I think we're going to get started just to let you know we had to switch the posters out there. So just make sure everyone's in the right session. We're here. The Extended Release Buprenorphine for Vulnerable Populations with Opioid Use Disorder Clinical Challenges Pharmacokinetics and Outcomes. So next door is the alcohol use disorder and path one. So sorry about that. Thanks for. Oh yeah. Ned's here. So thank you for attending. Thanks Ned. We'll start there. So I'm Sandy Springer. I am a professor of medicine at the Yale School of Medicine in the section of infectious disease and I'm also an addiction medicine physician and I'm really excited to be here with my colleagues. And we have a session that we're going to discuss something like that. I think Ned and others and I have always talked about our lessons learned through research and how could this improve or you know can make changes in clinical care. So I was just going to briefly introduce the panelists and then our discussants and then when they can't come up they can give more information about their background. So we have Manesh Dr. Gopaladis who's at Columbia and he's a co-chair. We have Michelle Strong from Prisma Health Care and we have Dr. Rachel Luba from Columbia as the panelists and then we have discussants Dr. Alan Whitwin Dr. Francis Levin and Dr. Ned Nunez who's on every session so far and I'm glad you got your nap. So let's see if we can do this. These are our disclosures learning objectives I'm not going to read through but really the bottom line of this is you know as you saw vulnerable populations. This is the group we work with and we're really trying to help and we I'm going to start this off with a preview of an ongoing clinical trial that's really trying to help this particular population and then we're going to discuss some of important caveats things that we've learned and how this could potentially influence or you know at least make you ponder how we should consider treatment of opioid use disorder and importantly we're talking about extended release buprenorphine here. So I don't need to tell you all about the opioid overdose and drug overdose epidemic and this is unfortunately older data now that we have now surpassed drug overdoses over one hundred and seven thousand individuals in this country and as we know synthetic opioids are really fueling this. I'm not. We also have of course a stimulant epidemic as well but we're going to be really focusing on improving treatment for opioid use disorder in this particular population and I'm an infectious disease clinician and just the point of this study that we're going to discuss and some of these other points is that in addition to overdose and morbidity related to substance use and opioid use in general we also are fueling this opioid epidemic is fueling new infections across the country including acute hepatitis C HIV HIV is not over. I have to remind everybody that brand new HIV epidemics occurring among people who use drugs not just through sharing and injection drug use equipment but also condomless sexual intercourse in Medicaid and non Medicaid expansion states. We also have importantly have seen acute hospitalizations related to other infections so serious bacterial and fungal infections endocarditis. This is older data but I just use it to show the marked increase since the earlier the epidemic started with prescription opioids transitioning to heroin with 50 percent increase in hospitalizations related to serious infections related to opioid injection and you know there's many reasons for why we're seeing these but importantly talking about the silos of care and really we should be integrating care and trying to improve identification of substance use disorders opioid use disorders in all settings. I'm in the hospital I rarely see somebody doing a DSM 5 assessment for opioid use disorder and people who are admitted with infections when they come in. We really should be doing that also for all substances. And you know it's a particularly vulnerable population. Here we're going to be talking about hospitalized patients but in general most of these patients have been treated punitively and are not assessed for how we could actually give them treatment while they're hospitalized not just for their infections but of course their opioid use disorder. So just a brief snippet I just have to say this trial started out as a project commit unfortunately the screeners cut it off coordinating opioid use treatment through Medicaid management with infection treatment. It's a UO one funded by NCATS and there's a multiple P.I. project myself Ned Nunez Francis Levin Kathleen Brady and then Alan Litwin and others as co-investigators and it's a multi-site trial and I just have to say how it started. I was Ned was on a V.A. study that executive committee so as many Patraka's are co-P.I.s on a V.A. study and I went over to Ned and I said what do you think about integrating infectious disease treatment in patients who are hospitalized with infections and treating them together. And he's like ah so treating infectious disease like an addiction. I like it. And next thing you know he's on the phone talking to Kathleen Brady Francis Levin everyone and we put together this trial and it was funded in 2019 backwards. So the study aims are really trying to test at the time was a new model of care and I'm really happy to say in 2023 we're seeing more and more hospital settings trying to integrate opioid and treatment in patients who are hospitalized. This was just a new model of care integrating infectious disease treatment management with opioid use disorder management using long acting buprenorphine in this case it was the FDA approved treatment of sub locate that was clinically available. So and what we wanted to do is have hospitalists infectious disease clinicians others trying to help improve integrating of this care compared to treatment as usual. So a person might have an opioid use disorder would be referred to whatever treatment was available in the hospital and then the specific aims the primary one was to assess would that integrated care model improve the likelihood of receipt of a form of medication treatment for opioid use disorder three months after that initial assessment and randomization. We also wanted to look at of course other secondary outcomes reduction in substance use opioid use overdose nonfatal and fatal and also improving infections management. So as a three site study Connecticut and then also in Pennsylvania and Greenville South Carolina so our eligibility I'm not going to read them off here but really meant to be you know really inclusive and not exclusive and the exclusion criteria are really related to ability to have long acting buprenorphine in this case sub locate and then the rest were just any infection that they were hospitalized with and it included hepatitis C viral load detectability hepatitis B active viral load HIV as well as obviously in fact infections with bacterial fungal and having a moderate to severe opioid use disorder and of course being hospitalized. So it's a random randomization one to one but I want to really point out and this is going to be discussed by Michelle that there was a really wonderful model of this nurse care model and they would we had educational pieces people telling people and informing them of their opioid use disorder diagnosis which in some cases might have been the first time really talking about harm reduction other forms of MOU D how to access them giving them educational materials and importantly talking about that after discharge plan about how to get access and then helping them with transportation to get to treatment and their medical appointments which could be associated with follow up with their infections or other medical comorbidities as well as with their opioid use disorder. So that was really critical. So the intervention as I said was a three month intervention and we had a six month follow up to a time point and they received injection of long acting buprenorphine while they were hospitalized and we had an IND also to do rapid induction. So it could occur within one to three days and then because it was an IND we also monitored them for over two hours after the first injection. The details are in the protocol paper so I'm not going to go through all of that but you can scan that and I'll tell you what what we did. So this you aren't meant to read but just want to say this was the consort diagram as of August when we submitted this and we had one hundred and sixty five consented out of the 200 now we have over one hundred and eighty consented to meet. We might be shy of the 200 goal but just at the top point we screened over two thousand individuals now it's close to three thousand individuals who had never been identified with substance use related issues in the hospital and that's like a detailed identification protocol that we came up with. It's not just searching ICD 9 or 10 codes but really looking at laboratory data hepatitis C drug overdose and other things and then really showing you the numbers of individuals and why they might have declined really on another form of MOUD or wanting another form and importantly in majority which will be interesting will be discussed later wanting methadone which was is really interesting and this is 2019 when the study started and it's ongoing now in 2023 and you'll see some others but we've randomized to TAU and long acting buprenorphine there and I just want to end the point I'm not going to we obviously are going to talk about primary outcomes but really the vulnerable population like I said we have now over 180 individuals so this is 158 you know happy to say that about almost 50 percent are female have identified as female which I think is important about 50 percent 56 percent had some form of insurance and not surprisingly 40 percent unfortunately are unhoused and many have significant psychiatric comorbidity including depression PTSD ADHD also 20 percent alcohol use disorder and I think Manasha is going to talk about this but by the time we get to see them some of them have already been on some form of opioids and I have to say this population was super super sick so you think about it septic emboli to the brain multiple might have undergone cardiovascular surgery or awaiting that spinal embolization that spinal osteomyelitis so there's a lot of severe infections and that's going to be important when you hear about the buprenorphine blood levels and considerations because these patients were excluded in any trial with sublocade for FDA approval the infections so I was just mentioning this in the top three were bacteremias abscesses not skin abscesses but abscesses elsewhere in the body and