Hi, welcome everyone. I'm Dr. John Mariani. I'm going to be talking to you today about managing opioid use disorder in the era of fentanyl. I'm on the faculty at Columbia University Irving Medical Center and New York State Psychiatric Institute. Little housekeeping, this event is being brought to you by the PCSS MOUD program. Content and discussions during this event are prohibited from promoting or selling products or services that serve professional or financial interests of any kind. I have one disclosure to make, which is that I have served as a consultant and received speaking fee from Indivier, which manufactures a product that is talked about during this presentation and this relevant financial relationship has been mitigated. In certain instances where medication's only available from a single manufacturer or there are different proprietary formulations of a type of medication, which we'll talk about today, injectable buprenorphine, we've at times used brand names to help distinguish the different products in that space because their generic names would not distinguish how they're different. I've used a generic name followed by the trade name in parentheses on the slides. This is in no way meant to endorse any commercial entity, but is done in the interest of understanding by the audience. The overarching goal of PCSS is to train healthcare professionals in evidence-based practices for the prevention and treatment of opioid use disorders, particularly in prescribing medications, as well as for prevention and treatment of substance use disorders. Our educational objectives for today, at the conclusion of this activity, we're hoping that participants should be able to identify aspects of fentanyl pharmacology that complicate opioid use disorder pharmacotherapy, review the data supporting the use of medications for treating patients using fentanyl with an emphasis on extended release injectable products, and discuss other clinical strategies for managing fentanyl-using patients. So why talk about fentanyl? Well, fentanyl use is a critical public health problem in the US that's led to a dramatic rise in overdose fatalities. There's been a collective loss of confidence in the proven treatment methods in the clinical and in somewhat patient communities. And this uncertainty is driven in part by a paucity of scientific evidence. And I'll get into this more specifically during the talk, but basically clinicians and patients have a lot of questions about using buprenorphine when fentanyl is the primary drug being used. Clinicians, patients, and families and policymakers are unsure of how to address this rapid and deadly change in the nature of the US illicit drug supply. So just illustrative journal article titled, Everything's Not Right Anymore, Buprenorphine Experiences in the Era of Illicit Fentanyl. And I think that message, the idea that using fentanyl is a different experience for patients and treating them is different, I think is something that I've certainly witnessed in my own practice. But as I go through the presentation, objective evidence supporting that is not in large supply, at least presently. But we're gonna pull this apart as we go through the talk. So I'll just talk a little bit about my own experience. In September of 2017, I had a patient who was able to override a naltrexone blockade, extended release naltrexone injection blockade, despite that they were getting it every three weeks. And they were using fentanyl. It was able to reestablish the blockade when I returned the injectable naltrexone to every twice a week dosing, which is not what the package insert says to do. But I was able to reestablish opioid blockade with that dose. I also around the same time had two private patients who were very experienced with being treated with buprenorphine and they had nothing to do with each other. And it was actually the same day that I saw them. And they had the same kind of general experience that they reported where they had discontinued buprenorphine, they used heroin for several days, and then withdrawal symptoms didn't start in the normal timeframe, it was delayed. And then when they tried to start buprenorphine again on their own, two or three days after the last use of heroin, they precipitated withdrawal. And then in the research clinic that I run, we were in our staff discussions, noting that we were having a little bit more trouble with the first day of buprenorphine treatment. And so we said, well, let's start testing all the patients in the clinic, the research clinic who are reporting using heroin and see whether they're positive for fentanyl. And 90% of them were positive for fentanyl, which we hadn't been testing for, we didn't realize it. So this was back in September of 2017. And 2017 is really the year in New York City that fentanyl really penetrated the heroin supply. And what we're seeing nationally is that overdose deaths continue to rise. They're, you know, this is, you know, through the pandemic and even after, you know, we're seeing continued rise in overdose deaths. It's, you know, mainly, you know, it's both genders, it's being, it's mainly due to opioid use. And I'll show you in a second that it's mainly due to primarily fentanyl. So fentanyl is the green line that you see, you know, kind of taking off after 2016, 2017. And I mean, there are other drivers of this. You see a relatively sharp increase in psychostimulant, you know, particularly methamphetamine use leading to overdose, increased overdose deaths. But fentanyl is the prime driver for the overdose crisis we're having in the United States right now. So one question is why are so many people dying? Well, you know, fentanyl and other highly potent synthetic opioids, and I'm gonna probably mostly refer just to fentanyl during this talk, but there's a whole group of fentanyl analogs, drugs that are like fentanyl, have similar structure, and even some other highly potent synthetic opioids have different structures. But really what these drugs all have in common is that they're extremely potent, they're highly lipophilic, and they're just more dangerous to take. Fentanyl is probably 50 to 100 times more potent than morphine. Carfentanil, which is a fentanyl analog, is probably 10,000 more times potent than morphine. And so this high potency for fentanyl has implications for both the overdose risk and also how effective standard opioid use disorder treatments, particularly pharmacotherapy, are. So just looking at the mu opioid receptor, you know, morphine binds to the receptor, you know, there on the top, that's outside the cell, and that, you know, the receptor subunits then move in space in response to being activated and then, you know, cause the result of opioid agonism inside the cell. So you have basically, that's how opioids work on our bodies. And, you know, what is fentanyl doing different? Well, fentanyl is getting into the central nervous system very, very quickly. They're highly lipophilic. That's what they were designed to do. They rapidly cross the