What is the ideal time to begin tapering opioid agonist treatment? A protocol for a retrospective population-based comparative effectiveness study in British Columbia, Canada.

INTRODUCTION: Opioid agonist treatment (OAT) tapering involves a gradual reduction in daily medication dose to ultimately reach a state of opioid abstinence. Due to the high risk of relapse and overdose after tapering, this practice is not recommended by clinical guidelines, however, clients may still request to taper off medication. The ideal time to initiate an OAT taper is not known. However, ethically, taper plans should acknowledge clients' preferences and autonomy but apply principles of shared informed decision-making regarding safety and efficacy. Linked population-level data capturing real-world tapering practices provide a valuable opportunity to improve existing evidence on when to contemplate starting an OAT taper. Our objective is to determine the comparative effectiveness of alternative times from OAT initiation at which a taper can be initiated, with a primary outcome of taper completion, as observed in clinical practice in British Columbia (BC), Canada. METHODS AND ANALYSIS: We propose a population-level retrospective observational study with a linkage of eight provincial health administrative databases in BC, Canada (01 January 2010 to 17 March 2020). Our primary outcomes include taper completion and all-cause mortality during treatment. We propose a 'per-protocol' target trial to compare different durations to taper initiation on the likelihood of taper completion. A range of sensitivity analyses will be used to assess the heterogeneity and robustness of the results including assessment of effectiveness and safety. 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.

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.

Ligne directrice canadienne pour la prise en charge clinique de la consommation d'alcool à risque élevé et du trouble d'utilisation de l'alcool.

CONTEXTE: Au Canada, on note que les équipes soignantes et les personnes qui bénéficieraient de soins ciblés connaissent peu les interventions fondées sur des données probantes pour la prise en charge clinique du trouble d'utilisation de l'alcool. Pour combler cette lacune, l'Initiative canadienne de recherche sur l'abus de substances a créé un comité national dans le but d'élaborer une ligne directrice pour la prise en charge clinique de la consommation d'alcool à risque élevé et du trouble lié à la consommation d'alcool. MÉTHODES: L'élaboration de cette ligne directrice s'est faite selon le processus ADAPTE, et est inspirée par une ligne directrice britanno-colombienne de 2019 pour le trouble lié à la consommation d'alcool. Un comité national de rédaction de la ligne directrice (composé de 36 membres de divers horizons, notamment des universitaires, des médecins, des personnes ayant ou ayant eu des expériences de consommation d'alcool et des personnes s'identifiant comme Autochtones ou Métis) a choisi les thèmes prioritaires, a passé en revue les données probantes et atteint un consensus relatif aux recommandations. Nous avons utilisé l'outil AGREE II (Appraisal of Guidelines for Research and Evaluation Instrument II) et les principes de divulgation des intérêts et de gestion des conflits lors du processus de rédaction des lignes directrices (Principles for Disclosure of Interests and Management of Conflicts in Guidelines) publiés en anglais par le Réseau international des lignes directrices (Guidelines International Network) pour nous assurer que la ligne directrice répondait aux normes internationales de transparence, de qualité élevée et de rigueur méthodologique. Nous avons évalué les recommandations finales à l'aide de l'approche GRADE (Grading of Recommendations Assessment, Development, and Evaluation). Les recommandations ont fait l'objet d'une revue externe par 13 spécialistes et parties prenantes d'ici et de l'étranger. RECOMMANDATIONS: La ligne directrice comprend 15 recommandations qui concernent le dépistage, le diagnostic, la prise en charge du sevrage et le traitement continu, y compris les interventions psychosociales, les pharmacothérapies et les programmes communautaires. Le comité de rédaction de la ligne directrice a reconnu la nécessité d'insister sur la sous-utilisation des interventions qui pourraient être bénéfiques et sur les modes de prescription et autres pratiques d'usage courant qui ne reposent pas sur des données probantes et pourraient aggraver les effets de la consommation d'alcool. INTERPRÉTATION: La ligne directrice se veut une ressource à l'intention des médecins, des responsables des orientations politiques et des membres des équipes cliniques et autres, de même que des personnes, des familles et des communautés affectées par la consommation d'alcool. Ces recommandations proposent un cadre fondé sur des données probantes pour alléger le lourd fardeau du trouble d'utilisation de l'alcool au Canada et combler les besoins en matière de traitements et de soins.

