An Australian retrospective observational cohort comparison of the use of long-acting injectable buprenorphine products.

INTRODUCTION: In early 2019, Australia became the first jurisdiction to have two brands of long-acting injectable buprenorphine (LAI-B) products available. Previously published studies have mostly followed pre-planned dosing schedules and seldom compared use of both products. This study presents a retrospective analysis of the "real-world" dosing requirements of patients on LAI-B. METHOD: Five clinics provided data for patients commenced on LAI-B between 1 February 2019 and 30 June 2021 for buprenorphine doses and intervals between dosing. The study recorded basic demographic data including age, gender, and previous dose of transmucosal buprenorphine. The Local Institutional Ethics Committee provided approval. RESULTS: Over 3600 individual doses (59 % Buvidal® & 41 % Sublocade®) were administered to 340 individual patients (median age 40 years, 63 % male), with the longest duration in treatment of 856 days. Median estimated duration of a treatment episode was 16.5 months (95%CI: 14.3-19.1). Approximately 94 % transferred from transmucosal buprenorphine (median daily dose 16 mg, range 2-32 mg). Most common LAI-B doses were Sublocade® 100 mg (22.4 %) and Buvidal® Monthly 128 mg (21.5 %); Buvidal® Weekly 24 mg (0.8 %) was least used. 13 % transitioned between LAI-B products. Weekly dose intervals were a median 7 days and monthly doses were given a median of 28 days apart. Overall, 36 % discontinued LAI-B before the census date. DISCUSSIONS AND CONCLUSIONS: Most patients who started LAI-B remained in treatment, with similar rates in both products. A small, but appreciable number of people switched brands, suggesting that it remains important to have treatment options available.

Cytochrome P450-2D6 activity in people with codeine use disorder.

Compound-analgesics containing codeine (CACC) have been a common source of codeine for people seeking opioid replacement therapy (ORT) for codeine use disorder (CUD). Our previous work demonstrated no relationship between pre-treatment CACC and ORT buprenorphine doses; we hypothesised that CYP2D6 activity would partially account for this disconnection. One hundred six participants with CUD were compared to a published population sample of 5408 Australian patients. Mean age of participants with CUD at treatment entry was 35 years, with mean 6.1 years duration of CUD. Mean codeine dose was 660 mg/day (range 40-2700 mg). Mean calculated CYP2D6 activity scores were significantly higher in the codeine group (CUD 1.65 + 0.63 vs. Gen pop 1.39 + 0.65, Wilcoxon W = 347,001, p < 0.001). Pre-treatment CACC dose weakly predicted sublingual buprenorphine doses overall; there was a stronger relationship within ultrarapid metabolisers. While normal and ultrarapid metabolisers of codeine were more likely to have a diagnosis of CUD, poor or intermediate CYP2D6 metaboliser status may protect against CUD.

Telephone-based motivational interviewing enhanced with individualised personality-specific coping skills training for young people with alcohol-related injuries and illnesses accessing emergency or rest/recovery services: a randomized controlled trial (QuikFix).

BACKGROUND AND AIMS: Recent meta-analyses of motivational interviewing (MI) for reducing risky alcohol use in young people have reported modest effects. Few studies have targeted individual patient factors to increase MI effectiveness. This study determined if MI enhanced with individualised personality-specific coping skills training (QuikFix) was more efficacious than standard MI or an assessment feedback/information (AF/I) control among young people with alcohol-related injuries or illnesses. DESIGN AND SETTING: Single-centre, single-blind, three-group superiority randomized controlled trial with 1-, 3-, 6- and 12-months follow-ups. Telephone intervention, Brisbane, Australia. PARTICIPANTS: A total of 398 young people (16-25 years; M age = 20.30 years, SD = 2.12; 54% female) with alcohol-related injuries and/or illnesses were recruited from an emergency department (ED) or rest/recovery service (RRS). MEASURES: The primary outcome was total standard (10 g ethanol) drinks in the past month (Timeline Follow back [TLFB]) at 12 months (primary time point). Secondary outcomes were total drinking days and standard drinks per drinking day (TLFB) in the past month and the frequency of alcohol-related problems in the past 3 months (Rutgers Alcohol Problem Index). INTERVENTIONS: Young people were randomized to two sessions of QuikFix enhanced with individualised personality-specific coping skills training (n = 132), two sessions of MI (n = 136) or one session of AF/I (n = 130), all delivered by telehealth. FINDINGS: QuikFix resulted in greater reductions (all P < 0.0017) in the primary outcome of total standard drinks (M = 19.50, CI 99.75% = [11.31, 27.68]) than both MI (M = 32.61, CI 99.75% = [24.82, 40.40]; Cohen's D = 0.40) and AF/I (M = 34.12, CI 99.75% = [26.59, 41.65]; D = 0.45) at 12 months (retention n = 324/398, 81%). QuikFix had greater reductions on drinking days (M = 3.16, CI 99.75% = [2.37, 3.96]) than both MI (M = 4.53, CI 99.75% = [3.57, 5.48];D = 0.38) and AF/I (M = 4.69, CI 99.75% = [3.73, 5.65];D = 0.42) and fewer drinks per drinking day (M = 5.02, CI 99.75% = [3.71, 6.33]) than AF/I (M = 7.15, CI 99.75% = [5.93, 8.38;D = 0.47) at 12 months. CONCLUSIONS: Young people with alcohol-related injuries and/or illnesses who attended ED and rest/recovery services and received an individualised personality-specific coping skills training intervention (QuikFix) had greater reductions in the amount of alcohol consumed at 12 months compared with those who received motivational interviewing or an assessment feedback/information intervention.

