Okay, in the interest of time, we're actually going to get started. We know people will still trickle in, but we have a lot to say, because how can you not on this topic? I'm Alexis Rippo. I'm the chair of this workshop, along with Dr. Ilona Balsanova from Nebraska, Dr. Daniela Rokossovic from Northwestern, and Dr. Chris Blazes from Oregon. So today we'll be talking about a topic near and dear to our hearts, and apparently also to yours, benzodiazepines. So a line many of us have probably heard from some patients, it's the only thing that works, so helping patients recover from chronic benzodiazepine use. No relevant financial disclosures for Dr. Balsanova, Dr. Blazes is on the board for a non-profit, the Alliance for Benzodiazepine Best Practices, and I'm actually contracted with that same non-profit as their medical director. Objectives, so we're going to review the pharmacology of benzodiazepines with a focus on the mechanism for developing tolerance and the risk of acute and protracted withdrawal, evaluate the current evidence for different approaches to benzodiazepine withdrawal management on an inpatient versus outpatient basis, and the associated risks and benefits of the different approaches, and also utilize a case-based discussion of how to approach withdrawal management in patients with sedative use, hypnotic disorder, or other co-occurring substance use disorders. Hopefully this will stay connected. So first, the pharmacology. Many of this group, this is not new information, but still useful to go back over, and good things to be able to teach our learners. So benzodiazepines enhance the neurotransmitter GABA at the GABA-A receptor, thereby leading to a different site from GABA itself, and have what is called an allosteric effect. They're enhancing the effect of GABA, pulling it to the receptor, and increasing the amount of chloride going through the channel, and the amount of times that that channel opens. So overall, increasing the inhibition in the nervous system, and increasing the resistance to excitation. Tolerance develops, right? You get chronic administration, this chronic inhibition of the nervous system. Our system constantly wants to be in homeostasis. It continues to try to adjust and keep, as I tell my patients, right, keep you awake, alive, breathing, eating, moving, walking. And so what is it going to do if we're chronically inhibiting it? It's going to say, I'm going to decrease how much endogenous GABA I'm exposing my system to. I'm going to down-regulate the GABA-A receptors, and just try to decrease how much inhibitions in the system. And I'm going to increase all the excitatory, compensatory impulses I can, increase glutamate, increase endogenous norepinephrine and serotonin. Another definition we should all be quite familiar with, but right, tolerance is when you get less effect from the same amount. After repeated dosing, it varies for different therapeutic effects with different substances. So with benzodiazepines, the sedative hypnotic effect has been found to diminish after one to two weeks. So not uncommon, right? Our patients get these medications to help with acute insomnia, and one to two weeks later they're finding, I can't fall asleep if I only take the half pill, I need the full pill now. Anxiolytic effects have been shown to last up to four to six months. Also most of the studies only really followed people up to that amount of time. The anaconvulsant effects can diminish over weeks to months. And at the same time, the overall tolerance to the effects on cognition and memory don't seem to occur. So this is kind of similar to what we see, right, with opioids you don't get tolerant to the respiratory depression, benzodiazepines you don't get really tolerant to those cognitive and memory effects despite chronic use. I would say many patients are less aware of the effect it's having on their cognition until you do something like a mocha, but it does not, you don't get tolerant to it. And so we can overall think of tolerance as a variety of neuroadaptations that occur, including this uncoupling of how responsive the receptor is to pulling GABA to the receptor. And suddenly we're just not getting the same effect. Withdrawal. Many of our patients truly are not well informed when they start these medications, that if you take this medication every day for two to four weeks and certainly beyond that, increasingly a majority of you will develop a physical dependence to this medication. And if you try to stop it abruptly or decrease it too quickly, you will experience withdrawal symptoms. We know that the longer you take this and we know that the higher dose, especially with the more potent ones, the increased chance you will have withdrawal if you stop abruptly, but also if you decrease too quickly. I can't tell you how many patients I've seen where maybe they were told that when they started it 20 years ago, probably not, but then someone told them, oh, you're getting older, you really shouldn't be on this medication and didn't say, but don't stop it abruptly. And these patients are coming to me now for a taper, but only after they had a withdrawal seizure because they tried stopping a few milligrams of alprazolam suddenly. So it's a really, really important point that we need to get across to our patients. The other thing is that during withdrawal, we end up in this sticky situation of, are these uncomfortable feelings that our individuals are having, insomnia, anxiety especially? Is that the original psychiatric reason or symptom that this medication was prescribed for? Or is it actually because in the acute withdrawal, we're getting a rebound of a bunch of symptoms and the nervous system's all excited and suddenly we're having actually symptoms of withdrawal. So another reason to tell patients we don't want to stop these too quickly is to try to tease that apart and not have people feel like they have to stay on these medications indefinitely because they think I'm not going to be able to sleep without it. There are many physical and psychological symptoms of withdrawal. I'll go through a table in a little bit that goes through them a little more clearly. And when they're abruptly stopped, as we said, acute withdrawal reactions, of course, making sure our patients understand they could have a seizure, especially high dose, long-term, and that the seizure could kill them. There's also an increased risk of a more protracted withdrawal experience, and two words I'll come across in the literature, admittedly, one that is related to a paper I've written, one that's related to a paper Dr. Blais has written that are overlapping concepts we presented on last year, called Bunsen Diagnosis of Pain-Induced Neurological Dysfunction and Complex Persistent Dependence. These are not set diagnoses. These are observations of a constellation of symptoms that we see of the protracted withdrawal syndrome. For those that want to use a scale when assessing acute withdrawal, not protracted but acute withdrawal, there are two scales that have been developed. They have not been particularly well validated, so it's probably why we don't see them used a whole lot. Of course, the Clinical Institute Withdrawal Assessment for benzodiazepines will sound familiar, because it's the benzodiazepine version of the CYA that we use for alcohol, 22-item questionnaire, and the score ranges from 1 to 80, indicating the severity of withdrawal. The benzodiazepine withdrawal symptom questionnaire uses a no, yes, moderate, yes, severe, or 0-1-2 scoring, 20 items, and the total score is out of 40 to estimate the current severity of acute withdrawal. This table summarizes the benzodiazepines that are currently used in the United States, so it's a slightly different list than other countries. I will point out that actually flirazepam has been discontinued in the U.S., had a patient that unfortunately abruptly stopped that when they ran out, and it had been discontinued and did not have a good outcome. Flirazepam, dolmane, is no longer in production in the U.S. I think it was about last May, or at least that's when my patient ran out of their supply. I will point out when you think of dose equivalence, that's a clinical estimate, so based on what people report, the one that you see the most variety for is clonazepam, so some people will say that clonazepam, like if you look at the Ashton Manual, clonazepam and alprazolam are equal potent, and others will say, whoo, I just changed that, yeah, I just changed the feeling in the room, okay, others will say that clonazepam's even, what does it say here, 0.25, even more potent than alprazolam, but I will point out, clonazepam, alprazolam, and flirazepam, right, are most commonly outpatient prescribed medications, are very potent, and then there's also thinking about onset of action, as well as half-life, and remembering, just like with opioids, anxiolytic effect, insomnia effect, or hypnotic effect, is not the same as half-life, so people can get different effects, even if you have long half-life versus short half-life, so that's a whole, could be a whole other line. So, the withdrawal phase, shorter acting, right, withdrawal's going to come on sooner, average two days, we're thinking mostly alprazolam, flirazepam being the more common short acting, peak around five to seven days, and then kind of have that tail, longer acting, takes longer, right, to get out of your system, so you might see a peak at five days, I'd also like to remind everyone, right, our diazepam, our liver slows as we get older, a good rule of thumb for diazepam that I found in actually my diuretics quotes, is that the half-life is equal to someone's age in years, so you're 70 years old, the half-life of diazepam's going to be 70 hours, multiply that by five, divide it by 24, you start to see the half-life are using diazepam in older individuals. We know in folks that take benzodiazepines regularly more than six months, that 50 to 80% will experience withdrawal when they stop them, or if they stop them. And that many can develop this protracted phase in the last weeks, months, even years. The difference in the withdrawal symptoms, so on the left is the list, so this comes from Heather Ashton, kind of the psychiatric grandmother of benzodiazepine, tapering, hopefully most everyone here has heard of the Ashton Manual, you can get it, find it for free online. She had her own group of patients that she helped taper from benzodiazepines, and studied them and wrote up about