Thanks everybody for joining today. It's morning for me. I'm coming to you from San Francisco. I understand this is being recorded. We have some participants that are here live. Thank you for joining. And I want this to be as useful as it possibly can be to you. You get special priority because you're here in person. So I encourage you to have questions that you put into the chat or any specific things that you're grappling with in terms of use of long-acting injectables for treatment of OUD. My name is Soraya Zari. I'm an associate professor at UCSF. I'm going to dive right into the material because there's a lot to cover. So just please put your questions in the chat as they arise. So at the end of this talk, what I'm hoping you'll be able to do is to understand the pharmacokinetics of Bup-XR. Remember, Bup-XR has the trade name or brand name Sublacade. I'll spend a lot of time reviewing that and its use. We'll also talk about another commercial product called Brixadi that has recently been approved for use. But for the purposes of this presentation, I'll primarily use the terms Bup-XR. And we'll talk about how that relates to just common patient treatment scenarios. I want you to be familiar with the evidence base for use of Bup-XR. Is it superior to Bup-sublingual? Really, what have we seen in high-quality studies in terms of outcomes? We'll also talk about insurance coverage of Bup-XR. We'll talk about emerging data with regard to macroinductions, which refers to the process of sort of very rapidly putting people on very high doses via injection. And then we'll talk about how much protection is conferred from Bup-XR for decreasing your risk of overdose. I'll also make a very small mention about use of iamnaltrexone, aka Vivitrol, which is also approved as a long-acting agent for treatment of OUD. And I'll share some comments about where it is most useful clinically. So we'll start with a case. These are real cases. It's a 56-year-old man with severe opioid use disorder, alcohol use disorder, and sustained recovery, chronic pain, diabetes, and obesity, who's currently on Bup now, 24 milligrams per day. That's in divided dosing, so 8 milligrams TID. And he's on a lot of medications. He has dry mouth. And he's just tired of the bad taste of the films. If you're an addiction doctor and you prescribe the films, you've heard this a lot, right? It's the worst tasting but fastest to dissolve. So that's what he's complaining about to you today. These are the other medications that he's on. In terms of his OUD history, he has a prescription opioid use disorder. This started after he was given morphine for treatment of his pancreatitis. He stopped alcohol while he was on opioids, but then he developed misuse of the prescription opioids with problems at home and asking for early refills and being very, very preoccupied with just opioids as a pain treatment. And his doctor made a diagnosis of prescription opioid use disorder and induced him onto Bup now, and he's actually done quite well. His urinotoxidating clinic is positive for buprenorphine and positive for THC. His labs are shown there, and he has a normal belly and an ALKFOS. So we have, again, for the small number of participants that are on the line, I want you to just to, I don't know, for me, I have trouble paying attention during Zoom talks. So if there's questions, it helps me lock in. But I'm wondering if this patient that I've told you about might be a good candidate for bup XR. So A, no, he's not a good candidate. His urine is positive for THC. B, yes, and he may need additional overlap of his strips for the first two months. C, no, bad candidate because he has chronic pain. Or D, no, we can't get him to that dose of 24 milligrams per day using the injection. And if you can, if you're so brave, please put guesses into the chat in terms of whether this patient might be a good candidate for bup XR. All right. So I'm going to try and convince you that yes, he is a good candidate for bup XR, and we might actually have to start the injection and then give him some strips as he starts. So good job, Caroline. And thank you for putting a question or an answer into the chat. I appreciate you. So we're just going to review kind of what the products are. Again, many of us are more used to the brand names right here. And hopefully you can see my mouse floating around. But this is Sublocade, right? This is what's currently available to us. This is the Q28 day injection. And what you'll see, it's a sub-Q injection, and it forms this solid pellet in the sub-Q space. And then you have, there's this controlled release mechanism over time. That's how it lasts as long as it does. Brixadi is a, it's an extended release formulation. It can be given once a week and in smaller doses. We'll talk about Brixadi versus Sublocade. Brixadi is also known as Buvidol. It's been used in countries outside of the United States for quite some time. And so Buvidol was the brand name outside of the United States. In the U.S. it's being marketed as Brixadi. It's now been approved by the FDA, and it has a similar mechanism, right? With, but it makes a liquid crystal gel and then has like a slow release formula. The key thing, and I encourage questions if there are any with regard to this, but Sublocade or Bupexar is a painful injection. So a lot of my time treating patients has been in search of making this a more pleasant experience for patients, because people will compare it to like having an orange like squeezed into your skin. I've heard just really vivid and unpleasant descriptions of this injection. We've found ways to make it much more just doable for our patients. As I'll talk about, this is a controlled substance. So you have to order it through a specialty pharmacy or your hospital-based pharmacy. I'll give you a resource about how to look up a specialty pharmacy if you've never done this. It needs to be delivered to your clinic close to the date that you plan to inject the patient. It should never be given directly to the patient. The patient arrives for the appointment, and in your clinic refrigerator you take out the box of the Sublocade and you just, you know, do a bedside sub-Q injection. You're