Okay, good afternoon, everybody. Thank you for coming to today's AOAAM webinar, Clinical Implications of the Relationship between Naltrexone Plasma Levels and the Subjective Effects of Heroin in Humans, by Dr. Felipe Castillo. My name is Julie Kamik, and I'm going to be your moderator for this session. This is the second of our summer webinars on hot topics in the treatment of opioid use disorders and stimulant use disorders. So I'd like to introduce our speaker today. It's Dr. Felipe Castillo, who received his BA from Cornell University and MD from Tulane University. He completed his adult psychiatry residency at Montefiore Medical Center in the Bronx, New York. In addition, he completed an NIH T32 and Addiction Psychiatry Fellowship at Columbia University, New York State Psychiatric Institute with the Division of Substance Use Disorders, pursuing both research and clinical interests in addiction. He has researched topics ranging from attitudes towards medications for opioid use disorder by clinicians to the role that comorbid drug use plays among patients with opioid use disorder and the shading treatment. Today, Dr. Castillo will take questions during his presentation, so please enter those in the Q&A section of the chat down below. If you have questions about you're having problems with the webinar, enter them into the chat box and our staff will respond to those. So I'd like to turn it over to Dr. Castillo. All righty. Thank you so much, Dr. Cormack. And thanks, everybody, for jumping on to this webinar. I hope that it's some useful information that can guide your clinical decision making in the future. Hopefully, it will also confirm some of the things that you may have seen in the field. And, of course, if you see anything that you want to engage with me about during this presentation, please, like, interrupt. Feel free to ask questions, have them pop in the chat, and we'll take them as the presentation goes. I'm going to do, first, I'm going to do my disclosures, of which I have none. And what I would like to do in the time that we have is that I'd like to foment some increased confidence surrounding long-term naltrexone, long-acting injectable, the long-term naltrexone use, and have some improved patient care and patient outcomes. If we educate our patients on what we know, they're empowered to take better decisions for themselves, and that's going to lead to better patient outcomes. And I guess it's a typo already. I see no financial conflicts of interest. The professional practice gap that we have currently, and I'll revise these slides, the gap that we have right now is that for our patients for whom we prescribe naltrexone and we give them naltrexone injections, right, sometimes there's this, we see that the effect wears off early. And right now it's indicated every 28 days. And sometimes our patients either have cravings earlier or have a return to use. And the gap that I want to talk about is how often should we be administering naltrexone? Who should be getting it sooner rather than later? And what are some of the, what are the evidence, what are the data that support this? And I'm going to take a look at the chat. I see some questions already. They're mostly just about sound and some other, yeah. Great. All right. And then learning objectives, right? What do I hope to impart in terms of learning, rather teaching, right? There's currently three FDA approved medications for opioid use disorder. And I want to be able to have people in the audience, providers in the audience, be able to explain the mechanism of action of extended or released naltrexone. So some background information. Right. And then describe how the therapeutic effect of naltrexone in the plasma is dependent on, so the therapeutic effect is dependent on the naltrexone plasma level. That's what's actually imparting the effect. And that's what's driving the effect to go away or to cease as the naltrexone is metabolized. So a bit of background on opioids, and they're derived from the APAPI, but can also be synthetic. They have analgesic and euphoric properties. The agonists decrease the respiratory drive. That's the most dangerous effect from opiates that we're concerned about. So a decreased respiratory drive leading to respiratory arrest is what can lead to cardiac arrest. And so these medications and substances are potentially harmful. The use itself is reinforcing. They're rewarding. They have a rewarding quality to them. And opioid use disorder is a disorder that affects many people worldwide. And it has a lot of downstream effects, right? The sequelae of the disorder range from medical to social to problems at the individual level, problems at the societal level, and a high degree of mortality as well, as I said before, with the potential for overdose. Relatively simple pharmacology in terms of that it's the most common form of opioid use disorder that there are agonists, antagonists, there's partial agonists. We care about binding affinity. And essentially, you know, once the opioid is in the system, it gets metabolized, and there can be active metabolites. So that's basically the, there's a huge class of, this class is a pretty large, it's a pretty large, there's a lot of compounds in this, in this class. And the target sites are both in the central nervous system and peripheral, peripheral nervous system. There's mu, delta and kappa, there's, they're all G-coupled receptors. And, and