them. So on the left is what you see common symptoms with anxiety, but can also see in benzodiazepine withdrawal, and on the right are symptoms that are gonna be very much more specific to benzodiazepine withdrawal. What I know from this list, is that a lot of the symptoms we actually see in other withdrawal states, right? This abnormal sensations like formication, things crawling on you, sensory hypersensitivity, depersonalization, hallucinations, muscle twitches, tinnitus. I would add akathisia, I guess that kind of even with some of the motor things, but that's been one of the most debilitating symptoms I've seen, especially in the more protracted phase. This, the British word for seizures, psychotic symptoms, confusion, delirium. Protracted can happen estimated, at least from Ashton, we don't have a lot of great research on this, but 10 to 15% of individuals may experience a more prolonged protracted withdrawal. For some, it gradually declines over time. Time is the greatest healer. A lot of people experience what they call windows and waves, kind of what we've seen with long COVID, with certain stressors, illnesses, other things, they find their symptoms recur, and then maybe wax and wane over time. So we need a lot more research for this. I had told you about the kind of the two different concepts that are related, complex persistent benzodiazepine dependence kind of being within the umbrella of benzodiazepine induced neurological dysfunction. Again, a whole nother talk in its own. So you can look up our slides from last year, we can send them to you. It's certainly something we like to talk about. Oops, oh no, okay, wrong button. And the symptoms that folks experience with protracted withdrawal, it can be an anxiety. One of the things they've described it as is like a sheer terror, especially if they go down too quickly. And that sheer terror can also create an increased likelihood of suicidal thoughts. Insomnia, depression, cognitive impairment, kind of that brain fog, ongoing perceptual symptoms, motor symptoms and GI symptoms. So in the benzoaffective community, they'll talk about benzo belly and just this kind of general unrest, bloating, discomfort, difficulty digesting GI symptoms. Again, all of this was observed by Heather Ashton, published in 2002, but she started her work way before that. So this was out there and we're still going all over. Soon it will change colors too. Okay. So here are just the definitions. So the idea that BIND is functionally limiting neurologic symptoms, physical, psychological that occur because of this neural adaptation with chronic use, as well as likely a neurotoxicity. And that these can occur while you're taking benzodiazepines, when you begin to taper and even after you're off of them. Complex persistent benzodiazepine dependence is a clinical concept to describe patients that experience significant psychological or functional decline during or after a benzodiazepine taper. So these are those patients that just really struggle during the taper, might really decompensate and kind of fall apart in the setting of trying to taper them off their benzodiazepine. point. Okay. Hello, everyone. My name is Daniela Rokossovic. So I run the outpatient clinic at Northwestern. I live in the outpatient world, out in the wild. Okay. And I was just wondering, this is a pretty full room by the show of hands. Have you ever had a patient that was prescribed oprazolam for more than 30 years? Okay. A lot of hands there. Okay. And then have you ever had a patient who has tried multiple SSRIs for management of anxiety, found them useless, a lot of side effects, hard to tolerate, but clonazepam is the only thing that really truly helps? Okay. Okay. Wonderful. I'm not alone. That is really reassuring. Okay. How about having a 74-year-old patient who needs to take opioids for management of chronic pain, cannot sleep due to said pain, but benzodiazepines are the only medication that provides restful sleep? Yes. We had the patient. Excellent. And then on top of that, you have senior patients that fell three times in the last six months, right? They refuse the idea that this can be somehow related to lorazepam that they're taking scheduled instead of PRN as it was prescribed because in the 15 years that they have been taking it, nobody told them that this was a problem. Okay. So we have all been there. Now my favorite is having a new patient, new intake that seeks a new psychiatrist because previous one has retired and primary care provider is not comfortable prescribing Xanax 2 milligrams TID. I mean, I'm not either, but okay. And then for all of us that live in the epic mystery land and have to deal with our in-baskets every morning when you have a patient that messages you seven times via MyChart about that clonazepam prescription that needs to be approved. This is my life this morning. Okay. So let's talk a little bit about how can we handle this in the outpatient setting? So the first thing that I like to do when I have someone who comes to me with potential issues related to benzodiazepine use, they ask this question, are we having an issue with chronic prescription benzodiazepine use or are we having a sedative, hypnotic, anxiolytic use disorder? Okay. This is a basic thing for a lot of us addiction psychiatrists, but you will be surprised how not basic that is for some of our colleagues. So I think it's important for us to educate. So in both conditions, we're going to have increased tolerance. We're going to have physiological dependence and withdrawal. But in the first group of our patients that have chronic prescription benzodiazepine use, they're going to use their prescriptions as prescribed, right? They're not going to be up to no shenanigans. There's not going to be early refills, no red flags. They do have attachment to medication. This medication is important because it immediately alleviates something unpleasant. It's normal to have attachment to something like that, right? So on the other hand, in a second group, we are going to have a lot of red flags and we know what the red flags are, right? We review PDMP and then surprise, surprise, there are multiple providers, multiple prescriptions, multiple states. And that is when your patient is not obtaining stuff over the dark web, right? And early refills, boundary pushing, probing, right? Asking for a specific benzodiazepine like Xanax is my least favorite in that setting. And then patients disclosing that they're using benzodiazepine from friends, family, or obtaining them from street. Okay, so this is introduction to deprescribing, right? We as physicians, we're used to prescribe, to treat, right? We love to help patients. We love to make them feel better. But we now have a lot of patients that have a bunch of medications that have interactions, right? We need to slim down the medication protocol and we have a unique challenge with benzodiazepines. So deprescribing is actually the planned and supervised process of dose reduction or stopping of medication that may be causing harm or simply no longer providing benefit, right? So the goal is to reduce medication burden and to improve quality of life and improve long-term consequences or not improve them, prevent them from happening, right? So who would be a candidate for deprescribing? I would say anyone who uses benzodiazepine for more than one month. Okay, have you ever had a patient who used benzodiazepine for less than one month and comes to you for deprescribing or anything? No, no, no. That's a rare occasion. Now age consideration is important adverse effect if somebody has a decreased function, right? Is there some life-threatening interactions with opiate medications, right? Tolerance, loss of efficacy, and finally patient's preference. We sometimes do have patients that recognize that this medication is somehow adversely affecting their quality of life, right? And benefits are plentiful. We're going to have improved psychomotor or cognitive function, reduced mortality, less motor vehicle accidents, less falls, decreased drug interactions. I mean this is how it looks on paper. It all makes sense, right? This is the recommendation and this is what we should do. Okay, let's see. So I want to make you think about some of the risks of deprescribing, okay? So we know that 15 to 44 percent of chronic patients with chronic benzodiazepine use will experience moderate to severe withdrawal if they stop their benzodiazepines abruptly, right? But Alexis mentioned this, 10 to 15 percent of patients experience a protracted syndrome that can last months to years, right? Some people never get rid of these symptoms, okay? So this is the data that we have from Ashton Manuel's supplement from 2011. I would love for someone to think about researching how can we get more information. What is the real percentage of patients that go through protracted benzoidrawal and how do we recognize them? Who is at risk? Like what is the risk gratification here? I love that we now have maybe emerging name for this syndrome which is BIND, benzodiazepine-induced neurological disorder, and sometimes with deprescribing some of our patients with small percentage have very, very serious side effects. They have akathisia, they experience suicidality, and this is a point when you have to tweak your treatment goals, right? So how do we set this cage? I'm curious how many of you really, really enjoy benzodiazepine tapers? So-so, right? Okay, there was Alexis, okay. So I'm not seeing anyone jumping up and down from joy. So this is something that's difficult. It's difficult for our patients, it's difficult for us, it's strenuous, it takes a lot of work, it takes a lot of emotional fortitude, right? It's hard work. So you will be more successful if you set the stage, right? I think strongly that deprescribing should be collaborative. It should be a process between me as a physician and my patient. And when we talk about providing informed consent, this is something that I do verbally, okay? I talk about risks and benefits. Why is it good to take less benzodiazepines and why it would be potentially bad to take this dose until the day you die, okay? And if deprescribing is declined or attempted, too difficult to monitor for adverse effects, right? And I like to-I do say that nagging is my superpower. So I like to readdress this issue at future appointments. It is not nagging, it's just revisiting that treatment plan, that little goal, okay? Have you thought about us, like have