Individual differences in GHB consumption in a new voluntary GHB self-administration model in outbred rats.

BACKGROUND AND PURPOSE: The use of the recreational drug gamma-hydroxybutyric acid (GHB) has increased over the past decade, concomitantly leading to a higher incidence of GHB use disorder. Evidence-based treatment interventions are hardly available and cognitive effects of long-term GHB use remain elusive. In order to study the development of GUD and the causal effects of chronic GHB consumption, a GHB self-administration model is required. EXPERIMENTAL APPROACH: Long Evans rats had access to GHB in their home cage according to a two-bottle choice procedure for 3 months. Intoxication and withdrawal symptoms were assessed using an automated sensor-based setup for longitudinal behavioral monitoring. Rats were trained in an operant environment according to a fixed ratio (FR) 1, 2, and 4 schedule of reinforcement. Addiction-like behaviors were assessed through progressive ratio-, non-reinforced-, and quinine-adulterated operant tests. In addition, the novel object recognition test and elevated plus maze test were performed before and after GHB self-administration to assess memory performance and anxiety-like behavior, respectively. KEY RESULTS: All rats consumed pharmacologically relevant levels of GHB in their home cage, and their intake remained stable over a period of 3 months. No clear withdrawal symptoms were observed following abstinence. Responding under operant conditions was characterized by strong inter-individual differences, where only a subset of rats showed high motivation for GHB, habitual GHB-seeking, and/or continued responding for GHB despite an aversive taste. Male rats showed a reduction in long-term memory performance 3 months after home-cage GHB self-administration. Anxiety-like behavior was not affected by GHB self-administration. CONCLUSION AND IMPLICATIONS: The GHB self-administration model was able to reflect individual susceptibility for addiction-like behavior. The reduction in long-term memory performance upon GHB self-administration calls for further research into the cognitive effects of chronic GHB use in humans.

Patients' perspectives on tapering programmes for prescription opioid use disorder: a qualitative study.

OBJECTIVES: Approximately 10% of chronic pain patients who receive opioids develop an opioid use disorder (OUD). Tapering programmes for these patients show high drop-out rates. Insight into chronic pain patients' experiences with tapering programmes for prescription OUD could help improve such programmes. Therefore, we investigated the perspectives of chronic pain patients with prescription OUD to identify facilitators and barriers to initiate and complete a specialised OUD tapering programme. DESIGN: A qualitative study using semi-structured interviews on experiences with initiation and completion of opioid tapering was audio recorded, transcribed and subject to directed content analysis. SETTING: This study was conducted in two facilities with specialised opioid tapering programmes in the Netherlands. PARTICIPANTS: Twenty-five adults with chronic pain undergoing treatment for prescription OUD participated. RESULTS: Participants indicated that tapering is a personal process, where willingness and motivation to taper, perceived (medical) support and pain coping strategies have an impact on the tapering outcome. The opportunity to join a medical-assisted tapering programme, shared decision-making regarding tapering pace, tapering location, and receiving medical and psychological support facilitated completion of an opioid tapering programme. CONCLUSIONS: According to patients, a successful treatment of prescription OUD requires a patient-centred approach that combines personal treatment goals with shared decision-making on opioid tapering. Referral to a specialised tapering programme that incorporates opioid rotation, non-judgmental attitudes, and psychological support can create a safe and supportive environment, fostering successful tapering and recovery.

Towards adherence monitoring using breath or oral fluid as a matrix in a methadone maintenance treatment program for patients with a chronic heroin use disorder: Issues and interpretation of the results.

Urine has been the preferred matrix for monitoring heroin and methadone adherence due to its large detection window. Drawbacks such as privacy concerns and adulteration however require other matrices. The study aims to determine if oral fluid and exhaled breath are suitable alternatives for heroin and methadone monitoring and to assess the detection time in exhaled breath. Forty-three participants, all on methadone and heroin-assisted treatment, were studied. Participants were monitored after the first and right before the second dosage of heroin. At both time points, oral fluid and exhaled breath samples were collected with urine at the second time point. All samples were screened for opiates, methadone and other drugs using immunoassay and LC-MS-MS. At the second time point, 98% of oral fluid samples and all exhaled breath samples tested positive for 6-monoacetylmorphine (6-MAM). Regarding morphine detection, the findings were reversed (100% in oral fluid, 98% in exhaled breath). Methadone-related results were 100% positive across all matrices, as expected. Notable is the detection of the heroin marker acetylcodeine in oral fluid and exhaled breath samples, which resulted in relatively low negative predictive value (average 54.6%). Oral fluid and exhaled breath are suitable alternatives for heroin and methadone maintenance monitoring. Clinicians should consider ease of collection, adulteration risk, costs, turn-around time and the substance of interest while choosing a matrix. In addition, even in cases when medicinal heroin is used, medical professionals should be aware of the presence of acetylcodeine in these alternate matrices.

Patients' Perspectives on the Development of Prescription Opioid Use Disorder in Patients with Chronic Non-Cancer Pain.