the effects in the central nervous system are, are the ones that are, that have the analgesic, the euphoric properties, the, the properties of decreasing respiratory drive. The ones in the peripheral nervous system, those are the ones that are responsible for like pupil constriction, constipation. And then the, the experience that people have as they take over the experience that people have as they take opiates is that they're, they're going to develop tolerance. They're, they're going to have dependence and withdrawal. So the three medications that are currently approved in, in the United States by the FDA, if anybody wants to type them into the, to the webinar, this is a pretty easy response. Let's see if we've got some people that know. I'm going to talk about one of them. I'm going to focus on They're popping up in the Q&A box. Oh, they're popping up in the Q&A box. Yeah, methadone, buprenorphine, naltrexone. Okay, great. Oh, okay, there we go. Yes, now I have the Q&A. Good stuff. All right, good stuff. I'm going to put the Q&A box on my other computer, on my other screen. Great. Yes, so methadone, buprenorphine, and naltrexone. And then as we see, okay, and chat seems to say, well, okay, so just Q&A. I'm going to keep an eye on the Q&A then. Next slide. Okay, so methadone is a full mu receptor agonist and an MDA antagonist. And this is a medication that's used for OUD as well as quote-unquote detox or medical management of withdrawal. And it's used in pain management. So that's methadone. We're not going to be talking about that today. Next one is buprenorphine is used in OUD and pain management, and it's a partial mu receptor agonist. This one is an office-based medication. I believe it's the most commonly used medication for OUD currently. And we're also not going to focus on that one today. We're going to focus on naltrexone, which has FDA approval for opioid use disorder, alcohol use disorder, and obesity. And that's sort of with an asterisk because it's a medication that's a dual medication with bupropion. And then within OUD, does insurance routinely cover naltrexone for AUD and obesity treatment? My understanding is that it does for AUD. I'm not so sure for obesity. I don't have experience prescribing it for obesity. I do have plenty of experience prescribing it for alcohol use disorder. And I believe it's, why is it used for obesity? I believe it's a side effect. Sometimes people have decreased appetite. It's not the most effective medication for obesity, but it seems to, you know, some patients seem to develop a side effect of less appetite, less interest in eating, and they do lose some weight. But it's not everybody. And I'm not terribly experienced in naltrexone for obesity. So naltrexone for OUD has to be given, it's approved for the injectable version of naltrexone. So oral naltrexone is not approved for OUD. Can anybody answer why it might not be approved for the oral version of naltrexone, might not be effective in OUD? Right. It's an adherence issue. So we have a response saying compliance taking it, right? So what we've learned is that patients can come off of it, can come off of naltrexone within a day. They don't take the pill. They don't take the tablet at home or wherever they live. They don't have it in their system. The naltrexone wears off. It's metabolized within a day. And by the next day, the therapeutic effects are no longer there. And somebody can use an agonist. So the rate of return to use is very high and very quick. And that's very concerning. That's what we try to avoid when we put our, when we put our patients on naltrexone. Right. So, so, yes. So sometimes we would like to make sure that for inducting somebody on, on intramuscular extended release naltrexone, we want to give them a trial of the oral version of naltrexone, of the PO version of naltrexone. And my understanding is that insurance will cover that because it's part of the induction. What, what we, what we don't use oral naltrexone for in opioid use disorder is that we don't use it for long-term, we don't use it for long-term coverage. Yes. And it also happens with alcohol that patients will self-discontinue the oral naltrexone and, and have the effects of alcohol. The, the, the difference between alcohol and, and, and heroin, for example, is that the, the return to use of heroin can lead to an overdose and the person has lost their tolerance. Whereas stopping naltrexone for somebody that has alcohol use disorder and they, they stop taking their naltrexone, they return to drink, they return to consuming alcohol, it's, it's less, less of a danger. Typically, typically I have patients on naltrexone for alcohol and, and sometimes they will take a holiday, so to speak, a medication holiday and, and, and increase their, their alcohol consumption. The difference is that alcohol can still be consumed while some, while somebody is on naltrexone. Whereas heroin, if it is consumed when somebody is on naltrexone, it's going, and then naltrexone is going to completely block the effect. Whereas naltrexone will only partially block the effect of alcohol. Dr. Castillo, when the questions come in, I can read them to you because our audience that's going to be watching this that gets recorded aren't going to be able to see them. So yeah, I can, I can do that so you don't have to respond to them, but that way everybody will know what you're talking about when they're watching