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Evidence-Based Reviews


When patients can’t sleep

Updated guide to workup and hypnotic therapy

Vol. 5, No. 1 / January 2006
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Careful investigation can often reveal insomnia’s cause1—whether a medical or psychiatric condition or poor sleep habits. Understanding why patients can’t sleep is key to effective therapy.

Insomnia is associated with increased risk of accidents, work-related difficulties, and relationship problems.2 Long-term sleeplessness may even increase risk of new psychiatric disorders—most notably major depression.3

Primary Insomnia

DSM-IV-TR criteria for primary insomnia include:4

  • For at least 1 month, the patient’s main complaint has been trouble going to sleep, staying asleep, or feeling unrested.
  • The insomnia or resulting daytime fatigue causes clinically important distress or impairs work, social, or personal functioning.
  • The insomnia does not occur solely in the course of a breathing-related or circadian rhythm sleep disorder, a parasomnia, or as part of another mental disorder such as delirium, generalized anxiety disorder, or major depressive disorder.

The International Classification of Sleep Disorders outlines discrete insomnia types that are unrelated to other medical, mental, or sleep disorders.5 These include, among others, adjustment sleep disorder and psychophysiologic insomnia.

Adjustment sleep disorder. Acute emotional stressors—such as bereavement, job loss, or hospitalization—can cause insomnia or daytime sleepiness. Symptoms typically remit soon after the stressors abate, so this insomnia usually lasts a few days (acute) to a few months (short-term). It can also become chronic, lasting3 months or longer.

Psychophysiologic insomnia. Once insomnia begins—regardless of its cause—sleep problems may persist well after precipitating factors resolve. The mechanism may be related to somatized tension and learned sleep-preventing associations (trying too hard to sleep and conditioned arousal to the bedroom). Thus, short-term insomnia may develop into long-term, chronic difficulty with recurring episodes or a constant, daily pattern of insomnia.

Treatment for both adjustment sleep disorder and psychophysiologic insomnia with behavioral therapies and hypnotics6 is warranted if:

  • sleepiness and fatigue interfere with daytime function
  • the patient is significantly distressed
  • a pattern of recurring episodes develops.5

Psychiatric Disorders and Insomnia

Depression. Up to 80% of depressed persons experience insomnia, although no one sleep pattern seems typical.7 Depression may be associated with:

  • difficulties in falling asleep
  • interrupted nocturnal sleep
  • early morning awakening.

Anxiety disorders. Generalized anxiety disorder (GAD), panic attacks, and posttraumatic stress disorder (PTSD) are associated with disrupted sleep. Patients with GAD experience prolonged sleep latency and fragmented sleep, similar to those with primary insomnia.

Some patients experience panic symptoms while sleeping, possibly in association with mild hypercapnia. Those patients tend to have earlier onset of panic disorder and a higher likelihood of comorbid mood and other anxiety disorders.8

In patients with PTSD, disturbed sleep continuity and increased REM phasic activity—such as eye movements—are directly correlated with PTSD symptom severity. Nightmares and disturbed REM sleep are hallmarks of PTSD.9

Workup of Sleep Complaints

The patient history is an important part of the evaluation and treatment of insomnia and other sleep disturbances (Algorithm).12

Acute. Many short-term insomnias—lasting a few weeks or less—are caused by situational stressors, circadian rhythm changes, or poor sleep hygiene (Table 1).1 A logical approach is to begin sleep hygiene measures and explore the patient’s life situation to uncover what might be causing the insomnia. Hypnotic agents may be considered if insomnia is associated with daytime sleepiness or occupational impairment or if it seems to be escalating and your assessment indicates that it is a primary condition.

Chronic. For longer-term insomnias—lasting more than a few months—consider a more thorough evaluation, including medical and psychiatric history, physical examination, and mental status examination. A differential assessment can be made on the basis of whether a patient has difficulty falling or staying asleep (Table 1). Ask about cardinal symptoms of disorders associated with insomnia, including:

  • snoring or breathing pauses during sleep (sleep apnea syndrome)
  • restlessness or twitching in the lower extremities (PLMD/RLS).

If possible, question the patient’s bed partner, who may be more aware of such symptoms than the patient.

Carefully review the patient’s weekday and weekend sleep patterns, bedtime habits, sleep hygiene habits, and substance and medication use.

Sleep clinic referrals. Consider an evaluation by a sleep disorders center when the diagnosis remains unclear or treatment of the presumed condition fails after a reasonable time.

