Insomnia is a common but often underdiagnosed complaint in the elderly population.1 It is defined as the inability to obtain sleep of sufficient quality or quantity to feel refreshed the following morning.2,3 Insomnia is characterized by difficulty initiating and/or maintaining sleep. More than 50% of geriatric patients have reported repeated difficulty falling and staying asleep, trouble waking, waking up too early, or needing to nap without feeling rested.1 Changes in the amount and quality of sleep are associated with advancing age.4
It has been reported that up to 40% of people with insomnia use OTC products or alcohol to self-medicate.5,6 Nearly $1 billion is spent annually in the United States on medications to improve sleep.7 The total cost to American society associated with insomnia is estimated at $100 billion annually.3 This includes indirect costs such as medical expenses, ramifications of accidents, reduced work productivity, and absenteeism. Because of their access to the general public and expertise in drug therapy, pharmacists are uniquely qualified to assist patients with insomnia. Thus, the purpose of this paper is to equip pharmacists to educate patients on the causes and treatment of insomnia; review basic principles of good sleep hygiene; and discuss the use of OTC sleep aids, dietary supplements, and prescription medications for insomnia.
ETIOLOGY OF INSOMNIA
Insomnia can be categorized in numerous ways. One way to classify insomnia is in three categories based on duration. Transient insomnia is often self-limited and usually lasts no longer than 7 days; short-term insomnia lasts for 1 to 3 weeks; and chronic insomnia lasts longer than 3 weeks. Chronic insomnia is usually associated with medical, psychiatric, psychological, or substance-use disorders. Insomnia also can be classified as primary or secondary. Primary insomnia is not caused by a health problem; it is a sleep disturbance that cannot be attributed to a medical, psychiatric, or environmental cause. Secondary insomnia, on the other hand, is caused by an underlying medical condition or a medication.
Changes in sleep architecture are common with advancing age. Sleep initiation is more difficult in the elderly, and thus more time is spent awake in bed before falling asleep. Delta-wave sleep decreases, and sleep becomes more fragmented.1 Waking earlier than planned is another common complaint in the elderly. Changes in the circadian rhythm caused by the normal aging process dictate patterns of falling asleep and waking up earlier in the older population. Daytime napping can also compound the problem. For these reasons, insomnia is more common in people over the age of 65. While some accept this as a typical part of aging, others seek medical or pharmaceutical care.
Insomnia can be caused by stress or by disturbances in the normal sleep-wake cycle. Comorbidities such as physical disability, respiratory problems, medication use, depressive symptoms, environmental factors, poor living conditions, and loss of a spouse, close friend, or relative have all been associated with higher rates of insomnia in individuals over the age of 65.1 Conditions such as depression, anxiety, asthma, chronic obstructive pulmonary disease, congestive heart failure, thyroid disease, gastroesophageal reflux disease, pain, sleep apnea, and neurologic disorders also are linked to the development of insomnia. Depression and dementia, which are quite common in the elderly, have been associated with sleep disturbances in this population.
Several types of medications have been known to cause insomnia in older people. These include central nervous system (CNS) stimulants (diet pills or amphetamines), antidepressants, corticosteroids, diuretics, anticonvulsants, and certain antihypertensives (e.g., beta-adrenergic blockers). Additionally, alcohol and nicotine can have a profound negative effect on the quality and quantity of sleep.
From the foregoing discussion, it follows that the causes of insomnia usually fall into one of three types: 1) medical and psychiatric, 2) iatrogenic, and 3) psychosocial (TABLE 1).
TREATMENT OVERVIEW
Nonpharmacologic Therapy
It is imperative that pharmacists conduct a brief medical history when counseling patients with insomnia, asking specifically about diagnosed medical disorders, medications, herbs and supplements, caffeine, alcohol, tobacco, and sleep hygiene. Sometimes chronic insomnia can be a red flag for conditions that require medical referral (e.g., depression).
Attention to the underlying causes of sleeplessness is critical to alleviating both short-term and long-term insomnia. The pharmacist may be the initial point of contact for patients with insomnia, and they can provide referrals to physicians. Pharmacists can give patients and their physicians important feedback whenever treatable or reversible underlying causes of insomnia are suspected. Proper sleep hygiene should be explained to the patient (TABLE 2); for example, patients should be instructed to establish routine times for retiring and waking and to avoid daytime naps, alcohol, caffeine, and stimulant decongestants. It is important to reduce ambient lighting at least 1 hour prior to bedtime; this signals the pineal gland to release melatonin, a hormone that promotes sleep in response to darkness. Although regular exercise is important, the patient should be advised to avoid exercising close to bedtime. The bedroom must be kept quiet and be used only for sleeping, reading, or sexual activity (e.g., not for work-related activity). Stressful activities should be avoided close to bedtime. Patients should be discouraged from eating large meals or heavy snacks right before bedtime, and fluid intake should be restricted as well.
