Pharmacologic management of chronic insomnia.

Abstract: Chronic insomnia is a common disorder that is under recognized, under diagnosed and under treated. Initial assessment should focus on identifying and treating, if present, any secondary causes of insomnia. Primary insomnia can be treated with behavioral and/or pharmacological therapy. A thorough sleep history can identify the type of insomnia present, its severity, and can consequently guide therapy. Behavioral therapy has been shown to be equivalent to or superior to pharmacologic therapy, at least in some patients. It is a reasonable initial approach, although there are barriers to its use. There are several pharmacologic agents available, some of which are more effective at reducing time to fall asleep and others for maintaining sleep. There is some evidence to indicate that combining the approaches may impair outcomes. There is little data on the long-term use of pharmacologic agents.

Key Words: insomnia, hypnotics

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Chronic insomnia affects about 10 to 15% of the US adult population. (1,2) Despite the common occurrence of insomnia, it is under recognized, under diagnosed, and as a result, under treated. (3) Roughly two thirds of patients who have symptoms of insomnia do not communicate this information to their physician and physicians may not always inquire about sleep patterns. (4)

The American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) defines insomnia as difficulty initiating or maintaining sleep or non-restorative sleep that causes clinically significant distress or impairment in social, occupational, or other important areas of functioning. (5) Insomnia lasting between one night and a few weeks is referred to as acute insomnia, while insomnia occurring at least three nights per week for one month or more is referred to as chronic insomnia. (6) Insomnia can be classified as primary or secondary. (6) Primary insomnia has no known pathogenesis, but evidence suggests a state of hyperarousal. Secondary insomnia is due to other causes, such as psychosocial stressors, poor sleep hygiene, medical conditions, and medication or substance use. This article will focus on the pharmacologic management of chronic primary insomnia. However, it should be noted that behavioral modification plays a significant role in the management of insomnia.

Pharmacological Therapy

Treatment of insomnia should address all components of insomnia, including sleep onset, sleep maintenance, sleep quality and next-day functioning. Identifying previous treatments and their outcomes would also prove useful. Polysomnograms may be useful for those who fail to respond to appropriate treatment. There are several medications for the treatment of insomnia (Table). The choice of medication is influenced by whether the patient is experiencing primarily sleep-onset insomnia or sleep maintenance insomnia.

Benzodiazepines 

Currently in the United States, there are five benzodiazepines approved for the short-term treatment of insomnia: flurazepam (Dalmane), estazolam (ProSom), quazepam (Doral), temazepam (Restoril), and triazolam (Halcion). Long-term studies beyond 6 months have not been reported. Benzodiazepines bind to the gamma subunit of the GAB[A.sub.A] receptor, also known as the benzodiazepine or omega receptor. These agents are differentiated by their pharmacokinetic properties. Flurazepam and quazepam have long half-lives due to their metabolites (48-120 h), estazolam and temazepam have intermediate half-lives (10-24 and 8-15 h, respectively), and triazolam has the shorter half-life (2-5 h). These agents are metabolized in the liver. Concomitant administration with alcohol or other CNS depressants can potentiate the CNS effects.

Benzodiazepines are associated with next day sedation, psychomotor impairment, and cognitive impairment. (7) All of these are of concern when these agents are used in the elderly, especially those with a longer half-life. Long-acting agents have also been associated with increased risk of falls resulting in hip fractures in the elderly as a result of residual sedation and impaired motor coordination and currently have a limited role in the management of insomnia. (8) Short-acting agents are associated with rebound insomnia and anterograde amnesia. (8) In addition, all benzodiazepines have the risk of patients developing tolerance, abuse, and dependence. (7,8) Benzodiazepines are pregnancy category X and thus are contraindicated in these patients. They are also not recommended in children for treating insomnia. They should be used with caution in patients with seizure disorders, respiratory depression, severe hepatic disease, or renal impairment. Starting doses for the short and intermediate agents are: estazolam 1 to 2 mg at bedtime, temazepam 15 mg 30 minutes before bed, and triazolam 0.25 mg at bedtime. Doses should be reduced by 50% in the elderly or those with hepatic impairment.

