Their withdrawal went down, back up a little bit, but not a real big deal. Came back down to an eight. We did another two milligrams. It crept up a little bit. We waited for it to like crest and start to come back down because we didn't want to keep pushing the bup. In this way, we were a little bit shy at this point about how to push the butte. So we waited for it to crest and come back down, and then they continued to get dosed and were in a much better mild withdrawal to almost no withdrawal state. And they still got up to eight milligrams on that first day. And then this person is a similar story where they came in, it took a while for their cows to come up anyways. This is actually something I've noticed with the folks who use fentanyl quite a bit is that it takes a lot longer for them to get to a cows that would be appropriate to start dosing. And they sometimes they just like... It's not like a linear increase in withdrawal like you might see normally with heroin or oxycodone. They seem to get stuck at certain points, which again, I think just speaks to the high variability in how the fentanyl is being cleared from their system. But this person, again, this we considered this a very successful buprenorphine induction. So even though that worked, it kind of worked, and then there were some people where it just didn't work as well, and we had to keep adjusting our protocol. Again, this is for a clinical trial, and the clinical trial itself was actually an opioid withdrawal study. We were doing a buprenorphine taper where we were looking at a sleep medication that we thought could improve opioid withdrawal outcomes and improve sleep outcomes as well. So the bup part of this wasn't really what was being investigated. We expected it to be very routine, and it actually turned out that the hardest part of the trial was not getting people to wear sleep equipment and stuff while they were in withdrawal, it was getting people on the bup. So we started using other PRN medications to help control the withdrawal while we were giving people enough time away from their fentanyl. Clonidine, you could easily use lophexidine as well, which is actually the FDA approved version, but we would use this as needed for withdrawal. Clonidine works pretty well. It's not gonna cure withdrawal, but it does take the edge off. Andansetron and promethazine for stomach issues, nausea issues, dicyclamine for cramping, and methylcarbamol, which is a muscle relaxer. We actually found this worked very well at treating some aspects of withdrawal, and it's actually a medication that I'm interested in looking at more in another study. But even with that stuff, we still would precipitate withdrawal periodically. It was just really... It was just really hard to predict. And so we went even further to some... We had people come in early, up to three days before the study would start, and we would house them in our residential unit. We would use hydromorphone and diazepam to keep their withdrawal low for a day or two before letting them... The natural withdrawal emerged that we could then know how to dose the buprenorphine. That worked much better. Our goal here was to have 72 hours of opioid abstinence before we would start the bupe, and I wanted to see clear physical withdrawal symptoms, not anxiety, not like, oh geez, I feel restless. I wanted to see a tremor, I wanted to see snot, I wanted to see lacrimation, and I wanted to see physical signs of withdrawal before I would introduce bupe. The other thing we did that isn't mentioned here is that we started to break the two milligram tablets in half and give them one milligram. When I did that, I never precipitated withdrawal. So I do think, and we're gonna talk about this a lot in a few slides, but I do think that this going even lower dose on the buprenorphine is a very smart move. And I think somebody in the comment section, Jan Weiderman, has already mentioned this. I was just wondering, in terms of using quantity, and sometimes I feel like that blurs the picture a little bit too, because it can suppress some of those withdrawal symptoms, and then it's even harder to know. I mean, that's the practice that I'll use as well to help get people into it and microdosing, but it always makes me wonder, okay, maybe they would have more withdrawal if I hadn't given them the clonidine to take for this last 24 hours. Yeah, I think I have this in the slide. So sometimes when we were using the ConMed approach, it was like, I actually like to see them, if their withdrawal would break through the ConMeds, then I really knew it was time to start the buprenorphine. And if it didn't, then it was like, okay, they're not in such bad shape right now. This is all residential, so I think it's harder when it's outpatient, right? Because you need to either time it just right, or there's gotta be some other strategy, like sending people home to be abstinent isn't gonna be a real smart choice for most people. Yeah, so that's definitely something to consider though, when you start layering all these different medications, you're playing whack a mole with the withdrawal symptoms, and then it's like, well, wait a minute, when do I start bup? When it's actually safe. Yeah, I would still, if the withdrawal symptoms broke through, then I would start bup, or I would just start to take away the ConMed so I could see it happen naturally. Clonidine's pretty short too, right? I mean, the effects last like three or four hours, so if you're in a residential setting, you have time to let that wear off. So that was a good question. I'm very interested in hearing other people's experiences with buprenorphine inductions as