you closer maybe to thinking about us trying to decrease the dose a little bit? Some patients will not be able to taper completely. A more suitable goal would be reduction or maintenance of the current dose. I do think that because this is such a challenging process for all of us, the preparation is the key and the building rapport and trust with your patient is very important. And I think that starting this process from a place of compassion and empathy is very helpful, okay? This is very hard when you have 10, 15, 20 patients in your outpatient clinic and they are very complex because our patients with co-occurring disorders, right, they're always very simple. They're always very complicated, right? And there's always a lot of emotions in the office. I'd like to utilize shared decision making and to establish a plan that's flexible and gradual. I like to talk about lifestyle modifications. Hey, there are a lot of different things that we can do for you to feel better. It's not just one thing that's going to help improve your quality of life. It's diet, it's exercise, it's sleep hygiene, it's meditation, it's connections with other humanoids, okay, including myself, that these are things that are important. So with that said, I like to stabilize the dose of benzodiazepine and address the intra-dose withdrawal if it's present, okay? If it's a shorter half-life benzodiazepine, I like to dose maybe more frequently, space them evenly so there is not enough peaks and troughs in the blood levels. Switching abruptly is not recommended. Alternatively, if patients are still experiencing intra-dose withdrawal, substitute an equivalent dose of a longer half-life benzodiazepine. So you will see that there are interesting data about this in the literature. I'm curious about how you do it in your own clinics. I know it's my personal preference. And the goal of TAPR is to decrease withdrawal effects, manage rebound symptoms, and address recurrence of underlying target symptoms. And that's a lot of goals. So we are going to have higher dropout rates from these TAPRs if we are tapering patients off of a shorter-acting benzodiazepine, right, compared to long-acting. And this is this paper, Soyka from 2017, that said on the other hand, switching from a short half-life benzodiazepine to a longer half-life benzodiazepine is not necessarily associated with better outcomes. I have personally never really successfully tapered anyone who was on really high doses of Xanax successfully from Xanax. That was very challenging for patients, for me, so I personally prefer to switch to a my preference is clonazepam. I love clonazepam. I'm comfortable with that. Maybe you guys have maybe a different preference. I would love to hear what you do, but I think it's safer. I think it's more comfortable, and that's just how I do it. I think clinical evaluation and seeing your patient frequency is always going to be your guide. We're psychiatrists. We are in training. We're nurses, PAs, right? We talk to our patients. We assess them. We assess on every visit how to adjust our treatment plan. It's what we do. We're going to skip this for the sake of time because Alexis had this similar. Okay. Now, this is where the rubber meets the road. Do we have official guidelines for benzodiazepine tapers? Briefly, no, but with an important caveat, as we were preparing ourselves for this workshop and so on, ASAM, American Society of Addiction Medicine, actually made a very nice, very robust draft for clinical practice guidelines for benzodiazepine tapering, and this was an effort that was FDA-funded and very generously funded. The report, the draft is, as I said, more than 100 pages long, and it really involves collaboration with a lot of different specialties like family medicine, OB-GYN, internal medicine, addiction medicine, zero addiction psychiatrists on that list. I have a lot of thoughts and feelings about that. I am a proponent of a collaboration between addiction psychiatry and addiction medicine, strong collaboration, and also very proud that I'm an addiction psychiatrist. I think we have superpowers. With that said, I think one major shift that happened in this particular guideline is that there was a recognition that tapers need to slow down. Do not start tapers more than 5 to 25 percent from the starting dose, and then when you decide to go down, yes? Actually, there's a lot of them on that list. I've heard they're likely to be 10 percent or less. Good, excellent, because this draft was actually open for comments mid-June to mid-July. When I was reading this, I was thinking to myself, this is a lot, 5 to 25 percent for my patients that are taking Xanax for 30 years. This is not going to be good. We're not doing 25 percent. I'm glad that there was recognition that this is a pretty robust first dose, and then no more than 5 to 10 every two weeks, right? Let's skip further. As you have noticed, our clicker is having issues. Wonderful. I think just for the sake of time and the flow of this workshop, we're going to take all the questions at the end. That's a very good question. Please remind me. In the very process of taper, we can use a lot of different things that we have in our toolkit to address some of the symptoms that patients are experiencing. We can treat depression. We have some limited evidence, gabapentin, pregabalin, propranolol. Maybe we should not dabble too much with GABAergic agents, Chris. I know that you had a slide about that. For insomnia, we have a plethora of safe, boring, non-controlled substance options. I love medications that are boring. That medication that is not a controlled substance, that is safe, that makes my day. For anxiety, for insomnia, we have nice options. Obviously, thoughtfully, we are not going to give Benadryl for a senior patient. We're going to be mindful about that. Flumazenil as antagonist for rapid benzodiazepine reversal is a no-no. That is not something that should be done, and it's considered purely experimental. I am very old school in the sense that I don't think that you can do effective medication management without simultaneously doing therapy with your patient and actually connecting as a human being and developing rapport. I try to teach my residents and my fellow that. I think this is the way to go. Just how separating mental health and addiction is artificial, I think medication management and psychotherapy being on opposite sides of the spectrum do not make any sense for me. Yes, sometimes benzodiazepine taper reveals a lot of underlying non-anxiety. Anxiety is the tip of the iceberg. Trauma, poor distress tolerance, overwhelm, maybe patient being neurodivergent. There's a bunch of stuff that starts to show up, and we have to deal with it. We sometimes need to send our patients and say like, CBT would be a good fit for you, or DBT. We want to work on your coping skills. Sometimes we need to implement such strategies for help with sleep. Tapering principles, best chances for success. As much as you can, ask your patients to maybe make some decisions. How much are we going to taper? That's how I like to do it. Which dose are we going to tackle? Morning, afternoon, night. Giving patients that agency. I just got my five-minute warning, so we're just going to really skip through. Dose reduction of less than 5 to 10% of the total dose tends to be best tolerated. In case of too rapid dose reduction, we are going to have more severe withdrawal symptoms. Tapers require patients, patients, and patients, and they're really the ultimate delayed gratification for both the physician and the patient. You have to prepare yourself for the long game. I think sometimes three months, six months, 18 months, two years. You have to be realistic with your patients. I want you to be comfortable. I want you to improve your functioning, but we have to do this safely, especially in patients that are experiencing bind. I'm going to skip this. Briefly, two major strategies for taper. One is cut and hold. This is what we do in our patient clinic. We tell patients, split the tablet in half and then half and half. That's a quarter. Then we do that. A great advantage of that is that you are working with the preparations, with formulations that you have available. This advantage is that even that small decrease in the dose can be too large for your patients and can trigger some withdrawal symptoms. When you do that little decrease, you hold until withdrawal symptoms subside. The other technique that is awfully bullish is microtaper. With microtaper, we are talking about very small, very slight decreases in daily doses. They are consistent. Every day, you peel back a little. For example, the target for a month is 5% or 10%. They are tolerated generally better. You can go down on a subreddit hole and just read a lot of patients' experience with this type of stuff. But it's challenging. Well, this clicker is challenging. Very much so. Are these for patients who have a use disorder or not? No, so we can talk about that. I would say that this is for chronic prescription benzodiazepine use, right? You're telling me, I know. Okay, let's see this. So, with taper methods, you know, there are some things that are going to be available, like manufacturer's oral liquid, compounded prescriptions. Some people use precision scales and pulverize the medication. You know, all of these options are not approved. They're not controlled. They're better tolerated, but they're very much off-label. So I'm curious if any of you had any success with perhaps using microtapers in your outpatient settings. Okay, so we are going to quickly go back to this one. One thing that I want you to think about it, flexibility is the key, and patience is something that's a must. We're talking about delayed gratification for yourself, for your patient. You need to be ready for the long game, and really be ready to, you know, understand that for some patients, further decrease of the dose is not possible, or any decrease of the dose is not possible without causing bind. With that, I will stop, and I will give the stage to Chris. Here you go, Chris. So I'm gonna talk a little bit about that other population when people have a use disorder, and they are unable to successfully do a taperer as an outpatient. And I'll just say, in my career, I have never once been able to successfully complete a benzodiazepine taper in somebody who's had an underlying benzodiazepine use disorder. So what do we do in that situation? It's quite challenging, but