Trial data demonstrates that benzodiazepines produce significant subjective improvements in total sleep time, number of awakenings, and sleep quality as compared with placebo. (9,10) Results on sleep latency have been conflicting. Those agents with intermediate and long half-lives have been shown to reduce wake time after sleep onset and number of awakenings, which results in improved sleep maintenance. (9) Triazolam has a greater effect on sleep latency. (9)

Nonbenzodiazepines

Zolpidem. Zolpidem (Ambien) acts on the GABA[.sub.A] receptor benzodiazepine site. It has an onset of action of 30 minutes, a half-life of 2.5 hours and its effects will last for up to eight hours. (11) Zolpidem controlled release (Ambien CR) immediately releases 80% of the dose with the remainder being released 3 hours later. Zolpidem undergoes hepatic metabolism to inactive metabolites. Antiretroviral protease inhibitors may inhibit the metabolism of zolpidem resulting in excessive sedation. Likewise, alcohol and other CNS depressant drugs may have additive effects on psychomotor performance when used with zolpidem. Side effects are dose related and include drowsiness, amnesia, dizziness, headache, and gastrointestinal complaints. (11)

Zolpidem has not been evaluated for use in patients under the age of 18. Zolpidem controlled release is classified as pregnancy category C, while the regular release is category B. There are no adequate, well-controlled studies in pregnant women. Although there are no absolute contraindications, it should be used cautiously in patients with hepatic impairment, chronic obstructive pulmonary disease or depression. The recommended doses are 10 mg at bedtime in healthy adults and 5 mg in older patients, those with hepatic dysfunction or patients on another drug which causes CNS depression. For the extended release product, 12.5 mg or 6.25 mg should be used, respectively.

Zolpidem has been shown to produce similar effects on sleep latency and total sleep time with fewer next-day residual effects as compared with benzodiazepines. (9,12-14) It may also improve sleep efficiency (ratio of time asleep to time in bed), but it has not consistently shown improvement over placebo in reducing wake time after sleep onset or number of awakenings. Zolpidem's benefit in sleep seems to be a result of its effect on sleep onset rather than sleep maintenance. Zolpidem has been studied for up to 5 weeks of continuous use and for 12 weeks of intermittent use. (9,12-14) Short-term tolerance has not been noted in these studies. In addition, after discontinuation of zolpidem, rebound insomnia is rare with short-term use.

Zaleplon. Zaleplon (Sonata), like zolpidem, binds to the GAB[A.sub.A] receptor benzodiazepine site but with less affinity. It has an onset of action of 20 minutes, a half-life of 0.5 to 1 hour, and its effects will last about 4 hours. (15) It is primarily metabolized by the liver to inactive metabolites. Drugs that have CNS depressant effects (eg, alcohol, anxiolytics, barbiturates) may potentiate the CNS effects of zaleplon. Zaleplon contains tartrazine dye and thus should not be used in patients with an allergy to this dye. (15) Its safety has not been established in children. It is pregnancy category C with no studies in pregnant women. Zaleplon should be used cautiously in patients with depression or respiratory insufficiency and is not recommended for those with severe hepatic disease. The most common side effects include headache, drowsiness, dizziness, nausea, and dyspepsia. The recommended dose is 10 mg at bedtime, although 5 mg is recommended for the elderly, those with mild to moderate hepatic impairment or in patients taking another CNS depressant medication.

