Impact of Depressive Symptom Severity on Buprenorphine/Naloxone and Methadone Outcomes in People With Prescription-Type Opioid Use Disorder: Results From a Pragmatic Randomized Controlled Trial.

OBJECTIVE: To evaluate the impact of depressive symptom severity on opioid use and treatment retention in individuals with prescription-type opioid use disorder (POUD). METHOD: We analyzed data from a multi-centric, pragmatic, open-label, randomized controlled trial comparing buprenorphine/naloxone to methadone models of care in 272 individuals with POUD. Opioid use was self-reported every two weeks for 24 weeks using the Timeline Followback. Depressive symptom severity was self-reported with the Beck Depression Inventory at baseline, week 12 and week 24. RESULTS: Baseline depressive symptom severity was not associated with opioid use nor treatment retention. At week 12, moderate depressive symptoms were associated with greater opioid use while mild to severe depressive symptoms were associated with lowered treatment retention. At week 24, moderate depressive symptoms were associated with greater opioid use. CONCLUSIONS: Ongoing depressive symptoms lead to poorer outcomes in POUD. Clinicians are encouraged to use integrative approaches to optimize treatment outcomes. This study was registered in ClinicalTrials.gov (NCT03033732) on January 27th, 2017, prior to participants enrollment.

Does This Patient Have Alcohol Use Disorder?: The Rational Clinical Examination Systematic Review.

Importance: The accuracy of screening tests for alcohol use disorder (defined as a problematic pattern of alcohol use leading to clinically significant impairment or distress) requires reassessment to align with the latest definition in the Diagnostic and Statistical Manual of Mental Disorders (Fifth Edition) (DSM-5). Objective: To assess the diagnostic accuracy of screening tools in identifying individuals with alcohol use disorder as defined in the DSM-5. Data Sources and Study Selection: The databases of MEDLINE and Embase were searched (January 2013-February 2023) for original studies on the diagnostic accuracy of brief screening tools to identify alcohol use disorder according to the DSM-5 definition. Because diagnosis of alcohol use disorder does not include excessive alcohol use as a criterion, studies of screening tools that identify excessive or high-risk drinking among younger (aged 9-18 years), older (aged ≥65 years), and pregnant persons also were retained. Data Extraction and Synthesis: Sensitivity, specificity, and likelihood ratios (LRs) were calculated. When appropriate, a meta-analysis was performed to calculate a summary LR. Results: Of 4303 identified studies, 35 were retained (N = 79 633). There were 11 691 individuals with alcohol use disorder or a history of excessive drinking. Across all age categories, a score of 8 or greater on the Alcohol Use Disorders Identification Test (AUDIT) increased the likelihood of alcohol use disorder (LR, 6.5 [95% CI, 3.9-11]). A positive screening result using AUDIT identified alcohol use disorder better among females (LR, 6.9 [95% CI, 3.9-12]) than among males (LR, 3.8 [95% CI, 2.6-5.5]) (P = .003). An AUDIT score of less than 8 reduced the likelihood of alcohol use disorder similarly for both males and females (LR, 0.33 [95% CI, 0.20-0.52]). The abbreviated AUDIT-Consumption (AUDIT-C) has sex-specific cutoff scores of 4 or greater for males and 3 or greater for females, but was less useful for identifying alcohol use disorder (males: LR, 1.8 [95% CI, 1.5-2.2]; females: LR, 2.0 [95% CI, 1.8-2.3]). The AUDIT-C appeared useful for identifying measures of excessive alcohol use in younger people (aged 9-18 years) and in those older than 60 years of age. For those younger than 18 years of age, the National Institute on Alcohol Abuse and Alcoholism age-specific drinking thresholds were helpful for assessing the likelihood of alcohol use disorder at the lowest risk threshold (LR, 0.15 [95% CI, 0.11-0.21]), at the moderate risk threshold (LR, 3.4 [95% CI, 2.8-4.1]), and at the highest risk threshold (LR, 15 [95% CI, 12-19]). Among persons who were pregnant and screened within 48 hours after delivery, an AUDIT score of 4 or greater identified those more likely to have alcohol use disorder (LR, 6.4 [95% CI, 5.1-8.0]), whereas scores of less than 2 for the Tolerance, Worried, Eye-Opener, Amnesia and Cut-Down screening tool and the Tolerance, Annoyed, Cut-Down and Eye-Opener screening tool identified alcohol use disorder similarly (LR, 0.05 [95% CI, 0.01-0.20]). Conclusions and Relevance: The AUDIT screening tool is useful to identify alcohol use disorder in adults and in individuals within 48 hours postpartum. The National Institute on Alcohol Abuse and Alcoholism youth screening tool is helpful to identify children and adolescents with alcohol use disorder. The AUDIT-C appears useful for identifying various measures of excessive alcohol use in young people and in older adults.

