Welcome to our workshop on the management of alcohol use disorders in the liver transplant population. So, let me share an anecdote. I just finished the update on transgender medicine, and at 12.30 I thought I'd grab some lunch and go to the pool and have a nice relaxing lunch. And then I get a call from Dr. Mufti. Dr. Mufti is a hepatologist. I'll introduce him. He said he's in Jacksonville. I said, what are you doing in Jacksonville? So, someone with a flight developed some chest pain, so they diverted the flight to Jacksonville. So, Dr. Mufti is joining us by Zoom. He's at a Hyatt in Jacksonville and joining us by Zoom. So, I'll show you his picture. He's right there. So, you can all wave to him. So, let me move this back. All right, sorry. Stephen, how do I move this back? It didn't even take me one minute. So, now you can see how technologically challenged I am. Sorry. He might have to hang out there, unfortunately. There we go. Wonderful. He's gone. Sorry, folks. Thank you. So, again, once again, welcome. And alcoholic liver disease is the most common indication for liver transplant in the country. And historically, the role of the addiction psychiatrist has been in kind of figuring out, what are the risk factors pre-transplant? Who's going to drink after transplant? Who's not going to drink? And we have spent a lot of time and money on trying to figure that out. And I don't think we have a consensus on that. So, rather than kind of focusing on that, I think we really need to help our patients maintain sobriety post-transplant, which is very critical to a successful transplant outcome. Because, as Dr. Murthy will show in his slides, about 4 in 10 patients of post-transplant will go to some level of alcohol use, leading to increased mortality and morbidity. So, focusing on post-transplant care is critical. And I always tell my patients, alcoholism is a brain disease. It's not a liver disease. And when you get a liver, you're not taking care. You still are struggling with your alcohol use disorder. So, the role of the addiction psychiatrist is essential and needs to be integrated within the transplant team. And at UD Southwestern, we have an excellent collaborative relationship with the transplant team. Our transplant hyperologists are a group of very caring and compassionate physicians who truly understand alcohol use disorders and the chronic disease model. I'm going to start off with introducing our speakers. Our first speaker is Dr. Gabriela Velasco. Dr. Velasco earned her M.D. degree from the Catholic University in Ecuador. This was followed by general psychiatry residency training at Texas Tech University in El Paso. And she started her addiction psychiatry fellowship at UD Southwestern this past July. Her interests are addiction treatment in the acute hospital setting and the intersection of reproductive psychiatry and substance abuse disorders. Dr. Velasco will set the stage with the case presentation and discuss the role of the addiction psychiatrist in the transplant process. Our next speaker is Dr. Mufti. Dr. Mufti is a transplant hyperologist who has been at UD Southwestern since 2013 with a rank of associate professor in the Department of Internal Medicine. He's the medical director of the UT Southwestern's liver transplant program. Sorry, the living donor liver transplant program and the GI fellowship program director. Dr. Mufti will discuss the natural history of alcoholic liver disease and its management. He'll also discuss post-transplant alcohol use and the current status of liver transplant in acute severe acute alcoholic hepatitis. Dr. Velasco and Dr. Mufti will go back and forth in their presentation as the case evolves. I've been a faculty at UD Southwestern since 2003 with a rank of professor in the Department of Psychiatry. I'm the clinical director for the Addiction Psychiatry Service and the Addiction Psychiatry Fellowship Program Director. I will talk about the pharmacological management of alcohol use disorders, both FDA and non-FDA approved, and also briefly discuss two agents, Nalmefene and GHP, that are approved in the European Union but not here in the U.S. Then I have a couple of slides on the recent studies on psilocybin and alcohol use disorders and ketamine studies in alcohol use disorders. I'll just briefly mention them. Let me start off with a presentation. We have no disclosures. These are our objectives. Discuss the epidemiology of alcohol use and alcohol use disorders in the liver transplant population. Discuss the impact of alcohol use in the same population and discuss treatment strategies that should be employed post-transplant and the use of pharmacotherapy in this population. I will hand over the stage to Dr. Velasco for the case presentation. Thank you so much. We will start today with the case presentation. We will talk about our patient. This is a 37-year-old male with a history of alcohol use disorder and alcoholic hepatitis. The patient started drinking when he was around 19 years old, and he had his first intoxication when he was 20 years old. The patient started drinking daily approximately when he was 32 years old, and the patient reported drinking about 5 to 12 beer ounces daily, but most likely the patient was underreporting his drinking due to his complicated clinical presentation. Just to have a brief history from his substance use, he didn't have any history of complicated withdrawals. He just had a history of mild withdrawals in the past. He had some legal issues, including a DWI, years before we started evaluating this patient, and he didn't have any type of treatment before. No pharmacologic treatment or any participation in AA meetings or any type of groups. He didn't have any past psychiatric history or any other substance use. And patient, important to mention his social situation. He was living with his parents, and they were the main support system, very supportive, and he wasn't taking any medications prior to our evaluation. Here we can see the pre-transplant hospitalization. So he had multiple hospitalizations until he got his liver transplant at the beginning of 2021 at UT Southwestern. So most of the presentations were pretty similar. The patient presented with decompensated alcoholic hepatitis with GI bleeding, anemia, and hepatic encephalopathy. In treatment, it required massive blood transfusions and banding. So in his first admission to the hospital, this was like at the beginning of 2020, patient had, as I mentioned, decompensated alcoholic hepatitis, which is consistent with his labs, an AST of 299, an ALT of 118, and a total bilirubin of 8.7. Patient was admitted for about a month, and during that admission, patient was evaluated for liver transplant, but due to positive PEP, patient was rejected. PEP is a folfatidyl ethanol, which is, as we know, is a marker in the blood after you start drinking alcohol. It can be positive for about four weeks after the last drinking, and the more you drink, the higher the levels of the PEP. So then patient, as I mentioned, he was rejected for liver transplant, and he continued outpatient visit with hepatology in Montana. Patient was from Montana, so previous to going to UT Southwestern, he continued. He had his care at Montana. So during those months, patient was kind of stable, or he didn't have any more decompensated admissions to the hospital, but later in that year, around September, patient again decompensated, was admitted, and you can see the labs. Well, this time, ASC were 84, ALT 38, and the total bilirubin 16.5. Patient later have three more admissions, but the one that I want to mention is the one on the end of 2020. So patient during this admission have two live threading GI bleedings, and patient, again, was evaluated for liver transplant, but again, due to the positive PEP, patient was rejected. After his last admission, patient was referred to UT Southwestern, and at the beginning of 2021, patient was evaluated and was accepted for liver transplant. During this evaluation at UT Southwestern, patient was referred to addiction psychiatry, but patient did not show to his first appointment pre-transplant. So later, patient got his transplant in the same month. So now we can see the post-transplant visit. So as I mentioned, patient did not show up to addiction psychiatry, patient got his liver transplant, and he showed to his first pathology visit like a month after the liver transplant. So during this admission, patient reported sobriety. However, as you can see, his PEP was 534. So patient was not maintaining sobriety. So this time, patient was again referred to addiction psychiatry, and finally he showed up to his first addiction psychiatry evaluation. So we did a complete evaluation, and patient presented to this visit with his mother. Patient again reported, as I mentioned, that he was only drinking 5, 12-ounce beer, but mother was there, and she said, okay, patient is not drinking that amount, he's drinking way more, and this was consistent with his most recent PEP at that time. It was 343. So we discussed with patient about the treatment options, and he agreed to be started on naltrexone. So we started him on 25 milligrams, and then further titrated to 15 milligrams. Patient was also reporting some symptoms of depression, so we started mirtazapine, and we saw the patient like a month later. So after this, patient was doing much better, actually. He continued taking his medications, and he reported sobriety. And as you can see, this was consistent with his PEP of 25. Also patient started working with a counselor in Montana. So as I mentioned, this was the first time that patient has been ever involved with any type of treatment for his alcohol use disorder, and a month later he was doing much better. Then we saw the patient one more time, like six months later. Patient was pretty stable, and he reported sobriety, and this was consistent with the PEP. And at that time, because of the telehealth policies, we notified patient that he needed to come and visit. As I mentioned, he