OPTIMA
Optimizing patient centered-care: A pragmatic randomized control trial comparing models of care in the management of prescription opioid misuse
Available Data
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Protocol
The study protocol provides detailed information about the research objectives, methodology, and procedures. It is available for direct download below for those who wish to learn more about the study design.
Data Dictionary
The data dictionary contains detailed descriptions of all variables included in the dataset, along with their definitions and coding information. It is available for direct download below.
Background
In response to the overdose crisis and limited access to treatment for people with opioid use disorder (OUD), the Canadian Research Initiative on Substance Matters (CRISM) launched the OPTIMA trial in 2017. The trial aimed to support a more flexible approach to opioid agonist therapy by comparing standard methadone with flexible buprenorphine/naloxone (BUP/NX) models of care in real-world clinical settings for individuals with prescription-type OUD (POUD). OPTIMA was a multicenter, open-label, two-arm, noninferiority, randomized pragmatic trial involving 272 participants requiring agonist therapy. It was conducted at seven sites in BC, Alberta, Ontario, and Quebec.
Recruitment ran from October 2, 2017, to March 23, 2020. The COVID-19 pandemic led the study team, after consulting the DSMB, to stop recruitment at 272 participants, just shy of the planned 276, with negligible impact on statistical power.
Eligible participants were treatment-seeking adults aged 18–64, diagnosed with OUD related to prescription-type opioids (licit or illicit, including fentanyl) and requiring opioid agonist therapy (OAT). Exclusion criteria included unstable psychiatric or medical conditions preventing safe participation, pain requiring opioids, heroin as the primary opioid in the past 30 days, enrollment in OAT within 30 days before screening, use of medications that interact with study drugs, history of severe adverse reactions to study medications, or pending legal actions preventing study completion. Pregnant and breastfeeding women, as well as women planning to conceive, were also excluded.
After receiving a full explanation of the study, eligible participants provided written consent at the screening visit. They were then randomized in a 1:1 ratio to receive either buprenorphine/naloxone or methadone. Randomized participants met with a study physician to receive their prescription and discuss their treatment plan and induction procedures. Treatment initiation began within 14 days post-randomization. Participants attended follow-up visits every two weeks for 24 weeks, providing urine samples and updating demographic, drug use, and medical information.
Treatment Initiation
Most participants started buprenorphine/naloxone treatment at a 4 mg/1 mg dose. Additional doses, up to 12 mg/3 mg, were given sublingually on the first day. Titration continued over the following days as needed, up to a maximum recommended daily dose of 24 mg/6 mg. Clinically stable participants could receive take-home doses at their physician’s discretion, typically one-week carries within two weeks of initiation and two-week carries within four weeks, unless deemed unsafe or clinically inappropriate.
Participants in the control group started methadone with a maximum oral dose of 30 mg on day one. Doses were gradually increased by 5–10 mg every four or more days, with typical target doses of 60–120 mg/day. After two to three months of supervised ingestion, stable participants could take home doses at their physician’s discretion, following Canadian local guidelines.
Take home dosing
Among retained participants, the mean maximum (± SD) dose during the study was 20.3 (± 7.4) mg for buprenorphine (n=32) and 81.8 (± 37.3) mg for methadone (n=45).
The proportion of participants who switched to another OAT was 22.5% (31/138) in the buprenorphine/naloxone group and 11.9% (16/134) in the methadone group.
The proportion of participants who received take-home doses was 73.8% (76/103) for buprenorphine/naloxone and 32.1% (34/106) for methadone. The average time (± SD) from treatment initiation to the first take-home dose was 12.7 (± 20.3) days for buprenorphine/naloxone and 85.2 (± 39.8) days for methadone.
When take-home doses were first prescribed, participants received an average of 4.1 (± 3.2) buprenorphine/naloxone doses or 2.1 (± 1.8) methadone doses. The mean maximum (± SD) number of consecutive days of take-home doses was 13.1 (± 12.3) days for buprenorphine/naloxone and 4.9 (± 5.1) days for methadone.
Outcome Measures
Primary outcome
Our primary outcome was opioid use, measured by the proportion of opioid-free urine drug screens (UDS) over 24 weeks. Missing values were counted as positive. UDS from participants who discontinued their assigned treatment, switched to another OAT, or attended a visit outside the ±7-day window were also considered positive. Specimens were tested for morphine, oxycodone, fentanyl, benzodiazepines, cocaine, amphetamine, methamphetamine, 9-tetrahydrocannabinol, buprenorphine, methadone, and tramadol.
We expected an absolute mean difference of 7.5% in opioid-free UDS between the methadone (75%) and buprenorphine/naloxone (67.5%) groups, with a 25% standard deviation (SD). Following consultation with addiction specialists and researchers, the non-inferiority margin was set at 15%. Based on these assumptions, a power calculation (0.05 one-sided alpha, 80% power, 1:1 allocation, R software v3.3.1) resulted in 276 participants (138 per group).