blood-brain barrier. The other thing that they do is they rapidly distribute to the peripheral tissue and then have a slow return to the central compartment. So fentanyl is potent for a number of different reasons. There are different pharmacologic characteristics. The first thing is that fentanyl and its analogs are highly lipophilic. They are, that's how they were designed. They get into the blood-brain barrier very quickly. What they also do is get into the peripheral fat tissue also and we're gonna come back to this a little bit, but one of the phenomena that occur with chronic fentanyl use is that you have a accumulation of fentanyl in peripheral fat tissue. And then that, even when patients stop using, the fentanyl returns to the central compartment gradually and is, because it's such a potent drug, even in low levels, it's active. It's very highly efficacious. And the concept I wanna raise here is that when it binds to the receptor, it's doing something different. I'm gonna go back to the last slide for a second. When we see where morphine is here, when fentanyl is interacting with these subunits of the receptor, the conformational change, that the three-dimensional shapes move past each other is different and you just get a different amount of opioid agonism from, if you compare one molecule of fentanyl activating one opioid receptor, you get a higher degree of agonism from that, from one molecule of morphine activating the receptor. So it's not a receptor affinity issue, which is something that we talk about with buprenorphine. Actually, fentanyl has a lower mu-opioid receptor affinity than buprenorphine, which is why buprenorphine precipitates withdrawal in patients who are using fentanyl because it displaces and stays stuck on the mu-opioid receptor. But so it's not receptor affinity. It is this idea of being more efficacious, basically, in the nature of the interaction with the receptor. But some of this is theoretical and we ultimately don't know exactly why fentanyl is more potent, but that's our thought. So conceptually, and these numbers are not precise, this is just to illustrate this point. If you wanna think about one molecule of morphine causing 100 units of opioid agonism, buprenorphine, which is a partial agonist, when it activates the mu-opioid receptor, you only get 50 units of opioid agonism. But when fentanyl, one molecule of fentanyl binds to the mu-opioid receptor, you get 150 units of opioid agonism. So what you see is that fentanyl's more potent than morphine but also, and we'll come back to this, when buprenorphine displaces a fentanyl molecule from a receptor, you get, the delta is bigger. So you're dropping from 150 units to 50 and that's in some ways why the precipitative withdrawal potentially is more severe with fentanyl when using buprenorphine. So there's a lot of implications for the standard dosing of current opioid use disorder medications. The medications that we use, methadone, buprenorphine, naltrexone in various forms, they are always leaving some of the receptors unoccupied and the dosing that we develop for people using oxycodone and heroin is probably not appropriate, I think, for fentanyl because relatively fewer unoccupied receptors by the therapeutic drugs, fentanyl can get on and then still cause clinically relevant opioid effects. So we'll talk more about this as we work through the presentation. So what's the impact of fentanyl on existing treatment approaches? Well, medications for opioid use disorder are the standard of care. The main medication treatments, buprenorphine, methadone, naltrexone, all act on the mu-opioid receptor. The unoccupied mu-opioid receptors are an opportunity for fentanyl to cause opioid effects and chronic exposure to higher potency opioids lead to a greater degree of physiologic dependence. So another consequence of chronic fentanyl use is you're just exposing the central nervous system to a higher degree of opioid agonism than maybe you would experience with heroin or certainly oxycodone. And the other last issue is, just circling back to this idea of chronic fentanyl use leading to accumulation of fat tissue and then getting re-released back into the systemic circulation. And then those relative low levels, even though they're low, because fentanyl is so potent, they still can have a clinical effect. So let's talk about buprenorphine treatment just in general. So buprenorphine is currently in the United States available either as a sublingual medication or a long-acting injection. It is a so-called partial agonist at the mu-opioid receptor which basically means it doesn't cause as much agonism as standard full agonists like morphine or methadone or oxycodone or fentanyl. In some ways, fentanyl in that model is like a super agonist in that it's causing more agonism than what we think of full agonist causing. Buprenorphine has a very strong receptor affinity for the mu-opioid receptor compared to other studied opioids. And this is really like one of the reasons why buprenorphine is such a great drug for treating opioid use disorder because it out-competes other opioids and stays stuck on the receptor and in effect blocks it. So it's both activating the receptor partially which helps treat craving and withdrawal, but it's also acting as a block on using other opioids. Now it depends on the dose because it depends on the fraction of the available mu-opioid receptors that are occupied by buprenorphine. So it's a very dose dependent phenomenon, but the higher the dose of buprenorphine and certainly at very high doses of buprenorphine, you can really occupy almost all the receptors. One way to think about it is, I described drug receptor interactions like a key in a lock, right? There's a three-dimensional relationship in space, only a particular key will open the lock. Buprenorphine, when it goes in the lock, it kind of turns the cylinder a little bit but gets stuck. It doesn't really fully activate it. And so, and then it doesn't come out. Then the key doesn't come out, so another drug can't get on. And so this, you're providing both agonism that reduces craving withdrawal and you're also blocking the ability of other opioids to act on the opioid receptor. So then what's happening with fentanyl users? Like some of those cases I described early on from back in 2017, what were those patients complaining of? Well, we don't really know. And I'll show this a little later in the talk. There's not really systematic evidence that this is happening. There's a bunch of case reports that clinicians are reporting, and I've certainly seen this too, that it seems like the use of buprenorphine is different with fentanyl. And this is probably due to its pharmacokinetic and pharmacodynamic properties. Now, whether that really changes the outcome of treatment is a different question. But I think subjectively, it feels a little bit different. Fentanyl is very high lipophilic, it accumulates in adipose tissue. So even though fentanyl does not have a long half-life itself, effectively, when you use it