was in Montana. But he decided to continue care in Montana. So the patient continues seeing hepatology, and as I mentioned, patient continues sobriety. Actually, he maintains sobriety for one year, and this was consistent with the PEP results, negative for a year. He was doing much better. He completed his work with physical therapy, and he was not only working with a counselor every two weeks, but also started attending group meetings. So as we can see the difference between pre-transplant patient and post-transplant patient, the importance of the involvement of addiction psychiatry in the treatment of these specific populations. Before we saw this patient, he had never even heard about any type of treatment for alcohol use disorder. So as soon as he started the treatment, we saw how good he was doing, and he was able to maintain sobriety for a long time. So now, Dr. Mufti is going to talk about the epidemiology of alcoholic liver disease. Thanks, Dr. Velasco. It's a pleasure to be here virtually. I apologize, I can't be there in person, but I'm glad we could make this work, and thank you to everyone there who facilitated this. So as Dr. Velasco said, alcohol use disorder and alcoholic liver disease is a huge public health crisis worldwide. Data from 2012 accounted for about 3.3 million net debt, or about 6% of all global debt, and alcoholic cirrhosis specifically accounted for almost 500,000 deaths, and about 48% of all debts are due to cirrhosis. The other thing is that in the youngest population, the 20 to 39 age group, a quarter of all debts are attributable to alcohol, and this will almost certainly go up when we get the data for the COVID-19 pandemic as well. When we think about, you know, we have models that predict the mortality due to alcohol-related liver disease in the US as we predict going forward, and if we look at the status quo, looking at the number of deaths with status quo, it's expected to continue to rise, so a million. If we have moderate intervention just under that and strong intervention, about 700,000. But the problem is that this continues to be a huge public health crisis with no end in sight, and because of the COVID-19 pandemic, we've actually seen a big uptick in the number of patients that we are seeing specifically that we're evaluating for liver transplant, and I'll show you some data to back that up. When we think about alcohol consumption specifically in the US, and I'm not talking globally, about 140 million adults in the US drink alcohol. The interesting thing is only about 10% of the population consumes three-quarters of all alcohol that's drunk, and most of the consumption is by men, and the patterns are highly regional, and as you can see, it seems like if it's cold, so if you look at North Dakota, they like their beer, which is the black square you can see at the top, but spirits, again, higher volumes of spirits, more wine in California, perhaps unsurprisingly, but the idea is, and also binge drinking, which is obviously very dangerous, you can see the darker you see the map on the bottom right-hand corner, the more binge drinking that we see, and that's the most dangerous form for our patients. And alcohol use is particularly harmful because it's the third leading cause of preventable death in the US, and excessive drinking accounts for about one in 10 deaths among working-age adults who are between the ages of 20 and 64, so hugely, hugely consequential for our patients. Affected individuals have a significantly shortened lifespan by an average of 30 years, and when the economic cost was last evaluated back in 2010, it was $250 billion, and it's certainly much, much higher than that now. As Dr. Wakhlu mentioned, and we have data, we basically get data every three years, this is the data for 2019 for listing. As you can see, the green bar that you see where you see the plummeting listing category is for hepatitis C because of direct-acting antiviral therapies, and the purple bar that you see with the rapid rise is alcoholic liver disease, and we'll continue to see that rise even further because what we've seen during the COVID pandemic is about 50% of patients that we're listing during COVID have been for alcohol-related disease with alcohol cirrhosis or alcohol-associated hepatitis. And so this is a study that was published last year. It's a little bit small for you to see, but going from left to right, what you can see is the mortality for the number of patients that we see, and you can see a big spike after the COVID-19 pandemic on the very right-hand side. What that means is because we've seen an increased number, we've seen an increased number of transplants for alcoholic hepatitis, and in association with that, we've seen a big increase in the amount of beer, wine, and liquor that's sold. So everything correlates. We sell more alcohol, people drink more, increased mortality, increased patients are listed for transplantation. But this means that we urgently need a solution for these patients in terms of having a robust way of evaluating them and then supporting them both in the pre-transplant phase and from our perspective at our transplant center in the post-transplant phase, because that's where these patients have often been let down in the past. And as Dr. Wakhloo said very aptly, alcohol use disorder is not a liver disease, it's a brain disease. There are genetic and we know epigenetic factors which strongly are associated with sort of the predisposition for drinking and then there are triggers, which is where obviously addiction psychiatry is hugely helpful to us to try and help patients from that perspective. And then lots of our patients have comorbid conditions. If you have PNPLA3 as a gene, that predisposes to damage. If you're female, you're more likely with lower volumes of alcohol to get damage if you have comorbid conditions, if you have viral hepatitis, if you have fatty liver disease, which a huge proportion of patients do. So there are two hits that the liver is taking. And so one of the questions that patients always ask us is what is safe drinking? And according to the NIAAA and U.S. Department of Health and Human Services, for men no more than two drinks and no more than a day and no more than 14 drinks a week, and for women basically one drink a day and no more than seven drinks a week, and this does not include binge drinking. Binge drinking is, as I said, a very harmful form of drinking for our patients. And patients will often mistakenly tell us why I don't drink the hard stuff. I only drink wine or beer. But what we struggle and try very hard to make patients understand is a drink is a drink is a drink, whether it's a 12-ounce beer, and you notice that Dr. Velasco had mentioned he was drinking five 12-ounce beers because that's often very important to us because some of these patients will be drinking 40s or 24 ounces, and it's very important for us to ascertain that up front so that we understand what we're dealing with. And so a drink is a drink is a drink, and that's our mantra for our patients. As I already mentioned, there are other factors associated with the development of alcoholic liver disease, including the more you drink, the more likely you are to damage your liver, fatty liver disease, mild hepatitis, and then genetic factors. I have a cup of coffee here right now. We know we have known for years that coffee is protective. It's an association, not a sort of a direct link, but we know the patients who drink caffeinated coffee more than two drinks a day back since we hepatitis C trials were carried out. Those patients tend to develop less fibrosis or scarring of the liver, and that remains the case. As I said, there is an association between alcohol intake and liver disease, and a lot of our data comes from a large prospective study which was done in Denmark, and 13,000 patients had a self-administered questionnaire where they were asked about their use of alcohol. The overall rates of alcohol-induced cirrhosis were about 2.2% in men and 0.03% in women. This is where we get some of our drinking limits from as well, where if you look at the dotted line is women and the filled-in line, the dark line, is men. In terms of when we see an increase in relative risk for men, it's around 14 drinks. For women, it's around seven drinks. What's the natural history of alcoholic liver disease and alcohol use disorder? This is one of the things. It's obviously a secret that we keep that really only one in five patients at most with alcohol use disorder will end up developing cirrhosis of the liver. Essentially, patients can present in a number of different ways. Patients have to be drinking significant amounts of alcohol. When we think about alcohol, we think about 60 grams for men and about 40 grams for women. You can develop significant steatosis. A percentage of these patients will develop steatohepatitis, so fat with inflammation. Then a percent of these patients will develop alcoholic hepatitis in association with that. As I said, about 40% will develop a degree of scarring, and about 20% of patients will develop cirrhosis. It's very important to distinguish between alcoholic cirrhosis and alcoholic hepatitis. Alcoholic cirrhosis is end-stage liver disease due to long-term alcohol use. It's associated with the presence of complete nodule formation on liver biopsy. The second part is that patients present, so they'll have a gradual deterioration. Patients will present with decompensated liver disease. Alcoholic hepatitis, on the other hand, is a distinct clinical syndrome and can have a very rapid presentation. Patients present with jaundice, typically we say they have to be drinking within two months or 60 days. As I already mentioned, associated with heavy drinking, so 60 grams a day for men, 40 grams a day for women. The bilirubin has to be greater than 3. The AST to ALT ratio, AST has to be greater than 50, but typically the ratio of AST to ALT is 2 to 1, but anything greater than 1.5 meets criteria. In terms of how