Morvan syndrome and related disorders associated with CASPR2 antibodies
Jan. 18, 2022
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The author explains the basics of alcohol-related sleep disorders. She discusses the acute and chronic effects of alcohol on sleep as well as the management of sleep disorders during alcohol withdrawal and in recovering alcoholics. Insomnia in abstinent alcoholics is a common clinical problem that can increase the risk of relapse. Unfortunately, this is an area of only limited clinical research, though there are some data for the utility of cognitive-behavioral therapy for the treatment of insomnia in recovering alcoholics. The potential usefulness of ramelteon, gabapentin, and acamprosate for this condition is also discussed. New research has focused on the effects of ethanol on circadian rhythms. Child and adolescent sleep disturbances may predict alcohol abuse.
• Alcohol can have sedating effects on sleep initially, but can become sleep disruptive with chronic use.
• Objective and subjective sleep disturbances have been observed several years after drinking has stopped in recovering alcoholics.
• Persistent sleep disturbances are common and are related to relapse.
• Studies have shown that childhood and adolescent sleep disturbance may play a role in future drinking.
• Pharmacological and nonpharmacological treatments (eg, cognitive behavioral therapy for insomnia) have been shown to improve sleep in recovering alcoholics.
Alcohol, long recognized for its hypnotic effects, was a staple of early medicine for both analgesic and sedative benefits. Even now, consuming alcohol before bed is used to ease pain, anxiety, or depression, and aid in falling asleep among other ailments (42). Moderate consumption of alcohol, particularly wine, has been associated with a more active lifestyle and a better perception of health in Spanish elderly individuals (37). Other studies showed that even 1 moderate dose of alcohol at night leaves the individual more tired the next day and that chronic use of alcohol exacerbates several sleep disorders. Thus, the "nightcap," a highly esteemed folk medicine, is in fact a great thief of the night's sleep and the day's alertness. This has been shown repeatedly and in large samples of individuals who consume heavy alcohol weekly (95).
A person who drinks alcohol close to bedtime but does not meet criteria for alcohol abuse or dependence could be given a diagnosis of “inadequate sleep hygiene.” Nomenclature for The International Classification of Sleep Disorders, 3rd ed: Diagnostic and Coding Manual (ICSD-3) maintains the “due to drug or substance” diagnosis for sleep apnea, sleep related hypoventilation, parasomnias, sleep related movement disorder, insomnia, and hypersomnia. However, the ICSD-3 now acknowledges the difficulty in distinguishing between primary and secondary insomnia because insomnia may precede or become an independent disorder in the context of the drug or substance disorder. Therefore, ICSD-3 suggests it is inappropriate to use the term “secondary insomnia.” The ICSD also provides the ICD-10-CM coding for substance-induced disorder (eg, F10.xxx-F19.xxx), which contains the codes for substance-induced sleep disorders (01).
A single alcoholic beverage taken before bedtime (in non-alcoholics) can decrease sleep latency and increase total sleep time. However, many studies show that after alcohol consumption, there is more consolidated sleep in the first half of the night compared to the second (32; 72). Larger quantities of alcohol or the use of alcohol on a chronic basis to improve sleep, however, actually worsen sleep quality (65). In a crossover design study with a single night of either low (0.03% blood alcohol level) or high (0.1% blood alcohol level) alcohol ingestion, the high blood alcohol level resulted in increased stage 1 (the lightest stage of sleep) during the second half of the night (34). Moderate alcohol (eg, 2 or 3 standard drinks) leading to a blood alcohol level of 0.05% may also disrupt sleep, and this is worsened by the length of time the individual has gone without sleep and by the time of day the alcohol is ingested (85). High alcohol consumption (BrAC of 0.11 ± 0.01 g%) at bedtime has also been shown to result in sleep disruption, which appears to be more significant in women than in men (06). A separate study also found that higher amount of alcohol consumption has been shown to be significantly correlated with self-reported insomnia in females, even after controlling for potential confounding factors (41).