what I would argue is that doing it in a monitored or residential setting is probably the best way to accomplish that. So I'm gonna borrow some of the literature from alcohol withdrawal, because I'll just start by saying that the literature we have for treating benzodiazepine withdrawal is very scant. So one of the things is that we've become habituated to just thinking that when somebody has, you know, alcohol dependence or benzodiazepine dependence, that using a benzodiazepine to treat the withdrawal is just our habit, and that's what we do. So why even consider doing something different? Well, there's a growing body of literature that shows that there are other alternatives other than benzodiazepines that have been successful, and there's plenty of pitfalls with using benzodiazepines. Like, for example, patients like their benzodiazepines, and they can increase, exaggerate their symptoms in order to, you know, elevate their CEWA score to get more benzodiazepines. Also, sometimes benzodiazepines themselves can prolong the period of withdrawal and can exacerbate the underlying delirium that happens from this. So, you know, another thing to be aware of is that benzodiazepines, you know, themselves, they need GABA to be present in order to be effective, whereas other things like phenobarbital actually don't need GABA to be present in order to have efficacy at the GABA receptor, and that makes them more effective, because people with these chronic alcohol and benzo use disorders are often GABA depleted. All right, so this is just a quick review of a Cochrane review that basically stated that the data revealed that studies were small, had large heterogeneity, had variable assessment outcomes, and most did not reach statistical significance. Ultimately, the only statistical significant finding was that benzodiazepines were more effective than placebo to prevent withdrawal seizures. However, they were not shown to be superior to anticonvulsants or other agents, and so this is just some justification that it's reasonable to start looking at other agents. So, quick review, benzodiazepines have a depressant effect, and they act at the GABA receptor, and GABA is the primary inhibitory neurotransmitter, and it's counterbalanced with glutamate, which is the primary excitatory neurotransmitter, and glutamate acts predominantly at the NMDA receptor, and so the balance between the two is key for kind of physiologic homeostasis, and there was an article that came out that estimated that 90% of all neurotransmission in the brain has GABA or glutamate present in it, and so when we think about the degree of attachment that people have to this, this really explains why, and so when this disruption happens, it can become problematic psychologically and physiologically, so what do we do in that case? So, normal physiology, GABA is counterbalanced with the NMDA and the glutaminergic receptor, but if somebody has supplemental GABA, like using alcohol or benzodiazepines, then obviously that gets weighted, and there's not enough NMDA activity in order to counterbalance that, that leads to sedation, but the body knows you need to be alert in order to escape from a tiger, so what does it do? It increases the glutaminergic activity, it increases the NMDA, and so if somebody stops using their benzodiazepine and their alcohol, you're left with elevated glutaminergic tone or NMDA activity, and this is the pathophysiologic cause of many of the complications with benzodiazepine or alcohol withdrawal syndromes. So, what do we do in this situation? Classically in the past, we've been habituated to just supplement the GABA side of things, and that's helpful in some circumstances, but why do we limit ourselves to that, right? Because we can also start to dampen the glutaminergic tone, and this makes much more sense to me, and so we, through what I'm gonna talk about, some of the mechanisms to dampen the glutaminergic tone, and look at it from both sides. So, what are some of the other alternatives that we can use, and then we're gonna talk a little bit about GABApentin, anti-epileptics, phenobarbital, carbamazepine, valproate, and also kind of a modified version of the Maldonado Protocol, which talks a lot about the use of alpha-2 agonists, and just as a quick review, if you haven't read this article, definitely read it. This is borrowing from alcohol literature, but it really elegantly describes how the pathophysiologic derangements associated with benzodiazepine or alcohol withdrawal syndromes would be better treated by dampening the glutaminergic tone, and the use of alpha-2 agonists in addition to anti-epileptics. And so, why alpha-2 agonists? So, in my practice, I don't consider these adjuncts. I use these in every single patient, and I use different alpha-2 agonists. So, Clonidine is the one we're most familiar with. If you're not familiar with it in patch form, if the insurance covers it, it's really a wonderful option. You just put on a patch, and after 24 hours, it reaches steady state, and then it's slow, even distribution over time. And so, when I'm treating patients as an inpatient, I actually will combine two patches with additional oral Clonidine on top of that. So, Clonidine is the most readily available, but don't ignore some of the other ones, like Guanfacine, which, as you guys know, is used classically to treat the hyperactivity associated with ADHD, and sometimes the side effects of stimulants. It's thought to be more specific for the alpha-2A receptor, and therefore, causes less sedation. So, that's an alternative to use. Dexmedetomidine, as the ER doc, I love this medication. It's great in drip form. It's now available in sublingual form. It's super expensive, and I haven't had the opportunity to use that yet. Lufexidine, of course, is a very expensive alpha-2 agonist used for opiate withdrawal, but if they happen to have it, it could be helpful. But don't ignore Tizanidine, which is a muscle relaxant, which has alpha-2 activity as well. So, just to keep these in mind. So, you know, thinking about the different antiepileptics. So, what's been studied most in both the literature for alcohol and benzodiazepine withdrawal is Depakote, or valproic acid, and carbamazepine. From my experience, patients don't tolerate those well, both in an inpatient and an outpatient setting. So, I'd like to focus on some of the other antiepileptics and some of the reasoning why I think that they're superior. And there is some literature for all of these, but again, there's not a lot. So, gabapentin, if you think about it, we all know it has activity at the GABA receptor. We're not 100% sure how it works, but it does have efficacy there. But what many of us might not know is it actually has NMDA antagonism properties, and it also has alpha-2 agonist properties. So, this really adds up like it's getting it from both sides, so it's a great medication for this. So, oxcarbazepine, which we know is trileptal. It's a structural analog of carbamazepine, which has been shown to be similarly effective with a much better side effect profile. This enhances the GABAergic activity, but it also has some NMDA antagonism properties. So, you're getting at it from both sides as well. And then, my favorite, which is phenobarbital. We'll talk more about it specifically, but it has GABAergic activity through different mechanisms, but it also has NMDA antagonism. And so, the theme here is you're getting at it from both sides. You're dampening the glutaminergic tone as well as supplementing GABA. So, this is just for your review if you want to geek out about the specific Maldonado protocol from his article. We don't have time to go through that. But, you know, the spirit of this is that why not do both? Let's not just supplement the GABA. Let's dampen the glutaminergic tone. And although I'm presenting this about monitoring in a residential setting, you can actually use these medications in an outpatient setting. For example, I oftentimes will supplement with a little bit of gabapentin or clonidine when people are going through an outpatient taper and they're having significant symptoms for the first few days of the decreased dose of their taper, I will supplement with alpha-2 agonists or one of these other anti-epileptics. And I found that to be very effective. But you don't want to continue it throughout the entire taper because then the body will just equilibrate through it. So, you just use it for a first few days after the dose reduction. So, we all like evidence. We need to know there's some evidence. This was an article that was published in JAMA in 2022 which just showed when Kaiser implemented benzodiazepine sparing protocols for alcohol withdrawal that it was shown to be very effective and it actually decreased their ICU use and decreased the hospital length of stay. So, it's nice to know that there's people out there that are doing this and that there is efficacy and a reason to continue to try this in our own worlds. But now we're gonna focus a little bit on phenobarbital which is my favorite medication for treating benzodiazepine withdrawal. And is it safe and effective to use in a residential rehab setting which I did and I was very successful and I found it to be safe. And is it effective? So, phenobarbital acts at the GABA receptor. It increases GABA activity. It's a positive allosteric modulator. But it actually, what it does is it increases the duration that the channel is open as opposed to benzodiazepine which just increases the frequency. So, that's helpful with efficacy. But the other thing to be aware of is that phenobarbital does not need GABA to be present to have efficacy. So, sometimes if somebody's in severe withdrawal, they're hospitalized, they're on super high doses of benzos, they're not working, well, that's because their GABA depleted. Whereas if you put them on phenobarbital, you could very quickly see a response. So, it's a very effective medication in my opinion. Also, as we talked about before, it has NMDA antagonism properties. So, it dampens the glutaminergic side. It has a very long half-life which can be a positive and it can be a negative. From my experience, what I found is that I treat people for a total of usually about three or four days and then it's in their system for a week afterwards. So, it's kind of like it's an auto taper and that could be beneficial. The reverse side of that is that if somebody like leaves against medical advice, they're gonna have phenobarbital in their