Sexually transmitted and blood-borne infection risk reduction with methadone and buprenorphine/naloxone among people with prescription-type opioid use disorder: Findings from a Canadian pragmatic randomized trial.

INTRODUCTION: People who use drugs are disproportionally affected by sexually transmitted and blood-borne infections (STBBIs). While the benefits of methadone in reducing injecting-risk behaviours are well documented, less is known on its impacts on sexual-related risks, as well as its comparative effectiveness to buprenorphine/naloxone, particularly in the context of highly potent opioids. The aim of this study was to estimate the relative effects of buprenorphine/naloxone and methadone on injecting and STBBI risks among people with prescription-type opioid use disorder (POUD). METHODS: Secondary analysis of a pan-Canadian pragmatic 24-week randomized clinical trial comparing methadone and buprenorphine/naloxone models of care among 272 people with POUD (including licit or illicit opioid analgesics, fentanyl). The Risk Behaviour Survey was used to collect injecting and sexual risks at baseline, and weeks 12 and 24. RESULTS: In total, 210 participants initiated treatment (103 buprenorphine/naloxone and 107 methadone). At baseline, 113/205 (55.1%) participants reported recently injecting drugs, 37/209 (17.7%) unsafe injection practices and 67/162 (41.4%) high-risk sex. Both methadone and buprenorphine/naloxone were associated with reductions in the prevalence of injection drug use and high-risk sex at weeks 12 and 24 with no interactions between treatment arm and time. CONCLUSION: Methadone and buprenorphine/naloxone were similarly effective in reducing injecting and sexual risk behaviours among people with POUD. CLINICAL TRIALS REGISTRATION: clinicaltrials.gov NCT03033732.

Associations of Methadone and BUP/NX Dose Titration Patterns With Retention in Treatment and Opioid Use in Individuals With Prescription-Type Opioid Use Disorder: Secondary Analysis of the OPTIMA Study.

INTRODUCTION: Methadone and buprenorphine/naloxone (BUP/NX) titration parameters (eg, range, duration, and rate) can vary during opioid use disorder (OUD) treatment. We describe methadone and BUP/NX titration patterns and their associations with treatment outcomes among individuals with a prescription-type OUD. METHODS: We used data from a 24-week open-label, multicenter randomized controlled trial, including N = 167 participants aged 18-64 years old with prescription-type OUD who received at least a first dose of treatment. Descriptive analyses of methadone and BUP/NX titration patterns were conducted, that is, range and duration from first to maximum dose, and rate (range/duration ratio). Outcomes included percentage of opioid-positive urine drug screens (UDS) and treatment retention. Adjusted linear and logistic regressions were used to study associations between titration patterns and percentage of opioid-positive UDS and treatment retention. RESULTS: Methadone doses were increased by a mean dose range of 42.4 mg over a mean duration of 42.2 days. BUP/NX doses were increased by a mean dose range of 8.4 mg over a mean duration of 28.7 days. Only methadone dose titration range (odds ratio: 1.03; 95% CI, 1.01 to 1.05) and duration (odds ratio: 1.03; 95% CI, 1.01 to 1.05) were associated with higher retention. Only methadone dose titration rate was associated with lower percentage of opioid-positive UDS at weeks 12-24 ( B : -2.77; 95% CI, -4.72 to -0.81). CONCLUSIONS: Specific parameters of methadone titration were associated with treatment outcomes and may help in personalizing treatment schedules. Sustained methadone dose titration, when indicated, may help increase retention, whereas faster dose titration for methadone may help decrease opioid use.

The FASTER-BUP Study, Extended-Release Injectable Buprenorphine for the Treatment of Opioid Use Disorder Among Individuals at High Risk of Overdose: Protocol for an Observational Prospective Study.

