Sle ep Disorder s : Ca uses, Effe cts, and Solutions

G. MichaelTibbitts, MDa,b
KEYWORDS  Sleep function and benefits  Sleep deprivation  Sleep disorders  Sleep medication

Sleep is something that allows humans to feel good, even refreshed, both mentally and physically. This article first explores the nature and function of good sleep with its benefits. This topic leads to the undesired effects of sleep deprivation.
AN EXPLANATION AND DEFINITION OF SLEEP

Thomas Bailey Aldrichs poem, Human Ignorance, ponders a question that was common in the nineteenth century: What probing deep/Has ever solved the mystery of sleep?1 Today we know that sleep is a natural vital process that most animals need to maintain health and well being. Without sleep, animal life would become disordered, and death would ensue. Most people experience episodes of sleepiness. Excessive daytime sleepiness affects about 20% of the adult population, and 16% of those affected experience impairment in daily function.2 Disordered sleep commonly is related to medical or psychiatric conditions. Also, young children and elderly adults experience sleep disruption more commonly than persons of other ages. What is sleep and how much does a person need each day? Sleep is an active process. While the body is at rest, the brain actively prepares for the next period of wakefulness. The American Academy of Sleep Medicines International Classification of Sleep Disorders defines more than 80 different disorders of sleep. Also, research produces thousands of articles each year. Sleepiness is classified as mild, moderate, or severe when excessive sleepiness is a complaint or difficulty in maintaining desired wakefulness or a complaint of excessive amount of sleep.3
Types of Sleep

The circadian rhythm or sleep-wake cycle is composed of alternating stages of sleep, which, along with the architecture of those stages, provide a healthy or disordered
Family Medicine, Sanford School of Medicine of The University of South Dakota, 1400 West 22nd Street, Sioux Falls, SD 57105, USA b Sanford USD Physicians, Medical Bldg 1, 1200 S. Euclid Ave, Ste 104, Sioux Falls, SD 57105, USA E-mail address: gtibbitt@usd.edu Prim Care Clin Office Pract 35 (2008) 817837 doi:10.1016/j.pop.2008.07.006 primarycare.theclinics.com 0095-4543/08/$ see front matter 2008 Elsevier Inc. All rights reserved.
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period of rest. The sleeping period is divided into two main states. Rapid eye movement (REM) sleep and nonrapid eye movement (NREM) sleep progress in a common pattern throughout the period of sleep. NREM sleep has four stages. In healthy younger adults, sleep onset usually occurs less than 30 minutes after lying down. Sleep progresses through stages 1 to 4 of NREM sleep and then into REM sleep. Sleep tends to deepen with progression into the next stage. Stage 1 NREM is considered a transition into sleep. When aroused from this stage, an individual may not realize that he or she was asleep. Stage 2 NREM sleep is considered intermediate sleep and accounts for 40% to 50% of sleep. Stages 3 and 4 of NREM sleep are deep sleep and usually occupy 20% of sleep time. These two stages combined are called slow-wave sleep because the electroencephalographic pattern shows deep delta slow-wave patterns. These stages are associated with restoration of alertness and energy. Arousal also is more difficult. REM sleep function is more complex and is less well understood. Bursts of rapid eye movements are common in REM sleep along with loss of voluntary skeletal muscle tone. Dreams and memory consolidation seem to take place during this time. The amount of time spent in REM sleep rebounds when REM sleep has been diminished during previous sleep periods. The architecture of the sleep pattern shows four or five sleep cycles per night. These sleep cycles last 90 to 120 minutes and move up and down the stages of sleep. In an early sleep cycle, wakefulness may occur when passing into stage 1. In later sleep cycles, stage 2 NREM and REM sleep alternate. As the sleep time progresses, REM sleep increases in length at the expense of slow-wave sleep. Abnormalities in the sleep architecture may suggest sleep disorders such as narcolepsy, depression, or medication withdrawal. Also, in the elderly, slow-wave sleep declines, and light sleep increases with more frequent sleep arousals. The net effect is increased wakefulness.4
Function of Sleep

The function of sleep is still debated. Sleeping well for about 8 hours per day is needed to maintain mental and physical health. The outcomes of inadequate or dysfunctional sleep are well documented. Those consequences affect general health, metabolism, memory, immune functions, and the safety of the individual and of others. The restorative theory of sleep proposes that sleep renews the body in preparation for the next day. The feeling of being refreshed upon awakening from normal sleep is common. Growth hormone production is increased during sleep. In youth, other proteins for development are produced in the brain during REM sleep.5 The effect of sleep loss on the next days performance and well being seems obvious. In a similar theory, a role for sleep in memory reinforcement and consolidation is proposed. REM sleep seems to improve memory function.6 The adaptive theory suggests that sleep during the night has a survival benefit: in the jungle daytime activity is safer than activity at night with dangerous, dark-adapted animals. The energy conservation theory proposes the importance of saving energy by lowering metabolism during sleep at night and reducing the amount of the time spent in active energy use each day. Thermoregulation also is impaired with sleep deprivation. The relationship between REM and NREM sleep on brain development in neonates has been noted. The function of this interrelationship for normal awakening patterns in adults is being studied also.7
Optimal Sleep and its Benefits

Optimal sleep is related to the quality of sleep that an individual enjoys. The quality of sleep is affected by the duration and architecture of the sleep period. Frequent arousals with short periods in deep sleep reduce sleep quality and the experience

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of restfulness the following day. In their editorial in the issue of the Archives of Internal Medicine devoted to the relationship of sleep and health, Phyllis Zee and Fred Turek state, Sleep is an indicator of health, and sufficient sleep quantity and good quality should be considered as an essential component of a healthy lifestyle, as much as exercise and nutrition.8 The benefits of sleep are understood by most people when they contrast their physical, mental, and emotional feelings after a good nights sleep with their experience after a night of little or interrupted sleep. Sleep at night clarifies mental and emotional states and motor skill activities undertaken during the day and even can improve the performance of those tasks the next day.9 It also is well known that the body seeks to regain the sleep that has been lost in previous sleepless periods. These long-term benefits are understood by describing the effects of sleep deprivation on health and well being.10
Effects of Sleep Deprivation

