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.