Pharmacological Approaches to the Management of Narcolepsy

EP: 1.An Overview of Excessive Daytime Sleepiness (EDS)

EP: 2.Signs and Symptoms of Narcolepsy

EP: 3.Pathophysiology and Risk Factors for Narcolepsy

EP: 4.Differential Diagnosis of Patients with Narcolepsy

EP: 5.Behavioral Approaches to the Management of Narcolepsy

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EP: 6.Pharmacological Approaches to the Management of Narcolepsy

EP: 7.Recent Approvals of Pitolisant and Solriamfetol for EDS

EP: 8.The Impact of COVID-19 on the Management of Narcolepsy

EP: 9.Future Improvements in the Management of Narcolepsy

Phyllis Zee, MD, PhD: 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?

Alon Avidan, MD, MPH: 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.

Phyllis Zee, MD, PhD: 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.

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Transcript Edited for Clarity