going to clean the skin and pinch the skin, as you'll see here in figure six, and then using a 45 degree angle with the needle that they give you, you do a sub-Q injection. And then the figure above shows you the different spots where you can actually do the injection, and each month you switch where the person has it. You should actually, when they come back a month later, you'll be able to feel a knot, a little pellet, from where they had their last injection. And so that and your chart notes will tell you kind of which new location to pick. How to alleviate the pain. The most useful things that I've seen some clinics buy, it sounds silly, but just on a, you know, from a commercial site you can get little tiny square ice packs and put them in your clinic freezer, and you can just put one of these ice packs right onto the skin, you know, for five minutes before you do the actual injection. That's probably the easiest thing, and it doesn't require, you know, taking lidocaine from a clinic supply. I understand many of you are psychiatrists, so you probably don't have clinic spaces that have vials of lidocaine like I do in my general medicine clinic. So if you can, it's worth the investment of the six dollars to buy little square size ice packs that you can put on the patient's skin prior to injection for about like five or ten minutes. The other thing that we do, if you have access to lidocaine, is most one percent lidocaine comes in little sort of glass bullets of like two mL containers, and you can take that two mLs of lidocaine, and using a small syringe, you can inject the space before you give the the bup-xr injection, and it really alleviates the pain. So about one to three mLs sub-q into that space before you do the bup-xr, and I've had patients, you know, they don't even bat an eye. People will also tell you that the 300 milligrams gets a larger volume, so the 300 milligram dose is much more painful than the 100 milligram dose. This is the dosing schedule, right, as recommended by the pharmaceutical company and what was tested. So the, essentially, you start by giving a person the 300 milligram sub-q dose, and you do it twice, right, 28-day intervals, and then you drop down to the 100 milligram dose every 28 days. Alternatively, you can also continue with the 300 milligram dose, but as we'll talk about, each of these dosing schedules is going to lead to a different serum level of buprenorphine. So if you go 300, 300, and then drop down to 100, you're going to end up with a sort of concentration in the blood of two to three nanograms per mL of bup. Remember these numbers, we'll come back to them later. If you do the high doses, you're going to end up with this concentration of about five to six nanograms per mL in the serum. Over here, this orange graph just shows you there's different regimens, right, different schedules of bup, and what does this translate to in terms of the sublingual dose I'm giving them, right? So this comes up a lot. So if you're giving, if you look at the way bottom of this table, if you give 300 milligrams every month, this is the sublingual equivalent of giving greater than 32 milligrams per day of buprenorphine, right? So these are high doses of buprenorphine. As we'll talk about, people on 300 milligrams once a month are people with very, very high tolerances and cravings, and they're going to end up with these higher average serum buprenorphine levels. And then there's different sort of permutations here, right, about what's the dose and what does that translate to in terms of a sublingual equivalent. This is important because, in contrast, as you can see, these are high buprenorphine doses. Some patients are on very low doses of buprenorphine. So this is sort of where Bruxade has entered the market because you can approximate lower doses with the weekly injectable compared to this 28-day injectable. So why do we care about a bup serum concentration? Well, these are sort of the sort of formative or foundational studies that they use for us to understand the efficacy of this medicine, which is that if you have a serum concentration of two nanograms per ml of buprenorphine, then 70% of your mu opioid receptors are occupied with buprenorphine. And if you have 70% blockage, you will, this is a so-called blocking dose, right? We talk about this in addiction medicine all the time. That blocking dose means that, if a person uses a full agonist on top of that, they won't feel it, right? For the most part, it's harder to feel it. This is one of the complaints you can hear about buprenorphine for a patient that's maybe not ready for full abstinence. The thing that they don't like about buprenorphine is that you can't get high. And so this comes to this issue of how many mu opioid receptors are occupied. Sorry about that. I'm not sure why the slide advanced. I was going to still talk about that, but that's the key principle is the percentage of mu opioid receptors that are occupied. If you occupy 50% of your receptors, then that's sufficient to suppress physical withdrawal symptoms. So that's the genesis. I want to show you here, this is the average concentration that they saw in people's serum, and then the probability of abstinence. And so what you can see here highlighted, if you have a serum level of about two to three, you have about a 65% probability of abstinence that's in users that were not injecting. I should be really explicit that these studies were done pre-fentanyl. And so I think that there's a lot of this work that needs to be redone now that we primarily are seeing fentanyl being used among people with opioid use disorder. On the right is meant to represent people that inject, people that have much higher tolerance. And so if you give them a higher, this is why they sort of make this recommendation of 300 milligrams every 28 days, is at these higher serum levels, you do see that the graph ticks up a little bit and you get to that 65% probability of abstinence with this higher dose. Realize that this is not 100% abstinence, right? So this is not a perfect medication by any means. The other thing to know is that after you do the person's first shot, and so the little blue picture