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Sleep, sleepiness, sleep disorders and alcohol use and abuse
Sleep Medicine Reviews, Vol. 5, No. 4, pp 287–297, 2001 doi:10.1053/smrv.2001.0162, available online at http://www.idealibrary.com on
SLEEP MEDICINE reviews
CLINICAL REVIEW
Sleep, sleepiness, sleep disorders and alcohol use and abuse Timothy Roehrs and Thomas Roth Sleep Disorders and Research Center, Henry Ford Hospital, Department of Psychiatry and Behavioral Neuroscience, School of Medicine, Wayne State University, Detroit, Michigan, USA KEYWORDS ethanol, normal sleep, daytime sleepiness, sleep disorders
Summary The study of ethanol’s effects on sleep has a long history dating back to the work of Nathaniel Kleitman. This paper reviews the extensive literature describing ethanol’s effects on the sleep of healthy normals and alcoholics and the newer literature that describes its interactive effects on daytime sleepiness, physiological functions during sleep, and sleep disorders. Ethanol initially improves sleep in non-alcoholics at both low and high doses with disturbance in the second half of the night sleep at high doses. Tolerance develops to the initial beneficial effects. In alcoholics sleep is disturbed both while drinking and for months of abstinence and the nature of the abstinent sleep disturbance is predictive of relapse. Ethanol interacts to exacerbate daytime sleepiness and sleep-disordered breathing, even inducing apnea in persons at risk. Ethanol’s effects on other physiological functions during sleep and other sleep disorders has yet to be documented. 2001 Harcourt Publishers Ltd
INTRODUCTION Ethanol affects sleep, daytime alertness, physiological function during sleep and hence sleep disorders. Its impact on human sleep has received much scientific study dating back to Kleitman’s early experiments described in his 1939 book Sleep and Wakefulness, in which he described the effects that ethanol given 60 min before bedtime had on body temperature and motility during sleep in healthy normals [1]. In the 1970s much research was conducted on the sleep of alcoholics and, with the
Correspondence should be addressed to: Timothy Roehrs, Sleep Disorders and Research Center, Henry Ford Hospital, 2799 W Grand Blvd, CFP-3, Detroit, Michigan 48202, USA. 1087–0792/01/040287+11 $35.00/0
emergence of the field of sleep disorders medicine, recent attention has focused on the impact of ethanol on primary sleep disorders. Ethanol is a small, water soluble molecule that is distributed throughout the body and its effects are ubiquitous. It deleteriously affects many organ systems and in some way disrupts almost all neurobiological mechanisms. Thus, it has been very difficult to ascertain the specific mechanism(s) by which alcohol affects the different aspects of sleep and its disorders. In addition, the mechanism(s) organizing sleep and the NREM–REM cycle of sleep are not fully defined. Nonetheless, the possibility that ethanol’s sleep effects may play a role in the initiation and maintenance of alcoholism is recognized. With a better understanding of the mechanisms by which ethanol affects sleep and the 2001 Harcourt Publishers Ltd
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Table 1 Ethanol dose and approximate breath ethanol concentration (BrEC) Dose
BrEC (%)
0.2g/kg1 0.4g/kg2 0.6g/kg2 0.8g/kg2 1.0g/kg3
0.02 0.03 0.05 0.07 0.09
(0.011) (0.008) (0.015) (0.005)
Number of 12-oz US beers 1–2 2–3 3–4 4–5 5–6
1
From reference [83]. From reference [50]. 3 From reference [84]. 2
consequent adaptive processes that ensue in alcoholic drinking, more specific prevention and treatment initiatives can be developed.
ETHANOL EFFECTS ON THE SLEEP OF HEALTHY NORMALS Ethanol dosing and measurement Ethanol dosing and measurement can be somewhat variable and complex, making comparisons among studies difficult. An ethanol dose administered on a g/kg basis can yield different breath ethanol (BrEC) concentrations as a function of a number of factors including: ethanol concentration of the beverage, type of beverage, speed of consumption, contents of the gastrointestinal tract, and the total body water – which varies with sex, age, and height. To facilitate the interpretation and comparison of studies, Table 1 provides an approximate dose to BrEC conversion at peak concentrations, of ethanol given administration to fasted men in a 1:4 ratio mixed in a tonic water beverage, consumed over 30 min, and tested 30 min later allowing for its absorption. To place the dose and BrECs further into context, in the USA a 0.08% to 0.10% BrEC is considered legal intoxication in most states and in some states 0.05% is considered impaired, a lesser offense. In many European counties a 0.05% BrEC is considered intoxication legally. In the USA breathanalyzers are calibrated by industry standards such that a BrEC of 0.10% is the equivalent of a blood ethanol concentration (BEC) of 100 mg ethanol per 100 ml blood. Breath-analyzer calibrations differ among European countries and from the USA.
Effects on sleep physiology In the typical sleep study ethanol is administered at night 60–30 min before bedtime. Ethanol effects in healthy normals have been extensively studied at doses from 0.16 to 1.0 g/kg, yielding BrEC values as high as 0.105% [2–11]. A few studies have reported reduced sleep latency [5,6,9,10] and one study found increased sleep time at the low dose, 0.16 g/kg, but no effects at 0.32 and 0.64 g/kg [7]. When analyzing the sleep period by halves, studies report increased wake or light stage 1 sleep in the second half of the sleep period [10,11]; the second half sleep disruption is generally interpreted to be a ‘‘rebound’’ effect following the completed metabolism of ethanol. Given the typical peak BrEC of 0.06–0.08% measured before sleep and metabolism of 0.01– 0.02% BrEC per hour, ethanol metabolism would be completed within 4–5 h of sleep onset. Hence, the second half sleep disruption follows clearance of ethanol from the body. In addition to these effects on sleep induction and sleep maintenance, consistent effects of ethanol on sleep staging are found. Most studies report a dosedependent suppression of REM sleep at least in the first half of the sleep period [2,3,8,10,11] and some studies find increased stage 3/4 sleep in the first half of the sleep period [6,9,10,11]. In those studies showing REM suppression during the first half of the night, a REM ‘‘rebound’’ in the second half of the night is reported and, thus, the REM percentage for the complete night is not different from placebo. The metabolic "rebound" mechanism discussed above is again the probable mechanism. Several studies have assessed ethanol effects over repeated nights of administration and clear tolerance to sedative and sleep stage effects develops within three nights [5,8]. The percentages of stage 3/4 sleep and REM sleep return to basal levels. Discontinuation of repeated nightly administration of ethanol is followed by a REM sleep ‘‘rebound’’, that is an increase in REM sleep beyond basal levels [3,4]. However, not all studies have found a REM ‘‘rebound’’ on discontinuation [5,6] and this variability in results may relate to any number of methodological factors, including basal level of REM, degree of REM suppression, extent of prior tolerance to REM suppression, and dose and duration of ethanol administration.
