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Sodium Oxybate


Sodium Oxybate

Article Author:
Alvio Dominguez
Article Author:
Lucia Soca Gallego
Article Editor:
Mayur Parmar
Updated:
9/3/2020 10:36:28 AM
For CME on this topic:
Sodium Oxybate CME
PubMed Link:
Sodium Oxybate

Indications

Sodium oxybate is the sodium salt of γ-hydroxybutyrate, an endogenous metabolite of the inhibitory neurotransmitter GABA. Sodium oxybate was approved in 2002 by the U.S Food and Drug Administration (FDA) for cataplexy or excessive daytime sleepiness (EDS) treatment in patients with narcolepsy who are seven years of age and older. Cataplexy is the most severe symptom of narcolepsy, which can result in the impairment of everyday living. If a patient has narcolepsy with cataplexy, the term for this condition is narcolepsy type I (NT1). In patients with narcolepsy, sodium oxybate has shown to increase slow-wave sleep duration, delta power, and improve sleep quality.[1]

Sodium oxybate is limited for distribution to patients enrolled in the drug manufacturer's Risk Evaluation and Mitigation (REMS) program. The program originated to mitigate the risk of abuse and misuse. To prescribe the sodium oxybate, all prescribers are required to enroll and comply with all requirements of the program. A central pharmacy will only dispense sodium oxybate to patients enrolled in the REMS program who have been counseled on the risks as well as on proper use of sodium oxybate.

Mechanism of Action

The precise mechanism by which sodium oxybate improves symptoms in patients with narcolepsy is not well understood. There is a hypothesis that the effects of improved sleep might be due to the increased time spent in Stages N2 and N3, and the decrease shift to stages N1/Wake/REM, resulting in a deeper sleep.[2]

Several studies have shown that the drug has effects that mimic that of ethanol. It does this particularly by binding to GABA and extra-synaptic GABA. [3] When compared to a placebo group, a controlled group of alcoholic dependent subjects will show up to a 34 percent increase in abstinence.[3] The idea supports the already established use of sodium oxybate in countries like Australia and Italy, which have used the drug for over 25 years as an agent for alcohol withdrawal syndrome (AWS) and to maintain abstinence.

Administration

Sodium oxybate comes as an oral solution (0.5 g/ml), with two equal doses administered daily. Initially, patients can begin taking 4.5 g/night, the patient should take the first dose of 2.25 g before bed, and the second dose of consisting of another 2.5 g should be taken 2.25 to 4 hours after the first dose. The dosage can increase based on the tolerability and efficacy response of the patient; the maximum dose is 9 g/ night.

Patients should lie down quickly after taking the first dose due to the possibility of abruptly falling asleep. A placebo-controlled study showed that improvements of symptoms with sodium oxybate occur in a dose-dependent manner at 4.5 g, 6 g, and 9 g per night; patients report a decrease in cataplexy attacks as well as diminished excessive daytime sleepiness.[2][4]

Adverse Effects

The most frequent side effect of sodium oxybate is nausea and vomiting. Other reported symptoms include dizziness, headache, urinary incontinence, and sleepiness. Overall, the incidence of side effects increases at higher doses and tends to subside with discontinuation of treatment.[2] More serious side effects are rare, but researchers have noted severe acute psychosis, anxiety, and suicidal ideation.[5]

Additionally, patients taking sodium oxybate often experience weight loss.[6] The speculation is that the weight loss is due to an increase in physical activity and a decrease in caloric intake. In the study, weight loss was most significant in patients with a higher body mass index (BMI).[6] In conclusion, weight loss might be a possible benefit of sodium oxybate treatment in patients with a high BMI who suffer from narcolepsy. 

Most reported serious side effects of sodium oxybate are due to illicit drug consumption. Abuse or misuse of γ-hydroxybutyrate (GHB) with other agents that cause changes in alertness (or consciousness) has implications pointing to severe side effects such as difficulty breathing, seizures, altered mental status (AMS), and death.[7]

Contraindications

Patients should not be prescribed sodium oxybate if they are receiving treatment with sedative-hypnotic agents such as benzodiazepines. Moreover, patients should not be prescribed sodium oxybate while consuming alcohol or if they have a succinic semialdehyde dehydrogenase enzyme deficiency.[7] General recommendations that patients who are taking other CNS depressants such as diazepam not be prescribed sodium oxybate; however, if a prescription is necessary, then prescribers should consider adjusting the dosage.

Monitoring

While taking sodium oxybate, patients require monitoring for symptoms of excessive CNS depression, such as bradycardia or respiratory depression. Recommendations are for prescribers to start at a low dosage and adjust it according to the patient’s response. Patients should also engage in alcohol abstinence and strict adhesion to the drug regimen. The former can result in excessive CNS depression, and the latter can result in symptoms of increases CNS activation such as tachycardia and hypertension.

For lactating mothers, it is important to note that γ-hydroxybutyrate is excreted in breast milk. It is crucial to monitor the health of their infants. It is the prescriber’s responsibility to weigh the benefits and potentially harmful effects that can be caused by sodium oxybate. A 2016 case report study presented a 27-year-old primigravida patient who was taking sodium oxybate for symptom control. The patient was seeking lactation advice; health experts advised her to avoid breastfeeding 4 hours after taking a dose. Using follow-up phone interviews, the mother explained that she did not experience any difficulties with breastfeeding. There were no noted adverse effects on the infant. Based on the pediatrics chart record, the infant showed appropriate milestones.[8] This case is the only instance in the literature where a lactating mother was followed-up for potential harmful effects.