importantly active hepatitis c 50 percent had viral low detectability we aren't going to talk about it here but I just have to point out that six months after and when we look at the people who've completed the trial nobody was offered DAAs or direct antiviral treatment for curative hepatitis c treatment so a missed opportunity and although we didn't have very many who had HIV we also did HIV testing sexual and injection drug use risk assessment and prep eligibility pre-exposure prophylaxis majority met prep eligibility and no one was offered prevention treatment for HIV in this population so the DSM-5 substance use disorders lots of comorbidities not surprising besides opioid use disorder a lot of stimulant and you'll see the timeline follow-back this is any use in the past 30 days at prior to baseline majority of reporting heroin use and then this is the dark green fentanyl use again we started in 2019 cocaine and then the stimulant methamphetamine really this is we're seeing in our South Carolina site in Connecticut it's cocaine cocaine cocaine and then the mean days of use in the past 30 days again they were reporting in the timeline follow-back over about 18 days of heroin use in the last 30 days and then fentanyl about 10 days and then we're also now seeing and we're recording it now but lots of xylosine now intentionally that I'm going to end but I just wanted to say we talked about this at AAAP in Florida in December but we put together a case series of that rapid induction in the some of these patients using low dose transitions and it really talks about some of the protocols that we've used to help safely get people on to extended release buprenorphine while they're seriously sick while they're on long-acting opioids for pain control or might have been put on methadone so I think that's just important to talk about and really looking at these clinical characteristics so I am we're going to do the takeaways later but one of the things that we have to think about is when we initiate treatment it's not just going in right a lot of people aren't ready maybe for treatment or they're seriously ill and we saw this with COVID if anybody was taking care of patients in the hospital multiple trials coming at them multiple medications vaccine trials and you know this asking someone to participate in research when you're seriously ill and then also trying to change and how we present access to treatment for very vulnerable populations has been challenging but we have an amazing group of people and you'll hear from Michelle too about some of the things that we really should be considering not just offering a form of medication treatment for opioid use disorder but the really important other services do they have housing how can we help you transportation do you have a cell phone do you have a form of identification all of these things that are really really critical so what we're going to do is we're going to turn it over to Michelle now to talk about that and then what will be interesting is we've been capturing buprenorphine blood levels in some of these patients and Manesh and Sarah are going to talk about that. Okay so I'll leave it to you guys and then I'm going to go down here. Thank you. My name is Michelle Strong. I'm a nurse practitioner. I work at Prisma Health in Greenville, South Carolina. I'm the clinical lead for our inpatient addiction medicine consult service and one of the clinical leads on the commit study as well. I'm going to talk a little bit about the real world challenges of initiating on these patients. Dr. Springer really set the stage for that but understanding who these patients are and what we're working with I think is really important to think about as we get into what are we dealing with what are the results of this trial and things that Dr. Cabaldas and Dr. Lippa will discuss. So first if we want to talk about who's in the study we have to talk about who's not in the study. So patients that declined study participation were ones that typically preferred a specific form of MOUD. Overwhelmingly in this category it was patients who preferred methadone. This was patients also discharged prior to enrollment. So all of our patients who were consented to the study needed to be consented and randomized while they were still hospitalized. We know that this is a challenge for patients with opioid use disorder despite how sick that the majority of them are. I think we've all been called to understand that in these patients there are things outside of their health care that matter to them sometimes more in a way that many of us can't seem to understand but priorities like housing, job security, food security, family security and then the call of addiction I think also pull these patients out of the hospital at faster rates than others. So unfortunately you know many patients that we had approached for study participation who would have qualified fit the study criteria and been fantastic happened to discharge either self-discharge or you know were discharged by the primary team before we were able to enroll them. We also had challenges with patients denying any opioid use. So when they were approached by study clinicians or study staff not being open to discussing their opioid use with us I think is something that is a newer challenge that we're starting to hopefully see the edge of as more hospital teams are approaching opioid use as a part of comprehensive care, as more hospital programs have addiction medicine teams that are able to help support these patients while they are inpatient. Being in the hospital is a really vulnerable time for a lot of our patients so openly discussing their use and feeling like they aren't going to be addressed, aren't going to be treated compassionately or met with care is challenging. So while we may have had urine drug screens or other factors that led us to believe that patients used opioids for the commit study patients had to self-report opioid use and again with DSM-5 criteria patients have to be willing to participate in that activity with you as the clinician to be able to make a diagnosis. Again we discussed implant discharge and then patients declined wanting to participate in research. Dr. Springer said at best our patients are so sick they are hospitalized for reasons that you know would keep them there some of them for weeks on end awaiting surgery, septic emboli, osteomyelitis, all of the above. So sometimes the thought of participating in research or something outside of just their basic care at that point was too much for them to handle. Into patient complexity. So again all of these patients had to be hospitalized. Being in the hospital is uncomfortable. If I was hospitalized for weeks I would be the worst patient in the world. If I couldn't go for a walk, get my own water, grab a salad, I mean anything, it would be terrible. I think we can all understand how challenging of an environment that is for our patients. So again that plays into what we are working with here and who is in this study. These complex infections we are dealing with you know things that could take antibiotics weeks to correct at best. The majority of our patients were bacteremic or septic. Many had endocarditis that were requiring a valve replacement. So the challenges of figuring out how we are going to enroll, randomize, get patients engaged in buprenorphine treatment and then on to a long-acting injectable while dealing with the fact that they are waiting for surgery added a lot of complexity to what we were working with here. Again with that you know into the medication interference. What are they on for clinical care that is going to make starting a patient on buprenorphine challenging? Is that always an issue? No. Again we talked about it last year. We used a lot of low-dose inductions and transitions to get these patients on to sublingual buprenorphine safely so then we could go ahead and administer that long-acting. And you know clinical readiness for injection is something that has to be considered. Again we you know worked really hard with these patients to develop a clinical readiness assessment to figure out when the appropriate time to give long-acting buprenorphine is. We had the IND that would allow us to inject as soon as day two post-sublingual but sometimes that wasn't you know appropriate based on all of the other treatments that all these patients were undergoing. That clinical readiness tool allowed our providers to go through a checklist analyzing other medications that the patients were taking, lab data, etc. that would make patients either high or low risk for potential you know adverse outcomes or concerns for injecting that early. So that was a tool that was very helpful through this process to figure out who as sick as these patients are is appropriate for the injection now and who we might need to wait a little bit longer, keep on sublingual buprenorphine for a few more days, allow them to stabilize, allow their care to stabilize before we were able to give that injection. This is some anecdotal data. I'm not even going to call it data. These are some anecdotal remarks that I think will set the stage for what became our PK study that Dr. Capaldis and Dr. Lubow will discuss with you. So just take these as they are. Keep them in the back of your mind as we move into the next sections. What are the patient's concerns with extended release buprenorphine, sublucate specifically? Concern for inadequate coverage for that first month? Concern for breakthrough withdrawal symptoms? What's going to happen if I get the injection and I have withdrawal? What am I going to do? How are you going to be able to help me? And then what is the need for supplemental buprenorphine? So our study provided sublucate for three months to these patients. Now, if they were clinically being seen in the outpatient environment and they got this injection covered through insurance, if there was a need for supplemental buprenorphine, what would happen? Would the insurance allow that? Would they deny that? In South Carolina specifically, we have a lot of clinical challenges with patients who are receiving sublucate or extended release buprenorphine who may still be experiencing breakthrough withdrawal symptoms and cravings and then we can't get additional sublingual buprenorphine covered on top of that. So these are all just things to think about as we are talking about what is the shared decision making process for putting a patient on a long acting injectable product and something I think will be further discussed by the rest of our team. And then again the recruitment implications talking about what it is to get patients on a research study. Nobody wants to do anything extra right. Everybody just wants to do what they