All right, thanks for being here on this late afternoon. We have the paper session three, or paper session C. We will start with Dr. Aquino. Very excited, actually, to hear about his paper. He is an assistant professor of psychiatry 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 assessment, and clinical trial methodologies to develop innovative therapeutics for patients dealing with chronic pain and opioid addiction. He aims to enhance treatment strategies and improve outcome for this population. So he's going to talk to us about the Delta 9 tetrahydrocannabinol modulates pain sensitivity among persons receiving opioid agonist therapy for opioid use disorder. And his study is a within-subject randomized placebo-controlled trial. All right, there you go. Thank you, Dr. Vizay, for the lovely introduction. Thank you, everyone, for being here. So just click the green, or? OK. So here are my disclosures. I 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-Azrinabinol 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. 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 both days for three months. And there is 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. 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 and get cannabis or constituent cannabinoids in lieu of methadone or buprenorphine, even though we don't have data to suggest this approach would work. And 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 antinociceptive 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, next to a common experimental model of pain, you need much less morphine than if you give a 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, not cannabis. Not only that, but there was a synergistic effect of THC and oxycodone for antinociceptive model, experimental pain. But that's this 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 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 THC when given with hydromorphone, 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. And 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 oral THC on pain, abuse potential, and cognitive performance in this population, people who get methadone for OUD. And 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. You know, 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. On 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. We 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, OED. And conversions from methadone to MME are a bit tricky because methadone for OED 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. So 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. On 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 what the 180 minute mark, which is around when the peak effects of THC or THC tend to occur. And 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 in the, right after people remove 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. We didn't, 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 in the SPI-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 CB-1 receptor agonist studies, because the hippocampus is very rich in CB-1 receptors. So to summarize, there was preliminary evidence of analgesic dose of THC in 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 brainwashing 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 low-period risk 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, participants, all the funders, especially the Patterson Trust. I'll take any questions. Thank you. Go back three slides. Say it again, sorry? Go back three slides and let me know. This one? So really interesting work, but what is the rationale of the thoughts behind that though? Lower dose provided more relief than the higher dose. Could I make a question? You saved the questions. I mean, again, we only have, we don't have the third presenter, so I guess we don't have the paper. So we can decide the way we were going to have 10 minutes of presentation followed by Q&A, but if it's easier to do the, no, we'd like to switch and let's get it over with. All right. Okay, fine, all right. So please hold off on the question at all. I'm saying some of us might want to see a paper in a different room, so we can't wait to do the Q&A. Followed by the paper. Yeah, all right, if that's okay with everybody, I think we have time. We are not under time pressure, so all right. How much time do we have? Maybe 10 minutes of time for this paper? Sure, all right. So the question was about what's the rationale for the lower dose providing superior, a superior risk-benefit profile as opposed to higher dose. Is that? 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 antinociceptive 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. Well, the Hopkins one is one example where a tiny dose of Dronabinol, that study administered 2.5, 5, and 10. And the only dose that provided an analgesic synergy was the lower dose. 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. 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. And 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? If you think about pain and anxiety, again, it also leads to panic attacks. Yeah. More, therefore, rationale for pharmaceutical grade medications. Yeah, 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 that there could, well, there's no evidence that what's in the label is not in the bottle. Ryan Vandrie at Hopkins published a few papers on that topic. So, yes, thank you. Karen Drexler. Okay. Karen Drexler from Emory, hi. 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, relatively small deficits in working memory, but as you said, it looks like this dose, this step down dose response for verbal learning problems. Yeah. Yeah, so that seems pretty consistent to me. That's all about, yeah. Yeah, I think that's fair. And 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 kind of, 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. You know, 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, and I think both types of studies are needed. Thank you. Sure. Are there any other questions? I do have a question. Conflate. You tested DHC, 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, and the pain paradigm is a derivative of this. We have more, it's a more comprehensive assessment of pain, and it's also a pharmaceutical grade product. It's Epidiolex, which is the only FDA-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 that's it. Because I think the addictive potential is DHC, so that would be good to test. 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 do you interpret? So I, the way I understood is the pain sensitivity is lower 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 my, I think majority of them are also on MOUD, and I always worry that, does the combination really change anything? And particularly, we hear about the drug-driving accidents, the perceptual changes, and does this combination, are you planning to study that in future? Yeah, thank you for those questions. The first, yeah, I think the confusion stems from the fact that pain threshold and tolerance, so pain threshold, it means at what level, in this case of thermal stimulation cold, does the person report the first pain, right? 