The 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.
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, 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.
Particularly 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.
The 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.
Competing Interests
CONFLICT OF INTEREST STATEMENT: Dr. Rafael Wespi, Dr. Dario A. Dornbierer, and Dr. Hans-Peter Landolt are listed as inventors on a pending patent on “Dexmedetomidine for the treatment of sleep disorders” (UniTectra Fall-Nr. UZ-231534a) that is assigned to University of Zurich, Zurich, Switzerland. Dr. Dario A. Dornbierer declares that he co-founded Reconnect Labs, an academic spin-off company of the University of Zurich, focused on the development of dexmedetomidine-based products for the treatment of sleep disorders. Dr. Hans-Peter Landolt has received consultation fees from Heel Biologische Heilmittel GmbH.