This chapter describes the risk evaluation and mitigation strategies for opioids. Extended-release/long-acting (ER/LA) opioids were prescribed to approximately 3.8 million patients annually between 2000 and 2009. The longer lasting agents provide steady-state analgesia to negotiate daily pain. Chronic pain promotes disability, lost productivity and diminished quality of life. Opioids have been a standard treatment for various types of chronic pain. In 2011, the Food and Drug Administration (FDA) announced the REMS requirement for ER/LA opioids. Patient education and addiction risk, overdose and misuse represent the highlights of this program. REMS agents include morphine ER, hydromorphone ER, oxycodone, oxymorphone ER, tapentadol ER, morphine-naltrexone ER, methadone, fentanyl formulations, buprenorphine systems and naloxone (Suboxone).