Waking up is the hardest thing I do all day: Sleep inertia and sleep drunkenness

Summary

Introduction

“Sleep inertia” refers to the transitional state between sleep and wake, marked by impaired performance, reduced vigilance, and a desire to return to sleep. The intensity and duration of sleep inertia vary based on situational factors, but its effects may last minutes to several hours. Sleep inertia is a normal phenomenon, but one with potentially dangerous ramifications, e.g., in health care workers or military personnel who are woken abruptly in the night and required to make cognitively-taxing decisions [1, 2]. In some disease states, a transitional period akin to markedly pronounced sleep inertia is present and is sometimes referred to as “sleep drunkenness”. Such pronounced sleep inertia is a core feature of idiopathic hypersomnia (IH), a potential consequence of delayed sleep phase syndrome (DSPS), and a contributor to non-REM (NREM) arousal parasomnia severity [3]. Difficulty awakening is also common in people with mood disorders and may be an important treatment target [4–6].

For this review, PubMed was searched for “sleep inertia”, “sleep drunkenness”, “sleep-wake transition”, “sleep-wake transitions”, “wake up”, “wake-up”, “waking up”, “waking-up”, “awaken”, “awakening”, “neural inertia”, “sleep offset”, and “sleep-offset”. The former two terms were also queried at clinicaltrials.gov. Reference lists were reviewed to identify additional manuscripts.

Epidemiology of sleep inertia

Assessment of subjective sleep inertia at the population level suggests that difficulty awakening is a common experience. Difficulty getting up almost every morning is reported by 42% of adolescents [7], although confusion on awakening lessens with age in adulthood [4, 5]. Men and women endorse similar difficulties with awakening [8] and similar rates of confusion upon awakening [4, 5]. Chronotype influences difficulty with awakening through interaction with sleep time, such that night owls report more sleep inertia on workdays but sleep inertia is independent of chronotype on non-work days [9]. Shift and night work increase the risk of confusion on awakening [4].

Neurophysiology and neuroimaging of sleep inertia

From an evolutionary standpoint, sleep inertia is counterintuitive, as sudden transitions to wakefulness seem clearly more adaptive. To some extent, the potential harm of slow transitions to cognitive baseline may be mitigated by changes in sleep inertia intensity based on sleep timing, composition, and duration (see below), such that there are times when a sudden awakening impairs cognition to a lesser extent. Despite this, worsened cognitive performance after even some awakenings is still potentially problematic. Sleep inertia is thus hypothesized to reflect the contradictory needs of maintaining sleep and allowing behavioral responsiveness [10] or the brain’s need for a more gradual awakening process due to its complexity [11]. Mechanistically, it has been hypothesized that awakening may occur before adenosine is fully cleared, resulting in sleep inertia [12]. Because adenosine levels are increased by sleep restriction and gradually decrease over hours of subsequent sleep, especially in the basal forebrain [13], such a hypothesis could account for the finding of more intense sleep inertia following awakenings from recovery sleep than from baseline sleep [14, 15]. An adenosine-sleep inertia hypothesis is concordant with the widespread practice of drinking coffee (containing the adenosine antagonist caffeine) upon awakening [12], but morning caffeine ingestion could alternatively reflect only a response to caffeine-withdrawal. Additionally, an adenosine hypothesis does not well account for the finding that performance after a short nap can be worse than performance immediately prior to the nap during sleep deprivation [16]. The decay of subjective sleepiness after awakening closely parallels the time courses of both extremity cooling and the cortisol awakening response, suggesting possible links of both thermoregulation and the hypothalamic-pituitary-adrenal axis to sleep inertia [17, 18]. However, the substrate for sleep inertia remains incompletely understood [19, 20].

Experimental manipulation: factors that increase sleep inertia

Numerous studies have evaluated the factors that influence sleep inertia presence and severity. Studies performed prior to 2000 have been reviewed in detail [39] and are not further reviewed here. Taken together, these early studies suggested that sleep inertia was most pronounced when awakenings coincided with the circadian trough of body temperature, was intensified by SWS awakenings and prior sleep deprivation, and was present following both short and long sleep periods. Type of task effects were prominent across studies, with a suggestion that speed was more impaired than accuracy [39].

Because cognition is affected by homeostatic and circadian processes as well as sleep inertia, forced desynchrony protocols offer a unique opportunity to study the relative impact of these processes. In a forced desynchrony protocol designed to tease apart these factors, Burke et al demonstrated that the largest effect sizes from sleep inertia were on selective visual attention (on a spatial search task) and subjective sleepiness [40]. Forced desynchrony studies have confirmed that impaired performance on awakening is most prominent during the biological night, when awakening at or within 120° before the core body temperature minimum [41, 42]. On a serial addition task, circadian variation in number correct was much more pronounced immediately upon awakening (best-to-worst difference of 2.6 additions) than it was 20 minutes after awakening (best-to-worst difference of only 0.8 correct additions), suggesting an interaction between sleep inertia and circadian rhythm [41]. These forced desynchrony studies have reached discordant findings about the effect of sleep stage at awakening [41, 42], possibly reflecting difference in task or participant age (see Table 1). Other laboratory studies, without forced desynchrony, have also found mixed results on the effect of stage at awakening (see Table 2).