The effect of alcohol on REM sleep appears to be dose related, with significant reductions in REM sleep in the first part of the night. Some studies have shown increases in slow wave sleep in the first half of the night (32), whereas others have not (69; 70). A 2012 study utilizing actigraphy technology to assess sleep in the home environment revealed that participants who drank less alcohol than the mean alcohol consumption of the group (85 mL of alcohol/night) had reduction in sleep time associated with increased wakefulness in the second half of the night, a truncated sleeping period, and increased waking fatigue. Those who drank more alcohol than the mean of the group had fatigue the following day but no rebound wakefulness (36). Individual, methodological, and sample differences may also be playing a role in our understanding of these effects (51).
Alcohol also appears to have a biphasic effect on alertness, such that it increases alertness and prolongs sleep latency on the ascending limb of the breath alcohol concentration and decreases alertness and sleep latency on the descending limb (64); this effect persists irrespective of circadian phase at which the alcohol is consumed (84).
Chronic alcohol abuse and alcoholism usually start in adolescence or early adulthood and are major causes of hospital admissions of adults in the third and fourth decade of life. Sleep disturbances can develop almost immediately and become progressively worse with continued alcohol abuse. A number of studies have now shown a bidirectional relationship between alcohol use and sleep disturbance (25; 45; 46), ie, sleep disturbances may also contribute to alcohol use and abuse, making it difficult to know whether poor sleep contributes to alcohol abuse/dependence or vice versa. In a sample of nearly a thousand European college students, estimation of high sleep quality represented a significant protective factor for problematic drug use, with an odds ratio of 0.8 (CI95%: 0.76-0.99) as measured by 2 alcohol screening tests (61). In a 2-wave study of nearly 10,000 adults in a Norwegian health study, there was a bidirectional relationship between high consumption of alcohol and sleeplessness but only among men (73).
During acute alcohol withdrawal, sleep latency is usually increased, and total sleep time is typically decreased. However, findings from a large-scale survey study (n=approximately 3000) suggests that effect of sleep duration should also be considered when evaluating the relationship between daytime sleepiness and heavy drinking. An interaction between decreased sleep duration and an increased heavy drinking frequency was found to predict increased daytime sleepiness (18).
Abstinence for alcoholics and chronic alcohol abusers is commonly associated with chronic, sleep-onset and sleep-maintenance insomnia, usually of mild-to-moderate severity.
The presence of comorbid psychiatric disorders, like depression, as well as the physical symptoms of withdrawal have also been found to be associated with insomnia during early recovery from alcohol dependence (53). Alcohol use also exacerbates other existing sleep disorders. Obstructive sleep apnea can be worsened by any alcohol use before bed, though men may be more vulnerable to this effect of alcohol than women. In an epidemiological study, increasing daily alcohol use was associated with an increased risk of obstructive sleep apnea, even in nonalcoholics. In some cases, there may be little or no apnea without the prior use of alcohol. Increased snoring particularly in those with habitual snoring (71) and restlessness during sleep after alcohol use suggest this condition. The apneas occur more frequently in older alcohol abusers, suggesting an age interaction for the alcohol effects on sleep apnea. In patients with obstructive sleep apnea, however, moderate alcohol ingestion does not appear to increase the required therapeutic setting of nasal continuous positive airway pressure.
Acute alcohol use is well known to impair driving ability. Impairment is worse in sleep-deprived individuals; alcohol at legal blood alcohol concentrations increases sleepiness and impairs driving simulator performance following partial sleep deprivation. Women are more aware of this impairment than men, possibly contributing to the lower incidence of alcohol- or sleep-related crashes in women compared with men. Next day hangover effects continue to affect performance; notably, worse performance is noted on tests requiring both sustained attention and speed (74).
Once alcohol use is stopped, recovery to normal sleep and daytime alertness occurs within a few days for moderate drinkers. Alcoholics show a more gradual recovery that may take as long as 2 years; recovery to essentially normal sleep is usual except in severe cases when there is concurrent memory or other neurologic impairment.
Sleep disturbances affect 36% to 91% of recovering adult alcoholics in the United States and more than 60% in a Polish sample (92). Increasing severity of sleep disturbance occurring during abstinence indicates increasing risk of returning to drinking, possibly because of increased tolerance, attempts to reduce their symptoms, or both. Thus, the long-lasting sleep disorders of abstinent alcoholics appear to contribute to instability of abstinence.
