CME Information : A Systematic Review and Meta-analysis of Ketamine as an Alternative to Opioids for Acute Pain in the Emergency Department

Background: Opioids are commonly prescribed in the emergency department (ED) for the treatment of acute pain. Analgesic alternatives are being explored in response to an epidemic of opioid misuse. Low-dose ketamine (LDK) is one opioid alternative for the treatment of acute pain in the ED. Objectives: This systematic review and meta-analysis sought to quantify whether LDK is an effective and safe opioid alternative for acute pain reduction in adults in the ED setting. (PROSPERO Registration Number CRD42017065303). Methods: This was a systematic review of randomized controlled trials comparing intravenous opioids to LDK for relief of acute pain in the ED. Studies where the control group initially received opioids prior to ketamine were excluded. A research librarian designed the electronic search strategy. Changes in visual analog scale or numeric rating scale pain scales were analyzed to determine the relative effects of LDK and opioids in the treatment of acute pain. Results: Three studies met the criteria for inclusion in this meta-analysis. Compared to pain scale reduction with morphine, ketamine was not inferior (relative reduction = 0.42, 95% confidence interval = –0.70 to 1.54). No severe adverse events were reported in any study, but higher rates of nonsevere adverse events were observed with ketamine. Conclusions: Ketamine is noninferior to morphine for the control of acute pain, indicating that ketamine can be considered as an alternative to opioids for ED short-term pain control. Acute pain is one of the most common causes of emergency department (ED) presentations with up to 78% of visits including pain as a presenting complaint. Timely, effective, and compassionate pain management is a critical element of patient care, and opioids are one well-accepted, readily available, and time-tested option to treat pain in the ED. Despite increasing reliance upon opioids for acute analgesia in the ED, oligoanalgesia is still common, particularly in African Americans and women as well as the young From the Division of Public Health Sciences (CRTS, GAC) and the Division of Emergency Medicine (CRC, ESS), Washington University School of Medicine (NK, CHS, MD), St. Louis, MO; St. Louis, MO; Maimonides Medical Center (SM), Brooklyn, NY; and the Department of Emergency Medicine, Bergan Mercy Medical Center (JM), Omaha, NE. Received February 19, 2018; revision received May 30, 2018; accepted June 8, 2018. The authors have no relevant financial information or potential conflicts to disclose. Author contributions: NK—study design, acquisition, analysis, drafting, revision, and statistics; CHS—drafting and revision; CS—study design, analysis, revision, and statistics; MD—data acquisition; CRC—study design, analysis, and revision; GAC—study design, analysis, revision, and statistics; SM—acquisition and revision; JM—acquisition and revision; and ESS—study design, drafting, and revision. Supervising Editor: James Miner, MD. Address for correspondence and reprints: Evan S. Schwarz, MD; e-mail: schwarze@wustl.edu. ACADEMIC EMERGENCY MEDICINE 2018;25:1087–1097. © 2018 by the Society for Academic Emergency Medicine doi: 10.1111/acem.13502 ISSN 1553-2712 1087 and the very old. Several ED-based physician research groups, such as the Alternatives to Opioids (ALTO) program and the opioid-free ED program, are investigating methods and the efficacy of reducing ED usage of opioids for certain conditions while also improving overall pain control. While the goal is not to completely eliminate the use of opioids as they are useful, safe, and effective in the correct patient populations, demonstrating that these alternative analgesics are comparable to opioids is important if they are to be used, particularly if used as a replacement for opioids. Ketamine, one compelling opioid alternative, is a noncompetitive antagonist of N-methyl-D-aspartate receptors in the central nervous system. ED physicians safely administer ketamine for procedural sedations and intubation as well as prehospital agitation. Subdissociative-dose ketamine refers to intravenous (IV) administration of ketamine at doses of ≤0.5 mg/kg. As patients can still become dissociated or have psychiatric complaints, we shall instead refer to this as lowdose ketamine (LDK). Two previously conducted reviews evaluating LDK in the ED suffered significant limitations by including pediatric trials, trials where ketamine was administered with other analgesics, and patients where ketamine was administered for procedural sedation leaving the independent effect of ketamine on acute pain control unresolved. Our primary objective was to quantify the shortterm (≤60 minutes) analgesic efficacy of LDK, administered as an initial one-dose, single-agent IV bolus in adults between 18 and 65 years of age in the ED via a systematic review and meta-analysis. The decision to impose strict requirements provides this review additional accuracy as compared with prior reviews that could neither isolate effects of different routes of administration or the potential biases of noncontrolled studies. The secondary objective was to quantify the risk of adverse effects attributable to ketamine used as an opioid alternative for ED analgesia.