Current Issues in the Management of Insomnia in Critically Ill Patients

Approximately half of adult Americans experience occasional sleep disturbance each year, and between 10% and 15% suffer chronic insomnia. Chronic insomnia is not precisely defined, but generally refers to sleep disturbance three or more nights per week persistently or nightly sleep difficulty for at least 3 to 4 weeks. The criteria for insomnia include: (i) prolonged sleep latency (difficulty falling asleep), (ii) nocturnal awakenings with difficulty returning to sleep, and (iii) inadequate total sleep time.

In many instances, insomnia is secondary to or coexistent with an intrinsic sleep disorder such as obstructive sleep apnea, or with a comorbid medical, psychiatric or neurological condition. In some of these cases, daytime symptoms of drowsiness, dozing and napping, and both psychomotor and cognitive impairment may occur. These symptoms, in turn, may result in an increased risk of falls and fractures, poor job performance, and vehicular and industrial accidents. These consequences are less frequently seen in patients with primary insomnia.

An array of both non-pharmacologic and pharmacologic treatments is currently available for the management of insomnia, and generally the best results are achieved by a combination of behavioral and medical interventions along with successful treatment of underlying conditions. Although several classes of drugs have, over the years, been shown to be efficacious in the treatment of insomnia, many have been discarded because they are too toxic. Short- and intermediate-acting benzodiazepine hypnotic sedatives and newer non-benzodiazepine agents are currently the agents of choice.

This symposium was supported by an educational grant from Sanofi-Synthelabo.

Sleep Disorders and Insomnia in the Elderly

Jed Black, MD, Director of the Stan-ford Sleep Disorders Clinic at Stanford University Medical Center, began the symposium by outlining the predominant intrinsic sleep disorders.

Obstructive Sleep Apnea (OSA)
OSA is airflow reduction or cessation during sleep. It is seen in 10% to 20% of adult males and about half as many women. OSA increases in prevalence after the age of 50 years in both genders, and is often but not necessarily associated with obesity. The characteristic presentation is heavy snoring followed by silence as the tissues of the soft palate, those behind the base of the tongue and/or the lateral tissues of the pharynx collapse, and then by a snorting gasp as the individual strives instinctively to resume normal breathing and gas exchange. Brief episodes of apnea can occur from a few to up to several hundred times per night. Snoring is almost always present but it is not a necessary feature of OSA, particularly in women.

Up to one-third of individuals with OSA or the less common upper airway resistance syndrome also have insomnia. Deficits in daytime function are frequent but not universal in this combined population. Those with OSA have been shown to be at increased risk for vehicular or industrial accidents, drowsiness, impairment of cognitive and psychomotor function, or changes in personality and mood. The Sleep Heart Health Study and the Wisconsin Cohort Studies among many others have produced compelling evidence that the long-term medical consequences of chronic OSA may include hypertension, stroke, heart attack and premature death. The standard treatment for OSA is continuous positive airway pressure (CPAP), in which air pressure generated by a bedside pump and delivered by mask maintains constant pressure in the airway to prevent collapse of the upper airway soft tissues.

Restless Legs Syndrome (RLS)
RLS is common in the elderly. Patients frequently describe this as a “creepy-crawly” sensation that builds up in the legs that can be relieved only by moving. A minority of patients experiences RLS as pain. It usually occurs during the sleep latency period, thus postponing sleep; but it may also result in difficulty returning to sleep following a nocturnal awakening. In either case, RLS is a prominent cause of insomnia.

Periodic Limb Movement Syndrome During Sleep
Periodic limb movement syndrome during sleep may or may not occur in conjunction with RLS. Unlike RLS, in which the movements are voluntary in response to discomfort, periodic limb movement during sleep is involuntary. It may awaken the patient during the night and can be a cause of insomnia. The prevalence of this syndrome is approximately 25% in adults over the age of 65 years and 45% in the institutionalized elderly. Daytime sleepiness accompanied by cognitive impairment can occur as a result of fragmented sleep associated with this syndrome. Both restless legs syndrome and periodic limb movement during sleep are usually treated with dopamine agonists.

