Managing Insomnia: Pharmacologic and Non-Pharmacologic Approach *ACPE-Accredited*

(upbeat music) - What's going on, everybody? Welcome back to another episode of the Core Consult RX podcast. Joining me is always Colce Wonson. What is going on, man? - Doing great today, Mike. How about you, or tonight, I should say? Yeah, yeah, doing well, can't complain for a Monday, I guess. - Yep. - Anything new or exciting on your end, you wanna share with all of our eager listeners? - No, not really, other than almost dying of heat stroke every other day. Nothing else that's going on. - Yeah, it is unbearably hot, but you know, it is what it is. - So is it hitting like 95 hundred over there? Or, yeah, definitely around there. It's like 95 feels like 180 or whatever, it's terrible. I think I've said this a couple times already, this season, but I feel like every time summer comes around, especially when it's like June, July, I'm just, I have this conversation with myself and I'm like, "Why do I still live in this stage?" - There's people who don't have to deal with this on it. - Yeah, there's people who live in Montana and have like nice weather. - Yeah, you know what else I've got to deal with is like a spider infestation, not my house, but just in this general area. Last year, you know how, you know, banana spiders or the garden spiders? - Yeah, yeah. - So it's not that, but imagine a different, just slightly smaller version of that, called Joro spiders that just are everywhere around your house in the bushes, in the trees, on the power lines everywhere. And last year when I came here, I thought they were the banana spiders, but then, you know, quickly figured out that they weren't and I was like, "What in the world are these things?" And it turns out that it's some Asian spider that is now endemic or whatever it's an invasive species. It only popped into the US in 2014 and the ground zero for its infestation was 30 miles from our life. - Oh, sweet. - Yeah, so they're venomous? Are they dangerous or just, 'cause like those garden spiders freak everybody out, but they just kind of chill. - Yeah, I like the garden spiders, 'cause you'll get like two or three of 'em, they look pretty cool, big webs, they eat the bugs, all's good. These are everywhere. Like there's just wings all over the place. - Overstead, they're welcome. - So they're not cool. I don't like them. They're not dangerous or anything, but I found this weird. People, I guess people listening may not like this, but I found this really awesome spray that just like takes 'em out super close. (laughing) - That's somebody that's like an arachnologist. - That's what I was walking around doing today. - It's just fine to get everybody's murdering spray. - Just murdering spiders. - But they're up on the eaves of my house, and so now I'm looking into like this extendable pole and like contraption to squeeze the aerosol spray, 30 feet in the air, so that was what I was doing today. - So, you know, that's a pretty exciting afternoon. - Yeah, yeah. - It's the most middle-aged pot, cut pot, as of all time now. - Yeah. - How times have changed? - Yep. - Yep. - That's cool. I haven't killed any spiders or anything. I haven't had anything that exciting. Just the same little, I got sunburned. Like, I've never been sunburned before in my life 'cause I'm an idiot. - Oh god. - Thought, oh, I got a base tan. I'm good. No sunscreen necessarily at the beach. Just fell asleep. I'm like, Joucher or whatever, woke up. Just blistered and pretty sure I have like, fourth degree burns on my shoulders. - Since I got married, I don't think I've had a sunburn. - Yeah, well, I did the whole, no, I'm good. I don't need any. She's all right. - I'm glad that works for you. - Yeah, well, you gotta put some time in, but yeah, eventually it does, but then you have to. - But then you have to hear about it for the next, you know, week. - Oh, are you sure? - I'm trying to do it. - Yeah, she knew exactly what she was doing. That's the thing. She knew what she was doing. - Yeah, letting you not have sunscreen on. - Yeah, it was, it was actually, it was probably some sort of covert mission on her part. - Exactly. - Let me get a burn. So, but yeah, that was my weekend, so that was wonderful. - Nice. - But, yeah. And one of the, I guess side effects of a sunburn is it was been very difficult to sleep the last couple nights 'cause every time I'd even slightly think about turning over, waking up, yelling at myself, we're not wearing sunscreen. There's some people dealing with that in a much more regular basis, not due to sun, sun burns, but the inability to sleep and stay asleep, fall asleep, whatever it may be, sometimes both. And that's gonna be our topic of discussion tonight in Somnia. This is going to be an accredited episode. And one, you know, we have covered in the past as we've started to cycle through all of our, you know, major topics. And is expired as far as obtaining, you know, continuing education credit for it. So, figured we would kind of do another run down of the pharmacotherapy used to treat in Somnia and make it so that people can still get their continuing education credit for this topic. And so, our friends over at FreeCE, those of you who are members of their platform, any of our episodes that are accredited, you can get one hour of continuing education credit. And so, at some point during the episode, we will give you a password that you can use to access the post-activity test that is available on FreeCE.com's website. And you pass that. You tend to question multiple choice tests and you will get one hour of continuing education credit for pharmacist and nurses. And so, obviously, if you're already a member, you know all the great content that they have available on the website, if you're not a member, you've participated many, many times, check them out. They have all kinds of great learning opportunities just waiting for you to soak up. So, make sure you give them a look through it if you're not already a member. The big thanks to them for continuing our partnership. And, you know, we're gonna jump into this, kind of give some background information, talk about, you know, some of the diagnostic criteria, you know, if you need a, if you're trying to get a definitive diagnosis which is a good idea, obviously, versus just treating arbitrarily. But insomnia is something that is very prevalent and something that a lot of primary care deals with. It's not just, you know, psychiatry. But a lot of specialties, even neurology, pulmonology, things like that will be running into insomnia. So, I feel like it's an important one. And can be very disruptive to someone's quality of life. So, something we should be familiar with. So, we'll run through the various medications and all that and kind of do a summary of all the pharmacotherapy options that are out there. And then, you know, go from there. - Yeah, and I think that the, a lot of the medicines we'll talk about get about rap because of the side effects associated with them, especially