Neuroendocrines during sleep Sleep and wake are organized in a circadian rhythm
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and in humans core body temperature and melatonin secretion are typically used as markers of circadian phase. As noted above, Kleitman first reported that ethanol administered 60 min before nocturnal bedtime affected body temperature relative to placebo. Core temperature was reduced initially and this was followed by a ‘‘rebound’’ increase in temperature [1]. Such a hypothermic effect of ethanol has been observed in many other studies. A number of pituitary hormones also show circadian variations with secretory peaks occurring during the usual sleep period. Some of the hormones are linked to sleep, so that if sleep is delayed their secretory peaks are also delayed, while the nocturnal peaks of others remain fixed temporally. Growth hormone typically peaks with the onset of slow wave sleep and it is linked to sleep [12]. In an early study 0.8 g/kg of ethanol suppressed growth hormone, despite increasing the percentage of slow wave sleep [8]. A later multiple dose study (0.5 and 1.0 g/kg) similarly found suppression of growth hormone in a dose-related manner [13]. This dissociation of growth hormone and slow-wave sleep by ethanol is further supported in the results of the earlier study [8]. Growth hormone remained suppressed over the three nights of ethanol administration, although tolerance to the slow-wave sleep enhancement of ethanol did develop. However, the clinical implications of these inhibitory effects on growth hormone and the dissociation of growth hormone and slow-wave sleep are not clear. It should also be noted that a growth hormone and slow wave sleep dissociation is also reported to occur with the benzodiazepine flurazepam [14]. Prolactin also is linked to sleep with its peak occurring 4–5 h after sleep onset [15]. The prolactin levels were not affected by ethanol in the ethanol dose study [16]. However, ethanol plasma concentrations, even at the 1.0 g/kg dose, may not have been sufficient at the 4–5 h post-sleep onset time point to affect prolactin, given metabolism of 0.01 to 0.02% BrEC per hour. Prolactin was not assayed in the earlier study [8]. Thus, whether or not ethanol affects prolactin remains to be determined.
Neurobiology of ethanol’s sleep effects The currently accepted primary mechanisms for the CNS effects of low-dose ethanol are GABA
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facilitation and glutamate inhibition; these transmitter systems are also critically involved in sleep– wake states [16]. The major inhibitory neurotransmitter system in the CNS is GABA. Evidence from in vivo preparations, chloride influx, and electrophysiological studies all indicate that ethanol at low doses enhances GABA-activated chloride flux [17] and at high doses directly enhances chloride flux [18]. This observation is significant in that many hypnotic drugs also act by modulating GABA function (i.e. barbiturates, benzodiazepines, and the newer non-benzodiazepine GABA agonists). It has long been felt that GABA has a major role in sleep [19]. GABA interneurons are present in the brainstem reticular activation system intermingled among the excitatory glutamatergic neurons (see below) and also in the thalamus, hypothalamus, and the basal forebrain, all areas that are involved in slow wave sleep generation. Thus, facilitation of GABA-mediated inhibition may explain ethanol’s sedative and slow wave sleep promoting effects. The major excitatory neurotransmitter in the CNS is glutamate, for which four receptor subtypes have been identified [20]. Among the four is the NMDA receptor. Ethanol has been shown to inhibit NMDA receptor function in numerous biochemical and electrophysiological studies [20]. Anatomically, glutamate is present in the reticular activating system of the brainstem and glutamatergic neurons project to the forebrain [19]. NMDA agonists produce seizures and some glutamatergic antagonists are used as sedatives and anesthetics [19]. Thus, glutamate is particularly involved in wakefulness and activation, and ethanol inhibition of NMDA function may be another mechanism by which ethanol has its sedative effects. In addition to GABA facilitation and NMDA inhibition, adenosine has recently become a candidate as a mediator of sleep–ethanol effects. Adenosine has an inhibitory, neuromodulatory action in the CNS [18]. Ethanol appears to facilitate the inhibitory, modulatory effects of adenosine in the CNS through several mechanisms, including synthesis enhancement, inhibiting cellular return of adenosine, and enhancing adenosine receptor function [21]. Adenosine has been hypothesized to function as the sleep homeostat [22]; the levels in brain rise during waking and decline during slow-wave sleep. Thus, ethanol may also promote slow-wave sleep and rapid sleep onset by promoting adenosine function.
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The mechanism for ethanol’s REM suppression is unclear. The transmitter long considered important for REM sleep is acetylcholine [23]. However, evidence documenting a substantive ethanol effect on acetylcholine is minimal and what evidence there is indicates that ethanol’s effects occur through the nicotinic receptor [24]. The cholinergic induction of REM sleep is through muscurinic receptors [23]. Glutamate is also involved in the induction of some of the REM sleep phenomena [23] and inhibition of glutamate by ethanol was noted above [20]. The sedative and REM-suppressive effects of ethanol can be experimentally dissociated. In a recent report caffeine (150 mg) reversed the sedative effects of ethanol (0.5 g/kg), but had no effect on its REMsuppressive effects. Although unlikely at the low dose used, caffeine’s own REM-suppressive effects may have been responsible for the REM suppression observed [25]. In summary, ethanol’s REM suppressive effects may occur through glutamatergic mechanisms, while the sedative effects occur through GABA mechanisms.
SLEEP IN ALCOHOLICS AND ETHANOL EFFECTS ON THEIR SLEEP Ethanol effects on the sleep of alcoholics The sleep of alcoholics and the effects of ethanol on the sleep of alcoholics has been assessed in a large number of studies. During periods of heavy drinking sleep onset in alcoholics is relatively rapid, but sleep duration is relatively short and mostly composed of NREM sleep. If a 8-h bedtime is required, during the second half of the night there are frequent awakenings and reduced amounts and disruptions of REM sleep [6,26,27]. Patients often state that they are unable to fall asleep without drinking, but that after drinking their sleep is truncated prematurely. Thus, in a behavioral study involving free access to alcohol, alcoholics were found to drink and sleep in short alternating bouts. These sleep and drinking bouts were distributed across the whole 24-h day [28].
Acute ethanol discontinuation Acute ethanol discontinuation is characterized by a decrease in the percentage of slow-wave sleep [29].
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REM sleep is altered showing more frequent REM episodes and shortened NREM–REM cycles, but without increased REM durations [30]. It has been hypothesized that the hallucinations of alcohol withdrawal are in essence the intrusions of REM sleep into wake as a result of a REM ‘‘rebound’’ and the fragmentation of REM sleep [31]. However, not all patients studied have shown REM ‘‘rebound’’, even while showing a severe ethanol withdrawal syndrome, including hallucinations [32]. Nonetheless, it has been hypothesized that REM suppression and a subsequent REM ‘‘rebound’’ is a marker of physical dependence. Such a pattern is shown with other drug classes that produce physical dependence including the opiates, barbiturates, and some stimulants (e.g. amphetamines).
Sleep after prolonged abstinence The sleep of sober alcoholics is extremely disturbed; sleep latency is prolonged, sleep is fragmented and light with reduced amounts of delta sleep, and shortened sleep times overall [6,26,27,29–37]. The studies suggest that the sleep disturbance of alcoholics may endure for up to 2 years of abstinence. Given these reduced amounts of stage 3/4 sleep compared to age-matched controls, investigators in the 1970s attempted to relate stage 3/4 status to the level of cognitive impairment associated with a patient’s alcoholism and furthermore to predict the extent of physiological recovery during abstinence. More recently, studies have reported that indices of sleep in alcoholics predict relapse. REM sleep measures indicative of ‘‘REM pressure’’, such as shortened REM latency, high REM percentages, or high REM density, predicted relapse [38–41]. Additionally, a low percentage of stage 3/4 sleep was also predicative of relapse in a study of alcoholics from another center [41]. The administration of ethanol after an acute period of abstinence improves the sleep of the alcoholic, but only initially [42,43]. Sleep then returns to its disturbed, shortened, and fragmented characteristics.
ETHANOL EFFECTS ON DAYTIME ALERTNESS While classified as a depressant drug, ethanol has both sedative and stimulatory effects. These differential effects, described as biphasic, are dependent on dose and the phase of plasma concentration [44].
