Hello, and welcome to the Comprehensive Review of Alcohol Use Disorders part of the AOAM Review Course. My name is Dr. Steve Wyatt, and I am an addiction psychiatrist. I am the director of the Addiction Psychiatry Fellowship at the Mountain Area Health Education Center in Asheville, North Carolina. I'm a board-certified addiction psychiatrist, and I am an adjunct professor of psychiatry at the University of North Carolina. I completed a National Institute of Drug Abuse Clinical Research Fellowship in addiction psychiatry at the Yale School of Medicine. I am a past president of the American Osteopathic Academy of Medicine, and the current chair of the North Carolina Psychiatric Association Addiction Psychiatry Committee, and chair of the Coalition of Physician Education in Substance Use Disorders, which is a national organization focused on the improvement of addiction medicine education and medical school education. I don't have any disclosures to give you today. So the objectives of this presentation is to first provide some basic understanding of the epidemiology of alcohol use disorders to help you recognize the individual susceptibility of this disease and how understanding this can lead to individualized prevention. I hope after the completion of the program that you'll have a better understanding of the importance of screening and some of how to screen for alcohol use disorders, understand the biologic markers of this disease, and then lastly understand the medications that are helpful in the treatment of alcohol use disorders from withdrawal recommendations to post-abstinence care. So alcohol is highly prevalent in our society and actually around the world. About 84% of people 18 years and older have reported having drank alcohol at some point in their lives, and over 67% report having drank in the last year. About 53% have drank in the last month, and over 23% of those folks have drank at an excessive amount that is above the recommended amount of alcohol that should be drunk at any one time. And that's really the potential for leading to more acute problems. And then about 6.3% of individuals over 18 years old have reported heavy drinking. And we'll go through what that means a little later in the presentation. But various studies have suggested that during the pandemic, about 25% of people drank more than usual, and this was often to cope with stress of the pandemic and the changes in our lives and the lack of the normal communication and interaction that we were having with people prior to that. And interestingly, this was reported most prevalently in the increase in hard liquor sales or spirits, and that really accounted for a significant amount of the increase. So that was also very interesting, that it was not necessarily beer and wine. It was really hard liquor sales. So alcohol has a huge impact on the health of our nation and again around the world. About 178 individuals died from excessive alcohol use in 2023. That meant about 117,000 people died from chronic illnesses associated with the use of alcohol. And about 61%, excuse me, 61,000 died from acute injuries associated with use of alcohol. These numbers have made alcohol the third leading preventable cause of death in our country, with the first being tobacco products, the second being diet and exercise. So globally, alcohol misuse is the seventh leading risk factor for premature death and disability. And alcohol misuse costs the country around $2.5 billion a year. That is the misuse of alcohol and all the various problems that come from alcohol use problems. In the United States, the National Survey on Drug Use and Health estimated about 14.5 million people had an alcohol use disorder in 2017. And more than 10% of US children live with a parent with alcohol problems. And this also was according to the 2017 National Survey on Drug Use and Health. And I would point out that this association of raising a child in a household where misuse of alcohol is going on is an indication of an adverse childhood event. It creates significant problems for the child in terms of the consistency and potential neglect by a parental figure. So a review of hundreds of studies by Griswold and others in 195 locations, so this was sales, consumption, and a whole variety of different sources resulted in an analysis of the health impact of alcohol consumption and found that, again, alcohol was the seventh leading cause of death in the world, as I pointed out earlier. About 2% of females are, this is a primary indicator of problems, and 7% of males have a significant alcohol use disorder around the world. People ages 15 to 49 years old, alcohol was the leading risk factor for death and disability worldwide. And that was associated with physical illnesses like tuberculosis, and in fact, makes people more susceptible to tuberculosis and other infectious diseases because of the decrease in the immune response that comes with chronic alcohol use. Road injuries are a huge factor, and self-harm is also a factor. So a significant number, considered to be a little over 20% of suicides are associated with the use of alcohol. Older adults and cancers related to alcohol use were top causes of death in older adults. Some protection from light drinking was identified in heart disease and diabetes in some groups, but this has been refuted in a variety of research efforts in the last 10 years, and there's been a few reports, some of you may have seen, that really the healthiest level of drinking is no drinking. Low risk is not no risk. Drinkers have problems if they drink too quickly, and they can have a variety of different health problems, and we need to be particularly sensitive to and talk to people 65 years and older that their tolerance of alcohol goes down and their risk of injury goes up. The impact on pregnancy is significant. Preclinical and clinical studies have failed actually to establish a safe drinking level during pregnancy. Alcohol passes through the umbilical cord quite easily and can result in miscarriage, stillbirths, a range of lifelong physical problems, one of which is fetal alcohol syndrome, and behavioral and intellectual disabilities in children. So fetal alcohol syndrome disorders is a variety of things all listed here, and some of those we can see quite easily in children, and those are some of the facial features, small head size, shorter than average height, low body weight, poor coordination. These are things that are picked up in developmental reviews early in the child's life, but one of the things that has been identified later that can be more subtle are some of the learning disabilities and speech and language delays and intellectual disability or low IQ, and these have been done in large population studies. One of the most famous was in Chicago looking at elementary school age children and seeing and equating some of the children that were having specific problems with alcohol use during pregnancy. Alcohol affects a variety of organs in our bodies. One of the things to think about is that when we drink alcohol, which we're drinking alcohol in grams over time, and it really invades all areas of the body. It's absorbed very rapidly, and it literally is affecting every area of the body. One of the things that's not listed here is skin, and I often take the light and point it out to patients that they just look so much better after they've reduced or discontinued their alcohol use because there's improvements even in skin, but the three pointed out here, alcohol's effect on the heart, liver, and pancreas. In the heart, it's associated with cardiomyopathies, highly associated with arrhythmias, associated with particularly atrial fibrillation, can lead to stroke, and very highly associated with high blood pressure. Again, this is something that is seen very rapidly and often, and that is we get people's alcohol use under control, and they often have a reduction in their blood pressure many people even come off their blood pressure medications over time. It also affects the liver and the hepatic system. Heavy drinking can result in inflammation. This can lead to a variety of problems, including steatitosis and fatty liver, but then eventually alcohol hepatitis, potential fibrosis, and cirrhosis. Pancreatitis is the one that very frequently is presented to us because it's so painful. It's one of the more painful problems a person can experience. Alcohol causes the pancreas to produce toxic substances that can eventually lead to pancreatitis. This is a dangerous inflammation and swelling of the blood vessels in the pancreas that prevents proper digestion, and again, just can be a very, very painful experience for the patient. And more than once, I have one patient right now that's had a couple of experiences with this, and it is the driver to the patient actually doing something about it and making some changes in his use of alcohol. Alcohol is also highly associated with a variety of cancers. There is a consensus of the association between alcohol and cancer. Alcohol beverages are known to be a human carcinogen, and an estimate of about 3.5% of all cancers in the U.S. are related to alcohol. It's associated with head and neck cancers, with esophageal cancers, liver cancers, breast cancer, and in breast cancer, for every 10 grams of alcohol consumed, that's less than one drink, which we typically think of as 14 grams, researchers have observed 7% to 12% increase in the risk of breast cancer. So in those women that have a family history of breast cancer, they're really taking a real chance if they continue to drink alcohol. They're increasing their chances of developing the disease themselves. And then colorectal cancer, and in many of these, it is the repetitive irritation resulting in a mutation of normal cells that is the result of the cancer. And then as I pointed out in talking about tuberculosis around the world and its association with the use of alcohol, is the effect alcohol has on the immune system, and that drinking too much can weaken our immune system, and chronic drinkers are consequently more liable to contracting a variety of diseases. And they were particularly susceptible actually during the COVID epidemic. Alcohol also has an impact on various mental health problems, primarily associated with its onset secondary to the mental health problem. Not listed here is the effect on PTSD, but it is one of the ones that's more closely associated with the onset of a drug use disorder, as is schizophrenia, mood disorders, and on the next slide, I'll show you anxiety. But what's happening here in schizophrenia is that it often takes place in younger people with schizophrenia, males with schizophrenia, and this is associated with they're beginning to feel uncomfortable with something that's happening in their system, something that they're actually often picking up in their interaction with others, that they're being identified as having some kind of problem and being excluded from their normal interactions and their normal opportunities to communicate with others and be in their social group. And they start to use drugs to reduce some of that anxiousness, but unfortunately, this then contributes to their not being adherent with medication recommendations that can reduce their symptoms, that can actually, in a young person, reduce some of the severity of the illness, even going forward in the progression of the illness in their lives. It reduces their ability to deal with psychosocial problems, increases symptomatology of their disease, can then result in more chronic medical problems and rehospitalizations. Something somewhat similar takes place in mood disorders, where a person begins to feel either depressed or manic, and it affects how they're responding then to the illness. The symptoms of bipolar disorder, in particular, may emerge during a chronic alcohol intoxication or withdrawal so that it can be enhanced during that period of time and people begin to really recognize it. But then as a person really develops the illness