Comparative Efficacy and Safety of Intranasal Opioids versus Intravenous Morphine for Acute Moderate-to-Severe Pain: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

Background Intranasal (IN) opioids may provide non-invasive analgesia without delays associated with intravenous (IV) access, but their efficacy and safety versus IV morphine remain uncertain. Objectives To synthesize randomized evidence comparing IN opioids with IV morphine for acute moderate-to-severe pain. Methods PubMed, Scopus, Web of Science, and the Cochrane Library were searched from inception to May 2026 for randomized controlled trials (RCTs) in adults or children with acute moderate-to-severe pain in emergency, prehospital, procedural, or postoperative settings. Eligible trials directly compared IN opioids with IV morphine. The primary outcome was change in pain score from baseline at 20 and 30 minutes. Secondary outcomes included rescue analgesia and adverse events. Outcomes were pooled as standardized mean differences (SMD) or risk ratios (RR) using random-effects models. Results Ten RCTs involving 1,164 participants were included. IN opioids showed comparable analgesic efficacy to IV morphine at 20 minutes (SMD = −0.05, 95% CI: −0.24 to 0.14; p = 0.59; I² = 11.94%) and 30 minutes (SMD = −0.05, 95% CI: −0.24 to 0.15; p = 0.64; I² = 0.00%). Rescue analgesia was comparable (RR = 1.00, 95% CI: 0.81 to 1.25; p = 0.98). No significant differences were observed in overall adverse events, serious adverse events, respiratory complications, hypotension, gastrointestinal events, dizziness, or rhinorrhea. Dysgeusia was borderline increased. Conclusion IN opioids provide analgesic efficacy comparable to IV morphine at 20 and 30 minutes, with no clear increase in systemic adverse events. Larger trials should confirm safety for rare serious events and optimize dosing.