Many studies have shown that humans require about 8 hours of sleep per night. Varying from this ideal are individuals who sleep only 4 to 6 hours per night, but fewer than 4 hours or more than 10 hours of sleep have been shown to result in increased rates of mortality. Sleepiness can be confused with, accompany, or cause tiredness, fatigue, weariness, or loss of energy.10 The close relationships among these conditions can complicate survey measurements of daytime sleepiness. Such studies, however, show that about one in five adults suffers from daytime sleepiness.2 The physical effects of excessive daytime sleepiness involve numerous areas of human function from mild short-term cognitive losses to increased mortality in longitudinal studies. One study in healthy adults restricted sleep to 4, 6, or 8 hours of sleep per night for 2 weeks. Participants restricted to 6 hours or more of sleep per night showed cognitive losses in attention, motor skills, and information processing. Sleepiness ratings showed the subjects were largely unaware of their cognitive losses.10 In addition, sleep-deprived rats showed impaired immune function and reduced host defenses. In this study, complete sleep deprivation resulted in septicemia and death.11 Healthy young adults, who were deprived of sleep for 40 hours showed increased circulating pro- and anti-inflammatory factors.12 Persons who had insufficient sleep also showed significantly increased plasma interleukin-6 levels and increased self-rated pain levels over a 10-day period. The association of sleep deprivation, pain, and inflammatory processes is seen in a variety of medical disorders and conditions.13 Apnea spells with episodes of oxygen desaturation have been linked to sleep deprivation and sleep fragmentation. This association is particularly important during anesthesia and surgery, because both can affect sleep architecture adversely. Patients who have unrecognized obstructive sleep apnea seem to be at increased risk for adverse outcomes during and following surgery.14 Studies suggest that sleep loss may be related to increased eating and obesity. The percent of adults in the United States sleeping less than 7 hours at night more than doubled in the last 40 years (from 16% to 37%).15 Similarly, in this country from 1960 to 1994 the prevalence of obesity nearly doubled (from 12.8% to 22.5%).16 Sleep studies in healthy young men have shown that sleep restriction lowers levels of glucagon and the appetite-suppressing hormone leptin and elevates the appetiteincreasing factor ghrelin. Increased hunger and consumption of calorie-dense foods with a high carbohydrate content was noted. It is postulated that sleep deprivation produces increased hunger and appetite. This effect may be related to the loss of slow-wave sleep with resulting glucose intolerance and risk of diabetes.17,18

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Emotional and psychiatric effects

Sleep deprivation is interrelated with emotional and psychiatric conditions. Sleep loss may induce adverse conditions such as depression. The problem also may flow in the other direction, with depression inducing sleep disorders.8,19 The relationship is strong either way. Sleep loss is associated with loss of vigilance and executive function, emotional and mood dysregulation, and even increased risk for adolescent suicidal behavior.20 A study of 53 healthy adults compared their rested responses with those they gave after 53 hours of wakefulness. These sleep-deprived subjects showed impairment in the emotional and cognitive-integration abilities needed in making moral judgments.21
Societal and financial costs

The direct and indirect costs for untreated insomnia in a group of more than 200,000 adult patients who had health insurance in the United States were 25% higher for persons who had insomnia than for the controls.22 A larger study in Australia estimated that all costs for all sleep disorders in their health system (with a population of 20.1 million people) was $7.5 billion. The equivalent expense for to the population of the United States (293 million people in 2004) would have been $109 billion. This projection included the cost of work injuries, motor vehicle accidents, and other sleeprelated illnesses and problems. At that time, the expense for sleep disorders was figured to be among the 10 highest health conditions in Australia.23 Excessive daytime sleepiness is a major cause of traffic accidents, of work injuries, and potentially of medical errors by sleep-deprived resident physicians.24
COMMON SLEEP IMPAIRMENTS Insomnia

A simple definition of insomnia is unsatisfactory sleep with a loss of daytime functioning. The poor quality of sleep is related to difficulty initiating sleep, frequent nighttime or morning awakenings, and the feeling of an insufficient duration of sleep in the morning.
Incidence

Insomnia is the most common type of sleep disturbance. Surveys show 30% to 50% of people experience isolated episodes of insomnia, with 9% to 15% of this group experiencing significant chronic daytime loss of well being.
Etiology

Primary insomnia has no identifiable etiology except increased autonomic hyperarousal. Secondary or comorbid insomnia has an underlying etiology that often results from psychiatric or medical conditions.25 Insomnia is a symptom rather than a disease. This condition has a variety of associated factors and causes. Studies have shown that the risk of insomnia is increased in elderly people, women, individuals of lower socioeconomic status, and those who have limited education. Surveys, however, can use flawed study methods.26 Employment requirements for shift work or excessive hours of work are associated with increased insomnia. Factors that cause transient or short-term insomnia include stressful events, acute illness, changes in sleep timing (jet lag and shift work), environmental problems (room temperature or noise), and stimulant use.
Symptoms and signs

Insomnia is a symptom that most people experience at one time or another. Insomnia may lead to feelings of fatigue, inattention, irritability, lack of energy, or anxiety the

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next morning. Insomnia may be transient, short-term, or chronic. Chronic insomnia may lead to problems with depression, learning difficulties, and poor job or school performance.27 Insomnia is graded as mild, moderate, or severe based on the degree of social and occupational impairment that it causes and the severity of associated daytime symptoms.3 Conditions that may make insomnia worse include a stressful lifestyle, physical inactivity, and lack of uniform bedtime pattern. Heavy caffeine use, regular alcohol use, and cigarette smoking are apparent risk factors for insomnia.25 Medical causes of insomnia include heart disease (ischemic heart disease, nocturnal angina, and congestive heart failure), chronic obstructive pulmonary disease, asthma, peptic ulcer disease, reflux esophagitis, fibromyalgia, and other painful medical conditions. Common neurologic conditions associated with insomnia are Alzheimers disease, Parkinsons disease, cerebrovascular infarction, sleep-related headaches, and traumatic brain injury.27 Many psychiatric disorders are associated with sleep disorders as well.
Evaluation

