I want to welcome everyone to Benzodiazepines and Beyond, Updates on Management of Alcohol Withdrawal. So, we're going to have some review, and we're also going to have some new information, hopefully, for most of you. So, my name is Michael Weaver. I'm a professor in the Department of Psychiatry. I'm the medical director of the Center for Neurobehavioral Research on Addiction, and I want to introduce all of my colleagues here for today's presentation. So, we'll start off with the fact that all of us are from the University of Texas Health Science Center at Houston. And this is Dr. Nhi Ola-Yinke, and I also want to introduce a couple of our residents. So, Nhi and I are faculty members, but the real praise for this presentation, the hard work, goes to these two, which are our residents in the psychiatry program. This is Dr. Namrata Walia and Dr. Maroja Manohar. And so, I want you to give them a warm welcome for presenting today on this topic. In addition, I do want to throw in a shameless plug for the new School of Behavioral Health Sciences that we're starting at UT Houston Health. This is going to have graduate programs in multiple disciplines, psychology, social work, practical counseling, and also residency program in psychiatry. And so, those programs are going to be starting up in 2025. If you have some interest in the programs or interest in becoming a faculty member in a warm, wonderful Houston, then there are some flyers on the back seats, if they're still there, that have a QR code if you want to scan that for more information. All right. Without further ado, let's go ahead and get started talking about alcohol withdrawal management and its updates. All right. Thank you. Thank you, Dr. Weaver. I'm Dr. Olani Olayinka. I work in the inpatient unit. I run the dual diagnosis inpatient treatment program at UT Health, UT Houston. So this is our disclosure. We have no financial disclosures. That's fine. This will be fine. And then here are four objectives. So we hope, at the end, we're able to explain the neurotransmitter imbalances that lead to the symptoms of alcohol withdrawal, identify different skills used to measure and treat alcohol withdrawal. We're going to explain short- and long-term negative side effects of using benzodiazepines in the treatment of alcohol withdrawal, and draw from some of our own experience, and then identify non-pharmacological and non-benzodiazepine pharmacological treatments for alcohol withdrawal. So we'll start with an overview of the overview and neurobiology of alcohol use disorder. But before I delve into it, it's important for us to know that the alcohol industry is a multi-billion dollar industry. And the national survey that was done in 2019, these are all data coming from the United States, shows that 85%, approximately 86% of Americans ages 18 and older had drank at some point in their life. When they asked about past year prevalence, they had about 70%, approximately 70%. And over half had alcohol exposure in the past month. Now we're going to go over a few terms, terminologies, before I discuss some of the evidences in terms of the neurobiology of alcohol withdrawal. The National Institute on Alcohol Abuse and Alcoholism defines binge drinking. You have women consuming four or more standard alcoholic beverages in one occasion. And for men, if you consume five or more, that's considered binge drinking. And when I say standard alcoholic beverage, I'm referring to 12-ounce can of beer. We have approximately 26% of Americans binge drinking in the past month. And in terms of heavy use, consuming eight or more standard alcoholic beverages for women and 15 or more for men is considered heavy drinking. And all these are important in that the risk for alcohol withdrawal, of course, increases with heavy alcohol use. Here is one early study that I found very interesting, where 10 healthy adults were asked to drink for up to 90 days, that's three months, they were given a high concentration of alcohol, 95%, and at the end of 90 days, they basically withdrew alcohol. This graph shows that virtually all of the volunteers had at least mild symptoms of alcohol withdrawal. You have six here because four of those 10 actually dropped out. Early studies have been conducted, again, showing that if you drink heavily for a while and you stop drinking or you cut down, you likely would experience some of the symptoms. We had three had delirium, two seizures, and perceptual disorders in two of those volunteers. So now in terms of the neurotransmitter imbalances, and I know I'm preaching to the choir, when it comes to our understanding of the neurotransmitters that are involved, what we all know is that GABA is involved, the gamma-aminobutyric acid, there's an inhibitory neurotransmitter in the central nervous system. We have excess glutamatergic transmission, neurotransmission, and then we have no epinephrine. So more recent evidence, when I say recent, of course, in the 80s and 90s, there are studies that have shown that no epinephrine is involved in alcohol withdrawal syndrome. So now I'll start off with this very interesting molecule, GABA. That's the pentameric structure, have different binding sites, and in health, most of us will have certain subunits, like half a subunit, we have the beta subunits, and we have the gamma subunits that predominate. The binding of alcohol, so GABA itself will bind to its own GABA site, usually at the junction of the alpha and beta subunit. And when it binds, what happens is the pore, this is right in the middle of the structure, allows the influx of chloride ion, and basically that hyperpolarizes the neuron and inhibits neurotransmission. Alcohol and many other substrates, they are halosteric modulators, in that they don't necessarily bind to the same site as GABA, but they bind to other sites that modulates or potentiate the activity of GABA. This is a study, for those, in case you don't believe that GABA neurotransmitters are involved, there's a study that was conducted by Montpied, early studies that was conducted, 12 adult male rats were exposed to ethanol vapor for 14 days. Have in mind that there are earlier studies that have shown that if you expose rats to this amount of alcohol for this long, and you stop administering alcohol, they will develop, they would have developed tolerance, and of course, it manifests symptoms of alcohol withdrawal. They had six controls, and they basically sacrificed all these rats on stopping alcohol exposure for 14 days. The cortices, cerebral cortices were examined for GABA A receptor. So GABA, there are multiple receptors, but here specifically, we're talking about the GABA A receptor. This slide shows what they found. If you look to the left of this autoradiograph, it shows that once they stopped administering ethanol, which is the psychoactive substance in alcohol, there was downregulation of GABA A receptor, the half a subunit, at the end of 14 days. And that's what you see in this slide. They went a step further to show that other factors that can impact GABA concentrations were kind of modified or were not affected. So in this instance, you have GAD, which is glutamic acid carboxylase that helps convert glutamate to GABA. You see that the change wasn't that much in God. And then if you had alcohol disrupting the cell membrane, causing GABA to leak in one way or the other, the beta-acting actually shows that that had little impact on the downregulation of GABA A receptor subunits. So that's evidence in support of GABA neurotransmission, the receptors downregulating following prolonged exposure to alcohol. The next neurotransmitter involved is glutamate. This diagram shows NMDA, actually. Glutamate has three commonly described receptors. So one, you have the NMDA. You have HAMPA, which a lot of us are aware of. And then also we have kinase. In the alcohol withdrawal, all of them actually affected with NMDA slightly more, just because of the characteristic of the NMDA receptor itself. This is a study that shows that following chronic alcohol exposure, NMDA receptors was upregulated. There was increased expression. And the way they found out is basically to find an antagonist of NMDA receptor, which is HAMPKH01. And you can see that the binding of HAMPKH01 increases after prolonged exposure. That shows you that glutamate receptors are upregulated, have increased in number. And they found this more in the hippocampus cerebral cortex. The hippocampus actually has a lot of glutamate receptors. And it's also very sensitive to any insult to the brain. So you can imagine someone has repeated seizure, the hippocampus will probably atrophy after a while, just because of how sensitive it is, just because of how much glutamate receptor density it has. So this diagram shows, again, comparing the controls to those who were exposed to alcohol, we see that there was increased expression in the frontal cortex and the parietal cortex, but more importantly, in the hippocampus. Again, evidence showing that we have glutamate receptors involved. A separate study by Grant et al, this is in 1990, you know, replicated the same thing. Increase in NMDA receptor complexes in the brain. In this particular study, they went a step further. What they did was to administer NMDA itself to see if seizure activity following prolonged alcohol exposure increased or decreased. And then they gave the antagonist. And then you can basically just see what they found. I want us to focus on the right side of the slide that shows that after exposure to alcohol for seven days, and withdrawal of alcohol, those who administered NMDA, and there's a dose-dependent relationship, because we can see 30 milligrams per kilogram by the way of NMDA being administered to the rats, they were more likely to have severe seizure