Introduction: Currently, using various combinations of narcotic and analgesic drugs has received attention for induction of sedation and analgesia due to their synergy in controlling pain and anxiety. The present study was designed with the aim of comparing dexmedetomidine-fentanyl combination with midazolam-fentanyl in this regard. Methods: In this randomized clinical trial, patients diagnosed with distal radius fracture who had visited the emergency department (ED) were allocated to either the group receiving the combination of fentanyl-midazolam or the one receiving dexmedetomidine-fentanyl for procedural sedation and analgesia (PSA) and were compared regarding analgesic characteristics, time to recovery and side effects. Results: 80 patients with the mean age of 42.08 ± 12.17 (18 - 60) years were randomly allocated to 2 groups of 40 (83.80% male). The 2 groups did not have a significant difference regarding baseline characteristics as well as pain severity. Mean pain score at the time of procedure was 3.47 ± 1.37 in dexmedetomidine and 2.85 ± 1.05 in midazolam group (p = 0.025). In addition, time to recovery in dexmedetomidine and midazolam groups was 6.60 ± 1.86 minutes and 12.70 ± 1.70 minutes, respectively (p < 0.001). Out of the 9 patients who experienced treatment failure, 8 (88.90%) patients were in dexmedetomidine group and 1 (11.10%) was in midazolam group (p = 0.029). Absolute risk increase rate of treatment failure in case of using dexmedetomidine instead of midazolam was 17.50% (95%CI: 4.19 – 30.81) and number needed to harm was 6.00 (95% CI: 3.20 – 23.80). Conclusion: Although the combination of dexmedetomidine-fentanyl had a shorter time to recovery compared to midazolam-fentanyl for induction of sedation and analgesia, the treatment failure rate in case of using dexmedetomidine with 1 µg/kg increased 17.5% and about 1 out of each 6 patients needed a rescue dose
