Optimal pain relief requires a balance between adequate analgesia and risk of adverse effects. Opioids remain the cornerstone for managing moderate to severe pain, but are associated with opioid-induced respiratory depression (OIRD) and gastrointestinal complications. Opioids exert their analgesic effects predominantly via G-protein signaling, however, adverse effects including OIRD are mediated by the β-arrestin pathway. Oliceridine is the first of a new class of biased opioid agonists that preferentially activate G-protein signaling over β-arrestin, which would theoretically improve analgesia and reduce the risk of adverse effects. Oliceridine is approved by the Food and Drug Administration (FDA) for the treatment of moderate to severe acute pain. The efficacy of Oliceridine was mainly established in two randomized controlled Phase III clinical trials of patients experiencing moderate to severe pain after bunionectomy (APOLLO-1) and abdominoplasty (APOLLO-2). The results of the APOLLO studies demonstrate that Oliceridine, when administered via patient-controlled analgesia (PCA) demand boluses of 0.35mg and 0.5mg, provides superior analgesia compared to placebo, and is equianalgesic to PCA morphine 1mg demand boluses, without significant difference in the incidence of respiratory complications. In a more pragmatic trial of surgical and non-surgical patients, the ATHENA observational cohort study reported rapid onset of analgesia with Oliceridine given with or without multimodal analgesia. However, these studies were designed to evaluate analgesic efficacy, and it is still uncertain if Oliceridine has a better safety profile than conventional opioids. Although several post hoc analyses of pooled data from the APOLLO and ATHENA trials reported that Oliceridine was associated with lower OIRD and gastrointestinal complications compared to morphine, prospective studies are needed to elucidate if biased agonists such as Oliceridine reduce the risk of adverse effects compared to conventional opioids.