of the needle here is meant to represent the bup-XR injection, about 24 hours after you get the injection, your serum levels are going to peak. That's why you see this pointy little mountain here, right? That's the serum levels spiking up. And then they're going to come down and they're going to sort of equilibrate here over the four weeks. And then you sort of get your next shot. After you get that next shot, you can see that this line, this horizontal line is going to step up, right? As the serum levels increase in the patient, their serum levels of buprenorphine. So the reason I say that people might need strips as backup when they first start their bup injections is because they're not yet to steady state. This is a long acting injectable medication. And so if you give them their first shot and they have a serum bup level of two nanograms per ML, they may not feel sufficiently covered, right? To resist opioid temptations or cravings. And so it is common where I will give people some additional strips as backup when they're in this period of induction. This shows you sort of a longer term view of what happens to your, again, this is your buprenorphine plasma concentration after six consecutive injections. And so they sort of posit that, right, it can take six injections, four weeks apart to actually reach a steady state level of buprenorphine levels. And so that's really key to think about when you're working with your patient who's just starting this medication. And then similarly, right, this is your, again, these plasma concentrations are going to depend on what, how you're dosing the patient and what their schedule is. I will tell you that the bup XR also persists in the system, right? After the injection, it has a tail. So it sticks around for four to six weeks. And so many people may not necessarily come back right at that 28 day mark. And that's another thing that we've seen pretty commonly. So I told you I was going to sort of go through this in terms of Brixadi. That's, again, that's the brand name, but it's another formulation of bup XR. I show you here, these are the dosing schedules. So the dose, we're not in the dose of 300 milligrams and 100 milligrams anymore. This has totally different numbers for milligrams with the Brixadi. I also have not used this yet clinically, but essentially you can give a weekly shot of eight, 16, 24, or 32 milligrams. And it also comes in a monthly shot. The way that they started people on this weekly shot is they took people that were in mild to moderate withdrawal. They gave them a four milligram bup sublingual test dose. They observed them for an hour. And if they were fine, they went straight to the 16 milligram weekly dose. So again, this is, you know, as we start to roll out protocols about how to use Brixadi, how to, you know, this is good for people that we want to see weekly, right? Maybe people that need a higher touch for their induction. I think Brixadi is going to be something that we use more and more. And essentially what you can see is here in gray, I give you the dose of daily sublingual buprenorphine. And as you can see, now there is a Buvidol or Brixadi dose on a weekly basis that can approximate these low doses of sublingual bup. Again, we have a lot of people that are just maintained just fine on two milligram sublingual BID, right? And if they want to go to an injectable medication, Brixadi would be a better product for them in the sense that they've really tested whether we get people to these low amounts. And so I also am giving you here with different Brixadi injections, the weekly and the monthly, what average serum bup concentration does that correspond to? So again, sort of that, we talked about that, you know, if you've got a bup serum level of about two nanograms per ml, right? We think that that should occupy about 70% of the mu opioid receptors. This is mainly put in here for reference and you all can look at it. It's kind of the same as the slides I showed you before for bup XR for sublicate, which is that, right, there's this period of fluctuations in your serum levels of bup as you start these agents and come to steady state. So this is a good summary comparison slide. Again, as Brixadi enters the market and we have to decide which injectable to give the patient, we're gonna have to say to the patient, what are the pros and cons of the two different long-acting injectables? The key thing with Bruxade is that this can be stored at room temperature. Sublicate has to be refrigerated, right? So that's a big difference, especially if you're in a private practice where you don't even have sort of a refrigerator to hold patient meds. The other thing is that Bruxade is a much smaller needle, so it's less painful, and it's a smaller volume that's injected. This also sort of corresponds to the fact that there's more sites that you can inject, right? The Bruxade, you can go in the glutes, you can go in the thighs, the abdomens, and the arms, and it doesn't leave this unsightly lump. There's pictures of people online, you know, with like these lumps from their sublicate shots, not speaking positively about them, right? Something not good for bikini season by any means. It is visible, the lump. So Bruxade, that would not happen. This is also really helpful for patients on less than eight milligrams per day. And then again, you can actually do day one inductions, right? So that, what did they do? They gave four milligrams sublingual, waited an hour, and then gave the weekly shot, and they tested that, right, in studies. And sublicate, that's really not how sublicate was investigated. Those people were stable on sublingual buprenorphine, and then they started their sublingual injections, right? They had been on for a week or more of sublingual buprenorphine, and then they got their sublicate. Bruxade from the get-go was studied as a day one injection shot. So that's really interesting. And then, you know, so what can we say about sublicate? Well, many people like sort of the monthly schedule. Many people don't mind the knot in the abdomen. You know, we know that this is actually covered by our insurance plans. So there's obviously still gonna be a place for