Psychiatric Annals

CME 

The Use of Hypnotics to Treat Sleep Problems in the Elderly

Catherine McCall, MD; John W. Winkelman, MD, PhD

Abstract

Sleep problems are common in the elderly, with a prevalence of close to 50% in those older than age 65 years. Older adults may suffer from disturbances of sleep that are related to medical problems, to psychiatric illness, to primary sleep disorders, to use or withdrawal from drugs/medications, and/or to poor sleep habits. Loss of sleep in older adults is associated with significant morbidity, low quality of life, and mortality. When approaching the diagnosis and management of sleep disorders in elderly patients, it is important to evaluate and treat comorbid conditions. Pharmacologic treatments for sleep, although increasingly common, present significant challenges due to age-related changes in drug metabolism and clearance, side effects, and drug-drug interactions. When possible, it is preferable to manage sleep problems with nonpharmacologic approaches. This review discusses current pharmacologic and nonpharmacologic treatments for sleep problems in the elderly. [Psychiatr Ann. 2015;45(7):342–347.]

Abstract

Sleep problems are common in the elderly, with a prevalence of close to 50% in those older than age 65 years. Older adults may suffer from disturbances of sleep that are related to medical problems, to psychiatric illness, to primary sleep disorders, to use or withdrawal from drugs/medications, and/or to poor sleep habits. Loss of sleep in older adults is associated with significant morbidity, low quality of life, and mortality. When approaching the diagnosis and management of sleep disorders in elderly patients, it is important to evaluate and treat comorbid conditions. Pharmacologic treatments for sleep, although increasingly common, present significant challenges due to age-related changes in drug metabolism and clearance, side effects, and drug-drug interactions. When possible, it is preferable to manage sleep problems with nonpharmacologic approaches. This review discusses current pharmacologic and nonpharmacologic treatments for sleep problems in the elderly. [Psychiatr Ann. 2015;45(7):342–347.]

One-third of all adults have difficulties with sleep. The prevalence of these issues increases with age, reaching close to 50% in those older than age 65 years.1,2 One common misperception is that the increased prevalence of sleep problems in older adults is a result of normal aging; however, poor sleep in the elderly is often related to medical, psychiatric, and primary sleep disorders.1,2 The ramifications of sleep problems in the elderly are serious and may include falls and impairments in attention, memory, concentration, and driving ability. In addition, poor sleep is a risk factor for depression, suicide, hypertension, stroke, heart disease, cancer, Alzheimer’s disease, low quality of life, subjective cognitive decline, and mortality.1,3–7

According to the US Census Bureau,8 the percentage of the US population older than age 65 years was 13% in 2010, and it is projected to reach 20.9% by 2050. As the percentage of the population older than age 65 years increases, awareness of how to diagnose and effectively treat sleep problems in this population will become increasingly relevant to clinicians.

Etiologies of Sleep Disturbances in the Elderly

One of the most common categories of sleep problems at any age is insomnia. In the Diagnostic and Statistical Manual of Mental Disorders, fifth edition,9 insomnia is defined as a predominant complaint of dissatisfaction with sleep quantity or quality associated with sleep initiation, maintenance, and/or early morning awakening. The problem that causes the distress or impairment, occurs at least 3 nights per week, is present for at least 3 months, occurs despite an adequate opportunity for sleep, and must not be attributable to another sleep-wake disorder, to substance use or abuse, to a mental disorder, or to a medical disorder.9 Risk factors for insomnia include female gender; age older than age 45 years; being divorced, separated, or widowed; having a lower level of education; using tobacco or alcohol; and having reduced physical activity.2 Additional factors that impact insomnia include poor sleep hygiene (including watching television or other electronic devices at night), napping excessively, having variable sleep times, becoming more anxious at bedtime, and using stimulating substances (such as caffeine). Recent studies have suggested that in older adults, genetic factors and neurologic changes also play a role in the development of insomnia. Variation in “clock” genes has been associated with sleep parameters (such as time to sleep onset, wake time after sleep onset, and wake onset times) in older adults.10 Lower numbers of galanin-immunoreactive cells in the intermediate nucleus of the thalamus have been associated with fragmented sleep in older adults.5