Insomnia
Insomnia is defined as difficulty initiating and/or maintaining sleep. The normal sleep cycle consists of two types of sleep — non-rapid eye movement (NREM) and rapid eye movement (REM). NREM consists of four stages of sleep, each becoming progressively deeper. Stages 3 and 4 are considered slow-wave or deep sleep and are thought to play a particular role in the restorative nature of sleep. The cycle recurs every 1.5 hours or so, often with brief awakenings of which the individual may be unaware. Periods of REM sleep usually follow bouts of NREM sleep and typically occur at roughly 90-minute intervals throughout the night. As the end of the night approaches, however, the cyclic rhythm changes, resulting in more REM sleep and less slow-wave sleep. In individuals with insomnia, however, the awakenings are often prolonged and the distribution of the sleep cycles is altered. In the elderly, failure to maintain sleep once initiated, or so-called “sleep-maintenance insomnia,” is the most common form of insomnia. Another common presentation of insomnia is characterized by advanced-phase syndrome. This consists of achieving sleep early and easily, followed by early morning awakening with failure to fall back to sleep. Difficulty initiating sleep is a less common complaint among elderly patients.

Transient insomnia (less than 30 days’ duration) affects approximately 50% of the adult population annually, but among individuals 65 years or older the prevalence rises to as high as 75%. Chronic insomnia (more than 30 days’ duration) is reported to occur in 10% to 15% of the general adult population but to rise dramatically among older individuals.

Chronic insomnia is frequently a comorbid condition, existing along with an underlying medical condition such as congestive heart failure, diabetes, chronic obstructive respiratory disease, benign prostatic hyperplasia and diseases associated with chronic pain. Some psychiatric disorders (e.g., depression) and some neurological conditions (e.g., dementia) are associated with insomnia. Many medications taken by older individuals may also induce insomnia. Comorbid insomnia is most effectively treated when the organic condition is also managed effectively. The breadth of impairments associated with insomnia, together with the potential severity of the associated risks (e.g., accidents from falling asleep at work or while driving, fractured hip from falls, elevated risk for subsequent clinical depression), makes it imperative that clinicians be alert to symptoms of insomnia and be prepared to treat it.

Between 20% and 50% of individuals who have insomnia have no underlying medical or psychiatric cause, and are thus said to have primary insomnia.

When evaluating insomnia, it is essential to determine if it is chronic or transient; if it is associated with a recent event such as personal loss or institutionalization; if it consists predominately of prolonged sleep latency, frequent awakenings, diminished total sleep time or nonrestorative sleep quality; if the insomnia is associated with debilitating daytime sequelae; and if the patient takes one or more sleep-altering medications. The patient’s 24-hour sleep/wake pattern should be evaluated by utilizing a 14-day sleep diary. The presence or absence of daytime sleepiness provides an important diagnostic clue. It is important to note that sleepiness often does not occur in patients with primary insomnia since these patients frequently have “hyperarrousal” as part of the underlying problem. The Epworth Sleepiness Scale, which measures drowsiness under specified circumstances from watching television to driving, may be helpful in determining the severity of daytime sleepiness. Any patient with an Epworth score greater than 14 or 15 needs a sleep evaluation. Evaluation should be considered for patients in the 10- to 15-point range.

A multi-component cognitive and behavioral therapy approach with or without pharmacologic intervention often results in optimum long-term treatment outcomes. This therapy has multiple components including sleep hygiene practices, education, relaxation techniques (used at night only after mastering them during the day), sleep restriction to improve sleep efficiency, bright light therapy, stimulus control instruction, cognitive restructuring and relapse prevention. Improving sleep hygiene includes standardizing the bedtime/ waketime schedule, avoiding sleep-altering substances including caffeine for several hours before bedtime, placing the clock out of sight, and preserving the bedroom as a sanctuary for sleep. Relaxation training may include progressive muscle relaxation, biofeedback and abdominal breathing. In bright light therapy, the patient is exposed to 5,000 to 10,000 lux of intensity 45 to 60 minutes before attempting to sleep to set the biological clock back, or upon rising in the morning to set the clock forward, depending on whether the patient suffers from advanced-phase or delayed-phase syndrome. Most non-pharmacologic techniques for treating insomnia preclude daytime napping. Paradoxically, however, alterations in the sleep/wake schedule including planned napping may be sufficient therapy for some elderly patients.