sublicate. Okay, so next question. How, so JR is like, right, he's got a bad, he's got dry mouth, right? He doesn't like the strips anymore. He wants something different. And if he says to you, you know, Doc, how do the strips compare to the shot, right? What do we know? Is it A, bup-XR outperforms methadone maintenance for treatment of severe OUD? B, six-month retention with bup-XR is close to 80%. C, bup-XR is associated with a 7% reduction in utox positivity for opiates compared to bup-sublingual. Or D, tolerability is worse with bup-XR compared to bup-sublingual. And if, again, if you're willing and if you're able and still listening at this point, please, in between bites of lunch, please throw an answer into the chat, right? How does bup-XR measure up to bup-sublingual? You know, we're always sort of practicing evidence-based medicine. These shots are very expensive. So we really have to like push ourselves, like are there clear superior medical outcomes, right? That would make us choose one versus the other. Okay, I'm gonna guess by the lack of responses that maybe people aren't super familiar with this, in which case that's great. Let's talk about it. Okay, so essentially C is the correct answer and I'll tell you why. So sorry, this is a busy slide, but this is sort of a lot of the data, the high quality studies that were done on bup-XR. And so I'll take you through the highlights of each paper. Sort of the very early studies, as you might imagine, these are industry sponsored. The first thing they did was bup-XR versus placebo and they followed people for 24 weeks. And I'll show you here, their primary outcome was about urine toxicology screens. And they saw that 40% at the different doses had urine toxins that were negative for opioids versus 5% in the placebo arm. And so obviously that's a huge difference compared to the placebo. So this is part of how it gained its FDA approval. There was another study looking at sort of bup-XR versus sublingual bup, also industry sponsored. This was double blind and a double dummy sublingual versus XR study. So what that means is that, so everybody in the two groups, everybody got a shot and they got a sublingual tab, right? And, but then in for half of those people, their shot was a placebo and they were getting real sublingual tabs. And then the opposite was true for the other arm. So that was nice, right? How did those two measure up? And again, you just see that bup-XR had a marginally larger percentage of opioid negative urines in this study. Bup-XR versus methadone has not been studied. So that's why that's not the correct answer. People have done some work about sort of what is bup-XR for your quality of life, right? For a lot of people, this is chosen for lifestyle purposes. And they did a 12 month follow-up study of the industry sponsored RCTs. And they found that people were highly satisfied with bup-XR, that they had high scores on their health related quality of life. And they saw this marginal benefit that maybe the bup-XR was associated with more patients gaining employment. So again, this is meant to convey to you that this is not a perfect medication. This isn't gonna solve our opioid epidemic, right? Or our overdose crisis. And what you see is maybe a slightly superior outcome. I wanna cast a light specifically on a new paper that just came out last year. This is with regard to the carceral system for any of you that practice in that setting. But Josh Lee and collaborators at NYU essentially did a study in New York City jails of, it was a very small sample size. So that's important to point out. They looked at people that were very close to release from jail on sublingual buprenorphine. It was open label, right? So we didn't have good use of placebos. Everybody knew what the patients were getting, but it was randomized. And the two groups were sublingual bup versus bup-XR. And the bup-XR was started about a week before they were released from jail. And then they followed them, right? For 12 weeks after their release from jail to see how they did. And they found pretty, this is a pretty impressive outcome. This is non-industry sponsored, but treatment retention at eight weeks for XR bup was 69% of patients or 18 out of 26 patients versus sublingual bup. It was just like a third of patients. We also saw more opioid negative urine tests in the XR bup study compared to sublingual bup. So lots of enthusiasm for using XR bup in the carceral system right now because of this paper. So I think we're just gonna keep accumulating more data. I'm not gonna go through this. This is the consort diagram for one of the studies that I told you about. And the thing I want you to look at is the big yellow box where I just point out the fact that as they were recruiting for these trials, 57% of the patients that they screened were excluded from participation. And I show you some of the reasons that they excluded patients. Any meds for OUD in the last 90 days, any diagnosis that they had to be on chronic opioid therapy, moderate to severe alcohol use disorder, moderate to severe cocaine or cannabis use disorder. So they picked a very sort of idyllic population in the studies of bup XR. And I just think that's interesting because practically speaking, I see a lot of people wanting to use bup XR in our patients that are struggling more. And so there was some selection bias in these trials looking for a really pure form of OUD. And so we always have to wonder, could that selection bias, is it going to affect our ability to generalize these results to our patient population? And so again, as we're sort of giving injections to the patient with OUD and really severe alcohol use disorder, because we don't think they can manage the sublingual films, is that the population that was originally studied in these papers? It wasn't. So just to put that caveat out there. And then similarly, these are the JAMA, this is the JAMA paper of CAM. CAM was the name of Bruxadi before it was given a brand name. So some of you might've worked at sites where they were studying CAM. This included many emergency department sites. Actually here in the East Bay, our Highland Hospital was one of the sites doing