Association between benzodiazepine coprescription and mortality in people on opioid replacement therapy: a population-based cohort study.

OBJECTIVE: To investigate the association between opioid replacement therapy (ORT) and benzodiazepine (BZD) coprescription and all-cause mortality compared with the prescription of ORT alone. DESIGN: Population-based cohort study. SETTING: Scotland, UK. PARTICIPANTS: Participants were people prescribed ORT between January 2010 and end of December 2020 aged 18 years or above. MAIN OUTCOME MEASURES: All-cause mortality, drug-related deaths and non-drug related deaths. SECONDARY OUTCOME: ORT continuous treatment duration. ANALYSIS: Cox regression with time-varying covariates. RESULTS: During follow-up, 5776 of 46 899 participants died: 1398 while on coprescription and 4378 while on ORT only. The mortality per 100 person years was 3.11 during coprescription and 2.34 on ORT only. The adjusted HR for all-cause mortality was 1.17 (1.10 to 1.24). The adjusted HR for drug-related death was 1.14 (95% CI, 1.04 to 1.24) and the hazard for death not classified as drug-related was 1.19 (95% CI, 1.09 to 1.30). CONCLUSION: Coprescription of BZDs in ORT was associated with an increased risk of all-cause mortality, although with a small effect size than the international literature. Coprescribing was also associated with longer retention in treatment. Risk from BZD coprescription needs to be balanced against the risk from illicit BZDs and unplanned treatment discontinuation. A randomised controlled trial is urgently needed to provide a clear clinical direction. TRIAL REGISTRATION NUMBER: NCT04622995.

Superiority and cost-effectiveness of monthly extended-release buprenorphine versus daily standard of care medication: a pragmatic, parallel-group, open-label, multicentre, randomised, controlled, phase 3 trial.

Background: Daily methadone maintenance or buprenorphine treatment is the standard-of-care (SoC) medication for opioid use disorder (OUD). Subcutaneously injected, extended-release buprenorphine (BUP-XR) may be more effective-but there has been no superiority evaluation. Methods: This pragmatic, parallel-group, open-label, multi-centre, effectiveness superiority randomised, controlled, phase 3 trial was conducted at five National Health Service community-based treatment clinics in England and Scotland. Participants (adults aged ≥ 18 years; all meeting DSM-5 diagnostic criteria for moderate or severe OUD at admission to their current maintenance treatment episode) were randomly assigned (1:1) to receive continued daily SoC (liquid methadone (usual dose range: 60-120 mg) or sublingual/transmucosal buprenorphine (usual dose range: 8-24 mg) for 24 weeks; or monthly BUP-XR (Sublocade;® two injections of 300 mg, then four maintenance injections of 100 mg or 300 mg, with maintenance dose selected by response and preference) for 24 weeks. In the intent-to-treat population (senior statistician blinded to blinded to treatment group allocation), and with a seven-day grace period after randomisation, the primary endpoint was the count of days abstinent from non-medical opioids between days 8-168 (i.e., weeks 2-24; range: 0-161 days). Safety was reported for the intention-to- treat population. Adopting a broad societal perspective inclusive of criminal justice, NHS and personal social service costs, a trial-based cost-utility analysis estimated the Incremental Cost-effectiveness Ratio (ICER) per quality-adjusted life year (QALY) of BUP-XR versus SoC at the National Institute for Health and Care Excellence threshold. The study was registered EudraCT (2018-004460-63) and ClinicalTrials.gov (NCT05164549), and is completed. Findings: Between Aug 9, 2019 and Nov 2, 2021, 314 participants were randomly allocated to receive SoC (n = 156) or BUP-XR (n = 158). Participants were abstinent from opioids for an adjusted mean of 104.37 days (standard error [SE] 9.89; range: 0-161 days) in the SoC group and an adjusted mean of 123.43 days (SE 4.76; range: 24-161 days) in the BUP-XR group (adjusted incident rate ratio [IRR] 1.18, 95% confidence interval [CI] 1.05-1.33; p-value 0.004). The incidence of any adverse event was higher in the BUP-XR group than the SoC group (128 [81.0%] of 158 participants versus 67 [42.9%] of 156 participants, respectively-most commonly rapidly-resolving (mild-moderate range) pain from drug administration in the BUP-XR group (121 [26.9%] of 450 adverse events). There were 11 serious adverse events (7.0%) in the 158 participants in the BUP-XR group, and 18 serious adverse events (11.5%) in the 156 participants in the SoC group-none judged to be related to study treatment. The BUP-XR treatment group had a mean incremental cost of £1033 (95% central range [CR] -1189 to 3225) and was associated with a mean incremental QALY of 0.02 (95% CR 0.00-0.05), and an ICER of £47,540 (0.37 probability of being cost-effective at the £30,000/QALY gained willingness-to-pay threshold). However, BUP-XR dominated the SoC among participants who were rated more severe at study baseline, and among participants in maintenance treatment for more that 28 days at study enrolment. Interpretation: Evaluated against the daily oral SoC, monthly BUP-XR is clinically superior, delivering greater abstinence from opioids, and with a comparable safety profile. BUP-XR was not cost-effective in a base case cost-utility analysis using the societal perspective, but it was more effective and less costly (dominant) among participants with more severe OUD, or those whose current treatment episode was longer than 28 days. Further trials are needed to evaluate if BUP-XR is associated with better clinical and health economic outcomes over the longer term. Funding: Indivior.

