Impact of baseline methamphetamine/amphetamine use on discontinuation of methadone and buprenorphine/naloxone among people with prescription-type opioid use disorder in Canada.

BACKGROUND AND OBJECTIVES: Although concurrent stimulant use is common among people with opioid use disorder (OUD), there is little evidence on its impacts on opioid agonist therapy (OAT) outcomes. This study sought to determine the impact of baseline methamphetamine/amphetamine use on discontinuation of OAT among individuals with prescription-type OUD (POUD) initiating methadone or buprenorphine/naloxone as part of a pragmatic randomized trial in Canada. METHODS: Secondary analysis of a pan-Canadian pragmatic trial conducted between 2017 and 2020 comparing supervised methadone versus flexible take-home dosing buprenorphine/naloxone models of care. Cox proportional hazard models were used to evaluate the effect of baseline methamphetamine/amphetamine use (measured by urine drug test [UDT]) on two discontinuation outcomes (i.e., assigned OAT discontinuation, any OAT discontinuation). RESULTS: Two hundred nine (n = 209) participants initiated OAT, of which 96 (45.9%) had positive baseline methamphetamine/amphetamine UDT. Baseline methamphetamine/amphetamine use was associated with shorter median times in assigned OAT (21 vs. 168 days, hazard ratio [aHR] = 2.45, 95% confidence interval [CI] = 1.60-3.76) and any OAT (25 days vs. 168 days, aHR = 2.06, CI = 1.32-3.24). No interaction between methamphetamine/amphetamine and assigned OAT was observed for either outcome (p > .05). CONCLUSION AND SCIENTIFIC SIGNIFICANCE: This study offers novel insights on the impact of methamphetamine/amphetamine use on OAT outcomes among people with POUD. Methamphetamine/amphetamine use was common and was associated with increased risk of OAT discontinuation. Supplementary interventions, including treatment for stimulant use, are needed to improve retention in OAT and optimize treatment outcomes in this population.

Cannabis use, mental health, and problematic Internet use in Quebec: A study protocol.

BACKGROUND: Problematic Internet use is characterized by excessive use of online platforms that can result in social isolation, family problems, psychological distress, and even suicide. Problematic Internet use has been associated with cannabis use disorder, however knowledge on the adult population remains limited. In Quebec, cannabis use has significatively increased since 2018, and it is associated with various risks in public safety, public health, and mental health. This study aims to identify factors associated with problematic Internet use among adult cannabis users and to better understand their experiences. METHOD: This project is a mixed explanatory sequential study consisting of two phases. Phase 1 (n = 1500) will be a cross-sectional correlational study using probability sampling to examine variables that predispose individuals to problematic Internet use, characteristics associated with cannabis use, Internet use, and the mental health profile of adult cannabis users in Quebec. Descriptive analyses and regression models will be used to determine the relationship between cannabis use and Internet use. Phase 2 (n = 45) will be a descriptive qualitative study in the form of semi-structured interviews aimed at better understanding the experience and background of cannabis users with probable problematic Internet use. DISCUSSION: The results of this study will support the development of public policies and interventions for the targeted population, by formulating courses of action that contribute to the prevention and reduction of harms associated with cannabis use and problematic Internet use. Furthermore, an integrated knowledge mobilization plan will aid in the large-scale dissemination of information that can result useful to decision-makers, practitioners, members of the scientific community, and the general population regarding the use of cannabis and the Internet.

Absence of Evidence for Sustained Effects of Daily Cannabidiol Administration on Anandamide Plasma Concentration in Individuals with Cocaine Use Disorder: Exploratory Findings from a Randomized Controlled Trial.