sort of the CAM study. And just to say that, again, a fair number of people were excluded in this trial. And then there were quite a few people that actually dropped out in the middle of treatment, just making the point again that this is not a perfect medication. This I'm going to skip, because we talked about this, right? The main thing that we saw, bup sublingual versus bup XR. Again, if you're explaining to JR, what's the difference between the injection and the sublingual film, I think you can say that, right, we have studies showing that there's, right, 7% more patients have non-reactive urine tox screens, right, with the injection. But in many ways, they're quite similar in terms of outcomes. Okay. The other thing I get asked about a lot is like, can, because bup XR has this tail of metabolism, right, it sort of stays in your system and then it metabolizes in this very, and your serum levels decrease at this very slow rate. A lot of people are interested in whether they can use it to taper people off of buprenorphine. You know, there's surveys in different treatment centers and different populations, you know, asking patients, you know, do you want to be off buprenorphine? The large percentage, you know, want to be off of meds. It's somewhat controversial in the sense that we also know that return to opioid use after stopping medications is quite high. This is a high lethality disorder. And so in general, you know, more and more we're pushing maintenance, but we also have to work with what our patient is giving us. And if abstinence or being off meds is a high priority for them, or some people work in fields where it's a requirement for employment, then we have to think of these ways to taper them off. Here is just this tiny, tiny little case series that they did at the University of Colorado where they basically looked at patients that were prescription opioid use disorder patients. They were put on bup and the patients couldn't get off bup. You'll hear this, right? Difficult stories from patients about getting off the sublingual films. And in this tiny case series, again, this isn't two thirds of patients, this is three patients, right? They decided to put people on XR-Bup and essentially what they found is that for two out of the three patients, they went to XR-Bup and they did great. And one of the patients, they just gave a hundred milligram dose too, right? Just as a starting dose. The person got a couple symptoms of opioid withdrawal about two weeks after their shot, but then they were off completely. So I think we're in a really early stage of how do we dose the XR-Bup to taper people completely off? This is sort of evidence that's accumulating. I'll disclose, I have a patient now who's trying to do this very thing and we're actually just injecting part of the bup-XR syringe. I'm not wild about it, right? Because I don't know exactly how many milligrams I'm giving her, but it's really driven by sort of patient choice. I'm happy to also, we can take more questions about that if that's something you guys are dealing with. I wanna just review. So I'm a doctor in California. We have a generous Medicaid program. So I can't say that this generalizes to every place where you all are practicing, but in the state of California, Medi-Cal covers bup-XR and STRIPS. You can actually give both to a patient simultaneously. I will say for my patients on Medicare that need bup-XR, this usually requires prior authorization. So there's some paperwork involved, it's very annoying. There are patient assistance programs, but generally speaking, this is just prohibitively expensive. So I don't really pursue patient assistance programs because while there's some discount upfront, there are more costs later on, but it's something that you can explore. It's always interesting, our pharmaceutical companies come up with like amazing medications like this, but they're also obviously trying to make profit. It's sort of interesting to note that Supplicade was actually approved in 2017. And right when you're approved, you get three years of exclusive access to US markets. And it tried to designate itself as an orphan drug, which gives you seven years of exclusive access to markets. But keep in mind that an orphan drug is something that treats people, it's meant to treat just a handful of patients that have a very rare disease and opioid use disorder is not that. It's orphan drug status was actually revoked in 2019. Now that Bruxade is on the market, what we're hoping is that the price of both of these injectables comes down precipitously, because we have a free market and now we have competition. So anyway, hopefully we'll see some changes to the affordability of this product. This is the website I mentioned to you that where you can look up a specialty pharmacy that is near your state zip code. And that specialty pharmacy can deliver the Supplicade to your clinic or practice site. And in the prescription with this specialty pharmacy, you would have to give the date that you plan to give the patient the Supplicade injection. So again, this is a lot of work, but for the patients that this works for, it really works great and they're very happy with it. So I encourage you to really explore this if you haven't done so already. This is the link to the Supplicade REMS instructions. Basically, when that Supplicade gets delivered to you, it should be in a secure location. Ours is in a clinic refrigerator and there is a locked door before you access the refrigerator. It should be in cold, but it's okay for up to seven days outside of the refrigerator. Supplicade is never supposed to be dispensed to a patient. This is just to say you as the practitioner treating your patient with Supplicade, you do not have to be certified by the Supplicade REMS program. You only have to be certified by the REMS program if you are now sort of stocking a large quantity of Supplicade, right? If you're ordering, right? Prescribers that intend to keep a supply of Supplicade in stock at their healthcare settings and obtain Supplicade from a distributor must certify their healthcare setting or practice in the Supplicade REMS. So just that's an important distinction. Okay, case