TOC | NEURO
Current Concepts: Management of Insomnia
David J. Kupfer, Charles F. Reynolds III.
NEJM-- January 30, 1997 -- Vol. 336, No. 5
Insomnia is a common symptom, and clinicians need a diagnostic approach that allows them to choose from among many different types of therapy.
Reports of insomnia tend to increase with age and are more prevalent among women, even though laboratory studies show that older men have more disrupted sleep. People who are divorced, widowed, or separated report having insomnia more often than married people; lower socioeconomic status is also a correlate of insomnia.
The course of insomnia can vary over time, but insomnia tends to be persistent or recurrent in both clinical and community samples. Persistent insomnia is both a risk factor for and a precursor of mood disorders. Thus, effective treatment of insomnia may represent an opportunity to prevent major depression. Chronic insomnia is also associated with an increased risk of automobile accidents, increased alcohol consumption, and daytime sleepiness. Thus, patients with insomnia merit serious attention.
Insomnia: Symptom versus Syndrome
Patients who report having insomnia often have several problems, including sleep that is unrefreshing or nonrestorative as well as the inability to fall asleep or to remain asleep. The duration of a patient's insomnia has important diagnostic implications.
The duration of the symptom is important both in determining the differential diagnosis and in evaluating secondary problems, including the use and misuse of alcohol and drugs -- which can be both a cause and an effect of chronic insomnia -- and obsessive concern about an inability to sleep (which often becomes a self-fulfilling prophecy). The diagnostic and pharmacotherapeutic considerations depend on whether symptoms are short term or chronic.
The diagnosis of chronic primary insomnia requires difficulty in initiating or maintaining sleep or the presence for at least one month of nonrestorative sleep that causes marked distress or impairment in social, occupational, or other important areas of functioning. The sleep disturbance of primary or psychophysiological insomnia is not due to another sleep disorder, a mental disorder, or the effects of a drug or medical condition. Thus, it is typically a diagnosis of exclusion, reached after more specific medical and psychiatric diagnoses have been ruled out.
Often, patients are intensely worried about not sleeping and engage in self-defeating behavior, such as following irregular or unpredictable sleep-wake schedules or spending excessive amounts of time in bed.
Evaluation: Principles and Pitfalls
Physicians should try to determine the cause of insomnia, remembering that it may have more than one cause. There are effective treatments for specific conditions, and physicians need to understand the cause of chronic insomnia to establish a long-term approach to its management.
The first step is to define the chief sleep symptom
Physician must consider the possible causes, which include:
It is often useful to have the patient complete a two-week log or diary indicating the patient's usual bedtime and time of arising, the timing and quantity of meals, use of alcohol, exercise, medications (prescribed and over-the-counter), and descriptions of the duration and quality of sleep each day. Such information may reveal aspects of the patient's lifestyle that can be destructive to sleep.
If the patient has a bed partner, it is also important to ask that person whether the patient snores loudly, behaves abnormally during sleep (e.g., has episodes of confusion or combativeness), or is excessively sleepy during the day. Such collateral information can provide important clues to a differential diagnosis. Physicians should refer patients suspected of having sleep-disordered breathing for an evaluation that includes electroencephalographic sleep staging and simultaneous electrocardiography and monitoring of respiration and limb movements.
(For more on sleep apnea and its management, see Strollo and Rogers.) A task force of the American Sleep Disorders Association also recommends referring a patient if chronic insomnia persists after behavioral and pharmacological intervention (as described below) or if the sleep symptom is not adequately explained by the type or degree of the patient's medical illness or medications.
The most common pitfall in diagnostic evaluation is the failure to understand that chronic insomnia has many causes. Despite the complexity of the condition, a systematic, long-term approach to management and to working through sleep disorders can lead to success in therapy.
After evaluating any medical and psychiatric problems, physicians' primary goals are to remove or mitigate these underlying problems, to prevent progression from transient to chronic insomnia, and to improve the patient's quality of life. Achieving these goals involves
Educational and Behavioral Intervention
It is essential to educate patients about the kinds of behavior that disrupt
sleep (stimulus control) and to stabilize sleep-wake schedules (temporal
A behavioral intervention called stimulus-control therapy is useful, simple, and effective. Patients should be instructed to go to bed only when sleepy and to use the bedroom only for sleep and sex and not for reading, watching television, eating, or working. If patients are unable to sleep after 15 to 20 minutes in bed, they should get out of bed and go into another room. They should read with a dim light and avoid watching television, which radiates full-spectrum bright light and therefore has an arousing effect, and they should return to bed only when sleepy. The aim is to reestablish the psychological connection between the bedroom and sleeping, rather than the bedroom and insomnia. Patients should get out of bed at the same time each morning regardless of how much they slept during the previous night. This stabilizes the sleep-wake schedule (temporal control) and enhances sleep efficiency (the percentage of time in bed actually spent sleeping). Finally, daytime napping should be minimized or avoided in order to increase the drive to sleep at night. If the patient needs it, a 30-minute nap early in the afternoon probably will not disrupt sleep at night.