activity. And those who administered NMDA antagonist, basically zero. But again, this is time-dependent. So you see within two hours what happened, four hours, up until 24 hours. But it's remarkable seeing that NMDA, because of course you have many NMDA receptors available for the NMDA antagonist to bind to, seizure activity following withdrawal of alcohol was more pronounced. So that's evidence in support of the glutamatergic neurotransmission alcohol withdrawal. Now one that maybe a few of us are aware of is norepinephrine is also involved. And almost automatically you can imagine dopamine increases, dopamine is compared to norepinephrine. So definitely norepinephrine must be involved, especially in the early phase. So what they found, this slide basically shows that not only can you measure norepinephrine, but of course the surrogate is to measure the metabolites of norepinephrine in the CSF, central cerebrospinal fluid, which is the 3-HPG, I will try not to call the name. But the metabolite increases in the early stages of alcohol withdrawal. Corticotropin-releasing hormone also increases. Of course this is a stressful state. So the increase not only will increase cortisol, but through extra hypothalamic production of CRH, you can also still have norepinephrine increasing because of projections of the locus cereleus in the brainstem. They've seen a correlation between norepinephrine increase, corticotropin-releasing hormone increase, and diastolic blood pressure elevation in those healthy phase. What is interesting, though, again, I keep stressing, this is early phase. As you progress in the withdrawal state, norepinephrine tends to decrease. And the question is, why does this happen? I've mentioned extra hypothalamic production of CRH that can increase norepinephrine. Initially dopamine increases in intoxication. If you're in withdrawal, it will go down, but of course dopamine is compared to norepinephrine. What some have found also is the alpha-2-adrenergic receptor, which if you agonize that receptor, what you expect is this negative feedback where norepinephrine production is decreased, but there's self-sensitivity in those healthy phases of alcohol withdrawal. This makes sense because you have a stressful state, you have so much norepinephrine, and then it becomes self-sensitive. It's more like the receptor itself developing tolerance to norepinephrine. And norepinephrine is just in the system causing excessive pathogenic activity. If you gave one of the medications we'll be discussing, that can help potentiate the alpha-2-adrenergic receptor agonistic activity. I think that's my last. This is the last slide I have. And again, this is just a summary of what I showed earlier. GABA down-regulation because alcohol is a suppressant, and so GABA goes to sleep. The receptors down-regulate because you have too much alcohol. You remove alcohol, you already have up-regulation of NMDA receptors. And then the final one that talks about alpha-2-adrenergic receptor self-sensitivity. That's all I have. All right. Thank you very much. So this gives us an idea of the neurobiological underpinnings for some of the medications that we'll talk about a little bit later. Before we move on, are there any questions? We have time for maybe one or two questions about some of the neurocircuits and neurobiology related to the withdrawal syndrome. If you do have any questions now, or we'll also have plenty of time for questions at the end, I encourage you to use the microphone there that's at the center of the room. The session is being recorded, so it'll be available on demand later. So for folks that are going to be watching it on demand, we'd like you to use the microphone so that they can hear all the questions. So please keep that in mind when we do do questions between the speakers and at the end. All right. Seeing no folks with questions, we'll move on to our next session. So Dr. Vaulea will talk about assessment and initial treatments for alcohol withdrawal. Thank you for being here, everybody. I'm a PGY2 at UT Houston, and this is my third APA. It's always exciting to come back to APA and present, especially with my mentors. So after talking about all the neurobiology, we're going to talk about how to diagnose alcohol withdrawal syndrome. I'm sure everybody has seen this graph multiple times, so we'll just quickly go over it one more time. So mild withdrawal symptoms, which are mainly defined as like having headaches, tremors, sweating, tachycardia, GI disturbances, or anxiety, they could start up to like six hours from the last drink and can continue for 24 to 48 hours. Just keep in mind that the patients would have an intact sensorium during those symptoms. So moderate to severe alcohol withdrawal symptoms can start at like the 24-hour mark and can last up to five days or present at the five-day mark as well. And those include hallucinations, illusions. The autonomic stability is still seen in those patients at this time. Seizures, we see a lot of seizures in our patient population at UTHealth. So the withdrawal seizures, the tonic-clonic seizures, they can present any time between the six-hour mark to 48-hour mark. And then the last, the DTs, the delirium tremens, we start seeing those around like 48 to 72-hour mark, but the prevalence goes down after that. But we've still seen patients presenting with DTs as late as nine to ten days since the last drink. So the symptoms would include tremors, sweating, tachycardia, anxiety. Patients are not alert and oriented during these symptoms, and then agitation as well. These are some of the commonly used scales we use to measure alcohol withdrawal. I'm sure SEVA is probably the most common or at least very commonly used at our institution. That list is pretty new to me. I think apart from two or three, I've never used or heard of any other scales. I would actually open it to you all, like apart from SEVA, is there any other scale that is commonly used in your practice, in institutions or private practices? Or it's SEVA for everybody? Yes. Okay. Okay. Good to know that. Our default has always been SEVA, but doing this literature search, I was excited to learn about many more scales that are available and validated as well. The RAS, you mean the Richmond Agitation Scale, it was initially developed for ICU assessment of agitation, but it has been used for withdrawal assessment as well, not just from alcohol. All right. So all these scales typically report very common measures. This is a review article that I found. This is from like two decades ago, but still pretty relevant, I feel. So they reviewed all the scales that were existing back then and reviewed the commonly and less commonly reported measures. So more commonly included measures include anxiety, restlessness, GI disturbances like nausea, vomiting, diarrhea, tremors, altered orientation, sleep disturbances, and then hallucinations like auditory or tactile hallucinations. Not surprising, the very less commonly reported measures included hypertension, changes in heart rate, or changes in body temperature. That is a snapshot of the SEVA scale that we most commonly use, or I've heard from other residents as well at other institutions that they, you know, by default go to SEVA scale. The parameters are rated between 0 to 7. The total score more than 15 is at increased risk for severe alcohol withdrawal. So higher the risk, the greater the—higher the score, the greater the risk for alcohol withdrawal. And then patients scoring 10 or less, they do not need medication. So typically, at our institution, if a patient has scored less than 10 for 24 hours or more, we just stop the SEMA monitoring altogether. So the commonly used, once we have these scores, the commonly used medications are often benzodiazepines. If you're in an ER setting or a setting that has an IV-accessed diazepam is very commonly used. It has a rapid onset of action, longer half-life, can be given orally as well, but very commonly used as an IV benzodiazepine. Chlorodipoxide is an oral option, again, long half-life. Ativan is our favorite so far. Multiple modes of action, including sublingual, which was completely new for me. I learned from this presentation. So intermediate onset of action and shot acting as well, and then another option we have is oxazepam. The question is, if the SEVA's doing all the right things, why are we even talking about it right now? Everybody knows about it. So going through residency, I think a lot of our residents were often talking about SEVA is usually based on human judgment, so it's all subjective measures. What if one clinician is measuring it differently than the other clinician? We're depending on how the patient is giving the answers or how nurses or other healthcare professionals are measuring the scales. Are we totally relying on something that's just purely on human judgment and we have no objective measures? That's what actually instigated this topic and we researched more. Upon literature search, I did find that there are a couple of articles, Dr. Olienka did tell us about this, that both are coming from Canada. Nothing wrong with it, but so we found these two articles that actually talked about SEVA that might be an unreliable tool in the management of alcohol withdrawal and then there are challenges in predicting or diagnosis or treating patients just based on SEVA. So the limitations that these papers and some other papers also reported are the ones that I just mentioned, that these are mostly subjective parameters that are based on human judgment. The nurse or whoever is on the unit, how they're judging patient's anxiety or how the patient is reporting could be completely different from how somebody else would do it. And then autonomic signs, vital signs are not