Rama M. Kamal

Gamma-hydroxybutyrate detoxification by titration and tapering

Objective: To determine the effectiveness and safety of a new detoxification procedure in γ-hydroxybutyrate (GHB)-dependent patients. GHB is an endogenous inhibitory neurotransmitter and anesthetic agent that is being abused as a club drug. In many GHB-dependent patients a severe withdrawal syndrome develops that does not respond to treatment with high dosages of benzodiazepines and often requires an admission to an intensive care unit. Methods: Based on the knowledge of detoxification procedures in opioid and benzodiazepine dependence, we developed a titration and tapering procedure. A consecutive series of 23 GHB-dependent inpatients were transferred from illegal GHB (mostly self-produced) in various concentrations to pharmaceutical GHB. They were given initial doses that resulted in a balance between sedation and withdrawal symptoms. After this titration period, patients were placed on a 1-week taper. Results: We have found that after titration the patients experienced a low level of withdrawal symptoms. During tapering these symptoms decreased significantly and no patient developed a delirium or a psychosis. None of the patients had to be transferred to a medium or intensive care unit. Conclusions: This detoxification procedure proved to be safe and convenient in patients with moderate to severe GHB dependence.

A Case Series of Pharmaceutical Gamma-Hydroxybutyrate in 3 Patients With Severe Benzodiazepine-Resistant Gamma-Hydroxybutyrate Withdrawal in the Hospital

Received January 23, 2014; revised March 7, 2014; accepted March 7, 2014. From Department of Psychiatry, Leiden University Medical Center, Leiden, The Netherlands (M.S.vN); Novadic-Kentron Addiction Care Network, Vught, Nijmegen, The Netherlands (R.M.K., B.A.G.D.); Nijmegen Institute for Scientist-Practitioners in Addiction (NISPA), Nijmegen, The Netherlands (R.M.K., C.A.J.); Department of Intensive Care Medicine, Leiden University Medical Center, Leiden, The Netherlands (R.M.). Send correspondence and reprint requests to Martijn S. van Noorden,MD, PhD,Department of Psychiatry, LeidenUniversityMedical Center, P.O. Box 9600, 2300 RC Leiden, The Netherlands; e-mail: m.s. van_noorden@lumc.nl & 2015 The Academy of Psychosomatic Medicine. Published by Elsevier Inc. All rights reserved. 1 Both authors contributed equally. Introduction

The Neurobiological Mechanisms of Gamma-Hydroxybutyrate Dependence and Withdrawal and Their Clinical Relevance: A Review

Objective: γ-Hydroxybutyrate (GHB) has gained popularity as a drug of abuse. In the Netherlands the number of patients in treatment for GHB dependence has increased sharply. Clinical presentation of GHB withdrawal can be life threatening. We aim, through this overview, to explore the neurobiological pathways causing GHB dependency and withdrawal, and their implications for treatment choices. Methods: In this work we review the literature discussing the findings from animal models to clinical studies focused on the neurobiological pathways of endogenous but mainly exogenous GHB. Results: Chronic abuse of GHB exerts multifarious neurotransmitter and neuromodulator effects on γ-aminobutyric acid (GABA), glutamate, dopamine, serotonin, norepinephrine and cholinergic systems. Moreover, important effects on neurosteroidogenesis and oxytocin release are wielded. GHB acts mainly via a bidirectional effect on GABAB receptors (GABABR; subunits GABAB1 and GABAB2), depending on the subunit of the GIRK (G-protein-dependent ion inwardly rectifying potassium) channel involved, and an indirect effect of the cortical and limbic inputs outside the nucleus accumbens. GHB also activates a specific GHB receptor and β1-subunits of α4-GABAAR. Reversing this complex interaction of neurobiological mechanisms by the abrupt cessation of GHB use results in a withdrawal syndrome with a diversity of symptoms of different intensity, depending on the pattern of GHB abuse. Conclusion: The GHB withdrawal symptoms cannot be related to a single mechanism or neurological pathway, which implies that different medication combinations are needed for treatment. A single drug class, such as benzodiazepines, gabapentin or antipsychotics, is unlikely to be sufficient to avoid life-threatening complications. Detoxification by means of titration and tapering of pharmaceutical GHB can be considered as a promising treatment that could make polypharmacy redundant.