Another helpful behavioral intervention with demonstrated efficacy consists of curtailing the amount of time spent in bed to the actual amount of time spent sleeping. The efficacy of this approach, known as sleep-restriction therapy, has been demonstrated in a randomized clinical trial with elderly subjects. This method allows a slight sleep debt to accrue, which increases patients' ability to fall asleep and to stay asleep. The time allowed in bed is increased incrementally, as long as a desired sleep efficiency is maintained. For example, if a patient with chronic insomnia is sleeping 5.5 hours nightly, the time in bed is limited to 5.5 to 6.0 hours. The patient then adds approximately 15 minutes per week to the start of each night's time in bed, rising at the same time every morning, as long as at least 85 percent of the time in bed is spent sleeping.
Physicians should supplement stimulus control, temporal control, and sleep restriction with education about health practices, such as diet, exercise, and substance use, and environmental factors, such as light, noise, and temperature, that may be detrimental or beneficial to sleep. More specialized approaches involve relaxation therapies, such as progressive muscular relaxation and biofeedback, to reduce arousal. Cognitive-behavioral treatment for insomnia targets maladaptive patterns that perpetuate insomnia. This approach has been shown to be of value in producing long-term benefit.
Five basic principles characterize rational pharmacotherapy for insomnia, especially chronic insomnia, in both adult and geriatric patients: use the lowest effective dose; use intermittent dosing (two to four times weekly); prescribe medication for short-term use (i.e., regular use for no more than three to four weeks); discontinue the medication gradually; and be alert for rebound insomnia following discontinuation. In addition, agents with shorter elimination half-lives are generally to be preferred in order to minimize daytime sedation. Alcohol and over-the-counter agents (such as antihistamines) are only minimally effective in inducing sleep, further impair the quality of sleep, and adversely affect performance the next day. Table 1 lists commonly prescribed sedative hypnotic agents, with information about the dose (adult and geriatric), onset of activity, elimination half-life, and presence or absence of active metabolites. Table 2 lists several widely used over-the-counter sleeping medications and their ingredients. Table 3 lists the most common medications that interfere with sleep.
With respect to clinical-efficacy trials in adult patients with chronic insomnia, we reviewed 123 controlled medication studies (with a total of 9114 patients) and 33 controlled behavioral-intervention studies (1324 patients). We concluded that subjective symptoms and objective signs of chronic insomnia respond to short-term behavioral and pharmacologic intervention. Both types of intervention typically reduce the amount of time it takes to fall asleep by 15 to 30 minutes as compared with pretreatment times and the number of awakenings by one to three per night. Although pharmacologic agents appear to act more reliably in the short run and behavioral interventions appear to produce more sustained effects, no direct comparisons with respect to long-term efficacy are available. On the basis of the data from controlled trials, benzodiazepines, zolpidem, antidepressants, and melatonin (only one controlled trial) are effective pharmacologic agents. Stimulus control, sleep restriction, relaxation strategies, and cognitive-behavioral therapy are effective behavioral interventions for short-term management.
We have examined the randomized, double-blind trials in elderly patients with chronic insomnia of various causes. In 23 trials with 1082 patients, including 516 psychogeriatric inpatients or residents of nursing homes, we found scientific support for the short-term (up to three weeks) efficacy of zolpidem and triazolam in the elderly, as well as temazepam, flurazepam, and quazepam, but not chloral hydrate.
Since the introduction of chlordiazepoxide 30 years ago, all pharmacologic clinical trials in adult patients and geriatric patients have addressed only short-term interventions (lasting several days to several weeks) and their immediate responses; there are no data from randomized clinical trials about the ability of interventions to produce sustained effects for more than 35 days. Questions remain unanswered about the long-term efficacy of medications in a disorder that is typically chronic and relapsing. This deficiency, along with the risk of physical dependence, led the Food and Drug Administration to establish guidelines that discourage the use of benzodiazepine hypnotic agents for more than four weeks.
