Activity Transcript

David Neubauer, MD: Hello. I'm David Neubauer, associate professor of Psychiatry in Behavioral Sciences in Baltimore, Maryland. I'm joined today by Rexford Muza, a sleep physician in London, and by Liborio Parrino, a professor of neurology in Italy. Welcome to this program, "A Look Back at 2022; A Review of What's New in Insomnia."

Liborio, are there any new data or changes around the diagnosis of insomnia disorder this year?

Liborio Parrino, MD, PhD: Thank you, David, and I think that there are no big changes since 2013, when the DSM-5 manual was published. The new classification tells us that insomnia is not only a symptom; it's rather a disease, or it's a complex condition, of which there are nocturnal indicators, there are diurnal dysfunction and there are also some severity and temporal issues to cover. So, it's not only a matter of saying, "I have difficulty in initiating sleep, maintaining sleep, early morning awakening," but it's also a condition of dissatisfaction of sleep quality or quantity. And most of all, there's this big pie to cover which is the daytime dysfunction, which means mood, vigilance, concentration, memory, cognitive functions, behavioral difficulties. So there's a lot to put together in this new approach, Unfortunately, the diagnosis of insomnia is not supported by objective measures, and this is another important issue to cover in the future and probably can be, in certain cases, integrated by a more objective approach.

Dr Neubauer: It's such an important point, because by definition, insomnia is a subjective disorder. It is that complaint of difficulty falling asleep or staying asleep during the night. And it's so good that now we have built into the diagnostic criteria these daytime symptoms, these complaints of daytime functioning, and those are so critical, because that's really what brings people in for help, I believe. They may tolerate problems at nighttime, but when their symptoms are affecting how they're feeling and functioning in the daytime, that puts them over the edge, turning to a healthcare provider looking for help with their sleep.

But while we have made a lot of progress in terms of defining insomnia disorder, there's still a lot more room for progress in actually identifying and treating patients. Rexford, what's your experience, and can you give us a little bit of background on some of the data on the degree to which people are going to their doctors and other providers for sleep problems?

Rexford T. Muza, MMED, FRCP: Thank you, David. I think we still have a challenge in front of us. We still have got targets which we have not yet met. I think this is quite well illustrated in a recent study in the US of the primary-care physicians and the sleep specialists, where we're looking at whether patients were being listened to if they presented with insomnia complaints. Of course, the primary-care physicians, 66% of them said they asked about sleep, but on the other hand, only 27% of the patients with sleep complaints said they were asked the relevant questions about sleep. The truth is somewhere in between, but certainly we're not doing enough.

Perhaps there's still that background historical thinking, which Liborio was saying, that it is not being taken seriously enough. The traditional way of looking at insomnia, was that it was just a nuisance by some of the physicians: a byproduct of some other medical condition, not a disease in its own right.

We should take insomnia seriously as a disease in its own right; a disease which is prevalent; a disease which is long-term; a disease which has consequences in the short term and in the long term, not only physical consequences such as diabetes and hypertension, but psychiatric comorbidities, and then in the workplace, in the home, this presenteeism, absenteeism...there are so many consequences of insomnia, and the daytime symptoms which have already been mentioned. So it is a challenge to the physicians which they have to rise up to. They should be asking more questions about insomnia when patients present to them.

Dr Neubauer: Yes, routinely, perhaps. Part of a review of systems along with all of the other symptoms that you might have.

Dr Muza: Exactly.

Dr Neubauer: We'll move on now to talk about the recent guidelines, and especially interesting lately was the American Heart Association adding good sleep as one of the life's essentials. So there are 8 on the list and they include things that we advocate anyway, in terms of healthy eating and exercise and of course, controlling blood pressure and not smoking, but it's great to see that sleep has been added to that list as well.

Liborio, have any other new guidelines or recommendations been published this year that affect how we manage people with insomnia?

Dr Parrino: Well, the guidelines are helping us to have some light on where we have to go, how to manage. The last ones, there is a revision process going on in Europe and certainly also in the United States. So, it's good to update every 5 or 6 years what has been written, also because there's new bibliography, new references, new meta-analyses.

There are some recommendations also on the correct use of light exposure in the morning and in the evening hours, because people sometimes don't realize that light can be an enemy or a risk factor to deteriorate or impair a good sleep quality. So, it's important also to have figures: amounts of light exposure, time of light exposure.

So light is one important aspect which should be included when we talk about the guidelines of how we should understand insomnia and prevent insomnia, and eventually, also treating insomnia. It's not only a single item that can solve your sleep quality; it's a lifestyle that is very important there.

