Welcome back to the review course and I'll be talking about a comprehensive review of benzodiazepines this morning. I know you've been watching a lot of your computers and I hope that this will be of value to you. You've heard this before. I'm an addiction psychiatrist practicing in Charlotte, North Carolina and I've had a variety of opportunities to work with people around the country on a variety of projects and have been in North Carolina the last six years. I have no financial disclosures. We're going to talk about benzodiazepines first, the pharmacology and pharmacodynamics of benzos and really looking at or coming from the idea that it's important to understand how they work to then better understand the safety profile, the adverse effects of these drugs and where they can be most effective, like which of the benzodiazepines are most effective in what the patient is presenting with in terms of their problems. We'll talk about some of the strengths and weaknesses of these drugs. I was just stating to Dr. Kamek that recently the FDA did put out a statement that they are going to put a black box warning on benzodiazepines in terms of their potential for misuse and dependence. At the same time, I think it's really us that understand that but at the same time understand the value of them and the importance of using them appropriately and really helping people with them instead of getting them into trouble. We'll talk a little bit about those patterns of misuse and then understand the clinical withdrawal procedures that we have and that are recommended in terms of tapering people off benzodiazepines. I show this slide of two people just to think about some of the difficulties that we all face with benzodiazepines. The first is a 40-year-old patient with a known history of anxiety associated with their depression who we've been treating with an SSRI. She presents with a personal trauma that took place a week ago. There is a description of not having slept more than four hours, of real inconsistent sleep a night over the last week. She's very tearful and really has this existential dread and anxiousness that she presents with. The second patient is a 67-year-old who treated for 10 years with a history of anxiety and depression. In recent months, the anxiety has been quite manageable and he's been doing well and his depression is more stable. Neither of these problems are causing significant social impairment. You've been treating the patient with an SSRI and a high-potency short-acting benzodiazepine for those 10 years, which we'll talk about. Now we're switching to she's scheduled for a total knee replacement in a month with anticipation that she'll be needing an opioid medication for the pain. A discussion ensues concerning the potential complications of co-administration of the benzodiazepine in an opioid. The mere discussion of tapering, much less discontinuing the benzodiazepine, results in a significant distress and resistance. That really speaks to the dependency that people get on these medications. The understanding that those times when they were without their benzodiazepine for sometimes a short period of time, depending on the benzodiazepine, they start to feel more anxious. Any consideration of stopping them is very distressing. Chlorodiazepoxide was synthesized in 1955 and the first benzodiazepine to be brought to the market as Librium in 1960. The class of medications gained favor over barbiturates rapidly, secondary to their efficacy. They do work well and reduced sleep onset latency and also their favorable safety profile. So those were the real key points that just launched it into being a medication that then went on to be a very highly prescribed medication. The idea that it has less respiratory depression and a higher therapeutic index subsequent to that, they were also thought to have less potential for misuse and dependence, which we've found otherwise over these 60-70 years. So over time, these different formulations have been found to also have other clinical applications as anticonvulsants and muscle relaxants and others. And then the 80s, the non-benzodiazepine or Z-drugs, Zolpidin and others, were marketed for insomnia because of specific properties of those medications. This is just one of the ads that were relatively commonly seen in the medical literature in journals and various places. At that time, there wasn't a lot of this going on in publications like magazine or something, but it was pushed very heavily in the medical literature. So this was from 1967 and it was gaining public renown. Mother's Little Helper in the Rolling Stones song is about benzodiazepines, Valium. So these classes of medication with similar mechanisms, that's the benzodiazepines and the non-benzodiazepines, Z-drugs, continue to have an important role in a variety of areas of health care. But there's been concern for a number of years of the over-prescribing of these medications and the potential adverse effects. There's very clear cognitive effects and with wider availability, there's been greater misuse and greater potential for development of a drug use disorder with these medications. These concerns have been associated in part with the building of tolerance, that is, people started a lower dose and continue to go up to get the same effect that they were looking for. And then the really big one, as I mentioned in the case presentation, is rebound anxiety. You miss a couple of doses and you have then this compensatory response, which we've talked about in a few of these lectures, and that is unbridled at that point and the anxiety comes back with a vengeance. Along with that is then when the decision is made and