high, if the AST is much higher, and I know the criteria are 300, 400, anything higher than 300 and 10 year up, is there something else that's going on that's causing this, such as autoimmune hepatitis, for example. In terms of what are the clinical features of alcoholic hepatitis, typically patients present between the ages of 40 and 60, although we've seen a huge uptick in the number of young patients that we've seen presenting over the last five years, and especially over the last three years since COVID. It's more common in men than women, and as I said in that Danish study, this was true as well, and the important thing to remember when we think about alcoholic hepatitis is that about 80% of patients have cirrhosis at the time of presentation. The type of alcohol does not affect risk, and patients will often have stopped alcohol a few weeks before coming in, partly because they feel so crummy at that time, because they have this inflammatory milieu in their liver, they feel bad, they're jaundiced, and their liver disease is progressing. How do we assess severity? So we can assess severity with the MELD score, which is Model for End-Stage Liver Disease Score, or MELD sodium, and now we have MELD 3.0 coming in as well. And then specifically for alcohol-specific criteria, we have the True, Tried, and Trusted Madry's Discriminant Function. We have the LEAL score, which came out of France, the ABIC score, and the Glasgow Associated Hepatitis score as well. Madry's is the one that's best known, and Dr. Madry carried out a landmark placebo-controlled study to look at the effects of steroids. He's actually at UT Southwestern, so we've had a chance to talk to him about this, and essentially, these patients got 28 days of steroids. The reason they got 28 days of steroids is that's what the drug company would give him. And the reason they got 40 grams of prednisone, or prednisolone, is that's what the drug company that was sponsoring it would give him. That's why these patients don't get a taper of steroids, because that's what they had prescribed. So Madry's Discriminant Function was described as a predictor of survival, and essentially, the Madry's Discriminant Function was greater than 32. The four-week mortality was about 30 percent, 35 percent, and with steroids, this mortality was decreased to 6 percent. The thing to remember is the original Madry study came out in 1978, and the modified Madry in 1989, where they adjusted the way PT was calculated. So it's not clear that there's a, you know, we're not really comparing apples to apples when we compare the two studies. We're really comparing apples to oranges, but overall, nevertheless, it remains true that a Madry score greater than 32, typically, we think about as being, these patients being sicker. And so what are the treatment options for our patients? We tell our patients all the time, abstinence, abstinence, abstinence, supportive care, and specifically with supportive care, we're talking about nutrition. These patients are malnourished, and it's vitally important as they heal, nutrition is crucial. And I'll go through some of the specific therapies, and really out of this, steroids remain a mainstay. NAC, I believe, actually has a role to play, although we don't have great data yet. And Pentoxvinyl is no longer used, and obviously, we can transplant these patients. This was, well, as I said, abstinence is important. Most patients, if they're going to get liver recovery, will get recovery within three months. As we know, the liver regenerates all the time. So as an example, if we do a living donor liver transplant, we remove 70% of a patient, a donor's liver. For that donor, that 30% remnant will grow back to 100% of its original size within two months. So the liver has this great capacity to regenerate, which is why abstinence is important, because the liver needs to stop taking these hits so that it can recover. And so in compensated cirrhotics, if you, if one looks at abstinence, the dotted line is patients who are absent, the 10-year survival is actually excellent, it's over 90%. And even in patients who are not absent, as long as you remain compensated, the 10-year survival is above 60%. However, if you have decompensated cirrhosis, which is a lot of our patients, even with abstinence, the 10-year survival is about 60%, and significantly lower at 30% in patients who are not abstinent. What's clear is in both the compensated and decompensated population, abstinence matters and is crucially important. Lots of different studies have been done with alcohol hepatitis and steroids. This was a nice meta-analysis by Matran and colleagues that came out in 2011. And they looked at five randomized controlled trials which used steroids and alcohol hepatitis. And what they saw was an improvement in 28-day survival. And it was statistically significant, so 80% versus 65%. And so the mantra was that these patients should be considered for steroids if the discriminant function is greater than 32. The biggest study that we've had is the STOP-AH or STOP-R study out of the UK. And it was a multi-center study. It was a two-by-two double-blind trial study where they had placebo. Patients got placebo and pentoxyphiline or prednisolone and placebo or prednisolone and pentoxyphiline or just placebo. And they had about 270 patients in each category. And the patients were diagnosed if they had alcoholic hepatitis and had a discriminant function of greater than 32. They could not have been jaundiced for more than three months, because if you remember, the definition is within two months. And they could not have been absent for more than two months. And the primary endpoint was mortality at 28 days. And what we saw was that one of the things is that in the placebo group, normally we would expect a mortality of about 30% in this patient population, as I've already discussed. So the mortality in the placebo group was not very high, of only about 17%. What's clear is pentoxyphiline did not improve survival. And prednisolone was associated with a 28-day mortality benefit, but that did not reach significance and no improvement in outcomes at 90 days. Nevertheless, there was some improvement. What we now use is the LIOR score. And it's a prognostic model to identify which patients will respond to therapy. So instead of giving 28 days of steroids for these patients, we now will give them seven days of steroids. And the LIOR model, it's a plug-in numbers, and utilizes a change in bilirubin at seven days. And if you have a LIOR score of less than 0.45, it means that patients will respond. And if you look at the graph on the right, the six-month survival for these patients is well above 85%. Whereas for patients who have a GLIA score greater than or equal to 0.45, they only have a 25% survival at six months. So this is a way of identifying patients who will respond to steroids without submitting an immunorelatively functioning immunosuppressed population to 28 days of steroids without needing to do so. And so one of the things that we've had to battle, thankfully we see this less, but something that we still see is, you know, the dreaded six-month rule, the abstinence rule, which was the pre-transplant requirement at over 50% of transplant centers where patients have to have regular attendance for licensed counseling or AA. And there was no exception for patients with high MELD scores. And this would preclude transplantation for acute alcoholic hepatitis, because these patients tend to have high bilirubins. They often have renal failure. They have a horrible, we've already discussed, 28 days mortality of up to 35%, six-month survival of 25%. So very sick group of patients who are basically completely disempowered by this rule. My joke always is, I always say that this was probably, you know, a bunch of hepatologists who were sitting in a pub having a drink whilst they came up with this. And this was a collaboration between the American Association for the Study of Liver Disease and the American Society of Transplant. And they tried to come up with minimal criteria. And what they said was that patients had to have reported abstinence for six months at the time of listing. However, one thing even at that time that was recognized was that there was one caveat, exceptional patients with alcohol liver disease who have not been abstinent for six months yet who have, you know, we as a transplant program believe are good candidates for transplantation can be referred to a regional review board for consideration. What practically happened though is insurance companies said, if you're not absent for six months, you're not going to get a transplant and can't be done. And the vast majority of centers in the US and actually across the world adhere to this rule. What were the purported benefits? Allows the time for the liver to stabilize and recover, prevents unnecessary liver transplantations, challenges patients' commitment to sobriety, decreases the likelihood of relapse post-transplant putatively, and it's easy to apply across centers. That's undoubtedly true and is still endorsed by many insurers. And I can tell you, I have to do appeals once a week for this. But one of the things to consider is when we think about drinking, there are different forms of drinking. And return to drinking, there are different forms of drinking. One of our pet peeves at our transplant program is we don't use the term recidivism because recidivism literally means a return to criminal activity. And this reflects how we have thought about alcohol use disorder, alcoholic and alcoholic hepatitis in the past, where it's a very moralistic way of thinking about this. But as Dr. Waklu said, it's a brain disease as much as it is a liver disease. These patients, and we need to distinguish between slips, patients who have temporary return to drinking, which could be harmful, but which results in renewed efforts to stop drinking, and then relapse, where patients have more sustained presumption of alcohol use, which can be