Two Medications for Narcolepsy with Cataplexy
Sodium oxybate and pitolisant are two highly effective medications for treating narcolepsy with cataplexy, with sodium oxybate being the only FDA-approved medication that treats both cataplexy and excessive daytime sleepiness simultaneously. 1, 2
First-Line Treatment: Sodium Oxybate
The American Academy of Sleep Medicine strongly recommends sodium oxybate as first-line therapy for both cataplexy and excessive daytime sleepiness in adults with narcolepsy. 1, 2
Mechanism and Efficacy
- Sodium oxybate works through GABAB receptor modulation and demonstrates clinically significant improvements in cataplexy, excessive daytime sleepiness, disrupted nocturnal sleep, hypnagogic hallucinations, and sleep paralysis 1, 3
- It is the only medication FDA-approved to treat both major symptom domains of narcolepsy with cataplexy simultaneously 4, 5
- Clinical trials show moderate-quality evidence supporting its use, with benefits clearly outweighing risks 1
Administration
- Given as a liquid in two divided doses at night: first dose at bedtime, second dose 2.5-4 hours later 1, 3
- Patients must remain in bed after each dose due to rapid onset of sleep (within 5-15 minutes) 4
Safety Considerations
- FDA Schedule III controlled substance (sodium salt of GHB) with black box warning as a CNS depressant 3, 4
- Common adverse effects include nausea, dizziness, nocturnal enuresis, headache, and sleep disturbances 1
- Available only through REMS program with certified pharmacies 1, 4
- Contraindicated with other CNS depressants, alcohol, or sedatives due to risk of respiratory depression 4
Second Medication: Pitolisant
Pitolisant is a histamine-3 receptor inverse agonist that effectively treats both cataplexy and excessive daytime sleepiness, with the advantage of not being a controlled substance. 6, 7
Mechanism and Efficacy
- Works by increasing histamine synthesis and release in the brain while modulating norepinephrine and dopamine release 8, 9
- FDA-approved for excessive daytime sleepiness in adults with narcolepsy 7
- Demonstrated statistically significant improvement in cataplexy attacks (rate ratio 0.51 for weekly attacks and 0.07 for daily attacks compared to placebo) 7
Dosing
- Initiated at 4.45 mg once daily, titrated weekly based on response and tolerability 7
- Maximum dose: 35.6 mg for patients ≥40 kg, 17.8 mg for patients <40 kg 7
- 65-72% of patients reach maximum stable doses 7
Advantages
- Not a federally controlled substance, unlike most other narcolepsy medications 6
- Single daily dosing improves adherence compared to twice-nightly sodium oxybate 7
Clinical Pitfall to Avoid
Never initiate medications affecting adrenergic systems without monitoring for cataplexy exacerbation, as the loss of orexin/hypocretin neurons in type 1 narcolepsy makes adrenergic systems critical downstream mediators. 6 This is particularly important when considering antidepressants as alternative cataplexy treatments, as they can paradoxically worsen symptoms if not carefully monitored.