Prescription opioid-related mortality is increasing in Australia. Real-time Prescription Drug Monitoring Programs (PDMPs) have recently been implemented as a strategy to reduce opioid-related harm. PDMPs enable prescribers and dispensers to view patients' prescription history before writing or dispensing a high-risk medication. This article considers the complexity of accurately evaluating PDMP effectiveness. To ensure sustainable implementation of these systems in Australia, a wide range of outcomes need to be measured. These include any unintended consequences and impacts on comprehensive patient care. Furthermore, intervention evaluation may be disrupted by concurrent interventions, limited methodologies and the shortcomings of the current approach.