characterized as harmful. And so we do have good data. We know from UPMC, Dr. Demartini, as far back as 2006, they looked at five-year follow-up post-transplant patients. These are patients who had been abstinent for six months, had followed the six-month rule criteria, and one in five of these patients had had a drink by the first year. Forty-two percent, so four in 10, which is what Dr. Waklu mentioned, had had a drink at five years. And what matters more is that by five years, 26% had a heavier or binge pattern and 20% drank in a frequent manner. So what's really important is groups four and five. These are patients who have late-onset harmful use that can be identified, and we can get addiction psychiatry as our addiction psychiatry colleagues to help us, and the early and continued severe harmful use. The patient that Dr. Velasco used as an example for this had this very early and significant harmful use because his PET score was over 500 within a month of transplantation. Those are the patients that historically would have done very, very poorly because, essentially, we used to obsess over the six-month rule. Once patients got transplanted, we used to forget about them, but that's really a loss of the time. We obviously need to help them in the pre-phase, but in the post-phase, we need to help these patients. So the manner and pattern of drinking is just as important. And with that, I'll hand over to Dr. Velasco to talk about what role addiction psychiatry plays in helping us to manage these patients, and I can say that at our transplant center, we work hand-in-glove with addiction psychiatry, and one of the ways we actually get our patients approved for transplant is because we have a very engaged addiction psychiatry group, and it's something that a lot of insurance companies want us to mandate addiction psychiatry in the post-transplant phase. So with that, I'll hand over to Dr. Velasco. I cannot move Dr. Mufti back to... Where? Oh, okay. So, as Dr. Mufti mentioned, right now in the workshop we are going to discuss the role of dedicated psychiatrists in this specific population of patients. So when we evaluate these patients, seven categories are very important to focus on because as Dr. Mufti mentioned, from the transplant team perspective, it's very important to make sure that this patient is going to take care of the liver, right? So these seven categories are how severe is the alcohol use. So how do we assess that? So how much the patient is drinking, based on the severity, based on the DSM-5, if there's any history of family, family history of alcohol use disorder, when did the patient start drinking, and for how long the patient has been drinking. If there was any period of abstinence before the patient got the liver, if there was any previous treatments, any pharmacologic treatment, any involvement in AA meetings, if there were any episodes of long periods of abstinence, and if the patient was in any type of treatment, if the patient was compliant with this treatment. Then we assess for any other comorbidities because if we don't assess any other psychiatric comorbidities or any substance use, most likely the patient is going to relapse again in alcohol. We also assess the cognition, the memory, and the executive function. And one of the most important categories is the social category. If the patient has a partner, family, is anyone supporting the patient, if the patient is living in a supportive, clean circumstances, and if the patient is an employer or not. And also the personal category, if the patient motivated to do this change, and if the patient is able to actually follow this change. So specifically in our patient, patient, as I mentioned, who was drinking five, 12-ounce beer daily, but he started drinking at a very early age, and he didn't have a history of alcohol use disorder, but his alcohol use was severe. He had two or three months of abstinence previous to the liver transplant, but the thing is that those months, the patient was hospitalized. So yeah. And he wasn't in any type of treatment or any AID meetings. He didn't have a long standing period of sobriety, and the compliance was expected to be fair because as I mentioned, there was a lot of family involvement. As I mentioned before, mom presented to all the follow-ups appointments with addiction psychiatry, and he didn't have a psychiatric history or any other substance use. His memory and executive functions were intact, and as I mentioned, socially, a patient had a really good support system. When we, in the personal category, patient was motivated, but still he had some limitations. So in this case, it was very important to continue doing motivational interview, intervention, and regular addiction follow-ups. That's what we did. We started seeing the patient monthly, and then after, of course, he continued care in Montana. So these are kind of the same things, but yeah, we continue providing information about substance use risk. We advise patient to stop, and as I mentioned, we started patient in Altrexan, and patient continue attending follow-up appointments. And patient had the motivation to do it, but he had some limitations. But as I mentioned, he had a really good support system, and this played a very important role in the outcome of this specific patient. So when we evaluate this patient, we kind of categorize them into low risk or high risk. Why is this? Because the level of care will be different for each group. So when we talk about the low risk, who we need to be involved in the care of the patient. So we need addiction psychiatry with the transplant team, and what type of interventions do we need for this patient. So motivational interviewing, counseling, relapse prevention, and pharmacotherapy. And mostly these patients can be managed in the outpatient setting. But when we talk about the high risk patients, we need a more comprehensive treatment. And these patients will benefit from having a more comprehensive type of setting as well, like partial hospitalizations, IOPs, or even in patient long-term residential treatment programs. And then, of course, very important to address the comorbid other substance use or psychiatric comorbidities. And specifically in my patient, in our patient, he had a lot of risk factors, but he also had protective factors, as I mentioned, a very good support, supportive family that I think plays a really important part in the outcome of our patient. So the risk factors, he had a very severe alcoholic hepatitis due to the heavy alcohol use. And one of the other risk factors that he tend to minimize, we didn't know exactly how much the patient was actually drinking, and he started drinking very early. And the protective factors that he didn't have any other drug use, he didn't have any psychiatric history, and a really good support system. Now Dr. Mufti is going to talk about the role of early transplantation for alcoholic hepatitis. So let me unmute you. Thank you, Dr. Velasco. So as I already mentioned, there are very few things in medicine where we see such a big delta in terms of outcomes for patients where if we transplant versus don't transplant. Because we know that at six months, these patients with severe alcoholic hepatitis do terribly. We have patients who get chemotherapy for a five-month increased survival, 18 months is thought to be amazing. And yet here we have a condition, alcoholic hepatitis, where if you look at this graph, this was a study of seven transplant centers from France, took MELDS greater than 32, a non-responsive medical therapy, and they selected who could be transplanted. So they had stringent criteria, only about 2% of patients were eligible, but what you can see is that the six-month survival is about 80% in patients transplanted, 25% in those not transplanted, and most of those patients are alive at two years. And the two-year mortality, essentially, if you live beyond six months, you're going to survive, but again, 20%. So almost a 50% to 60% delta. There are very few things in medicine that do this. And so this has been recapitulated now across North America. There's the North American experience with XLR8-AAH, we're now part of a slightly different consortium with alcoholic hepatitis, and these are patients with early transplant, no specific sobriety period, one-year survival was 94%, three-year survival was 84%. And at one year, about 10% of patients had sustained alcohol use after transplant, and about 17% at three years. And that's obviously what we want to do and work on and improve. And the mortality without transplant was up to 70% at six months. But the one thing you'll note is the data I presented earlier from UPMC, it was very similar. The patients who drank beyond, who drank after transplant, and who had sustained alcohol use was about 17% to 18%. So that absence period, which was often used to differentiate these patients, is not very, very helpful as far as we're concerned. And a large number of patients who could benefit from transplant are actually dying. At UT Southwestern, we changed our protocol around 2018, and that's when we started to reach out to Dr. Waklu and the addiction psychiatry group. So we have a long experience of this at our center. And this is just looking at our data. We've transplanted 34 patients for severe alcoholic hepatitis, and done 89 transplants for alcohol-related cirrhosis. And out of this, 92% of those patients who are evaluated were illicit, because we'll only really evaluate patients if it's a first-time presentation, they've never been told to stop drinking before, they have good social support, they have insight as well. And we work with patients to help make them candidates. And when we look at the profile of alcoholic hepatitis patients versus cirrhosis patients, unsurprisingly, these patients are younger, with young children often, and that makes these decisions very difficult. They're employed, and will have private insurance. They have an equal gender split, they tend to be sicker, and they