Sodium oxybate

K K Jain MD†

Neuropharmacology & Neurotherapeutics

Updated 09.04.2021
Released 12.18.2005
Expires For CME 09.04.2024

Sodium oxybate

Author: K K Jain MD†

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Sodium oxybate

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Introduction

Historical note and terminology

Sodium oxybate is a medical formulation of gamma-hydroxybutyrate, which occurs naturally in many human tissues as a metabolite of gamma-amino butyric acid. Gamma hydroxybutyrate was first synthesized in 1960 and used as an anesthetic, but use for this purpose was abandoned due to poor analgesia and adverse effects, including seizure-like activity. Gamma-hydroxybutyrate, classified as a schedule I controlled substance in the United States, was used in the 1970s and 1980s and showed promise for various symptoms of narcolepsy.

Over-the-counter sales of this substance were banned in 1990 because of overdosing by weightlifters and recreational abusers. It got a bad reputation as a "date-rape" drug. Clinical development of gamma-hydroxybutyrate in narcolepsy started in 1996. A bill, passed in the United States Congress in 2000, supported the continued development of medically formulated gamma-hydroxybutyrate, and sodium oxybate is now classified as a Schedule III controlled substance by federal law. Although initially approved by the Food and Drug Administration in 2002, release for marketing was delayed pending further safety trials. In 2005, sodium oxybate was finally cleared by the Food and Drug Administration to treat excessive daytime sleepiness in patients with narcolepsy. It is the first and the only FDA-approved medication for the treatment of cataplexy associated with narcolepsy. Due to the known drug abuse of sodium oxybate, the approval of this drug is contingent on a risk management plan that restricts distribution through a single central pharmacy and requires use of a specific prescription form.

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.

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

	• Myoclonus and essential tremor
	• Treatment for alcoholism. Sodium oxybate is safe and effective in the treatment of alcohol withdrawal syndrome and in the prevention of relapses; it is approved in Italy and Austria for this indication (25). Data from some randomized clinical trials suggest that sodium oxybate is better than naltrexone and disulfiram for maintenance of abstinence and prevention of craving for 3 to 12 months (07). Despite this evidence, concerns such as ineffectiveness against hallucinations in alcohol withdrawal need further investigation (16).
	• Efficacy and tolerability of sodium oxybate was demonstrated in a retrospective evaluation of children ranging from 6 to 16 years old, suffering from narcolepsy with cataplexy (14).
	• Treatment of drop attacks in Coffin-Lowry syndrome, associated with mental retardation, characteristic facial features, skeletal deformities, and tapering fingers.
	• Posttraumatic stress disorder
	• Tardive dyskinesia (08)
	• Posthypoxic myoclonus
	• A phase 3 clinical trial has provided supportive evidence that sodium oxybate therapy has important benefits across multiple symptoms in subjects with fibromyalgia (27).
	• Sodium oxybate has been successfully used to manage patients with rapid eye movement sleep behavior disorder where other treatments had failed (15).
	• Cluster headaches (12)
	• Vocal tremor, which accompanies spasmodic dysphonia with a poor response to botulinum toxin injections, has been treated successfully with sodium oxybate (24). An open-label study has shown that sodium oxybate improved voice symptoms in 82.2% of alcohol-responsive patients with spasmodic dysphonia and voice tremor (23).
	• Polysomnography data from a randomized, placebo-controlled trial of sodium oxybate on patients with a diagnosis of narcolepsy, including symptoms of cataplexy and excessive daytime sleepiness due to nighttime sleep disruption, showed improvements in nocturnal sleep quality (22).

Special considerations

Black Box Warning:

Sodium oxybate has abuse potential with some important CNS adverse events (including death). Even at recommended doses, the use of Xyrem has been associated with confusion, depression, neuropsychiatric events, and respiratory depression.

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.

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.

