Safety of High-Dose Buprenorphine Initiation Among Fentanyl-Exposed Patients

We aimed to evaluate the safety, tolerability, and feasibility of initiating high-dose buprenorphine (BUP) in fentanyl-positive emergency department (ED) patients with untreated opioid use disorder (OUD). We hypothesized that a 32 mg initiation dose would be safe and well tolerated compared with standard 12 mg dosing.

This multi-site, open-label, serial-cohort, dose-escalation trial enrolled adults with moderate-to-severe OUD in withdrawal (COWS ≥ 8) and fentanyl-positive urine drug screens. Participants received either standard-dose BUP (12 mg; 8 mg + 4 mg) or high-dose BUP (32 mg; 16 mg + 16 mg). Cohorts began with 10 participants and expanded by 5 if any grade ≥3 treatment-emergent adverse event (TEAE) occurred; dose escalation required Data Safety Monitoring Board approval. Participants were observed for 4 hours post-dose and followed for 7 days. Primary outcomes were grade ≥3 TEAEs, respiratory depression (RR < 8/min or SpO₂ < 88%), and precipitated withdrawal (PW; COWS increase ≥12 within 90 min). Secondary outcomes included nausea/vomiting, sedation, cognitive impairment, craving, drug use, and engagement in care.

Twenty-six individuals enrolled; one withdrew after consent and one after PW. Eight participants had had a COWS increase of 5 (7 standard-dose, 1 high-dose) of which three (20%) experienced PW all in the standard-dose cohort, prompting expansion to 15 participants; no PW occurred in the high-dose cohort. No other grade ≥3 TEAEs occurred. Sedation occurred in two standard-dose participants. Nausea occurred in 18 participants (11 standard-dose, 7 high-dose); vomiting in 4 (2 per cohort). Two standard-dose participants had transient cognitive impairment. Participants reported opioid abstinence on 78% of follow-up days (76% standard-dose vs 79% high-dose). Mean craving scores were 46.3/100 (12 mg) and 29.4/100 (32 mg), a 37% reduction with high-dose initiation. 7-day engagement in care was low (2 standard-dose, 1 high-dose)

High-dose (32 mg) BUP initiation in fentanyl-positive ED patients was safe, well tolerated, and feasible. Paradoxically, PW occurred exclusively in the standard-dose cohort, undermining long-standing caution around higher induction doses. Findings support advancing high-dose BUP to multicenter efficacy testing.