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When patients can’t sleep Practical guide to using

Karl Doghramji, MD areful investigation can often Professor of psychiatry and human behavior reveal ’s cause1—whether Director, Sleep Disorders Center a psychiatric or medical condition Thomas Jefferson University or poor sleep habits. Understanding why patients Philadelphia C can’t sleep is key to effective therapy. Acute and chronic sleep deprivation is associ- ated with measurable declines in daytime perfor- Tips to effective workup mance (Box). Some data even suggest that long- term sleeplessness increases the risk of new psychi- and treatment of insomnia— atric disorders—most notably major depression.3 whether acute or chronic PSYCHIATRIC DISORDERS AND INSOMNIA and associated with almost any Depression. Many depressed persons—up to 80%—experience insomnia, although no one psychiatric or medical disorder. sleep pattern seems typical.2 Depression may be associated with: • difficulties in falling asleep • interrupted nocturnal sleep • and early morning awakening. Anxiety disorders. Generalized anxiety disorder (GAD), social phobia, panic attacks, and post- traumatic stress disorder (PTSD) are all associat- ed with disrupted sleep. Patients with GAD

40 VOL. 2, NO. 5 / MAY 2003 and choosing therapy

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Box have disrupted sleep patterns. These include The sleepless society: prolonged sleep latency, fragmented sleep with Chronic insomnia’s impact frequent arousals, decreased slow-wave sleep, variable REM latency, and decreased REM ne-half of adult Americans experience insomnia rebound after sleep deprivation. Despite Oduring their lives, and 10% report persistent sleep investigations going back to the 1950s, no spe- difficulties (longer than 2 weeks). Individuals who cific link between REM sleep and psychosis complain of insomnia report: has been found.6 Interestingly, increases in • daytime drowsiness REM sleep time and REM activity have been • diminished memory and concentration associated with an increased risk of suicide in • depression patients with schizophrenia.7 • strained relationships Adjustment sleep disorder. Acute emotional • increased risk of accidents stressors—such as bereavement, job loss, or • impaired job performance. hospitalization—often cause adjustment sleep disorder. Symptoms typically remit Despite these complaints, a surprising 70% of those with insomnia never seek medical help. Only 6% soon after the stressors abate, so this tran- visit their physicians specifically for insomnia, and sient insomnia usually lasts a few days to a 24% address sleep difficulty as a secondary complaint. few weeks. Treatment with behavioral ther- Many (40%) self-medicate with over-the-counter sleep apies and hypnotics8 is warranted if: aids or .2 • sleepiness and fatigue interfere with Insomnia becomes more frequent with aging, daytime functioning associated with increased rates of medical and • a pattern of recurring episodes psychiatric illness and an age-related deterioration develops.9 in the ’s sleep-generating processes.3 Psychophysiologic insomnia. Once initiat- ed—regardless of cause—insomnia may persist well after its precipitating factors experience prolonged sleep latency (time needed resolve. Thus, short-term insomnia may develop to fall asleep after lights out) and fragmented into long-term, chronic difficulty with recurring sleep, similar to those with primary insomnia. episodes or a constant, daily pattern of insomnia. Subjective sleep quality may be impaired in Sufferers often spend hours in bed awake focused patients with social phobia. Some patients expe- upon—and brooding over—their sleeplessness. rience panic symptoms while sleeping, possibly in which in turn further aggravates their insomnia. association with mild hypercapnia. Patients with Adjustment sleep disorder and psychophysio- sleep panic attacks tend to have earlier onset of logic insomnia are included within DSM-IV’s and a higher likelihood of comor- term “primary insomnia.” bid mood and other anxiety disorders.4 In patients with PTSD, disturbed sleep con- OTHER CAUSES OF INSOMNIA tinuity and increased REM phasic activity—such Medications that may affect sleep quality include as eye movements—are directly correlated with (Table 1),10,11 antihypertensives, severity of PTSD symptoms. Nightmares and antineoplastic agents, bronchodilators, stimulants, disturbed REM sleep are hypothesized hallmarks corticosteroids, decongestants, diuretics, hista- of PTSD.5 mine-2 receptor blockers, and smoking cessation Schizophrenia. Patients with schizophrenia often aids.

