A novel bedtime pulsatile-release caffeine formula ameliorates sleep inertia symptoms immediately upon awakening

Abstract

Sleep inertia is a disabling state of grogginess and impaired vigilance immediately upon awakening. The adenosine receptor antagonist, caffeine, is widely used to reduce sleep inertia symptoms, yet the initial, most severe impairments are hardly alleviated by post-awakening caffeine intake. To ameliorate this disabling state more potently, we developed an innovative, delayed, pulsatile-release caffeine formulation targeting an efficacious dose briefly before planned awakening. We comprehensively tested this formulation in two separate studies. First, we established the in vivo caffeine release profile in 10 young men. Subsequently, we investigated in placebo-controlled, double-blind, cross-over fashion the formulation's ability to improve sleep inertia in 22 sleep-restricted volunteers. Following oral administration of 160 mg caffeine at 22:30, we kept volunteers awake until 03:00, to increase sleep inertia symptoms upon scheduled awakening at 07:00. Immediately upon awakening, we quantified subjective state, psychomotor vigilance, cognitive performance, and followed the evolution of the cortisol awakening response. We also recorded standard polysomnography during nocturnal sleep and a 1-h nap opportunity at 08:00. Compared to placebo, the engineered caffeine formula accelerated the reaction time on the psychomotor vigilance task, increased positive and reduced negative affect scores, improved sleep inertia ratings, prolonged the cortisol awakening response, and delayed nap sleep latency one hour after scheduled awakening. Based on these findings, we conclude that this novel, pulsatile-release caffeine formulation facilitates the sleep-to-wake transition in sleep-restricted healthy adults. We propose that individuals suffering from disabling sleep inertia may benefit from this innovative approach.Trials registration: NCT04975360.

Conflict of interest statement

The authors declare no competing interests.

© 2021. The Author(s).

Figures

Figure 1

Illustration of the study procedures of the in vivo validation study (A) and the pharmacodynamic study (B). Timepoints of blood withdrawal are indicated as grey drops (drop symbols). Sleep episodes are highlighted as hatched areas. In both studies, sleep was continuously recorded by polysomnography. In the pharmacodynamic study, participants were kept awake until 3:00. Immediately after awakening from a restricted 4-h nocturnal sleep episode (at 07:00), volunteers performed a 1-h testing battery (referred to as “Testing”) to quantify behavioral, cognitive, emotional and physiological markers of sleep inertia. At 8:00, the participants were given a 1-h nap opportunity, while the latency to fall asleep and the sleep profile were recorded with polysomnography. Sleep inertia assessment, CAR measurements and physiological sleepiness testing were only performed in the pharmacodynamic study.

Figure 2

Evolution of the caffeine plasma concentration over time for the in vivo validation study (A) and the pharmacodynamic study (B). Black dots indicate mean caffeine plasma concentrations, error bars indicate standard errors (SEM). The horizontal dashed line at 5 μM indicates the threshold concentration of caffeine efficacy. Time point ‘0’ on the x-axis refers to 22:30 when the caffeine was administered. Sleep periods are indicated as hatched areas.

Figure 3

Median PVT reaction time (left) and number of lapses (right) at 2:30 and 7:05. Mean values (dots) and standard error of the mean (vertical lines) are shown. Grey lines indicate the placebo condition; black lines indicate the caffeine condition. ***p < 0.001 (Benjamini–Hochberg corrected).

Figure 4

Post-awakening (7:15–8:00) assessments of subjective state. ASIQ = Acute Sleep Inertia Questionnaire (administered at 07:45). CAQ = Caffeine Acute Questionnaire. PANAS-positive = positive affective scale (administered at 07:15). PANAS-negative = negative affective scale (administered at 07:30). *p < 0.05; **p < 0.01 (Benjamini–Hochberg corrected).

Figure 5

Salivary cortisol awakening response (CAR). Mean salivary cortisol concentration (dots) and standard error of the mean (vertical lines) are shown. Grey lines indicate the placebo condition; black lines indicate the caffeine condition. *p < 0.05 (Benjamini–Hochberg corrected).

Figure 6

Visually-sored sleep variables in (A) the 4-h nighttime sleep episode (03:00–07:00); (B) the final 10 min before scheduled awakening (06:50–07:00); and (C) the 1-h nap sleep opportunity (08:00–09:00) are shown. SOL, sleep onset latency; N1-3, non-rapid-eye-movement sleep stages N1-3; REM, rapid-eye movement sleep; *p < 0.05; **p < 0.01 (Benjamini–Hochberg corrected).