Project summary Emergency departments (ED) in the US have experienced a significant increase in admissions for opioid-related overdoses and suicide attempts during the COVID pandemic. Individuals with opioid use disorder (OUD) have a lifetime prevalence of suicide attempts exceeding 40%, along with elevated odds of a completed suicide. Among the 100,000 drug-related overdose deaths in 2021—the largest number ever recorded in a 12-month period— 30% or more of such events may in fact be suicides. In 2017, there were over 960,000 ED visits in the US for a non-fatal overdose, making the ED a critical setting in which to intervene. Behavioral interventions like Screening, Brief Intervention, and Referral to Treatment (SBIRT) in the ED improve alcohol outcomes, but multiple trials have failed to show any benefit of SBIRT for individuals with OUD. Structural barriers like ED crowding and lack of follow up for addiction and psychiatric treatment also mar efforts to treat these diseases. Despite the increased utilization of medications for OUD (MOUD) in the ED setting, most patients still do not receive MOUD in the ED, and among those who do, the majority do not continue treatment after discharge. Therefore, there is a critical need for research to identify treatments that can be delivered effectively and sustainably in the ED for individuals with OUD particularly for those who are endorsing suicidal ideation. Ketamine has garnered interest due to its potential in treating psychiatric disorders, rapidly diminishing depressive and suicidal symptoms among individuals with treatment-resistant depression. Sub-anesthetic doses of ketamine administered in either single or multiple sessions in conjunction with psychotherapy has shown beneficial effects for patients with alcohol, opioid, and cocaine use disorders. A major advantage of ketamine is that it is already an accepted pharmacotherapy used routinely in the ED for procedural sedation, agitation, and acute pain. If ketamine could be used as an effective pharmacotherapy for OUD and suicidal ideation in the ED, the approach would be consistent with Screening, Treatment Initiation, and Referral (STIR) which may be more beneficial than the traditional SBIRT approach. However there remains a significant gap in understanding the safety of ED-initiated ketamine for those with OUD in the ED. To fill this need, we propose to conduct a pilot, double-blind, placebo- controlled randomized trial with the primary aim of assessing the safety of administering ketamine in the ED to OUD patients who are endorsing suicidal ideation. Those who are eligible will be randomly assigned to receive either a single infusion of ketamine or saline placebo. Vital signs, side effects, psychiatric adverse effects, opioid withdrawal, and cravings for opioids and ketamine will be monitored closely throughout the ED admission. As a secondary aim, we will determine the preliminary efficacy of ketamine on opioid- and suicide-related outcomes. Mechanisms of behavior change will be explored. If successful, this line of research will help establish the safety of ketamine administration for OUD in the ED, and facilitate the design of a larger efficacy trial.

PROJECT NARRATIVE Opioid overdoses and suicides continue to be major public health problems that often converge in the emergency department (ED). The proposed study aims to establish the safety of administering ketamine to individuals with opioid use disorder who are endorsing suicidal ideation in the ED, and evaluate the preliminary efficacy on opioid- and suicide-related outcomes. Results from this study will help lay the foundation for an adequately powered efficacy trial of ketamine as a treatment option in the ED to improve opioid- and suicide-related outcomes.