The elimination half-lives of sedative hypnotic agents vary widely. Adverse events such as memory impairment, falls, excessive sleepiness, and accidents occur more often at higher doses and when active metabolites accumulate. Flurazepam and quazepam have the longest elimination half-lives (36 to 120 hours) and therefore have the advantages of providing next-day anxiolytic action and lowering the likelihood of rebound insomnia. However, prolonged use of these agents can lead to daytime sleepiness, cognitive impairment, incoordination, and worsening of depression. Agents with intermediate elimination half-lives (10 to 24 hours) and no active metabolites include temazepam and estazolam. They are less likely to be associated with excessive daytime sleepiness. Agents with very short elimination half-lives (2 to 5 hours) include triazolam and zolpidem.
The efficacy of zolpidem, an imidazopyridine, has been found to be similar to that of benzodiazepines in studies of acute and chronic insomnia. Although both zolpidem and benzodiazepines exert their effect through modulation of the (gamma)-aminobutyric acid (GABA)-receptor complex, zolpidem may be less likely than benzodiazepines to disturb the architecture of sleep and to cause cognitive and psychomotor side effects (and may have fewer withdrawal effects). Although these potential advantages suggest that zolpidem may prove useful in the treatment of acute and chronic insomnia, because it acts through the GABA-receptor complex it theoretically carries the same risks, including dependence, as the benzodiazepines, and as a result its use for more than four weeks is discouraged.
Before prescribing any sleep medication, physicians need to consider general issues of safety. For example, pregnant women, as well as patients with possible sleep apnea -- which may be exacerbated by sleep medications -- and patients with renal and hepatic insufficiency, may be at greater risk for sedative side effects.
Clinicians' concern about the possibility of dependence on and the side effects of benzodiazepines and zolpidem, together with regulatory requirements such as that for triplicate prescription, have contributed in recent years to a 30 percent decrease in benzodiazepine prescriptions and a 100 percent increase in the use of antidepressants as hypnotic agents. There is, however, little controlled evidence bearing on the effects of antidepressants on chronic insomnia in the absence of a mood disorder. The single reported study used trimipramine, which produced subjective improvements in the quality and quantity of sleep and objective improvements as measured by polysomnography. Trimipramine and other sedating tertiary tricyclic agents (e.g., amitriptyline and doxepin) have troublesome atropinic side effects and pose a risk of more serious conditions, such as orthostasis and cardiac dysrhythmias. An additional risk posed by tricyclic antidepressants as compared with benzodiazepines and zolpidem is the danger of overdose. However, the risk associated with ingesting alcohol with a benzodiazepine or zolpidem and the risk of dependence on either drug also remain dangers. Patients and their families must be educated about the appropriate use of sleep medications.
Serotonin-specific antidepressants, such as trazodone, nefazodone, and paroxetine, alleviate the sleep disturbance that accompanies depression and have fewer side effects than tertiary amine antidepressants. The potential benefit of serotonin-specific antidepressants in chronic insomnia has not been systematically evaluated. However, given the side effects of benzodiazepines and zolpidem (and the additional risks of dependence, withdrawal, and rebound insomnia) and the danger of overdose with traditional tricyclic agents, controlled evaluation of serotonin-specific antidepressants in the treatment of chronic primary insomnia should become a priority in insomnia research, particularly since chronic insomnia is an established risk factor for major depression. It is possible that the use of a safe antidepressant medication could diminish the burden of chronic insomnia and prevent major depression. Antidepressants are now used widely and are prescribed at much lower doses for the treatment of insomnia than for depression. This practice has developed without data from controlled clinical trials. It is possible that the use of a medication for which the antidepressant dose is lower (e.g., 20 mg of paroxetine per day) would both improve sleep and help prevent depression in chronic insomnia.
Melatonin has received considerable attention in the lay press in the context of sleep and circadian rhythms. A single double-blind, placebo-controlled study of the effects of melatonin on chronic insomnia unrelated to circadian disturbances found melatonin (2 mg per day) superior to placebo in improving sleep efficiency in the elderly.
Although chronic primary insomnia defies easy diagnosis and treatment, clinicians should recognize the importance of determining the cause of insomnia while bearing in mind that it may have multiple causes in the same patient. Taking a long-term approach to the management of chronic insomnia and working through insomnia complaints systematically help to achieve success in therapy, even in patients with complex cases -- especially since chronic insomnia is often a relapsing disorder. More data are needed about preventive strategies and the long-term efficacy of both behavioral and pharmacologic approaches. We view sleep-restriction therapy and selected antidepressant medications (especially serotonin-specific antidepressants) as promising candidates for studies of long-term efficacy.
Supported in part by grants (MH-30915, MH-52247, MH-24652, MH-37869, and MH-00295) from the National Institute of Mental Health.
From the Department of Psychiatry, Western Psychiatric Institute and Clinic, University of Pittsburgh Medical Center, 3811 O'Hara St., Pittsburgh, PA 15213-2593, where reprint requests should be addressed to Dr. Kupfer.