Brain opioid receptor binding in early abstinence from alcohol dependence and relationship to craving: an [11C]diprenorphine PET study.

The importance of the opioid receptor system in substance dependence is increasingly recognised. We used PET with the non-selective tracer [11C]diprenorphine to examine opioid receptor binding in early abstinence from alcohol dependence and the relationship to craving. We recruited 11 alcohol dependent patients and 13 controls. Subjects underwent one [11C]diprenorphine PET scan in early abstinence from dependent alcohol use (approximately 2 weeks) and 2 months later if continuously abstinent. Global and regional [11C]diprenorphine volumes of distribution (VD) were increased in alcohol dependent patients compared with controls but did not reach significance. We demonstrated a correlation between global and regional [11C]diprenorphine VD and craving in alcohol dependent patients which persisted in the anterior cingulate cortex into extended abstinence. This confirms previous work showing increased opioid receptor availability in early abstinence from substances of abuse and correlation with craving suggesting that the opioid system plays a fundamental role in this phase of addiction.

Brain dopamine response in human opioid addiction.

BACKGROUND: Drugs of dependence cause dopamine release in the rat striatum. Human neuroimaging studies have shown an increase in dopamine in the equivalent region in response to stimulants and other drugs. AIMS: We tested whether opioids provoke dopamine release and its relationship to the subjective experience. METHOD: In two combined studies 14 heroin addicts on methadone maintenance treatment underwent two positron emission tomography brain scans of the dopamine system using [(11)C]-raclopride following an injection of placebo and either 50 mg intravenous diamorphine or 10 mg subcutaneous hydromorphone in a double-blind, random order design. RESULTS: Both opioids produced marked subjective and physiological effects, but no measurable change in [(11)C]-raclopride binding. CONCLUSIONS: The absence of a dopamine response to opioid agonists contrasts with that found with stimulant drugs and suggests dopamine may not play the same role in addiction to opioids. This questions the role of dopamine in the subjective experience of heroin in opioid addicts.

Reduced thalamic grey matter volume in opioid dependence is influenced by degree of alcohol use: a voxel-based morphometry study.

The aim of this study was to make a comparison of brain structure between a group of opioid-dependent subjects and healthy controls. We report the results of an ;optimized' voxel-based morphometry study on a sample of nine opioid-dependent subjects with no comorbid substance misuse disorders versus 21 healthy controls. We found a significant reduction in grey matter volume of the thalamus after controlling for age and total grey matter volume. Regression analysis of substance use variables in the opioid-dependent sample shows that only level of alcohol use negatively predicts grey matter volume for this region of difference. We suggest that level of nondependent alcohol use could influence reduced thalamic grey matter volume in opioid-dependent subjects.

Brain opioid receptor binding in early abstinence from opioid dependence: positron emission tomography study.

BACKGROUND: Although opioid receptor function in humans is clearly reduced during opioid dependence, what happens to the receptor in early abstinence is not understood. AIMS: This study sought to examine changes in opioid receptor availability in early abstinence from opioid dependence. METHOD: Ten people with opioid dependence who had completed in-patient detoxification and 20 healthy controls underwent [11C]-diprenorphine positron emission tomography. Clinical variables were assessed with structured questionnaires. Opioid receptor binding was characterised as the volume of distribution of [11C]-diprenorphine using a template of predefined brain volumes and an exploratory voxel-by-voxel analysis. RESULTS: Compared with controls, participants with opioid dependence had increased [11C]-diprenorphine binding in the whole brain and in 15 of the 21 a priori regions studied. CONCLUSIONS: This study suggests that opioid receptor binding is increased throughout the brain in early abstinence from dependent opioid use. These data complement the findings in cocaine and alcohol dependence.

Using [11C]diprenorphine to image opioid receptor occupancy by methadone in opioid addiction: clinical and preclinical studies.