and the illness gets worse, it can be used to self-medicate, either to prolong the pleasurable effect. And some of you that may have had either taken care of someone with a bipolar illness or have an association in some way, know them, maybe not be their provider, have recognized that sometimes people don't want to lose that opportunity to have mania periodically and they like that experience before it gets being too profound and starts to cause significant problems for them. And alcohol can just make it even more profound. There have been depictions of this in movies and in the literature over time. It also can result in beginning to sedate the agitation associated with alcohol. So people can start to get agitated, can get angry, can have problems, and alcohol can start to slow them down. Alcohol use and withdrawal may affect some of the same neurotransmitters in bipolar disorder. Alcohol actually affects most of the neurotransmitters in our brain, and I'll go through that a little later in the program. But this allows one disorder to change the clinical course of the other and thus really promoting bipolar disorder. So it actually makes the disease worse, certainly makes the symptoms worse, but creates problems in the brain that actually make bipolar disorder in general worse in the individual. The like likely that this relationship is not simply a reflection of cause and effect, but rather that it's a complex bi-directional problem. And I can tell you, working in a treatment center that I worked in Connecticut in particular, where I saw a lot of people coming in for alcohol and drug use disorders, of course, there were a number of people that came in saying they had bipolar disorder. We would sit down, do a full evaluation. They would tell me the history of their bipolar disorder, all the different medications they've been on and problems. And then we'd go through all the substance use problems that often had started in adolescence and progressed from there if I'm seeing them at 35, 40 years old. And I would ask them, so how did your psychiatrist, you know, respond to what was the discussion around your substance use, and they very often would say, we never talked about that. Again, so often, sometimes the degree of alcohol and drug use disorders can actually present as bipolar disorder, and until you really break it down, you can't fully understand the complexity of the bipolar disorder itself. It clearly has an effect on anxiety. This is probably one of the ones that the lay public even know quite well, and that is get anxious, have a drink or two, and things can kind of slow down, settle down a little bit, and people can feel more comfortable. It does work directly on the GABA receptor, which is an inhibitory receptor, so the odds ratio characterizing comorbidity between alcohol use disorder and anxiety disorders ranges between two and three, the odds over the expected that would take place by chance alone. That is two or three times greater expectancy. Anxiety disorders are more strongly associated with alcohol dependence than alcohol misuse, and people with anxiety disorders are more likely to become dependent on alcohol to self-medicate, so if certain anxiety disorders really is a precursor to the development of a chronic alcohol use disorder, and alcohol use disorders in these individuals may also be artifacts of alcohol withdrawal, so again, not infrequently, once we get the alcohol under control, we can see a reduction in a person's anxiety, and sometimes people get sort of hooked into that idea that if they don't drink alcohol, they get more nervous, they have just even a physical response that's uncomfortable, and some of that is associated with just withdrawal from alcohol itself. There are certain anxiety types that differ in their association with alcohol use disorder. People with disorders actually have a lower relationship, a lower incidence of a relationship with the use of alcohol. They feel a little uncomfortable because they're not able to actually follow through on some of the compulsions that they feel they need to do in order to move forward in their lives. Social phobias, that is like getting on an airplane or what other simple phobias, you know, certain foods, you know, certain places are not terribly different than the community estimates of the use of alcohol, but social phobias, that is being comfortable in a group has a significant increase in incidence of alcohol use compared to community estimates. There is a difference also in genders, and alcohol-dependent men have about a 36% co-occurrence with anxiety disorders, whereas women, there's a greater incidence of anxiety being the precursor, being one of the drivers potentially in a woman to develop an alcohol use disorder. Alcohol use disorders are more strongly predictive in later life alcohol dependence among women, so it is something to be conscious of and be, again, these are all things that can increase our index of suspicion to look at what's going, you know, have we asked about alcohol? Are we thinking about this combination of problems and its association with alcohol on reason that we should be giving some advice or actually screening for it and attempting to treat it? So genetics are also a significant precursor to the development of alcohol use problems. It has been reported numerous times that about 50% of the vulnerability of an alcohol use disorder is associated with genetics, and I will tell you this very likely could be something that's on your exam if you're taking the course in preparation for an exam. So to tell you this very clearly, alcohol liking and disliking is linked to families, nations, through two specific enzymes, alcohol dehydrogenase and acetaldehyde dehydrogenase. So certain alcohol dehydrogenase alleles, that's the ADH1B and 1C, and I don't think that'll be on your exam, encode for alcohol dehydrogenase enzymes. When this is increased, it results in more rapid conversion of alcohol to acetaldehyde. And these alleles then have a protective effect on the risk of alcoholism. So why is that? That's because acetaldehyde is the toxin, is the breakdown product of alcohol that makes us get headache, gives us an upset stomach. It is what causes hangovers. And those people that break down alcohol to acetaldehyde dehydrogenase, or excuse me, acetaldehyde, have a very quick rise in that acetaldehyde, and so consequently, they have no tolerance. They drink, you know, a couple of beers and that acetaldehyde rises to that limit that they already are feeling sick. And then when you couple this to a variant of acetaldehyde dehydrogenase, the ALDH2 gene, which essentially inactivates the acetaldehyde enzyme, this also then slows the metabolism of acetaldehyde and results in an accumulation and a protective effect is the result. So in the first case, we have a rapid metabolism to acetaldehyde. And in the second case, we have a slowing in the breakdown, the metabolism of acetaldehyde. And so these individuals are, if they have both of these, the chances of them becoming an alcoholic are extremely slim. Whereas if someone has a low level of alcohol dehydrogenase, they're metabolizing alcohol in a very slow way. So they're producing less acetaldehyde. And so they have an easy tolerance. They're the teenager that can drink others under the table because they are not producing that toxin that makes them feel so uncomfortable. And if they also have high levels of acetaldehyde dehydrogenase, they're getting rid of that acetaldehyde more rapidly. And they consequently don't get hangovers easily. So they're in high school or in college. They're the, you know, they're the guy, the gal that can drink easily and they never get a hangover and they just have a lot of fun at the party. But they're also the ones that are potentially cursed with liking alcohol too much and having all the physical problems or the social problems associated with the onset of a significant alcohol use disorder. There are certainly other aspects to the pathogenesis of alcohol use disorder. These include environmental influences. These can be inter-family influences and this could be associated with the genetics. So a family that drinks together also can have some of those members go on to develop significant alcohol problems. And it's a family that had high tolerance and little in the way of hangovers. This unfortunately also increases the potential for prenatal exposure and parental parenting patterns. And peer influences are also environmental influences that can have a significant effect on the liking of alcohol, the association associated alcohol with every social event. And then, of course, general availability. We know that if there's more sales of liquors, liquor stores in a specific community, there's often increased alcohol use. I've already reviewed the mental health comorbidities that are associated with the development of alcohol use disorders. And then there are specific personality traits that can be associated with this. This sometimes is linked to some of the mental health comorbidities, but it includes people that have just low hedonic tone and general hopelessness often. Anxiety sensitivity without actually reaching the level of having an anxiety disorder, people with higher sensation seeking personalities or impulsive, higher impulsivity. And these can be associated with ADHD and other mental health disorder that's also associated with the early development of substance use disorders in general, if not treated appropriately. Cognitive functioning can also have an effect. Interestingly, again, cognitive dysfunction does have a higher association with the development of a substance use disorder. And this is thought to be associated with that idea that if a person has a cognitive disorder, has difficulty finding a peer group, feels excluded, they drink to reduce some of the distress of not being accepted or able to involve themselves as easily in our environment or society. All right. So let's talk a little bit about assessment. And this is, of course, a rather humorous cartoon or picture of two gentlemen sitting down for a couple of beers. And I will tell you, having gone to Oktoberfest in Germany back in the late 70s, I was really struck with the steins of beer that were certainly more than a 12 ounce can of beer that would be typically thought of as one drink. These are the standards for how we're thinking and talking to patients about one drink. So it would be one beer, 5% beer, 12 ounce bottle or can, a glass of wine, 12 ounces, excuse me, 12% alcohol, 5 ounce glass of wine, which I often say you only get for, you know, $20 in a gourmet restaurant. You know, people do not drink five ounces of wine typically at home. It's a pretty small amount of wine. Interestingly, when I first started doing more virtual intakes during COVID into a treatment center, I was doing an intake of a woman that it was actually for an opioid use disorder, a pharmaceutical opioid use disorder. Nice home. She was in decent shape. We just needed to talk about how she was using her pharmaceutical opiates that were being prescribed. And I asked her about her use of alcohol. She said, oh, I have a glass of wine or two every night. And I said, well, about how large is the glass of wine that you that you're drinking from? And, you know, one of the few, actually, things that I find important or better about virtual meetings is that people are in their homes. And she walked from where she was to the kitchen and brought out a tumbler that she poured her wine into. I asked where on this does she pour the wine, and it was about three quarters the way up this tumbler. Clearly 10 to 15 ounces of alcohol. So it can be important to try to figure that out with people. One of the ways that I find it to be most useful is to ask how they buy it. Do they buy a case of beer? Well, then how often do they buy a case of beer? Do they buy boxes of wine? How often do you buy a box of wine? Do they buy fifths or half gallons of liquor? How often? Because people have generally an idea of how quickly they go through these quantities that they're buying. The other thing that I'll point out on this slide that people don't always understand, and I think it can be very helpful in thinking through the various percentages that we now see in beer and certainly in wine and alcohol. So certainly there's alcohol is greater than 80 proof, which would be 40% alcohol. If you take the percentage and multiply that times the quantity, a single drink equals 60. So 5% beer, 12 ounces, 60. 