included in a lot of scales and then relying on patient's ability to answer the questions. If they're alert and oriented, that's fine, but if they're not, we don't even have those measures. Relying on staff to, same point again, but relying on staff to do these, then they're a little time consuming and could lead to overuse of medications due to subjective nature of the scale. And since we primarily use benzodiazepines for the treatment, there are side effects associated with benzodiazepines, including risk of misuse, worsening of confusion if they're already disoriented, delirium, respiratory depression, and risk of falls as well, especially in the elderly. When we were trying to figure out what we can do better or what changes we can propose, although it'll have to be a system-wide change because we rely so heavily on CEVA, Dr. Manohar actually introduced us to the scale called PAWS. It's not our work, it was proposed and validated by clinicians at Stanford, UCSF, and some other institutions as well. I know one of the lead, Dr. Maldonado, was attending APA. I tried to invite him for the conference, but I don't think he's here, or we would have better insight on the scale. But why we like the scale is because it's a good way to predict who will actually develop severe alcohol withdrawal and reduce the use of benzodiazepines. And it's also useful in identifying the risk of complicated alcohol withdrawal in medically ill patients. So if you look at the survey, I don't know if it's clear enough, it is. So it's asking questions like, it's taking into account your blood alcohol level, it's taking into account your history of seizures, or if you've ever had DTs in the past. So it's a good predictor of how you should go forward. That will be it for me. I would like to invite Dr. Manohar to take us through the options where we can, other medications we can use, where we can spare benzodiazepines and use different medications that are available. Thank you. And are there any questions right now? We can take one or two questions if people have questions about assessment, some of the different scales, things like that. Or comments. Yes. Do you wanna use the microphone? So you were mentioning that Ativan or Lorazepam is the favorite amongst your institution. Just curious because where I practice in Florida, Valium or Diazepam is more readily used, especially if liver dysfunction is not an issue. So just curious to know what makes you reference that one in particular. We'll get to that. So the next section, we're talking about is about medication. Yeah, I can just give a one-liner. We are a psych-only facility. We don't have IV access. So our go-to is Ativan IM or oral if the patient can do that. Hello, Cameron Ritchie from MedStar Washington Hospital Center. We have had real problems with shortages of Ativan and Valium, and some of you are nodding. I'm pretty much interspersing the other ones, whatever we can use, or going to ones that we'll talk about later, I'm sure, phenobarb, et cetera. Any advice if you need to switch from one benzo or are they functionally equivalent? Very good, and we will talk about alternatives to benzodiazepines altogether in the next few minutes. So stay tuned. Where I practice, we use a lot of clonazepam. Is there a reason why not? I mean, you said you're just oral only. Is that because clonazepam comes in IV, well, and oral. So is there a reason why you don't use clonazepam? Yes, these are all excellent questions, and we will definitely cover more about medications in the next few minutes. All right, I'm gonna ask a question about the scales. I'm sure many of us in this room know, but the CWO was never normed on women when it was originally developed, and there's been some scoping reviews, especially recently, about that. Do you know if this one was, I mean, it's much more recent. It was a sex-gender analysis done with this scale? Right, so the CWO is one of the oldest. It's been around for decades. I was using it 30 years ago. Its utility is for the assessment of the severity of withdrawal, and it does have a lot of subjective components to it, and so those have been widely recognized as limitations. It does have a little bit of utility as a predictor. In other words, how likely is it that the withdrawal will get bad, that you will need to treat it, or that they will have complications? The pause has a different purpose. It's not so much for severity of withdrawal, moment-to-moment assessment. It's more about how likely is someone that you don't know if they're going to go into withdrawal yet is going to go into withdrawal, or is going to go into withdrawal that is going to get more severe and with complications like delirium. So its utility is as a predictive tool as opposed to as an assessment tool once you already know that someone's in withdrawal and is your treatment going to be effective or not. That's where the real utility of the CWO score comes in, is if you are starting to treat someone, is that treatment getting better? Are the scores going down versus going up? As far as your question, they didn't do gender stratification for the pause, but they did include women as part of the population. So it was all comers, and this was Northern California, I believe, where they looked at this particular scale and its utility. But again, it's predictive power more than anything else. So very good question. Good point. As far as inter-rater reliability, I mean, nurses are usually doing this. They can be trained to do this. And when you were looking at these different kinds of scales did anyone ever use like heart rate or blood pressure? Because those would be things that would be readily measured. So some more recent iterations of the CWO, and the CWO is actually the revised version. There have been more than one previously, although the revised version has been around for decades. But some people add on above and beyond that to include vital signs as a part of the score. So for a range where someone's blood pressure or heart rate is going up, that can be an additional either predictor or indicator of ongoing severity. Some of the other scores that were on the previous slide also do look at vital signs, primarily blood pressure and heart rate as an indicator of severity of withdrawal. Some of the more recent scales, you know, the BAS and the SAS have the utility that they are very brief, usually only three to four items to be able to indicate more about severity of withdrawal so that you have less of an issue with inter-rater reliability. But that being said, a lot of these, you can train someone, nurses predominantly, to assess patients using the criteria for the scale and to do it as consistently as possible. And even something like the CWO, which has more than half a dozen different elements in it, takes far less than five minutes to be able to assess, even though a lot of it is subjective. As long as the patient's answering, you can go through it pretty quickly. So these are some good questions. We'll go ahead and move on with Dr. Manohar, and she will answer some of the questions that have already been asked regarding medications and alternatives to benzodiazepines. Hey, so I'm Roja Manohar. I'm also a PGY-2 at UT Houston. It's my first APA, so excited to be here. I just wanted to start with a little anecdote of what actually made me interested in this topic, and it was back when I was a medicine intern on Night Float, Wards, and I had kept getting paged about a patient who, the nurses were concerned that he was needing too much Ativan for his withdrawal syndromes, and they were like, he needs to go to the ICU, you need to come see him, you need to send him to the ICU. So before seeing him, I talked to the ICU, see if he had a bed, did the whole thing, and then I went to go see the patient. I was like, I wanted to lay eyes on him, see what the actual alcohol withdrawal symptoms were. Before I walked in the room, I asked the nurse what his most recent CWAS score was, and she said it was like 25, and I was like, oh my gosh, that's horrible, and she was showing me everything that she scored, and she was giving him max scores for tactile hallucinations, max scores for visual hallucinations, and I was asking her, because I went and looked at this man, and he was yellow, he was knocked out in bed, just kind of wiggling around a little bit, just really, really, clearly encephalopathic. I asked the nurse, how did you give him max scores for tactile hallucinations, because when I tried to talk to him, he could not talk at all, so I was like, how did you know that he's having tactile hallucinations? And she said that when she talked to him, he kind of itched his hand a little bit, and did this, and she gave him max scores for that. And so I was like, it ended up being like, this man, we ended up stopping the CWA, because he was just extremely encephalopathic, because of his terrible liver, terrible hepatic encephalopathy, but they thought that he was withdrawing. And so, we didn't send him to ICU, but that was kind of the topic that made me, like, that was kind of the situation that made me really see how limited we are in some of our assessments of alcohol withdrawal, and kind of made me interested in this topic. So yeah, so now going through some of our non-pharmacological managements. So this algorithm is based on what Dr. Wally was talking about before, the PAWS, and it was developed by Dr. Maldonado and colleagues at Stanford. And so we'll get into this a little bit more, like, after we talk about some of the medications, but essentially, they have, you do a PAWS scale to see at what risk somebody is for withdrawing, and then based on their risk, you either do no treatment if they're at low risk, or supportive treatment, or you do a withdrawal prophylaxis