Dr Neubauer: Quite agree with that, and it's been so nice to see the quantification of some of the recommendations. We've told people for a long time to dim light in the evening and try to sleep in a dark room, and more recently, we've been advocating that people spend more time outside and getting more sunlight. But there are guidelines that were published just this year that highlight exactly what the amount of light should be in terms of lux: what we should have in the daytime, the decrease in light, which is probably much less than people are following, for a few hours before bedtime, and then how dark it should be in our bedrooms. We know that a lot of people have the television on and have their screens in bed with them, and now there is clear evidence that those have detrimental effects on our sleep, but our metabolic health as well.

And there was a really interesting study that was just published this past year. It came out from Phyllis Zee's group in Chicago, and they were looking at the effects of light within the bedroom, and they found that habitual light at night in older age is associated with concurrent obesity, diabetes and hypertension. They recognize that further research is needed to understand the long-term effects of light at night on cardiometabolic effects, but there is very clear evidence now that even a small amount of light in our bedrooms can have a detrimental effect.

Now, clearly there's a need to balance safety and a little bit of light from a night light, maybe, is okay, but it should be absolutely minimal and perhaps at a low level on the wall so it's not affecting us when we're in bed. So everything that we can do to reinforce the robustness of our circadian clock in terms of daytime activity and daytime light exposure and darkness at nighttime and dim light as we approach bedtime, all of that represents the foundation of the circadian rhythm, which profoundly affects our sleep-wake cycle. We know that there are evidence-based treatments for insomnia disorder, and we'll talk more about those, but the foundation really is doing the best that we can to maintain that robustness and regularity of our circadian system.

Dr Parrino: Also because, to complete this point, maybe doctors and patients don't know that light destroys melatonin, your own melatonin which you produce in your pineal gland, but also, and we made these studies in Parma, we also demonstrated that light destroys the melatonin that you take exogenously. So this means that we have to be careful, as you were stressing before; that the exposure to light is something that can have a lot of consequences. Even if you're convinced that your melatonin is covered by the exogenous administration, it's not that clear and you have to be careful. So, protect your eyes in the evening and expose yourself to these minimum amounts of recommended dim lighting in evening and strong light in the morning to regulate your circadian clock. Very important.

Dr Neubauer: There's the intensity of light that's very important, but also the wavelength. So, we want to have that bluer end of the spectrum early in the day, and try to eliminate that as much as possible in the evening. Sometimes patients who have trouble getting to sleep ask me whether or not they should try melatonin. My response to them is try your own melatonin. Follow efforts to decrease all of the light that is suppressing your own melatonin. Give your own melatonin a chance to work by not having those screens right in front of your eyes, the ambient lights around your house or apartment. Keep them dim and try to use these newer high-tech LED bulbs that may be able to transfer to the reddish end of the spectrum.

A lot of people end up using many different types of medications. On the one hand, there are guidelines. On the other hand, there are things that people actually do, and in some cases, things that healthcare providers will prescribe that don't necessarily make sense or are in-keeping with the guidelines.

One example is in the list of the top 300 medications in the United States. Now, we don't think that a sleep medication should be at the top of the list. We don't think that everybody should be prescribed sleep medications. However, the relative positioning on the list really is revealing. And so, the top 300 drugs (and this was just reported weeks ago – the most recent data are for 2020, but the latest publication is new), and you have to go down to the ranking order of the 21st most commonly prescribed medication, and that's trazodone. Now, trazodone is an antidepressant. It's not indicated for treating insomnia, but I suspect that nearly 100% of the trazodone prescriptions are for people who are complaining of sleep difficulty. So that's number one, which is totally outside of the guidelines. Perhaps there's a sedating effect and some people may benefit from it, but it's prescribed without concern about the safety, or really, the efficacy, because there simply aren't data and we don't have good prescribing recommendations for those. So, trazodone is number 21, and you have to go all the way down to number 47 to find a medication in the US that's actually approved by the FDA for treating insomnia, and that is zolpidem, and you have to go way down further to find any of the other approved medications.

So it's a good time here to talk about new approvals for medications that regulatory bodies like the FDA, and NICE in the UK, have approved. So most recently has been the approval of daridorexant in this new category of dual orexin receptor antagonists. In the United States, we have 3 now. First there was suvorexant, then lemborexant, and now daridorexant. Daridorexant has now been approved in the EU as well. So that's 1 element of a recommendation over the past year.