chronically, it turns, it looks more like methadone. It turns into a longer half-life drug because even after you stop taking it, there's like a reserve supply, a reservoir of it in the fat tissue that keeps getting released. So if you stop using on Sunday night, maybe you'll start having withdrawal the next day, but there's still a lot of fentanyl around. And pre-fentanyl, I used to tell patients, you can start buprenorphine 12 to six hour, I'm sorry, 12 to 16 hours after your last dose of a short-acting opioid use, like oxycodone or heroin. And if you're long, you're having some mild to moderate withdrawal, it doesn't have to be severe. If that amount of time has passed and you haven't used and you're feeling a little bit sick, not terrible, you could take buprenorphine and you're gonna be fine. That really isn't reliable, that time course isn't necessarily reliable with fentanyl. And it seems to be because there's enough of it around still that when you take buprenorphine, you're displacing fentanyl from the receptors and you're having that drop in opioid agonism because buprenorphine does not activate the receptors to the same degree fentanyl does. And the difference is bigger than even when you would displace morphine with buprenorphine So that's the mechanisms, any kind of buprenorphine precipitative withdrawal is displacement of a drug that has greater agonist properties with buprenorphine just leads to like an abrupt reduction in the amount of agonism and that's withdrawal. So what are the clinical difficulties of inducting fentanyl using patients onto buprenorphine? Well, there's been a bunch of case series, but there was this big study that came out recently, this trial is not over yet, it was kind of like an interim report of 1200 enrolled patients that most of them were fentanyl positive and they only recorded like having very strict criteria for precipitated withdrawal. They only reported nine cases of precipitated withdrawal, which is not that many for that size of a population. And so what does that mean? Well, I still think that the withdrawal time course is more protracted due to this third space effect through fentanyl accumulating in the fat tissue. I've seen patients hospitalized in a research study, search very thoroughly, not using, be positive for fentanyl eight days after admission. If you do look at the literature, you can see examples of longer than that. I would not say that the fentanyl status, the fentanyl positive status necessarily indicates the risk for precipitated withdrawal because these patients I've given naltrexone to, injectable naltrexone to, which is a full antagonist and then be able to tolerate it. So urine testing doesn't necessarily tell you, and you can't get quantitative levels of fentanyl back quickly. So urine testing, I don't think in my view, the current technology doesn't really tell us whether you can start buprenorphine or not. I still think it's more of a clinical decision of just waiting till the person's having significant enough withdrawal symptoms. And then I think, I'm gonna give you some evidence for this, but then I think kind of just pushing through, even if they have some mild withdrawal after you give them buprenorphine and just keep going. So the difficulties, the tendency for buprenorphine to cause precipitated withdrawal, and I'm somewhat contradicting myself saying that there's this large study that didn't see a lot of it, but when you talk to clinicians, they say it's a big deal. I think both things are true. I think if you're applying very objective kind of dispassionate standards, you don't see a lot of bad stuff happening when you give buprenorphine to people who are fentanyl users. Like it's not that bad. On the other hand, if you talk to clinicians and talk to patients, particularly people that have experience for a number of years, it does feel different. So I think that there's a subjective difference, although it's probably not that meaningful clinically. It seems like it is, but there's not evidence that it is yet. And so I don't think one perspective is necessarily right or wrong. I think both are true. I think that it feels different, but I don't think in the end it's that big of a deal that you should abandon the buprenorphine induction. And so I think you have more under the current situation where people are confused and worried about this. I think you see more failed initial inductions where the patient and the clinician both lose confidence in what they're doing. And I think you see more of what I would call secondary inductions, which is patients who are taking sublingual buprenorphine, they know how to restart the medicine. They've done it before on their own, but they've lost confidence too because they're afraid they're gonna get sick. So here's another, like a letter to the editor from a couple of years ago, like, should you even use buprenorphine for fentanyl treatment, which I think is not the case. I'm not advocating this, but I think the fact that this kind of thing is showing up in the literature is evidence of the confusion and controversy that we're kind of dealing with right now. So, does fentanyl affect opioid use disorder treatment outcomes? Not is there some subjective differences with how induction is used to go pre-fentanyl, but is there any evidence that the treatment outcomes are different? And the D'Onofrio series of 1,200 patients, no, those patients did fine. And there's a few other chart reviews and other multi-site trials that have not, we've not seen big studies that are applying objective criteria for kind of a failed induction or precipitative withdrawal, seeing very significant issues, right? Which I think is reassuring. That doesn't mean that there's not some subjective differences in treating patients who are using fentanyl with buprenorphine. I do this a lot. I think there are subjective differences. It's just that it doesn't, I don't think that it means that we need to rethink what we're doing from start to finish because there's not any evidence that we need to do that yet. So, a little kind of just argument in favor of buprenorphine for treating fentanyl users. This was an intravenous study of buprenorphine to kind of just look, can it block fentanyl? And it does. Giving high dose buprenorphine can interfere with respiratory depression from fentanyl. So, buprenorphine is a good drug to have in your system if you're going to use fentanyl because it has the potential to inhibit the problems with respiration. So, an area that I want to talk about is the use of injectable medications, injectable buprenorphine medications for treating opioid use disorder, in particularly with regards to fentanyl users. So, buprenorphine became available in the United States in 2002. It was approved in 2002. It became available a year or two later. And, you know, it's an effective treatment. It's been adopted widely. You know, the main disadvantage is a sublingual form of noncompliance and diversion. We can debate how much of an issue that is. I think noncompliance