Sodium Oxybate for Narcolepsy: Explaining Untoward Effects and Recommending New Approaches in Light of Prevailing Receptor Pharmacology

Abstract

Objective: Gamma-hydroxybutyrate (GHB) has been an abused and illicit substance for decades, but the antinarcoleptic medication Xyrem (sodium oxybate), the sodium salt of GHB, was approved just in 2002 for increasing wakefulness. We present a case of coma induced by co-ingestion of prescription GHB and ethanol and describe the response to naloxone treatment, by first responders, without evidence of opiate exposure. The purpose of this report is to bridge updated knowledge on GHB and ethanol pharmacology with the clinical sequence of events in a patient co-ingesting these compounds and to theorize on a potentially better pharmacological approach to narcolepsy. Case Summary: The patient was a 25-year-old woman with a history of narcolepsy. She suddenly collapsed at home but became transiently responsive after being administered naloxone in the ambulance. She presented to the emergency department with apnea, poor responsiveness with a Glasgow Coma Score of 7, and urinary incontinence. While undergoing intubation, the patient spontaneously and abruptly awoke. Labs were unremarkable except a blood alcohol concentration of 0.123%. The dosage of, and adherence to, GHB was unknown in this case. Discussion: The case is described in light of the most recent pharmacological advancements on these co-ingestants. A conceptual dose-response curve is shown to facilitate understanding of the complex pharmacology of GHB. Conclusions: Approved and potential alternatives to GHB, for achieving wakefulness, are discussed. Potential new strategies should bear low to no risk of coma with accidental overdose or co-ingestion of ethanol. In addition, promising antidotes for future consideration are discussed.

Keywords: GHB; Xyrem; gamma-hydroxybutyrate; naloxone; narcolepsy; oxybate; toxicology.

Figure 1.

Current knowledge of γ-hydroxybutyrate (GHB) targets and theoretical dose–response relationship. (A) GHB receptor targets in the central nervous system. GHB activates GHB receptors to increase glutamate release from neurons. GHB also activates inhibitory receptors, GABA_A and GABA_B. Ethanol activates GABA_A receptors to enhance the overall inhibitory potential in the neuron. (B) GHB exhibits a dose-dependent biphasic effect on clinical symptoms as a result of its receptor targeting. At low concentrations GHB has a predominant excitatory effect from GHB receptor activation. At higher concentrations, that is, micromolar to millimolar, GHB begins to activate low-affinity inhibitory receptors (GABA_A and GABA_B). Thus, toxicity equates to loss of consciousness. Whether enhanced daytime wakefulness from taking GHB at night is a result of more productive sleep or GHB-induced stimulation at low concentrations experienced in the morning, or both, is unknown. Ethanol allosterically raises the inhibitory GABA_A activity, thus reducing the threshold for coma via GHB.