Baclofen to Prevent Relapse in Gamma-Hydroxybutyrate (GHB)-Dependent Patients: A Multicentre, Open-Label, Non-Randomized, Controlled Trial

CNS Drugs https://doi.org/10.1007/s40263-018-0516-6 SHORT COMMUNICATION Baclofen to Prevent Relapse in Gamma-Hydroxybutyrate (GHB)Dependent Patients: A Multicentre, Open-Label, NonRandomized, Controlled Trial Harmen Beurmanjer1,2 • Rama M. Kamal3 • Cor A. J. de Jong2 • Boukje A. G. Dijkstra1,2 • Arnt F. A. Schellekens2,4 Ó The Author(s) 2018 Abstract Background Gamma-hydroxybutyrate (GHB) dependence is associated with a severe, potentially lethal, withdrawal syndrome and relapse rates as high as 60% within 3 months of detoxification. Baclofen has been shown to decrease self-administration of GHB in mice and reduce relapse in a case series of GHB-dependent patients. Controlled studies on the effectiveness of baclofen to prevent relapse in GHBdependent patients are lacking. Aim The aim of this study was to assess effectiveness of baclofen in preventing relapse in GHB-dependent patients. Methods This was an out-patient, multicentre, open-label, non-randomized, controlled trial in GHB-dependent patients (n = 107) in the Netherlands. Treatment as usual (TAU, n = 70) was compared with TAU plus baclofen 45–60 mg/day for 3 months (n = 37). Outcome measures were rates of lapse (any use) and relapse (using GHB on average once a week or more), based on self-report. Side effects were monitored with a baclofen side-effects questionnaire. Treatment groups were compared using Chi Electronic supplementary material The online version of this article (https://doi.org/10.1007/s40263-018-0516-6) contains supplementary material, which is available to authorized users. & Harmen Beurmanjer 1 Novadic-Kentron, Vught, The Netherlands 2 Nijmegen Institute for Scientist-Practitioners in Addiction (NISPA), Nijmegen, The Netherlands 3 GGZE, Eindhoven, The Netherlands 4 Department of Psychiatry, Donders Institute for Brain, Cognition and Behaviour, Radboudumc, Nijmegen, The Netherlands square analyses, with both per-protocol (PP) and intentionto-treat (ITT) analyses. Results GHB-dependent patients treated with baclofen after detoxification showed no reduced lapse rates, but reduced relapse and dropout rates, compared with patients receiving TAU only (24 vs 50%). While both ITT and PP analyses revealed similar results, the effectiveness of baclofen prescribed PP was slightly higher than in ITT analysis. Patients reported overall limited side effects, with the most frequently reported being feeling tired (28%), sleepiness (14%) and feeling depressed (14%). No serious adverse events were reported. Conclusions This study showed potential effectiveness of baclofen in preventing relapse in patients with GHB dependence after detoxification. Though promising, future studies with longer follow-up and a randomized doubleblind design should confirm these findings before recommendations for clinical practice can be made. Clinical trial registration Netherlands Trial Register with number NTR4528. Key Points Baclofen up to 60 mg daily might be effective in preventing relapse and increasing treatment adherence in patients with GHB use disorder. The use of baclofen up to 60 mg daily in patients with GHB use disorder seems safe, when prescribed according to the protocol. H. Beurmanjer et al. 1 Introduction 2 Methods In Europe, misuse of gamma-hydroxybutyrate (GHB) has increased over the past decade, particularly in the Netherlands, Norway, Spain and the UK [1]. GHB originally emerged in the 1990s 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 [2]. Physical dependence on GHB can develop within weeks, when used daily [3]. GHB dependence is associated with a severe, potentially lethal withdrawal syndrome and high relapse rates of 60% within 3 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 [5]. It occurs naturally in the brain, predominantly in the hypothalamus and basal ganglia [6, 7]. GHB binds to GABA-A receptors, GABA-B receptors and GHB receptors [8]. It has a rapid onset of action after ingestion, reaching maximum concentration (Cmax) in a short period (Tmax = 20–60 min), and a short half-life (T‘= 30–60 min). The clinical effects of GHB include sedation, euphoria and, in higher doses, hypoventilation and coma; see [9] for further details. Baclofen might be an adequate substitute for GHB. It is a high-affinity GABA-B receptor agonist, similar to GHB [10, 11], but with a longer half-life (T‘ = 2–6 h). This has the theoretical advantage of more stable drug-plasma levels, and subsequent GABA-B activation, with less frequent dosing (i.e. 3 times daily, instead of 12) [4]. Indeed, one animal study in mice showed that baclofen reduced GHB self-administration [12]. To date, only one case series on baclofen treatment (30–60 mg/day) in GHB dependence has been reported, showing 3-month abstinence in nine out of eleven cases [13]. Baclofen has also been shown to increase abstinence rates and reduce craving and anxiety in alcohol-dependent patients [14–18]. However, several studies failed to replicate these effects [19, 20]. 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 in GHB use disorders have been published. 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 hypothesis that patients receiving baclofen on top of treatment as usual (TAU) after GHB detoxification have decreased relapse rates compared with patients receiving TAU. 2.1 Study Design The effectiveness of baclofen was assessed in a multicentre, open-label, non-randomized, controlled clinical trial (see protocol publication [21]). After detoxification from GHB, patients received TAU or TAU combined with baclofen, based on patient preference. Participants provided written informed consent. The study was approved by the Medical Ethics Committee, Twente Medical School (METC/14015.am) study number NL40321.044.13. The study was registered in the Netherlands Trial Register with number NTR4528. 2.2 Participants GHB-dependent patients (according to DSM-IV criteria of substance dependence) were recruited at six addiction care facilities (IrisZorg, Mondriaan, Novadic-Kentron, Tactus, Victas and VNN) in the Netherlands, when admitted for detoxification. Inclusion criteria comprised completed GHB detoxification, wish for abstinence, continuing outpatient treatment after detoxification, age between 18 and 40 years, and comprehension of Dutch. Exclusion criteria comprised physical contra-indications for baclofen (e.g. liver problems, renal impairment, hypertension, diabetes mellitus, seizure disorder and pr (...truncated)