A phase 3 randomised double-blind placebo-controlled trial of mirtazapine as a pharmacotherapy for methamphetamine use disorder: a study protocol for the Tina Trial.

BACKGROUND: There are no approved pharmacotherapies for methamphetamine use disorder. Two preliminary phase 2 randomised controlled trials have found mirtazapine, a tetracyclic antidepressant, to be effective in reducing methamphetamine use. The proposed Tina Trial is the first phase 3 placebo-controlled randomised trial to examine the effectiveness and safety of mirtazapine as an outpatient pharmacotherapy for methamphetamine use disorder. METHODS: This is a multi-site phase 3 randomised, double-blind, placebo-controlled parallel trial. Participants are randomly allocated (1:1) to receive either mirtazapine (30 mg/day for 12 weeks) or matched placebo, delivered as a take-home medication. The target population is 340 people aged 18-65 years who have moderate to severe methamphetamine use disorder. The trial is being conducted through outpatient alcohol and other drug treatment clinics in Australia. The primary outcome is measured as self-reported days of methamphetamine use in the past 4 weeks at week 12. Secondary outcomes are methamphetamine-negative oral fluid samples, depressive symptoms, sleep quality, HIV risk behaviour and quality of life. Other outcomes include safety (adverse events), tolerability, and health service use. Medication adherence is being monitored using MEMS® Smart Caps fitted to medication bottles. DISCUSSION: This trial will provide information on the safety and effectiveness of mirtazapine as a pharmacotherapy for methamphetamine use disorder when delivered as an outpatient medication in routine clinical practice. If found to be safe and effective, this trial will support an application for methamphetamine use disorder to be included as a therapeutic indication for the prescription of mirtazapine. TRIAL REGISTRATION: Australian and New Zealand Clinical Trials Registry ACTRN12622000235707. Registered on February 9, 2022.

96-week retention in treatment with extended-release subcutaneous buprenorphine depot injections among people with opioid dependence: Extended follow-up after a single-arm trial.

BACKGROUND: The most recent formulation of buprenorphine treatment is extended-release depot injections (BUP-XR) that are administered subcutaneously by health care professionals. This study aimed to observe treatment outcomes of BUP-XR delivered in standard practice during a 96-week follow-up period in a community setting. METHODS: This study is an extension of the CoLAB study, a prospective single-arm, multicentre, open label trial (N=100, 7 sites in Australia) among people with opioid dependence who received monthly injections of BUP-XR to evaluate the retention in treatment. Participants were followed for 96 weeks, comprising 48 weeks of the CoLAB study followed by a 48-week extension. RESULTS: Of 100 participants at baseline, 47 were retained on BUP-XR at 96 weeks. The median time retained on monthly depot was 90 weeks. Heroin use (adjusted OR=0.19, P=0.012) in the month prior to baseline was associated with lower odds of retention on BUP-XR. Older age at first opioid use (adjusted OR= 1.08, P=0.009) and longer duration in OAT at baseline (adjusted OR= 1.12, P=0.001) were associated with increased retention. Prevalence of past four-weeks opioid use was estimated at 4% at 96 weeks of treatment (prevalence 0.04, 95%CI: 0.00-0.11) compared to 15% at baseline. Quality of life and medication treatment satisfaction improved over time for those retained in treatment. CONCLUSION: This is one of the few studies to describe long term (96 week) retention in treatment with BUP-XR in a community setting. It displayed retention rates with 47% of participants completing 96 weeks of treatment with BUP-XR. Patient reported outcomes suggest improvements in client wellbeing. FUNDING: Indivior.

Buprenorphine versus methadone for the treatment of opioid dependence: a systematic review and meta-analysis of randomised and observational studies.