do and go about their lives. These patients specifically you know those who have come to understand research love it. Those who have come to understand the care and the additional things that can be provided by a research study I think speak very highly of it. Again Dr. Springer shared that you know through research we were able to provide transportation to these patients and that became foundational in how they were following up what access they were able to have to get to not only you know their appointments with the research team but sometimes appointments that they would not have been able to make on their own. Again many of our patients did not have cell phones have limited access to housing or unstably housed for many days throughout the month. So research became an avenue for them to having a cell phone being able to check in with our team having additional people in their corner working through this process of the early stages of potential recovery no matter what that looks like for them. I think the beauty of this study is you know treatment as usual and randomization to treatment as usual as an option did not necessarily mean medication for all of our patients. We hoped that that was the majority of the way that they would go and we would help connect them to care with that. But medication was not required as part of the treatment as usual arm. So we did have many patients who continue to engage with us in the research process despite not choosing to be on medication. So I think that was also an interesting piece of how are we able to keep and support patients in this vulnerable population with or without medication. And then obviously you know progress of their hospitalization. So where are they in this hospitalization process. Are we able to use buprenorphine on them appropriately and are we able to move to the point that they would be appropriate for injection of long acting buprenorphine Hi everyone I'm Rachel Luba. I'm a clinical psychologist and recently became assistant professor of clinical psychiatry at Columbia University. I'm not directly involved in the project but have a lot of overlapping interests and was a co-fellow with Manesh and kind of that's how I became involved. So today I'll speak briefly about our understanding kind of what we know what we don't know about the impact of high potency synthetic opioids primarily fentanyl on initiation of MOUD and for the topic of this talk primarily buprenorphine. And so we're all extremely familiar with this graph. We know that there is a stark and devastating rise in opioid overdose deaths primarily attributable to fentanyl. We also hopefully know that there are a lot of drivers of fentanyl proliferation. That mean it is likely to stick around in opioid and drug supplies for the future. And that mean that fentanyl has replaced it and is continuing to replace heroin in most drug markets. Just some recent data suggesting that between 53 to 83 percent of individuals presenting for treatment presenting for research are testing positive for fentanyl that varies regionally and also some recent data from the National Drug Early Warning System suggesting that between January and June there have been 48000 non-fatal fentanyl overdoses. So I think while it's extremely urgent and important to focus our attention on overdose we also now have many people most people with opioid use disorder who have chronically been using fentanyl for many years. And we still don't really know whether that that raises differences in how we treat opioid use disorder whether these high potency synthetic opioids and fentanyl specifically will change our approach to treatment. OK. And part of why we don't have a lot of answers is because we don't have a lot of good pharmacokinetic or pharmacodynamic data on fentanyl at least not the way that it's being used today. Most of our data comes from highly controlled clinical trials or surgical settings anesthesia which is very different from the way that people are using fentanyl now. What is published what's there suggests that in terms of new opioid receptor binding fentanyl has a similar affinity to morphine but I put a question mark there again because there are limitations to what we know. It does seem to be slightly more potent than morphine in terms of potency and efficacy for GPCR activation. We know that it's significantly fast has a significantly faster onset of action crossing the blood brain barrier much more rapidly than than heroin and morphine. And it's highly lipophilic. So obviously the faster onset of action has implications for overdose and respiratory depression. But as we heard yesterday from Fernando Montero's talk it also drastically impacts people's experience of opioid use. So someone who might have used heroin once every six hours once every eight hours is now using fentanyl every one to two every one to three hours and that's extremely disruptive to people's lives it's extremely economically disruptive. And I would I would imagine it's also presenting pharmacological differences right if someone's using that frequently what does that mean for me opioid receptor occupancy and our ability to use treatments and it's highly felicity is still sort of a an unanswered question. What does it mean when someone's testing positive 12 days after they said they stopped using what are the differences that lead to those differences and what does that mean for starting treatment and so there are also a lot of clinical concerns regarding fentanyl and what it means for starting treatment. We know that there was early studies from patients asking patients to compare their experience with fentanyl versus heroin and overall they said they found fentanyl withdrawal to be more severe having a faster onset and lasting longer compared to heroin withdrawal. We know that among clinicians there are concerns about buprenorphine precipitated withdrawal and among patients there's been a lot of case reports published documenting the incidence of precipitated withdrawal in the context of buprenorphine and some guidelines for potentially mitigating that risk or avoiding that risk. There's been other data suggesting that it's actually maybe not that prevalent but again an unanswered question that I think is unfortunately driving a lot of people away from a highly effective medication. And so this leaves me with the question of does do these shifting patterns of use does fentanyl shift or necessitate a higher dose in order to be therapeutic. And so to take a step back sort of what is a therapeutic dose of buprenorphine and what do we know. I really like this date this graphic that depicts sort of the association between buprenorphine plasma concentration and occupancy of opioid receptors distinguishing between the agonist effects of buprenorphine and helping to control craving and withdrawal and the blockade effects of buprenorphine to reduce drug liking reduce loops the reinforcing effects of opioids and potentially to reduce self-administration. So the earlier modeling data which is mostly done with sublingual buprenorphine suggested that a dose between two to three nanograms per milliliter was necessary to reach the therapeutic threshold to sufficiently reduce craving and withdrawal and to control or reduce self-administration. And that's thought to be associated with between 68 to 75 percent mu opioid receptor occupancy. And there's been a recent reanalysis of some of the pivotal trials that led to the initial approval of sublocade by Lafont and colleagues to just sort of further refine and explore what plasma what ideal and optimal plasma levels are associated with clinical outcomes. So the gray bar here is signifying that that dose range of two to three nanograms per milliliter. And here we see that that dose range is sufficient to suppress drug liking in individuals administered hydromorphone six milligrams and eight milligrams and that dose range that plasma range also significantly reduces self-administration of hydromorphone. This was from the phase two trial and then the larger phase three trial again recently reanalyzed that same dose range two to three nanograms per milliliter was associated with increased percentage of opioid free urine drugs urine drug samples and a higher percentage of zero or very low craving scores. So this would suggest that with sublocate as has been demonstrated with sublingual buprenorphine that dose range of two to three that plasma concentration of two to three nanograms per milliliter seems to be associated with optimal therapeutic benefit. There was some evidence in this reanalysis that perhaps a slightly higher plasma concentration is needed to fully suppress opioid withdrawal symptoms. But the authors do note that even at lower plasma concentrations many participants still had craving scores of zero or in the very mild to low range. So this is sort of an unanswered question. I think one caveat of all this data even though I think it's really useful and interesting is that these trials were carried out in 2014 and 2015 long before fentanyl was where it is today. So we still we don't know if this is still the case for high potency synthetic opioids. So will our will our understanding of therapeutic dose shift. Should it continue to shift. I sort of naively asked yesterday like wait our clinicians measuring plasma buprenorphine levels and was told no. And so that leads me to think like well should we be is that useful. And if it's not and if we can't how can we respond to patients who say I'm at a therapeutic dose and I'm still feeling craving I'm at a therapeutic dose and I'm still using more than I want to. And I think that comes down to really being responsive to individual variability. All right. My name is Manesh Kapaldas I'm an addiction psychiatrist and also a T32 clinical research fellow at Columbia. I get to work with this fantastic team. I'm very excited to actually share preliminary data from Project Commit focusing on buprenorphine blood levels as well as outcomes related to fentanyl use primarily. OK so this is a busy slide but obviously we're going to get through it. So in this study buprenorphine blood samples were obtained from 36 participants who are randomized to the extended release buprenorphine treatment arm. So three samples were collected from each participant and at least you can see the time period. So sample one was one hour prior to or up to eight hours after the first injection was given sample to 24 to 48 hours after the first injection and then sample three around the four week mark so 21 to 35 days after the first extended release buprenorphine dose was given. So importantly this was before the second injection was given to the participants. So what you see at least in this graph we split up the participants