Decision rules for GHB (gamma-hydroxybutyric acid) detoxification: A vignette study

BACKGROUND GHB dependent patients can suffer from a severe and sometimes life-threatening withdrawal syndrome. Therefore, most of the patients are treated within inpatient settings. However, some prefers an outpatient approach to treatment. The aim of this study was to develop decision rules for addiction physicians to determine whether an outpatient or inpatient setting should be chosen for a safe GHB detoxification. METHODS A prospective vignette study was performed. Forty addiction medicine specialists from various treatment settings and residents of the Addiction Medicine postgraduate Master training were asked to contribute vignettes of GHB dependent patients. A focus group of 15 psychiatrists and addiction medicine specialists was asked to recommend an outpatient or inpatient setting for GHB detoxification treatment per vignette. Finally, five addiction medicine specialists, experts in GHB dependence treatment in the Netherlands, assessed the bio-psychosocial reasons for the choices of the focus group and formulated the recommended criteria. RESULTS Based on the bio-psychosocial state of twenty vignette patients, addiction physicians and psychiatrists established the criteria and conditions recommended for the indication of an outpatient GHB detoxification. Intensity of addiction (GHB dose ≤32 g/d and frequency of abuse ≤2 h) was stated as the primary criterion in determining the setting as well as the complexity of the psychiatric comorbid disorders. The importance of a stable support system was emphasised. CONCLUSION The vignette study resulted in a set of criteria with which addiction medicine specialists can make a weighted decision as to an outpatient or inpatient setting for GHB detoxification.

Pharmacological Treatment in γ-Hydroxybutyrate (GHB) and γ-Butyrolactone (GBL) Dependence: Detoxification and Relapse Prevention

The misuse of γ-hydroxybutyrate (GHB) for recreational purposes has resulted in an increase in GHB-related problems such as intoxications, dependence and withdrawal in several countries in Europe, Australia and the US over the last decade. However, prevalence rates of misuse of GHB and its precursor, γ-butyrolactone (GBL), are still relatively low. In this qualitative review paper, after a short introduction on the pharmacology of GHB/GBL, followed by a summary of the epidemiology of GHB abuse, an overview of GHB dependence syndrome and GHB/GBL withdrawal syndrome is provided. Finally, the existing literature on management of GHB detoxification, both planned and unplanned, as well as the available management of GHB withdrawal syndrome, is summarized. Although no systematic studies on detoxification and management of withdrawal have been performed to date, general recommendations are given on pharmacological treatment and preferred treatment setting.

Baclofen as relapse prevention in the treatment of gamma-hydroxybutyrate dependence: a case series

Abstract In the last decade, gamma-hydroxybutyrate (GHB) abuse and dependence have increased. It has been reported that GHB dependence has a high rate of relapse, serious complications of intoxication, and a potentially life-threatening withdrawal syndrome. Nevertheless, in clinical practice, there is no known medical treatment to support GHB relapse prevention. We describe a case series of patients who were supported through an off-label treatment with baclofen to avoid a relapse into GHB abuse, for a period of 12 weeks. Nine of 11 patients did not relapse while taking a dose ranging from 30 to 60 mg per day, one patient relapsed after 5 weeks, and one stopped after 7 weeks. Baclofen was well tolerated; patients reported mild side effects such as fatigue, nausea, dry mouth, excessive sweating, and depressive feelings. Although systematic evidence is still lacking, our practice-based experience suggests that treatment with baclofen to assist abstinence might be effective in patients with GHB dependence. Further systematic controlled studies are necessary to establish the exact efficacy and safety of baclofen as relapse prevention for GHB-dependent patients.