With 9% to15% of the members of society living with moderate to severe insomnia disorders and with the condition lasting for more than 5 years in 40% of those afflicted, the need for evaluation and treatment is obvious. Also, surveys show that 70% of patients who have chronic insomnia never discuss the problem with their physician.28 In other surveys, physicians were unaware that severe insomnia existed in 60% to 66% in those reporting the problem.28 Screening for insomnia is the first step in the evaluation process. The focus should be on those at highest risk: persons who have depression, stressed lives, emotional distress, medical or psychiatric illness, prescribed or illicit drug use, night-shift employment, and those who frequently travel across time zones.27 A comprehensive sleep history would focus on the associated features of the sleep problem: the hour of bedtime, the time needed to fall asleep, problems with staying asleep, early morning arousal, wakeup time, the amount of sleep, sleep quality, and daytime fatigue. The seriousness of the problem could be rated on a scale of 1 to 10 with 1 as mild and 10 as severe. It is important to know the number of nights each week the problem is experienced. These questions need to be answered: Is the problem getting worse? and Is the condition acute, short term, or chronic in nature? Pre-bedtime activities that might impair sleep include watching television or reading in bed; having a meal, working, or engaging in physical activity shortly before bedtime, and consuming caffeine or alcohol within several hours before sleep. It is helpful to know what the patient has tried or is trying for treatment, such as prescription drugs, over-the-counter medications, or behavioral therapies.28 The physical examination should look for possible disorders that are related to insomnia. Only occasionally are laboratory studies and formal sleep studies indicated for this clinical disorder.27 In some situations, other methods of evaluating sleep quality might be helpful. Patients can use sleep logs or diaries to self report bedtime, sleep latency, arousals, time of arising, sleep duration, and sleep quality. Reporting also might include daytime naps, daytime functioning, and the use of sleep aids. Sleep questionnaires, psychologic assessment, and actigraphs (a wrist watch-like device that measures movement) also can be useful in defining the type of insomnia.28
Treatment

Therapy should begin by applying the behaviors of good sleep hygiene: establishing stable bed and rising times; a sleep time of 7 to 8 hours with not more than 8 hours

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in bed; regular exposure to light during the daytime but not before bedtime; a quiet, dark sleeping space; avoiding hunger at bedtime but not eating a meal before sleeping; no consumption of caffeine, alcohol, or nicotine for several hours before bedtime; regular exercise but not within 2 hours of bedtime; avoiding watching the clock; and using relaxation procedures before sleep. A self-help educational intervention in adults who had insomnia showed modest but significant improvement in subjective sleep parameters when compared with control patients.29 A list of resources for health care providers and patients is provided in the Appendix. Cognitive behavioral therapies include relaxation techniques and stimulus control. Sleep restriction and behavioral therapy are more active forms of treatment for insomnia. These treatments promote relaxation of the mind and body, reduced time awake in bed, reduced learned wakefulness in the bedroom, and the correction of misconceptions about sleep. Studies have shown cognitive-behavioral therapies to be more effective than pharmacologic therapy in the short-term treatment of insomnia and in the maintenance of sleep improvement in young, middle-aged, and older adults.30,31 In summary, as mentioned earlier, the treatment of insomnia requires diagnosing and treating other sleep disorders and medical and psychiatric conditions. The sleep environment, bedtime routines, and medications (both prescribed and over the counter) should be adjusted to promote restful sleep. A randomized, placebocontrolled trial of 72 elderly adults (mean age, 65 years) who had primary insomnia was performed for 8 weeks with a 24-month follow-up. The four trial arms included cognitive-behavioral therapy (stimulus control, sleep restriction, sleep hygiene, and cognitive therapy), pharmacotherapy (temazepam), both interventions, or placebo. The time awake after sleep onset was reduced by 63.5% with the combined therapy, by 55% with cognitive-behavior therapy, by 46.5% with the pharmacotherapy, and by 16.9% with the placebo control. In this study, the long-term outcomes of patient satisfaction were higher and more sustained with the behavioral approach.30 Other studies have shown similar results.27,31 Randomized, controlled studies of elderly community-dwelling adults who had moderate sleep complaints demonstrated significant improvement in self-rated sleep quality, latency, and duration though a 16-week program of moderate-intensity exercise compared with control participants and through a 24-week program of tai chi compared with low-impact exercise.32,33 Diphenhydramine and doxylamine are used for night-time sedation by individuals who have insomnia. A cross-over study of driving performance in 40 licensed 25- to 44-year-olds performed 1 hour after ingestion of 50 mg of diphenhydramine, 60 mg of fexofenadine, a, amount of alcohol calculated to produce a blood level 0.1%, or placebo showed the poorest performance in those taking diphenhydramine. Another study showed that extended use of diphenhydramine impaired older individuals scores on the Mini Mental Status Examination. The riskbenefit ratio of these antihistamines fails to support their use in the treatment of insomnia.27 The efficacy and safety of nonprescription agents such as melatonin, valerian, kava, and St. Johns wart have not been well studied for use in insomnia. For this reason their use generally is discouraged.27 Small studies of the short-term use of melatonin indicate that it may be safe, but its benefit is not certain. Again, melatonin is not recommended for the treatment of insomnia.27 Table 1 shows the benefits and adverse effects of prescription medications for the treatment of insomnia and other sleep disorders. Benzodiazepines commonly used to treat insomnia include estazolam, flurazepam, quazepam, temazepam, and triazolam. They generally shorten sleep latency and unscheduled waking. They are associated with lingering daytime effects of cognitive and psychomotor impairment and some

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hangover effect, however. Discontinuance of these medications is associated with rebound insomnia, anxiety, and irritability. Therefore, the use of minimal effective doses for short periods (1 month) and tapering the dose at discontinuance are recommended.27 The nonbenzodiazepine drugs include zolpidem, zaleplon, and eszopiclone. They are selective agonists of the of the benzodiazepine receptor complex and produce sleep benefits that are similar to those of the benzodiazepines but have fewer side effects. Each of these drugs has a distinct clinical profile. Table 1 provides many of those details.34 Remelteon is a melatonin receptor agonist that acts more specifically than melatonin on the pineal gland receptors for sleep induction. Studies in adults, including the elderly, have shown significant reduction in sleep latency and increases in total sleep time. Next-day residual effects, withdrawal, and rebound insomnia were not noted. This drug should be avoided in patients who have severe liver disease.34,35 In 2007 the Food and Drug Administration issued a warning that all these hypnotics have a risk of serious allergic reactions and complex sleep behaviors, including driving while asleep.27 Although studies show that 10% to 15% of patients use hypnotics for longer than 1 year, the benefit of long-term use is not supported by well-controlled studies.27 Patient referral should be considered if the diagnosis of the sleep disorder remains uncertain, the patient has ongoing daytime sleepiness, or another underlying medical or psychiatric disorder is suspected.
Circadian Rhythm Disorders: Jet-Lag and Shift-Work Disorders Incidence and etiology