is probably a bigger issue. There was an injectable version, and we're calling for this presentation BXR, extended release buprenorphine, buprenorphine extended release for injection. The first, and this is one of those examples that we're using some brand names just to distinguish the products because they're different, sublicate was approved in 2017. It was available commercially starting in 2019. Comes in two strengths, 300 and 100 milligrams, and it's a subcutaneous abdominal injection every four weeks. There was another buprenorphine extended release product that was approved by the FDA in 2018, although it only became available last year in the United States. It's been available in other countries under the brand name. So, the brand name in the U.S. is Berksotty. It was in other countries under Buvidal. It's been available for a few years in the EU and Australia. But for reasons we're not going to get into, even though it was approved, you weren't able to, actually, it wasn't available on the shelves until middle of 2023. This is a different drug, and this is one of the reasons we're using the brand names just to distinguish them because their strategies, their dosing strategies are different. Berksotty has both weekly and monthly injections available. Sublicate only has monthly, and the weekly is available in these strengths that you see on the screen, 8, 16, 24, 32, and the monthly is 64, 96, and 128. There's various, according to the package insert, you could do abdominal, but you can also do some other sites like in the arm or the buttocks. You could do other subcutaneous injection sites. So, just comparing these two different formulations, they've not been compared in any studies, and even the studies to get them approved are hard to compare to each other. Berksotty was non-inferior to sublingual buprenorphine, and sublicate was superior to placebo. So, Berksotty was compared to an active comparator, sublingual treatment as usual, and sublicate was compared to placebo. I would just, for the sake of thinking about this, is that they're both effective treatments for treating opioid use disorder, and if you're going to distinguish them, maybe it would just be on the dosing differences that you have. So, Berksotty is, again, available in weekly and monthly formulations that gives you good dosing flexibility. Because sublicate's been out longer, and I have less experience with Berksotty, although I participated in the clinical trial, the registry trial that got approved. I'm not sure, I mean, the induction recommends using the weekly. I'm not sure if that's really going to be necessary in the end, but that's how they got it approved. I'm not sure, like when I give injectable products, I prefer to give things that are longer acting, like that's part of the benefit. I'm sure there will be use cases where why a weekly injection could be helpful. I couldn't tell you that yet, what that is. But I think these are two long-acting injectable buprenorphine products, and it's great that we have them. I'm going to talk a little bit about it, why I think that they're good for fentanyl users. The package inserts, sublicate, you need to be on sublingual buprenorphine for seven days before you give the first injection. Berksotty, that's how it was studied. I think that there's been some other studies that have shown, including ones that we've done at Columbia, that have shown that that's not... Small studies to give it sooner in the process. Berksotty was studied by giving a single four milligram sublingual dose of buprenorphine followed by two smaller injections during the first week. It's great to have these options, but there's a lot to be learned. One question I have is, should all patients be getting one of these products to start with? We don't have data yet suggesting that these products are superior to sublingual, and we don't know who the subgroups are, if there were differences that would be, but I think that's a question that needs to be answered in the next few years is, is it everybody? Is it some subgroups of patients? Potentially that you should go straight to the injectable product. I guess what I'm saying here is the tendency when new drugs come out is to the standard treatment, the people who fail standard treatment get the new product. That's certainly something to do here, but I think as we get more information, we'll learn more about people who should probably be started on injectable right away. For the buprenorphine extended release, sublocade version, this is some dosing. If you're converting people who have been on standing sublingual doses of buprenorphine, like what the injection schedule should be, this is taken from the package insert. Same idea for the BXR version of the Bruxade version of extended release buprenorphine for injection. This is another conversion table. Again, I'm taking these right from the package insert, so you could refer to that, but some guidance on how to gauge the dosing when you're converting people from sublingual to the extended release product. This is some blood level data. There's a busy slide, but I'm going to say the top row, draw your attention to it. If you look at the C average in nanograms per ml, you see 24 milligrams of transmucosal buprenorphine at 2.84. The steady state, this is not after one injection, but the steady state of the 300 milligram sublocade, you see that you're at 6.32, which is a little more than twice the blood level of the 24 milligram sublingual. If you look down, the next lower box is for Bruxade. If you look at the C average for Bruxade monthly, you see it's a 3.9, which again is maybe one and a half times a 24 milligram sublingual dose. A property of these injectable products is that for some patients that it's clinically appropriate to do so, you could reliably deliver relatively high doses of buprenorphine, arguably higher than what people would take sublingually. I find that patients, if anything, tend to take too little sublingual buprenorphine. I think in the fentanyl error, I think having more buprenorphine on board for cases that it's appropriate to do that is an advantage. That's true for both of these products. This is just what the dosing curve, like what the pharmacokinetics look like. This is the sublocade version of VXR where on the arrow pointing up at the bottom is when they got the injection. You see about 24 hours later, you get a peak. Then after a couple of days, it drops. Then you see a day 28 when they got the next shot over here, you see that the baseline now is higher. Each dose lasts longer than a month. You get this stacking effect as you give each injection. This is again for the sublocade version of VXR. You see the dark blue is like the 300 milligram strategy and the light blue is the 300, 300 followed by 100 milligram every month dosing strategy. You see that it takes a while to equilibrate. This is after six months, you're getting that very high plasma level of the 300s. Then the 300, 300, 100, you get something around two nanograms per mL, which