BACKGROUND: Opioid dependence is associated with substantial health and social burdens, and opioid agonist treatment (OAT) is highly effective in improving multiple outcomes for people who receive this treatment. Methadone and buprenorphine are common medications provided as OAT. We aimed to examine buprenorphine compared with methadone in the treatment of opioid dependence across a wide range of primary and secondary outcomes. METHODS: We did a systematic review and meta-analysis in accordance with GATHER and PRISMA guidelines. We searched Embase, MEDLINE, CENTRAL, and PsycINFO from database inception to Aug 1, 2022; clinical trial registries and previous relevant Cochrane reviews were also reviewed. We included all RCTs and observational studies of adults (aged ≥18 years) with opioid dependence comparing treatment with buprenorphine or methadone. Primary outcomes were retention in treatment at 1, 3, 6, 12, and 24 months, treatment adherence (measured through doses taken as prescribed, dosing visits attended, and biological measures), or extra-medical opioid use (measured by urinalysis and self-report). Secondary outcomes were use of benzodiazepines, cannabis, cocaine, amphetamines, and alcohol; withdrawal; craving; criminal activity and engagement with the criminal justice system; overdose; mental and physical health; sleep; pain; global functioning; suicidality and self-harm; and adverse events. Single-arm cohort studies and RCTs that collected data on buprenorphine retention alone were also reviewed. Data on study, participant, and treatment characteristics were extracted. Study authors were contacted to obtain additional data when required. Comparative estimates were pooled with use of random-effects meta-analyses. The proportion of individuals retained in treatment across multiple timepoints was pooled for each drug. This study is registered with PROSPERO (CRD42020205109). FINDINGS: We identified 32 eligible RCTs (N=5808 participants) and 69 observational studies (N=323 340) comparing buprenorphine and methadone, in addition to 51 RCTs (N=11 644) and 124 observational studies (N=700 035) that reported on treatment retention with buprenorphine. Overall, 61 studies were done in western Europe, 162 in North America, 14 in north Africa and the Middle East, 20 in Australasia, five in southeast Asia, seven in south Asia, two in eastern Europe, three in central Europe, one in east Asia, and one in central Asia. 1 040 827 participants were included in these primary studies; however, gender was only reported for 572 111 participants, of whom 377 991 (66·1%) were male and 194 120 (33·9%) were female. Mean age was 37·1 years (SD 6·0). At timepoints beyond 1 month, retention was better for methadone than for buprenorphine: for example, at 6 months, the pooled effect favoured methadone in RCTs (risk ratio 0·76 [95% CI 0·67-0·85]; I·=74·2%; 16 studies, N=3151) and in observational studies (0·77 [0·68-0·86]; I·=98·5%; 21 studies, N=155 111). Retention was generally higher in RCTs than observational studies. There was no evidence suggesting that adherence to treatment differed with buprenorphine compared with methadone. There was some evidence that extra-medical opioid use was lower in those receiving buprenorphine in RCTs that measured this outcome by urinalysis and reported proportion of positive urine samples (over various time frames; standardised mean difference -0·20 [-0·29 to -0·11]; I·=0·0%; three studies, N=841), but no differences were found when using other measures. Some statistically significant differences were found between buprenorphine and methadone among secondary outcomes. There was evidence of reduced cocaine use, cravings, anxiety, and cardiac dysfunction, as well as increased treatment satisfaction among people receiving buprenorphine compared with methadone; and evidence of reduced hospitalisation and alcohol use in people receiving methadone. These differences in secondary outcomes were based on small numbers of studies (maximum five), and were often not consistent across study types or different measures of the same constructs (eg, cocaine use). INTERPRETATION: Evidence from trials and observational studies suggest that treatment retention is better for methadone than for sublingual buprenorphine. Comparative evidence on other outcomes examined showed few statistically significant differences and was generally based on small numbers of studies. These findings highlight the imperative for interventions to improve retention, consideration of client-centred factors (such as client preference) when selecting between methadone and buprenorphine, and harmonisation of data collection and reporting to strengthen future syntheses. FUNDING: Australian National Health and Medical Research Council.

Characteristics and circumstances of volatile solvent misuse-related death in Australia, 2000-2021.