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Stimulatory effects are evident primarily at low to moderate doses and as ethanol concentrations ascend to a peak. Sedative effects follow on the descending phase of the plasma concentration curve and occur with higher doses. Thus, those night-time studies that showed reduced sleep latencies in healthy normals typically raised ethanol concentration above 0.06% BrEC [5,6,9,10] and administered ethanol 30–60 min before sleep, allowing for ethanol concentration to peak before bedtime. A daytime study using electrophysiological methods (a modified Multiple Sleep Latency Test (MSLT)) found increased sleep latencies at peak breath concentrations relative to placebo, and consistent with ethanol’s stimulatory effects. Thereafter, on the descending phase sleep latencies were reduced relative to placebo [45]. In other studies, all done on the descending phase, ethanol reduced sleep latency, as measured by a standard MSLT, and impaired attention and reaction time performance in a dose-related fashion. These impairing effects remained for at least 2 h after the ethanol had been completely metabolized, as evidenced by BrECs of zero [46,47]. A series of studies has been conducted exploring the modulation of these daytime sedative and performance-disruptive effects of ethanol by the basal level of sleepiness. In these studies nocturnal sleep time is either shortened or extended and then ethanol is administered the following day. Thereafter levels of sleepiness/alertness and psychomotor performance are assessed for approximately 8 h. The studies have found that the level of sleepiness/ alertness at the time of ethanol administration alters the subsequent sedating and performance-disruptive effects of ethanol. These interactive effects were demonstrated in sleepy versus alert healthy, normal subjects [48] and were also shown in subjects before and after both sleep restriction and sleep extension [49,50]. Finally, the interactive effects were shown within subjects at times of the day when the levels of sleepiness are known to differ according to the typical circadian rhythm of sleepiness–alertness [50]. To summarize, increased alertness diminishes ethanol’s effects and increased sleepiness compounds ethanol’s effects.
nocturnal sleep and daytime alertness have been described. However, this relationship may, in fact, be bi-directional. There are some survey and laboratory data that suggest variations in the duration of nocturnal sleep and level of daytime sleepiness may be important modulatory variables for ethanol drinking. A survey from the UK found a negative correlation between sleep times and alcohol consumption in men (i.e. shorter sleep was associated with heavier drinking) [52]. A US study of young adults found that those reporting they needed 6 h of sleep or less had an earlier age of drinking onset and drank more per month than did longer sleepers [53]. These data led Shuckit and Bernstein to hypothesize that short sleep is associated with heavy alcohol intake. Short sleep time in healthy adults is clearly associated with elevated levels of daytime sleepiness [54]. Laboratory studies of ethanol and mood show some interesting relationships between daytime sleepiness–alertness and drinking. Ethanol preference is studied in the laboratory by giving subjects beverage choices presented in color-coded cups. Using this ethanol preference self-administration procedure, it was found that moderate drinkers who preferred ethanol in laboratory testing had lower self-rated levels of alertness and vigor than non-preferring subjects [55,56]. Furthermore, when drinking ethanol in the laboratory those showing ethanol preference experienced ethanol as increasing their elation and vigor. In contrast, those who did not prefer ethanol in the laboratory experienced ethanol as increasing their sleepiness. In an ethanol challenge study the drinking history of the healthy, young men predicted their subjective response to ethanol [57]. Greater ethanol drinking was related to less self-rated sleepiness after the laboratory ethanol challenge. Whether these individual differences in response to ethanol reflect different physiological states or a difference in the perception of a common physiological state is unknown. If the difference is one of perception, the different perceptions of the effect of ethanol may be due to differential expectations regarding ethanol’s effects.
NOCTURNAL SLEEP, DAYTIME ALERTNESS, AND ETHANOL DRINKING
ETHANOL EFFECTS ON SLEEP DISORDERS
So far in this article, the effects of ethanol on
Given the profound effects of ethanol on sleep and daytime alertness and ethanol’s ubiquitous effects
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on most organ systems and biological processes, it is no surprise that ethanol affects sleep-related pathologies and sleep disorders. Some sleep disorders have been studied extensively to assess ethanol’s effects, while others have not. In some cases the effect of ethanol may be initially beneficial and then later disruptive, while in other cases it is clearly disruptive.
Insomnia Persistent difficulty in falling asleep, maintaining sleep, or non-restorative sleep is reported by about 10–15% of the general population [58,59]. About 30% of persons with persistent insomnia from the general population report having used alcohol to help them sleep in the past year, and 67% of those report it was effective [59]. The studies of healthy normals sleeping at their usual bedtimes, reported above, do not adequately represent the hypnotic potential of ethanol in persons with insomnia. In healthy, normal subjects sleep latency and sleep efficiency are already optimal and further improvement is difficult to demonstrate. Thus, as noted above, the reports of ethanol’s effects on measures of sleep induction and maintenance in healthy normals are inconsistent. Furthermore, the doses used in those studies are generally much larger (i.e. BrEC>0.06%) than insomniacs typically report using (i.e. 1–3 drinks). A recent study compared the effects of low-dose ethanol (0.5 g/kg) on the sleep of insomniacs and age-matched healthy normals [60]. The sleep of the insomniacs was improved with ethanol relative to placebo and the second half of the night sleep disruption found in normals at the higher ethanol doses was not observed. Specifically, slow-wave sleep was increased to the level of the age-matched controls. When given an opportunity to choose between a previously experienced color-coded ethanol or a placebo beverage before sleep, the insomniacs chose ethanol and normals chose placebo [60]. The average nightly dose self-administered (up to a 0.06 g/kg was possible) by the insomniacs was 0.045 g/kg, which is similar to the dose which improved the sleep of the insomniacs. The question is whether the preference for ethanol at bedtime by insomniacs compared to noninsomniacs, found in the Gallup data and in this study, is the use of ethanol to self-medicate for a sleep problem, the use of ethanol to improve mood
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or, initially, a sleep-medication which then shifts to ‘‘mood-altering’’ behavior. If it initially is, or ultimately becomes, ‘‘mood-altering’’ behavior, what are the ‘‘mood-altering’’ effects for the insomniac that serve to reinforce ethanol drinking? Does tolerance to the sedative effects develop in insomniacs as it does in normals? Does the ethanol dose used escalate over repeated nights? Does hypnotic use generalize to daytime use? And ultimately, what are the risks associated with the use of ethanol as a hypnotic? All these issues are yet to be addressed. But these data again suggest that the ethanol-sleep relationship is interactive; that is, disturbed nocturnal sleep increases the likelihood of ethanol use.
