Can you all hear me? Yeah. All right. Thanks for being No? All right, so then. at Yale. He specializes in treating individuals with substances disorders as well as co-occurring medical and psychiatric conditions. He employs behavioral pharmacology, computerized pain Modules modulates pain sensitivity, pain sensitivity among persons receiving opioid agonist therapy. I've received funding from NIDA, a couple of private foundations I've also partnered with pharmaceutical companies in the form of medication provision for clinical trials and consultancy. None of these disclosures are relevant for this talk, though. Our goals today are to understand how changes in cannabinoid attitudes and policy might be impacting the treatment of people with OUD. We're going to review the findings of this recently completed human lab study, looking at the risk-benefit profile of orally administered THC as renabinol to relieve pain in people with OUD. And finally, we'll talk a little bit about insights regarding exposure to THC during OUD treatment and how that may inform future clinical trials. So on the left, you see the cover of Time magazine in 2002. And it asks this question, is America going to pot? And on the right, you have the cover 20 years later, and I think we can confidently say yes. And this coincided with, as this audience is well aware, an unprecedented opioid crisis since from 2016 to 2021, we've seen a staggering 275% increase in overdose deaths. And though the main culprit is fentanyl, the role of inadequately treated chronic pain in this crisis is often overlooked. About 40% of people with opioid disorder also live with chronic pain, defined as pain that occurs in most days for three months. And there's emerging data showing that chronic pain is associated with more severe craving, more frequent use of non-medical opioids, and also dropping out of treatment, which can increase mortality. Oops, there was supposed to be a title here. So this slide is about changes in attitudes. In most states, at the state level, pain is the most qualifying condition. So for the states that have medical cannabis law, about 90% of them, pain is the most common one. Last time I counted, six states, mostly in the Northeast, have added conditions, quote unquote, such as alternative to opioids or opioid treatable conditions. And in some states, that has been interpreted as OUD itself, meaning someone could go to a dispensary or get cannabis or constituent cannabinoids in lieu of methanol or buprenorphine, even though we don't have data to suggest this approach would work. Because cannabis, there's also some clinical evidence suggesting that cannabis can help some forms of chronic pain, but thinking about trade-off is important, especially for a population that already has a substance use disorder. And we know that chronic pain in epidemiological studies is associated with converting from medical use to non-medical use of cannabis and cannabinoids. So balancing risks and benefits is important. Here you see the distribution of cannabinoids and opioid receptors, and you see they're co-localized in the periphery, in the spinal cord, and also in supraspinal areas. There's a lot of, not only anatomic co-localization, but crosstalk between these two systems. So for example, if you administer THC, the prototypical CB1 receptor agonist to animals, you increase opioid precursor genes. If you give animals a cannabinoid antagonist called rimonabant, you can block the analgesic effects of morphine. So there's convergent evidence suggesting that these systems talk to each other all the time, influencing both pain and reward-related outcomes. And this notion of opioid sparing effects is grounded in meta-analyses in which co-administering THC, again, the prototypical CB1 receptor agonist with morphine, can augment the antinosusceptive effects of morphine by up to tenfold. So basically what that means is if you give THC plus morphine and you put an animal in a hot plate, a common experimental model of pain, you need much less morphine than if you give morphine alone. And this is one example. I apologize because of the titles. I don't know what happened with them in the slides. But in this study, this is a preclinical study in which the animals were trained to self-administer oxycodone and they received vaporized cannabis. And that led to less frequent self-administration of oxycodone once they were exposed to THC and not cannabis. Not only that, but there was a synergistic effect of THC and oxycodone for antinosusceptive model experimental pain. But this is preclinical data. And more recently, human studies have started to emerge. This one was conducted by Kelly Dunn and Claudia Campbell at Hopkins. And what they did was they got healthy people which don't have clinical pain. And so you eliminate the confounding of variation in clinical pain from day to day. They evoked pain in the laboratory with this technique called quantitative sensory testing. So what that means is they'll do a pressure pain threshold and cold pain threshold and look at several different modalities. And what they found is that a small dose of dronabinol or OTHC when given with hydromorphone did, there was a modest effect of synergistic analgesia. However, people liked the combination more. So that was the trade-off. A little bit more analgesia, but also some evidence of abuse potential. And again, these are healthy people without clinical pain, without a substance use disorder. But they don't have OUD. So our patients with OUD, their brains look very different. They have these massive opioid-induced neuroadaptations that might influence how people respond to THC, both for pain outcomes but also reward outcomes. They're also more likely to use cannabis and cannabinoids than people who don't have OUD. So that's why we did this study. And the aim is to examine the acute, immediate effects of OTHC on pain, abuse potential, and cognitive performance in this population, people who get methadone for OUD. This is funded by the Patterson Trust. You may ask, why didn't you give them