system and if they go out and they use other sedative hypnotics or opioids, it can be a dangerous thing. So, just be aware of that. It's not reinforcing like benzodiazepine which is a positive and so that's pretty obvious to us. So, how do we go about doing this and what are the options if you wanna implement phenobarbital as a mechanism for tapering within a residential facility? It can be done in multiple different ways. It's been used as a solo agent in fixed dose protocols. It's been used as a solo agent with symptom-based protocols. You'll see protocols out there for a loading dose plus a CEWA Ativan protocol, a loading dose only which I've heard described as the Vanderbilt protocol where half-life is long enough that that's all you have to do is the loading dose and you can use it in combination with benzodiazepines and so all these different protocols can be a little bit overwhelming and how do you choose what to use? And we'll talk a little bit about that. And unfortunately, like we talked about before, there's not a huge amount of data to describe that this one way is specifically more superior to the others. So, I'm gonna highlight a little bit of the literature which I think is important to know, a couple articles. This was a great article that came out a few years ago and it shows like very simple ways to do between a four or six day protocol with fixed doses to treat. This is actually phenobarbital use for alcohol withdrawal and so I'll just keep this in here for your reference. It was a very simple protocol and if you look at the results, it's pretty impressive. The number of ICU stays was decreased, ICU days was decreased by two full days. The hospital stay was decreased by two and a half days in the phenobarbital arm of the study which was 60 in each arm. And if you look at the ventilator use, that's really impressive, right? So there were 14 patients in the CEWA benzodiazepine arm required intubation whereas only one in the phenobarbital protocol. And this type of data is consistent with what I've seen in my clinical practice as well. So it's nice to see that things are emerging even though these are smaller studies. So I'll just put these up. You can geek out about them later if you're curious. We don't have time to get into the specifics but this is another study that came out in 2019 which shows that there's similar efficacy with benzodiazepines as opposed to using phenobarbital when there was a shortage of benzodiazepines. And this was a systematic review that came out in 2017 which showed that use of oral and IV phenobarbital as monotherapy for alcohol withdrawal syndrome has been studied in the heterogeneous patient samples in numerous studies with variable study designs and comparable groups. And in summary, it appears that phenobarbital by either route is as effective as benzodiazepines for the management of alcohol withdrawal syndrome. So just we have enough data to support that we can implement this if we have a curiosity about it. And what I will add to that is that having worked through multiple different institutions with helping them transition to phenobarbital and having discussed this with many people across the country, I've never come across somebody who's made the transition to phenobarbital that would ever go back to using benzodiazepines. So it's really a remarkable medication. This is just a great study that showed that 85 patients in an ICU sample comparing benzodiazepines to phenobarbital and 48%, 50% basically in the benzodiazepine side ended up having withdrawal delirium whereas zero in the phenobarbital side had withdrawal delirium. It's simply a more effective medication. So we'll skip past that and you can geek out about these later. So is it possible to do it in a residential setting? So I worked in a residential rehab which had minimal nursing staff. It was only available for three to four hours per day. There was no nursing staff at night and we were able to implement a protocol where we used phenobarbital orally and I was very nervous about doing this from the beginning because I hadn't had much experience doing it and so we hear a lot of kind of concerning stories about the sedative properties of phenobarbital but what I will tell you, it is definitely possible and even with minimal nursing involvement. So what I did is I start off with the spirit and what I end up with is you have a loading dose which you give and that's between two and 10 milligrams per kilogram and I usually end up at around the five milligram loading dose but the key about the loading dose is that you give it, in my opinion, I think a lot of people are getting into the habit of giving it at a single interval but I divide it into like Q one hour times three because even given orally, phenobarbital will reach its peak serum level at one hour so I give a third of the dose at time one, I wait an hour, I evaluate them, I give the second dose at an hour, I wait an hour and as long as they're not overstated, I'll give the third dose so I divide it over three hours so it's kind of a little bit resource heavy at the beginning but it pays off significantly later and then I transition to a fixed dose protocol either between 32 to 64 milligrams three times a day and the reason those doses seem kind of weird is just this is the way the oral pills come in, they come in like 64 milligram doses and also I combine a clonidine patch so as soon as they start to have any withdrawal syndromes, I put on a clonidine patch and in addition to ordering 0.1 milligrams to use three times a day and then after 24 hours, I will reevaluate their blood pressure, I'll put on a second clonidine patch and continue to have the oral clonidine available. From my experience, clonidine is significantly underdosed. If people were not in the middle of withdrawal syndrome, it certainly could affect their pressure but I have never seen it affect the pressure of somebody who's actually in active withdrawal and it makes sense because you're really just treating the elevated glutaminergic tone. All right, so a couple of pearls about using phenobarbital. Always use the ideal body weight because it doesn't distribute well into the tissues so you could end up with doses that are too high and cause over sedation if you use, especially in people who are obese. And again, when dosing with the loading dose, do it divided over Q1 hour times three because that can eliminate over sedation as well. One of the problems that we often happen is people come in and they're going through withdrawal syndromes from more than one drug and oftentimes it's opiates as well so how do you manage combining buprenorphine with the use of phenobarbital? And so what I did in my practice is I did the initial loading doses on phenobarbital and the clonidine initially and then 24 hours later I would start the buprenorphine induction slowly after that. I myself have not done this in combination with methadone but I have colleagues who are doing that as well. I'd be a little bit more, I would not do that in an outpatient setting in my opinion. I would only do that in a monitored setting with 24 hour nursing, that's just my opinion. The other key, frequent re-evaluations and have the capacity to make adjustments over time. If you commit to evaluating the patient multiple times in the first 24 hours, you make the adjustments and the rest is gonna be super smooth. And just to mention, I was very apprehensive when I started, I was nervous and I started with really, really low doses but after you do it for a couple of months you'll realize these patients will all tolerate it if they're already showing withdrawal and you'll be more comfortable with the higher doses. So contraindications, porphyria, severe respiratory insufficiency, severe hepatic impairment pregnancy. Also be aware phenobarbital is a P450 inducer so it can actually lower the serum levels of buprenorphine and whatnot. Side effects like dizziness, ataxia, fogginess and paradoxical hyperactivity can happen as well. So I'll end with this slide and that's just to say that people are very afraid with the idea of starting phenobarbital and it's something where if you wanna start this in your institution you really have to have a champion, somebody who really is passionate about it and wants to do it and has had experience or borrow the experience of some of us who've done it before, we're always happy to help. And getting the buy-in from the nurses is key because the nursing staff is often very afraid of this medication just as I was initially when I started. But it's well worth it, I've made the transition myself and I've worked with multiple other institutions and everyone who's made the transition has not regretted it and would never go back. So I will pass this off to Dr. Balasanova. A lot shorter, okay. So good afternoon, that was an excellent segue into what I will be talking about because I was the champion at my institution to begin our inpatient phenobarbital protocol. So just to set the stage here, The University of Nebraska Medical Center is where I'm based. Nebraska Medicine is the name of our clinical partner. It's our hospital, 700 bed. It's the largest one that we have in our state. And it is co-located with the medical school. So everything is all on one campus. So prior to 2021, symptom-triggered CWOA, either with oral or IV lorazepam, was the only order set available for management of either alcohol or benzodiazepine withdrawal. Now earlier somebody asked about using some of these protocols for benzodiazepine use disorder versus dependence. I will say in my experience, the outpatient tapers tend to work much better for those with simple physiological dependence after chronic benzodiazepine What I am going to describe is really for those severe benzodiazepine use disorder patients, patients who are drinking alcohol in conjunction with using benzodiazepines, and really those severe cases that require medical monitoring in the general medical hospital. So prior to 2021, we collaborated, my consult service, the Addiction Psychiatry Consult Service, with Critical Care Medicine at our hospital. And we developed a scheduled phenobarbital protocol. We reviewed the literature. We reviewed many of the protocols Dr. Blazes just went over, and really created one that we thought would be appropriate for our institution. So we implemented it in June of 2021. And initially, because of some of those concerns of nursing, we actually restricted it to intensive and progressive