this a little bit later. Right. Sorry about that. No problem. So I believe I am up to Melanie McLennan's question. What happened with alcohol and naltrexone if you stopped taking it, does it not work? And, and to answer that question, it's, it's that alcohol will now be more rewarding than it was when naltrexone was on board. Whereas heroin will, could potentially be fatal. Whereas previously it was being blocked. ASAM. Oh, okay. Sorry. I'll let you read. Oh, that's all right. It's just a comment that the ASAM medication for alcohol use guidelines did away with mandated oral naltrexones before doing the IM formulation. And then somebody had commented that they know people who used opioids over Vivitrol and ended up in the hospital with, I guess, respiratory suppression or not. Yeah. Okay. Yeah. Maybe instead of going through this, if we can get through some of your slides and the questions should be more, you know, like at the end, if you have something about like patient questions or something related to that. But if you have some pertinent questions about like something on the slide that you don't understand, we can, we can take a break for, for that. Cause I'm afraid. Yeah. These are great questions. This is, you know, and we're getting into like, how does it, you know, how does it work? Where, where does it work? What, what kind of patient, you know, what kind of patients are the ideal candidates for this medication? You know, when, and what are the other variables? So so yes, I want to answer those questions, especially, you know, like what, what happens if somebody is on the medication, but they still use and they end up in the hospital. So but yeah, right now I'm like one third of the way through my slides, but I think, I think we're in a good pace. Right. And I think, I think some of the times you might answer some of these things coming up too, when you get through your presentation. Absolutely. Yeah. Okay. So, okay. So, so the, the injectable form, the long acting injectable form of naltrexone is, is approved for prevention of relapse. It's approved for decreased cravings. It's going to, again, the therapeutic effect is dependent on the plasma level of what's circulating of naltrexone molecule is what's going to be acting on the receptors. And, and what I'm presenting on today is, is, is, it's, it's a study where we wanted to understand the minimally effective level of naltrexone in the plasma and its clinical implications. Like as it decays, what, what does that mean for protection against relapse, against return to use and overdose? So how, how does that, how does that change over time based on a data set that we had? It's, it's a competitive antagonist. It's high affinity and, and it's going to work while it's, while it's in the body. And what's also going to work is the active metabolite of six beta naltrexone. It's a little less potent, but it's also a receptor antagonist. So, and it's going to use, we have to have a patient who is opioid free to avoid precipitated withdrawal. And there are many sort of protocols for getting towards getting somebody onto naltrexone. I'm not going to comment on them today because that's beyond the scope of today's lecture, but you can look them up and, you know, they, some, some involved buprenorphine, some involved naloxone. And there's, again, there's no single best strategy for inducting somebody on naltrexone. I think one thing that's really important is eliciting a good history from, from the patient and trying to understand, you know, what, what, what, what, what, what, what, what, what, what, what prior attempts they've had on, on medications for opioid use disorder and what they've liked, what's worked well for them, what kind of withdrawal experiences they've had, how much they can tolerate withdrawal, which symptoms are the worst for them, which symptoms are a little bit more manageable, which adjunctive medications work for them, which ones do not work for them. So it's really in the history taking, I think that a lot of the decision-making can, can sort of fall into place. And, and yeah, there are, there is no best strategy. There's, there's, there's something that's come out and said, this is superior than the rest. I think it's really individualized. We're just too, there's just too much variability. I will say though, that people that seek out naltrexone and long acting injectable medications typically are those that are those patients with OUD that tend to be in like safe, safety sensitive positions, maybe, maybe healthcare providers, maybe transportation professionals, people that want to ensure that the medication that they're taking is not going to have any sort of effect on their mentation or cognition. And, and, and want to make sure that like no state board is going to question the medication that they're on. So again, that that's a little bit beyond like the scope of this lecture, but that's typically the patient that is going to be interested in, in a long acting injectable version of naltrexone for their opioid use disorder. I do have a question that came in, I think related back to a little bit where you said that there was poor adherence with naltrexone tablets, but this is related to a question about opioid supersensitivity that was noted in some early studies on naltrexone. And then they put an article in the, in the chat box there too, but it says, do you feel this is clinically