protocol, or a treatment protocol. And in most of these protocols, we are focusing on using non-benzodiazepines and only using benzodiazepines as a rescue measure if needed. So this is kind of touching back on what Dr. Olenka was talking about, the big three neurotransmitters involved in the symptoms of alcohol withdrawal. And so we have GABA, glutamate, and alpha-2 norepinephrine. And so I feel like we focus a lot on the GABA with our benzodiazepines, and so we looked into other medications that target our glutamate, target our norepinephrine. And we also have some non-benzogaba agents. So I'll touch base on each of those a little bit. So some of our non-benzogaba agents, we have Phenobarb, Propofol are two of the big ones. Phenobarb acts differently than GABA in that it prolongs duration of the chloride channel openings also has effect on NMDA receptors inhibiting them. There's a few studies that showed there's actually no difference in an ED length of stay or symptom control when compared to benzyl. And then it actually showed that, there was a study showing that giving a single dose of Phenobarb in the ED and then adding benzodiazepines symptomatically after that was associated with fewer ICU admissions. Propofol is a direct GABA A receptor activator, it increases chloride conductance. One good thing about it is it's extremely rapid onset, extremely short half-life, so it's really easy to titrate. Of course, everyone knows, extreme risk of respiratory depression and you have to be on mechanical ventilation to use it. And so this is often used in refractory cases that are non-responsive to benzos in patients who are already in the ICU and on ventilation. And then going through some of our anti-convulsants, which I think are really underutilized in treating alcohol withdrawal. Most of our anti-convulsants are glutamate modulators. So just kind of really touching base on some of the mechanism actions of them. Carbamazepine stabilizes our sodium channels, reduces firing frequency, also does potentiate GABA receptors and then inhibits glutamate release. Depakote valproic acid increases availability of GABA and inhibits our NMBA subtype of glutamate receptors. Gabapentin increases GABAergic tone and inhibits glutamate synthesis. And it also does have effect on norepinephrine and dopamine release and reduces that. Going to a little bit more detail on some of the data on some of this. Carbamazepine is actually quite well tolerated. It's rapidly absorbed after oral administration. Studies show that there's better response to treatment. Patients were calmer, less dysphoric, less irritable. And there was improved symptom relief and anxiety and hallucinations. The duration of DTs was actually shortened and there was a decreased incidence of withdrawal seizures. It's useful in that the metabolism's largely unaffected by liver damage. Of course, there are cons. Carbamazepine has a lot of interaction with numerous medications, so it might be less useful in some of our patients who have numerous comorbidities on other CYP inhibitors. And Oxcarb actually has comparable effects to carbamazepine. Depakote or valproic acid also has been shown to have fewer seizures and patients on this require less rescue medication, so less benzos were used when patients were placed on Depakote for treating alcohol withdrawal. We're a little bit limited by some of its side effects, somnolence, GI disturbance, and of course, in our patients who are heavy alcoholics, they might have liver damage and so it might be limited in those patients who use Depakote. Gabapentin, I think, is a big one. It's actually quite comparable to Ativan in the treatment of acute mild to moderate alcohol withdrawal syndrome. Lots of benefits compared to Ativan or other benzos. Decreased daytime sedation, decreased alcohol cravings. I'm sure a lot of you guys know that Gabapentin can be used for the treatment of alcohol use disorder in addition to alcohol withdrawal syndrome. It's metabolized extrahepatically, so you don't have to worry about liver damage in our patients with alcohol use disorder. It is a little bit, it's less effective in patients with severe alcohol withdrawal syndrome because there's less effect on withdrawal seizures, but it's really, I think it's something that really needs to be utilized more in our early, less severe alcohol withdrawal patients, which we see a lot of at our institution. It's a, like Dr. Walia was talking about, we have, we work at a standalone psychiatric hospital and so our patients usually have, if they do have symptoms, they're much less severe and if they do have more severe symptoms, we usually send them out to the medical hospital. Just touching base a little bit on other anti-epileptic agents that can be used. Lamotrigine, Topiramate have also been shown to reduce withdrawal severity, reduce dysphoric mood, and reduce the need for supplementary diazepam administration. Some evidence shown in Pregabalin and Vicabitrin and Tagabine as well. And then Topamax actually has evidence in the treatment of alcohol use disorder dependence. And then touching base on our Alpha-2 agents. So, like Dr. Olenka was talking about, a lot of the severity of alcohol withdrawal symptoms are related to the amount of norepinephrine release, which is why Alpha-2 agents have a big role in treating it. So, there's three different receptor subtypes. You have receptor A, B, and C. The Alpha-2A agonists work to promote sedation, analgesia, neuroprotection. Alpha-2B, this is less relevant in alcohol withdrawal syndrome, but suppress shivering, induce vasoconstriction of peripheral arteries. And then Alpha-2C, modulate cognition, regulate epinephrine flow. Three of the big ones that we think about are Clonidine, Presidex, and Guanfacine. And they're really useful as adjunctive treatments for alcohol withdrawal syndrome. So, going into each of them, and I'll kind of summarize everything at the end, but Clonidine, shown to have really great improvements in some of the autonomic symptoms we were talking about. So, blood pressure, heart rate, that aren't always captured on some of those scales. Really great in anxiety, and it's useful as an adjunctive therapy to benzos. Presidex is actually eight times more specific for the Alpha-2 receptor than Clonidine. And you can actually use it without intubation. So, you can use it in ICU settings in patients who aren't intubated. And there's been animal models showing that there's efficacy in managing all phases from mild to severe alcohol withdrawal syndrome. And they've been shown to have a reduced need for benzos use when you use Presidex. Guanfacine, a little less evidence in human models, but there's lots of effectiveness in animal models so far. And similar to Clonidine, there's less hypotension, less sedation when you use it. Okay, so this is kind of like the big thing I wanted to touch on. So, this was a meta-analysis looking at different non-benzo options to treat alcohol withdrawal. So, they looked at about 30 randomized control trials. And they found that Gabapentin was actually favored over Librium and Ativan for reducing alcohol withdrawal severity. The meta-analysis also favored Carbamazepine over Oxazepam and Ativan in reducing CWAS scores. So, going kind of a little bit more specific, the Gabapentin outperformed Librium and Ativan for CWAS scores of seven through 15. And then the Carbamazepine outperformed the Oxazepam and Lirazepam for CWAS scores of 10 to 20. And they found that numerous non-benzos outperformed the benzos in autonomic, motor, and psychiatric symptoms. So, some of the ones that they looked at were Gabapentin, Pregabalin, Carbamazepine, Topamax, Lamotrigine. And they all were found to reduce CWAS scores compared to using benzos. The only thing that was kind of a limitation to this was that they found that delirium tremens resulted in treatment cessation in both groups, in both benzo groups and non-benzo groups. So, that's something important to kind of keep in mind. In general, sedation and fatigue were more prevalent in the benzo groups, and seizures were more prevalent in the non-benzo groups. But I think kind of one thing to kind of keep in mind is that we're not saying don't use benzos because you can come to them when you need them, but we can start off with non-benzo options to reduce some of the side effects that Dr. Walia was talking about. And then if we do get to a severe point of alcohol withdrawal where you're having a seizure, where you're having severe symptoms, you can use benzos as a rescue option if needed. This is another really interesting study where they looked at a benzo-sparing order set. And so this kind of actually goes back to, I'll go back to it in a second, the algorithm that Dr. Maldonado and team came up with. And so this was a study done at Casa Permanente. They basically looked into a kind of cascading order set is what they called it. So there was three different risk categories based on PAWS and CWAS score. And so they kind of put you at a risk of, like what risk of alcohol withdrawal severity you're at. So for low risk, which was they considered CWAS scores under eight or PAWS under four, they put you on an observation pathway. So this was like supportive care. So the kind of going back to that. So PAWS that were low, so under four, no immediate intervention needed. So you are getting supportive care, you're getting fluids, thiamine, you can use PRNs for like insomnia. So the ones they used in the study were melatonin, doxepin, hydroxazine, PRN for anxiety. And they use much less benzos and you'd only kind of progress to the next step if the patient's symptoms progressed. I'm sorry, going back to this. So that was kind of the first one. So low risk, PAWS under four, CWAS under eight, supportive