INTRODUCTION: Volatile solvent misuse-related death is associated with neuropsychiatric, cardiovascular, respiratory and renal pathology, as well as sudden death. The study aimed to determine: (1) the circumstances of death and case characteristics of volatile solvent misuse-related death in Australia, 2000-2021; (2) the toxicological profile of cases; and (3) the major autopsy findings. METHODS: Retrospective study of volatile solvent misuse-related death in Australia, 2000-2021 retrieved from the National Coronial Information System. FINDINGS: One hundred and sixty-four cases were identified, 79.9% male, mean age 26.5 years (8.5% aged 40 years or older). Circumstances of death were unintentional toxicity (61.0%), unintentional asphyxia (20.1%), intentional self-harm (12.2%) and traumatic accident (6.7%). The most commonly reported acute presentation prior to death was sudden collapse (22 of 47 witnessed events). The most frequently used solvents at the fatal incident were gas fuels (35.4%), gasoline (petrol) (19.5%) adhesives/paints (19.5%), aerosol propellants (12.8%), and volatile anaesthetics (12.8%). The most commonly detected volatile substances were butane (40.7%), toluene (29.6%), and propane (25.9%). Cannabis was present in 27.6% and alcohol in 24.6%. The prevalence of acute pneumonia amongst autopsied cases was low (5.8%) which, together with reports of sudden collapse, suggests that in many cases, death was extremely rapid. There were low levels of major organ pathology. CONCLUSIONS: While the average age of volatile solvent misuse-related death was in the mid-twenties, a substantial proportion occurred amongst people aged 40 years or older. Reflecting availability, gas fuels predominated. In many cases, death appeared to have been rapid.

Presentations to the emergency department with self-harm or suicidal behaviours: A role for digital mental health services?

Emergency Department (ED) is an important site for assessing people presenting with self-harm or suicidal behaviors. Digital mental health services (DMHS) offer evidence-based interventions for mental health issues, but are often under-utilised, and information about them is rarely provided in ED. This feasibility study explored whether offering information about a DMHS to individuals presenting to ED with self-harm/suicidal behaviors resulted in self-enrolment in DMHS interventions for anxiety, depression and/or chronic pain. METHODS: all individuals aged 18+ presenting with self-harm/suicidal behaviors to a metropolitan ED were screened for symptoms of anxiety, depression and/or chronic pain. Those with these symptoms were invited to participate in a study investigating enrolment with a DMHS. Study participants were provided with information about DMHS and followed up at one month. RESULTS: 260 individuals presented with self-harm/suicidal behaviors over the 6-month study period. Many reported low mood (73.5%, n = 191) anxiety (67.2%, n = 174) and/or chronic pain (18.5%, n = 48). Half of those eligible for DMHS agreed at point of ED discharge to be contacted about participation in the DMHS study (51.4%, n = 108). One-third of these participated in the study (35.2%, n = 38). Rates of past-month high-risk SB (65.8%, n = 25), depression (92.1%, n = 35), anxiety (78.9%, n = 30) and chronic pain (57.9%, n = 22) were very high. Of these, 39.5% (n = 15) self-enrolled with the DMHS; almost all (80.0%, n = 13) engaged with an online intervention. CONCLUSIONS: A subset of people presenting to emergency department with suicidal behaviors will engage with DMHS. Better understanding is needed of factors contributing to uptake of DMHS in this group.

Examining the cost and impact of dosing fees among clients in opioid agonist treatment: Results from a cross-sectional survey of Australian treatment clients.

INTRODUCTION: Opioid agonist treatment (OAT) clients frequently bear costs associated with their treatment, including dosing fees. This study aimed to explore the financial and social impact of dosing fees upon clients. METHODS: Cross-sectional survey of people who use opioids regularly (N = 402) between December 2017 and March 2018, conducted in Australia. Dosing fees were calculated and expressed as percentage of income, by OAT type. Consequences and strategies for difficulties making payments were examined as proportions. RESULTS: A total of N = 360 participants had ever been in OAT and N = 245 participants currently engaged in OAT reported data on dosing fees, of them 53% (n = 129) reported paying dosing fees. Compared to clients with high levels of dosing supervision, those with moderate or low levels of supervision were more likely to pay dosing fees. The median 28-day dosing fee was AUD$110 (interquartile range AUD$80); median 28-day income was AUD$1520 (interquartile range AUD$700). For those who paid dosing fees, the fee comprised <10% of total monthly income for 70% of participants; however, 23% of participants paid fees comprising 10% to <20%, and 7% of participants paid fees comprising 20% or more of monthly income. Among those that had ever been in OAT, 72% experienced difficulties in paying treatment costs; 36% left treatment earlier than intended and 25% had been excluded due to payment difficulties. DISCUSSION AND CONCLUSIONS: Negative consequences of treatment costs to clients, particularly dosing fees, are evident. These costs impact treatment access and retention that may negatively impact clients' physical health, mental health and social wellbeing.