Substitute methadone prescribing is one of the main modes of treatment for opioid dependence with established evidence for improved health and social outcomes. However, the pharmacology underpinning the effects of methadone is little studied despite controversies about dosing in relation to outcome. We therefore examined the relationship between methadone dose and occupation of opioid receptors in brain using the positron emission tomography (PET) radioligand [(11)C]diprenorphine in humans and rats. Eight opioid-dependent subjects stable on their substitute methadone (18-90 mg daily) had an [(11)C]diprenorphine PET scan at predicted peak plasma levels of methadone. These were compared with eight healthy controls. No difference in [(11)C]diprenorphine binding was found between the groups, with no relationship between methadone dose and occupancy. Adult male Sprague-Dawley rats that had been given an acute i.v. injection of methadone hydrochloride (0.35, 0.5, 0.7, or 1.0 mg kg(-1)) before [(11)C]diprenorphine showed a dose-dependent increase in biodistribution but no reduction in [(11)C]diprenorphine binding. We suggest that the lack of a dose-dependent relationship between methadone dose, either given chronically in human or acutely in rat, and occupancy of opioid receptor measured with [(11)C]diprenorphine PET is related to efficacy of this opioid agonist at very low levels of opioid receptor occupancy. This has implications for understanding the actions of methadone in comparison with other opioid drugs such as partial agonists and antagonists.

The clinical use of buprenorphine in opiate addiction: evidence and practice.

Buprenorphine is a partial µ-opioid receptor agonist that is being increasingly used in clinical practice in the treatment of opioid dependence in the UK, USA, and, elsewhere. Its unique pharmacological properties mean it is a relatively safe drug, it can be given by alternate day dispensing, and it is associated with relatively mild symptoms on withdrawal. The interpretation of the research literature on buprenorphine is however, complex, and often appears to be in conflict with how buprenorphine is used in clinical practice. This article describes these apparent contradictions, their likely explanations, and how these may further inform our clinical practice. The article also describes the clinically relevant pharmacological properties of buprenorphine, compares it to methadone, relates the evidence to clinical experience, and provides practical advice on how to manage the most common clinical techniques. The best quality evidence suggests that very rapid buprenorphine induction is not associated with a higher drop-out rate than methadone, that buprenorphine is probably as good as methadone for maintenance treatment, and is superior to methadone and α-2 adrenergic agonists for detoxification. However, buprenorphine cannot yet be considered the 'gold standard' treatment for opiate dependence because of the higher drop-out rates that may occur on induction using current techniques, its high-cost relative to methadone, and because the place of buprenorphine in treatment is still continuing to evolve.

Functional connectivity analysis of the neural circuits of opiate craving: "more" rather than "different"?

We investigated the functional connectivity of brain regions activated during opiate craving. Previously we used recorded autobiographical scripts to induce opiate craving in 12 abstinent opiate-dependent subjects while they were undergoing positron emission tomography (PET) scanning using the regional cerebral blood flow (rCBF) tracer H2 15O. SPM99 was used to examine the connectivity patterns associated with the primary brain regions activated in response to drug-craving memories (anterior cingulate, AC) and correlated with opiate craving (orbitofrontal cortex, OFC). Two separate connectivity patterns were identified associated with the OFC and AC regions. The AC region was associated with activity in the left temporal region. The left OFC region activity correlated with activity in the right OFC, and left parietal and posterior insular regions. There was also a positive association with the hippocampus and brainstem. Both the AC and OFC regions showed a negative association with posterior visual areas. We suggest that the patterns of functional connectivity reflect the ability of drug-related stimuli to activate attentional and memory circuits to a greater degree than non-drug-related stimuli. This argues that neural circuits of dependence and craving are not specific "craving" or "addiction" brain regions but are "normal" circuits activated to a greater degree.

Brain imaging studies in human addicts.

Addiction provides fertile ground for the application of the tools of functional neuroimaging. They can be divided into studies of neural activity and neurotransmitter function. Using the former, both opiates and stimulants cause a global decrease in brain metabolism. Against this background, acute doses have still been shown to produce relative increases in brain activation in specific regions, e.g., anterior cingulate, thalamus, and amygdala. These are also regions frequently found with cue-exposure paradigms. Our own work on cue-exposure has shown that heroin-related stimuli provoke activation of the anterior cingulate and orbitofrontal regions. Brain metabolism has also been shown to increase in drug withdrawal from alcohol and cocaine. Neurotransmitter studies have shown that in alcohol dependence, GABA(A)-benzodiazepine (GABA-BDZ) receptors are reduced in a number of brain regions and suggest that there may be 'capacity within the system' in some benzodiazepine functions, but tolerance to others, e.g., time asleep. Finally, 11C-Ro15-4513 offers new opportunities for imaging the GABA-BDZ system.