well, before we continue. So questions I have for the audience is, if you have a minimum abstinence criteria, is there a certain amount of time you wanna see people not using opioids before you'll start bup? Are people using different cows thresholds, or is there a starting dose that you're more comfortable with? I think you had already mentioned about Jan Wiederman making a comment, and I don't know that these are open to... That the participants can see them, so I'm just gonna say what he had said, that he had done over 100 fentanyl detoxes since July. He microdoses starting six hours after the last use, with smaller 0.5 milligrams every two hours for four doses, and then one milligram every two hours for two doses, two milligrams, and so on. And he said that he knows that this is very effective for him, and he's in Philadelphia, and he hasn't had any precipitated withdrawal. And I think you're gonna go into microdosing a little bit more, so. Yeah, no, this is very close to what I'm gonna talk about in a few slides. But that's it. That's a good approach. Definitely, we have had people... One of my good friends here at Hopkins Hospital, who just moved over to Penn in Philly, had come up with a similar strategy for the bup inductions that happened in the hospital, and he was having really good success with that. Yeah. Yeah. We had another participant, Kathleen Rogelio, who had mentioned that they have a microinduction or a low dose initiation in the hospital, starting with buccal buprenorphine, 300 micrograms. Yeah. I mean, that's another... I think this is gonna be a reoccurring theme. If you can just get a little bit into the system, make sure they tolerate it, get a little bit more into the system, make sure they tolerate it. Once you get it on board, you can start to push higher doses, but the trick is getting it on board. So I think that's a good strategy as well. Right. And she'd mentioned too that... And I know that this happens in other facilities, but the hospital won't allow you to cut the two milligram strips into smaller pieces, so that's why they started with that. And of course, I've heard of other people using the Butrans patch in the hospital as well for starting microinductions. Yeah. I just... That's something that we had talked about years ago, and I just haven't done it myself. I haven't seen anybody do it. If it works, I think that's great. One challenge with Butrans is that if they did start to precipitate withdrawal, it'd be hard... You have to take it off. There still could be a bup depot in there, on their dermis. But it should work. I mean, it's another... I've heard about it. So if other people are having success, then I think that's good. Yeah. As far as the people I know of, through our inpatient medicine, they've had success using that method as well. And then we had another participant say that they wait at least 24 hours after fentanyl use, but they still start at four milligrams. And they don't precipitate withdrawal? I'm not sure about that yet. That would be from Kelsey Ellis. And we have another participant who had mentioned that in corrections, they're limited to tablets which are not scored and therefore can't be split, so two milligrams is the lowest possible mass. That's where you gotta wait. Yeah, you can break a tablet, it's just... It's not very accurate. The strips are better for that. Because the bup itself within the tablet is in the center of the tablet. But you can... I mean, I know people on the street break them, and it's something that they do. But if you can't, if your facility won't let you, then I don't know what else you can do with it. You gotta use two, and then you gotta wait. I mean, this is what we've learned in this clinical trial, because we were kind of beholden to using the two milligram dose for a long time. You just had to wait it out, let them go deep into withdrawal before you start the bup. Almost until... It was kind of like, I would wait until they got mad at me for not giving them bup, and then we were usually safe. My experience, and I know this has to be other people's experience too, is that sometimes patients, they just adamantly, they don't wanna take it, they wanna wait longer. And so they wanna wait, I know I can't take this for three days after I last used, because they have had an experience of precipitated withdrawal, and they don't want to repeat that. And sometimes that turns them off completely from starting on buprenorphine, like you'd mentioned in the introduction about, we can't have this kind of problem, because this is one of our most widely used medicines for treatment of opioid use disorder. Yeah. Yeah, no, we are definitely seeing that people that have gone through precipitated withdrawal are way turned off to using it. And there's other options too, but it's like there's regional differences, like in Baltimore, we have a lot of methadone clinics, we have a lot, there's pretty good capacity. That's not the case all over the US, for sure. And I know a lot of opioid treatment programs who just gave up on buprenorphine for a while, and we're just... Everybody that came in was going on methadone, because everybody's fentanyl positive, and people are starting to use these micro dosing approaches or low dose approaches to get people safely on. Yeah, but still, you get a challenge with the people who just don't want it anymore. Somebody else had commented that they use micro dosing and don't start until 24 hours after the last use of fentanyl. Yeah. Somebody asked a question about using tramadol to bridge off of fentanyl to buprenorphine, and if so, what doses? So I have a tramadol slide at the end, so if you stick around