relevant considering higher discontinuation rates? And the article was published back. It's by, it's called naltrexone induced opioid receptors. Yeah. Yeah. I I've met her. So yeah, this is Einstein neuroscience. What is, let me look at this article. Is this, is this is in humans? I can't access the article right now. Jonathan, is this article in humans? Because when I met Dr. Zukin, the first author, I don't think she was. Right. Yeah. Mouse modeling. I can't section human brains, of course. Yeah. Because when I met her and Dr. Zukin was working in mice, but this is from 1982. So okay. Right. So there, there may be, there may be, let me see. Right. Inducing supersensitivity. So the concern is that by administering naltrexone, you make the patient more sensitive to, to opiates, to opioid agonists later. If I understand, is that what I'm understanding? I'm understanding the question correctly, Jonathan. Yes. Okay. So, so there could be something there. There could be something there. The, the thing is, is that those people wanted the people that will seek out well, the people that will seek out naltrexone typically have the goal of abstinence. And, and so the, the return to use is, is, is going to be something that they're going to want to avoid now that they're going to feel it more. Yes. We could counsel. We could counsel them on like, you know, like more of the, more of the like a worse outcome with return to use for them because they're hypersensitive. I think most patients will know that. I think most patients, yeah, yeah. The, the ethical and the ethical consider, yeah. The ethical implications of prescribing this medication. Yeah. It's definitely something that, that is, is, is valid to struggle with. But I think, I think patients know that. I think patients know how, how much of a risk it is to return to use and when they're getting the medication versus when it's worn off is there, there, I believe that they're in a different state sort of weighing their own risks benefits. So yeah, it is concerning. I think it's also something that it's a little bit outside of our hands of like, there's, there's, there's a, there's time that passes between when the medication is given and, and when people come off of it. And that's just something that is, you know, like having worked in other parts of psychiatry with long acting injectables for antipsychotics, we, we have the same problem there as, as the effect of the medication wears off, the, the person will, will have, may have a different thought process. And I'm going to go to the next slide, further considerations for clinical use. Yeah, it's also useful for patients who do not want to take or cannot take opioid agonist medications. Another thing that I wanted to mention is for our patients who are pregnant, it is not recommended. However, I will say, though, that if a patient is on naltrexone and then they become pregnant, it can be continued with this discussion with the patient, whether it is worth it to them if they want to continue with that. Dr. Kaye, I think there was another question. Yeah, I'm going to hold that one until the end. Okay. That's good. So let's get to the research article. And we're about halfway with the slides, so we're a bit on time. This research article is from a couple of years ago. And we're taking a look at the clinical implications, looking at the subjective effects on one hand, and then the plasma levels that were correlated with those effects. So essentially, it's a study, it's a secondary analysis of a study in the lab. So this is using human research subjects and their data. They came into the lab. These are non-seeking treatment, and these are participants that were not seeking treatment. These are participants who, and I have more data here, these are participants who had an average of 10 years of heroin use. They were in early 30s, late 20s, were using, I mean, this is around the year 2000, they were using about $50 worth of heroin a day. Most were smokers. Some other drug use, but mainly opioid use. So this is a small dataset. And what we looked at was, we looked at the subjective effects of a heroin challenge plotted against the plasma levels after getting a naltrexone injection. So all the participants, the 12 participants received were detoxed and inducted onto a long-acting version of naltrexone. This actual version is not on the market. It's a, it was, I want to say it was like 300 milligrams, no, I'm sorry, 384 or 192. And the version that's currently available is the 300 version. So this is a version of naltrexone that's a product that's not on the market. I don't think it never made it. I think there wasn't a big enough market maybe for it. And the one that did make it, Vivitrol, is very similar. So they were inducted onto, successfully inducted onto this naltrexone product. And then they were invited into the challenge session. The challenge session is basically a room where participants were monitored one at a time or two at a time. It's double blind. And they were given different samples and different challenges of heroin, different heroin doses from zero to 25. And then while they're given these doses, they're rating, they're giving subjective ratings of what the dose makes them feel like. If they like it, if they felt good, if they felt that it was a dose that they would buy again or wouldn't buy again. So it's a lab session that's designed to sort of like get at