BACKGROUND: Increases in prescribing of buprenorphine for pain or opioid use disorder (OUD) have led to concerns regarding its interactions with other drugs used concomitantly and risk of adverse clinical outcomes.

OBJECTIVE: To synthesize current evidence on associations between buprenorphine-drug interactions and clinical outcomes among patients with pain or OUD.

METHOD: A systematic review was conducted by searching MEDLINE, CINAHL, APA PsycINFO, and Web of Science from inception through June 2025 on studies examining buprenorphine-drug interactions and clinical outcomes. The PRISMA 2020 guideline was used for assessing and reporting data quality. Reviews were included if they reported clinical outcomes such as OUD, opioid overdose (OD), all-cause mortality, or emergency department (ED) visits. Data extraction and risk of bias assessment were performed independently by 2 reviewers. Heterogeneity of interacting drug exposure and outcomes studied precluded meta-analysis.

RESULTS: Seven studies were included. All studies were observational in design, focused on patients with OUD, and evaluated only pharmacodynamic, not pharmacokinetic, interactions involving buprenorphine with central nervous system depressants. The reviewed studies showed an increased risk of OD in patients who co-used buprenorphine with benzodiazepine, Z-drugs, pregabalin, gabapentin, clonidine, or oxycodone (vs. buprenorphine only), with mixed results for non-fatal OD being noted in concomitant buprenorphine-benzodiazepine use. An increased risk of drug-related poisoning (including opioid overdose) was observed in patients with co-use of buprenorphine and benzodiazepine, with null results being noted in patients with co-use of buprenorphine with gabapentin or prescription amphetamines (vs. buprenorphine only). An increased risk of all-cause mortality was observed in patients with co-use of buprenorphine with Z-drugs or pregabalin, with mixed results being noted in concomitant buprenorphine-benzodiazepine use (vs. buprenorphine only). Only one study showed an increased risk of all-cause ED visits in patients with buprenorphine-benzodiazepine use vs. with buprenorphine alone.

CONCLUSION: This review suggests inconclusive evidence on potential adverse outcomes associated with concomitant buprenorphine-drug use compared with buprenorphine use only. Further population-based studies with rigorous study designs are needed to elucidate associations between buprenorphine-drug interactions and clinical outcomes.

REGISTRATION

PROSPERO CRD420251052355.