Phyllis C. Zee, MD, PhD

What do you know about any new things on the horizon for the treatment of narcolepsy? What is exciting on the horizon for me is the potential development of orexin receptor agonists. Until now, our medications have mainly targeted symptoms and perhaps part of the pathophysiology but not the orexin system directly. We think this is 1 of the primary causes of narcolepsy, so those are under development. Anything else that you think is exciting in telemedicine?

Absolutely, the orexin receptor agonists are exciting, in a similar fashion that the orexin receptor antagonists were initially proposed for the management of insomnia. Remember, we always tell our patients and colleagues never to use this orexin antagonist on patients with narcolepsy. We are certainly appreciating that the mechanism targeting orexin by agonists is exciting. The other agents on the horizon are the low-sodium formulation of oxybate, which is certainly interesting. The once-a-day oxybate formulation is interesting. Remember, when we tell patients to take sodium oxybate, they have to take it twice before going to bed, and they have to wake up 2 to 4 hours later to take a second dose. Certainly, with using some of the GABA-B receptor agonists, the norepinephrine inhibitors, it is exciting that we have even more interest in a focused approach for idiopathic hypersomnia that has remained a rather elusive and forgotten area as a disease state. We have often applied treatments for narcolepsy that do not really work for those types of patients.

By having these pharmacological therapies that target mechanisms, such as something like pitolisant targeting the histamine system, we are probably going to see more of those in development. There are also other H3 inverse agonists in the pipeline. 

Let’s wrap this up by thinking about some of the take-home messages for our viewers. I can start: It is that excessive daytime sleepiness is common. It is common in patients with neurological disorders, and narcolepsy is a neurological disorder. Although it may be less common, it is something that we need to be aware of, and there are some distinct symptoms and signs. Identifying cataplexy is probably key, and it can be quite subtle. Therapies need to be targeted at the individual, and we have a broader set of behavioral strategies as well as pharmacological strategies to tailor therapies for our patients. First, the most important thing is to think about narcolepsy in your patients with excessive daytime sleepiness, even if they have depression, obstructive sleep apnea, or other neurological conditions. It is still something to be aware of to raise that awareness. Dr Avidan, I will let you give your take-home messages.

Thank you, Dr Zee. It was a pleasure working with you again. I echo the same sentiments that you mentioned. I would add also that narcolepsy is often a forgotten disorder, particularly in pediatrics. It is not thought as a pediatric condition, yet most patients with narcolepsy will present to the pediatrician, so this is a real opportunity. 

The other issue relates to the fact that more than two-thirds of patients with narcolepsy who are on treatment will report persistent daytime sleepiness. It tells us that most patients find their medication is helpful, but it does not address all attributes of narcolepsy, and it does not address the daytime sleepiness to its optimal level. This is the most debilitating symptom for these patients, yet the majority feel that there is still room for improvement.

Here is an anecdote to leave our audience: Keep seeing your patients to see how well they are doing, particularly postpandemic, and screen and look for the emergence of cataplexy. We have seen a number of patients with type 2 narcolepsy and no history of cataplexy present with cataplexy much later in time. 

We should be seeing these patients, screening out for other symptoms of narcolepsy that may emerge later on, and being mindful of looking out and screening patients when they have persistent daytime sleepiness, and looking for sleep apnea. A lot of these patients may gain weight, particularly in the setting of the pandemic, and they may develop sleep apnea. Depression can also increase weight through inactivity and through the use of antidepressants. We owe it to our patients to keep looking, following up in time, and tailoring therapy as time progresses according to new challenges and symptoms that they may develop.

Thank you, Dr Avidan, for joining us in this discussion. Great information. I personally enjoyed this tremendously. Thank you for watching this NeurologyLive® Peers & Perspectives® program. Please subscribe to the e-newsletter to receive upcoming Peer Exchanges® and other great content in your in-box.

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Expert neurologists discuss advancements in the management of narcolepsy including new drug formulations and provide take-home messages for how to improve diagnosis and treatment in the future. 

Future Improvements in the Management of Narcolepsy

 It is difficult during this time of COVID-19 [coronavirus disease 2019] not to talk about the challenges of even diagnosing or treating patients with narcolepsy, following them up, and developing goals for remote telemedicine. We have been following most of our patients by telemedicine, which has been OK. The big challenge for me is how exactly I monitor their blood pressure. How do I look at some of their vital signs? Some of my patients buy blood pressure monitors, so they already know. They put it into my chart, but it is not ideal. It is certainly something that has allowed our patients to be self-monitoring a bit more, especially when they are on some of these medications that we may have some concerns about.

