Background and aims Opioid formulations with properties to deter abuse (abuse‐deterrent formulations; ADFs) have been developed as one response to the prescription opioid 'epidemic'. As for all medicines, ADFs undergo evaluation of safety and efficacy prior to registration for marketing. However, reduced extra‐medical use (the primary intended outcome of ADFs and reason for their introduction) can only be established in post‐marketing observational studies, comparing them to opioid formulations without abuse‐deterrent properties. This has implications for various features of study design and analysis. We discuss proposals for the design, conduct, governance and reporting of post‐marketing studies on the effectiveness of pharmaceutical and opioid ADFs. Methods A review of current guidance documents, public work‐shops and forums and our own experience with post‐marketing studies of ADFs. Results and conclusions Research questions for post‐marketing studies on ADFs of opioids should reasonably be framed around detecting any probable intended or unintended clinical and/or meaningful changes in specific aspects of extra‐medical use (e.g. injection use) and harms. Outcomes reported by prevalence and frequency of occurrence and disaggregated by specific product and route of administration can illustrate the magnitude of ADF impact. We argue that a multi‐faceted approach is required, using data from both general population and sentinel high‐risk cohorts and from primary and secondary data sources. The comparator (historical non‐ADF formulation of that opioid, equivalent current generic or similar opioid product), duration of monitoring and analytical approach require justification and should be sufficient to add weight to conclusions of causality. To maximize transparency, we recommend explicit declarations of funding and conflict of interest, establishment of an advisory committee, publication of study protocol and access to study results.