Activity Transcript

Charlene Gamaldo, MD: Hello, I'm Dr Charlene Gamaldo, professor of neurology at Johns Hopkins. Welcome to this program titled, 2022 Insomnia Year in Review: Insights Into the Optimal Management. Joining me today is Dr Phyllis Zee, who is the Benjamin and Virginia T. Boshes professor in neurology at Northwestern. Welcome, Phyllis.

Phyllis C. Zee, MD, PhD: Thank you, Charlene.

Dr Gamaldo: Well, let's get started, and we will begin with a brief review of the diagnostic criteria for insomnia disorder. When differentiating insomnia as a symptom versus a disorder, the first essential element is the frequency and duration component. Remember the rule of threes. Symptoms of sleep disruption occur at least three times a week for at least three months. Next, the sleep disruption should be described as difficulty initiating sleep, maintaining sleep, or waking earlier than intended, plus an expressed concern or dissatisfaction about their sleep.

Dr Zee: Yes. So really, in addition to these nighttime symptoms, it's really important to also ask your patients about the daytime symptoms. Insomnia is really a 24-hour problem. And the daytime symptoms are probably what brings our patients in to see us as much as the nighttime symptoms, so these can include fatigue, mood disturbances like irritability, and also behavioral issues. But more importantly, it also affects the family, affects the caregivers, affects the children and the entire family. So, there are a lot of issues also with social and interpersonal relationships, but on top of that, insomnia is often comorbid with medical and psychiatric conditions. So, a couple studies have really shown, it depends on what you read, but probably about patients with insomnia are almost twice as likely to have, for example, heart disease, hypertension, and if you think of any really medical disorders. So, a lot of data showing that there's a bidirectional relationship between insomnia and comorbid medical and psychiatric conditions. It's really important to ask about those, because you really have to treat both the insomnia and optimize the treatment of the medical comorbidities.

Dr Gamaldo: Thanks, Phyllis. And as medicine in general looks towards more personalized approaches to delivering healthcare, the same can be said for treating insomnia. We are embarking on more personalized approaches to delivering both CBT-I, which is the first line method for treating insomnia, as well as personalized approaches in the choice of pharmacotherapy.

Dr Zee: Yeah, so CBT-I is indeed the first line recommended treatment for insomnia, and this is across all guidelines, whether we're talking about European Sleep Research Society or the American College of Physicians and also the American Academy of Sleep Medicine. So, what is it? Behavioral cognitive behavioral therapies basically consist of behavior therapy, cognitive therapy, and the behavior therapy is really mainstream. And one of the most important parts of this is sleep restriction therapy. There are great benefits to CBT-I, this is why it's the first line. It has durable treatment gains, but also very importantly it can be used in conjunction with pharmacological therapy and perhaps even to reduce the amount of pharmacotherapy that is needed. There are really no real harms necessarily to CBT-I, except for one, which is the sleep restriction therapy. So initially patients can be tired or sleepy because you're restricting their time in bed, so something to be aware of. So, in addition to CBT-I, I think there's really more evidence now, especially last year or so, that light exposure is really important to both maintaining wakefulness during the day, but also it can actually improve sleep during the night. So, there's been some new recommendations regarding light exposure, increased daytime light exposure, if you're indoors, to about 250 lux of daylight. But very importantly, to diminish light 3 hours before bedtime, can dim your lights and try to sleep in as dark of an environment as possible.

Dr Gamaldo: Thanks, Phyllis. And as introduced earlier, in the spirit of precision and personalized treatment strategies, a study utilizing culturally tailored CBT-I proved to be more effective than general CBT-I. In this case, the version infused culturally specific elements based on the input of black women with insomnia, black sleep providers, and providers with experience treating patients from diverse backgrounds. Demonstrating the benefit of tailored CBT-I is not only being explored, however, based on ethnic or ancestry background, but even by age groups and specific groups who may suffer from insomnia along with similar comorbid conditions such as depression, anxiety, substance use disorder, and attention deficit. Many of the disorders that Phyllis had mentioned in a previous slide.

Dr Zee: Right, Charlene. So, although there's all these benefits that we discussed about with CBT-I, there are some challenges. And perhaps it's underutilized partially because of lack of trained therapists, psychologists for example, like in my institution with one. Also, insurance coverage for CBT-I is scarce, and some do, and some don't. And I think it's also a tough therapy, because the patients have to be willing to engage and it's not immediate fix. It does take for you to get the full benefits of that somewhere between 6 to 8 weeks. So, there's some challenges, but despite that, I think it is really important that we really use this as our first-line therapy.