in older people. - Yeah. - But sleep is just so important. And insomnia can be completely debilitating. So, it's just one of those things where you have to do a cause. - Sometimes you have to work around them. - You've got to work around it. - Sometimes you just get to say, hey, take the pills. - Well, they will happily take the pills. It's just, you know, it's, it's like, - It's really, it's pharmacist, you know, screaming at people for, for using them. - That is true. - Yeah, yeah, pharmacists are the biggest ones that are, you know, it's not been enough time. You get to refill yet. How dare you? - In good faith, you know. - Yeah. - We, all that. - Obviously, we're not, don't shit. I mean, I might have been just a touch, but it's okay, cause it's never too shade. - Let's hop in with, just talking about sleep a little bit, because some of the medications we'll talk about affect and act in different stages or can help with different types of sleep issues that people have. So as far as the physiology goes, there's two primary pieces or sections of sleep. - Some categories. - Categories, I guess, yeah. Non-rapid eye movement sleep, which is most of what a person will experience throughout the night, it makes up about 75% of the total sleep time. Other type is rapid eye movement sleep or REM sleep, which is the other 25%. With non-rapid eye movement, there's three stages, in one, in two, and in three. In the in one stage, that's more of the transition state between wakefulness and sleep. That's the highest risk for kind of jerking and slapping your partner in the bed as you're transitioning from that wake mode to sleep mode. At least that's what my wife does to me. The in two stage, there are lighter alpha wave sleep, or it's the lighter alpha wave sleep that's characterized by sleep spindles and cake complexes. In three is delta sleep or slow wave sleep that's considered the most restorative sleep. It promotes protein synthesis, wound healing, restoration of immune function. And that's non-rapid eye movement sleep. REM sleep, the other 25% possibly plays a role in memory consolidation. It can aid in sensory motor system development, that kind of thing. That's the two categories we're dealing with with sleep. And when it comes to insomnia, it's just its basic definition. It's the inability to initiate or maintain sleep. It can be a combination as well. And that can obviously be associated with not just the annoyance of that process of trying to fall asleep and whatnot, but actually cause problems during the daytime as a result, as you can imagine. Now, acute insomnia, which sometimes you hear for two, is like adjustment insomnia. The symptoms are present for less than three months. And those symptoms typically occur in response to some sort of an identifiable stress or something's going on in the patient's life. Whether it be just stress from work or life in general or some kind of event that's caused anxiety or what have you. But it's an acute thing. It's not something that's been longstanding. Now, if you get to the stage of chronic insomnia, that's where symptoms have occurred at least three times per week. And that schedule is persisted for at least three months or longer. So it is kind of important to differentiate between those two and get a good patient history to kind of figure out how intense you need to go with therapy or if your therapy's even warranted at minimum. When I say therapy, obviously medication and psychotherapy. But it is good to identify kind of the history of the symptoms and figure out how long this patient's been dealing with this. We'll talk through both types of therapies. A few other subtypes would be isolated sleep onset and insomnia, basically difficulty falling asleep. It's defined as taking 30 minutes or more to fall asleep. So people experience this on and off. It's a regular thing, not uncommon. And if it's periodic and it's not affecting the patient's quality of life, not necessarily something that would need medication therapy. But this tends to happen to me when I have some side project that I'm really excited about or sometimes people get anxious in their minds of racing or whatever trouble falling asleep. Sleep maintenance is difficulty sleeping through the night or waking up too early in the morning. Definitely not a problem that I have. But being awake for more than 30 minutes after waking in the middle of the night would be an example of sleep maintenance insomnia. Then you can have mixed versions where the patient has issues with sleep onset sometimes or maintenance sometimes or both on certain nights. So it can present in all those ways. And that can-- having it classified by either or the combination can sort of steer you in one direction of the other as far as treatment to. So again, important to kind of identify and classify the patient's insomnia and not just, say, general insomnia without any specifiers. It's for us like the diagnostic criteria to actually give the patient a true diagnosis. The first part of it is a predominant complaint of dissatisfaction with sleep quantity or quality. And it has to be associated with one or more of the following symptoms. So difficulty in initiating sleep. And then in children, it's also noted that this may manifest as difficulty in initiating sleep without caregiver intervention. Difficulty maintaining sleep, which is characterized by frequent awakenings or problems returning to sleep after awakenings. And then three early morning awakening with inability to return to sleep. You also have to have the sleep disturbance causes clinically significant distress or impairment in social, occupational, educational, academic, behavioral, or other important areas functioning. Also note the sleep difficulty occurs at least three nights per week or more. The sleep difficulty is present for at least three months. The sleep difficulty occurs despite adequate opportunity for sleep. Obviously, if your schedule allows you for two hours of sleep, that doesn't count as insomnia. And hopefully you get a better schedule. But also, the insomnia is not better explained by and does not occur exclusively during the course of another sleep wake disorder. So a patient with narcolepsy, some sort of like breathing related sleep disorder, circadian rhythm, sleep wake disorder, parasomnia, something along those lines. And then also the insomnia is not attributed to the physiologic effects of a substance. Whether that be just prescribed medication, a drug that a patient may be abusing, something like that. And obviously, if the patient is taking a medication like a stimulant to help with ADHD, and having insomnia as a result, you're not going to necessarily classify that patient as having true insomnia. And there are cases where the patient may have both conditions. But if the insomnia wasn't present until the drugs was started, that doesn't count as true insomnia just by itself without much further investigation, I'll say. And then also coexisting mental disorders and medical conditions