Goroll: Primary Care Medicine, 4th ed., Copyright © 2000 Lippincott Williams & Wilkins
Approach to the Patient with Insomnia (Chapter 232)
JEFFREY B. WEILBURG
Approximately 40% of the general population experiences intermittent or chronic insomnia at least once. Epidemiologic studies find that between 10% and 17% of the population have some kind of insomnia at any given point in time and approximately 7% of the population have insomnia (persistent difficulty falling or staying asleep that compromises daytime functioning) of sufficient severity to warrant formal diagnosis and treatment. Insomnia affects patients of all ages and backgrounds but is especially prevalent in the elderly and in people of lower socioeconomic status.
The consequences of insomnia are significant, including impairment of work and social function, increased risk of motor vehicle accidents, and disturbance of mood. The cost of these problems combined with the cost of medication and other treatments has been estimated to exceed $100 billion/yr. The primary care physician needs to be skilled in the assessment and initial therapy of insomnia.
PATHOPHYSIOLOGY AND CLINICAL PRESENTATION
Sleep physiology is examined by using the polysomnogram, a continuous all-night recording of respiration, eye movements, electroencephalogram (EEG), muscle tone, blood oxygen saturation, and electrocardiogram.
Normal Sleep versus Insomnia.
Normal sleep can be divided into two basic phases: rapid eye movement sleep (REM) and non-REM (NREM). REM is a state of mental and physical activation. Pulse and respiration are increased but muscle tone is diminished, so little body movement occurs. The brain is active, and the EEG shows a pattern similar to that seen during waking. Most dreaming occurs during REM. In contrast, NREM is a time of deep rest. Pulse, respiration, and EEG all slow, and the patient goes from light sleep, called stages 1 and 2, to deep or delta sleep, called stages 3 and 4. REM and NREM normally cycle in a reciprocal pattern, giving a typical "architecture" to the polysomnogram. The entire cycle lasts about 90 minutes and is repeated smoothly four or five times during the night.
Insomnia is best regarded as a symptom, or complaint, which may be produced by a variety of underlying pathophysiologic processes. Therefore, insomnia has no single or pathognomonic polysomnographic pattern. Some insomniacs have slightly shorter than normal sleep times, some have less stages 3 and 4 sleep, but most have normal-appearing polysomnograms. Slight disruptions of the normal smooth cycling caused by frequent brief arousals may be related to subjectively unsatisfying sleep. Psychologic variables appear to strongly influence an insomniac's perceptions of restfulness and sleep.
Finding the underlying problem (often there are multiple problems operating simultaneously) producing the complaint is the key to effective management of insomnia.
appear to be the underlying cause in about half of all cases. Among patients presenting to primary care physicians, insomnia may be the initial manifestation of depression. Patients with major depression complain of either difficulty falling asleep or of waking in the early morning and being unable to return to sleep. Diurnal variation of mood is often noted. Severe depression with agitation may lead to markedly diminished total sleep and overall exhaustion (see Chapter 227) . Patients in the manic phase of a bipolar affective disorder may report difficulty falling asleep or staying asleep, but they do not report feeling tired during waking times.
Patients suffering from dysthymic disorder (a variant of depression; see Chapter 227) typically complain of feeling tired, irritable, have difficulty falling asleep, and report that they cannot get enough sleep to feel rested. Sometimes they deny feeling sad or depressed and focus only on their physical complaints. Insomnia may be their major presenting complaint.
Patients with anxiety and obsessive disorders frequently have great difficulty falling asleep because they lie in bed and ruminate. Character disorders make up about 40% of the other psychiatrically based insomnias. Patients with narcissistic or borderline character disorders characteristically feel angry or entitled and may have difficulty falling asleep. They lie in bed, furiously trying to make themselves sleep. Such patients may use their insomnia as a justification for their inability to function or to get ahead in life. Their lack of sleep is viewed as the source of all their troubles. Some even use it as a rationale for their inability to comply with the treatment of the insomnia itself.
Active psychosis of any type (e.g., schizophrenia) produces disturbed sleep and accounts for the other 10% of psychiatric insomnia. Hallucinations, delusions, and other signs and symptoms of psychotic illness present with the insomnia, facilitating recognition.
Drugs and Substance Abuse.
Drugs and alcohol account for about 10% to 15% of all cases. Alcohol induces sedation, but the resulting sleep is often shallow, fragmented, and not restorative. Alcoholics can have prematurely "aged" sleep (i.e., shallow and short) during and for months after cessation of drinking.