OTC Therapy
Once underlying medical, psychosocial, or iatrogenic causes have been addressed and appropriate sleep hygiene has been initiated, OTC sleep aids may be considered. Antihistamines such as diphenhydramine (e.g., Benadryl) and doxylamine (e.g., Unisom) are widely available OTC, but should be used with caution in the elderly. A variety of herbal preparations (e.g., valerian, chamomile) and dietary supplements (e.g., melatonin) are available. When recommending nonprescription therapy to older patients, it is important to consider the risk of possible drug interactions because this population is more likely to take multiple medications. Elderly patients also are more sensitive to the side effects of medications.
Antihistamines: Diphenhydramine and doxylamine are the two most widely available OTC medications marketed as sleep aids. Both are ethanolamine derivatives with potent histamine1 (H1) receptor antagonist activity and anticholinergic properties.7 There are few well-designed placebo-controlled trials clearly documenting the effectiveness of diphenhydramine and doxylamine for treating insomnia.8-10 A review of these studies indicates that diphenhydramine is effective at dosages ranging from 12.5 mg to 50 mg taken 30 to 60 minutes before bedtime. The effective dose for doxylamine is 25 mg before bedtime. These studies indicate that patients who have no prior history of using antihistamines for sleep respond best, and that next-day "hangover" sedation may occur in some patients. No symptoms of drug dependence have been observed.8 Because of their prolonged sedating and anticholinergic properties, the use of diphenhydramine and doxylamine generally is not recommended in the elderly population.11
Pharmacist-to-Patient Counseling Tips: The geriatric population is especially sensitive to the anticholinergic properties of nonprescription and prescription antihistamines. Diphenhydramine may cause confusion and sedation and is not recommended for use as a hypnotic agent in the elderly.11 Diphenhydramine and doxylamine may cause dizziness, sedation, confusion, dry mouth, constipation, and urinary retention, effects that are more pronounced in elderly patients. Older men with prostate disease (e.g., benign prostatic hyperplasia) are particularly susceptible to urinary retention. The consumption of alcoholic beverages concurrently with antihistamines should be discouraged because of additive CNS-depressant effects. Pharmacists should remind patients that these drugs may impair motor activity and that it is therefore unadvisable to drive or operate heavy machinery when taking diphenhydramine or doxylamine.12,13 Patients using OTC antihistamines for sleep may develop tolerance to the sedative effects of these medications.5 Generally, patients should be advised to use these drugs for no more than 10 consecutive days.5
Valerian (Valeriana officinalis): Valerian root has been used for its sedative and hypnotic effects for centuries. It was used to treat shell shock during World War I.14 The active ingredients appear to be valepotriates (thought to be responsible for the sedative effects) and valeric acid, which bind to the same receptors as benzodiazepines and mediate the release of gamma-aminobutyric acid.15,16 Randomized, placebo-controlled trials suggest that valerian improves sleep quality and reduces sleep latency (time it takes to fall asleep), with no hangover effect in the morning.17,18 Habituation and addiction have not been reported.
The recommended dose of valerian for insomnia is 300 mg to 600 mg standardized to 0.8% to 1% valerenic acid per dose at bedtime. Studies have shown that valerian is most effective when it is used continuously, and results are not usually noted for 2 to 4 weeks.16 Mild side effects include paradoxical stimulation (restlessness and palpitations), especially with long-term use.18 Valerian may have an additive effect with other CNS depressants, and patients should be cautioned not to operate machinery when initiating therapy until they are accustomed to the effects. Other side effects seen in clinical trials included headaches, excitability, and uneasiness.18
Chamomile (Matricaria recutita): Although few studies in humans have been performed on chamomile, the herb is cultivated worldwide for use as a sedative, spasmolytic, anti-inflammatory, and wound-healing agent. The active component apigenin has been shown to bind to the same receptors as benzodiazepines to exert an anxiolytic and mild sedative effect in mice.19 Apigenin also has been shown to reversibly inhibit irritant-induced skin inflammation in animals and to exert antispasmodic effects in the intestines.20,21 It also contains coumarin, which contributes to its antispasmodic activity.22 No coagulation disorders have been reported to date, but close monitoring of patients on anticoagulants is advised. In vitro, chamomile has been shown to be bactericidal to some Staphylococcus and Candida species.23
Chamomile is considered safe by the FDA but it should be used with caution in individuals who are allergic to ragweed, as cross-allergenicity may occur. Symptoms include abdominal cramping, tongue thickness, tight sensation in throat, angioedema of the lips or eyes, diffuse pruritus, urticaria, and pharyngeal edema.24,25 Because of its sedative effects, caution should be used in conjunction with medications with sedative side effects or with alcohol. The oral dose is 400 mg/day to 1,600 mg/day in divided doses, standardized to 1.2% apigenin per dose. Chamomile is commonly consumed as a tea for its calming effect. It can be brewed using 1 heaping teaspoon of dried flowers steeped in hot water for 10 minutes and may be consumed up to 3 times per day.