Background: Cannabidiol (CBD) has been proposed to have a therapeutic potential over a wide range of neuropsychiatric disorders, including substance use disorders. Pre-clinical evidence suggests that CBD can increase anandamide (AEA) plasma concentration, possibly mediating some of its therapeutic properties. Whether CBD exerts such an effect on AEA in individuals with cocaine use disorder (CUD) remains unknown. Aims: To explore the sustained effects of daily CBD administration on AEA plasma concentrations compared with placebo in CUD. Methods: We used data from a randomized, double-blind, placebo-controlled trial evaluating CBD's efficacy in CUD. Seventy-eight individuals were randomized to receive a daily oral dose of 800 mg CBD (n = 40) or a placebo (n = 38). Participants stayed in an inpatient detoxification setting for 10 days, after which they were followed in an outpatient setting for 12 weeks. AEA plasma concentration was measured at baseline and at 23-h post CBD ingestion on day 8 and week 4. A generalized estimating equation model was used to assess CBD's effects on AEA, and sensitivity analyses were computed using Bayesian linear regressions. Results: Sixty-four participants were included in the analysis. Similar mean AEA plasma concentrations in both treatment groups (p = 0.357) were observed. At day 8, mean AEA plasma concentrations (± standard deviation) were 0.26 (± 0.07) ng/mL in the CBD group and 0.29 (± 0.08) ng/mL in the placebo group (p = 0.832; Bayes factor [BF] = 0.190). At week 4, they were 0.27 (± 0.09) ng/mL in the CBD group and 0.30 (± 0.09) ng/mL in the placebo group (p = 0.181; BF = 0.194). Conclusion: While not excluding any potential acute and short-term effect, daily CBD administration did not exert a sustained impact on AEA plasma concentrations in individuals with CUD compared with placebo. Registration: clinicaltrials.gov (NCT02559167).

Characterising methamphetamine/amphetamine use among opioid agonist therapy-seeking adults with prescription-type opioid use disorder in Canada.

INTRODUCTION: There has been a significant increase in methamphetamine/amphetamine use in North America, particularly among people who use opioids. Despite its association with several negative health consequences, the population of people who use methamphetamine/amphetamine with opioids is not well characterised. The aim of this study was to investigate correlates of methamphetamine/amphetamine use among adults with prescription-type opioid use disorder (POUD) starting methadone or buprenorphine/naloxone as part of a pragmatic randomised treatment trial in Canada. METHODS: Multivariable logistic regression analyses were used to determine factors associated with baseline methamphetamine/amphetamine use (measured by urine drug test [UDT]) among participants of a pan-Canadian pragmatic trial conducted between 2017 and 2020 comparing supervised methadone versus flexible take-home dosing buprenorphine/naloxone models of care in people with POUD (e.g., licit or illicit, including fentanyl, prescribed or not). RESULTS: The sample included 269 participants, of which 142 (52.8%) had positive baseline methamphetamine/amphetamine UDT. In the multivariable model, positive fentanyl UDT (adjusted odds ratio [AOR] 13.21, 95% confidence interval [CI] 6.45, 28.30), non-fatal overdose in the last 6 months (AOR 2.26, CI 1.01, 5.17) and a lifetime history of opioid agonist therapy exposure prior to study entry (AOR 2.30, CI 1.09, 4.87) remained positively associated with baseline methamphetamine/amphetamine use. DISCUSSION AND CONCLUSIONS: In this sample of people with POUD, methamphetamine/amphetamine use was associated with markers of complex and severe OUD, including overdose risk. This suggests the need for targeted interventions to optimise treatment outcomes and prevent future overdoses in this population. CLINICAL TRIAL REGISTRATION: Available at: ClinicalTrials.gov NCT03033732.

Determinants of psychological distress during the COVID-19 pandemic among people who use drugs in Montreal, Canada.

INTRODUCTION: Limited data exists on psychological impacts of the COVID-19 pandemic among people who use drugs (PWUD). This study aimed to determine the prevalence and correlates of severe psychological distress (PD) among PWUD in Montreal around the beginning of the pandemic. METHODS: We conducted a rapid assessment study from May to December 2020 among PWUD recruited via a community-based cohort of people who inject drugs in Montreal (Hepatitis C cohort [HEPCO], N = 128) and community organisations (N = 98). We analysed self-reported data on changes in drug use behaviours and social determinants since the declaration of COVID-19 as a public health emergency, and assessed past-month PD using the Kessler K6 scale. Multivariable logistic regression was conducted to examine correlates of PD distress (score ≥13). RESULTS: Of 226 survey participants, a quarter (n = 56) were screened positive for severe PD. In multivariable analyses, age (1-year increment) (adjusted odds ratio = 0.94, 95% confidence interval [0.90, 0.98]) and a decrease in non-injection drug use versus no change (0.26 [0.07, 0.92]) were protective against severe PD, while positive associations were found for any alcohol use in the past 6 months (3.73 [1.42, 9.78]), increased food insecurity (2.88 [1.19, 6.93]) and both moving around between neighbourhoods more (8.71 [2.63, 28.88]) and less (3.03 [1.18, 7.74]) often compared to no change. DISCUSSION AND CONCLUSIONS: This study documented a high prevalence of severe PD among PWUD during the COVID-19 pandemic compared with pre-COVID-19 data. Social determinants such as food insecurity and mobility issues, alongside demographic and substance use-related factors, were linked to distress. Evidence-based risk mitigation strategies for this population could reduce negative consequences in future pandemics or disruptions.

