Michael J. Thorpy, MBChB

 We’re coming to a close. Let’s talk about what sort of advice you might give to physicians, treating physicians. For the physicians out there, are there particular pieces of information that you really feel they ought to know when it comes to the diagnosis and management of insomnia? Erinn?

 I think one of the biggest pieces of information is to ask, and for the general internist to not be afraid to ask about it, and not to be afraid to address it. I think that is a big thing in primary care. A lot of these medications are controlled, and so therefore, primary care physicians might be resistant to address it, and then have to start writing [prescriptions] for them. I think the biggest thing is to ask, and to realize that it is impacting the entire patient, their health, psychosocial aspects, everything. You may be missing the mark on a lot of your other goals of health care if you’re not addressing their insomnia and what’s going on. I think that would be one thing to do. The other thing would be to keep abreast of these newer agents that are coming up. Try to find a sleep medicine doctor in your area or at one of your local health care facilities or teaching hospitals who you can tap into. You may not be able to get all of your insomniacs to see a specialist like you are, but to be able to say, “OK, I tried this, this is what’s going on, what would my next step be?” I think the biggest thing that I would recommend to physicians is don’t be afraid of it. I think for many years, we’ve kind of been, “I don’t know, I don’t want to go there.” It isn’t something for which there are enough sleep doctors for us to refer everybody to.

 Karl, what do you find are the most important things that you want physicians to know about the diagnosis and management of insomnia? Are there certain take-home points that you would like them to hear about?

 I agree with Erinn, No. 1, don’t be afraid to ask. No. 2, once you do ask, develop a systematic approach to evaluate the problem, like you would with hypertension, with high blood sugar levels, step 1, step 2, step 3, do a differential diagnosis. What are the inventories you’d like to use? What are some of the tests? When would you refer? We already spoke about some of these, but you may want to develop a systematic method to address these in your office. And No. 3, how would you treat the problem, developing a strategy to do that? Which hypnotic for what disorder? And No. 4, when do you refer? I think as sleep specialists, we of course see a lot of referrals for insomnia. And I would say don’t be afraid to refer to the specialists. We have a lot we can do in terms of diagnostic approaches to be able to help your patients.

 I think it is very sound advice. Insomnia is such a common problem for all physicians, and they see it all the time. But there are a lot of things that they certainly can do. Taking a good history is most important for a start, working out what the associated factors are, whether comorbid conditions are worsening it. If there are underlying psychiatric conditions, which are really common, then treating those at the same time as treating the insomnia is essential. I think physicians tend to think, “Well, if the patient’s primary medical or psychiatric problem goes away, then the insomnia is going to go away as well.” But that’s not the case in most cases.

You do need to treat the insomnia. Consider the behavioral treatments we’ve talked about. I personally, as I mentioned, believe that controlling the timing of sleep within 24 hours is the most essential point. Thus, having the person go to bed at the same time, get up at the same time, and be in bed for an appropriate amount of time, which as I mentioned is no more than 8 hours, I think is essential for anyone with insomnia. Avoiding those daytime naps as well. And then, if you can have access, as you said, to cognitive behavioral therapists and be able to get them that specific treatment, that’s good. But most physicians are not going to have access to that. But there are things that they can do in the office, as we’ve talked about, concerning dealing with sleep restriction, about stimulus control, having them only go to bed when they’re sleepy, and then get up at the same time in the morning. Deal with some of those misunderstandings about sleep, for example, the patient who feels that the end of his life is really occurring because he’s got insomnia, but trying to tell the patient that there is help, that they can improve and that they don’t necessarily need to let this affect their life. And take a positive attitude, remove those negative sort of connotations with sleep, turn it into something more positive that they can do and that they’re going to make headway. Then consider, as we’ve mentioned, the newer medications, and it’s exciting that there are new drugs becoming available in the future. Particularly, that there are new mechanisms of action, I think that’s particularly exciting. Thus, there’s a lot that a physician can do.

I think we’ll bring this program to a close. I’d like to thank Karl, Erinn, Nathaniel, and Vikas, for their involvement with this discussion on insomnia. I think it has been very useful. I’ve certainly learned a lot from you all. I hope our audience has also picked up a lot of useful information. Once again, thank you very much for this very comprehensive and informative discussion.