And the other domain is within cognitive and behavioral approaches, and so there are a number of different apps and prescription digital therapeutics that are now available, and there are very good data to support the efficacy of both of these in conjunction with the more traditional cognitive behavioral therapy. And, Rexford, can you comment on your experience and what's happening in the UK with this?

Dr Muza: Yes. We accept, and I'm sure you do, that cognitive behavioral therapy should be integral in the management of patients with insomnia. The challenge we face, and I'm sure is the challenge which most other people face, is that it's not that readily accessible. We do not have many well-trained therapists who can deliver meaningful cognitive behavioral therapy.

Dr Neubauer: So, there's some evidence that even these digital types of cognitive behavioral therapy can offer some benefit, even though we think that probably the one-on-one or the group approaches are.

Dr Muza: I think that's an important point. So, if the therapist-led cognitive behavioral therapy has got the most benefit for the patient, especially the individual face-to-face therapist-led CBTI. And then in my department we try to do group therapies with the therapist supervising a class of maybe 10, 15 patients, and that works as well. Not as good as the individual, but digital-based cognitive behavioral therapy has a place. It is accessible. It is easy to do. I think the pandemic taught us a big lesson: that we cannot always see patients face to face and we now have to learn, embrace these new technologies, and use them to the benefit of our patients, and we should do the same in sleep medicine.

Dr Neubauer: I saw that there was a report just this year that showed that in some areas in the UK, there were in fact overall healthcare cost savings, probably due to a decrease in prescribing of medications in an area where the Sleepio app had become available.

Dr Muza: Absolutely. So, the Sleepio app is approved by the NICE, National Institute for Health and Care Excellence. There's some other digital-based insomnia websites such as Sleepstation, Sleepful.Me, which are quite useful. So, it just depends on what is available to you. So, I would encourage primary care physicians to be referring their patients for cognitive behavioral therapy which is digitally-based if they can't access the therapist-led therapies.

Dr Neubauer: Yeah. I see that there was another report that came out just this year that actually was able to look at the effect size of one-on-one cognitive behavioral therapy, which had the best efficacy, followed by the group, and then the digital, but they still had a reasonable effect size.

Dr Muza: Still a very reasonable effect size, and the main advantage is it's what you are going to be able to access most of the time. So we should go for it.

Dr Neubauer: Yes. Okay. Well, we talked a bit earlier about new medications being approved, and one of the major publications in this domain in 2022 was by Emmanuel Mignot and colleagues in Lancet Neurology, and this was looking at 2 pivotal phase 3 studies for daridorexant, and they found that there was significant improvement vs placebo in polysomnographically determined sleep latency and wake-after-sleep onset with the 50 milligram dose and for the WASO as well for the 25 milligram dose.

Also, there were patient reported improvements in the total sleep time with both doses, and the daytime function with the 50 milligram dose as represented by a sleepiness domain score. And interestingly, the rates of the adverse effects were similar between the groups; that is, the medication doses and the placebo. The most common AEs were nasopharyngitis and headaches for all of the groups. So, it was pretty well tolerated.

There also have been some interesting reports lately about possible adverse effects with the whole range of medications that are prescribed for sleep. So that's always a concern, that we have the immediate effects during the nighttime or perhaps the following morning. There were studies looking at adults and older adults who had been prescribed zolpidem and trazodone and benzodiazepines, showing that there was a higher risk for falls compared to matched controls without sleep disorders. There also was a report this year looking at individuals with hepatic cirrhosis who had been prescribed zolpidem, and by de-prescribing the medication there was a reduction in falls among those individuals.

So, Liborio, any thoughts on your end about these new approvals and the new data and the implications for clinical practice?

Dr Parrino: Well, as sleep clinicians, as physicians in general, we're always excited when new options, when new drugs arrive, because they offer new tools for personalizing and trying to define the correct treatment for the single patient. In addition, the new drug, which is arriving now, daridorexant, is offering also a new paradigm because it's not acting on the conventional target, which are the GABA receptors; it's acting on a new mainstream, which is the neuropeptide the of the hypothalamus, which is orexin. So, it also offers us a new way to open our minds and to have new challenges to understand better the pathophysiology of insomnia in trying to identify the phenotype, which is mostly handled and improved by this new potential treatment. So we're very, very excited and very curious for the future.

Dr Neubauer: And, Rexford, what's the message for the primary-care physician and other care providers in your area, in terms of the use of the cognitive behavioral approaches and for the new medications that are coming along?

Dr Muza: It's a very important point you raise. Cognitive behavioral therapy, like I said before, should be part of the insomnia treatment, and we are now encouraging our primary-care physicians to be referring patients for cognitive behavioral therapy.