Who would try (or use more) cannabis if it were legal?

INTRODUCTION: This study sought to determine: (i) whether decriminalisation of cannabis use would increase the proportion who would try the drug; and (ii) the proportion who would use more cannabis; and (iii) explore their characteristics. METHODS: Australian National Drug Strategy Household surveys were used to address (i)-(iii). Significant independent predictors of (i) and (ii) were identified using logistic regression. RESULTS: An estimated 4.2% of the population aged 14 and over (n = 882 708) who have never tried cannabis before would try it, if use of the drug were made legal, while 2.6% of the population aged 14 and over (537 000) would use more cannabis if its use were made legal. Respondents were more likely to say they would try cannabis if they were male, younger or suffered from a mild, moderate and/or severe level of psychological stress. Respondents were more likely to say they would use more cannabis if they were male, younger, psychologically stressed and not currently frequent users of the drug. DISCUSSION AND CONCLUSIONS: Decriminalisation of cannabis use is likely to result in an increase in consumption of the drug among young people with mental health problems. If cannabis use is decriminalised, Australian State and Territory Governments should make provision for a possible increase in demand for drug treatment and for public education on the risks associated with frequent/prolonged cannabis use.

Barbiturate-related hospitalisations, drug treatment episodes, and deaths in Australia, 2000-2018.

OBJECTIVES: To determine the characteristics and population rates of barbiturate-related hospitalisations, treatment episodes, and deaths in Australia, 2000-2018. DESIGN, SETTING: Analysis of national data on barbiturate-related hospitalisations (National Hospital Morbidity Database, 1999-2000 to 2017-18), drug treatment episodes (Alcohol and Other Drug Treatment Services National Minimum Data Set, 2002-03 to 2017-18), and deaths (National Coronial Information System, 2000-01 to 2016-17). MAIN OUTCOME MEASURES: Population rates directly age-standardised to the 2001 Australian standard population; average annual percentage change (AAPC) in rates estimated by Joinpoint regression. RESULTS: We identified 1250 barbiturate-related hospitalisations (791 cases of deliberate self-harm [63%]), 993 drug treatment episodes (195 cases with barbiturates as the principal drug of concern [20%]), and 511 deaths during the respective analysis periods. The barbiturate-related hospitalisation rate declined from 0.56 in 1999-2000 to 0.14 per 100 000 population in 2017-18 (AAPC, -6.0%; 95% CI, -7.2% to -4.8%); the declines in hospitalisations related to accidental poisoning (AAPC, -5.8%; 95% CI, -9.1% to -2.4%) and intentional self-harm (AAPC, -5.6%; 95% CI, -6.9% to -4.2%) were each statistically significant. Despite a drop from 0.67 in 2002-03 to 0.23 per 100 000 in 2003-04, the drug treatment episode rate did not decline significantly (AAPC, -6.7%; 95% CI, -16% to +4.0%). The population rate of barbiturate-related deaths increased from 0.07 in 2000-01 to 0.19 per 100 000 population in 2016-17 (AAPC, +9.3%; 95% CI, +6.2-12%); the rate of intentional self-harm deaths increased (AAPC, +11%; 95% CI, +7.4-15%), but not that of accidental deaths (AAPC, -0.3%; 95% CI, -4.1% to +3.8%). CONCLUSIONS: While prescribing and community use of barbiturates has declined, the population rate of intentional self-harm using barbiturates has increased. The major harm associated with these drugs is now suicide.