Polysomnography studies have demonstrated that changes in sleep typically develop throughout the adult lifespan and include an increased wake time after sleep onset and decreased sleep efficiency (defined as time asleep divided by time spent in bed). Total sleep time at night decreases from 10 to 14 hours in children, to 6.5 to 8.5 hours in young adults, to 5 to 7 hours in older adults, and it plateaus after the age of 60 years. Moreover, daytime sleep increases in older adults. Sleep stage distribution also changes in the elderly, with lesser amounts of slow wave sleep and rapid-eye movement (REM) sleep, and increased time spent in stage 1 and 2 non-REM sleep.3

Approach to the Management of Sleep Problems in the Elderly

Management of sleep problems in older adults begins with the appropriate screening, diagnosis, and management of medical, psychiatric, and primary sleep disorders1,7 (Table 1). Review of medications should be undertaken to minimize use of agents that disrupt sleep and predispose to drug interactions.7 Medications are increasingly used to treat sleep problems in older adults.11 Unfortunately, there are risks to using hypnotics, including the risk of drug-drug interactions, age-related changes in drug metabolism and clearance, risk of cognitive impairment, side effects, falls, and the development of tolerance. Older adults have nearly a 5-fold increased risk of unwanted cognitive effects from the use of hypnotics.12 Thus, when possible, it is preferable to use nonpharmacologic approaches to treat sleep problems in the elderly.

Factors that Commonly Contribute to Sleep Problems in the Elderly

Table 1.

Factors that Commonly Contribute to Sleep Problems in the Elderly

When choosing a hypnotic agent for an older adult, both pharmacodynamic and pharmacokinetic factors should be considered. It is desirable to use a hypnotic with a rapid onset of action for sleep-onset insomnia, and with a long enough duration for sleep maintenance insomnia, but with a short enough duration to avoid residual daytime sedation. Other considerations include age-related decreases in metabolism by cytochrome P450 isoenzymes, which can increase the half-life and the duration of drug action.13 Similarly, additive pharmacodynamic effects with other medications should be considered.

Pharmacologic Options for Treating Insomnia in the Elderly

The following sections discuss both US Food and Drug Administration (FDA)-approved and non–FDA-approved medications for the treatment of insomnia in older adults. Table 2 provides details regarding FDA indications, geriatric dosages, half-lives, and adverse effects for commonly used hypnotics.

US Food and Drug Administration (FDA)-Approved Medications for Insomniaa

Table 2.

US Food and Drug Administration (FDA)-Approved Medications for Insomnia

Benzodiazepine Receptor Agonists

Benzodiazepine receptor agonists (BzRAs), which include both benzodiazepines and nonbenzodiazepine receptor agonists (NBRAs) or “Z drugs,” are gamma aminobutyric acid (GABA)A receptor agonists that potentiate the action of GABA when bound to receptors. Benzodiazepines, some of the earliest medications used for the treatment of sleep problems, bind at the alpha1, alpha2, alpha3, and alpha5 GABAA receptor subunits, which mediate both the sedative and anxiolytic properties of these medications. Nonbenzodiazepines, such as zolpidem and zaleplon, are, in general, more selective for the alpha1 subunit, which primarily mediates the sedative/hypnotic effect as well as the amnestic effects of these agents. Some NBRAs, such as eszopiclone, are less selective for GABAA receptor subtypes, and thus may help with both insomnia and anxiety. Half-life is the major distinguishing feature among this class of drugs. Some of these drugs (eg, diazepam, clonazepam, flurazepam) have a very long half-life, whereas others (eg, lorazepam, temazepam, eszopiclone) have an intermediate half-life, and still others (eg, zolpidem) have a short or very short half-life (eg, zaleplon). Combined with the dose, half-life is the predominant predictor of adverse effects of hypnotic drugs in the elderly, as they predispose to an increased vulnerability to side effects and to reduced drug clearance.13

BzRAs have been effective for the short-term treatment of insomnia in the elderly, with the greatest efficacy evident in improving sleep latency and sleep quality, and the least efficacy in enhancing total sleep time.7,12,13 Adverse effects include next-day sedation, confusion, hypotension, dizziness, falls, depression, suicide, tolerance, and rebound.12 Tolerance to the hypnotic effects of both benzodiazepines and NBRAs, except eszopiclone, is well established; however, eszopiclone has not been assessed for long-term use in the elderly. NBRAs also have negative effects on balance, gait, and equilibrium, factors that predispose to an increased risk of fracture, as well as tolerance, psychosis, delirium, amnesia, and complex sleep-related behaviors.13,14 Recently, in a large cohort of patients attending a primary care clinic in the United Kingdom, anxiolytic and hypnotic drugs were associated with a significantly higher mortality rate with a dose-dependent pattern over a 7-year follow-up period.15