till the end. I mean, that's how... We've talked about that too, because we... Well, we'll go through this later, but we did a clinical trial like bup versus tramadol versus clonidine for opioid withdrawal treatment, and tramadol was at least as good as buprenorphine, maybe better at treating opioid withdrawal in that study. And yeah, it kind of begs the question, like, why don't we just use tramadol as a bridge, or if it's straight up a detox... I mean, it's kind of like, what's your angle? If you're trying to get people onto buprenorphine, maybe you can switch them to tramadol for a couple of days, then do the bup. But if you're just... If you're doing a withdrawal treatment, maybe you don't need to do the bup at all. Well, you did also mention too about using hydromorphone, and that wouldn't be something that would really lend itself to clinical practice at this point. Yeah, it's funny, I mean, that's our thought about it too, but we had talked to people at NIDA about the same question, because now we have a study where the whole purpose is to induct people onto bup. People who use fentanyl onto bup, and it's a sleep study too, I won't go into all... It's a very complicated study, but we have this hydromorphone bridge built in, and that was my thing. It was like, why not make this more clinically relevant? And my contact at NIDA was like, well, if nobody does this and publishes it, it will never be clinically relevant, so why don't you just keep it in there, and maybe that gets adopted down the road. Okay. We have one question here too about, what do you do when somebody's having a COWS of 36? Because some patients can get violent with some withdrawal symptoms. I mean, we didn't have... We weren't... We don't keep a rescue full meopioid agonist for that study, at least we didn't at that point. So you just ride it out. It was like not... I saw a couple where the COWS got into the high 20s. This one where it hit 36 was definitely the worst I've ever seen. I mean, there's nothing you can do. If you can get them to hold down a CONVEDS, then you can try different combinations of CONVEDS. Yeah. I work on our inpatient withdrawal management unit as well, and we've had this happen in the past, and typically it's... In an inpatient setting, it's easy, especially hospital based, is IV fluids, but also giving... You can try giving an increased dose if they'll take it, try to max out that dose of buprenorphine, but also giving lorazepam or a benzodiazepine to help with some of those symptoms. And then... Yeah, I just didn't have those tools in my toolbox at that stage of the game. Later in the clinical trial, once we had done a lot more, we started keeping those kind of meds in house so that we could pull people out or at least make them more comfortable if it happened. Are you gonna be talking about macro dosing at all? I'm gonna talk about the concept of it. I don't have any data on it and I don't have any recommendations for it. Okay, because we do have a question on that, but I'll hold off on that. I can keep going with my slides a little bit. Yeah, I'll kind of go through some of these. So we've got a lot of questions in here, so I think the big ones were answered so far. Okay. Okay, so these are a couple of things that we... A lot of stuff that we just talked about. So for buprenorphine initiation and maintenance, there is this low dose approach, which some people call micro dosing. There's a different version of this where you actually use a full agonist as a bridge, but you actually micro dose during the full agonist, and I'll talk about that. There's a high dose approach, which Dr. Kmic just mentioned. I'm gonna mention it here, but I don't have any actual data on it, so I'm not gonna endorse it myself. And then there's the kind of opioid drought approach that we used in our study, in our case series that I showed there, where you're just trying to give people as much time away from fentanyl as possible before you start buprenorphine. And then there's some other considerations about maintenance that these folks who are using fentanyl daily generally have higher tolerance than the people who use oxycodone or other prescription meds or even heroin, and they're often requiring higher maintenance doses. And then there's also a very strong risk of relapse. There are new long acting buprenorphine injectables or implants that are available that give people long coverage to protect against relapse and overdose, and those medications really aren't being used as much as I think they could be, especially for people who use fentanyl who are at such high risk, I think could be a good strategy. So these are some potential strategies for low dose buprenorphine inductions. One would be to use Buprenex or an IM, intramuscular small doses of buprenorphine, just to get it on board without precipitating withdrawal. A similar approach, if that won't work in your setting, is to cut the film strips. There was a study published about cutting buprenorphine film strips that showed if you cut them in half down to one milligram, you actually still got pretty decent... Another word I'm looking for, each half was one milligram. It was pretty accurate, but then if you cut down to 0.5 milligrams, it got a little bit inaccurate, but I don't know, I think for the purposes of this low dose induction strategy, if your purpose is to just give them a little bit at a time, you could cut it down further if you felt more comfortable with that. The general idea is just to use low doses, several of them in a single day, just to build up buprenorphine in the system without kicking off too many fentanyl molecules off of the receptor and avoiding