Sedatives, especially barbiturates, when used on a regular long-term basis lead to shallow fragmented sleep. Rebound insomnia and rebound anxiety prompt reuse, and tolerance leads to dose escalation, so patients get caught in a vicious cycle. Sedatives and alcohol depress respiratory function, which can lead to very poor quality sleep in patients with sleep apnea.
such as caffeine, amphetamine, pemoline, or methylphenidate; activating antidepressants (e.g., fluoxetine, sertraline, venlafaxine, desipramine, bupropion, phenelzine, protriptyline); and the phenylpropanolamine found in many over-the-counter decongestant, cold, and diet remedies can induce significant difficulty falling asleep. The caffeine and other stimulant xanthines found in tea, coffee, cola drinks, and chocolate are well recognized and often used for their ability to keep one awake. In those who are sensitive, even small amounts will prevent sleep. Nicotine and other substances found in cigarette smoke disrupt sleep induction and continuity. Bronchodilators such as aminophylline and beta-agonists can make sleep difficult when given before bed.
are responsible in approximately 10% of cases. Chronic pain is a leading, though often overlooked, factor (e.g., that experienced by elderly persons with degenerative joint disease). Delirium is another important cause in the elderly, resulting from unrecognized infection or medication toxicity (as from anticholinergic agents used in over-the-counter sleep remedies). Cardiopulmonary dysfunction may contribute by causing orthopnea, paroxysmal nocturnal dyspnea, or nocturnal angina.
is a disorder characterized by repeated apneic periods due to soft tissue upper airway obstruction followed by disruption of sleep. In severe cases, behavioral changes, pulmonary hypertension, cardiac arrhythmias, and death can occur. Patients are unaware of how disrupted their sleep is, though spouses may be kept awake by loud snoring and frightened by the apneic periods. Patients complain of marked daytime sleepiness (see Chapter 46) .
due to infection, prostatism, diabetes, or poor timing of diuretic use are among other important disrupters of sleep. Often, it is the nocturia and disturbed sleep that causes the patient with prostatism to finally seek definitive therapy.
Primary Sleep Disorders make up another 10% of insomnia cases. In primary or idiopathic insomnia, patients have objectively verified difficulty initiating or maintaining sleep in the absence of any identifiable underlying pathology. Such patients may need more, rather than less, sensory input to fall asleep, rather like hyperactive children who require stimulants to control their activity. Others have a persistent complaint of insomnia with no objective evidence. Although they believe they awaken, their polysomnographic studies reveal that they are actually sleeping. There is sleep state misperception. Their polysomnographic studies are entirely normal. A final group have poorly understood polysomnographic aberrations, such as the intrusion of alpha EEG into delta sleep.
In conditioned or " psychophysiologic" insomnia, patients begin to associate bedtime with frustration, anxiety, and sleep-preventing behaviors. In this learned disorder, they typically sleep very well while away from their usual bedroom (e.g., while on vacation or on the living room couch).
Circadian rhythm disorders may present with insomnia. In the delayed sleep-phase syndrome, the patient falls asleep later than the usual bedtime, sleeps well, and gets up later than is socially acceptable. This common disturbance often presents in adolescents. Other common forms are due to alternating shift work or jet travel across time zones (" jet lag" ), in which the inability to rapidly reset one's diurnal rhythm to local time leads to insomnia. For travel westward across time zones, the typical experience is awakening in the middle of night local time (morning at home) and being unable to fall back to sleep despite feeling tired. Restful sleep is not achieved. Moreover, there is marked afternoon or early evening sleepiness (bedtime at home). The inability to attain restful sleep culminates in exhaustion and the patient requests help for insomnia. Endogenous disruptions of the brain's internal circadian rhythm setter can produce a similar picture.
Nocturnal myoclonus can produce poor quality sleep and lead to the complaint of "insomnia." It is characterized by repetitive twitching of the legs, which is often unrecognized by the patient.
The most recent official version of the psychiatric diagnostic system--the Diagnostic and Statistical Manual of American Psychiatric Association, 4th edition (revised)--classifies insomnia as primary (idiopathic) and secondary (related to a primary psychiatric, medical, or substance abuse disorder). Table 232.1 provides a listing useful for primary care practice based on these categories.
It is important to note that not all persons who sleep less than average each night have insomnia. There are natural " short sleepers," persons who regularly have less than 7 hours of well-maintained sleep yet suffer no problems other than too much time on their hands at night. Those who have a brief time-limited disturbance of sleep related to stressful events in their lives are not regarded as having a sleep disturbance. The same pertains to normal elderly patients who experience as part of the natural aging process a decline in total sleep time, depth, and continuity.
TABLE 232-1 -- Causes of Insomnia
I. Psychiatric Disorders
II. Medical/Surgical Problems
III. Primary Sleep Problems
When the complaint is persistent, when the sleep latency (the time between lights out and falling asleep) is consistently greater than 60 minutes, and when the insomnia is associated with compromised daytime functioning, a search for an underlying etiology should be undertaken.
