Optimal buprenorphine exposure to treat patients with opioid use disorder in the era of fentanyl and polysubstance use.

Background: In recent years, the United States opioid epidemic has been characterized by rising polysubstance use and increasing deaths due to fentanyl overdose, with stimulants playing a key role. We conducted an integrated analysis to evaluate the impact of fentanyl and polysubstance use on buprenorphine exposure-response relationships and to assess whether higher buprenorphine exposures may be required. Methods: Data from two large clinical trials of extended-release buprenorphine (BUP-XR) conducted before and after the widespread emergence of fentanyl in patients with moderate-to-severe opioid use disorder were integrated for analysis (N = 989). Approximately half of participants in the most recent study reported daily fentanyl use at baseline, with 29.2% reporting co-use of amphetamines/methamphetamines. Non-linear mixed effects models were developed to characterize treatment effects on opioid use and opioid craving. Time-to-event modeling was applied to evaluate treatment retention. Results: While sustained buprenorphine plasma concentrations of 2-3 ng/mL were adequate for most patients, higher concentrations of 5-6 ng/mL conferred additional benefits in specific subgroups, particularly among patients reporting daily fentanyl use in combination with amphetamines/methamphetamines. Additionally, patients from the most recent study required longer treatment duration to achieve maximum effects on opioid abstinence (6 months on average, although associated with large inter-patient variability). Frequent fentanyl use (≥2 times per day) was associated with higher levels of craving, especially among patients reporting injection as their primary route of administration. High craving emerged as a key determinant of treatment discontinuation, with a twofold higher dropout rate when craving >20 on a 100-mm visual analog scale. Older age and Black/African American race were associated with a lower dropout risk. Conclusion: Altogether, these analyses provide important insights into optimal buprenorphine exposure targets and advance understanding of patient treatment journey in the era of synthetic opioids and stimulant co-use.