Opioids frequently produce adverse CNS side effects in ambulatory settings, providing a rationale for improving opioid analgesia by minimizing adverse effects. LNS5662 is a flavonol which is thought to activate PgP efflux of pump ligands at the blood brain barrier. In this pilot study, we tested the hypothesis that LNS5662 improves the tolerability and safety of oxycodone without impairing analgesia. Healthy subjects (N=65) undergoing third molar removal were randomly allocated to receive 500 mg oral LNS5662 or matching placebo at 1 hr prior to surgery. All subjects received 10 mg oral oxycodone immediately prior to surgery. As expected, pupil size decreased with increasing oxycodone plasma concentration. Oxycodone concentrations did not differ between groups prior to surgery, at 1 hr, or at 4 hr. Total Nausea and Vomiting Score (TNVS) was calculated for the time from dosing through 24 hr. More subjects in the LNS5662 group (67%) than in the placebo group (56%) experienced “no” nausea or vomiting. Median TNVS was 0.39 (LNS5662) and 0.56 (placebo). No subjects in the LNS5662 group experienced the most severe level of nausea or vomiting vs 3 in the placebo group. Fewer subjects in the LNS5662 group (33.3%) than the placebo group (43.8%) requested anti-emetic, and the placebo group tended to request anti-emetic sooner (280 vs 306 min). Importantly, the LNS5662 treated group had lower mean pain intensity than the placebo group. All subjects except one requested additional analgesic doses; there was no difference in median time to request for a second analgesic (120 and 131 min, respectively). LNS5662 given 1 hr prior to oxycodone may ameliorate the severity of nausea and vomiting while not interfering with analgesic efficacy. A study with additional LNS5662 doses and a larger sample size is needed to confirm these results.