A full description of the problem is essential and facilitated by having the patient keep a sleep log or diary, which includes time in bed, estimate of time asleep, any awakenings, time of morning arousal, estimate of sleep quality, and comments on unusual events and any associated symptoms (e.g., orthopnea, urinary frequency, pain, palpitations). Entries are recorded by the patient directly on getting up each morning. Close attention must also be given to use of sedatives, hypnotics (including over-the-counter preparations), and stimulants. Screening for abuse of alcohol and other substances is essential . It is most important to listen carefully for and inquire directly about symptoms of depression, bipolar disease, anxiety disorder, and psychosis . Occupational and travel patterns should be noted. Whenever possible, interviewing the spouse, bed partner, or family member is of great value, particularly for symptoms suggestive of sleep apnea (e.g., excessive snoring, apneic episodes, disturbed sleep). Past and family medical and psychiatric histories are sometimes revealing.
The pertinent physical examination is a function of the history. One checks for upper airway soft tissue obstruction in the patient with suspected sleep apnea; for jugular venous distention, rales, wheezes, heaves, and gallops when there is concern about a cardiopulmonary etiology; for moist skin, tachycardia, proptosis, goiter, and tremor when hyperthyroidism is under consideration; and for prostatic enlargement in the elderly male with sleep-disturbing nocturia. Any reported sources of pain should be evaluated and confirmed by physical examination. A careful mental status examination helps in the detection of psychiatric disease.
Testing should be limited, selective, and based on evidence from the history and physical examination (e.g., thyroid-stimulating hormone for suspected hyperthyroidism, chest x-ray for cardiopulmonary disease, toxic screen for substance abuse). Immediate referral to the sleep laboratory is indicated only if a primary sleep disorder, such as central sleep apnea or nocturnal myoclonus, is suspected. Testing is very expensive and time consuming. Home monitoring for apnea and oxygen desaturation may prove a cost-effective screening alternative to the sleep laboratory for patients with suspected obstructive sleep apnea (see Chapter 46) . Psychiatric evaluation is indicated only when character problems interfere with diagnosis or management or if the nature of a suspected mental or emotional problem is obscure.
PRINCIPLES OF MANAGEMENT
For a problem with as broad a spectrum of etiologies as insomnia, the best treatment is etiologic. Nonspecific measures are unlikely to be of much help and can be harmful. Careless use of sedative/hypnotics can be especially dangerous (e.g., giving the patient with sleep apnea or alcohol abuse a benzodiazepine). Precise diagnostic assessment allows for maximally safe and effective management. For those with substance abuse, proper withdrawal and complete abstinence from drugs and alcohol are critical.
Depression and Other Affective Disorders.
All antidepressants are equally effective for the treatment of depression. Although the evidence is still incomplete, it has been suggested that patients with affective disorders who present with insomnia may benefit from a trial of a relatively sedating antidepressant, such as mirtazepine, paroxetine, citalopram, nefazodone, or nortriptyline. Full doses of antidepressants should be used if affective symptoms remain after insomnia resolves . When insomnia is due to use of an activating antidepressant, such as desipramine or a fluoxetine, adding a small amount of trazodone (50 mg qhs) or clonazepam (0.5 to 1.0 mg qhs) may be helpful. Antidepressant therapy can be started at a modest dose but should be advanced to adequately treat the underlying depression (that is the cause of the sleep disturbance).
Transient insomnia due to situational stress is a common nonthreatening problem, which by definition resolves on its own and often responds well to support, reassurance, and simple behavioral advice (see below). For anxiety disorders and character disorders complicated by insomnia, benzodiazepines can be used safely and effectively . Zaleplon and zolpidem are nonbenzodiazepines that act at the benzodiazepine receptor complex and behave clinically similar to the benzodiazepines without producing some of their undesirable side effects (see below). The use of benzodiazepines for anxiety-related depression has declined relative to the use of small doses of sedating antidepressants (e.g., nortriptyline 25 to 50 mg qhs) or trazodone (25 to 100 mg qhs). The efficacy and safety of this practice has yet to be fully established.
Pharmacologic Therapy: Short-term versus Chronic.