Rethinking Substance Use as Social History: Charting a Way Forward.

Physicians have traditionally asked about substance use within the Social History section of the consultation note. Drawing on social science theory and using the authors' own experiences as generalists and addiction scholars, we consider the possible unintended harms associated with this approach. The inclusion of the substance use history within the Social History reproduces the discourse of substance use disorders as "life-style choices" rather than medical conditions, and reinforces stigma among healthcare workers through the attribution of personal responsibility for complications associated with problematic substance use. The ongoing placement of the substance use history within the Social History may lead to a failure to diagnose and make appropriate management plans for clients with substance use disorders. These missed opportunities may include inadequate withdrawal management leading to discharge before medically advised, insufficient use of evidence-based pharmacotherapy and psychotherapy, polypharmacy, medical complications, and repeated admissions to hospital. We argue instead that the Substance Use History should be a stand-alone section within the consultation note. This new section would reduce the invisibility of substance use disorders within our medical systems and model that these chronic medical conditions are amenable to prevention, treatment and harm reduction through the application of evidence-based practices.

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.

Canadian guideline for the clinical management of high-risk drinking and alcohol use disorder.

BACKGROUND: In Canada, low awareness of evidence-based interventions for the clinical management of alcohol use disorder exists among health care providers and people who could benefit from care. To address this gap, the Canadian Research Initiative in Substance Misuse convened a national committee to develop a guideline for the clinical management of high-risk drinking and alcohol use disorder. METHODS: Development of this guideline followed the ADAPTE process, building upon the 2019 British Columbia provincial guideline for alcohol use disorder. A national guideline committee (consisting of 36 members with diverse expertise, including academics, clinicians, people with lived and living experiences of alcohol use, and people who self-identified as Indigenous or Métis) selected priority topics, reviewed evidence and reached consensus on the recommendations. We used the Appraisal of Guidelines for Research and Evaluation Instrument (AGREE II) and the Guidelines International Network's Principles for Disclosure of Interests and Management of Conflicts to ensure the guideline met international standards for transparency, high quality and methodological rigour. We rated the final recommendations using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) tool; the recommendations underwent external review by 13 national and international experts and stakeholders. RECOMMENDATIONS: The guideline includes 15 recommendations that cover screening, diagnosis, withdrawal management and ongoing treatment, including psychosocial treatment interventions, pharmacotherapies and community-based programs. The guideline committee identified a need to emphasize both underused interventions that may be beneficial and common prescribing and other practice patterns that are not evidence based and that may potentially worsen alcohol use outcomes. INTERPRETATION: The guideline is intended to be a resource for physicians, policymakers and other clinical and nonclinical personnel, as well as individuals, families and communities affected by alcohol use. The recommendations seek to provide a framework for addressing a large burden of unmet treatment and care needs for alcohol use disorder within Canada in an evidence-based manner.

Worsening stimulant use disorder outcomes coinciding with off-label antipsychotic prescribing: a commonly unrecognised side effect?

Antipsychotic medications exert their effects via dopamine antagonism and are widely used off-label among persons with substance use disorders (SUD). While dopamine antagonists are recognised to stimulate food craving and weight gain, outside of possibly increasing nicotine craving and use, their impact on other SUD outcomes is poorly recognised. In this context, research has demonstrated that antipsychotic therapy can produce 'supersensitivity' to dopamine, enhancing the motivational effects of addictive drugs. Worsened drug craving and higher rates of substance use have also been observed in double-blind placebo-controlled trials. Nevertheless, widespread off-label antipsychotic prescribing among persons with SUD implies that the risks of worsening SUD outcomes are overall poorly recognised in both primary care and among specialists. We present a typical case of worsening stimulant use disorder in a patient prescribed antipsychotic medication for low mood and insomnia, highlighting that this is likely a widely under-recognised adverse effect of off-label antipsychotic therapy.

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.

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.

Opioid agonist therapy switching among individuals with prescription-type opioid use disorder: Secondary analysis of a pragmatic randomized trial.