Melatonin: Melatonin is an endogenous hormone secreted by the pineal gland that may have some utility in treating circadian rhythm-based sleep disorders.3,5 Elderly people, individuals who are blind, and people experiencing jet lag typically exhibit poor sleep efficiency and reduced nocturnal plasma melatonin levels.26 According to several small trials, administration of oral melatonin in doses that raise plasma melatonin levels to the normal nocturnal range can improve sleep quality, duration, or onset.26-30 In a study of 33 patients, melatonin improved quality and depth of sleep and increased sleep duration without producing drowsiness, early-morning hangover, or daytime adverse effects relative to placebo.29 In this study, melatonin also contributed to a feeling of "freshness" in the morning and during the day and improved daytime functioning. The dosage used was flexible; the mean stable effective dose was 5.4 mg/day. Benefits were most apparent during the first week of treatment.29 Most studies use lower doses and sustained-release forms of melatonin (0.1-3 mg/day) 1 to 2 hours before bedtime.
Pharmacist-to-Patient Counseling Tips: Owing to the widespread availability and marketing of the aforementioned nutraceuticals for insomnia to the general public, their use often is not supervised by pharmacists. However, the pharmacist may be on the receiving end of consumers' questions about the safety and efficacy of these products. The information in TABLE 3 can guide pharmacists in counseling these patients.
The use of herbs and supplements for chronic insomnia that is not medically supervised should be discouraged because an underlying, treatable cause of insomnia may otherwise be masked. The pharmacist should first address sleep hygiene and other nonmedical or psychiatric causes of insomnia before recommending these supplements. The pharmacist should remind patients that dietary supplements such as valerian, chamomile, and melatonin are not supported by large, prospective, placebo-controlled studies. Patients should be advised to take the same dosage and frequency that have been studied in clinical trials and not to exceed labeled amounts. The purchase and use of natural products that do not list the exact amount contained in each dosage unit should be discouraged. The pharmacist should elicit a careful history from the patient regarding any allergies, especially to ragweed and daisies, keeping in mind that many patients with allergic rhinitis may not know which allergens trigger their attacks. Patients who are allergic to ragweed and flowers in the daisy family (asters, chrysanthemums) may have allergic reactions to products containing chamomile.
Prescription Medication
Benzodiazepines: The currently marketed benzodiazepines and their respective usual doses for insomnia are listed in TABLE 4. The use of benzodiazepines for insomnia is somewhat controversial because of their potential to produce euphoria and their potential association with withdrawal symptoms after prolonged use. Abuse, dependence, and addiction are another concern, especially in patients with a history of substance abuse. Unlike other hypnotic agents, benzodiazepines are effective anxiolytics. Drug accumulation due to decreased renal clearance is a consideration in the elderly.4 If benzodiazepines are used in geriatric patients, the lowest available dose should be initiated (e.g., temazepam 7.5 mg).
Benzodiazepines differ primarily in their pharmacokinetic profile, such as rate of absorption, elimination of half-life, pathways of metabolism, and lipid solubility--factors that contribute to the overall effect by influencing the onset and duration of action. Long-acting benzodiazepines can accumulate and lead to an increased risk of dizziness, confusion, hypotension, and cognitive impairment. Active metabolite accumulation is even more problematic in the elderly because of the slowed hepatic and renal metabolic activity that is part of the aging process.11 Drugs with a short half-life have specific risks, such as a more intense withdrawal syndrome and rebound anxiety. When restricted to short-term use (e.g., less than 2-3 weeks), however, short-acting hypnotics such as temazepam, triazolam, and estazolam are preferred since they do not cause as much daytime somnolence as longer-acting agents.4
Benzodiazepines can produce undesirable side effects such as psychomotor impairment, amnesia, and withdrawal symptoms. Commonly reported withdrawal symptoms are anxiety and insomnia; others include tinnitus, involuntary movements, perceptual changes, confusion, and depersonalization. Withdrawal symptoms can be attenuated by using the smallest dose and shortest duration possible and by tapering the dose gradually. The pharmacist should counsel patients to restrict their intake of alcohol and other CNS depressants concurrently with benzodiazepines.