cannabis, why dronabinol? A couple of reasons. One, we wanted to look at the effect of pain for a prolonged period of time, several hours. Dronabinol, so that's one. We know from healthy human studies that dronabinol and cannabis have equivalent analgesic effects on experimental models of pain. But dronabinol, because of the gradual plasma increase and increasing plasma levels, again, you get a prolonged benefit and the abuse liability tend to be much lower than cannabis. Your lungs are the size of two tennis courts, you absorb a lot more THC. So the ratings of liking and wanting more tend to be much higher with cannabis than dronabinol, which is why dronabinol used to be a Schedule II drug and now is a Schedule III. So primarily the pharmacokinetic reasons. This study, again, was a randomized placebo control within subject design. It had three sessions. Every one was their own control. So everyone got all the dosing conditions. One day they randomized to get 10 milligrams of THC, the other day 20, the other day placebo. These doses were derived from cancer pain literature in which people get long-term opioid therapy for pain. And the test sessions were separated by 72 hours to limit carryover effects. The primary outcome was pain measured by the cold presser test, which is a commonly used method to evoke pain in a laboratory and is believed to have predicted validity to treat chronic pain. That's how a lot of the analgesic drugs like pregabalin, vilifexin were developed. And also self-reported pain, things like pain intensity and quality with the McGill Pain Questionnaire. They also looked at abuse potential and in cognitive performance. Everyone was on methadone. And they got the THC at trough methadone level, so 24 hours after the last methadone dose. There were 25 participants who completed the study. About 25% were women. As you can see, they were getting a pretty high dose of methadone on average, over 90 milligrams a day. They did need to test negative for cannabinoids before the first session. And no one met criteria for any other substance use disorder except for tobacco use disorder. And of course, OUD. Conversions from methadone to MME are a bit tricky because methadone for OUD is dosed once a day as opposed to several times a day in the pain literature. But this isn't a perfect conversion. The point of showing this is these people, again, they're getting these pretty massive doses of opioids. And it's really hard to extrapolate data from clinical trials or human laboratory studies where people don't get such a high dose of opioids or no opioid at all. So what you see here is the cold pressure test data. In the left, you see pain threshold, which is when people report the first pain after immersing their hand in a circulating cold water bath. And on the right, you have pain tolerance, which is when people unambiguously remove their hand from the cold water bath. And in the y-axis, you see time. So left is time to report the first pain, and on the right is time to when the pain becomes unbearable and the person removes the hand. And these finds were not statistically significant, but we saw there was a little bit of a discernible trend for the 10 milligram condition of THC, the one in green, at the 180 minute mark, which is around when the peak effects of THC tend to occur. Our hypothesis was that lower doses would be associated with pain and anxiety are very intertwined, that lower doses could be anxiolytic and therefore analgesic, because this notion of biphasic effects of THC. And we did see that right after people removed their hand from the cold water bath, we asked to rate their pain intensity and quality with the McGill Pain Questionnaire. And here, both doses differentiated from placebo, and in the PulseHawk analysis, the 10 milligram dose compared to both placebo and the 20 milligram dose was associated with the pain intensity was reduced, which again aligns with the notion of biphasic effects. Now the adverse effects, this is subscales of the DEQ, or Drug Effects Questionnaire. You can combine them, and you can look at stimulatory effects, which are things like I feel stimulated, pleasurable, I feel high, I want more of the drug, and aversive is I don't want the drug, and other items of the Drug Effects Questionnaire. It's a visual analog scale on the y-axis. For stimulatory effects, both doses differentiated from placebo, but we didn't see that for neither pleasurable or aversive effects. We also look at opioid withdrawal, and here the finds are not significant. Again, they were a trough opioid methadone level, so it's an outpatient study, it was very early signs of opioid withdrawal, so we didn't see a significant difference here. And finally, cognitive performance, so here we did see, we did note some cognitive impairments induced by THC, mostly in verbal memory, which is at the bottom. Not so much in attention, statistically significant for attention for both doses on the upper right corner, but very small differences. Most of the effect was seen for verbal memory, which is examined by asking people to remember lists of words, and that tends to be a pretty consistent finding in these CB1 receptor agonist studies, because the hippocampus is very rich in CB1 receptors. So to summarize, there was preliminary evidence of an analgesic dose of THC on an experimental pain model with the lower dose. Some evidence of abuse potential, although limited, and inconsistent dose-dependent cognitive deficits, something to do with this, but reinforcing the need to think about dosing in future clinical trials, that was the last part of that sentence. So to summarize, there's an urgent need to understand the impact of cannabinoids, not just THC, but other cannabinoids in people with opioid use disorder. Preclinical data can be a goldmine of insights to then implement in experimental studies. We do need to measure both risks and benefits, and that requires a conceptual methodological combination of both pain and addiction research, and we can use those human lab studies to make decisions about what