Dr Gamaldo: Yes, Phyllis, for sure, and that's why there appears to be new avenues to look at CBT-I based on some of the challenges you mentioned. Some of those alternative modes of CBT-I delivery are really being explored, including prescription digital CBT-I. Evidence has shown cost savings with the digital CBT-I platform with one study reporting a reduction in prescription costs. Although the efficacy of digital CBT-I does not appear to be quite as robust as an in-person individual CBT-I or in person group CBT-I, internet delivery did show moderate effect size, and serves as a viable option when these in-person options are not available or accessible or patients face the challenges that Phyllis had mentioned. One example of CBT-I digital prescription is the FDA cleared Somryst program. It represents the next generation of personalized insomnia care by combining the Shuti digital program content with the clinical dashboard, allowing insomnia providers the opportunity to make real-time adjustments in behavioral recommendations. The results of the Somryst open label study are presented here. Subjects who completed the program demonstrated improvements in their ISI scores from baseline that remained after 2 months and up through 1 year.

Because it requires a prescription, however, it is worth mentioning some key safety considerations with Somryst. First, it must be done under the supervision of a healthcare provider to assess the appropriateness of the patient for the program, also whether it should be delivered as a monotherapy or as a part of a combined therapy. Finally, input from a treating provider is necessary to tailor the specific education, instruction, and safety concerns, alluding back to Phyllis's point about sleep restriction, particularly for individuals at high risk for experiencing either occupational injury or those in health, safety, or transportation related occupations. So, another area of investigation is looking at behavioral alternatives to comprehensive CBT-I. In this study, patients were given an unguided internet-based CBT-I program, and another group was given instructions to keep a, quote, "Three Good Things diary", whereby subjects write down three positive thoughts prior to bedtime. Both unguided internet CBT-I and the Three Good Things exercise showed improvement on the PSQI after one and two months compared to those awaiting treatment on a wait list.

Another option that has also shown some promise is the use of apps. In this case, an app that simply provides a nightly sleep prompt to promote good sleep performed better than placebo. What remains exciting is the creativity surrounding the development of new avenues to deliver behavioral treatment of insomnia to include more immersive options like virtual reality headsets and programs focus specifically on incorporating techniques such as mindfulness. Phyllis, what do you think? Can you discuss other CBT-I options that perhaps we haven't covered up to this point?

Dr Zee: Yes, absolutely. I think when we discuss Somryst, it does require a referral. Like you said, it requires oversight by a healthcare professional, and even that could be a challenge for some of our patients, and especially the cost of it. So, there are some other availabilities. For example, apps that you can get on your phone or iPad. One of my favorite ones is called CBT-i Coach, which was developed by the VA, so it's actually free. And I did tell my patients to go ahead and try that from the very start while they're waiting, for example, to get into a more formal CBT-I program. They're also workbooks that can be done. So just really take a look at the different apps. Many of them are quite good. Another area that has been gaining a lot of attention is the insomnia that's comorbid in patients with sleep apnea, or patients with sleep apnea who also have insomnia.

It's been estimated that maybe about anywhere from 20% to 30% of people with sleep apnea also have insomnia, and that actually limits perhaps the compliance with CPAP and the efficacy of CPAP, which is really, really important for these patients with insomnia. So other things, clearly medications, we have some concerns about using hypnotic medications in this group, especially if they're not treated adequately for sleep apnea. But along the CBT-I line, there's some new data showing that you can use CBT-I in patients with insomnia who also has sleep apnea. And some of the early data really shows that it may be quite useful. And so, this is something that we should be looking into the future, which means very importantly, in all our patients with OSA, we should be also inquiring about insomnia.

Dr Gamaldo: You're right, Phyllis, and this is an example of exactly that. An example of how strides are being made with CBT-I precision therapy for insomnia patients sharing similar occupations and comorbid conditions. In this case, military personnel with insomnia and OSA showed improvement in their sleep after CBT-I.

Dr Zee: So now let's move towards pharmacological therapy. I think at the end of the day what's important is what do patients want and what would they expect from a pharmacologic therapy. So, this was a study in which they actually looked at patient's perspective, patients that we want to improve our sleep abnormalities, so decrease the time to fall asleep, increase total sleep time, decrease awakenings during the night, and I guess overall the quality of sleep and perhaps daytime performance. But the medication ideally should have really minimal side effects. So, safety was quite important to patients as well. Amnesia, dizziness, sedation, headache, all of these are actually common side effects of many of our hypnotic, and certainly the earlier hypnotics. So, keeping that in mind, I wanted to just think now what are the recommendations by our guidelines? And probably the most prominent these is American College of Physicians guidelines, and I think we ought to pay attention to this.