tend to have a higher CPAT score in terms of better insight, in terms of candidacy for transplant, tend to be good candidates most of the time. And there was no difference in the amount of alcohol at peak between these two categories. And the SALT score is a score that we can use, where if you have greater than 10 drinks per day at hospitalization, multiple rehab attempts, prior alcohol-related legal issues, or illicit substance use, and essentially, it's a good negative prognostic sign. If your SALT score is greater than 5, you're less likely to do well in the long term, and to stay abstinent. When we think about relapse, as I already mentioned, prolonged is any consumption of alcohol for greater than 100 days, frequent is any consumption for four days or more per week for at least a month. Binge drinking is more than six drinks or four drinks per day for women. And then SIPS, alcohol consumption that does not meet criteria for either frequent, any consumption for four or more days, or binge drinking. And then problematic relapse is the one we obviously think about, which is prolonged or frequent or binge drinking can be part of the problematic relapse group. And so what we try and do is define what type of relapse our patients have had. As I said, we don't use the term recidivism. We think it's a very loaded term so that we can help our patients. All of our patients at our transplant center have done well. Some of that is selection criteria. Some of that is like this patient that we have talked about. This patient would have done very, very poorly had he been transplanted five, six years ago, because he would not have received the support post-transplant from addiction psychiatry with their expert management and then local support in terms of when he went back home to continue to get counseling, to continue to engage services there as well. And this is, as I said, our criteria, our data. All our patients essentially did well. No significant difference between patients transplanted with alcoholic hepatitis or alcoholic cirrhosis. The one thing, interestingly, that we did see was that in patients with alcoholic hepatitis, they tended to have a little more rejection. Now whether that's related, it's unclear why that is. But we know that increased alcohol use post or increased ongoing alcohol use post is associated with poor outcomes in these patients and earlier graft loss, which ultimately is very important. So this is our current model. People with alcoholic hepatitis, if their MELD score is greater than 20 or discriminant function is greater than 32, if they can get steroids, we typically will rule them out from infection. We wait for a few days. There's no rush. All Madry's paper, they use steroids within 60 days of the last drink. The same for the STOP-AH study, 60 days of the last drink. And that's one of the big mistakes that people often make is they're in a rush to get patients on steroids. The patients are infected and they do poorly. So we check that steroids aren't contraindicated. And then if they're contraindicated, we support them. So we give them nutritional support. And often they do smart recovery in the hospital. They do a virtual AA now, which is also available whilst they're in the hospital. If steroids aren't contraindicated, we give seven days of steroids, assess the allele score and sometimes give NAC. But if these patients are poor responders, at that point, we will refer them for transplant and refer them early. That's typically our mantra at our center. And so with that, I'll hand over to Dr. Wakalu, obviously, when these patients then either on the pre-transplant side, if we decide to go down the transplant route, but they're drinking or have had recent alcohol use, we want them to engage services, get help. And Dr. Wakalu and his team, we want them to be engaged. And he will talk about some of the pharmacological therapies that we employ for these patients. Thank you so much. Thank you. I would like to start off by saying thanks a ton to Steven. He's done a great job making this possible. And the AAAV staff are great, John White and Michelle. So thanks a ton to them. So I will talk about alcohol pharmacotherapy, talk about FDA-approved agents, Tazolafram, oral naltrexone, the depo-naltrexone, and Ecamproside, and then talk about non-FDA-approved treatments, Gabapentin, Topramine, Baclofen, and Prezosin, and then talk about the two medications approved in the European Union, Nalbufein and GHB, and then briefly mention the ketamine and the psilocybin studies. So talking about the first agent, Tazolafram, Tazolafram was synthesized in 1881 by German chemist M. Grotsky. In the 30s, Tazolafram was used in the rubber industry in the U.S. and Sweden for vulcanization of rubber. There was an occupational medicine physician by the name of Dr. E. E. Williams. He noticed that when workers went back home and they tried to drink, they became violently ill. He wrote up a case report, he said, you know, about this, and he said this could be a possible treatment for alcoholism, but nothing more was done. Fast forward 1945, Copenhagen, Denmark. Worm infestation is a major problem among children and the dairy industry in Copenhagen, Denmark. So the dairy industry approaches these two investigators at the pharmaceutical company called Medicinalco and says, hey, could you please find us a solution? You know, our milk consumption is really reduced when our animals are infested. So these two investigators, Dr. Jacobson, who was a physician, and Dr. Hall, who was a PhD, they started working on Tazolafram as an antihelminthic in 1945. Now these two investigators had a unique habit of trying every medication that they tested. So they both took antabuse, they went to a cocktail party, they drank and they got sick. And so that was the serendipitous discovery of Tazolafram in 1945. But at that time, they had no interest in pursuing any studies. They didn't want to pursue alcohol use disorder studies. So two years later, in 1947, at the urging of Dr. Olaf Martensen-Larsen, who was a psychiatrist in Denmark, they started performing studies in doses of one to three grams. Now that's important to remember because all these scary side effects about Tazolafram that we talk about, the fulminant hepatitis, the ophthalmolitis, the psychosis, all comes from the Danish data. And that has unfortunately led to a major underutilization of this very effective treatment. And antabuse was named Antibus, anxiolyzed to Antabuse, and that's the origin of the name. We are all familiar with the first mechanism. It inhibits ALDH1A1 resulting in the Tazolafram ethanol reaction. But Antabuse also has a second mechanism. It inhibits the enzyme dopamine beta-hydroxylase, increasing synaptic dopamine levels, and decreasing alcohol cravings. So it's a dual mechanism. It's just not a deterrence, but also helps decrease alcohol cravings. Signs and symptoms of a Tazolafram ethanol reaction include nausea, vomiting, flushing, tachycardia, palpitations, and hypertension. And most DERs are self-limited, lasting anywhere from 30 minutes to several hours. They're highly uncomfortable, but they are self-limited. And side effects of Tazolafram include dizziness, metallic taste in the mouth, urticaria, acne form, eruptions, and headaches. And the two most common being dizziness and metallic taste in the mouth. That's what most patients complain about. And like I said, it rarely causes optic neuritis, peripheral neuropathy, and parotoxicity. And all these reports about these dangerous life-threatening side effects have come from the Danish data that used 1 to 3 grams, not from 250 to 500 milligrams. Its half-life is about 60 to 120 hours. Once daily dosing with 250 to 500 milligrams per day, I generally start my patients on 250 milligrams daily. The only time I increase the dose to 500 is if a spouse calls me and says the patient drank on 250 milligrams and it didn't make them sick. That's the only time I'll increase the dose to 500. But there is no benefit in increasing the dose to greater than 500 milligrams daily. You warn patients about hidden alcohol. These days, hand sanitizers are a big issue because I've had patients who had reactions from just using hand sanitizers. So you warn patients about hand sanitizers, cooking wines, cough syrups, back rubs, perfumes, anything that contains alcohol. Tazolafram administration should never take place until the patient has abstained from alcohol for at least 12 hours. And patients should avoid alcohol and alcohol-containing products for at least 14 days after discontinuing Tazolafram. I have a patient, she stopped Tazolafram 14 days back, and then she tried to drink and had progetyl vomiting. I mean, she threw up. So I tell patients, wait, please, I tell them it's a long half-life. So cannot start Tazolafram if baseline LHTs are greater than three times upper-liver normal and the total bilirubin is greater than 3 milligrams per deciliter. In the transplant population, we do not initiate Tazolafram if MELD is greater than 20 and the MDF is greater than 32. Chronic therapy is associated with mild serum immunotransplant elevations in up to 25% of patients, and the estimated incidence of acute liver injury is 1 per 10,000 to 30,000 patient years of Tazolafram treatment. And the injury usually arises within two to 12 weeks of starting Tazolafram. So what is the evidence? The meta-analysis of 22 randomized controlled trials with N of over 2,400 participants compared the success rate of Tazolafram in controls. And success was defined as total abstinence, percentage of abstinence days, mean days of alcohol use, likelihood of no relapse, longer time to first heavy drinking, or three or more weeks of consecutive abstinence. And Tazolafram was associated with higher success rate than controlled conditions only in open-label studies with no statistically significant association in blinded trials. Despite the lack of evidence from clinical blinded trials, supervised ingestion of Tazolafram was associated