treatment. And then for a PAWS over four and a CWAS over eight, under 15, that was considered like a higher risk of alcohol withdrawal or if they're having alcohol withdrawal syndromes actively. Then you kind of go into two different pathways. There's a prevention pathway and there was active withdrawal pathway, which was on that slide here. And these essentially differed in kind of the doses and the medications they used. But what they did is put patients either on scheduled gabapentin or Depakote, just depending on the patient's profile. So if they have liver damage, if they have renal damage, they avoided gabapentin and used Depakote. If they have liver damage, they used gabapentin over Depakote. And the dosages differed between the prophylaxis pathway and the withdrawal pathway. And then they also added clonidine, which we talked about was our alpha-2 agent. And they only used benzos as needed for a breakthrough. Again, they used the PRNs as needed for things like insomnia, anxiety, that patients would have hallucinations. They used Haldol, PRN. And so all of this actually, they found that there was, sorry, going back to this, okay, decreased ICU admissions, which I think is really important. And in general, they had a decreased use of benzodiazepines, like, oh, sorry, decreased use of benzodiazepines overall and an increased use of clonidine, gabapentin, thiamine, and Depakote, and decreased hospital length of stay. And so overall, like, inpatient mortality was improved using this benzodiazepine sparing order set. And then briefly kind of touching on some of our non-pharmacological interventions, which I think we don't always do super well, at least at our hospital. I don't know if other people want to talk about that. You can, but I think we really underplay the importance of delirium preventions, delirium precautions in our patients. Dr. Maldonado's study showed that early mobilization, aggressive PT, OT, or if patients are in bed rest and daily passive range of action, passive range of motion, clustered care, so making sure patients get at least six hours of sleep, trying to cluster blood draws, vital checks, and things like only at night and in the morning, making sure they have fluids, electrolytes, all repeated, vitamins, thiamine, and then our basic delirium precautions that we think of, like lights on during the day, windows open, try to get patients awake, talking to their family, talking to nurses, and then at night, minimize as many interactions as possible, so lights off, TV off. And I think those actually, the studies, it's old, 1983, but they showed that patients, that the CWAS scores improved in the group that had both the Ativan PRN and delirium precautions compared to not having delirium precautions. So important, something to keep in mind as well. And so, yeah, that's our talk. Thank you to everyone for coming. Thank you to my co-residents and Dr. Lincoln, Dr. Weaver, Dr. John for supporting us. We'll start for questions, yeah? Okay. So what we've tried to do is give an overview of some of the neurobiology to give the underpinnings for why certain medications have utility for treating alcohol withdrawal. And it's not just GABA, there's more going on. There's norepinephrine, adrenergic activity that is part of the withdrawal syndrome as well, which is why things like the alpha-2 agonists make sense. And that's what we're seeing getting more utility clinically in more recent years as benzosparing regimens. So the other aspect of withdrawal that is challenging is the fact that it's very unpredictable. So it's quite variable in terms of how much or how long someone has been drinking, minimum standards, or if someone's been drinking on a daily basis for a couple of weeks, then the risk of withdrawal goes up. How much do you have to drink? Some folks have just done a couple of drinks. And of course, there's recall bias. As I like to say, patients don't remember where they stopped drinking, they remember where they stopped counting. So it may be a little bit challenging to get a really accurate estimate of how much someone is drinking on an ongoing basis. But if they are drinking on an ongoing basis, that in itself is a clue that someone is likely to go through alcohol withdrawal. But it's so hard to predict who's going to go into withdrawal and how severe is it going to be. Rough correlation with how much they're drinking and how long, but only very rough. My personal experience, and this is reflected in others as well, you can have petite, little old ladies who swear they only have two cocktails a night, and they go through terrible withdrawal syndrome, presenting with seizures. And then you have other folks that they come in, you know they're drinking like fish. But for whatever reason, their withdrawal is mild. Now they get shaky, they get sweaty. A couple of days later, they're fine. No seizures, no delirium tremens. So it can be really challenging to tell who is going to go through withdrawal. Really the best predictor is if they've gone through withdrawal before. So kindling effect. We see this with epilepsy. The more seizures you have, the more seizures you're likely to have. Same thing with alcohol withdrawal. The more times you go through it, the more severe it gets, the more likely you are to go through it again and it to be severe. So the key is prevention. And that's why more recent scales have focused on prediction with the PAWS scale and then the LARS, the Lubeck scale developed in Germany. Its utility is also to predict who's going to go into severe withdrawal. In other words, the ones you really wanna use benzos for from the beginning. More recent research has also focused on for the folks that don't get withdrawal that's really severe, then how can you treat that? They just get kind of shaky and sweaty and it gets better, but you really don't want it to progress. You also don't want them to be too uncomfortable and too difficult to deal with. And so that's why we have a lot of these other regimens now with medications that are less disinhibiting and less sedating. So that patients don't get too much of a good thing and they are able to take medication that's not going to be too detrimental for what else you're trying to treat while they're in a hospital, whether it's a psychiatric hospital or a medical ward. So it's very important to focus also on the population that well, they're probably not gonna go through DTs, but we can prevent withdrawal from being a problem or getting to the point where risk of DTs is higher. That being said, if someone comes in and they give a history of past withdrawal or they've had multiple seizures in the past, you probably are not going to spend a lot of time dithering about, are we going to use a benzo-sparing regimen? You're gonna go right to benzodiazepines. And there's more than one way to skin a cat. So you can use something that you're familiar with. There are long, intermediate, and short-acting benzodiazepines. And so they've been around for decades. And so they are very useful medications that we know work for treatment of withdrawal. It's less important about folks that swear by a particular one than it is having one that you're familiar with and knowing how to use it judiciously. So that's one of the clinical underpinnings that we want to try to let you know about today. But what our talk is focusing on is what else can you do, including ways to treat patients who you've put on benzodiazepines and maybe they aren't responding the way that you had hoped they would. So there is a subpopulation of patients that have very severe withdrawal. These are the ones that you get calls about needing to go to the ICU. But some patients do seem to be resistant to benzodiazepines. And that can be for a variety of reasons related to liver impairment or the severity of the withdrawal or not having it started in adequate time before the symptoms get really severe with really high scores on one of these assessment scales. So that's the other clinical point to make is that prevention is really the key and you really want to know that if you're going to use a benzodiazepine, go ahead and use what you need in order to get the symptoms under control because you really don't want it to progress. All right, we do have plenty of time for questions. We see a line there at the microphone. So we'll go ahead and get started and we'll do our best to answer. I was wondering, I was once taught that the alcohol withdrawal syndrome was due to membrane fluidity changes due to steadily high alcohol concentration. Has it been tried supplying patients with high doses of arachidonic acid? I'm not aware of any. It hasn't been tried. Yeah, arachidonic acid for the management of alcohol withdrawal? No. So alcohol is a really simple molecule and it certainly passes very easily through membranes. The effects that we worry about have to do with its effects more on specific types of receptors. So we're looking at GABA and how that impacts glutamate. So ultimately it has to do with ion channel opening and closing that leads to membrane polarization and potentially leads to blood clotting. That leads to membrane polarization and potentiation. So it's less about what you're doing at the membrane level than what it is you're doing at the ion channel receptor level. And so the therapies that have shown the most utility are the ones that are most specific related to ion channel receptors. That's why the alpha-2 agonists and the GABA agonists and then benzodiazepines, which are GABA agonists, have shown most utility for the concerning effects of alcohol withdrawal. That being said, there are some adjuncts. Everybody knows about vitamin replacement and things like that. But something like arachidonic acid hasn't really been looked at in studies