A 35-year-old man presented to his primary care doctor complaining of fragmented, nonrestorative sleep. A careful history by the patient’s internist elicited that he had gradually increased his drinking after his divorce 3 years before. The patient admitted to drinking at least 1 case of beer per day throughout the day. He was advised to stop drinking. A tapering dose of lorazepam allowed the patient to cease alcohol consumption without significant withdrawal symptoms. However, he now complained of great difficulty initiating sleep. The patient began drinking again several months later.
Comment. Persistently disturbed sleep is common in abstinent alcoholics and may contribute to relapse.
The ubiquitous use of alcohol in the evening occurs largely for social reasons. Nocturnal use of alcohol sets the stage for subsequent sleep disruption and exacerbation of existing sleep disorders.
Acute alcohol use leads to sleepiness and promotes sleep onset particularly in lower doses (no more than 1 to 2 drinks per day), but with chronic use at moderate (3 to 7 drinks per day) or greater doses, patients report increasing difficulty falling asleep and staying asleep. Acute alcohol use suppresses REM sleep during the first part of sleep, thereby increasing slow-wave sleep, and reduces sleep latency. Later in sleep, when blood levels of alcohol are falling, REM times and wakefulness are both increased, rebounding from the suppression in the first part of the night.
In rats with sleep disturbance, low-dose ethanol (1 and 2 g/kg) decreases sleep latency, total wake time, and NREM sleep, whereas there is no effect in rats without sleep disturbance (62). On a cellular level, Thakkar and colleagues suggest that the sleep promoting effects of ethanol are the result of a decrease in the number of basal forebrain wake-promoting neurons with c-Fos via a mechanism (81; 82). Studies exploring underlying neuronal functioning reveal that acute ethanol increases adenosine, and this system plays a role in photic glutamatergic and nonphotic input to the circadian clock. This has also been shown in a circadian rhythm study of breath alcohol level concentrations (76). Chronic ethanol consumption leads to downregulated adenosine signaling, which underlies insomnia, a major predictor of relapse (75).
Preclinical studies in mice and rats exposed to ethanol have shown mixed results. Some studies show that chronic ethanol exposure disrupted circadian rhythms. In particular, chronic forced ethanol exposure disrupted the timing of locomotor activity and impaired the ability of the circadian clock to phase reset (09; 40). Another study in which mice were exposed to a single day of ethanol exposure on postnatal day 7 did not modify circadian cycles. Instead, slow wave sleep was disrupted and the mice exposed to ethanol had more memory impairments (88).
Alcohol also appears to affect interleukin-10 (IL-10), an antiinflammatory cytokine. Studies show that it is upregulated during withdrawal from chronic EtOH exposure. In 1 study, IL-10 was increased after 1 hour after a single intoxicating dose of alcohol (5 g/kg, intragastric) in Sprague Dawley rats. IL-10 also regulated GABAergic transmission in the dentate gyrus neurons in the brain, suggesting that IL-10 might be involved in disorders of altered GABAergic functioning, such as sleep disturbances (79).
With chronic alcohol use in humans, the alpha pattern commonly occurs along with the delta waves; slow eye movements characteristic of lighter sleep also become pronounced and persist for much of the sleep tracing. Thus, the biological effects of alcohol on sleep paradoxically include concurrent increases in the usual EEG markers of both deep sleep and arousal. Acute alcohol use also increases cerebrospinal fluid cyclic adenosine monophosphate and 5-HIAA in the same patients, showing increased slow wave sleep and decreased REM.
Alcohol also has effects on circadian markers in humans. Circadian genes have been found to be related to drinking behaviors. For example, the “Per 2” gene has been found to regulate alcohol intake in adults and the “Per3” gene is associated with both impaired sleep drive and heavy drinking in adolescents (24). Mouse models of Per 3 suggest that this period homolog is linked to circadian rhythms, stress response, and alcoholism. When treated with alcohol, there was increased expression of Per 3 in the mouse hippocampus and this interacted with stress response (86), suggesting that expression of Per 3 may be involved in response to alcohol.