two. You see how I'm doing in time, sort of famous for not having the best time management. So this is SL, it's a 32-year-old with a history of severe OUD who's brought to the ED following an unintentional overdose. This patient is primarily using fentanyl. She's given four milligrams of intranasal naloxone times two in the field. She expresses that she's just tired of getting high and she's just wondering like, what's up with this shot? And you'll hear this a lot, right? People who, they're in that moment of change and they wanna be done with it. And this idea of like, just give me the shot can be really appealing. We wanna make sure that we're not sort of capitalizing on just some impulsive thoughts and really making them understand what this medication does and how it makes you feel, right? For the month that you're on it. But some people, this really does work for them because she's just gotten naloxone. She has a cows that's elevated at eight which is consistent with mild withdrawal. So you're now an emergency medicine doctor and she's asking about the shot. She wants to know what's up with that. She's already in withdrawal from the naloxone. Do you wanna just give buprenal eight milligrams given moderate withdrawal? Do you wanna give me bup two milligrams and observe the patient? Do you wanna give bup XR 300 milligrams or this sounds like something that hasn't been fully studied? I don't think there's any emergency medicine doctors. So I wouldn't expect you to know the answer for this but what I'm hoping to do is have us talk a little bit about is there a role for buprenal XR and bup XR to decrease the risk of overdose for patients that are at really high risks is sort of a new area of study. So, and is it a good time to start people post overdose? When somebody comes in for an overdose, I don't have the paper here but when you bring a person with overdose to the emergency department and then release them from the emergency department and follow them over time, essentially the first three months is extremely risky for that individual and there's a high risk of mortality. I believe the mortality rate in the first three to six months is on the order of five to six percent. That's very high. And so more people are sort of interested in like, you know, should we be trying to do something that day that prevents this high risk group of individuals? So this is a case series, again, sort of low quality evidence, but a case series from Virginia where they had some decent follow-up on these individuals. They had 732 patients that came in with unintentional non-fatal overdose cases. About 37 of those patients, they approached, they consented them, and they talked to them about giving them bup XR. They made sure that they could see these patients again in seven days. What they did with 19 of the patients is they gave them one dose of four milligrams sublingual, and then they went straight to the bup XR. And this population, on average, they were 46 years old. The majority were Black or African American. Then they followed this group, right? These 19 people, they followed them for six months. And they saw that none of these patients, right, in that really high risk for six months after overdose, none of these patients came back to the ER with repeat overdose, and none of them died, right? And then they looked at all these other people, right, these 540 patients that didn't get anything. That's a separate problem, right? All patients coming to the ER with overdose really should be offered life-saving treatment with methadone or buprenorphine. But when you follow these patients that were not treated for six months, 18% of them, again, this is what I was talking about, 18% had a repeat overdose and 6% died within six months of their index overdose. Going back to the people that actually got the bup injection, 79% actually came to one follow-up visit. And the mean number of visits over that six months was actually 13. So they got people to come back, right? That's the holy grail for addiction care is, right, how do we retain you? And they saw that at least 80% got one follow-up visit. This was sort of the breakdown, you know, how many people kept up with their shots. You know, 42% received greater than four out of the seven shots. 47% just got one shot, right? But they saw that there were no deaths in that six-month period after they were seen and got that one shot. They saw no cases of precipitated withdrawal, like buprenorphine precipitated withdrawal. That's what that BPOW acronym stands for. Obviously, we think about this all the time when we have a patient that's using fentanyl and we try and induce them with bup, right, is this specter of precipitated withdrawal. And so if you do these rapid starts and put them on the injectable bup, will you precipitate withdrawal from any residual fentanyl in their system? They did not see that in this case series. So again, this is out this year. I would say sort of exciting data that we need more of. This is another sort of demonstration case series from work in Berlin. This was not post-overdose. This is just treatment-seeking people. They have a cows greater than eight. They gave them four milligrams of bup and then they gave them bup XR unless their cows increased by six points after this four milligrams of bup. And I should say this research institute in Berlin, it's like a treatment program, and they were inpatient, right? It's like a detox facility. And they watched them for 48 hours. This study really attempted to determine how many people get buprenorphine precipitated withdrawal from the XR shot. Of these 24 people, again, these are tiny case series. They only saw that two out of 24 people had that increase in their cows of greater than six. So I think what we can say is that as far as we know, also importantly, only five people reported that they were using fentanyl, but 71% of the patients had urines that were positive for fentanyl. This is very common as fentanyl takes over the drug market. So I think this tells us that same day, again, if you get that same day start of your injectable, your risk of buprenorphine precipitated withdrawal appears to be low. And other case series