is probably around 16 milligrams or so, the sublingual. I've treated a lot of patients with this medicine. These drugs are different than the sublingual because you get this accumulation and the dosing, it's imprecise. It's hard to really know where they are. I guess you could draw blood levels. I haven't done that, but it's more based on side effects and your intoxicology results. Is the person still using? I tend to keep going up like you would do with methadone. If the patient is having side effects and not using, then there could be a reason to back off and lower the dose. In terms of discontinuing, this is again with BXR version, the supplicated version of BXR, where you see this is modeled so it looks smoother than it is in practice. I'll just draw your attention to the bottom graph. This is at 32 weeks is the last injection of 300 milligrams. They're still above the two nanogram per mL line at 52 weeks. That's 20 weeks later after getting their last shot. They're still on what is probably quite effective dose of buprenorphine. This has a lot of implications for clinical treatment. One is even if patients miss doses, the blood level does not drop that fast, which is different than say extended release naltrexone where really after that three to four week period, the drug is ineffective. These drugs last a long time. There's probably for a particular kind of clinical situation of discontinuing people from sublingual buprenorphine, this kind of like very gradual decay in the blood level, I think is a good fit for that. This is the Brixati version of BXR. This is the weekly form, like with the different dosing curves. Again, the same thing, except it's only over a week. We look here, you're going to see on the same kind of stacking effect that you get when the left-hand graph you're looking at, other than the circle points, which are the weekly form, the squares and the other sharp angled ones are the monthly version, which is the same thing where you get this kind of consistent blood level throughout the month. Switching over to methadone. Methadone is an orally administered medication used to treat opioid use disorder. It's a full opioid agonist with a long half-life. It acts as an opioid agonist therapeutically. Methadone reduces craving and treats withdrawal or prevents withdrawal. It does not really block the effects of other opioids, but rather patients on methadone are receiving a lot of opioid agonism that basically raises their tolerance out of the reach of other opioid agonists. You don't have the same precipitated withdrawal issue as you do with fentanyl, like with buprenorphine, because it doesn't block anything. There's really minimal literature on fentanyl users with methadone. In many ways, methadone is a good fit because of the degree you're worried about precipitated withdrawal. I think what I would predict, just knowing the pharmacology, I think that the adjustment to make is that fentanyl users are likely to need higher doses of methadone to achieve clinical stability, but we don't have a lot of information about that. There's been more renewed interest in methadone recently. There were some prescribing regulations that were loosened during the pandemic. Some provisional evidence that limited harm came from less regulation, but there's not a lot of scientific evidence yet. Clinicians view it as easier to use than buprenorphine for treating fentanyl users, certainly in terms of those initial doses, but I don't know that methadone as a treatment overall is just an easier treatment to access. Excuse me, compared to buprenorphine. We're in a period of time where there is advocacy going on to regulators to widen access in response to the fentanyl overdose crisis. My personal opinion is I think there's an area that there should definitely be more studies conducted. I think we need to know more information about it and maybe liberalizing access to methadone could be part of the response. I have trouble believing it's the primary mechanism though. What about extended release naltrexone for injection, which is available in the United States under the name Vivitrol? The oral formulation of naltrexone was approved in 1984 for opioid use disorder, but the evidence that oral naltrexone is effective for opioid use disorder is not there. I mean, in some studies, if you do it, monitored oral administration can have some benefit, but just prescribing oral naltrexone for patients with opioid use disorder doesn't seem to really have any benefit. Extended release naltrexone for injection was approved in the US for opioid use disorder in 2010 to IM gluteal injection every four weeks. Some situations give it every three because there seems to be a decay in the blood level that last week, which is probably more relevant in the fentanyl era. It's an evidence-based treatment. I can say personally, I've treated many patients. I've participated in a lot of research studies using extended release naltrexone. It's a good treatment. It's been shown to be associated with increased treatment retention, decreased relapse, decreased cravings, outpatients, inpatients. The trick in using it, the difficulty in using it is you need this opioid-free period of at least seven to 10 days to avoid precipitated withdrawal to get on it. You can't give an antagonist too soon after someone has been using an agonist. We've done some work using a shorter induction onto naltrexone, but that data was collected pre-fentanyl. I'm less sure that that's possible with fentanyl. We don't have good data about using vivitrol during the fentanyl era. This is some data that we had in a study where we were getting fentanyl users onto vivitrol. What I would point out here is not the relative difference. This was a study looking at a drug called lacasarin versus placebo. That part, I don't think, is of interest here. Lacasarin is off the market now. I would just say that the rates of induction onto extended-release naltrexone for fentanyl-positive users were fine. They weren't really lower in this study. The numbers are small, so I don't want to make any comparisons, but we were able to do it. I wouldn't say that you can't get people onto extended-release naltrexone that are using fentanyl. There's an experienced research clinic in dealing with this, but I would say that it's possible. This was another study that we did. What was interesting was the patients being fentanyl-positive, we were able to get 57% of them onto, they got the first injection of extended-release naltrexone. The thing I'll also point out, just from a point I made earlier, that seven of the eight using fentanyl participants that we got onto vivitrol were fentanyl-positive on the day of the injection. The status of the urine test for fentanyl doesn't really tell you whether you can successfully do this or not. These patients all had naloxone challenges before getting the extended-release naltrexone injection. These are small studies. I'm just using as an example that it is possible to use extended-release naltrexone in patients who