P11 Interim results of the fentanyl or esketamine for traumatic pain (FORE-PAIN) trial: a double-blind multi-arm randomized non-inferiority trial

Background Fentanyl and esketamine are standard of care for treatment of acute severe traumatic pain in the military prehospital setting in the Netherlands. Both analgesics can be administered intravenously (IV) or intranasally (IN). However, comparative evidence regarding efficacy and safety is lacking. This study aims to assess the efficacy and safety of fentanyl IN, esketamine IV and esketamine IN as compared to fentanyl IV for management of acute severe traumatic pain in the prehospital setting. Methods This is a double-blind, double-dummy, monocentre, multi-arm, randomized non-inferiority trial in the civilian prehospital setting in the Netherlands. Adult subjects receiving emergency care from Emergency Medical Services and suffering from acute severe traumatic pain are randomized in a 1:1:1:1 ratio to receive fentanyl IV (1.0 µg/kg), fentanyl IN (1.25 µg/kg), esketamine IV (0.2 mg/kg) or esketamine IN (0.625 mg/kg). Nasal medication is administered through a mucosal atomization device. The primary endpoint is reduction in Numeric Rating Scale (NRS, 0–10) score at 10 minutes after first administration of study medication. Other endpoints include reduction in NRS score at other timepoints, need for additional analgesia, patient satisfaction and adverse events. An unplanned interim analysis for safety was performed in April 2025 following reports of insufficient pain relief in some subjects. Criterium for discontinuation of a study arm was ≥50% of non-responders in a study arm. A non-responder was defined as a subject having ≤ 1 point NRS reduction at 10 minutes AND requesting additional analgesia at 10 minutes. Data for continued study arms remained blinded to the study team, while data for discontinued study arms was unblinded to the study team after interim analysis. Results 115 subjects were included in the interim analysis. Median age was 70 years (IQR 58 – 77), 71% were female, most common injury was extremity fracture (75%) and median baseline NRS was 8 (IQR 7–9). The Data Safety Monitoring Board (DSMB) advised discontinuation of fentanyl IN due to a percentage of non-responders of 54%. Consequently, unblinded data for this study arm were made accessible to the study team. Twentynine subjects were allocated to the fentanyl IN group. Median age was 67 years (IQR 34 - 81), 83% were female, most common injury was extremity fracture (90%) and median baseline NRS was 8 (IQR 8 - 9) (figure 1). Median NRS reduction at 10 and 20 minutes was 1 (IQR 0 - 2) and 3 (IQR 2 - 5), respectively. Median patient satisfaction with prehospital analgesia was 6 (IQR 4 - 8). Conclusion Interim analysis of the FORE-PAIN trial shows that 1.25 µg/kg fentanyl IN administered through a mucosal atomization device does not provide adequate immediate analgesia in acute severe traumatic pain in adults in the civilian prehospital setting. Conflicts of Interest All authors declare no conflicts of interest. Ethics Statement The institutional review board of the Amsterdam UMC approved this study (EU CT number: 2022-500176-63-00, date of approval: 29 August 2023). Abstract P11 Figure 1 Pain intensity at 0, 10 and 20 minutes. Error bars display interquartile range