Hello, everyone, and thank you for your attention. I'm Chris Blazes from Oregon Health and Science University, and I'm here with Dr. Jeffrey Gold, who's an advanced practice psychiatric pharmacist based in Colorado and faculty at University of Colorado, and Alexis Ritvo, who is faculty at University of Colorado as well and an addiction psychiatrist. And we're excited to be presenting on the topic of benzodiazepines, challenges and solutions. And thank you for your attention. So we don't have any significant financial disclosures, but these are here for your reference. So in terms of learning objectives, at the end of the session, participants will be able to develop a better understanding of complex persistent benzodiazepine dependence, also understand the term bind, which is benzodiazepine induced neurologic dysfunction, as well as to apply diversified strategies for tapering benzodiazepines and to recognize the historical perspective and its importance to where we are now with the situation with benzodiazepines. So I'm just going to jump right in. So I think what's happening with benzodiazepines in the modern world actually reminds me of a brave new world. So I invite you to think back to probably your high school days when maybe you read this book by Aldous Huxley, who's one of my favorite authors. And just as a quick refresher, this was a chemical dystopia where Henry Ford was reversed, was worshipped as the prophet, there was assembly line efficiency and homogeneity and predictability. And everyone was made happy because Soma cured all pain. So essentially, it was oppression through making happy. And any individual effort to create, to evolve or to change was painful. And if anyone experienced this painful call to action, they were given Soma, because Soma made everything acceptable and comfortably numb. And so this was a famous poster from the book Soma, a gram is better than a dam. But as we know from the architect in the matrix, pain has a purpose. It's a call to action. And so what happens when we lose that purposeful call to action? So just as a review, we're going to talk about benzodiazepines and they act at the GABA receptor and they're positive allosteric modulators, which just means that they alter the structure of the receptor in order to increase the activity. It actually does get more complicated than that with the GABA activity. There's a GABA A receptor and a GABA B receptor, and this does actually have clinical relevance. So let's go into that just briefly for a second. So the GABA A receptor, it's kind of like the tortoise in the hare. The GABA A receptor is a ligand gated ion channel that mediates large and rapid increases in neuronal inhibition. And it's kind of the usual suspects that act here, benzodiazepines, Z drugs, barbiturates and alcohol. But the GABA B receptor is a G protein coupled receptor and it more slowly maintains the inhibitory tone. And some other medications act at the GABA B receptor, including baclofen, phenibut, as well as GHB. And there might be some clinical relevance to these as we'll discuss later. So GABA is the primary inhibitory neurotransmitter and it's in counterbalance to glutamate, which is the primary excitatory neurotransmitter and the glutamate acts at the NMDA receptor. And the balance between the two is key. So GABA and glutamate are in counterbalance with each other and for proper functioning of the CNS in order to develop physiologic homeostasis, maintaining the opposite forces that acting independently is an important aspect. So GABA and glutamate are present in practically all functions in the CNS. There was a study that estimated that together, that GABA and glutamate are involved in over 90% of all neurotransmission in the brain. And that's an impressive number if we think about it. So if we're wondering why these medications are so powerful and they have such a profound effect on people, it's because it's involved in almost all neurotransmission in the brain. And this is why people become so attached to their medications, both physiologically and psychologically. So let's face it, benzodiazepines are powerful medications and they really seem to work for people. They really seem to dissolve away anxiety, at least temporarily. And they really seem to help people sleep. And so it can be very invalidating when a patient comes in and says, you know, doc, this is the only medication that works for me because in some sense it feels like that's the case. But it's our responsibility to understand what are the consequences and what's the cost because there's no free lunch out there, right? And so we're going to review some of that. So benzodiazepine are used for a lot of different things. You know, for the most part they're used for anxiety and insomnia. And as you can see from this data, anxiety and insomnia are two of the most prevalent conditions that people struggle with, you know, in the Western world. But as a reminder, benzodiazepines are powerful medications that are used for other things in terms, including muscle relaxation as a sedative hypnotic for anticonvulsants and for alcohol withdrawal. And in my opinion, I think the pendulum has perhaps swung a little bit too far. I often encounter trainees who are reluctant to use benzodiazepines for acute agitation in the emergency department or in ICUs or for alcohol withdrawal. So in the right place, these are powerful, effective medications, but they're just perhaps not best to be used on a chronic daily basis in most situations. So this is the story of what's happening when there's a lot of suffering out there and there's money to be made. So now we're going to talk about the historical perspective. So it started off with barber chariots when they arrived on the scenes and we were told some facts about these medications, that this was the new wonder drug that was safer than opiates for sleep and anxiety. So now we're starting to have reminders of soma in a brave new world. But then, and barber chariots, I'm going to review some kind of dark historical advertising relative to sedative hypnotics. And I think it's important that we understand our history so as to be protective from going down those pathways again. And barber chariots were farmers early attempts to convince us that we need a pill to cope. And many of these advertisements were directed specifically towards women. This was one where it says, now she can cope for just take butazole. This is a daytime sedative for everyday situational stress, like playing with your children. A gram is better than a dam. So when she overreacts to any situation, sedation without a sedative daze. But then we learned they weren't safe, right? Marilyn Monroe, Judy Garland died from overdoses. So then we were told some new facts, then benzodiazepines arrived on the scene. And the facts that we were told that they were safer than barber chariots. The first was chlorodiazepoxide, which came out in the 1950s. And it was actually marketed by Arthur Sackler, who was working for Roche Pharmaceuticals at that time as an independent contractor. And it was heavily marketed to treat the stressors of life, like going to college, raising kids, marriage, getting older, responsibilities in general. So it was encouraging people that would need to take a pill to feel normal. So again, a gram is better than a dam. So again, the marketing was very heavy with benzodiazepines. And in a way, actually, pharma created their own demand by pathologizing normal conditions. This one is for C-rex. You can't set her free from this cage of mops, but you can help her feel less anxious. A gram is better than a dam. And this marketing was a grand success, right? The marketing destigmatized anxiety, and it was mostly directed towards women. So just like Prozac destigmatized depression, Alprazolam destigmatized anxiety. And between 1969 and 1982, diazepam was the most prescribed medication in America, with over 2.3 billion doses sold in 1978. So how effective was all this marketing? So Donovan Mauss estimated in 2018 that 12.6% of the population in the United States were prescribed a benzodiazepine with a two-to-one female-to-male ratio. And it's also estimated that a significant percentage of even high school seniors are prescribed benzodiazepines. But more important for our population, it's estimated that up to 25% of people who are taking Suboxone, Methadone, or another opiate are prescribed benzodiazepines. And I estimate it might even be higher than that. So this is an excerpt from an article published in JAMA in 2015, which shows two disturbing trends. One, which we already addressed, which is that the female-to-male ratio is about two-to-one. But the other is that the likelihood that you'll be prescribed a benzodiazepine is directly proportional in a linear relationship to age in years. So as we age, the likelihood that we will be prescribed a benzodiazepine goes up significantly. And this is problematic because as we age also, as we know, we're more vulnerable to the side effects of benzodiazepines. So we'd like to say that it's just the drug company's fault, but also I think we have to recognize that the government has some responsibility here as well. So we all know that benzodiazepines