to be able to say that as an adjunct it has a beneficial effect on alcohol withdrawal. Let me add something on the GABA receptor. So I was just going to comment on the GABA receptor. So, again, I mentioned there's a pentameric structure. For benzodiazepine sensitivity, it has to have the gamma subunit. So in health, usually we have the two alphas, two betas, and one alpha, one gamma. So if someone had, say, they don't have the GABA subunit, the gamma subunit, they're less likely to be sensitive to the effect of benzodiazepine. And, again, just listening to what you mentioned, some population of patients will not even respond well adequately to benzodiazepine. Thank you for the excellent presentation. So I'm an addiction psychiatrist, and I'm from Canada. And I'm working for the last five years in a unit that we are managing medical supervised withdrawal management for complex medically and psychiatric patients. So what I did find challenging is that we don't have a very specific strategy when we are starting the withdrawal management. So if our mixing strategy is going to be a disaster, so if I'm going with symptom trigger or I'm going with schedule, we have to know. I'm going to load or I'm not going to load. If I'm using benzo, I have to be straight about using benzo. If I'm mixing benzo and the gabapentin, it's going to be a disaster because gabapentin is going to cover my symptoms, and then the nurse is not going to detect the high SIVA. So basically, let's say that now my question is, if you are choosing gabapentin, how we are going to load that, and would you be able to load it or not? Because we are doing PRN, for example, clonidine with symptom trigger benzo management. But if a patient comes to me and an outpatient doctor already started the gabapentin to facilitate the withdrawal management, being under the impression that it's going to prevent seizure, I'm going to be in trouble because I'm unable to prevent seizure without loading the benzo, and when I'm loading the benzo with 900 milligrams three times a day of gabapentin, my patient is drowsy. Okay. So, yes, these can be very complex clinical situations with patients that have multiple comorbidities, medical and or psychiatric, in addition to withdrawal, and that can mask the constellation of symptoms that we're trying to look for to make a determination of which therapy do you choose and when do you initiate it, and trying to use something like symptom-triggered therapy, which has been shown to be very effective for reducing the amount of total benzodiazepines that patients have to give or have to receive compared to something like a standard protocol where everybody gets the same thing. And being able to use symptom-triggered therapy means you have to be able to adequately assess the patient. So the big drawback is the fact that you have to have nurses, residents, other medical personnel who are familiar with the scale that you're using and can do it quickly, decisively, and accurately so that you know, okay, this is a patient that needs this particular dose, and you can escalate it quickly, or you can determine that, well, the scores are low, they're not getting much, and so they don't continue to get doses that they don't need. When you throw in medical and psychiatric comorbidities, that really complicates the picture and makes it hard to decide. This is where some hybrid types of protocols can actually be very successful. So you have a relatively low-threshold, low-dose initiation of medication for patients to start out with where everyone does get the same protocol, but then patients who diverge from that, who are requiring more or less based on assessment, so it still requires an accurate assessment, can get more or less medication or benzos versus non-benzodiazepines. And so this is where you can separate out who is likely to have more problems and who's not, but everybody is going to get minimal therapy in order to help weed out the ones that you can manage with less staff time and effort. Does that make sense so far? All right. So what we need to focus on, and this is where more research really is needed, is how to parse apart patients that have additional complications, whether it's liver impairment or whether it is a delusional disorder with psychotic symptoms that can really make the scales that we rely on with subjective symptoms much more difficult to use. So this is an area where more research is needed. Right now, all we have is the clinical acumen of the folks like yourselves that are actually treating these patients. That's why we have sessions like this to try to get input and feedback, and if people have specific comments about what you're doing that's working at your institution, that's something that we are interested in. But it's still a challenging clinical question, and everyone does have a little bit of a different answer. We can tell you the kind of things that we do at our institution, but we're also interested in what other people do at their institutions, and getting this out there, sharing it, spreading the word is also going to be important as well. I know that's kind of a long-winded answer, but I don't have a definitive answer for you, unfortunately, in what you do in all the different cases. Okay. Yes, thank you. I echo that concern of using mixed strategies, especially with the data that you presented, that the non-benzodiazepine agents have higher risk of seizures, and so that question of, are we masking a subjective CEWA score by controlling symptoms with our other medications, alpha-2 agonists, things like that, and then we're actually not seeing risk or worsening symptomatology that result in a seizure. I do echo that concern. My specific question is related to the mixing, and how you're working with maybe different partners and different specialties. So we have started to really like phenobarbital given in the ER loading doses, but we've run into some challenges of maybe the ER has already given them a benzo. The ICU then is worried about multiple effects on respiratory depression, where we put the patient in the system, and even some pushback of, well, now you've chosen, or the ER chose for us, a benzo strategy. We're not going to kind of permit you to try or add on other strategies for fear of increased risk. So just wanted to hear about those issues or system issues that you might be facing as well. Okay. So we don't use phenobarb that much on the inpatient unit, or haven't, but it's something that I'm thinking about, just to let you know. But, of course, this is going to be oral phenobarbitone, totally different from what you would find in an ED setting or ICU. Again, we're worried because of the very narrow therapeutic index, and some people think it does have a wide therapeutic index, but I'm really, really very careful when it comes to phenobarbitone, just because of the duration. Opening the GABA channel for so long to reverse can be a little difficult. I will say from my experience, I've used phenobarbital for decades and find it to be a very forgiving drug. You do have to know how to use it. So if you're unfamiliar, don't experiment, but work with someone who is familiar with it, or get familiar with it by using it with patients that aren't the most complex until you have an idea of, oh, okay, yeah, this is not so difficult to use, because it really does have a very long half-life. That being said, one of the issues that you brought up was using mixed regimens. As an ICU colleague of mine said, every breath is a new decision. So you can always change the plan. Just because the ER has given one thing doesn't mean that you can't start another protocol as soon as they hit your floor, and that's okay. And if you have something that you know works, it's all right, especially because this is not something that is going to get better in just a couple of hours. So you've got time in which you can see, okay, is this working or is this not? And we tend not to combine non-benzos and benzos unless you're shifting the plan from recognizing that you've gone down the non-benzo road and it is not working. The last thing I'll say is that in terms of outcomes, what you want to prevent are seizures and delirium tremens with the autonomic dysregulation that leads to the morbidity and mortality that we see with alcohol withdrawal. So it is always better to err on the side of caution and give them too much rather than not enough. Because giving them not enough is what leads to the significant morbidity and mortality. If you give them too much, worst case scenario, someone has to go to an intensive care unit. They may end up on a mechanical ventilator for 48 hours until whatever they've gotten too much of wears off. They wake up, they're out of withdrawal, you have solved the problem. That's a lot better than having to deal with patients who have already developed really severe delirium tremens and have had multiple seizures by that point in time. So it's better to err on the side of caution and overtreat rather than undertreat. Hello, good afternoon. My name is Smith, I'm from the Philippines. My particular interest is on management of patients in the severe spectrum of the withdrawal. So one is, is there a daily ceiling dose for the yazepam? Number two, what is the utility of intramuscular haloperidol in patients who are severely agitated, very disruptive in the ward, who are in acute withdrawal? And number three, any tips on how to handle patients who come to the clinic? Of course, we do get patients who have medical comorbidities, like in alcohol withdrawals, say for example, a patient in alcohol withdrawal who has like hepatic encephalopathy or traumatic brain injury, and then you give the yazepam. So is there like a safety strategy there, considering that if you