BACKGROUND: Engagement and retention in opioid agonist therapy (OAT) remains a challenge. This study evaluated the impact of initial randomized OAT allocation on subsequent switching among people with prescription-type opioid use disorder (POUD). METHODS: Secondary analysis of a 24-week Canadian multicenter, pragmatic, randomized trial conducted between 2017 and 2020 comparing flexible take-home buprenorphine/naloxone versus supervised methadone models of care for POUD. We used Cox Proportional Hazards modeling to assess for impact of treatment assignment on time to OAT switching, adjusting for important confounders. For clinical correlates, we analyzed data from baseline questionnaires on demographic, substance use, and health factors as well as urine drug screen. RESULTS: Of 272 randomized participants, 210 initiated OAT within 14 days per trial protocol, of whom 103 participants were randomized to buprenorphine/naloxone and 107 to methadone. Within 24-week follow-up, 41 (20.5%) of all participants switched OAT with 25 (24.3%, median 27 days, 88.4 per 100 person-years) and 16 participants (15.0%, median 53.5 days, 46.1 per 100 person-years) switching from buprenorphine/naloxone and methadone arms, respectively. In adjusted analysis, allocation to buprenorphine/naloxone was associated with significantly higher risk of switching (aHR = 2.31, 95% CI 1.22 - 4.38). CONCLUSIONS: OAT switching was common in this sample of individuals with POUD, with individuals randomly allocated to buprenorphine/naloxone being more than twice as likely to switch versus methadone. This may reflect a stepped care approach in OUD management. More research is needed to evaluate overall retention and outcomes with the different observed risks of switching between methadone and buprenorphine/naloxone.

Universal Precautions for People at Risk of Opioid Overdose in North America.

This viewpoint discusses and suggests clinical interventions to be implemented by clinicians and health systems in North America to reduce opioid overdose deaths among at-risk patients.

7-Deazaguanines in DNA: functional and structural elucidation of a DNA modification system.

The modified nucleosides 2'-deoxy-7-cyano- and 2'-deoxy-7-amido-7-deazaguanosine (dPreQ0 and dADG, respectively) recently discovered in DNA are the products of the bacterial queuosine tRNA modification pathway and the dpd gene cluster, the latter of which encodes proteins that comprise the elaborate Dpd restriction-modification system present in diverse bacteria. Recent genetic studies implicated the dpdA, dpdB and dpdC genes as encoding proteins necessary for DNA modification, with dpdD-dpdK contributing to the restriction phenotype. Here we report the in vitro reconstitution of the Dpd modification machinery from Salmonella enterica serovar Montevideo, the elucidation of the roles of each protein and the X-ray crystal structure of DpdA supported by small-angle X-ray scattering analysis of DpdA and DpdB, the former bound to DNA. While the homology of DpdA with the tRNA-dependent tRNA-guanine transglycosylase enzymes (TGT) in the queuosine pathway suggested a similar transglycosylase activity responsible for the exchange of a guanine base in the DNA for 7-cyano-7-deazaguanine (preQ0), we demonstrate an unexpected ATPase activity in DpdB necessary for insertion of preQ0 into DNA, and identify several catalytically essential active site residues in DpdA involved in the transglycosylation reaction. Further, we identify a modification site for DpdA activity and demonstrate that DpdC functions independently of DpdA/B in converting preQ0-modified DNA to ADG-modified DNA.

Alcohol use disorder with comorbid anxiety disorder: a case report and focused literature review.