Melatonin Receptor Agonists

Melatonin is a hormone secreted by the pineal gland at the onset of darkness, and it exerts its effect on circadian rhythm via the hypothalamus. However, it is not clear whether melatonin levels decrease with advancing age. Ramelteon is currently the only melatonin receptor agonist approved by the US Food and Drug Administration (FDA); it has potent activity at both MT1 and MT2 receptors.13

Ramelteon is FDA-approved to treat sleep-onset insomnia. It has had mixed results for altering total sleep time and sleep maintenance insomnia.16 Night-time administration of ramelteon has also been effective for the prevention of delirium in the elderly; however, it is not clear to what extent the sleep-promoting effects contribute to this observation.17 Adverse effects of ramelteon include hormonal changes (such as increased prolactin and decreased serum cortisone) and possible next-day sedation. However, its use has not been associated with cognitive impairment or gait instability.13,18

Tricyclic Antidepressants

Several large-scale studies on the sleep effects of doxepin led to its approval (in low doses) by the FDA in 2010 for the treatment of insomnia characterized by difficulty with sleep maintenance. Doxepin inhibits the reuptake of serotonin and norepinephrine, and causes cholinergic, histaminergic, and alpha1-adrenergic receptor blockade. At doses under 10 mg, its main effect is predominantly via its antihistaminergic effects.19

Two randomized, double-blinded, placebo-controlled trials studied doxepin in elderly patients with primary insomnia.19,20 In one study, patients were randomized to 4 weeks of treatment with either 6 mg per night of doxepin or placebo.20 Use of doxepin led to significant improvements in patient-reported wake time after sleep onset, total sleep time, and sleep quality; endpoints that were sustained throughout the trial.20 In another trial, use of doxepin (1 mg and 3 mg) administered nightly for 12 weeks resulted in significant improvements in objectively measured sleep efficiency, wake time after sleep onset, and total sleep time, as well as subjective improvements in sleep latency onset, total sleep time, and sleep quality.19

Although TCAs can be problematic when used at higher doses in the elderly (secondary to their anticholinergic properties), doses of 3 to 6 mg did not produce next-day sedation or induce significant adverse effects.19,20

Phenylpiperazine Antidepressants

Trazodone is one of the most widely used agents to treat insomnia in older adults; however, the practice is for an off-label indication.11 At low doses, the sedating effect of trazodone is attributed primarily to antagonism of 5-HT2A receptors, H1 receptors, and alpha1-adrenergic receptors.21

Despite its widespread use, few studies have examined the efficacy of trazodone in the elderly. In elderly depressed patients, one randomized, double-blind study noted improvement in subjective reports of sleep, but it failed to reveal a statistical significant difference between doses.21 Adverse effects include daytime sedation, orthostatic hypotension, arrhythmias, and impaired cognitive and motor function, which are important considerations in the elderly population; priapism is a rare phenomenon.21

Noradrenergic and Specific Serotonergic Antidepressants

Mirtazapine is another antidepressant commonly used (off-label) to treat insomnia, often in patients with depression. It is a tetracyclic antidepressant with potent inhibition of 5-HT2, 5-HT3, and central alpha2-adrenergic receptors, and with minimal monoamine uptake. 5-HT2 antagonism may improve insomnia. Mirtazapine is metabolized by CYP2D6 and CYP3A4 and it undergoes renal excretion, which may require dosage reduction for patients with renal impairment.22

One study that examined the efficacy of mirtazapine in the elderly found improvement in subjective sleep quality and a decrease in the actigraphic sleep fragmentation index in older adults with depression, but it failed to show improvement in wake time after sleep onset, total sleep time, or sleep efficiency.23 Adverse effects include prolonged next-day impairment in motor reaction and driving performance, orthostatic hypotension, and weight gain, which are significant side effects in the elderly.22

Sedating Antipsychotics

As an atypical antipsychotic, quetiapine is an antagonist at the 5-HT1A, 5-HT2, D1, D2, H1, alpha1, and alpha2 receptors. Its sedating quality is likely due to its antihistaminergic action.

