Pharmacodynamic interactions of a solid formulation of sodium oxybate and ethanol in healthy volunteers

Abstract

AIMThe pharmacologic effects of sodium oxybate (SO) have a number of similarities with those of alcohol. This study evaluated the pharmacodynamic interaction of SMO.IR (a solid immediate release formulation of SO) and alcohol (0.7 (males) or 0.57 (females) g kg -1 alcohol using 40% vodka). METHODSIn a randomized, double-blind, double-dummy, crossover trial, 24 healthy volunteers received randomly a) 2.25 g SMO.IR and placebo alcohol preparation, b) 2.25 g f SMO.IR and alcohol, c) 2.25 g SMO.IR matching placebo and alcohol and d) 2.25 g of SMO.IR matching placebo and placebo alcohol preparation. Objective and subjective cognitive parameters, adverse events and vital signs were assessed before, 15 and 165 min after treatment administration. RESULTSAlcohol produced the expected cognitive impairment and the expected subjective sedation rapidly after intake (from 15 min). The objective effects of SMO.IR were much less pronounced than those of alcohol. The reverse was observed for subjective complaints, which were related to lesser stimulation and greater sedation. Nevertheless, 165 min after administration this sedation feeling was less with SMO.IR than with alcohol. There was a significant interaction between SMO.IR and alcohol at 15 min (i.e. increase in alertness and stimulation and decrease in sedation). In addition, an isolated mild decrease in digit vigilance accuracy occurred at 165 min post-dose after the combination. The co-administration of SMO.IR and alcohol was safe and well-tolerated. CONCLUSIONSMO.IR and alcohol have distinct adverse effect profiles. The objective effects of SMO.IR are much less marked than those of alcohol. No deleterious interaction was observed. WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Sodium oxybate (SO) has been approved for the treatment of alcohol dependence in Europe. Post-market surveillance has found no significant safety issues in alcohol relapsing patients taking SO, even though SO and alcohol share several pharmacological targets and effects.• Illicit SO (also called 'street GHB' or 'liquid ecstasy') can lead to abuse, misuse, addiction, criminal use and/or overdosing, and may have long term neurotoxic effects.• SMO.IR, a solid immediate-release formulation of sodium oxybate, is being developed to reduce the risk of criminal or accidental misuse of the drug and to obtain worldwide approval for the treatment of alcohol dependence. WHAT THIS STUDY ADDS• SMO.IR and alcohol have distinct adverse effect profiles. The objective sedative effects of SMO.IR are much less marked than those of alcohol and no interaction was observed.• The dose of SMO.IR used in this study (2.25 g) is in the upper range of the therapeutic interval for alcohol dependence and is 30%-80% higher than commonly prescribed doses.• The low level of interaction between alcohol and SMO.IR may account for the good safety profile of the drug even in the context of alcohol relapses. IntroductionSodium oxybate (SO) is the name of the sodium salt of gamma-hydroxybutyric acid when used as a therapeutic agent. Gamm...

Mechanisms for the Specific Properties of γ‐Hydroxybutyrate in Brain

“…Alcohol is a more common example in this field. This substance has a number of pharmacologic similarities with GHB at high doses but also differently marked effects, especially in human . In spontaneous human genetic disease affecting SSADH activity or in a similar model of SSADH −/− transgenic mice, an accumulation of GABA and GHB is observed in the cerebrospinal fluid (CSF).…”

“…This substance has a number of pharmacologic similarities with GHB at high doses but also differently marked effects, especially in human. [41][42][43] In spontaneous human genetic disease affecting SSADH activity 44 or in a similar model of SSADH −/− transgenic mice, 45,46 an accumulation of GABA and GHB is observed in the cerebrospinal fluid (CSF). This seems to indicate that when the access to the Krebs cycle is blocked, the synthesis of GABA and GHB is increased and the other routes for GHB degradation 47 are not active enough to maintain normal GHB concentrations.…”

A Brief Up-Date of the Use of Sodium Oxybate for the Treatment of Alcohol Use Disorder

“…In addition, no side effects due to the combination of SMO 50 mg/kg and alcohol were observed in those SMO-treated alcoholics who were still drinking during the treatment [ 11 , 12 , 15 ]. This was also confirmed by a recent randomized, double-blind, double-dummy, cross-over trial in healthy volunteers aimed at exploring the pharmaco-dynamic interaction of the solid immediate release formulation of SMO and alcohol, which clearly showed that SMO and alcohol have separate adverse effect profiles, and that the objective effects of SMO are much less marked than those of alcohol, without any deleterious interaction [ 17 ]. However, larger clinical trials with alcohol dependent patients aimed at investigating a possible negative interaction during the concurrent intake of alcohol and SMO have not been performed, so that the suggestion not to drink during SMO administration represents a crucial message for physicians before prescribing this medication for AUD.…”

“…This study demonstrated a borderline significance in favor of SMO in reducing CAD [ 11 ]. Considering SMO as a possible treatment option for reducing alcohol consumption, concerns remain about the side effects of the combination with alcohol.No additional sedative effects induced by drinking during SMO treatment were found in healthy subjects [ 17 ]. Moreover, considering that SMO is utilized both for treating AWS and to maintain abstinence, according to clinical practice, then complete abstinence from alcohol should not be considered an exclusion criterion for treatment with SMO [ 14 ].…”

Sodium oxybate plus nalmefene for the treatment of alcohol use disorder: A case series

“…Indeed, with respect to the single high dose of SMO used to induce sleep in narcoleptic patients (Alshaikh et al, 2012; Pardi and Black, 2006), or the intravenous administration for anaesthetic procedures, SMO doses employed to treat alcohol dependent patients are very low and fractioned up to six daily administrations, so that a sedation effect is never achieved (Cruz et al, 2004). Moreover, a recent randomized, double-blind, double-dummy, cross-over trial in healthy volunteers aimed at exploring the pharmacodynamic interaction of the solid immediate release formulation of SMO and alcohol has clearly shown that SMO and alcohol have separate adverse effect profiles, and that the objective effects of SMO are much less marked than those of alcohol, without any deleterious interaction (Pross et al, 2015). Consistently, we did not observe any additional sedative effect in our patients while drinking during the treatment with SMO.…”