It's part of the shared decision making, but here's what it says. Short-term use of medication, so this is that should be used short term, although we know insomnia is oftentimes a chronic problem, and to decide whether to add a pharmacological therapy after we've initiated CBT-I or in conjunction with CBT-I. Same thing, very similar with the European guidelines, only if CBT-I is not effective or not available, and the American Academy of Sleep Medicine has very similar... It's really CBT-I is the first line, and then pharmacologic therapy as a second line in conjunction with CBT-I or if CBT-I is not available. I think this is a very reasonable recommendation for our patients. So what medications, just to review very quickly? Hypnotic medications are really categories based on their mechanism of action. The earlier ones really, benzodiazepines like temazepam, perhaps most common, and then also benzodiazepine receptor agonists like zolpidem or zopiclone, and then also we also have on the market ramelteon, which is a melatonin receptor agonist. And we'll talk a little bit later about some of the dual orexin receptor antagonists a little more in detail, because they're a novel mechanism of action.

And then also some of you may have heard about doxepin, but here we're not talking about high dose doxepin, we're talking about doing about 3 or 6 milligrams, because at this lower dose it's really antihistamine and not so much with the anticholinergic side effects. But having said that, I think it's also important, Charlene, to think about what the Beers Criteria is recommending. They actually think that medication, especially in older adults, may be inappropriate, but this is, again, before the dual orexin receptor antagonists were on the market. So, the reasons are really mainly side effects, other adverse effects, and concerns, especially in the elderly, about falls, cognitive impairment, and perhaps also some of the anticholinergic side effects, especially of the over-the-counter medications, which very common, such as Benadryl for example, or any of the antihistamines in the market.

Dr Gamaldo: You are right, Phyllis. And despite the growing number of medications with insomnia indication, first and foremost, we have to always say that CBT-I still represents the first-line treatment in practically all the treatment guidelines, as Phyllis has shown. When it comes to pharmacotherapy, though, on the other hand, the recommendation's not as consistent. And the differences in pharmacotherapy recommendations can be based on what the guidelines may have given higher consideration to, whether it be safety, whether it be efficacy, a combination of the 2, and even the amount of published efficacy data that's available. This slide displays a summary, though, of various treatment outcomes based on a meta-analysis looking at just that where it's comparing placebo on the top right alongside three of the most commonly prescribed insomnia medications on that same top row along with the DORA class of medications on the bottom row, which represents a newly approved pharmacotherapeutic class.

However, on the other hand, the safety profile appears consistently better with the newer class of DORA medications versus the older generation of insomnia medications. A greater spotlight as well is being placed on the consideration of the patient's treatment goals and where they place the greatest value. In one study, patients noted improvement in daytime function as their top priority even if it had to be achieved at the expense of experiencing some side effects. Why is this important? It's because it circles back to the whole idea of patient-centered care, but also, it's to remind us that the functional component is actually an essential element of the diagnostic criteria of insomnia. The new class of medications we showed earlier are referred to as the DORAs. This is an acronym based on the mutual mechanism of action as dual orexin receptor antagonists. We point out here that the half-life and the Tmax do serve as one distinction between the three available DORA medications. Studies are also being done to look at the effect of DORAs in specific populations.

Phyllis had mentioned how there's considerations about what medications would be more appropriate in our elderly patients versus our younger patients, and these types of studies are looking just exactly at that. In this study, elderly patients taking the DORA lemborexant showed no significant difference in reports of adverse events at the five milligram and the 10-milligram dose compared to placebo. Those taking lemborexant also showed greater improvement at both doses compared to placebo with symptoms of daytime fatigue that remained at the six-month mark. Looking at similar outcome metrics of sleep, latency, efficiency, and wake after sleep onset. This slide shows that both zolpidem and lemborexant at the five milligram and 10-milligram dose were superior to placebo.