are using fentanyl, but there's not really a lot of data available on that. These are small studies. Naloxone, which is used as an overdose reversal agent, is a mu-receptor antagonist. When fentanyl became available in the community, there were a lot of reports, I think many people have heard of this already, that multiple doses of naloxone have been required to reverse overdose. The length of time between substance use and death seems to be shorter with fentanyl. Patients die faster. That's one of the problems with fentanyl overdoses is that you have less of an opportunity to revive patients. There's been a recognition of this problem with naloxone, and there's now higher doses of naloxone available. There's a four milligram nasal spray now, which is a higher dose than it used to be. Then there's this much higher dose now where you have this by prescription. Naloxone's over the counter now, but it's under the trade name Galoxido, which is a naloxone kit that's eight milligrams, but only available by prescription. There's also some efforts to modify naloxone to make it more lipophilic. Early stages of this, but certainly there's been innovation in this area to try to reformulate naloxone to be more effective against fentanyl overdoses. Okay, so what are the best practices for managing fentanyl using patients with opioid use disorder? Well, there's limited evidence-based recommendations on how to treat fentanyl users. PCSS has some clinical guidelines. If you go to the PCSS website, we put out some guidelines on this topic, but I'll tell you, because I participated in helping to write them, there's not a lot of hard science backing up some of these recommendations. There's some science, but we're early in understanding this phenomenon on how best to treat it. I think a trend has been to say, well, we have to throw out everything we know and do all these other strategies using low-dose strategies or rapid high-dose strategies, and there could be circumstances where those are good things to do, but there's really not a lot of evidence supporting that either. I'm going to just run through them a little bit just to review what we know and what we don't know, but I would say, and this is what the PCSS guidelines that we came out with say, is generally speaking, you want to use the standard evidence-based approaches for treating opioid use disorder with the mindset of modifying them based on the clinical circumstances, but the fentanyl positive status of the patient doesn't mean that everything that we know about how to treat opioid use disorder is no longer relevant. There's been a bunch of case studies looking at low-dose. I resist saying microdosing because it's not microdosing. It's not micrograms. It's not micro amounts of the drug. It's lower doses than we normally use, like maybe half a milligram rather than four milligrams to start the induction. These are strategies that were adapted from converting people from methadone to buprenorphine with the idea being that you gradually introduce small amounts of buprenorphine and slowly occupy more and more of the new opioid receptors. If you start low and go slow, you don't precipitate that much withdrawal. I think that there's a logic to doing that with fentanyl. I said earlier in this talk that chronic fentanyl users in a lot of ways look like they're on methadone because they have this potent drug that lasts a long time in their system and it's easy to precipitate withdrawal. I understand why people are interested in that, but there's not a lot of data to support it yet. I would say that the problem with it is that it extends over multiple days and you're not on a therapeutic. You're delaying the time to getting to somebody for a therapeutic dose. There's consequences to that also. An alternative approach has been looked at is like a high-dose strategy, like go up to 20 milligrams on the first day. There's been a few studies in ERs doing this and giving a starting dose. They're not seeing a lot of precipitated withdrawal with that. There's a chart review, not a prospective study. There's people experimenting with different approaches and there's evidence developing. I think over time, we're going to know better which approaches maybe for which patients and also in the setting, which setting you're in, I think impacts this also. If you're in an inpatient detox and you have all the time in the world, if you delay, if you prolong the induction for five days, maybe it doesn't matter. If the person's outpatient and you just give them a little bit and they're leaving, maybe that's not so great because maybe if you got more buprenorphine into them, they would be protected until the next day. That's just speculation on my part. I think we don't have data on this yet, but it's good that people are interested in trying to figure this out. Just to summarize the state of the evidence for these standard low and high-dose buprenorphine inductions, there's no published prospective controlled studies examining treatments for fentanyl users. There is no evidence base that's like A-class evidence for treating fentanyl users. We don't have it yet. Nearly all the evidence is from case series and retrospective chart reviews, which are limited in extrapolating to all situations. While fentanyl is certainly more deadly, the clinical management seems to be subjectively different from heroin or oxycodone, there's not evidence that the standard treatments are less effective. Now, that doesn't mean that evidence isn't going to emerge. That could be the case, but right now, that's not the case. I'm going to give you some preliminary evidence for some other approaches to think about too. I've been involved in some of this, putting people onto extended-release buprenorphine rapidly. These extended-release buprenorphine products were in development before fentanyl came around, but now that we have them, I personally think they're a good fit. We've been interested in developing a protocol to giving the sublocated version of BXR in a single day. We did five patients where we did them in two or three days. Remember that the package inserts, as you're supposed to do over seven days on sublingual buprenorphine before getting the shot, we took a few patients, five patients that were fentanyl users, we put them within two or three days on the 300-milligram shot after some sublingual dosing, and that went well. Then we said, why don't we do it in one day? We did five patients on a one-day induction. We have R21 looking at a larger population where we're comparing this approach to just sublingual standard treatment as usual. We don't have the results of that yet. We're still running it. On another study, at the bottom line there, I'll collect 19 emergency department patients received four-milligram sublingual buprenorphine and then the sublocated 300. That's the same strategy that Brixada uses just to give four milligrams and go right to the shot. I think that's probably where things are going to go. If I had to redesign the studies that we ran, we