Updates in the Management of Excessive Daytime Sleepiness and Narcolepsy

NeurologyLiveOctober 2023
Volume 6
Issue 5

A group of sleep experts discuss the importance of timely and accurate diagnosis, recent approvals, and available treatment options for managing a chronic disorder and its symptoms.

Karl Doghramji, MD, FAASM, DFAPA; Debra Stultz, MD; Michael J. Thorpy, MD; Anne Marie Morse, DO, FAASM; and Thomas E. Scammell, MD

Participating in the panel are, from left, Karl Doghramji, MD, FAASM, DFAPA; Debra Stultz, MD; Michael J. Thorpy, MD; Anne Marie Morse, DO, FAASM; and Thomas E. Scammell, MD

NARCOLEPSY IS A chronic neurological disorder affecting the brain’s ability to control sleep-wake cycles, leading to issues with psychological, social, and cognitive functions. The most typical symptoms include excessive daytime sleepiness (EDS), sleep attacks, cataplexy, sleep paralysis, and hallucinations. Patients may also experience symptoms such as fragmented sleep and insomnia, as well as automatic behaviors that include temporary sleep episodes that can be brief, lasting only seconds.

There are 2 major types of narcolepsy, type 1 and type 2, which differ slightly. The diagnosis for type 1 is based on an individual either having low levels of brain hormone (hypocretin) or reporting cataplexy and having EDS on a special nap test. Patients with type 2 narcolepsy experience EDS but usually do not have muscle weakness triggered by emotions. This group tends to have less severe symptoms and more normal levels of hypocretin.1 Over the years, the ways in which EDS and narcolepsy have been treated have changed, with several new medications entering the fold.

To keep the clinical community up-to-date on the latest advances in this field, NeurologyLive® assembled a panel of experts from institutions across the United States to offer insight. Moderated by Michael J. Thorpy, MD, director of the Sleep-Wake Disorders Center at Montefiore Medical Center in Bronx, New York, the group covered the burden, diagnosis, available resources, and goals of therapy for patients with narcolepsy.

Available Resources and Goals of Narcolepsy Treatment

Anne Marie Morse, DO, FAASM, a pediatric neurologist and sleep medicine specialist at Geisinger Medical Center in Danville, Pennsylvania, gave an overview of the available options for those with suspected narcolepsy symptoms. Morse strongly encouraged patients to be as educated as possible, noting that education is associated with better outcomes.

“It’s not uncommon that I’ll refer to them to resources like Project Sleep, Wake Up Narcolepsy, the Narcolepsy Network, and the Hypersomnia Foundation,” she said. “Many times, I encourage them to look at all of them because they all have different resources that may not be present in another. Maybe they have a support group for women, and maybe they have a different toolkit.”

Morse mentioned advocacy organizations that provide valuable information, including the American Academy of Sleep Medicine and sleepeducation.org. Based on the type of narcolepsy and influence of cataplexy, the resources patients seek can make a difference, said Debra Stultz, MD. Stultz, who runs the Stultz Sleep and Behavioral Health psychiatry specialty clinic in Barboursville, West Virginia, noted that “cataplexy can be so subtle and present in different ways with different people and change over time. That’s one area where I recommend they seek out more information.”

The panel continued to discuss the goals of narcolepsy treatment, noting 3 main objectives: awareness, symptom reduction, and safety. Awareness remains critical for patients with narcolepsy, as the field continually introduces medications that might help patients. In addition, the field has seen behavioral strategies implemented as more of a routine part of managing narcolepsy.

Pharmacological Treatment Options for Narcolepsy

Karl Doghramji, MD, FAASM, DFAPA, medical director of the Jefferson Sleep Disorders Center at Thomas Jefferson University Hospital in Philadelphia, Pennsylvania, led the discussion on the therapeutic options for patients with narcolepsy. He noted he still uses some older medications such as amphetamines and methylphenidate; however, he cautioned that these could cause significant adverse events, including cardioacceleration, hypertension, and reduction of appetite. He also noted that these Schedule II agents have an elevated risk for abuse and misuse.

“Some of the newer medications for promoting wakefulness are safer in this regard,” he said. “For example, modafinil, armodafinil, solriamfetol, and pitolisant. Pitolisant is completely unscheduled, as you know, but some of these other agents are less problematic in terms of abuse and misuse and have a lower potential for some of these adverse effects.”

