A non-inferiority randomized controlled trial comparing nebulized fentanyl and intravenous morphine for acute pain management in the emergency department

Why clinicians should know about it

• Picked for Emergency Medicine (paper of the day, 24 October 2026): Randomized ED trial of noninvasive acute analgesia

Abstract

INTRODUCTION: Intravenous (IV) morphine is the standard treatment for acute pain in emergency department (ED), but is limited by invasiveness and adverse effects. Nebulized fentanyl is a noninvasive alternative. This study aimed to assess the efficacy of nebulized fentanyl compared with IV morphine for acute pain relief 15 min after administration. Secondary outcomes included pain score trends, adverse effects, and rescue analgesia requirements at 30, 45, and 60 min. METHODS: We conducted a double-blind, randomized controlled trial in patients aged 18 to 65 years who had severe pain (numeric rating scale(NRS) score ≥ 7) originating from headaches, musculoskeletal conditions, or cancer. Patients with abdominal pain, unstable vital signs, and chronic opioid use were excluded. Participants were randomly assigned to received either nebulized fentanyl (4 mcg/kg) or IV morphine (0.1 mg/kg). Pain scores, adverse events, and rescue analgesia were recorded at 15, 30, 45, and 60 min by emergency medicine residents who were blinded to treatment allocation. Non-inferiority margin was established if the upper limit of the 95% confidence interval (CI) for the mean NRS difference did not exceed 3 points. RESULTS: Seventy-two patients were enrolled, with comparable baseline characteristics and NRS scores (nebulized fentanyl: 7.94 ± 1.09; IV: 8.14 ± 0.90). Both groups showed significant pain reduction at 15 min (nebulized fentanyl: 5.56 ± 1.66; IV: 5.67 ± 1.85; p < 0.001), with no significant difference in mean NRS reduction (p = 0.83). At all measured time points (15, 30, 45, and 60 minutes), the upper limit of the 95% confidence interval (CI) for the mean difference in pain reduction remained below the predefined non-inferiority margin of 3. CONCLUSIONS: Nebulized fentanyl is a non-inferior, non-invasive alternative to IV morphine for severe acute pain in the ED. However, this finding applies predominantly to stable adults aged 18 to 65 years with musculoskeletal pain. It demonstrated a comparable short-term efficacy and preliminary safety profile within a 60-minute observation window. However, given the small sample size and restrictive exclusion criteria of this study, further larger-scale trials are required to fully establish its safety profile, particularly in broader and higher-risk patient populations." CLINICAL TRIAL NUMBER: TCTR20240624001. The Registration Date was 21 June2024.

Abstract as published, via PubMed.