North America is facing an unprecedented public health emergency of opioid-related morbidity and mortality. The mortality benefits of oral medication treatment for opioid use disorder (MOUD), such as methadone or buprenorphine, are well documented. However, barriers to access and long-term engagement have prevented maximizing their benefits. Long-acting injectable buprenorphine formulations were developed to address some of the challenges associated with oral MOUD. The "Pilot study to assess the feasibility, efficacy, and safety of extended-release injectable buprenorphine for the treatment of opioid use disorder among individuals at high risk of overdose" (FASTER-BUP) was developed to explore this treatment option in populations at high risk of overdose in a real-world Canadian setting. FASTER-BUP is a 24-week observational prospective study evaluating the feasibility and clinical utility of extended-release injectable buprenorphine (XR-BUP) for the treatment of opioid use disorder (OUD) among 40 adults at high risk of overdose (ie, lifetime history of overdose or a positive urine drug test (UDT) for fentanyl within 30 days prior to screening) in Vancouver, BC. The primary outcome is retention in treatment and secondary outcomes include: use of unregulated opioids, safety, overdose events, treatment satisfaction, changes in drug-related problems, changes in quality of life, opioid cravings, health service utilization, and criminal activity. FASTER-BUP is the first study to explore XR-BUP among individuals at high risk of overdose in a real-world Canadian setting. This commentary provides a brief narrative about the study thus far and presents insights on key adaptations to the study protocol, including those adopted to mitigate recruitment challenges.

The Association Between Self-Reported Anxiety and Retention in Opioid Agonist Therapy: Findings From a Canadian Pragmatic Trial.

BACKGROUND: Prescription-type opioid use disorder (POUD) is often accompanied by comorbid anxiety, yet the impact of anxiety on retention in opioid agonist therapy (OAT) is unclear. Therefore, this study investigated whether baseline anxiety severity affects retention in OAT and whether this effect differs by OAT type (methadone maintenance therapy (MMT) vs. buprenorphine/naloxone (BNX)). METHODS: This secondary analysis used data from a pan-Canadian randomized trial comparing flexible take-home dosing BNX and standard supervised MMT for 24 weeks. The study included 268 adults with POUD. Baseline anxiety was assessed using the Beck Anxiety Inventory (BAI), with BAI ≥ 16 indicating moderate-to-severe anxiety. The primary outcomes were retention in assigned and any OAT at week 24. In addition, the impact of anxiety severity on retention was examined, and assigned OAT was considered an effect modifier. RESULTS: Of the participants, 176 (65%) reported moderate-to-severe baseline anxiety. In adjusted analyses, there was no significant difference in retention between those with BAI ≥ 16 and those with BAI < 16 assigned (29% vs. 28%; odds ratio (OR) = 2.03, 95% confidence interval (CI) = 0.94-4.40; P = 0.07) or any OAT (35% vs. 34%; OR = 1.57, 95% CI = 0.77-3.21; P = 0.21). In addition, there was no significant effect modification by OAT type for retention in assigned (P = 0.41) or any OAT (P = 0.71). In adjusted analyses, greater retention in treatment was associated with BNX (vs. MMT), male gender identity (vs. female, transgender, or other), enrolment in the Quebec study site (vs. other sites), and absence of a positive urine drug screen for stimulants at baseline. CONCLUSIONS: Baseline anxiety severity did not significantly impact retention in OAT for adults with POUD, and there was no significant effect modification by OAT type. However, the overall retention rates were low, highlighting the need to develop new strategies to minimize the risk of attrition from treatment. CLINICAL TRIAL REGISTRATION: This study was registered in ClinicalTrials.gov (NCT03033732).

Pharmacogenetics of Biochemically Verified Abstinence in an Opioid Agonist Therapy Randomized Clinical Trial of Methadone and Buprenorphine/Naloxone.

Methadone and buprenorphine/naloxone are opioid agonist therapies for opioid use disorder treatment. Genetic factors contribute to individual differences in opioid response; however, little is known regarding genetic associations with clinical outcomes in people receiving opioid agonist therapies. Participants diagnosed with opioid use disorder, principally consisting of prescription opioids (licit or illicit), were randomized to methadone or buprenorphine/naloxone for 24 weeks of daily treatment (NCT03033732). Urine was collected at 12 biweekly study visits and analyzed for non-treatment opioids. Variants in genes involved in methadone metabolism (CYP2B6, CYP2C19, and CYP3A4), buprenorphine metabolism (CYP3A4 and UGT2B7), and µ-opioid receptor function (OPRM1) were genotyped and analyzed for their association with the number of non-treatment opioid-free urine screens. Primary analyses focused on the last 12 weeks (6 study visits, post-titration) of treatment among those reporting White ethnicity. Additional sensitivity and exploratory analyses were performed. Among methadone-treated participants (n = 52), the OPRM1 rs1799971 AA genotype (vs. G-genotypes, i.e., having one or two G alleles) was associated with greater opioid-free urine screens (incidence rate ratio = 5.24, 95% confidence interval (CI) = 2.43-11.26, P = 0.000023); longitudinal analyses showed a significant genotype-by-time interaction over the full 24 weeks (12 study visits, ß = -0.28, 95% CI = -0.45 to -0.11, P = 0.0015). Exploratory analyses suggest an OPRM1 rs1799971 genotype effect on retention. No evidence of association was found between other genetic variants, including in metabolic variants, and non-treatment opioid-free urine screens in the methadone or buprenorphine/naloxone arms. Those with the OPRM1 rs1799971 G-genotypes may have a poorer response to methadone maintenance treatment, an effect that persisted through 24 weeks of treatment.