Table 1

Possible causes of sleep complaints

Acute, transient

Recent or recurring stress

 

 

Change in sleeping environment

 

 

Acute illness or injury

 

 

New medications

 

 

Jet lag or shift change

 

Chronic

Difficulty staying asleep

Difficulty falling asleep

 

Medications

Poor sleep hygiene

 

Drug or alcohol use

Conditioned insomnia

 

Psychiatric disorder

Restless legs syndrome

 

Medical disorder

Circadian rhythm disorder

 

Sleep-disordered breathing

Advanced sleep-phase syndrome

 

Periodic limb movement disorder

 

 

Restless legs syndrome

 

Source: Adapted and reprinted with permission from reference 13

Behavioral Treatments

Behavioral treatments—with or without hypnotics—are appropriate for many insomnia complaints, including adjustment sleep disorder and psychophysiologic insomnia. Behavioral measures may work more slowly than drug therapy, but their effects have been shown to last longer in patients with primary insomnia. It may be useful to start with both hypnotic and behavioral treatments and withdraw the hypnotic after behavioral measures take effect.

Sleep hygiene. Many individuals unknowingly engage in habits that impair sleep. Those with insomnia, for example, often try to compensate for lost sleep by staying in bed later in the morning or by napping, which further fragment nocturnal sleep. Advise these patients to adhere to a regular awakening time—regardless of how long they slept the night before—and to avoid naps. Other tips for getting a good night’s sleep are outlined in Table 2.14

Caffeine has a plasma half-life of 3 to 7 hours, although individual sensitivity varies widely and caffeine’s erratic absorption can prolong its effects. Advise patients with insomnia to avoid caffeine-containing beverages—including coffee, tea, and soft drinks—after noon.

Relaxation training. Muscle tension can be reduced through techniques such as electromyography (EMG) biofeedback, abdominal breathing exercises, or progressive muscle relaxation. Relaxation training is usually effective within a few weeks.

Psychological counseling. Counseling can help identify and dispel tension-producing thoughts that may be disrupting sleep, such as preoccupation with unpleasant work experiences or school examinations. Reassurance may help patients overcome fears about sleeplessness; suggest that they deal with anxiety-producing thoughts during counseling sessions and at times other than bedtime.

Table 2

How to get a good night’s sleep

  • Maintain a regular waking time, regardless of amount of sleep the night before
  • Avoid excessive time in bed
  • Avoid naps, except if a shift worker or elderly
  • Spend time in bright light while awake
  • Use the bed only for sleeping and sex
  • Avoid nicotine, caffeine, and alcohol
  • Exercise regularly early in the day
  • Do something relaxing before bedtime
  • Don’t watch the clock
  • Eat a light snack before bedtime if hungry

Prescribing Hypnotics

Sedative-hypnotics are indicated primarily for short-term insomnia management. Most are used at bedtime until insomnia dissipates or the physician advises the patient to take a break.

Treatment principles. Because many insomnias are recurrent, prolonged hypnotic treatment given in short bouts is often optimal. Longer treatment—months to years—is clearly needed by a few patients with chronic insomnia. In these cases, carefully monitor for tolerance, as manifested by dosage escalation. Hypnotic treatment is generally not suitable for patients with drug abuse or dependence histories.

Although chloral hydrate and barbiturates are effective hypnotics, adverse effects limit their safety and usefulness. Benzodiazepines and more recently introduced agents have milder side-effect profiles (Table 3). Choose agents based on the patient’s situation, preferences, and effects of prior trials with similar agents. Guidelines for hypnotics discourage chronic use to minimize abuse, misuse, and habituation (Table 4).

Elimination half-life is one of the most important pharmacological properties that differentiates the hypnotics from each other:15

  • longer half-life: flurazepam, quazepam
  • intermediate half-life: estazolam, temazepam, eszopiclone
  • short half-life: triazolam, zolpidem, zolpidem ER, zaleplon, ramelteon.

Hypnotic agents with relatively longer halflives tend to be associated with greater potential for residual daytime effects such as sedation, motor incoordination, amnesia, and slowed reflexes. These effects may impair performance and increase the risk of auto accidents and injuries, especially hip fractures in the elderly.

Benzodiazepine receptor agonists. Of the all the drugs in class, zalepon—because of its ultra-short half-life—is least likely to cause residual daytime effects when administered at bedtime. At 10-mg doses, its side effects seem to last no more than 4 hours after administration. Zaleplon can be safely taken after nocturnal awakenings if the patient remains in bed 4 hours or longer after taking it.17

An ultra-short half life is less desirable for patients with difficulty with sleep initiation and discontinuous sleep throughout the night. For them, longer elimination half-life agents—such as zolpidem, zolpidem extended release (ER), and eszopiclone—may be more predictably effective for the entire night.18

Short half-life hypnotics do not offer anxiolysis for patients with daytime anxiety, as the longer half-life agents do.