say that if you get the precipitated withdrawal, it makes you like sick for a day and then you feel fine afterwards, right? Because it treats it with the very high serum levels of buprenorphine. So people are making different protocols. How do I start the person same day? Mariani has done lots of work on this. They give 24 milligrams and then go straight to the shot. And this actually shows you, this is from the Berlin group, right? What happens to the cow's score after you give the bup XR? And just as you might imagine, you know, it falls down, it falls sort of beautifully, right? Okay. And so this same gal is wondering about the interaction of bup XR and fentanyl, both the fentanyl that she uses and the fentanyl she will get for an upcoming procedure. So, A, you tell her that the procedure will be fine with bup XR, B, you tell her that there's some evidence that it may protect from fentanyl induced respiratory depression, C, you tell her that if she uses fentanyl and you will stop the bup XR, D, you tell her that it's best to use fentanyl later in the month when her bup levels decrease. So this is, so, oh no. Okay. For some reason, sometimes it goes forward a little too fast, but this was a tiny little trial sponsored by Endivier, a pharmaceutical company. And what they did is they brought people into a lab and they got them on buprenorphine and they established a serum level of buprenorphine, right? Above two nanograms per ML, right? And what they did is they challenged them with fentanyl, right? And they watched their minute ventilation, right? It's like, can we have them stop breathing? So on the left here, what this graph shows you is that you'll see this is their minute ventilation on the X axis. And then these are the, and so obviously they're breathing, they're breathing, they're breathing here. And then as they get an injection of fentanyl, their breathing goes down as you would expect. And then it gradually comes back up. They get fentanyl again, their breathing, their minute ventilation goes down. Fentanyl again, their minute ventilation goes down, et cetera. Okay. So now here on the right, they gave people bup so that their serum level was, their serum level was above two nanograms per ML. And of course that's like the serum level that we accomplish when we give an injection of XR bup, right? So when people have this level of buprenorphine in their system and you bring them into a lab and you give them those same injections of fentanyl, right? They give fent one, fent two, fent three, fent four, up to boluses of 700 micrograms of fentanyl. What you see is that there, you don't have a drop in their, in their minute ventilation. And this at the bottom here shows you their O2 saturation, right? And so the, the thought is that, you know, could, does bup, can it protect people from overdose, right? Again, talking about that trial I just showed you, really high risk period after you overdose, could bup XR, you know, be this long acting agent that could protect people from dying, right? In those, in those dangerous first three to six months. Again, this is all pretty preliminary. But it's also, you know, it's fine to put people in a lab and give them like pharmaceutical grade fentanyl, right? But there's no quality control for what my patients are using that they buy from their dealers, right? It could be xylosine, it could be carfentanil, it could just be very high doses of so-called clean or isofentanil. And so it's hard to say that, yes, if we get everybody's serum level to two nanograms per ml of bup, they're going to be protected from overdose. But, but people are wondering this. Just again, because we also are seeing so many deaths. You know, the other thing that you should know is that when you look at deaths that have been coded by the medical examiner as overdose, and you look like who has evidence of buprenorphine in their system for overdose deaths, obviously, it's quite, quite small. In this series from Rhode Island, only 5% of patients actually had detectable bup. Meaning that, right, bup is obviously, it's much safer, it really doesn't have any sort of potential for overdose. In the cases where people that died were positive for bup, they always had co-ingestions, right? And you see, the biggest co-ingestion here was fentanyl. So again, bup in general is quite protective. So I realized that this is supposed to be a talk about sort of long acting injectables for OUD. And I spent all this time talking about long acting injectable buprenorphine, and sort of neglected the other FDA approved medication for opioid use disorder, which is im-naltrexone, aka Vivitrol. This is also an injectable that's given on a monthly basis by us in the office. This one's actually a little bit more difficult to prepare. I'm happy to answer questions about how to prepare it. It's also approved for use in alcohol use disorder. So you see it for both those indications. The thing that made us, you know, sort of think more about im-naltrexone and part of their FDA approval for OUD was the XBOT trial in 2018. It was a big deal that was also done in New York. And they looked at naltrexone, im-naltrexone versus bup-nal in patients in detox programs. And essentially this third bullet, the outcomes they saw, like once you were on XR naltrexone and bup naloxone, your outcomes in terms of your OUD outcomes, like, you know, utoxes and retention and care, the outcomes were similar. The issue is that it was very hard to start many people on XR naltrexone. There were lots of people that didn't even qualify for the study, people that were excluded at the outset because you had to detox completely off of opioids to start im-naltrexone. So while you can say that, you know, this study showed equivalent outcomes, you have to consider what patient this will apply to, right? This is what patient can be completely detoxed off of opioids to then start their im-naltrexone. So that's the main caveat about use of im-naltrexone. For a lot of my patients, it's very difficult for them to completely detox. And so this isn't a medicine I use frequently for OUD. There's also this idea, right, that you're going to really alter somebody's tolerance, right, when