INTRODUCTION: In the past decade, prescription opioid use increased exponentially and concomitantly opioid use disorders (OUD) are becoming more common. Several risk factors for developing OUD have been identified, but little is known regarding the patients' perspective on developing a prescription OUD. METHODS: We recruited 25 adults undergoing treatment for prescription OUD. In-depth, semi-structured interviews focussed on experiences with long-term opioid use, knowledge and attitudes regarding opioids, and access to opioids. A directed content analysis was conducted on the transcribed interviews using NVivo. RESULTS: Participants showed that the development of an OUD is affected by various factors which could be grouped into three themes: (1) experiences driving initiation, (2) experiences driving continuation, and (3) experiences with prescription OUD. Besides the need for pain management, the dynamics of patient-provider communication, care coordination, provider vigilance, and environmental support all contributed to the way patients used their opioids. CONCLUSION: Patients' experiences illustrate that the first stage of the development of prescription OUD differs from the development of other substance addictions. Negative reinforcement might play a more prominent role in the early phase of prescription opioid use. Patients expressed a lack of guidance, both at the start of use and long-term use, easy access to new prescriptions and a lack of monitoring as main drivers of the development. Poorly controlled pain and subjective stress fuelled continuous opioid use.

An Overview of the Putative Structural and Functional Properties of the GHBh1 Receptor through a Bioinformatics Approach.

The neurotransmitter γ-hydroxybutyric acid (GHB) is suggested to be involved in neuronal energy homeostasis processes, but the substance is also used as a recreational drug and as a prescription medication for narcolepsy. GHB has several high-affinity targets in the brain, commonly generalized as the GHB receptor. However, little is known about the structural and functional properties of GHB receptor subtypes. This opinion article discusses the literature on the putative structural and functional properties of the GHBh1 receptor subtype. GHBh1 contains 11 transmembrane helices and at least one intracellular intrinsically disordered region (IDR). Additionally, GHBh1 shows a 100% overlap in amino acid sequence with the Riboflavin (vitamin B2) transporter, which opens the possibility of a possible dual-function (transceptor) structure. Riboflavin and GHB also share specific neuroprotective properties. Further research into the GHBh1 receptor subtype may pave the way for future therapeutic possibilities for GHB.

Cognitive Impairments in Patients with GHB Use Disorder Predict Relapse in GHB Use.

BACKGROUND: The recreational use of gamma hydroxybutyrate (GHB) is associated with frequent overdoses, coma and the risk of developing GHB use disorder (GUD). Several studies suggest negative effects of GHB use or related comas on cognition. Since relapse rates are high in GUD and cognitive impairment has been associated with relapse in other substance use disorders, we aimed to (1) investigate the prevalence of cognitive impairment before and after detoxification, (2) analyse the relationship between GHB use, comas, and cognitive impairment, and (3) explore the association between cognitive impairment and relapse after detoxification in GUD patients. METHODS: In these secondary analyses of a prospective cohort study, a consecutive series of patients with GUD (n = 103) admitted for detoxification were recruited at six addiction care facilities in the Netherlands. The Montreal Cognitive Assessment (MoCA) was used to screen for cognitive impairments before and after detoxification. The follow-up duration for the assessment of relapse in GHB use was 3 months. RESULTS: A substantial number of patients with GUD screened positive for cognitive impairment before (56.3%) and after (30.6%) detoxification. Impairment on the MoCA memory domain was most frequent (58.8%). Cognitive impairment was not related to the severity of GUD or number of GHB-induced comas. Logistic regression analysis showed that only the memory score independently predicted relapse. DISCUSSION: Cognitive impairment seems highly prevalent among patients with GUD, possibly related to the risk of relapse. The absence of a relationship between the severity of GUD, level of GHB use, the number of GHB-induced comas, and cognitive impairment suggest that other factors may also contribute to the observed cognitive impairment.

Characterization of the GHB Withdrawal Syndrome.

The gamma-hydroxybutyric acid (GHB) withdrawal syndrome can have a fulminant course, complicated by severe complications such as delirium or seizures. Detoxification by tapering with pharmaceutical GHB is a safe way to manage GHB withdrawal. However, a detailed description of the course of the GHB withdrawal syndrome is currently lacking. This study aimed to (1) describe the course of GHB withdrawal symptoms over time, (2) assess the association between vital signs and withdrawal symptoms, and (3) explore sex differences in GHB withdrawal. In this observational multicenter study, patients with GHB use disorder (n = 285) were tapered off with pharmaceutical GHB. The most reported subjective withdrawal symptoms (SWS) were related to cravings, fatigue, insomnia, sweating and feeling gloomy. The most prevalent objective withdrawal symptoms (OWS) were related to cravings, fatigue, tremors, sweating, and sudden cold/warm feelings. No association between vital signs and SWS/OWS was found. Sex differences were observed in the severity and prevalence of specific withdrawal symptoms. Our results suggest that the GHB withdrawal syndrome under pharmaceutical GHB tapering does not strongly differ from withdrawal syndromes of other sedative drugs. The lack of association between vital signs and other withdrawal symptoms, and the relative stability of vitals over time suggest that vitals are not suitable for withdrawal monitoring. The reported sex differences highlight the importance of a personalized approach in GHB detoxification.