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Recreational drugs, such as Table 1 , often cause insomnia. Antidepressants’ effects on sleep and wakefulness and can cause insomnia following long- Activating , , most selective term use and during withdrawal. agents reuptake inhibitors, , monoamine Other disorders known to dis- oxidase inhibitors turb sleep include periodic limb Sedating , , , nefazodone, movement disorder (PLMD), agents , restless legs syndrome (RLS), Neutral , sleep apnea syndrome, disrupted agents circadian rhythms (as with travel or shift work), cardiopulmonary disorders, chronic pain, diabetes, hyperthyroidism, hot flashes associated with Carefully review sleep patterns on weekdays and menopause, seizures, dementia, and Parkinson’s weekends, bedtime habits, sleep hygiene habits, disease, to name a few. and substance and medication use. Sleep clinic referrals. Consider an evaluation by a WORKUP OF SLEEP COMPLAINTS sleep disorders center when: Acute. Most short-term insomnias—lasting a few • the diagnosis remains unclear weeks or less—are caused by situational stressors, • or treatment of the presumed conditions circadian rhythm alterations, and sleep hygiene fails after a reasonable time violations. A logical initial approach, therefore, is to combine sleep hygiene measures with support- BEHAVIORAL TREATMENTS ive psychotherapy. Hypnotic agents may be con- Behavioral treatments—with or without hyp- sidered for apparent daytime consequences—such notics—are appropriate for a wide variety of as sleepiness and occupational impair- insomnia complaints, includ- ment—or if the insomnia seems ing adjustment sleep disorder, to be escalating. psychophysiologic insomnia, and Chronic. For longer-term insom- Behavioral measures depression. Behavioral measures may nias—lasting more than a few take longer to take longer to implement than drug ther- weeks—consider a more thor- implement but last apy, but their effects have been shown to ough evaluation, including longer than drug last longer in patients with primary insom- medical and psychiatric history, therapy nia. In many cases, it may be useful to start physical examination, and men- with both hypnotic and behavioral treat- tal status examination. Inquire ments and withdraw the hypnotic after about cardinal symptoms of disorders associated behavioral measures take effect. with insomnia, including: Sleep hygiene. Many individuals unknowingly • snoring or breathing pauses during sleep engage in habitual behaviors that impair sleep. (sleep apnea syndrome) Those with insomnia, for example, often try to • restlessness or twitching in the lower compensate for lost sleep by staying in bed later extremities (PLMS/RLS). in the morning or by napping, which further Question the bed partner, who may be more fragment nocturnal sleep. Advise these patients to aware of such symptoms than the patient. adhere to a regular awakening time—regardless continued on page 47

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continued from page 43 of how long they slept the night before— Table 2 and to avoid naps. Other tips for getting a How to get a good night’s sleep good night’s sleep are outlined in Table 2.12 Caffeine has a plasma half-life of 3 to • Maintain a regular waking time, regardless of 7 hours, although individual sensitivity amount of sleep the night before varies widely and caffeine’s erratic • Avoid excessive time in bed absorption can prolong its effects. Advise • Avoid naps, except if a shift worker or elderly patients with insomnia to avoid caffeine- • Spend time in bright light while awake containing beverages—including coffee, tea, and soft drinks—after noon. • Use the bed only for sleeping and sex Relaxation training. Muscle tension can be • Avoid , caffeine, and alcohol reduced through electromyography • Exercise regularly early in the day (EMG) biofeedback, abdominal breath- • Do something relaxing before bedtime ing exercises, or progressive muscle relax- • Don’t watch the clock ation techniques, among others. • Eat a light snack before bedtime if hungry Relaxation training is usually effective within a few weeks. Psychotherapy. Cognitive-behavioral therapy can help identify and dispel tension-pro- dard textbooks but is clearly needed by a small ducing thoughts that are disrupting sleep, such as number of patients with chronic insomnia. In preoccupation with unpleasant work experiences these cases, carefully monitor for tolerance, as or school examinations. Reassurance may help manifested by dosage patients overcome fears about escalation. Long-term hyp- sleeplessness; suggest that patients notic treatment is not suitable deal with anxiety-producing Prolonged hypnotic for patients with drug abuse or thoughts during therapy sessions treatment given in dependence histories. and at times other than bedtime. Although hydrate and barbi- short bouts is often Insight-oriented psychotherapy turates are effective hypnotics, adverse best for recurrent may enhance patients’ awareness of effects limit their safety and usefulness. psychological conflicts from their insomnias and more recently past that may be producing anxiety introduced agents have milder side and contributing to sleeplessness. effect profiles (Table 3). Choose agents based on the patient’s situa- PRESCRIBING HYPNOTICS tion, preferences, and effects of prior trials with -hypnotics are indicated primarily for similar agents. Guidelines for hypnotics discour- short-term management of insomnia. Most are age chronic use to minimize abuse, misuse, and used prophylactically at bedtime until insomnia habituation (Table 4). dissipates or the physician advises the patient to Elimination half-life is the primary pharma- take a break. cokinetic property that differentiates the hyp- Treatment principles. Because many insomnias are notics from each other:13 recurrent, prolonged hypnotic treatment given in • longer half-life: , short bouts is often optimal. Longer treatment— • intermediate half-life: , months to years—is not recommended by stan-

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Table 3 Actions and available doses of common hypnotics

Class/drug Onset Half-life Active Doses of action (hrs) (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 Rapid <6 No 0.125, 0.25, 0.5

