Narcolepsy is a chronic, debilitating neurological disorder of sleep-wake state 
instability. This instability underlies all narcolepsy symptoms, including 
excessive daytime sleepiness (EDS), symptoms of rapid eye movement (REM) sleep 
dysregulation (ie, cataplexy, hypnagogic/hypnopompic hallucinations, sleep 
paralysis), and disrupted nighttime sleep. Several neurotransmitter systems 
promote wakefulness, and various neural pathways are involved in regulating REM 
sleep-related muscle atonia, providing multiple targets for pharmacologic 
intervention to reduce EDS and cataplexy. Medications approved by the US Food 
and Drug Administration (FDA) for the treatment of EDS in narcolepsy include 
traditional stimulants (eg, amphetamines, methylphenidate), wake-promoting 
agents (eg, modafinil, armodafinil), and solriamfetol, which mainly act on 
dopaminergic and noradrenergic pathways. Sodium oxybate (thought to act via 
GABAB receptors) is FDA-approved for the treatment of EDS and cataplexy. 
Pitolisant, a histamine 3 (H3)-receptor antagonist/inverse agonist, is approved 
by the European Medicines Agency (EMA) for the treatment of narcolepsy with or 
without cataplexy in adults and by the FDA for the treatment of EDS in adults 
with narcolepsy. Pitolisant increases the synthesis and release of histamine in 
the brain and modulates the release of other neurotransmitters (eg, 
norepinephrine, dopamine). Antidepressants that inhibit reuptake of serotonin 
and/or norepinephrine are widely used off label to manage cataplexy. In many 
patients with narcolepsy, combination treatment with medications that act via 
different neural pathways is necessary for optimal symptom management. Mechanism 
of action, pharmacokinetics, and abuse potential are important considerations in 
treatment selection and subsequent medication adjustments to maximize efficacy 
and mitigate adverse effects in the treatment of patients with narcolepsy.