do not adequately explain the predominant complaint of insomnia in making sure that, again, you're ruling out other things that could have be cut the cause and actually making sure that it's truly insomnia that the patient is dealing with. As far as other factors you want to consider, you need to specify if it's episodic. So the symptoms last at least one month, but less than three months if it's persistent. So that would be lasting longer than three months or recurrent. And that's just two or more episodes within the space of one year, which to me is not a whole lot in a year. Of note, acute and short-term insomnia. So symptoms lasting less than three months, but otherwise meeting all criteria, regarding frequency, intensity, distress, impairment, would be they would be consider that and other specified insomnia disorder. So it's a little less specific. And then you would want to specify if it's with a mental disorder, kind of like Mike was mentioning, including substance use disorders with other medical conditions, with another sleep disorder. And this is partially associated with the billing in what the ICD-10 code is going to be in the patient's start, but also helping to appropriately classify what type of insomnia they have. And I mean, for those of you who are working in the clinic setting, the coding and getting as specific as possible definitely is important, as far as reimbursement rates and patients risk scores and things like that when it comes to like Medicare patients and all that so, definitely important to get that correct, or as accurate as possible. I feel like that's always a big topic of discussion at the provider meetings is like, all right, we're not billing correctly again. You know, some of the older providers and stuff that didn't have all these fancy specifiers and whatnot are like, yeah, now. Insomnia is unspecified, yeah. Next, when it comes to thinking along lines of like treatment, it doesn't have to be a situation where we automatically jump right to medications. And some patients don't even want medications. I will say during annual wellness visits and things, if I'm conducting those in the clinic setting, one of the things I do ask about is sleep and quality of sleep. And there's patients that I'll find that do have general concerns about sleep or just have trouble sleeping in general, whether it's maintenance or onset. And if I bring up, you know, have you ever tried Medicaid? Oh, no, I don't want any medication for it in a way. And, you know, so medication is definitely not the end to be all patients may not even want it to begin with. But I do feel like some that we often, you know, kind of either don't think about or don't have it the forefront of our treatment algorithm is cognitive behavioral therapy, which they actually have cognitive behavioral therapy specifically for insomnia. That's the preferred treatment for chronic insomnia and adults. And it essentially addresses common thoughts and behaviors that are, you know, very oftentimes interfering with the patient's sleep. And some of the behavioral components of CVT for insomnia would be the establishment of a sleep and wake time. You know, and that's something that patients should follow seven days per week. This whole, you know, catch up on sleep on the weekends. You know, or people, you know, there's, there's workships, you know, change throughout the week thing that can really throw a wrench into, you know, patients overall sleep quality and worse than, you know, somebody who's already struggling with insomnia for sure or cause it the first place. But it also addresses stimulus control, you know, going to bed when, and only when a patient's actually feeling sleepy, saving the bedroom specifically for, you know, only sleep insects. And that's it. Not having a, you know, be a place where you're just hanging out during the day and kind of having it as a place for your body just automatically associates it with sleep, even if it's subconsciously. And then, you know, encouraging patients to kind of note that how long they've been laying in bed. So if it's been more than 20 minutes, they're not asleep yet, actually getting up and trying again in a later time. So that it doesn't start this spiral of, you know, watching the clock and then starting to become anxious of, you know, the fact that they're not sleeping and then that just kind of causes this vicious cycle. And then also addresses the, you know, napping during the day, which a lot of times someone doesn't get good sleep. They want to take a nap during the day and then that kind of again, just sort of promotes that poor cycle, you know, and schedule. And then, you know, besides the stimulus control and the sleep schedule itself, just kind of going through various aspects of sleep hygiene as a whole, you know, and making sure that certain habits that a lot of us are probably guilty of, you know, aren't underlying factors that are worsening, you know, the patients insomnia in the first place. So those are, you know, some of the things that will be addressed and it's something that can be very effective, you know, for a lot of patients assuming, you know, bad access to that. - I'm surprised to say that I'm actually much better about those things than I used to be. And again, I can probably thank my wife for that. For instance, she would not allow like a TV in the bedroom and which seems kind of obvious now that I'm just thinking about it, but I had always had one through college and pharmacy school and stuff. So I thought that was, I was like, what, no TV, like you can't lay in bed and watch TV, like I love laying in bed and watching TV. But I certainly appreciate that now. - Though the get, like no sleep during the week and the catch up on the weekend kind of thing is unfortunately that's me, but then I just never catch up on the weekend, you know? - Yeah. See, that's funny, it's about the TV thing. If I were to take the TV out of our bags, I'd never watch TV in our bedroom, but if I were to take the TV out, I would be executed on say, no chance, she would be okay with that. - No, that was a hard no, no TV in the bedroom. And I'm probably being pretty unhappy about that. - You're like, well, that's great. - That's great. - 'Cause then like we make it. - It's true. We just like sleep in and the, our room and there's no other reason to really be in there. So, you just hang out in the living room. So other things that CBT can help with, addressing anxious thoughts, which is why we recommended in other conditions as well, especially focusing on the ones that patients experience at bedtime, relaxation techniques like mindfulness, meditation, progressive muscle relaxation. The only time I've really had insomnia that I probably would have made that criteria was in pharmacy school, probably a combination of just very poor sleep hygiene and you know, stressed about school and whatnot. And I remember, I think I saw a commercial for like an app that was supposed to help us sleep and I downloaded it. And it was