Comparative Analysis of Instrumental Variables on the Assignment of Buprenorphine/Naloxone or Methadone for the Treatment of Opioid Use Disorder.

BACKGROUND: Instrumental variable (IV) analysis provides an alternative set of identification assumptions in the presence of uncontrolled confounding when attempting to estimate causal effects. Our objective was to evaluate the suitability of measures of prescriber preference and calendar time as potential IVs to evaluate the comparative effectiveness of buprenorphine/naloxone versus methadone for treatment of opioid use disorder (OUD). METHODS: Using linked population-level health administrative data, we constructed five IVs: prescribing preference at the individual, facility, and region levels (continuous and categorical variables), calendar time, and a binary prescriber's preference IV in analyzing the treatment assignment-treatment discontinuation association using both incident-user and prevalent-new-user designs. Using published guidelines, we assessed and compared each IV according to the four assumptions for IVs, employing both empirical assessment and content expertise. We evaluated the robustness of results using sensitivity analyses. RESULTS: The study sample included 35,904 incident users (43.3% on buprenorphine/naloxone) initiated on opioid agonist treatment by 1585 prescribers during the study period. While all candidate IVs were strong (A1) according to conventional criteria, by expert opinion, we found no evidence against assumptions of exclusion (A2), independence (A3), monotonicity (A4a), and homogeneity (A4b) for prescribing preference-based IV. Some criteria were violated for the calendar time-based IV. We determined that preference in provider-level prescribing, measured on a continuous scale, was the most suitable IV for comparative effectiveness of buprenorphine/naloxone and methadone for the treatment of OUD. CONCLUSIONS: Our results suggest that prescriber's preference measures are suitable IVs in comparative effectiveness studies of treatment for OUD.

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).

Opioid agonist treatment outcomes among individuals with a history of nonfatal overdose: Findings from a pragmatic, pan-Canadian, randomized control trial.

BACKGROUND AND OBJECTIVES: History of nonfatal overdose (NFO) is common among people who use opioids, but little is known about opioid agonist treatment (OAT) outcomes for this high-risk subpopulation. The objective of this study was to investigate the relative effectiveness of buprenorphine/naloxone and methadone on retention and suppression of opioid use among individuals with opioid use disorder (OUD) and history of NFO. METHODS: Secondary analysis of a pan-Canadian pragmatic trial comparing flexible take-home buprenorphine/naloxone and supervised methadone for people with OUD and history of NFO. Logistic regression was used to examine the impact of OAT on retention in the assigned or in any OAT at 24 weeks and analysis of covariance was used to examine the mean difference in opioid use between treatment arms. RESULTS: Of the 272 randomized participants, 155 (57%) reported at least one NFO at baseline. Retention rates in the assigned treatment were 17.7% in the buprenorphine/naloxone group and 18.4% in the methadone group (adjusted odds ratio [AOR] = 0.54, 95% CI: 0.17-1.54). Rates of retention in any OAT were 28% and 20% in the buprenorphine/naloxone and methadone arms, respectively (AOR = 1.55, 95% CI: 0.65-3.78). There was an 11.9% adjusted mean difference in opioid-free urine drug tests, favoring the buprenorphine/naloxone arm (95% CI: 3.5-20.3; p = .0057). CONCLUSIONS AND SCIENTIFIC SIGNIFICANCE: Among adults with OUD and a history of overdose, overall retention rates were low but improved when retention in any treatment was considered. These findings highlight the importance of flexibility and patient-centered care to improve retention and other treatment outcomes in this population.

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.

Amphetamine-Related Emergency Department Visits in Ontario, Canada, 2003-2020.

