Effects of sub-anesthetic oro-mucosal dexmedetomidine on sleep in humans: A pharmacokinetics-pharmacodynamics study

Abstract

Background: The locus coeruleus noradrenergic (LC-NE) system may provide a potential new target for pharmacological insomnia treatment, particularly in patients suffering from elevated stress. The selective alpha-2 noradrenergic agonist dexmedetomidine (DEX) attenuates LC-NE activity in sub-anesthetic doses, yet no adequate non-parental delivery systems of DEX are currently available. To examine the feasibility of oro-mucosal DEX administration, we developed two distinct - one sublingual and one buccal - oro-mucosal, fast-disintegrating DEX formulas tailored for self-administration. Here we established their pharmacokinetic and pharmacodynamic (PK-PD) profiles. Methods: In two separate studies in 8 male good sleepers and 17 men with subclinical insomnia, we administered sub-anesthetic doses (20 & 40 ug) of the two formulas following a randomized, double-blind, placebo-controlled, cross-over design. 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. Results: Particularly buccal DEX was rapidly absorbed and exhibited excellent dose-proportionality with minimal between-subject variation in exposure. In poor sleepers, 40 ug of buccal DEX shortened the sleep latency by 11 min, increased the time spent in non-rapid-eye-movement sleep by 38 min, and elevated electroencephalographic slow wave energy (0.75-4.0 Hz) in the first half of the night by 23 % (pall < 0.05). Rapid-eye-movement sleep latency was dose-dependently prolonged (20 ug: 48 min; 40 ug: 117 min; pall < 0.01). Nocturnal cortisol, melatonin and heart rate, and morning cortisol were not significantly affected by DEX, nor did post-awakening orthostatic regulation, subjective sleepiness and mood, and psychomotor vigilance differ among the conditions. Conclusions: The favorable PK-PD profile of oro-mucosal DEX 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.