Pharmacologic Treatment of Insomnia

It is estimated that individuals over the age of 65 years take 35% to 40% of all hypnotics prescribed in the United States. Although several classes of drugs are effective for treating insomnia in the older population, many of them have safety profiles that are not satisfactory for the elderly, a group with increased sensitivity to CNS-acting drugs. Thus, in the modern history of hypnotic drug development, the goal has been to preserve efficacy while improving safety progressively.

Cynthia K. Kirkwood, PharmD, BCPP (Virginia Commonwealth University) emphasized the importance of ruling out medication-related causes of insomnia (Table 1). If a decision is made to initiate hypnotic therapy, it is important to match the pharmacologic profile of the selected drug to the patient’s sleep complaint. Specifically, prolonged sleep latency requires an agent of rapid onset such as triazolam (a benzodiazepine), zaleplon or zolpidem (non-benzodiazepines), whereas frequent awakenings call for an agent such as temazepam (a benzodiazepine) or zolpidem (a non-benzodiazepine).

The newest class of drugs for treating insomnia is the non-benzodiazepine hypnotic sedative class (zaleplon and zolpidem). These agents are from different chemical classes and are not structurally similar to benzodiazepines. Since they bind preferentially only to the benzodiazepine-1 receptor, unlike most benzodiazepines which bind with all three benzodiazepine receptors, their effect is more sleep-specific with overall safer profiles. Their principal disadvantage is their cost compared with the generic benzodiazepines.

Zolpidem has a rapid onset of action — within 30 minutes — and an average half-life of 2.5 hours in younger adults and 2.9 hours in the elderly. Its duration of effect is 6 to 8 hours. Zolpidem has been shown to decrease sleep latency, reduce the frequency of awakenings, increase total sleep time and improve the quality of sleep in adults of all ages. The most common adverse effects associated with zolpidem are drowsiness, dizziness, headache and gastrointestinal distress. Zolpidem lacks the anxiolytic, anticonvulsant and muscle-relaxant effects of benzodiazepines and has less rebound insomnia and fewer withdrawal effects. There has been a low incidence of abuse with zolpidem and when it occurs, it is usually associated with very high doses in individuals with histories of substance abuse.

The dose of zolpidem is 5 mg for patients over the age of 65 years and for patients with hepatic impairment. Zolpidem is metabolized via multiple cytochrome P450 pathways. Thus, the incidence of drug-drug interactions is minimized, with few clinically significant interactions. There are additive effects, however, with alcohol, chlorpromazine and imipramine. Zolpidem has been safely co-administered with fluoxetine and sertraline.

Zaleplon, the newer of the non-benzodiazepine agents, is also selective for the benzodiazepine-1 receptor. Its half-life is approximately 1 hour, but its duration of action is only 3 to 4 hours. At the recommended 10 mg dose, it does not increase sleep time or decrease the number of awakenings. Since it has a short duration of action, however, zaleplon can be taken to resume sleep after middle-of-the-night awakening if 4 or 5 hours remain prior to intended morning awakening. Thus, zaleplon can be used for symptomatic rather than preventive treatment of poor sleep maintenance. The dose of zaleplon is 5 mg for elderly patients.

Because of zaleplon’s short half-life, residual effects during the day are unlikely. Zaleplon is metabolized primarily by aldehyde hydroxide and minimally through the 3A4 system. Cimetidine has been shown to increase zaleplon concentrations by 80%. Similar effects may be seen with ketoconazole and erythromycin. Rifampin reduces zaleplon levels. The adverse effects of zaleplon observed in controlled clinical studies include headache, drowsiness, dizziness and nausea.