Circadian rhythm sleep disorders (CURDs) are divided by the International Classification of Sleep Disorders-2 into six distinct types with a persistent or recurrent pattern of sleep disturbance due primarily to alterations in the circadian timekeeping system or a misalignment between the endogenous circadian rhythm and exogenous factors that affect the timing of sleep.3 Sleep is driven by the burden of an individuals sleep debt that normally is lowest in the morning daylight at 9 AM and highest at 9 PM in the dark of night. Light is the stimulus in the exogenous system. Light passing through the neuropathways of the eyes promotes wakefulness. The circadian clock or endogenous system is the other method for control of sleepiness. Here, the highest alerting drive for wakefulness is at 9 PM, and the nadir of the drive for wakefulness is at 8 AM. These CURD types are referred to as syndromes or disorders in other sleep classifications. These disorders can produce social and occupational impairments and other limitations. At times, other conditions such as obstructive sleep apnea may be better explanations for sleepiness than a CURD.36 The best-known and probably the most common CURDs are the jet-lag type and the shift-work type. These two types of CURDs are related to changes in the exogenous external factors that interfere with the normal function of the internal circadian clock (central pacemaker). The other types of this disorder involve malfunction of the internal endogenous circadian system. Thus the demand for sleep or wakefulness by the central sleep pacemaker is placed at odds with societal or environmental signals for the opposite action of wakefulness or sleep.37 Although the incidence of CURDs is not known, hundreds of thousands of people are undertake jet travel on any given day. Many of those people probably experience jet lag. Also, 20% of the work force in modern societies is engaged in shift work. Not all but a large percent of those individuals experience temporary or chronic sleep disturbance.36
Signs and symptoms

Shift work sleep disorder (SWSD) is suspected when excessive sleepiness, hypersomnia, or unrefreshed feelings upon awakening are associated with a work shift.

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Table 1 Pearls and perils regarding medications used to treat insomnia* Drug Class Melatonin receptor agonists Ramelteon (Rozerem) Dose: usual dose 8 mg taken 30 minutes before bedtime. Do not take after high-fat meal. Half-life: 1.2 h Rapidly absorbed. Specific action on sleep-onset process. Four metabolites also are active for sleep induction with their half-life of 13 h. Multiple studies showed reduced sleep latency, improved sleep time, and no rebound, withdrawal, or next-day residual effects. 2% bioavailability because of rapid liver metabolism. Elimination mainly by the urine, a concern in elderly patients. Reduced absorption after high-fat meal. 5% discontinuation rate because of adverse effects versus 2% rate for placebo. Most common side effect is headache (7% with drug and with placebo) Half-life about 1 h. High-fat meal interferes with absorption. Increased awakenings. Questioned sleep time improvement. Pearls Perils

Medications approved by the Food and Drug Administration (FDA)

Benzodiazepine receptor agonists Zaleplon (Sonata) Dose: 510 mg/d per day; 5 mg/d in elderly or patients who have hepatic disease. Take immediately at bedtime or at least 4 h before awakening. Half-life: 1 h Zolpidem (Ambien) Dose: 510 mg (Zolpidem, 5 mg in elderly; Ambien CR, 6.25 mg in elderly) Half-life: 1.24 h Extended-release zolpidem should be taken whole, not divided, and should be ingested only at bedtime. Dose: 6.2512.5 mg Half-life: 1.64 h Rapid absorption with peak level at about 1 h. Inactive metabolites. Improved sleep onset. No morning memory impairment, rebound insomnia, withdrawal,or tolerance noted in elderly. Rapid absorption and onset in 30 minutes. Reduced sleep latency and increased total sleep time. Inactive metabolites. Improved sleep quality and quality of life. No decrease in performance the next day.

Headache, drowsiness, fatigue, and dizziness reported (14%28%). Impaired memory in sleep. Reduced sleep quality. Elderly rebound sleep noted on discontinuation. Rapid discontinuation may result in withdrawal symptoms and rebound sleep.

Eszopiclone (Lunesta) Dose: 13 mg/d with starting dose of 2 mg (3 mg. if needed) 1 mg for patients who have severe liver disease, taking potent CYP3A4 inhibitorsa, or elderly Half-life: 6 h Benzodiazepines Triazolam (Halcion) Dose: 0.1250.25 mg Half-life: 1.55.5 h Temazepam (Restoril) Dose: 7.530 mg Half-life: 11 6 h. Greatest effect on sleep latency and sleep time. Estazolam (Prosom) Dose: 12 mg Half-life: 1024 h Good effect on sleep time. Quazepam Dose 7.515 mg Half-life: 24 h Better effect on sleep time than sleep latency. Flurazepam (Dalmane) Dose: 1530 mg Half-life: 74 24 h Improved sleep onset and maintenance in short term treatment.

Improved sleep onset, sleep quality, sleep time, next-day alertness, function, and well being. 12 months of nightly use was well tolerated and without withdrawal symptoms.

Adverse effects of medication versus placebo: unpleasant taste (34% versus 3%), headache (17% versus 13%) and dizziness (7% versus 4%).

For the benzodiazepines, as a group, the lowest dose for the shortest time period needed for effective therapy is recommended. Treatment of insomnia with this class of drugs is generally considered safe and effective.

Group adverse effects: Daytime sedation, altered sleep architecture (less deep sleep), cognitive and psychomotor impairment. Headache, dizziness with discontinuation, withdrawal symptoms, and rebound insomnia. Tolerance and dependence noted with long-term use. Elderly patients with slower drug metabolism are at potential increased risk for side effects and falls. Patients who have a history of seizure may be at more risk of a seizure with rapid discontinuation of medication.

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Table 1 (continued ) Drug Class Trazodone Commonly used dose of 2550 mg at bedtime is much lower than FDA recommended dose for depression. Other sedating antidepressants show similar results and effects. Half-life: 6.4 h in adults and 11.6 h in the elderly Diphenhydramine Common dose: 12.550 mg at night Other sedating antihistamines show similar results and effects. Pearls Absorbed well on empty stomach. Small studies showed minimal benefits compared with controls. Low cost of these medications is a potential reason for their use. Perils Common side effects: headache, somnolence, dry mouth, dizziness, constipation, difficulty awakening, blurred vision. Cardiovascular complications are possible. Longer half-life in elderly is a concern. Morning sedation in 10%25% of patients. Dry mouth and eyes, constipation, urinary retention, blurred vision and delirium are reported. Dizziness is common and may affect driving. Seizure threshold may be lowered. Few rigorous treatment studies performed. Common adverse effects: fatigue, drowsiness, headache, dizziness and irritability. Mood changes, gastrointestinal distress, hyperglycemia, and hypotension noted. High doses have effects on fertility. There are case reports of coagulation disorders, seizures, and psychotic symptoms.

