Determining the underlying cause of insomnia is important when developing an effective treatment plan.

Approximately one third of adult Americans have significant insomnia at some time during their life.^1-3 Transient insomnia related to situational factors affects nearly 85% of the US population at some time.⁴ Although insomnia may begin at any age, it is more common in elderly individuals and in women.^5,6

Although an occasional sleepless night is not harmful, prolonged wakefulness results in an impaired ability to perform complex tasks consistently. Patients with chronic insomnia also complain of daytime fatigue, feel bad on awakening, and are often tense, lonely, and sad. The distressing effects of insomnia may cause patients to seek help from their physician.

Causes of Insomnia
Insomnia is a symptom, and its proper treatment depends on finding the cause of sleeplessness and treating the underlying etiology. For example, insomnia is treated differently when it is due to depression than when it is due to dyspnea related to congestive heart failure.

The most common type of insomnia is transient insomnia due to acute situational factors. Typical factors include stress, attempting to sleep in a new place, changes in time zones, and changing bedtimes due to shift work. Chronic insomnia is most commonly caused by psychiatric disorders such as dysthymia (mood disorder), depression, anxiety disorders, and substance abuse.

Numerous medical disorders can cause insomnia that is a result of pain, nausea, paresthesia, dyspnea, gastroesophageal reflux, anxiety, and fear of death. In the elderly, seriously fragmented sleep may be a sign of delirium. Other less common causes of insomnia are sleep apnea and myoclonus (spasm or twitching of muscles).

Many drugs have been implicated as causing insomnia (Table 1). At times, it is difficult to know whether insomnia is due to a medication prescribed for an illness or to the underlying illness itself. For example, dyspnea due to asthma may cause insomnia, but theophylline is also a potential cause.

General Treatment Principles
The underlying cause or causes of insomnia should be treated whenever possible. Pain should be treated with analgesics. Depression should be treated with antidepressants. Gastroesophageal reflux should be treated with elevation of the head of the bed, antacids, and/or histamine H2-receptor antagonists. Specific appropriate treatments are selected for each underlying etiology.

General measures to promote sleep may also be helpful. Patients should be encouraged to go to bed at the same time each night, avoid excessive napping, avoid exercise near bedtime (regular daytime exercise is helpful), and maintain a comfortable temperature and level of light and noise in the bedroom.

Patients should get out of bed if they are not asleep in an hour, engage in quiet, nonstimulating activity, and return to bed when sleepy. In order to promote an association between going to bed and sleeping, the bed should be used only for sleep and sexual activity. Other activities, such as reading and watching television, should be done elsewhere.

Relaxation techniques may be helpful to some patients, particularly compulsive patients who ruminate when they go to bed. More serious psychologic concerns may require psychotherapy and/or treatment with psychotropic medications.

Pharmacotherapy
The primary indication for use of hypnotic agents in patients with insomnia is transient sleep disruption caused by acute stress. In properly chosen patients, these agents can effectively avoid the consequences of insufficient sleep (irritability, daytime drowsiness, exhaustion, and reduced alertness). In patients with chronic insomnia and marked variability in morning awakenings, sedatives usually are not recommended, and they should be avoided in patients with a history of chemical dependency because of the risk of relapse.

Benzodiazepines are the most commonly prescribed hypnotic drugs. Other agents that have been used for insomnia are zolpidem, zaleplon, trazodone, chloral hydrate, and melatonin.

Benzodiazepines
The major benzodiazepines are compared in Table 2. Clorazepate, flurazepam, diazepam, and quaz-epam are absorbed quickly from the gastrointestinal tract, and reach peak plasma levels within a short time; therefore, onset of sleep is rapid. Excessive drug accumulation may occur with flurazepam, which is an older agent. Benzodiazepines that are absorbed more slowly should be taken 1 to 2 hours before sleep is desired, which is a decided disadvantage compared with rapidly absorbed agents.

Table 2. Comparison of properties of various benzodiazepines.

An additional factor influencing selection of agents is metabolism. Triazolam may be a good initial choice in patients who have difficulty falling asleep; because of a short half-life, it is quickly eliminated and causes no next-day sedation. Reported effects of disinhibition and confusion have led to concerns about triazolam and efforts to ban its use, but many clinicians have seen great success and few problems with this agent.

All benzodiazepines are metabolized through conjugative mechanisms, and most are also metabolized through oxidation. Oxidation declines with age and liver dysfunction; thus, inordinate drug accumulation with resultant sedation may occur. However, lorazepam, oxazepam, and temazepam are eliminated by conjugative mechanisms only; the metabolism of these benzodiazepines is therefore less severely affected by age and liver dysfunction. Excessive accumulation of these agents because of metabolic insufficiency is less likely, making them particularly useful in elderly patients. In elderly patients, the recommended initial dose of all benzodiazepines is half that prescribed for younger patients.

Although benzodiazepines are well tolerated and safe, they can cause side effects that should be considered in prescribing. Daytime drowsiness and resultant performance deficiencies can be adverse consequences of benzodiazepine use. For example, in one study,⁷ 45% of patients who received flurazepam showed a decline in cognitive test scores the next day. Corresponding decrements in test scores were found in 13% of patients after a 30-mg dose of triazolam, but 0.25 mg of triazolam did not produce morning deficits.⁷ Quazepam has been found to produce somewhat less somnolence.⁸ Daytime drowsiness is found with all agents given in repeated doses, and is especially prominent with agents that have a long half-life. Thus, knowledge of the elimination half-life of various benzodiazepines is helpful when selecting an agent for a given patient.

