What is sodium oxybate, its uses, and considerations for patients, particularly those with a history of substance abuse?

What is Sodium Oxybate

Sodium oxybate is a Schedule III controlled substance and CNS depressant that is the sodium salt of gamma-hydroxybutyrate (GHB), strongly recommended by the American Academy of Sleep Medicine as first-line treatment for narcolepsy with cataplexy in adults, addressing excessive daytime sleepiness, cataplexy attacks, and disrupted nocturnal sleep. 1, 2

Mechanism and Formulation

• Sodium oxybate is the sodium salt of gamma-hydroxybutyric acid, an endogenous cerebral inhibitory neurotransmitter that increases serotonin turnover, interacts with opioid systems, and may act as a GABA-B receptor agonist 3
• The medication is rapidly absorbed and eliminated with a mean elimination half-life of only 30-60 minutes, necessitating twice-nightly dosing 3, 4
• A lower-sodium formulation (Xywav) containing 92% less sodium than the original formulation (Xyrem) was developed to reduce cardiovascular risks associated with high sodium intake, which at standard doses (6-9 g/night) adds 1100-1640 mg of sodium to daily dietary intake 5

Clinical Uses and Efficacy

• The American Academy of Sleep Medicine provides a STRONG recommendation for sodium oxybate as treatment for narcolepsy in adults, based on moderate-quality evidence from 6 RCTs and 6 observational studies demonstrating clinically significant improvements in cataplexy, excessive daytime sleepiness, and disease severity 1, 2
• Sodium oxybate is the only medication that directly addresses all core symptoms of narcolepsy: cataplexy, excessive daytime sleepiness, and disrupted nocturnal sleep, unlike stimulants which only treat daytime sleepiness 2, 6
• The medication is also FDA-approved for idiopathic hypersomnia in adults, showing efficacy in reducing excessive daytime sleepiness and other symptoms 5
• Sodium oxybate improves REM behavior disorder symptoms in narcolepsy patients, with significant improvement in REM sleep atonia index and remarkable reduction in complex movements during REM sleep 7

Administration Protocol

• Sodium oxybate is administered as a liquid in two equally divided doses at night: the first dose at bedtime and the second dose 2.5-4 hours later 2, 7
• The medication is only available through the FDA Risk Evaluation Mitigation Strategy (REMS) program using certified pharmacies due to its controlled substance status and abuse potential 1, 2
• Starting dose should be reduced by half in patients with hepatic impairment due to increased drug exposure 8

Critical Safety Warnings

Black Box Warning

• Sodium oxybate carries an FDA black box warning as a CNS depressant that may cause respiratory depression, and must be used with extreme caution in patients with any respiratory conditions 1, 2, 8
• The medication is an FDA Schedule III controlled substance and is the sodium salt of GHB (a Schedule I controlled substance), with abuse or misuse associated with seizures, respiratory depression, decreased consciousness, coma, and death, especially when combined with alcohol or other CNS depressants 1, 8

Common Adverse Effects

• Frequently reported adverse events include nausea, dizziness, nocturnal enuresis, headache, chest discomfort, sleep disturbances, and confusion 1, 7
• In pediatric patients, serious adverse reactions include central sleep apnea, oxygen desaturation, depression, suicidal ideation, neuropsychiatric reactions (acute psychosis, confusion, anxiety), and parasomnias including sleepwalking 8
• Sleep-disordered breathing has been reported and requires monitoring 1

Special Considerations for Substance Abuse History

Abuse and Dependence Risk

• Physicians must carefully evaluate patients for a history of drug abuse and follow such patients closely, observing for signs of misuse or abuse including increase in size or frequency of dosing, drug-seeking behavior, and feigned cataplexy 8
• Illicit GHB is abused in social settings, and cases of severe dependence and craving have been reported when the drug is taken around the clock 8
• Patterns of abuse indicative of dependence include: (1) use of increasingly large doses, (2) increased frequency of use, and (3) continued use despite adverse consequences 8

Withdrawal Syndrome

• Withdrawal symptoms following abrupt discontinuation of illicit GHB use at high doses (18-250 g/day) include insomnia, restlessness, anxiety, psychosis, lethargy, nausea, tremor, sweating, muscle cramps, tachycardia, headache, dizziness, confusion, and in severe cases, visual hallucinations, agitation, and delirium 8
• These withdrawal symptoms generally abate in 3-14 days, though severe withdrawal may require hospitalization 8
• In clinical trials at recommended doses, withdrawal symptoms were minimal, with isolated reports of insomnia, anxiety, and increased cataplexy frequency after abrupt discontinuation 8
• Clinical studies suggest potential cross-tolerance with alcohol 8

Special Populations

• Based on animal data, sodium oxybate may cause fetal harm, with insufficient human data to determine risk; the balance of risks and harms is different for pregnant and breastfeeding women 1, 2
• In elderly patients (65 years and older), discontinuations due to adverse reactions were increased (21% vs 19%), and frequency of headaches was markedly increased (39% vs 19%); dose selection should start at the low end of the dosing range 8
• Safety and effectiveness for cataplexy or excessive daytime sleepiness in pediatric patients below age 7 years have not been established 8

Monitoring Requirements

• Regular follow-up is necessary to assess treatment efficacy and adverse effects, particularly respiratory depression, enuresis, nausea, and headache 7
• Patients should be monitored for signs of misuse, abuse, or dependence, especially those with a history of substance abuse 7, 8
• Avoid combination with alcohol or other sedating medications due to risk of respiratory depression 2