Question: What is the real-world effectiveness of different treatment pathways for opioid use disorder?

Findings: In this comparative effectiveness research study of 40 885 adults with opioid use disorder that compared 6 different treatment pathways, only treatment with buprenorphine or methadone was associated with reduced risk of overdose and serious opioid-related acute care use compared with no treatment during 3 and 12 months of follow-up.

Meaning: Methadone and buprenorphine were associated with reduced overdose and opioid-related morbidity compared with opioid antagonist therapy, inpatient treatment, or intensive outpatient behavioral interventions and may be used as first-line treatments for opioid use disorder.