Imidazopyridine Rapid 2.5 No 5, 10

Pyrazolopyrimidine Rapid 1 No 5, 10, 20

• short half-life: triazolam, zolpidem, zale- the patient remains in bed 4 hours or longer after plon (Table 3). taking it.14 Whereas benzodiazepines bind to benzodiaze- Some patients feel that taking zaleplon only pine receptor types 1 and 2, zolpidem and zalep- when needed allows them to use hypnotics more lon (and possibly quazepam) bind selectively to sparingly. On the other hand, zaleplon’s ultra- type 1. This selectivity may explain why zolpi- short half-life makes it less dem and zaleplon are more eas- useful for patients who have fre- ily tolerated. quent episodes of sleep-interrup- Hypnotic agents with rela- Drinking alcohol tion insomnia every night. For them, a tively longer half-lives tend to be at bedtime can longer elimination half-life agent such associated with greater potential impair sleep quality, as zolpidem may be more predictably for residual daytime effects such resulting in daytime effective for the entire night.15 Short half- as sedation, motor incoordina- drowsiness life hypnotics have many advantages, but tion, amnesia, and slowed reflex- they do not offer anxiolysis for patients es. These effects may impair per- with daytime anxiety, as the longer half- formance and increase the risk of auto accidents life agents do. and injuries, especially hip fractures in the Tolerance and rebound. Tolerance can develop fol- elderly. lowing repeated dosing with benzodiazepines— . Because of its ultra-short primarily triazolam—and rebound insomnia can half-life, zaleplon is least likely to cause residual follow abrupt discontinuation. Despite wide- daytime effects when administered at bedtime. At spread concerns, neither tolerance nor rebound 10-mg doses, its side effects seem to last no more insomnia has been well documented. Never- than 4 hours following administration. Zaleplon theless, both can be minimized by using benzodi- can be safely taken after nocturnal awakenings if azepines at the lowest effective dosages and for

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brief periods. Gradual tapering when Table 4 discontinuing the drug can help con- Guidelines for safe use of hypnotics trol rebound. Tolerance and rebound seem to be • Define a clear indication and treatment goal less of a concern with the newer • Prescribe the lowest effective dose hypnotics than with benzodiazepines. • Individualize the dose for each patient In preliminary uncontrolled trials, • Use lower doses with a CNS or alcohol zolpidem and zaleplon did not show evidence of these problems in 1 year of • Consider dose adjustment in the elderly and in patients with hepatic or renal disease continued use. • Avoid in patients with sleep apnea syndrome, pregnancy, and history of abuse NONHYPNOTIC SLEEP AIDS • Limit duration of use Sedating antidepressants. Physicians often prescribe low doses of sedating • Consider intermittent therapy for patients who antidepressants to control insomnia, a need longer-term treatment practice supported by some controlled • Taper doses to avoid abrupt discontinuation clinical trials. For example, poly- • Re-evaluate drug treatment regularly; assess both somnography showed that patients who efficacy and adverse effects took doxepin, 25 to 50 mg at bedtime, had enhanced sleep efficiency (ratio of time slept to time spent in bed) yet no change in Alcohol. Patients with insomnia often self-med- sleep latency. abnormalities, leukopenia, icate with agents that are not specifically indicat- and thrombopenia developed in a few patients.16 ed to induce sleep. Alcohol is widely used at bed- Controlled studies have also shown subjective time because it enhances sleepiness and induces efficacy of trazodone17 and trimipramine18 in treat- a more rapid sleep onset.20 Drinking a “nightcap” ing insomnia. is a poor choice, however, because alcohol— Some physicians advocate using the more especially after prolonged use—can impair sleep sedating antidepressants—at dosages needed to quality, resulting in daytime somnolence. treat depression—to control insomnia in Alcohol is also associated with rapid develop- depressed patients. Evening dosing can minimize ment of tolerance. daytime sedation. If you choose an activating Patients who use alcohol report unrefreshing , the potential of insom- and disturbed sleep, with frequent nocturnal awak- nia can be managed by judicious use of hypnotic enings even after prolonged abstinence. Alcohol agents. Little is known about antidepressants’ also can further impair sleep-related respiration in effects on sleep quality after the first 6 to 8 weeks patients with obstructive sleep apnea syndrome. of treatment.19 and over-the-counter prod- Although possibly helpful as sleep aids, anti- ucts whose main active ingredients are antihista- are also associated with side effects. mines—such as and diphenhy- Trazodone, for example, may cause daytime dramine—can cause unpredictable efficacy and sedation, , and . side effects such as daytime sedation, confusion, As a class, the are associated with anti- and systemic effects.21 cholinergic effects such as dry mouth, urinary is a dietary supplement used in flow difficulties, and cardiac dysrhythmias. dosages of 0.5 to 3,000 mg. Anecdotal reports

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Bottom Line mance. Clin Pharmacol Ther 1989;45:15-21.

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