EFFECTS OF LOW-DOSE ORO-MUCOSAL DEXMEDETOMIDINE ON SLEEP AND THE SLEEP EEG IN HUMANS: A PHARMACOKINETICS-PHARMACODYNAMICS STUDY

Abstract

Background: Insomnia is common and causes immense disease burden. Current sleep medications show suboptimal clinical features, leaving an unmet need for pharmacological innovation to improve both sleep and waking functions. The locus coeruleus noradrenergic (LC-NA) system may provide a potential new target for pharmacological insomnia treatment, particularly in patients with elevated stress. The selective alpha-2 noradrenergic agonist dexmedetomidine (DEX) attenuates LC-NA activity. In current use as intravenous anesthetic, DEX could thus be a promising repurposing candidate for stress-related insomnia. Methods: We developed two distinct, fast-disintegrating, oro-mucosal - one sublingual and one buccal - DEX formulas tailored for self-administration and established their pharmacokinetic and pharmacodynamic (PK-PD) profiles. In two separate studies, the first comprising 8 healthy male good sleepers and the second including 17 men with subclinical insomnia, we administered sub-anesthetic doses (20 & 40 microgram) of the two formulas. Both studies followed a randomized, double-blind, placebo-controlled, cross-over design. We complemented the PK assessments during sleep by all-night polysomnography, nocturnal cortisol and melatonin measurements, assessments of cardiovascular functions during and after sleep, cortisol awakening response, and examination of post-awakening subjective state and vigilance. Results: Particularly buccal DEX was rapidly absorbed and exhibited excellent dose-proportionality with minimal between-subject variation in exposure. Additionally, DEX shortened the latency to fall asleep, increased the time spent in non-rapid-eye-movement (NREM) sleep, and elevated electroencephalographic slow wave energy (0.75-4.0 Hz), a marker of NREM sleep depth. Rapid-eye-movement (REM) sleep latency was dose-dependently prolonged. Nocturnal cortisol, melatonin and heart rate, as well as 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 delivery of sub-anesthetic DEX doses warrants further dose-finding and clinical studies, to establish the exact roles of the LA-NA system in pharmacological sleep enhancement and alpha-2 receptor agonism as novel mode of action in alleviating stress-related insomnia.