Age is another factor that affects unwanted sedation. Elderly patients are particularly vulnerable to sedative effects, which must be carefully avoided because of the high occurrence of falls resulting in hip fractures and other injuries. Long-acting benzodiazepines are especially dangerous in this regard.

Memory impairment caused by benzodiazepines relates to cognition that requires conscious recall; the acquisition and storage of information are the factors adversely affected. The extent of memory interference depends on patient age, route of administration, dose, and pharmacokinetics of the particular agent.

Rebound insomnia is commonly induced by long-term use, especially of short-acting benzodiazepines. For several nights after discontinuation of a continuously used agent, sleep worsens. Longer times are required for sleep onset, more wakefulness is experienced throughout the night, and the total amount of sleep is diminished. Rebound insomnia is dose-dependent. Abrupt termination of a benzodiazepine, especially after prolonged use of high doses, vastly increases vulnerability to poor sleep for several nights. The phenomenon is greatly ameliorated by slowly tapering off the dose and by limiting the duration of use.

Zolpidem
Zolpidem is a nonbenzodiazepine imidazopyridine hypnotic agent that binds selectively to the benzodiazepine or omega brain receptor. It is rapidly absorbed and has a short half-life and rapid onset of action. Metabolites of zolpidem are inactive and eliminated through the kidneys.

Zolpidem is available in 5- and 10-mg tablets. The 10-mg tablet is used most often, but elderly or medically ill patients are given the 5-mg tablet at night.

Zolpidem is not a drug of abuse potential. In general, it does not impair cognitive ability or psychomotor performance the morning after nocturnal dosing. Sleep studies demonstrate decreases in REM sleep without significant alterations of other sleep stages.⁹ This, plus the absence of significant abuse potential, may be advantages over benzodiazepines.

Side effects of zolpidem are mild and most often consist of headache, nausea, and drowsiness. Rebound symptoms on withdrawal have not been observed; however, this medication is considerably more expensive than most other options.

Zaleplon
Zaleplon is a nonbenzodiazepine pyrazolopyrimidine hypnotic agent that, like zolpidem, binds selectively to the benzodiazepine or omega brain receptor; however, unlike zolpidem, zaleplon is ultra-short-acting; it has an elimination half-life of 1 hour.¹⁰

Unlike benzodiazepines, zaleplon appears to increase slow-wave sleep and shorten slow-wave sleep latency,¹¹ thereby increasing the efficiency of sleep. These characteristics, along with an ultra-short half-life, are considered the main features of zaleplon. Zaleplon is well tolerated,¹¹ and has little or no potential for abuse.

Trazodone
Marketed as an antidepressant, trazodone is an inexpensive triazolopyridine derivative that improves sleep in depressed patients and also in nondepressed patients with insomnia. A 100-mg dose is commonly used as a nocturnal soporific (an agent that produces sleep). Half this dose is recommended for most elderly patients.

Trazodone has a short half-life and significantly increases deep sleep without greatly affecting normal sleep architecture. Morning sedation after nighttime dosing may be a problem in some patients. Tolerance usually does not develop, and addiction is not a clinical concern.

Although trazodone lacks significant anticholinergic effects, it has alpha-adrenolytic properties that can precipitate orthostatic hypotension, resulting in falls, especially in older patients. Rarely, its use causes priapism (a prolonged, painful erection).

Chloral Hydrate
Introduced in the latter half of the 19th century, chloral hydrate is an inexpensive agent that quickly induces sleep. The mechanism of action is unknown. It has a half-life of about 8 hours. Doses usually range from 500 to 2,000 mg.

The most common adverse effects are gastrointestinal upset and diarrhea. Use of this drug is usually limited to no more than 2 weeks because of the rapid development of tolerance and risk of habituation. Nevertheless, chloral hydrate is useful for stress-related, transient insomnia (as a sedative the night before surgery).

Melatonin
Melatonin is a hormone produced by the pineal gland, a tiny gland in the brain. Melatonin secretion from the pineal gland is synchronized with dusk and offset by dawn. It is heavily regulated by circadian (rhythmic) processes, including both day-night cycles and seasonal changes.

Over-the-counter melatonin is sometimes used as a hypnotic, but experience with the agent is limited because of its short time on the market. One double-blind, placebo-controlled study found that 5 mg of melatonin significantly increases sleep propensity.¹²

Investigational Agents
Ramelteon represents the first truly novel mechanism of action for a drug in the area of sleep research in many years. Ramelteon specifically targets the MT1 and MT2 receptors (sleep receptors) in the brain, which are believed to be critical in the regulation of the body’s sleep-wake cycle. In the clinical research program for ramelteon, which has included more than 4,200 patients, the drug appears to be effective and safe.^13,14

Tiagabine, a gamma-aminobutyric acid (GABA) reuptake inhibitor, is used as an antiepileptic compound. In a pilot study, tiagabine has been shown to increase sleep efficiency and levels of delta sleep in aging adults.¹⁵ In a more extensive investigation with 26 subjects,¹⁶ bedtime administration of tiagabine produced a significantly greater amount of total sleep time than placebo, and less wake after sleep onset as compared with placebo.

John D. Zoidis, MD, is a contributing writer for Sleep Review.

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