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 yeah, so placebo is the column in purple. The 10 milligrams is the one in green, and then 20 is in red. The y-axis is in seconds. So here, basically, is when a person says, this is painful, this is not just cold. The other one is when they, again, unambiguously remove the hand from the cold water bath. Yes, which, yeah, I mean, those finds are not significant, but yeah, that's the trend. But that would be consistent with higher doses leading to hyperergesia. And you know, what's a high dose? It may vary depending on the patient population. Are they tolerant to the effects of THC, right? What's the route of administration? And the second part of the question was, yeah, the 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, the 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's 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. And so I think there's a lot of questions embedded within that question. You know, what I tell patients is really approach the discussion from risk-benefit profile, right? And it could be that, you know, 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. Like 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. So longer-term use, I think, needs to be looked at. And also when, you know, 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 favorable or it might not be. I think we need to do those types of studies. Thank you. All right. So our second paper is on a topic near and dear to my heart, alcohol withdrawal management. So Dr. Johnson is going to, he is a graduate of Yale University 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, LLC. 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, so the current state of alcohol withdrawal management in the Department of Veterans Affairs. So, welcome. Let's see. Let me just test this clicker first. Is it this thing? Oh, there's two green buttons. Wrong green button. All right. There we 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 of other systems are also, and how when these larger systems can sometimes differ from place to place in terms of how these either different protocols or treatments are being put into place, and how we basically handle that in the VA, which is the largest system across the US, and hoping that the takeaway is that you see how in some of these larger situations or larger systems that you could possibly do the same if you feel that there's discrepancies across different places. 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 poor 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 within their own sub-teams, essentially, to really get this going. And it was through this that we were 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 100% 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, 100%. 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 100 pieces of the VA out there. The 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 breakdown there, and here it also shows what department or setting from which they're responding. So psychiatry still makes up the bulk of that, given how much 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 of 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 a bit interesting. And then the other one that I wanted to point out is 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, did we change this? I think that was a different slide. Nonetheless, here is a brief breakdown of the settings in which responses came from. 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 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, how are these evaluations being done regarding even figuring out 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 CIWA, mostly CIWA. So that's very consistent across the board, but it was one of the actually relatively few consistencies. So amid what was submitted from all these different sites, you can see on the left under SOPs, this basically demonstrated how much variation was coming in. They're 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 were 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 share 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 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 that there's a little bit less deviation to keep up with the guidelines through ASAM and through AAAP. This year, I'm not going to have you read this, this is 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 it 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? So, on that note, a 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 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 3 or a 4 or something very low. And then when looking into the history, we would 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 dosing, whether it's loading, or how to continue with the dosing of 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 want to add to that? No. I mean, so I'm Brian Ferland, 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 a 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 going to receive the trainings, and that they had a plan to do it. 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. You know, very few facilities had what I would call a poor SOP, you know, 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. Yeah. Yeah, you know, and the idea is like Matt was saying, it's, the VA is the largest healthcare system in the country, it's the second largest branch of the government, and there, you know, 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, 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 chlorodiazepoxide 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 individual choice at that point. 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, 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, 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. J.P. was my other chief resident also, so they were both my chief resident. I don't take any credit for any of this, but I just wanted to shout out that. He'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 ongoing pharmacotherapy for AUD? Right, yeah. And, yeah, or other gabapentin-analyzed pregabalin. Yeah, I don't think I have that. So it's a really good question. So there's evidence that gabapentin is good for post-acute withdrawal syndrome. And 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 going to 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, and how much they're drinking if that was increasing? Yeah. So it's a good question. And 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, it's not a good idea to use gabapentin. But I think it's of alcohol use disorder, I'm not sure that there's any clear guidelines that would say, you know, 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? Yes. We've been using gabapentin for more than a decade now. In combination with 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 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 underdosed. So no wonder it didn't work. But 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 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 going to hear this. Typical dose for maintenance for alcohol use disorder hovers around 1,800 milligrams a day, so 600 milligrams TID. 