Zaleplon has been shown to be effective in reducing sleep latency as compared with placebo, but lacks data supporting it effects in maintenance of sleep when administered at sleep onset. (16,17) Zaleplon is useful for patients who have frequent nocturnal awakening because it can be taken in the middle of the night without causing next-day impairment, as long as it is taken 4 hours before time needed to awaken. (18)

Eszopiclone. Eszopiclone (Lunesta) is believed to interact with the GABA-receptor complex at binding domains close to the benzodiazepine receptor. Its pharmacologic properties are similar to those of benzodiazepines, including anxiolytic, hypnotic, and sedative activity. Eszopiclone has a half-life of 5 to 7 hours and a duration of about 8 hours. (19) Eszopiclone is hepatically metabolized to two metabolites, one with minimal potency and one which is inactive. Use of eszopiclone with alcohol or other CNS depressants may have additive effects. The most common side effects include bitter taste, dry mouth, drowsiness, and dizziness. (19) Its safety in children has not been established. Eszopiclone is pregnancy category C. There are no published reports on its use in pregnant women. It should be used with caution in patients with pre-existing respiratory depression or those with depression. (19) The starting dose is typically 2 mg at bedtime, although the dose can be titrated to 3 mg as needed. Elderly patients or those with severe hepatic impairment should begin with 1 mg. No dosage adjustment is necessary in mild to moderate hepatic impairment.

Eszopiclone has demonstrated a significant reduction in sleep latency and improved measures of sleep maintenance, such as wake time after sleep onset and number of awakenings as compared with placebo. (20-24) In addition, eszopiclone showed no evidence of clinically significant tolerance after 6 months of treatment and it has been studied for up to 12 months in an open-label extension trial. (20,24) This is the first sedative hypnotic with data to support its continuous use for up to 12 months.

Ramelteon. Ramelteon (Rozerem) is a highly selective agonist for the melatonin M[T.sub.1]/M[T.sub.2] receptors and the newest FDA-approved agent for insomnia. Melatonin is believed to mediate the circadian rhythm in mammals. It is also the first hypnotic agent that is not classified as a controlled substance. Ramelteon has an onset of action of 30 minutes and a half-life of 1 to 2 hours. (25) It is metabolized by the liver to several metabolites with varying degrees of activity, although they are much less potent than the parent compound. Concurrent administration with the SSRI fluvoxamine significantly increases the serum concentrations of ramelteon, and thus these medications should not be used together. Other medications that could inhibit the metabolism of ramelteon include agents such as ciprofloxacin, norfloxacin, and mexiletine. Without any data, the concomitant use of over-the-counter melatonin is not recommended. Alcohol does not directly affect ramelteon, but it may still result in additive effects on psychomotor performance. Potential adverse effects include somnolence, dizziness, nausea, fatigue and headache. (25) Serum prolactin increased in 32% of patients in one study. (25) Assessment of prolactin and testosterone concentrations should be considered in patients with unexplained amenorrhea, galactorrhea, decreased libido, or problems with fertility. Its use is contraindicated in children, nursing mothers, and those with severe hepatic disease. It is pregnancy category C with no well-controlled human studies. Ramelteon should be used cautiously in those with pre-existing neurologic disease, mild to moderate hepatic disease, endocrine disease, seizure disorder, or the elderly. (25) The recommended dose is 8 mg taken within 30 minutes of going to bed.

Ramelteon has been shown to be significantly more effective than placebo in reducing sleep latency, increasing total sleep time and sleep efficiency in studies for up to 5 weeks in duration. (26-31) Ramelteon had no effect on any behavioral and cognitive performance tests, and showed no potential for abuse.

Trazodone. Trazodone (Desyrel), an antidepressant with sedating properties, is commonly prescribed for the treatment of insomnia, although it lacks FDA approval for this use. It inhibits the reuptake of serotonin, [alpha]-adrenergic blocking action and modest histamine blockade. It is metabolized in the liver to inactive metabolites. It can interact with numerous medications, including other medications affecting serotonin (eg, selective serotonin reuptake inhibitors), other CNS depressants (eg, alcohol), ketoconazole, and itraconazole. The most common side effects include drowsiness, dry mouth, nausea, vomiting, constipation, headache and blurred vision. Trazodone is not approved for use in children and it is pregnancy category C. It should be used with caution in patients with hepatic or renal impairment. The recommended dose for treatment of insomnia is 50 mg at bedtime. If it is also being used for depression, higher doses will be used.