you put them on im-naltrexone. And then if they relapse, right, and you've dramatically reduced their tolerance, there's this specter of an increased risk of overdose. And they have seen that there's evidence that treatment with naltrexone for OUD is associated with a higher mortality than treatment with methadone or buprenorphine. This is from, apologies for that, this is mainly, it's very difficult data to look at, but this is from a lot of, has been put out by Australia and New Zealand. And so that is a thing that sort of gives me pause about use of im-naltrexone for opioid use disorder. I do want to acknowledge though that it is still used in many settings, particularly also for adolescents, professionals that have opioid use disorder, and it's still in our armamentarium of treatments that we give to people. But those are the caveats about use of im-naltrexone. I'm happy to take any other questions about that. I feel like it didn't get an equivalent number of slides as the buprenorphine, but hopefully you all have some familiarity with naltrexone, and those points are review items. So in summary here, we talked about what are the outcomes of bup-XR versus bup-sublingual. They're marginal, but you do see sort of better results on your intoxicology screens, and then better retention in your utox results in carceral populations. Patients enrolled in trials were relatively stable. Consider this when you're making patient treatment decisions. And due to the pharmacokinetics of bup, some of your patients may require additional sublingual films for the first two months. And there are small trials that suggest that bup-XR and a certain serum level of buprenorphine can suppress the respiratory depressant effects of fentanyl up to doses of 700 mics of fentanyl. And there's really ongoing work that's examining same-day starts of bup-XR for severe OUD. With that, I'll stop. It's like two minutes. If there's any questions, please feel free to put them into the chat or to unmute yourself, and thanks so much for joining today. You can also email me at soraya.azaria.ucsf.edu if you have any questions. Thank you so much, Dr. Azari. I know we might have a question. We have... No, I'm not seeing that. I thought I saw a question. Oh, there is a question. Oh, there's a comment. I'm sorry, I can't see. Okay. So, thanks, Robert. So, can you say something about your patient's view of XR naltrexone? So, full disclosure, I work in a methadone program. I work on the addiction care team in our hospital, and then I work in a primary care-based embedded addiction clinic. And so, I only see people on public insurance, and I work in our safety net hospital. My patients have been, like, disproportionately victims of racism and are dealing with lots of stressors in their life. So, I would say that I see sort of, like, higher acuity, right, addictive disorders. And so, there's just a lot of people that I see that cannot completely detox off of all of their opioids. I mean, I see people with 20-, 30-year histories of severe opioid use disorder. So, that's not a person that's a good indication for XR naltrexone, right? It's a person that needs maintenance therapy. So, some of you probably have different practices and might see different patients. So, that's number one. The other thing is, you know, XR naltrexone, it's a painful injection also. And, you know, so I definitely talk about that with patients. I use it much more for alcohol use disorder, I think, because of the population that I work with. But I know, especially addiction psychiatrists, that, you know, some are treating, like, physicians with OUD and, you know, people that work in areas where IM naltrexone is really the only viable sort of treatment option. And so, the key thing is, what I will say, there is a group of individuals that are on bup and they want to go to XR naltrexone because their recovery is going so well. And a lot of people are interested, when can I start the XR naltrexone? When they've tapered off their bup, right? And lots of people are talking about this. And the naltrexone, the pills, right, come as 50s, right? And you can cut it up. But it's kind of scary because with XR bup, right, you have this tail where you still have bup in their system, and you don't know how much bup is in their system. And so, some people, you know, obviously, what we classically do is a test dose of naltrexone oral, like 25 milligrams oral, and then sort of gradually increase the dose. The other way to do this is to try and go smaller and, you know, micro dose the naltrexone. So, let's say you give them bup XR 100 milligrams, and now it's eight weeks out. I don't know exactly what their serum levels of bup are, but now they're telling me, I want to go on Vivitrol. I want to be off, off, off, off. So, what I would do is, you know, just again, people, this is not super evidence-based, but people are doing this like micro dosing of naltrexone, right, to make sure that you're not making them sick. And then you're going to give escalating doses of naltrexone. Once they tolerate 50 or 100 milligrams of oral naltrexone, you can give Vivitrol. I'm not sure if that's what your question is, Robert, but this is something that people are talking about a lot. I can't recommend, you know, there's like things I read on Twitter, and so I don't want to like recommend things I read on Twitter. I would say that there's lots of people out there that are taking tablets of naltrexone, liquefying them, and taking small amounts. That's really difficult because then you don't know how much naltrexone you're giving a person. But that is a sort of a clinical issue that we're going to be dealing with, right, is as for the people that come off buprenorphine, and they are electing to do Vivitrol for their OUD. I really encourage any other comments from you all about that, or tips, or pearls. Oh, sounds like Robert has to go, but I'm over time, but I appreciate the high-level question. If there's any other questions, please reach out to me, and thanks to you all for joining today.

long-acting injectables

opioid use disorder

Bup-XR

Sublocade

pharmacokinetics

injectable naltrexone

Vivitrol

evidence base

Bup-sublingual