Preferences of Young Adults With Psychosis for Cannabis-Focused Harm Reduction Interventions: A Cross-Sectional Study: Préférences des jeunes adultes souffrant de psychose pour les interventions de réduction des méfaits axées sur le cannabis : une étude transversale.

OBJECTIVES: Cannabis use is common in people with early-phase psychosis (EP) and is associated with worse treatment outcomes. Few targeted interventions for cannabis use behaviour in this population exist, most focusing on abstinence, none focusing on harm reduction. Many people with EP will not seek treatment for their cannabis use with current therapeutic options. Understanding preferences for cannabis-focused harm reduction interventions may be key to improving outcomes. This study aimed to determine preferences of young adults with EP who use cannabis for cannabis-focused harm reduction interventions. METHODS: Eighty-nine young adults across Canada with EP interested in reducing cannabis-related harms were recruited. An online questionnaire combining conventional survey methodology and two unique discrete choice experiments (DCEs) was administered. One DCE focused on attributes of core harm reduction interventions (DCE 1) and the second on attributes of boosters (DCE 2). We analysed these using mixed ranked-ordered logistic regression models. Preference questions using conventional survey methodology were analysed using summary statistics. RESULTS: Preferred characteristics for cannabis-focused harm reduction interventions (DCE 1) were: shorter sessions (60 min vs. 10 min, odds ratio (OR): 0.72; P < 0.001); less frequent sessions (daily vs. monthly, OR: 0.68; P < 0.001); shorter interventions (3 months vs. 1 month, OR: 0.80; P < 0.01); technology-based interventions (vs. in-person, OR: 1.17; P < 0.05). Preferences for post-intervention boosters (DCE 2) included opting into boosters (vs. opting out, OR: 3.53; P < 0.001) and having shorter boosters (3 months vs. 1 month, OR: 0.79; P < 0.01). Nearly half of the participants preferred to reduce cannabis use as a principal intervention goal (vs. using in less harmful ways or avoiding risky situations). CONCLUSIONS: Further research is required to see if technology-based harm reduction interventions for cannabis featuring these preferences translate into greater engagement and improved outcomes in EP patients.

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.

Mediating effect of craving on the impact of buprenorphine/naloxone and methadone treatment on opioid use: Results from a randomized controlled trial.

BACKGROUND: The relationship between opioid craving and opioid use is unclear. We sought to determine to what extent craving mediated the relationship between opioid agonist therapy and changes in opioid use. METHODS: Data came from a pragmatic, 24-week, pan-Canadian, multi-centric, open-label, randomized controlled trial comparing flexible buprenorphine/naloxone take-home doses to standard supervised methadone models of care for the treatment of prescription-type opioid use disorder. Participants were randomly allocated to buprenorphine/naloxone or methadone models of care. 270 people with prescription-type opioid use disorder were included in analyses. There were 93 women (34.4%) and 2 transgender (0.7%) participants. Most participants were white (67.4%), 45.9% reported unstable living conditions, and 44.8% had psychiatric comorbidities. Generalized linear mixed models followed by mediation analysis estimated the direct effect of treatment group on Timeline Followback-reported next-week opioid use and the indirect effect through past 24-hour opioid craving measured using the Brief Substance Craving Scale at week 2, 6, 10, 14, 18 and 22. RESULTS: Upon mediation analysis, the average direct effect of treatment on opioid use was 0.465 (95 % CI = 0.183 to 0.751, p < 0.001). The average causal mediated effect was 0.144 (95 % CI = 0.021 to 0.110; p < 0.001). Craving accounted for 23.6 % of the effect of treatment on opioid use (p < 0.001). CONCLUSIONS: Past 24-hour craving was associated with increased next-week opioid use; however, craving only partially mediated the effect of buprenorphine/naloxone and methadone on next-week opioid use. Research is needed to develop a comprehensive understanding of factors mediating opioid use during opioid agonist therapy.

