To illustrate a system-level, simulation-based approach for evaluating mitigation strategies to address the dramatic rise in abuse, addiction, and overdose deaths associated with the use of pharmaceutical opioid analgesics to treat chronic pain. Making available drug formulations with increased tamper-resistance, prescriber education programs, and programs that reduce rates of medical user-related abuse and addiction. Number of overdose deaths of medical users of pharmaceutical opioid analgesics, including those who abuse or have become addicted. A demonstration system dynamics model is developed, tested, and used to evaluate the impact of candidate mitigation strategies on the outcome measures. Tamper-resistant drug products will likely reduce overdose death rates but may not reduce overall deaths if there is increased prescribing. Prescriber education would likely reduce deaths through a reduction in patient access to pharmaceutical opioid analgesics. The system dynamics approach may have potential for opioid-related policy evaluation. However, metrics must be carefully selected, and trade-offs may be involved. For example, it may be difficult to limit negative outcomes associated with pharmaceutical opioids without adversely affecting chronic pain patients' access to pharmaceutical treatment. Ultimately, a combination of metrics and value judgments will be needed to properly evaluate mitigation strategies.