A system dynamics simulation model helps explain historical trends in the United States regarding the nonmedical use of pharmaceutical opioids and its associated adverse outcomes. Drawing data from the National Survey of Drug Use and Health and guided by a panel of experts, model parameters were calibrated to replicate opioid use data from 1995-2005, and various policy interventions were simulated between 2006 and 2011. The simulation reproduces historical trends in nonmedical opioid use. Differential equations represent each of the three major components: 1) Peer initiation is modeled as the infection of a susceptible population by peers, which functions as a reinforcing feedback loop;2) Global availability of opioids for nonmedical use varies as a function of the number of opioid users and the amount of free leftover medicine obtained from prescription holders; and 3) limited personal accessibility motivates users to transition to alternative opioid sources that require payment. Interventions that have already been implemented, such as prescription drug take back days and school-based educational initiatives, are assessed for their downstream impacts on initiation and negative outcomes. Interventions currently under consideration, such as expanding and simplifying prescription drug returns, and rescheduling hydrocodone products to Schedule II, are also assessed for distal impacts. We conclude that system dynamics is an effective method for evaluating potential interventions and for understanding the complex system of pharmaceutical opioid misuse and its adverse outcomes.