are DEA Schedule 4, right? And then Schedule 4 actually, with the definition of that is that it has a low potential for abuse and a low risk of dependence. So these were the facts that we were told by the DEA and it appears that that's, I think most of us would agree that that's likely inaccurate. So this is an important study because there's still kind of debate out there, are benzodiazepines drugs of abuse? And so what kind of defines a drug of abuse is if it causes dopamine release in the reward circuit in the nucleus accumbens. And this was a nice study that was published in Nature in 2010 that shows that benzodiazepines directly activate dopamine release in the reward pathway. So there's really no debate. Benzodiazepines are drugs of abuse. So we're going to review now some of the consequences and side effects and complications of benzodiazepine use. Just as a quick review, it's been known for decades that benzodiazepines can cause cognitive impairment while people are taking the medications. But kind of the more relevant topic of debate now is, will this be a durable effect? So there were multiple studies that came out over the last 10 or 15 years that show that there's an association with benzodiazepines and Z drugs and the increased likelihood of dementia. They're saying it's more associated with higher doses, with longer acting benzodiazepines and long-term use as we would expect. But this is actually controversial because there were two papers that came out in the last few years which are arguing against that. So this was a paper that came out in 2020. It was a very large study following 235,000 patients over a period of six years, and they did not find an association between benzodiazepine and Z drugs use and subsequent dementia. And some of their results were actually compatible with a protective effect. And their theory is that insomnia and anxiety are known risk factors for dementia. And so if you're treating them, then the likelihood of dementia developing might decrease. And then in 2019, there was another slightly smaller study which showed similar findings. This was a study of following 8,000 patients over a 10-year follow-up, and they did not find any evidence of increased risk of dementia associated with benzodiazepines or anticholinergic. So this came out in 2021, and this was a review of reviews. And they did find that there is a link between benzodiazepine use and cognitive decline and dementias, but specifically in older adults. And for those of us who kind of see these patients on a daily basis, I think most of us would agree in a certain population, there is absolutely evidence of cognitive decline. And we're going to talk about some examples of that later. So there's overwhelming evidence, experimental and epidemiologic, that benzodiazepines and Z drugs are implicated in fatal and non-fatal MBAs. We don't have to get into the specifics of that. But this is a study that's worth mentioning. It was published in 2014. They followed about 35,000 patients for 7 1⁄2 years, and they determined that the age-adjusted hazard ratio for all-cause mortality was about 3.5 after adjusting for confounders. And so that's some pretty concerning data. The fact that you're on a benzodiazepines means that you're 3.5% times more likely to die as a result. It's always nice to have corroborative data. This was published in JAMA in 2020. They followed 35,200 patients for a median of 6.7 years. And they also found that there was a significant increase in all-cause mortality that was associated with benzodiazepine and opioid co-treatment, but also with benzodiazepine without opioids. And the hazard ratio was a little bit more modest at 1.6, but nonetheless corroborative data. So benzodiazepines, they are an independent risk factor for suicide. Dodds released an article in 2017, which was a review of 17 studies, and they found that there was a significant association between benzodiazepines, Z-drugs, and suicide. And they felt that it was more mediated by aggression, which may be related to paradoxical responses, or behavioral disinhibition. But once I became aware of this, it was striking how often this actually shows up. In my clinical experience, I find it most commonly with clonazepam, and I find it most commonly within the first month of it being prescribed. And there is actually data to support that as well. So zolpidem and suicide, there's a similar association. This was a case control of about 2,200 patients. And they also found that zolpidem was associated with a two-fold greater risk of suicide after adjusting for multiple confounders. So this is a real association, which I think we should be aware of and ask about. There's decades of evidence implicating benzodiazepines in falls, and falls are a big deal, right, especially in the elderly population. It can lead to significant morbidity and even mortality. So this was something that surprised me a little bit. Benzodiazepines have been shown to increase the relative risk of pneumonia. This was a meta-analysis of 10 studies involving more than 120,000 pneumonia cases. And they found that the odds for developing pneumonia were 1.25-fold higher when a patient was taking a benzodiazepine. So now we're at a place in history where many folks have been on benzodiazepines for a long time. And now we understand the addictive nature of these medications. And it's really hard in many circumstances to get people off these medications. Long-term use itself or attempts to taper can even lead to psychological or physiologic consequences and stressors. So now we're going to talk about benzodiazepine-induced neurologic dysfunction. So Dr. Ritvo, thank you for presenting. Yeah, thank you so much, Dr. Blaisdell. So now I want to talk to you about a new term for something that many of us have seen for a while now. So I'll talk about some of the previous terms for it, but we're now trying to suggest that it be called benzodiazepine-induced neurological dysfunction or BIND. So hopefully many of you are aware of this, but I think a lot of important things, maybe it didn't get as well disseminated as it should have. But in September 2020, the FDA updated their black box warning for all benzodiazepines to address the serious risk of addiction, abuse, physical dependence, and withdrawal reactions. And so what I want to focus on here is that risk of physical dependence and withdrawal reactions and how to better understand it. So as part of this FDA boxed warning in 2020, they had received a number of reports that led to updating their warning and found that symptoms of protracted withdrawal, which we're suggesting be called BIND, can last 12 months or more for some individuals. And that addiction and abuse or misuse of benzodiazepines is most common in the context of individuals who are also using and at times misusing other illicit or addictive substances. However, anyone taking a benzodiazepine, whether prescribed or not prescribed and taking it regularly, is at risk for physical dependence and a potential protracted withdrawal. And so the recommendations from the black box warning was to standardize the warning labels across all medications in this class, to continue to urge more judicious prescribing, and to really highlight that when it is possible to always try to do a more gradual taper off of this class of medications. The FDA further highlighted what we are all aware of is that physical dependence is one component of addiction. However, individuals can and do experience symptoms of physical dependence in both tolerance and withdrawal and may not meet full criteria for addiction. In order to have addiction, have to have the other criteria, including loss of control of use, consequences from use, and cravings. And in the FDA review, they had 104 reports to their adverse outcome database and found that for many people, these adverse events occurred when they were taking a benzodiazepine as prescribed for therapeutic use. I will point out, and this was brought up when talking about this with other colleagues, you know, we're not trying to say that this isn't also occurring in folks that do develop a benzodiazepine use disorder. I have seen it happen, and I think that's another important place for us to consider how to address this. But we also know it's happening a lot in people that are just taking these medications regularly, whether prescribed or not. The average length of withdrawal in these cases was nine and a half months, and the report found that individuals developed physical dependence to the benzodiazepine weeks and on average about 14 days after starting to take this medication regularly, and that these adverse events worsened when folks stopped suddenly or tapered too quickly. Other common themes in this report were that there was a misdiagnosis of benzodiazepine withdrawal and instead was seen as ineffectiveness of the benzodiazepine and further increased dose of benzodiazepine, that individuals were told they could just stop the benzodiazepine they were on abruptly because they were on, quote, a low dose, and that many were told to taper too quickly, for instance, having their current dose, so decreasing by 50 percent, resulting in worsening of withdrawal