Project Summary Pain is one of the most common reasons for children to visit an emergency department (ED) and is associated with short- and long-term consequences when inadequately treated. Intravenous (IV) morphine is the prototypical and most commonly administered parenteral analgesia for treating moderate to severe acute pain in children. However, IV morphine is associated with acute adverse events such as respiratory depression and hypotension. In addition, there is hesitation amongst caregivers and clinicians to administer opioids to children, leading to withholding or under-dosing analgesics in children with pain and thereby perpetuating the undertreatment of pain and the resulting short- and long-term sequelae. Ketamine is an NMDA-antagonist that has the potential to improve both short- and long-term sequelae of acute pain experienced by children presenting to the ED. IV ketamine has been shown to be an effective and safe analgesic when given using sub-dissociative doses to adults with acute pain in the ED or pre-hospital setting. Sub-dissociative ketamine's analgesic efficacy and favorable safety profiles make it an attractive alternative to morphine. In addition, ketamine may improve pain-related function and decrease potential long-term sequelae of acute painful events such as chronic pain and medication dependency, post-traumatic stress disorder, anxiety and depression. The aims of this study are to demonstrate that IV sub-dissociative ketamine is as effective as IV morphine for treating acute pain in children and that its rate of cardiorespiratory events is substantially less compared to morphine. Additionally, we aim to determine if children who receive ketamine will have better levels of pain-related function during the first week after ED presentation, and have greater odds of experiencing more favorable post-traumatic stress, anxiety and depression outcomes up to 6 months following their ED visit. We will achieve these aims by conducting an 8-site phase 3 randomized clinical trial within the Pediatric Emergency Care Applied Research Network (PECARN) comparing IV sub-dissociative ketamine to IV morphine in children presenting to the ED with acute pain. We will enroll 1010 children 6 to 17 years of age with moderate to severe acute pain and require IV morphine for analgesia. In addition, we will study children who most commonly receive parenteral opioids in the ED, namely those with abdominal pain or extremity fractures. We will collect measures of pain intensity and analgesic efficacy and assess for acute adverse events during the child's ED course and conduct follow-up procedures assessing pain-related function, analgesic use/misuse, mental health and behavioral outcomes up to 6 months after the index ED visit. The findings of this study have the potential to fundamentally change how acute pain is managed in children and improve both their short- and long-term health. Achieving our aims would provide the necessary evidence to inform guidelines and support a transition from morphine to a non-opioid analgesic such as sub-dissociative ketamine as the primary treatment modality for children with moderate to severe acute pain.

Project Narrative Pain is common in children presenting to the emergency department but is frequently undertreated, leading to both short- and long-term consequences. Morphine is the standard treatment for children with moderate to severe acute pain, but its use is associated with serious side effects and caregiver and clinician concerns related to opioid administration. Our research aims to demonstrate that sub-dissociative ketamine is as effective as morphine and a preferable alternative for treating acute pain in children because of its more favorable side effect profile and potential long-term benefits related to pain-related function, analgesic use/misuse, and mental and behavioral health outcomes.