Sleep-disordered breathing Obstructive sleep apnea syndrome has a prevalence of about 3% in the US population and the known risk factors are snoring, obesity, and being male [61]. While the prevalence of sleep apnea is less than that of chronic insomnia, its clinical importance and the potential of ethanol to worsen the disorder is generally recognized. During wakefulness ethanol is a mild respiratory depressant, but during sleep it can exacerbate obstructive sleep apnea and it also may precipitate sleep breathing disorders in those at risk. Patients with moderate obstructive apnea (respiratory disturbance index (RDI)=22) received 300 ml of bourbon 2 h before bedtime and the RDI was increased to 28 [62]. In another study patients with a range of sleep breathing disorders were studied [63]. An unspecified dose of ethanol increased the indices of every patient among the apnea patients with RDIs of 14–54. In two patients with COPD and apnea ethanol further exacerbated their hypoxia, reducing mean SaO2 from 78 to 62. Finally, in two patients with a snoring history ethanol induced apneas during the first 2 h of sleep. A later study convincingly showed that asymptomatic snorers with no apneas develop apnea after ethanol administration [64]. While it is clear that ethanol before sleep exacerbates existing apnea and induces apnea in those at risk for apnea, the findings for asymptomatic persons without risk factors have been inconsistent. Healthy, normal women, either pre- or post-menopausal, do not develop apnea after bedtime administration of moderate ethanol doses [65,66]. Even in men who are non-obese and do not snore,
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ethanol has little or no effect on breathing during sleep [67,68]. However, several studies have reported small increases in apnea in men and particularly older men [69]. Infrequent apneas can be found in asymptomatic men, but night-to-night consistency of the apnea is very low [70,71]. In part, the inconsistency of the apneas can be due to body position and it should be noted that none of the studies above controlled for body position. Body position is one of several important variables in the development of an apnea event and, thus, also in the capacity of ethanol to induce or exacerbate apnea. In normal breathing, during the inspiratory phase, negative intra-pharyngeal pressure is produced by the diaphragm and the upper airway muscles must overcome this negative pressure to maintain airway patency. In the supine position gravitational forces can add to the negative inspiratory pressure increasing the likelihood of airway collapse. The direct effect of ethanol on the airway is also critical; ethanol in animal and human studies has been shown to have a depressant effect on the upper airway muscles. Ethanol decreases genioglossal muscle tone by reducing the firing of the hypoglossal nerve [72,73]. Further supportive of the depressant effect of ethanol on airway muscles is the observation that greater levels of continuous positive airway pressure (CPAP) are necessary to prevent snoring and apnea after ethanol ingestion [64]. Finally, ethanol suppresses the arousal response to airway occlusion, the result being a tendency to lengthen apneas and to increase the associated hypoxemia [74]. Given the clear effects of acute ethanol on upper airway breathing mechanisms, the question arises as to the impact of chronic ethanol exposure on these mechanisms. Several studies in abstinent alcoholics have documented an increased frequency of sleep-disordered breathing compared to ageand weight-matched control subjects [75,76]. The unanswered question is whether the chronic ethanol has permanently altered ventilatory control and upper airway motor function. The disturbed and fragmented sleep of the abstinent alcoholic, described earlier, may itself increase the likelihood of airway collapse. In both animal and human studies it has been demonstrated that sleep fragmentation increases apnea [77,78]. The most probable mechanism is that the fragmentation increases sleepiness and the sleepiness reduces upper airway muscles responsivity.
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In addition to ethanol’s effects on the nocturnal pathophysiology of sleep disordered breathing is its potential to exacerbate the daytime symptomatology of the syndrome. The most prominent symptom of sleep disordered breathing is daytime sleepiness. Earlier, studies were cited showing that the basal level of sleepiness–alertness interacts with the daytime sedative and performance-disruptive effects of ethanol. While this potential interactive effect of ethanol with the sleepiness of apnea patients has not been documented, it is reasonable to assume that such an interaction would be found in apnea patients. The levels of sleepiness produced in the healthy normals in the cited studies were similar to those found in apnea patients using the MSLT as the measure of sleepiness [79]. The interactive potential may be greater in the apnea patients as their sleepiness is chronic as opposed to the acute sleepiness produced in those healthy normals.
Other sleep disorders The effect of ethanol on other sleep disorders has not been studied to any great extent. However, given the known depressant and sedative effects of ethanol and the ubiquitous nature of those effects, some hypotheses can be formulated and the known clinical information can be discussed.
Narcolepsy Similar to sleep disordered breathing, the most prominent symptom in narcolepsy is daytime sleepiness. Again one would predict interactive effects of daytime ethanol in narcoleptics. Interestingly, narcoleptics report avoiding the use of alcohol. This may be because the sleepiness of narcolepsy develops at the stage of life when first exposures to alcohol typically occur. Thus, the narcoleptic learns that the sedative effect of ethanol worsens his/her daytime sleepiness. This developmental pattern differs from that of apnea where the disease and its symptoms develop in mid-life, long after drinking habits have been established.
Restless leg-syndrome (RLS) and periodic leg movements (PLMS) Nocturnal ethanol may have a beneficial effect on RLS and PLMS, at least acutely, until tolerance develops. The longest sleep latencies reported in a case series of patients with insomnia were those in
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patients with RLS [80]. Ethanol would be expected to shorten those long latencies in the short-term as was shown in the primary insomnia study cited above [60]. In cases of PLMS, the sleep-disruptive effects of PLMS are the brief arousals and awakenings that occur in conjunction with the movements. While never tested, one would predict that ethanol would suppress the arousal response just as it does in apnea. As noted above it is likely that tolerance develops to this effect. However, alcoholism may be associated with RLS and PLMS. RLS and PLMS are heterogenous in etiology, although polyneuropathy is among the known causal factors [81]. To the extent that the alcoholic develops polyneuropathy one would predict the possibility of RLS and PLMS. Also, RLS and PLMs are associated with deficiencies in iron, ferritin, magnesium, and vitamin B12 and to the extent that the alcoholic has any of these deficiencies RLS and PLMS may be expected.
NREM parasomnias These parasomnias include sleep drunkenness, night terrors, and sleep walking. Clinically it has been observed that the frequency of episodes of these disorders increases after the consumption of alcohol [82]. This is consistent with the fact that a number of variables which increase slow wave sleep and increase the difficulty of arousal from sleep are known to be triggering and predisposing factors in NREM parasomnias.
CONCLUSION Ethanol has extensive effects on sleep, sleepiness, and sleep disorders. In healthy normals at acute higher doses it disturbs sleep, while in insomniacs at lower doses it may be beneficial. Tolerance to its beneficial effects probably develops rapidly, based on the data from healthy normals. The concern is that the tolerance development may lead to excessive ‘‘hypnotic’’ use and possibly excessive daytime use. In alcoholics sleep is disturbed when actively drinking and for months of abstinence. The nature of the sleep disturbance in alcoholics is predictive of relapse. The effects of ethanol appear to be bi-directional; nocturnal sleep quantity and daytime sleepiness influences the sedative and performance impairing effects of ethanol and may also relate to rates of alcohol drinking. With the exception of sleep-disordered breathing, the effects of
ethanol on sleep disorders has not been extensively evaluated. However, for sleep-disordered breathing it is clear that ethanol exacerbates apnea and even induces apnea in persons at risk. Ethanol’s effects on other physiological functions during sleep and other sleep disorders have yet to be documented fully.
ACKNOWLEDGMENTS Supported by NIH-NIAAA grant no. R01-AA11264. Practice Points 1. Disturbed sleep after acute and chronic use of alcohol is well documented and alcohol must be considered as a primary or contributory factor in any insomnia complaint. 2. Clinicians should advise insomniacs against the use of alcohol to facilitate sleep as its benefical effects are limited and short-term and tolerance to its effects develops rapidly. 3. Alcohol exacerbates daytime sleepiness and clinicians must caution sleepy patients about its daytime use. 4. Alcohol clearly exacerbates sleep-disordered breathing and may also contribute to other primary sleep disorders and parasomnias, which clinicians must consider in their diagnoses and treatments.
Research Agenda 1. The mechanisms for alcohol’s effects on sleep and REM sleep must be better clarified. 2. The effects of alcohol on neuroendocrine function during sleep must be documented and the clinical significance of those effects outlined. 3. The etiologic or contributory effects of alcohol on sleep disorders other than sleepdisordered breathing must be better documented and understood.