what's going on with the participant as they're consuming heroin in a controlled, monitored environment. So this dose of heroin, as I'm sure some of you can tell, it's not the dose of heroin that people are currently using. This is pre-fentanyl as well. So I'm sure it will come up, what is the validity in the fentanyl era? And I think that's a reasonable limitation of this study and a reasonable challenge to bring up. But, you know, this was a smaller dose. This 25 was the highest dose of heroin. And it still produced euphoric effects once participants were off of naltrexone. And we saw that as they went through the study in time, the secondary analysis, what this study does is that actually this secondary analysis, what it does is that it takes a look at the actual levels of naltrexone in the plasma and compares that with the subjective response, something that hadn't been done in the initial publication. And how do we do that? How do we compare those two things? We had to do sort of like a prediction interval. And what it was is that it used some mixed effect models to provide like a 95 prediction interval for changes in liking scores. So it's not exactly the liking score per se. It's the change in liking that we looked at and we looked at the prediction intervals. So like at what level of naltrexone could we predict that 95% of the responses would be below a certain threshold? And the threshold has been established in the literature to be a 20 millimeter change in the visual analog scale. That anything below that is essentially no changes, that somebody doesn't feel it, quote unquote, right? They're not feeling the heroin. So essentially we confirmed that levels above two nanograms per milliliter blocked nearly all the ratings of drug liking after getting heroin. So the two nanogram threshold is what the manufacturer has published, I believe, to be necessary to prevent the effects of an opioid agonist. And we confirmed that. So that's what we see in this figure. But as naltrexone levels are above two, this is the threshold right here. And this is logarithmic. So as we get, quote unquote, good naltrexone levels, we get good blocking. When we have lower naltrexone levels, it's a bit more unpredictable. And when we have very low naltrexone levels, our participants are describing that they like the heroin challenge. So that's what this figure shows. And the bands are the 95 percent prediction interval. And we can predict much better when it's above two nanograms per milliliter. But then as we're below, as naltrexone is being metabolized, we lose that sort of predictability. Any questions from this figure? No, none that are coming in at this point. And I just want to point out here that there's variability. There's folks that are in this one to two nanograms per milliliter range, and they're not showing any response to heroin. And I think that that's sort of what we see in the real world, that it's a little bit hard to predict. This is naltrexone only. The graph for the metabolite is very similar, and I'm not showing it. So sorry, the question was that, is this graph for naltrexone only or metabolite also in the serum? And I'm not showing the 6-beta naltrexone. I cannot remember if there's a figure in the publication for 6-beta naltrexone. There might be, and the reference will be at the end. But again, just focusing on the one to two nanograms per milliliter level, that's when the variability starts to show that there are some folks for whom one nanogram per milliliter may be enough. But again, we don't know that ahead of time. So the more conservative conclusion is that the two nanogram threshold is going to capture more. Okay. Next slide. Yeah, it's essentially what I've described, that the participants that had the serum level at two nanograms per milliliter, minimal changes from placebo. So they couldn't distinguish heroin from placebo. And then in contrast, when they were below two nanograms per milliliter, that's when we saw greater variability. And below one, we could add one other bullet point here, is that below one nanogram, most folks had a, here we go, below one, most had a response to heroin, and below half a nanogram, it's like pretty much everybody. And I think that also, going back to a question about naltrexone-induced hypersensitivity, this figure could be capturing some of that. We give naltrexone, they might start feeling the effects of heroin earlier, some might be feeling the effects of heroin later. So I think it's, again, that high variability, that different people are different. I see one question, it says, what are the effects of naltrexone on Q-inducing craving for opioids? I think we can table that one for the end if we have time, because this study or other studies, I'm not sure, this study definitely didn't look at Q-induced craving, and I'm not sure off the top of my head what other studies have shown. Okay, this is another way to look at the data that, again, oh, this is when we separate out the groups, and it's really not that different, except that the 2-nanogram threshold was not there for some of the participants who had the lower dose of naltrexone. So this sort of confirms that the larger dose of naltrexone is the one that we should be using, that we don't really reach good plasma levels when we're giving an injection of 192. It looks like, too, from your data, that there's at least one individual where their plasma level went