OBJECTIVES: Despite unregulated amphetamine use increasing, there are limited data on related emergency department (ED) visits in Canada. Our primary objective was to examine trends in amphetamine-related ED visits over time in Ontario, including by age and sex. Secondary objectives were to examine whether patient characteristics were associated with ED revisit within 6 months. METHODS: Using administrative claims and census data, we calculated annual patient- and encounter-based rates of amphetamine-related ED visits from 2003 to 2020 among individuals 18+ years of age. We also performed a retrospective cohort study of individuals with amphetamine-related ED visits between 2019 and 2020 to determine whether select factors were associated with ED revisit within 6 months. Multivariable logistic regression modelling was used to measure associations. RESULTS: The population-based rate of amphetamine-related ED visits increased nearly 15-fold between 2003 (1.9/100,000 Ontarians) and 2020 (27.9/100,000 Ontarians). Seventy-five percent of individuals returned to the ED for any reason within 6 months. Psychosis and use of other substances were both independently associated with ED revisit for any reason within 6 months (psychosis: AOR = 1.54, 95% CI = 1.30-1.83; other substances: AOR = 1.84, 95% CI = 1.57-2.15), whereas having a primary care physician was negatively associated with ED revisit (AOR = 0.77, 95% CI = 0.60-0.98). CONCLUSIONS: Increasing rates of amphetamine-related ED visits in Ontario are cause for concern. Diagnoses of psychosis and the use of other substances may serve to identify individuals who are most likely to benefit from both primary and substance-specific care.

Comparison of Treatment Options for Refractory Opioid Use Disorder in the United States and Canada: a Narrative Review.

Amidst the opioid overdose crisis, there are increased efforts to expand access to medications for opioid use disorder (MOUD). Hospitalization for the complications of substance use in the United States (US) provides an opportunity to initiate methadone, buprenorphine, and extended release naltrexone and link high-risk, not otherwise engaged, patients into outpatient care. However, treatment options for patients are quickly exhausted when these medications are not desired, tolerated, or beneficial. As an example, we discuss the case of a man who was hospitalized 27 times over 2 years for complications related to his opioid use disorder (OUD), including recurring methicillin-resistant Staphylococcus aureus vertebral osteomyelitis, increasing antimicrobial resistance, new infections, and multiple overdoses in and out of the hospital. The patient suffered these complications despite efforts to treat his OUD with methadone and buprenorphine while hospitalized, and repeated attempts to link him to outpatient care. We use this case to review evidence-based treatments for refractory OUD, which are not approved in the US, but are available in Canada. If hospitalized in Vancouver, Canada, this patient could have been offered slow-release oral morphine and injectable opioid agonist therapy, as well as access to sterile syringes and injection equipment at an in-hospital supervised injection facility. Each of these approaches is supported by evidence and has been implemented successfully in Canada, yet none are available in the US. In order to combat the multiple harms from opioids, it is critical that we consider every evidence-based tool.

Benzodiazepine Use and Hepatitis C Seroconversion in a Cohort of Persons Who Inject Drugs.

OBJECTIVES: To examine the relationship between benzodiazepine (BZD) use and HCV seroconversion in 2 linked prospective cohorts of persons who inject drugs (PWID). METHODS: We examined prospective cohorts of 440 PWID (baseline BZD users: n = 102; 23.2%) from the AIDS Care Cohort to Evaluate Access to Survival Services (ACCESS) and the Vancouver Injection Drug Users Study (VIDUS) cohorts, followed-up from 1996 to 2013 in Vancouver, Canada. RESULTS: At baseline, the prevalence of HCV was higher among those who used BZD (80.5% vs 61.5%; P < .001). After adjustment, BZD use remained independently associated with increased rates of HCV seroconversion (adjusted rate ratio = 1.67; 95% confidence interval = 1.05, 2.66). CONCLUSIONS: BZD use is independently associated with HCV seroconversion in a population of PWID.

Association of patterns of methadone use with antiretroviral therapy discontinuation: a prospective cohort study.