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SLEEP MEDICINE reviews
CLINICAL REVIEW
Sleep, sleepiness, sleep disorders and alcohol use and abuse Timothy Roehrs and Thomas Roth Sleep Disorders and Research Center, Henry Ford Hospital, Department of Psychiatry and Behavioral Neuroscience, School of Medicine, Wayne State University, Detroit, Michigan, USA KEYWORDS ethanol, normal sleep, daytime sleepiness, sleep disorders
Summary The study of ethanol’s effects on sleep has a long history dating back to the work of Nathaniel Kleitman. This paper reviews the extensive literature describing ethanol’s effects on the sleep of healthy normals and alcoholics and the newer literature that describes its interactive effects on daytime sleepiness, physiological functions during sleep, and sleep disorders. Ethanol initially improves sleep in non-alcoholics at both low and high doses with disturbance in the second half of the night sleep at high doses. Tolerance develops to the initial beneficial effects. In alcoholics sleep is disturbed both while drinking and for months of abstinence and the nature of the abstinent sleep disturbance is predictive of relapse. Ethanol interacts to exacerbate daytime sleepiness and sleep-disordered breathing, even inducing apnea in persons at risk. Ethanol’s effects on other physiological functions during sleep and other sleep disorders has yet to be documented. 2001 Harcourt Publishers Ltd
INTRODUCTION Ethanol affects sleep, daytime alertness, physiological function during sleep and hence sleep disorders. Its impact on human sleep has received much scientific study dating back to Kleitman’s early experiments described in his 1939 book Sleep and Wakefulness, in which he described the effects that ethanol given 60 min before bedtime had on body temperature and motility during sleep in healthy normals [1]. In the 1970s much research was conducted on the sleep of alcoholics and, with the
Correspondence should be addressed to: Timothy Roehrs, Sleep Disorders and Research Center, Henry Ford Hospital, 2799 W Grand Blvd, CFP-3, Detroit, Michigan 48202, USA. 1087–0792/01/040287+11 $35.00/0
emergence of the field of sleep disorders medicine, recent attention has focused on the impact of ethanol on primary sleep disorders. Ethanol is a small, water soluble molecule that is distributed throughout the body and its effects are ubiquitous. It deleteriously affects many organ systems and in some way disrupts almost all neurobiological mechanisms. Thus, it has been very difficult to ascertain the specific mechanism(s) by which alcohol affects the different aspects of sleep and its disorders. In addition, the mechanism(s) organizing sleep and the NREM–REM cycle of sleep are not fully defined. Nonetheless, the possibility that ethanol’s sleep effects may play a role in the initiation and maintenance of alcoholism is recognized. With a better understanding of the mechanisms by which ethanol affects sleep and the 2001 Harcourt Publishers Ltd
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Table 1 Ethanol dose and approximate breath ethanol concentration (BrEC) Dose
BrEC (%)
0.2g/kg1 0.4g/kg2 0.6g/kg2 0.8g/kg2 1.0g/kg3
0.02 0.03 0.05 0.07 0.09
(0.011) (0.008) (0.015) (0.005)
Number of 12-oz US beers 1–2 2–3 3–4 4–5 5–6
1
From reference [83]. From reference [50]. 3 From reference [84]. 2
consequent adaptive processes that ensue in alcoholic drinking, more specific prevention and treatment initiatives can be developed.
ETHANOL EFFECTS ON THE SLEEP OF HEALTHY NORMALS Ethanol dosing and measurement Ethanol dosing and measurement can be somewhat variable and complex, making comparisons among studies difficult. An ethanol dose administered on a g/kg basis can yield different breath ethanol (BrEC) concentrations as a function of a number of factors including: ethanol concentration of the beverage, type of beverage, speed of consumption, contents of the gastrointestinal tract, and the total body water – which varies with sex, age, and height. To facilitate the interpretation and comparison of studies, Table 1 provides an approximate dose to BrEC conversion at peak concentrations, of ethanol given administration to fasted men in a 1:4 ratio mixed in a tonic water beverage, consumed over 30 min, and tested 30 min later allowing for its absorption. To place the dose and BrECs further into context, in the USA a 0.08% to 0.10% BrEC is considered legal intoxication in most states and in some states 0.05% is considered impaired, a lesser offense. In many European counties a 0.05% BrEC is considered intoxication legally. In the USA breathanalyzers are calibrated by industry standards such that a BrEC of 0.10% is the equivalent of a blood ethanol concentration (BEC) of 100 mg ethanol per 100 ml blood. Breath-analyzer calibrations differ among European countries and from the USA.
Effects on sleep physiology In the typical sleep study ethanol is administered at night 60–30 min before bedtime. Ethanol effects in healthy normals have been extensively studied at doses from 0.16 to 1.0 g/kg, yielding BrEC values as high as 0.105% [2–11]. A few studies have reported reduced sleep latency [5,6,9,10] and one study found increased sleep time at the low dose, 0.16 g/kg, but no effects at 0.32 and 0.64 g/kg [7]. When analyzing the sleep period by halves, studies report increased wake or light stage 1 sleep in the second half of the sleep period [10,11]; the second half sleep disruption is generally interpreted to be a ‘‘rebound’’ effect following the completed metabolism of ethanol. Given the typical peak BrEC of 0.06–0.08% measured before sleep and metabolism of 0.01– 0.02% BrEC per hour, ethanol metabolism would be completed within 4–5 h of sleep onset. Hence, the second half sleep disruption follows clearance of ethanol from the body. In addition to these effects on sleep induction and sleep maintenance, consistent effects of ethanol on sleep staging are found. Most studies report a dosedependent suppression of REM sleep at least in the first half of the sleep period [2,3,8,10,11] and some studies find increased stage 3/4 sleep in the first half of the sleep period [6,9,10,11]. In those studies showing REM suppression during the first half of the night, a REM ‘‘rebound’’ in the second half of the night is reported and, thus, the REM percentage for the complete night is not different from placebo. The metabolic "rebound" mechanism discussed above is again the probable mechanism. Several studies have assessed ethanol effects over repeated nights of administration and clear tolerance to sedative and sleep stage effects develops within three nights [5,8]. The percentages of stage 3/4 sleep and REM sleep return to basal levels. Discontinuation of repeated nightly administration of ethanol is followed by a REM sleep ‘‘rebound’’, that is an increase in REM sleep beyond basal levels [3,4]. However, not all studies have found a REM ‘‘rebound’’ on discontinuation [5,6] and this variability in results may relate to any number of methodological factors, including basal level of REM, degree of REM suppression, extent of prior tolerance to REM suppression, and dose and duration of ethanol administration.
