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Ask the Narcolepsy Expert: Guidance for Treatment Selection  

  • Authors: Michael J. Thorpy, MD
  • CME / ABIM MOC Released: 2/1/2023
  • Valid for credit through: 2/1/2024, 11:59 PM EST
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  • Credits Available

    Physicians - maximum of 0.25 AMA PRA Category 1 Credit(s)™

    ABIM Diplomates - maximum of 0.25 ABIM MOC points

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    • ABIM MOC points

Target Audience and Goal Statement

This activity is intended for neurologists, psychiatrists, primary care physicians, pulmonologists, and other clinicians who treat patients with narcolepsy.

The goal of this activity is for learners to be better able to recognize FDA-approved options for the management of narcolepsy, available long-term efficacy/safety data, and factors that impact patient selection for the available medications.

Upon completion of this activity, participants will:

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    • Clinical data for FDA-approved therapies indicated for the management of narcolepsy
    • Clinically relevant factors that differentiate FDA-approved therapies for the management of narcolepsy


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  • Michael J. Thorpy, MD

    Professor of Neurology
    Albert Einstein College of Medicine
    Director, Sleep-Wake Disorders Center
    Montefiore Medical Center
    Bronx, New York


    Michael J. Thorpy, MD, has the following relevant financial relationships: 
    Consultant or advisor for: Axsome Therapeutics, Inc.; Balance Therapeutics; Eisai Pharmaceuticals; Flamel/Avadel; Harmony Biosciences; Idorsia Pharmaceuticals; Jazz Pharmaceuticals; NLS Pharmaceuticals; Suven Life Sciences Ltd.; Takeda Pharmaceutical Co., Ltd; XW Pharma


  • Kathy Merlo

    Medical Education Director, Medscape, LLC 


    Kathy Merlo has no relevant financial relationships. 

  • Megan Breuer, PhD

    Medical Writer, Medscape, LLC 


    Megan Breuer, PhD, has the following relevant financial relationships:
    Consultant/advisor: Paratek Pharmaceuticals, Inc.
    Owns stock (publicly traded) in: Bristol Myers Squibb Company, Johnson & Johnson, Paratek Pharmaceuticals, Inc., Vertex Pharmaceuticals, Inc.

Compliance Reviewer

  • Amanda Jett, PharmD, BCACP

    Associate Director, Accreditation and Compliance, Medscape, LLC


    Amanda Jett, PharmD, BCACP, has no relevant financial relationships.

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Ask the Narcolepsy Expert: Guidance for Treatment Selection  

Authors: Michael J. Thorpy, MDFaculty and Disclosures

CME / ABIM MOC Released: 2/1/2023

Valid for credit through: 2/1/2024, 11:59 PM EST


Narcolepsy is a sleep disorder that can have a significant impact on patient quality of life and livelihood. Though it usually manifests in adolescence, it can start prior to the age of 10 in a small percentage of patients. Medscape recently sat with Dr Michael J. Thorpy, professor of neurology at the Albert Einstein College of Medicine, to discuss the characteristics of narcolepsy, and the currently approved treatments to help patients manage the disease.

Medscape: What is narcolepsy, and what are the common symptoms?

Michael J. Thorpy, MD: Narcolepsy is a chronic disorder of hypersomnia that can have a significant impact on patient quality of life and livelihood, and is characterized by instability of sleep-wake transitions. Sleepiness tends to be worse with inactivity, and sleep can often be irresistible to the patient. Sleep attacks may occur suddenly, and may be brief enough to manifest as a lapse in consciousness.[1] Although they are very sleepy, patients with narcolepsy generally cannot stay asleep for long periods; their sleep tends to be extremely fragmented, and they may wake up several times during the night.[1] Narcolepsy can be categorized into type 1, which includes cataplexy, or sudden loss of muscle tone while the patient is awake, and type 2, which does not include cataplexy. Cataplexy often begins in the facial muscles and can manifest with a slackening of the jaw or brief dropping of the head. Episodes can be more dramatic, however, if the trunk and limb muscles are affected, which can result in the patient dropping to the ground.[1] The prevalence of narcolepsy type 1 is between 25 and 100 per 100,000 people.[1] It usually begins in adolescence, and in approximately 10% to 15% of patients, narcolepsy can start before the age of 10 years.[2]