BACKGROUND: Alcohol use disorder (AUD) and anxiety disorders (AnxD) are prevalent health concerns in clinical practice which frequently co-occur (AUD-AnxD) and compound one another. Concurrent AUD-AnxD poses a challenge for clinical management as approaches to treatment of one disorder may be ineffective or potentially counterproductive for the other disorder. CASE PRESENTATION: We present the case of a middle-aged man with anxiety disorder, AUD, chronic pain, and gamma-hydroxybutyrate use in context of tapering prescribed benzodiazepines who experienced severe alcohol withdrawal episodes during a complicated course of repeated inpatient withdrawal management. After medical stabilization, the patient found significant improvement in symptoms and no return to alcohol use with a regimen of naltrexone targeting his AUD, gabapentin targeting both his AUD and AnxD, and engagement with integrated psychotherapy, Alcoholics Anonymous, and addictions medicine follow-up. CONCLUSION: Proper recognition and interventions for AUD and AnxD, ideally with overlapping efficacy, can benefit individuals with comorbid AUD-AnxD. Gabapentin, tobacco cessation, and integrated psychotherapy have preliminary evidence of synergistic effects in AUD-AnxD. Meta-analysis evidence does not support serotoninergic medications (e.g. selective serotonin reuptake inhibitors) which are commonly prescribed in AnxD and mood disorders as their use has not been associated with improved outcomes for AUD-AnxD. Additionally, several double-blind placebo-controlled randomized trials have suggested that serotonergic medications may worsen alcohol-related outcomes in some individuals with AUD. Areas for future investigation are highlighted.

Harm reduction in the hospital: An overdose prevention site (OPS) at a Canadian hospital.

BACKGROUND: Substance use management in hospitals can be challenging. In response, a Canadian hospital opened an overdose prevention site (OPS) where community members and hospital inpatients can inject pre-obtained illicit drugs under supervision. This study aims to: (1) describe program utilization patterns; (2) characterize OPS visits; and (3) evaluate overdose events and related outcomes. METHODS: A retrospective chart review was completed at one hospital in Vancouver, Canada. All community members and hospital inpatients who visited the OPS between May 2018 and July 2019 were included. Client measures included: hospital inpatient status, use of intravenous access line for drug injection, and substances used. Program measures included: number of visits (daily/monthly), overdose (fatal/non-fatal) events and overdose-related outcomes. RESULTS: Overall, 11,673 OPS visits were recorded. Monthly visits increased from 306 to 1198 between May 2018 and July 2019 respectively. On average, 26 visits occurred daily. Among all visits, 20% reported being a hospital inpatient, and 5% reported using a hospital intravenous access line for drug injection. Opioids (56%) and stimulants (24%) were the most common substances used. Overall 39 overdose events occurred - 82% required naloxone reversal, 28% required transfer to the hospital's emergency department and none were fatal. Overdose events were more common among hospital inpatients compared to community clients (6.6 vs 2.2 per 1000 visits respectively; p value = 0.046). CONCLUSIONS: This unique OPS is an example of a hospital-based harm reduction initiative. Use of the site increased over time among both groups with no fatal overdose events occurring.

Impact of fentanyl use on initiation and discontinuation of methadone and buprenorphine/naloxone among people with prescription-type opioid use disorder: secondary analysis of a Canadian treatment trial.

BACKGROUND AND AIMS: Fentanyl is primarily responsible for the current phase of the overdose epidemic in North America. Despite the benefits of treatment with medications for opioid use disorder (MOUD), there are limited data on the association between fentanyl, MOUD type and treatment engagement. The objectives of this analysis were to measure the impact of baseline fentanyl exposure on initiation and discontinuation of MOUD among individuals with prescription-type opioid use disorder (POUD). DESIGN, SETTING AND PARTICIPANTS: Secondary analysis of a Canadian multi-site randomized pragmatic trial conducted between 2017 and 2020. Of the 269 randomized participants, 65.4% were male, 67.3% self-identified as white and 55.4% had a positive fentanyl urine drug test (UDT) at baseline. Fentanyl-exposed participants were more likely to be younger, to self-identify as non-white, to be unemployed or homeless and to be currently using stimulants than non-fentanyl-exposed participants. INTERVENTIONS: Flexible take-home dosing buprenorphine/naloxone or supervised methadone models of care for 24 weeks. MEASUREMENTS: Outcomes were (1) MOUD initiation and (2) time to (a) assigned and (b) overall MOUD discontinuation. Independent variables were baseline fentanyl UDT (predictor) and assigned MOUD (effect modifier). FINDINGS: Overall, 209 participants (77.7%) initiated MOUD. In unadjusted analyses, fentanyl exposure was associated with reduced likelihood of treatment initiation [odds ratio (OR) = 0.18, 95% confidence interval (CI) = 0.08-0.36] and shorter median times in assigned [20 versus 168 days, hazard ratio (HR) = 3.61, 95% CI = 2.52-5.17] and any MOUD (27 versus 168 days, HR = 3.32, 95% CI = 2.30-4.80). The negative effects were no longer statistically significant in adjusted models, and no interaction between fentanyl and MOUD was observed for any of the outcomes (all P > 0.05). CONCLUSIONS: Both buprenorphine/naloxone and methadone may be appropriate treatment options for people with prescription-type opioid use disorder regardless of fentanyl exposure. Other characteristics of fentanyl-exposed individuals appear to be driving the association with poorer treatment outcomes.