The addition of new drugs on the market gives us a very, very good alternative. The search is still there for a perfect drug: a drug which will work immediately, a drug which will work throughout the night, a drug which won't give you morning grogginess, which won't give you memory impairment, which will not affect your driving, your concentration, which is quickly washed out of the system, which doesn't cause dependency and tolerance, and obviously, you want a drug which will be perhaps safe in overdose. So, we still are looking for that drug.

But in the clinic with your patient in front of you, you still have to personalize: take your patient there and then choose the drug which is best for that patient. Does your patient have sleep apnea? You might want to avoid a hypnotic sedative. Is your patient alcoholic? You might want to avoid a drug which will cause dependency. Does your patient have psychiatric comorbidities? You have to choose accordingly. Does your patient have sleep-initiation insomnia, sleep maintenance or early morning awakening? You want a drug which will cover those stages of sleep. So yes, we've got another drug, another alternative to use, but we still have to choose the appropriate drugs for the right patient in front of you.

Dr Neubauer: Very good. Looking back over the past year at the topics that are published, but also presentations at the meetings, there has been a very strong focus on the daytime functioning. We've talked about how important that is diagnostically and in the patient experience.

One of the reports looked at lemborexant in particular, with regard to fatigue in older individuals. They had looked at one of the phase 3 studies and particularly focused on the older individuals, and there were 134 of them who ranked high in terms of their fatigue at baseline. And it was shown that with treatment over a 6-month period, there was a significantly greater improvement in their fatigue score with the lemborexant doses compared to placebo during that treatment period.

There also have been recent reports with daridorexant looking at daytime functioning improvements during the phase 3 trials. There are many different ways of looking at daytime functioning, and so far, there's really hasn't been a consistent scale until now. There was a development of the Insomnia Daytime Symptoms and Impacts Questionnaire, the IDSIQ, that's been used in clinical trials recently. And so, there were some new reports clarifying the size of a clinically meaningful change for this scale, and this may be useful going into the future. Again, we know about how patients are able to define their nighttime sleep problems. It's been more difficult to get a good sense of the many domains of daytime difficulties in terms of a scale.

Liborio, are these data on daytime functioning meaningful? Are they what you would expect from the mechanism of these drugs that inhibit orexin signaling?

Dr Parrino: Well, orexin is a very typical neuropeptide which is linked to eating and to wakefulness. So, if you modulate the receptors of this neuropeptide, you're certainly also modulating vigilance and feeding. But let's take away feeding, and we will talk about it maybe later. What we are interested in trying to understand is if vigilance can be preserved during the day and impaired or remodulated during the night. And I'm sure that the preliminary data are encouraging in this sense. It seems that daridorexant direction is doing its correct work, decreasing arousal during the night and preserving a correct amount and level of arousal during the day. If we can balance these 2 extremes, we're approaching this ideal hypnotic dream that we are chasing for so many years.

Dr Neubauer: And it gives us an opportunity more to personalize the medications. As I mentioned, in the US, we now have the suvorexant, lemborexant, daridorexant... There are others that are under development. So this is a very exciting new pharmacodynamic direction that we think really makes a big difference in terms of the daytime benefits that people may experience. Rexford, what is your take-home message for primary-care providers on this topic of daytime functioning?

Dr Muza: I think that's a very important aspect of insomnia. We've known now for a long time that insomnia is a 24-hour condition which ruins the night and ruins the day, and in the treatment of insomnia you want something which will improve the night and improve the day as well. So, you should measure the improvement in the nighttime indices and the daytime indices. If you give a drug that will knock out the patient and they sleep like a log at night but they're zombie-like during the day, they cannot drive, their concentration is poor, their memory is poor, you're not doing the patient any favors. So, we should be measuring daytime functionality. We should emphasize that this is part of the treatment of insomnia we should look at from diagnosis to treatment and to monitoring treatment outcome.

Let's continue with the theme of mechanisms and turn to neurobiology. Liborio, this is an interest of yours in terms of mechanisms and medications and matching this up with what types of insomnia to select different treatments for among patients.

Dr Parrino: Yeah. When the patient comes to our office, we're trying to understand what kind of insomnia, because the phenotype of difficulty falling asleep or the phenotype of early morning awakening is quite easy to interpret, but it's not clear when the patient says, "I have problems in sleep maintenance," because sleep is like a train with 5 wagons and each wagon has approximately a 90-minute duration, which means the sleep cycle, including the non-REM and REM sleep of each cycle.