There is controversy as to the proper frequency and duration of therapy when insomnia due to a long-standing anxiety disorder or characterologic disturbance is chronic. Most believe it is best to treat such insomnia with a short (1-week) course of benzodiazepine therapy to help reestablish a more normal sleep pattern and then to stop. However, an occasional patient requires a program of benzodiazepine use two to three times per week over much longer periods. If chronic benzodiazepine therapy is contemplated, one first needs to review with the patient the importance of assiduous compliance, the risks of tolerance and withdrawal, and the possibility of physical dependence if the medication is not taken as prescribed (see Chapter 226) . In addition, one must screen carefully for contraindications (e.g., sleep apnea, substance abuse). Concurrent use of alcohol and other sedatives must be prohibited because of the risk of oversedation.
For patients requiring prolonged therapy, careful monitoring is essential to ascertain efficacy, check for adverse effects, and ensure proper dosage and frequency. Drug holidays and attempts at alternative treatment are important components of any therapeutic program that involves prolonged benzodiazepine intake. The risks of tolerance and withdrawal should be reviewed with the patient before initiating such therapy. Withdrawal symptoms may develop within 3 to 20 days after cessation of chronic benzodiazepine use, especially if abrupt. It is best to taper therapy slowly over several weeks in patients with a history of prolonged intake .
Choice of Agent.
Debate continues on the drug of choice for sleep. The benzodiazepines and benzodiazepine-like agents are preferred. The optimal agent would have a rapid onset yet short (48-hour) duration of action and would cause no rebound insomnia or mental problems such as hangover, motor incoordination, or memory disturbance. There are now several agents marketed for the treatment of insomnia, but none has been clearly shown to be significantly superior to any other, and all have some problems associated with their use .
The benzodiazepines used for insomnia can be divided into the short-, intermediate-, and long-acting agents. The shortacting drugs (e.g., triazolam, estazololam, zaleplon) are best prescribed for those whose primary problem is falling asleep. Triazolam should be used in the lowest possible doses (not to exceed 0.125 mg/d in the elderly) and should be tapered to avoid rebound insomnia and anxiety. Zaleplon may have somewhat lower propensity to produce rebound effects, but more experience with this new agent is required to confirm this.
The intermediate-acting agents such as temazepam and quazepam may be useful for those patients who complain of problems with sleep continuity. The possible increased receptor selectivity of quazepam has not been shown to be clearly clinically relevant. Zolplidem fits into the intermediate-acting group; lorazepam and diazepam may be recommended as lower cost generic alternatives. Long-acting agents (e.g., flurazepam, clonazepam) are considered when daytime anxiety compounds the discomfort.
Sedating tricyclic antidepressants such as nortriptyline (10 to 25 mg qhs) may help some patients with generalized anxiety and insomnia, as may buspirone (10 to 30 mg qhs) or trazodone (25 to 50 mg qhs). Antipsychotic agents can relieve insomnia and agitation in psychotic or delirious patients.
In rare instances where benzodiazepines are contraindicated (e.g., history of drug or alcohol dependence) and sedating antidepressants have not helped, antihistamines such as diphenhydramine may be used. However, the elderly and very young may experience delirium or paradoxical excitation from such drugs. Chloral hydrate should rarely be used, and there is almost never a place for treating new cases of insomnia with barbiturates, meprobamate, or over-the-counter remedies.
Psychotherapy and behavioral therapies may be used quite effectively in conjunction with medications for patients with psychiatric or stress-related problems. Cognitive and behavioral approaches, including education and support, stimulus control (attention to sleep hygiene), and sleep restriction therapy (gradual matching of time in bed to time asleep) can be combined with, and may be superior to, medication, especially in the elderly. Relaxation and biofeedback produce more modest improvements in sleep.
Melatonin use is associated with some beneficial effects when prescribed to treat jet lag. In a placebo-controlled study of flight crews, use at bedtime on return from overseas flying and nightly thereafter for several days proved superior to placebo in minimizing the symptoms of jet lag. Proper dosage and mechanism of action (hypnotic effect versus resynchronization of circadian rhythm) remain to be established. Until there is standardization and quality control of preparations (some is derived from pineal glands of cows) and until there are reliable data on optimal dosing and side effects, it is advisable to defer melatonin use. Case reports of depression, gynecomastia, vasoconstriction, and low sperm counts argue for caution in use.
Treatment of Insomnia in the Elderly.
The importance of cause-specific treatment is most poignantly experienced in caring for elderly persons with insomnia. In instances where the underlying cause is minor, emphasis on sleep hygiene (see below) and empathetic support are often the best course. Explanation on how the normal aging process affects sleep is appreciated by those wondering why they seem to sleep less. Sedatives should be used in reduced dose and with caution, if at all . Falls with catastrophic consequences (hip fracture, pulmonary embolization, disability, and death) are a major risk with sedative use in the elderly. The newer short-acting sedatives (see above) may be less likely to produce falls from motor incoordination or cognitive impairment during arousals than the older agents. When depression presents as difficulty sleeping, treatment should be etiologic and tailored to the special needs of older persons . Use of melatonin for chronic insomnia in the elderly has not been well studied, although the substance is widely used by patients because it can be obtained without prescription. The importance of adequate treatment of pain and any underlying medical problems cannot be overemphasized. Chronic pain should be addressed and effectively treated .