Medications not approved by the FDA for the treatment of insomnia

Few controlled studies. One study showed improved sleep quality and sleep duration but not improved sleep interruption or severity of insomnia.

Melatonin Dose: 0.35 mg taken 30120 min before bedtime. Safety in those < 18 years is unknown, and drug is not recommended. For jet-lag sleep disturbance: Melatonin 1.0 mg before desired sleep may help but not studied well enough to recommend. Half-life: less than 60 min with uncommon morning effects

Benefit for insomnia and jet-lag sleep improvement is suggested but not backed by rigorous study. Long-term use for up to 2 years of doses up to 5 mg/d is considered safe.

Valerian (valerian root): commonly used for anxiety and insomnia. Dose: 1.53 mg of the root, 400900 mg of extract, or tea prepared with 1.53 mg of root; taken at bedtime.

FDA recognition: generally regarded as safe. Reported randomized clinical trials show short-term reduction in sleep latency, improved sleep maintenance, and sleep satisfaction. No clinical trials on tolerance, dependence, rebound, or withdrawal with discontinued use.

Mild effects of dizziness, hangover, and headache noted but not more frequent than with placebo. Withdrawal tachycardia and possible hepatotoxic effect. Additive sedation with other products unknown. No FDA control on preparation. Not recommended for those younger than 18 years of age.

* Barbiturates such as chloral hydrate, methaqualone, qlutethimide, and others are seldom used because of a lack of effectiveness, loss of cognition, abuse potential, overdose toxicity, and even risk of death. L-tryptophan and kava (kava kava) have some sedative qualities, but there are major health concerns with their use. Kava is considered unsafe because of reported cases of hepatotoxicity at suggested bedtime doses. L-tryptophan should be used with caution because of associated eosinophilic-myalgia syndrome. Other herbal products (chamomile, passion flower, coenzyme Q10, hops, lemon balm, lavender, and skullcap) are used for sleep but have not been studied sufficiently for effect and safety. a Medicines that are potent CYP3A4 inhibitors are ketoconazole, clarithromycin, and nelfinavir. Data from Morin AK, Jarvis CI, Lynch AM. Therapeutic options for sleep-maintenance and sleep-onset insomnia. Pharmacotherapy 2007;27(1):89110; Pagel JF. Medications and their effects on sleep. Prim Care Clin Office Pract 2005;32:491509.

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Variations in coping ability influence an individuals sleeping difficulty with the shiftwork or jet-lag disorders. Additional factors that may make these disorders more serious include advanced age, domestic responsibilities, diurnal sleep preference, and the type of work schedule.38 Jet-lag disorder is a temporary circadian clock misalignment of the sleep/awake cycle caused by moving too rapidly across several time zones. Eastward flight increases the deepness of the sleepiness and the difficulty in adapting to the new time zone. Eastward travel results in trouble in falling asleep, and westward travel causes trouble in maintaining sleep. Jet-lag symptoms usually are temporary and include insomnia, excessive daytime sleepiness, malaise, and impaired performance. Gastrointestinal and urinary demands may become problematic. Other causes of sleepiness, such as primary sleep disorders and drug or alcohol dependence, need to be considered.37
Evaluation and treatment

To evaluate SWSD, sleep logs or diaries are kept for 2 to 4 weeks to evaluate the timing, quality, and quantity of sleep. Actigraphy (as discussed previously) may supplement the diary findings. This information helps with development of the sleep plan. Occasionally other, less commonly used tools may be clinically helpful. These tools include phase markers of circadian/sleep misalignment such as core body temperature and melatonin rhythm studies.36 The treatment of SWSD involves multiple modalities. The treatment needs to be tailored to the individual patients situation. Specific considerations include the patients need and desire for treatment, the patients support system, and the type of shift schedule.34 Planned napping before shifts and short naps during shifts improve alertness during work, reduce accidents, and improve sleep after work.36 Realigning the circadian rhythm to the shift with bright light treatment during work has been shown to be helpful. Wearing dark goggles when returning from work may help the patient adjust to the desired sleep phase by avoiding exposure to bright light.38 Melatonin or even melatonin agonists are available and are used for phase-shifting benefits to improve daytime sleep for night workers. Research is still in progress to determine the appropriate dose and timing for benefit in these conditions. Studies have shown benefit with melatonin use particularly when combined with light therapy.36,37 Melatonin is marketed as a nutritional supplement. Concerns have been raised about the purity of available melatonin preparations and the reliability of the stated doses.36 Hypnotic drugs promote daytime sleep but may affect performance and safety adversely during the following night at work.36 The evaluation of jet-lag disorder is related to the symptoms of the mismatch between the biological clocks drive for sleep or wakefulness and the environmental light/dark cycle at the new destination. Symptoms usually are short lived, but occasional errors in judgment may have serious effects. Older individuals may have less difficulty than younger people. Gender differences are not known. With the possible exception of sleep logs, assessment methods have proved useful only in the laboratory setting at this time.36 Treatment is intended to speed the re-entrainment of the circadian pacemaker to the new time zone. For short trips, one level 2 study showed a benefit in remaining on the home sleep schedule at the new destination, but one third of the participants preferred to adopt the destination sleep schedule to be in synch with local activities. A sleep-simulation study of altering the sleep schedule to an eastward destination time zone before travel showed some small benefits.36 A level 2 simulation experiment with bright light exposure for 3 days before travel to an eastward destination showed

