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

Abstract

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.

Fig. 1.

Experimental design and pharmacokinetic profiles of dexmedetomidine after sublingual and buccal orodispersible tablet intake. (A) Time points of blood draws (drops) , saliva sampling (tubes), and postawakening testing (#) are indicated on the x-axis. The study drugs (0/20/40 µg dexmedetomidine) were administered at 11:00 pm when lights were switched off (black light bulb) and the polysomnographic (PSG) recording was initiated (time point 0). The participants were awoken and lights were turned on at 7:00 am (time point 8). (B) Evolution of dexmedetomidine plasma concentration after sublingual dexmedetomidine intake (n = 8). (C) Evolution of dexmedetomidine plasma concentration after buccal dexmedetomidine intake (n = 17). Yellow lines connecting black dots: 20 µg dexmedetomidine. Orange lines connecting black triangles: 40 µg dexmedetomidine. Yellow and orange shadings indicate standard deviations.

Fig. 2.

Visually scored sleep variables after intake of sublingual (left; n = 8) and buccal (right; n = 17) oromucosal dexmedetomidine formulations at bedtime. (A) Sleep latency until three consecutive epochs of N1 or deeper sleep stages. (B) Latency to first rapid eye movement (REM) sleep episode. (C) Total duration of non–rapid eye movement (NREM) sleep stages N2 and N3. Box plots: Horizontal lines mark the median, lower and upper hinges correspond to the 25th and 75th percentiles, and whiskers extend to the last value within 1.5 times the interquartile range. Dots: Individual data points. Blue, placebo; yellow, 20 µg dexmedetomidine; orange, 40 µg dexmedetomidine. Statistically significant differences between conditions are denoted by asterisks. *P < 0.05; **P < 0.01; ***P < 0.001 (Benjamini–Hochberg corrected).

Fig. 3.

The electroencephalography slow-wave energy in the 0.75 to 4.0 Hz range in non–rapid eye movement sleep stages N2 and N3 was quantified in the first (0 to 4 h after intake) and second (4 to 8 h after intake) halves of the nights after buccal dexmedetomidine administration at bedtime. Box plots: Horizontal lines mark the median, lower, and upper hinges that correspond to the 25th and 75th percentiles, and whiskers extend to the last value within 1.5 times the interquartile range. Dots: individual data points (n = 17). Blue, placebo; yellow, 20 µg dexmedetomidine; orange, 40 µg dexmedetomidine. Note that the values are presented on a logarithmic scale. The asterisk indicates the significant difference between the 40 µg dexmedetomidine and placebo conditions in the first half of the experimental nights. *P < 0.03 (Benjamini–Hochberg corrected).