Real-world effectiveness of medication-assisted treatment and psychotherapy for opioid use disorder: a national multi–health care organization analysis

Background Harm reduction strategies for opioid use disorder (OUD) emphasize pragmatic, evidence-based approaches that reduce overdose risk, relapse, and other adverse outcomes without requiring abstinence. Medication for opioid use disorder (MOUD) and structured psychotherapy represent core harm-reduction modalities, yet their real-world comparative effectiveness, alone and in combination, remains underexplored at scale. Methods A retrospective cohort study was conducted using the TriNetX Research Network, comprising de-identified electronic health records from 112 U.S. health systems. 18,047 adults aged 18–45 were identified with a diagnosis of opioid dependence (ICD-10 F11.20) between 2016 and 2025. Subjects were assigned to eight mutually exclusive treatment cohorts: no treatment (Cohort 1); buprenorphine alone (Cohort 2); methadone alone (Cohort 3); psychotherapy alone (30 minutes (Cohort 4), 45 minutes (Cohort 5), or 60 minutes (Cohort 6)); buprenorphine + psychotherapy (Cohort 7); and methadone + psychotherapy (Cohort 8), with combination treatments defined within a ±30-day window. Cox proportional hazards models estimated adjusted hazard ratios (aHRs) for remission (F11.21, F11.11) within 12 months. Results Buprenorphine (aHR = 2.33; 95% CI: 1.85–2.94), methadone (aHR = 2.50; 95% CI: 2.05–3.04), and psychotherapy (30 min: aHR = 2.18; 45 min: aHR = 2.38) were each independently associated with significantly higher remission compared to no treatment. The combination of buprenorphine + psychotherapy yielded the strongest effect (aHR = 5.26; 95% CI: 2.68–10.32). Anxiety diagnoses and gabapentinoid prescriptions were positively associated with remission; benzodiazepine co-prescription was negatively associated. Conclusions In this first national-scale, multi–health-care-organization analysis, both pharmacologic and psychosocial harm-reduction interventions were independently associated with improved OUD remission, with additive benefit when integrated. These findings underscore the value of embedding comprehensive, multimodal harm-reduction services within routine care and support policies promoting equitable access to both MOUD and behavioral health supports across diverse health systems.