down pretty significantly quickly. What did you think of that? Yeah. I mean, I'm sure, I think, you know, in this cohort, I'm sure we had, like, rapid metabolizers. That's my understanding. I think that they were also on, so patients were also on, participants were also on an inpatient unit, and they may have had their, like, cigarette use change throughout the study. I think they had permission to use cigarettes, but they, this was, you know, late 90s, early 2000s. They had available smoke breaks, but they could only smoke so many cigarettes during the smoke breaks. So I think sometimes, like, that will, that will change the metabolism rate. But yeah, that's what I made of the variability and how quickly the levels came down. Right. And especially, sometimes some patients will complain about, they feel like, you know, towards week three, it's not as effective for them, and they want to, you know, either take some tablets or they could get their dose, their injection a little bit sooner, but sometimes we have problems with insurance covering that. Right. Right. And I think, I think that's, that's exactly the take home that I want people to, to, to have in this, in this presentation, that, that there are going to be folks for whom they're metabolizing naltrexone quicker, and they would benefit from that injection in week three and not four. And it could be because their plasma levels are below two. So that's, I think that that's, that's something that, like, for, that I really want folks to be empowered to make that argument. I'm not sure who's on the other side of, you know, the insurance companies who, who may not want to pay for an earlier dose. I'm not sure that they might be convinced. I would hope they would be, because this is the data, this is the evidence. But yeah, that's, that's exactly what, what I want to impart. And that's the knowledge that I want to share with you all, that there may be folks for whom they reach that, that threshold in like week, like late in week two, this is almost week four. And yeah, those, some of them after week four, but not everybody. So, and that sort of correlates also with like the liking when we do liking and cross weeks. It really increases past week four. So let's see, I have a question. I can read the question from Alan Robbins. If, if your patient who refuses MOED except oral naltrexone and only takes that in high risk situations, is you basically using this Clare method, the question is, does he stay sober when not taking the, when not not taking the naltrexone? And if he does, then he's using naltrexone as an insurance policy to prevent use. Yeah. Yeah, I mean, that's a, I think that's one way to conceptualize it. I would want to engage that patient a little bit more and see if there's like. Other, if there's other avenues for reducing the harm. Oh, there's a response. Okay, gotcha. Sorry. Sorry about that. But yeah, I mean, that, yeah, that's, that's a good way, that's a reasonable way to conceptualize it. And, and also leaves a lot of other avenues for, for reducing harm. So, yeah, maybe don't, maybe that's, they're refusing to, to use other methods. Use other MOVDs. So maybe that's not where the conversation should head. I have a question. Yeah. About any pharmacogenomic testing performed on these test subjects? Yeah. The answer is no, I don't think we did. I'm pretty sure we did not. This was back in 2002. That was, the original site was published and I'm pretty sure I can pull it up real quick. But I'm pretty sure we did not. Nope, we did not do any pharmacogenomics, unfortunately. Excellent, it could be an excellent sort of like way to sort of argue, right, that like this is the genetic profile of somebody that rapidly metabolizes naltrexone, and then for that person, insurance would cover the early shot of ivitrol. So yeah, I like that. I like that idea of like, can we do some pharmacogenomic testing? Can we get patients their individualized medication frequency? So the conclusions of this study are that a plasma level range of one to two, right, so that's like one to two, like, is what's like recommended. Our study says that maybe a higher level going above two is, across the board, maybe a better, maybe a better piece of information to provide to our patients. And I didn't show these data, but the six beta and naltrexone levels being at or above five nanograms per milliliter are also what's necessary to block clinically subjective effect of heroin, i.e., liking heroin. And then that there is a high degree of inter- and intrasubject naltrexone plasma level variability, and that should be accounted for when treating patients and when providing medications for them. When we have somebody that rapidly metabolizes naltrexone in three weeks or two weeks and change, that that person should be entitled to having a Vivitrol shot sooner rather than later. So that's the take home. How we get there, how we get to discovering who those patients are that need it sooner is something that's like the future steps of medication research. And I think that's something that's worth pursuing because then we can deliver patient-centered treatment. And in the meantime, you know, we can listen to our patients. We can track who's returning to use at week three, who's having those slip-ups, if that's what they're calling them. Like, who are the patients who need the extra support at that time after their last injection? How can we