Evaluation of audit and feedback to family physicians on prescribing of opioid analgesics to opioid-naïve patients: A pragmatic randomized delay trial.

BACKGROUND: Exposure to opioid analgesics have historically raised concern for a risk of developing opioid use disorder. Prescriber audit-and-feedback interventions may reduce opioid prescribing, but some studies have shown detrimental effects for current users. We examined the effectiveness of an audit and feedback intervention, named Portrait, to reduce initiation of opioid analgesics among opioid-naïve patients experiencing pain. METHODS: REDONNA was a single-blinded, two-arm (Early vs Delayed mailing) randomized trial of a portrait for eligible family physicians (FPs) in British Columbia (BC), Canada. The primary outcome was the change in the number of initiations of opioid analgesic prescriptions written by FPs for acute/chronic pain management. We compared outcomes for a 6-month window before vs. after each mailed intervention, using differences in percent differences (DPD) with 95% confidence intervals (CI) and odds ratios (OR) from logistic regressions adjusted for clustering of patients by FP. RESULTS: In the Early (n = 2260) and Delayed (n = 2156) groups, opioid initiations per month were the same in the Before (2.10 Early; 2.06 Delayed) and After (1.94 Early; 1.95 Delayed) windows. The DPD was -2.1% (CI: -4.4% to 0.3%), and ORs were: 0.98 (CI: 0.96 to 1.01) for any opioid, 0.97 (CI: 0.94 to 1.01) for codeine (62% of initiations), and 1.0 (CI: 0.97 to 1.07) for tramadol (25% of initiations). There were no differences in mean quantity of tablets, mean milligrams of morphine equivalents (MME), or mean number of days. CONCLUSION: Portrait had no impact on FPs' rates of prescribing opioid analgesics to opioid-naïve patients experiencing pain. TRIAL REGISTRATION: The study was registered prospectively on 30 March 2020 at the ISRCTN Register (https://www.isrctn.com/ISRCTN34246811).

Correlates of nonfatal overdose among treatment-seeking individuals with non-heroin opioid use disorder: Findings from a pragmatic, pan-Canadian, randomized control trial.

INTRODUCTION: Misuse of prescription and synthetic opioids is a primary contributor to the escalating overdose crisis in North America. However, factors associated with nonfatal overdose (NFO) in this context are poorly understood. We examined individual and socio-structural level correlates of NFO among treatment-seeking adults with an opioid use disorder (OUD) not attributed to heroin (nonheroin opioid use disorder [NH-OUD]). METHODS: The study drew data from OPTIMA, a pan-Canadian, multicenter, pragmatic, two-arm randomized control trial comparing supervised methadone and flexible take-home dosing buprenorphine/naloxone models of care among adults with NH-OUD conducted between 2017 and 2020. We used bivariable and multivariable logistic regression to determine factors associated with a lifetime history of NFO among participants enrolled in the trial. RESULTS: Of 267 included participants, 154 (58%) reported a NFO in their lifetime, of whom 83 (55 %) had an NFO in the last 6 months. In multivariable analyses, positive urine drug test (UDT) for methamphetamine/amphetamine (Adjusted Odds Ratio [AOR] = 2.59; 95 % confidence interval [CI]: 1.17-5.80), positive UDT for fentanyl (AOR = 2.31; 95 % CI: 1.01-5.30), receiving income assistance (AOR = 2.17; 95 % CI: 1.18-4.09) and homelessness (AOR = 2.40; 95 % CI: 1.25-4.68) were positively associated with a lifetime history of NFO. CONCLUSIONS: We found a high prevalence of NFO history in treatment-seeking adults with NH-OUD, particularly among participants with certain drug use patterns and markers of socio-structural marginalization at the time of enrollment. Given the known impact of prior NFO on future harms, these findings highlight the need for comprehensive care approaches that address polysubstance use and social determinants of health to mitigate future overdose risk.

Opioid use and COVID-19: a secondary analysis of the impact of relaxation of methadone take-home dosing guidelines on use of illicit opioids.

