Baclofen in gamma-hydroxybutyrate withdrawal: patterns of use and online availability

European Journal of Clinical Pharmacology https://doi.org/10.1007/s00228-017-2387-z PHARMACOEPIDEMIOLOGY AND PRESCRIPTION Baclofen in gamma-hydroxybutyrate withdrawal: patterns of use and online availability Christopher N. Floyd 1,2 & David M. Wood 1,2 & Paul I. Dargan 1,2 Received: 11 September 2017 / Accepted: 26 November 2017 # The Author(s) 2017. This article is an open access publication Abstract Purpose Gamma-hydroxybutyrate (GHB) withdrawal is a life-threatening condition that does not always respond to standard treatment with benzodiazepines. Baclofen has potential utility as a pharmacological adjunct and anecdotal reports suggest that it is being used by drug users to self-manage GHB withdrawal symptoms. Here, we investigate current patterns of use and the online availably of baclofen. Methods Data triangulation techniques were applied to published scientific literature and publicly accessible Internet resources (grey literature) to assess the use of baclofen in GHB withdrawal. An Internet snapshot survey was performed to identify the availability of baclofen for online purchase and the compliance of retailers with the UK regulations. Data were collected according to pre-defined criteria. Results A total of 37 cases of baclofen use in GHB withdrawal were identified in the scientific literature, as well as 51 relevant discussion threads across eight Internet forums in the grey literature. Baclofen was available to purchase from 38 online pharmacies, of which only one conformed to the UK regulations. Conclusions There is limited published evidence on the use of baclofen in GHB withdrawal, but both scientific and grey literature suggests clinical utility. Online pharmacies are readily offering prescription-only-medication without prescription and due to inadequate regulation, pose a danger to the public. Keywords Pharmacotherapy . Drug abuse . Clinical toxicology . GABA Introduction Gamma-hydroxybutyrate (GHB) is a naturally occurring metabolite of the neurotransmitter gamma-aminobutyric acid Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00228-017-2387-z) contains supplementary material, which is available to authorized users. * Christopher N. Floyd David M. Wood Paul I. Dargan 1 Clinical Toxicology, Guy’s and St Thomas’ NHS Foundation Trust and King’s Health Partners, London, UK 2 Faculty of Life Sciences and Medicine, King’s College London, London, UK (GABA) and was first synthesised as an anaesthetic agent in 1964 [1]. A high incidence of adverse effects during early clinical trials restricted its use in anaesthesia, but at lower doses, it has found some clinically utility and is licenced for treating sleep disorders (particularly narcolepsy with cataplexy) and alcohol dependence [2]. In addition, it has been used illicitly in both bodybuilding and as a recreational drug [3, 4]. Use of GHB and its precursors (gamma-butryolactone (GBL) and 1,4-butanediol (1,4-BD)) have a dose-dependent effect on glutamate and dopamine release. At low dose, stimulation of GHB receptors increases dopamine release resulting in stimulant-like effects, whilst at higher doses, binding to GABA-B receptors results in hypnotic effects and eventually coma [5]. There is no specific antidote for GHB and so acute toxicity is managed by supportive care which, in the case of significant consumption, may include endotracheal intubation for airway protection [6]. The first reports of physical dependence and consequent withdrawal syndrome were the result of both supervised Eur J Clin Pharmacol clinical and unsupervised recreational use [7–9]. Dependence results from modulation of baseline neuronal excitability in a mechanism that is analogous to that seen with alcohol and benzodiazepines dependence [10]. A terminal half-life of approximately 40 min means that those with dependency need to dose GHB/GBL every few hours [11], and interruption to this schedule results in a withdrawal syndrome typified by sympathetic over activity, florid delirium and profound neuropsychiatric features [6, 12]. Standard treatment involves high dose benzodiazepines (often up to 200 mg/day diazepam equivalent) with the possible addition of a range of other drugs including antipyschotics, barbiturates and anticonvulsants [13]. Benzodiazepines however are positive allosteric modulators of GABA-A receptors rather than GABA-B where GHB acts, and so despite their action to maintain GABAergic stimulus and prevent harmful neuronal excitability, they may not be the ideal pharmacotherapy [14]. It has therefore been suggested that the use of specific GABA-B agonists such as baclofen may provide clinical benefit in the management of withdrawal beyond that offered by benzodiazepines [6]. Baclofen is a direct agonist at GABA-B receptors [15] and has been widely used for the control of spasticity since the 1960s, where it acts to inhibit spinal afferent pathways and reduce motor neurone activity [16]. Animal work in both small mammals and primates has demonstrated that chronic GHB administration induces cross tolerance to baclofen [17, 18], and one case report described the use of baclofen as rescue therapy when increasing benzodiazepine dose failed to control GHB withdrawal [19]. Anecdotal reports from inpatients treated for GHB/GBL dependence and withdrawal describe dependent users purchasing baclofen from the Internet to self-medicate. The primary aim of this work was to understand and catalogue the use of baclofen in the management of withdrawal from GHB and its precursors. Triangulation of data from published scientific literature and publicly accessible Internet resources has enabled us to address the following objectives: (i) review scientific literature for reports of baclofen use by healthcare professionals, (ii) review Internet forums for reports of baclofen use by the public and (iii) assess the availability of baclofen to purchase online. Methods Scientific literature MEDLINE/PubMed was searched up until the 7th of February 2017 for all articles containing the keyword ‘baclofen’. The same keyword was used to search TOXLINE and EMBASE (up until the 12th of October 2017) and the abstracts of the European Association of Poisons Centres and Clinical Toxicologists (EAPCCT) and North American Congress of Clinical Toxicology (NACCT) congresses (from 2002 to 2016). All potentially eligible manuscripts were reviewed in full to identify those that investigated the use of baclofen in the treatment of GHB/GBL withdrawal. A secondary search was performed on the references of all eligible manuscripts to identify further relevant publications. Grey literature Publicly accessible Internet resources were searched in March 2017 for descriptions of baclofen being used to manage GHB/GBL withdrawal. The search term ‘baclofen’ was entered into the Internet search engine google.co.uk with the search terms ‘GHB’, ‘GBL’ and ‘withdrawal’ added separately and in combination. Search (...truncated)