symptoms. And the overall conclusion is that there's a lack of awareness or misconceptions among prescribers about appropriate management of patients taking benzodiazepines. Additionally, things that came up, so I already talked about the common themes from the FDA, that there was a lack of informed consent among patients when they were started on these medications, that they were unaware that they would be at risk for physical dependence and subsequent potential for bind or protracted withdrawal if they stopped this suddenly or tapered too quickly, and that there should be more of an informed consent process about these potential risks when starting these medications. Additionally, that there was a lack of medical support so that medical community was not aware or knowledgeable about this risk of physical dependence and tolerance, were often misdiagnosing these symptoms, only identifying acute withdrawal, but not identifying when there was a more protracted withdrawal or bind, and had a misconception that overall any withdrawal symptoms should resolve within 10 to 28 days depending on the half-life of the medication. Additionally, that there was a real lack of deprescribing support for patients from their prescribers. I will point out that the FDA has since funded a deprescribing guideline, which is in the works, being headed up by ASAM and then members from AAAP and several other organizations, and hopefully will be out in about the next year. I think it's really important to highlight the patient experience, so I will talk about a survey that a group conducted, which I've been part of another group that's analyzed some of the results, and the survey was of individuals that identified being harmed from benzodiazepines, and one quote was, it's important that we be believed when we report how horrific the symptoms are that we have experienced, and they can go on for many, many years. I will just say that I have likened what I've seen with bind to long COVID, or maybe also chronic fatigue. It's kind of this hidden illness or disability. It presents with a myriad of symptoms, as I'll discuss, and just because there's no definitive test, many patients feel like they're not taken seriously, or their symptoms are dismissed, overlooked, or discredited. In this survey, which was of over 1,200 individuals that were either taking, tapering, or had discontinued a benzodiazepine, it found that in this sample of individuals, they were taking a prescribed benzodiazepine and reported taking it as it had been prescribed, that vast majority of the individuals in the sample, 40%, were taking it as prescribed. Individuals in the sample, 40%, were already completely off of their benzodiazepine, but somewhere in the midst of tapering and another percentage still on their full dose. And then you can see the most common being clonazepam and alprazolam, followed by lorazepam, diazepam, and they could be on multiple, so that's why the percentages don't add up. So, there have been three papers published looking at this data in various forms. Again, this is a survey. It took place between October 2018 and January 2019. And the group that have published the results, including myself, some addiction psychiatry colleagues from Vanderbilt, Christy Huff, who is a cardiologist, who herself was harmed by benzodiazepines, and works for another one of our partner organizations, the Benzoinformation Coalition, and Dee Foster is our statistical person, also harmed by benzodiazepines. You'll see a theme here. And so, there are all parts of different organizations really looking at how to improve the safety of benzodiazepines and benzodiazepine tapering. So, as I mentioned, I mean, folks experiencing BIND experience a huge array of symptoms, and it can be really hard to tell, and we don't have enough good research yet to say which symptoms are truly attributable to the BIND versus which ones are maybe exacerbated by BIND but are existing for other reasons. And overall, this protracted benzodiazepine withdrawal or benzodiazepine-induced neurological dysfunction really can last for a long, long time for many people. And overall, how severe it can be and how long it can last seems to be really underappreciated. As far as a way to look at the symptom categorization, Heather Ashton, who is a psychiatrist from the UK who devoted much of her career to helping people taper off benzodiazepines, created a manual, often referred to as the Ashton Manual, and really categorized what she observed among the many hundreds of patients she helped, and she did publish some of it and some of the better research we have on it, although certainly points to our need for greater kind of randomized control work in the future. So you can see the most common symptoms. As Dr. Blaise has mentioned, reasonings, these are often started, things like anxiety, fear, nervousness, sleep disturbance, but also low energy, and then those cognitive complaints, difficulty focusing, distraction, among many others. I know I've seen akathisia be one of the most debilitating and bothersome and hard to get relief from, uncontrollable crying and anger, among many others, GI difficulty referred to as benzobellies. And overall, kind of two groups emerge. So these ones that occur more frequently and for longer periods that would be more associated with a binder-protracted picture, the ones at the top that I mentioned, and then these less frequent, shorter-lived ones associated with acute withdrawal, so things like seizures, hallucinations, body trembling, that we often think of when we think of acute withdrawal picture. And so looking at this survey, a group, including the authors, but then 23 experts total, went through a process of voting on different terms that we thought might be useful rather than just calling it protracted withdrawal or post-acute withdrawal, worried that it didn't help capture how pervasive the symptoms that individuals experienced were, and so came up with the name benzodiazepine-induced neurological dysfunction, which we've defined as a constellation of functionally limiting neurologic symptoms, both physical and psychological, that are the consequence of neuroadaptation and or neurotoxicity to benzodiazepine exposure. These symptoms may begin while taking or tapering benzodiazepines and can persist for weeks, months, or even years after discontinuation. Of note, what we found in the survey is that individuals that were experiencing more severe symptoms had more serious life effects, so found that they had major impacts on their careers and income, healthcare relationships, mobility, independence, and overall self-esteem. So parallel to what we can see in the setting of a use disorder as well, and like I said, I don't think they're mutually exclusive, but I think there is a group that experience use disorder and may also experience BIND, and then there's a group that doesn't meet criteria for use disorder because they haven't lost control of their use, and the consequences are, you know, from taking this as prescribed, and they don't necessarily want to be on and off of it, but end up in this BIND about feeling worse, both on it and trying to get off of it. And so this is just presenting the data again in another way, but I think of important notice, the highlighted life consequence that 54% of individuals reported that as a consequence of their withdrawal experience, they had had suicidal thoughts or attempted suicide, and unfortunately, this is seen commonly. Like I said, akathisia is one of the symptoms I've heard often contributing to suicidal thoughts, as well as just this feeling like completely lack of control or understanding of why they're feeling the way they are and not being able to identify anything that seems to make it better. And so with that, I will hand it back over to Dr. Blais is to describe a little more about kind of a subset within BIND that has been identified. So before I met Dr. Ritvo and the team that kind of came up with the term BIND, I had actually already been in the process of publishing a paper describing a different heuristic, and we're going to get into that now. So we've all met that sweet elderly granny, who's been on clonazepam, 0.5 milligrams, twice a day for 30 years, and is actually quite stable. But because of what we learned about the dangers of benzodiazepines, it's appropriate to try to taper. And during the taper, things change and things go badly, and these changes can persist beyond the acute phase of withdrawal and may even be permanent. So there was a paper that came out of, you know, about four years ago now called Complex Persistent Opioid Dependence. And just as a quick review, you know, people who are on long-term opioid prescriptions, as tolerance progresses, or more commonly when they were forced to taper or discontinue for one reason or another, they would develop worsening pain, declining function, clinical instability, and aberrant behaviors. And one of the key aspects about this is that this can mimic addiction. So people who would have been stable on a stable dose for a long period of time, all of a sudden could develop aberrant behaviors consistent with addiction. And this kind of has resonated as very true, and