5% or 12% alcohol, wine, 5 ounce glass is 60. 40% alcohol in a liquor, 1.5 ounces or shot of liquor equals 60. So it's an easy way just keeping that number 60 in mind to then figure out or help people. And again, I'll say this a few times during this presentation. People that drink are interested in these things, and it can allow you to engage them about things concerning alcohol that they didn't understand, even though they've been drinking heavily or at least consistently for 10, 15, 20, 40, 50 years. So when we look at then this idea of screening and brief interventional referral to treatment, I think this is a interesting cartoon in that it's really depicting how bad do we want it to get before we actually are going to do something about it? How difficult is it to get to us and a review that we may be making with a patient in order for something to actually take place? So don't wait for your patient to come to the office with an alcohol-related problem before talking to them about how much they're drinking. So screening brief intervention. Patients are likely to be more receptive, open, and ready to change than you might expect. Most patients don't object to being screened for alcohol by clinicians and are open to hearing advice afterwards. You're just asking them some questions. Sometimes the sort of agitation can be a little bit of a leader to, this could be more of a problem than was expected. And I'll sometimes point that out to them. It seems like you're a little sensitive about this, that there have been some problems associated with it. There's a wife giving you problems or whatever it might be. But that can be an opening, a crack in the door to then start to discuss some of the difficulties that they're having around it as opposed to the standard screening. Most primary care patients who screen positive for heavy drinking or alcohol, these disorders show some motivation for readiness to change. They can be interested in hearing about what are healthy drinking standards. Those with the most severe symptoms are often the most ready to change. They know there's a problem. One of the classics that I often bring up was a fellow that I took care of while I was working at a hospital in a behavioral health clinic associated with the hospital. And he came in, he was actually a hospital employee, came in because he had come into work intoxicated. He was working in the laundry and he had described to me that he really wants to get his drinking under control, but he doesn't want to stop entirely. And then we went through the fact that he graduated high school, actually graduated college, fortunately for him, in hotel restaurant business and had gone on to being a well-respected manager in a restaurant. And it was a chain, but then he started working for the chain and started going to these restaurants that were having more problems. And during this time, his alcohol use just started to escalate more and more and more. And eventually he lost that job, he had a period of homelessness, he's been in and out of various recovery houses and situations, and was currently living in a recovery house while working in the laundry, and was close to being asked to leave there, and so there were multiple problems associated with the use, but it was clear that there had been this long-term social drift in his ability to actually drink alcohol successfully and worsening alcohol problems, and at the end of the interview he looked at me and said, I probably shouldn't be drinking alcohol at all, should I? which is just so fascinating, if we can help people recognize the worsening of their lives, the difficulties in their lives associated with alcohol, so that they really do tie it to that, as opposed to the perception of life through the lens of alcohol, which often is very difficult to understand, we know the world through our own eyes, and it's hard to recognize the biases or the lens in which we're actually seeing our own reality. So there's one tool that's very commonly used, it's been developed actually and accepted by the World Health Organization, and that's the audit, and many of you probably use this tool and understand it, but I'll go through it briefly, it is a self-report instrument, there's 10 questions, gaining more qualitative information, and then some of the other, then the cage, let's say, which really is only looking at, the cage is looking at dependent drinking, it doesn't pick up risky drinkers, or even people that are low risk, and you just want to give them some information, so the audit may be useful in multiple populations, it's useful in women, men, minorities, adolescents, young adults, there's little research in using it with older adults, but it certainly is used in older adults, and part of the value of it is it looks at quantity, frequency, binge drinking, dependent symptoms, and alcohol-related problems, a positive screen is greater than eight for men, greater than four for women, and this is the audit, so it's looking at how often do you drink, how many drinks containing alcohol do you drink in a typical day, how often do you drink more than six or more drinks in an individual occasion, how often during the last year have you found yourself unable to stop drinking, how often during the last year have you failed to do what was normally expected, how often during the last year have you needed the first drink in the morning to get yourself going, how often during the last year have you felt guilty or remorseful after drinking, how often during the last year have you been unable to remember what happened the night before, have you or someone else been injured as a result of drinking, and has a relative or friend, doctor, or other health worker been concerned about your drinking or suggested you cut down, and so these are the 10 questions, and again it goes through quantity, the ability to cut back, and then problems associated with the use of alcohol. Three of these are quantity associated, and they're marked as the C's here, and five of them are PC, and used most frequently as a briefer screening tool in primary care, so the consumption is those first three, and those are how often do you have a drink of alcohol, how many drinks do you have on a typical day, and how many drinks do you have in a particular occasion of drinking. The audit C is more effective in identifying heavy drinking, but doesn't distinguish between active or post-drinking problems, so it's not going to make the diagnosis, but it is going to give someone a first look at is this a person that's drinking, and drinking at a risky level. The audit C can be included in many standard history questions, general health intakes, questionnaires in primary care, just to determine whether you want to do more of an evaluation. It's used in emergency departments, psychiatric and inpatient hospital settings, and other at-risk populations where the audit C is indicated is pregnant women, as I said, just to be able to give them information on any level of drinking could be risky. College students and how they're often then in situations where high-risk drinking can lead to more high-risk behaviors and injuries, and then in people arrested or incarcerated, particularly those with DUIs, domestic violence offenders, and those sorts of things, so it's used very frequently in these places where you just want to get a sense of how they're drinking. The audit PC, on the other hand, does begin to include some of the indicators of a alcohol use disorder, that is, goes through some quantity, but then looks at have you found that it's sometimes difficult to stop drinking? Have you failed to complete expected social or occupational obligations? And then how often the last year have you been unable to remember what took place the night before? And again, that's associated with more a binge drinking behavior. I don't say this later in the talk. Binge drinking is associated with these blackouts because blackout drinking is associated with the speed in which alcohol gets into our brain, so drinking two, three drinks in a session is going to increase that. It's part of the reason why the combination of benzodiazepine and alcohol increases the potential for blackout drinking because benzodiazepines and alcohol both work on the GABA receptor that's involved in this occurrence of blackout. Secondary prevention can be effective at the primary care level with early detection of hazardous drinking, and then it's then coupled with time-limited interventions aimed at decreasing alcohol consumption and the likelihood of subsequent harm and dependence. So it's a tool in which we can determine there's something going on here and then decide to do a brief intervention. So it's five of the 10 items of the audit, and they've been validated first by Pisanelli in the British Medical Journal in 1997, and findings are quite sensitive, and that is there's not going to be some false negatives, many false negatives, and and quite specific, is that right, it's quite specific. So sensitivity is the ability to see within the general population all those that are have false negatives. That is, we're going to pick up the majority of people, even though not all of those people would necessarily be specific for a use disorder, whereas specificity is associated with specifically looking at a use disorder, and it's also quite high. The diagnostic evaluation then be offered to those with a positive test. We also have a variety of biomarkers that can be helpful in identifying people with an alcohol use disorder or following people that have a disorder to just get a sense of how they're doing. One of the more common ones is the gamma glutamyl transferase, and this has, again, a decent sensitivity, but a low specificity because it's also associated with a variety of other illnesses, digestive diseases, pancreatitis, prostatic disease, and actually other liver diseases. They all can raise the GTT, and so once again, easy to say, you know, if you have a suspicion, you see an elevation here, they don't have these other illnesses. Yes, there could be, it could be a marker that there's a problem, but it's not highly specific. Similar to that is the AST-ALT. It's a strong indicator of liver disease, but not highly specific for alcohol. It indicates heavy drinking in the last few weeks if there isn't other problems, but it can also indicate moderate sensitivity and moderate specificity for an alcohol use disorder. It can be affected by excessive coffee consumption, lowering these, the level of AST, and primarily affects liver damage that's often related to alcohol, so ALT appears to be less sensitive, but more specific than AST and found in other organs than the liver. One of the other ones that I often find interesting because it's so frequently available, and that is the mean capuscular volume. You know, we so frequently get a CBC on patients, and if it's greater than 100, it's just something to consider. You know, have I asked about alcohol? Because it is an indicator of heavy alcohol use, and it often lasts for months because it takes a long time to repair. There's moderate sensitivity, and a variety of other conditions obviously can cause it, but false positives can include hemolysis, bleeding disorders, hypothyroidism, hyperglycemia, and folate deficiency, but this really comes from people not having a good diet, and consequently higher mean capuscular volume. The other, one of the more sensitive and specific indicators is carbohydrate deficient transfer, and this is an