dose can be used in a clinical trial, what route of administration, in a relatively fast and cost-effective way. I'd like to thank all the members of my lab at Yale, all of our patients, research participants, all the funders, especially the Patterson Trust. So, the question was about what's the rationale for the lower-dose providing superior risk benefit profile as opposed to the higher-dose, is that? Yeah. Yeah. So, there is some preclinical data suggesting, again, biphasic effects of THC. What that means is it can lead to different pharmacodynamic effects at different doses. And those biphasic effects have not been shown consistently for anti-nosusceptive outcomes, but they have been shown for outcomes that are adjacent to the experience of pain, such as anxiety, negative affect. And now there are a couple of ongoing studies. The Hopkins one is one example where a tiny dose of adrenaline, that study administered 2.5, 5, and 10. And the only dose that provided an analgesic synergy was the lower dose. Right. So, I think now there's some convergent evidence that if the outcome is pain relief, that there might be a therapeutic window. Right. As you say, that's a real thresholding type of a phenomenon. Yeah. And it might be narrow, which is a problem because the cannabinoids that people are consuming, people want harder, better, faster, stronger. And we've seen more people in ER settings. There's actually some evidence of experimental pain studies suggesting that high-dose THC and high-potency cannabis by dry weight can lead to hyperalgesia. Right. And if you think about pain and anxiety, again, it also leads to panic attacks. I mean, more, therefore, rationale for pharmaceutical-grade medications. Yeah. Right. So, yeah. This is an FDA-approved medication, not for this condition, but for chemotherapy-induced nausea, dronabinol, and HIV-associated anorexia. What people get in a dispensary, it's not FDA-regulated. Well, there's now evidence that what's in the label is not in the bottle. Ryan Vendry at Hopkins published a few papers on that topic. So, yes. Thank you. Karen Drexler. Is this on? I don't know. Okay. Karen Drexler from Emory High. Thank you for a wonderful presentation, and also for being so careful in your experiment. Oftentimes, we see headlines about benefit, but not careful monitoring for harms. So, my question, if you could, I don't know if you can go back to the slide about the memory, because it seems to me that you did several tests, and you saw something. You know, relatively small deficits in working memory, but as you said, it looks like this step-down dose-response for verbal learning problems. Yeah. Yeah. So, that seems pretty consistent to me. That's all about... Yeah. Yeah. Yeah. I think that's fair. I have to say, having done those studies in healthy people, like people with OUD, I thought that their responses were a bit blunted. I don't know if because these are patients who are, quote-unquote, very used to hard drugs, or there's some cross-tolerance between cannabinoid agonists, opioid agonists, which exists in preclinical literature, but not for the verbal memory. They're still vulnerable to the verbal memory deficits. Okay. And so, that's similar to what you see in healthy control studies. Excellent. So, am I interpreting this correctly, that your experiment really does speak not just a pharmaceutical grade, but the importance of the FDA approval process, which determines a therapeutic window and recommended doses, and then also oversees the manufacturing so that you get a consistent dose whenever you... Whenever I prescribe an FDA-approved medicine, I have confidence that my patient's taking what I prescribe, whereas if I sign a permission slip to go to the dispensary, what they get is all over the place. Yeah. No, thank you for bringing that up. That's such an important point. I often hear people say, prescribe cannabis, and what I tell patients is like, we prescribe the jocks, and we don't prescribe digitalis, a plant, right? So, we prescribe isolates that are pharmaceutical-grade isolates that have been... When you certify people for cannabis use, that's different. Often the person making recommendations about dose or schedule or administration is the bartender, which like a bartender is someone... They can provide a psychoactive drug in a licensed establishment, but they're not a healthcare professional. So, the word prescribe implies that you're talking about a pharmaceutical-grade, produced under GMP conditions, and I do think it's important not to conflate... We have to look at... I think cannabis would have been more ecologically valid, right? This is a human lab study, and there's a catch-22, as we're having a discussion with a colleague today. Here we can afford a lot of experimental control, and then you have what people are doing in the real world. I think both types of studies... You tested THC. That's what you have been showing. How about the effect of CBD for analgesic effects? That's another project that we're finishing right now. So in the pain paradigm is that a derivative of this we have more It's a more comprehensive assessment of pain and and it's also a pharmaceutical great product. It's a epidiolex Which is the only if the approved formulation of CBD so far for rare forms of seizures in children So hopefully next year. I'll share those data. We're finishing that project now, but The addictive potential is the TSC so that would be good. Yeah. Thank you So Thank you, dr. Aquino that was actually very very well studied Project I have few questions if you can go back to your slides about the pain sensitivity and the pain threshold and Can you highlight like how how do you interpret? So I the way I understood is the pain sensitivity is lower With with the placebo and it goes higher the sensitivity improves with the cannabinoids but the tolerance Can you explain the tolerance part a little bit? And then the second part of my question is since in this era at least 80% of my patients are using cannabis and And my I think majority of them are also on moud and I