Oral Dexmedetomidine Promotes Non-rapid Eye Movement Stage 2 Sleep in Humans

Abstract

Background: The administration of dexmedetomidine is limited to highly monitored care settings because it is only available for use in humans as intravenous medication. An oral formulation of dexmedetomidine may broaden its use to all care settings. The authors investigated the effect of a capsule-based solid oral dosage formulation of dexmedetomidine on sleep polysomnography.

Methods: The authors performed a single-site, placebo-controlled, randomized, crossover, double-blind phase II study of a solid oral dosage formulation of dexmedetomidine (700 mcg; n = 15). The primary outcome was polysomnography sleep quality. Secondary outcomes included performance on the motor sequence task and psychomotor vigilance task administered to each subject at night and in the morning to assess motor memory consolidation and psychomotor function, respectively. Sleep questionnaires were also administered.

Results: Oral dexmedetomidine increased the duration of non-rapid eye movement (non-REM) stage 2 sleep by 63 (95% CI, 19 to 107) min (P = 0.010) and decreased the duration of rapid eye movement (REM) sleep by 42 (5 to 78) min (P = 0.031). Overnight motor sequence task performance improved after placebo sleep (7.9%; P = 0.003) but not after oral dexmedetomidine-induced sleep (-0.8%; P = 0.900). In exploratory analyses, we found a positive correlation between spindle density during non-REM stage 2 sleep and improvement in the overnight test performance (Spearman rho = 0.57; P = 0.028; n = 15) for placebo but not oral dexmedetomidine (Spearman rho = 0.04; P = 0.899; n = 15). Group differences in overnight motor sequence task performance, psychomotor vigilance task metrics, and sleep questionnaires did not meet the threshold for statistical significance.

Conclusions: These results demonstrate that the nighttime administration of a solid oral dosage formulation of dexmedetomidine is associated with increased non-REM 2 sleep and decreased REM sleep. Spindle density during dexmedetomidine sleep was not associated with overnight improvement in the motor sequence task.

Fig. 1.

MST performance. (A) The Motor Sequence Task (MST) involves typing a 5-digit sequence (4–1–3–2–4) as quickly and correctly as possible for 12 rounds of 30 second intervals. (B) MST performance during both the placebo and dexmedetomidine study visits. Placebo visits showed visibly improved overnight performance (average of first three testing sequences - average of last three training sequences), whereas oral dexmedetomidine immediate performance appeared similar between training and testing sessions. (C) Improvement in MST performance (%) met our threshold for statistical significance for the placebo (p=0.003) but not for the dexmedetomidine (p=0.900) study visits. There were no statistically significant differences in immediate (p = 0.078) performance between groups. (D) Spindle density during non-REM stage 2 sleep and overnight MST improvement after oral dexmedetomidine were not correlated (Spearman’s Rho= 0.1, p = 0.748, n = 13; Spearman’s Rho= 0.1, p = 0.820, n = 15 after data imputation). (E) We confirmed the previously described^, positive correlation between spindle density during non-REM stage 2 sleep and overnight MST improvement post placebo (Spearman’s Rho= 0.54, p = 0.058, n = 13; Spearman’s Rho= 0.57, p = 0.028, n = 15 after data imputation).

Fig. 2.

PVT performance. (A) Testing lapse 400 during the placebo study visit was increased from training lapse 400 (p = 0.036). Testing lapse 400 during the dexmedetomidine study visit was also increased from training lapse 400 (p = 0.009). There was no statistically significant difference in testing lapse 400 between groups after controlling for training lapse 400 (p = 0.281). (B) The average testing reaction time during the placebo study visit was increased from the average training reaction times (p = 0.012). The average testing reaction time during the dexmedetomidine study visit was also increased from the average training reaction time (p = 0.014). There was no statistically significant difference between the average testing reaction times between groups after controlling for the average training reaction times (p = 0.295).