the precipitated withdrawal. The opioid drought method would use several concomitant medications and just wait until the withdrawal symptoms break through. This is more appropriate for like a residential or inpatient setting, because the timing can be very unpredictable. And I would say this is generally very difficult for patients, especially if you're trying to wait like several days before introducing buprenorphine. That's a long few days for them, often not getting very much sleep. They're never getting too bad withdrawal, but they never feel good either. And it just kind of wears on them. I just wanted to break in, because we've had a few questions about like using these other treatments that don't have an indication for opioid use disorder or opioid withdrawal based on the data 2000, but also going back to Narcotic Addiction Treatment Act, and then, you know, way back to the Harrison Act. So like using things like hydromorphone or the buprenorphine injectable medication, or maybe even, you know, the butranspatch or the buprenorphine, they're not technically allowed by the FDA. You know, they have to have an indication for pain for those other buprenorphine products. And I think a lot of times people will do that in a hospital setting, because they do have, patients often have pain as well. Right. Can you just comment a little bit, you know, when you've mentioned about somebody at NIDA talking about hydromorphone and... Yeah, I mean, this, you know, it's definitely an approach that carries some liability, right, if you're gonna go off the script. The only thing that's approved for opioid withdrawal specifically is lofexidine that I'm aware of. I think buprenorphine and methadone are generally approved for opioid use disorder. I don't, I'd have to look at the actual label to see if it was for withdrawal, but yeah. So then every medication outside of those FDA approved medications carries some liability risk. This was actually came up when we had run the tramadol study. That wasn't my study, it was some colleagues. I had come in on like the back end of it. And that was a bit of a criticism of the study was it was like, well, we know we could use tramadol, but why wouldn't we just use buprenorphine? Because that's what's approved. And then, you know, you're using the medication that's approved. And the problem from the research front is that it's like, if you wanna get a medication approved by the FDA for an indication, like that's a long and expensive process. And most of these drugs are generic like that I'm talking about. So who's paying for the generic drug to get approved for an indication, right? Like, and who's running the studies? It's a really big challenge, I think, right now in OUD medication development, because there's some drugs that we know work well in this population that we should be doing more rigorous clinical trials to actually show that they work and people are confident in prescribing them. Some of that work is being done, but there's a difference between like me running a clinical trial, which is already a very involved process and me running like an FDA grade clinical trial that could require multiple trials and the FDA can change their mind at any minute about what they wanna see. There's a lot of practical barriers there. Sorry, I think that was a bit of a tangent on my end. So quickly, I'll talk about macro dosing. There are some case reports that I am aware of of people just straight up using a high dose of buprenorphine to bypass the precipitated withdrawal. The idea here is that you flood the receptors with buprenorphine. So that even if you're kicking off fentanyl, basically you're occupying almost all the available receptors and that this counteracts. Like I said, I've heard of this. I've never seen it. I have never seen the actual data. I'm not advocating for macro dosing because if it went wrong, I think it would be a disaster, but maybe it would work. I just need to see research on it. But you could use a hybrid approach similar to this where you could use the low dose initially to get people safely onto bup and then go with a high dose with the hopes that you're gonna satiate quickly. And that would make more sense to me. I will note that in our previous study, we had several people who got up to 16 milligrams of buprenorphine and it didn't adequately suppress withdrawal. They never felt good on the buprenorphine. And like I said before, it was actually a taper study. So we were just getting them on for a few days to taper them back off. And most of those people actually were happy to be tapering back off. Like they just didn't like the way the buprenorphine had worked. Oh, Jan Waterman brought up a good point here. You are permitted to use a full agonist for 72 hours. To treat opioid use disorder. That's a really good point actually. As far as like data on the macro dosing, there was a study published as retrospective looking from an ED in Oakland, California, looking at that and they've had good results starting on that, but it was a retrospective study. Yeah, so in the San Francisco Bay area, that study I think was done in like 2018 or 2019. I don't think they had a lot of fentanyl there. They didn't, you can double check this cause I'm just going by memory. But I remember this study and I think they never talk about fentanyl in the study. They just talk about heroin. So I don't know if what they showed actually translates to the folks that we're seeing who are using fentanyl every day. I have colleagues out in San Francisco who say that now fentanyl is starting to pick up a lot out there. Whereas before they were just, even like on the East Coast, we're seeing a