with significantly better outcomes. Moving on to the next agent, naltrexone. Naltrexone is a full antagonist of the mu-opiate receptor, the kappa-opiate receptor, and to a lesser extent, the delta-opiate receptor. It was approved in 1994 for alcohol dependence with the brand name of Revia. It reduces drinking via several mechanisms. It reduces the positively reinforcing effects of alcohol by reducing the mesolimbic opiatrgic activity. It enhances the sedative effects of alcohol and decreases cravings for alcohol. So cravings, talking about cravings, as you know in clinical practice, a good number of patients, you know, when I offer naltrexone to patients, a good number of patients say, Dr. Wakhloo, I don't have cravings. And I think the main effect of naltrexone is the way some of my patients describe it. When they take naltrexone, they'll say, Dr. Wakhloo, I don't obsess over alcohol anymore. I can have a drink or two and then I can stop. I don't go from two to four to six and I'm off to the races. So that's that blunting of the euphoria and that decrease in the dopamine surges that happen when people take naltrexone. I think it's really the key way naltrexone works. And of course, when people drink on naltrexone, they become sleepy. They go out to sleep. It terminates drinking. And yeah, for a subgroup of our patients, it does help decrease cravings. But not all our patients who are early abstinent have cravings. Like Dr. Velasco talked about the patient, we generally start our patients at 25 milligrams at bedtime for seven days, increase to 50 milligrams daily. The reason for the bedtime dosing is people complain about sedation. It's not like Trastor kind of puts you to sleep, but people just don't feel very, they want to take a nap. So it's all generally a bedtime dosing works for most of my patients. And I may increase the dose to 100 milligrams daily. But most of my patients do fairly well on 50 milligrams. It has an active metabolite, 6-beta-naltrexone, half-life of naltrexone is four hours, half-life of 6-beta-naltrexone is 13 hours. Time to peak plasma levels is 60 minutes. We obtain LFTs at baseline then once every six months and cannot start naltrexone at baseline. LFTs are three times the upper level enamel and the total buildup is greater than three milligrams per deciliter. In the transplant population, we do not initiate naltrexone if MELD is greater than 20 and or the MDF is greater than 32. Side effect profile is benign. The most common side effects are the nausea and sedation, headaches and dizziness, nausea and sedation being the most common. It helps patients abstain as well as decrease alcohol use. So again, if the patient's goal is drinking less, it's a good harm reduction tool. And a meta-analysis of 16 studies over close to 2,400 patients showed a risk decrease for return to any drinking associated with naltrexone 50 milligrams daily. And naltrexone was also associated with the reduced risk of binge drinking 19 studies within close to over 2,800. Moving on to the depot, the intramuscular preparation. So it's a Medisorb drug delivery technology. Naltrexone is embedded within biodegradable polymer microspheres released over at least 30 days. The recommended dose is 380 milligrams every four weeks. IM given in the gluteal region, in the upper outer, the ventrolateral aspect of the gluteal region, not the ventromedial because the sciatic nerve is present in the ventromedial area, as you know. So it has two peaks, two hours and three days. The elimination half-life of naltrexone and 6-beta-naltrexone following IM administration is 510 days. And after day 14, levels tend to decline. For some patients, effects wear off between day 21 to day 24 and they may need additional treatment with oral naltrexone until they're due for the next injection. Now my goal is I like to offer IM naltrexone to all my patients because it really, compliance really improves when you offer IM naltrexone. And I will give a 90-day supply of oral naltrexone to all my patients to keep so that they can, if they need to, they can take it from day 21 to day 24. If you look at the pharmacokinetics of naltrexone, I think the dosing needs to change from every four weeks to every three weeks. It's for a good number of patients. It just does not last the entire 28 days. It improves compliance with treatment, hepatically safer since it bypasses the first pass metabolism and helps patients abstain as well as decrease alcohol use. So some of my younger patients who are not interested in complete and total absence, who are seeing Dr. Waghlu, alcohol, if I don't drink, I will have no social life. I can't date, I can't, so they want to go from harmful, unsafe drinking to safer so you can help patients drink more safely when you give them naltrexone. In a placebo-controlled trial of long-acting naltrexone, the median monthly number of binge drinking days declined from 13.3 in the placebo group to 6.0 per month, 14.8 in the 190 milligram group to 4.5 per month, and 16.2 in the 380 milligram group to about 3.1 per month, so the decrease in the 380 milligram group was significantly greater than in the placebo group. Moving on to our third FDA-approved acamprosate. Acamprosate was approved in 2005. There were three European multicentral trials that supported the FDA-approved acamprosate. It's a partial NMDA receptor antagonist. It blocks the increased glutamate release in the nucleus accumbens during withdrawal and normalizes alcohol-induced decrease in basal GABA concentration, so thereby decreasing arousal, cravings, and dysphoria. The recommended dose is 66 milligrams, two tablets three times a day, but this dosing regimen is not really very patient-friendly, so I, in my practice, I dose it three tablets BID rather than two tablets TID. It's just easier because patients, most patients tend to forget the afternoon dose. There is no hepatic metabolism. It's really excreted in unmetabolized form. No dose adjustment is required in mild renal disease. Dose adjustment is necessary in moderate renal disease. That is creatine clearance of between 30 to 50 mL per minute, CKD3, and it's contraindicated in patient with CKD4 and 5 with a creatine clearance of less than 30 mL per minute. The most common side effects are nausea, loose stools. Loose stools are one main reason why people don't want to take acamprosate. The thing about acamprosate is study results have been mixed. The European data for acamprosate has been more robust than the US data. There was a 2010 Cochrane analysis by Ross et al. that reviewed 24 randomized controlled trials with over close to 7,000 participants that showed acamprosate to be an effective treatment for abstinence, but the Landmark combined study and the Predict study in Germany failed to find efficacy for acamprosate. So this is my story about acamprosate. When I begin to lose faith in acamprosate, someone refers a patient to me, or I start acamprosate on someone and it works. And they say, they come back and say, Dr. Barclay, you know, acamprosate was a game changer. And it's like I said, and it's about one in 10. For some of my colleagues, they say one in 20. For me, it's about one in 10. But it does work. There's a small subset that it does work for. So I'm not quite ready to give up on acamprosate. So it's. You combine it with the naltrexone? Oh yeah, I do. I sure do, sir. Absolutely, absolutely, yeah. So moving on to the non-FDA-approved agents, gabapentin. Gabapentin inhibits calcium channels and stimulates inhibitory GABA-B receptors. Its half-life is about five to seven hours. Time to peak plasma concentration is two to four hours. And gabapentin is reported to reduce alcohol consumption, improve sleep, and decrease alcohol craving in subjects with alcohol use disorders. In a study that compared naltrexone, gabapentin plus naltrexone and placebo found added effects of the combination improvement sleep in the combined medication group in the dose range of 900 to 1,800 milligrams per day. Another randomized controlled trial, which was done more recently in 2020, that gabapentin titrated to 1,200 milligrams per day is efficacious in promoting absence and reducing drinking in patients with alcohol use disorders, especially those with more severe withdrawal symptoms. And both these studies are primarily from MUSC in Charleston. And again, we faced this problem in our practices about systemic review showed that about 1% of the general population misused gabapentin, either alone in combination with other substances, including alcohol. Topiramide. Topiramide was originally synthesized as an anti-diabetic agent. It's approved for partial onset and primary generalized tonic-clonic seizures. Its bioavailability is about 80%. Its half-life is 19 to 23 hours. There is no hepatic metabolism. It's about 50 to 80% is excreted unchanged in urine. It increases GABA-A-facilitated neuronal activity. It also antagonizes AMP and kinetoglutamate receptors. Shown in large randomized placebo-controlled trials to reduce heavy drinking and promote absence and decrease medical consequences of alcoholism, the dose titrated at 25 milligrams daily and slowly titrated to 200 to 300 milligrams per day over eight weeks. Common side effects, paresthesia, states perversion, anorexia, decreased cognition, and ocular side effects. So this is what I've experienced in the last five to seven years. I've had about two or three patients who had significant visual field effects that they do to see a retina specialist. You know, we all, as psychiatrists, we're all familiar with the cognitive dulling, but even the ocular side effects are something that we need to discuss with our patients. I mean, it's not, they're not common, but they're not rare either. There's a lot of data on ocular side effects secondary to teperamide. It's not FDA-approved, but its use is endorsed by the NIAAA based on strong evidence for efficacy, and teperamide is recommended as a first-line agent by the VADOD practice guidelines along with the three FDA-approved