Intranasal Fentanyl for Acute Pain Management in Children, Adults and Elderly Patients in the Prehospital Emergency Service and in the Emergency Department: A Systematic Review

**Background:** Pain is a common symptom in emergency settings, yet oligoanalgesia (undertreatment of pain) affects up to 57% of ED patients, disproportionately impacting children and the elderly. Intranasal administration of fentanyl (INF), a highly lipophilic opioid, offers rapid absorption (therapeutic levels within 2 minutes, peak arterial concentration at 7 minutes) with a bioavailability of 71–89% and a plasma half-life of 60 minutes, avoiding the hepatic first-pass effect. This systematic review evaluated the efficacy and safety of INF at the standard concentration of 50 µg/mL for acute pain in prehospital emergency services (PHES) and emergency departments (ED).

**Methods:** The review followed PRISMA 2021 guidelines and was registered in the Open Science Framework (DOI: 10.17605/OSF.IO/PHMC8). Seven databases (MEDLINE, SCOPUS, EMBASE, SCHOLAR, CENTRAL, LILACS, ClinicalTrials.gov) were searched on 31 December 2022. Two independent reviewers screened titles/abstracts and extracted data. Included studies were RCTs, prospective, or retrospective studies evaluating 50 µg/mL INF for acute moderate-to-severe pain from trauma or medical illness in PHES or ED. Excluded were studies on procedural sedation, perioperative pain, cancer pain, chronic pain, or concentrations >50 µg/mL. Risk of bias was assessed using Cochrane RoB 2.0 for RCTs and MINORS criteria for observational studies.

**Key Results:** Of 911 identified studies, 23 were included (18 in children, 5 in adults, 1 subgroup in elderly), encompassing 10,280 patients (1,203 in PHES, 9,077 in ED). In children (8 RCTs, 9 observational, 1 PS in PHES), INF was effective in reducing pain at multiple time points (e.g., Cole et al. 2009: baseline pain 8/10 reduced to 2 at 10 min and 0 at 30 min; Saunders et al. 2010: VAS from 70 mm to 21 mm at 10 min). INF was as effective as comparators in 6 RCTs (Borland et al. 2011, Frey et al. 2019, Graudins et al. 2015, Quinn et al. 2021, Reynolds et al. 2017, Ruffin et al. 2022) and more effective than placebo at 20 min (Fein et al. 2017, p=0.048) and IM morphine at 10 min (Younge et al. 1999, p=0.014). Three studies showed reduced time to first opioid administration with INF (Akinsola et al. 2018: 29±15 min vs 77±44 min, p<0.0001; Kelly et al. 2018: 29±16 min vs 78±57 min, p<0.001; Schaefer et al. 2015: 20.43±11.54 min vs 42.04±31.55 min, p=0.038). In adults (2 RCTs, 3 observational), INF was effective for renal colic (Belkouch et al. 2015: VAS from 82.2 mm to 8 mm at 30 min, p<0.001) and equivalent to IV morphine (Assad et al. 2023: pain reduction 17.25% vs 17.15%, p=0.1). One RCT found INF less effective than IV fentanyl at most time points except 30 min (Nazemian et al. 2020). In the elderly (Tanguay et al. 2020, n=380), INF was effective and safe, with a greater proportion experiencing pain relief despite a lower dose (50 µg). Safety data showed no serious adverse events. Minor adverse events included sedation (16–42% in children), transient hypoxia (13%), hypotension (8%), nausea (4–8%), dizziness (1–17%), and nasal burning (13%). INF had fewer adverse events than IN ketamine (e.g., Quinn et al. 2021: sedation 0% vs 64%, p=0.004; dizziness 9% vs 64%, p=0.02).

**Clinical Implications:** INF at 50 µg/mL is a safe, effective, and rapid analgesic for acute pain in children and adults in ED and PHES, particularly when IV access is not needed. It is at least as effective as IV/IM morphine and IV fentanyl, with a better safety profile than IN ketamine. The review underscores the need for more high-quality RCTs in prehospital and elderly populations.