(115) Higher Buprenorphine Doses Improve Treatment Engagement and Outcomes in Opioid Use Disorder

Background & Introduction: Buprenorphine is a gold-standard medication for opioid use disorder (OUD) and remains the most widely prescribed option in office-based addiction treatment.1 Despite its proven efficacy, premature treatment discontinuation remains common, increasing the risk of relapse and overdose.2 Emerging evidence suggests that sustained treatment engagement depends on adequate dosing rather than medication initiation alone, a concern heightened by widespread fentanyl exposure.3 Current clinical guidance reflects this, emphasizing individualized titration (typically 12–24 mg/day, with doses up to 32 mg/day based on clinical response) rather than a fixed ceiling. Despite this shift, real-world evidence linking specific dose levels to the multifaceted patient outcomes, including adherence, retention, and critical events such as opioid overdose, remains limited.4,5
To address this gap and inform precision-dosing strategies, this study examined the association between buprenorphine dose and adherence, retention, and opioid overdose risk in a large, multi-state, commercially insured population with OUD. By applying advanced longitudinal modeling to real-world claims data, this study provides new evidence on how buprenorphine dose variability influences engagement and clinical outcomes, offering critical insights for buprenorphine management in the fentanyl era.

Methods: We conducted a retrospective longitudinal cohort study using the Merative MarketScan Commercial Database (2017–2019). The cohort included individuals aged 16 years or older with an OUD diagnosis who initiated buprenorphine treatment, defined as at least 30 consecutive days of therapy at a dose of ≥4mg. Patients were followed for 180 days from initiation. Based on buprenorphine prescription fill patterns and days supplied, the average daily dose (ADD) received was calculated, and patients were categorized into four groups: low (4– < 8 mg), moderate (8– < 16 mg), high (16– < 24 mg), and very high (24–32 mg).
Treatment adherence and retention across these dose categories were assessed using group-based trajectory modeling and Kaplan–Meier estimation, respectively. Adherence was defined as the proportion of days covered (PDC) during follow-up, with PDC ≥0.8 indicating adherence. Retention was measured as the continuous duration from initiation until discontinuation, defined as a ≥15-day gap between prescription fills.
The association between the ADD categories and the time to first opioid overdose was evaluated using a discrete-time survival model with a complementary log–log link. To minimize confounding, we balanced demographic, clinical, and treatment covariates, measured prior to buprenorphine initiation, across the dose groups using inverse probability of treatment weighting (IPTW).

Results: A total of 5,107 patients met the study inclusion criteria. The cohort was distributed across average daily dose categories as follows: 1,726 (33.8%) in the low-dose group, 2,033 (39.8%) in the moderate-dose group, 613 (12.0%) in the high-dose group, and 735 (14.4%) in the very-high-dose group. After IPTW, all baseline characteristics were well-balanced across dose groups (absolute standardized mean differences [ASMD] < 0.1).
Group-based trajectory modeling identified three distinct adherence patterns: steadily adherent, gradually declining, and rapidly declining. A clear dose-response relationship was observed, with the proportion of patients in the "steadily adherent" group increasing from 51.4% (low-dose) to 61.1% (moderate-dose), 62.5% (high-dose), and 68.5% (very-high-dose). Conversely, the "rapidly declining" trajectory was most prevalent in the low-dose group (29.1%) and decreased with each higher dose category (20.0%, 14.0%, and 12.4%, respectively).
Treatment retention analysis revealed a similar pattern. The mean (SD) days to buprenorphine discontinuation increased consistently with dose: 83 (2.0) days for low-dose, 130 (2.4) days for moderate-dose, 138 (4.9) days for high-dose, and 156 (7.8) days for very-high-dose therapy.
After IPTW adjustment, higher dosing was associated with significantly lower overdose risk overall (HR, 0.54; 95% CI, 0.48–0.61). In dose-specific comparisons against the low-dose group, the risk reduction was 6% for moderate-dose (HR, 0.94; 95% CI, 0.90–0.98), 32% for high-dose (HR, 0.68; 95% CI, 0.57–0.79), and 57% for very-high-dose therapy (HR, 0.43; 95% CI, 0.31–0.56).

Conclusion & Discussion: These real-world findings demonstrate that higher buprenorphine doses are associated with greater adherence stability, longer retention, and reduced overdose risk. The results provide empirical support for evolving clinical guidance that encourages individualized dose titration up to 32 mg/day, a strategy of critical importance amid the widespread prevalence of high-potency synthetic opioids.3 While this large, multi-state cohort strengthens generalizability, the observational design limits causal inference, and claims data may underreport clinical nuances such as actual drug exposure, symptom severity, and concurrent psychosocial interventions. Furthermore, the findings may not be generalizable to patients covered by other insurance types, such as Medicaid or Medicare, or those who are uninsured.
Despite these limitations, these findings provide actionable evidence that optimizing buprenorphine dosing can meaningfully enhance patient engagement and safety. Dose optimization could represent a pragmatic, evidence-based strategy to improve OUD outcomes, reduce mortality, and inform future clinical and policy frameworks for opioid addiction treatment. Prospective studies are warranted to confirm these causal relationships and refine precision-dosing protocols.

References: 1. Volkow ND, Frieden TR, Hyde PS, Cha SS. Medication-Assisted Therapies — Tackling the Opioid-Overdose Epidemic. New England Journal of Medicine. 2014;370(22):2063-2066. doi:10.1056/NEJMp1402780
2. Chua KP, Nguyen TD, Zhang J, Conti RM, Lagisetty P, Bohnert AS. Trends in Buprenorphine Initiation and Retention in the United States, 2016-2022. JAMA. 2023;329(16):1402-1404. doi:10.1001/jama.2023.1207
3. Chambers LC, Hallowell BD, Zullo AR, et al. Buprenorphine Dose and Time to Discontinuation Among Patients With Opioid Use Disorder in the Era of Fentanyl. JAMA Network Open. 2023;6(9):e2334540-e2334540. doi:10.1001/JAMANETWORKOPEN.2023.34540
4. Weiner MG, Livshits A, Carozzoni C, et al. Derivation of Malignancy Status from ICD-9 Codes. AMIA Annual Symposium Proceedings. 2003;2003:1050.
5. Food and Drug Administration. Modifications to Labeling of Buprenorphine-Containing Transmucosal Products for the Treatment of Opioid Dependence. Federal Register. December 27, 2024. Accessed October 24, 2025. https://www.federalregister.gov/documents/2024/12/27/2024-30776/modifications-to-labeling-of-buprenorphine-containing-transmucosal-products-for-the-treatment-of