care levels of care, meaning that somebody would have to start in the ICU or step down in order to initiate this protocol. And the reason for that was those are the only places in our institution that allow for Q30-minute nursing checks because otherwise the ratios do not allow for that on the general medical floors. So it was 8 scheduled doses plus PRN dose available. And this is what it looks like. It is a 4-day protocol. So you begin your loading day in the ICU. And we have 10 mg per kg of ideal body weight, which we separate out by 4 mg per kg, followed by 3 mg per kg, followed by another 3 mg per kg. And each of those is 3 hours apart. So you get your first dose, 3 hours later you get your next dose, 3 hours after that you get your next dose. Thereafter, we have oral doses of 64.8, again because that's how the tablets come, BID, subsequently 32.4 BID, and 32.4 ones daily. Oftentimes patients are discharged on that day. So they'll receive their dose and their discharge later that day. Oh, before I actually mention that, there are also PRNs available. So this is a scheduled taper. However, at all times there is the availability of either an IM or oral PRN of 65 mg of phenobarbital if two of the following conditions are met. And that is a heart rate over 95, systemic blood pressure over 165, diastolic over 95, if somebody is visibly diaphoretic or tremulous as visualized from outside the room. As we know, some of our patients only become tremulous when we walk in. So our inclusion and exclusion criteria, so we use the prediction of alcohol withdrawal severity scale as we initially created this for alcohol withdrawal. And we had that scale performed. And if you had a 4 or higher, or you had a history of prior seizures, or a history of utilizing the taper, I will say many times for the patients for whom we use this with benzodiazepines, their presenting symptom is a seizure. They get admitted after having had a seizure. And then we subsequently initiate this protocol. Sometimes patients are initiated on CWOA before we transition to this. And if they have consistently high CWOA scores, then we transition to this protocol. Exclusion criteria, fulminant liver failure, renal impairment, again the porphyria as previously mentioned, acute neurological problems, i.e. having a stroke. And of course we monitor for risks of over sedation, but we do this on patients on methadone, on patients on other opioids just with very close clinical monitoring. So this was the instruction that was given to the nursing staff and the specific nursing orders. So after each dose of phenobarbital on day one, nursing should check vital signs, cue 30 minutes times 2. So for the first hour, the nurses were supposed to check the vital signs. We were concerned about the possibility of over sedation as well as vital sign abnormalities. Specifically we instructed that CWOA should not be utilized. And this has been a problem at my institution as that was what was historically used and some people don't recognize even now that CWOA has nothing to do with the scheduled protocol and is completely not related to what we're doing here. So as you'll see a little bit later on, people are still sometimes checking CWOA despite it not being in any way necessary. So again, initially the protocol had to be initiated in progressive or ICU level of care. And then once the patient was on the taper phase, then they could be transferred to a regular medical floor. So what we often ended up seeing was patients would get admitted to the ICU just for that one day for the monitoring and then subsequently would move down to the floor. So we did an initial safety evaluation to see, is this really necessary? Do we really need to have them go to the ICU and use up that very precious resource? So we looked at a retrospective chart review from when we first started the protocol. Recall it was in June of 21. And we looked at July to October of that year, looked at only adults. So in the state of Nebraska, the age of majority is 19, not 18 as everywhere else in the world. And so we looked at adults 19 years and older and those that were there for alcohol withdrawal specifically. These were our patient characteristics, predominantly men, 84%, middle-aged men. And looking at their blood alcohol levels which were widely variable. The pause, whether or not the CWOA was baseline performed, whether the patient, what team they were on, critical care surgery versus critical care medicine, whether they started in progressive or critical care, and then the average length of stay in the ICU. And as you can see it was 1.3. So very little time actually spent in the ICU. The safety outcomes that we were most concerned about, and our N was 50 in this initial safety analysis, was the need for respiratory support. We did not have one patient that required intubation. We had 10 that needed nasal cannula and that was it. We did not really have much hypotension either, nor did we have any zero over sedation using the RAS. So we were really excited. We thought this was great. Our outcomes seemed to show that this is safe and perhaps we no longer need to have this restriction to the ICU. And so it was removed. We went through all the hospital processes since we did not have respiratory depression, hypotension, et cetera, and a very short ICU level of care stay. So we thought it was safe. We removed the restriction. And so instead of the Q30 minute vital sign checks, we reduced it to Q1 hour vital sign checks. So times 1, so 1 hour after the initial dose and the loading day. And then now we could do it on the medical floor, which widely expanded our ability to utilize this protocol, which now as you'll later see is much more popular than using CY. So then we changed the nursing-specific orders accordingly to check vitals 1 hour after each loading dose on day 1. And again, the same with CY should not be checked. You should contact a physician if there's, you know, aberrancies in the vital signs. So we evaluated the effectiveness of this specific protocol. And again, this is such a nice segue from Dr. Blazes since we evaluated a lot of the same parameters that some of these other studies evaluated. So we looked at phenobarbital versus benzodiazepines for treatment of severe alcohol withdrawal, which we defined using the PAWS. And again, while our research specifically looked at alcohol withdrawal, this is the protocol we use for benzodiazepine withdrawal. So countless times we have had patients with benzodiazepine withdrawal whom we have put on this protocol with great success. So our objective was to see really what these main outcomes were, right, the length of hospital stay, the safety, whether or not they needed adjunct dexmedetomidine or whatnot. It was retrospective at our academic medical center. It was all of the patients that were admitted to either the ICU or progressive care who received either benzodiazepines or phenobarbital from July 2018 to July 2022. Of course, this protocol began in 21. So all of the dates preceding really were the controls for the benzodiazepines. So this is just baseline characteristics of our patient population. Again, really predominantly men, 80% and 76%. Also this middle-aged category, the sort of 30 to 50 age group, which is what we saw also in our initial safety analysis. We did look at urine drug screens leaving before medically advised, whether or not they were baseline on an antipsychotic medication so we could compare whether or not they needed to initiate an antipsychotic medication later, and so on. So measurements and main results. So we found that our protocol was actually greatly successful in a variety of ways. So the patients who received phenobarbital versus benzodiazepines had a significantly shorter length of hospital stay compared to those who received benzodiazepines. Those who received phenobarbital also had a shorter length of ICU stay and a shorter time in the progressive care unit. Lower incidence of dexmedetomidine rescue and lower incidence of antipsychotic administration or initiation for agitation. Also one patient in the phenobarbital group compared to 6 patients in the benzo group needed mechanical ventilation. Recall in the initial safety analysis nobody needed mechanical ventilation. In this follow-up study one person did for phenobarbital and then 6 for benzodiazepines. However the duration of ventilation was similar for both groups. So primary and secondary outcomes. When I saw the slide like this that Dr. Blazes presented I giggled to myself because we looked at literally the exact same outcomes for our particular study. So looking at mechanical ventilation, benzodiazepine administration, the amount of phenobarbital administered, whether or not dexmedetomidine was needed and then which antipsychotics were needed, if any, as well as in-hospital mortality of which there were none in the phenobarbital group and there were two in the benzodiazepine group. So our conclusions based on outpatient population in this protocol that we initiated was that scheduled phenobarbital was associated with a decrease in hospital stay, decrease in ICU stay, decrease in initiation of adjunct to pharmacotherapy and decreased incidence of mechanical ventilation as compared to benzodiazepines for severe alcohol withdrawal. So then really is a fixed-dose protocol associated with a decrease? And the answer is yes. Those were our main findings. We used this retrospective cohort study, about 200 patients in all I believe and we really thought that at least for our patient population phenobarbital really did offer an advantage over benzodiazepines. So since we initiated this protocol, the changes in hospital utilization of the protocol have been really striking. And as I said, it's become very popular. This is now much more popular than CIWA, which is used a minority of the time, which as we all know is very problematic for patients with benzodiazepine use disorder because they know exactly what to say to get the benzodiazepines they need as one of the symptoms of their benzodiazepine use disorder. So we will sometimes have these patients complain when they are put on phenobarbital and that, oh, it's not working and yet they're vital signs and everything is totally normal with a normal range. It absolutely is working, but it does not offer that same euphoria that immediate benzodiazepines do. And it does have this longer onset, longer mechanism of action and it really is a much safer medication in that regard, both