I believe helps us describe a category of patients that might not have addictions. Because once we diagnose somebody with a use disorder, the best that they will ever have for their entire life is in sustained remission, and there are consequences to that. So if they truly don't have an underlying use disorder, I think it's best to avoid making that diagnosis. So myself and a couple of colleagues from OHSU kind of piggybacked off that article and defined a heuristic called complex persistent benzodiazepine dependence. And as Alexis alluded to, this is really kind of a subtype of bind. So they are not mutually exclusive. This is probably just a subtype. So in some chronic users, benzodiazepines can profoundly change people's brains and the chemistry and the circuitry, and it can lead to endurance. And so just as in with complex persistent opioid dependence, during a taper as tolerance develops or after discontinuation, a certain percentage of people can develop worsening anxiety and insomnia, declining function, clinical instability with psychosis, regression, and profoundly diminished frustration tolerance. They can also develop aberrant behaviors. And I've seen this become so severe that patients are unable to function. They're unable to take care of themselves. And the regression to earlier phases of life, there's a childlike feel to many of these patients, and this can be debilitating. And we call it complex persistent benzodiazepine dependence. So in some sense, let's think of it just as a severe form of bind. So what do we do about the treatment for bind or complex persistent benzodiazepine dependence? Well, we can do a lot for bind or complex persistent benzodiazepine dependence. So one way I look at it is that it's almost like the nervous system is dialed to 11 out of 10. And so everything is hyperacute and people become hypersensitive to sensations or even emotions. There's absolutely no literature on this except for what Alexis and I are presenting today. So it's something that certainly needs to be studied more. I think it's akin to treating the elderly agitated patient. What we found is that nothing is a magic bullet that works all the time. Some things work well. Some things don't work at all. But finding patterns that can be generalized across the board is very challenging. So I think in some sense, what I do is I kind of treat it like post-acute withdrawal. And there is some literature about treating post-acute withdrawal for alcohol. And that literature talks about anti-epileptics and alpha-2 agonists. And there's even some discussion about using Baclofen. And so what I've done in my practice is I've used these principles to treat complex persistent benzodiazepine dependence as well as bind in my practice. So interestingly, there's a group that's trying to study the use of flumazenil. And we would, of course, not recommend this be used during the acute phase of withdrawal because that could be dangerous and precipitate refractory seizures. But after people have been successfully tapered, have been stabilized, attaching an antagonist to the receptors is thought to speed up the process of homeostasis. So this is where we're working in the future. So why do these extreme situations happen, right? So I think that in some sense, people who have been on benzodiazepines for a long period of time, there might have been a sense of something like arrested development. We all go through stages of development throughout our lives. The development doesn't stop, you know, after we exit our teenage years. And so benzodiazepines taken daily, it may preclude people from developing the resiliency and coping mechanisms, you know, from aging that help us, you know, handle the slings and arrows of life. So as a reminder, I just say to myself that these could be challenging patients, but I have to have compassion. I have to be patient. I have to know like what Alexis alluded to that this can be extraordinarily challenging and complex. And so oftentimes, in addition to pharmacological interventions, I rely on going back to basics. I find that people do well with DBT skills, and even if they can get involved with DBT groups, that could be helpful. There's this little app on, or like a video, if you type in triangle breathing into YouTube, it's this slow video that shows geometric figures expanding and contracting, and people breathe along with the expansion and exhale with the contraction. And things like this can actually help people learn how to kind of ride out the waves of these acute episodes of distress. And so that can be helpful in addition to other things that are alternative things like, you know, acupuncture can be helpful as well. So sometimes complex persistent benzodiazepines can be refractory to all treatments, and patients can be profoundly suffering so much and can be profoundly dysfunctional that the most appropriate management is actually to restart the patient on the benzodiazepines. And this is kind of, it's been a controversial thing that has come up, but it's happened multiple times in my practice that I've tried for years to successfully taper people from benzodiazepines, and their level of function never returned to baseline. But so what I would do is I would start them on a low-dose benzodiazepine, and they would return to a stable function. And then, of course, it could be monitored more closely, understanding about the consequences of what happened. So I've seen this develop in folks who've been on benzodiazepines for a few months, or I've seen it happen who people have been on it for many years. So I think it's difficult to predict who it's going to happen to. And so we don't really know what the predisposing factors are to this. So this is part of what we need to do in further study. So one thing that I would say is that when I'm working in the emergency department, I will have my mind focused to look for complex persistent benzodiazepine dependence, because once we start looking for it, it'll show up more prominently. So now I'm going to pass it off to Dr. Gold, who's going to talk about the next phase of management. Thank you, Dr. Blazes, and thank you, Dr. Ritvo. Again, my name is Jeff Gold, and I'm a psychiatric clinical pharmacy practitioner, and I work at a VA medical center. And essentially what that means is that I have prescriptive authority under a scope of practice working with a psychiatrist, a supervising psychiatrist, and I also have my own DEA number. And while I work in general outpatient mental health, my specialty has been for many years working in a benzodiazepine tapering clinic. And so today we're going to talk about tapering, the reasons to taper, how to taper, and the challenges that arise therein. Beginning with indications for deprescribing, essentially if there are adverse effects limiting a patient's functioning, or there is a loss of efficacy or tolerance to the medication, or the patient requests a taper, or you feel that the medication cannot safely be used, or the patient feels that the medication may not safely be used, then this is an indication to explore tapering the benzodiazepine. The benefits of tapering would be reduced anxiety, improved psychomotor and cognitive functioning, reduced all-cause mortality, reduced incidence of accidental overdose. There's a reduction in motor vehicle accidents, falls, and drug interactions. Some individuals on chronic benzodiazepine develop symptoms that lack an alternative neurophysiologic explanation, and these symptoms may improve or they may not. And this is really what Dr. Blazes and Dr. Ritvo were discussing with respect to chronic persistent benzodiazepine dysfunction as well as FIND. Roughly 15 to 44 percent of chronic benzodiazepine users experience some degree of moderate to severe withdrawal when the medications are discontinued. And some of the factors that may increase the risk of withdrawal are kindling or repeated benzodiazepine use and cessation. They've had multiple attempts at reducing the medication. An estimated 10 to 15 percent of patients who experience protracted, that is the long-term withdrawal symptoms, suggest that this can last on the course of years and even indefinitely, resulting in benzodiazepine-induced neurological dysfunction or FIND. And this might occur in patients even despite a very gradual taper. In some patients, this can lead to very severe outcomes, as the data from Dodds was discussed earlier by Dr. Palazos, that this can result in increased suicidal thinking and akathisia. Fear and ambivalence about no longer taking benzodiazepines is very common. In my clinical practice, for many patients who've been taking these medications for many years, there's a fear of what will the normal range of the human experience be like without taking these medications. It's a very emotional process for them, and not just for the physiologic, but the psychological reasons that are associated with coming off the medication. How quickly do we see tolerance to these medications, or how long does somebody need to be taking a benzodiazepine for them to potentially develop withdrawal upon discontinuation? There's a lot of data on this that's controversial, and this is still an area of exploration, and