Sections

Narcolepsy

Medication

Medication Summary

The main focus of pharmacologic therapy for narcolepsy is symptomatic treatment of excessive somnolence and cataplexy with central nervous system (CNS) stimulants and antidepressants. Stimulants improve wakefulness, and antidepressants (eg, clomipramine, fluoxetine, duloxetine, and venlafaxine) reduce cataplectic attacks.

Sodium oxybate, a CNS depressant and a salt of gamma hydroxybutyrate (GABA metabolite), is indicated for cataplexy or excessive daytime sleepiness (EDS) in patients with narcolepsy.

Solriamfetol, a dopamine/norepinephrine reuptake inhibitor, is indicated for EDS in patients with narcolepsy.

Pitolisant is a nonscheduled, first-in-class histamine3 (H3) receptor antagonist/inverse agonist indicated for excessive daytime sleepiness in adults with narcolepsy.

Class Summary

Stimulants increase wakefulness, vigilance, and performance. They are thought to alter midbrain dopaminergic activity, but the precise mechanism of action is unknown. Interpatient variability in the dosage required to alleviate excessive daytime sleepiness (EDS) is considerable and unpredictable. In some patients, daytime sleepiness is completely relieved with methylphenidate 5 mg/day; in others, higher dosages are required. Initiate treatment at low dosages, and individualize therapy as appropriate.

Methylphenidate (Ritalin)

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Methylphenidate is a piperidine derivative that is the most commonly prescribed treatment for narcolepsy. Its efficacy has been demonstrated in randomized, double-blind, dose-response, and placebo-controlled trials.

Modafinil (Provigil)

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Modafinil is pharmacologically distinct from other stimulants. It does not appear to act via the dopaminergic system.

Armodafinil (Nuvigil)

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R-enantiomer of modafinil (mixture of R- and S-enantiomers). Elicits wake-promoting actions similar to sympathomimetic agents, although pharmacologic profile is not identical to sympathomimetic amines. In vitro, binds dopamine transporter and inhibits dopamine reuptake. Not a direct- or indirect-acting dopamine receptor agonist. Indicated to improve wakefulness in individuals with excessive sleepiness associated with narcolepsy, obstructive sleep apnea-hypopnea syndrome (OSAHS), or shift-work sleep disorder.

Class Summary

Cataplexy in patients with narcolepsy can be treated with the CNS depressant sodium oxybate. Other agents that are used off-label for cataplexy are tricyclic antidepressants (TCAs; eg, clomipramine, desipramine, and imipramine), selective serotonin reuptake inhibitors (SSRIs; eg, fluoxetine, paroxetine, and sertraline), and serotonin-norepinephrine reuptake inhibitors (SNRIs; eg, venlafaxine and duloxetine). The strongest evidence is for clomipramine, fluoxetine, and sodium oxybate.

Sodium oxybate (Lumryz, Xyrem)

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Sodium oxybate, also known as gamma hydroxybutyrate (GHB), is a CNS depressant used to treat patients with EDS and cataplexy. The onset of therapeutic effects is often delayed. The precise mechanism by which sodium oxybate produces an effect on cataplexy is unknown. Xyrem requires twice-nightly dosing, whereas Lumryz may be administered once before bedtime.

Calcium/magnesium/potassium/sodium oxybates (Xywav)

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Xywav is a mixture of calcium oxybate, magnesium oxybate, potassium oxybate, and sodium oxybate (gamma-hydroxybutyrate). GHB is an endogenous compound and metabolite of the neurotransmitter GABA. It is hypothesized that the therapeutic effects of Xywav on cataplexy and excessive daytime sleepiness are mediated through GABA_B actions during sleep at noradrenergic and dopaminergic neurons. The exact mechanism of action for narcolepsy is unknown. It is an oral solution indicated for the treatment of cataplexy or excessive daytime sleepiness (EDS) in patients 7 years and older with narcolepsy.

Class Summary

The mechanism of action by which solriamfetol improves wakefulness in patients with excessive daytime sleepiness associated with narcolepsy is unclear, but is thought to be mediated through its inhibition of dopamine/norepinephrine reuptake.