In small studies of elderly patients with primary insomnia or dementia, quetiapine was found to increase polysomnogram or actigraphic total sleep time at doses starting at 25 mg.24 Adverse effects include weight gain and glucose intolerance. Atypical antipsychotics have a class-related black box warning for sudden cardiac death and higher mortality rates in the elderly.25

Orexin Antagonists

Orexin (hypocretin) is a peptide produced in the posterior lateral hypothalamus that regulates alertness through its interaction with brainstem nuclei responsible for arousal. Levels of orexin rise with waking and they decrease at night. Deficiency of orexin-producing neurons has been found in patients with narcolepsy. Suvorexant is the first orexin-receptor antagonist approved by the FDA (in August 2014) for the treatment of insomnia. This medication binds to both OX1R and OX2R orexin receptors and is thus considered a dual orexin-receptor antagonist (DORA).26

Studies have demonstrated the efficacy of orexin in both sleep onset and maintenance in the elderly. Two randomized, double-blind, placebo-controlled studies in older adults found that doses of 15 mg and 30 mg were effective for subjective and polysomnogram-measured sleep latency and sleep maintenance.26 Due to concerns about next-day sedation, it was approved by the FDA at doses of 10 to 20 mg.

Adverse effects include next-day somnolence as well as safety concerns (as demonstrated in driving tests), muscle weakness, vivid dreams, sleep behaviors, and suicidal ideation. Suvorexant was not found to increase the risk for abuse, dependence, or rebound/withdrawal effects after 3 to 12 months of use.26

Nonpharmacologic Options for the Treatment of Insomnia in the Elderly

Nonpharmacologic treatments for insomnia provide a safe and effective means to treat sleep problems in the elderly without adverse effects and drug-drug interactions associated with use of medications. These approaches are suitable as an initial step in the treatment of insomnia.

Single-modality approaches are the most common and simple treatments for insomnia; these include relaxation therapy, bright light therapy, exercise, massage therapy, and improvements in sleep hygiene. Sleep hygiene promotes stable sleep patterns and an appropriate environment to optimize sleep. Sleep restriction and sleep compression strategies may also be effective for older adults with chronic insomnia.7

Cognitive-behavioral therapy for insomnia (CBT-I) is a comprehensive therapeutic modality that focuses on maladaptive beliefs and behaviors that worsen insomnia. It includes cognitive restructuring along with various behavioral treatments, including improved sleep hygiene, sleep restriction, and stimulus control. CBT-I has been effective in older adults; computer-based CBT-I may also be efficacious.7,27–30

Nonpharmacologic approaches may also be used in conjunction with medications; one study found maximal benefits with the combination of CBT-I and pharmacotherapy, with improved remission rates for those who tapered their pharmacotherapy.28

Conclusion

Sleep problems are prevalent in the elderly, a population whose numbers are increasing at a dramatic rate. Sleep problems may be caused by a variety of conditions, including medical, psychiatric, and primary sleep disorders. Screening for (and managing) these disorders, in addition to their comorbid sleep problems, is of great importance. Sleep problems in the elderly lead to a deterioration of medical, neurologic, and psychiatric function, to cognitive impairments, and to an increased risk of poor quality of life, suicide, and mortality from other causes.

The elderly are at higher risk for adverse effects from medications, including the risks from drug-drug interactions; therefore, nonpharmacologic interventions should be initiated prior to pharmacologic treatments whenever possible. Initiating a medication for insomnia in an older individual should take several factors into consideration, including comorbid disorders, drug-drug interactions, dosage, duration of action, impairments in hepatic and renal function, risk of cognitive impairment, and risk of falls.

Both FDA-approved and off-label medications for insomnia are available, and the use of off-label medications continues to rival that of approved medications.31 Medications may be selected based on the presence of comorbid conditions (such as depression, dementia, or neurodegenerative conditions). In some populations, such as elderly substance abusers, there is a paucity of evidence to determine whether agents used in younger adults are safe or effective in the elderly. Clinicians would benefit from additional research focused on specific subpopulations of older adults with insomnia.

