Reducing opioid-related harm is a major patient safety priority. This simulation study used a mathematical model to predict the effect of existing opioid misuse interventions on opioid overdose mortality. The researchers compared the expected decline based on the current trend over time versus the effect of a 50% faster reduction in misuse. Their calculations suggest that interventions such as prescription drug monitoring programs and insurance coverage changes will result in only a small absolute decrease in opioid overdose deaths. The authors call for developing and testing other strategies for opioid safety. An Annual Perspective discussed the extent of harm associated with opioid prescribing and described promising practices to address opioid misuse.