Experience and response to a randomised controlled trial of extended-release injectable buprenorphine versus sublingual tablet buprenorphine and oral liquid methadone for opioid use disorder: protocol for a mixed-methods evaluation.

INTRODUCTION: Opioid use disorder (OUD) is a debilitating and persistent disorder. The standard-of-care treatment is daily maintenance dosing of sublingual buprenorphine (BUP-SL) or oral methadone (MET). Monthly, extended-release, subcutaneous injectable buprenorphine (BUP-XR) has been developed to enhance treatment effectiveness. This study aims to investigate the experiences of participants who have been offered BUP-XR (evaluation 1), health-related quality-of-life among participants who have opted to receive BUP-XR longer term (evaluation 2) and the experiences of participants allocated to receive BUP-XR or BUP-SL or MET with the offer of adjunctive personalised psychosocial intervention (evaluation 3). METHODS AND ANALYSIS: Three qualitative-quantitative (mixed-methods) evaluations embedded in a five-centre, head-to-head, randomised controlled trial of BUP-XR versus BUP-SL and MET in the UK. Evaluation 1 is a four-centre interview anchored on an OUD-related topic guide and conducted after the 24-week trial endpoint. Evaluation 2 is a two-centre interview anchored on medications for opioid use disorder-specific quality-of-life topic guide conducted among participants after 12-24 months. Evaluation 3: single-centre interview after the 24-week trial endpoint. All evaluations include selected trial clinical measures, with evaluation 2 incorporating additional questionnaires. Target participant recruitment for evaluations 1 and 2 is 15 participants per centre (n=60 and n=30, respectively). Recruitment for evaluation 3 is 15 participants per treatment arm (n=30). Each evaluation will be underpinned by theory, drawing on constructs from the behavioural model for health service use or the health-related quality-of-life model. Qualitative data analysis will be by iterative categorisation. ETHICS AND DISSEMINATION: Study protocol, consent materials and questionnaires were approved by the London-Brighton and Sussex research ethics committee (reference: 19/LO/0483) and the Health Research Authority (IRAS project number 255522). Participants will be provided with information sheets and informed written consent will be obtained for each evaluation. Study findings will be disseminated through peer-reviewed scientific journals. TRIAL REGISTRATION NUMBER: 2018-004460-63.

Extended-release pharmacotherapy for opioid use disorder (EXPO): protocol for an open-label randomised controlled trial of the effectiveness and cost-effectiveness of injectable buprenorphine versus sublingual tablet buprenorphine and oral liquid methadone.