References

01: Abad VC. An evaluation of sodium oxybate as a treatment option for narcolepsy. Expert Opin Pharmacother 2019;20(10):1189-99.** PMID 31136215
02: Addolorato G, Lesch OM, Maremmani I, et al. Post-marketing and clinical safety experience with sodium oxybate for the treatment of alcohol withdrawal syndrome and maintenance of abstinence in alcohol-dependent subjects. Expert Opin Drug Saf 2020;19(2):159-66.** PMID 31876433
03: Barker EC, Puchowicz M, Letterio J, Higgins K, Sharkey KM. GHB levels in breast milk of women with narcolepsy with cataplexy treated with sodium oxybate. Sleep Med 2017;36:172-7.** PMID 28668666
04: Berner J. Sodium oxybate intolerance associated with familial serum acylcarnitine elevation. J Clin Sleep Med 2013;9(1):71-2. PMID 23319908
05: Black J, Houghton WC. Sodium oxybate improves excessive daytime sleepiness in narcolepsy. Sleep 2006;29(7):939-46. PMID 16895262
06: Bosch OG, Esposito F, Dornbierer D, et al. Prohedonic properties of gamma-hydroxybutyrate are associated with changes in limbic resting-state functional connectivity. Hum Psychopharmacol 2018;33(6):e2679. PMID 30426556
07: Busardò FP, Kyriakou C, Napoletano S, Marinelli E, Zaami S. Clinical applications of sodium oxybate (GHB): from narcolepsy to alcohol withdrawal syndrome. Eur Rev Med Pharmacol Sci 2015;19(23):4654-63. PMID 26698265
08: DʼArrigo AM, Campiglio L, Casellato C, et al. Tardive myoclonic dyskinesia responsive to sodium oxybate. Clin Neuropharmacol 2018;41(5):194-6. PMID 29927806
09: Drakatos P, Lykouras D, D'Ancona G, et al. Safety and efficacy of long-term use of sodium oxybate for narcolepsy with cataplexy in routine clinical practice. Sleep Med 2017;35:80-4. PMID 28619187
10: Frase L, Schupp J, Sorichter S, Randelshofer W, Riemann D, Nissen C. Sodium oxybate-induced central sleep apneas. Sleep Med 2013;14(9):922-4. PMID 23834969
11: George CF, Feldman N, Inhaber N, et al. A safety trial of sodium oxybate in patients with obstructive sleep apnea: Acute effects on sleep-disordered breathing. Sleep Med 2010;11(1):38-42. PMID 19897413
12: Hidalgo H, Uhl V, Gantenbein AR, Sándor PS, Kallweit U. Efficiency of sodium oxybate in episodic cluster headache. Headache 2013;53(9):1490-1. PMID 23463909
13: Husain AM, Bujanover S, Ryan R, Scheckner B, Black J, Profant J. Incidence and duration of common, early-onset adverse events occurring during 2 randomized, placebo-controlled, phase 3 studies of sodium oxybate in participants with narcolepsy. J Clin Sleep Med 2020;16(9):1469-74.** PMID 32356515
14: Lecendreux M, Poli F, Oudiette D, et al. Tolerance and efficacy of sodium oxybate in childhood narcolepsy with cataplexy: a retrospective study. Sleep 2012;35(5):709-11. PMID 22547897
15: Liebenthal J, Valerio J, Ruoff C, Mahowald M. A case of rapid eye movement sleep behavior disorder in Parkinson disease treated with sodium oxybate. JAMA Neurol 2016;73(1):126-7. PMID 26595534
16: Mannucci C, Pichini S, Spagnolo EV, et al. Sodium oxybate therapy for the treatment of alcohol withdrawal syndrome and the maintenance of alcohol abstinence. Curr Drug Metab 2018;19(13):1056-64. PMID 29219048
17: Mayer G. The use of sodium oxybate to treat narcolepsy. Expert Rev Neurother 2012;12(5):519-29. PMID 22550980
18: Mayer G, Plazzi G, Iranzo Á, et al. Long-term compliance, safety, and tolerability of sodium oxybate treatment in patients with narcolepsy type 1: a postauthorization, noninterventional surveillance study. Sleep 2018; 41(9). PMID 29986085
19: Owen RT. Sodium oxybate: efficacy, safety and tolerability in the treatment of narcolepsy with or without cataplexy. Drugs Today (Barc) 2008;44(3):197-204. PMID 18536781
20: Plazzi G, Pizza F, Vandi S, et al. Impact of acute administration of sodium oxybate on nocturnal sleep polysomnography and on multiple sleep latency test in narcolepsy with cataplexy. Sleep Med 2014;15(9):1046-54. PMID 25087195
21: Plazzi G, Ruoff C, Lecendreux M, et al. Treatment of paediatric narcolepsy with sodium oxybate: a double-blind, placebo-controlled, randomised-withdrawal multicentre study and open-label investigation. Lancet Child Adolesc Health 2018;2(7):483-94.** PMID 30169321
22: Roth T, Dauvilliers Y, Guinta D, Alvarez-Horine S, Dynin E, Black J. Effect of sodium oxybate on disrupted nighttime sleep in patients with narcolepsy. J Sleep Res 2017;26(4):407-14. PMID 27807903
23: Rumbach AF, Blitzer A, Frucht SJ, Simonyan K. An open-label study of sodium oxybate in spasmodic dysphonia. Laryngoscope 2017;127(6):1402-7.** PMID 27808415
24: Simonyan K, Frucht SJ. Long-term effect of sodium oxybate (Xyrem®) in spasmodic dysphonia with vocal tremor. Tremor Other Hyperkinet Mov (N Y) 2013;3;pii: tre-03-206-4731-1. PMID 24386608
25: Skala K, Caputo F, Mirijello A, et al. Sodium oxybate in the treatment of alcohol dependence: from the alcohol withdrawal syndrome to the alcohol relapse prevention. Expert Opin Pharmacother 2014;15(2):245-57. PMID 24283802
26: Smits TA, Gresnigt FM, Attema-de Jonge ME, Franssen EJ. Can emergency department clinicians diagnose gamma-hydroxybutyrate (GHB) intoxication based on clinical observations alone? Emerg Med J 2021;38(7):520-523.** PMID 33674275
27: Spaeth M, Bennett RM, Benson BA, Wang YG, Lai C, Choy EH. Sodium oxybate therapy provides multidimensional improvement in fibromyalgia: results of an international phase 3 trial. Ann Rheum Dis 2012;71(6):935-42. PMID 22294641
28: Steffen AD, Lai C, Weaver TE. Criteria for gauging response to sodium oxybate for narcolepsy. J Sleep Res 2018;27(4):e12628.** PMID 29205601
29: Weaver TE, Cuellar N. A randomized trial evaluating the effectiveness of sodium oxybate therapy on quality of life in narcolepsy. Sleep 2006;29(9):1189-94. PMID 17040006
30: Xyrem International Study Group. Further evidence supporting the use of sodium oxybate for the treatment of cataplexy: a double-blind, placebo-controlled study in 228 patients. Sleep Med 2005;6(5):415-21. PMID 16099718