Videos

Closing their discussion on insomnia, panelists share final thoughts and advice for community physicians.

Managing Insomnia: Practical Advice for Community Physicians 

 Karl, there’s a drug that was mentioned by Nate called daridorexant. It’s a new drug. Can you tell us a little bit about this and what’s new and different about it?

 As Nate mentioned, it’s a dual orexin receptor antagonist [DORA], and it seems to have a shorter half-life than the other DORAs. And it may, for that reason, have different clinical effects. But one of the interesting things about the clinical development of this medication is that it’s also been looked at for daytime functioning disturbances with insomniacs. It has been shown to have some improvement in some areas of daytime functioning, which I think is very interesting, since we’ve been speaking about daytime functioning as being a critical area for insomniacs. I think we need more studies like this. It would be very helpful in the future if we could also develop more objective ways of quantifying daytime dysfunction with insomniacs and see if these medications could be helpful. This medication was also studied in, I believe, a 3-month trial where there was a rapid discontinuation. Of course, that’s a clinical issue with many of our patients who discontinue sleep medications, stop taking them. In this particular case, there was no rebound insomnia, which was very interesting to find out.

 Yes, this is interesting. You mentioned having effects on daytime functioning. When you survey patients, you find that daytime functioning is the biggest complaint, and I think you mentioned that at the beginning of the program. The fact that this medication has shown some benefit, not only at night, but also during the daytime, I think is a good direction. Hopefully, we will have other medications for insomnia that will address this as well and look at various daytime consequences of insomnia, not just look at how it’s improving the nighttime.

 Another medication, Michael, I want to mention in the pipeline is something called IMB-115; it does not have an official name yet. It is a medication being developed for not only insomnia, but also for insomnia associated with alcohol cessation. It actually acts at the receptors that are important for both pain as well as for mood and other issues and those susceptive receptors. And interestingly, it may have some effects on drug addiction as well. Thus, it has been developed as a way of possibly treating alcohol cessation insomnia as well as insomnia, period.

 Yes, I think this is particularly interesting because it’s a whole new different mechanism of action for a hypnotic [medication]. As you said, it’s affecting these pain receptors, it’s a pain receptor agonist. This medication is under investigation at the present time. What’s yet to be seen is whether it will eventually get FDA approved, of course. But it’s nice to think that there are new receptor types that could be affected by medications to help people sleep and not just the traditional ones.

Expert panelists share their excitement for novel agents that may impact the insomnia treatment landscape.

Improving Insomnia Management: Novel Agents in the Pipeline 

Vikas, there are quite a number of different medications that are FDA [Food and Drug Administration] approved for the treatment of insomnia. Would you like to give us a little rundown on what the approved medications are, what groups are there?

 Sure. There’s a variety of groups that exist. Traditionally, we’ve had our benzodiazepine medication hypnotics, medications like estazolam [Prosom], lorazepam [Ativan], diazepam [Valium], triazolam [Halcion], and clonazepam [Klonopin]. And then there were newer agents introduced that worked on the benzodiazepine receptor more specific to the alpha-1 receptor, which tends to drive sleepiness, and those are what many patients are familiar with—zolpidem, or Ambien, Silenor [doxepin], or Sonata [zaleplon], and eszopiclone, or Lunesta. There are also some other agents that have been used, like low-dose doxepin, ramelteon [Rozerem], is a medication that works on melatonin receptor agonists. And then we also have some newer agents with dual orexin receptor antagonists. We definitely have a wide variety of choices to pick from, especially when we’re considering BZRas [benzodiazepine receptor agonists], and benzodiazepines, many of them have a pretty quick onset of action. Generally, for sleep latency, many of these medications can be helpful, but it’s really for sleep maintenance where these medications have a varying half-life. And that’s where it can be important in weighing the pros and cons of trying to use something to help with sleep maintenance, while also trying to minimize that sort of hangover effect into the day.

Yes. Is there much rationality these days in using the more traditional benzodiazepines versus the newer ones? We have these Z drugs that you mentioned, are they really the main form of benzodiazepine type agent that we would use there, or is there still a place for the older benzodiazepines?