Karl Dogrhamji, MD, FAASM, DFAPA, discusses the various therapeutic options for patients with narcolepsy, as Debra Stultz, MD, listens on.

Karl Dogrhamji, MD, FAASM, DFAPA, discusses the various therapeutic options for patients with narcolepsy, as Debra Stultz, MD, listens on.

The conversation switched toward some of the newer medications, with Thomas E. Scammell, MD, providing his thoughts. Scammell, a professor of neurology in the Division of Sleep Medicine at Harvard Medical School in Boston, Massachusetts, said most agents promote wakefulness by increasing the levels of neurotransmitters such as dopamine and norepinephrine. Clinicians often turn to antidepressants, although therapies that increase norepinephrine or serotonin can still be effective in suppressing cataplexy.

“The one medicine I glossed over is sodium oxybate, which I would say the short answer is, we don’t know how it works,” he said. “But it probably somehow acts through GABAB receptors in the brain, and then through some complex mechanism, it makes people more awake and have less cataplexy during the day.”

Pitolisant and Solriamfetol

Pitolisant and solriamfetol are 2 of the newer, more commonly used medications for EDS in patients with narcolepsy; each has different mechanisms of action. Pitolisant is a selective histamine H3 receptor antagonist/inverse agonist that works to increase the synthesis and release of histamine, acting as a wake-promoting neurotransmitter. With its approval in 2019, solriamfetol became the first dual-acting dopamine and norepinephrine reuptake inhibitor approved to treat EDS in adults living with narcolepsy or obstructive sleep apnea.2,3

Regarding pitolisant, Scammell stated, “Part of the appeal here is we think that with normal spontaneous wakefulness and the wakefulness promoted by the orexin/hypocretin system, there’s an activation of all these systems during wakefulness. One of the things potentially appealing about pitolisant is that it’s increasing all these wake-promoting neurotransmitters, and there may be some synergy between them, which you don’t [typically] get.”

Thorpy added, “[Patient symptoms] can be controlled with pitolisant just by itself. But…we often use it as an add-on medication to give that extra help for patients with narcolepsy.” Because it is an unscheduled agent and does not lend itself to abuse, pitolisant can offer another benefit to certain patients. Whether a patient has a history of drug abuse or misuse of alcohol stimulants can be a factor, according to Doghramji. For patients who continually escalate the use of an amphetamine compound, clinicians may want to consider whether this patient is doing so because of another effect that is not necessarily connected to sleeping.

“I’ve had patients like this, who were, for example, on amphetamines at 40 mg, 50 mg, whatever, who will come back and say even 60 mg is not enough of an amphetamine,” he stated. “There we can begin to wonder if there’s something else going on. Should I switch them over to another compound, for example, pitolisant, which may not be addictive?”

Solriamfetol, designed to block dopamine and norepinephrine reuptake transporters, produces a wake-promoting effect that has a half-life of about 7 hours. It typically is administered once daily, and was approved in doses of 75 mg and 150 mg. The 300-mg dose was not approved by the FDA because of concerns with blood pressure.

“The thing I find appealing about solriamfetol: It does seem to have pretty good potency,” Scammell added. “In the clinical trials, the amount of change you see in some of these measures of sleepiness is better than what you see with some of our other medications. When I see a patient who’s got pretty solid sleepiness, I’m often thinking of solriamfetol.”

1. Narcolepsy. National Institute of Neurological Disorders and Stroke. Updated September 20, 2023. Accessed September 27, 2023. https://www.ninds.nih.gov/health-information/disorders/narcolepsy
2. FDA approves expanded use of Wakix for narcolepsy. News release. Harmony Biosciences. October 17, 2020. Accessed September 7, 2023. https://aasm.org/fda-approves-expanded-use-of-wakix-for-narcolepsy
3. Jazz Pharmaceuticals announces U.S. FDA approval of Sunosi (solriamfetol) for excessive daytime sleepiness associated with narcolepsy or obstructive sleep apnea. News release. Jazz Pharmaceuticals. March 20, 2019. Accessed September 7, 2023. https://investor.jazzpharma.com/news-releases/ news-release-details/jazz-pharmaceuticals-announces-us-fda-approval-sunositm
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