Should sodium oxybate (Xyrem) be used as first-line treatment for narcolepsy?

Should Sodium Oxybate Be First-Line for Narcolepsy?

Sodium oxybate should be first-line treatment only when cataplexy is present; for narcolepsy without cataplexy, modafinil, solriamfetol, or pitolisant are the appropriate first-line agents for excessive daytime sleepiness. 1

Treatment Algorithm Based on Symptom Profile

Narcolepsy WITH Cataplexy

• Sodium oxybate is the strongly recommended foundation therapy when cataplexy is present, as it uniquely addresses all three core symptoms: cataplexy, excessive daytime sleepiness, and disrupted nocturnal sleep. 1, 2
• The American Academy of Sleep Medicine provides a strong recommendation based on moderate-quality evidence from 6 RCTs and 6 observational studies showing clinically significant improvements in cataplexy attacks, disease severity, and quality of life. 2
• Start with 4.5 g per night (2.25 g per dose) administered as two equal nightly doses—first at bedtime, second 2.5–4 hours later—and titrate weekly until cataplexy frequency is adequately reduced. 1, 2
• If residual excessive daytime sleepiness persists despite cataplexy control, add pitolisant or modafinil rather than switching away from sodium oxybate. 1, 2

Narcolepsy WITHOUT Cataplexy

• Modafinil is the first-line wake-promoting agent for excessive daytime sleepiness alone, with a strong recommendation based on moderate-quality evidence. 1
• Initiate modafinil 200 mg orally each morning; increase to 400 mg daily if sleepiness persists. 1
• Alternative first-line options include:
  • Solriamfetol: Strong recommendation with high-quality evidence for reducing excessive daytime sleepiness, but does not treat cataplexy. 1
  • Pitolisant: Strong recommendation with the unique advantage of being the only narcolepsy medication not subject to DEA scheduling, and it treats both excessive daytime sleepiness and cataplexy if cataplexy emerges later. 1, 2

Critical Safety Considerations for Sodium Oxybate

Black Box Warning and Regulatory Restrictions

• Sodium oxybate carries an FDA black-box warning for respiratory depression as a central nervous system depressant. 1, 2, 3
• It is a Schedule III controlled substance (sodium salt of gamma-hydroxybutyrate/GHB) available only through a REMS program using certified pharmacies. 1, 2, 3
• Healthcare providers must be specially certified to prescribe, and patients must be enrolled in the XYWAV and XYREM REMS with documentation of safe use. 3

Respiratory Monitoring Requirements

• Use with extreme caution in patients with any respiratory conditions, as increased central apneas and clinically significant oxygen desaturation (≤55%) have been documented in both adult and pediatric patients. 3
• In one study of 50 adults with obstructive sleep apnea, three patients (6%) experienced clinically significant oxygen desaturation, with one withdrawing from the study. 3
• Prescribers should be aware that sleep-disordered breathing is more prevalent in obese patients, men, postmenopausal women not on hormone replacement, and patients with narcolepsy. 3

Common and Serious Adverse Effects

• Frequently reported adverse events include nausea, dizziness, nocturnal enuresis, headache, chest discomfort, sleep disturbances, and confusion. 1, 2
• Depression and suicidal ideation can occur; in clinical trials, two suicides and two attempted suicides occurred in patients treated with sodium oxybate. 3
• Patients with previous history of depressive illness or suicide attempts require careful and immediate evaluation if depression emerges. 3
• Must not be combined with alcohol or other sedating agents due to risk of profound respiratory depression. 1, 3

Why Sodium Oxybate Is Not Universal First-Line

Evidence Hierarchy Supports Symptom-Specific Approach

• The American Academy of Sleep Medicine guidelines explicitly differentiate first-line treatment based on whether cataplexy is present. 1
• For excessive daytime sleepiness alone, modafinil has a strong recommendation with moderate-quality evidence, while solriamfetol has a strong recommendation with high-quality evidence—the strongest evidence grade among all narcolepsy medications. 1
• Traditional stimulants (dextroamphetamine, methylphenidate) and armodafinil receive only conditional recommendations based on very low to moderate-quality evidence and are reserved for second-line use. 1

Practical Considerations

• Sodium oxybate requires twice-nightly dosing with a mandatory awakening 2.5–4 hours after the first dose, which may be burdensome for patients without cataplexy who could achieve adequate control with once-daily wake-promoting agents. 1, 2
• The REMS program requirements, controlled substance scheduling, and need for certified pharmacies create access barriers that may be unnecessary for patients without cataplexy. 3
• Modafinil is Schedule IV (lower abuse potential), while pitolisant is not scheduled at all, making them more appropriate initial choices when cataplexy is absent. 1

Monitoring During Sodium Oxybate Treatment

• Use the Epworth Sleepiness Scale to quantify sleepiness and assess treatment response at each visit. 1
• Regularly evaluate cataplexy frequency and severity to gauge therapeutic efficacy. 1, 2
• Monitor for respiratory depression at each dose increase, particularly in patients with underlying respiratory conditions. 2, 3
• Schedule more frequent follow-up visits during medication initiation or dose adjustments. 1
• Assess for signs of misuse or abuse, including increase in dosing frequency, drug-seeking behavior, or feigned cataplexy. 3