Narcolepsy Medication

Updated: May 04, 2023
  • Author: Sagarika Nallu, MD; Chief Editor: Selim R Benbadis, MD  more...
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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)

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)

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

Armodafinil (Nuvigil)

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.


CNS Depressants

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)

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)

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 GABAB 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.


Dopamine/Norepinephrine Reuptake Inhibitors

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)

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


Histamine H3 Antagonist/Inverse Agonist

Pitolisant (Wakix)

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