Performance is generally worsened after awakening from recovery sleep compared to baseline sleep [14, 15]. This is thought to reflect increased sleep pressure following sleep deprivation, suggesting that SWS amount during sleep should correlate with cognitive impairment upon awakening [44]. Evidence in support of this hypothesis has been mixed, with some [44, 45], but not all [46–48], studies demonstrating a relationship between SWS amount or percentage and waking cognitive performance (Table 2). Relative little attention has been paid to sleep inertia in children, but nocturnal SWS awakenings impair their behavioral responsiveness considerably [43].

The duration of sleep needed to induce sleep inertia has been evaluated using precise durations of measured sleep (see Table 3). After nocturnal time in bed of 5 hours, daytime nap sleep times up to 20 minutes do not convey sleep inertia effects, while sleep inertia is clearly apparent after 30 minutes of measured sleep [49–51]. However, under more pronounced sleep deprivation, naps shorter than 30 minutes time in bed may sometimes result in sleep inertia [16, 46, 52].

In real-life occupational settings, timing nap duration based on elapsed sleep time is impractical, and thus recommendations about nap duration must be made based on time to spend in bed rather than amount of measured sleep to obtain. In this regard, field studies are particularly valuable (see Table 4). Although on first glance these studies appear to demonstrate a minimal amount of sleep inertia, the design of these studies often resulted in a substantial delay between awakening and testing. Field studies are frequently designed to balance the detrimental effects of sleep inertia on cognition against the subsequent beneficial effects of having napped, in part accounting for these differences. Other laboratory studies of sleep inertia are summarized in Table 5. These studies highlight the degree to which sleep inertia is affected by protocol. For example, using the same measure, an investigative group found different effects of a 10 minute nap opportunity when the nap was taken at 0400 versus 0710 [16, 45].

Experimental manipulation: factors that reduce sleep inertia

Multiple strategies to decrease sleep inertia have been tested. Drinking caffeine just before a nap has been suggested as a useful countermeasure for sleepy drivers [53]. Both caffeine infusion during sleep deprivation (0.3 mg/kg/hr) and caffeine gum chewed for five minutes immediately after awakening (~85 mg caffeine) lessen sleep inertia following naps [12, 54]. Simple exposure to light of varying intensities, either during or immediately after sleep, does not meaningfully impact sleep inertia as measured subjectively or objectively [55, 56]. In contrast, dawn simulators, which gradually increase the lux of light before awakening, have preliminary promise. Three studies have found improvements in subjective sleepiness on awakening, with modest objective performance benefits in one [57–59]. All three studies reported financial support from the simulator manufacturers. Pink noise at 75 decibels improves performance following a nap at midnight, but may have limited generalizability given that it also worsens performance following a rest at 0400 [60]. Application of a cold wet cloth and fan breeze improves post-nap performance [61] and is consistent with the hypothesis that sleep inertia is modulated by changes in body temperature [17]. Further work is needed to clarify the role of these interventions in dissipating sleep inertia, especially in occupational settings.

Sleep inertia/sleep drunkenness in people with sleep disorders

Sleep inertia has important implications in sleep disorders. Exaggerated sleep inertia is a core feature of IH, a common consequence of DSPS (because patients are required by external commitments to awaken near their core body temperature nadir, when sleep inertia is most pronounced, and because patients tend to be chronically, partially sleep deprived), and a factor that can worsen the NREM arousal parasomnias (by exacerbating confusion upon awakening from deep sleep) [3]. The association with idiopathic hypersomnia will be focused on here.

The syndrome of “hypersomnia with sleep drunkenness” was proposed by Bedrich Roth based on patients examined since the 1940s [62, 63]. In 58 patients, he described sleep drunkenness manifesting as confusion, slowness, incoordination, and a tendency to return to sleep lasting up to 4 hours, which was sometimes more problematic than daytime sleepiness itself [62]. Such sleep drunkenness was much more severe than the physiologic sleep inertia that occurs in healthy individuals, with patients often requiring the assistance of another person to be able to wake up. During the period of sleep drunkenness, hypersomnia patients exhibited ataxia, orthostatic disequilibrium, and hypo-reflexia [63]. Roth ultimately concluded that this syndrome was a variant of IH and reported a frequency of sleep drunkenness of 55.1% in IH [64]. Subsequent clinical series have confirmed the high rate of sleep drunkenness in this disorder (see Table 6).

The reason for sleep drunkenness in IH patients is unknown. It is sometimes characterized as an exaggerated and more severe form of physiologic sleep inertia [3]. Many IH patients have a need for extended sleep times (e.g., >11 hours) that cannot be fulfilled, and so are functionally sleep deprived; this sleep deprivation would be expected to worsen sleep inertia [63]. Additionally, IH patients have a tendency toward delayed sleep phase, which itself worsens sleep inertia [65], and IH patients with sleep drunkenness are more likely to be evening types than IH patients without sleep drunkenness [66]. However, some of the findings of Vernet et al [66] suggest that sleep drunkenness may be a phenomenon that is distinct from sleep inertia. In particular, measured sleep times and sleep efficiency do not differ between those IH patients with and without sleep drunkenness, and SWS near the time of awakening (after 0600) is no more common in those with sleep drunkenness.