it's certainly not consistent between patients. But when a benzodiazepine is used for two to four weeks consistently, it should be tapered to avoid potential withdrawal. The factors that are associated with a higher risk of developing withdrawal symptoms are high dose and long-term use. Also during this time, symptoms of pre-existing psychiatric conditions may recur potentially to a greater severity during the pre-treatment period and may continue for a prolonged period of time. Certainly in my practice that when I'm tapering somebody off of a benzodiazepine, it's not uncommon for their anxiety to get worse, for their sleep to worsen. Oftentimes, they're just the sense that they're out of control or that there's a lot more fear about how they feel, and this can manifest in a variety of ways. There are many physical and psychological withdrawal symptoms, many of which have been characterized by Dr. Ashton and have been reviewed throughout this presentation. But essentially, when stopped abruptly, the risk of this most severe reactions and really that one of the biggest reasons to taper is to prevent the most severe of outcomes. I've often said to some of my colleagues when they see how long some of the tapers that I engage in with the patients are, why would you make it so long? Why would you draw it out so long? My response is that when somebody makes their way to me and they've had severe consequences or taking high-dose benzodiazepines, or they've been taking them for many, many years and they're particularly fearful about it, that we're treating to prevent the worst possible outcomes. We're treating to prevent the worst possible outcomes such as somebody having a seizure or having suicidal thoughts resulting in an attempt, and just like using a statin to prevent a heart attack. Not everybody who does not take a statin will have a subsequent heart attack and not everybody who has an abrupt or taper of a benzodiazepine will have a severe outcome, but we're trying to prevent those worst possible outcomes. There are some withdrawal rating scales that I use in my clinical practice. There's the CWAB and also the BWSQ. There's also some measures that look at anxiety or different symptoms. There's a checklist from the book on tapering benzodiazepines that I use in clinical practice. These can be helpful objective markers when you're tracking progress towards the goal of tapering. Generally speaking, the withdrawal symptoms that occur in about 50-80 percent of people who have taken these medications for more than six months and the acute phase of withdrawal can develop into the protracted phase that can last for weeks, months, or even years. Generally speaking, the withdrawal symptoms peak at around 10 days, but gradually progress up until that point, in which case the more acute short-term symptoms taper off after that 10th day, but then those long-term and potential protracted withdrawal symptoms can develop thereafter. The protracted withdrawal symptoms generally develop as you see both the short-term and the long-term begin to attenuate. The acute withdrawal phase, again, with acute benzodiazepine withdrawal from a pharmacological perspective may persist anywhere from 5-28 days, 10 days being generally the peak or 14 in that range. After this time, most symptoms should return to the extent that they were prior to the discontinuation. Then benzodiazepine withdrawal symptoms include the most common ones would be anxiety. This is a list. This is actually from Dr. Heather Ashton who developed the Ashton Manual. She's, of course, the fairy godmother of developing of characterizing benzodiazepine withdrawal and for many years in the UK ran a benzodiazepine tapering treatment center. These were some of the most commonly characterized acute withdrawal symptoms. In my practice, I'd say the ones that I hear patients report the most would be anxiety, insomnia, mood changes. I also hear commonly about dizziness. I hear about the benzo belly and nausea, general GI discomfort. Also, the sensation of electricity running through people's body or the sensation of your muscles tighten or spasm without any good cause. It's a very uncomfortable sensation. More rarely, I have seen patients that have experienced suicidal thoughts when the medication have been tapered. Generally, this is better. All these things should be better with a progressive, thoughtful, and careful taper. But there are instances where I've been involved in litigation where a patient has been rapidly discontinued or discontinued without any taper. I have seen successful suicide attempts. I've also seen cases of actually documented seizures. These were with patients taking high doses of benzodiazepines for long periods of time and where there was not an appropriate taper. The protracted withdrawal phase is often more difficult for patients and providers to determine the extent of the symptoms. I've heard some psychiatrists and psychologists describe and characterize that when a benzodiazepine has become a big part of somebody's life, a way of how they think about coping with the stressors of day-to-day living, to take that away from somebody, even in a progressive, stepwise, careful manner, it leaves them without a coping skill that perhaps has been really fundamental to them managing the challenges of their life on a daily basis. Some of those things can persist for years. How long does it take for you to relearn something that's been a useful tool to you? For many years, it can take significant time to do that. But patients often describe that benzodiazepine withdrawal symptoms and severe anxiety even when they're tapering these medications. You could understand that this is a very difficult process. For some patients, these more long-term or protracted withdrawal symptoms disappear over time, over the course of months to years. But for some people, they may never completely disappear. For an estimated 10% to 15% of people, these protracted symptoms may never fully disappear, may episodically appear throughout the rest of their life or linger to varying degrees of severity periodically. These are some of the most common protracted benzodiazepine withdrawal symptoms, as again, described by Dr. Ashton. Anxiety, insomnia, depression, cognitive impairment, long-term perceptual disturbances such as tinnitus, again, GI discomfort, paresthesia, tingling, that electrical sensations throughout their body. A number of motor symptoms are also described. So when you're considering tapering a patient from a benzodiazepine, some things to keep in mind. The goals for a successful taper are to decrease withdrawal effects and manage rebound symptoms, as well as recurrence of underlying symptoms that are being managed with the benzodiazepine. You want this to be comfortable. I utilize a shared decision-making model with the patients in my clinic. And we'll talk about the situations where this may not work, but I want this to be something that the patients feel that they're a part of. It's my belief that medications are started, adjusted and stopped in the context of a relationship. And many patients who have had problems coming off of a benzodiazepine are very sensitive to what I sometimes call the demonization of benzodiazepines, that perhaps, as Dr. Blaisdell suggested, the pendulum has swung too far and there's a bit of shame about taking these medications and a fear of being without them. So I want to make sure the patient understands first and foremost that I will make certain that whatever we do is medically safe and appropriate, but I want them to be able to say when they're ready to proceed with another dose reduction or if they need to stay another week or if something comes up in their life and they want to stay yet another week. But that's something that we are always discussing between each other. You always want to review lifestyle modifications, diet, exercise, sleep, hygiene, meditation, stress reduction that have a significant medical issue that's not well managed or not well treated or their other lifestyle considerations. That is a significant impact on my clinical experience how successful a taper will be. I recently worked with a patient who had an eight-year-old CPAP machine for obstructive sleep apnea. And really, it was thought that how much of their sleeping difficulty in the tapering process could be related to withdrawing from the benzodiazepine versus untreated sleep apnea. And after procuring them, they an updated CPAP with adjusted settings. That seemed to be the biggest factor in them getting good rest again. So these things should always be evaluated. Some general principles that you also want to consider is to stabilize the dose and to address inter-dose withdrawal. So that is that you don't want the patient to be using the medication as needed. If the dose is variable from one day to the next, it makes it very hard to engage in a taper. And for some individuals, substituting to an equivalent long-acting agent is preferred. Now, the data on this is not great, but it's not uncommon to convert somebody to a more long-acting benzodiazepine. So for example, you're avoiding tapering somebody using Alprazolam or Xanax. And you might prefer a taper