the patient clearly understands that there's going to be withdrawal, then there can be real complications to withdrawal, including potential seizure. So there can be significant disinhibition, typically resulting from misuse of the medications in a vulnerable population. So probably all of you, you've all seen this, where a patient is either taking an excessive amount or it's co-administered with alcohol and it turns into very crazy behavior and people can get in a lot of trouble. This is mostly young people but certainly, you know, older people that are struggling with one thing or another and take too much or drink with it and end up getting themselves into real trouble, either physical trouble or just emotional trouble when saying things to people that they wish they hadn't said. And there has been more isolated concern in two populations and that's the elderly and then of course these folks that do already have a drug use disorder and then start using these appropriately. But with the elderly, it's a real problem in terms of that cognition, falls, all kinds of, you know, problems along with co-administration of opioids. So the truth, however, and this, you know, we deal with more difficult patients and their benzodiazepines, but the truth is most patients will take these medications, if prescribed, for less than a month. So most of the time, and a big study was done in California, Medicaid patients, and this was the late 90s or early 2000s, where they really established that most patients took the medication as prescribed. However, 12% of the population do go on to, or 12% of the population have had exposure to a benzodiazepine in the last year and that's a big number, you know, and so one out of ten people have used a benzodiazepine in the last year. Six months, six months use occurs in about 3% of the population and about 1% of the population has been on benzodiazepines for longer than a year and there's no clear indication for that. So there's no, there have been some indicators in terms of people with significant insomnia, chronic insomnia, that's been well documented that the drugs and some of the benzodiazepines have been very helpful and will continue to be helpful with them, but that's a very small population. Most people, that's not why they're having difficulty sleeping. And then there are some chronically persistent, people with chronic and persistent mental illness that will be on them, but even there, within the APA guidelines, there's not clear indications that that's particularly helpful and it's not recommended. So long-term users are then noted to be older, female and with more significant health and emotional problems, which of course, again, is a population that really can get into trouble with these medications. About 30% of psychiatric patients have received a benzodiazepine at some point and the greatest use in patients with affective disorders and long-term mental illness and those with higher psychiatric services are the ones that are typically, you know, at some point they've been prescribed a benzodiazepine for agitation or for a bridge to initiating another medicine. Generally, most patients tend to decrease anxiolytic doses over time. These are prescribed medications and there's recognition that, you know, they're just not thinking as clearly. And the use of antidepressants to treat anxiety has increased in, excuse me, has increased in, excuse me, the use of antidepressants to treat anxiety has increased in recent years and the use of anxiolytics has fallen, partly because of people recognizing that these, you know, they're controlled substances that begin to wonder where are we going with a patient and the recognition that the benzodiazepines long-term are not as effective as using an antidepressant, particularly the SSRIs. There are certain groups of high-risk patients where long-term use and misuse is greater than in patients with anxiety disorders. So sometimes it's the patients with anxiety disorders that initially got some help but then get on to more maintenance treatment with medications that get closer to the source of their anxiety, let's say, instead of just masking it or inhibiting it. So benzodiazepines certainly complicate our work. Illicit users of benzodiazepines have been found to be on higher doses of methadone. They're troubled patients, I will say that. It is sometimes an indicator that there's other things going on and there's other problems that we should be attending to other than maybe just their opiate use disorder or something like that. So there's often a lot of chaos in their lives, so they're high-risk takers, so there's a greater percentage of people with HIV and hep C, indicators of high-risk sexual behavior or injection drug use, greater poly drug use, so they're just trying to do something to feel better or do better, and higher levels of psychopathology and social dysfunction. Though the research is limited, we need more research to really understand what are the causes and how much of it is because of these underlying psychopathology and social dysfunctions that are often apparent, or is it the effect of the drug? And I would contend that it's really a combination of the two. Unfortunately, so often, as I talked about some yesterday, adverse childhood events, all kinds of problems in the household, and underlying psychiatric problems can result in early traumas, but then drug use just perpetuates the trauma. Benzodiazepine use is higher among Medicaid beneficiaries with mental illness and co-occurring substance use disorder than those with mental health problems alone. So the Drug Abuse Warning Network, which was set up to monitor emergency departments, identified 