agents. Baclofen, Baclofen is a GABA-B receptor agonist. So Baclofen has kind of made a comeback ever since the deceased cardiologist, Dr. Oliver Emerson's book came out, The End of My Addiction. So Dr. Emerson struggled with alcoholism for years. He went to multiple rehabs. He attended over 700 AA meetings. He tried medication that nothing worked for him, and then he self-treated himself to about 270 milligrams of Baclofen in about 2005, and then stayed on that for a few months, and then gradually brought himself down to about 120 to 150 milligrams of Baclofen, and stayed sober till he had a massive MI in 2013, in eight years. I mean, he stayed sober eight years, and prior to that, he was never able to stay sober. And so his book, and then he published his own case report in the Journal of Alcohol and Alcohol Studies, has kind of, Baclofen has made a comeback. And thankfully, Baclofen is also safe. Baclofen has minimal metabolism through the liver, so it's safe for patients with alcoholic cirrhosis. There was a study done in Italy that found Baclofen to be safe and effective in alcohol-dependent patients with liver cirrhosis. And the only country where it's approved is in France, on a case-to-case basis, France approved Baclofen in 2012. In a meta-analysis of 13 randomized controlled trials with N of 1,400, Baclofen was associated with a significantly greater time to first lapse of drinking, and a greater likelihood of absence during treatment, with no greater difference in higher doses. Unlike what Dr. Emason, Dr. Emason's work was, the higher you go, the better off you are, but that's not what this meta-analysis reported. So, and persons who drank heavily at the study entry had a greater association of absence with Baclofen. Prezocin, Prezocin, as you know, an alpha-1 blocker. Onset of action is about 30 to 90 minutes. Elimination half-life of Prezocin is about two to three hours and duration of action is about 10 to 24 hours. And a recent double-blind randomized controlled trial of Prezocin for alcohol use disorder without PTSD showed promise as a pharmacological agent. 92 participants randomized assigned to receive Prezocin or placebo in a 12-week double-blind study. Medication was targeted to a target dose of 16 milligrams in divided doses by the end of week two. And the Beryl platform was medication management. 80 participants completed the titration period. Rate of drinking and heavy drinking showed a greater decrease over time for participants in the Prezocin condition compared to those in the placebo condition. And participants in the placebo condition were more likely to report drowsiness and edema. Moving on to the two agents that are approved in the EU and not here in the U.S., Nalumafine. Nalumafine is a mu-opioid receptor antagonist, but it's a partial agonist of the kappa-opioid receptor and antagonist of the delta-opioid receptor. So that's how it's different from Naltrexone because it's a partial agonist of the kappa-opioid receptor. Also has a longer half-life and greater bioavailability and reduced hepatotoxicity. European studies have shown to be effective in decreasing the amount of alcohol consumption and number of drinking days. And it's approved for use in the EU 18 milligrams daily only as needed. It's not daily dosing. Only as needed when patients perceive that an elevated risk of alcohol consumption. In the meta-analysis of five randomized controlled trials and for 2,500, Nalumafine was assisted with a reduction of 1.6 more binge drinking days per month than placebo at six months and 1.6 more binge drinking days per month at one year. In 2004, a 12-week randomized controlled trial in the U.S. evaluated three doses of Nalumafine, five, 20, and 40 milligrams, and found no differences between the three groups. Common side effects are nausea, dizziness, insomnia, headaches, and somnolence. And the data supporting the EU approval of Nalumafine has been criticized because the evidence for efficacy was limited to a subgroup of patients that were defined retrospectively. Outcome measures and sentencing analysis were not defined priori. And medication was only compared to placebo rather than active comparator like Naltrexone. The next agent which is approved in the EU and not in the U.S., GHP. GHP is inhibition at both GABA-A and GABA-B receptors. It's used clinically for treating the cataplexy part of narcolepsy. And GHP was found to be effective for treating alcohol use disorder in a placebo-controlled trial conducted in Europe. And a form of GHP known as sodium oxibate, or Xyrem, is approved for alcohol use disorder treatment in several European countries. GHP reduces cravings for alcohol in preventing alcohol withdrawal and allostasis. And the abuse potential of GHP has been noted in some European studies. So the next two slides are from the Kranzler article in JAMA in 2018, that's where most of the studies that I've talked about in the presentation are from. So this is a treatment algorithm that I've developed, you know, MDF greater than 32 or malignant 20. I give patients a trial of camprosate depending on their response. If a good or partial response, continue with the camprosate. If a partial response, augment with GABA-Benton in doses of 600 nanograms daily to further decrease cravings and help with insomnia. If it's an inadequate response, Baclofen in dose range of 60 to 120 milligrams daily in divided doses. And depending on their response, continue with Baclofen, augment with GABA-Benton if there's an inadequate response, treat with topiramide. In the MDF less than 32 or malignant less than 20, we start off with an oral naltrexone. Good or partial response, continue the oral if the patient is willing, then switch them to the intramuscular preparation. And then augment with GABA-Benton as required. Inaccurate response, try a camprosate if the response is not adequate, consider desultoram, Baclofen, topiramide, or presociin. So this is just an algorithm that I use. So future developments, a lot of media interest about psychedelics and alcohol use disorders. This is a study by Dr. Bogle-Jones and his group from NYU. A double-blind clinical trial with 93 participants, a percentage of heavy drinking days during the 32 weeks of follow was significantly lower in the psilocybin group than in the Benadryl group. The results in this trial show that psilocybin administered in combination psychotherapy produced robust decreases in the percentage of heavy drinking days compared with those produced by active placebo and psychotherapy. Now the trouble with the study is that, how do you maintain a blind study when you're comparing psilocybin to Benadryl? You just can't, it's such a bias. So again, I'm not saying there's a potential there, but the bias is quite inherent. And second study with ketamine, a recent study demonstrated that treatment with three infusions of ketamine was well-tolerated in patients with alcohol use disorder and was assisted with more days of absence from alcohol at six-month follow-up. There was some interest in corticotropin-releasing factor antagonists, which have had some negative results, and there's some work being done on neurokinin-1 receptor and neurokinin-3 receptor antagonists to see if there's some value in alcohol and alcohol use disorders. So this is our last slide, so we'll just open it up for questions, and thank you so much, appreciate it. Thank you. Steve and I did it, so questions, comments, your experiences? Yes, sir. So someone has, like you said, has a hepato-renal syndrome. So yeah, right. So again, depending on what, where they are in this CKD category, you know, that's a clinical decision. I mean, if four and five, you just can't use a camprosate, and three, you have to reduce the dose. One and two, you can save it. It just depends on where they are. And that would be a consultation with the nephrologist. And we frequently, I frequently, I'll just pick up the phone and talk to Dr. Mufti or other transplant nephrologists as to what should I do. Just this Wednesday before coming here, I had a patient with a fibroscan showed about moderate fibrosis, just on the borderline between, you know, just cancerosis, very motivated. So I asked him, I said, on a scale of zero to 10, how confident are you that you will not drink on disulfiramine? He said 10. He said, I want to stop. If I don't stop, my marriage will end. I want to stop. Brought the husband in. Husband is a faculty at UT Southwestern. And the husband said, I'll monitor the disulfiramine. So I called one of the transplant nephrologists. I said, this is a scenario. Look at the labs. What can we start? She said, yeah, I would start and just closely monitor. So I started the patient 125. But I'm not sure if you're muted. I can't hear anything. If there is a discussion going on, I apologize. Sorry. My apologies. You have to unmute. I thought I did, but Stephen, you'll have to help me out here. Sorry. I thought I was doing good. Oh, my God. My sincere apologies, Dr. Mufti. The question was, what about someone with hepatorenal syndrome? And my response was, depending on where they are and what level of CKD they're in. And then I was talking about how we collaborate with you and your group on determining what we can start a patient on. And like I said, so finally I spoke to Dr. Tuya. She's one of our hepatologists. She said, I would just start him on a lower dose so I started him on 125 milligrams daily. We're going to check LFTs in two weeks and then see and go up to 250 and then keep closely monitoring the LFTs. So again, the risk period is two to 12 weeks. So that's where we are. But there's such a value in using disulfiram here because I don't want this man to go from the current fibrosis to full-blown cirrhosis. So I think it's worth a trial of disulfiram here. I hope that answers your question. Let me, I just, so Dr. Moorthy, someone in the audience said the group in Denmark is called the Death Battalion, that's what they were called. And were they called the Death Battalion because they would, I