Pharmacology

Pharmacodynamics. Sodium oxybate is a CNS depressant with anticataplectic activity in patients with narcolepsy. Its precise mechanism of action is unknown. In patients with narcolepsy with cataplexy, the effects of sodium oxybate produces polysomnographic nighttime recordings, including an increase in slow wave sleep, which does not have a physiological microstructure, a moderate decrease in periodic and isolated limb movements that is likely mediated by a disinhibited dopaminergic neuronal activity, or an improvement on daytime mean sleep latency (20). Sodium oxybate increases regional cerebral blood flow in limbic areas such as the right anterior insula and the anterior cingulate cortex leading to euphoria and sexual arousal, which explain its popularity as a drug of abuse (06).

Pharmacokinetics. The primary metabolic pathway involves GHB dehydrogenase, which catalyzes the conversion of sodium oxybate to succinic semialdehyde, which is then biotransformed to succinic acid by the enzyme succinic semialdehyde dehydrogenase. Succinic acid enters the Krebs cycle where it is metabolized to carbon dioxide and water.

A second mitochondrial oxidoreductase enzyme, a transhydrogenase, also catalyzes the conversion to succinic semialdehyde in the presence of alpha-ketoglutarate. An alternate pathway of biotransformation involves beta-oxidation via 3,4-dihydroxybutyrate to carbon dioxide and water. No active metabolites have been identified.

The half-life of sodium oxybate is 0.5 to 1.0 hour and it follows nonlinear pharmacokinetics. The clearance of sodium oxybate is almost entirely by biotransformation to carbon dioxide, which is then eliminated by expiration. On average, less than 5% of unchanged drug appears in human urine within 6 to 8 hours after dosing. The pharmacokinetics of sodium oxybate have been observed in narcoleptic patients after chronic treatment, and the only changes observed in the kinetics of oxybate after several weeks of treatment are a significant increase in peak concentration and systemic exposure as indicated by area under the curve.

Clinical trials

Three randomized, double-blind, placebo-controlled trials in patients with narcolepsy were the basis for FDA approval of sodium oxybate in 2005. Significant clinical trials since then are listed in Table 1.

Table 1. Clinical Trials of Sodium Oxybate

A review of acute as well as chronic clinical studies demonstrated sodium oxybate's efficacy in decreasing cataplectic attack frequency with withdrawal rates of approximately 3% to 10% due to adverse events (19).

Indications

Sodium oxybate oral solution is indicated for the treatment of cataplexy in patients with narcolepsy. The FDA has expanded its indication to include excessive daytime sleepiness associated with narcolepsy. Sodium oxybate is the first-line therapy for patients with narcolepsy and catalepsy.

Off-label uses

Contraindications

Sodium oxybate is contraindicated in patients with succinic semialdehyde dehydrogenase deficiency, an inborn error of metabolism variably characterized by mental retardation, hypotonia, and ataxia.

Goals and duration of treatment

The goal is to treat excessive daytime sleepiness, and in sodium oxybate clinical trials, approximately 80% of patients with narcolepsy maintained concomitant stimulant use. It can be used for long-term treatment, and there is no evidence of withdrawal symptoms after discontinuation. In a retrospective study, sodium oxybate provided good efficacy and acceptable safety in clinical practice for the long-term treatment of patients suffering from severe narcolepsy with cataplexy who were refractory to other treatments (09). In contrast to the antidepressants and stimulants commonly used to treat daytime sleepiness associated with narcolepsy, sodium oxybate addresses both sets of symptoms and, when used properly, is less likely to lead to the development of tolerance and other undesirable side effects. An analysis of pooled data from 2 randomized, placebo-controlled, double-blind, multicenter 4- and 8-week trials of sodium oxybate for narcolepsy with cataplexy shows that 46% reduction in weekly cataplexy attacks and 12% reduction in Epworth Sleepiness Scale can be used to determine clinical response (28). Results of a long-term (approximately 18 months) surveillance study (NCT00244465) on patients who were prescribed sodium oxybate showed minimal adverse effects, good patient compliance, and low incidence of abuse (18).

A review of publications and results from 11 randomized control trials concluded that sodium oxybate is an effective therapy for cataplexy, disrupted nocturnal sleep, and excessive daytime sleepiness (01).

Dosing

Sodium oxybate is effective at dosages of 6 to 9 g/day. The recommended starting dosage of sodium oxybate is 4.5 g/day divided into 2 equal doses of 2.25 g, which can then be increased to a maximum of 9 g/day in increments of 1.5 g/day (0.75 g per dose). Two weeks are recommended between dosage increases to evaluate clinical response and minimize adverse effects. Sodium oxybate is to be taken at bedtime and again 2.5 to 4 hours later.

