Effectiveness and safety of intranasal fentanyl for pain management in infants aged 0–6 months of age: a systematic review

Objective: The objective of this review is to evaluate the effectiveness and safety of intranasal fentanyl for the management of procedural pain in infants aged 0–6 months. Introduction: Procedural pain in early infancy is frequently undertreated, with limitations in both pharmacological and non-pharmacological interventions. Retinopathy of prematurity (ROP) screening is a painful procedure for infants, and although sucrose and topical anesthetics are standard, their analgesic effect is often inadequate. Intranasal fentanyl may offer an effective adjunct; however, its use in infants under 6 months has not been systematically reviewed. Eligibility criteria: This review included randomized controlled trials evaluating intranasal fentanyl in infants ≤6 months of corrected age undergoing painful procedures, compared to placebo, no treatment, or alternative analgesics. Studies with <20% of infants in this age range or focused on chronic pain were excluded. Methods: This systematic review followed JBI methodology and adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. A 3-step search strategy was performed in MEDLINE, Embase, CINAHL, Scopus, and the Cochrane Library in November 2024, with no date or language restrictions. The studies were selected and critically appraised by 2 independent reviewers. Data were extracted and synthesized using a meta-analysis or narrative summary, as appropriate. The certainty of the evidence was assessed using a standardized approach. No deviations from the protocol were observed. Results: Two randomized controlled trials (n=153 preterm infants) evaluated intranasal fentanyl (2 mcg/kg) during ROP screening. In one trial, adding intranasal fentanyl to sucrose (plus topical anesthetic, containment) reduced PIPP-R pain scores versus sucrose alone whereas another trial found that intranasal (2 mcg/kg) and intravenous (1 mcg/kg) fentanyl without routine sucrose did not outperform sucrose. Serious adverse events were not observed; transient apnea/desaturation resolved with minimal stimulation. Certainty was low to very low due to imprecision and inconsistency. Findings are specific to preterm infants undergoing ROP screening. Conclusions: Intranasal fentanyl may reduce procedural pain in stable preterm infants with no serious safety concerns. However, the findings were based on 2 small trials with methodological limitations and moderate risk of bias. Further high-quality research is needed to confirm the efficacy, optimize dosing, and assess the safety in broader infant populations. Review registration: PROSPERO CRD42024551524