Baclofen as relapse prevention in the treatment of Gamma- Hydroxybutyrate (GHB) dependence: an open label study

Kamal et al. BMC Psychiatry Baclofen as relapse prevention in the treatment of Gamma- Hydroxybutyrate (GHB) dependence: an open label study Rama M Kamal 0 1 Arnt Schellekens 1 Cornelis AJ De Jong 1 Boukje AG Dijkstra 1 0 Novadic-Kentron Addiction Care network , Vught , the Netherlands 1 Nijmegen Institute for Scientist-Practitioners in Addiction (NISPA) , Hogedwarsstraat 3, PO Box 243, Vught 5260 AE , the Netherlands Background: GHB dependence is a growing health problem in several western countries, especially the Netherlands. Attempts to stop using GHB are often followed by relapse shortly after successful detoxification. Craving for GHB use and co-morbid psychiatric symptom levels are thought to be the major factors contributing to the high relapse rates. Given its pharmacological profile, baclofen might prove an effective anti-craving agent for patients with GHB dependence. The aim of the current study is to assess the potential of baclofen as an anti-craving agent relapse prevention intervention in GHB dependent patients. Methods/Design: In an open label non-randomized trial treatment with baclofen to a maximum of 60 mg/day will be compared with treatment as usual (TAU) in recently detoxified GHB dependent patients (n = 80). The primary outcome measure will be the level of GHB use. Secondary outcome measures are craving levels, psychiatric symptom levels and quality of life. Questionnaires will be administered during 12 weeks of baclofen treatment and at follow-up (six months after the start of treatment). Discussion: It is hypothesized that baclofen treatment compared to TAU will be associated with significantly reduced GHB use. In addition, we hypothesize that baclofen treatment will be associated with decreased craving and anxiety levels, and higher quality of life. If results are in line with our hypotheses, further studies on the efficacy of baclofen using placebo controlled designs and long term follow-up are warranted. Baclofen; Gamma- Hydroxybutyrate; GHB dependence; Relapse; Craving - Background GHB use is a growing public health issue in several Western countries, including the Netherlands [1]. Recreational use of GHB has gained popularity over the past decades [2]. As a result, its addictive potential has become more apparent [3]. Little is known about the exact prevalence of chronic GHB dependence in the USA and Europe due to the absence of surveillance and systematic reporting mechanisms [4]. Nevertheless the number of GHB users seeking help increased over the past years [5]. For example, the number of GHB dependent patients admitted in addiction treatment facilities sharply increased in the Netherlands, over the last five years from 60 in 2008 to almost 800 patients in 2013 [6]. Gamma-hydroxybutyrate (GHB) is a short-chain fatty acid that is an endogenous precursor and metabolite of gamma-aminobutyric acid (GABA). GHB administered systemically can cross the bloodbrain barrier where it acts both as neurotransmitter and a neuromodulator [7]. It has a plasma half-life of approximately 3060 minutes [8]. GHB has high affinity for the GABA-B receptor and to a lesser extent for subtypes of the GABA-A receptor [9]. GHB has impact as neuromodulator via both GABAergic effects and direct effects on a wide variety of other neurotransmitters, including glutamate, dopamine, serotonin, noradrenaline, acetylcholine, opioids, and GABA [10-12]. GHB has various therapeutic applications, like general anesthesia [13], treatment of sleep disorders as narcolepsy [14], and the treatment of alcohol [15] and opioid withdrawal [16]. GHB tolerance occurs rapidly when used daily, inducing physical dependence at higher doses. Discontinuation of GHB can produce severe withdrawal symptoms as anxiety, delirium with auditory and visual hallucinations, seizers, and coma, which may be life threatening [17,18]. Recent studies have shown safety of strategies for the detoxification in GHB dependence, using tapering with pharmaceutical GHB or benzodiazepines [19]. Nevertheless, high relapse rates hamper long-term recovery, despite psychological treatment and counseling. Forty-five percent of the cases reporting to addiction care facilities had previously been in treatment for GHB dependence [19]. Indeed, shortterm relapse rates up to 64% have been reported [20]. Selfreported reasons for relapse include social pressure, craving for and loss of control over GHB use and increased anxiety and depression after stopping GHB use [21]. Here we present a study protocol investigating the potential of baclofen in relapse prevention and its anticraving properties in recently detoxified GHB dependent patients. Baclofen is a high affinity GABA-B receptor agonist with a half-life ranging from 2 to 6 hours [22]. The pharmacological overlap between baclofen and GHB suggests that the relatively long-acting baclofen may serve as a substitute for the short acting GHB. Moreover, baclofen is thought to modify brain reward function, through its indirect effects on dopamine, which has been suggested to be a key neurotransmitter for craving [23-25]. Finally, baclofen is thought to have anxiolytic effects through its agonist effects on the GABA-B receptor [26]. Overall, it could be speculated that baclofen may be effective in relapse prevention in GHB dependent patients. Indeed, animal data have shown beneficial effects of baclofen on GHB self-administration in mice [27]. Aims and hypotheses The primary aim of the current study is to assess the potential of baclofen to prevent relapse in recently detoxified GHB-dependent patients. We hypothesize that administration of baclofen to GHB-dependent patients after detoxification is associated with decreased relapse rates as compared to treatment as usual (without baclofen). We also hypothesize that treatment with baclofen is associated with reduced levels of craving for GHB and reduced psychiatric symptoms levels, including anxiety, and increased quality of life. We expect baclofen treatment to cause minimal side effects in these patients. Finally, we expect a lower drop-out rate from adjuvant therapy (TAU) in the intervention group. Netherlands. The study is part of the Dutch national GHB Monitor 2.0 and data collection will take place between May 2014 and December 2015. After successful detoxification of GHB, patients will receive either baclofen on top of treatment as usual (TAU + baclofen) or treatment as usual (TAU) only. Assignment is based on in- and exclusion criteria and on patient preference (informed consent). Ethical considerations The study was approved by the Medical Ethics Committee, Twente Medical School, Institute for Applied Scientific Research (METC/14015.kam) study number NL40321.044.13. Participants are informed about the trial and about the voluntary nature of their participation with both written and verbal communications. Participants are only included following the provision of informed consent. Participants Recruitment Participants a (...truncated)