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Sodium oxybate

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Also Relevant

Drug-induced memory disturbance
Drug-induced sleep disorders
Hypersomnolence
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Myoclonus
- Narcolepsy
- Neuropharmacology
- Sleep disorders
- Stimulant-dependent sleep disorder
- Tardive dyskinesia

Study	Results
Patients were weaned from anticataplectic medications and randomized to receive different doses of sodium oxybate nightly or placebo for 8 weeks; those receiving 6 and 9 g doses were titrated to their final dose in weekly 1.5 g increments (30).	Sodium oxybate was highly effective for the treatment of cataplexy and improvements are dependent on the dosage of sodium oxybate as well as on the duration of treatment. Weekly dose titration is well tolerated.
A randomized trial of the nocturnal administration of sodium oxybate in patients with narcolepsy (29).	Sodium oxybate was associated with statistically significant and clinically relevant improvements in functional status.
A double-blind, placebo-controlled, multicenter study of sodium oxybate in narcolepsy with modafinil for the placebo group (05).	Sodium oxybate and modafinil are both effective for treating excessive daytime sleepiness, producing additive effects when used together.
A prospective, double-blind, placebo-controlled, randomized-withdrawal, multisite study in pediatric narcolepsy (21).	Results show efficacy of sodium oxybate for the treatment of both excessive daytime sleepiness and cataplexy in narcolepsy in children.

Sodium oxybate

Sodium oxybate

Introduction

Historical note and terminology

Pharmacology

Clinical trials

Table 1. Clinical Trials of Sodium Oxybate

Indications

Off-label uses

Contraindications

Goals and duration of treatment

Dosing

Special considerations

Black Box Warning:

Interactions

Adverse effects

References

Contributors

Author

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Also in This Category

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Sodium oxybate

Introduction

Historical note and terminology

Pharmacology

Clinical trials

Table 1. Clinical Trials of Sodium Oxybate

Indications

Off-label uses

Contraindications

Goals and duration of treatment

Dosing

Special considerations

Black Box Warning:

Interactions

Adverse effects

References

Contributors

Author

This is an article preview. Start a Free Account to access the full version.

Questions or Comment?

Also in This Category

Telehealth and cognitive behavioral therapy for insomnia (CBT-I)

NonREM parasomnias

Neurologic disorders associated with obesity

Hypersomnolence

Sleep disorders in women

Serotonin syndrome

Sleep, stroke, and vascular dementia

Parasomnia overlap disorder and status dissociatus

This is an article preview.
Start a Free Account
to access the full version.