 I personally don’t tend to use benzodiazepines as often as I use BZRAs these days. Why? I mean, at least, when you look at risk for tolerance, risk for withdrawal symptoms, difficulty in getting off of these medications when used chronically, there can be definitely some difficulty in patients who have been put on traditional benzodiazepines for long, long periods of time, several years, they’re on these medications. Whereas at least with many of the BZRAs, we don’t necessarily see as much of that. I’ve traditionally used more BZRAs in my own practice, more so than benzodiazepines.

OK. Nate, with regards to the low-dose doxepin and ramelteon, these are medications that a lot of physicians are not that familiar with. I mean, how useful have you found these agents? And if you’re going to prescribe a medication to a patient then, who might you give those to?

 Well, the low-dose doxepin is effective for people with sleep maintenance insomnia, so they’re waking up in the middle of the night and having difficulty falling back asleep. It doesn’t seem to have any anticholinergic side effects, and it’s fairly safe. That would be a consideration in that particular type of insomnia. Ramelteon, when it originally came out was quite attractive because it’s a melatonin MT1 and MT2 receptor agonist. It was kind of utilizing what we might consider to be the more natural process of falling asleep, at least in the way that endogenous melatonin or melatonin that our pineal gland secretes works within our bodies. However, clinical trials have found it to be perhaps not as effective as some of these other medications and certainly in some of the patients that have trialed it in, I’ve had mixed results as far as success. But I would think about the sleep onset insomnia patient with that, and maybe in one that had a circadian rhythm sleep disorder. It’s, for instance, Karl mentioned earlier delayed sleep phase syndrome. If you had somebody with insomnia that ramelteon might be a good choice there. Doxepin is a tricyclic antidepressant, getting back to that. Thus, to the extent that there may be some kind of effect on mood as well, you might consider it in the patient that has mood and insomnia-related issues.

All right. Now, Karl, there are some newer hypnotics that are available to us now, and they tend to affect the orexin system. Can you tell us a little bit what’s the orexin system and what are these drugs and why are they effective?

 The orexin system is a neurotransmitter system localized to the brain, which is important we think in the maintenance of arousal or wakefulness and also important for the coordination of a number of the other arousal systems, like epinephrine, or norepinephrine, cholinergic systems in the brain. Its lack or its difficulties with the orexin system highlighted a disease called narcolepsy, which we’re not talking very much about today. But some hypnotic agents have been developed to antagonize the orexin system, and thereby producing sleep. And the 2 that are available currently are lemborexant [Dayvigo] and suvorexant [Belsomra]. Suvorexant was the first to be introduced. Both of these are indicated for sleep initiation and maintenance difficulties, [eg] sleep problems falling asleep and staying asleep. And they’ve been developed in various ways. For example, lemborexant was developed in a study which compared the knowledge of placebo, but also to interest these open and extended release, showing that, and this is one of the very few had had studies with hypnotic agents, showing that it has some superiority, knowledge to placebo, but also to zolpidem in terms of sleep maintenance issues. This was a polysomnographic or a sleep laboratory study. But both of these agents have been said, over a long period of time, showing a lack of development of tolerance and maintain efficacy for many, many months of treatment.

 Yes. There’s some recent evidence, I think, with regards to suvorexant, indicating that it may be helpful in people with Alzheimer’s disease. What are some of the problems in using hypnotics in elderly people and people with Alzheimer’s?

 Well, as you know, Michael, the American Geriatric Society has warned us against using benzodiazepine at nights in particular, as well as the antipsychotics in elderly patients as primary treatments for insomnia. Because of the obvious difficulties with falls, hip fractures, cognitive difficulties, and so on. And interestingly, this agent was utilized with a group of patients with Alzheimer’s, where insomnia is very, very common, showing improvement in sleep measures in this population with minimal side effects in terms of daytime, memory decrement, amnesia, motor abnormalities, and so on. Thus, this is an interesting agent, which really has some usefulness it seems in this population.

Shared insight on the pharmacologic treatment landscape of insomnia, with a focus on mainstay drug classes. 

Managing Insomnia: An Overview of Pharmacologic Agents 

Let’s talk about prescription medications now. The clinician is often faced after he’s tried some behavioral techniques, or even at the time when he’s actually initially trying behavioral techniques, he’s considering should this patient be treated with a medication for insomnia. What do you think, Nate, is the most important thing in making that decision as to which patient should get a sleeping pill, a hypnotic, or which patient should not?

