The ongoing opioid crisis in the US requires clinicians to strike a balance between the benefits of adequate postsurgical analgesia and opioid related risks. This balance is not limited to the immediate postoperative period, but extends to potential prolonged opioid usage. The objectives of postoperative pain management include: (1) efficacious and safe analgesia to minimize suffering while aiming to spare and replace opioids; (2) promoting functional recovery and mobility enabling early discharge; (3) providing options for continued opioid-free regimens at discharge while avoiding a transition from acute to chronic pain. New treatment guidelines and their impact on clinical practice will be critically reviewed. In the search for efficacious non-opioid analgesics with a favorable adverse effect profile, recently approved analgesics for acute pain provide opportunities but may also have drawbacks. For new development candidates, suitable regulatory guidance to support appropriate methods, endpoints, and labeling targets related to reduction or replacement of opioids is required.