Nonbenzodiazepine Hypnotics: Zolpidem (Ambien), eszopiclone (Lunesta), and zaleplon (Sonata) are nonbenzodiazepine sedative-hypnotic drugs approved for the short-term treatment of insomnia. Ramelteon (Rozerem) is a melatonin receptor agonist approved for the treatment of insomnia characterized by difficulty initiating sleep onset. Zaleplon is indicated only for the short-term treatment of insomnia. These agents have been proven to significantly improve sleep latency. They have less potential for abuse and addiction than benzodiazepines and thus should be tried before benzodiazepine therapy is initiated.31-33 Nonbenzodiazepine hypnotics have selective affinity for the benzodiazepine receptor subtype 1 and are more rapidly eliminated.34 They also have a lower risk of producing muscle hypotonia, behavioral disturbances, and retrograde amnesia, compared with benzodiazepines.35
Nonbenzodiazepine hypnotics have less potential for producing pharmacologic tolerance and do not possess anticonvulsant or anxiolytic properties when used at hypnotic doses.34 In elderly patients, it is important to consider the elimination half-life of hypnotics. Compared with other nonbenzodiazepine hypnotics, eszopiclone has the longest half-life, about 5 hours in geriatric patients; zaleplon, with a half-life of 1 hour, has the shortest half-life.34 Elderly patients thus are more likely to experience adverse effects from eszopiclone.
In the elderly, it is important to initiate nonbenzodiazepine hypnotic therapy at the lowest possible effective dose. This will help prevent dose-related adverse effects such as daytime drowsiness, falls, and sedation. Alcohol use should be discouraged. Patients should be educated about the possible side effects associated with nonbenzodiazepine hypnotic therapy, and they should be advised to report any abnormal cognitive or behavioral changes to their physician. Nonbenzodiazepine hypnotics should not be taken with or after a high-fat meal. The most common side effects of eszopiclone are headache and dizziness. Patients should not take zolpidem unless they can devote 7 to 8 hours to sleep. The most common side effects of zolpidem are drowsiness, headache, dizziness, and diarrhea; activities such as driving, cooking, or eating while asleep also have been reported.34 Headache is the most commonly reported side effect of zaleplon; headache, somnolence, dizziness, and fatigue are the most common adverse effects associated with ramelteon.34
Tricyclic Antidepressants: Antidepressant drugs with sedating properties have been studied in insomnia because of their central anticholinergic or antihistaminic activity.36-39 These agents include doxepin and trazodone (TABLE 4). Although these medications are utilized to help relieve insomnia in patients with depression, they should be used with extreme caution in older patients. Because of their anticholinergic effects, these agents have similar cautions as those for OTC agents, previously discussed (see section on antihistamines). Antidepressants should not be used in patients with urinary retention or chronic constipation. Because these drugs can prolong ventricular repolarization, extreme caution should be exercised in patients also receiving drugs that prolong the QT interval (quinidine, type 1a antiarrhythmics, phenothiazines, etc.).
Trazodone is not indicated for use as a hypnotic in nondepressed patients, and it possesses safety concerns for the elderly. Adverse effects associated with trazodone are orthostatic hypotension, dizziness, and blurred vision, which are especially problematic in the geriatric population owing to the increased potential for falls.40 Rarely, the drug has been associated with priapism (a sustained and painful penile erection). Because trazodone has essentially no potential for addiction and limited potential for abuse, it may be preferred to benzodiazepines in patients with a history of substance abuse. Trazodone has fewer cardiovascular side effects than amitriptyline and other tricyclic antidepressants, but it should be used with caution in patients with a history of cardiovascular disease.36
Pharmacists should instruct patients taking antidepressants to avoid alcohol consumption. The risk of serotonin syndrome may be increased with concurrent use of valerian or St. John's wort and an antidepressant medication, and the combination should be strongly discouraged. Serotonin syndrome is characterized by a constellation of symptoms including agitation, motor restlessness, diarrhea, nausea, fever, hyperreflexia, tachycardia, and other autonomic changes.
Patients should be educated about the potential side effects with trazodone use. These include drowsiness, lightheadedness, dizziness, nausea, dry mouth, and constipation.40 The pharmacist should ensure that patients understand the risks associated with trazodone use and report to their physician any suicidal ideation, chest pain, irregular heartbeat, or worsening of their condition.40
CONCLUSION
Insomnia that worsens or persists beyond 3 weeks may signal an underlying medical, psychiatric, iatrogenic, or psychosocial disorder. The pharmacist should refer these patients for medical follow-up. The pharmacist may wish to consider providing feedback to a patient's physician whenever treatable or reversible causes of insomnia are suspected, especially in drug-induced cases.
In the elderly, nonbenzodiazepines such as zolpidem, eszopiclone, zaleplon, and ramelteon are safer and better tolerated than tricyclic antidepressants, antihistamines, and benzodiazepines. Pharmacotherapy should be recommended only after sleep hygiene is addressed, however. Patients with chronic insomnia may be advised to contact national organizations that provide free support materials to people suffering from insomnia (TABLE 5). The pharmacist also can refer patients to a sleep specialist, if available. Finally, the pharmacist should promote principles of good sleep hygiene and take a thorough medication history to rule out any iatrogenic causes of the insomnia.
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