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The United States is in the midst of a nationwide public health emergency: an epidemic of opioid misuse and abuse that has been called the deadliest drug crisis in American history. This article reviews the current status of the opioid epidemic, the trends over the last 30-40 years that may have contributed to the epidemic, and a population health approach to addressing the epidemic. The epidemic is conceptualized from a population health perspective—an upstream and midstream perspective focusing on prevention and a downstream perspective targeting access to evidence-based interventions and maximizing health whether using or abstaining. Within the context of acute care, this approach will include patient screening for opioid use and other risk factors for addiction, use of opioid-sparing analgesics, and follow-up care that addresses pain and pain relief without opioids. For individuals who need addiction treatment, a gradualism philosophy is put forward. Gradualism recognizes the incremental nature of behavior change and recommends strategies to maximize health and functioning—through harm reduction—at all points along the journey to overcome addiction. Working within communities to address the broad factors that contribute to opioid-related substance use disorder is also essential.