Background: An exemption to existing U.S. regulation of methadone maintenance therapy after the onset of the COVID-19 pandemic permitted increased take-home doses beginning March 2020.Objectives: We assessed the impact of this exemption on opioid use.Methods: A pre/post study of 187 clients recruited from an OTP who completed a survey and consented to share their urine drug testing (UDT) data. Use of fentanyl, morphine, hydromorphone, codeine, and heroin was assessed via UDT. Receipt of take-home methadone doses was assessed from clinic records for 142 working days pre- and post-COVID exemption. Analysis was conducted using a linear regression model to assess the association between increased take-home doses and use of illicit opioids.Results: In the pre- vs. post-COVID-19 SAMHSA exemption periods, 26.2% vs. 36.3% of UDTs were positive for 6-acetylmorphine respectively, 32.6% vs. 40.6% positive for codeine, 34.2% vs 44.2% positive for hydromorphone, 39.5% vs. 48.1% positive for morphine, 8.0% vs. 14.4% positive for fentanyl (p-value < .001). However, in the unadjusted descriptive data, when grouped by change in substance use, those clients who experienced a decrease in the use of morphine, codeine, and heroin post-COVID-19 were given significantly more take-home doses than the groups that had no change or an increase in the use of these substances. In the adjusted model, there was no significant relationship between change in opioid use and increased receipt of take-home methadone doses.Conclusions: Although take-home doses post-COVID-19 nearly doubled, this increase was not associated with a significant change in use of illicit opioids.

Associations of methadone and buprenorphine-naloxone doses with unregulated opioid use, treatment retention, and adverse events in prescription-type opioid use disorders: Exploratory analyses of the OPTIMA study.

BACKGROUND AND OBJECTIVES: Buprenorphine/naloxone (BUP-NX) and methadone are used to treat opioid use disorder (OUD), yet there is insufficient evidence on the impact of doses on interventions' effectiveness and safety when treating OUD attributable to other opioids than heroin. METHODS: We explored associations between methadone and BUP-NX doses and treatment outcomes using data from OPTIMA, a 24-week, pragmatic, open-label, multicenter, pan-Canadian, randomized controlled, two-arm parallel trial with participants (N = 272) with OUD who primarily use opioids other than heroin. Participants were randomized to receive flexible take-home BUP-NX (n = 138) or standard supervised methadone treatment (n = 134). We examined associations between highest BUP-NX and methadone doses, and (1) percentage of opioid-positive urine drug screens (UDS); (2) retention in the assigned treatment; and (3) adverse events (AEs). RESULTS: The mean (SD) highest BUP-NX and methadone dose were 17.31 mg/day (8.59) and 67.70 mg/day (34.70). BUP-NX and methadone doses were not associated with opioid-positive UDS percentages or AEs. Methadone dose was associated with higher retention in treatment (odds ratio [OR]: 1.025; 95% confidence interval [CI]: 1.010; 1.041), while BUP-NX dose was not (OR: 1.055; 95% CI: 0.990; 1.124). Higher methadone doses (70-110 mg/day) offered higher odds of treatment retention. DISCUSSION AND CONCLUSION: Methadone dose was associated with higher retention, which may be related to its full µ-opioid receptor agonism. Future research should notably ascertain the effect of pace of titration on a wide range of outcomes. SCIENTIFIC SIGNIFICANCE: Our results extend previous findings of high doses of methadone increasing retention to be applied in our population using opioids other than heroin, including highly potent opioids.

Comparative effectiveness of urine drug screening strategies alongside opioid agonist treatment in British Columbia, Canada: a population-based observational study protocol.

INTRODUCTION: Urine drug tests (UDTs) are commonly used for monitoring opioid agonist treatment (OAT) responses, supporting the clinical decision for take-home doses and monitoring potential diversion. However, there is limited evidence supporting the utility of mandatory UDTs-particularly the impact of UDT frequency on OAT retention. Real-world evidence can inform patient-centred approaches to OAT and improve current strategies to address the ongoing opioid public health emergency. Our objective is to determine the safety and comparative effectiveness of alternative UDT monitoring strategies as observed in clinical practice among OAT clients in British Columbia, Canada from 2010 to 2020. METHODS AND ANALYSIS: We propose a population-level retrospective cohort study of all individuals 18 years of age or older who initiated OAT from 1 January 2010 to 17 March 2020. The study will draw on eight linked health administrative databases from British Columbia. Our primary outcomes include OAT discontinuation and all-cause mortality. To determine the effectiveness of the intervention, we will emulate a 'per-protocol' target trial using a clone censoring approach to compare fixed and dynamic UDT monitoring strategies. A range of sensitivity analyses will be executed to determine the robustness of our results. ETHICS AND DISSEMINATION: The protocol, cohort creation and analysis plan have been classified and approved as a quality improvement initiative by Providence Health Care Research Ethics Board and the Simon Fraser University Office of Research Ethics. Results will be disseminated to local advocacy groups and decision-makers, national and international clinical guideline developers, presented at international conferences and published in peer-reviewed journals electronically and in print.