Dr Zee: So, Charlene, this is one of the few studies where in the same study you have both zolpidem and a DORA, another medication. It's not really head-to-head, but I think it's really important to see that a DORA was effective, similar to that zolpidem. Furthermore, I think one of the paradox in our clinical practice is that insomnia is typically a chronic disorder, but there's this common perception that they should be used for short-term use only. Some of this is really due to the concerns about adverse effects, tolerance, and safety, as we talked about in the elderly falls and cognitive impairment, with the long-term use of these medications. Most of that data comes from data of the earlier insomnia medications like the benzodiazepines and the benzodiazepine receptor agonists. So, I just wanted to, I don't know, show some data on the DORAs and the long-term efficacy but also safety of these medications. So almost all of these DORAs have now performed studies that are about more than six months placebo controlled and extending it over to a year.

So, in this study of suvorexant, they looked at long-term efficacy as well as safety. This was a one-year placebo control study of suvorexant, and you can see that for both means objective sleep latency as well as total sleep time the efficacy was sustained for the entire year. In another study with lemborexant, this was also a 1-year study. The first part was a placebo-controlled trial where it was for 6 months, and then there was another 6-month extension period. And again, you can see with self-reported sleep latency, as well as a decrease in the amount awake after sleep onset, that the efficacy was sustained across the 6-month placebo-controlled period as well as during the 6-month extension period. Similarly, a study was done with daridorexant, which is the newest of the DORAs, and here again you can see that the placebo-controlled trial first was a 12-week period, and there was this 40-week extension study again showing that if you look at subjective total sleep time in this graph that it was sustained across the entire 40 weeks.

So, all this data I think indicate that the DORAs are having shown to be efficacious. They can maintain their efficacy across at least a year period. Although, as I think Charlene already mentioned, that the DORAs have an improved safety profile, there are still some safety issues that need to be raised with your patients. For example, one of the most common side effects was daytime sleepiness or somnolence the next morning, headache can also occur as well as dizziness and also these abnormal dreams. Usually these are very vivid dreams, and I tell my patients if they experienced that to let me know. And also, there is, while very uncommon, some patients have reported sleep paralysis. So, something to really warn your patients about so that they're aware of that.

Dr Gamaldo: Phyllis, I could not agree with you more. And going back to some of the points you had mentioned earlier, a lot of times some of the challenges we face when we're now turning to pharmacotherapeutics is to think about which one to start with, how do I balance the adverse effects, and thinking about things in particular along the lines of any sort of daytime sleepiness, that hangover feeling with medications that may still be on board. So, this study actually looked at just that, both efficacy outcomes as well as looking at the impact of the presence of daytime sleepiness. So, this was done with daridorexant, and it's at the 3 available doses of 10, 25 and 50 milligrams, and it was found to have benefit in latency, maintenance, and increased total sleep time compared to placebo, but this was found in only the 25 and the 50 milligram doses. When it comes to daytime functioning, though, it was only the 50-milligram dose that showed a decrease in daytime sleepiness.

This next slide shows some of the latest data evaluating, again, the presence of daytime sleepiness and improvement corollary of that in daytime alertness for 2 of the DORAs compared to placebo. In the case of lemborexant, the 10-milligram dose alone demonstrated significantly better improvements in next day alertness compared to placebo or the 5-milligram dose, but this difference was not present at the 9- and 12-month mark. On the right side, a study showed both 15 and 20-milligram doses of suvorexant showed significant improvement in feeling refreshed compared to placebo, which was maintained, in fact, at the 3-month mark. Some more studies too, looking at the effect of daridorexant at the 3 available doses of 10, 25, and 50 milligrams, again assessing daytime functioning, this time it was done utilizing a validated IDSIQ questionnaire, and they found improvement at the 50-milligram dose alone, which did remain at 3 months.

Dr Zee: I think what we're seeing now, Charlene, from the wonderful summary that you provided is that these medications, whereas pharmacotherapy and perhaps even for cognitive behavior therapy, it's that it has to improve daytime function. We're paying attention to daytime function, daytime performance, which is something that many pharmacological trials in the past had not basically done. So, one of the challenges that we have in the clinic is tapering our patients off of the hypnotic medication that we prescribed maybe for 2 or 3 months, or sometimes for some of our patients for maybe six months or over a year. So, there's been several withdrawal studies. Most of those are in patients for 65 years and older. And most of these studies relate to the benzodiazepines or the Z-drugs. So, the successful withdrawal rates really vary depending on the type of interventions, and for example, is there psychological support in the approach, are you using CBT-I, for example, in the approach, and also the speed at which we are tapering.