Special considerations

Black Box Warning:

Essential limitations that should be considered before starting the treatment include sleep-related breathing disorders, alcohol intake, hypnotic and sedative comedication, and epilepsy (17). Sodium oxybate has been implicated in several cases of worsening sleep-related breathing disturbances. A safety trial of sodium oxybate in patients with obstructive sleep apnea showed that nighttime administration of a 9 g dose in patients with mild to moderate obstructive sleep apnea does not negatively impact sleep disordered breathing, but it might increase central apneas and cause oxygen desaturation in some individuals (11). A case has been reported where de novo central sleep apnea episodes were induced by sodium oxybate in a patient without preexisting sleep-disordered breathing (10). Respiratory status of patients on long-term treatment with sodium oxybate should be periodically evaluated with nocturnal oximetry.

Sodium oxybate should be used with caution in depressed patients. Salt restriction is advised as the drug has a very high sodium content.

Renal dysfunction does not affect the pharmacokinetics of sodium oxybate.

Sodium oxybate undergoes significant hepatic first-pass metabolism. In patients with hepatic dysfunction, it is recommended to reduce the starting dose by half.

Pediatric. Response of pediatric patients to sodium oxybate therapy is like that in adults.

Geriatric. The pharmacokinetics of sodium oxybate in patients older than 65 years of age has not been studied.

Pregnancy. Reproductive studies in pregnant animals have not shown any evidence of teratogenicity. There are no adequate studies in pregnant women, and this drug should be used during pregnancy only if clearly needed. It is not known whether sodium oxybate is excreted in human milk and caution should be exercised when sodium oxybate is administered to a nursing woman. Despite its short half-life, gamma-hydroxybutyrate (GHB) concentrations remained 2 to 5 times higher than endogenous levels 4 hours after both nighttime doses, and to prevent excessive GHB exposure, breastfeeding mothers who take sodium oxybate are advised to express and discard their morning milk (03).

Anesthesia. No contraindications are reported for patients on sodium oxybate therapy undergoing anesthesia. An injectable formulation of sodium oxybate has been used in obstetric anesthesia, and newborns had stable cardiovascular and respiratory measures but were very sleepy. The long-term effects on growth and development are not known.

Interactions

Sodium oxybate has little pharmacokinetic interaction with other drugs due to biotransformation without active metabolites and short half-life. No pharmacokinetic drug interactions of sodium oxybate have been identified with protriptyline hydrochloride, zolpidem tartrate, and modafinil–drugs commonly used in patients with narcolepsy.

Adverse effects

The following more common adverse effects have been reported in clinical trials: headache, nausea, dizziness, pain, somnolence, pharyngitis, and infection. Nonsedative effects such as agitation, combativeness, and bizarre or self-injurious behavior can also occur in gamma-hydroxybutyrate toxicity. Variation in human mitochondrial metabolism may affect sodium oxybate tolerability. Two cases are reported where sodium oxybate intolerance may be related to a preexisting metabolic disorder: 1 with painful cervical dystonia and the other with sleep-related eating disorder (04).

An analysis of early-onset adverse events associated with sodium oxybate use in adults with narcolepsy, which occurred during 2 randomized, placebo-controlled clinical trials, were generally of short duration and their incidence decreased over time (13). These adverse events accounted for few discontinuations of the drug overall.

Sodium oxybate has been approved in Italy and in Austria for the treatment of alcohol use disorder and postmarketing clinical safety data show that adverse events are transitory and do not require discontinuation of treatment (02). Sodium oxybate abuse or dependence are extremely rare in patients without psychiatric comorbidities or poly-drug use.

Management. There are no significant management issues with proper use of sodium oxybate or discontinuation in case of adverse effects. As it is a potent sedative-hypnotic agent and a potential drug of abuse, overdose may require treatment. Physicians can fail to diagnose gamma-hydroxybutyrate intoxication based on clinical observations alone. Although urine toxicology screen is used, a rapid reliable initial analytical test in addition to clinical judgement is needed to reduce false negative diagnosis of gamma-hydroxybutyrate intoxication (26).

General symptomatic and supportive care should be instituted. Physostigmine is reported to attenuate the sedative effects of several drugs, including gamma-hydroxybutyrate, but there is insufficient scientific evidence to support the routine use of physostigmine in the treatment of sodium oxybate overdose or toxicity.