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Factors that Commonly Contribute to Sleep Problems in the Elderly

Medical   Angina pectoris   Arthritis   Autoimmune disorders   Congestive heart failure   Chronic obstructive pulmonary disease   Gastroesophageal reflux   Hyperthyroidism   Malignancy   Menopause   Musculoskeletal pain   Urinary disorders Neurologic   Dementia   Movement disorders   Stroke Primary Sleep Disorders   Circadian rhythm disorders   Periodic limb movements in sleep   Rapid eye movement behavior disorder   Restless legs syndrome   Sleep-related breathing disorders Psychiatric   Anxiety   Depression Medications   Central nervous system stimulants   Beta-blockers   Bronchodilators   Calcium channel-blockers   Corticosteroids   Decongestants   Stimulating antidepressants   Thyroid hormone Recreational Drugs   Alcohol   Caffeine   Nicotine Psychosocial Factors   Bereavement   Lack of exercise   Partner sleeping habits   Retirement   Social isolation Poor Sleep Habits   Excessive time in bed   Heavy meals/fluids before bedtime   Nighttime light exposure

US Food and Drug Administration (FDA)-Approved Medications for Insomniaa

Category Medication, Generic (Trade) FDA Indication Recommended Initial Geriatric Dose (mg) Tmax(h) Half-Life (h) Most Common Adverse Effectsb
Benzodiazepine receptor agonists Temazepam (Restoril; Mallinckrodt, Bethlehem, PA) Short-term treatment of insomnia (7–10 days) 7.5 1.5 3.5–18.4 Drowsiness, fatigue, lethargy, dizziness, hangover, anxiety
Triazolam (Halcion; Pfizer, New York, NY) Short-term treatment of insomnia (7–10 days) 0.125 2 1.5–5.5 Drowsiness, headache, dizziness, nervousness, lightheadedness, ataxia, nausea/vomiting
Eszopiclone (Lunesta; Sunovion, Marlborough, MA) Insomnia (no time limitation) 1 1 9 Headache, unpleasant taste, dyspepsia, pain, diarrhea, pruritus, dry mouth, abnormal dreams, neuralgia, urinary tract infection
Zaleplon (Sonata; Pfizer, New York, NY) Short-term treatment of insomnia (up to 30 days) 5 1 1 Abdominal pain, somnolence, eye pain, paresthesia, tremor, amnesia
Zolpidem (Ambien; Sanofi-Aventis, Paris, France), also available as sublingual (Edluar; Meda, Solna, Sweden) and oral spray (Zolpimist; ECR, Bridewater, NJ) Short-term treatment of sleep onset insomnia (up to 35 days) 5 1.6 1.4–4.5 Drowsiness, dizziness, diarrhea
Zolpidem ER (Ambien CR; Sanofi-Aventis, Paris, France) Sleep onset and/or maintenance insomnia 6.25 2 1.6–5.5 Headache, somnolence, dizziness, nasopharyngitis
Zolpidem, sublingual (Intermezzo; Sanofi-Aventis, Paris, France) Sleep maintenance insomnia with at least 4 hours of sleep time remaining 1.75 0.5–1.25 1.4–3.6 Drowsiness, dizziness, diarrhea
Melatonin receptor agonists Ramelteon (Rozerem; Takeda, Deerfield, IL) Sleep onset insomnia 8 0.75 1–2.6 Dizziness, somnolence, nausea, fatigue, exacerbation of insomnia
Antidepressants Doxepin (Silenor; Pernix, Morristown, NJ) Sleep maintenance insomnia 3 3.5 15.3 Somnolence, upper respiratory tract infection, gastroenteritis, nausea, hypertension
Orexin antagonists Suvorexant (Belsomra; Merck and Co., Kenil-worth, NJ) Sleep onset and maintenance insomnia 10 2 10–22 Headache, somnolence, dizziness, diarrhea, dry mouth, upper respiratory tract infection, abnormal dreams, cough
Authors

Catherine McCall, MD, is a Resident, Harvard Longwood Psychiatry Residency Training Program, Beth Israel Deaconess Medical Center, Brigham and Women’s Hospital; and a Clinical Fellow in Psychiatry, Harvard Medical School. John W. Winkelman, MD, PhD, is the Chief, Sleep Disorders Clinical Research Program, Department of Psychiatry, Massachusetts General Hospital; and an Associate Professor of Psychiatry, Harvard Medical School.

Address correspondence to John W. Winkelman, MD, PhD, Massachusetts General Hospital, 1 Bowdoin Square, 9th floor, Boston, MA 02114; email: jwwinkelman@partners.org.

Disclosure: John W. Winkelman has received consulting fees from UCB Pharma, Xenopart, INSYS Therapeutics, Merck & Co., and Flex Pharma; has performed contracted research for Purdue, Xenopart, UCB Pharma, and Neurometrix; and has provided expert testimony for Canter Colburn. The remaining author has no relevant financial relationships to disclose.

10.3928/00485713-20150626-05

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