Improving GHB withdrawal with baclofen: study protocol for a feasibility study for a randomised controlled trial

Lingford-Hughes et al. Trials (2016) 17:472 DOI 10.1186/s13063-016-1593-9 STUDY PROTOCOL Open Access Improving GHB withdrawal with baclofen: study protocol for a feasibility study for a randomised controlled trial Anne Lingford-Hughes1,2* , Yash Patel1, Owen Bowden-Jones1, Mike J. Crawford1,2, Paul I. Dargan3,4, Fabiana Gordon5, Steve Parrott6, Tim Weaver7 and David M. Wood3,4 Abstract Background: GHB (gamma-hydroxybutyrate) and its pro-drugs GBL (gamma-butyrolactone) and 1,4-butanediol (1,4-BD) are central nervous system depressants whose street names include ‘G’ and ‘liquid ecstasy’. They are used recreationally predominately for their stimulant and pro-sexual effects or for sedation to help with sleep and/or to ‘come down’ after using stimulant recreational drugs. Although overall population prevalence is low (0.1 %), in some groups such as men who have sex with men, GHB/GBL use may reach 20 %. GHB/GBL dependence may be associated with severe withdrawal with individuals presenting either acutely to emergency departments or to addiction services for support. Benzodiazepines are currently prescribed for GHB/GBL detoxification but do not prevent all complications, such as behavioural disinhibition, that may require hospitalisation or admission to a high dependency/intensive care unit. The GABAB receptor mediates most effects of GHB/GBL and the GABAB agonist, baclofen, has shown promise as an adjunct to benzodiazepines in reducing withdrawal severity when prescribed both during withdrawal and as a 2-day ‘preload’ prior to detoxification. The key aim of this feasibility study is provide information about recruitment and characteristics of the proposed outcome measure (symptom severity, complications including delirium and treatment escalation) to inform an application for a definitive randomised placebo controlled trial to determine the role of baclofen in the management of GHB/GBL withdrawal and whether starting baclofen 2 days earlier improves outcomes further. Methods/design: This is a prospective, randomised, double-blind, placebo-controlled feasibility study that will recruit participants (aged over 18 years) who are GHB/GBL-dependent and wish to undergo planned GHB/GBL detoxification or are at risk of acute withdrawal and are inpatients requiring unplanned withdrawal. We aim to recruit 88 participants: 28 unplanned inpatients and 60 planned outpatients. During detoxification we will compare baclofen 10 mg three times a day with placebo as an adjunct to the usual benzodiazepine regimen. In the planned outpatient arm, we will also compare a 2-day preload of baclofen 10 mg three times a day with placebo. Ratings of GHB/GBL withdrawal, sleep, depression, anxiety as well as GHB/GBL use will be collected. The main data analyses will be descriptive about recruitment and characterising the impact of adding baclofen to the usual benzodiazepine regimen on measures and outcomes of GHB/GBL withdrawal to provide estimates of variability and effect size. A qualitative approach will evaluate research participant and clinician acceptability and data collected to inform cost-effectiveness. (Continued on next page) * Correspondence: ; 1 Central North West London NHS Foundation Trust’s Club Drug Clinic, 69 Warwick Rd, London SW5 9HB, UK 2 Centre for Psychiatry, Division of Brain Sciences, Imperial College London, Burlington Danes Building, Hammersmith Hospital site, Du Cane Rd, London W12 0NN, UK Full list of author information is available at the end of the article © 2016 The Author(s). Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Lingford-Hughes et al. Trials (2016) 17:472 Page 2 of 11 (Continued from previous page) Discussion: This feasibility study will inform a randomised controlled trial to establish whether adding baclofen to a benzodiazepine regimen reduces the severity and complications of GHB/GBL withdrawal. Trial registration: ISRCTN59911189. Registered 14 October 2015. Protocol: v3.1, 1 February 2016 Keywords: GHB, Gamma-hydroxybutyrate, GBL, Gamma-butyrolactone, GHB/GBL withdrawal, Baclofen, Benzodiazepine, GABAB, GHB/GBL dependence Background GHB/GBL use and dependence GHB (gamma-hydroxybutyrate) and its related analogues GBL (gamma-butyrolactone) and 1,4-butanediol (1,4-BD) are central nervous system depressants and their street names include ‘G’ and ‘liquid ecstasy’ [1, 2]. GBL and 1,4BD are converted to GHB after ingestion and, therefore, all three drugs have similar pharmacological actions and profiles [1, 2]. There is limited use of 1,4-BD in the UK and, therefore, hereafter we will use the term GHB/GBL to refer to these compounds. They are used recreationally predominately for their stimulant and pro-sexual effects, although some individuals use them for their sedative effects and/or to help ‘come down’ after using stimulant recreational drugs [3–5]. Although overall population prevalence of use is low, the Crime Survey for England and Wales reported that use significantly rose from 0.0 % in 2010/11 to 0.1 % in 2011/12; subsequent surveys did not collect GHB/GBL data [6]. However, the use of these drugs is more common in a number of subpopulation groups. In particular, in populations such as clubbers and men who have sex with men (MSM), lifetime prevalence of GHB/GBL use ranges from 3.9 to 14.3 %, with lastmonth prevalence of use of up to 4.6 % [7]. Almost a quarter of those surveyed in ‘gay-friendly’ South London dance clubs in July 2011 reported GHB/GBL use that night, second to mephedrone at 41 % [8]. Similarly, attendees at two London sexual health clinics (December 2013 to March 2104) reported lifetime prevalence of use of GHB at 19 % and GBL at 13 % [9]. Reports from the UK’s Advisory Council on Misuse of Drugs [10] and European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) [7] have highlighted the potential for both significant acute toxicity and also dependence associated with GHB/GBL. The latest data from Public Health England reports that the numbers of people presenting to treatment services with problems with GHB/GBL continue to rise from 18 (2 % of new presentations involving ‘club drugs’ (methamphetamine, mephedrone, ketamine, ecstasy, and GHB/GBL)) of those seeking treatment in 2005–2006 to 249 (5 %) in 2013–2014 [11] and the number of deaths implicating GHB are also rising from none in 1993 to 12–20/year in 2008–2012 [12]. Our clinical experience is consistent with this. Presentations with acu (...truncated)