this kind of mindfulness progressive muscle relaxation thing, which I would never have done anything like that before. But I tried it and it was tremendous. It really helped. Like I, yeah, I mean, I just, I did a couple of the things and it just, it's just this dude talking really mellow and like having you relax, different muscles like one by one or whatever. And then I would just kind of do it in my mind for I fell asleep and I would just like, I would fall asleep while I was doing it. So it actually helped a lot. It's often not an option for people because there's cost involved. Patients have to go to appointments. So there's time and it depends on if there's a therapist available in their area. And it doesn't work for everybody. So just because it happened to work for me 10 years ago, doesn't mean it would work for me now and doesn't mean it would work for somebody else. But certainly worth trying because there's no side effects of you know, meditating. So yeah, other than. It's supposed to be good for you. I think cramped knees, you know, if you sit, if you sit crisscross applesauce for too long. Yeah. Oh, yeah. - You can't actually do the full on. - No, I wasn't. - I was laying in bed. But how are you supposed to do it? You're crisscross applesauce? - Yeah, I'm not, I've heard great things about it. I know people who swear about it. I can't say that I'm a huge meditating guy. - I cannot imagine you meditating. - It is really like I, it just, not even specifically meditating, but anything that gets you to kind of stop and just be bored and inward for a little bit. It is, it is, it's hard to say that it's not beneficial even though I never do it. It is, anytime I have done it, it is very beneficial. - You want me to be alone with my thoughts. Are you crazy? I'm not doing that. No, I, yeah. - Pumping as much stimulus as possible than not having to be alone with you. - Yeah, I don't want to hear myself think ever. No, just kidding. But yes, CVT is obviously very, the common and widely available, but specifically for insomnia, a lot more limited resources, like Cole mentioned. I will touch on some of the components of good sleep hygiene. We've already mentioned some of them like maintaining regular bed times and awakenings and all that, not going to bed unless you're sleepy. And then making sure that you sleep long enough to avoid feeling tired the next day, but not over-sleeping either. So, you know, the whole catching up on sleeping, "Oh, I slept 14 hour." I mean, in some cases, if you're super sleep deprived maybe, but just in general, not great. It's just because you can or have the time to sleep more than your body needs doesn't necessarily mean that's a good idea. And then making sure that the bedroom is optimized for sleep. So, you know, there's no light or as little light as possible. The temperature is cool, you know, the noise is limited or at least, you know, noise that is sleep inducing, like, you know, some people, like me included like either white, noise, brown, noise, something like that. If it's too quiet, that creeps me out. But also developing sort of a bedtime routine that kind of allows you to, you know, physically and mentally unwind. And then, like we mentioned, is if the, you're not actually going to sleep, or if you cannot go to sleep, or, you know, you wake up in the middle of the night and can't go back to sleep, make sure that you're not just staying in laying in bed for more than 15 to 20 minutes, you know, staring at the clock, actually get up to go to a different part of the house to quiet. And, you know, all that still doesn't mean going to living room and pop TV on, but do something else like reading, you know, something like that that's, you know, maybe boring. But you don't go back into your room to try to fall asleep until you actually feel sleepy again. Try not to get a bed hungry. And also, at the same time, you don't want to be overly full. Like, you know, stuff yourself with snacks before going to bed. And, you know, something to keep, you know, if yourself satisfied, but kind of that good middle ground, if you will. And then, avoiding activities in the bedroom, like we talked about, bedroom should be for sleeping sex only, and not something that, you know, your mind, you know, subconsciously associates with, you know, other things. And then, avoiding naps during the day, like we said. And then also avoiding other things like stimulants, caffeine, nicotine, throughout the day, avoiding alcohol, because it can definitely lead to what they would refer to as fragmented sleep, you know, so the whole idea of a nightcap and all that, you know, to get a better night's sleep is actually very, very much not backed up by science. And also making sure that you're exercising regularly, but that the exercise is taking place during the day, and, you know, not close to bed done. Now, I will say just as a disclaimer, you know, this is sleep hygiene techniques that should be implemented for someone who is suffering from insomnia. Not necessarily, you know, if a patient is, you know, not doing, or is doing some of these things, or, you know, that they shouldn't be, but they're not having any problem sleeping. That I wouldn't spend a lot of time harping on sleep hygiene. So I just want to throw that out there. That's more for, you know, obviously students and things like that, because I've heard students counseling on sleep hygiene, and I'm listening to the student, go through it, I'm like, eh, they don't, but they said they don't have any trouble falling asleep or staying asleep when they actually need to. So telling them not to work out in the evening, if it's not a bother, you know, bothering them, you know, isn't necessarily an important thing to discuss, but, you know, I just throw that out there. Sleep hygiene is good, you know, for everybody, but especially for those obviously suffering from insomnia. - Yep. We didn't talk about it with comorbidities, but, you know, being evaluated for sleep apnea, of course. - Yeah. - If you do a risk for that, it would be very important. - All right, so let's hop into some of the medications starting with some hypnotic medications that act on benzodiazepine receptors. So these would be considered non benzodiazepine, benzodiazepine receptor agonists, kind of a mouthful. - Yeah. - So weird class. - In kind of just a little background on benzodiazepine receptors. There's a couple, the benzodiazepine one receptor contains the alpha one isoform. It's highly concentrated in the cortex, thalamus, cerebellum. It's responsible for the sedative effects and anterior grade amnesia. The benzodiazepine two receptor contains the alpha two isoform. It's highly concentrated in the limbic system, motor neurons, the dorsal horn of the spinal cord. It mediates the ansiolitic and myotrolaccent effects of benzodiazepines. Non benzodiazepine, benzodiazepine receptor agonists. So the stroke class are selective for the first receptor at the benzodiazepine one receptor. - Yeah, and to start off, we'll talk