• Laura K Schnider, Marta Ratajczak, Rafael Wespi, Jacqueline G Kientsch, Francesco Bavato, Laurenz Marten, Jonas Kost, Maxim Puchkov, Corinne Eicher, Martina Boxler, Clarissa D Voegel, Oliver G Bosch, Eus van Someren, Dario A Dornbierer, and Hans-Peter Landolt.
• Institute of Pharmacology & Toxicology, University of Zurich, Zurich, Switzerland.
• Anesthesiology. 2024 Nov 27.

BackgroundThe locus coeruleus (LC) noradrenergic system may provide a potential new target for pharmacological insomnia treatment, particularly in patients suffering from elevated distress. The selective α2 noradrenergic agonist dexmedetomidine attenuates LC activity in sub-anesthetic doses, yet no adequate non-parental delivery systems of dexmedetomidine are currently available. To examine the feasibility of oro-mucosal dexmedetomidine administration, we developed two distinct - one sublingual and one buccal - oro-mucosal, fast-disintegrating dexmedetomidine formulas tailored for self-administration. Here we established their pharmacokinetic and pharmacodynamic (PK-PD) profiles.MethodsIn a pilot study (sublingual formulation; n=8 good sleepers) and a main study (buccal formulation; n=17 poor sleepers), each following a randomized, double-blind, placebo-controlled, cross-over design, we investigated sub-anesthetic doses (20 & 40 µg) of the two formulas. We complemented the PK assessments with all-night polysomnography, nocturnal cortisol and melatonin measurements, assessments of cardiovascular functions during and after sleep, cortisol awakening response, and post-awakening examination of subjective state and vigilance.ResultsParticularly buccal dexmedetomidine was rapidly absorbed and exhibited excellent dose-proportionality with minimal between-subject variation in exposure. In poor sleepers, 40 µg of buccal dexmedetomidine shortened the sleep latency by 11.5 min, increased the time spent in non-rapid-eye-movement (NREM) sleep by 37.2 min, and elevated NREM sleep electroencephalographic slow wave energy (0.75-4.0 Hz) in the first half of the night by roughly 23 %. REM sleep latency was dose-dependently prolonged (20 µg: 55.0 min; 40 µg: 115.3 min). Nocturnal cortisol, melatonin and heart rate, and morning cortisol were not significantly affected by dexmedetomidine, nor did post-awakening orthostatic regulation, subjective sleepiness and mood, and psychomotor vigilance differ among the conditions.ConclusionsThe favorable PK-PD profile of oro-mucosal dexmedetomidine delivery warrants further dose-finding and clinical studies, to establish the exact roles of α2 receptor agonism in pharmacological sleep enhancement and as possible novel mechanism to alleviate stress-related insomnia.Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Society of Anesthesiologists.

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