indirect marker, but it indicates greater than four drinks per day for at least two weeks. There's a moderate to high specificity to alcohol dependence, and values could be altered by obesity and smoking, both associated with alcohol use, but as sensitivity, it's as sensitive as as GGT, but more specific, and consequently, it most frequently is followed by those people that are actually working with someone that's looking at the potential for relapse, because it does stay on, it does stay positive for a a longer period of time, and does give an indication of a higher amount drinking during whatever period of time you're looking at. Other biomarkers to monitor current alcohol use are alcohol blood concentrations, so this would be a breathalyzer and or blood. One drink in an hour raises the blood alcohol concentration by 0.1% and or higher, and breathalyzer sensitivity is approximately 24 hours, so we can pick it up within 24 hours. Blood sensitivity is only sensitive for a 12-hour period. The others are ethylglucuronide and ethylsulfate, and these are more frequently used in in treatment centers or clinics that you're working with people with with substance use problems. You can have cups with ethylglucuronide or ethylsulfate, and it's a direct analytic indicator of non-oxidative breakdown of alcohol, and it's highly sensitive. It can detect even a single drink. It's effective by extraneous alcohol and other products, so you need to be careful about that, but greater than a thousand nanograms per milliliter is an indicator of recent heavy drinking, 500 to 1,000 low positive, and 500 to 500 for more distant heavy drinking or recent drinking, but you'll be surprised or, you know, there'll be some people that will come in with 4,000 or 5,000, 8,000 nanograms per milliliter and then tell you, you know, Saturday night, you know, I had a binge, and you're picking this up on Monday morning, and I've done this in particular or seen this in people that I'm following with opioid use disorders that then clearly have started to use alcohol more as they are in treatment for their opioid use disorder. The last is phosphatidylethanol or referred to as PETH. This is a direct marker. It indicates alcohol concentration, and the incubation time is directly proportional to the quantity of PETH produced. It's linked to the red blood cell, and PETH is in blood promising for characterizing a pattern of drinking and differentiating light drinking from binge drinking can be picked up. I will tell you that this is very becoming a very common indicator that hepatologists follow for helping to or getting a sense of the level of drinking that a person that has that is now on the list for liver transplant that they're watching, okay? So, we want to see typically most that I see is a six-month period of no alcohol intake, and this is one of the markers that hepatologists are often watching to just have one more indicator beyond the patients actually indicating whether they've been drinking or not. This is just all of these indicators put together, and you see those that are screening for heavy drinking compared to those that identify relapse, especially to heavy drinking, and then what's the period of time that they actually can be used, and then really indicating in terms of just monitoring abstinence, like no drinking, and you're watching this frequently, is the ethyl glucuronide and ethyl sulfate. But I would have you take a look at PETH. This is not so much newer, but it is being used more frequently, and could be something that you would see on a exam. So, we get all this information, and then how do we actually make the diagnosis of an alcohol or drug use disorder, and these are taken from the DSM-5. These are the same criteria in the DSM-5-TR, and what you're seeing is the need for at least two of these to indicate low level of low disease disorder, and then greater than six or greater, indicating a real problem, and you're looking at amounts, larger amounts, and longer periods of time than originally anticipated, and then you're looking at the amount of people who have a high level of a real problem, and you're looking at amounts, larger amounts, and longer periods of time than originally intended, desire or attempt to cut down but unable to, large amounts of time spent getting, using, and recovering from drug, which then can result in not fulfilling certain obligations and be associated with cravings, with just an urge to use alcohol, and inability to not to stop, and consequently causing more problems at work or social problems, interpersonal problems. It can result in giving up, then, of participation in other activities. I mean, if you're losing alcohol for longer, larger amounts for longer periods of time, then you're drinking alcohol and not doing some of the things that you used to enjoy doing. Recurrent use of alcohol in physically hazardous situations and continued use of alcohol despite having physical or psychological problems caused or exacerbated by alcohol, so you know there's problems going on, but you continue to drink, and then two that are going to happen with continued use, and that's tolerance and potential withdrawal symptoms. All that I told you about the genetic predisposition to these problems, we can induce those enzymes, we can change things in some ways to develop tolerance, even if we don't have the genetic predisposition for tolerance and anyone that drinks with it to access for extended periods of time is going to have some neurobiologic changes that I'm going to show you in a few minutes that are associated with withdrawal symptoms. So again, for mild disorder, it's two to three, moderate four to five, and six or greater is six of these specific criteria. We do have specifiers, and that is if they've been in a controlled situation for an extended period of time, and they are now in remission, but in a controlled setting, whether they're in early remission, that is greater than three months, but less than a year, or sustained remission, and that's greater than 12 months. All right, in terms of then intervention, what are we going to do when we determine that a person meets criteria for an alcohol use disorder, either on a screening tool or in doing a diagnostic evaluation? We look at brief intervention goals, investigate a potential problem, try to find that problem, and again, in the patient that I told you about, it was a matter of kind of starting from the beginning and have him recognize as he relates his history, some of the problems that occurred as his alcohol use began to increase. Establish the level of motivation. What we're looking for is client-directed motivation, that is their own recognition, thus a motivation, and then additional, potential additional treatment. So as that awareness goes up, then they begin to ask, what do I need to do? And sometimes it is, I just want to cut back on my drinking, we try that, and then potentially they come back saying, that was more difficult than I thought. Dr. Silkworth, who was one of the early people involved in AA and working with, and the development of treatment for alcohol use disorders, said as way back in 1935, for God's sake, stop preaching. Tell them about the obsession and the physical sensitivity they are developing and say it's a lethal as cancer. A drunk must be led, not pushed. Give them insights, help them understand it without beating them over the head. Often seeing that crack in the door where you can talk about it, where it has been a problem in their marriage or has been a problem at work, or they're recognizing that these physical problems are irritating to them. In that way, I'm describing a teachable moment. When a person's been injured or acutely ill, presents with a unique opportunity for behavior change. Brief motivational interviewing works well in a non-confrontational stance. It is the opposite of arguing with a patient. And I will tell you, we're all susceptible to getting irritated with a patient that we think is not telling us the truth or continues to use in the face of a variety of problems. And when that happens, for me, I step back and say, okay, stop. I'm telling myself to stop. And then say to the patient, you probably recognize I'm starting to get irritable. It's not with you, it's with this disease. It's recognizing the impact that it has on people and how difficult it is for them. And that sort of identifying our own agitation with it is not the individual as much as it is the disease. And therefore, looking at those specific problems and making it more patient-centered. So it's education and authority of a medical staff that can be so difficult for a patient as opposed to individual responsibility and their desire to change. That's what we want to try to boost. We want to try to help the patient gain greater insight. And those are the real tenets of motivational interviewing and enhancement. So once we've decided that the patient has a problem, then we can use one tool that can be used is the American Society of Addiction Medicine criteria. They just recently came out with the fourth edition. And this is really looking at this multi-dimensional assessment that looks at one of these patients dimensions is acute intoxication and withdrawal potential. Do they need medical attention now if they're going to make a change? Biomedical conditions and complications that is associated physical problems, emotional, behavioral, cognitive conditions or complications, that's mental health problems. Would they be better served in an integrated mental health setting? I will tell you in the fourth edition, there's discussion of all people taking care of this should be capable of identifying the concurrent mental health problems and doing an initial engagement of the patient, even if they have a co-occurring mental health disorder, not immediately saying they need to be treated somewhere else. And then looking at readiness of change, which is much of what I just described, how motivated is the person coming into treatment or considering treatment? What's the relapse or continued use potential? And where are they living? What's the impact of their current household? So the toxic household in terms of either the degree of alcohol or other drug use in the household, or just the consideration for this being a disease and the ability for those that the person may live with to support them as they try to do this work. All right, so if they are in a position where the first thing that needs to be done, if they're motivated to do this, is to withdraw from alcohol. And it's clear that their use of alcohol is such that they may be at risk for problems. So in looking at this neurobiology of alcohol intoxication, and it's important to recognize that alcohol, as I said earlier, it hits all over the body and it hits all areas of the brain. It just gets absorbed everywhere. And consequently, the intoxication aspect has to do with opioids. And those are endogenous opioids that affect our liking of the substance, alcohol, and thus a release of dopamine into the nucleus accumbens, which many of you have heard and think about that as the pleasure center in the brain. And then GABA, direct influences on GABA. So first we have opioids and the endogenous, that's really the endogenous opioids. Dopamine, which plays a role in a variety of places, but is the prominent inducer of pleasure within, stimulator within the nucleus accumbens. GABA, which is the GABA immunobutyric acid, this is an inhibitory neurotransmitter and allows us to feel more calm and comfortable initially with the use of alcohol. It's effect on glutamate as a glutamate antagonist, and glutamate is an excitatory neurotransmitter. There's differences in this as a person is getting intoxicated as opposed to coming off the drug, but it's what many people don't realize, glutamate is the most prevalent neurotransmitter in our brain. In many ways, GABA and serotonin really modulate the glutamate in our brain and the influence it has on the glutamate receptor, the NMDA