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Sodium Oxybate

A Review of its Use in the Management of Narcolepsy

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Summary

Abstract

Sodium oxybate (Xyrem®) is the sodium salt of the CNS depressant γ-hydroxybutyric acid (GHB) and is therefore subject to prescription restrictions. It is approved in the US for the treatment of cataplexy and excessive daytime sleepiness (EDS) in patients with narcolepsy, and in the EU for the treatment of narcolepsy with cataplexy.

Sodium oxybate is generally well tolerated and effective in the treatment of symptoms of narcolepsy with cataplexy. While its short half-life necessitates twice-nightly administration, it is highly effective in reducing the frequency of cataplexy, improving sleep architecture and reducing EDS in patients with narcolepsy. Sodium oxybate therefore offers a valuable alternative or addition to the use of TCAs, SSRIs and stimulants in the treatment of the symptoms of narcolepsy including cataplexy and EDS.

Pharmacological Properties

A naturally occurring GABA metabolite, GHB acts as a neurotransmitter by binding to high- and low-affinity G-protein-coupled GHB receptors. At pharmacological doses GHB also activates GABAB and may modulate GABAA and GABAC receptors. Oral GHB alters sleep architecture in healthy volunteers and in patients with narcolepsy, primarily by improving the continuity of sleep. GHB is a drug of abuse and, during GHB intoxication at high doses, CNS depression, bradycardia, hypotension and severe respiratory depression have been observed.

Oral sodium oxybate is rapidly absorbed; the dose-dependent mean maximum plasma concentration (Cmax; 27–90 μg/mL) was achieved in a mean time (tmax) of 25–75 minutes after a single oral dose of sodium oxybate 2.25–4.5g. Administration of a second dose 4 hours later produced a 1.4- to 2.2-fold increase in mean Cmax, and nightly administration for 8 weeks did not increase plasma concentrations substantially. Absorption is slowed and decreased by food; tmax is increased 2.7-fold, while Cmax is decreased by 58% and the area under the plasma concentration-time curve is decreased by 35%.

The elimination of sodium oxybate from the circulation is rapid, with an elimination half-life of 20–53 minutes after one dose, or two doses administered 4 hours apart.

Therapeutic Efficacy

In two randomised, double-blind, placebo-controlled trials, sodium oxybate 9 g/ night, but not 3 or 6 g/night, significantly reduced the median frequency of cataplexy attacks by 69% in patients with narcolepsy (all of whom had associated cataplexy) after 4 weeks of treatment, while sodium oxybate 4.5–9 g/night for 8 weeks significantly reduced the median frequency of cataplexy attacks by 57–85% in a dose-related manner.

In addition, sodium oxybate reduced EDS in both 4- and 8-week trials, with dose-related 6–30% reductions in median Epworth Sleepiness Scale scores and 20–43% reductions in the median frequency of inadvertent daytime sleep attacks. In a third trial, sodium oxybate as monotherapy or in addition to the stimulant modafinil induced 5% or 26% increases in mean sleep onset time in a maintenance of wakefulness test.

In patients with narcolepsy with cataplexy, sodium oxybate improved sleep architecture by increasing slow-wave sleep duration and delta power and decreasing rapid eye movement sleep duration and nocturnal awakenings. Global function and health-related quality of life were also improved in sodium oxybate recipients in a dose-related manner.

Tolerability

Sodium oxybate is generally well tolerated and the most common drug-related adverse events are nausea, vomiting, dizziness and urinary incontinence. The few adverse events observed during withdrawal may, in fact, reflect the return of narcolepsy symptoms rather than withdrawal symptoms. Serious adverse events have seldom been reported.

Although concerns regarding its narrow safety margin and the potential for abuse/misuse remain, strict risk-management strategies and rigorous adherence to the up-titration schedule may help alleviate some of these difficulties.

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Notes

  1. The use of trade names is for product identification purposes only and does not imply endorsement.

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Authors and Affiliations

  1. Wolters Kluwer Health | Adis, 41 Centorian Drive, Private Bag 65901, Mairangi Bay, Auckland, 1311, New Zealand

    Dean M. Robinson & Gillian M. Keating

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Correspondence to Dean M. Robinson.

Additional information

Various sections of the manuscript reviewed by: N.T. Feldman, St Petersburg Sleep Disorders Center, St Petersburg, Florida, USA; C. Guilleminault, Sleep Disorders Clinic and Research Center, Department of Psychiatry and Behavioral Sciences, Stanford University, Palo Alto, California, USA; G.J. Lammers, Department of Neurology and Clinical Neurophysiology, Leiden University Medical Center, Leiden, The Netherlands; M.D. Lemon, Veterans Affairs Black Hills Health Care System and College of Pharmacy, South Dakota State University, Fort Meade, South Dakota, USA; M. Littner, Veterans Affairs Greater Los Angeles Healthcare System and University of California Los Angeles School of Medicine, Sepulveda, California, USA; M. Mamelak, Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada; M.B. Scharf, Tri-State Sleep Disorders Center, Cincinnati, Ohio, USA.

Data Selection

Sources: Medical literature published in any language since 1980 on ‘sodium oxybate’, identified using MEDLINE and EMBASE, supplemented by AdisBase (a proprietary database of Adis International). Additional references were identified from the reference lists of published articles. Bibliographical information, including contributory unpublished data, was also requested from the company developing the drug.

Search strategy: MEDLINE and EMBASE search terms were (‘sodium oxybate’ or ‘sodium-hydroxybutyrate’ or ‘gamma-hydroxybutyrate’) and (‘narcolepsy’ or ‘cataplexy’ or ‘daytime sleepiness’). AdisBase search terms were (‘sodium oxybate’ or ‘gamma-hydroxybutyrate’) and (‘narcolepsy’ or ‘cataplexy’ or ‘daytime sleepiness’). Searches were last updated Mar 3 2007.

Selection: Studies in patients with narcolepsy who received sodium oxybate. Inclusion of studies was based mainly on the methods section of the trials. When available, large, well controlled trials with appropriate statistical methodology were preferred. Relevant pharmacodynamic and pharmacokinetic data are also included.

Index terms: Sodium oxybate, cataplexy, daytime sleepiness, narcolepsy, pharmacodynamics, pharmacokinetics, tolerability, therapeutic use.

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Robinson, D.M., Keating, G.M. Sodium Oxybate. CNS Drugs 21, 337–354 (2007). https://doi.org/10.2165/00023210-200721040-00007

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