about a drug that I'm sure all of us have run into at some point whether dispensing or at least doing truck reviews and whatnot. But under the brand name Ambian, or chemical name Zolpedem, again mechanistically, it binds to that benzodiazepine receptor one selectively. It does carry a box warning for the potential to cause complex sleep behaviors and that can include sleep walking, wait for it, sleep driving, not great. - Not ideal. - And this is one of the culprits behind a lot of these stories here where in fact, we had a professor when we were in pharmacy school that used to tell a story about a colleague of his that basically was on Ambian, got up in the middle of the night, drove to the store, bought a turkey, came home, cooked, started the process of cooking, said turkey, like prepared it and woke up the next morning, thought someone broke into his house. And I guess it was like security camera footage that was able to like piece it together, but it shows them like walking through the story and like no recollection of it. So obviously can be very dangerous and it's not something that happens to everybody, but there's definitely enough of case reports and things like that that should at least warrant a discussion with the patient before they just jump on something like this. - You have to wonder if you came across somebody in that state, if it would be the same, just like a sleep walker or if they're more with it, but then they just forget it. Like it's the kind of amnesia piece, you know what I mean? I don't know. - I would just, I don't even think would, like the way that the ones that I've experienced, I wouldn't check them out at the register with a turkey, you know what I'm saying? Like I would see that person and be like, this person's not okay. So I wonder if it's kind of like a middle ground or something. I don't know. - Probably, I mean, definitely I think, I mean, I've had, I've like been on vacation with like friends and stuff like that word, like somebody was prescribing me and took it and like was getting ready for bed kind of thing. And I could like tell, like it was kicking in, just based on sleep or speech patterns and stuff like that where I'm like what? But I think it's more so like you said on the amnesia side of things that it can be problematic. - Concerned. - But also too, it's like you probably would just assume, if you saw somebody walk into the store, you'd just assume that they were on something or intoxicated somehow and you'd just be like, "Oh, this poor person is. " - It is of course highly effective. - Making it my only experience with it was on a plane. We were flying us out of Africa, so it was an extremely long flight in the, somebody I was with, person next to me, took it for the flight or was prescribed it for, specifically for the flight. And she was asleep for 10 hours and she was like she could have been dead. Like that is just laying on her tray, you could lift up her arm and drop it or whatever and just out and after that it was like, I don't think I want to take that medicine. - Yeah, I think I'll just, I think I'll just not do that. - You know, I had a buddy of mine, he's a medical provider now, but back in the day it was a green beret and he was an officer as well. And he had been given basically doses of ambient to give out to his guys under him for like they had like a super long overseas flight or something and he gave it two pills. He's like, you can take one, you know, leave and then save you the one for whatever. And he's like almost everybody just took both of them right then and there. And he's like something entire like, you know, 'cause whatever you call it, the squadron or whatever. And that's not the right term. But it was just zonked out and he's like, I chewed so many things. I was like, you morons and he's like, I had a bunch of, I don't know, technically adults that had just taken too much ambient 'cause we're supposed to be just soldiers and you guys are taking, he's just, he's funny here in himself, the story. Especially now as a medical professional. - Right. - This is like, it's crazy. But anyway, the other thing is the effects itself just kind of from a statistical standpoint. It does tend to affect females a little bit more so than males and same with elderly patients seems to be a little bit more of an effect. And so, you know, typically 10 milligrams for younger males would be kind of the standard dose and then five milligrams for females and elderly patients. Definitely not always the case, but you see a lot of patients just get put on 10 milligrams sort of as like the standard dose. And it does tend to affect females and elderly patients a little bit more intensely. It should be taken on an empty stomach if possible. Food does delay the onset of action by as much as an hour or two, which can be problematic if you're taking it close to bedtime. And there are various formulations that are available. The most commonly seen version is the immediate release tablet. And it's for studies and things. Advocacy has been seen for up to 35 days. None of these have like really long term studies and that's definitely something to consider. You'll see patients that have been on these for years and years in some cases and never reassessed. There is a controlled release tablet of Zopodem as well. Advocacy has been seen with the controlled release form for up to six months without tolerance developing. But again, you'll see patients aren't much longer than that. There's also a sublingual tablet under the brand name Intermeso. And it's got smaller doses that are available at 1.75 and 3.5. And it's indicated more so for middle of the night awakening where the patient has at least four hours left to sleep. And there's even a sublingual spray. If you're trying to get real fancy, but that's under the brand name Zopomis and does need to be primed prior to the first use. Adverse effects besides obviously the pucks warning and things, drowsiness the next day, dizziness, headache, just residual effects of the drug the following morning. So making sure that the patient takes it for the first time, either at a lower dose and kind of see how it affects them or making sure that they take it when there's nothing super pressing or important the next day. Just until they know how it's going to affect them. And needless to say, this is a controlled substance because there's an obvious abuse potential with this drug and many like it. So it has to follow all the same laws and whatnot that are implemented for controlled substances. So again, something to at least consider. - Yep. Before we go on to the rest of the meds, do you want to go and do the password before we forget? - Yeah, yeah, let's do that. All right, so for those of you who are free to eat members, make sure you go to the website, find this episode. If you go to like the learn tab, click on the category that says podcasts, find this episode, and then what it asks for the password, use sleep, all capital letters, sleep, and then the number 25. So it's