Economic analysis of out-of-pocket costs among people in opioid agonist treatment: A cross-sectional survey in three Australian jurisdictions.

BACKGROUND: Out-of-pocket costs for opioid agonist treatment (OAT) constitute a barrier to treatment entry and retention.This study examines OAT clients' total out-of-pocket costs (including dispensing fees, travel costs and OAT-related appointment costs) in different treatment settings (public clinics, community pharmacies, and private clinics). METHODS: Cross-sectional survey of 402 people with opioid drug use (OUD) in New South Wales (NSW), Victoria (VIC), Tasmania (TAS), Australia; 266 clients (66%) currently receiving methadone, buprenorphine or buprenorphine-naloxone treatment were asked about dispensing fees, travel costs and OAT-related appointment costs in the past 28 days. A two-part regression model was used to deal with non-normal distributions of costing data (right skew and excess zeros). RESULTS: Among clients currently receiving OAT, 87% paid out-of-pocket costs. Among those who paid out-of-pocket costs (N=194), travel costs accounted for more than half of total costs (52%), followed by dispensing fees (44%). The mean monthly total out-of-pocket costs were AU$135 (SD: AU$121) for public clinics, AU$161 (SD: AU$110) to AU$214 (SD: AU$166) for community pharmacies and AU$355 (SD: AU$159) for private clinics. Compared to participants in NSW private clinics, those at public clinics paid one third the total out-of-pocket costs (coefficient = 0.33; 95%CI = 0.23-0.48) and those at NSW, TAS, VIC pharmacies paid approximately half the costs (coefficient = 0.58; 95%CI = 0.42-0.79; coefficient = 0.51; 95%CI = 0.36-0.72; coefficient = 0.47; 95%CI = 0.34-0.66, respectively). People in OAT for more than a year paid half the total out-of-pocket costs, compared with those in OAT less than a year (coefficient = 0.49, 95%CI = 0.31-0.77). CONCLUSIONS: Participants in the current study spent one-eighth of their income on out-of-pocket costs associated with OAT representing a substantial financial burden. Total out-of-pocket costs disproportionately affects those who are newer in treatment and receiving fewer unsupervised doses. Considering and addressing total out-of-pocket costs, especially travel costs and dispensing fees, to clients is critical to prevent cost from being a barrier from receiving effective care.

Rates, characteristics and manner of cannabis-related deaths in Australia 2000-2018.

BACKGROUND: The most commonly used illicit substance worldwide is cannabis. To date, no national level study of cannabis-related death has been undertaken in Australia. The current study aimed to investigate the rates, characteristics and manner of cannabis-related deaths recorded in Australia (2000-2018). METHODS: A retrospective case review of medicolegal files was undertaken through the National Coronial Information System (NCIS) (1/07/2000-31/12/2018). RESULTS: A total of 559 cases were identified, with a mean age of 35.8 years, 81.2% were male. The crude mortality rate per 100,000 people ranged between 0.10 (CI = 0.06-0.15) and 0.23 (CI = 0.17-0.30). The manner of deaths were: accidental injury (29.9%), suicide (25.0%), polysubstance toxicity (17.0%), natural disease (16.1 %), natural disease and drug effect/toxicity (7.9%), assault (3.0%) and unascertained (1.1%). No deaths were solely due to cannabis toxicity. Men were over-represented in this group and were three times as likely to die of accidental injury than women who died from cannabis-related deaths. Motor vehicle accidents were the leading cause of accidental injury. Cardiovascular (14.3%) and respiratory conditions (9.7%) were the most common disease types recorded in cause of death. The median Δ-9-tetrahydrocannabinol blood concentration was 0.008 mg/L (range 0.0005-19.00 mg/L). Other drugs were cited in the cause of death alongside cannabis (81.4%), the most common being alcohol (47.2%). CONCLUSIONS: Low all-cause crude mortality rates remained relatively stable over the study period. No deaths were due to direct cannabis toxicity, but death due to accidental injury was prominent.