Tapering with Pharmaceutical GHB or Benzodiazepines for Detoxification in GHB-Dependent Patients: A Matched-Subject Observational Study of Treatment-as-Usual in Belgium and The Netherlands

CNS Drugs https://doi.org/10.1007/s40263-020-00730-8 ORIGINAL RESEARCH ARTICLE Tapering with Pharmaceutical GHB or Benzodiazepines for Detoxification in GHB‑Dependent Patients: A Matched‑Subject Observational Study of Treatment‑as‑Usual in Belgium and The Netherlands Harmen Beurmanjer1,2 · J. J. Luykx3 · B. De Wilde3,4 · K. van Rompaey3 · V. J. A. Buwalda1 · C. A. J. De Jong2 · B. A. G. Dijkstra1,2 · A. F. A. Schellekens2,5 © The Author(s) 2020 Abstract Background The gamma-hydroxybutyric acid (GHB) withdrawal syndrome often has a fulminant course, with a rapid onset and swift progression of severe complications. In clinical practice, two pharmacological regimens are commonly used to counteract withdrawal symptoms during GHB detoxification: tapering with benzodiazepines (BZDs) or tapering with pharmaceutical GHB. In Belgium, standard treatment is tapering with BZDs, while in the Netherlands, pharmaceutical GHB is the preferred treatment method. Though BZDs are cheaper and readily available, case studies suggest GHB tapering results in less severe withdrawal and fewer complications. Objectives This study aimed to compare two treatments-as-usual in tapering methods on withdrawal, craving and adverse events during detoxification in GHB-dependent patients. Methods In this multicentre non-randomised indirect comparison of two treatments-as-usual, patients with GHB dependence received BZD tapering (Belgian sample: n = 42) or GHB tapering (Dutch sample: n = 42, matched historical sample). Withdrawal was assessed using the Subjective and Objective Withdrawal Scales, craving was assessed with a Visual Analogue Scale and adverse events were systematically recorded. Differences in withdrawal and craving were analysed using a linear mixed-model analysis, with ‘days in admission’ and ‘detoxification method’ as fixed factors. Differences in adverse events were analysed using a Chi-square analysis. Results Withdrawal decreased over time in both groups. Withdrawal severity was higher in patients receiving BZD tapering (subjective mean = 36.50, standard deviation = 21.08; objective mean = 8.05, standard deviation = 4.68) than in patients receiving pharmaceutical GHB tapering (subjective mean = 15.90; standard deviation = 13.83; objective mean = 3.72; standard deviation = 2.56). No differences in craving were found. Adverse events were more common in the BZD than the GHB group, especially delirium (20 vs 2.5%, respectively). Conclusions These results support earlier work that BZD tapering might not always sufficiently dampen withdrawal in GHBdependent patients. However, it needs to be taken into account that both treatments were assessed in separate countries. Based on the current findings, tapering with pharmaceutical GHB could be considered for patients with GHB dependence during detoxification, as it has potentially less severe withdrawal and fewer complications than BZD tapering. * Harmen Beurmanjer Harmen.beurmanjer@novadic‑kentron.nl Extended author information available on the last page of the article Vol.:(0123456789) H. Beurmanjer et al. Key Points Tapering with pharmaceutical gamma-hydroxybutyric acid (GHB) led to a milder withdrawal syndrome than tapering with benzodiazepines in patients with GHB use disorder during detoxification. Patients with GHB use disorder had a one in five chance of developing delirium during detoxification when tapering with benzodiazepines, compared with 1 in 40 when tapering with pharmaceutical GHB. There were no differences in GHB craving levels during detoxification between patients with GHB use disorder receiving pharmaceutical GHB tapering or benzodiazepine tapering. 1 Introduction Gamma-hydroxybutyric acid (GHB) is a short-chain fatty acid biosynthetically derived from the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) [1], it binds to GHB and GABA-B receptors [2]. GHB is mainly used in Australia, the USA and Europe [3–5] for its euphoric and sedating effects [6–8]. GHB has a very narrow bandwidth between the plasma concentrations for desired clinical effects and overdose, often resulting in temporary coma [9, 10]. A GHB overdose can however be fatal, especially when combined with other substances [9]. Regular GHB use can lead to GHB use disorder (GUD) [6]. While the prevalence of GHB use is still limited in Europe, between 0.1 and 1.5% of the adult population, it has been rising in the past decade [6]. Little is known about the number of people with GUD, but it is estimated that up to 21% of GHB users develops GUD [10]. GHB use disorder is characterised by frequent GHB administration (every 1–3 h) to prevent withdrawal [6]. The GHB withdrawal syndrome often has a fulminant course, with a rapid onset and swift progression of severe withdrawal symptoms [6, 7]. Withdrawal symptoms include: tremor, nausea, vomiting, tachycardia, insomnia, diaphoresis, anxiety and nystagmus. Adverse events during withdrawal include hypertensive crisis, severe agitation, delirium and epileptic seizures [6]. The severity and complexity of GHB withdrawal pose clinical challenges during detoxification. In clinical practice, two pharmacological treatment regimens are commonly used to counteract withdrawal symptoms during GHB detoxification: tapering with benzodiazepines (BZDs) and tapering with pharmaceutical GHB. Benzodiazepines have an allosteric effect on GABA-A receptors, resulting in an increased sensitivity for GABA [11]. The benefits of BZDs compared with pharmaceutical GHB are the wide availability in medical settings, low costs and that tapering with BZDs allows patients to directly quit using GHB. However, several case studies describe BZD resistance [12], where despite extremely high doses of BZDs, in one case up to 700 mg of diazepam per day, delirium still develops [13, 14]. Others describe the necessity of additional sedating medication, such as phenobarbital [15] and propofol [16], to treat delirium. Pharmaceutical GHB has the same pharmacological properties as ‘street GHB’. GHB-assisted tapering requires up to 12 doses (every 2 h) a day [17]. GHB tapering has been shown to be associated with a high success rate of 85% and limited adverse events in several large non-randomised trials (n = 450). Reported adverse events during detoxification were mainly hypertension (7%) and delirium (2%) [17, 18]. It is suggested that tapering with pharmaceutical GHB might be preferable over BZD treatment, owing to its pharmacological similarity with street GHB. Benzodiazepines mainly act at GABA-A receptors, whereas GHB mainly acts at GHB and GABA-B receptors. Benzodiazepines might therefore be less effective in supressing GHB withdrawal because they target different receptors to GHB. A disadvantage of GHB tapering is its shorter half-life, requiring GHB administration throughout the night, which interferes with sleep. Continued GHB use could also be seen as reinforcing compulsive substance use, potentially maintaining symptoms, such as craving [19] (...truncated)