Diagnosis is a little tougher because how do we do that MSLT [multiple sleep latency test] or that polysomnography? We are now open, so we are able to do that most of the time. What has been your experience with treating and diagnosing patients during COVID-19?

It has been fascinating, Dr Zee. Similarly, we have done all our visits by telemedicine. What I can tell is that the volume of patients has probably doubled because everyone is able to show up. Here in Los Angeles, taking the freeway to see your doctor is a half-a-day ordeal thanks to taking time away from work and commuting. Telemedicine has actually made access a lot better. It has provided us the ability of seeing the patients who live 3 hours away and need to have their CPAP [continuous positive pressure therapy] for sleep apnea evaluated for compliance monitoring a lot easier. The rate-limiting stuff, of course, is technology and the internet, but people are getting used to it. For older patients, their grandchildren are critically important in getting the video visits set up. We always tell the patients to look to their neighbors, friends, and grandchildren, and it works pretty well.

Initially, when the pandemic struck last March, we saw a fairly large rise in patients coming in for insomnia. These are patients who have had problems with insomnia even before, but it seems like the pandemic has exacerbated and perpetuated it, as well as the worrying at night and participating in behaviors that you and I would never approve of, like watching TV and using electronics at bedtime. Interestingly, patients with previously diagnosed daytime sleepiness have gotten a bit better, and we recognize that it may be because they do not have to be at work at a particular time. What we have found is that they go to bed late and wake up late. You may have seen the same. It was almost a delayed pattern.

 Patients also do not have to commute. In many ways, they are decreasing that, and some of my patients with narcolepsy can now take naps between their Zoom meetings. They are taking a nap here and there, which is much easier because they are in their own homes rather than at work where there may not be any opportunity to take naps. It looks as if we have come a long way in both diagnostic tools as well as therapeutic approaches. We clearly still need a lot more with regard to efficacy. We talked about safety being something that continually needs to be developed, especially pharmacological therapies. Even cognitive behavior therapy for narcolepsy is being developed right now by some of our behavior sleep medicine folks, and that would be an important aspect in the future.

To your point, from a vaccination point of view, I want to go back to the issue of the H1N1 vaccination campaign, which resulted in a rise in folks with narcolepsy in Scandinavia. I do not know if you have seen anything, Dr Zee, in type 1 narcolepsy in relationship to the Moderna and Pfizer coronavirus vaccines, but it is probably a good thing to keep our eyes on to see what the rates end up looking like. 

The data are probably stronger regarding the vaccine and the adjuvant setting, and it is probably stronger with the infection itself. We have not seen that in the reports at least, other than insomnia being more common in these patients. On the other hand, a patient with preexisting autoimmune disorders may already be at increased risk to begin with.

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Key opinion leaders consider the impact of the COVID-19 pandemic on the diagnosis and treatment of narcolepsy and comment on improvements in symptom management at home.  

The Impact of COVID-19 on the Management of Narcolepsy 

 Let’s talk a bit about the newer MOAs [mechanisms of action]. Tell me a bit about what you think is interesting about the new mechanisms of action with the newer medications that have been recently approved. 

As you correctly said, Dr Zee, having the new approval of a drug for children over age 7 using sodium oxybate is exciting. That is a group of patients about whom we do not often talk because there were no treatments in sleep medicine for children until recently. This is a forgotten group, in a way. In terms of the mechanism of action, it is exciting. Whenever we hear about a new drug in sleep medicine, that certainly is different from what we are used to. It is different from a treatment that is focused on enhancing the alertness by increasing epinephrine or dopamine-like type mechanisms or a drug that improves sleep by working as a hypnotic, in the case of sodium oxybate. 

One of the newest agents on the block is pitolisant. Pitolisant has a unique mechanism of action in that it works on histamine. It blocks the H2 receptors from inhibiting their own release and synthesis. It is a fascinating mechanism of action; it is an inverse agonist at its own receptors. Histamine, as most of you know, is a wake-promoting neurotransmitter. You all know it because, when you are taking an antihistamine, you feel tired. Histamine gets released during the nighttime, and when we are using an antihistamine, we are blocking it, so we can sleep a bit longer. Histamine during the day is important, as we talked about with narcolepsy, because being able to promote histamine by blocking the inhibition of histamine release from the CNS [central nervous system] would allow histamine to be more alerting. It is an interesting mechanism of action.