give benzodiazepines, that might worsen the consciousness of the patient? So I'll answer the haloperidol piece and then I'll defer to Dr. Weaver. So my concern with haloperidol is the fact that it can lower seizure threshold on its own. So if I'm dealing with someone who, this is pure alcohol withdrawal, right? Nothing else, no psychotic agitation, then I would rather use a benzodiazepine, and that's that. I've in mind that seizure starts six hours, post-withdrawal, and then an early withdrawal, and then 24 hours beyond, the risk for seizure basically decreases. So again, the time course of how the withdrawal symptoms are evolving is important in terms of what do I administer. Just the thing is, sometimes we do get patients who have like CEWA scores of 25 or above, like 25, so they are severely psychotic. So how do you manage that? Do you give more diazepam or benzodiazepines, or do you give an adjunct of like an antipsychotic? Also using psychotic agitation, in that instance, I'll give both if I'm concerned. But that's how I do it. Right, so if someone is psychotic, they're hallucinating from just the alcohol withdrawal, then adding an antipsychotic isn't necessarily going to solve the problem. They basically have a GABAergic deficit. So you need to fill that. You need to fill the tank first. So even if it does take high doses of benzodiazepines, that's what's necessary, that's what they need if they have been drinking heavily for a significant period of time. So that's if the psychotic symptoms are due to withdrawal, as opposed to an independent psychotic disorder. So you shouldn't need haloperidol for just psychotic features of alcohol withdrawal. Now, if they have alcohol hallucinosis, which is a separate diagnosis, so that is someone who is not in withdrawal yet, they can still be intoxicated, but they will be having hallucinations, then that's someone that, haloperidol still doesn't have a lot of utility, partly because if they're still at risk for withdrawal, it can lower the seizure threshold. Usually alcohol hallucinosis will abate on its own within 48 hours at the most. I haven't seen it last longer than that, but that is a separate condition. Now, to get to your other question about, is there a ceiling dose for diazepam and other things? Again, these are patients who have a deficit of GABAergic substances. That's what they're used to having on board at any given time in the form of alcohol. So theoretically, there's no upper limit. You can give them what they need until they respond clinically. There are a subset of patients that seem to be substandard responders. That's where some of these adjunct medications, so propofol and dexmedetomidine. Typically, by the time you have given them large doses of benzodiazepines, you're already considering a transfer to the intensive care unit, but that's where these medications are completely appropriate, even something like propofol, which is very sedating. It's okay, and you can use those as benzodiazepine-sparing regimens, and that's been looked at in the literature as well, where patients have received very high doses of diazepam, lorazepam, chlordiazepoxide, or whatnot, and then you can use dexmedetomidine, propofol, phenobarbital has also been looked at as well to see if those can help with additional mechanisms above and beyond just the GABAergic to try to get someone's symptoms under control quickly, and those have proven generally positive from the findings. Sorry, for my last question. Any tips on how to manage patients with alcohol withdrawal with comorbid, like encephalopathy or traumatic brain injury? Right, so again, with the comorbid conditions, the primary concern of the moment is gonna be the withdrawal. Because if they don't survive that, then the other things don't matter. So the first focus is get that under control. Now, if you do have someone that does have significant liver impairment, such as they're encephalopathic, then you're gonna have to recognize after the fact that yes, they may be more significantly sedated for a longer period of time. Those are cases where you may take into account the fact that different benzodiazepines have different forms of metabolism. So lorazepam and oxazepam have much less liver metabolism. They're just glucuronidated and excreted. So those would be better choices, even though they're more intermediate acting as opposed to long acting, it's still going to prevent you from being in a situation where the patient has much more significant sedation for a much longer time, while the liver has to still work at a reduced level of metabolism of all those secondary metabolites that make other benzodiazepines longer acting. But the main answer is treat the withdrawal first, then other conditions are generally secondary because alcohol withdrawal is life-threatening. Even when treated, the mortality is not zero. Hello, I have two questions. The first one is, could you comment on the dosing for like the baseline regimen that you think that like everyone should be on? And then obviously it would be adjusted based on how the patient is doing. But for example, like, you know, should I put everyone who's an alcohol withdrawal on Gabapentin 800 three times a day, Depakote 500 twice a day, and throw some like Clonidine like 0.1 three times a day? Or like, what do you think? Anyone want to take a crack? Yeah, hold on, I'm opening up, it's okay. So there have been a number of different regimens published in the literature. And different studies have actually used different doses. So it's not entirely clear that there is one best dose. Again, there is so much variability with alcohol withdrawal in terms of onset severity and prediction that you have to get a fairly large number of patients. So you really want to rely on meta-analyses as opposed to just one or two individual studies, because the populations can certainly differ. So we don't always have enough data to say, yes, this is the median dose for these particular medications. You also have to know your own patient population to be able to say, well, I have a higher risk population with more complications. Or for the individual patient I'm seeing, they have comorbidities that would limit the utility of something like Clonidine because of hypotension or tachycardia or something like that. I can kind of just touch base on the regimen that Dr. Maldonado's paper suggested, since I was pulling it up. But for the pharmacological treatment, the arm of the protocol, so what they said was for the Alpha-2 agents, they use transdermal Clonidine, so Clonidine patches. They did 0.2, and they did two patches, so total of 0.4. And then plus they added Clonidine 0.1 by mouth or IV Q8 hours. And then they added a Glutamate, and that was on a schedule. And so, I'm sorry, I said Glutamate, Gabapentin. And that was started with, on day zero, they did a 1,200 milligram loading dose, followed by 800 three times a day. And then, they did that for three days. Starting on day four, they went to 600 TID. And then starting on day five, they did 300 TID. And they DC'd by day eight. That was kind of the one that they mentioned on this specific protocol. And again, that may need to be individualized based on are you seeing patients on a medical unit where they may have more cardiac problems or respiratory problems. So, those are suggestions based on a limited number of studies. All right, thank you. My second question is, when using Gabapentin or Pregabalin in people who have alcohol use disorder, like to treat their concomitant anxiety and to decrease their alcohol cravings, is it, can you comment on the safety profile of using these medications in people who are still drinking on a daily basis? Yes, so, Gabapentin, the good thing about it, again, it has a very wide therapeutic index. And that's why people can go really high dose. What I typically do on the inpatient unit, tend to start with 400 milligrams four times daily. And I can cut down to, say, 900 to treat off-label for alcohol use disorder. Because I believe the studies that have shown its effectiveness in decreasing craving, usually hits about 900 milligram minimum in managing the alcohol use disorder. In terms of safety, if they continue to drink, again, I haven't seen any issues with patients who are on Gabapentin and they continue to drink. If anything at all, we say, hey, if they continue to take the medication, hopefully, as your craving decreases, then this is an harm reduction strategy where the number of alcohol that you drink, the amount that you consume daily, would decrease over time. It's almost the same with Naltrexant. As Rosha said, with Gabapentin, it's primarily excreted through the renal system. So you don't have to worry as much about liver impairment, which is definitely a concern in patients that you are considering Gabapentin for their alcohol use disorder. So it's relatively safe, even in the patients that we tend to worry about the most. For outpatient basis use, the doses that have been most effective for cravings for alcohol use disorder, so longer term treatment, not just treatment of the acute withdrawal, have clustered around 1,800 milligrams a day in divided doses. So whatever is going to be most effective for the patient to tolerate. Some patients do better only having to take it twice a day. Others, just because of side effects, want it more often during the day in smaller doses. But around 1,800 milligrams is the dose that's been shown to be most effective, but you can go up to essentially twice that dose if necessary. Thank you. So I know a few people always say, hey, Gabapentin has this black box warning, respiratory depression, because we do have patients who have opioid use disorder, they're on opioid methadone, and they have alcohol use disorder as well. And