for the psychological aspects as well as the physiological aspects. So on our Addiction Psychiatry Consultation Liaison Service, we teach about this protocol so that our students, our residents, our physician assistant students all learn how it is used. We define what that risk populations are. We provide them with this handout with some of the graphics that I previously showed you as well. And that we really make teaching about phenobarbital an essential component of rotating on our service, which is part of the third year psychiatry clerkship, because this is such an important medication that so many people are either not aware of or afraid of, as previously mentioned. And so really alleviating those worries, normalizing its use, I have found to be very effective for those same medical students becoming residents and then later using that protocol on their patients. And that is all I have. So I will pass it back off to Dr. Ritvo for some cases. »» Well, also, I know we're always kind of balancing up against time. So we'll also look at questions. I did actually want to point out, if you're like me, I had trouble initially finding where the slides are this time. Has everyone else found them? So they're not in each workshop. But actually, if you go into the table in the app, the like menu, it's under info, which is an obvious place. And then, yeah. And then all the workshop slides are there. That includes all of our cases. And most of our cases we kind of answered what happened. We'd be happy to discuss them. But in the interest of time, there are microphones if folks want to start stepping up if they have questions. They're trying to record this. We'll start with some questions and we can always revert to the cases. »» Thank you. I was just curious about the feasibility of phenobarbital in very typical, very simple, office-based outpatient practice. I know that we've been talking about PO doses, so I was just curious about that. »» I guess I'd love a show of hands. Is anyone here doing outpatient phenobarbital? So I know of, the only thing I know of is I know at the VRVA, I don't know about some of the others, they do some outpatient phenobarb for alcohol use disorder. I don't know if they're doing it for more of a benzo use disorder. But people have to come in multiple days per week. So I don't know if you've seen it at all. »» I know people who are doing it. I do not do it myself. »» Yeah. And this is coming, I will say, from someone that's trained as both an emergency medicine physician and a psychiatrist. So I have yet to hear a lot of people that feel like it has a safe enough profile to be using an outpatient. It's probably worth studying if people can think of a supported environment to do it in. Next. »» How comfortable are you guys with alcoholic steatosis? Not necessarily cirrhosis, but you're kind of concerned they might be edging that direction. Do you guys just go ahead and use phenobarb anyways, even though they've got that in their mind? »» I'm seeing head nods from both of Dr. Balsanova. »» I know. I wish I could. This is taped here so I can't. I don't know if you all want to come. »» Yeah. With steatosis we don't even blink an eye. So absolutely. I mean even sometimes with compensated cirrhosis we'll also use it. »» And the only thing I would say is in a residential rehab setting I would be less inclined. So in a monitored inpatient hospital stay, absolutely. »» So 24-hour nursing at least. »» Thank you. I work in an intermediate setting of residential detox and rehab. And we don't have access to labs ordinarily upon entry. So I have a question about what labs you would feel uncomfortable using phenobarbital without? »» So if someone had significant comorbidities, I would probably, if possible, I would like to get lab work back before I start the phenobarbital. So typically I order a complete metabolic panel, synthetic function, and that's usually kind of the predominance of what I check. And as long as the synthetic function is for the most part normal or just very mildly elevated, and the T-billy is, if anything, just mildly elevated, I'll proceed. But also just if they don't pass the look test. And this is where the emergency medicine physician comes in. If something is off, they just don't look right, then I will be apprehensive in the type of setting that we're talking about. »» I think what I heard is if there are no known comorbidities or no known relevant comorbidities and the patient doesn't look sick, you wouldn't feel the need for labs. »» Correct. »» Thank you. That's very helpful. »» I also wanted to mention I was puzzled by the phenobarb IM since absorption is less complete unless there's gastric bypass or another reason to impair intestinal absorption. And eventually I figured out you want to get this stuff on board fast and that's what might have been why you went to intramuscular use. And then another comment, it doesn't take very much phenobarbital to rev up CYP3A4 and drop your buprenorphine or methadone levels precipitously. And I've been there. No fun. »» Yeah, that's an important point to remember. It is a very real thing that is clinically relevant. »» First of all, thank you again for doing this presentation for a very important clinical topic but often overlooked in conferences. So I'm Shubh Bharman, I'm an addiction psychiatrist based in Milwaukee, Wisconsin. I have a couple of points. One of them is that I have used a modified Maldonado protocol in my previous institution using primarily anticonvulsants like gabapentin, the valproic acid. And we've had similar results to what you described with the phenobarb. So that's also very much an option for benzodiazepines and alcohol. And we've shown that less ICU stays. I was curious about whether you were also tracking the outcomes post-hospitalizations, like engagement of patients in actual treatment for alcohol use disorder. That was one point I had about this, that anticonvulsants, the other kind, may also be helpful. The other one is how do you approach the more novel designer benzodiazepines when you're factoring in? Because, you know, all this, we know this is for things that we know about, has been there for decades. What about the etizolams of the world? Because they exist. And some of the labs out there are starting to test for it. 99% of labs don't, but it's a real problem in the clinical sphere. So I'm curious about a couple of things. Yeah, thank you so much for mentioning that. As you were talking, I literally thought to myself etizolam, because we've had several people, etizolam, bromazolam, even phenobut. I mean, it runs the gamut. And we use phenobarbital for all of them. And we've seen success for all, particularly phenobut, actually. We've seen great success for that. We had several case reports back several years ago when it was first becoming a thing on that. So that is something that we use. Oh, they told us. The patient told us. They just said, this is what I've been using, and they told us the dosage. Because that's the only way, honestly. Yeah, pretty much. Yeah. One thing I'll mention about that is that most of the designer benzos are the triazolyl ring benzodiazepines, which are similar to alprazolam, which kind of has a different, it's much more challenging to treat. So alprazolam, I think of it almost like a different molecule. It's been shown to have more complications in the withdrawal phase. It's shown to be less likely to respond to classic treatments like clonazepam and things like that. So there's a huge variability with the designer benzos, but most of them are kind of like in the class of the triazolyl ring. So I think of them similar to alprazolam. Hi. Go ahead. Jim Halicus. I'm old enough that I was in the business doing phenobarb detox before the benzos came along. And then we flirted with the benzos and ultimately have sort of gone back to it. So what's old is new again. Very, very safe. And one of the advantages is that patients don't get fond of it the way they get fond of the benzos. Now, my question is the question I asked earlier, which is what is the rationale for detoxing or reducing the dose of a patient who Why am I perturbing? OK, so can you give me, in this hypothetical patient, maybe the age range? Let's say 50 to 60. 50 to 60. 50 to 70. 50 to 70. OK, so that's, that's, OK. A patient who's been compliant and now comes to you because the last patient, the last doctor. Good question. So I think this question stems from something that all good physicians do, and that is, if it ain't broken, don't fix it, right? Because if you rock the boat too much, you're going to create more trouble. Well, I think the situation is a little bit more complex when it comes to benzodiazepines, because what we are learning is that long-term use of benzodiazepines actually causes functional brain injury in a way. So what I would dare to bother this pseudo-balance is actually having in mind not the immediate condition that a patient is in, but also the future of the patient. That's burying the headline. That's what you do with, you tell the patient, the long-term data of high-dose benzos in Europe is that it seems to accelerate or bring forward a dementia. So maybe we ought to think about reducing the dose. Yeah, that's a very good point. But also, I think a lot about falls, because one hip fracture and your mortality risk goes up exponentially. So decreasing this risk is very important. Does this answer your question? I would say that the vast majority of people I get referred are folks that have now hit 65, 70. They've been on it for two, three decades. I have two former lawyers that were doing great on pretty high doses. And now, one definitely has dementia that has predisposing risks for it. The other doesn't, but is very concerned. And now we're trying to get them off three milligrams of Xanax that they've been. And they were stable and functioning. But it becomes a challenge. That's the rationale for moving in that direction. Yeah, so I think it's that. I mean, usually I just set the stage. And I say, ultimately, this is going to be a decision we make together and that you lead. But I want to make sure that you can tell me what you understand to be the benefits and the risks of us continuing as things are and if that's to change. Like, you're noticing changes in your memory, your cognition, your steadiness, how we're going to proceed. And then it doesn't. I think we get really stuck in thinking all or nothing. But just even, we start to try to get you on