into two groups. So those who reached this threshold this target threshold that Rachel just mentioned versus those who did not reach this threshold. So in the figure you see on the y axis is buprenorphine levels buprenorphine blood levels and then on the x axis is the sample sample one two and three. So the observations and I've also placed with the dotted line the target concentration of two nanograms per milliliter. So really what you see here in red again are the participants who did not reach this target concentration and that represents the majority of this sub sample. So 78 percent or 28 did not reach while only eight people reach that target threshold. So each line represents a particular participant and then those who did not reach are shown in red and then those who did reach that threshold are in green. So this is just another way to represent the same data. So essentially here what you see is the relationship between buprenorphine blood levels and time and this is time in days. So again you know the majority of the individuals as you see in red did not reach this target concentration or this threshold of two nanograms. And again importantly prior to the second injection while only eight of the 36 or 22 percent reached this threshold which you see in green. So this is a table at least just to try and understand you know maybe who who's in which group. So baseline demographic characteristics of the participants with blood buprenorphine levels. So the first column is overall so the total sample and then the next two is by threshold. So those who did not reach and then those who did reach. So I understand you know here that data collection is still ongoing and also the sample sizes you know in some of these specific cells are low. So there's no P values yet but you know at least it's us you know to get some understanding of you know who may be in these groups. So you know compared to those who did not reach threshold those who did reach threshold are more likely to be female less likely to be homeless more likely to be married and less likely to earn income of less than 10000 a year. So this is getting at perhaps you know something also that I'm interested in is perhaps the social determinants that affect our patient population. So here are just a few clinical characteristics of the sample. So again overall and then by threshold you know you'll notice at least the low percentage of individuals testing positive for opioids. Now again this is on you talks. So several reasons you know why this actually may be you know as Dr. Springer mentioned you know these are participants or these patients who come into the hospital you know they are hospitalized and you know they it varies when the you talks you know can actually be done by the clinical team and also they are already a lot of them actually the majority of them are actually already on OUD treatment at the time of this test so that may explain it and also you know particular opioids some of them actually have you know they may have already metabolized and won't actually be picked up in the urine fentanyl on the other hand you know it ranges so it could still actually be positive several days or even several weeks and that's why also you see that that it's a little bit higher but essentially you know this is you know a population that is using high potency synthetic opioids so really also what you see from this table is that compared to those who did not reach threshold you know those who did are at least I'm looking at the percentages now you know are at least more likely to report that they are or at least less likely to to report that they're using heroin and fentanyl and then also have fewer days on average of heroin and fentanyl dose or at least usage so this is actually just showing longitudinal data so again part of the study we at least one of the things that was done was to collect at time points so baseline then week 4 week 8 week 12 as well as week 24 so here you're seeing at least self-reported heroin use you know again divided among you know those who are not at that threshold which is shown in blue and then those who are at that 2 nanogram per milliliter threshold which is shown in green sorry in orange so compared to those who did not reach the threshold after the first injection those who did reported less heroin use and then importantly less heroin use over time you know I should have probably put the percentages but you know where you see the blue bar there's no orange bar but that essentially means it's 0% so those who reach threshold were less likely to test positive for opioids and primarily you know what we're measuring here is heroin those who reach threshold reported less fentanyl use and also less fentanyl use over time and those who reach threshold also are less likely to test positive for fentanyl so at least confirming the information provided by self-report so this is at least showing a mean opioid craving by buprenorphine plasma level so this score craving at least is measured on a scale of 1 to 10 you know it's low for both groups as you can see and again you know this is somewhat challenging to measure especially you know if the population or at least our patients are receiving opioid use disorder treatment you know there's some separation after week 8 but again you know these numbers you know perhaps not even clinically significant and then finally just wanted to show some data regarding withdrawal so as measured by the cow so this is a mean cow score by plasma buprenorphine level so those who reach threshold had a higher cow score on average you know until about week 11 you know again low for both groups you know because primarily receiving medication treatment and again you know is this really clinically significant so challenge to measure these things but at least you know trying to understand a little bit in terms of the differences and what happens beyond the first injection looking at weeks you know 4 8 12 and 24 can we actually capture some of this it's at the end so yeah just prior to the second injection yeah good only only at the end of the first injection so prior to yeah so by we exactly yeah no that's a good clarification point all right I'm gonna turn it over to our fantastic discussants you know obviously we are all available for questions I have a ton of questions myself you know so I you know I think you know probably will open it up so we're gonna have you know obviously Ned and Francis have to be at every session and be a discussant and then of course now we have Alan Litwin so they're gonna discuss and probably ask questions and then we also want to have this interactive session too so feel free to ask questions as well so you guys go ahead okay I think you alluded to the drug level question rarely we would do dosing for kind of looking at diversion for people on decreased pickup schedules and very interesting small numbers you know there was only eight people who didn't have who were in the adequate level of more than equal to two but they noticed the craving was the same and so I guess the question is what you know what are the thoughts for kind of doing some you know serum bup levels based on this data and other people's experiences yeah you're saying just clinically do you think there's you know kind of what we learned whether yeah it should be potentially you know doing some levels yeah the proof you know I mean I think it's I think it's helpful to understand and even see what potentially may happen over time I can actually give you an idea you know as early as that first window of one month what potentially may happen over time but yeah also understanding you know that this information is biased by when the data is collected and also if it's already being addressed so yeah sorry it's there you go yeah so I'm struck that even a day you know at sample to four patients are under the threshold so and there's tremendous inter individual variability in the blood levels that are achieved and I think this is consistent across all the extended release formulations of everything that we whatever we have this is a trough no that was trough that was trough so yeah so you know we hear this with Vivitrol all the time the patient gets to day 21 and they're craving and they're starting to use again and actually we've looked at Vivitrol blood levels also it's the same thing it's a ton of patients that have really low naltrexone blood levels by even 14 days after the shot and definitely 21 days so you look at the package insert prescribing information you see these nice blood level graphs, those are means, those are averages. And there's all this, you know, scatter, which, I mean, you guys show this, it's really striking. Yeah, this really focuses on, you know, first injection. Well, that's, yeah, but that's fine, right? So it's supposed to accumulate and everything, maybe it'll get better, but still, you look at the means, you'd expect it to be better. I mean, the controversial questions might be to give buprenorphine on top of, sublingual buprenorphine on top of the injectable until you get that second and third dose injected and then you get a high, because if you look at the graphs, they generally do ratchet up after the second and third dose, and maybe the patients or participants are doing that themselves because the levels are low, you know. I think the other thing is that these guys, these people were really sick, and some of them were still febrile, had infections, we don't really know, you know, the other question is inflammation, how could that affect, you know, some of these blood levels, differences in populations, and none of these patients were ever included in those original trials, so I think those are other things. Yeah, I see, I guess I just wanted to respond real quick. I think the other thing important about these levels, right, is because it helps to confirm, you know, what our, it helps to confirm what our participants and our patients are saying, right, because they come in and they are actually saying, hey, this is not enough, and then, no, this is on, and it may, you know, it's very easy just to dismiss or at least say, hey, you should be fine with this injection, things will be okay, but it actually, you know, helps to confirm, verify, and, you know, back it, you know, with data, so it's actually that, you know, the vast majority of people are actually below this threshold. Are you moderating, or who's going to pick the question? Yeah, no, no, I saw your hand up. Do you need more time? There's a... Okay. Is it on? Tap it, see if it's... Yeah, there we go. What's the relationship between the blood level and the receptor binding? I think I may be operating off old information, but my understanding when I first trained