The development of narcolepsy is associated with a selective loss or dysfunction of orexin (also known as hypocretin) neurons in the lateral hypothalamus.[2] Orexin-A and orexin-B are wake-promoting neuropeptides that are believed to promote and sustain wakefulness, and to stabilize sleep-wake states, via the activation of wake-promoting neurons. These peptides also reinforce inhibitory circuits that regulate wakefulness, rapid eye movement (REM) sleep, and non-REM sleep.[3]

Several biomarkers have been identified to aid clinicians in diagnosing narcolepsy; these include polysomnography findings of sleep-onset rapid eye movement sleep periods (SOREMPS), positivity for HLA-DQB1*06:02, and orexin deficiency in cerebrospinal fluid.[2]

Narcolepsy is characterized by[1]:

  • Excessive daytime sleepiness (EDS)
  • Sleep attacks
  • Cataplexy
  • Sleep paralysis
  • Sleep hallucinations

Narcolepsy can have an acute course, in which symptoms develop within a few days or weeks after a triggering event, such as a vaccination, stress, or head trauma. Patients with a chronic course may have an onset of symptoms that is difficult to determine; those with a progressive course can have an onset of symptoms that might be separated by years, or even decades.[2] Diagnosis of narcolepsy is often delayed, with the average time from the onset of symptoms to diagnosis ranging from 8 to 22 years. However, with awareness on the rise, the efficiency of the diagnostic process is improving, and this delay should lessen accordingly.[1] Narcolepsy should be considered in the differential diagnosis for chronic excessive daytime sleepiness, and the diagnosis should also be based on the patient's history. The patient's history should include specific questions about the hallmark features of narcolepsy, including cataplexy, sleep paralysis, and sleep-related hallucinations.[1]

While nonpharmacologic treatments, such as regular sleep-wake schedules and planned naps, can be helpful, more than 90% of patients with narcolepsy require pharmacologic treatment.[1,4]

Medscape: What are the current guidelines for narcolepsy treatment?

Dr Thorpy: Currently, the American Academy of Sleep Medicine (AASM) recommends several therapies for the management of narcolepsy (Table).[5]

Table. Summary of the AASM Recommended Interventions for Narcolepsy[5,6]


Usual Daily Dose for Adults

Critical Outcomes Showing Clinically Significant Improvement

Excessive Daytime Sleepiness


Disease Severity

Quality of Life

Strength of Recommendation: Strong


100 to 400 mg



4.5 to 9 mg



9 to 36 mg



75 to 150 mg


Strength of Recommendation: Conditional


100 to 250 mg




5 to 60 mg




10 to 60 mg




Treatment decisions can be driven by the type of narcolepsy, and consideration is given to the use of either a single therapy that can target multiple symptoms, or a combination of treatments that each target a specific symptom. Other considerations include dosing regimens, tolerability of the treatment, and any potential drug-drug interactions.[7]

Medscape: What are the indications and mechanisms of action of currently approved treatments?[3,8]

Dr Thorpy:

Modafinil and armodafinil. Modafinil is an approved wake-promoting therapy for narcolepsy; it consists of a racemic mixture of R- and S-enantiomers, of which the R-enantiomer, armodafinil, is also an approved narcolepsy therapy.[3,8] The exact mechanism of action of both treatments remains unclear, though they are thought to bind to the dopamine transporter and inhibit dopamine reuptake. In randomized, placebo-controlled clinical trials, both modafinil and armodafinil demonstrated efficacy in the reduction of EDS in patients with narcolepsy but did not have a significant effect on cataplexy.[3,8]

Common adverse events associated with these treatments include headache, nausea, anxiety or nervousness, and insomnia.[3]