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significant benefit compared with dim light exposure but required strict compliance with the dark-light schedule. One field trial with artificial light exposure after westward travel failed to show improved measures of sleep or performance.36 Twelve doubleblinded, placebo-controlled field trials studied treatment with melatonin for jet lag following travel across multiple time zones. Five reports were level 1 studies, and seven were level 2 studies. Two studies produced negative results; the others showed melatonin treatment improved sleep and reduced jet-lag symptoms. Immediate-release formulations with doses of 0.5 to 5 mg were effective and were better than sustained-released formulations. Only a few studies monitored and reported side effects. Those that reported side effects showed no increased adverse effects compared with placebo. Strategically timed melatonin administration also has been shown to reduce jet-lag symptoms and to improve sleep following long flights.36 Only two small level 2 studies of the effects of caffeine on jet lag have been reported. Daytime sleepiness was less with caffeine use than with melatonin or placebo. Entrainment of the circadian rhythm with caffeine was similar to melatonin and better than placebo. Sleep onset was longer, however, and awakenings were more frequent with the caffeine.36 Three level 1 and six level 2 studies show that hypnotics improved short-term insomnia, but their effect on daytime jet-lag symptoms is not known. Also, when concomitant alcohol use is expected, safety during daytime activities makes the value of hypnotic use uncertain.36 In conclusion, treatment for jet-lag disorder could include the use of immediaterelease melatonin at bedtime. Smaller doses seem to be as effective as larger doses. Caffeine helps with daytime sleepiness but may interfere with restful sleep. In new environments hypnotics should be used only with care. Entrainment of the circadian pacemaker with light therapy may be helpful but is cumbersome to achieve.

Other Sleep Problems Medical conditions and sleep

Sleep disorders are related to poor health outcomes, increased risk of anxiety, depression, cardiovascular disease, and respiratory disorders, and amplification of pain.7,39 On the other hand, psychiatric disorders including psychosis, mood disorders, anxiety disorders, panic disorders, and alcoholism/drug abuse commonly cause sleep disturbances. Dementia produces poor sleep efficiency, frequent awakenings, and possible wanderings at night. A common presenting complaint in Parkinsons disease is insomnia.40 Sleep quality is bad in patients who have coronary artery disease, sleep apnea, chronic obstructive pulmonary disease, asthma, and allergic rhinitis. Multiple sclerosis, uncontrolled seizures, and chronic pain interfere with sleep and produce daytime sleepiness.7,40 Obstructive sleep apnea is associated with a number of medical disorders including an increased risk for hypertension, transient ischemic attacks, stroke, and other cardiovascular diseases.41 Sleep disorders are interrelated with psychiatric and medical diseases, so the assessment of medical and psychiatric disease is necessary in patients who have sleep difficulties, and vise versa.7,42 Medications may disrupt sleep and cause physical side effects. Their relationship with these problems needs to be considered; dose adjustment or discontinuation of medication may be indicated. The treatment of insomnia or sleep apnea may improve sleep and thereby improve associated medical or psychiatric conditions. Similarly, the treatment of pain or anxiety might solve the sleep problem.

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The effect of medications on sleep

Medications are prescribed to improve and control many medical conditions. In addition, patients buy over-the-counter substances hoping to improve function and treat minor ailments. Many patients also use alcohol, tobacco, and caffeine for social and personal reasons. Substance abuse is common and has increased lifetime prevalence in individuals who have mental disorders.43 Many of these compounds have the potential to interfere with sleep efficiency, resulting in difficulty sleeping and excessive sleepiness the following day. Common medications that effect sleep are discussed later. Polypharmacy (taking more than five medications daily) is more common in the elderly, as would be expected. Surveys have shown that 46% of persons more than 65 years old take five or more medications, and 39% take more than 10 medications. The likelihood of drug-to-drug and drug-to-disease adverse interactions on sleep is more common in older adults.43 (Common drugdrug interactions are listed in Table 2). Medications affect each of the three major types of sleep disorders: insomnia (difficulty in falling or staying asleep with nonrestorative feelings the next day), disorders in which the primary symptom is daytime sleepiness, and disorders involving arousal-disruptive sleep behaviors. Although medications to treat these conditions are available, the mediation may have limited efficacy, serious side effects, addiction, and lethal toxicity in overdose.44 In treatment it is important to limit side effects and the potential for addiction or overdose. It also is prudent to avoid writing sleeping prescriptions for conditions resulting from the adverse effects of other medications. Excessive daytime sleepiness is a common sleep complaint and may be described by the patient as sleepiness, drowsiness, fatigue, sluggishness, or a similar state.44 According to The Physicians Desk Reference,43 drowsiness is a commonly reported side effect of almost 600 medications. This problem is noted commonly with the anticholinergic medications and certain antihistaminergic medications such as diphenhydramine. These drugs have soporific effects and also have the potential to interfere with the regulatory neurotransmitters for wakefulness. This interference may result in waking drowsiness and cognitive impairment. Similar effects are seen with antipsychotic, antispasmodic, antiemetic, and antiparkinsonian drugs.43 Ethanol also is widely used to help induce sleep, but diminished sleep quality, development of tolerance, dependence, and overdose are possible. Opiate pain medications may interfere with sleep efficiency and produce daytime sleepiness. Other medications interfere with sleep by activating the brain. This effect is particularly problematic if the medication is taken before bedtime or when the long half-life of the drug continues the alerting effect into the sleep period. Other over-the-counter medications that interfere with sleep are caffeine, ephedrine, and pseudoephedrine, which are common in cold/flu and pain medications. b-Agonists, corticosteroids, and theophylline are used to treat chronic lung conditions but can interfere with sleep maintenance. Activating antidepressants such as buproprion, desipramine, reboxetine, venlafaxine, and most selective serotonin reuptake inhibitors can interfere with the initiation and maintenance of sleep. Other activating medications include dextroamphetamine (Dexedrine), methylphenidate, modafinil, and selegiline. If the use of troubling medications cannot be stopped, they should be taken as far from the time of sleep as possible.43 Some medications may worsen medical and psychiatric conditions, thereby interfering with sleep. Anti-inflammatory medications may worsen heart failure, potentially producing central sleep apnea and nocturia. Lipophilic b-blockers (metoprolol, pindolol, and propranolol) are associated with insomnia and daytime sleepiness. Nocturnal gastroesophageal reflux may be caused by calcium-channel blockers and nitrates. Confusion, urinary retention, and nocturia may be caused by anticholinergic

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Table 2 Drug^drug interactions Drug Digoxin Warfarin Possible Interacting Drugs Amiodarone, cyclosporine, loop diuretics, propafenone, quinidine, verapamil Amiodarone, aspirin, barbiturates, capecitabine, cimetidine, dipyridamole, erythromycin, fluconazole, metronidazole, nonsteroidal anti-inflammatory drugs (NSAIDs), quinidine, sulfonamides, ticlopidine, thyroid products, zafirlukast, 17-akyl androgens, Gemfibrozil