Solriamfetol (Sunosi)

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Dopamine/norepinephrine reuptake inhibitor (DNRI). It is indicated to improve wakefulness in adults with excessive daytime sleepiness associated with narcolepsy.

Pitolisant (Wakix)

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Selective histamine 3 (H3) receptor antagonist/inverse agonist. It is indicated for treatment of excessive daytime sleepiness (EDS) in adults with narcolepsy.

Questions

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Author

Sagarika Nallu, MD Assistant Professor, Pediatric Neurologist and Epileptologist, Adult and Pediatric Sleep Specialist, Department of Pediatrics, University of South Florida, Morsani College of Medicine

Sagarika Nallu, MD is a member of the following medical societies: American Academy of Neurology, American Academy of Sleep Medicine, American Epilepsy Society, Child Neurology Society

Disclosure: Nothing to disclose.

Chief Editor

Selim R Benbadis, MD Professor, Director of Comprehensive Epilepsy Program, Departments of Neurology and Neurosurgery, Tampa General Hospital, University of South Florida Morsani College of Medicine

Selim R Benbadis, MD is a member of the following medical societies: American Academy of Neurology, American Academy of Sleep Medicine, American Clinical Neurophysiology Society, American Epilepsy Society, American Medical Association

Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: Bioserenity, Ceribell, Eisai, Jazz, LivaNova, Neurelis, Neuropace, SK life science, Sunovion, Takeda, UCB<br/>Serve(d) as a speaker or a member of a speakers bureau for: Aquestive, Bioserenity, Eisai, Jazz, LivaNova, Neurelis, SK life science, Stratus, Sunovion, UCB<br/>Received research grant from: Cerevel Therapeutics, Ovid Therapeutics, Neuropace, Greenwich Jazz, SK Life Science, Xenon Pharmaceuticals, UCB, Marinus, Neuroelectrics Corporation, Longboard, Janssen, Equilibre Biopharmaceuticals.

Additional Contributors

Ali M Bozorg, MD Assistant Professor, Comprehensive Epilepsy Program, Departments of Neurology and Neurosurgery, University of South Florida College of Medicine

Ali M Bozorg, MD is a member of the following medical societies: American Academy of Neurology, American Epilepsy Society, American Academy of Sleep Medicine

Disclosure: Received honoraria from Cyberonics for speaking and teaching; Received honoraria from UCB, Inc. for speaking and teaching.

Dani J Thomas, DO Fellow in Sleep Medicine, University of South Florida College of Medicine

Dani J Thomas, DO is a member of the following medical societies: American Thoracic Society, Society of Critical Care Medicine

Disclosure: Nothing to disclose.

Acknowledgements

Carmel Armon, MD, MSc, MHS Professor of Neurology, Tufts University School of Medicine; Chief, Division of Neurology, Baystate Medical Center

Carmel Armon, MD, MSc, MHS is a member of the following medical societies: American Academy of Neurology, American Academy of Sleep Medicine, American Association of Neuromuscular and Electrodiagnostic Medicine, American Clinical Neurophysiology Society, American College of Physicians, American Epilepsy Society, American Medical Association, American Neurological Association, American Stroke Association, Massachusetts Medical Society, Movement Disorders Society, and Sigma Xi

Disclosure: Nothing to disclose.

Matthew J Baker, MD Consulting Staff, Collier Neurologic Specialists, Naples Community Hospital

Disclosure: Nothing to disclose.

Jose E Cavazos, MD, PhD, FAAN Associate Professor with Tenure, Departments of Neurology, Pharmacology, and Physiology, University of Texas Health Science Center at San Antonio; Co-Director, South Texas Comprehensive Epilepsy Center; Director of the Epilepsy Center, Audie L Murphy Veterans Affairs Medical Center

Jose E Cavazos, MD, PhD, FAAN is a member of the following medical societies: American Academy of Neurology, American Clinical Neurophysiology Society, American Epilepsy Society, American Neurological Association, and Society for Neuroscience

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Reference Salary Employment

Narcolepsy Medication

Medication Summary

Stimulants