L-E-E-P, 25, and sleep is in all caps. - Nice. - And that is your password for today. - Sure, sure. So the next medicine is Lunesta Espoclone. It interacts with GABA receptor complexes located near or allosterically coupled with benzodiazepine receptors. So a little less direct, but gets the kind of same job done. With high affinity for the alpha-3 subunit of the GABA receptor, it also has the box warning for complex sleep behaviors, including sleep walking, sleep driving, what not. It should be taken immediately before bed, and when the patient will be in bed for at least seven to eight hours on an empty stomach, food also delays the onset of action one to two hours, and then adverse effects. You can imagine drowsiness, dizziness, headache, metallic taste has been reported as well, and it's also a controlled substance. - I feel like the metallic taste is something that is more prevalent as far as side effect of Lunesta than, you know, I would typically assume. I've had a lot of patients not continue it because of that side effect. - Interesting. - Yeah, interesting. - All right, another non-benzo hypnotic is, not, that's not nearly as widely utilized, but I do think has a pretty decent, you know, place and therapy, if you will. But that's zeleplon, Sonata was the brand name for it that I don't think it's available anymore, but, you know, zeleplon is still available as a generic. Mechanistically, and it's pharmacologically similar to Zolpa-Dem, it also carries the same box warning like the others, where it can cause sleep, or complex sleep behaviors. And then the kind of the unique thing about this from a kinetic standpoint is the short half-life that zeleplon has, but it's half-life's only about one hour. And so typically we're gonna cause fewer problems, you know, the following morning, if the patient's having, you know, residual like groginess or whatnot, from what other medications this might be, and option for them, it does not prolong sleep time, or the number of awakenings. So it's definitely for, you know, the onset, and where I've actually utilized this in clinic, yeah, it's only been a handful of times, but basically having it as a needed option for, you know, a patient who may either not be taking anything for sleep onset, you know, initially, or is on something to help with sleep onset, but is still waking up every so often, kind of in the middle of the night. Having this is a, you know, a lower dose, you know, as needed to be taken in those cases where they do wake up, even though they've already taken something and have, you know, enough time where they can take a dose of this, and because of the short half-life, it'll be out of their system, and they'll be ready to go for the next morning. So I have seen cases like where the patient's on, like a 5 milligram ambient, you know, that they take most nights or every night, and then have this as like a backup that they use once or twice, you know, a month or maybe a little bit more frequently, but definitely like more of that PRN thing. This also should be taken in every stomach because of the delayed onset, if taken with food, same kind of side effect profile, does have data showing efficacy for up to 30 days, and is also a controlled substance. So, you know, if you are going to put somebody on this, this is like an as-needed thing on top of a different, you know, if not, you definitely document that and communicate that with the pharmacy so that you don't get a phone call wondering what in the world you're doing. Right. Okay, moving on to the benzodiazepines. So, backing directly on the benzodiazepine receptors. Just some background. Of course, these are typically a hard know that for most things that we try to avoid. And while they're not first line, again, sleep and quality sleep is important to patients' quality of life. So, in general, they're considered safe in patients who aren't at high risk. They're effective. They're usually well tolerated. But of course, they have the dependency issue within older patients' concerns around cognition and falls. All the things you would imagine. Five are primarily used as sedative hypnotics because they're rapidly absorbed and produce central nervous system actions more quickly than most anxiety agents. Someone with problems initiating sleep would most likely benefit from an agent with a quick onset, but short duration of action. Someone with problems maintaining sleep in the middle of the night might respond better to a drug with a longer half-life. And just to kind of give you an idea of some of the agents that are the benzos that are intended for, using for insomnia specifically, if you need one with a short duration of action, short half-life, triazolam, halcyon is the option there with a half-life of only two to six hours. And then there are a couple intermediate duration of action, or intermediate benzos, where tomazapam and estazolam are the two that would fall into that category. And then there are a couple that you almost would never see just because their half-life can potentially be very long, like 48 to 120 hours, which would be fuller azapam and core azapam. I don't think I've ever actually seen those two in being utilized in a patient. I've seen research and stuff being done with them, but not something you're going to run in two very often. Right. They, like I said, bind to the benzodiazepine receptors on the postsynaptic gabinarons. They decrease sleep latency and increase stage into sleep, total sleep time. They reduce delta sleep, which is the stage three and REM sleep. They have box warnings for risks of concomitant use with opioids. There's the abuse and addiction potential. And then there's dependency and withdrawal reactions for patients who come off of them. Notably, after treatment for several months, up to 40% of patients develop tolerance and dependence. It can cause rebound insomnia, especially with the agents, like mentioned, that are shorter acting, has the side effects of drowsiness, dizziness, headache, and is also a controlled substance. And of note, like triazolam being the shorter of the mentioned benzoes, it has been associated with daytime anxiety, which is most likely related to that withdrawal that patients experience in kind of between doses. Also, of note, using caution and producing the dose if triazolin is taken with a moderate, or even a weak CIP-3A4 inhibitor. And then, definitely using caution and patients with some kind of a compromised respiratory function, and the same would apply for a stasolam. And then for phlorazapam and chorazapam, they may impair the ability to operate machinery for even several days after discontinuing the medication, which is one of the reasons why we very seldomly would ever see that being utilized. Definitely not recommended in elderly patients in almost all cases. And then the chorazapam increases the concentration of CIP-2B6 substrates. Of note, bepropryon would be a commonly used medication that would fall into that category. But 2B6 is definitely not one that I