identify them better? And how can we say, okay, it's time for another injection? So I think that that's the conclusion I would like to have. Okay. So we do have a question and you alluded to this. What do you think would happen with fentanyl? Are there any plans maybe to test this with fentanyl going forward? Yeah. So I think first is that we would need to do some like naturalistic studies seeing if naltrexone is performing worse. So in the randomized control trials, naltrexone did not perform worse when successfully initiated, when successfully inducted. But the naturalistic studies may show that it does, or maybe it doesn't. I don't think we have those data yet. So the first step I would say are sort of like, it would be studying what's out there clinically, like what are we seeing? Are people that are on naltrexone, are they returning to use at a higher rate than those on methadone and buprenorphine? Are they experiencing overdoses at a higher rate than those on buprenorphine and methadone? And then yes, I think the field of the human lab should move into fentanyl challenges and seeing how people respond to fentanyl, because that's what people are using in the real world. So that's where I think the future is. And we did have a question from earlier on as well. That was, does naltrexone extended release have overdose prevention data? How does it compare to buprenorphine and overdose prevention? Right. I think those data, there may be a few studies that are pretty recent that are coming out. And I think my understanding is that it doesn't perform as well. So I think there are going to be more studies coming out. I think overdoses for some reason and fatal overdoses were not something that we were looking at very closely or as closely as we should be looking at them. So yeah, I think that that's something that needs, as we have more numbers, unfortunately, of overdoses, we can take a closer look. But I think what's come out so far is that buprenorphine and methadone perform a little bit better. And there was another question a little bit earlier on about what are the effects of naltrexone on Q-induced craving for opioids? Yeah, that's one that we didn't take a look at in this study. And my understanding is that naltrexone is helpful for cravings. That's what my patients have reported to me, that it does decrease their cravings. The problem with Q-induced is that when you look at these studies, that's not how Qs come up in the real world, right? You're not in a study. Qs can come out of nowhere. Life is extremely variable. Who you run into, what they talk about is completely out of your hands. Whereas when we do Q-induced studies in the laboratory, the participant is in the study. I'm not sure if you're able to answer this one because it is on alcohol use, but have you noticed the effect of wearing off at three weeks when somebody is using the extended release naltrexone for alcohol use disorder? Because this participant has had some patients complain about that. Right. I haven't, but that makes sense to me. That makes sense to me based on these data that I just presented on. Yeah, that's the last slide. And then these are the references. And I can stop sharing so it's easier for me to see the screen. We also had another question come in. Are there any studies about naltrexone plasma levels correlating with therapeutic response in the context of alcohol use disorder? Yeah. I think there's one for sure. When I was writing this paper, I came across one. Maybe it's the first author is Bigelow, if I'm not mistaken, but off the top of my head, that's what I remember that there may have been just one therapeutic, yeah, that did a therapeutic response and compared it against plasma levels. There may be more, but I know there's at least one. And then I can read the other comment. Yeah. Regarding overdose prevention relative to buprenorphine to the context of X-Bot. Right. So the X-Bot study is one that I referenced earlier. And the, let me see. Yeah. The sort of the survival analysis Yeah, that's right. And greater risk for overdose on naltrexone compared to buprenorphine. Yeah. Yeah. So that's, that's what's come out. Well, there should be more studies coming out that compare the overdose risk. And, and yeah, I guess that should inform our clinical decision making. We do not want to set up our patients for failure. So, so it's, it's something that's, that's definitely on my mind. I hope it's on your mind too. Like, this is a valuable medication and there are risks and benefits to using it. So the more we know about the risks, the better a job we do. Yeah. And the, yeah, the overdose risks. So yeah, based on claim data. Yeah. That's yeah. Okay. Well, it looks like we're getting towards the six o'clock hour. I don't see any other questions coming in. I'd like to thank Dr. Castillo for his presentation today. And also thanks SAMHSA for the sponsoring this ORN series through their generous grant. And I'd like to remind you all to come next week for our webinar. And again, it'll be at five o'clock and we look forward to seeing you next week. So again, thank you, Dr. Castillo. And I hope to see you all next week. Yeah. And thank you all for giving me this opportunity. Really appreciate it. You're welcome. Thanks so much. Bye-bye.

naltrexone

heroin

plasma levels

subjective effects

individualized treatment

fentanyl

overdose prevention

buprenorphine

pharmacogenomic testing