using Chlordaz epoxide or diazepam. I'll tell you that in my clinical experience, I find that patients often prefer doing this. I had one patient who really insisted on being tapered on Xanax and about 80% of the way through his taper requested then agreed to rather to taper off using diazepam. And he found that the course of withdrawal symptoms was so much more smooth once converted. He gave me the guidance of, and Dr. Gold, I think in the future, you should encourage this more strongly than you did with me with other patients that you're working with. So these are just considerations for you to entertain. Some general tapering principles, a symptom-based patient-directed approach is best. Again, there's no one true way to do this, but this is a good place to start. You might initiate a test reduction of the smallest increment possible, a 5% or less reduction in the dose. I know this is a very small increment. And then allow the patient to lead subsequent reductions in amounts and intervals based on tolerability and withdrawal symptoms. I do not suggest making a change more often than every two weeks. For some people, it's longer. This is a marathon. It's not a sprint. And lived experience really suggests that that reduction of 5% to 10% per month is best tolerated. I kind of see where they start and how they tolerate that first taper. It's a shared decision-making process through and through. I'm routinely seeing these patients every week or every other week, and certainly at the very least once a month. Skipping doses, supplemental rescue doses, or up-dosing is not recommended. It might be necessary in some situations. I certainly have found, and as Dr. Blais has suggested, that some patients at the end of their taper, their quality of life is just better on some amount of benzodiazepine. And I'm not reluctant at all to restart benzodiazepines in those individuals where it's really clear to them first and foremost that their life is better, that they can manage this, that they understand the consequences of long-term benzodiazepine use. And there are no aberrant behaviors. Their urine drug screen is not concerning. Their prescription drug monitoring database checks come out as anticipated. And if there's no explicit safety risk, their quality of life is better, and it's something that they want and consent to, there's no reason in my mind to withhold it from them. Some other tapering principles. Dose reduction should be smaller as the taper progresses. And this is, again, based on the percentage of the medication that you're tapering. For many patients, a gradual taper over three to six months can be implemented. But there are many patients that take upwards of a year, a year and a half, and even two years. It really depends on them and the experience of the taper process. The nervous system hypersensitivity is very common among, it's very common during the withdrawal period. And any foreign substances can have adverse effects. So caution is advised when you're starting other new medications. That is that the patients can become more sensitive to other psychoactive compounds. This is an example of some various tapers. And really what I want to draw specific attention to is just looking at the example C, that this would be using more controlled, slow, systematic reductions versus no degree, no attempts at tapering, resulting in an increased incidence of withdrawal symptoms, or a taper that's too fast, causing an increased incidence and withdrawal symptoms relative to a very slow stepwise taper. Some other tapering techniques. Again, we talked about stabilizing the dose, substituting with a long-acting agent, and avoiding agents with a shorter half-life, avoiding PRN uses of these medications. Many practitioners continue to follow these recommendations and converting from one agent to another. But again, this is somewhat anecdotal. There's not great evidence on doing this. There are some medications that are thought to be best avoided, specifically Xanax, Alprazolam, and Clonazepam, Klonopin. And the reason for this, and there's data on this as well, the potency of these medications make it harder to use them in a taper. That there's a, they have a greater ability to change the conformation of the benzodiazepine receptor. And because of that, they are, it's more difficult to come off of these medications, that there are more physiologic changes. And so it was really suggested to explore alternative medications for the taper. One potential taper technique is the cut and hold method. This is what I most commonly use in my clinical practice. And this is where you reduce the dose by a percentage every so many, over every so many weeks. So this can be accomplished by, let's say that a patient's starting on 20 milligrams of diazepam and you're reducing by 5%, let's say every two weeks. So you'd make a reduction of roughly one milligram for so many weeks. And as you get lower into, or further into the taper, if they're tolerating the one milligram reduction, this might be reasonable throughout the course of the taper. But as you get to a smaller dose, it might be advisable to let's say taper by 0.5 milligrams. It really depends on the patient. I found that most patients in my clinical practice would, this would be a more than sufficient taper throughout the course. I do find that it's more difficult at those last stages to get to come off that last amount of benzodiazepine. There's a big difference between having no benzodiazepine in your system and having even the most minuscule amounts. So the pros of this that can be accomplished with existing dosage formulations of the drug, you don't have to have the medication compounded. The con is that the symptoms from larger dose reductions may be more intense, particularly if you're getting to the end of the taper and it's not really feasible to make a 0.3125 milligram diazepam dose from a one milligram tablet that becomes difficult to do. Another potential taper technique, it's not something that I routinely use in my clinical practice. I have known of patients who have done it, but this is called the micro taper. And this involves daily micro reductions in the dose. So the benefits of this is it may allow for finer adjustments and symptom control. Since commercially available benzodiazepines come in a dose that's too large to taper comfortably for some patients. And many report that this is better for symptom control. Again, most patients that I work with have tolerated the reductions in the cut and hold technique, but there are patients I know that have used a micro taper. The con is that it's off label and it can be subject to accuracy issues. And what I've seen some patients do is have the medication compounded. Some Walgreens and other commercial retailers, pharmacies do offer tapering or do offering compounding services for such tapers. And I've had patients actually go to Walgreens and get micro doses of let's say diazepam is typically what I've seen them use and to help a patient complete a micro dose taper. So in this example, that 20 milligram initial diazepam dose would be cut down by 0.07 milligrams per day. And that would over the course of the month be a 10% reduction in the dose. I won't go into too much detail regarding this, but this just kind of goes over some of the different what's available to people who are involved going through the tapering process in terms of getting the liquid versus getting a compounded formulation. And furthermore, these are the formulations and the doses of each four of the most commonly used benzodiazepines on the market. So you could see that which ones, what's the lowest dose that they are manufactured in as a tablet and do they come as an oral solution? What's the roughly equivalent dose of each of these medications and the associated half-life? This is just for your reference. You will find many different sources of converting from one benzodiazepine to another, many of which I found to be reasonable. This is just, this is what we are using. This would be an example of a taper that is too fast for most people. The patient is starting on clonazepam one milligram TID. And you could see in the first dosage reduction, it was one milligram, then 0.5, then one milligram. And that first reduction in dose would be a roughly 17% reduction. There are many people that tolerate this. And I wouldn't say that this is an unreasonable place to start, but it might not work for everybody. And certainly patients that are more sensitive would benefit from a smaller reduction in the dose. Perhaps you went down by 0.25, which again, I know is still, again, larger than that 5% reduction. But I think that the essence of what I would want somebody to take away from this is that you're really working closely with the patient to see what works for them. You want to set them up for success. You want to minimize withdrawal symptoms as much as possible. And in that first dosage reduction, even if you were more aggressive, such as this example, which I think is too fast, greater than 10%, you would be making adjustments in subsequent reductions and going down by, maybe you would try the next reduction at 0.25 or even smaller if necessary, even 