Harmen Beurmanjer

79 Baclofen for GHB-Dependent Patients 6 Introduction In Europe misuse of gamma-hydroxybutyrate (GHB) has increased over the past decade, particularly in The Netherlands, Norway, Spain and the United Kingdom (European Monitoring Centre for Drugs and Drug Addiction, 2016). GHB originally emerged in the nineties as an innocent party-drug, but later proved to be highly addictive. Precise prevalence rates are unknown due to a lack of systematic surveillance on GHB use (T. Brunt & Schrooten, 2014). Physical dependence on GHB can develop within weeks, when used daily (McDaniel & Miotto, 2001). GHB dependence is associated with a severe, potentially lethal, withdrawal syndrome and high relapse rates of 60% within three months of detoxification(4). However, studies on relapse prevention in GHB dependence are lacking. GHB is a short-chain fatty acid, which is biosynthetically derived from the inhibitory neurotransmitter GABA (Tarabar & Nelson, 2004). It occurs naturally in the brain, predominantly in the hypothalamus and basal ganglia (Bessmann & Fishbein, 1963; O. C. 3rd Snead & Morley, 1981). GHB binds to GABA-A-receptor, GABA-B-receptor and GHB-receptor (Laborit, 1964). It has a rapid onset of action after ingestion, reaching maximum concentration (Tmax) in a short period. GHB’s clinical effects include sedation, euphoria, and in higher doses hypoventilation and coma, see (Kamal et al., 2017) for further details. Baclofen might be an adequate substitute for GHB. It is a high-affinity GABA-B receptor agonist, similar to GHB (Crunelli, Emri, & Leresche, 2006; Cruz et al., 2004), but with a longer half-life (T½=2-6hours). This has the theoretical advantage of more stable drug-plasma levels, and subsequent GABA-B activation, with less frequent dosing (i.e. three times daily, instead of twelve)(Dijkstra et al., 2017). Indeed, one animal study in mice showed that baclofen reduced GHB self-administration (Fattore, Cossu, Martellotta, Deiana, & Fratta, 2001). To date, only one case series on baclofen treatment (30-60mg per day) in GHB dependence has been reported, showing three-month abstinence in nine out of eleven cases(Kamal, Loonen, et al., 2015). Baclofen has also been shown to increase abstinence rates and reduce craving and anxiety in alcohol-dependent patients (G. Addolorato et al., 2002; Giovanni Addolorato et al., 2007; Agabio, Preti, & Gessa, 2013; Cryan & Kaupmann, 2005; Terrier et al., 2011). However, several studies failed to replicate these effects (Beraha et al., 2016; Muller et al., 2015). These findings warrant further studies on the potential efficacy of baclofen in the treatment of GHB use disorders. To our knowledge, no clinical studies on the effects of baclofen inGHBusedisorders havebeenpublished. Here, we investigated the effectiveness of baclofen in recently detoxified GHB-dependent patients to prevent relapse in an open-label, non-randomized, controlled clinical trial. Specifically, we tested the hypotheses that patients receiving baclofen on top of treatment as usual (TAU) after GHB detoxification have decreased relapse rates compared to patients receiving TAU.