Oxybate. The effect of oxybate is thought to be regulated by gamma aminobutyric acid receptor B (GABA-B) activity at noradrenergic, dopaminergic, and thalamocortical neurons.[9,10] The results of several clinical trials have shown that treatment with oxybate reduces EDS, as well as cataplexy, and can improve nighttime sleep, including increases in slow wave sleep and reducing the number of awakenings.[3]

The spectrum of adverse events tends to fluctuate between patients, though potential adverse events include nausea, confusion, anxiety, depressive symptoms, and enuresis.[3]

Pitolisant. Pitolisant is an N-piperidyl derivative, and is a first-in-class histamine H3 receptor antagonist/inverse agonist, with wake-promoting and anticataplectic effects.[3,4,11,12] Pitolisant increases histamine synthesis and release, increasing histamine transmission in the brain. Pitolisant also increases the release of other neurotransmitters that promote wakefulness, including acetylcholine, dopamine, and norepinephrine.[3] Clinical trial results demonstrate that pitolisant treatment is effective at reducing EDS, dysregulation of REM sleep, and cataplexy.[3,4]

The most commonly reported adverse events include headache, insomnia, and nausea.[3]

Solriamfetol. Solriamfetol is a wake-promoting treatment that works via dopamine and norepinephrine reuptake; it is used to treat EDS associated with narcolepsy or obstructive sleep apnea.[3,13] Clinical trial results have shown that treatment with solriamfetol had robust effects on EDS, especially on the Maintenance of Wakefulness Test.[3] Despite solriamfetol's effects on norepinephrine uptake, it does not have a significant clinical impact on cataplexy.

Commonly reported adverse events include insomnia, headache, nausea, diarrhea, decreased appetite, anxiety, and noncardiac chest discomfort.[3]

Amphetamine and methylphenidate. Amphetamine and methylphenidate have been used often in the past for the treatment of EDS in narcolepsy. These stimulants work by inhibiting dopamine reuptake from the synaptic cleft, and in the case of amphetamine, increasing release of dopamine from presynaptic neurons.[3] These treatments are now considered to be second- or third-line options, because newer therapies have been developed with a lower abuse potential and better tolerability.[3]

Since both amphetamine and methylphenidate enhance dopaminergic transmission in the nucleus accumbens, these agents are associated with an increased risk of abuse and addiction.[3] Withdrawal from amphetamines may result in a rebound in hypersomnolence. Methylphenidate use may result in increases in heart rate and blood pressure, and these cardiovascular events may be a cause for concern given the possible lifelong need for treatment in patients with narcolepsy.

Medscape: What are the current clinician perspectives on when to use these treatments in clinical practice?

Dr Thorpy: Treatment choices should be individualized based on patient age; pregnancy status and reproductive planning; comorbidities, including cardiovascular disease; allergies/history of adverse events; and risk of dependence/potential for drug misuse.[5,7] Interventions may change over time, as the patient ages and with patient life experiences (eg, changes in employment, family demands).[5] Since treatment for narcolepsy is lifelong, the patient should also be an active participant in treatment decisions. Discussions should focus on the available treatment options and determine which treatment would best fit the patient's symptoms, goals, and lifestyle.[7]

For example, a college student may prefer not to receive treatment with oxybate, because of the difficulties associated with storing the medication and the potential for misuse by others. Pitolisant may be a desirable option for patients who are unable to take oxybate, or those who prefer to take a daytime medication. Women who are taking, or may begin taking, oral contraceptives should receive solriamfetol instead of modafinil, armodafinil, or pitolisant, as the latter agents may have an impact on the effectiveness of the contraceptive.[3,7] Amphetamine and methamphetamine use is not recommended in older patients, as these treatments are contraindicated for patients who have comorbid cardiovascular disorders or glaucoma.[7]

Combination therapy is often required for the treatment of narcolepsy, and if excessive sleepiness is not adequately controlled using oxybate or pitolisant, the addition of solriamfetol, modafinil, or armodafinil may be more effective.[7]

This transcript has been edited for style and clarity.

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