Sensitivity to change of generic preference-based instruments (EQ-5D-3L, EQ-5D-5L, and HUI3) in the context of treatment for people with prescription-type opioid use disorder in Canada.

PURPOSE: Using data from a randomized controlled trial for treatment of prescription-type opioid use disorder in Canada, this study examines sensitivity to change in three preference-based instruments [EQ-5D-3L, EQ-5D-5L, and the Health Utilities Index Mark 3 (HUI3)] and explores an oft-overlooked consideration when working with contemporaneous responses for similar questions-data quality. METHODS: Analyses focused on the relative abilities of three instruments to capture change in health status. Distributional methods were used to categorize individuals as 'improved' or 'not improved' for eight anchors (seven clinical, one generic). Sensitivity to change was assessed using area under the ROC (receiver operating characteristics) curve (AUC) analysis and comparisons of mean change scores for three time periods. A 'strict' data quality criteria, defined a priori, was applied. Analyses were replicated using 'soft' and 'no' criteria. RESULTS: Data from 160 individuals were used in the analysis; 30% had at least one data quality violation at baseline. Despite mean index scores being significantly lower for the HUI3 compared with EQ-5D instruments at each time point, the magnitudes of change scores were similar. No instrument demonstrated superior sensitivity to change. While six of the 10 highest AUC estimates were for the HUI3, 'moderate' classifications of discriminative ability were identified in 12 (of 22) analyses for each EQ-5D instrument, compared with eight for the HUI3. CONCLUSION: Negligible differences were observed between the EQ-5D-3L, EQ-5D-5L, and HUI3 regarding the ability to measure change. The prevalence of data quality violations-which differed by ethnicity-requires further investigation.

Differential effect of cannabis use on opioid agonist treatment outcomes: Exploratory analyses from the OPTIMA study.

INTRODUCTION: Conflictual evidence exists regarding the effects of cannabis use on the outcomes of opioid agonist therapy (OAT). In this exploratory analysis, we examined the effect of recent cannabis use on opioid use, craving, and withdrawal symptoms, in individuals participating in a trial comparing flexible buprenorphine/naloxone (BUP/NX) take-home dosing model to witnessed ingestion of methadone. METHODS: We analyzed data from a multi-centric, pragmatic, 24-week, open label, randomized controlled trial in individuals with prescription-type opioid use disorder (n = 272), randomly assigned to BUP/NX (n = 138) or methadone (n = 134). The study measured last week cannabis and opioid use via timeline-follow back, recorded at baseline and every two weeks during the study. Craving symptoms were measured using the Brief Substance Craving Scale at baseline, and weeks 2, 6, 10, 14, 18 and 22. The study measured opioid withdrawal symptoms via Clinical Opiate Withdrawal Scale at treatment initiation and weeks 2, 4, and 6. RESULTS: The mean maximum dose taken during the study was 17.3 mg/day (range = 0.5-32 mg/day) for BUP/NX group and 67.7 mg/day (range = 10-170 mg/day) in the methadone group. Repeated measures generalized linear mixed models demonstrated that cannabis use in the last week (mean of 2.3 days) was not significantly associated with last week opioid use (aß ± standard error (SE) = -0.06 ± 0.04; p = 0.15), craving (aß ± SE = -0.05 ± 0.08, p = 0.49), or withdrawal symptoms (aß ± SE = 0.09 ± 0.1, p = 0.36). Bayes factor (BF) for each of the tested models supported the null hypothesis (BF < 0.3). CONCLUSIONS: The current study did not demonstrate a statistically significant effect of cannabis use on outcomes of interest in the context of a pragmatic randomized-controlled trial. These findings replicated previous results reporting no effect of cannabis use on opioid-related outcomes.

Cost-effectiveness of flexible take-home buprenorphine-naloxone versus methadone for treatment of prescription-type opioid use disorder.