Neuroendocrines during sleep Sleep and wake are organized in a circadian rhythm
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and in humans core body temperature and melatonin secretion are typically used as markers of circadian phase. As noted above, Kleitman first reported that ethanol administered 60 min before nocturnal bedtime affected body temperature relative to placebo. Core temperature was reduced initially and this was followed by a ‘‘rebound’’ increase in temperature [1]. Such a hypothermic effect of ethanol has been observed in many other studies. A number of pituitary hormones also show circadian variations with secretory peaks occurring during the usual sleep period. Some of the hormones are linked to sleep, so that if sleep is delayed their secretory peaks are also delayed, while the nocturnal peaks of others remain fixed temporally. Growth hormone typically peaks with the onset of slow wave sleep and it is linked to sleep [12]. In an early study 0.8 g/kg of ethanol suppressed growth hormone, despite increasing the percentage of slow wave sleep [8]. A later multiple dose study (0.5 and 1.0 g/kg) similarly found suppression of growth hormone in a dose-related manner [13]. This dissociation of growth hormone and slow-wave sleep by ethanol is further supported in the results of the earlier study [8]. Growth hormone remained suppressed over the three nights of ethanol administration, although tolerance to the slow-wave sleep enhancement of ethanol did develop. However, the clinical implications of these inhibitory effects on growth hormone and the dissociation of growth hormone and slow-wave sleep are not clear. It should also be noted that a growth hormone and slow wave sleep dissociation is also reported to occur with the benzodiazepine flurazepam [14]. Prolactin also is linked to sleep with its peak occurring 4–5 h after sleep onset [15]. The prolactin levels were not affected by ethanol in the ethanol dose study [16]. However, ethanol plasma concentrations, even at the 1.0 g/kg dose, may not have been sufficient at the 4–5 h post-sleep onset time point to affect prolactin, given metabolism of 0.01 to 0.02% BrEC per hour. Prolactin was not assayed in the earlier study [8]. Thus, whether or not ethanol affects prolactin remains to be determined.
Neurobiology of ethanol’s sleep effects The currently accepted primary mechanisms for the CNS effects of low-dose ethanol are GABA
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facilitation and glutamate inhibition; these transmitter systems are also critically involved in sleep– wake states [16]. The major inhibitory neurotransmitter system in the CNS is GABA. Evidence from in vivo preparations, chloride influx, and electrophysiological studies all indicate that ethanol at low doses enhances GABA-activated chloride flux [17] and at high doses directly enhances chloride flux [18]. This observation is significant in that many hypnotic drugs also act by modulating GABA function (i.e. barbiturates, benzodiazepines, and the newer non-benzodiazepine GABA agonists). It has long been felt that GABA has a major role in sleep [19]. GABA interneurons are present in the brainstem reticular activation system intermingled among the excitatory glutamatergic neurons (see below) and also in the thalamus, hypothalamus, and the basal forebrain, all areas that are involved in slow wave sleep generation. Thus, facilitation of GABA-mediated inhibition may explain ethanol’s sedative and slow wave sleep promoting effects. The major excitatory neurotransmitter in the CNS is glutamate, for which four receptor subtypes have been identified [20]. Among the four is the NMDA receptor. Ethanol has been shown to inhibit NMDA receptor function in numerous biochemical and electrophysiological studies [20]. Anatomically, glutamate is present in the reticular activating system of the brainstem and glutamatergic neurons project to the forebrain [19]. NMDA agonists produce seizures and some glutamatergic antagonists are used as sedatives and anesthetics [19]. Thus, glutamate is particularly involved in wakefulness and activation, and ethanol inhibition of NMDA function may be another mechanism by which ethanol has its sedative effects. In addition to GABA facilitation and NMDA inhibition, adenosine has recently become a candidate as a mediator of sleep–ethanol effects. Adenosine has an inhibitory, neuromodulatory action in the CNS [18]. Ethanol appears to facilitate the inhibitory, modulatory effects of adenosine in the CNS through several mechanisms, including synthesis enhancement, inhibiting cellular return of adenosine, and enhancing adenosine receptor function [21]. Adenosine has been hypothesized to function as the sleep homeostat [22]; the levels in brain rise during waking and decline during slow-wave sleep. Thus, ethanol may also promote slow-wave sleep and rapid sleep onset by promoting adenosine function.
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The mechanism for ethanol’s REM suppression is unclear. The transmitter long considered important for REM sleep is acetylcholine [23]. However, evidence documenting a substantive ethanol effect on acetylcholine is minimal and what evidence there is indicates that ethanol’s effects occur through the nicotinic receptor [24]. The cholinergic induction of REM sleep is through muscurinic receptors [23]. Glutamate is also involved in the induction of some of the REM sleep phenomena [23] and inhibition of glutamate by ethanol was noted above [20]. The sedative and REM-suppressive effects of ethanol can be experimentally dissociated. In a recent report caffeine (150 mg) reversed the sedative effects of ethanol (0.5 g/kg), but had no effect on its REMsuppressive effects. Although unlikely at the low dose used, caffeine’s own REM-suppressive effects may have been responsible for the REM suppression observed [25]. In summary, ethanol’s REM suppressive effects may occur through glutamatergic mechanisms, while the sedative effects occur through GABA mechanisms.
SLEEP IN ALCOHOLICS AND ETHANOL EFFECTS ON THEIR SLEEP Ethanol effects on the sleep of alcoholics The sleep of alcoholics and the effects of ethanol on the sleep of alcoholics has been assessed in a large number of studies. During periods of heavy drinking sleep onset in alcoholics is relatively rapid, but sleep duration is relatively short and mostly composed of NREM sleep. If a 8-h bedtime is required, during the second half of the night there are frequent awakenings and reduced amounts and disruptions of REM sleep [6,26,27]. Patients often state that they are unable to fall asleep without drinking, but that after drinking their sleep is truncated prematurely. Thus, in a behavioral study involving free access to alcohol, alcoholics were found to drink and sleep in short alternating bouts. These sleep and drinking bouts were distributed across the whole 24-h day [28].
Acute ethanol discontinuation Acute ethanol discontinuation is characterized by a decrease in the percentage of slow-wave sleep [29].
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REM sleep is altered showing more frequent REM episodes and shortened NREM–REM cycles, but without increased REM durations [30]. It has been hypothesized that the hallucinations of alcohol withdrawal are in essence the intrusions of REM sleep into wake as a result of a REM ‘‘rebound’’ and the fragmentation of REM sleep [31]. However, not all patients studied have shown REM ‘‘rebound’’, even while showing a severe ethanol withdrawal syndrome, including hallucinations [32]. Nonetheless, it has been hypothesized that REM suppression and a subsequent REM ‘‘rebound’’ is a marker of physical dependence. Such a pattern is shown with other drug classes that produce physical dependence including the opiates, barbiturates, and some stimulants (e.g. amphetamines).
Sleep after prolonged abstinence The sleep of sober alcoholics is extremely disturbed; sleep latency is prolonged, sleep is fragmented and light with reduced amounts of delta sleep, and shortened sleep times overall [6,26,27,29–37]. The studies suggest that the sleep disturbance of alcoholics may endure for up to 2 years of abstinence. Given these reduced amounts of stage 3/4 sleep compared to age-matched controls, investigators in the 1970s attempted to relate stage 3/4 status to the level of cognitive impairment associated with a patient’s alcoholism and furthermore to predict the extent of physiological recovery during abstinence. More recently, studies have reported that indices of sleep in alcoholics predict relapse. REM sleep measures indicative of ‘‘REM pressure’’, such as shortened REM latency, high REM percentages, or high REM density, predicted relapse [38–41]. Additionally, a low percentage of stage 3/4 sleep was also predicative of relapse in a study of alcoholics from another center [41]. The administration of ethanol after an acute period of abstinence improves the sleep of the alcoholic, but only initially [42,43]. Sleep then returns to its disturbed, shortened, and fragmented characteristics.
ETHANOL EFFECTS ON DAYTIME ALERTNESS While classified as a depressant drug, ethanol has both sedative and stimulatory effects. These differential effects, described as biphasic, are dependent on dose and the phase of plasma concentration [44].