There are currently five benzodiazepines that have FDA-approved indication for insomnia: estazolam, flurazepam, quazepam, temazepam and triazolam. As a class, these drugs have rapid onset of action. However, only quazepam binds preferentially to the benzodiazepine-1 receptor. The non-preferential binding of other benzodiazepines at all three benzodiazepine receptors may contribute to their broad spectrum of adverse events. The overall safety of benzodiazepines is related, in part, to age-dependent body functions. Fat-soluble benzodiazepines have an increase in volume distribution and lower clearance, so an increase in body fat may contribute to accumulation. Changes in metabolism and reduced excretion due to lower hepatic blood flow and glomerular filtration may also contribute to accumulation.

Table 2 presents comparative pharmacokinetics of these agents. The use of long-acting agents such as flurazepam and quazepam should be avoided in the elderly, and diazepam, chlordiazepoxide and clonazepam should be avoided in older patients except in cases of documented failure when taking short-acting agents because of risks associated with daytime effects. These include falls and fractures, cognitive and memory impairment, impaired coordination, sedation, and the potential development of tolerance.

Triazolam is a short-acting drug and estazolam and temazepam are intermediate-acting drugs, none of which have metabolites that accumulate. The intermediate-acting agents have durations of approximately 8 hours, and may be ideal for inducing a full night’s sleep. Triazolam, although a short-acting agent, has been associated with a high prevalence of rebound insomnia and with daytime anxiety, confusion and agitation in elderly individuals taking doses above 0.25 mg/day (Wysowski DK et al. Arch Intern Med 1991;151:2003). Dosage is very important when using temazepam in older patients, as significant cognitive impairment has been associated with high doses (Morgan K. Drugs 1990; 40:688).

Benzodiazepines are contraindicated for patients with OSA or COPD because they may reduce the respiratory drive center in the brain. Benzodiazepines should not be used in patients with histories of substance or alcohol abuse. Combination of benzodiazepines and alcohol can be toxic. Additive effects occur when benzodiazepines are used in conjunction with any other drug with central nervous system effects. Nefazodone, erythromycin and anti-fungal agents all increase triazolam concentrations.

Chloral hydrate, an older non-barbiturate, non-benzodiazepine agent, is used very infrequently. Low-dose trazodone, an antidepressant, has been used as a hypnotic for a decade. Daytime sedation is common with this agent, and dizziness, orthostatic hypotension and priapism have also been reported. On the favorable side, trazodone is not a controlled (scheduled) drug and does not suppress respiration.

The efficacy and safety of non-prescription antihistamines as hypnotics have not been established in older patients. However, they are associated with anticholinergic effects and are contraindicated in patients with narrow angle glaucoma, benign prostatic hyperplasia, constipation or dementia. Cognitive impairment has also been reported.

Studies of melatonin, a neurohormone that is involved in the circadian regulation of sleep, have been equivocal in the general adult population. The major problem is that because melatonin is not an FDA-regulated drug, there is significant variability among products. Melatonin may worsen depression in the elderly. Because melatonin can be a vasoconstrictor, it is contraindicated for patients with vascular disease (Chase JE et al. Ann Pharmacother 1997;31:1218; Weekly LB. Clin Autonomic Res 1993; 3:45). Auto-immune diseases can be aggravated by melatonin (Pepping J. Am J Health-Syst Pharm 1999;56:2520; Sandyk R. Int J Neurosci 1992;62:65).

Valerian, an herbal product, appears to have weak GABA agonist effects that induce sleep. Its effect may not be seen for 2 to 4 weeks after the initiation of therapy. Like melatonin, it is not regulated and concentrations of the active molecule vary widely among commercial products. Valerian should not be used by individuals with hepatic impairment or by pregnant women.

Based on available clinical evidence, Dr. Kirkwood concluded that short- and intermediate-acting benzodiazepines, zolpidem and zaleplon are safe and effective hypnotic choices. Because of cost considerations, however, many clinicians prefer to reserve the non-benzodiazepines for second-line therapy.

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