always worry that does the combination really change anything in particularly these here about the drug driving accidents the Perceptual changes and does this combination are you planning to study that in future? Thank you for those questions the first step I think the confusion stems for the fact that pain threshold and tolerance the so pain threshold isn't It means at what level in this case of thermal stimulation cold does the person report the first pain? like at what level of Cold stimulation the brain registered. This is no longer just cold, but it's pain So ideally you want the threshold to be a little higher not lower for tolerance the other way around more tolerance is good Less tolerance is bad. So so yeah, so Placebo is the column in purple The 10 milligrams is that's the one in in green and then 20 is in red. The y-axis isn't a second. So Here basically is when a person says this is painful Yeah, I mean though those fines are not significant, but yeah, that's that's the trend but that would be consistent with higher doses Follow-up, we're doing a study where we're combining THC and CBD, and it's still a human lab study. It's still dose finding, and we're looking at risk-benefit profile. Gabriel here, who's in the audience, is a post-doc with us, has looked at retention rates in cannabis exposure in the real world, and I think the finding was the jury is still out. So there are some studies suggesting that people drop out of MOUD treatment earlier if they are exposed to cannabis, others suggesting that they're retained, others it makes no difference. I think there's a lot of questions embedded within that question. What I tell patients is really approach the discussion from risk-benefit profile. It could be that, this is an acute administration study, I don't know if the small effect that we saw on pain intensity would be retained over time as people become tolerant to it. If you break your back and you get a benzo, you might have some acute relief of muscle spasms. It could go away as you become more tolerant. Longer-term use, I think, needs to be looked at, and also when you have induction onto MOUD, you also have transitions from one form of MOUD to the other. There could be points of time where the risk-benefit might be. to my heart, alcohol withdrawal management. So Dr. Johnson is going to, he is a graduate of Yale University's Psychiatry Residency, where he served as a chief resident at the West Haven VA Psych Emergency Room. He is also a Marine Corps veteran himself, and thank you for your services, and the owner of Encompass Psychiatry LLCs. So through which, he completes the independent consultation of veterans. He is also a medical director for eating disorders program at Robert Wood Johnson University Hospital in Somerset, New Jersey, and assistant professor of psychiatry at Rutgers Medical School. So he is going to tell us about the results of a national environmental scan done in the VA. This is the current state of alcohol withdrawal management. There's two green buttons wrong green button All right. There you go. Hi everyone. My name is Matthew Johnson I appreciate the brief introduction and also one point of clarity while we're going to be talking about alcohol withdrawal management it's from the perspective of operating procedures and Standardization of what those protocols are. So we'll get to that in just a moment So see a big list of names there a lot of people involved in this study, which we'll also touch on So no disclosures, right There we go, all righty, oh Right in front of me All right So the point of us talking about this today is more about how large the VA system is and how large a lot? into place and how we basically handle that in the VA, which is the largest system across the U.S. So a little bit of background is there was a VA study done that looked at approximately 30 VA sites and A lot of variance was occurring between these different sites in terms of what protocols were either being used or how protocols are being instituted Whether it was inpatient outpatient Whatever the case everything was looked at and too much variance that was a little bit inconsistent with the guidelines Resulting in some poorer outcomes in a number of cases it was those poor outcomes that also led to the office of the inspector general or OIG putting out a report commenting on those and It's from that report that an entire team was developed of more than 50 people each with then their own sign kind of like sub teams essentially to really get this going and It was through this that we're able to Get these standard operating procedures more standardized and that's the current phase that we're in. So you see on here There's three phases. The earliest phase was again more preparation kind of getting this information Synthesizing what needs to happen? Phase two is what we had pretty much Submitted here and is what the presentation is because at that time is when we were just about to get into phase three So we'll touch on that in a moment as well So what had basically occurred was we did an environmental scan Which is essentially a survey that went across all the VA systems So you can see there's a hundred percent participation and the way that that was able to happen is because it was actually mandated So rather than sending out a survey and hoping for responses where then you comment on whatever that rate is. Well hundred percent so mandate So What that led to was then the development of these work groups that were then kind of broken up from that Group, and we ended up having the 250 responses. There's more than a hundred Pieces of the VA out there that 250 responses comes from because sometimes we had multiple responders from each VA site Which brings us into here who responded so I'm not going to go through every little detail here But for the most part it was physicians who responded but you can see there's nurses psychologists social workers And there's a little bit of a break down there and in here It also shows what department are setting from which they're responding. So psychiatry