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.

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.

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.

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.

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).

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.

Influence of Manufacturing Process on the Microstructure, Stability, and Sensorial Properties of a Topical Ointment Formulation.

The manufacturing process for ointments typically involves a series of heating, cooling, and mixing steps. Precise control of the level of mixing through homogenization and the cooling rate, as well as temperature at different stages, is important in delivering ointments with the desired quality attributes, stability, and performance. In this work, we investigated the influence of typical plant processing conditions on the microstructure, stability, and sensorial properties of a model ointment system through a Design of Experiments (DoE) approach. Homogenization speed at the cooling stage after the addition of the solvent (propylene glycol, PG) was found to be the critical processing parameter that affects stability and the rheological and sensorial properties of the ointment. A lower PG addition temperature was also found to be beneficial. The stabilization of the ointment at a lower PG addition temperature was hypothesized to be due to more effective encapsulation by crystallizing mono- and diglycerides at the lower temperature. The in vitro release profiles were found to be not influenced by the processing parameters, suggesting that for the ointment platform studied, processing affects the microstructure, but the effects do not translate into the release profile, a key performance indicator. Our systematic study represents a Quality-by-Design (QbD) approach to the design of a robust manufacturing process for delivering stable ointments with the desired performance attributes and properties.

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

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

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.

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

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

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

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

Effects of Buprenorphine/Naloxone and Methadone on Depressive Symptoms in People with Prescription Opioid Use Disorder: A Pragmatic Randomised Controlled Trial.

OBJECTIVE: This study aimed to evaluate the effectiveness of flexible take-home dosing of buprenorphine/naloxone (BUP/NX) and methadone standard model of care in reducing depressive symptoms in people with prescription-type opioid use disorder (POUD). This trial also evaluated whether improvements in depressive symptoms were mediated by opioid use. METHODS: Analyzed data came from the OPTIMA study (clinicaltrials.gov identifier: NCT03033732), a pragmatic randomised controlled trial comparing flexible take-home dosing of BUP/NX and methadone standard model of care for reducing opioid use in people with POUD. A total of 272 participants were recruited in four Canadian provinces. Participants were randomised 1:1 to BUP/NX or methadone. After treatment induction, past two-week opioid use was measured using the Timeline Followback every two weeks for a total of 24 weeks. Depressive symptoms were measured with the Beck Depression Inventory at baseline, weeks 12 and 24. RESULTS: Both BUP/NX and methadone significantly reduced depressive symptoms at week 12 (aß ± SE = -3.167 ± 1.233; P < 0.001) and week 24 (aß ± SE = -7.280 ± 1.285; P < 0.001), with no interaction between type of treatment and time (P = 0.284). Improvements in depressive symptoms were only partially mediated by a reduction in opioid use (proportion mediated = 36.8%; 95% confidence interval = -1.158 to -0.070; P = 0.015). CONCLUSIONS: BUP/NX and methadone showed similar effectiveness in decreasing comorbid depressive symptoms in people with POUD. This effect was partially explained by a reduction in opioid use. As both treatments seem equally effective, clinicians are encouraged to tailor the selection of OAT to patients' needs and characteristics.

Buprenorphine/naloxone and methadone effectiveness for reducing craving in individuals with prescription opioid use disorder: Exploratory results from an open-label, pragmatic randomized controlled trial.

BACKGROUND: Craving reduction is an important target in the treatment of prescription-type opioid use disorder (POUD). In this exploratory analysis, we compared the effectiveness of BUP/NX flexible model of care relative to methadone for craving reduction in individuals with POUD. METHODS: We analyzed data from a multicentric, pragmatic, 24-week open-label randomized controlled trial conducted in participants with POUD (N = 272) who were randomly assigned to BUP/NX model of care with flexible take-home dosing (n = 138) or the standard model of care with closely supervised methadone (n = 134). Treatments were prescribed and administered according to local guidelines, in diverse clinical settings. Craving was measured using the Brief Substance Craving Scale at baseline, week 2, 6, 10, 14, 18 and 22. RESULTS: Cravings decreased in both treatment groups over 22 weeks (BUP/NX adjusted mean difference = -5.52, 95% CI = -6.91 to -4.13; methadone adjusted mean difference = -3.95, 95% CI = -5.28 to -2.63; p < 0.001), and were overall lower in the BUP/NX group (adjusted mean = 4.04, 95% CI = 3.43-4.64) than the methadone group (adjusted mean = 5.13, 95% CI = 4.51-5.74; p < 0.001). The time by treatment group interaction (favoring BUP/NX) was statistically significant at week 2 (adjusted mean difference = -1.58, 95% CI = -3.13 to -0.03; p = 0.041). CONCLUSIONS: Compared to the standard methadone model of care, flexible take-home dosing of BUP/NX was associated with lower craving in individuals with POUD. These findings can contribute to guiding shared decision-making regarding OAT treatment in this population.

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.

Patient With Very High Opioid Tolerance Enrolled in Opioid Agonist Treatment: A Case Report.

BACKGROUND: Fentanyl and fentanyl analogs have invaded the street-sourced opioid market in North America which has resulted in an unprecedented number of unintentional opioid overdoses. Existing guidelines to treat opioid use disorder are based on evidence that was developed when heroin was the primary street-sourced opioid and proposed dosages of opioid agonist treatments are increasingly inadequate to address patients with high opioid tolerances. CASE SUMMARY: The authors examine one case study of a patient with an extremely high opioid tolerance and review how responsive dose adjustments outside of the recognized maximum doses allowed for meaningful functional outcomes. DISCUSSION: This case demonstrates how patient-centered dose responses with a focus on functional outcomes supersede existing opioids agonist treatment dosing ranges, especially in the context of a patient with a higher than typical opioid tolerance.

The OPTIMA study, buprenorphine/naloxone and methadone models of care for the treatment of prescription opioid use disorder: Study design and rationale.

BACKGROUND: Rates of non-medical use of opioids, and opioid use disorders (OUD) have been rising throughout North America. Methadone and buprenorphine/naloxone are the recommended first-line treatment options for OUD in Canada. Most studies to date have been conducted among heroin users, in controlled settings, and using similar strict dosing schedules (i.e., daily witnessed ingestion) despite buprenorphine/naloxone's superior safety profile, which allows a more flexible take-home dosing schedule. This study was designed to assess the relative effectiveness of buprenorphine/naloxone- and methadone-based models of opioid agonist therapy (OAT) for the treatment of prescription opioid use disorder (POUD) in routine clinical care. METHODS: OPTIMA is a multicenter, open-label, pragmatic, randomized, two-arm, non-inferiority, 24-week study comparing the relative effectiveness of buprenorphine/naloxone (provided via flexible take-home doses) to methadone (provided via daily witnessed ingestion) models of OAT for the treatment of POUD. Approximately 276 non-pregnant adults meeting DSM-5 criteria for OUD, currently not in OAT, will be randomized across 7 Canadian sites. The primary outcome is reduction of non-medical opioid use, measured by bi-weekly urine drug screens during the 24-week study period. Secondary outcomes include treatment retention and satisfaction, safety, medication adherence, and patient engagement. DISCUSSION: The OPTIMA study is the first randomized clinical trial to compare the relative effectiveness of buprenorphine/naloxone (flexible take-home doses) versus methadone (daily witnessed ingestion) models of OAT for POUD in real-world clinical settings. This study will generate urgently needed evidence towards treatment options to guide the health system response to the ongoing opioid crisis. CLINICAL TRIAL REGISTRATION: NCT03033732.