In addition, we all talk about the promotion of alertness through working on dopamine and adrenaline, but when we are talking about histamine release, it would allow the patient to have improved daytime sleepiness during the day, and it also has a good effect on cataplexy. Pitolisant now has efficacy not only for excessive daytime sleepiness in the setting of narcolepsy but for the management of cataplexy as well. Unlike sodium oxybate, it is a drug that is available to be taken in the morning. Unlike the other agents, it is not a controlled substance, which is somewhat of an advantage for a lot of patients. That is the unique attribute on pitolisant. It was initially studied and developed in Europe, and it made its way to the United States, and the more recent approval is indeed for cataplexy.

It is fascinating that pitolisant is the first to be approved in this class of what we call the histamine H3 receptor inverse agonists, which then really becomes an agonist. It then increases and probably also helps stabilize wakefulness during the day together with orexin and some of the other agents, so it is pretty exciting. As you said, it is approved for the treatment of both excessive daytime sleepiness and cataplexy in patients with narcolepsy.

What is also interesting about this new mechanism of action is that, as you said, it is not scheduled. It is not a scheduled medication in our pharmacological armamentarium. I do not remember if this is exactly accurate, so remind me, but I think some of the trials were done in conjunction with other medications. Pitolisant was given and can be used in conjunction with some of the other medications. Of course, there are known safety concerns, such as the QT interval with these other areas. Safety is still something that we always try to think about with our medications.

 Absolutely. If I may say, especially as we are managing patients across the life cycle, the 3 medications that we need to be particularly mindful of are those that can influence the cytochrome P450 in the liver because they can potentially render oral contraceptives ineffective. Those drugs include modafinil, armodafinil, as well as pitolisant. Those are agents one may need to have a bit more review, particularly in women of childbearing age. If the patient is using these medications, then they should be considering a barrier method of contraception. That is critical. 

The other thing that is unique about pitolisant, as you mentioned, is the prolongation of QT wave in the ECG [electrocardiogram]. As a general rule, I like to order ECGs whenever I place patients on stimulants. With pitolisant, it reminds me that, if a patient reports a history of arrhythmias or a family history of 1 of the more congenital cardiac arrhythmias, then getting an ECG is probably a good idea. Particularly because if the patient is using an antidepressant in addition to pitolisant, there may be some underlying facilitation of arrhythmias. That has not been demonstrated or studied well, but one has to be mindful of drug-drug interaction in that capacity.

 Yes, that is a good idea. I have not systematically done ECGs in my patients. Certainly, for the amphetamine-like treatments, that has been recommended as something to follow up on. I have not done that, but it is a good thought to have.

In the last year or so, solriamfetol is another recently approved medication for the treatment of mainly excessive daytime sleepiness in patients with narcolepsy and obstructive sleep apnea. But it does not have effect on cataplexy, correct? 

Correct. Exactly. Solriamfetol is a dual-acting specific dopamine and norepinephrine reactive inhibitor, and we have seen some other agents that probably have a dopamine-type mechanism of action, which is perhaps related to how modafinil or armodafinil work, potentially. As you said, its action improves daytime sleepiness in the setting of narcolepsy as well as obstructive sleep apnea. We have seen the latter indication also being applied for modafinil or armodafinil, but it is a unique mechanism. It is yet another drug that can be used, particularly in the morning.

As you know, Dr Zee, when we are treating insomnia, it is hard to know who is going to respond to what. In some individuals, I have tried both. I have tried solriamfetol, and I have tried sodium oxybate. After a while, you find that a patient is responsive to drugs that you would not have predicted would work for them. It is nice to have that extra ability to move across this agent. More important, as you said, this is particularly so when you have clinical data on medications when added in combination as dual therapy as is the case of pitolisant and sodium oxybate, for example, and it demonstrates that the pharmacokinetic properties are not being impacted. That is an advantage. 

We often use combination therapy in an on-demand fashion by putting patients on a wake-promoting agent or an agent to promote alertness in the morning, and we then give them a medication to enhance alertness strategically during the daytime. You can also potentially use this combination of therapy where you are keeping the dose of both agents low enough to not promote or to reduce the onset of agitation or anxiety.