still makes up the bulk of that Given how much to overlap but there's also a big component to medicine who is responding especially given that this is more inpatient kind of focused This slide points out a couple things that were interesting because the VA being the largest system is very resource rich We have a lot of things at our disposal across the board regardless of what state what situation? And the fact that it's federal rather than even state Yet out of 250 responses that top wrong right there 211 of those stated that we don't have the resources So bit interesting and then the other one that I wanted to point out It's the one in blue kind of in the middle 97 responses state that we lack the experts or staff relative to that that could mean more specifically trained addiction Psychiatrists or addiction medicine specialists, but nonetheless here we are the largest system and we lack resources. We lack staff and expertise and Then we have here some grouped levels of care Let's see, do we change this I think that was a different slide Nonetheless here is a brief breakdown of the settings in which responses came from again So quite a bit from the inpatient level of care whether it was detox Inpatient whether it was psych consults and then we also have like the residential level PHP IOP emergency room and the ambulatory setting from which these responses were coming from and Then here part of that scan was also to divvy up, you know How are these evaluations being done regarding even figuring out, you know, how significant is the withdrawal? So the audit PC was the most used but you can see there's a couple others that are used pretty significantly as well and then In terms of assessing the actual withdrawal the predominant one was the C one Mostly see one. So that's very consistent across the board, but it's one of the actually relatively few consistencies So amid what was submitted from all these different sites you can see on the left under SOP is This basically demonstrated how much variation was coming in They are sending in things with different titles different protocols And when you start to read them you start to see how differing these actually are from site to site despite having similar guidelines across the board on The right side there the policies and directives are what we're starting to be the result of that when we started to take into play What are we receiving? What are we seeing? That's different. What are we taking from it? That's bad and getting rid of it What's good? What are we keeping? How do we take 250 responses across more than a hundred sites and start to put that into a deliverable essentially Which brings us to this? This looks like nothing because it pretty much is at the forefront But what this is is with there being different settings whether it's inpatient outpatient There's no one specific way to treat alcohol withdrawal So the idea is that these shared drives are being created so that depending on what site you're in and what type of? Situation you're in you're able to go to this share drive open it up and pull from it What fits your your particular location and setting and then from there? You're able to then put it into an order set most of us are probably dealing with epic But can I get a brief show of hands who here has worked at the VA before in some form a? Lot of people so everyone knows CPRs. Sorry Nonetheless It's not all that easy to deal with and despite it being a national system and everything connected There's also a lot of things that have to be done at the local level Hence again making a deliverable which brings us into CPRs and giving that deliverable so you can see here where there's a lot of things to be able to click on and Included in there, which I don't have a picture of is Not so much like a share drive but it's something accessible for everyone within the VA to be able to go through and get Directions on how to be able to implement these different protocols and actually create order sets to again keep up with the consistency So there's a little bit less deviation to keep up with the guidelines through a Sam and through a AAP This year I'm not gonna have you read this it's not meant for you to be read right now But more of just one thing that was submitted from a particular VA. This was from Portland This is one of the better SOPs that were actually submitted that again pulling information from and trying to use as a little bit of Guide pulling what was better amongst what was sent Again, just page two here Effectively what was done was with taking these we created a model SOP that was meant to be delivered So by creating that model SOP There would be a few highlighted portions or bracketed portions where then each individual site and location would effectively put in their information Their specific location their specific site or setting and then take from what we developed and Implement that into their operating procedure for each individual entity or in each individual type of entity So again, that's what led to the standardization Back in I think was August or late summer is when a directive was made so that they had a limited amount of time So December coming up is the end of that period. So we're looking at going into the new year finally with having these things A little bit more set in stone and standardized across the board So the big takeaway here is despite how large a system may be there are ways to be able to operationally get things To function whether it's through a mandate or a directive, but being able to pull the information that already exists pull out of it What's bad keep in what's good? Synthesize it and create a deliverable that can be sent to each individual hospital or each group of hospitals So if the VA can do it you can I'm not Brian. He's right here Any questions On that note, little plug, I'm actually presenting on this tomorrow as well in one particular way. I'll kind of allude to that. One of the things that we started to notice was with the CEWA protocol, the protocol itself doesn't include like blood