Moderate amounts of alcohol reduce nocturnal melatonin levels in healthy adults. In substance abusing teens, the time interval between dim light melatonin onset and wake time was significantly and positively related to the Substance Problem Index (SPI), a scale of the severity of substance use. In adult male abstinent alcoholics, a lower level of melatonin during the early part of the night and a delay in the nocturnal rise of melatonin was found. This finding was supported in a separate study that included male and female subjects (26). The alcoholics also demonstrated a slower rate of rise of melatonin secretion in the early part of the night. This lower plasma melatonin level in alcohol dependent patients has also been inversely correlated with intestinal permeability, which may promote endotoxemia, a common consequence of chronic heavy alcohol use (80). Moreover, tendency to go to bed late, or being a “late chronotype,” has been found to be moderated by alcohol drinking and smoking (89). A relationship between late chronotype and alcohol and tobacco use was also found by using the Morningness-Eveningness-Stability-Scale in a large sample of young adults in Mexico (07). These findings suggest that alcohol may play a role in circadian dysregulation. However, this may be associated with the amount and timing of alcohol ingestion. A sophisticated study on the effect of a single dose of alcohol was tested to determine if alcohol would alter the circadian phase advances or phase delays to light in humans. Alcohol did increase or decrease the phase shifts to light, but the effect of alcohol versus placebo on phase shifts to light was smaller than 30 minutes (15).
The sleepiness associated with alcohol-related sleep disorders occurs both because of the direct sedating effects of the alcohol and because of the arousal occurring during sleep, limiting the restoration of wakefulness. The sedating effects of alcohol are particularly a problem for persons who are already sleepy, either because of a preexisting sleep disorder or because they have chosen to live a moderately sleep-deprived existence. These factors combine to produce significant sleepiness. Alcohol also contributes to impaired judgment about the degree of sleepiness (56).
The majority (67%) of individuals in early abstinence report insomnia (38). For alcoholics and chronic alcohol abusers, early abstinence (49) brings decreased deep sleep, sleep fragmentation, shorter sleep times and, sometimes but not always, increased REM sleep.
However, subjective sleep ratings using the Pittsburgh Sleep Quality Index (PSQI) improve in early abstinence. This was supported in a sample of alcoholics in a 1-month residential treatment program (p< .001). Interestingly, only age was associated with improvements in sleep disturbances during this time and not gender, use of hypnotics, hazardous alcohol use, or comorbid psychiatric diagnosis (54). A novel measure called the Sleep Regularity Index was used to assess sleep timing and duration. This actigraphy-based measure showed slightly improved sleep quality and regularity during alcohol treatment between weeks 1 and 3 of treatment (10).
Research has been accumulating to suggest that acute alcohol also affects the homeostatic sleep drive. Sleep EEGs during protracted abstinence show lighter sleep, sleep fragmentation, increased arousal during sleep, and a profound decrease in slow wave sleep, with a gradual recovery occurring at least for some subjects. One study related the decrease in slow-wave sleep and the degree of recovery to the amount of atrophy shown on CT scans during abstinence. Even when undergoing a sleep “challenge,” ie, staying awake 3 hours later than their typical bedtime, alcoholic men showed a blunted response to the challenge as measured by deep slow-wave activity in the EEG (13). Slow-wave activity dissipation across the night in alcohol-dependent men and women showed a blunted SWA response to sleep delay with significantly lower slow-wave activity than the control group (04). In an animal model, mice underwent experimentally induced acute (1 day) and chronic sleep deprivation for (3 days). Acute sleep deprivation resulted in reduced SWA and adenosine tone for at least 2 weeks. Mice that were chronically sleep deprived for 3 days and then tested 24 hours later were less sensitive to the effects of alcohol (21).
These studies suggest a possible interaction between sleep restriction, alcohol intake, and sleep compensatory mechanisms.
PSG studies suggest that it may require as many as 2 years before normal levels of slow wave sleep are seen in recovering alcoholics, and this may not occur for all subjects. However, the duration of sobriety, ranging from approximately 1 month to 2 years, did not necessarily predict the level of improvement in EEG spectral power measures over time in a study. Studies have shown some changes in the electrophysiological components of sleep (eg, amplitude of K complexes, a characteristic of stage 2 sleep) over time in abstinent alcoholics (23; 22). Whether these changes reflect the improvement of sleep over time is still unclear. Other physiological differences have been detected in the sleep of recently recovering alcoholics. For example, reduced heart rate variability, a sign of poor autonomic nervous system functioning, was found in the first part of the night, compared to age and sex matched healthy controls (30). These lingering effects of alcohol on sleep undoubtedly reflect 1 of the major toxic effects of alcohol on the central nervous system.