Toxicity

orrelatesSodium oxybate appears to be a safe drug with the most common side effects being minor gastrointestinal upsets such as nausea and vomiting. More dangerous side effects have been attributed to illicit use of the drug, often taking a dose substantially larger than the therapeutic amount.[9]

If there is a suspected case of overdose, then supportive treatment should start immediately. Clinicians have successfully used atropine to reverse the bradycardia-associated overdose. Patients detoxifying from an overdose might experience withdrawal syndrome. Symptoms include insomnia, confusion, tachycardia, and hypertension, among others. Benzodiazepine administration seems to be the first-line treatment, while baclofen or propofol is an option as a second-line treatment.[10]

Narcolepsy is a multifactorial sleep disorder that results in a disrupted sleep-wake cycle, which c with the loss of hypocretin (orexin). Even though it is the most common cause of EDS, it often goes undiagnosed due to a lack of experience of clinicians or because it is confused as other psychiatric disorders. Early diagnosis is crucial as it has shown to improve the outcome of the patient.[11]

Enhancing Healthcare Team Outcomes

Prescribers need to be cautious when prescribing a Schedule III controlled substance such as sodium oxybate due to the high potential for abuse. It is the responsibility of the entire healthcare team, such as physicians, nurses, and pharmacists, to work together to improve the outcome for the patient. It is crucial to instruct the patient on proper dosing and step by step instruction on taking sodium oxybate to minimize side effects or potential injuries. Furthermore, patients need to receive counseling regarding the possible side effects as well as the importance of strict adherence to the treatment regimen. An extensive risk management program from the drug manufacturer can help to prevent the misuse of sodium oxybate. The program focuses on limiting drug distribution and educating patients on the proper use of the drug.[7]

The healthcare team must ensure that patients are not taking any other CNS depressants. A 2009 forensic multi-drug intoxication fatality involving sodium oxybate presented a patient with sleep apnea who had mistakenly also received prescriptions for various CNS depressants, including sodium oxybate. Concomitant use of CNS depressant and the patient’s health history resulted in an unintentional overdose.[12]


References

[1] Staud R, Sodium oxybate for the treatment of fibromyalgia. Expert opinion on pharmacotherapy. 2011 Aug;     [PubMed PMID: 21679091]
[2] 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. Journal of sleep research. 2017 Aug;     [PubMed PMID: 27807903]
[3] van den Brink W,Addolorato G,Aubin HJ,Benyamina A,Caputo F,Dematteis M,Gual A,Lesch OM,Mann K,Maremmani I,Nutt D,Paille F,Perney P,Rehm J,Reynaud M,Simon N,Söderpalm B,Sommer WH,Walter H,Spanagel R, Efficacy and safety of sodium oxybate in alcohol-dependent patients with a very high drinking risk level. Addiction biology. 2018 Jul;     [PubMed PMID: 30043457]
[4] Black J,Pardi D,Hornfeldt CS,Inhaber N, The nightly use of sodium oxybate is associated with a reduction in nocturnal sleep disruption: a double-blind, placebo-controlled study in patients with narcolepsy. Journal of clinical sleep medicine : JCSM : official publication of the American Academy of Sleep Medicine. 2010 Dec 15;     [PubMed PMID: 21206549]
[5] Plazzi G,Ruoff C,Lecendreux M,Dauvilliers Y,Rosen CL,Black J,Parvataneni R,Guinta D,Wang YG,Mignot E, Treatment of paediatric narcolepsy with sodium oxybate: a double-blind, placebo-controlled, randomised-withdrawal multicentre study and open-label investigation. The Lancet. Child     [PubMed PMID: 30169321]
[6] Schinkelshoek MS,Smolders IM,Donjacour CE,van der Meijden WP,van Zwet EW,Fronczek R,Lammers GJ, Decreased body mass index during treatment with sodium oxybate in narcolepsy type 1. Journal of sleep research. 2019 Jun;     [PubMed PMID: 29504180]
[7] Carter LP,Pardi D,Gorsline J,Griffiths RR, Illicit gamma-hydroxybutyrate (GHB) and pharmaceutical sodium oxybate (Xyrem): differences in characteristics and misuse. Drug and alcohol dependence. 2009 Sep 1;     [PubMed PMID: 19493637]
[8] Gashlin LZ,Sullo D,Lawrence RA,Rosen-Carole C, Treatment of Narcolepsy with Sodium Oxybate While Breastfeeding: A Case Report. Breastfeeding medicine : the official journal of the Academy of Breastfeeding Medicine. 2016 Jun;     [PubMed PMID: 27057786]
[9] Langford J,Gross WL, Psychosis in the context of sodium oxybate therapy. Journal of clinical sleep medicine : JCSM : official publication of the American Academy of Sleep Medicine. 2011 Dec 15;     [PubMed PMID: 22171207]
[10] Schep LJ,Knudsen K,Slaughter RJ,Vale JA,Mégarbane B, The clinical toxicology of γ-hydroxybutyrate, γ-butyrolactone and 1,4-butanediol. Clinical toxicology (Philadelphia, Pa.). 2012 Jul;     [PubMed PMID: 22746383]
[11] Miskoff JA,Chaudhri M, Off-label Sodium Oxybate in Childhood Narcolepsy: A Comprehensive Report. Cureus. 2018 Apr 24;     [PubMed PMID: 29942729]
[12] Akins BE,Miranda E,Lacy JM,Logan BK, A multi-drug intoxication fatality involving Xyrem (GHB). Journal of forensic sciences. 2009 Mar;     [PubMed PMID: 19187456]