with buprenorphine was that it binds really tightly to the receptor. You really don't need much of it for it to do what it does, and we're talking about blood levels, and I like that because we can measure it, and we don't really know what's going on with the receptor, but is there a lot more heterogeneity than I was trained to know, that you really do need a lot more buprenorphine than I thought I did? Because I thought... Yeah. When I was taught, it was anything beyond four milligrams, there's really no difference in terms of how much receptor binding there is. If you had been here 20 or 25 years ago, there were these Suboxone 101 courses, and if you said that you were giving more than 12 milligrams, it was considered heresy. And literally, I remember people like saying, well, I'm in my practice, and I have to give 16, and you would get, like, shot down for saying that, and I think that even though there's... The thought was if you occupied 70 percent, it would do enough, but you still have those unoccupied receptors, and if you have something like fentanyl, it may override the... I mean, that's my understanding of what might go on with... Right. Which gets into a whole other question. I thought fentanyl bound at a separate site on the mu receptor. Yeah, it's complicated. There's a physicality to the mu receptor, and that... But I think the PET scan studies show that you really needed to get up to high doses to fully occupy the receptors, if I understand that study correctly. But do we understand, like, what... In terms of blood levels, yes, but do we know how that correlates with how much is actually binding to the receptors? Well, the PET scan measures what's on the receptors. Okay. They're actually PET scans of the brain, so you're actually measuring receptor occupancy in the brain with the PET scan. So we can kind of use the two synonymously. Well, no, you're asking a very good question, which is... There are a bunch of, like, equations, too. Yeah, there's equations and stuff, but... Try to calculate it, but it's an estimate. I think the take-home is just there's a lot more variability, probably, than you would be led to believe if you just read the package insert and look at the PK averages. Does the take-home message just use more? Yeah, probably. Yes. I think this gentleman's going to say the same thing. Oh, okay. Hi, I'm Dave Kunda from Milwaukee, Washington, and I am one of Cindy Grandy's and Mark Greenwald's co-authors on the review of leupopenorphine dose limits. If you look at page three of Dr. Grandy's article, which we cribbed from the suboxone package insert, you see it's even more dismaying than that, because if you look at the scatter plot of drug-liking scores to 18 milligrams of hydromorphone compared to serum level of buprenorphine, it turns out that you only get everybody out of the almost-as-bad-as-placebo drug-liking level once you get above about 3.1 to 3.3. And even then, you got a few patients, you got a few outliers, until you get to about 5 nanograms per mL, you got a few patients who have drug-liking scores above placebo still. So there's a red zone there, and I argued for a yellow zone between 3.3 and about 5.1. Wow. So our patients are telling us something, right? Yeah, my co-author said, Dave, you're making it too complicated with an extra color. But anyway, the thing is that even if absorption were consistent, which it is not, turns out the relationship of blood levels, and absolutely yes, every other drug I know, we decide on a therapeutic target, modify it by patient safety concerns, and that's the dosing range. Buprenorphine we got to by, well, we thought it would do the job. We accepted a few patients' worth of anecdotal data. We ignored what our patients were telling us. We didn't meet therapeutic targets. And the safety concerns for the individual patient are nothing. And the safety concerns for society are pretty darn low. So I don't want to go too far on and on, but I think that it's dismal. We got to get to blood levels. We have to start thinking in terms of therapeutic targets. And we have to start, we have to stop accepting considerations other than safety considerations as the basis for our dose limits. Thank you. Yeah, I can throw in a question first. Yeah. Rachel. Rachel, you talked about the mechanism that it's somewhat more potent. Like it's similar affinity to morphine or heroin and somewhat more potent. I thought it was like a lot more potent. But can you talk, what's the speculation about why it's actually, it's 50-fold or more more potent in terms of respiratory depression? What we think is going on at the receptors? Is it this thing called intrinsic efficacy? Or what is it? From what I understand, partially it might be due to the lipophilicity. Actually, my notes are not updated here. But the Greenwald paper suggested that the higher lipid solubility of fentanyl compared with morphine means that more enters the cell membrane, leading to higher concentrations of fentanyl around the mu opioid receptor. It's not just acting on the mu opioid receptor, but also around it. So that's part of it. Great. Thank you. I just wanted to add one quick comment to the previous comment. There was an important paper by Chambers, I think at JAMA Network Open, right? Yeah. I was going to cite your paper and then also that paper. And that was, I think, last year or this year, maybe September of this year. And basically it showed that it was during the fentanyl era in Rhode Island, over 6,000 patients between 2016 and 2020. And they showed that at 24 milligrams, only 10 percent were on 24 milligrams. Most were on 50 percent, were on 16 milligrams. But there was a 20 percent increase in retention at six months, you know, at that dose. And they wanted to look at higher doses, which you've certainly suggested, even 32. But do you have further thoughts on that? We have not yet found the upper bound on the improvement of retention rates with higher sublingual doses. We know that there is still some incremental effect all the way up to the top study dose of 32 milligrams per day. However, everybody is an individual. The amount to give is the amount that does the job. And the other good paper this year on dose limits has been the Coyle et al. group out of Denver, which I think is even more convincing than the Chambers paper. Thank you. I threw this back up there just for a second. Patients are people, right? Like, we can nerd out on science all day here. It's really fun. I think we all really like it. Patients are human beings. And the things they tell us have to matter. So the things that they bring to the table help inform what we do next, help inform how we change practice. And I think as clinicians, the most important thing is to pay attention to that. They were telling us. They've told us all along that this isn't enough. It's not working for me. I'm stuck. I get to this point. I'm at day 16. Ned said the same thing with Vivitrol. I get to day 16, and I just can't. It's like the wheels fall off. I don't understand why isn't this working. So, you know, when a patient brings you a concern, I know the package inserts are beautiful and perfect and lovely, and they're not all totally real, right? Those are means based on data from a ton of people. Bring it back down to the individual level. Who is sitting in front of you, and what do they need? And that's how I think we meet patients better where they are. I agree with you. Thank you. That's an important comment. My name is Howard Moss, and my question has to do with the variability of blood levels and whether or not you guys have calculated the apparent volume of distribution and whether we need to be like pediatricians and base our dosing on body weight or body mass index. It's interesting. They do that. So it's the same amount of drug in a larger volume versus a smaller volume. You get a concentration difference. Yeah, I mean ADHD meds work that way. They'll do it by child size and weight and all of that, and we tend not to do it. I mean, what's funny is you think about it like methadone. I mean, it was one point, again, where I'm old enough and other people here are old enough, like 40 milligrams was the dose, right? And it was ridiculous. In New York, you know, you sometimes have to go to 110 or 140, where you think about all our psychiatric meds. I'll speak for myself, but how many times have I had to go over the FDA approved dose for depression or buprenorepropion or whatever? And I think, and particularly me with ADHD with medications with substance users, I have to go to higher doses. So I think we've been somehow in this buprenorphine, we've been set in this way and really need to rethink it, particularly in the fentanyl era. But we do it in other meds. I don't know why we're so specific about buprenorphine. But you guys do have heights and weights on your patients. It should be pretty straightforward to calculate the apparent volumes of distribution. And to add to that a little bit, we did do a secondary analysis a few years ago kind of looking at fentanyl clearance based on body mass and body weight. And those who were heavier did take longer to test negative and to clear it, of course. So that seems to be a factor that we need to account for and measure. Thank you. Yeah, and, you know, regarding the variability, it's also, you know, something that we were thinking about is also, you know, these individuals are very sick. They have multiple co-occurring illness. I mean, not only psychiatric, other substance use, but infections and how that, you know, also interferes or at least contributes to the variability. Dr. Mariani. Just also, like, even these hospitalized patients, to your point, Sandy, you know, are they third spacing, giving a lot of fluids, decreased albumin, you know, who knows in the subcutaneous administration, drug-drug interactions, you know, when they leave, obviously cocaine issues. It's just interesting, you know. It's a different population. No. No, I don't think so. That's a good question. No biorepository? Do we have a biorepository? I can't remember. We have it at Week 12. John is being formed. Okay, John. Nice to see all my Columbia colleagues up there. So, Rachel, conversations I've had with Sandy, Sandy Comer, and other things that I've read indicate that there's, like, per receptor that's occupied, there's more opioid agonism occurring with fentanyl. I mean, if we take aside the lipophilicity and the rapid onset, do you have information that contradicts that or? No, I don't think so. I think maybe some of my slides were limited in that they were coming from that older data from clinical samples and from anesthesiology data that it's probably not fitting the doses of fentanyl that people are using now. Because I think the concept