The effects of alcohol on the upper airway appear to further enhance the relaxation occurring during sleep, thereby exacerbating obstructive sleep apnea. Alcohol may also exacerbate sleep apnea by blunting chemoreceptor response to blood gases or by raising the arousal threshold. The effects of alcohol on periodic limb movements in sleep are not well established, nor is there any known pathogenesis or pathophysiology for this relationship.
A majority of alcohol abusers and alcoholics experience the sleep disorders described herein, depending largely on the dose and duration of alcohol use. Alcoholism and chronic alcohol abuse occur in about 14% of the population of the United States and for these affected individuals, the associated sleep disorders are common and serious clinical problems.
Identification of sleep problems early in life may help to reduce drinking alcohol to self-medicate. A longitudinal study showed that sleep problems observed by mothers in children as young as 3 to 5 years old predicted early onset of substance use between ages 12 to 14, as well as substance-related problems between ages 18 to 20 (90; 91). Data from the Longitudinal Study of Australian Children (LSAC) also show that children with heavy prenatal alcohol exposure have 1.13 more sleep problems across childhood (2 to 9 years) relative to children whose mothers are abstainers (19). Children of alcoholics tend to get less sleep, and this decreased sleep time has been associated with decreased ability for these children to regulate their behaviors and emotional state (43).
A number of studies have now shown a bidirectional connection between sleep and future alcohol use during the teenage years. Sleep problems during adolescence are associated with more alcohol use along with internalizing and externalizing problems (67). The etiology of these findings may be related, in part, to the stronger preference for adolescents to be awake in the evening, or for “eveningness” (44). Two large population studies support a sleep-substance use connection. A sample of approximately 14,000 teens who participated in the National Longitudinal Study of Adolescent Health, binge drinking was positively and significantly associated with sleep disturbance, independent of psychiatric condition (68). Another population-based study of approximately 9300 teenagers (16-19 years of age) living in Norway revealed that not getting enough sleep, differences in bedtimes, and insomnia were all associated with greater risk of alcohol and drug use (78).
A large longitudinal study also revealed that sleep plays an important role in substance use (45; 46). The study followed 696 adolescents in Pittsburgh (12 to 19 years of age) with alcohol use disorder and sleep disturbances showed that greater insomnia complaints predicted an increase in alcohol symptoms at 1 year and variability in sleep duration predicted an increase in alcohol symptoms at 3- and 5-year follow-up. Additional longitudinal data from the same research group showed that lower duration and quality of sleep in boys at age 11 was associated with substance use at age 20 to 22 years (58). Similarly, a cross-sectional study of 127 low income ethnic minority teens (mean age=13) showed that difficulty falling asleep and daytime sleepiness were associated with frequency of alcohol use, even when parental monitoring and psychopathology were adjusted (57).
An online survey of college students who drank alcohol (n=1878) revealed that students who reported poor sleep and who were motivated to drink alcohol to cope or to fit in also reported having more alcohol-related consequences, even controlling the drinking amount (52). The relationship between sleep and alcohol does not appear to be related to sociodemographic or mental health status (83).
In college students, other factors like impulsive personality traits or perception of not getting “adequate sleep” may also contribute to drinking (59). Moreover, university students who reported having more sleep problems and emotional dysregulation in their first year of college were more likely to have higher depressive symptoms and alcohol use by graduation time 4 years later (77).
In an adult sample, mood disorders have been shown to play a role in the relationship between alcoholism and sleep. A longitudinal study found that among 364 alcohol-dependent individuals, depression and drinking quantity separately predicted insomnia severity even when controlling for age, time, and gender (93).
It has been suggested that adolescents with insomnia may benefit from therapeutic interventions for sleep disturbance independent of other treatments for comorbid psychiatric disorders.
Individuals with a history of trauma, particularly combat-related trauma, are at greater risk of sleep problems (particularly difficulty falling asleep) and of misusing alcohol (55).
Public education is specifically needed to discourage alcohol drinking when a person is tired or having difficulty sleeping or is sleepy (eg, when sleep deprived or late in the evening). In general, alcohol use should be avoided for 2 to 4 hours before bed.
Hypersomnia or insomnia due to primary sleep disorders generally show a more persistent pattern and do not vary in severity in relation to the history of alcohol use. The clinician should inquire about symptoms of depression. Disturbed sleep is common in both alcoholics and depressed patients. Depression is highly comorbid with alcoholism.