BACKGROUND: Our objective was to examine the cost-effectiveness of flexible take-home buprenorphine-naloxone (BNX) versus methadone alongside the OPTIMA trial in Canada. METHODS: The OPTIMA study was a pragmatic, open-label, noninferiority, two-arm randomized controlled trial, to assess the comparative effectiveness of flexible take-home BNX vs. methadone in routine clinical care for individuals with prescription-type opioid use disorder. We evaluated cost-effectiveness using a semi-Markov cohort model. Probabilities of overdose were calibrated, accounting for fentanyl prevalence and other overdose risk factors such as naloxone availability. We considered health sector and societal cost perspectives, including costs (2020 CAD) for treatment, health resource use, criminal activity, and health state-specific preference weights as outcomes to calculate incremental cost-effectiveness ratios. Six-month and lifetime (3% annual discount rate) time-horizons were explored. RESULTS: Over a lifetime time horizon, individuals accumulated -0.144 [CI: -0.302, -0.025] incremental quality-adjusted life years (QALYs) in BNX compared with methadone. Incremental costs were -$2047 [CI: -$39,197, $24,250] from a societal perspective, and -$4549 [CI: -$6332, -$3001] from a health sector perspective. Over a six-month time-horizon, individuals accumulated 0.002 [credible interval (CI): -0.011, 0.016] incremental QALYs in BNX compared with methadone. Incremental costs were -$307 [CI: -$10,385, $8466] from a societal perspective and -$1111 [CI: -$1517, -$631] from a health sector perspective. BNX was dominated (costlier, less effective) in 49.7% of simulations when adopting a societal perspective over a lifetime time horizon. CONCLUSIONS: Flexible take-home BNX was not cost-effective versus methadone over a lifetime time horizon, resulting from better treatment retention in methadone compared to BNX.

Implications of Cannabis Legalization on Substance-Related Benefits and Harms for People Who Use Opioids: A Canadian Perspective.

In 2018, Canada enacted the Cannabis Act, becoming only the second country (after Uruguay) to legalize the recreational consumption of cannabis. Although there is ongoing global disagreement on the risk-benefit profile of cannabis with increasing legalization in many parts of the world, the evidence of rising cannabis use prevalence postlegalization has been consistent. In contrast, postlegalization changes in various cannabis-related metrics have been inconsistent in Canada and other parts of the world. Furthermore, the implications of cannabis legalization on substance-related harms and benefits for people who use unregulated drugs, particularly opioids, remain unclear. Finally, although Canada did not legalize cannabis to address the opioid crisis, there is rising scientific and popular interest in the therapeutic potential of cannabis to mitigate opioid-related harms. This perspective highlights the implications of cannabis legalization on substance-related benefits and harms for people who use opioids, the current state of Canadian research, and suggestions for future directions.

The Cannabis-Dependent Relationship Between Methadone Treatment Dose and Illicit Opioid Use in a Community-Based Cohort of People Who Use Drugs.

Background: Methadone maintenance treatment (MMT) is an effective treatment for opioid use disorder. However, subtherapeutic dosing may lead to continued opioid use by failing to suppress opioid withdrawal and craving. Preclinical and pilot experimental research suggests that cannabinoids may reduce opioid withdrawal and craving. We sought to test whether the association between low methadone dose and illicit opioid use differs according to concurrent cannabis use patterns. Methods: Data for this study were derived from two community-recruited cohorts of people (≥18 years old) who use illicit drugs in Vancouver, Canada. We used generalized estimating equations to estimate the adjusted association between lower daily MMT dose (<90 mg/day) and daily illicit opioid use, testing for interaction between dose and daily cannabis use. Results: Between December 2005 and December 2018, 1389 participants reported MMT enrolment and were included in the study. We observed a significant interaction (p<0.01) between daily cannabis and lower MMT dose on concurrent daily illicit opioid use: lower MMT doses increased the odds of daily illicit opioid use by 86% (adjusted odds ratio [AOR]=1.86, 95% confidence interval [CI]=1.61-2.16) during periods of no or low-frequency cannabis use and by 30% during periods of daily cannabis use (AOR=1.30, 95% CI=1.01-1.67). Discussion: This study provides preliminary observational evidence that cannabis may mitigate some of the negative effects of subtherapeutic MMT dosing, guiding future clinical investigations into the safety and efficacy of cannabis and cannabinoids as adjunct treatment for MMT.

Use of Cannabis as a Harm Reduction Strategy Among People Who Use Drugs: A Cohort Study.