typically thinking of when I'm thinking CIP interactions, right? But yeah. So drugs, benzoes, are you typically even see all that often, but those are the ones that are technically indicated for insomnia, right? There's also some antidepressants used for sleep. And we'll touch here at the end on kind of an algorithmic approach to what to choose and when you'll hear some of these and think like, oh, I don't know if I want to use that. We'll talk about it here at the end. So antidepressant-wise, there's doxapin, which is a tricyclic antidepressant to TCA. I had lower doses, three to six milligrams. It blocks histamine receptors, the H1 receptors. These do have a box warning for increased risk of suicidal. Thinking and behavior in children, not adolescents and adults. It's not to be used if patients have sleep apnea, untreated narrow angle glaucoma or severe urinary retention. It has a duration of action of about seven hours. There's a chance for morning effects. And it's kind of high because of the long half-life of both doxapin and it's active in tabolite, which is a nordoxapin. Adverse effects would be headache, nausea, diarrhea, hypertension, dry mouth, next-day salmulants, especially if taken with food. Don't take within three hours of a meal. It was how it's recommended to be taken, but take within 30 minutes of bedtime. It's more helpful in reducing awakening's during the night compared to actually hoping with sleep onset. And then one of the, at least in my experience, one of the more commonly used medications, at least first line, would be, or second line, even, trasidone, mechanistically. It's inhibiting serotonin reuptake. But also blocks, it has to mean one receptors, as well as alpha-1, endrogenic receptors. Care is a box warning for increased risk of suicidal thinking behavior, but that's, again, more so associated with its use as an antidepressant. The most evidence with trasidone is in patients that have concominant depression, along with insomnia, and there has been some data to suggest an SSRI plus trasidone can be effective, even in generalizing anxiety disorder. From a side-effect profile, the couple sort of things you should always think about when you think trasidone, orthostatic hypotension, and so patients who haven't get up in the middle of night to use the restroom, especially elderly patients, things like that, that can be really problematic, and I've actually seen someone in my family get up late for work after taking trasidone the night before, run up the stairs, and then just hit the floor and fell all the way down the stairs 'cause they had an orthostatic episode. So, and that is a patient, like, at the time, like in their early 30s. So, it's something that can happen in all age groups, and definitely something that should be discussed with patients before starting it. And then, trasidone can also cause pre-apism and males, as well, so kind of a unique side-effect as well with that, and something that should be discussed. - Agreed. All right, next is metasapine or remoron. This one is a tetracyclic antidepressant that works as an antagonist for central pre-synaptic alpha-2, it's for pre-synaptic alpha-2 antinergic effects. It increases release of norepinephrine and serotonin. It blocks the serotonin 2A receptor, resulting in basically no sexual dysfunction, no anxiety, and has sedation. Also, the 5-HT3 receptors, the serotonin 3 receptors, so it doesn't cause nausea, it doesn't really cause GI, disturbances, and then it also blocks the 5-HT2C receptors, which can lead to weight gain. And so typically increased appetite, really. So typically, or not typically, but you might see this use in patients who have appetite issues for various reasons being elderly or that kind of thing. It has a box warning for increased risk of suicidal thinking and behavior in children, adolescents and adults, as well, lower doses lead to more binding affinity to the H1 receptor, as the dose increases, the affinity decreases, and then it has adverse effects related to anticolonergic effects, QTC prolongation, of course, sedation at the lower doses, and as we mentioned, increased appetite and potential weight gain. Yeah, I think that something that's really important to think about because, like you said, the affinity for the histamine receptor is more prevalent at the lower doses, and even like the 7.5 may be more sedating than even the 15 milligram, 'cause as the dose goes up from 7.5 and starts to get closer to the max of 45 milligrams, not only do you lose some of the affinity for histamine, but you also get more alpha-endrogenic activity, which can be more of a stimulating effect. And so, there are situations where, it's the only drug I've told patients, it's one of the only drugs where maybe a lower dose actually will be more effective. And so, if they've been on the 15 milligrams and they feel like it's not all that effective, I actually have told some patients to cut it in half and see if that, and I've had some patients report back that seems to be more beneficial not whether or not that's placebo, versus just, you know, factual chemistry. I don't know, but that is from a receptor binding standpoint that is the case, you get more of the sedating effects at the lower doses. And if you are using it for depression, if the patient's like, "This is making me so tired," you know, as you're titrating the dose up, it gives them a little bit of comfort knowing that it will hopefully fade, although the appetite and stuff will not. Right. All right. Moving on to another class called the Orexin receptor antagonists, the first one that was approved in this class was Ceveroxent or Bellsomra. So think of Orexin as being like the neurotransmitter that is there to promote wakefulness. So you're kind of coming at the insomnia from the other angle. So instead of trying to induce sleep and have a hypnotic effect, this is trying to block the effects of wakefulness from the Orexin. And so Bellsomra blocks Orexin one and Orexin two receptors. It can definitely cause some daytime ambulance next day driving impairment as well, just like the hypnotics can. That are those side effects are going to be more prevalent in female patients and patients that have a BMI greater than 30. It's also been case reports of it causing sleep paralysis, hallucinations and kind of plexia. And so obviously we're doing a thorough patient history. Typically taken 30 minutes prior to bedtime and other common side effects cough, dry mouth, diarrhea, dizziness have been reported. If it's being taken with a strong C3A4 inhibitor, like ketoconzole orally, then starting dose should be should not be more than five milligrams. If it's being taken with a C3A4 inhibitor that's modern intensity, 3A4 inhibitor, like diltizum, 10 milligrams should be the max starting dose. - Yep. There's also limborexent, Davigo. It binds to both Orexin receptors with more affinity for the OX2 receptor. It can cause daytime somnolence and next day driving impairment, which is more common in female patients and