pressure or heart rate, but it's often considered within the protocols. We started to see a lot of benzos being used when we would see blood pressure or heart rate spiking, but often see that the CEWA score itself would be like a three or a four or something very low. And then when looking into the history, we'd see that a lot of these patients have hypertension or something else going on, so then it's, are we now having overuse of benzos versus using an alternative agent to try to get other things under control? With that, there was a lot of variation in either in like dosing, whether it's loading or how to continue with the dosing of like volume versus the Ativan tapers, whether it was used in conjunction, starting a taper automatically with the CEWA for symptom triggered beyond that versus doing symptom triggered only. So again, a lot of differences. And then if there's any additional information, do you have any other things you wanna add to that? No, I mean, so I'm Brian Furlin, everybody. Nita was also on our IPT. I was one of the chairs of the IPT. Matt was my chief resident last year, so I'm proud of the work Matt did on this project, but I'm continuing to work on the project. Matt's not, because he's graduated. So I have some more additional information if anybody's interested. I can probably answer most of your questions because I've been intimately involved. But sort of to get to your question, you know, we looked at, we asked, as part of the environmental scan, we asked facilities to submit their SOPs that they were using along with a variety of other things, order sets and other things. So we wound up looking at, you know, hundreds of submitted documents. And we did it sort of in a blinded way where we had one faculty member on the committee look at a certain subset of these and then rate them on a scale of one to five is how effective they thought these protocols were. And then we asked a second faculty member to do the same. And then we focused on the ones where both faculty members rated the SOP very highly. And then we took a collection of all of those and we basically created a model SOP, which we don't have up here because it's a little bit newer. But basically, the tasking that came down from central office, again, if you work at the VA, you know some of this terminology, but the tasking that came down from central office, it came out as a notice back in August. And there's 120 day window to comply with the notice. And it's basically that all facilities have to have an SOP that addresses certain criteria within their alcohol withdrawal management. So we provided a model SOP to the facilities and said, you can simply use this one that we created from these submissions that we got, or not, you don't have to, but you can use it if you would like. But your SOP, whatever you use, has to contain certain elements. And we outlined all of the elements that it has to contain. There were other things that facilities had to do as well. They have to have certain trainings on the use of CEWA and other trainings as well. They didn't have to provide to us the trainings that were being used. They just had to document that they were going to provide the trainings and who was gonna receive the trainings and that they had a plan to do it. And all facilities have until December 12th, I forget the date, but they have until December to comply with this notice that came out in December. So it all came from all these SOPs. Very few facilities had what I would call a poor SOP. Some were better than others. They included multiple medications. They included multiple algorithms. They included things like medications for alcohol use disorder in addition to detox. They included things like referral to residential treatment when that was appropriate. So some of them were very thorough, some of them not so much. So we focused on the ones that were thorough when we created the model SOP and the notice to the field. So hopefully that answered your question. That was very, very helpful. Yeah. Yeah, thank you. Yeah, and the idea is like Matt was saying, the VA is the largest healthcare system in the country. It's the second largest branch of the government. And we have 138, I forget the number of facilities. There's a little bit more if you include some of the, there's a lot of facilities. And there was a lot of variability out there. And our tasking with our group, which again was about 50 or so people, experts from around the country, some people who are here at this meeting that were on the group, was to try to make that as consistent as possible across all of these sites, given limited resources at certain sites. Some sites have, like where I am at the VA in Connecticut, we have Yale with us, and we have many, many, many experts in this there. And other facilities don't have a single addiction psychiatrist anywhere on staff. Some are in rural sites without access to a lot of things other sites have. So despite all of that, we, our tasking was to try to make management of alcohol withdrawal as consistent as possible and as effective as possible across this large system. Any other questions? Ricardo Restrepo from Long Beach VA, California. I have a question for you. And it's in reference to the different protocols. And I'm curious. Yesterday, some of us, we were in a conference that people, as we know these days, are using other approaches for the treatment of alcohol use disorder, especially for the detox, alpha-2 agonist, phenobarbital. But I'm curious if at the VA system, when you review the SOPs, people were moving away from the Benzo treatment and were trying to implement other approaches and how the VA responded to those SOPs. I'm not sure about the specific responses. He might have that. But in terms of other options, on the inpatient side of where we're at, there was actually a decent amount of use of gabapentin at a few points to be able to help with that process. And then it was really up to really personal choice. There was a lot of like chloride isopoxide being used. In the ER, we were using primarily the