Flexible Buprenorphine/Naloxone Model of Care for Reducing Opioid Use in Individuals With Prescription-Type Opioid Use Disorder: An Open-Label, Pragmatic, Noninferiority Randomized Controlled Trial.

OBJECTIVE: Extensive exposure to prescription-type opioids has resulted in major harm worldwide, calling for better-adapted approaches to opioid agonist therapy. The authors aimed to determine whether flexible take-home buprenorphine/naloxone is as effective as supervised methadone in reducing opioid use in prescription-type opioid consumers with opioid use disorder. METHODS: This seven-site, pan-Canadian, 24-week, pragmatic, open-label, noninferiority, two-arm parallel randomized controlled trial involved treatment-seeking adults with prescription-type opioid use disorder. Participants were randomized in a 1:1 ratio to treatment with sublingual buprenorphine/naloxone (target dosage, 8 mg/2 mg to 24 mg/6 mg per day; flexible take-home dosing) or oral methadone (≈60-120 mg/day; closely supervised). The primary outcome was the proportion of opioid-free urine drug screens over 24 weeks (noninferiority margin, 15%). All randomized participants were analyzed, excluding one who died shortly after randomization, for the primary analysis (modified intention-to-treat analysis). RESULTS: Of 272 participants recruited (mean age, 39 years [SD=11]; 34.2% female), 138 were randomized to buprenorphine/naloxone and 134 to methadone. The mean proportion of opioid-free urine drug screens was 24.0% (SD=34.4) in the buprenorphine/naloxone group and 18.5% (SD=30.5) in the methadone group, with a 5.6% adjusted mean difference (95% CI=-0.3, +∞). Participants in the buprenorphine/naloxone group had 0.47 times the odds (95% CI=0.24, 0.90) of being retained in the assigned treatment compared with those in the methadone group. Overall, 24 drug-related adverse events were reported (12 in the buprenorphine/naloxone group [N=8/138; 5.7%] and 12 in the methadone group [N=12/134; 9.0%]) and mostly included withdrawal, hypogonadism, and overdose. CONCLUSIONS: The buprenorphine/naloxone flexible model of care was safe and noninferior to methadone in reducing opioid use among people with prescription-type opioid use disorder. This flexibility could help expand access to opioid agonist therapy and reduce harms in the context of the opioid overdose crisis.

Prevalence and correlates of intentional substance use to reduce illicit opioid use in a Canadian setting.

Background: While preliminary evidence has begun to document intentional use of one substance to reduce the use of another, the phenomenon of drug substitution among people who use illicit opioids remains understudied. Therefore, we sought to estimate the prevalence and correlates of intentional substance use to reduce illicit opioid use among persons who use drugs (PWUD). Methods: We analysed data from three prospective cohorts of PWUD in Vancouver, Canada, using multivariable generalized estimating equations (GEE). Results: Between June 2012 and June 2016, 1527 participants were recruited and contributed 4991 interviews. Of those, 336 (22%) illicit opioid-using participants self-reported substitution to reduce illicit opioid use at least once during study period contributing 467 (9.4%) interviews. Among those interviews, substances substituted for opioids were alcohol (15 participants, 3.2%), stimulants (235, 50.3%), cannabis (129, 27.6%), benzodiazepines (21, 4.5%), and others (20, 4.3%). In multivariable GEE model adjusted for socio-demographic factors, reporting substitution to reduce illicit opioid use was positively associated with greater likelihood of daily cannabis use (Adjusted Odds Ratio = 1.56, 95% Confidence Interval: 1.24-1.96]. Conclusions: While daily cannabis use was associated with reporting opioid substitution attempts, additional study is needed to examine potential of cannabis/cannabinoids to reduce illicit opioid use.