Although sleep drunkenness is common in patients with IH, the presence of sleep drunkenness is not specific to this diagnosis. Classically, naps are refreshing in narcolepsy patients [3], while patients with IH may need to avoid naps because of problematic sleep drunkenness. Despite this, performance decrements in choice reaction and subtraction tasks are apparent upon awakening in patients with narcolepsy with cataplexy [68, 69]. Compared to controls, however, patients with narcolepsy with cataplexy have relatively preserved performance on a semantic priming task upon awakening from REM (compared to their own wake baseline) [70]. Clinical series suggest that patients with narcolepsy, with or without cataplexy, sometimes endorse sleep drunkenness (see Table 6). In children with narcolepsy, sleep inertia is reported to occur commonly [71], regardless of the presence of cataplexy [72]. On forced awakening from a three minute sleep episode, hypersomnolent patients frequently show high amplitude, frontal negative visual EP responses or a delayed visual P300 response [73]. Positive finding on this paradigm are common across hypersomnolence diagnoses (86% in narcolepsy, 79% in IH, and 100% in obstructive sleep apnea) but are not seen in controls [73]. Thus, while sleep drunkenness may be more characteristic of IH than narcolepsy with cataplexy, it is neither specific nor necessary for the diagnosis.

Clinical trials in patients with hypersomnolence disorders have typically not assessed sleep drunkenness, so an evidence-based approach to its treatment cannot be proposed. Review of clinicaltrials.gov identified only two studies referencing sleep inertia, both testing pharmacological effects of sedative-hypnotics. However, cases from the literature offer several treatment suggestions, including washing with cold water and dosing of stimulant medication at bedtime or 30 minutes before desired awakening [62]. Both slow-release melatonin (2mg) and protriptyline (10–20mg) at bedtime have decreased sleep drunkenness in small series of hypersomnolent patients, although details of the former series are unpublished [74, 75]. In a larger series of 46 IH patients, sodium oxybate (mean 4.3gm/night) improved sleep drunkenness in 71%, although discontinuation due to side effects was common [76], and this observation needs confirmation in a prospective, controlled trial. Improvement in sleep drunkenness has been reported in individual cases with transdermal and subcutaneous flumazenil, a nicotine patch, and etilefrine (the latter in a patient with comorbid hypotension) [77–80].

Difficulty awakening in people with psychiatric disorders

Individuals with mood disorders often have associated sleep symptomatology, including difficulty with awakening, and confusion upon awakening is strongly associated with psychiatric symptoms at the population level [4, 5]. In nearly 600 people with unipolar depression, having trouble getting out of bed was present in 74% of subjects, similar to difficulty falling asleep (72%), difficulty staying asleep (70%), and feeling sleepy (66%) [81]. Individuals with bipolar disorder and those at high-risk of developing it are also more likely than controls to endorse difficulty waking and getting out of bed [82]. On a 21-item sleep inertia questionnaire, depressed individuals endorsed higher levels of sleep inertia than controls on nearly every item [6].

Although the mechanism of difficulty in awakening in patients with mood disorders is not known, it may be related more to mood symptomatology than to sleep physiology, reflecting anhedonia or decreased motivation. In support of this, depressed subjects who endorse difficulty getting out of bed also commonly endorse wishing not to awaken [81] and depressed patients are much more likely than controls to endorse dread about starting the day [6]. EP studies also suggest that sleep inertia in mood disorders may differ from that in hypersomnolence disorders. Specifically, in forced awakening protocols, patients with psychiatric hypersomnolence tend to have responses similar to normal controls while sleep disorder patients do not [73, 83]. The relationship between mood and hypersomnolence is complex, however, so further work is needed before firm conclusions can be drawn.

As in IH, evidence-based guidance for sleep inertia treatment in mood disorders is presently unavailable. In children with treatment-refractory bipolar disorder, intranasal ketamine improved symptoms, including difficulty with awakening [84], but this finding may have limited generalizability. In those with subsyndromal winter depression or seasonal affective disorder, use of a dawn simulator improves some measures of sleep inertia (e.g., subjective ease of awakening) but not others (e.g., reported time to get out of bed) [85, 86].

In summary, physiologic sleep inertia is a transient period of decreased cognitive performance during the transition from sleep to wakefulness that is amplified by sleep deprivation, SWS, and awakenings during the biological night. In healthy individuals, its main significance may be in occupational settings, where immediate decision-making is sometimes necessary following abrupt awakenings, or when guidance regarding strategic nap timing and duration is needed. In patients with central disorders of hypersomnolence, especially idiopathic hypersomnia and perhaps narcolepsy type 2, a period resembling exaggerated sleep inertia is common and frequently problematic. In patients with mood disorders, difficulty with awakening is common, but might reflect mood dysregulation rather than an exaggerated form of sleep inertia.

Acknowledgments

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