lot of fentanyl. They kind of weren't seeing it as much out there. It was still a bit of a novelty. Now it's becoming more regular. So it would just be interesting. Yeah, I mean, I would really like to see it. I would like to see it in like a, like I want to know how much fentanyl that people have been using. I want to know what their blood levels were when you start the macro dosing. There's just a lot of things I would, a lot of questions I would have about that. Right, and the only other one I can think of too would be John Mariani at Columbia, getting people onto the buprenorphine Xtend release. He'll give them a one-time dose. Like he's had a couple of case studies or proof of concept, I guess, where they get started on buprenorphine, a higher dose. And I believe it was just one day with the 24 milligrams of buprenorphine. Yeah. And then giving them the injection. I think that was published last summer. Yeah, I'd have to look at that one again. Do you remember if they talked about fentanyl at all? Oh yeah, because he's focusing his research on high-potency synthetic opium. Yeah, yeah, because they would be seeing it there. Yeah, I mean, maybe it works. Yeah. Yeah, that's part of the challenge of the COVID pandemic is that I have not seen colleagues from other universities in like two years. I went to a conference in December in person and that was like the first time I had seen people in forever. But you lose some like the back and forth about this kind of stuff when everything is virtual and you can't travel. So hopefully this will start to pick up soon. Let me talk real quick about these other slides and then we'll answer the rest of the questions. So just so that we're not totally focused on buprenorphine, methadone is still out there. I think that the pandemic, one of the benefits maybe of the pandemic is that they loosen some of the restrictions on methadone. We'd like to see, personally, I'd like to see some of those restrictions stay loose so that we can get people onto methadone during an opioid overdose crisis. It makes sense to get people in treatment. Methadone shouldn't precipitate withdrawal. I've talked to methadone providers about what the challenges are and the people who are coming in just have higher tolerance. It's hard to get them titrated up. I'm sorry about that. It's hard to get them titrated up at a fast rate. So there's some talk about running studies where you increase the dose much more quickly. There's a risk-benefit ratio there, right? Like there's some cardiovascular risk to that, but the benefit would be relapse prevention. But again, there's many parts of the country where methadone is not very available. So it's not a national answer right now. There's also, what does this do to opioid withdrawal treatment? So people who do not wanna be maintained on a medication like buprenorphine or methadone, what might their withdrawal look like? Possibly, probably more severe, probably longer. And there's at least what we've seen anecdotally is that these folks are tending to have a more pronounced post-withdrawal syndrome slash protracted abstinence syndrome. That's mostly characterized by mood swings, depressive symptoms, increased craving and insomnia. That can last for weeks or months after they've actually gone through withdrawal. And now that everybody's on fentanyl, we need a lot of these research studies that were successful for heroin or for oxycodone need to be, we need to see what works for the people who are using fentanyl, right? And what are some strategies that we can use there to improve treatment across the continuum of care? So one thing I did wanna mention, this is the Tramadol paper. This is from my colleague, Kelly Dunn and Eric Strain. So this was a randomized controlled trial of clonidine versus buprenorphine versus Tramadol ER for opioid withdrawal. And in this study, people came in for 21 days to a residential facility. The first seven days, they were stabilized on morphine. The next seven days, they were tapered using one of these three medications. And then there was a final seven days where you could observe the post-taper withdrawal period. All double blind, double dummies. So people are getting medication the whole way through. It just changes from placebo to active. And on the left here is Kyle's scores. On the right is Sal's scores or subjective opioid withdrawal. We're often relying on these more for clinical trials because it's a little bit more sensitive. As you can see here, the clonidine performed kind of the worst during the taper, which you would expect buprenorphine and Tramadol were very close to one another. After you take away the buprenorphine, there's a predictable rebound withdrawal that happens about two or three days after their last dose. And that didn't happen with Tramadol, which kind of one of the conclusions of the study was that Tramadol is really not inferior to buprenorphine as a tapering medication and actually could have some benefits post-taper. It doesn't seem to show that this rebound withdrawal syndrome that the bup folks have. So that could be another medication option, maybe as a bridge to get people onto buprenorphine, maybe to actually treat withdrawal. Questions also emerged for extended release naltrexone. Do you need to wait longer to initiate extended release naltrexone because the fentanyl is sticking around in the system? I don't know. Does the blockade from extended release naltrexone protect against fentanyl use as to the same degree as it does other opioids? There is people who kind of push that blockade to see if they can get over the hump and get euphoric effects. And maybe people who use fentanyl would