receptors. Cannabinoids are also affected by this in terms of cannabinoid receptors, which are natural receptors in our brains that have some of the anxiolytic aspects of alcohol, serotonin, and then the corticotropin releasing factors that are also affected. So again, very complex and multiple, multiple areas, unlike opioids or stimulants where it's very clear how they're affecting the brain, alcohol is very clear, it's very clear how they're affecting the brain. Alcohol is all over the brain and affects the brain in many different ways. What we're looking at here in particular is intoxication and the effect on that nucleus accumbens that is the initial liking of alcohol by individuals. So ordinarily excitatory or glutamate and inhibitory GABA neuroreceptors are in homeostasis and that's tolerance, we get real excited about something, we start to modulate that in a way to bring us back to a easy normal position. Alcohol facilitates GABA neurotransmission, so it's down regulating the effects of glutamate and consequently as that takes place, we have a decrease in the number of GABA receptors that's down regulation and more alcohol is needed to produce the same effect. So we want to feel normal, I shouldn't say that, people's drinking don't wanna necessarily feel normal, but the brain wants us to get to that place of easy normal. We're constantly trying to, that's the allosteric effect, trying to get back to normalcy and this is what takes place, we have this decrease in the number of GABA receptors and so we need more alcohol to get that same effect. Alcohol works directly on the GABA receptor, again, this is different than benzodiazepines that work by augmenting the neurotransmitter GABA on the GABA receptor and that's why benzodiazepines have a very high safety profile, whereas alcohol has a clearly toxic level, you can drink too much to the point of death, compared to benzodiazepines. So this attempt at homeostasis, alcohol acts on the NMDA receptor where glutamate works as an antagonist, which decreases this excitatory tone and chronic alcohol then leads to an up regulation of the NMDA receptor and more glutamate production. We wanna stay alert, we wanna stay active, we wanna be able to walk around or talk or take care of things, even though we've put alcohol in the system and so when that's done chronically, we up regulate that glutamate significantly and we've already down regulated the amount of GABA. So withdrawal, it comes from essentially abruptly stopping the use of alcohol and that the inhibition of alcohol is reduced. So all of a sudden there's no governor on this increase in glutamate and decrease in GABA and profound excitation takes place that's really unopposed now because the alcohol was keeping it at this even state. This results in significant alcohol withdrawal and during alcohol use and withdrawal, there's an increase in dopamine, which also contributes to the autonomic hyperarousal and is involved in alcohol withdrawal hallucinosis. Obviously or not obviously, but I will tell you, norepinephrine is a direct result of this high level of glutamate that's now in the system and that's what causes the profound physical effects that take place with this sudden discontinuation of alcohol use. So alcohol management is a set of interventions aimed at managing acute intoxication and withdrawal. Supervised withdrawal management may prevent life-threatening complications of delirium tremors and death. Withdrawal management is not, however, an addiction treatment, okay? It only helps people get through this initial problem. So we look at treatment of alcohol use disorders as one, the evaluation, which I've gone through, stabilization, which I'm gonna talk about more, and then continued motivation in establishing the patient's plan for treatment that can often involve medications that I'll talk about towards the end of this program. So in treating withdrawal management, and this was often in the past referred to as detoxification, but we talk about it now as withdrawal management. Withdrawal management really refers to medical and psychological care of the patient who's experiencing withdrawal symptoms as a result of discontinuing or considerably reducing their use of a substance, and in this case, alcohol. And withdrawal management includes attenuation of the physiologic and psychological features of withdrawal and interruption of that habitual compulsive use. And then we have maintenance psychotherapy, which again, I'll talk about later in the program. And to just get people started and actually help them during withdrawal management, keeping them in treatment for their withdrawal, it includes motivational enhancement therapy, cognitive behavioral therapies, beginning to help them understand what things, what they're experiencing, how that's triggering their desire to get back out, use, and this can also be referred, or this can involve relapse prevention that's people, places, and things associated with their alcohol and drug use. And then family therapy, social supports, really starting to help them recognize the importance of really engaging in social supports, and that is AA, NA, smart recovery, various other things. So our goal with withdrawal management is to make it smooth and efficient. We don't want, we wanna try to prevent seizures. I think the best of programs have seen seizure periodically. It's hard to not see it at some point, depending on the severity of the patient's problem and minimal agitation or discomfort. We're typically able, we wanna help patients participate in the recovery program immediately, really starting to work with them to engage them in treatment. So this is the CEWA, the Clinical Institute Withdrawal Assessment that's most frequently used to monitor the degree of the patient's withdrawal symptoms. It's a 10-item scale. It can be used as a rapid assessment of the patient's status. There's fairly easily scored and administered by medical personnel. It's a self-assessment. The score is between zero and 67, and a score less than 10 is an indication the patient doesn't necessarily need treatment at that time, but may need continued monitoring, depending on how far into their recovery they are. Second, we look at mild, moderate, severe, and complicated scores on this CEWA scale. Mild is less than 10. This can be little anxiety, sweating, not sleeping well, but no tremor, no physical signs. Moderate, 10 to 18, is moderate anxiety, also sweating, can't sleep. And now you're showing some signs, mild tremor. Severe, you're looking at greater than 19. Severe anxiety, moderate to severe tremor, but typically still no confusion, hallucinations, or seizure. And then complicated, now we're really seeing these other significant physical findings that may be an indication for a higher level of treatment. So, these are all used to help us determine what level of treatment a patient needs to be in, and this complicated state may often indicate even an intensive care unit, but certainly a hospital care level. The ASAM criteria quantifies this as level 1 ambulatory or withdrawal management without extended on-site monitoring, so this can be someone that's not having severe problems after 24 hours, potentially they're coming into you with a problem or wanting to stop entirely. Ambulatory withdrawal, level 2 is ambulatory withdrawal with extended on-site monitoring, and these are ambulatory withdrawal settings, can be seen on a near daily basis. I did a fair amount of this in a partial hospital program and can be then extended or used in an intensive outpatient program. And then level 3 is where you're moving them into a place where you can observe them readily, and that's residential or inpatient withdrawal management, inpatient, not hospital inpatient levels. So, level 3 is an inpatient program, but is not a hospital level. So, it has nursing care, 24-hour nursing care, potentially different than a residential setting. And this level 3-2 is clinically managed residential withdrawal management, whereas levels 3-7, again, is with 24-hour nursing, medically monitored, monitoring of patients, and a provider, physician, APP is available 24 hours. And then there's level 4, which is an inpatient withdrawal management in a hospital setting. Appropriate ambulatory withdrawal management is typically patients with minimal risk or complications of withdrawal, typically the C.1 less than 10, patients likely to complete withdrawal and enter treatment, patients responding positively to emotional supports and treatment, they're really engaged, and they potentially have a safe place where there's another person, sober person available to them, and or they understand very clearly the instruction precautions if their problems were to get worse, and they then would be able to call for help. Those freestanding treatment facilities are often used because they're less restrictive and they cost less. The level of care is typically 24-hour supervision, observation, and support. It's typically for people that are medically stable, so they don't need oxygen, or they don't have other complicating cardiovascular problems, and biopsychosocial stability, so they don't have more profound mental health problems, and there's typically always 24-hour physician availability. Sometimes it's an APP. Level 4 is for more severe and complicated withdrawal management, and here it's people with a history of alcohol withdrawal delirium, alcohol withdrawal seizure, numerous prior withdrawal episodes in the patient's lifetime. There is a certain kindling to this as there is with potential seizures. The more the people have gone through this, the more difficult their withdrawal management could be. People with comorbid medical or surgical illnesses, especially, you know, history of traumatic brain injury, people at increased age where there's potential complications of falls or problems, and they're just at greater risk for cardiovascular problems associated with their withdrawal. People that have had very long duration of heavy alcohol use, and potentially these are people that start to have an elevated CWOP while they're still intoxicated because any lowering of their alcohol use puts them into mild withdrawal, mild to moderate withdrawal. Have they had seizures during the current withdrawal episode or multiple seizures in the past? Mark autonomic hyperactivity on presentation that is, you know, very tremulous, elevated blood pressure and pulse, concurrent physiologic dependence, that is, they've been taking GABAergic agents like benzodiazepines or barbiturates. And typically, these people with CWOPs greater than 15, blood alcohol greater than 0.3, particularly, again, if they start to have withdrawal symptoms at that level. You know, they're still, you know, I've seen patients at 2.7, 0.27 with withdrawal, you know, starting to go into withdrawal already, which is a significant intoxication. CWOP 10 to 19, but with a pulse of greater than 110 or blood pressure greater than 160 over 110. So, how do we treat this? The gold standard is benzodiazepines, and they can be used for moderate to severe withdrawal. Anticonvulsants, gabapentin, carbamazepine have strong evidence for treating mild to moderate withdrawal. And I will say I've done a lot of outpatient withdrawal management with carbamazepine. And people do very well. Load them quickly. It helps them sleep. It reduces some of their anxiousness. And this is similar to the use of gabapentin for these patients. Again, they should be monitored regularly if they're being treated in an outpatient setting. Phenobarbital is one of the oldest medications that we've used in the past. And quite honestly, I see it being used more frequently these days than I did even 10 years ago. It is easy to use. It's typically only done in an inpatient setting. But typically, we're able to load patients. You know, I've seen typically 10 to 20 mg per kilogram, but I've seen as high as 30 milligrams. But it is highly effective because you can load people and then taper them off fairly