89% increase in emergency department visits associated with benzodiazepines over that four or five-year period in the mid-2000s. And the estimated number of visits for alprazolam was more than twice the number for the next common benzodiazepine, clonazepam. And I would contend that that is because there's so much more alprazolam or Xanax prescribed than any other benzodiazepine. And this, you know, harkens back to the opioid problem. The more that it's being prescribed, the greater the potential that there's going to be drug on the street. And this is the importance, just like with opioids, that we talk to patients about, if they're not using the benzodiazepine any longer, then get rid of it, you know, dispose of it appropriately. The relative magnitude of the rates shown generally reflect prescription volumes. And 44 million Xanax prescriptions were written in 2008. In New York, the health department had shown that benzodiazepines were tied to more than 30% of the city's overdose deaths. And I'm not going to spend much time looking at that, the overplay, you know, the interplay between opioids and benzodiazepines. But it's maintained in that range, if not a little higher in some communities. And again, it's mostly when there is more benzodiazepine available. If it's there, then it's going to get spread around. You know, emissions have also increased and have continued to increase, though there's been some leveling off. It's been, you know, still very high. Again, that people will have it in their system. I'm going to show you, it's not often the drug of choice, but it's often used with other drugs. The majority of the emissions were male between the ages of 18 and 34. So this is still in a kind of higher risk, risk-taking community and non-Hispanic whites. Also almost all benzodiazepine emissions reported misuse of another substance, as I stated a moment ago, in addition to the benzodiazepines. So they're typically not coming in for benzodiazepine withdrawal or treatment of their benzodiazepine, but it is often associated with their other drug use and absolutely needs to be attended to. They need to understand those drugs and be aware of the fact that it's going to set them up for either relapse to their drug of choice or cause them problems, the drug itself. 82% reported primary use of another substance, 12% reported primary use of the benzodiazepine, and 61% of benzodiazepine and opiate combination admissions reported daily use of the substance compared to 35% approximately of other admissions. So they are going to use the opioid daily, but they're supplementing with a benzodiazepine for one reason or another that we'll talk a little bit about. So here's benzodiazepine misuse and as you can see, the biggest change is it's in the older population and this is a real high risk population, but if made available and are not watched closely, it can get out of hand. It's not infrequent that the older population, kids are out of the house, maybe they're retiring, they have more time, they start getting anxious about their health or their finances and turn to potentially some high risk behavior that they had been involved with as young people, but that certainly can include the use of benzodiazepines. So the VA did a study of concurrent opioid and benzodiazepine use and found that 27% of the veterans who received opioid analgesics were also being prescribed a benzodiazepine. Again, pain can cause a lot of anxiety and stress and people can be very upset about their situation and it can be associated with traumas. So PTSD and other things where it's thought, and it's true, benzodiazepines will bring that down, but unfortunately it also has resulted in, in this case, about half the deaths from overdose occurred with concurrent benzodiazepine. Whether that's setting someone up for slowing of respirations already and then compounding it obviously with an opioid and really changing the response within the medullary respiratory center and their response to CO2 and sleeping through it and dying. But also that not sure when I took the last this med or that med and really moving into real chaotic use of these potentially dangerous medications. So overdose deaths increased with a history of benzodiazepines, increased risk of death correlated with increased benzodiazepine dose. Tamazepam, Restorol was associated with a decreased risk of death from overdose compared to Klonazepam. Again, partly because of the quick onset, but also the longer duration of the medication and potential compounding the benzodiazepine. So here you see where there's been this significant influence of benzodiazepines on overdose deaths in the last 20 years. And it's definitely still a problem. And with the advent of fentanyl and the big spike in overdose deaths that took place in the last few years, benzodiazepines have certainly compounded that problem also. So past year prescription tranquilizer and sedative misuse in patients 12 and older showed that there has been some reduction actually in the use of benzodiazepines in the younger population. And it's thought that in some ways that is our kind of recognition that we need to be a little more careful with these drugs so that they're not just in every cabinet. And because when they're available, young people are going to get a hold of them and try them. And so that's where really talking to patients about the importance of keeping their medication safe and disposing of medications after you're done using them is really important. So now I'm going to go into what are these drugs? How do they work? And what are the good things and what are the things that we need to be careful about? So sedative hypnotics