 Well, if they are meeting the diagnostic criteria for chronic insomnia and they didn’t derive benefit or didn’t have access to cognitive behavioral therapy for insomnia [CBTI], and this is affecting, not only their nighttime sleep but their daytime functioning then I think you’re in a situation where it’s time to turn to medications. For some reason, it’s just really interesting in our society. There seems to be a negative association with medications for insomnia and when I talk to hesitant patients, I’d say, “Well, if you had hypertension, you wouldn’t be hesitant to take a medication to lower your blood pressure. You have insomnia, why are you hesitant to take a medication for that?” And I think there’s some pejorative association with falls, maybe daytime residual adverse effects with some of these treatments that we use. There’s been some cross-sectional studies associating treatment with dementing illness, although from my perspective that story has not been told. Nothing definitive there. And it may well, in fact, be in the sleep difficulty. That’s the problem. Not the treatment for it. Thus, I think oftentimes, we have a patient there in front of us, they have an insomnia complaint and you’re at the point where it’s time to begin to consider medical treatment and they’re hesitant I think for a lot of those reasons. The other thing I would say is we talked a lot about comorbidities. We definitely want to treat the comorbidities and see what happens to the insomnia. That would be how I would treat it. Some people would treat both at the same time but sometimes, if I find a comorbidity, let’s say it is obstructive sleep apnea, then insomnia is a common symptom of obstructive sleep apnea. I may well treat the sleep apnea first and see what happens to the insomnia before moving on to medical treatment. But nonetheless, I think there’s lots of effective medications with many different mechanisms of action that we have at our disposal that can really help people with this problem.

Yes. Erinn, for many patients who have insomnia, by the time they come to the decision, I really want to get a sleeping pill to help me, or I feel I need one, I mean, the insomnia has been going on for quite a number of weeks. And by the time they get an appointment that makes standard another couple of weeks to see their doctor. By the time they come into the doctor and say, “Look, I really don’t think I need a sleeping pill,” their insomnia has been going on for quite some time. But what about the people that have really severe acute insomnia lasting a few days? I mean, is there some benefit in those patients getting a sleeping pill? I mean, typically, they’re not going to be able to get a prescription very quickly within a couple of days. But what about the acute versus the more chronic patient from the point of view of medication?

 I think there’s a benefit of treating that acute insomnia and trying to hit it and get it under control sooner than later. Especially if it’s a stressor that we can identify that’s going to be short-lived. I find that those patients, if I do get them sooner, I might even be able to prevent them from becoming a chronic insomniac because I’m alleviating their fear of not sleeping. They’re actually the ones that I’m probably more apt to say, “OK, let’s do something now and get ahead of it” before they get into all those other cognitive thoughts of the not sleeping, what’s going to happen, things of that nature. Thus, I think that they are a unique population, too. I personally do think that they’re the ones to give some type of medication to use for a couple of nights maybe to get them back on to a more regular sleep cycle and break that, of course, while addressing there are other stressors that are going on.

Focusing on the pharmacologic setting of insomnia, experts consider when it is best to initiate therapy.

When to Initiate Pharmacologic Therapy for Insomnia 

Now, of course, many patients with insomnia are going to try to rely on over-the-counter [OTC] medications or take some substance to help them sleep. What about these substances and medications that you can buy in the pharmacy, are they useful for people? And what ones work, what ones don’t work?

Vikas Jain, MD, FAASM, FAAFP, CCSH, CPE: 

I guess that’s the million-dollar question so there are a variety of over-the-counter agents these days. It seems like there’s more and more going on the shelf because patients will come in saying, “Well, I’m using this. I’ve never heard of that one but let me add it to my list.” But there’s a lot of these agents that may provide a little bit of sedation. For example, antihistamines that you can take over the counter might make you a little drowsy. There’s melatonin available, L-tryptophan, valerian. The issue is so part of it is if you take something and you feel like it’s going to help you sleep and then you sleep better, then there may be some degree of placebo effect going on. The hard part is when you actually look at evidence-based reviews of many of these over-the-counter agents. They haven’t really been shown to provide consistent benefit in patients across the board and even in the guidelines that Nate had mentioned. They’re not generally recommended specifically for use in patients with insomnia itself. And then, the other over-the-counter medicine that’s not always mentioned is alcohol as well. There are a lot of patients that will sometimes drink wine, have a cocktail, and the issue with that is that while it may help them with their sleep latency, it generally fragments their sleep. And chronic use may lead to more chronic insomnia and more difficult to treat insomnia over time. Hence, it’s not a great practice.

