AEROfen: protocol for a phase I, open-label, randomised crossover study evaluating the efficiency of nebulised fentanyl in healthy volunteers – comparing facial versus intranasal administration via pharmacometric modelling

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INTRODUCTION: Pain accounts for approximately 80% of emergency department admissions. While intravenous morphine titration is commonly used for severe pain, non-invasive alternatives that bypass intravenous access are needed. Nebulised fentanyl, combined with pupillometry for objective monitoring of opioid impregnation, may offer a rapid and safe alternative for pain management. METHODS AND ANALYSIS: This phase I, open-label, randomised, exploratory, crossover, single-centre prospective controlled trial will employ pharmacokinetic-pharmacodynamic (PK-PD) modelling to assess the variability in bioavailability of nebulised fentanyl administered via intranasal route versus facial aerosol. 20 healthy volunteers will receive three repeated administrations of fentanyl over two visits. At each visit, blood samples (n=11) will be collected for fentanyl quantification by liquid chromatography-tandem mass spectrometry, and pupillary unrest in ambient light (PUAL) measurements (n=9) will be recorded. The resulting data will be analysed using Monolix 2024R1 to model PK-PD relationships, perform Monte Carlo simulations and determine the optimal dosing and timing required to achieve a reduction of more than 30% in PUAL, while also evaluating safety, comfort and tolerance. ETHICS AND DISSEMINATION: The study has been approved by the Ethic Committee Île-de-France VII (approval reference number: 000216, February 2024) and will be conducted in accordance with the Declaration of Helsinki. Informed consent will be obtained from all participants. Study findings will be disseminated through peer-reviewed publications, conference presentations and appropriate data-sharing platforms to support further research and clinical application. TRIAL REGISTRATION NUMBER: This trial is registered at ClinicalTrials.gov (Identifier: NCT06281951).

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