Opioid tolerance resulting from long-term opioid consumption for chronic pain or from substance use disorder adds a layer of complexity to managing pain in the critical care setting. This article discusses similarities and differences of these 2 conditions. The phenomenon of tolerance and opioid-induced hyperalgesia are presented. Prevention of opioid withdrawal, when patients are on methadone or buprenorphine, is described. An overview of the neurophysiology of pain and substance use disorder is presented. Practical clinical suggestions are given to assist the critical care nurse in caring for these complex patients.