Opioids are an indispensable step in the WHO pain relief ladder, but they also cause serious side effects and addiction. Alarmingly, in the US a fast rise in opioid use has been observed leading to an epidemic with large societal consequences. In the Netherlands, the use of opioids (especially oxycodone) has started to rise sharply from 2008 onwards. By now the first signs of increasing problematic opioid use become apparent, e.g. by an increase in the number of reports of oxycodone intoxications. In order to secure appropriate use of opioids and concomitantly preventing problematic use, we aim to get insight in the causes and effects of the increased opioid use, and to test potential interventions to prevent problematic use. First, epidemiological research will be performed, based on national and regional databases from several disciplines. Characteristics of users, risk factors for problematic use, and medical and societal effects will be investigated. Second, qualitative and quantitative research will be performed on perceptions of health care professionals, patients using opioids, and the general public. Topics are underuse and overuse, reasons for using and prescribing, and the illegal supply of opioids. A Delphi-study will further define problematic use of opioids. Third, screening instruments to identify patients at risk for problematic use will be developed and validated. Fourth, we will develop interventions to improve the process of prescribing and dispensing opioids (e.g. repeat prescriptions, redirection to a specialized pain team) and investigate these in pragmatic trials, the main outcomes being the level of pain control and the occurrence of problematic opioid use. Fifth, we will perform an impact analysis and develop implementation strategies (guidelines, education, toolkit). An advisory board (consisting of representatives of all scientific and societal consortium partners and related partners including patient organisations) will be involved in all stages of the research.