The mean (± SD) proportion of opioid-free UDS was 24.0 (± 34.4)% in the buprenorphine/naloxone group and 18.5 (± 30.5)% in the methadone group. The adjusted mean difference was 5.6% (95% CI = -0.3 to + highest possible value, p = 0.040), demonstrating non-inferiority in all mITT and per-protocol analyses. Post hoc analysis showed an adjusted mean difference of 8.7% (95% CI = 3.0 to + highest possible value, p = 0.0065) in the first 12 weeks, decreasing to 2.4% in the last 12 weeks (95% CI = -3.3 to + highest possible value, p = 0.24). The number of collected UDS did not differ by treatment group (buprenorphine/naloxone: 817/1655, 49.4%; methadone: 900/1596, 56.4%).
Retention
Retention in treatment, a secondary outcome, was defined as the proportion of participants with both an active prescription and a positive UDS for their assigned OAT at week 24. Participants who switched OAT during the trial were not considered retained in their assigned treatment. Retention on any OAT (buprenorphine/naloxone, methadone, diacetylmorphine, slow-release morphine, or hydromorphone) at week 24 was also assessed.
Participants receiving buprenorphine/naloxone had lower odds of retention in this treatment compared with methadone (adjusted OR = 0.47, 95% CI = 0.24–0.90, p = 0.024). This was also true when retention was defined simply as having a prescription at week 24. However, the odds of being retained on any OAT did not differ significantly between the groups.
Safety
We monitored all adverse events (AEs) and serious adverse events (SAEs) from screening until 30 days after the study ended. Study physicians graded the severity of each AE and assessed its relation to the study medication. An independent Data Safety and Monitoring Board reviewed participants’ safety data every six months.
The most common drug-related AEs were withdrawal symptoms, overdose, and hypogonadism. The risk of any drug-related AE or SAE was similar between groups (HR = 0.84, 95% CI = 0.32–2.25, p = 0.73). One death occurred in each group, but neither was linked to the assigned treatment.
Quality of Life
Quality of life, an exploratory outcome, was measured at baseline and every four weeks using the EuroQol-5D, which includes a visual analogue scale (EQ VAS; 0–100). Mean (± SD) quality of life increased significantly in both groups from baseline (buprenorphine/naloxone: 57.0 ± 21.4; methadone: 61.2 ± 20.0) to week 24 (buprenorphine/naloxone: 72.2 ± 20.2; methadone: 71.0 ± 18.5; probability of Type II error = 9.27, 95% CI = 5.14–13.39, p < 0.0001).
There was no statistically significant difference between groups (probability of Type II error = -4.20, 95% CI = -8.90–0.50, p = 0.080), but a significant time × treatment interaction was observed (p = 0.033). Quality of life changed differently over time depending on treatment: the buprenorphine/naloxone group showed a steeper initial increase, while the methadone group improved progressively.
Analysis of other secondary and exploratory outcomes—including medication adherence, treatment satisfaction, patient engagement, pain, proportion of participants initiating taper, and cost-effectiveness—is ongoing. Results are expected within 2022.
Implications
This pragmatic trial confirmed that a flexible take-home buprenorphine/naloxone model of care was safe and non-inferior to closely supervised methadone in reducing opioid use among Canadians with POUD. These findings add to the limited, low-quality evidence on non-supervised dosing strategies, which have shown no significant differences from close supervision for retention or opioid cessation. In this study, buprenorphine/naloxone was not only non-inferior to methadone for opioid-free UDS but also showed better outcomes across mITT and sensitivity analyses.
Results from OPTIMA provide valuable evidence on the effectiveness of OAT for prescription opioid use disorders. Publications from this study will also generate additional evidence on patient retention, best practices for OAT administration, and other critical areas such as mental health, cost-effectiveness, and overdose outcomes across different treatment options.
Publications
- Jutras-Aswad, D., Le Foll, B., Ahamad, K., Lim, R., … OPTIMA Research Group. (2022). 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. American Journal of Psychiatry.
- , , , , , , … OPTIMA Research Group. (2022). 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. Addiction. 117( 10): 2662– 2672.
- McAnulty, C., Bastien, G., Socias, E., Bruneau, J., Le Foll, B., Lim, R., Brissette, S., Ledjiar, O., Marsan, S., Talbot, A., Jutras-Aswad, D., OPTIMA Research Group. (2022). 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. Drug and Alcohol Dependence. Volume 239.
- Hassan AN, Bozinoff N, Jutras-Aswad D, Socias ME, Stewart SH, Lim R, Le Foll B; OPTIMA Research Group. (2022). Patient Satisfaction With Standard Methadone and Flexible Buprenorphine/Naloxone Models of Care: Results From a Pragmatic Randomized Controlled Clinical Trial. J Addict Med. 2022 Aug 2.