And I think what's important to note is that if done properly, it can be quite effective. It can be done without deterioration in sleep quality and really withdrawal effects. So, when we're in the clinic, I tend to think about this. Really make sure that you include the patient in this conversation about tapering withdrawal. Set those expectations early on. I always say let's try it for 3 months, and then we institute CBT-I, let's see what happens. I think setting those expectations is important. And for those who started on a Z-drug alone rather than benzodiazepine, they were more likely to be continued after discharge. So again, it's really important to think about the choice of medication now that we have many more tools and other mechanisms of action. It's, I think, also important to think about this gradual taper versus abrupt stopping. As I mentioned earlier, about 25% every two weeks is quite reasonable, and the data has shown that it can be more effective. Education is really material and expectations education.

I tell my patients, "If we're decreasing your dose, you may get some more insomnia. Your insomnia may return, but it doesn't mean that it's rebound. You need to give it some time and bear with that for a while, and if the symptoms are so severe, we can go back to thinking about restarting some of these medications." I mentioned earlier that CBT-I is really quite useful in tapering. Warren and others have shown that if you use CBT-I, you can actually help taper successful medications, including some of the Z-drugs. And really to be successful, it really takes a village here, that the patient has to be on board with you, and that you really always have to weigh the risk benefit ratio of whether there's a need to withdraw the medication or the speed of the withdrawal.

Dr Gamaldo: Phyllis, I am so glad that there are studies now about deprescribing. We talked about how it's sometimes a daunting task to figure out what to start with, but it's so true. It's equally daunting in terms of how to stop it and with what combination and that sort of thing. So, I think that this is wonderful that this provides some insight and guidance on how we can do it. And it really comes back to, again, personalized medicine, thinking about the person and a similar way of thinking about treat the person with the disease, not the disease itself. And as Phyllis mentioned, it often takes a village to help one with insomnia. But in addition to providing more personalized approaches for the patient, it's nice to see that there are also guidelines for personalized approaches for deprescribing in terms of the healthcare provider.

So, I really liked this slide, because it's an example of that. And it's giving recommendations customized to the clinical practice type on how you may approach deprescribing, in this case providing an approach based on the practicalities, of course we always want to know that the realistic resources that are available that may be different for a single practitioner compared to those in a group practice setting.

Dr Zee: Yeah, Charlene, I think this is really important, and here's where I want to stress CBT-I can be quite useful, which means if you can start pharmacologic therapy, you should also engage the patient in cognitive behavior therapy, because there's data to show that it can be helpful with tapering. And remember, CBT-I has that durability of the effect.

Dr Gamaldo: Absolutely. And there's more that suggests that it's helpful in treating maybe some of the other comorbid sleep conditions going on, so as we saw with OSA and insomnia, but perhaps it's even with other ones as well. And I really enjoyed chatting with you today, Phyllis, and getting an update on 2022. As we close this program, I did want to wrap up with some of the big take home messages for me in terms of this 2022 year in review of insomnia care. And number one for me is the fact that it's a growing armamentarium. It's really promising that we have new tools at our disposal for personalized therapeutic insomnia care, and this is both from the behavioral standpoint and the pharmacotherapeutic standpoint. Phyllis, what are your thoughts? What are some of the take home things for a 2022 year in review for you?

Dr Zee: Well, I totally agree with you. I totally agree with your assessment, and just want to really bring home the message that insomnia is a 24-hour problem. We do need to be paying attention to the daytime symptoms. We need to be asking our patients, "So how are you functioning during the day," not only, "How long does it take for you to fall asleep," for example. And I think our newer therapies are addressing that issue of daytime functioning, whether it's pharmacological therapy and/or cognitive behavior therapy. As you mentioned earlier, it is really a good time because insomnia treatment is challenging, but we have in 2022 newer tools, whether it's CBT-I digital, for example, that we can give to our patients, and also this combination of, I think, efficacious but also safer medications.

Dr Gamaldo: Absolutely. Balancing efficacy and safety and having the evidence to go along with it is a wonderful new advancement for us with insomnia care.

Dr Zee: Well, we still don't have a magic pill, right? We still don't have that. When we discuss what patients really want, where we've been optimal medication, we still don't have them. There are still some side effects, as we mentioned earlier. So, Charlene, thank you very much for this really engaging and great discussion.

Dr Gamaldo: It was a pleasure. Thank you, Phyllis.

Dr Zee: And thank you for participating in this activity. Please continue on to answer the questions to follow and complete evaluation. Thank you again.

This transcript has not been copyedited.