think Dr. Jacobson drank, put IV alcohol and then took antibiotics, is that the reason? I think of tyranny and saying, they nearly killed me. Nearly killed you, that's correct. They're extremists. OK, that's right. Your questions, please, yeah, yeah. So, Dr. Mufti, the question is what can we do for these patients before, what about using naltrexone pre-transplant? So my, this is what I would, I think I've been very well educated by my hepatology colleagues. I don't worry about naltrexone in the liver so much. If you look at the initial UPenn studies done by Dr. O'Malley and her group, of course, these were people who were drinking less, so I think the elevated liver enzymes came not from the naltrexone, but from drinking, right? And as you know, in a study, whenever there's any abnormality, that gets latched onto the medication. So I think that's how, I really do not worry about naltrexone in the liver so much as compared to disulfiram. So, and I clearly, I mean, if patients are willing, what we have done is also we sometimes admit patients to the inpatient unit, they leave before they discharge, they leave with a Vivitrol injection. And I have done Vivitrol even without a trial of oral naltrexone. I mean, there's no allergies to, I mean, there's no reason that you have to do oral naltrexone. I mean, when you look at the ADAPT2 study, of course, ADAPT2 was done for methamphetamine, it's a different study, but the active group got Vivitrol without even receiving oral naltrexone. So I don't think there's any issues. I totally agree. I think we really need to be more aggressive with using naltrexone oral as well as the injectable in the pre-transplant population. Yeah. Yeah. Yes, sir. Does that answer your question? Yeah. So, Dr. Mufti, the question is, post-transplant, how can we, if there's a relapse, how can we prevent it from becoming a fatal, you know, ongoing relapse? So... I didn't... I'll... I can chime in in the first part. Please, please. Part of that is on the hepatologist in terms of, you know, we obviously follow labs very closely. We see our patients initially once every... twice a week, then once a week, then, you know, once every two weeks, once a month. And we get labs at least once a month for the first year, and beyond that, once every three months, if they're very, very stable, but if we have a low index of suspicion. The other thing is PETH has been actually very helpful. So before we see abnormal LFTs, we get regular PETH levels. So we have a protocol for these patients in the post-transplant setting. What that means is that we're vigilant, where it's a point of emphasis for us. And then, obviously, if they're already plugged in with Dr. Wakoo and his group, then they can be seen there as well. The other point is if they start to miss appointments, if something else happens, that's also a trigger for us to think about some of these things. So I would say, from our perspective, it's team effort. It's not just the hepatologist. It's our coordinators, our transplant coordinators. It's family members, and then, obviously, the addiction psychiatry group, because they see these patients as well. Thank you, Dr. Mufti. And to add on to your... And we... Of course, they have a new liver, so you're not really worried about, I mean, the labs are monitored, and Dr. Mufti and his group, they get PETHs regularly. Even for patients who are doing well in absence, we, at least every six months, we want to get a PETH. Because we never know when a slip or relapse may happen. And then we employ all the pharmacotherapies that we... Including diacelifram, if it's really getting to the point that it's becoming very harmful drinking. So the similar strategies, and engaging them in AA, engaging them in smart recovery, whatever the option. As I said, some people are opposed to AA, so... And therapy. So, yeah. Similar interventions that you would do in the pre-transplant group. Thank you. Yeah. What is the differential death rate among post-transplant people who had alcoholic cirrhosis versus those who had cirrhosis for other reasons? Dr. Mufti, the question is... Yeah. I heard the question. You heard it? Okay. Wonderful. Yeah. The patients with alcoholic cirrhosis actually do very well. They have some of the best outcomes. We have to remember, we used to transplant patients with hepatitis C. Their five-year outcomes, survival was 65%, because we were unable to treat those patients post, and before the advent of direct-acting antivirals. So we, alcoholic cirrhotics, actually have a 90% one-year survival, 85% three-year survival. So they do extremely well, and the same is true for alcoholic hepatitis as well. Yes, sir. You mentioned naltrexone dosing at night. Is the sedative effect a benefit in these patients, and can you speak to the role of sleep in these patients in general? You'll have to repeat your question one more time. Sorry. You mentioned naltrexone dosing before bedtime. Is the sedative effect seen as a benefit in the patient, and what's the role of sleep in these patients in general? So, Dr. Mufti, the question was, I mentioned about dosing naltrexone at night, and was there a value in using that for sleep, and the importance of sleep? For some patients, not for everyone. Some patients, like I said, it's not a hypnotic-like triazodone that people just kind of go off to sleep, or doxepin, or any of the hypnotic agents, but it may, it helps some patients, but you still sometimes, what I most commonly do is augment with gabapentin, or triazodone, or any low-dose tricyclics, yeah. So, naltrexone alone is not an effective hypnotic agent for most patients. Occasionally, I will, a patient or two will say, you know, it helped me sleep too, that's great, yeah. And the other aspect is, once every six months, I will have a patient say, naltrexone, Dr. Patil, you told me to take naltrexone at night. I was wide awake. I couldn't sleep. I said, then just take it during the morning, yeah. Yes, ma'am, yeah. and I'm just curious sort of how your team approaches that. Dr. Murtry, did you hear the question? I did hear it. Okay, awesome. That's a great question. I think we are very realistic, but I think that's actually a fair point, what they said. If they never had problems with alcohol use, sort of why should they penalize? And so we are, we don't encourage drinking, but at the same time, if someone is candid and says I have a drink here and there, we don't have a problem with that. Even with alcohol use disorder, alcohol hepatitis, you know, our aim, ultimate aim, because we know 40%, up to 40% of these patients will have a drink, is to make sure that they don't have those dangerous patterns of drinking. With the understanding that we know that at some point, a significant minority of patients will drink. Again, this is where I think monitoring them, following them closely, getting to know our patients, following PET levels is really important. Because if we see a PET level of 300 or 700 in a NASH patient, we're just as worried as we would be in a patient with alcohol use disorder. And so that's why, as Dr. Walker was saying, we follow PET levels. We know that patients historically who were billed as fatty liver disease, 25% of those patients will have a significantly elevated PET level. So we'd under-diagnose alcohol use disorder in the pre-transplant setting. That's why we follow them in the post-transplant setting with PET as well. Thank you. Yes, ma'am. Going back to the case, so I may have got this wrong, but when he got his transplant two weeks after he was listed? That's correct. Yes. So that's incredible. I mean, I'm sorry. That's a great team at Unisuggested. They're a fabulous team, honestly. And they're so patient-centered. It's, yeah. That's wonderful. And I think we can all recognize that transplants happen when they happen, right? Your liver, you get the call, you go. So there are people who wait, who wait a long time. I mean, for all organs. And so have we all ever looked at, or has there been studies that look at individuals who have prolonged periods of waiting on the list, more psychosocial intervention, more treatment, and how they do versus people who are, your call is in, you're up in two weeks. So he looks like he doesn't need to be contemplated, but people can change if they're waiting six months. Right. How does that change? Well, I think that's where we have that data with patients who had six months of mandated abstinence, right? And we still see a 40% rate of alcohol use post, whether it's minimal, whether it's a small amount or a large amount. What's clear, and I think the previous question alluded to this as well, is some patients will have a drink at some point. The patients who are really, really sick, the Alkep patients tend to have very high MELD, so they get transplanted very quickly. And that's one of the ethical dilemmas that we have in our field, is you have patients with liver cancer. You have patients with all sorts of stuff who don't get the MELD exception in the same way and don't have these high MELD scores. These patients will automatically jump to the top of the list. And it's become even more acute during the pandemic because 40% of our listings were patients with Alkep. That's a huge number of patients who have the highest MELD, so they're taking the best organs, and they often tend to be younger than the other age groups. So this is a dilemma that we have right now in transplant in terms of how we move forward with this group of patients. Thank you, Dr. Mufti. Any more questions? Yeah. Thank you so much. You've been such a great group. And once again, Stephen, thank you so much for your help and the APS staff here. Thank you very much. I apologize. I couldn't be there. Dr. Mufti's slave travels to Dallas.

alcohol use disorders

liver transplant population

sobriety

successful outcomes

brain disease

new liver

addiction psychiatrists

alcoholic liver disease

excessive drinking

treatment strategies

relapse prevention

improved survival rates

comprehensive approach