0.125, or perhaps converting them to diazepam and tapering in even smaller increments to the patient's comfort. As far as withdrawal symptom management, I will let Dr. Blaisdell speak a bit more about this with respect to other interventions, such as using anticonvulsant medications. But generally speaking, the withdrawal symptoms are best managed by adjusting the taper rate, non-pharmacologic interventions. The addition of psychotherapy when tapering benzodiazepines can also lead to increased likelihood of a successful taper and also contribute to future abstinent rates in patients not already receiving treatment. And several modalities have been looked at, specifically cognitive behavioral therapy for anxiety, as well as cognitive behavioral therapy for insomnia or CBT-I. Adjunctive medications is what I'll let Dr. Blaisdell discuss in more detail. There's not great evidence for these practices, but I will tell you that in my clinical practice, this is something that I do routinely. I have used other GABAergic medications, such as gabapentin. Incidentally, I've used oxcarbazepine as well. And sometimes I've seen these medications used when a patient is not appropriate for a taper with a benzodiazepine. Let's say that their taper off of a benzodiazepine, it's not thought that it's safe for the patient to have benzodiazepines at home if they'll use the complete supply of a benzodiazepine very quickly, more quickly than the taper is calling for. And these adjunctive medications are to prevent these significant withdrawal symptoms that are related to the hypersensitivity that develops with long-term benzodiazepine use, but it's felt that a benzodiazepine is not safe to use, so you're using other GABAergic agents. Some potential pitfalls, again, physiologic dependence can occur in a matter of days and occur to prescribed therapeutic doses, stopping abruptly within, you know, if use is more than two weeks, increases risk of seizures, psychosis, death, and protracted withdrawal. Physiologic dependence is not synonymous with addiction due to the risks of abrupt cessation. Addiction treatment centers are not recommended. You do not want to discontinue, you don't want to discount symptoms that seem bizarre, such as agoraphobia, depersonalization, derealization, intrusive thoughts, burning nerve pain, irritable bowel. I found that I learned a new withdrawal symptom with every patient that I taper. There's always something uniquely described or perhaps a more common experience that's uniquely described by the patient, and I try to listen to what is their concern, what is it that's most challenging to them in the tapering process. The symptoms of benzodiazepine tolerance and withdrawal can mimic other conditions as well. This can lead to misdiagnosing and unnecessary testing of other potential medical illness. Published taper protocols are meant to be a guideline. Only flexibility is key, and the taper should be patient-led unless, again, there's an explicit safety concern. Let's say if somebody's using benzodiazepine and their urine is test positive for something that shouldn't belong there that's dangerous, then you're looking at a direct taper that's quick and abrupt for the reasons of safety. That might be a situation where you're considering, do they need a structured setting where they need to be taken off the medication? Are they appropriate for a treatment center? You also might, in these situations, be considering use of an adjunctive treatment strategy, such as a non-benzodiazepine GABAergic medication. The post-withdrawal recovery period can take on the scale of years. Some other things that have come up in my experience with tapering is you want to, if possible, avoid fluoroquinolone antibiotics. They can precipitate withdrawal. Alcohol and other GABAergic agents are also of concern. There's some caution with progesterone as well, and there's a lack of clinician consistency and not taking a similar approach to every patient, which is something I strongly recommend. I have in my mind this mantra, which is, for everyone, always. During the tapering process, I do random urine drug screens for all patients. I check the PDMP, the Prescription Drug Monitoring Program, routinely for all patients. I don't leave it up to my own projections about who I will and who I will not do this with. It's just part of how I maintain a safe clinical practice, doing the same thing for everyone throughout the taper process. And I will now turn it over to Dr. Blazes. So thank you, Jeff. That was very eloquently described what the standard of care is, but there are some circumstances where that does not work. So this was an article that was published in 2017 in the New England Journal describing the standards of care for tapering, and they said the overall consensus is that benzodiazepines should be discontinued gradually over a period of several weeks to avoid seizures and severe withdrawal symptoms. And as you learned from just Jeff's recent discussion, several weeks is probably too short a time for most places, but this is what people refer to as kind of like where the standard of care comes from. But this article was actually based on, you know, they quoted articles that were not directly relevant to benzodiazepine tapering. For example, in order to come up with that recommendation, they quoted the Amado Cochran review, which came out in 2010, which talked about benzodiazepine safety for alcohol withdrawal. And I understand why they did that, because there's a distinct capacity of literature when it comes to giving clinical recommendations for benzo withdrawal, but nonetheless, you know, so that's what they had to use. And then the darker Cochran review, which they also quoted as justification for those recommendations was comparing benzo withdrawal with the use of CBT and a taper versus a taper alone. So nonetheless, it's the best that was available, but not directly relevant to the topic of withdrawal. So, you know, as discussed before, this came from Heather Ashton's work, which we're all grateful for, but she did not really publish her data other than in this book. So we just have to be aware of that. And so I just ask everyone to question, you know, are long tapers effective for every patient? In my opinion, especially with people who have use disorders, and as Jeff alluded to, it may not be successful. So then what do we do when the prolonged tapers are not successful? So this was a meta-analysis that came out in 2015, which basically said that our review revealed that benzodiazepines and Z-drug deprescribing interventions are numerous, largely heterogeneous and poorly described. The pace of publication annually remains stable, indicating maintained interest in the fields, but generalizability is problematic. So we're grateful that ACM is coming out with some guidelines, but the fact is that there's really not great guidelines out there. So there's multiple different alternative discontinuation protocols. Rick Reese, I got his permission to use this slide, and what he likes to do is in an inpatient setting, as an option for people who kind of had failed to taper or prefer this, will do a rapid taper over a period of three days, and then cross titrating using anti-epileptics. And then he'll continue the anti-epileptics for at least a month, and also aggressively treat the symptoms for which they were started on the benzodiazepines in the first place. And I think that this is just one of many. I myself feel that hospitalization is an alternative, which is important to have in our arsenal for potential treatments. If I had a family member who had been on benzodiazepines for a long period of time, and they attempted to taper and were having challenges with it, I actually might recommend hospitalization for this. Now, in some circumstances, as in the modern world, it's actually really hard to get people to a medically monitored setting or a hospitalization, but there is some sources out there. For example, in the DOD guidelines for PTSD, the VA recommends that if people are on super therapeutic doses, that this should be done in a hospitalized setting. And even in Soyka's article in 2017, they said if they're on diazepam doses of 100 milligrams a day or greater, that this should be done in a medically monitored setting. And I put over there for your reference, just the maximum recommended doses for each of the most commonly used benzodiazepines. And so some people say it's kind of like ripping off the Band-Aid. So what are the alternative choices? So I would say if someone's having mild to moderate withdrawal, in my practice, I like using anti-epileptics plus alpha-2 agonists, or for more severe withdrawal in a monitored setting, phenobarbital with alpha-2 agonists has become my favorite medications. And we'll talk about each of those independently. So why do I like phenobarbital? So phenobarbital has activity at the GABA receptor, but it acts differently than the benzodiazepines. It increases the duration that the GABA channel is open. So it's really like a powerful punch, whereas the benzodiazepines just increases the frequency of the channel opening, and it's a little bit less of an effect. The other thing to be aware of is that