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 have some patients on that. So we don't have any particular data on that because we were focusing again more on the inpatient side of the treatment, which was like more of the specific withdrawal that was occurring. I'm not sure if anyone has anything they want to 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 going to wait three weeks versus one week. There's a big difference. 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. Yeah, the stimulant use disorder workshop that was just an hour or two ago, they mentioned topiramid, both the methamphetamine use disorder and cocaine use disorder, and you know, we know that it's being used also properly as a disorder, but again, all the limitations is tolerability, and I think they mentioned up to 200 milligrams for the methamphetamine, but that's usually around the level that it becomes hard to tolerate. I have a question, sir. Pro-AIDs are the bad old days. One of the other anti-seizure medications that are popular and given typically as a loading dose, and then you don't have to anywhere near as often as gabapentin, you can give it to you just once a day, so in that sense, it's more similar to the best of the AIDs. Did that die somewhere in the last 10 years? It's gone concurrently. Yeah, it's a short answer. Yeah, I mean, there were some protocols that did include other antiepileptics like Depakote, but it wasn't as common. I mean, if anybody would like to see the big samples I have, where we could put the fire out with the benzos, and when we added the valproate, you know, we stopped the delivery. 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. So, as an adjunct, it's there, but it wasn't the primary, really, for most of the protocols, but it's certainly there, and there was a slide you probably couldn't see that well, but that order set had all the adjuncts. I wanted to make a quick comment about gabapentin, you know, the patients who respond to gabapentin, if you look at the root cause, and they have chronic pain, it's a great alternative. For those with headaches, migraines, metabolic issues, diabetes, they tend to do a little bit better with dopiramine than the rest of those issues as well. So, that's some of the things you want to consider when choosing dopamine, as well as the adjunct. How does dopamine address the problem? Dopamine? It takes away appetite, and it also leads to decrease in blood sugar levels, and for patients who have migraines, it's already a pretty good bet. So, it helps, you know, patients who are, you know, wanting to lose weight, like all their issues with migraines, back pain, it's a good option, and that way you address the root cause that leads to distress, and leads to cravings, and all that. 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 galapentin, 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, what we're calling post-acute withdrawal syndrome. Right. Anyone else? So, DC Park from Bedford VA. I just wanted to make a comment on the galapentin. If I could list one medication that my patients abuse outside of the standard, you know, urine drug screen that we do, it's the galapentin, and it's across the board, and there are actually a number of factors for that. Galapentin 1 is very available, pervasively available. It's very convenient. It's not, a lot of, you know, VAs do not test for galapentin. 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. Galapentin, 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 galapentin, 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 galapentin because it's not a controlled substance. The state of Massachusetts does because they recognize the fact that it is the most often abused. We talk about, you know, so I have had patients who have benefited from high-dose galapentin, but more often than not, I have patients who actually, you know, end up having harms caused by high-dose galapentin. You know, it is very much abused. I've seen, so I'm talking about not just the alcohol withdrawal 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 galapentin, or if they have, you know, neuropathic pain, they're the ones asking for galapentin, 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 the opioid disorder, I think, from my perspective, I think it's everyone. If they have a chance to abuse one thing, that they're not going to be readily caught, and for our VA, that happens to be galapentin. It seems to be a misnomer where I'm from. It's not a controlled substance, but it's a monitored drug, and I'm against mental being part of the controlled substance board, because we need to know, like, what kind of, you know, bring up a valid point, but at the same time, when you look at the absolute number, everything that we do, risks and benefits, of course, if you see a signal that it's causing problems, you would be cautious, just like everything else, but at the same time, how many options do we actually have, and when you think about under-treating people, so... You know, so, right, no, so I think, no, because I just had to speak up, because everyone else was speaking about how wonderful galapentin is, and I'm like, like, and the... Right, and, you know, like... I've had patients having withdrawal seizures, because, you know, they are, they just have been taking galapentin, or, 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, you know, right. So, okay, so, and, so we do the, you know, if they're, if they're negative for alcohol, ethogen, ETS, okay. We do not have a chart paper. Okay. And I just wanted to comment on that. I think, not for the alcohol withdrawal management, but tropiramate, I think, there was a recent article that showed that the head-to-head trial against naltrexone is actually, tropiramate actually may be superior 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 American population. To me, tropiramate and naltrexone, you know, first or second line, you know, it's actually, you know, that's what I use. Tropiramate, you know, I agree that it does take long time to touch up to 150 milligrams twice a day. That's the minimum dose that I'm striving for. I just, you know, I was feeling a little bit nervous about the old appraisal of galapentin. So, yeah, thank you. Yeah, sorry, 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 galapetinoids 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. Thank you.

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