The overall promotion of good " sleep hygiene" is useful for many patients. Establishing a regular bed and wake time, avoiding any and all naps, having regular exercise (although not at night), using bed only for sleeping or lovemaking (rather than reading or watching TV), and getting in bed only when ready for sleep (leaving bed if sleep is not forthcoming) are useful suggestions. Avoidance of caffeinated foods, stimulants, cigarettes, and alcohol are necessary for some sensitive patients.
Instructing patients about these basic rules of sleep hygiene and helping them to avoid trying too hard to fall asleep are often useful. Disabusing patients of the myth that everyone must have 8 hours of sleep every night makes many people feel relieved. Also, informing patients that much of the time they spend in bed believing they are "only drowsy" is time actually spent in the lighter stages of sleep can ameliorate some patients' frustration.
If the insomnia is related to an underlying affective disorder, begin a sedating tricyclic antidepressant, such as nortriptyline (10 mg) or a selective serotonin reuptake inhibitor such as paroxetine 20 mg or mirtazepine 20 mg, taken an hour before bedtime every night for 2 weeks. See the patient frequently until symptoms resolve and increase the dose as needed to fully treat the depression.
If the insomnia is related to an anxiety disorder, use triazolam, starting at 0.125 mg qhs or zolpidem 10 mg when the main problem is falling asleep, or clonazepam (0.5 mg) or flurazepam (15 mg) at bedtime if daytime anxiety is present.
If symptoms recur after 2 weeks of treatment for anxiety-related insomnia, institute behavioral and relaxation therapies (see Chapter 226) and consider psychiatric consultation.
If the insomnia is related to a character disorder, seek psychiatric consultation, require close adherence to good sleep hygiene, and use benzodiazepines only with caution.
Make sure that a complete history of alcohol and substance use, including cigarettes, caffeine, nonprescription drugs, and stimulants, is obtained on every patient. Interview family members and obtain toxic screens of urine or blood when there is a doubt. Do not prescribe benzodiazepines for patients with current or past alcohol or drug use. Supervise withdrawal and abstinence, and seek psychiatric consultation when withdrawal symptoms or maintenance of abstinence is problematic.
Treat pain and underlying medical problems aggressively; a short course of benzodiazepines may help reestablish a normal sleep pattern in some patients.
Offer education and support to an elderly patient who has normal daytime function but who is lonely or upset as their sleep goes through the changes of normal aging.
Brzezinski A. Melatonin in humans. N Engl J Med 1997;336:186. (Comprehensive review that includes basic science review of melatonin' s contribution to sleep and the pharmacology of exogenous intake and its use.)
King AC, Oman RF, Brassington GS, et al. Moderate-intensity exercise and self-rated quality of sleep in older adults: a randomized controlled trial. JAMA 1997;227:32. (Evidence for exercise improving the quality of sleep.)
Kupfer DJ, Reynolds CF. Management of insomnia. N Engl J Med 1997;336:341. (Comprehensive review with excellent list of references.)
Lamberg L. Melatonin potentially useful but safety, efficacy remain uncertain. JAMA 1996;276:1011. (Review of its clinical use; cautionary note.)
Morin DM, Colecchi C, Steve J, et al. Behavioral and pharmacologic therapy for late life insomnia. JAMA 1999;281:991. (Good review of the data on treating insomnia in the elderly.)
NIH Technology Assessment Panel. Integration of behavioral and relaxation approaches into the treatment of chronic pain and insomnia. JAMA 1996:276:313. (Relaxation and biofeedback were found to be of only modest benefit for insomnia.)
Nowell PD, Mazumdar S, Buysse DJ, et al. Benzodiazepines and zolpidem for chronic insomnia: a meta-analysis of treatment efficacy. JAMA 1997;278:2170. (Both found to be effective given the data on hand, but available studies are limited in scope and duration.)
Reite M. Insomnia. In: Schatzberg AF, Nemeroff CH, eds. The American Psychiatric Press textbook of psychopharmacology, 2nd ed. Washington DC: APA Press, 1998. (Authoritative reference.)
Outlines in Clinical
Medicine on Physicians'
A. Normal Sleep
B. Causes of Insomnia 
C. Treatment of Insomnia [8,12] See outline "Sedatives"
D. Excessive Sleepiness
E. Narcolepsy 
F. Sleep Apnea 
Updated on: Oct 27, 2000
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