benzodiazepines need GABA to be present in order to have activity. And many patients who are chronically taking benzodiazepines or using alcohol might be GABA depleted. And so the efficacy of benzodiazepines is significantly diminished because there's not enough GABA around. Whereas with phenobarbital, this will work independent of the GABA being present. So phenobarbital also has some NMDA antagonism properties. And so it's almost like you're working at the withdrawal from both ends. You're supplementing the GABA, but you're dampening the elevated glutamatergic tone, which is what actually causes a lot of the problematic aspects of withdrawal from benzodiazepines. Phenobarbital also has an extraordinarily long half-life, which is both good and bad. In essence, it actually kind of has like an auto-tapering mechanism in itself. I've also found from my practice that it's not reinforcing. And so in certain patients who are prone to have a use disorder, they might exaggerate symptoms in order to get higher doses, and this doesn't happen with phenobarbital. So I use phenobarbital as my favorite option for kind of the ripping off the Band-Aid option. So there's not much data out there, but this was an article that was published out of Johns Hopkins in 2012, where they safely went through the detoxification process with patients who chronically use benzodiazepines, and they used a three-day taper using phenobarbital. They denied having any complications or any seizures in their cohort, but the one aspect that is limiting about this study is they actually discharged patients right after the third day, and so they didn't have exact, accurate follow-up as to what happened after they left. And from my experience when I'm tapering people from benzodiazepines, oftentimes it's not until day five, six, seven, or even later that some of the complications happen. So again, this is the best that we have, and we're grateful for the study, but it certainly has significant limitations. So I wanted to mention alpha-2 agonists and anti-epileptics. So in terms of alpha-2 agonists, I'm actually doing the same thing that Sojka did, is that I'm quoting an article that's about alcohol withdrawal, and again, this is because there's really nothing out there about this for the use of benzo withdrawal. But I highly recommend you read this article if you don't already know it. It elegantly describes how anti-epileptics and alpha-2 agonists more closely address the underlying pathophysiologic derangement that underlie the withdrawal syndromes more so than benzodiazepines. So you're actually dampening the elevated glutaminergic state with these medications in addition to supplementing the GABA. So in terms of alpha-2 agonists, I actually don't even consider these as adjunctive medications. I include them in all patients who I am doing a more rapid monitored management of. And also, I will use them intermittently with patients when I'm doing an outpatient withdrawal as well. So what I do in my practice in a medically monitored setting, I use phenobarbital. I usually use a loading dose of between 64 and 192 milligrams, variable depending upon their age, weight, or comorbidities. And then I'll do a fixed dose protocol, usually 32 to 64 milligrams four times a day, and have the option if their CEWA scores are high to add additional PRN doses on top of that. And from my experience, this usually takes between four and 10 days, and that's variable depending on the patient. So as what Jeff alluded to, we always have to have the readiness to reconsider and to adapt our protocols because patients, as much as I want to be able to predict who's going to do well and who's not going to do well, I find that I am wrong more often than not. So we're really looking for great scales that we can use to predict people's outcomes. But from my experience, I haven't been able to predict. So I'm also a big fan of the clonidine patch. And so when people come through the door, I'll put on one 0.1 clonidine patch and leave that on for the first 24 hours. I'll reevaluate them at 24 hours, and in many cases, add a second clonidine patch. And then I will also add 0.1 milligrams TID as needed on top of that for symptomatic control. And also, as Jeff alluded to as well, I'm a big fan of oxcarbazepine. This is an anti-epileptic, which is a structural analog of carbamazepine. Carbamazepine has been studied pretty extensively for alcohol withdrawal, has been studied for benzo withdrawal. But it's oftentimes not tolerated well by patients, and oxcarbazepine has a similar efficacy but is usually tolerated much better. So this is an opinion alert. There's not a lot in the literature, but many of us who do this every day are developing significant comfort with using it and have found it to be quite effective. So the big question is, when we're seeing somebody, how do we determine who's going to be a candidate for a taper and who's going to be more likely to need more closely monitored management? And so I think some of the key factors here are motivation. If somebody wants to get off the benzodiazepines, the likelihood of them tolerating an outpatient taper goes up exponentially in my mind. On the reverse side of that, if somebody has an underlying use disorder, I think the likelihood of a slow, successful taper is significantly diminished. And I have actually never had a success with that in somebody who's had an underlying use disorder or addiction, because they always tend to take the medications more than they're supposed to. And they end up oftentimes even going up on their dose, and the taper is just unsuccessful. So another factor I think that's helpful is if somebody has somebody at home who could be kind of like a coach or a partner to help them with their dosing and provide support, that the likelihood of them being able to be successful with an outpatient taper goes up exponentially. So I think I found that to be kind of the most significant helpful factors. All right, so in the future, well, I think that this is an important study to be aware of, that they estimated that 82 to 86% of people who were successfully tapered from benzodiazepines actually recommenced use within 15 months. And I think that what we have to be aware of here is that after somebody successfully completes the taper, if they haven't done things to manage the symptoms for which they started the benzodiazepines in the first place, and if that wasn't aggressively managed, or if their bind wasn't treated, or if their complex persistent benzodiazepine dependence wasn't treated, that there's a good likelihood that they'll end up back on benzodiazepines in the future. So just wanted to mention pause. So as we talked about before, this is not a DSM diagnosis. But it's something that clearly happens. But now, luckily, we're at a phase where we've come up with different terms for this. There is very little literature on this in the past. But just for your reference, I put this in here for your reference. And so this is review from before. So the symptoms of pause are very similar to the symptoms of benzodiazepine-induced neurologic dysfunction. And so we don't have to highlight any of these. In terms of the treatment, we talked about this before, anti-epileptics and alpha-2 agonists. But there's also some limited evidence for using baclofen, which is a GABA-B agonist. There's also some interest in using some medications that have some NMDA antagonism qualities, like acamprosate or adamoxetamine. But what we have to recognize is that there's not much guidance in the literature. And also, as I alluded to before, pay attention to other modalities, other than medications, like psychotherapy, CBT-I, behavioral therapy for those who have addictions or use disorders, group therapy, or 12-step. And having more tools in your toolbox is important for the management of this. And why is this important? I think this is really important because if somebody comes to you and they successfully completed a taper six months to a year ago, and they're still feeling irritable and frustrated and having cognitive difficulties, and now we can say that we understand what's happening here. This is something that we call benzodiazepine-induced neurologic dysfunction. This is something that we've recognized as complex persistent benzodiazepine dependence. And we know what it is, and there's often something that we can do to help treat it. And so if we can remind somebody and let them know that there's a potential that this too shall pass, we know what this is, that could be really helpful. And so as we talked about before, flamazenil is also a potential future area of research which may have some beneficial effects. So now I'm just going to finish up with some discussion about motivational interviewing and other alternatives which are necessary as part, but we don't have time to get into that. So this will just be in there for your reference. So at this point, we're going to open up for questions, and we listed a few options here just to kind of guide the discussion, and thank you all for your attention.

substances

nootropics

Kratom

phenibut

addictive potential

risks

consequences

withdrawal symptoms

adverse events

patient safety