OBJECTIVE: To review clinical trials of intravenous opioids for severe acute pain in the emergency department (ED) and to provide an approach for optimization of therapy. DATA SOURCES: Articles were identified through a search of Ovid/MEDLINE (1948-August 2010), PubMed (1950-August 2010), Cochrane Central Register of Controlled Trials (1991-August 2010), and Google Scholar (1900-August 2010). The search terms used were pain, opioid, and emergency department. STUDY SELECTION AND DATA EXTRACTION: The search was limited by age group to adults and by publication type to comparative studies. Studies comparing routes of administration other than intravenous or using non-opioid comparators were not included. Bibliographies of all retrieved articles were reviewed to obtain additional articles. The focus of the search was to identify original research that compared intravenous opioids used for treatment of severe acute pain for adults in the ED. DATA SYNTHESIS: At equipotent doses, randomized controlled trials have not shown clinically significant differences in analgesic response or adverse effects between opioids studied. Single opioid doses less than 0.1 mg/kg of intravenous morphine, 0.015 mg/kg of intravenous hydromorphone, or 1 μg/kg of intravenous fentanyl are likely to be inadequate for severe, acute pain and the need for additional doses should be anticipated. In none of the randomized controlled trials did patients develop respiratory depression requiring the use of naloxone. Future trials could investigate the safety and efficacy of higher doses of opioids. Implementation of nurse-initiated and patient-driven pain management protocols for opioids in the ED has shown improvements in timely provision of appropriate analgesics and has resulted in better pain reduction. CONCLUSIONS: Currently, intravenous administration of opioids for severe acute pain in the ED appears to be inadequate. Opioid doses in the ED should be high enough to provide adequate analgesia without additional risk to the patient. EDs could implement institution-specific protocols to standardize the management of pain.