that I keep in mind when I think about it or talk to patients or other clinicians about it is that compared to heroin or oxycodone, you need fewer unoccupied receptors with buprenorphine to be occupied with fentanyl to get opioid effects, and so that this is kind of driving this need to have higher doses to occupy a greater percentage of the receptors. And I guess the other thing, just to Frances' comment about, like, buprenorphine 101 from 20 years ago here, you know, it was a different problem. We were happy to have buprenorphine. We were very worried that it was going to get taken away again, right, that the government allowed it. It was a big deal. So we're just in a very different world, and I think it used to be, you know, we were very worried about diversion, and people were getting inspected by the FDA and the DEA, and it was just like a different ñ it was a whole different ballgame. And so I think we are just in a different world now, and higher doses are ñ you know, and I think it's hard because I don't think the education of people prescribing is caught up with it, where initially we were more cautious, you know, if we give people 32 milligrams a day and they sell half of it, we're going to get shut down. And I think now it's, you know, let's just give more, and I think that just makes more sense now. And so I think it's just a different time and place, and I think psychiatrists are always very conservative. You know, if this was an internal medicine meeting, they would just say give two antihypertensives, and why are you even debating this, right? And, you know, we're ñ It's nice to have a few times. And, you know, I guess over time, too, you get injection number two, injection number three, the blood level will increase, but you will lose people, right, in that 30-day period, the initial month. So, you know, we need to listen, we need to provide additional medication, because if you don't, you may not see them, and the risk of overdose is extremely high. Go ahead. Okay. Thanks, everyone. I'm Jay. I'm from St. Louis University in St. Louis, and I'm a medical student. But I have ñ this question is more geared toward just pharmacokinetics. I'm curious about just the depo effects of this drug. I know other drugs I'm familiar with, like Invegas, Astana, I've read a little bit about that, and the idea of, like, micelles or lipophilic particles breaking off of a larger ñ I don't know if this is making sense, but just the way depo formulations work, how does this depo formulation work? I was trying to look up research a few minutes ago. I couldn't find out kind of the pharmacokinetics behind that, and how does that interact with fentanyl and lipophilicity? Because I know as people get older, you know, your muscle kind of converts to fat. What does that mean for these patients? I have a lot of questions. Yeah, if anyone can answer one of those. It's a polymer, right? It's a hard polymer. It starts out as a suspension in a solvent, right, of some kind, and then when it's injected, when it hits the subcutaneous space, it turns into a solid, right? It congeals, yeah. It congeals into a solid, and then part of what bothers people sometimes is it's a lump. It's a hard lump, especially if the person is skinny, and then sometimes it gets inflamed. You guys have seen some of these reactions, right? Yeah. We were talking about that last night. Yeah, it's funny. We were talking about this at dinner. So the injection, when it comes out, it's pre-filled syringe. It's thick like honey. We tell that to all of our patients because it is incredibly viscous, and it takes more time to push in than compared to a flu shot or another injection that they may be familiar with. So it takes time. The burning sensation that the majority of the patients feel is as it is starting to congeal once it hits that subcutaneous tissue. Again, anything in the dermal space has the potential to react, cause breakdown. That's where you get that tissue necrosis at the injection site. I'm not sure what else on the questioning. The other thing about the subcute depot that's formed, it takes approximately three months for that original depot to dissolve. So by the time they are at that third-month injection, and I'm using my body as an example because we go around in a clock to help keep track of where we are injection-wise. By the time you are at that third injection, the first injection is mostly gone, if not completely gone, but patients can feel it. So we like to assure them that we're not turning them into lumpy potatoes. They will go away and dissolve, but they don't dissolve at that 28-day mark. They don't dissolve immediately. That depot is still there well into that second month after their first injection. And just a quick follow-up to that, just with these patients, who were these patients that were below threshold? I'm just wondering if anyone has a theory on was it something metabolic that was going on with them? Yeah, I mean, who? It's all of them, right? But we've seen the same thing with Vivitrol in people who aren't sick. I don't think we know. We don't really know why. Okay, thanks. I can give a hypothesis, though. 3A4, lots of variation among individuals. Even if nobody's eaten any grapefruit, there's a lot of variation, drug interactions. So, yeah, there's going to be a lot of disruption in the linkage, variability in the linkage, between even injected dose and serum levels. You've just got to go for the therapeutic targets, in my opinion. One thing I wanted to bring up, Michelle, while you have the mic, you talked about how the benefits of research, and we've talked about, and Manesh, you talked about losing patients in the first month. We've talked about this, like how to make clinical care more like research to hang on to people. So maybe you could talk a little bit about some of the strategies for finding people and keeping people in treatment that could make clinical treatment more like research. Yeah, I think that's a great point. Again, looking at whole person care, so what does that mean? If a patient has housing instability, do they really care about the other things in their life? If they don't know where their next meal is coming from, do they really care about their infectious disease treatment? Are they concerned with their treatment for opioid use disorder? Probably not. So kind of taking a step back and looking at the whole picture for these patients. Again, the majority of these patients, like we did not have cell phones. Research was able to give them cell phones. That allowed them to connect to more care, connect to more resources. What else? So you chase them, right? Yes, we chase them very hard. Contact information from multiple sources. All of these patients received a call from one of our research coordinators or nurse care managers weekly. So we were checking in on them weekly. We had a good idea of who was falling off, who was about to be at risk to be lost to care, lost to follow-up, or if things had changed or transitioned in their life that were potentially stressors that we didn't know about on the front end. So frequent contact touch points with patients despite having a long-acting injection, I think, is something important to consider. The injection by the package insert and everything else that we know says these patients should be held for 28 days. That's great. High-five them. See them in a month. And we found that that is not high-quality care. That is not evidence-based care. That is medicine, and that's fantastic. But whole-person care looks at all of these other touch points and things that we can see that impact whether they continue to come back for that wildly important medical care at the end of the day or not. I just wanted to remind everybody this data is from the trial. It does represent the individuals who are hospitalized. It's 36 of the 170 currently recruited. But this is what we're interested in, trying to understand this with the data that we have. Who are these people? And the majority are below this threshold prior to the second injection. But, yeah, trying to understand a little bit more about this sample with respect to characteristics, clinical and demographic. Who are these people? Go ahead. Hi. I'm an addiction psychiatrist and have found that I am the resident expert on bupe. But as we're talking about here, I'm not. I'm still trying to understand why one person responds one way and somebody else. And this is including, like, the not super medically sick. So I think what would be helpful to hear a little bit about is that for some reason, maybe because of the X waiver or whatever, bupe seems to land in the addiction psychiatrist's territory. But I don't know anything about pain management. And while in here we're talking about, like, yeah, just screw it. Just keep going up until they're, like, better, right? That's not generally medicine's approach, right? Or certainly not how pain management works. And so I'm curious, especially with the extended release bupe and these people being really sick and maybe having, like, INDs, surgical procedures, how was pain management done? And how did you speak to that? Because in non-academic systems, it's like I'm supposed to know how to do that. And like I was saying, we barely know how to do it when pain isn't even on the table. Yeah, sorry. We could have talked a lot about this. So we did man measure pain and first of all yeah. Where'd you go. Oh there. No it's very complicated. And but one thing we did measure and identify especially in that case series is published in jam that we briefly mentioned in those who we were able to do a transition on long acting opioids. So they were on for pain management on for maybe have started methadone while while they were waiting in the hospital before we got to them. They were able to safely transition to to long acting buprenorphine. We noticed that there was no difference in pain but one of the things we did just to get to the clinical question is working with the hospital teams and the other collaborators other groups that are working taking care of the patients is managing their pain. And so we didn't see any increase in pain and initiating extended release buprenorphine and we're able to continue to manage their pain with long acting opioids while they were transition transitioning to long acting buprenorphine. So but I think the bottom line is you do have to listen to your patients. You can treat their pain. You can initiate buprenorphine. You can initiate extended release buprenorphine. You can manage their pain and managing their opioid use disorder and craving at the same time and not. We had not precipitated withdrawal in anyone and we did not. And we did manage their craving. We don't know if our extended release