they're wondering, can I take both medication at the same time? Of course, I make them aware that it's a black box warning. FDA says, respiratory depression, Gabapentin, have the documented, I've indicated them on the risk benefits. And if they say, yeah, they understand it, then we go for it. Thank you. Thank you all for the presentation. Special shout out to Chief Olienko. I was surprised to see Depakote and Tegretol up there. So I'm assuming, first of all, for a female, they'll obviously do a pregnancy test, right? Can you speak up a little bit? I'm assuming, I was surprised to see Tegretol and Depakote up there. Obviously, for a female, they'll be getting a, not that the alcohol is gonna do the baby any good, but they'll be getting a pregnancy test, right? Both of those on the side effect profile, pancreatitis is on that, it's a little bit lower. In the research for those two medications for this condition, did you see any uptick in cases of pancreatitis at all? Well, this is a higher risk population for pancreatitis. But that being said, carbamazepine and valproate were looked at early on. Just clinically, they have been largely supplanted by gabapentin and, I'm blanking on it now. What's the, it begins with a T, oh, what's the other one? Hmm? Pancrevalol, yeah. Anyway, anyway, so, I'll think of it in a minute. But those were what the earlier studies were looking at. But for clinical reasons, most of the later studies have focused on gabapentin and others in order to have a better clinical profile. So those aren't used as much anymore for many of the reasons you have just mentioned. Thank you. Hello, can you hear me okay? Yes. I was hoping when you had a blank there that you were thinking phenobarb, but I don't know, yeah. So as you can probably guess, I'm from Boston where we love phenobarb. I'm a big fan of phenobarb at all. Yeah, yeah, yeah. So I kind of wanted to provide a little bit of the Boston perspective, which I'm not saying it's right, but it's just one perspective. And I really appreciate hearing different points of view and things that seem to be working well in different settings. I remember as a resident when I worked kind of, sounds like in a setting more similar to where you are right now, I was using different strategies than where I am now at a level one trauma center with patients that are like on all of the above still like seizing and NDTs. So, but I mean, I have seen themes in terms of things that work. So we have like four of the six addiction fellowships, addiction medicine and addiction psychiatry fellowships come through us at the Brigham. And one of the things I've really made a point of when I'm working with fellows and residents is to try to get them comfortable with phenobarbital. And cause I think it, I mean, there's just gonna be cases. I know we always talk about the seesaw analogy of excitatory versus inhibitory. Another analogy I like is gas and brake, right? So you have your excitatory system being the gas and your inhibitory system being the brake more. And yeah, we're hitting, we spend a lot of time talking about the brake. How can we hit that brake harder when sometimes that brake has kind of been, you've been driving on the parking brake for too long and the brakes just not working and you really need to figure out a way to lift that gas pedal off the floor. And that's one of the things I love about phenobarb is it has that dual mechanism of action. So anecdotally, we think it's less deliriogenic and the hospital loves it because people get out faster, right? You just load them, they're done. They're not like, you know, delirious. And you're like, do I get more benzo? Do I not? All this kind of stuff. So been really convenient. I just wanted to point out though, in terms of just some metrics to remember in terms of like where to start in those kinds of things. I mean, most patients are gonna be in the ballpark of 10 mgs per kg when they, and this is the Boston method. If you look in like the ASAM guide, they kind of use more of a gradual up titration, which I mean, probably works just as well as far as I can tell. But yeah, if you get 10 mgs per kg loading dose, remember that kilograms is not actual weight as we typically are using ideal body weight. So that's based on height, not weight. Fortunately, Epic has a smart phrase and just plug it in and it tells you right off the bat. And then from there, we're kind of correcting, we're giving these additional rescue doses of 65, 130, sometimes even double that. And we're getting people, and I tell the fellows as they're going along, and they might've gotten benzos, by the way. These patients might've gotten some benzos and they just didn't look good or they have a history of failing benzos in the past. Chart bloat is a huge issue right now. I have, I'll go through the chart and there's like 50 notes to say no history of DTs. And then the 51st note gives me this like detailed DTs vignette on the patient or seizures for that matter. So yeah, so we'll give these additional doses and then you get to the point where you're like at 15 mgs per kg. Maybe you've made some progress, but maybe you're just not where you need to be. And I tell them at that point, you want to start widening your differential, thinking about, because a lot of our patients are medically complex. Is there something I'm missing here? Like just a little pause. And you might, but it's okay to keep going. I mean, neurology loads phenobarb at 20 mgs per kg. So like we freak, I have pharmacists freak out sometimes when I'm like give them 10 and I have to like tell them, well, you know, patients could also seize if we underdose them. You know, we talk about, oh, we can always correct. Well, seizure happens pretty fast sometimes and you don't necessarily have time. So when we're getting close to 20, and this is something I've kind of picked up talking to colleagues and whatnot. That's when we, I think, if you're really not getting where you need to go and it's not that patient that always needs 25 of phenobarb when he comes in, there is that patient. You will see that patient and you just look in the chart to see him. But when you're getting to 20, you need to start thinking, what's my adjuvant agent going to be in addition to the phenobarb? And that's going to probably either be dexed or an antipsychotic. And you're going to kind of, I probably prefer dexed, but there will be the case where you see someone that feels a little bit less withdrawing, a little bit more psychotic-y, and that maybe you'll go with the Haldol dose. When dex is used, sometimes Clonidine is used after that is kind of when it's coming off. But I would say it's been pretty well tolerated. I mean, these are very complex patients and they tend to do pretty well, I got to say. And so it's been, I've been very impressed. Two other quick comments. I don't want to, for the person behind me, but article came out in the last year on phosphatidyl ethanol. And that's really, I didn't go to ASAM this year, but I went to AAAP and CLP, so I'm both consult liaison and addiction person. And both of them are starting to have talks on PETH. Should we be using PETH? Is PETH predictive? Can we just use PETH? If PETH is zero, that means no drinking in the last three weeks. End of conversation. Second comment, benzos. There's benzos and there's benzos, right? So, and for people online, I'm putting quotation marks when I say benzos here. So, and we treat those very differently, right? If we see PDMP benzos, so that really needs to be a talk next year. That's my request. Thank you. Thank you for your comments. And I will say, yeah, I've used phenobarbital, 90 milligrams every six hours. You do that for 48 hours, you can stop, it tapers itself. It's a very forgiving drug. All right, we have time for one last question. Thank you. We'll go as, can you hear me? Yeah. Yeah, oh, before you start, the other drug I was trying to think of was tapiramate. So gabapentin, tapiramate have more evidence now compared to the early phases with carbamazepine and valproate. So, all right. I appreciate you presenting all of the non-benzodiazepine options for alcohol withdrawal treatment, just if you're treating with benzos. I remember in the beginning of my residency, the teaching was for a standing benzodiazepine taper in what scenarios would you still do a standing taper versus just a symptom-triggered, CWAT-triggered dosing of benzodiazepines? So. No, I was just echoing what Dr. Weaver already said about symptom-triggered versus fixed. Again, patient-centered care. There are patients who, if a patient comes in, and I think they're really high-risk. Like you said, you don't under-treat. If, again, high-risk for having withdrawal seizures, you know, the kindling effect. There are times where if there's a true diagnosis of alcohol withdrawal syndrome, that a fixed schedule is okay. On the inpatient unit, all in which since it's standalone, we tend to do symptom-triggered, again, because we are concerned that patients come in who truly don't have alcohol withdrawal syndrome, and they're getting a lot of benzodiazepines. So in that instance, if there's no comorbid issues, we just would rather do the symptom-triggered versus the fixed. Yeah, so symptom-triggered is for when you don't know what's going to happen. If the chart says this patient always has DTs and it's bad, you're going to want to start at the top. So that's okay. All right, that's all the time that we have. Thank you very much for your time and attention. Enjoy the rest of the.

alcohol withdrawal

Dr. Michael Weaver

University of Texas Health Science Center

neurobiology

GABA

glutamate

norepinephrine

CIWA scale

PAWS scale

non-benzodiazepine alternatives

gabapentin

carbamazepine

customized management strategies