The clinical utility of conventional IV opioids is limited by the occurrence of opioid-related adverse events. Oliceridine is a novel G protein-biased μ-opioid receptor agonist designed to provide analgesia with an improved safety and tolerability profile. This phase III, double-blind, randomized trial (APOLLO-2 [NCT02820324]) evaluated the efficacy and safety of oliceridine for acute pain following abdominoplasty.Patients received a loading dose of either placebo, oliceridine (1.5 mg), or morphine (4 mg), followed by demand doses via patient-controlled analgesia (0.1, 0.35, or 0.5 mg oliceridine; 1 mg morphine; or placebo) with a 6-minute lockout interval. The primary endpoint was the proportion of treatment responders over 24 hours for oliceridine regimens compared to placebo. Secondary outcomes included a predefined composite measure of respiratory safety burden (RSB, representing the cumulative duration of respiratory safety events) and the proportion of treatment responders vs. morphine.A total of 401 patients were treated with study medication. Effective analgesia was observed for all oliceridine regimens, with responder rates of 61.0%, 76.3%, and 70.0% for the 0.1-, 0.35-, and 0.5-mg regimens, respectively, compared with 45.7% for placebo (all P  0.05 vs. placebo: 0.60 [2.82]). The RSB measure for morphine was 1.72 (3.86) (P < 0.05 vs. placebo). Gastrointestinal adverse events increased in a dose-dependent manner across oliceridine demand dose regimens (0.1 mg: 49.4%; 0.35 mg: 65.8%; 0.5 mg: 78.8%; vs. placebo: 47.0%; and morphine: 79.3%). In comparison to morphine, the proportion of patients experiencing nausea or vomiting was lower with the 2 equi-analgesic dose regimens of 0.35 and 0.5 mg oliceridine.Oliceridine is a safe and effective IV analgesic for the relief of moderate to severe acute postoperative pain in patients undergoing abdominoplasty. Since the low-dose regimen of 0.1 mg oliceridine was superior to placebo but not as effective as the morphine regimen, safety comparisons to morphine are relevant only to the 2 equi-analgesic dose groups of 0.35 and 0.5 mg, which showed a favorable safety and tolerability profile regarding respiratory and gastrointestinal adverse effects compared to morphine. These findings support that oliceridine may provide a new treatment option for patients with moderate to severe acute pain where an IV opioid is warranted.