Detoxification with titration and tapering in gamma-hydroxybutyrate (GHB) dependent patients : The Dutch GHB monitor project

BACKGROUND AND AIMS Gamma-hydroxybutyrate (GHB) detoxification procedures have been insufficiently studied for effectiveness and safety. Based on case reports, benzodiazepines are generally regarded as first-choice agents in GHB detoxification. Detoxification by titration and tapering (DeTiTap) with pharmaceutical GHB in an open-label consecutive case series of 23 GHB-dependent patients showed to be feasible, effective and safe. This study further explored the feasibility, effectiveness and safety of this detoxification procedure in a large group of patients. METHOD A large observational multicenter study was carried out in six addiction treatment centers in the Netherlands. GHB-dependent inpatients (229 unique patients, 274 admissions) were titrated on and tapered off with pharmaceutical GHB. RESULTS Successful detoxification was achieved in 85% of cases. Detoxification was carried out in 12.5days in most patients. The DeTiTap procedure proved to be feasible and significantly reduced the experienced withdrawal symptoms and craving (p≤0.001). Several symptoms were found to influence the course of subjective withdrawal symptoms. During detoxification, psychological symptoms such as depression, anxiety, and stress decreased (p≤0.05). The main complications were hypertension and anxiety. Six patients were sent to the general hospital for observation, but all six were able to continue detoxification in the addiction treatment centers. Most patients (69%) relapsed within three months after detoxification. CONCLUSIONS The DeTiTap procedure using pharmaceutical GHB seems a safe alternative to benzodiazepines as a GHB detoxification procedure. However, the high relapse rates warrant further investigation.

The Effect of Co-occurring Substance Use on Gamma-hydroxybutyric Acid Withdrawal Syndrome

Objectives:Gamma-hydroxybutyric acid (GHB) withdrawal is a complex syndrome which can be potentially life-threatening. Additionally, GHB-dependent patients frequently report co-occurring substance use of other psychoactive drugs. We assessed the add-on effect of co-use on GHB withdrawal symptoms. Methods:We conducted an open-label, pretest–posttest design study with 95 patients selected from 229 inpatients admitted for detoxification, who were divided into GHB only (GO, n = 40), GHB plus sedatives (GSE, n = 38), and GHB plus stimulants (GST, n = 17) groups. GHB withdrawal was evaluated by means of the Subjective Withdrawal Scale. Co-use add-on effects on the severity of withdrawal symptoms were evaluated 2.5 hours after the last illicit GHB self-administration (T1) when withdrawal was expected and 2.5 hours later, after administration of a very low dose of pharmaceutical GHB (T2). Results:The GO group reported high scores of psychomotor retardation symptoms at both T1 and T2, and also high cravings, agitation, and restlessness at T1, and anxiety at T2. The GSE group reported the highest score in psycho-autonomic distress symptoms at both T1 and T2, whereas the GST group reported the highest score in psycho-motor stress factor at T2. There was no significant difference in withdrawal intensity in all symptom clusters between T1 and T2 for both GSE and GO groups. However, after 5 hours, the GST group reported significant decreases in intensity for all symptoms except for psycho-motor stress. At T1, GST and GSE groups reported more muscle twitches than the GO group as a significant add-on effect to the GHB withdrawal. At T2, the GST group experienced more agitation (P = 0.009), restlessness (P = 0.001), and rapid pulse (P = 0.034) than the GO group. Conclusions:Co-use, especially of stimulants, caused an add-on effect on the GHB withdrawal symptoms within the first 5 hours.

Epidemiology of gamma-hydroxybutyrate (GHB) use and misuse and characteristics of GHB-dependent inpatients

Gamma-hydroxybutyrate (GHB) has been used as a recreational drug in the nightlife setting since the 1990s in many Western countries. Problematic GHB use and addiction has been observed in certain countries recently. In this chapter, the epidemiology of GHB addiction is described as well as characteristics of recreational GHB use as GHB-dependent clients. GHB often is combined with other substances of abuse and problematic groups more often use at home or at nonsocial settings. GHB-dependent clients are older than recreational users and have achieved a lower level of education. They show a high unemployment rate and co-use of stimulants, which is associated with higher dependence severity. They also show a high co-morbidity with psychiatric mood disorders. In summary, GHB seems to be used by users of lower social economic status, in comparison with other typical nightlife drugs. This should be taken into account in prevention and addiction care.