less. And look at all the other polypharmacy, right? Because there's other things that put them at great risk. And sometimes we don't need to go first for the benzodiazepine, but we can go for the other meds that are also putting them at risk. The other part of helping reduce the dose is by giving them a smaller dose, more pills. Because that's easier because it's hard to remember. First, you ask how they're taking it. Don't tell them, but ask them. Tell me how you're taking this. If they have a loved one and a support that can help them with making a pill box, that's been extremely helpful. I really struggle with the ones that are starting, individuals starting to have cognitive impairment, who now you're trying to institute a taper. And it gets real tricky. You have to get creative. One last thing on that is that in the paper that I wrote, the complex persistent benzodiazepine dependence, I talk about this exact issue. And I think everybody up here would agree that there are circumstances where the consequences of taking somebody off the benzodiazepine far outweigh the consequences of persistent benzodiazepine use. And as long as you address that in a very complete, informed consent within the chart, talking to the patient and their family, sometimes the most appropriate medical thing to do is to continue the benzodiazepine. And I think everybody up here would agree with that. I mentioned DALMANE. I had a patient abruptly stop. And with multiple psychiatric hospitalizations following that, looking psychotic. They never tried reinstituting. I finally convinced, before I'd even seen them, the ED to restart them on some diazepam. And I said, we have to give it time to build up. And they stabilized. And this was after months. They had two or three psychiatric hospitalizations. They were looking psychotic. They diagnosed them as having pseudobulbar affect, even though they didn't think they had MS. They were tried on a ton of antipsychotics. And at the end of the day, I was like, I'd rather them on some diazepam than on medications that have other risks and aren't helping them. And they were about to be institutionalized, so. I'm wondering if, at what point would you feel comfortable moving to an outpatient phenobarb detox? Do you just feel comfortable maybe after 24 hours or you wanna keep on going? How comfortable moving them to like a lower level of? If you do monitoring for a day, would you then feel comfortable moving them to an outpatient? And continuing. Oh yeah, I mean, I think, well, not with continuing phenobarb as an outpatient, I probably wouldn't. But from my experience, once the loading dose is on board, if it's a good loading dose, in some circumstances, that's really all they need. And sometimes the supplemental 32 or 64 milligram doses, they're more like treating us than actually treating the patient. From my experience, you get a good loading dose, and that's what kind of the Vanderbilt protocol is. The only thing I would be of concern is that if you send them out to an outpatient setting, are they going to be reliable and not use other sedative, hypnotics or alcohol or opioids, because that would be a concerning thing. And so if you trust them, it's probably reasonable. But I probably wouldn't do persistent ongoing doses. I will make a plug though, any of you that are looking at this, if you find ways to study and follow up with these patients afterwards, those are the other outcomes we really need, especially with benzodiazepines. As we're saying, we're not recommending for patients that are on chronic prescription use, taking it as prescribed, but we need more data to see who does return to benzodiazepine use, what does it look like afterwards? Hello, I'm Natalie, I'm a medical student. I'm curious for patients who are really accustomed to benzodiazepine-based withdrawal protocols to see what protocols, who have significant reservations about doing a phenobarbital protocol instead, what conversation you have with them about to build their buy-in for this different protocol? I've heard a lot of reservation pushback. Yeah, yes, and certainly, so my experience is more so on the side of those with use disorders that express reservations. And I explained to them that this is a much more potent medication, and when they're like, it's not working, I explain that it is, in fact, working, as their vital signs are totally normal, and they appear to be fine, and yet they're reporting a lot of internal distress. And so some patients that go to other hospital systems in Omaha, where I am, and they now know that we use this protocol, and they have stopped coming to our hospital system. So patients have caught wind of the fact that they are not going to be able to obtain benzodiazepines for this reason when they're hospitalized at our institution. Just to add to that, like in the rehab that I worked at, I stopped using benzos at all, because if one person in the milieu was on benzos, then everybody would wanna be on benzos. So if they came in, they were getting phenobarbital, and that's it. I have so many questions, so I'm gonna try not to do that. But you have a patient that comes in, that has opioid dependence, or Suboxone, and they're abusing benzos, and even from the black market, and then we also have alcohol, and then also throwing in some meth. So would you use phenobarbital in that setting, because it's gonna affect the buprenorphine? Or how much does it affect the buprenorphine, lower the? Yeah, I will say, we have a lot of patients with polysubstance use, meth being predominantly the illicit substance of choice, plus alcohol, plus or minus random straight pills, and we totally use phenobarbital, if they meet the criteria with the predictor of alcohol withdrawal severity scale. So we do use this validated instrument to assess for the severity of alcohol withdrawal, and then no matter what else is going on, if they meet that criteria, then we do use the phenobarbital. Do you change your dosing of the buprenorphine? We don't. Okay, so I was wondering. That being said, the caveat is that we don't have very many patients on buprenorphine, as opioid use disorder is not that common, believe it or not, in Nebraska. And I'll say that this is a really challenging situation in kind of freestanding residential rehab, and there are situations where the withdrawal syndrome is too complicated that it can't be done in a place that doesn't have enough nursing staff. So I have had to send patients out in that circumstance to a higher level of care, because it is a very real problem, and I've been an expert witness on cases where people have died in those circumstances. So we have to be careful. I think we'll finish up here. I don't know if we got. Can I just ask one quick question? Of course, I'm always dealing with the anxiety, and only benzos will help, and this is an inpatient 30-day setting. How effective, I mean, there's really nothing that's gonna compare to a benzo, as we know, for the patients. But in that case, and the antidepressants never work. Buspirone, gabapentin, clonidine are my other options. Is there something else I'm missing that maybe we could do for anxiety? Oh, well, I think thinking about, I mean, Chris had mentioned kind of this modified Maldonado. One of the cases I presented is actually one that I was, if his alcohol use had been under control, and we had him on monitored antabuse, and his parents monitoring his meds, I told him I would attempt an outpatient taper of his long-term clonazepam. He couldn't safely do that, so he went inpatient, did a phenobarb taper for alcohol and his benzodiazepines, and was very uncomfortable. Probably had some bind. He'd been on two milligrams of clonazepam for a really long time before his alcohol use. So I used some clonidine and oxcarbazepine. This was more in kind of a post-acute withdrawal. Unfortunately, he actually found it so helpful, he got hyponatremic on the oxcarb just at 300 BID, and still wanted to stay on it, and after the second hospitalization, despite getting salt and stuff, I was like, it's not safe. I now have him on some Depakote, and clonidine is overall doing pretty well. So I think those, the alpha agonist, and potentially another anti-epileptic are actually worth trying in those folks that have really had a chronic exposure to benzodiazepines. I don't know if you agree. Yeah. Hi, Mary and Cole. I know you hinted at that, that we need more studies on that, but do you have some knowledge about what happens to those people who did, like with benzodiazepine use disorder, who have been detoxed with phenobarb longer term with those protracted withdrawal symptoms? How well have you seen that the phenobarb was capturing some of that? Yeah, I mean, that's definitely a challenge, right? So I'm co-director of a consultation service in the General Medical Hospital, so we don't have a lot of data on the follow-up of these patients whom, in many cases, they don't have insurance, so they have to be admitted to the medical hospital because of Emtala for stabilization, and yet they cannot follow up in our outpatient clinic because our institution will not take uninsured patients outpatient. So it's really difficult to know, but that data would be very helpful, right, and useful for informing future treatment. I will say, I have an NF2, the one I just mentioned. I have another patient who was using Etizolam, and they did very well. We had them on gabapentin for quite a while and eventually tapered them off. I've now seen them over like three years, so a working professional who has been able to return to work and at one point had a recurrence of depression, so we now have them on, I think, mirtazapine for their depression, but they've done very well over three or four years. So it is highly variable who seems to have this difficulty. The individual I had now on Depakote and Clondine, and I think, actually, I have them on some methocarbamol, not ideal, but if it's that or drinking alcohol heavily, I'll take them being on a mix of meds, which is a different approach I take than someone who's been on a long-term prescription benzo, taking it as prescribed. Having symptoms, I'm gonna proceed more cautiously with adding more meds, but everything, as we know, is a risk, kind of benefit. Yeah, thank you. Thank you.

benzodiazepine

tapering

withdrawal management

pharmacology

dependency

tolerance

patient-centered approach

clonazepam

phenobarbital

GABA

glutaminergic tone

detox protocols

inpatient treatment