It is about balancing the adverse effects because the higher the dose, then the more adverse effects there are. With timing, I let my patients determine when they are going to take some of these medications after some time because it is aimed at function, whatever their function is.

Experts in neurology review the recent approvals of pitolisant and solriamfetol for the management of excessive daytime sleepiness (EDS) and compare their mechanisms of action.  

Recent Approvals of Pitolisant and Solriamfetol for EDS 

Most of our patients are probably going to need some type of pharmacological therapy because, by the time they come to see us, their symptoms are severe, and it is affecting their quality of life and their ability to function. We want to tailor our treatments to the needs of patients, and we certainly have a choice now. It is exciting that we have more choices for our patients. I am a bit older, so when you think about the good old days, it was mainly a lot of the amphetamine-like derivatives, and of course we know there are some downsides and adverse effects from those. 

How do you go about choosing pharmacotherapy for a patient who has excessive daytime sleepiness perhaps as their main symptom vs cataplexy? For many of our patients, it is really both. What is your strategy for starting out a patient?

 When contemplating pharmacotherapy for a patient with narcolepsy, my strategy is to recognize whether the patient has daytime sleepiness in conjunction with other symptoms, like disrupted nocturnal sleep and cataplexy. As you correctly and accurately said, the field of narcolepsy treatment is getting a bit crowded. In the last few years, we have had an introduction of newer agents, and it is hard to keep up with all the treatments available. Traditionally, as you said, the mainstream therapy has been the use of amphetamine-type compounds. Certainly, those have worked well, but they have adverse effects that, for some patients, are a bit difficult. They raise blood pressure, they make patients a bit agitated or nervous, and they are a bit more likely to associate with more risk of cardiovascular increase in blood pressure and heart rate.

In the last 2 or 3 decades, there has been more focus on treatment that is more aligned with perhaps working in the area of the brain that is at the cornerstone of narcolepsy. That lines up with how we generally manage the treatments. The first thing to think about is giving the patient a drug that would allow them control of excessive sleepiness throughout the day. It varies from 1 individual to another, but I would say that the 1 thing we have seen is that, for the folks who have disrupted nocturnal sleep, cataplexy, and daytime sleepiness, sodium oxybate–type compounds work reasonably well. Oxybate is sodium oxybate gamma hydroxybutyrate, and there are 2 forms that we can review in a bit.

However, if the patient does not have as much fragmented sleep and is not bothered by cataplexy as much, then the use of a traditional wake-promoting agent such as modafinil and its longer-acting isomer armodafinil are reasonable options as well. Those can be given during the day, and they will usually promote and improve alertness throughout the day. Now, patients may have times that they need to be alert when the wake-promoting agent may not last. For those individuals, we often recommend short-acting amphetamine-type compounds that can give them the level of alertness that would be required when driving, for example, or attending a meeting in the afternoon. One can use these strategically as needed, when daytime sleepiness is not controlled by the initial wake-promoting agent.

Yes. I do that too, Dr Avidan. That prevents tachyphylaxis or the loss of efficacy of some of these amphetamine-like agents, but they are good if you use them intermittently as needed. I totally agree with you: If a patient has both cataplexy and excessive daytime sleepiness, sodium oxybate will treat both of those symptoms and perhaps even that sleep disturbance during the night because it increases that slow-wave activity or slow-wave sleep to some degree. From my perspective, what have been most improved are the safety of many of the medications and the recognition of some of the comorbidities. 

Even with something like sodium oxybate, we are thinking that there is a new formulation of low-sodium sodium oxybate because the older formulation had high sodium content. That could be a consideration especially for older people or people with hypertension. We are seeing improved safety profiles as well as newer mechanisms of action, so that is pretty exciting. 

You also spoke about children. Initially, you said that this is a disorder that can begin in childhood, especially in teenage years. Just to mention it, sodium oxybate has been studied in children as well, and it is approved for use in children.

Key opinion leaders discuss pharmacotherapeutic options for the management of narcolepsy symptoms and examine the safety and efficacy of potential treatments. 

Phyllis C. Zee, MD, PhD

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Future Improvements in the Management of Narcolepsy

The Impact of COVID-19 on the Management of Narcolepsy

Recent Approvals of Pitolisant and Solriamfetol for EDS

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