Well, one of the most commonly used substances I think by people these days is melatonin, which really gets a lot of publicity. How useful is melatonin, really?

 I don’t think it’s very useful, Michael. It’s useful to treat circadian rhythm sleep disorders certainly. There’s perhaps a little bit of evidence that it’s helpful for insomnia but I think, as Vikas said earlier, placebo effect is very real and pretty powerful. When you look at a lot of the clinical trials for medications for insomnia, the difference between the effect between nothing and placebo is oftentimes as big as the difference between placebo and active treatment, if not bigger. It really is true, and I think to me, though it’s fascinating because that tells you that the ability to sleep better is in your mind already. And you just have to tap into that, and you tap into this belief that you can sleep better and try to understand that, find that belief without need of believing that you have to take something. Thus, tapping into the placebo effect while knowing about it essentially.

Karl, some years ago, the NIH [National Institutes of Health] did a meta-analysis on melatonin, and they came to the conclusion that it didn’t have any benefit for insomnia. But it did, as Nate said, have an effect on the circadian rhythms. Are there any patients with insomnia that have difficulty falling asleep at night that actually could benefit from the use of melatonin as a phase-shifting agent?

 It seems so. There are a couple categories of patients. One of the patients with delayed sleep phase syndrome, the youngsters who have this problem where they can’t fall asleep until the wee hours of the morning and then have difficulty waking up the next day. It’s typically something that occurs in adolescence. Melatonin administration earlier in the evening 2 or 3 or maybe even 4 hours before bedtime seemed to be helpful along with morning, bright, light therapy. The other category patients are the shift worker patients or jet lag sufferers, people who travel, there seems to be a circadian adjustment that melatonin can make, which is helpful. I might also say about the use of melatonin in indiscriminate insomnia patients. There have been a number of meta-analyses. The one you mentioned Michael was done by the NIH. There have been a few of them that have been published since that time. Some of them showing that it might have a modest effect of something like 6 minutes or 7 minutes improvement in sleep latency and total sleep time. Thus, the question, of course, always is with melatonin can you properly select the patient in whom it might help? Because it sounds as though if it may hurt some patients and not help others and this mixed bag is what we’re seeing, producing a mixed effect. Thus, possibly as you point out, selecting the patient of the circadian rhythm abnormalities may be better than just giving it any willy-nilly insomniac.

Panelists review suboptimal over-the-counter medications that patients may use to manage insomnia.

Managing Insomnia: Addressing Shortcomings in OTC Medications 

You mentioned relaxation. Erinn, what about some of these techniques like relaxation, mindfulness, treatment, yoga, hypnotherapy, for example? Have you found any of these to be useful in your population?

 Some of the relaxation techniques in bed, trying to get people’s minds off of catastrophizing. Oh, my gosh, somebody mentioned looking at the clock. “Oh, if I don’t fall asleep in the next 5 minutes then I’m only going to have 3 hours of sleeping.” Getting your mind off of thinking of other things is important. I found just even 5 15-minute apps. We try to tell people not to bring the phone into the bedroom with them, but if they can find a meditation that concentrates on deep breathing, get them thinking about something other than the fact that they’re not sleeping. I think that there is a role for that exercise throughout the day, not too close to bed. I do find that some of my patients, and it’s a combination therapy, but some people, if they exercise more during the day, yes, they might be able to fall asleep. Their body’s more ready to fall asleep. They’ve taken that hour to themselves to have all their catastrophizing thoughts during the day about their sleep so that they can lay down. Deep breathing. Just various techniques. I think the internet has become helpful with that. I don’t think it’s the end-all-be-all. It’s not CBTI [cognitive behavioral therapy for insomnia]. It’s not necessarily going to take the place of that, but I think it does at least give them something else to do and think about. And the other thing I tell people is that “The bed is for sleep and sex only.” If these don’t happen in 20 minutes, get out. Thus, I’ll tell people like, “If you need to do that meditation, get out, and do the meditation.” Like Vikas was saying, “I want you to see that bed and your body to feel sleepy.” That Pavlov’s dog-type situation instead of seeing that bed and saying, “It’s another night that I’m not going to sleep” and immediately you’re into that negative headspace. Doing some of these certain things inside the bed to help relax and tune down your body and turn it down. One of the other simple things I tell people to do, keep a pen and paper next to your bed. How many you know people say, “Oh, my gosh. I wake up and I think oh, I have to remember to do this and then I have to remember this and this.” And then, they wake themselves up because now they’re memorizing the list and now, they’re really getting themselves going. Thus, I tell people, “Don’t be afraid to quiet your mind down. Try not to be constantly thinking. Try some relaxation breathing.” I think it can be useful in some patients absolutely.