Zolpidem ER and eszopiclone do not have a limitation imposed on duration of use. Although zolpidem ER has not been investigated in controlled trials greater than 3 weeks, eszopiclone was evaluated during a 6-month study that demonstrated lack of tolerance during the entire period, and lack of rebound after rapid discontinuation.19 Eszopiclone is the only hypnotic indicated for long-term (lasting > 3 weeks) insomnia.

Melatonin receptor agonists. Ramelteon’s activity at MT1 and MT2 receptors is believed to contribute to its sleep-promoting properties. This agent has been found to reduce sleep latency,20,21 and it is indicated to treat insomnia characterized by sleep-onset delays. Although controlled, longterm studies are lacking, ramelteon does not have a limit on duration of use. It demonstrated a lack of abuse liability when compared with triazolam and placebo in subjects with a history of sedative/hypnotic or anxiolytic drug abuse.22

Tolerance and rebound. Tolerance can develop after repeated dosing with benzodiazepines—primarily triazolam—and rebound insomnia can follow abrupt discontinuation. Both can be minimized by using benzodiazepines at the lowest effective dosages and for brief periods. Gradual tapering when discontinuing the drug can help control rebound.

Tolerance and rebound seem to be less of a concern with the newer hypnotics than with benzodiazepines, as shown by controlled studies of eszopiclone19, zolpidem23, and zaleplon.24 However, periodic re-evaluation is still the prudent clinical standard for hypnotics prescribed over long periods of time.

Table 3

Actions and available doses of common hypnotics

Class/drug

Onset of action

Half-life (hrs)

Active metabolites

Doses (mg)

Benzodiazepines

  Flurazepam

Rapid

40 to 250

Yes

15, 30

  Quazepam

Rapid

40 to 250

Yes

7.5, 15

  Estazolam

Rapid

10 to 24

Yes

0.5, 1, 2

  Temazepam

Intermediate

8 to 22

No

7.5, 15

  Triazolam

Rapid

<6

No

0.125, 0.25, 0.5

Imidazopyridine

  Zolpidem

Rapid

2.5

No

5, 10

  Zolpidem ER

Rapid

2.5

No

6.25, 12.5

Pyrazolopyrimidines

  Zaleplon

Rapid

1

No

5, 10, 20

Cyclopyrrolone

  Eszopiclone

Rapid

6

Minor

2,3

Melatonin receptor agonist

  Ramelteon

Rapid

1 to 2.6

No

8

Table 4

Guidelines for safe use of hypnotics

  • Define a clear indication and treatment goal
  • Prescribe the lowest effective dose
  • Individualize the dose for each patient
  • Use lower doses with a CNS depressant or alcohol
  • Consider dose adjustment in the elderly and in patients with hepatic or renal disease
  • Avoid in patients with sleep apnea syndrome, pregnancy, and history of abuse
  • Limit duration of use
  • Consider intermittent therapy for patients who need longer-term treatment
  • Taper doses to avoid abrupt discontinuation
  • Re-evaluate drug treatment regularly; assess both efficacy and adverse effects

Nonhypnotic Sleep AIDS

Sedating antidepressants. Some physicians prescribe low doses of sedating antidepressants to control insomnia, a practice supported by controlled clinical trials of some tricyclic antidepressants (TCAs) such as doxepin,25 trazodone,26 and trimipramine.27 Some physicians also advocate using more-sedating antidepressants—at dosages needed to treat depression—to control insomnia in depressed patients.

Evening dosing can minimize daytime sedation. If you choose an activating antidepressant, the potential side effect of insomnia can be managed by judicious use of hypnotic agents. Little is known about antidepressants’ effects on sleep quality after the first 6 to 8 weeks of treatment.28

Although possibly helpful as sleep aids, TCAs are associated with anticholinergic effects such as dry mouth, urinary flow difficulties, and cardiac dysrhythmias.

Alcohol. Patients with insomnia sometimes selfmedicate with alcohol at bedtime because it enhances sleepiness and induces a more rapid sleep onset.29 Drinking a “nightcap” is a poor choice, however, because alcohol can impair sleep quality, resulting in daytime somnolence. Alcohol is also associated with rapid development of tolerance.

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