Harmen Beurmanjer

65 Tapering GHB or BZDs for Detoxification in GHB-Dependent Patients 5 Introduction Gamma-HydroxyButyric (GHB) acid is a short-chain fatty acid, biosynthetically derived from the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) (Wong, Chan, Gibson, & Snead, 2004), it binds to GHB and GABA-B receptors (Laborit, 1964). GHB is mainly used in Australia, the US and Europe (Louisa Degenhardt et al., 2003; Dines et al., 2015; Nicholson & Balster, 2001), for its euphoric and sedating effects (Beurmanjer et al., 2019; Busardo & Jones, 2015; Kamal et al., 2017). GHB has a very narrow bandwidth between the plasma level for desired clinical effects and overdose, often resulting in temporary coma (Brenneisen et al., 2004; Corkery et al., 2015). GHB overdose can however be fatal, especially when combined with other substances (Corkery et al., 2015). Regular GHB use can lead to GHB use disorder (GUD) (M. Van Noorden et al., 2016). While prevalence of GHB use is still limited in Europe, between 0.1%-1.5% of the adult population, it has been rising in the past decade(Kamal et al., 2017). Little is known about the number of people with GUD, but it is estimated that up to 21% of GHB users develops GUD(K. Miotto et al., 2001). GUD is characterized by frequent GHB administration (every 1-3 hours) to prevent withdrawal (Beurmanjer et al., 2019; Kamal et al., 2017). The GHB withdrawal syndrome often has a fulminant course, with a rapid onset and swift progression of severe withdrawal symptoms (Dijkstra et al., 2017; Kamal et al., 2017). Withdrawal symptoms include: tremor, nausea, vomiting, tachycardia, insomnia, diaphoresis, anxiety and nystagmus. Adverse events during withdrawal include hypertensive crisis, severe agitation, delirium, and epileptic seizures (Kamal et al., 2017). The severity and complexity of GHB withdrawal poses a clinical challenge during detoxification. In clinical practice two pharmacological treatment regimens are commonly used to counteract withdrawal symptoms during GHB detoxification: tapering with benzodiazepines (BZD) and tapering with pharmaceutical GHB. BZD have an allosteric effect on GABA-A-receptors, resulting in increased sensitivity for GABA (Lorenz-Guertin et al., 2019). Benefits of BZD compared to pharmaceutical GHB are the wide availability in medical settings, low costs and that tapering with BZD allows patients to directly quit using GHB. However, several case studies describe BZD resistance (M. S. van Noorden et al., 2015), where despite extremely high doses of BZD, in one case up to 700mg of diazepam per day, delirium still develops (Craig et al., 2000; Neu, 2018). Others describe the necessity of additional sedatingmedication, such as phenobarbital (Sivilotti et al., 2001) and propofol (Dyer et al., 2001), in order to treat delirium. Pharmaceutical GHB has the same pharmaco- logical properties as “street-GHB”. GHB-assisted tapering requires up to 12 doses (every 2 hours) a day (Dijkstra et al., 2017). GHB tapering has been shown to be associated with a high success rate of 85% and limited adverse events in several large non-randomized trials (n=450). Reported adverse events during detoxification were mainly hypertension (7%) and delirium (2%) (Beurmanjer H, Verbrugge CAG, Schrijen S & DeJong CAJ, 2016; Dijkstra et al., 2017). It is suggested that tapering with pharmaceutical GHB might be preferable