Good. Karl, how about hypnosis and acupuncture? Any thoughts on those? Are they useful at all?

 Believe it or not, there’s some papers that suggest that they are—acupuncture and hypnosis. Of course, there are difficulties finding trained therapists who can do these things. Of course, none of us here [are] trained to do acupuncture. In addition, biofeedback and relaxation techniques that diminish the activation of the mind and to direct signals that are provided in audio format have been known to be helpful. I also want to stress the importance of maybe broadening the discussion in the case of some insomniacs. These are worriers, right. Insomniacs tend to worry in general. Not just about their sleep but they tend to worry about everything. And sometimes, their worries are a result of family concerns, interpersonal concerns, their occupation, COVID-19, so on and so forth. I found it useful sometimes to expand the scope of the discussion from the immediate sleep issues to maybe some of their lives and to talk about what are their other concerns. Interestingly, I found some patients really benefit from that in terms of their sleep.

A brief discussion on the use of mind and body practices to aid in the management of insomnia.

Use of Mind and Body Practices to Manage Insomnia 

“Cataplexy is difficult to diagnosis, and physicians, one of the big mistakes they make is that they tend to ask the patient once about cataplexy and if they get a negative answer, they move on and they never ask the patient again, and that’s a really big mistake.”

 American Academy of Neurology Annual Meeting in Philadelphia, Pennsylvania, Michael Thorpy, MBChB, spoke with 

to discuss one of the major symptoms of narcolepsy: cataplexy.

The director of the Sleep&shy;-Wake Disorders Center at Montefiore Medical Center explained that cataplexy is the pathognomonic symptom of narcolepsy, however, it often goes undiagnosed. The course of cataplexy usually changes over time, and while the presentation may start out subtle it could become more pronounced as time goes on.

One symptom of cataplexy that’s rarely recognized is jerking of the muscles of the face, particularly around the eyes, and if a clinician notices that while evaluating a patient, they might also notice flattening of the face and drooping of the head which would give a clue to cataplexy. According to Thorpy, one of the biggest mistakes that clinicians make is asking patients only once about cataplexy. Clinicians should instead reinvestigate patients numerous times.

 The director of the Sleep-Wake Disorders Center at Montefiore Medical Center spoke about one of the major symptoms of narcolepsy and how to identify it during diagnosis.  

Michael J. Thorpy, MBChB: The Subtle Manifestations of Cataplexy

"Narcolepsy is an interesting disorder that's getting a lot of attention these days, so there's far more interest in it because people are recognizing it more even though there's still a very long delay from the onset of symptoms to the time of diagnosis."

At the SLEEP 2019 annual meeting, held in San Antonio, Texas, June 8&shy;—12, Michael Thorpy, MBChB, spoke about the challenges in diagnosing narcolepsy and the implications for a multimodal therapy approach.

To dive deeper into his presentation and the clinical features and signs that physicians should be aware of, Thorpy spoke with 

Thorpy explained that while physicians are aware that narcolepsy causes 2 major symptoms, excessive daytime sleepiness and oftentimes cataplexy, there are many patients that only present with excessive daytime sleepiness and not cataplexy, making this patient population more difficult to diagnose. When making a diagnosis of type 2 narcolepsy, one is very much dependent on the clinical features and symptoms in patients because patients are more than likely to have falsely negative MSLTs.

The director of the Sleep-Wake Disorders Center at Montefiore Medical Center spoke about the challenges in diagnosing narcolepsy, which often adds to the delay of diagnosis.
 