BACKGROUND: Sublingual tablet buprenorphine (BUP-SL) and oral liquid methadone (MET) are the daily, standard-of-care (SOC) opioid agonist treatment medications for opioid use disorder (OUD). A sizable proportion of the OUD treatment population is not exposed to sufficient treatment to attain the desired clinical benefit. Two promising therapeutic technologies address this deficit: long-acting injectable buprenorphine and personalised psychosocial interventions (PSI). This study will determine (A) the effectiveness and cost-effectiveness - monthly injectable, extended-release (BUP-XR) in a head-to-head comparison with BUP-SL and MET, and (B) the effectiveness of BUP-XR with adjunctive PSI versus BUP-SL and MET with PSI. Safety, retention, craving, substance use, quality-adjusted life years, social functioning, and subjective recovery from OUD will be also evaluated. METHODS: This is a pragmatic, multi-centre, open-label, parallel-group, superiority RCT, with a qualitative (mixed-methods) evaluation. The study population is adults. The setting is five National Health Service community treatment centres in England and Scotland. At each centre, participants will be randomly allocated (1:1) to BUP-XR or SOC. At the London study co-ordinating centre, there will also be allocation of participants to BUP-XR with PSI or SOC with PSI. With 24 weeks of study treatment, the primary outcome is days of abstinence from non-medical opioids during study weeks 2-24 combined with up to 12 urine drug screen tests for opioids. For 90% power (alpha, 5%; 15% inflation for attrition), 304 participants are needed for the BUP-XR versus SOC comparison. With the same planning parameters, 300 participants are needed for the BUP-XR and PSI versus SOC and PSI comparison. Statistical and health economic analysis plans will be published before data-lock on the Open Science Framework. Findings will be reported in accordance with the Consolidated Standards of Reporting Trials and Consolidated Health Economic Evaluation Reporting Standards. DISCUSSION: This pragmatic randomised controlled trial is the first evaluation of injectable BUP-XR versus the SOC medications BUP-SL and MET, with personalised PSI. If there is evidence for the superiority of BUP-XR over SOC medication, study findings will have substantial implications for OUD clinical practice and treatment policy in the UK and elsewhere. TRIAL REGISTRATION: EU Clinical Trials register 2018-004460-63.

Characteristics of non-fatal overdoses and associated risk factors in patients attending a specialist community-based substance misuse service.

Introduction: There are concerns about rising drug-related deaths and the potential contribution of prescription analgesics. There is limited understanding regarding the role of prescription analgesics in non-fatal overdoses (NFODs), nor is there a good understanding of what factors are associated with more severe overdose. Objectives: To explore risk factors and characteristics of NFODs among people attending a specialist community-based substance misuse service. Methods: After Caldicott approval, data on NFODs, in people attending the Tayside Substance Misuse Service (TSMS), were extracted from the Scottish Ambulance Service database, along with opioid replacement therapy (ORT) prescribing data. Statistical analysis was performed using R studio and Microsoft Excel. Results: 557 people (78% [434/556] male, mean age ± standard deviation 38.4 ± 7.95) had an NFOD. Repeat NFODs were more likely in males compared to females (p < .0065). Males were more likely to be administered naloxone (OR = 1.94, 95% CI = 1.10-3.40, p < .02). NFODs at home were more likely to be moderate to severe (categorized by Glasgow Comma Scale [p < .02, OR = 4.95, 95% CI = 1.24-24.38]). Methadone (321/557, 57.63%), benzodiazepines (281/557, 50.45%) and heroin (244/557, 43.81%) were the commonest substances: prescribed methadone overdose was more likely than buprenorphine (p < .00001). Opioids and benzodiazepines were often taken together (275/557, 49.40%), with almost all gabapentinoid NFODs also involving opioids (60/61, 98.40%). Conclusions: Polysubstance use with opioids prescribed for ORT, such as methadone, is highly likely to be implicated in NFOD, with males being at the highest risk of severe and repeat NFOD. Future work should focus on strategies to further reduce NFODs.

