Effects of Subanesthetic Oromucosal Dexmedetomidine on Sleep in Humans: A Randomized, Controlled Pharmacokinetics–Pharmacodynamics Study

Background: The locus coeruleus noradrenergic system may provide a potential new target for pharmacologic insomnia treatment, particularly in patients suffering from elevated distress. The selective α$_{2}$-noradrenergic agonist dexmedetomidine attenuates locus coeruleus activity in subanesthetic doses, yet no adequate nonparental delivery systems of dexmedetomidine are currently available. To examine the feasibility of oromucosal dexmedetomidine administration, the authors developed two distinct—one sublingual and one buccal—oromucosal, fast-disintegrating dexmedetomidine formulas tailored for self-administration. Here, the authors established the formulas’ pharmacokinetic and pharmacodynamic profiles. Methods: In 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 crossover design, the authors investigated subanesthetic doses (20 and 40 µg) of the two formulas. They complemented the pharmacokinetic assessments with all-night polysomnography, nocturnal cortisol and melatonin measurements, assessments of cardiovascular functions during and after sleep, cortisol awakening response, and postawakening examination of subjective state and vigilance. Results: Particularly buccal dexmedetomidine was rapidly absorbed and exhibited excellent dose proportionality with minimal between-subject variation in exposure. In poor sleepers, 40 µg buccal dexmedetomidine shortened the sleep latency by 11.5 min, increased the time spent in non–rapid eye movement sleep by 37.2 min, and elevated non–rapid eye movement sleep electroencephalographic slow-wave energy (0.75 to 4.0 Hz) in the first half of the night by roughly 23%. Rapid eye movement 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 postawakening orthostatic regulation, subjective sleepiness and mood, and psychomotor vigilance differ among the conditions. Conclusions: The favorable pharmacokinetic and pharmacodynamic profile of oromucosal dexmedetomidine delivery warrants further dose-finding and clinical studies to establish the exact roles of α$_{2}$ receptor agonism in pharmacologic sleep enhancement and as a possible novel mechanism to alleviate stress-related insomnia.