quickly because of the long-acting aspects of long half-life of phenobarb. When to use a short-acting sedative like chlorazepam, this is used in liver disease because chlorazepam is detoxified through glucuronidization compared to breaking it down in the liver. And so it's just not toxic on the liver. Patient is intoxicated and agitated. You can use it easily and quickly because you can use injectable chlorazepam. And then typically, we're using or excuse me, it's also often used when people have been using a variety of drugs. And if the clinician is uncertain whether the patient has early delirium tremors or early portal systemic encephalopathy and elevated ammonia levels. And so we can use this rapidly and effectively to bring them down. They may still need hospitalization, may still need to certainly go into ICU if their problem continues to escalate. But at least we can get it under control very rapidly. All right. So treatment of alcohol withdrawals symptoms, there is probably most frequently, it's used in a fixed dose regimen, 50 milligrams, use six hours, every six hours times four, and then dropping them down potentially to 25 milligrams every six hours for eight doses. Ativan, you know, two milligrams every six times four, one milligram every six times eight. Diazepam, 10 milligrams every six for four doses, and then dropping them down to a lower dose over the next couple of days. This is three days of meds. It's continued observation, certainly hold for sedation. But it's, you're not adjusting the medication management per ACWA. Ativan, one or two milligrams PO or IM as needed for more severe symptoms. And then we use a variety of ancillary medications. You know, you can use something for their dyspepsia or just other symptoms that they may be experiencing. There is symptom driven regimens. I've actually used this quite successfully in the past, but it does take more training of nursing personnel. So it's not typically used as frequently in general hospitals, but it is used with some regularity and in treatment centers, you know, medically managed outpatient regimens. Residential settings. Here you're using the ACWA scale serially. So you're using it to do adjust the amount of medication that you're going to deliver. You medicate as per the observed score. The pros are, it has shown to result in less medication being delivered and shorter hospitalizations. The cons are that it does require greater training and there's discharge flexibility. You can't say you'll be in the hospital or in our treatment setting for this number of days specifically. How this works is that if the score is greater than 10, then we'll say lorazepam, one milligram is used. That's a score greater than 10, but less than 20. One milligram or 25 milligrams chlorodioxide or Librium is given. If the score is greater than 20, then two milligrams of lorazepam or 50 milligrams of Librium, and it's assessed on the out watching people very closely. Until the score starts to come down. You monitor them every four to eight hours with ACWA until the score has been less than eight to 10 for 24 hours. So again, if the score is greater than 20, we're watching them very closely. But when it comes down to less than 20, then you can start to monitor them every four to eight hours. Withdrawal scales are not a substitute for clinical judgment. If they're not reporting their level of anxiety or some of the subjective symptoms on the ACWA, be careful and certainly feel comfortable delivering a higher level of medication. But we typically try to avoid going above 300 milligrams of Librium in a 24 hour period. This symptom triggered detoxification or withdrawal management was studied by Rich States and published in JAMA back in 1994. And here, looking at 111 patients, there was the use of Librium 25 to 100 milligrams every hour for ACWA greater than eight. And as it came down, then, excuse me. But if they had higher levels, then the, okay. There were two different arms to this. One was the symptom triggered and there they were using 25 to 100 milligrams every hour for ACWA greater than eight. There were fixed dose arm. They were using Librium 50 milligrams every six hours for four doses, and then 24, 25 milligrams every six or eight doses and then as needed. And this was what I described earlier. When they looked at these two, in terms of treatment duration, symptom triggered was significantly less than the fixed dose scheduled use. And the amount of Librium was also one fourth the amount of Librium used in the fixed dose schedule. The highest ACWA in both was the same. It was 11. And I will tell you that if you take a look, which you should, at the ASAM guidelines for alcohol and alcohol withdrawal, you'll see in reading through that, that a significant number of these patients can actually be treated in an outpatient or a lower level of care than a hospital setting. And to be able to do that, reduce the expenses and the potential morbidity that comes with in hospital or a more controlled setting can be significant. And so it is something to keep in mind that we probably are under utilizing outpatient management of alcohol withdrawal. But you want to be careful. Something that you may see on the exam is the idea of Wernicke encephalopathy or the development and the development of Korsakoff syndrome. Wernicke encephalopathy is a severe complication resulting from insufficient thiamine in the body. It's often characterized by reversible, initially reversible, acute confusion, abnormal gaze, nystagmus, ataxia, possible delirium. Untreated Wernicke's encephalopathy can result in chronic Korsakoff syndrome and irreversible syndrome that includes dementia and gait abnormalities. Alcohol use disorder patients are at risk of associated, of this associated illness as a result of thiamine deficiency. And thiamine is required for basic cellular functioning and carbohydrate metabolism. And patients that are unable to synthesize thiamine and often have daily ingestion taking place because of dietary changes. So not only are they unable to synthesize it, but they often are not having adequate intake. Patients with more severe disorder are susceptible because of these deficiencies and inadequate dietary intake and biological interactions between cellular enzymes and alcohol. Thiamine deficiency can result in increase in pyruvic acid, impaired oxygen intake and cerebral tissue damage. Again, true neurologic damage that results in Korsakoff syndrome. Typical dosing of oral thiamine is 100 milligrams PO daily for three to five days. However, oral thiamine is not well absorbed. Consequently, Wernicke encephalopathy, if it's suspected, then patients should be transferred to an inpatient setting and receive immediate, immediate parenteral administration of thiamine, where we can inject it. When looking at withdrawal hallucinosis, alcohol withdrawal can result in visual, auditory and tactile hallucinations. We most frequently hear about these tactile hallucinations. That's in part because they're somewhat specific for alcohol hallucinations. But auditory hallucinations are the most common. And patients will most frequently have intact orientation while they're having these problems. So they still know it's not right, which is different than true psychotic illnesses. They'll have normal vital signs often, or you can be controlling that, but they're having hallucinations. And they often last between one and six days. So they will continue through this period of time. They occur in about 25% of those who have been drinking heavily and then attempt to withdraw. They may require the addition of antipsychotics as symptomatic help, second-generation atypical antipsychotics, such as Risperidol, which is not necessarily a second-generation, but Quetiapine, Ciprazidone are more preferred because they have less seizure threshold compared to other antipsychotics like haloperidol, which was often the drug that was used, but it does lower seizure threshold. So, risperidol is one of the more commonly used antipsychotics that are used, at least had been in the past. I would say more frequently now, either suprazidone, quetiapine is used. Quetiapine you may see used fairly frequently in treatment centers for sleep, which is a bit of my nemesis because it's really using a medication somewhat inappropriately, but it can be very helpful to patients. And so, I don't, I just have my own thoughts on that because people often get out of the treatment center and want to stay on Seroquel for sleep, which is quetiapine, and that's often difficult. Diazepam may be considered a treatment option to reduce agitation associated with their psychosis, but again, you may be using other benzodiazepines at the time. In terms of looking at seizure disorders during alcohol withdrawal, the seizures are grand mal seizures can take place that way as and seen in 10 to 15% of patients. So, it's not, it's not highly uncommon, usually in the first six to 48 hours. So, this happens early on, but they may be seen in the first 10 days. They can occur before the blood alcohol reaches zero even, and particularly in those with severe alcohol use disorder. They're increased in those with history of withdrawal seizures. Again, there's a kindling effect to seizures. More episodes of withdrawal, alcohol withdrawal, higher the risk. And there may be multiple, but rarely status occurs. There may be multiple seizures, but rarely do we get into status epilepticus, and it may require diazepam drip if they, if they, you know, have these short bursts of seizures. The first episode is, or atypical seizure, evaluate other causes like genetic predisposition to, to seizure or epilepsy. About 30% of withdrawal seizures do progress to delirium. So, it is an indicator of a worsening withdrawal. And once again, a reason that they should be in a controlled setting if they have a seizure. And ongoing pharmacotherapy is not indicated after they get through the withdrawal, if it is determined to be a withdrawal seizure. Okay. So, they do not need to be on anti-seizure medicine after they leave the treatment center or your outpatient setting, which typically they're not going to be still in an outpatient setting. So, if they have a seizure, you monitor them closely every hour for 6 to 24 hours, deliver parenteral medications, and they may need IV fluids for hydration and to rebalance their electrolytes. Benzodiazepines are the first-line treatment. Fast-acting agents such as lorazepam and diazepam are preferred if they have a seizure. Phenobarb is, barbitol is certainly an option, less preferred for treatment of alcohol withdrawal symptoms and prevention of additional seizures, but more commonly used in an outpatient setting. Because again, we can load them and then they're covered. It's important to keep in mind that alpha-2 agonists and beta-adrenergic antagonists are not recommended to prevent or treat alcohol withdrawal seizures because they are ineffective, one, and beta-adrenergic antagonists can lower the seizure threshold. I've seen clonidine be used with some regularity in some outpatient settings. And just to keep in mind, yes, it can control their vital signs, their blood pressure and pulse, but it can complicate our treatment. And so, I don't typically use them, and I warn against, or just be aware of the fact that it can lower seizures thresholds. Dilandrin or phenanoin has been shown to be ineffective in treating withdrawal seizures and in preventing recurrence of seizure. It's not recommended unless the patient's been treated for a concurrent underlying seizure disorder. In terms of the treatment of DTs, this is really specialized treatment and typically treated in the intensive care unit. This is an acute, reversible, organic, psychosis, significant morbidity and mortality. It usually begins 48 to 72 hours after the last drink and may last two to six days, sometimes longer. Mortality increases with delayed treatment or inadequate treatment and concurrent medical conditions. So, concurrent medical conditions, doing