are very effective in modulating GABA amino butyric acid or GABA. And GABA is the major inhibitory neurotransmitter in our system. And there's GABA the transmitter and GABA receptors to that transmitter. And it suppresses the central nervous system activity, resulting in an anxiolytic effect, a hypnotic effect. So all of them will put you to sleep at certain doses. Many of them are anticonvulsants, not all of them. And some are more potent as anticonvulsants than others. Same with muscle relaxation. And they're often used as anesthesia and induction agents. So it works by GABA coupling to the GABA receptor at specific sites, resulting in influx of calcium and hyperpolarization of the receptor, resulting in inhibition of neurotransmission by diminishing the chance of a successful action potential. And it's really working on... It works in this inhibitory way and reducing the effects of glutamate primarily, but it's the excitatory neurotransmitters. And the important point is that it needs GABA to work. It augments the, or increases the potential for GABA to work more efficiently in a way, or the inhibition, these are chemical reactions, obviously, it happens more rapidly. And so the GABA receptor is a binding site for GABA. Different allosteric binding sites modulate activity, and there are direct agonists like the barbiturates and alcohol, and then those that enhance GABA binding, like benzodiazepines. And these allosteric sites are the targets for various drugs, benzodiazepines, non-benzos, benzoates, ethanol, neuroactive steroids, and inhaled anesthetics. And again, specific sites, and you have to have GABA for it to work. And that is the safety profile aspect of benzodiazepines. So there are specific considerations in the use of benzodiazepines. Major clinical advantages are they're highly effective and have relatively rapid onset, and some very rapid onset, and low toxicity that I've said now a few times. The rationale use requires consideration of large formulation differences in potency and elimination rate and requirements of an individual patient. What are we trying to do with this patient? And that would have to do then with selection of the specific medication. The adverse effects include psychomotor impairment, especially in the elderly, occasionally paradoxical excitement, that's that disinhibition. And long-term use will result in some tolerance, dependence, and withdrawal effects, so that counter-adaptation to the drugs. Unwanted effects can largely be prevented by keeping doses minimal and courses short. Most of the time, like the first patient I presented, it's because of a specific trauma or a change in medication or a specific phobia that they're going to fly across the United States, and these days, very afraid of it. But to give them a short-acting benzodiazepine, three pills or something, four pills, can be very helpful to people. But you need to be careful in your selection. And those people that have a history of significant alcohol or other drug use, you want to be very careful with. Long-term prescriptions is only occasionally required in very few patients, actually. There's also cardiovascular problems. There can be hypotension and bradycardia, particularly with rapid injection of these medications and valium or diazepam. Cardiopression is seen clinically relevant in patients with respiratory disease and certainly those that would be using other sedatives, alcohol, or barbiturates. Side effects of toxicity can result in morbidity and mortality for some patients. There could be lung, liver, kidney dysfunction that will augment the problems that one might see, and patients on other classes of medications, especially prone to toxicity. But the lethal overdose from a benzodiazepine alone is quite rare. It's mostly when it is associated with other drugs or compounded by other underlying disease. The results of 13 studies in this meta-analysis, benzodiazepine, their duration was one to 34 years that people had been using it. The average dose was approximately 17 milligrams per day of diazepam. So a couple of 10 milligram diazepams a day. The results suggested a decline in cognitive domains measured in all these different problems. It was very clear, and I'm sure many of you have helped get people off benzodiazepines in the past, and it's really amazing how they so frequently will say, wow, I am just thinking so much more clearly. I had no idea. Again, as I showed you in the talk yesterday morning, perception, if we're seeing it a certain way, it's like watching a child grow. We really don't conceive of the changes that are taking place, and pretty soon it becomes the norm. Tolerance also occurs. There's decreased responsiveness to the subunits of benzodiazepines over time. This results in a reduction in receptors, as it's been pointed out in other lectures, and their function. Tolerance is primarily a result of the pharmacodynamics and the neurobiologic adaptation. developments to disinhibition and sedation, euphoria, and drowsiness are seen with the benzodiazepines. Those are the things, particularly as no longer sleeping quite so well, they don't make me feel so great anymore, but now I'm dependent on them. Developments to anxiolytic effects is somewhat variable between individuals, and there's a couple of interesting studies showing that some of that is even placebo. Physical dependence becomes apparent when withdrawal occurs. They're discontinued. On withdrawal, these compensatory changes reduce the GABA receptor function manifested by anxiety, insomnia, all the things. When you see what they're doing, the counter to that would be all the things that are happening. If it sedates you, you take