be a little bit more risky in that regard. And then these are just some other kind of general treatment questions that we're very interested in for the folks who are using fentanyl. Do they have worse protective withdrawal, worse emotional dysregulation during recovery, worse sleep and stress and cravings? And then, so this is my last slide. And I just, I like to include this, just to think, people are working in different treatment environments. There's people who have opioid use disorder. There's not like one standard care for the treatment of OUD, right? Like, it's kind of like this choose your own adventure. And really, we need to get better at the entire continuum of care. There's definitely people who are more appropriate for residential programs and sober living environments. There's some people who are not interested in that level of care and who just want office-based service does mental health counseling, but figuring out how to really optimize these treatments to improve OUD outcomes, it's just so important during this current opioid crisis. So that's what I have. And again, I'd like to thank my colleagues from Johns Hopkins. And we have about four minutes to go through some more questions. I just wanted to ask one from a little bit earlier. I think somebody was, when you had mentioned about buprenorphine being the preferred medicine or more widely used medicine, they were saying, well, is that, are you actually saying you prefer that over methadone or suggesting that methadone is not recommended? Oh, no, no, no, I don't prefer any of them. I think it's like different strokes for different folks, you know, and I just, what I meant by that is that buprenorphine is the most often used, that the kind of idea behind buprenorphine is like, this is great, we can use this from an office-based setting because it's schedule three and there's less restrictions. But no, I mean, I'm a big fan of methadone treatment. I think that's the appropriate level of care or that's the appropriate choice for a lot of people. It's just like, you know, talking to people about their treatment goals as they're coming in and trying to match that to, you know, some evidence-based care that would work for them. One question about, do you have any data or studies on patients with higher use correlating with higher successful or stable maintenance doses? Clinically, I have not observed a correlation per se. So the thing is they have to have higher use correlating with higher success. Or higher doses of the buprenorphine. There was a buprenorphine. Yeah, that's what I'm interpreting here. I think there's some studies on that. Eric Strain did one like that for methadone years ago and showed a dose effect on relapse prevention. Somebody has to have done that in bup. I think what the studies are showing now are a lot more in terms of retention too. You know, different outcome measures. Maybe it affects opioid use. You know, it can decrease that, but definitely increases retention with higher doses. Yeah. Let's see. Will you treat fentanyl with higher maintenance dose of methadone or buprenorphine compared to heroin and other opioids? So I think that's kind of the same question. Do we need higher doses when somebody's using fentanyl? Yeah, I mean, the providers I talk to are all, especially the methadone folks, they're just using higher doses now. Okay. There's one question. How about inductions from methadone to buprenorphine if patients prefer not to go to methadone clinic and would rather transition to buprenorphine? Would a similar protocol of waiting 72 hours after last dose of methadone to start induction given relatively long half-life of weak agonism of methadone? Yeah. Actually, these like low-dose approaches were initially developed for methadone to buprenorphine transitions, so it should work. There's a couple of papers out on that. It's the Azor method and the Bernese method, but essentially it's the same. You're just trying to get at least 72 hours and you're using super low doses. Methadone's hard too because it's metabolized. There's a lot of variability in the way it's metabolized from person to person, so that gets unpredictable. But I think as long as you're microdosing and waiting enough time, you should be okay. Right, and the induction guidance that we'd received early on, from when, after buprenorphine was first approved, it was always with methadone starting at these lower doses, like two milligrams, and you want to wait at least 36, sometimes longer hours after their last dose of methadone and have them tapered down. But now there are, like you said, these other methods where they might be able to start and descend their dose of methadone while getting small doses of buprenorphine as well. Yeah. Well, I think that's all the time we have today. I want to thank you so much for this presentation. It's been very interesting. We've had a lot of good comments and feedback about it, that this is very helpful and timely because of the fentanyl problem that we have and having difficulty getting people on to buprenorphine. So thank you so much. I wanted to mention to everybody here that our next webinar is next week on April 20th at five o'clock. And Dr. Robin Polini, a researcher from West Virginia University, is going to present a webinar on drug stigma and health. And I'd like to thank the Opioid Response Network for being a partner with AOAAM and for SAMHSA for funding this initiative. So please join us next week for the webinar. And to get your CME certificates, go back to the website and complete the survey. Thank you, Dr. Hoon. Great. Thanks, everybody.

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