Introduction: While substance use contributes to a substantial burden of disease, access to evidence-based harm reduction interventions remains limited or inaccessible. Preliminary research suggests that some individuals use cannabis to reduce the harms associated with their use of other substances, including opioids and stimulants. This study examines factors associated with the self-reported use of cannabis for harm reduction among people who use drugs (PWUD). Methods: We drew data from three prospective, community-recruited cohorts of PWUD in Vancouver, Canada, between June 2016 and May 2018. Multivariable generalized linear mixed-effects modeling was used to examine factors associated with the primary outcome of "use of cannabis for harm reduction," defined as self-reported use of cannabis to substitute for other substances, treat withdrawal, or come down off other drugs. Results: One thousand nine hundred thirty-six participants contributed 5706 observations. In adjusted analyses, daily methamphetamine use (adjusted odds ratio [AOR]=1.43, 95% confidence interval [CI]: 1.09-1.89), experiencing barriers to accessing addiction treatment (AOR=1.92, 95% CI: 1.21-3.03), and enrollment in addiction treatment modalities other than opioid agonist therapy (AOR=1.64, 95% CI: 1.17-2.29) were positively associated with using cannabis for harm reduction. Older age was negatively associated (AOR=0.97, 95% CI: 0.95-0.98). Among 1281 (66.2%) participants who use cannabis, daily cannabis use and obtaining cannabis from unregulated dispensaries were also independent correlates of using cannabis for harm reduction. Discussion and Conclusions: Individuals who were more likely to use cannabis for harm reduction reported difficulty accessing addiction treatment or used substances, such as methamphetamines, where effective treatments are limited. These findings highlight the need to better understand the potential harm-reducing impacts of cannabis among PWUD in these scenarios.

Methadone Dose, Cannabis Use, and Treatment Retention: Findings From a Community-based Sample of People Who Use Unregulated Drugs.

OBJECTIVES: Lower daily methadone dose is negatively associated with retention in methadone maintenance treatment (MMT). Cannabis use during MMT is common, with many patients reporting its use for opioid withdrawal mitigation. We sought to test whether the association between lower MMT dose and treatment retention differs by concurrent high-frequency cannabis use in a community sample of people on MMT. METHODS: We obtained data from participants initiating MMT in 2 community-recruited prospective cohorts of people who use drugs in Vancouver, Canada. We built multivariable Cox frailty models to estimate the relationships between MMT dose (<90 mg/d vs ≥90 mg/d) and time to treatment discontinuation. We included an interaction term to test whether high-frequency (≥daily) cannabis use modified the measured effect of lower treatment dose on treatment retention. RESULTS: Between December 2005 and December 2018, 829 participants (54.1%) initiated at least 1 MMT episode and were included in the analysis. Lower MMT dose was strongly positively associated with treatment discontinuation regardless of concurrent high-frequency cannabis use (interaction P > 0.05). Structural factors including homelessness and incarceration were significantly and positively associated with treatment discontinuation. CONCLUSIONS: Although we previously found the magnitude and strength of the relationship between lower MMT dose and high-frequency unregulated opioid use to be tempered during high-frequency cannabis use periods, this effect measure modification does not appear to translate to time retained in treatment. Cannabis-based interventions to promote retention in MMT are unlikely to produce long-term benefit without addressing external factors that place MMT patients at increased risk of treatment discontinuation.

Patient Satisfaction With Standard Methadone and Flexible Buprenorphine/Naloxone Models of Care: Results From a Pragmatic Randomized Controlled Clinical Trial.

INTRODUCTION: Patient satisfaction is a critical measure of quality of care across health disciplines because it may affect clinical outcomes. OBJECTIVES: This study aimed to examine longitudinal patient satisfaction in individuals with opioid use disorder (OUD) randomized to receive either standard methadone or flexible buprenorphine/naloxone models of care, its predictors, and association with dropout/illicit drug use. METHODS: This study assessed patient satisfaction, using the 8-item version of the Client Satisfaction Questionnaire (CSQ), as a secondary outcome of a large phase IV pragmatic randomized controlled trial (OPTIMA). The effectiveness of standard methadone model of care was compared with flexible take-home buprenorphine/naloxone dispensation model of care in patients with prescription-type OUD. Of 272 participants recruited and followed up for 24 weeks, 183 were eligible for this study. RESULTS: Throughout the study, patients were "satisfied" with their treatment. The average CSQ score was not significantly different between weeks 4, 12, and 24 in the total sample (χ 2 = 0.35; P = 0.84). There was no significant difference in CSQ based on treatment assignment (methadone vs flexible buprenorphine/naloxone) either overall ( z = 0.87; P = 0.38) or over time (χ 2 = 0.65; P = 0.72). High levels of depression at baseline and decreased depressive symptoms over the follow-up period predicted positive changes in patient satisfaction ( P = 0.03 and P = <0.01, respectively). Satisfaction was significantly associated with treatment retention but not illicit drug use. CONCLUSIONS: This study demonstrates that patients with OUD on either standard methadone or flexible buprenorphine were generally satisfied with their treatment, with no difference in patient satisfaction based on treatment allocation. Given the ongoing opioid crisis, strategies to improve patient satisfaction should be further explored.