buprenorphine is better than treatment as usual which could be methadone something will be buprenorphine Vivitrol et cetera in a receipt of treatment post release post discharge. But I think one of the things we have looked at and we created in that protocol paper that I put up there is this detailed safety evaluation form that's available in that protocol paper that you can take and use yourself. And it talks about measuring and assessing pain other medications and how you can use that to safely help patients. But really the bottom line is collaborate with your other other clinicians that you can do this. And I'm curious Michelle like when these patients got onto the sublocated inpatient they were in often a lot of pain surgeries. They were on additional opioids on top of that often right. Yeah. So I think the thing to sort of consider is we're talking about two separate issues right. Opioid use disorder sits in one bucket and pain sits in another. Obviously there's an overlap but when we when we look at them we almost have to treat them separately to encourage others to treat pain as it is. So I guess my favorite example that I use with our hospitalist services and otherwise is if you have a patient with opioid use disorder who was maintained on buprenorphine methadone whatever it is and then breaks their arm do we do nothing for their pain. Obviously not. So you know thinking creatively that whatever their MOUD form is is their baseline. That is their cup of coffee for the morning. That is how they start their day. That is what they need to be able to function as a person living with opioid use disorder. Engaging in care for that problem pain needs to be treated separately so they should be treated as any of us who walked into the hospital with a broken arm. So whatever those pain regimens look like obviously we can consider how things would interact what we would need to do differently but they need to be treated for the pain that they have. The most challenging moments that we have with these patients is when they are on treatment for their opioid use disorder on a form of MOUD and everyone is like that's enough for your pain. It's not. We know it's not. That's their morning coffee. Right. I start my day two cups of coffee. That's how I do it. If I have a headache I take to Tylenol. OK. So this is the same thing there. You know their XR bup their methadone whatever it is that is their morning cup of coffee and they need to be treated for pain on top of that. So yes we had lots of patients that were initiated whether it was a low dose induction onto buprenorphine prior to getting the injection or if they were just standardly induced and get onto the injection still had complexities of surgery that was upcoming maybe planned or unplanned and we were still able to treat and manage their pain on top despite having the injection on board and people being very you know off put by the fact that what are we going to do with this. We treat it like anything else. So you have to get a little creative but it is absolutely possible. Yeah. I mean it totally depended on the patient case right. Like sometimes it was a short acting course of opioids if that was appropriate for how the patient should be managed based on what you know presentation and pain style was or are we getting creative with our other adjuvant therapies. A lot of times we let those go to the wayside. You know are we transitioning and shifting between Tylenol Motrin. Are we icing. Are we heating. Are we doing other things. Are we encouraging patients to get up move around be an active participant in their care. You know encouraging them that hey it's OK. Another piece of this is talking to your patients about your pain in a way that is real. You are going to experience pain. So we are very open with our patients of what we think that they are going to experience. It is OK. You are about to go through surgery. I expect that your pain is somewhere between a six and an eight and that is OK. If it's a 10 let's talk about it and let's figure out what we can do to get it down. If it's a two then OK that's you know that's a bonus. But I think also giving patients a realistic expectation of what their pain level should be is an important part of this because they're scared. Right. Have you ever been hurt before. It's very scary. You ever had surgery. You know not knowing where that's going to go. So little things like that that aren't even medication based can actually have a huge impact on your patient's perception of their pain their perception of how you are treating them where you are working with them to get and then their interaction with what pain medications they need on top. And I get it. Yes we also use ketamine which is a favorite. This is great. Thank you for all the spirals. I think this is great opportunity at this meeting to have a kind of very solid research and congratulations on a very ambitious and very complicated trial to send in the team but also the spirals about you know implementing this on the grounds which I think we rarely hear. Now this is a great opportunity right to talk about what's important now in the buprenorphine discussion. And I think the discussion that we're having right now is that those limits. Right. I mean we have to convince regulators we have to convince FDA. I think there is a hearing in New York State like in the next few weeks with Samson FDA trying to push for that reasoning for that dose limit change. And I'm wondering what would makes the most sense for us to convince regulator would that blood level data saying that there is some kind of theoretical in effect. We have to reach it in order to have this clinical response. So the medication dose shouldn't really matter as much as how much of the medication gets the brain or whether we should go. But patient tells us that they are not sufficiently treated and we should give them more. But remember. Right. But on the other hand remember that our patients are highly stigmatized when regulators think about our patients they're not going to really trust what patients are saying. And I'm wondering whether we're going to be more successful saying that we have science. However weak the science is we know. But there is some kind of science they would probably understand that we need to get to three nanograms per mil. And with long acting preparations we know from from that Vivitrol there is a huge variability and the longer the medication the more variability you have two or three times the blood levels difference managed you're not going to find anything I promise you you're going to have two or three hundred patients they're not going to be any predictors. I mean it's nice to look. Maybe you're lucky. We've looked at 250 Vivitrol blood levels of 250 patients multiple injections. We couldn't find any predictors. And I think the nature of those long acting preparations is that it's the parent medication but also the breakdown of the polymer is controlled by many factors. We have no idea. We're not going to find predictors. I like the idea that the first dose is the key. You know yes it's going to go higher. But those patients that will be there are not the ones that need to. We need to know how much to give the first dose. And we need to figure out how to determine. But anyway I just want to bring it up because that's what goes through my mind. It's supplement. But again patients may not take patients who are like at this level functioning. They're not going to take supplemental bill. We know patients who are in-house don't take you up. You have to give them the big dose. Not too much because they may be sick or. But anyway what what else you have said. I agree with you. And I think one of the things that we did with this trial was we had. I didn't mention it but we had this met the nurse led medical management so they called these patients every week. And while and when when they're in the hospital they're going by and checking with them. And like briefly how are you craving. And then they had a craving scale 1 to you know 1 to 10 and all of that and really listening to them. And then they could feedback like I wouldn't be there. I'm not their provider. Right. They we hook them up with a provider after the injectable buprenorphine was given but making sure that we could be a voice and many were given additional buprenorphine on top of that or could have been in the hospital setting. But I do agree with you. And I think the big I mean besides people not not listening to people who have opioid use disorder and assuming the worst assuming that they're just going to divert assuming that they're only asking for this because of some other ulterior motive. We don't do that with other. And like I'm an internist infectious disease doctor. You came in and saw me. I saw your sugar was up. You know I'm not going to withhold giving you more treatment for your diabetes. Right. You know I know I know. Believe me I'm talking. We should have the DEA here and we should have everybody here because I'm actually just fighting to get. Why can't. Why do we have these regulations on giving sublocated now Brick Saudi in a clinician's office. What's the point of that. Like the population that I treat. We can show through research that we can safely bring the injection to them and administer it to them and justice criminal justice settings unhoused on a mobile health unit. What have you. There's no diversion. But then you restrict it to only in a clinician's office and they can't make it right. And then also we're not listening to them in the day and age right now fentanyl when there's so many different analogs of illicitly manufactured not just fentanyl and others we don't even know how all of these are activating. So I agree with you. I agree. We collectively and in fact maybe an awesome session would have been having those types of folks at these meetings. I think the thing is also it's really complicated and challenging to provide this type of care in the real world right. Like you know is it. It's it's it's very time consuming but it also takes a lot to provide you know gold standard even quality care to this patient population they need way more than we are providing. But our system is not set up to do that and we don't pay for that. Right. So how are you going to convince other people to do this. So there's a lot of problems here. So one idea I'll throw for you to think about the colleagues in Australia. They are basically giving the second injection within two weeks as soon as the patient still is under treated. Now you can have a blood level and say yes this patient has a therapeutic level they should require a second dose or you can just say I don't know what you think. I know that we don't have any. know I agree with you. I