patients with a BMI greater than 30 interestingly. It can cause the patient to experience sleep paralysis, like the other one as well, who's nations cataplexy. We were discussing it beforehand, but we definitely brought up sleep paralysis in episode a long time ago, but it's a certainly an interesting phenomenon. It should be taken within 30 minutes of bedtime, high fat and high calorie meals decrease the max concentration by 23%. So that's a good thing for patients to know. Do not use if taking with strong or moderate C3A4 inhibitors and then if taking weeks, C3A4 inhibitors, the max dose is five milligrams. - And then the third option in that class is direct scent and mechanistically, again, blocking Orexin 1 and Orexin 2 receptors. It's same kind of side effect profile as well as daytime somnolence risk, next day driving impairment, things like that. It can cause the sleep paralysis and stuff just like the others. It's still taken 30 minutes prior to bedtime and should not be used if the patient is taking a strong or even moderate C3A4 inhibitor. - All right, and we'll, the last drug we'll talk about before we finish up with the algorithm will be Ramelltion Rosarim, which is, this is not, does not act on Orexin, this is a melatonin receptor agonist. So melatonin type one and type two receptor agonists, the type one receptor is what promotes sleep onset, type two receptors synchronize the sleep wake phases and it doesn't have activity on the type three receptor. It binds to melatonin receptors with higher affinity than actual melatonin. It should be taken within 30 minutes of bedtime on an empty stomach. It can increase prolactin levels in females and it can lower testosterone levels in males. Adverse effects associated with it would be morning sleepiness, fatigue and potentially exacerbating insomnia. It can be used with CIP-1A2 inhibitors. For example, fluvoxamine would be one. It's not typically associated with dependence or tolerance, which is certainly a positive thing. Only effective for isolated sleep onset in insomnia. And some guidelines recommend against its use or even over the counter melatonin because of a lack of efficacy. And so, I mean, there's some data that kind of shows melatonin, I mean, not even be effective at all, although some people swear by it. So I'm one of the minds that if you feel like it's helping by all means, go for it. But if you need a non-controlled substance option that this may be, something to consider. - That's right. - All right, let's put it all together. So I'll kind of cover the algorithm on the sleep onset in insomnia that's isolated now, and then call if you want to do the sleep maintenance or mixed insomnia. But if the patient has isolated sleep onset, then the first thing to consider is do we need to avoid a first line benzodiazepine, or non- benzodiazepine receptor agonist? And if the answer to that is yes, I think if patient has substance abuse, history of substance abuse disorder, something along those lines, you just want to avoid controlled substances in general, would have you, one of the first line options in that case would be the rumbaths on, like Cole was just talking about. You could also use over the counter melatonin as well, be a cheaper alternative, although efficacy definitely would be questionable. Or one of the sedating antidepressants. So mertazepine or trasodone, things like that. And then there's also some over-the-counter options, which we didn't really mention, but like Z-quillard, which is just essentially benedrial diphenidromane. There's also doxolamine, which is what's in like unisolm and whatnot. If you don't necessarily need to avoid the controlled substance options, consider things like the non-benedadazepine receptor agonist, like esypoclon, zalplons, opadem. And then you have all the others, as we mentioned just previously as well. But those are going to be your typical options when just sleep onset is the problem that you're addressing. - If the issue is sleep maintenance or mixed insomnia, similarly you have to determine whether the patient wants to avoid a benzodiazepine receptor agonist's first line. So if they do or if there's a reason why you need to, you can consider the erection receptor antagonist that we talked about, low-dose doxapine, retazapine, tracidome, even a different TCA like L-A-Vill. There's some data for gabapintin and over-the-counter, there's considerations for, like, diphenidromane or doxolamine though, I'd probably limit the use of those. If there's no issue with the benedizepine receptor agonist, then you can still consider all of the above, but you can also consider the non-benedizepine, benedizepine receptor agonist, lunesta, ambion, that sort of thing that we mentioned. And also the benedizepines if that pops up. - And just to kind of give you something to summarize and close on, there was a metanalysis that was published back in 2022 in the Lancet and it was compared to the effects of pharmacological interventions for the acute and long-term management of insomnia disorder and adults, just to give you some bullet points from that. Overall, S-Zipoclone and LimberExent had a favorable profile. As Zipoclone might cause substantial adverse effects and then safety data on LimberExent were inconclusive. So, you know, while a favorable profile and effective that is two things to consider, you know, a side effect profile wise, doxapin and Zipoclone were well tolerated. However, data on efficacy and other important outcomes were very scarce and didn't allow for the authors to make firm conclusions during the metanalysis. Benedizepines, deredixerant, server-accent and trasidone can be effective in the acute treatment of insomnia but are associated with poor tolerability or they know that information about long-term effects is not currently available. They also mentioned that melatonin and rheumatone did not show overall material benefits. So, again, more data to kind of suggest those aren't good options unless the patient is getting benefit from them but be very realistic with expectations if you insist on a patient starting on melatonin before anything else. Right, right. But I think we are out of time. We're actually a little bit over, so I apologize. But if any of you have questions, comments, concerns, definitely shoot us an email. Thanks to our friends over at freec.com. If you want more structured style material and don't want to hear our side stories and tangents, check out our Patreon.com/coreconciltarex, tons of different pharmacotherapy lectures and slide sets that go along with those lectures that you can download and cover vast array of common disease states. So, very good review in our humble opinion for phenopharmacotherapy management and whatnot. So, check that out if that is interesting to you. And other than that, like I said, reach out to us if you have any suggestions for topics or anything you want to let us know about. We'd love to hear from you. And then we will see you guys on the next episode. Have a great one. [BLANK_AUDIO]