Psychometric properties of the Montreal Cognitive Assessment (MoCA) in healthy participants aged 18-70.

Objectives: The Montreal Cognitive Assessment (MoCA) is a cognitive screen, available in three alternate versions. Aims of the current study were to examine the effects of age, education and intelligence on MoCA performance and to determine the alternate-form equivalence and test-retest reliability of the MoCA, in a group of healthy participants.Method: In 210 participants, two MoCA versions and an estimator for premorbid intelligence were administered at two time points.Results: Age, education and estimated premorbid intelligence correlated significantly with the total score (MoCA-TS) and the Memory Index Score (MoCA-MIS). Systematic differences between MoCA version 7.1 and alternate versions 7.2 and 7.3 were only found for the items animal naming, abstract reasoning and sentence repetition. Test-retest reliability of the MoCA-TS was good between 7.1 and 7.2 (ICC: 0.64) and excellent between 7.1 and 7.3 (ICC: 0.82). For the MoCA-MIS, coefficients were poor (ICC: 0.32) to fair (ICC: 0.48), respectively.Conclusion: Adequate norms are needed that take the effects of age, education and intelligence on MoCA performance into account. All three MoCA versions are largely equivalent based on MoCA-TS and the test-retest reliabilities show that this score is suitable to monitor cognitive change over time. Comparisons of the domain-specific scores should be interpreted with caution.Key pointsThe MoCA total score is a reliable cognitive measure.All three MoCA versions are largely equivalent.Age, education and intelligence are predictors of MoCA performance in healthy participants.Future studies should focus on collecting normative data for age, education and intelligence for use in clinical practice.

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.

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 GHB-dependent 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.

A Qualitative Approach in Understanding Illness Perception and Treatment Needs in Patients with Gamma Hydroxybutyrate Use Disorder.

BACKGROUND: The party drug gamma hydroxybutyrate (GHB) is highly addictive. GHB use disorder (GUD) has poor treatment outcome, with relapse rates over 60% within 3 months after detoxification. In order to get a better understanding of the limited treatment success, we explored GUD patients' illness perceptions and treatment needs. METHODS: In a qualitative cross-sectional observational study, using a semi-structured interview based on the works of Kleinmann, illness perceptions were explored among treatment seeking GUD patients (n = 20). The analysis was based on the principles of Grounded Theory by the 2 interviewers and an independent researcher. RESULTS: GUD patients had mainly positive views toward GHB. GHB was perceived as strongly rewarding and perceived as the solution to psychosocial problems, rather than the cause. After repeated readmissions, GUD patients perceived themselves as addicted to GHB and GHB use as more problematic. They reported a need for personalized treatment goals, which were mainly aimed toward dealing with psychiatric symptoms and social reintegration. CONCLUSION: GUD shares many characteristics with other substance use disorders, in line with gradual development from positive reinforcement in early-stage GUD to negative reinforcement in later stages of more compulsive GHB use. Future studies should investigate whether personalization of treatment goals, such as social reintegration, lead to better treatment outcomes.

Baclofen to Prevent Relapse in Gamma-Hydroxybutyrate (GHB)-Dependent Patients: A Multicentre, Open-Label, Non-Randomized, Controlled Trial.

BACKGROUND: Gamma-hydroxybutyrate (GHB) dependence is associated with a severe, potentially lethal, withdrawal syndrome and relapse rates as high as 60% within 3 months of detoxification. Baclofen has been shown to decrease self-administration of GHB in mice and reduce relapse in a case series of GHB-dependent patients. Controlled studies on the effectiveness of baclofen to prevent relapse in GHB-dependent patients are lacking. AIM: The aim of this study was to assess effectiveness of baclofen in preventing relapse in GHB-dependent patients. METHODS: This was an out-patient, multicentre, open-label, non-randomized, controlled trial in GHB-dependent patients (n = 107) in the Netherlands. Treatment as usual (TAU, n = 70) was compared with TAU plus baclofen 45-60 mg/day for 3 months (n = 37). Outcome measures were rates of lapse (any use) and relapse (using GHB on average once a week or more), based on self-report. Side effects were monitored with a baclofen side-effects questionnaire. Treatment groups were compared using Chi square analyses, with both per-protocol (PP) and intention-to-treat (ITT) analyses. RESULTS: GHB-dependent patients treated with baclofen after detoxification showed no reduced lapse rates, but reduced relapse and dropout rates, compared with patients receiving TAU only (24 vs 50%). While both ITT and PP analyses revealed similar results, the effectiveness of baclofen prescribed PP was slightly higher than in ITT analysis. Patients reported overall limited side effects, with the most frequently reported being feeling tired (28%), sleepiness (14%) and feeling depressed (14%). No serious adverse events were reported. CONCLUSIONS: This study showed potential effectiveness of baclofen in preventing relapse in patients with GHB dependence after detoxification. Though promising, future studies with longer follow-up and a randomized double-blind design should confirm these findings before recommendations for clinical practice can be made. CLINICAL TRIAL REGISTRATION: Netherlands Trial Register with number NTR4528.

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.