A careful history of alcohol use and sleep problems helps to determine their temporal relationship. Additional history about mental health problems can also be beneficial in examining this relationship. A number of sleep questionnaires have been used to characterize sleep complaints in the alcoholic population. One study validated the 4 sleep items from the Hamilton Anxiety and Depression Scale (the Short Sleep Index [SSI]) against the Pittsburgh Sleep Quality Index (PSQI) and found the 2 questionnaires correlate well with discriminant and convergent validity (66). Daily alcohol consumption has been shown to improve sleep latency in those with minimal to mild levels of anxiety, but it may decrease sleep quality in those with severe anxiety (20).
The sleep history should include: (1) sleep schedule, sleep onset, and awakenings; (2) activity during sleep such as snoring, movements, dreams, and sweating; and (3) alertness or sleepiness during the wake time, including questions about sleepiness during times when it is most likely to be apparent (eg, when sitting still or inactive, and during midafternoon, late evening, or night time). The sleep disorder should always be examined in relation to the history of alcohol use. Excessive alcohol use is associated with several laboratory test abnormalities, particularly liver function tests. An elevated serum GGT in particular commonly occurs with recent heavy alcohol use and when present in patients with a sleep disorder serves as a useful indication to inquire further about alcohol use. Determination of GGT levels is useful when there is an index of suspicion of an alcohol-related sleep disorder, but elevated levels do not prove excessive alcohol use. The test is not needed when the history is clear.
Cessation or reduction of alcohol use to a less problematic level is likely to result in improvements in subjective sleep quality, physical health, and general well-being (08). For the sleep disorders occurring during alcohol intake, cessation of alcohol use is often the only necessary treatment. Standard management for alcohol withdrawal, including benzodiazepines, usually ameliorates the insomnia associated with alcohol withdrawal. However, the use of benzodiazepines for insomnia in the context of substance use disorders is controversial (31).
Recognizing and treating persistent insomnia in alcohol use disorder is important, as this persistent insomnia may contribute to individuals being less likely to complete an intensive outpatient substance use disorder treatment program (87).
Gabapentin. Gabapentin has been used at doses of 300 to 1800 mg at bedtime for treating insomnia in abstinent alcohol-dependent outpatients. Gabapentin has been shown to be safe (47) and more effective than trazodone for insomnia in this population (50). However, a small pilot study found that the administration of gabapentin during early abstinence did not improve sleep compared to placebo, though it did delay the onset to heavy drinking (14).
A large multisite study tested the safety and efficacy of gabapentin enacarbil extended-release 600 mg twice a day of in individuals with alcohol use disorder. This medication group was compared to a placebo and a computerized behavioral intervention. The study did not show reduction in alcohol use or improvement in sleep problems after 6 months of daily GE-XR use compared to the other groups (33). Moreover, Modesto-Lowe and colleagues warned of the potential for gabapentin abuse (60) and on December 19, 2019, the U.S. Food and Drug Administration warned that serious breathing difficulties may occur in patients using gabapentin (Neurontin, Gralise, Horizant) or pregabalin (Lyrica, Lyrica CR) who have respiratory risk factors (FDA Drug Safety Communication 12/19/19). Gabapentin should only be considered if first-line drugs such as naltrexone and acamprosate cannot be used (02).
Trazodone. Superior sleep outcomes with trazodone versus placebo were found in 12 weeks of treatment in alcohol-dependent patients, but heavy drinking was higher in the trazodone-treated group (35). A combination of gabapentin with naltrexone for 16 weeks prolonged the time to first heavy drinking period in comparison with those who took naltrexone alone (03). Sleep disturbance was associated with more drinking in the naltrexone only group.
Quetiapine. Quetiapine XR at bedtime (with doses titrated from 50 mg to 400 mg across 1 week) (n=10) or placebo (n=10) were administered to recovering alcohol dependent patients with sleep complaints for 8 weeks. PSG assessed objective sleep and standard sleep questionnaires assessed subjective sleep. There was a reduction in PSG identified wake after sleep onset and improvement in subjective ratings of insomnia in those that took the quetiapine XR, but this improvement was not sustained across the 9-week assessment period (17). However, the risk of tardive dyskinesia and metabolic abnormalities associated with the use of atypical antipsychotics suggests that they should be used cautiously, if at all, for insomnia.