were giving like 24-milligram sublingual before we gave the shot all in one day. There are some advantages to that because you don't have to supplement afterwards. That's a lot of buprenorphine, but my view is it's better to give people the injection as soon as possible. So I like just four milligrams test dose and then moving towards it. This is some other secondary analysis that I wrote up based on a clinical trial. This is not perspective. This is just a convenient sample looking afterwards at a single-day induction of the sublocated version of PXR, four-milligram sublingual followed by the injection. Just looked at people who are fentanyl positive, fentanyl negative and see how they fared. What's interesting is both of them did fine with this. This is all like the first 24 hours where they got sublingual here, they got the four-milligram sublingual here and then got the shot here and then they were fine. That's really what we saw in the small open series that we did where once patients get the shot, they're really okay. I think that there's something about the first little bit of buprenorphine can precipitate withdrawal, but then more buprenorphine basically just overrides it. I think that this is going to be the way to go to just get people onto buprenorphine. There's another study that's ongoing now looking at this strategy of the four milligrams followed by the shot. Who are patients that would be good to give the extended-release buprenorphine products to? The key issue is that these are drugs that reliably provide effective medication for a prolonged period of time, which is a great thing for people with substance use problems who are at risk of overdose. I think clearly patients who are non- or partially-compliant, I think it provides protection. It also, in cases where diversion is a risk, it eliminates that risk also because the patient doesn't have any medication. However, there's limited clinical trial data comparing the oral and sublingual formulations and we don't really know which subgroups really differentiate, respond to one treatment versus the other. There's also no data comparing the different injectable formulations, although I think that's harder to show because they're pretty similar. Most clinical trial data that we have just in general for treating opioid use disorder was collected in the pre-fentanyl error. How best to treat fentanyl-using patients is mostly unknown. I've given you my interpretation of the literature and my research experience and my clinical experience treating these patients. I talked to lots of other clinicians about these problems. Some people have other views that differ from mine. Some people have the same. We don't know. I think sometimes there's also geographical differences in what the drug supply is like and certainly practice setting matters too. I think something that's easy to do in a residential treatment program or in a forensic setting is not the same thing to do in private practice or in a medical unit. I think there's lots of data that needs to be collected to guide clinicians on how to treat this problem. There's very limited data on BXR use in pregnancy. The concerns are mostly not over the buprenorphine, but the vehicle, like the gel that the drug is delivered in. I think in those cases, you have to weigh the potential unknown risks of the BXR formulations versus whether they're taking the buprenorphine or not. What about injectable naltrexone? Again, we don't have any comparisons. There's no studies comparing naltrexone for injection versus buprenorphine for injection in fentanyl users. This is mostly my opinion. I think it's easier to get people on to the injectable form of buprenorphine. It's just easier to get people on to buprenorphine than naltrexone. I don't have data to support this. I think that the overdose protection, particularly at high doses, because buprenorphine both raises the opioid tolerance and provides a blockade, is going to be better than Vivitrol. I think people, when they're on the injectable naltrexone, during the shot, there's some protection. I don't know if the current dose of how the available product for injectable naltrexone is on the market, the 380 milligrams. I don't know if that's adequate for fentanyl use, but certainly once the month is up, it's not active any longer. The extendedly released buprenorphine products, the monthly products, last longer than that. Who's the ideal injectable naltrexone treatment patient? Prescription painkiller users with low opioid tolerance I think are still good candidates. I think patients who, for some reason, either by preference or don't have poor reactions to buprenorphine, it's a good option. Who's the ideal injectable buprenorphine patient? Well, certainly patients who have failed some legible buprenorphine I think should get a trial of extendedly released buprenorphine for injection. I think fentanyl heroin users, I don't have data to support this, but I think that those are high-risk patients. As a clinician, just the idea that the patient has the drug reliably in their system, is a safer situation, even though I don't have data to support that yet. I think those are people that I'm thinking about. What's the role for extendedly released buprenorphine in the fentanyl era? Well, I think that it has all the pharmacodynamic advantages of some legal buprenorphine. It's a partial agonist and it has a strong receptor affinity. You get assured compliance and clinical effects. I'm saying greater than five weeks here. It's longer, I can tell you that. It depends on how many injections the patient's gotten. When somebody's gotten four or five injections, it's probably closer to two months. You have the potential, if you need to, to get a higher serum level than you would probably get people to take sublingually. Again, this is opinion. I don't have data to support it, but I think the induction is easier with fentanyl users. The problem I see is that clinicians and patients abandon sublingual inductions when they get tricky. With the injection, you're just committed. Even if the patient feels a little sick, it goes away. Really, the shot of either of these products is, in some ways, like a slow gradual induction because you don't get the release of the injection all at once. The injection releases itself over the first 24 hours. I actually think that these are good inductions to do. Everybody is just committed and you can't back out of it. I think the diversion compliance issue is for special populations. I can say I do some forensic consulting and the federal prisons in New York City have actually switched to this, just because it's less labor cost to deliver it. They have terrible, at least the prisons that I've worked in, have terrible problems with sublingual buprenorphine diversion. Criminal justice system, definitely, this costs more per month for the medication part, but it seems they're deciding it's worth it. Disadvantage, I hesitate to even say cost because when we're talking about the leading cause of death for people 