Approximately 2 million Americans live with opioid use disorder (OUD), most of whom also have chronic pain. The economic burden of chronic pain and prescription opioid misuse runs into billions of dollars. Patients on prescription opioids for chronic non-cancer pain (CNCP) are at increased risk for OUD and overdose. By adhering to the Center for Disease Control and Prevention (CDC) opioid prescribing guidelines, primary care providers (PCPs) have the potential to improve patient outcomes. But numerous provider, patient, and practice-specific factors challenge adherence to guidelines in primary care. Many of the barriers may be mediated by informatics interventions, but gaps in knowledge and unmet needs exist. This narrative review examines the risk assessment and harm reduction process in a socio-technical context to highlight the gaps in knowledge and unmet needs that can be mediated through informatics intervention.