a good history and physical as people are coming into your setting, is very important in determining, can we treat this appropriately in this setting? And that was part of the ASAM criteria in determining what level of withdrawal setting they should be in. Standard protocols for withdrawal are helpful in reducing the incidence, duration, and frequency of delirium among hospitalized patients. So, if we adequately treat their withdrawal symptoms early on, we can considerably reduce any development of delirium tremors. But it is a matter of getting people into the hospital early, recognizing that this is the problem, and treating it appropriately. Severe alcohol withdrawal symptoms, again, include tremor, significant tremor, sweating, diaphoresis, fever, confusion is the huge one, and often that's associated with leucinosis and agitation and disruption in sleep-wake cycle. It requires close nursing observation and supportive care in a quiet, well-lit room, often necessitates admission to the intensive care unit and frequent monitoring of vital signs like symmetry and cardiac status. The CYAR is not used for delirium because we need patients to give us report of symptoms. And there are some tools that are used in the ICU. I've only ever used the delirium detection score, but any one of these, and I actually am hearing more frequently confusion assessment method in ICU patients is being used with frequency. So, patients should be provided with enough medication to achieve a light somnolence. So, we want to almost put them to sleep, just really reduce their agitation. Benzodiazepines are the most commonly used medication to treat delirium. Intermittent IV administration of long acting medication and continuous IV infusion of short acting medications are both effective treatments for alcohol withdrawal delirium. Administering medication intravenously allows for rapid and accurate control over worsening vital signs and escalation of symptoms. It really tells us how much is in the system compared to when it's given orally. And certainly in this setting, this problem, we're not delivering medications orally any longer, but we're monitoring the fear that the patient's experiencing autonomic hyperactivity and hallucinosis. Because intravenous lorazepam and diazepam are both stabilized by propylene glycol, we need to watch for hyponatremia, you know, low sodium and metabolic acidosis. Antipsychotics may be indicated to control severe agitation and hallucinations. Symptom triggered escalating doses of diazepam or phenobarbital has been shown to reduce the need for high mechanical ventilation and showed trends towards reduction in ICU length of stay and patients admitted into the ICU. And so really this all goes with just monitoring the patient well and using medications appropriately. Resistant alcohol withdrawal is generally described as patients experiencing severe complicated withdrawal, despite high doses of benzodiazepines, having uncontrolled symptoms, despite having received doses of more than 150 to 200 milligrams of diazepam or 30 to 40 milligrams of lorazepam in the first three to four hours, so real significant amount, and yet they're uncontrolled. And in these cases, they may require the addition of phenobarbital, profavol, or dexmeda, topamine, topidine, or presidex. And quite honestly, I'm seeing people move to these much more quickly. So, the complication then, these patients need continuous monitoring. There's a risk of hypotension with profavol. The conclusion of one inclusion of one systemic review of observational studies evaluate the use of profavol, which is a risk of hypotension. Of observational studies evaluate the use of profavol was useful in reducing signs of alcohol withdrawal, but due to the risk of respiratory depression, it is only appropriate for patients that already require mechanical ventilation, unless other adjunct therapies and methods of benzodiazepine administration have been proved to be ineffective. So, that was a study done by Brotherson in 2016. And again, I'm seeing more dexmeda, topidine, or presidex being used more frequently actually than profavol now. But again, you know, this is intensive treatment. This is for patients that are being treated by intensivists in a hospital setting. There can be bradycardia when dexmeda, topidine is administered. Dexmeda, topidine is a alpha-2 agonist, a presynaptic agonist. So, it's, you know, in that way, it's similar to clonidine, but again, these are highly monitored patients. And often, that includes mechanical ventilation. All right. So, that was a lot of withdrawal management. And some of that, there will definitely be withdrawal management on your exams. But I hope that gives you a bit of an oversight and then looking through it more clearly. What we're going to go through now is really long-term treatment. And again, withdrawal, just like in opioids, withdrawal is not treatment. It's just getting the patient stabilized. Now, we're going to look at the actual treatment of the patient. This is a review again of the slide that I showed you around intoxication. These are the biologic changes that take place in the patient over time. And that as a patient has gone from intoxication and just the initiation of the use of the drug, which is the non-dependent A patient here, where you have significant stimulation of the nucleus accumbens. When you move into the B patient, we don't have nearly as great a stimulation. They're not enjoying it as much as they did those first few months or a year of using when they were a teenager in their 20s. And instead, we're moving into a period where the primary reinforcer is the negative aspects of not using. And that's not just withdrawal. That's just a place of agitation. The brain is saying something's just not right, and it's triggering craving to use drugs. So, it's the stress response that's a primary driver to continued use of alcohol as opposed to, oh, gee, I want to have a drink to, you know, because it was so much fun. And so, it again involves endogenous opioids, dopamine, GABA, glutamate, cannabinoid receptors, and serotonin, and the codotropic releasing factor. And that becomes more involved as time goes on. So, multiple systems are involved in the problems that the dependent patient experiences. And this results in greater agitation because of the balance between GABA and glutamate, and the involvement in glutamate antagonists, and thus, an involvement in the amygdala and a person feeling a certain stress associated with codotropic releasing factor, and elevation of norepinephrine. So, when we look at this in a schema that I find very helpful, and this was developed by John Littlefield at the College of Pharmacology at the University of Texas in Austin, and I've made a few changes in his initial presentation, but it's important to recognize that the unconditioned response is when alcohol was given the first time, and that's what I showed you with intoxication. We have an endorphin release, we have a GABA effects, which is just calming, and it's just an enjoyable response. That's going to happen to most people. Now, some people immediately are going to have an increase in acetaldehyde and a period of agitation, but for those that like it, let's say, that's the unconditioned response. The reward is alteration in these neurotransmitters resulting in relaxation, euphoria, and stress buffering. They don't feel as stressed. So, the associated stimuli is, I feel better. That's the interceptive response. Extraceptive can be the environment, the fun they had with other people. They've now got a taste for this particular whatever drink they liked, and sometimes even associated with smoking or other potentially negative activities, but sometimes positive activities, being around a group of friends. That's the extratropic response. Repetition makes the associated stimuli that I just talked about, the mood state or the environment, a conditioned stimuli. So, over time, that becomes conditioned and capable of eliciting anticipation of the reward, and they become positively reinforcing and potential causes for relapse. They're associated with craving. So now, the same unconditional response of alcohol has been adapted and alterations in neurotransmission that's designed to oppose the effects of alcohol because, as I showed you early on, the GABA is down, right? We're needing more GABA because alcohol is a GABAergic drug, and too much of it, the brain says, what's this? We've got this other GABAergic drug. We don't need as much as though the internal GABAergic neurotransmitter or, excuse me, it's more in the receptor. It down-regulates those proteins, the receptor, and we have an up-regulation in glutamate, so we have a change in the glutamate receptor also. So, those are the adaptations that take place, and consequently, now, with these mood states that precipitate, are precipitating, are the anticipation of the use of alcohol, and that's the interceptive response and the extraceptive response, the smell, people they're with, whatever. All of these are stimulating the use of alcohol because if we don't use it, we have a stress response because of those maladaptive changes in the brain that have taken place with the constant bathing of alcohol. So, in dependence, conditioned stimuli elicit CNS adaptations to alcohol, generating conditioned tolerance if alcohol is taken and pseudo-withdrawal if it's not taken, and they are now negatively reinforced and are the continued potential for relapse. I say negatively reinforced because it's more a, I feel, I feel a little uncomfortable. I need a, I need a drink of alcohol and it's not withdrawal. It's just, it's just the, the, the absolute changes in the brain. We can get a person through withdrawal successfully, but the brain hasn't fully, it definitely hasn't, you know, made all these adaptations that take place. So we got them through that, that period of vulnerability that I spent time describing to you. Now, now it's this, this distress feeling that they have, even though they may not have drank for five days, a week, three months. Yeah, it takes, it takes a good, you know, three months easily for that, that, that, that stress response to take place. And some of those stimuli can continue for a long period of time. They can, they can come up sometimes years later, not so much the stress that they feel, but just that, that, that, that thought of having a drink. So, as Ben described, there's genetic and environmental influences to how we respond to alcohol, either positive reinforcing or negative reinforcing when alcohol is there or when alcohol is reviewed, removed after a significant period of time. This results in either rewarding or punishing and can lead to a drink. The punishing can lead to early signs withdrawal because of all those unopposed neuro adaptations that have taken place in, in, in the brain. Okay. So this, all, all these things lead to continued drinking in a person that, that has enjoyed drinking, but now has had these adaptations take place. So relapse is associated with the interceptive, the mood states that precipitate drinking. And again, this is relapse after withdrawal, that precipitate drinking. And again, this is relapse after withdrawal, after successfully getting through this traumatic event in the hospital or treatment center or whatever, and a month or six weeks, or, you know, three days, sometimes later, the stress of not having a drink results in them starting to use again. And so it can be an interceptive mood state, secondary to glutamate antagonists and cortico-releasing factors, effects on the amygdala, the stress response area in the brain, or extraceptive, the environmental site of alcohol, drink, smell, taste, you know, driving past the liquor store. These are cues that are a result of priming associated with alcohol and opioid receptors that are stimulating that thought so that all of our cues are stimulated by endorphins. And the endorphins to alcohol use and other drug use are profound compared