3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (HMG CoAs) Verapamil Potassium-sparing diuretics Clonidine Macrolide antibiotics Sumatriptan Methotrexate Lithium Theophylline Tricyclic antidepressants Sildenafil Sibutramine Carbamazepine Allopurinol Cyclosporine Rifampin Ketoconazole Amiodarone Selegiline Lovastatin Rifampin Ergot alkaloids Monoamine oxidase inhibitors

Beta-blockers, carbamazepine, quinidine Potassium Beta-blockers HMG CoAs Selective serotonin reuptake inhibitors (SSRIs) NSAIDs, sulfonamides, salicylates/aspirin NSAIDs Cimetidine, fluoroquinolones, macrolide antibiotics Clonidine Nitrates SSRIs Macrolide antibiotics Azathioprine Phenytoin Oral corticosteroids Histamine-2 receptor antagonists Quinidine Venlafaxine Cyclosporine Oral contraceptives Macrolide antibiotics Amphetamines, SSRIs, sumatriptan, tricyclic antidepressants

Data from Zhan C, Correa-de-Araujo R, Bierman AS, et al. Suboptimal prescribing in elderly outpatients: potentially harmful drug-drug and drug disease combinations. J Am Geriatr Soc 2005;53(2):2627; and Peng CC, Glassman PA, Marks IR, et al. Retrospective drug utilization review: incidence of clinically relevant potential drug-drug interactions in a large ambulatory population. J Manag Care Pharm 2003;9(6):51322.

medications such as amitriptyline. Diuretics given too close to bedtime are associated with nocturia. Diabetic medications may cause hypoglycemic episodes with resulting nocturnal arousals. Primary sleep disorders such as restless legs syndrome and periodic limb movement disorder may be made worse by certain antidepressant medications, alcohol, benzodiazepines, caffeine, antihistamine withdrawal, and antipsychotic therapies. Cigarette smoking also is associated with sleep disturbances.45 Other medications

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are associated with worsened sleep architecture and interfere with sleep. High-dose niacin, some antibiotics, oral contraceptives, L-thyroxine, and the chronic use of some sedative/hypnotic drugs have been associated with insomnia. The patients medical history should include a complete listing of prescribed and over-the-counter medications that are taken. When the patient is taking more than five medications regularly, the difficulty of polypharmacy should be considered. It should be remembered that both prescribed and over-the-counter medications can interfere with normal restful sleep with resulting daytime sleepiness. Patient complaints of excessive daytime sleepiness or the report of such difficulties from family members should begin an investigation into the cause of the problem. It should be remembered that sleepiness or insomnia are symptoms with a diagnosis waiting to be made and an appropriate treatment instituted. An early review of the medications taken is easy to perform and may provide a potential solution to the problem. If a suspected medication is needed to treat another problem, one should consider changing the timing of administration of the drug. Also, the dose might be modified, or replacement medication might be given. Nonpharmacologic treatments for insomnia are available and might reduce the mediation burden. As with most medical treatment, pharmacology for sleep disorders should be approached with caution, and the smallest effective dose should be used for the shortest duration needed. These principles are particularly important in the elderly, many of whom already have an underlying loss of sleep efficiency, an increased burden of disease, and the likelihood of increased numbers of medications.
WOMEN AND SLEEP The Problem

In the National Sleep Foundation 2007 Sleep in America Poll, 1003 women, including women who were pregnant or had given birth within the last 6 months, were interviewed.46 In women aged 18 to 64 years, 67% experienced a sleep problem. Women under the age of 45 years were more likely than older women in the survey to be too sleepy for exercise (48%) or to run out of time to sleep (52%). Other activities that also were negatively affected were spending time with friends (39%), leisure activities (38%), eating a healthy meal (37%), and having sex (33%). Loss of daytime alertness was common, and 27% of those surveyed reported driving while drowsy. Working mothers (72%), single working mothers (68%), and stay-at-home mothers (74%) reported symptoms of insomnia. Poor mood was associated with sleep loss. Pregnant women spent more time in bed (8.25 hours), but 84% of this group still reported symptoms of insomnia. Menstruating women spent 7.45 hours in bed, but 67% experienced insomnia a few nights a week. Postpartum women spent 7.45 hours in bed, but 84% had frequent symptoms of insomnia. This survey showed a national trend for women at all ages and in varied life situations to have sleep that is inadequate for normal refreshment the next morning. To treat daytime sleepiness, women coped by just keeping going (80%), increasing their caffeine intake (65%), eating high-carbohydrate foods (46%), taking a nap (39%), and/or smoking a cigarette (21%). The 2005 National Sleep Foundation Sleep in America poll showed that women experience more sleep problems than men.
Common Conditions

The central circadian clock with its associated sleep/wake rhythm seems to be influenced by the estrogen and progesterone receptors near suprachiasmatic nucleus, home of the central pacemaker. This hormonal relationship may make the female shift worker more susceptible to additional heath disorders in addition to findings