As an antidepressant, trazodone has the advantage of treating insomnia while treating concurrent conditions like depression or psychological disorders. In addition, trazodone offers a low cost potential for long-term use, and a low abuse potential. However, there is limited data from double-blind, controlled studies on its efficacy for treating insomnia. Trazodone has been shown to be effective in two small trials in patients with concurrent depression without concurrent hypnotic use. (32,33) Even though trazodone has shown subjective improvement in ease of falling asleep and quality of sleep, it has also been associated with negative effects on ease of awakening and feelings at or after wakening. Studies have also shown a decline in efficacy after one to two weeks of treatment, suggesting the potential for development of tolerance. (33,34) Side effects of trazodone include orthostatic hypotension and blurred vision which can lead to falls, especially in the elderly. Other side effects include nausea, dry mouth, constipation, drowsiness, and headache. Trazodone has also been associated with rebound insomnia after withdrawal.

Over-the-counter agents. Sedating antihistamines such as diphenhydramine are marketed as sleep aids to induce sleep. They are readily available and relatively inexpensive and thus are often used by patients. However, data on the use of these agents is sparse and of short duration and poor quality. (35,36) In addition, they are also associated with next-day sedation, anticholinergic side effects, psychomotor impairment and the development of tolerance. (37,38)

Melatonin and valerian are alternative therapies which are also readily available. Melatonin has been shown to induce sleep in healthy volunteers, elderly patients and those with insomnia. (39-42) Its effects on sleep maintenance are less impressive with conflicting results. (40,41) The studies have involved small numbers of subjects treated for short durations. It appears to be well tolerated, at least for short-term use. Valerian has been shown to reduce sleep latency, and improve sleep maintenance, although large, well-designed trials are lacking. (43) It may take 2 to 4 weeks before significant effects are seen. Side effects may include next-day sedation, headache, uneasiness and excitability. Without more data on its efficacy and safety, it is not recommended at this time.

Summary and Recommendations

Before the diagnosis of primary insomnia is made, any secondary causes should be identified and treated. A reasonable approach is to first begin with behavioral therapy. Clinicians may provide this therapy themselves or refer patients to a sleep specialist. Realizing when referral is needed is very important for the primary care physician. Referral is appropriate for chronic, resistant and/or unexplained insomnia. Recognize that not all patients will adequately respond to behavioral therapy as it may not be effective in all subsets of patients.

Despite the fact that long-term data is lacking, patients who do not respond to behavioral therapy may proceed to pharmacolgical therapy. Efficacy, tolerance and side effects will need to be closely monitored. The two approaches should generally not be combined since this may reduce the long-term benefit of behavioral therapy, although this recommendation is based on somewhat limited data. However, pharmacologic therapy may be considered for short-term use when initiating behavioral therapy, especially in those who would benefit from the more rapid results. Combination therapy could be considered in patients who are willing to comply with the behavioral therapies. Zolpidem, zaleplon or ramelteon should be considered for patients primarily suffering from sleep onset insomnia. Ramelteon is the least likely of these agents to cause cognitive or behavioral impairment with short-term use, but long-term differences are unknown. Eszopiclone or an intermediate-acting benzodiazepine (eg, estazolam, temazepam) would be appropriate for insomnia that is predominantly associated with sleep maintenance. Zaleplon can also be used for those suffering from sleep maintenance insomnia when taken in the middle of the night. Long-term use of hypnotic agents is largely unsupported at this time.

Further research is needed on the long-term effects of pharmacologic therapy, comparing pharmacologic agents to one another, to determine which patients benefit most from behavioral therapy, and to clarify the role of combining behavioral and pharmacological therapy. Strategies to improve the availability of behavioral therapy and primary care clinician training are also encouraged.

References

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James R. Taylor, PharmD, Cristina M. Vazquez, PharmD, MPH, and Kendall M. Campbell, MD

From the Department of Pharmacy Practice, University of Florida College of Pharmacy, and the Department of Community Health and Family Medicine, University of Florida College of Medicine, Gainesville, FL.

