BackgroundVaso‐occlusive episodes (VOC) cause debilitating pain and are a common cause of emergency department (ED) visits, for people with sickle cell disease (SCD). Strategies for achieving optimal pain control vary widely despite evidence‐based guidelines. We tested existing guidelines and hypothesized a patient‐specific protocol (PSP) written by their SCD provider, may be more effective than weight‐based (WB) dosing of parenteral opiate medication, in relieving pain.MethodsProspective, randomized controlled trial comparing a PSP versus WB protocol for patients presenting with VOC to six EDs. Patients were randomized to a PSP or WB protocol prior to an ED visit. SCD provider wrote their protocol and placed in the electronic health record for future ED visits with a VOC Exclusion criteria included: pre‐existing PSP excluding parenteral opioid analgesia or out‐patient use of buprenorphine or methadone, or highly suspected for COVID‐19. Pain intensity scores, side effects and safety were obtained every 30 minutes for up to 6 hours post‐ED bed placement. The primary outcome was change in pain intensity score from placement in an ED space to disposition or six hours.Results328 subjects were randomized, 104 participants enrolled (ED visit, target n=230) with complete data for 96 visits. The study was unable to reach the target sample size and stopped early due to the impact of COVID‐19. We found no significant differences between groups in the primary outcome; patients randomized to a PSP had a shorter ED length of stay (p=.008); the prevalence of side effects was low in both groups. Subjects in both groups experienced both a clinically meaningful and statistically significant decrease in pain (27 mm on a 0‐100 mm scale)ConclusionsWe found a shorter ED length of stay for patients assigned to a PSP. Patients in both groups experienced good pain relief without significant side effects.