BACKGROUND: Methadone maintenance therapy (MMT) is a proven treatment strategy for opioid dependent patients. Although studies have demonstrated that MMT increases contact with the medical system and improves adherence to antiretroviral therapy (ART) in HIV-positive people who inject drugs (PWID), the effect of MMT discontinuation on ART discontinuation has not been well described. METHODS: We examined the impact of continuous MMT use, MMT non-use and MMT discontinuation on the time to ART discontinuation (defined as 90 days of continuous non-use following previous enrolment) in a community-recruited prospective cohort of HIV-positive PWID followed between May 1996 and May 2013 in Vancouver, Canada. Multivariate Cox proportional hazards regression was used to examine the association between MMT use patterns and time to ART discontinuation while adjusting for socio-demographic confounders. RESULTS: A total of 794 HIV-positive PWID were included during the study period. In an adjusted analysis, in comparison to those who were continuously on MMT, MMT non-use (Adjusted Hazard Ratio [AHR] = 1.44, 95 % Confidence Interval [CI]: 1.19-1.73) as well as discontinuing MMT (AHR = 1.82, 95 % CI: 1.27-2.60) were both found to be independently associated with time to ART discontinuation. CONCLUSIONS: This study reinforces the known benefits of MMT use on ART adherence and demonstrates how discontinuation of MMT is independently associated with an increased risk of ART cessation. These data highlight the importance of retaining PWID on MMT.

Initiation and/or re-initiation of drug use among people who use drugs in Vancouver, Canada from 2021 to 2022: a prospective cohort study.

OBJECTIVES: Widespread health service disruptions resulting from the COVID-19 pandemic coincided with a dramatic increase in overdose deaths among people who use drugs (PWUD) in Vancouver, Canada. Those with a history of injection drug use are known to be at heightened risk of substance-associated harms. Drug use patterns and associated sociodemographic and health care utilization trends have been understudied in this population since the pandemic onset. We sought to understand patterns of drug use initiation and/or re-initiation among people with a history of injection drug use (IVDU). METHODS: Data were obtained from three harmonized prospective cohort studies of PWUD in Vancouver. Participants with a lifetime history of IVDU who responded to a survey between June 2021 and May 2022 were included. The primary outcome variable was a composite of substance use initiation and re-initiation over the study period, labelled as drug (re)-initiation. A multivariable generalized linear mixed-effects model was used to examine factors associated with self-reported (re)-initiation of substance use over the past six months. RESULTS: Among 1061 participants, the median age was 47 years at baseline and 589 (55.5%) identified as men. In total, 183 (17.2%) participants reported initiating and/or re-initiating a drug, with 44 (4.1%) reporting new drug initiation and 148 (14.0%) reporting drug re-initiation (9 participants responded 'yes' to both). Overall, unregulated stimulants (e.g., crystal methamphetamine and cocaine) were the most common drug class (re-)initiated (n = 101; 55.2%), followed by opioids (n = 74; 40.4%) and psychedelics (n = 36; 19.7%). In the multivariable analysis, (re-)initiation of drug use was independently associated with recent IVDU (adjusted odds ratio [AOR] 2.62, 95% confidence interval [CI] 1.02, 6.76), incarceration (AOR 3.36, CI 1.12, 10.14) and inability to access addiction treatment (AOR 4.91, 95% CI 1.22, 19.75). CONCLUSIONS: In an era impacted by the intersecting effects of the COVID-19 pandemic and the overdose crisis, nearly one in five PWUD with a history of IVDU began using a new drug and/or re-started use of a previous drug. Those who reported drug (re-)initiation exhibited riskier substance use behaviours and reported difficulty accessing treatment services. Our findings underscore the need to provide additional resources to support this high-risk population.

Effect of Risk Mitigation Guidance opioid and stimulant dispensations on mortality and acute care visits during dual public health emergencies: retrospective cohort study.