Reprint requests to James R. Taylor, PharmD, University of Florida College of Pharmacy, PO Box 100486, Gainesville, FL 32610-0486. Email: [e-mail]

Accepted July 13, 2006.

RELATED ARTICLE: Key Points

* Physicians should routinely inquire about patients' sleep habits as patients may not report these on their own.

* Any secondary causes of insomnia should be investigated and treated before a diagnosis of primary insomnia is made.

* Behavioral therapy has been shown to be equivalent to, or superior to pharmacologic therapy, at least in some patients, and is a reasonable initial approach, although there are barriers to its use.

* Zolpidem, zaleplon or ramelteon should be considered for patients primarily suffering from sleep-onset insomnia.

* Eszopiclone or an intermediate-acting benzodiazepine (eg, estazolam, temazepam) would be appropriate for insomnia that is predominantly associated with sleep maintenance. Zaleplon can also be used for those suffering from sleep maintenance insomnia when taken in the middle of the night.

Table. Pharmacologic agents for the treatment of insomnia

Drug                       Indication

Benzodiazepines
  Flurazepam (Dalmane)     Sleep maintenance insomnia
  Quazepam (Doral)         Sleep maintenance insomnia
  Estazolam (ProSom)       Sleep maintenance insomnia
  Temazepam (Restoril)     Sleep maintenance insomnia
  Triazolam (Halcion)      Sleep-onset insomnia
Nonbenzodiazepines
  Zolpidem (Ambien or      Sleep-onset insomnia
    Ambien CR)
  Zaleplon (Sonata)        Sleep-onset or sleep maintenance insomnia
  Eszopiclone (Lunesta)    Sleep maintenance insomnia
  Ramelteon (Rozerem)      Sleep-onset insomnia
  Trazodone (Desyrel)
  Over-the-counter agents
    (antihistamines)

Drug                       Comments

Benzodiazepines
  Flurazepam (Dalmane)     Improves total sleep time and number of
                             awakenings but has long half-life.
                             Anxiolytic effects may be useful in
                             patients with anxiety disorder. More
                             daytime residual effects.
  Quazepam (Doral)         Improves total sleep time and number of
                             awakenings but has very long half-life.
                             Anxiolytic effects may be useful in
                             patients with anxiety disorder. More
                             daytime residual effects.
  Estazolam (ProSom)       Improves total sleep time and number of
                             awakenings. Anxiolytic effects may be
                             useful in patients with anxiety disorder.
                             May cause daytime residual effects.
  Temazepam (Restoril)     Improves total sleep time and number of
                             awakenings. Anxiolytic effects may be
                             useful in patients with anxiety disorder.
                             May cause daytime residual effects.
  Triazolam (Halcion)      Improves total sleep time with greater
                             benefit on sleep latency. Anxiolytic
                             effects may be useful in patients with
                             anxiety disorder. Associated with rebound
                             insomnia.
Nonbenzodiazepines
  Zolpidem (Ambien or      Improves sleep latency with less of an effect
    Ambien CR)               on total sleep time. May improve sleep
                             efficiency and number of awakenings. Less
                             daytime residual effects and rebound
                             insomnia.
  Zaleplon (Sonata)        Improves sleep latency but lacks data on
                             improving sleep maintenance. Less daytime
                             residual effects and rebound insomnia.
  Eszopiclone (Lunesta)    Improves sleep latency, total sleep time and
                             number of awakenings. Less tolerance.
  Ramelteon (Rozerem)      Improves sleep latency, total sleep time and
                             sleep efficiency. No abuse potential.
  Trazodone (Desyrel)      Limited data for insomnia. May improve sleep
                             latency and quality of sleep. May be useful
                             in patients with depression. Low risk of
                             abuse.
  Over-the-counter agents  Modest, short-term improvements in total
    (antihistamines)         sleep latency, number of awakenings, total
                             sleep time, quality of sleep.