20 to 45 in the United States, I don't think we should be debating whether something that costs $1,500 a month is too expensive versus $200 for the sublingual. The cost is not prohibitive, but it is an issue. I'm in New York State and we have a generous Medicaid program here. I bet there are other states that maybe it's hard to get. There is prior authorization issues and the shipping. There's one differentiation between the Bruxade and Sublocade versions is Bruxade does not need to be refrigerated and Sublocade does. Again, disadvantages with BXR formulations, I hesitate to bring this up because I think for the leading cause of death for young adults 20 to 45 in the United States being fentanyl overdose, I think we shouldn't be talking about something that costs $1,500 a month is too expensive. There's lots of medical treatments that cost a lot more than that per month that are not necessarily as impactful. I think on a conceptual level, I think it's actually obscene to talk about whether it's too expensive or not because it's just not, especially compared to how we spend other money in the medical system. It's like the cost of getting a CAT scan or something. But I do recognize that I'm in New York State and the Medicaid program here is generous and I think other states, you can have accessibility issues. Certainly, even here in New York, you have to get prior authorization often and there's the getting it shipped to you and your Sublocade needs to be refrigerated and it's a controlled substance. There has to be a lock on the refrigerator. Versati does not need to be refrigerated. The nodules are noticeable under the skin. Some patients complain about that. I don't think it's that big of a deal, but it does have some cosmetic. For a very thin person, you can see the nodules. People who have a little bit more adipose tissues, it's less noticeable. Just say something about xylosine because it's a related topic right now. It's a veterinary sedative, alpha-2 agonist. It's a super strong version of clonidine. Combined with opioids, it increases the risk of fatal respiratory depression. For reasons that are not understood, it seems to cause a lot of soft tissue infections. The start in Philadelphia, I can say it's all over New York now. There's definitely regional differences with this and it's hard to test for now. I think places may have it and not realize it. There's tests for it are being developed and even test strips to test the drug for it are being developed. It seems to be a strategy to augment the subjective effects of using the drug, but it seems to have horrendous consequences for people, particularly injecting it. Just talk about a couple of cases just to use as examples for this. A patient had with using intravenous heroin, had a regular compliance with transmucosal buprenorphine, had episodes of IV heroin use like one or two times a month. Drug screen was positive for fentanyl. He had had sexual dysfunction on 12 milligrams of sublingual buprenorphine and probably took less. What's the potential role for injectable buprenorphine? Well, this patient I gave injectable buprenorphine to for six months with a good therapeutic effect. He was using less and actually not at all towards the end of that. The subjective effects of injecting heroin were blocked. However, he had worse sexual dysfunction on a higher dose of buprenorphine and had this emotional flat feeling. I would say that this is the limitations that I see with being on particularly the higher doses of injectable buprenorphine. What I did was lower the dose. The patient I'm thinking of actually is still on it, but then you run into the problem of potentially they can use on lower doses. I think dialing in the dose is probably the clinical expertise here, which is to get people on an amount that treats their substance use disorder, but limits the side effects. Just a little fentanyl cognitive dissonance. I think clearly the fentanyl era, there's been important differences from prescription painkiller and heroin errors of the opioid overdose epidemic. Fentanyl is more dangerous. Subjectively, it feels different. However, from a treatment management perspective, things are not as radically different as some would say they are. I think we have to be careful about throwing out everything that we know. If I gave this lecture or I gave lectures like this a few years ago, I was probably more alarmist. I think I'm more in the middle ground now where I think things are different, but they're not as different as they may be seen. I think the proven methods of treating opioid use disorder work with some caveats. We need more data. I think in the meantime, I like giving people injectable long-acting buprenorphine who are using fentanyl because it just seems, in the absence of data saying it's better than the sublingual, it's still, to me, it just seems like a better solution. I certainly recommend it's the same active ingredient, you're just ensuring it's in the patient. I encourage clinicians to get experience with this modality because I think my prediction is, I think in the fentanyl era, we're eventually going to show that these injectable formulations are better for fentanyl users. We're not there yet. When I update this talk in two years, maybe we'll have some more data. Summary, fentanyl use continues to be a major public health problem in the US. Evidence-based treatment recommendations are scant. Clinicians, patients have experienced a loss of confidence in standard treatment approaches. There are ongoing studies that are eventually going to give us guidance for the best practices. In the meantime, I would begin with the standard evidence-based treatment recommendations and then modify them according to your clinical needs. For people who are accessing, you can access this online and take a look at the references. Also drew your attention that there's a PCSS MOUD mentoring program, which is a great fantastic research, I mean, resource. Generally speaking, I would, you know, you're listening to a PCSS presentation, so you've already found us, but, you know, the resources that PCSS offer are just tremendous. I mean, there's really nothing else like it and it's free. Tax dollars are paying for it. So it's a great resource poke around the website, you know, there's a lot of interesting resources here. You know, there's a way to get questions answered on the PCSS website. Here's some credits you know this is American Academy of addiction psychiatry and partnership. I'm going to plug in for the triple AP I'm the current president triple AP is a fantastic organization. We have a great meeting. Okay, and thank you for your time.

Substance Use Screening

Primary Care

Screening Tools

Implementation Guidance

Dr. Jennifer McNeely

Prevalence of Substance Use

TAPS Tool

Electronic Health Records

Referral and Treatment Options

opioid use disorder

fentanyl

evidence-based practices

treatment

overdose fatalities

pharmacokinetic

pharmacodynamic

buprenorphine inductions

naltrexone

tailoring treatment