OBJECTIVE: To determine the effect of opioid and stimulant Risk Mitigation Guidance (RMG) dispensations on mortality and acute care visits during the dual public health emergencies of overdose and covid-19. DESIGN: Population based retrospective cohort study. SETTING: British Columbia, Canada. PARTICIPANTS: 5882 people with opioid or stimulant use disorder who received RMG prescriptions for opioids (n=5356) and/or stimulants (n=1061) (535 received both) from 27 March 2020 to 31 August 2021. MAIN OUTCOME MEASURES: All cause and overdose specific mortality and acute care visits in the week after RMG opioid or stimulant dispensation. RMG recipients were matched 1:1 with controls through use of high dimensional propensity score matching. Marginal structural models, executed on weekly time steps, were used to measure the effect of dispensations on outcomes. RESULTS: RMG opioid dispensations of one day or more were associated with reduced all cause mortality (adjusted hazard ratio 0.39, 95% confidence interval 0.25 to 0.60) and overdose related mortality (0.45, 0.27 to 0.75) in the subsequent week. Dispensations of RMG stimulants (≥1 days) were not significantly associated with reduced all cause mortality (adjusted hazard ratio 0.50, 0.20 to 1.23) or overdose related mortality (0.53, 0.18 to 1.56). The protective effect of RMG opioid dispensations increased with the number of days the medications were dispensed in a given week. People who received four or more days of RMG opioid dispensations had reduced all cause mortality (adjusted hazard ratio 0.09, 0.04 to 0.21) and overdose related mortality (0.11, 0.04 to 0.32) compared with the control group. Opioid RMG dispensations did not significantly modify the odds of all cause or overdose related acute care visits. Dispensations of RMG stimulants were associated with a significant decrease in the odds of acute care visits for any cause but did not affect the odds of overdose related acute care visits. CONCLUSIONS: RMG opioid dispensations were associated with reduced overdose related and all cause mortality among a sample of people with opioid use disorder. Pharmaceutical alternatives to the illegal drug supply are promising interventions to reduce mortality in people with opioid use disorder.

Prescription psychostimulants for the treatment of amphetamine-type stimulant use disorder: A systematic review and meta-analysis of randomized placebo-controlled trials.

BACKGROUND AND AIMS: There is currently no standard of care for pharmacological treatment of amphetamine-type stimulant (ATS) use disorder (ATSUD). This systematic review with meta-analysis (PROSPERO CRD42022354492) aimed to pool results from randomized placebo-controlled trials (RCTs) to evaluate efficacy and safety of prescription psychostimulants (PPs) for ATSUD. METHODS: Major indexing sources and trial registries were searched to include records published before 29 August 2022. Eligible studies were RCTs evaluating efficacy and safety of PPs for ATSUD. Risk of bias (RoB) was assessed using the Cochrane RoB 2 tool. Risk ratio (RR) and risk difference were calculated for random-effect meta-analysis of dichotomous variables. Mean difference and standardized mean difference (SMD) were calculated for random-effect meta-analysis of continuous variables. RESULTS: Ten RCTs (n = 561 participants) were included in the meta-analysis. Trials studied methylphenidate (n = 7), with daily doses of 54-180 mg, and dextroamphetamine (n = 3), with daily doses of 60-110 mg, for 2-24 weeks. PPs significantly decreased end-point craving [SMD  -0.29; 95% confidence interval (CI) = -0.55, -0.03], while such a decrease did not reach statistical significance for ATS use, as evaluated by urine analysis (UA) (RR = 0.93; 95% CI = 0.85-1.01). No effect was observed for self-reported ATS use, retention in treatment, dropout following adverse events, early-stage craving, withdrawal and depressive symptoms. In a sensitivity analysis, treatment was associated with a significant reduction in UA positive for ATS (RR = 0.89; 95% CI = 0.79-0.99) after removing studies with a high risk of bias. In subgroup analyses, methylphenidate and high doses of PPs were negatively associated with ATS use by UA, while higher doses of PPs and treatment duration (≥ 20 weeks) were positively associated with longer retention. CONCLUSIONS: Among individuals with amphetamine-type stimulant use disorder, treatment with prescription psychostimulants may decrease ATS use and craving. While effect size is limited, it may increase with a higher dosage of medications.