symptom-triggered CEWA. And then looking at some alternative agents like clonidine to help with some of the more vital sign changes to really get to the root of what was going on to try to prevent the overuse. But it was still kind of coming down to a little bit more like individual choice at that point. Yeah, you know, what we pretty much recommended was the use of front-load, long-acting, mostly diazepam-driven protocols for inpatient. The focus of the IPT was inpatient. The OIG findings stemmed from poorer outcomes in inpatient medicine side of alcohol withdrawal management. So a lot of what we did sort of focused on that. And for that, you know, you have, if you have the ICU setting, you had different phenobar protocols that were up there. But for general inpatient medicine setting, most of the protocols out there and what we wound up recommending is a longer-acting, front-loaded, like mostly a diazepam-driven protocol. But having said that, like Matt mentioned, a lot of facilities are trying to focus on ambulatory detox. And there were a lot of protocols out there for ambulatory detox. Mostly, I would say gabapentin would be the most popular of the medication choices for the management of ambulatory detox. That's what we favor as well. We have a protocol. They were all, many of them were just a little different, but just variations of gabapentin. Some used other antiepileptics. Mostly, gabapentin was used for that. So it depends. But no, to answer your question, mostly it's still benzo-driven detox, at least in the inpatient setting. JP was my other chief resident also, so they were both my chief residents. I don't take any credit for any of this, but I just wanted to shout out that. It's been a great mentor. I'm curious, so did you look at, for the people who get gabapentin for aqua withdrawal, how many of them continue to get gabapentin as an ongoing pharmacotherapy for AUD? Right, yeah. Yeah, or other gabapentin-based pregabalin. Yeah, I don't think I know that. So it's a really good question. There's evidence that gabapentin is good for post-acute withdrawal syndrome. Our protocol, if we're just doing a gabapentin detox as a six-day taper in our outpatient setting, which is we use 400 TID for three days, BID for two days, once a day for one day, and then stop. That's just one variation. There's other variations. But we do often try to say, are you willing to stay on gabapentin longer than just the six days to use it as sort of a maintenance medication for alcohol use disorder, even though it's not one of the FDA-indicated medications? We'll often use it at least for a period of time to manage the post-acute withdrawal symptoms. So it's a really good idea. You know, it's not really necessarily something that we looked at on the protocols because the protocols were mostly focusing on detox. And then we had in there a section on the SOPs where they have to have referral to treatment for their alcohol use disorder, and much of that includes medications. But we focused on the FDA-approved medications. But gabapentin is a really helpful adjunct. Yeah. Just to add into that, actually, I mean, and again, I don't think we have anybody that I know of has data supporting the use of gabapentin after the actual initial detox. But in my current practice in Resource Hub, I've been giving gabapentin sort of harm reduction. And what I have observed is the amount of alcohol use has reduced significantly. And I'm gonna put in a page for Brian to look into that. And maybe we will hear about the VA data next year. I just want to follow up on the gabapentin, so if I found it helpful like long-term for alcohol cessation, but if a patient returns to drinking, like when would you be worried about the dose adjustment of gabapentin? Yeah so it's a it's a good question and you know again with gabapentin not being one of the FDA indicated medications for ongoing maintenance of alcohol use disorder I'm not sure that there's any clear guidelines that would say you know if if your patient returns to drinking you should lower the dose or increase the dose or you know switch to a different medication so I don't know if there's any clear data that would show that you can think of it as a harm reduction approach where you know maybe they would drink less but maybe not you know it doesn't really sort of have the same effect as naltrexone yeah do you want to add we've been using gabapentin for more than a decade now in combination of it naltrexone it's pretty much four out of five people respond to treatment of alcohol use disorder I'm not talking about just so and there's some evidence is dr. Rosenthal here I mean combination of naltrexone and gabapentin was shown to be more effective than either of them alone so the idea that you know we have to stop it doesn't make a lot of sense and that's not the clinical practice across the board you go to any any meeting you'll never see an FDA indication from gabapentin because it's been generic for a while they tried to have a branded formulation but it was very underdose so no wonder it didn't work but the most of the gabapentin literature validating the use in alcohol use disorder came from Barbara Mason's article about 10 years ago 2014 and that's that essentially validated what we were doing in practice for probably at least five years prior to that but that's the practice across the board you go to any conference you're gonna hear this typical dose for maintenance for alcohol use disorder hovers around 1,800 milligrams a day so 600 milligrams TID there are there is a subset of the population which responds to higher than that but that's not most patients and I'm talking about primarily alcohol use disorder patients when you have patients who are opioid use disorder we are a little more cautious using gabapentin like water but for primarily alcohol use disorder it has been a game-changer We don't have any particular data on that, because we were focusing, again, more on the inpatient side of the treatment, which was more the specific withdrawal that was occurring. I'm not sure if anyone