it away, it's going to make you very excitatory, and the opposite is true. Can occur after continued use of two to four months, and that's one thing I've had patients be in the hospital for a few days, be on benzodiazepines for a week, and come out and I'll say, well, you don't need any more of this, things seem to be good, and that's fine. And they'll immediately be going, oh, but I'm going to go, I'll go into withdrawal. You can't just stop them. Yes, you can. People do not develop tolerance over a very short period of time. And it's reported that 50% of the patients treated for four to six months will have withdrawal symptoms, and so it's not all of them, but you need to be very careful. Urine toxicity is another issue. Immunoassay screening techniques are very common. Most detect benzodiazepines that are broken down to hexazepam, so that's why we miss some of these, and the cutoff level is 200 nanograms, so some of the very high-potency medications like alprazolam and clonazepam will kind of fly under the radar, and 48 to 72 hours post a single dose, it can be picked up, and sometimes for as long as a week. In the US, chromatography mass spec, cutoff levels for metabolites are lower, and so qualitative screening of urine and blood may be performed, but rarely influences treatment decisions. Again, we use these to help the patient, not to catch them doing things. So you're watching them. They're not moving forward in the way that you want, that you expected from what they're telling you, so you get a tox screen to better determine where they're at and use those results to help move them forward. Elimination of benzodiazepines are hepatically eliminated and then renally excreted, either by oxidation or glucuronide conjugation, which is the primary way in which lorazepam is excreted, and consequently, it's not broken down in the liver, and it doesn't turn into oxazepam, so again, can be missed on some immunoassay to point of care testing. Most are oxidized to oxazepam, and lorazepam, oxazepam, temazepam are metabolized by conjugation alone. Clonazepam undergoes this nitro reduction. So again, if you're only looking, if your test is only looking at oxazepam, it's not going to pick up these quite common benzodiazepines. Here's a schemata of the breakdown, and it's something, you know, take a look at it, it might be something on the test, just trying to figure out why something's happening, because there's a lot of history problems, and so this will be on your slides that you have available to you. Limitations exist in screening benzodiazepines using traditional assays, immunoassays for benzodiazepines target, and I'm going over this again, nordiazepam and oxazepam, other benzodiazepine compounds are tested for their ability to cross-react with a target drug in immunoassays. So if you ask for specific things, or look at your immunoassay, it may be picking up some of these other cross-reactive medications. Some commonly prescribed drugs have limited cross-reactivity, like lorazepam, as I described, and clonazepam, and then there's limited cross-reactivity with traditional immunoassays due to the molecular structure, not common for a laboratory to obtain this negative immunoassay. So you then go on and get confirmatory testing, where you're specifically looking for, you know, on this panel sometimes up to 100 different medicines, but if there is something in particular that you want to look for, then you ask for it. How reinforcing are they? In animal studies, oral benzodiazepines showed not great evidence for reinforcing, that is, putting them in like a Skinner box, these were primates and rats, where they're not going to keep pressing for a benzodiazepine necessarily, but there was an injection use of it where it's more rapid onset, and I don't know if this has been stated to you before, but it is the speed in which a drug gets to the brain that we have that increases the addictive potential of the drug. So chewing coca leaves is less addictive than snorting cocaine hydrochloride, which is less addictive than smoking or injecting cocaine. So again, that ties into this reinforcement. Humans, normal light drinkers without anxiety or insomnia, that is prior to the test, don't prefer benzodiazepines over placebo. It's not highly reinforced, but those people that like that experience, like mild intoxication, moderate to heavier drinkers, have a greater chance for the development of a benzodiazepine dependency. Intentional misusers of benzodiazepines usually have other substance misuse problems. Benzodiazepines are usually a secondary drug of misuse, either to augment their high or to offset the adverse effects of other drugs, like strung out on methamphetamine, they'll take a benzodiazepine to just try to come down and get some sleep. So it can be used for that crash with cocaine. There can be this augmentation with people drinking alcohol, and up to 80% of people that misuse opiates have taken a benzodiazepine. It just gives them a more relaxed feeling. And most non-medical uses, occasional use of therapeutic doses for symptom relief, not associated with escalation or high dose misuse. So it's mostly kind of taking a little of this to take the edge off or to augment whatever the experience they're looking for. And so that is, it's not recreational use, it is, but it's not in a sense that it's not just by itself to have a great experience, it's to, you know, I'm feeling a little anxious because of whatever, as a person that already has a drug use disorder and they use it. Intentional misuse, so then most misuses is by those drugs that are short acting or rapid onset, the alprazolam, lorazepam, clonazepam, highly lithophilic, those