to some of the endorphins associated with wanting to eat or even sexual activity or a whole variety of things that are not as profoundly driven as this brain state that has been associated with use of alcohol. And this results in a dopamine effect in the nucleus accumbens and the desire to have a drink. The response then is anticipation of a reward and pseudo-withdrawal, potentially this agitation, and subsequently provides positive and negative reinforcement for relapse. So either the delight in thinking about it or the smell of it or the agitation associated with not drinking. So this is where we can understand how the medications that we use to help people with cravings can work. First of all, we can use disulfiram, which essentially inhibits acetaldehyde dehydrogenase and the breakdown of acetaldehyde. And so people just get really sick when they drink alcohol. Okay. That's how it works. The other is naltrexone, which has a blocking effect, doesn't block all endogenous opioids. So people can still enjoy food or a sexual encounter, but it does lower it enough so that people just don't have that continued drive to have a drink when they are triggered with people, places and things associated with their drinking. And in this way, it's used to lower people's use of alcohol as much as it is to stop it entirely. And in Europe, it's used that way. It's the Sullivan protocol that just helps people drink less. And we can use it that way. And I have certainly used it that way here, because sometimes people just aren't going to give it up entirely. So, but at the same time, it is important for them to be on this medication, because if they don't, they drink to excess. And I will say, I primarily give it with a medication that can help with any agitation, that stress response that they experienced early on. So the first couple of months, you would use it with gabapentin potentially to reduce that stress response and allow them to be more comfortable in their early recovery. Acamprosate is actually similar to gabapentin in reducing the glutamate response. So it's a glutamate antagonist. And topiramate is also, and both of these medications really reduce that that agitation that they feel early on. But they need to stop drinking for them to do this. And consequently, it is unlike naltrexone, which once again lowers that cue response that they would experience. Naltrexone and acamprosate can be used together and has been used together and can be used successfully, similar to how naltrexone and gabapentin can be used together. Topiramate has also been shown to be effective in reducing mood instability, most frequently associated with hypomania sometimes. It's not a great one for this, but it can be helpful. And so that's another thing that may be one of the reasons that it's helpful in treating long-term treatment of people with an alcohol use disorder. So this is somewhat of a complicated slide, but it really does show you how these medications work in a schemata. Again, disulfiram or anabuse inhibits the breakdown of acetylaldehyde. And so when people drink, they get sick, they get flushed, they have a bad headache. And it also inhibits dopamine synthesis to a degree and may play a role in reinforcing of alcohol or the response that they're experiencing. Efficacy is maintaining abstinence depends on patient's belief. So double-blind controlled experiments with this, they can't be done because if people drink, they know whether they took anabuse or not, because it doesn't do anything for someone until they drink. It's the thought of how sick they're going to get that is the deterrent. And in that way, it is most effective when it's used with someone else. It is the most effective way to stop drinking. It is. But it has to be, the only way it can be used most effectively is if it's done with someone else, often a spouse or someone that they take their anabuse in the morning, and they're good to go. They're not going to drink on it. If they do, they're going to get very sick. It is important to recognize that it can cause significant elevation in vital signs of people with cardiac disease and problems probably are not a good candidate for the use of disulfiram. And acid aldehyde toxicity is inevitable consequence of liver failure. And so it's something to recognize that it can cause real problems, although typically this is an acute problem because they're not going to take anabuse and drink on it again. Naltrexone, relative Mu, selective, competitive antagonist, that's opioid Mu receptor, inhibits endogenous opioid transmission released by alcohol. It reduces the rewarding effect of alcohol conditioned anticipation of alcohol. That targets positive reinforcement, seeing people's license and things associated with their alcohol use, getting that heightened response and it blunts it. Clinical trials, three months trials, about doubles placebo response. It can be very effective in preventing major relapse, five drinks or more. Long-term complication, compliance of oral naltrexone is not good. There may be some mild anhedonia. It's reported. I have had many patients though that just don't feel anything at all when they take it, particularly after the first month. In the first month, it can have more of effect than it does ongoing. We know that very clearly in patients that are using it for treatment of an opioid use disorder. But the depo injection is most effective. And anytime I can get a person to take the depo injection, I encourage them to. Very little in the way of side effects. Most frequent is, and almost inevitable, is a little sore butt for 24 hours, but not typically much longer than that. And the effect is significant. And often patients actually start to feel like they don't even want more, which is really nice for many people. Acamprosate, again, it indirectly inhibits NMDA receptors for glutamate, reduces withdrawal weekly. So that is the post-abstinence effect. And reduces conditioned pseudo-withdrawal targets the negative reinforcement of N-conditioning. That is the stress response that they were having because of that heightened glutamate release when they stopped drinking. And again, this is only for the first few months. Clinical trials, three to 12 months, doubles placebo response, includes behavioral therapy in doing this and preventing any sort of relapse of one or more drinks. It was not replicated in the combined study, a study that you should take a look at after the MATCH study. But it is clearly effective in reducing that stress response that people experience in the first few months after abstinence. Long-term adherence is good. Side effects are minimal. Occasional diarrhea, non-potent, you know, it's two grams a day, requires three doses. It is the 666 tablet, which sometimes people will remark about that it's 666. Tapiramate is a GABA enhancement leading to increased inhibition of excitation. And so, it's a glutamate inhibitor and targets that, again, negative reinforcement, conditioning, and mood stabilization. Clinical trials, 14 weeks, double-blind. Studies showed significant decrease in drinking days and reduction in GGT. Side effects were significantly greater than in the tapiramate group. It causes a little blunting of cognition, which people don't like. And this has not had significant uptake. The JAMA study was, however, a good study by Hank Krantzler. And there's clear indication that something as addiction specialists, you can keep in mind that it could be helpful, particularly if there's a mood instability that could be helped with tapiramate and be very effective. So, in treatment summary, patients experience powerful conditioned responses at positive and negative, resulting in powerlessness of feeling, just a profound drive, like to eat or to procreate or, you know, it's like, it's just something that people are like, I don't even know how I started again. It was just such an automatic response when I was in this particular setting. Medications can blunt these responses. So, watch for more refinement of matching patients in periods of greater neuroadaptability to treatment choice. There's all kinds of work going on around how we can refine these and add some of the psychotherapeutic treatments. And there's another presentation on the psychotherapeutic treatments that can be combined with this that can also be very helpful. But I would really most prominently encourage patients to consider injectable naltrexone. This is, I think, the last slide. And what this is really pointing out, it was first presented by Tom McClellan, is what he was showing is when we look at hypertension, we have a person with high blood pressure and we give them a specific drug, have them in specific treatment for a period of time, and then we take the drug away over a period of time, and their blood pressure goes back up, we say, this is an effective treatment. But in addiction, for some reason, because it's so associated with behavior and we think we have control over our behavior, but, you know, everyone should look at their own lives and think about, you know, I was going to not eat this thing, or I was going to exercise more, or I was going to get to bed on time and not watch this particular television show. We have a whole lot of other things that are involved in our behavior other than what we want, what we consciously say we want. But unfortunately, in addiction, this isn't looked at this way. We think of it as behavior. So, if we have a particular treatment, and we send people to a recovery center, and they're there for 28 days, or even three months, or longer, and we take the treatment away, we don't prepare them for ongoing care. And in alcohol, I would add to that ongoing pharmacologic treatment, if the patient is open to that, along with the behavioral treatments of understanding the people, places, and things associated with their continued abstinence, or lowering of their use of alcohol, it's going to come back. And consequently, when we put them in these treatments, just like put them through withdrawal management, and then send them out to the public, withdrawal didn't work. That's not a treatment. These changes that have taken place in the brain are there, and we need to be addressing them. We need to help people recognize this is an ongoing problem, and that treatment works. You got to continue it. And that may mean AA and NA, like a patient I took care of yesterday that's continuing to have some mood instability, but has been in AA for 12 years. And when I ask if he's still going, he pulled a pamphlet out of his pocket of the, you know, where the most recent meetings are going to be. So, it's an ongoing process, and people that have really suffered from this disease can accept that, and are willing to make those changes. Mm-hmm. Chronic treatment, the excessive poisonous use of alcohol by vast numbers of persons in this country cannot be solved by theory and speculation. It is not, it is no chance, it is a no chance condition, but comes from specific causes, many of which I've described to you. The medical profession must, through practical investigation, reveal these causes and the means to remedy and neutralize them. This was stated by Dr. Carruthers in 1883. We've known this is more than just, you know, you need to stop. There's just so much that goes into it. And with that, I hope that you do well on your exam, if that's what you're watching this for. And otherwise, I hope that this helps you improve your treatment identification and treatment of patients with alcohol use disorders. And thank you very much. I don't obviously have the opportunity to have you ask questions, but I do know that we're going to have an opportunity for questions that you'll get a notice of in an upcoming webinar. And we would be happy to entertain questions if you have them, if you send them into the AOA. Thank you very much.

Alcohol Use Disorders

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Alcohol Consumption

Heavy Drinking

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