BACKGROUND: High-dose opioid prescribing is associated with an increased risk of harms, including death. OBJECTIVE: The aim of this article is to discuss the concept of high-risk opioid prescribing, as well as relevant management strategies for patients on >100 mg oral morphine equivalent daily dose (OMEDD). The six 'Rs' approach to managing high-risk opioid prescribing (Rotation of opioids; Reduction; Replacement pharmacotherapy; Reversal with naloxone; Referral; Restriction of supply) is discussed. DISCUSSION: The six Rs is an aide-memoire that summarises the management options available to mitigate the risk of high OMEDDs. However, an effective therapeutic alliance between clinician and patient remains the foundation of all risk mitigation strategies.