The relationship between delusions and violence: findings from the East London first episode psychosis study.

IMPORTANCE: Psychotic persons who are violent often explain their violence as being due to delusions. However, research has failed to confirm associations between delusions and violent behavior. OBJECTIVES: To investigate which delusional beliefs and characteristics are associated with violent behavior during a first episode of psychosis and whether these associations are mediated by affect due to delusions. DESIGN: Population-based epidemiological survey of first-episode psychosis during a 2-year study period. SETTING: Three inner-city boroughs in East London, England. PARTICIPANTS: A total of 458 patients with first-episode psychosis who were 18 to 64 years of age. INTERVENTIONS: Patients were clinically assessed (using the Schedules for Clinical Assessment in Neuropsychiatry and the Maudsley Assessment of Delusions Schedule) and interviewed about their displaying violent behavior while experiencing psychotic symptoms during the 12-month period prior to interview. MAIN OUTCOME MEASURES: Violence was classified at 2 levels of severity: minor and serious violence. RESULTS: The prevalence of violence was 38% during the 12-month period, and 12% of the sample engaged in serious violence. Distinct sets of demographic and comorbid risk factors were associated with minor and serious violence. These were adjusted for in subsequent analyses. Anger was the only affect due to delusions that was positively associated with violence. The population-attributable risk percentage was 30.8% for minor violence and 55.9% for serious violence. A small number of uncommon delusional beliefs demonstrated direct pathways leading to minor violence. Three highly prevalent delusions demonstrated pathways to serious violence mediated by anger due to delusional beliefs: persecution (z = 3.09, P = .002), being spied on (z = 3.03, P = .002), and conspiracy (z = 2.98, P = .002). CONCLUSIONS AND RELEVANCE: Anger due to delusions is a key factor that explains the relationship between violence and acute psychosis. A subset of delusional beliefs may be causally linked to violence, and certain uncommon beliefs demonstrated a direct association with minor violence. Highly prevalent delusional beliefs implying threat were associated with serious violence, but they were mediated by anger.

Raised incidence rates of all psychoses among migrant groups: findings from the East London first episode psychosis study.

CONTEXT: Certain black and minority ethnic groups are at increased risk for psychoses. It is unknown whether risk for second- and later-generation black and minority ethnic groups in the United Kingdom is universally increased or varies by ethnicity, population structure, or diagnostic category. OBJECTIVES: To examine whether excess risk in black and minority ethnic groups varies by generation status and to determine whether this is explained solely by an excess of broadly defined schizophrenia. DESIGN: Population-based epidemiological survey of first-onset psychoses during a 2-year study period. SETTING: Three inner-city boroughs in East London, England. Patients Four hundred eighty-four patients with first-episode psychosis aged 18 to 64 years. MAIN OUTCOME MEASURES: Nonaffective or affective psychoses according to the DSM-IV. RESULTS: Raised incidence of both nonaffective and affective psychoses were found for all of the black and minority ethnic subgroups compared with white British individuals. The risk of nonaffective psychoses for first and second generations varied by ethnicity (likelihood ratio test, P = .06). Only black Caribbean second-generation individuals were at significantly greater risk compared with their first-generation counterparts (incidence rate ratio, 2.2; 95% confidence interval, 1.1-4.2) [corrected]. No significant differences between first and second generations were observed in other ethnic groups. Asian women but not men of both generations were at increased risk for psychoses compared with white British individuals. Patterns were broadly upheld for the affective psychoses. CONCLUSIONS: Both first- and second-generation immigrants were at elevated risk for both nonaffective and affective psychoses, but this varied by ethnicity. Our results suggest that given the same age structure, the risk of psychoses in first and second generations of the same ethnicity will be roughly equal. We suggest that socioenvironmental factors operate differentially by ethnicity but not generation status, even if the exact specification of these stressors differs across generations. Research should focus on differential rates of psychoses by ethnicity rather than between generations.