has anything they wanna add to it. Topiramid, we use that a lot, too. It's not as well tolerated as gabapentin, but I think topiramid got a bad name for itself because it was overdosed for the purposes that we were using it for. Neurologists use it routinely above 200 milligrams a day, and at those doses, you're likely to risk more cognitive problems, whereas for our purposes, we tend to get benefit under 200 milligrams a day, so it's typically a 25 BID, 50 BID, and then 100 BID for a few patients, and they respond quite well, but it's not tolerated. Plus, you have to remember the titration, you have to be a little more careful, whereas with gabapentin, you can titrate it in a week to 600 TID, and when your patients are struggling, they're not gonna wait three weeks versus one week. That's the reason why we use more gabapentin than topiramid, but it definitely has a role, and especially for co-occurring cocaine use disorders, it is one of the few medications that we've seen has at least somewhat of a signal of response in the actual real world. The Maldonado Protocol, the variations of which exist all over the country, if not the world, it is in the algorithm, and we have incorporated valproic acid, and especially for co-occurring benzodiazepine withdrawal, I think that has been quite helpful to have valproic acid. Just a quick comment and question, so I think for some of those medications, like if you look at the, you know, there will be bad analyses looking at, say, six different outcomes, and you know, you have return to alcohol use, you have reduction of percentage of heavy drinking days, and you know, for topiramide gallipedin, you do have, you know, support for one of these outcomes here, but I heard post-acute withdrawal a couple times, and I'm wondering if in these nationwide VA datasets, you can look at surrogate markers, like, you know, things like sleep quality that don't take a lot of time to collect, and are believed to be related to this, you know, post, what we're calling post-acute withdrawal syndrome. So, DC Park from Bedford VA, I just wanted to make a comment on the Galvapentin. If I could list one medication that my patients abuses outside of the standard, you know, urine drug screen that we do, it's the Galvapentin, and it's across the board, and there are actually a number of factors for that. Galvapentin 1 is very available, provisionally available, it's very convenient. It's not, a lot of, you know, VAs do not test for Galvapentin, you have to order separately for a confirmation test. And especially for, actually for our patients in the dom setting, the residential program, for all the controlled substances that are dispensed by our nurses, Galvapentin, although it's not controlled, it's only prescribed in a week's inclement, because it's that much abused. And when we get into, like, you know, epidemic of, like, you know, catching, you know, stash of supplies, or catching Galvapentin, it is the number one substance. So for the state of Massachusetts, in fact, the state PDMP, they don't have any obligation to report Galvapentin, because it's not a controlled substance. The state of Massachusetts does, because they recognize the fact that it is the most often abused. So I talk about, you know, so I have had patients who have benefited from high-dose Galvapentin, but more often than not, I have patients who actually, you know, end up having harms caused by high-dose Galvapentin. You know, it is very much abused. I've seen... Which form of patients are you talking about? So I'm talking about not just the alcohol-controlled patients, but I'm talking about patients, so patients who are usually, like, talking about generalized anxiety disorder, social anxiety disorder, they are the ones asking for Galvapentin. Or if they have, you know, neuropathic pain, they're the ones asking for Galvapentin. And for some of the outpatients, actually, a lot of... Some outpatients, they can handle that. They can manage that, you know, very much. But for some of our most high-risk patients, you know, with opioid disorder... Are they drug users or primarily alcohol users? I think it's... From my perspective, I think it's everyone. If they have a chance to abuse one thing, that they're not gonna be readily caught. And for our VA, that happens to be Galvapentin. So I think, because I just had to speak up, because everyone else was speaking about how wonderful Gall-Penten is, and I'm like, like, and, and, and, you know, like, I've had patients having withdrawal seizures because, you know, they are, they just have been taking Gall-Penten, you know, a lot without telling the doctors. Yeah, yeah. So, because, well, they're not positive for benzos, and we've done the benzo confirmation. They're not the positive, you know. So, okay. So, and, so we, we do the, you know, if they're, if they're negative for alcohol, and, and I just wanted to comment on that. I think not for the alcohol withdrawal management, but to Pyramid, I think there was a recent article that showed that the head-to-head trial against the naltrexone is actually, to Pyramid, actually may be superior to, to naltrexone. To, you know, so I've, so, right, a comprosate, at least in my American patients, and a lot of studies, they show that no really benefit for, for American population. To me, to Pyramid and naltrexone, you know, first or second line, you know, it's actually, you know, that's what I use. To Pyramid, you know, I agree that it does take a long time to, to touch up to 150 milligrams twice a day. That's the minimum dose that I'm striving for. I just, you know, I, I was feeling a little bit nervous about the old appraisal of Gall-Penten. I, so, yeah, thank you. Elizabeth Oliva from the VA. Just real quick, Dr. Park, I'll check in with you later, because I, we have been working with PBM on a evaluation of Gall-Penten within the VA system. I have to double check and see where things are at with that, but to your point, there is concern, so we are taking a look at it. So, thanks. Thank you.

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