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Stimulatory effects are evident primarily at low to moderate doses and as ethanol concentrations ascend to a peak. Sedative effects follow on the descending phase of the plasma concentration curve and occur with higher doses. Thus, those night-time studies that showed reduced sleep latencies in healthy normals typically raised ethanol concentration above 0.06% BrEC [5,6,9,10] and administered ethanol 30–60 min before sleep, allowing for ethanol concentration to peak before bedtime. A daytime study using electrophysiological methods (a modified Multiple Sleep Latency Test (MSLT)) found increased sleep latencies at peak breath concentrations relative to placebo, and consistent with ethanol’s stimulatory effects. Thereafter, on the descending phase sleep latencies were reduced relative to placebo [45]. In other studies, all done on the descending phase, ethanol reduced sleep latency, as measured by a standard MSLT, and impaired attention and reaction time performance in a dose-related fashion. These impairing effects remained for at least 2 h after the ethanol had been completely metabolized, as evidenced by BrECs of zero [46,47]. A series of studies has been conducted exploring the modulation of these daytime sedative and performance-disruptive effects of ethanol by the basal level of sleepiness. In these studies nocturnal sleep time is either shortened or extended and then ethanol is administered the following day. Thereafter levels of sleepiness/alertness and psychomotor performance are assessed for approximately 8 h. The studies have found that the level of sleepiness/ alertness at the time of ethanol administration alters the subsequent sedating and performance-disruptive effects of ethanol. These interactive effects were demonstrated in sleepy versus alert healthy, normal subjects [48] and were also shown in subjects before and after both sleep restriction and sleep extension [49,50]. Finally, the interactive effects were shown within subjects at times of the day when the levels of sleepiness are known to differ according to the typical circadian rhythm of sleepiness–alertness [50]. To summarize, increased alertness diminishes ethanol’s effects and increased sleepiness compounds ethanol’s effects.
nocturnal sleep and daytime alertness have been described. However, this relationship may, in fact, be bi-directional. There are some survey and laboratory data that suggest variations in the duration of nocturnal sleep and level of daytime sleepiness may be important modulatory variables for ethanol drinking. A survey from the UK found a negative correlation between sleep times and alcohol consumption in men (i.e. shorter sleep was associated with heavier drinking) [52]. A US study of young adults found that those reporting they needed 6 h of sleep or less had an earlier age of drinking onset and drank more per month than did longer sleepers [53]. These data led Shuckit and Bernstein to hypothesize that short sleep is associated with heavy alcohol intake. Short sleep time in healthy adults is clearly associated with elevated levels of daytime sleepiness [54]. Laboratory studies of ethanol and mood show some interesting relationships between daytime sleepiness–alertness and drinking. Ethanol preference is studied in the laboratory by giving subjects beverage choices presented in color-coded cups. Using this ethanol preference self-administration procedure, it was found that moderate drinkers who preferred ethanol in laboratory testing had lower self-rated levels of alertness and vigor than non-preferring subjects [55,56]. Furthermore, when drinking ethanol in the laboratory those showing ethanol preference experienced ethanol as increasing their elation and vigor. In contrast, those who did not prefer ethanol in the laboratory experienced ethanol as increasing their sleepiness. In an ethanol challenge study the drinking history of the healthy, young men predicted their subjective response to ethanol [57]. Greater ethanol drinking was related to less self-rated sleepiness after the laboratory ethanol challenge. Whether these individual differences in response to ethanol reflect different physiological states or a difference in the perception of a common physiological state is unknown. If the difference is one of perception, the different perceptions of the effect of ethanol may be due to differential expectations regarding ethanol’s effects.
NOCTURNAL SLEEP, DAYTIME ALERTNESS, AND ETHANOL DRINKING
ETHANOL EFFECTS ON SLEEP DISORDERS
So far in this article, the effects of ethanol on
Given the profound effects of ethanol on sleep and daytime alertness and ethanol’s ubiquitous effects
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on most organ systems and biological processes, it is no surprise that ethanol affects sleep-related pathologies and sleep disorders. Some sleep disorders have been studied extensively to assess ethanol’s effects, while others have not. In some cases the effect of ethanol may be initially beneficial and then later disruptive, while in other cases it is clearly disruptive.
Insomnia Persistent difficulty in falling asleep, maintaining sleep, or non-restorative sleep is reported by about 10–15% of the general population [58,59]. About 30% of persons with persistent insomnia from the general population report having used alcohol to help them sleep in the past year, and 67% of those report it was effective [59]. The studies of healthy normals sleeping at their usual bedtimes, reported above, do not adequately represent the hypnotic potential of ethanol in persons with insomnia. In healthy, normal subjects sleep latency and sleep efficiency are already optimal and further improvement is difficult to demonstrate. Thus, as noted above, the reports of ethanol’s effects on measures of sleep induction and maintenance in healthy normals are inconsistent. Furthermore, the doses used in those studies are generally much larger (i.e. BrEC>0.06%) than insomniacs typically report using (i.e. 1–3 drinks). A recent study compared the effects of low-dose ethanol (0.5 g/kg) on the sleep of insomniacs and age-matched healthy normals [60]. The sleep of the insomniacs was improved with ethanol relative to placebo and the second half of the night sleep disruption found in normals at the higher ethanol doses was not observed. Specifically, slow-wave sleep was increased to the level of the age-matched controls. When given an opportunity to choose between a previously experienced color-coded ethanol or a placebo beverage before sleep, the insomniacs chose ethanol and normals chose placebo [60]. The average nightly dose self-administered (up to a 0.06 g/kg was possible) by the insomniacs was 0.045 g/kg, which is similar to the dose which improved the sleep of the insomniacs. The question is whether the preference for ethanol at bedtime by insomniacs compared to noninsomniacs, found in the Gallup data and in this study, is the use of ethanol to self-medicate for a sleep problem, the use of ethanol to improve mood
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or, initially, a sleep-medication which then shifts to ‘‘mood-altering’’ behavior. If it initially is, or ultimately becomes, ‘‘mood-altering’’ behavior, what are the ‘‘mood-altering’’ effects for the insomniac that serve to reinforce ethanol drinking? Does tolerance to the sedative effects develop in insomniacs as it does in normals? Does the ethanol dose used escalate over repeated nights? Does hypnotic use generalize to daytime use? And ultimately, what are the risks associated with the use of ethanol as a hypnotic? All these issues are yet to be addressed. But these data again suggest that the ethanol-sleep relationship is interactive; that is, disturbed nocturnal sleep increases the likelihood of ethanol use.