are medicines that are going to get into the brain very rapidly, like valium or diazepam, short half-life or high potency drugs. So they're there and then they're gone. And clonazepam, high potency, long half-life, has been perceived as safe because it has this long half-life, but it's a very frequently misused drug on the street, partly, again, because it's so available. Withdrawal symptoms will typically only occur if the patient's taken it for a few months. The more severe withdrawal symptoms are seen most frequently in those taking benzodiazepines for more than a year at higher doses, using of agents with shorter immediate half-lives. Withdrawal symptoms can appear within 24, 48 hours of the short half-life drugs and within 72 hours or a week of the long half-life drugs, which makes sense. The way in which we withdraw people, the syndrome includes all the rebound from being highly sedated, let's say, to then having anxiety and restlessness, tremor, sweating. And there's rebound anxiety, as I've described, and reemergence of the anxiety symptoms. So they think, I've got the worst anxiety in the world. And use of non-addictive medications for treatment of anxiety. There's a variety of scales that you can use that are listed here. Don't have any particular recommendation. We use the CWEP for benzodiazepines. Very similar to the alcohol. Too often cited protocols are to reduce the current dose by 25% initially and then every two weeks until the lowest dose is obtained and then discontinue it. More frequently, people will start with higher drops in the medication, but then after a couple of weeks, a few weeks, drop down to 10% per week to the final discontinuation. Moderate reductions of higher doses and smaller reductions at lower doses to prevent excessive withdrawal symptoms. In patients who've failed a routine taper, you can consider a very slow taper over months. And it really depends on the patient. If it's somebody that you feel is at high risk and you're just really concerned about how they're using these, then you want to be more rapid. And those people that you trust and that have been taking the medication appropriately for a long period of time, but it's time to get off, you might take six months or longer to get them off. Taper augmentation with cognitive behavioral therapies can be extremely helpful and really should be put in place with the anxiety disorder from the beginning. A comparison of these efficacies in tapering benzodiazepines plus cognitive behavioral therapy alone showed that a combination of these two therapies was superior. So always give them some understanding of what their disease is and then tapering them down. We're going to talk about cognitive behavioral therapies in a later session. Alternate medications may be useful in successfully tapering benzodiazepines, including gabapentin, omipramine. The tricyclics can be actually very good anti-anxiety medications along with helping people sleep and maybe with underlying pain. Trazodone, comromazepine, valproate, all have been shown to be somewhat helpful. So here's another graph, I'd have you take a look at it. We're kind of running out of time, so I'm not going to go through this, but it's interesting to look at, the very idea that a half a milligram of klonopin is equal to 10 milligrams of valium. So we really need to be careful in how we're prescribing these drugs. Here's another list of ways in which you can reduce the benzodiazepines and taper people off safely that I'd have you take a look at and just understand these. I'm not sure how it would be placed in your test and most of the time, either you kind of have an idea how you want to taper someone or you look up one of these protocols and you use it to taper people off safely. There's, again, phenobarb can be very helpful. We do that in the hospital most of the time. And here you're essentially loading them and then tapering them off. And because phenobarbital is so long acting, you can really load them, taper relatively quickly and they're going to feather off or taper off nicely over the next few days, even after they leave the hospital, they're still covered. And then transient short term anxiety, limited to a few days, not exceeding two weeks for the hypnotics, occasional for intermittent use, formulation with medium duration of action is suitable. Anxiolytics, we're looking at treating the stress response, episodic anxiety. The use of these medicines intermittently is a really good way to go with those patients that you trust and that you've talked through. They're using some cognitive behavioral therapies, not taking them every day. That's the same with sleep. Sleep can be improved significantly with intermittent use. So I always want to throw in, you know, exercise, good sleep hygiene, decreased coffee, tobacco, alcohol, and potentially other deleterious substances are how the patient's really going to get healthy and in that way reduce their anxiety. So in summary, these medications can be extremely helpful if used appropriately and screened for these potential problems. It doesn't mean that we don't use a benzodiazepine in someone that's highly anxious and has a history of alcohol use disorder. No, you know, it's just like in pain. We still want to treat them and we may need to use a benzodiazepine, but then we want to just give a very short dose and until we're able to get them onto or into some other form of treatment and be very careful with the elderly and using these medications and those that are on opioids. And that's the end of my talk. So thank you very much.

benzodiazepines

pharmacology

FDA warning

misuse

withdrawal

dependence

cognitive effects

tapering