Digital Interventions for Recreational Cannabis Use Among Young Adults: Systematic Review, Meta-Analysis, and Behavior Change Technique Analysis of Randomized Controlled Studies.

BACKGROUND: The high prevalence of cannabis use among young adults poses substantial global health concerns due to the associated acute and long-term health and psychosocial risks. Digital modalities, including websites, digital platforms, and mobile apps, have emerged as promising tools to enhance the accessibility and availability of evidence-based interventions for young adults for cannabis use. However, existing reviews do not consider young adults specifically, combine cannabis-related outcomes with those of many other substances in their meta-analytical results, and do not solely target interventions for cannabis use. OBJECTIVE: We aimed to evaluate the effectiveness and active ingredients of digital interventions designed specifically for cannabis use among young adults living in the community. METHODS: We conducted a systematic search of 7 databases for empirical studies published between database inception and February 13, 2023, assessing the following outcomes: cannabis use (frequency, quantity, or both) and cannabis-related negative consequences. The reference lists of included studies were consulted, and forward citation searching was also conducted. We included randomized studies assessing web- or mobile-based interventions that included a comparator or control group. Studies were excluded if they targeted other substance use (eg, alcohol), did not report cannabis use separately as an outcome, did not include young adults (aged 16-35 y), had unpublished data, were delivered via teleconference through mobile phones and computers or in a hospital-based setting, or involved people with mental health disorders or substance use disorders or dependence. Data were independently extracted by 2 reviewers using a pilot-tested extraction form. Authors were contacted to clarify study details and obtain additional data. The characteristics of the included studies, study participants, digital interventions, and their comparators were summarized. Meta-analysis results were combined using a random-effects model and pooled as standardized mean differences. RESULTS: Of 6606 unique records, 19 (0.29%) were included (n=6710 participants). Half (9/19, 47%) of these articles reported an intervention effect on cannabis use frequency. The digital interventions included in the review were mostly web-based. A total of 184 behavior change techniques were identified across the interventions (range 5-19), and feedback on behavior was the most frequently used (17/19, 89%). Digital interventions for young adults reduced cannabis use frequency at the 3-month follow-up compared to control conditions (including passive and active controls) by -6.79 days of use in the previous month (95% CI -9.59 to -4.00; P<.001). CONCLUSIONS: Our results indicate the potential of digital interventions to reduce cannabis use in young adults but raise important questions about what optimal exposure dose could be more effective, both in terms of intervention duration and frequency. Further high-quality research is still needed to investigate the effects of digital interventions on cannabis use among young adults. TRIAL REGISTRATION: PROSPERO CRD42020196959; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=196959.

Perceptions and engagement of patients with chronic conditions on the use of medical cannabis: a scoping review.

CONTEXT: Studies generally focus on one type of chronic condition and the effect of medical cannabis (MC) on symptoms; little is known about the perceptions and engagement of patients living with chronic conditions regarding the use of MC. OBJECTIVES: This scoping review aims to explore: (1) what are the dimensions addressed in studies on MC that deal with patients' perceptions of MC? and (2) how have patients been engaged in developing these studies and their methodologies? Through these objectives, we have identified areas for improving future research. METHODS: We searched five databases and applied exclusion criteria to select relevant articles. A thematic analysis approach was used to identify the main themes: (1) reasons to use, to stop using or not to use MC, (2) effects of MC on patients themselves and empowerment, (3) perspective and knowledge about MC, and (4) discussion with relatives and healthcare professionals. RESULTS: Of 53 articles, the main interest when assessing the perceptions of MC is to identify the reasons to use MC (n = 39), while few articles focused on the reasons leading to stop using MC (n = 13). The majority (85%) appraise the effects of MC as perceived by patients. Less than one third assessed patients' sense of empowerment. Articles determining the beliefs surrounding and knowledge of MC (n = 41) generally addressed the concerns about or the comfort level with respect to using MC. Only six articles assessed patients' stereotypes regarding cannabis. Concerns about stigma constituted the main topic while assessing relationships with relatives. Some articles included patients in the research, but none of them had co-created the data collection tool with patients. CONCLUSIONS: Our review outlined that few studies considered chronic diseases as a whole and that few patients are involved in the co-construction of data collection tools as well. There is an evidence gap concerning the results in terms of methodological quality when engaging patients in their design. Future research should evaluate why cannabis' effectiveness varies between patients, and how access affects the decision to use or not to use MC, particularly regarding the relationship between patients and healthcare providers. Future research should consider age and gender while assessing perceptions and should take into consideration the legislation status of cannabis as these factors could in fact shape perception. To reduce stigma and stereotypes about MC users, better quality and accessible information on MC should be disseminated.

