Abstract
Acute moderate-to-severe pain is common after surgery, trauma, or musculoskeletal injury, but its management remains suboptimal. Current single-agent treatments are limited by safety concerns, narrow therapeutic windows, and abuse potential, leaving substantial unmet needs. Here, we aimed to review guidelines for the management of acute moderate-to-severe post-surgical, trauma-related, or musculoskeletal pain in adults and discuss existing and potential future analgesics in this setting. We searched PubMed to identify relevant guidelines and existing analgesics for acute pain. To identify compounds in development, we searched ClinicalTrials.gov and the European Union Clinical Trials Register. Guidelines universally recognize the limitations of single-agent analgesics (particularly those with a single mechanism of action [MoA]) and recommend a multimodal approach as an established standard for acute pain. The benefit-risk profiles of traditional treatments, including paracetamol (acetaminophen), nonsteroidal anti-inflammatory drugs, selective cyclooxygenase-2 inhibitors, and opioids, can be improved by combining agents targeting different pain pathways. In multimodal approaches, lower doses of constituent agents can be used to achieve the same or superior analgesic effects relative to the individual agents. In some cases, novel formulations and co-crystal technology offer enhanced physicochemical and pharmacokinetic properties over individual agents. Lastly, initiatives to increase patient awareness and education around pain management may improve treatment satisfaction and quality of life, and hasten recovery. In conclusion, management of acute moderate-to-severe pain remains inadequate. Multimodal analgesics may offer advantages over traditional single-agent treatments (that often have a single MoA) for acute moderate-to-severe post-surgical, trauma-related, or musculoskeletal pain in adults. Multimodal analgesics, combined with patient education initiatives and non-pharmacological measures, when necessary, offer promise in addressing unmet needs in this setting.