• Maarten van Lemmen, Albert Dahan, Yaming Hang, Simone C Jansen, Hong Lu, Melissa Naylor, Tina Olsson, Sarah Sheikh, Danielle Sullivan, Max Tolkoff, Rutger van der Schrier, Monique van Velzen, Philipp von Rosenstiel, Rebecca L Wu, and Seetha Meyer.
• Department of Anesthesiology, Anesthesia & Pain Research Unit, Leiden University Medical Center, Leiden, the Netherlands.
• Anesthesiology. 2025 Jan 13.

BackgroundOrexin neuropeptides help regulate sleep/wake states, respiration, and pain. However, their potential role in regulating breathing, particularly in perioperative settings, is not well understood. TAK-925 (danavorexton), a novel, orexin receptor 2-selective agonist, directly activates neurons associated with respiratory control in the brain and improves respiratory parameters in rodents undergoing fentanyl-induced sedation. This study assessed the safety and effect of danavorexton on ventilation in healthy men in an established remifentanil-induced respiratory depression model.MethodsThis single-center, double-blind, placebo-controlled, two-way crossover, phase 1 trial randomized (1:1) 13 healthy men to danavorexton (11mg [low-dose] then 19mg [high-dose]) or placebo, under remifentanil infusion, on two occasions separated by a ≥36-hour washout period. Remifentanil infusion was titrated under isohypercapnic conditions to achieve ~30% to 40% decrease in minute ventilation (from ~20 to ~14 L/minute) before danavorexton/placebo administration. Assessments included safety, ventilation measurements, sedation, and pain tolerance.Results4 (30.8%) danavorexton-treated participants and 1 (8.3%) placebo-treated participant experienced treatment-emergent adverse events (all mild in severity). Insomnia, lasting 1 day, occurred in 1 participant, and was considered related to danavorexton. Compared with placebo, low- and high-dose danavorexton significantly increased ventilation variables (observed mean [95% confidence interval] change, sensitivity analysis model-based p-values) including minute volume (8.2[5.0, 11.4] and 13.0[9.4, 16.5] L/min), tidal volume (312[180, 443] and 483[309, 657] mL), and respiratory rate (3.8[1.9, 5.7] and 5.2[2.7, 7.7] breaths/min) (all P<0.001). High-dose danavorexton significantly decreased sedation on visual analog scale (-29.7[-54.1, -5.3] mm, P<0.001) and Richmond Agitation Sedation Scale (0.4[0.0, 0.7], P<0.001), compared with placebo. Improvements in respiratory variables continued beyond completion of danavorexton infusion. No significant differences in pain tolerance were observed between danavorexton doses or between danavorexton and placebo (~13% increase from baseline; low-dose:P=0.491; high-dose:P=0.140).ConclusionsDanavorexton has effects on respiration and wakefulness in an opioid-induced respiratory depression setting without reversing opioid analgesia.Copyright © 2025 The Author(s). Published by Wolters Kluwer Health, Inc., on behalf of the American Society of Anesthesiologists.

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