Pain constitutes the predominant motive prompting individuals to seek emergency medical attention, accounting for 80% of admissions to emergency departments. Presently, it is imperative to employ expeditious and efficacious analgesia-sedation methodologies, obviating the necessity for intravenous administration, while ensuring the secure delivery of pharmaceutical agents. The objective of this study is to assess the feasibility and comfort of nebulized intranasal or facial aerosol administration of Fentanyl through the implementation of a pharmacokinetic/pharmacodynamic (PK/PD) study

The prompt identification, assessment, and management of pain are imperative in the context of emergency medicine, necessitating rapid and effective interventions. In the realm of pain management, the investigators deemed it crucial to concentrate on non-invasive approaches, such as opioid nebulization, while ensuring the safe and controlled delivery of the pharmaceutical agent. Intranasal analgesia emerges as a particularly suitable option due to its non-invasiveness, painlessness, ease of administration, cost-effectiveness, and lack of stringent aseptic requirements, making it especially convenient for patients in pain. However, the administration of medications in nasal drop form lacks precise control over the quantity of the active drug, potentially resulting in a hepatic first-pass effect and inactivation before systemic absorption, particularly with large quantities and subsequent swallowing.

Facial nebulization of opiates presents an alternative method for analgesic administration. Traditional pneumatic nebulizers, readily available in emergency settings, are economical aerosol generators. However, they pose challenges related to the reproducibility of administration and the potential for infectious contamination due to the dispersion of nebulized particles in the air between inhalations. Palladium vibrating screen aerosols, designed to produce optimal particle sizes for drug delivery to the lungs, show promise due to their more occlusive system, offering enhanced performance. Yet, these devices lack evaluation in the realm of opioids, particularly in terms of objective nociception measurement.

Pupillometry, specifically PUAL (pupillary unrest in ambient light), stands out as an objective technique capable of quantifying nociception or opioid impregnation. PUAL monitors variations in pupil diameter over time, and previous studies have indicated an inverse correlation between the analgesic response to opioid treatment and PUAL amplitude, suggesting it could serve as a marker of central opioid impregnation. However, scientific evidence in alert emergency medicine patients remains lacking. Additionally, standard clinical pharmacodynamic evaluation criteria for opioids are not well-suited to the variability of therapeutic responses in emergency situations.

Pharmacometric models offer a quantitative approach to understanding relationships between administered drugs, clinico-biological covariates, exposure, and responses (biomarkers, efficacy, safety) as they evolve over time in individual patients and populations. This pilot study aims to evaluate the feasibility, safety, effects, and robustness of nebulized fentanyl administration via facial aerosol or intranasal routes in a population of adult healthy volunteers, employing equivalent analgesic doses. PUAL will serve as an objective pharmacodynamic marker of central opioid impregnation, coupled with pharmacokinetic modeling of nebulized fentanyl administered via facial aerosol or intranasally. The development of a pharmacometric model using a population-based approach aims to establish fentanyl titration strategies based on the objective of reducing PUAL while ensuring central opioid impregnation.

Inclusion Criteria:

• Age ≥ 18 years and < 68 years
• BMI between 19 and 29 kg/m²
• Affiliation to a social security scheme
• Adult who has read and understood the information letter and signed the consent form
• Woman capable of procreating (a woman is considered capable of procreating, i.e. fertile, after menarche and until she becomes menopausal, unless she is definitely sterile ) having very effective contraception (combined hormonal contraception (containing estrogens and progestins) associated with inhibition of ovulation, progestin-only hormonal contraception associated with inhibition of ovulation, intrauterine device, hormone-releasing intrauterine system (IUS), bilateral tubal occlusion, vasectomized partner, sexual abstinence) for 1 year and a negative urine pregnancy test at inclusion and during the duration of the study.
• Woman definitely surgically sterile (hysterectomy, bilateral salpingectomy and bilateral oophorectomy). Postmenopausal woman: The postmenopausal state is defined by the absence of periods for 12 months without any other medical cause.

Exclusion Criteria:

• Weight < 50 kg
• Taking long-term painkillers or narcotics
• Sharp pain
• Stable chronic pain (>3 months, with or without long-term treatment)
• Known chronic pathology stabilized or decompensated (hypertension, renal, cardiac, hepatic insufficiency, etc.)
• Stable or decompensated chronic respiratory pathology
• Chronic neuropsychiatric pathology likely to modify the pain threshold
• Long-term treatment with an action on the nervous system such as respiratory depression: benzodiazepines, neuroleptics, agonist/antagonist of the opioid system
• Treatment or toxicant whose association is not recommended with fentanyl (alcohol, cannabis, etc.)
• Central nervous system modulator treatment
• Pathologies blocking the pupillary response: Claude-Bernard-Horner syndrome, Adie syndrome, Argyll-Robertson pupil, senile miosis, dysautonomic neuropathy (advanced diabetes, systemic amyloidosis), cataract
• Treatment responsible for fluctuation in PUAL measurements: parasympathetic modulators (clonidine, dexmedetomidine, droperidol, metoclopramide)
• No-indication to FENTANYL PIRAMAL 100µg/2mL, solution for injection in ampoule
• No-indication to PROAMP SODIUM CHLORIDE 0.9%, solution for injection
• Ongoing treatment with nasal vasoconstrictors
• Peripheral oxygen saturation less than 93%
• Alteration of cognitive state: comprehension disorder, language disorder, memory disorder, confusion
• Deaf or mute patient
• Usual heart rate such as HR< 40 bpm and/or hypotension with systolic blood pressure SBP< 100 mm Hg
• Atrioventricular block on ECG
• History of cataract surgery
• Confirmed or suspected covid 19 / active flu infection less than 15 days old
• Allergy to plastic
• Pregnant or parturient or breastfeeding woman or proven absence of contraception
• Person deprived of liberty by an administrative or judicial decision or person placed under judicial protection/under guardianship or curatorship
• Person participating in research participating in another trial / having participated in another trial within 2 weeks
• History of illness or psychological or sensory abnormality likely to prevent the subject from fully understanding the conditions required for participation in the protocol or preventing them from giving informed consent