Sleep-disordered breathing Obstructive sleep apnea syndrome has a prevalence of about 3% in the US population and the known risk factors are snoring, obesity, and being male [61]. While the prevalence of sleep apnea is less than that of chronic insomnia, its clinical importance and the potential of ethanol to worsen the disorder is generally recognized. During wakefulness ethanol is a mild respiratory depressant, but during sleep it can exacerbate obstructive sleep apnea and it also may precipitate sleep breathing disorders in those at risk. Patients with moderate obstructive apnea (respiratory disturbance index (RDI)=22) received 300 ml of bourbon 2 h before bedtime and the RDI was increased to 28 [62]. In another study patients with a range of sleep breathing disorders were studied [63]. An unspecified dose of ethanol increased the indices of every patient among the apnea patients with RDIs of 14–54. In two patients with COPD and apnea ethanol further exacerbated their hypoxia, reducing mean SaO2 from 78 to 62. Finally, in two patients with a snoring history ethanol induced apneas during the first 2 h of sleep. A later study convincingly showed that asymptomatic snorers with no apneas develop apnea after ethanol administration [64]. While it is clear that ethanol before sleep exacerbates existing apnea and induces apnea in those at risk for apnea, the findings for asymptomatic persons without risk factors have been inconsistent. Healthy, normal women, either pre- or post-menopausal, do not develop apnea after bedtime administration of moderate ethanol doses [65,66]. Even in men who are non-obese and do not snore,
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ethanol has little or no effect on breathing during sleep [67,68]. However, several studies have reported small increases in apnea in men and particularly older men [69]. Infrequent apneas can be found in asymptomatic men, but night-to-night consistency of the apnea is very low [70,71]. In part, the inconsistency of the apneas can be due to body position and it should be noted that none of the studies above controlled for body position. Body position is one of several important variables in the development of an apnea event and, thus, also in the capacity of ethanol to induce or exacerbate apnea. In normal breathing, during the inspiratory phase, negative intra-pharyngeal pressure is produced by the diaphragm and the upper airway muscles must overcome this negative pressure to maintain airway patency. In the supine position gravitational forces can add to the negative inspiratory pressure increasing the likelihood of airway collapse. The direct effect of ethanol on the airway is also critical; ethanol in animal and human studies has been shown to have a depressant effect on the upper airway muscles. Ethanol decreases genioglossal muscle tone by reducing the firing of the hypoglossal nerve [72,73]. Further supportive of the depressant effect of ethanol on airway muscles is the observation that greater levels of continuous positive airway pressure (CPAP) are necessary to prevent snoring and apnea after ethanol ingestion [64]. Finally, ethanol suppresses the arousal response to airway occlusion, the result being a tendency to lengthen apneas and to increase the associated hypoxemia [74]. Given the clear effects of acute ethanol on upper airway breathing mechanisms, the question arises as to the impact of chronic ethanol exposure on these mechanisms. Several studies in abstinent alcoholics have documented an increased frequency of sleep-disordered breathing compared to ageand weight-matched control subjects [75,76]. The unanswered question is whether the chronic ethanol has permanently altered ventilatory control and upper airway motor function. The disturbed and fragmented sleep of the abstinent alcoholic, described earlier, may itself increase the likelihood of airway collapse. In both animal and human studies it has been demonstrated that sleep fragmentation increases apnea [77,78]. The most probable mechanism is that the fragmentation increases sleepiness and the sleepiness reduces upper airway muscles responsivity.
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In addition to ethanol’s effects on the nocturnal pathophysiology of sleep disordered breathing is its potential to exacerbate the daytime symptomatology of the syndrome. The most prominent symptom of sleep disordered breathing is daytime sleepiness. Earlier, studies were cited showing that the basal level of sleepiness–alertness interacts with the daytime sedative and performance-disruptive effects of ethanol. While this potential interactive effect of ethanol with the sleepiness of apnea patients has not been documented, it is reasonable to assume that such an interaction would be found in apnea patients. The levels of sleepiness produced in the healthy normals in the cited studies were similar to those found in apnea patients using the MSLT as the measure of sleepiness [79]. The interactive potential may be greater in the apnea patients as their sleepiness is chronic as opposed to the acute sleepiness produced in those healthy normals.
Other sleep disorders The effect of ethanol on other sleep disorders has not been studied to any great extent. However, given the known depressant and sedative effects of ethanol and the ubiquitous nature of those effects, some hypotheses can be formulated and the known clinical information can be discussed.
Narcolepsy Similar to sleep disordered breathing, the most prominent symptom in narcolepsy is daytime sleepiness. Again one would predict interactive effects of daytime ethanol in narcoleptics. Interestingly, narcoleptics report avoiding the use of alcohol. This may be because the sleepiness of narcolepsy develops at the stage of life when first exposures to alcohol typically occur. Thus, the narcoleptic learns that the sedative effect of ethanol worsens his/her daytime sleepiness. This developmental pattern differs from that of apnea where the disease and its symptoms develop in mid-life, long after drinking habits have been established.
Restless leg-syndrome (RLS) and periodic leg movements (PLMS) Nocturnal ethanol may have a beneficial effect on RLS and PLMS, at least acutely, until tolerance develops. The longest sleep latencies reported in a case series of patients with insomnia were those in
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patients with RLS [80]. Ethanol would be expected to shorten those long latencies in the short-term as was shown in the primary insomnia study cited above [60]. In cases of PLMS, the sleep-disruptive effects of PLMS are the brief arousals and awakenings that occur in conjunction with the movements. While never tested, one would predict that ethanol would suppress the arousal response just as it does in apnea. As noted above it is likely that tolerance develops to this effect. However, alcoholism may be associated with RLS and PLMS. RLS and PLMS are heterogenous in etiology, although polyneuropathy is among the known causal factors [81]. To the extent that the alcoholic develops polyneuropathy one would predict the possibility of RLS and PLMS. Also, RLS and PLMs are associated with deficiencies in iron, ferritin, magnesium, and vitamin B12 and to the extent that the alcoholic has any of these deficiencies RLS and PLMS may be expected.
NREM parasomnias These parasomnias include sleep drunkenness, night terrors, and sleep walking. Clinically it has been observed that the frequency of episodes of these disorders increases after the consumption of alcohol [82]. This is consistent with the fact that a number of variables which increase slow wave sleep and increase the difficulty of arousal from sleep are known to be triggering and predisposing factors in NREM parasomnias.
CONCLUSION Ethanol has extensive effects on sleep, sleepiness, and sleep disorders. In healthy normals at acute higher doses it disturbs sleep, while in insomniacs at lower doses it may be beneficial. Tolerance to its beneficial effects probably develops rapidly, based on the data from healthy normals. The concern is that the tolerance development may lead to excessive ‘‘hypnotic’’ use and possibly excessive daytime use. In alcoholics sleep is disturbed when actively drinking and for months of abstinence. The nature of the sleep disturbance in alcoholics is predictive of relapse. The effects of ethanol appear to be bi-directional; nocturnal sleep quantity and daytime sleepiness influences the sedative and performance impairing effects of ethanol and may also relate to rates of alcohol drinking. With the exception of sleep-disordered breathing, the effects of
ethanol on sleep disorders has not been extensively evaluated. However, for sleep-disordered breathing it is clear that ethanol exacerbates apnea and even induces apnea in persons at risk. Ethanol’s effects on other physiological functions during sleep and other sleep disorders have yet to be documented fully.
ACKNOWLEDGMENTS Supported by NIH-NIAAA grant no. R01-AA11264. Practice Points 1. Disturbed sleep after acute and chronic use of alcohol is well documented and alcohol must be considered as a primary or contributory factor in any insomnia complaint. 2. Clinicians should advise insomniacs against the use of alcohol to facilitate sleep as its benefical effects are limited and short-term and tolerance to its effects develops rapidly. 3. Alcohol exacerbates daytime sleepiness and clinicians must caution sleepy patients about its daytime use. 4. Alcohol clearly exacerbates sleep-disordered breathing and may also contribute to other primary sleep disorders and parasomnias, which clinicians must consider in their diagnoses and treatments.
Research Agenda 1. The mechanisms for alcohol’s effects on sleep and REM sleep must be better clarified. 2. The effects of alcohol on neuroendocrine function during sleep must be documented and the clinical significance of those effects outlined. 3. The etiologic or contributory effects of alcohol on sleep disorders other than sleepdisordered breathing must be better documented and understood.
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