don't know what you see like the trial. You know you know that we should give it a right for weeks three weeks and then we don't have the data. But let's use science to convince regulators figure out how we can use numbers science to convince regulators. I think they'll be much more likely to. Sure. To follow them and to say what the patients say. For sure. Thank you. Thank you. I know we have. Yeah I think eight minutes but please five minutes. OK. OK. Really quick question. Ritu Vatnagar from Madison and we actually were successful in getting the buprenorphine injection three every three weeks for the people on Medicaid and we are a non Medicaid expanded state. So I just put it in as 21 to 28 days and then I just kept putting it through for supplicate and and so that it worked except the challenge was getting the people to come back for that second one. Yeah. I mean that's the challenge again. But this presentation really makes me feel good about doing that and the supplementing of the additional buprenorphine between the first and the second. I also wondered about since we see that the levels are taking some time to increase. What about in the emergency department like when people are coming in after overdose. Is that a time that you could do this safely. I mean this really seems like it wouldn't. You're not precipitating withdrawal. You said in any of these situations it's a really opportune moment to catch people. Right. I don't know. I mean is that an option. That there are already. But so it's it's possible. And and then one last question was on the other side of it where there people trying to if you're saying three months out there's still a little bit of a lump and still some level when people are ready to taper getting them off of that last half milligram of buprenorphine. Is this a possible way to use that there as well. And has that been done. Can people speak to that being studied in the CT and discontinuation trial. I'll just need to wait. Yeah. But I think lots of people are doing it even outside. But I agree that I've been doing Q3 week dosing on both supplicate and on Brookside. Not all the time. But when I find I can do it and people like. Oh sorry. So yeah I've been having some success with Q3 week dosing on both formulations and getting Maryland Medicaid to pay for sometimes a fight. But you do have to fight. Do you have other suggestions. You were the other questioner around kind of sublingual buprenorphine on top like standing giving everyone eight milligrams or PRN as needed. Like what are the best practices. I actually want to know from my patients like what do people do. What are you doing. I've been I've been certainly doing that and people say it's good. You tell them to take it every day or just as needed if they have. I've been mostly telling them to take it every day. I think that these are patients who struggle with knowing exactly how to dose things and I feel sideways I should take one of these and if just stick on it. The cup of coffee analogy you use let's just get you on a standard regimen. And who do you do that for. Just people that are having some craving or for anybody. People who continue to use or people who say that when I do attempt to overcome the blockade I can. I have a subjective effect. Those are all kind of these. Do you go higher than eight milligrams of supplemental. I haven't. I wouldn't not do it but I've done OK with eight. I was going to ask them in just general following this line of reasoning. How close are we. Or and if we're not there what level of evidence does it require to move the standard of care to say that we should be doing blood levels as part of our routine therapeutic monitoring both as practice but also to use as evidence to the point you were making about regulators. You know it's the way we dose lithium based on standard of care of therapeutic windows the way we dose nortriptyline. Should this be standard care. And if not yet if the evidence isn't there what's the threshold of evidence that would persuade people that it could be a barrier to implementation. Right. It would be. Yeah. So you wouldn't. It's a it's somewhat burdensome. It is burdensome. And yeah it's different than with lithium with the therapeutic index is so narrow and we hurt people as we are in a situation where people are still using or something else is going on. Yeah. Maybe could guide. Yeah. I mean like we said like in methadone programs they don't standardly do it but they may do peaks and drops to find out if somebody is rapidly metabolizing or whatever. And these are like for these virtual programs. Can you do dry blood spots for you know we do that for prep. People don't have to leave their house. Can you do quantitative levels for DBS. Does anyone know. I don't know. But you mean. Yeah yeah. Fingers. No I know but people do it for prep. I know but people do prep all the time just never leave in their home and it's just a way to kind of make it a little. Someone recently suggested to me considering oral fluids developing an assay to use oral fluids for this purpose. Anyone's interested. I think that could be really useful. Yeah. Because the other thing is how long is it going to take to come back and is it you know is it going to help you know in the moment. And you know I guess that's also another thing to move forward. But that's a really good point. I think you have maybe one more but you know we have to stay. But please go ahead. I'm still just trying to clarify. Like does buprenorphine actually blockade. I'm drawing a blank on it. Fentanyl. Yeah. Because the way the conversation usually goes with my patients is I'll bring up the idea of starting starting buprenorphine and what they will say is no no don't worry about it I'm a fentanyl guy. Because they know that they've been on buprenorphine before at usually at 16 milligrams a day 8 and 8. And then they use fentanyl and it works just like it did before. So I'm again I'm trying to I'm trying to figure this out. Was it was the was the buprenorphine dose just not high enough. Correct. Yeah. Yeah. When they use the fentanyl. And again that's the way I think this usually goes. They don't don't worry about exactly morphine. I'm a fentanyl guy. So I've talked to patients you know who have received who have received sublocade and they say they had that they do test the block right. And but they say actually you know what I don't actually feel this the euphoria the high. So because you know so these individuals who receive the injection and you know then they say yes they used and it's actually not enjoyable and that's you know actually you know negative. You know and that's one of the reasons I love coming to these lectures. It challenges my kind of belief that slowly accretes over time where I can go back and say hey listen other patients have tried this and it actually did blunt the fentanyl. Yeah. And also just how have they tried it. Right. It's also so variable that are they doing it themselves which is OK. Right. That's maybe one method but you know just to get a sense of like how was this done and did they you know actually take it as as you know eight and eight or 16 or was it 24 and what dose. So there's a lot of variability there. And I think it's a call for all us researchers to make sure we're we're testing you know we're not just we're assessing for withdrawal symptoms with cows we're assessing for craving we're doing these blood levels trying to have the science and assist and I think also other things listening to our patients. So and then having these other knowing their other comorbidities their other social determinants of health other things that could be interplaying with craving and other other issues. But I think we all have to be measuring these things listening to our patients so that we are collectively as a whole have more weight to go to the powers that be that are going to decide these changes to these regulations. So the other thing I would add is like again having been involved in training from 20 years ago it was it was like heresy to do at home inductions and you were really it was like a bad thing and I and now it's standard practice. So I think that you know besides papers that were written it was also just the groundswell from people in the field saying that that just doesn't work and we're going to you know patients go home and do it want to take their Gatorade and be at home. So I think that it is possible to change if we all are sort of clamoring and saying the same thing back. Yeah. Triple AP sessions. Oh I guess you get the last word. Thanks Dave. Again in response to Dr. B saga the schedule I have is that the examination the federal examination of the scientific basis for dose restrictions is coming up this coming Monday. The 11th. There is a link for participation basically I think auditing that link is not particularly well publicized and that's deliberate but it is public and I believe I'm allowed to share it. I wanted also to follow up on the colleague who asked a question about pain medication. I'm pretty comfortable with what you will and won't do for pain. Turns out buprenorphine is a very nice medicine for chronic pain. It's not a very good medicine for acute pain acute pain needs PR ends and buprenorphine PRN for hour to hour symptoms is a lousy idea. Yeah I think the idea is that you can have opioid agonists on board with the buprenorphine and that it's not going to harm. Absolutely. You can layer that you can layer an agonist on top of buprenorphine. You usually need higher doses. You need to monitor more carefully. Skilled people can do it. Unskilled people should leave it alone. Yeah. But our colleague is having the problem that as the buprenorphine prescriber she's having surgeons drop post operative pain control on her. That's not fair. It's not something her drug or her skills. Yeah. We need each other. We need teams. And so that's like at Yale and others where I'm at is really coming together. So wherever she is addiction psychiatry addiction medicine cardiothoracic surgery and have you know having these these groups and for us it was in the beginning Yale cardiothoracic surgeons were refusing to operate on anyone that was on buprenorphine and was and so that has changed because addiction medicine and others have you know kind of come together. Was that to take them off the medication. Yeah. I take them off. Yeah. Well anyways we could go on and on and on and it's been really awesome. But thank you so much for coming.

extended-release buprenorphine

opioid use disorder treatment

vulnerable populations

target concentration

medication levels

heroin use

fentanyl use

craving and withdrawal symptoms

individualized treatment

high-potency opioids

patient concerns

inflammation

research