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.

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.

Associations Between Buprenorphine\Naloxone and Methadone Treatment and non-Opioid Substance Use in Prescription-Type Opioid Use Disorder: Secondary Analyses From the OPTIMA Study: Associations entre le traitement avec la buprénorphine/naloxone et avec la méthadone et l'utilisation de substances non opioïdes dans le trouble lié à l'usage d'opioïdes de type sur ordonnance : analyses secondaires de l'étude OPTIMA.

OBJECTIVES: There is limited evidence on how opioid agonist treatment (OAT) may affect psychoactive non-opioid substance use in prescription-type opioid use disorder (POUD) and whether this effect might explain OAT outcomes. We aimed to assess the effect of methadone on non-opioid substance use compared to buprenorphine/naloxone (BUP/NX), to explore whether non-opioid substance use is associated with opioid use and retention in treatment, and to test non-opioid use as a moderator of associations between methadone with retention in OAT and opioid use compared to BUP/NX. METHODS: This is a secondary analysis of data from the OPTIMA trial, an open-label, pragmatic, parallel, two-arm, pan-Canadian, multicentre, randomized-controlled trial to compare standard methadone model of care and flexible take-home dosing BUP/NX for POUD treatment. We studied the effect of methadone and BUP/NX on non-opioid substance use evaluated by urine drug screen (UDS) and by classes of non-opioid substances (i.e., tetrahydrocannabinol [THC], benzodiazepines, stimulants) (weeks 2-24) using adjusted generalized estimation equation (GEE). We studied the association between non-opioid substance-positive UDS and opioid-positive UDS and retention in treatment, using adjusted GEE and logistic regressions. RESULTS: Overall, methadone was not associated with non-opioid substance-positive UDS compared to BUP/NX (OR: 0.78; 95%CI, 0.41 to 1.48). When non-opioid substances were studied separately, methadone was associated with lower odds of benzodiazepine-positive UDS (OR: 0.63; 95% CI: 0.40 to 0.98) and THC-positive UDS (OR: 0.47; 95% CI: 0.28 to 0.77), but not with different odds of stimulant-positive UDS (OR: 1.29; 95% CI: 0.78 to 2.16) compared to BUP/NX. Substance-positive UDS, overall and separate classes, were not associated with opioid-positive UDS or retention in treatment. CONCLUSION: Methadone did not show a significant effect on overall non-opioid substance use in POUD compared to BUP/NX treatment but was associated with lower odds of benzodiazepine and THC use in particular. Non-opioid substance use did not predict OAT outcomes. Further research is needed to ascertain whether specific patterns of polysubstance use (quantity and frequency) may affect treatment outcomes.

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.

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).

Three noteworthy idiosyncrasies related to Canada's opioid-death crisis, and implications for public health-oriented interventions.

Canada has been experiencing a prolonged public health-crisis of high rates of overdose deaths caused by exceptionally potent/toxic, illicit opioid use. While many key features of this drug death epidemic are well-documented, several idiosyncratic aspects with relevance for public health-oriented interventions are not adequately recognised. These include: (i) the discrepant opioid patterns pan-Canada, with large majorities of opioid deaths caused by illicit fentanyl drugs in Western, but not Eastern regions where prescription-type opioid prevail; (ii) the environments of overdose deaths, where vast majorities occur in 'residential' or other shelter-type settings, presenting barriers for emergency interventions rather than health protection; and (iii) shifting drug use modes, where now majorities of overdose deaths are associated with drug 'inhalation' (instead of 'injection') in contexts of potent/toxic drug supply. We briefly describe these factors and related implications for intervention programming towards an improved response to the drug death-crisis.