Melatonin. The melatonin receptor agonist ramelteon is an option for treating insomnia in recovering alcoholics, though controlled trials are lacking. Ramelteon is not a controlled substance and has essentially no abuse liability. It is approved for the treatment of insomnia characterized by difficulty with sleep onset. The standard dose is 8 mg, taken within 30 minutes of going to bed. It is metabolized by cytochrome p450 enzyme 1A2 but does not appear to inhibit or induce this enzyme. It should not be used in combination with fluvoxamine, a strong 1A2 inhibitor. One study to date has tested ramelteon in recovering alcoholics. Four weeks of 8 mg nightly in 5 recovering alcoholic patients resulted in a reduction of scores on an insomnia questionnaire, a reduction in latency to sleep, and 1 additional hour of total sleep time (12).
Another therapeutic option may be agomelatine, which is a melatonin-agonist that has been used for the treatment of depression (29; 28) and has been shown to improve sleep. A small study of 9 alcohol dependent patients with sleep problems who took between 25 mg to 50 mg of agomelatine nightly had improved subjective sleep quality after 6 weeks. Mean Pittsburgh Sleep Quality Index scores dropped from 13.1 (+/- 1.7) to 7.8 (+/-1.7) post treatment (39). Hepatoxicity, a common concern with agomelatine, was not evident in these doses.
Approved medications to treat alcohol use disorder. Alcohol use disorder therapies such as disulfiram, acamprosate, naltrexone, and nalmefene reduce the craving and risk of relapse into heavy drinking. A metaanalysis reviewed the impact of these medications on sleep and found that disulfiram reduced REM sleep (63). Acamprosate showed no/little effect on self-reported sleep but improved sleep continuity and architecture measured by polysomnography. The metaanalysis showed more insomnia and daytime sleepiness in those taking naltrexone compared with the placebo. Overall, the currently available evidence shows more sleep problems with the opioidergic drugs (especially naltrexone).
Acamprosate is a glutamate modulator that is FDA approved for the maintenance of abstinence from alcohol in patients with alcohol dependence who are abstinent at treatment initiation.
Gamma-hydroxybutyrate. A review on gamma-hydroxybutyrate, a medication approved for the treatment of narcolepsy, examined whether gamma-hydroxybutyrate might be effective in treating alcohol withdrawal syndrome and in maintaining abstinence. Although there are few randomized control studies, dosage of 50 mg/kg divided in 3 or 4 administrations per day increased the number of abstinent days, reduced alcohol craving, and decreased the number of drinks per day (16).
Cognitive behavioral therapy for insomnia and other nonpharmacological therapies have been shown to be associated with improvements in sleep in the alcohol dependent patient, but few studies have been conducted (11). Specifically, components of cognitive behavioral therapy for insomnia including stimulus control, sleep restriction, and cognitive restructuring have been shown to improve subjective sleep quality (27; 05) and daytime functioning (05) in recovering alcoholics.
When treating insomnia in the context of alcoholism, one might consider that depressive symptoms have been shown to mediate the relationship between drinking and insomnia severity, even when controlling for time, age, and gender (94).
Alcohol use should be avoided during pregnancy. The potential adverse physical and neurocognitive effects, including fetal alcohol syndrome (FAS), of maternal alcohol consumption on the developing fetus have been extensively reviewed. Research has clarified the effects of prenatal alcohol consumption on a child’s postnatal sleep. Maternal prenatal consumption of alcohol results in infant postnatal sleep fragmentation as well as the suppression of spontaneous movements during sleep at 6 to 8 weeks of age. In a sample of 40 children with fetal alcohol spectrum disorder (1.8 to 17.5 years, median age 9.4 years), 100% had insomnia, 93% had circadian rhythm disorder, and 85% had restless sleep (48). In utero alcohol exposure results in altered neonatal autonomic control during sleep, possibly increasing the risk of sudden infant death syndrome.
Deirdre A Conroy PhD
Dr. Conroy of the University of Michigan has no relevant financial relationships to disclose.See Profile
Antonio Culebras MD FAAN FAHA FAASM
Dr. Culebras of SUNY Upstate Medical University at Syracuse received an honorarium from Jazz Pharmaceuticals for a speaking engagement.See Profile
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