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

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.

Introduction

Sleep inertia is a disabling state of reduced physical and mental drive following awakening¹, which typically lasts for less than 30 min but symptoms may persist for several hours in susceptible individuals^2,3,4. A large portion of healthy adolescents report persistent difficulties to rise in the morning⁵ and many shift and on-call night workers exhibit impaired performance and grogginess after awakening, which raises important safety concerns in operational settings^6,7. Furthermore, impaired post-awakening vigilance and mood is highly prevalent in a broad range of neurological and psychiatric conditions^7,8,9,10.

Several biological and environmental factors influence the manifestation of sleep inertia. For example, abrupt awakening from deep sleep (also referred to as slow-wave sleep or stage N3 of non-rapid-eye-movement [NREM] sleep) is associated with more severe sleep inertia symptoms when compared to awakening from more superficial NREM sleep and rapid-eye-movement (REM) sleep^11,12. This finding may suggest that neurophysiological processes underlying sleep and particularly deep NREM sleep carry over into wakefulness and contribute to behavioral and cognitive deficits associated with sleep inertia¹³. The proportion of deep sleep and the odds of awakening from N3 sleep is increased when a sleep opportunity is shorted such as in sleep restriction. Accordingly, abrupt awakening during sleep restriction enhances sleep inertia symptoms⁴.

The neuromodulator adenosine is a key regulator of deep sleep¹⁴ and adenosinergic neuromodulation may play an essential role in the manifestation of sleep inertia¹⁵. Consistent with this view, the adenosine receptor antagonist, caffeine, is widely used to counteract sleep inertia. Besides attenuating sleepiness and deficits in vigilance^16,17, caffeine augments cardiovascular and respiratory functions¹⁸ and promotes the release of cortisol, a key hormone of the hypothalamic–pituitary–adrenal (HPA) axis¹⁹. The HPA axis regulates several psycho-vegetative aspects of the wake-up process, including the cortisol awakening response (CAR). The CAR reflects HPA axis function^20,21 and may be associated with the propensity of sleep inertia²².

Because the impairments are most severe immediately upon awakening, proactive strategies aiming for optimal sleep length and timing have been recommended to minimize sleep inertia symptoms⁶. Nevertheless, it is not always possible to plan and obtain sleep of sufficient length and quality and at the optimal time of day. On the other hand, currently there exists no convincing evidence that reactive countermeasures to sleep intertia, i.e. strategies implemented upon wake-up, are sufficiently effective⁶. Although caffeine is the best available option, coffee takes 20–30 min to have an alerting effect²³. The bioavailability of reactive oral caffeine intake prevents effective amelioration of sleep inertia symptoms for at least 12–18 min upon waking¹⁷, unless it is taken as a proactive countermeasure prior to a short sleep or nap bout^16,24. When taken before sleep, however, caffeine can delay sleep onset, reduce total sleep time and attenuate the amount of deep slow wave sleep when a pharmacologically active concentration is present in the organism during sleep^24,25.

The time-controlled administration of pharmaceuticals in accordance with the sleep–wake cycle provides an essential pillar in the emerging concept of chronopharmacology and chronotherapeutics^26,27. We aimed at developing a chronotherapeutic caffeine formulation that ameliorates impaired subjective state, vigilance and performance immediately upon awakening without disturbing the quality of the preceeding sleep episode. For this purpose, we invented a delayed, pulsatile-release caffeine delivery system targeted to reach an efficacious plasma concentration approximately 7 h after intake. When ingested at habitual bedtime, we hypothesized that this formula would improve vigilance and mood, elevate the CAR, and reduce sleep propensity on the subsequent morning after wake-up from nocturnal sleep. We tested these hypotheses in two separate studies. First, we examined the in vivo release properties of the engineered caffeine formula throughout a nocturnal sleep episode. Then, we comprehensively investigated in randomized, double-blind, cross-over, placebo-controlled manner its effects on behavioral, emotional, neurocognitive and physiological symptoms of sleep inertia in sleep-restricted healthy young men.

Methods

Participants and permission

A total of 32 healthy young men (mean age: 25.6 ± 3.7 years) participated in the two studies (in vivo validation study: n = 10; pharmacodynamic study: n = 22), whereof 5 subjects participated in both experiments. The following criteria were required for inclusion: (i) male sex in order to avoid the potential impact of menstrual cycle on sleep physiology or HPA axis activity, (ii) age within the range of 18–34 years, (iii) a body-mass-index below 25, (iv) an Epworth Sleepiness Score (ESS) below 10, (v) habitual sleep onset latency below 20 min, (vi) regular sleep–wake rhythm with bedtime between 10 pm and 1 am, (vii) absence of any somatic or psychiatric disorders, (viii) no acute or chronic medication intake, (ix) non-smoking, (x) no history of drug abuse (lifetime use > 5 occasions, with exception of occasional cannabis use), and (xi) caffeine consumption of less than 4 units per day (coffee, tea, chocolate, cola, energy drinks).

The participants were instructed to abstain from illicit drugs and caffeine during the entire study, starting two weeks prior to the first experimental night until the end of the study (the day after the second experimental night). No alcohol was allowed 24 h before the expermental nights. The minimal wash out period before the experimental nights was 7 days. Participants were also instructed to keep an individual regular sleep–wake rhythm (23:00–07:00 or 22:00–06:00 depending on the volunteers’ habitual bedtime) during the entire study, starting 2 weeks prior to the experimental night. All included participants chose to keep either a 22:00–06:00 rhythm or a 23:00–07:00 rhythm. To ensure adherence to the regular sleep–wake pattern, participants were instructed to wear a rest-activity monitor on the non-dominant arm and to keep a sleep–wake diary.

The studies were approved by the Cantonal Ethics Committee of the Canton of Zurich (BASEC: 2018-00533) and registered on ClinicalTrials.gov (Identifier: NCT04975360). All participants provided written informed consent according to the declaration of Helsinki.

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Dornbierer, D.A., Yerlikaya, F., Wespi, R. et al. A novel bedtime pulsatile-release caffeine formula ameliorates sleep inertia symptoms immediately upon awakening. Sci Rep 11, 19734 (2021). https://doi.org/10.1038/s41598-021-98376-z