But the first part of sleep, particularly the first 3 carriages, which are approximately covering the first 4 to 4 and a half hours of sleep duration, are dominated by a neurotransmitter, which is GABA, which is different from the transmitter which is modulating and preparing wakefulness in the morning, which is underneath the final 2 wagons of the train. So, we show to our patients – and this can be done also by the general practitioners in his or her daily routine activity – asking the patient, "If you wake up in the night, when and where in this train in this analogy do you?" Because it's different also in terms of strategies, because if you wake up in the first part, probably you need a GABAergic, and if you wake up in the second part, you don't need the GABAergic solution. Maybe it's better to use something that modulates the acetylcholine neurotransmitter.

And now that we have daridorexant, which means a new target of receptors, we will try to understand when and where should we use this kind of drug. As Rexford was saying before, we need to understand a person has personalized tools for the different phenotypes. But for the first time, the patient, when he sees the train, he understands or she understands that there's a way to follow and to realize that there is a personalized approach and not a generic saying, "Well, you don't sleep well?" No, there is a certain and well-clarified explanation, and this helps also in a positive interaction and good feeling between patient and physician.

Dr Neubauer: Yeah, I quite agree, and again we'll emphasize the point that our pharmacopeia has been expanded with these dual orexin receptor antagonists, which can just give us more choices in terms of the actual complaints that people have at nighttime during the daytime. Another really interesting area that's been reported recently has been the interaction of sleep and food, and Liborio, do you want to comment on these findings?

Dr Parrino: We know that if we eat correctly in the evening, and the Mediterranean diet could be a possible recommendation, we probably help the sleep software to work better. So, we should always consider that good sleep is not only with a pill, with CBT, or with a combination. It's a lifestyle. If we understand this and if we are correct and appropriate also, and you were saying before also the light, darkness, it's a combination of several things to put together, features to put together, and absolutely, food is a topical and important helper of sleep. If we don't consider food, we probably can use all the ideal drugs, but maybe they won't work.

Dr Muza: I like what you said that it's a lifestyle, and I think we have to look at it as a lifestyle and change what we can change in our management, which brings us to what I always tell my patients when I see them. The first thing I try to emphasize is the sleep hygiene. Reduce light at night: we've talked about light. Have a sleep anchor: wake up at the same time. Reduce the noise at night, the bedroom for sleep and intimacy only. And the food you eat before you go to bed, eat it at the right time, and the right food. So it should be part and parcel of your general day-to-day lifestyle.

Dr Neubauer: Right. And the recent studies suggest that it is foods with high fiber and fruits and vegetables primarily that are going to be associated with better quality of sleep. So, it is a lifestyle at the foundation. It will not necessarily cure the insomnia disorder, but it is the foundation of that treatment, and frankly, beneficial for all of us to do that to improve our sleep.

There's been interesting research that has been bringing together all of those rhythms: circadian rhythms, when we're eating, the regularity of our sleep-wake cycle. All of those can have a robust effect in improving the quality of our nighttime sleep and the quality of our daytime functioning.

Physiologically we're designed to be eating during the biological daytime and fasting during the biological night and stopping eating several hours prior to our planned bedtime is very likely advantageous in terms of our sleep-wake cycle, but certainly in terms of the metabolic consequences. We know that a late-evening meal is much more deleterious to us metabolically than that exact same meal might be earlier in the daytime.

Well, as we wrap up, I'll summarize where we started, and that is we need to do more to help identify those patients who are suffering from insomnia and get them directed towards effective treatment. And also, I'll point out that we have great evidence for the efficacy of cognitive behavioral therapy strategies, a variety of medications that are now well studied and approved, and we have the opportunity to provide more personalized care for patients. Last words, Rexford? Anything else you want to conclude with?

Dr Muza: No. I'm not going to add anything new. My main conclusion is that insomnia is a very important condition which should be taken seriously. Let us address the patient's concerns when they visit us. Let us ask about insomnia the same way we would ask questions around a patient coming in with a stroke or with any other condition, and let us put efforts to treat the patient in front of us appropriately.

Dr Neubauer: Very good. And Liborio, last words?

Dr Parrino: We have to make sleep more friendly, because sleep is a natural friend of ours, and it has been given to everybody. Not everybody has diabetes. Not everybody has bad diseases, but everybody sleeps. So we have to be proud of sleeping and happy of sleeping, because sleep is a natural benefit.

Dr Neubauer: Couldn't agree more. Thank you, Rexford; thank you, Liborio, for this valuable discussion, and thank you for your attention, and please continue on to answer the questions that follow and complete the evaluation.

This is a verbatim transcript and has not been copyedited.