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noted earlier. Fifty-three percent of nurses during shift work reported dysmenorrhea or changes in menstrual flow and in the length and duration of menstrual flow. Another survey of 2264 women working a shift schedule found an increase in dysmenorrhea and menstrual irregularity. Increased levels of progesterone associated with the postovulatory phase of the cycle influence the circadian rhythm, sleep, and mood. These effects may contribute to maladaptation to shift work. The association of night shift work with the change in the menstrual phase results in a reduced subjective quality of good sleep with increased irritability and decreased alertness. When compared with day workers, young women working shift schedules had greater risks of firsttrimester miscarriage and of babies born with reduced birth weight and at an earlier gestational age.47 Such associated clinical findings, although important, may be related as much to individual adaptation to shift work as to hormonal changes that also are taking place. The relationship of the menstrual cycle physiology with shiftwork difficulties should be considered when women present with such difficulties. A potential aid for a female night-shift worker to improve nighttime function and sleep the next morning is the use of bright light exposure during the night shift. Epidemiologic studies have shown a larger-than-expected increase in breast cancer in women working various types of shift schedules. It is proposed that melatonin may have an oncostatic function in the suppression of such cancer, and melatonin is suppressed by the bright light therapy. Although this association is interesting, shift work also is associated with nutritional deficits, weight gain, and other changes. The association of bright light therapy and breast cancer is still being investigated. Additional studies are in progress at this time.48 Shift workers have altered meal times, and they have been reported to eat fewer meals than those who work day hours. The methods they use to stay awake include increased snacking, eating unhealthy sweets and high-energy foods, drinking more caffeinated drinks, and smoking. Weight gain, higher body mass index, and lower participation in exercise are noted also. Female shift workers have a reported increased risk of hypertension, diabetes mellitus, elevated cholesterol, coronary artery disease, and myocardial infarction. Gastrointestinal symptoms and disorders are increased in shift workers.47 Female shift work also has significant negative effects on personal psychologic health and on domestic and family life. Sleep time is reduced because of the additional domestic responsibilities following the night shift. Family and spousal relationships are affected. A survey comparing shift and nonshift workers (84% of those surveyed were female) showed although overall happiness and life satisfaction was maintained, other quality indices were affected. The shift workers reported less opportunity to improve their psychologic health and personal growth. They also reported lower scores in their spiritual being (personal values, standards, and spiritual beliefs) and fewer opportunities to become involved in domestic, school, or volunteer activities.49 Low back pain, temporomandibular joint disorder, and tension headaches are more common in women than in men and may interfere with restorative sleep. Perhaps of greater concern, women have a higher incidence for a group of chronic pain conditions that likewise interfere with sleep. These conditions are grouped together as the functional somatic syndromes (FSSs), which include fibromyalgia (1%3% of women), irritable bowel (3%20% of women), and chronic pelvic pain (7% to 8% of women). The close relationship between nonrestorative, fragmented sleep and the perpetuated central processing of pain and the activation of immune/inflammatory regulation are not well defined. This problem needs further research. In the FSSs, the chronic persistence of the symptoms of dysphoria, profound fatigue, and cognitive impairment place a heavy burden on many women.50

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As discussed earlier, insomnia, with a reported prevalence between 2% and 11%, is more common in women. A positive family history, particularly in the patients mother, is a significant risk factor for insomnia. Female hormones (pregnancy, menstruation, and menopause) and care of a child at night or eldercare may increase the rate of insomnia in women. A sleepless young child and the late return of an adolescent son or daughter typically increase maternal vigilance and sleep impairment.
Treatment

A womans lifestyle with multiple roles can make sleep more difficult. Setting up a routine for good sleep will help with general sleep maintenance. The routine should include relaxing activities before sleep (avoiding television, strenuous exercise, or late meals); a dark, quiet, cool sleep environment; avoiding caffeine drinks, alcohol, or nicotine for several hours before sleep; and initial help with the care of a new baby. Twenty-one percent of women snore at night, and 19% have symptoms of restless leg syndrome. If these symptoms persist, interfere with sleep, or cause daytime sleepiness, the cause for the symptom should be brought to the physicians attention. Women who sleep with a child (9%) or a pet (14%) in bed may have sleep disruptions and should find another place for the child or pet to sleep.48 The FFSs (e.g., fibromyalgia) still are not well understood. Whether early treatment of the pain or sleep disturbance would modulate the development of immune inflammatory mediators is not known, but such treatment may be helpful. Each of the FSS disorders has evaluation and treatment recommendations that ameliorate the condition. General medical and specialist care may be needed to maximize the treatment plan.50 Future research probably will provide a better understanding of FSSs and improved treatment options. Studies of medical and sleep disorders related to SWSD are complex, and additional information is in development. The use of light exposure during shift work and naps before work or during the work period can align the central circadian clock to extend the sleep period. These measures improve alertness, performance, and safety at work and improve next-day sleep efficiency. Efforts to reduce sleep debt in shift work may be healthy. Naps are a method to counteract the effect of sleep loss and improve work vigilance. Improved sleep may reduce the effects of abbreviated shift work, such as obesity, hypertension, and endocrine changes. The short-term use of hypnotics or melatonin may improve sleep time. Caffeine and other stimulants such as modafinil may increase workers attention during the work shift.47 Better understanding of the effects of shift work on women is needed for development of public policy for such work and the development of new treatment options. Insomnia can be treated with pharmacologic and psychologic interventions. Both types of intervention can be beneficial. A combination of the two types has been tried. Nonpharmacologic treatments such as cognitive-behavioral therapy are time consuming to initiate but have long-term benefits when compared with medication prescription. In some places trained therapists may be difficult to find.35 Table 1 presents pharmacologic and herbal products used for treatment of sleep loss. The table shows the benefits of those medications and concerns regarding their use. In conclusion, this article has discussed briefly the function and benefits of sleep. The consequences of sleep impairment with a few associated sleep disorders were noted. Importantly, it has addressed insomnia, the most common sleep disorder, and has discussed the current approach to this common and debilitating problem. A listing of additional resources for continued study by health professionals and patients is provided in the Appendix. By probing deep,1 one finds that excellent treatments for sleep disorders do exist. Much has yet to be learned, but improved care is being developed for patients who have those disorders.

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APPENDIX Resources for Providers

National Heart Lung and Blood Institute. Problem sleepiness in your patient (free PDF downloadable version). Available at: http://www.nhlbi.nih.gov/health/prof/ sleep/index.htm; Accessed March 27, 2008. Guide to selected publicly available sleep-related data resources. National Center on Sleep Disorders Research, July, 2006. Available at: http://www.nhlbi.nih.gov/ about/ncsdr/research/sleep-datasets-july-06.pdf. Accessed March 27, 2008. The American Academy of Sleep Medicine offers on-line resources for CME, current journal articles, training, and practice standards. Available at: http:// www.aasmnet.org/ProfDev.aspx. Accessed April 1, 2008.
Resources for Patients

National Sleep Foundation (English and Spanish versions) sleep information, sleep logs, learning tools, and much more. Available at: http://www.sleepfoundation. org. Accessed March 10, 2008. National Heart, Lung and Blood Institute. Your guide to healthy sleep (60-page publication: free downloadable PDF or purchase for $3.50). Available at: http:// www.nhlbi.nih.gov/health/public/sleep/healthy_sleep.pdf. Accessed March 27, 2008. National Heart Lung and Blood Institute. Star sleeper for kids (interactive website for kids, parents, and teachers). Available at: http://www.nhlbi.nih.gov/health/ public/sleep/starslp/index.htm Accessed March 27, 2008. Sleep disorders from Medline Plus health topics. U.S. National Library of Medicine and the National Institutes of Health. Available at: http://www.nlm.nih.gov/ medlineplus/sleepdisorders.html#cat64; Accessed March 25, 2008.

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