Insomnia Update: Evaluation and New Treatments
November 1, 2006 30 minutes read
Insomnia Update: Evaluation and New Treatments
Author: Rebekah Wang, MD, Clinical Professor of Medicine, Medical College of Wisconsin; Private Practice, St. Helena, CA.
Peer Reviewer: Barbara Phillips, MD, MSPH, Professor, Department of Internal Medicine, University of Kentucky College of Medicine, Lexington; Director, Sleep Disorders Center, Samaritan Hospital, Lexingon, KY.
Introduction
Because of its impact on quality of life, insomnia is one of the most common problems for which patients seek help from the primary care physician. Insomnia affects virtually everyone at some time in life, but chronic insomnia is becoming increasingly more common in adults, particularly in women during perimenopause, in men with nocturia from prostatic hyperplasia, in people with psychiatric diagnoses, and in the elderly who have other comorbidities. The medical costs of insomnia are estimated to be almost $16 billion annually in the United States, with several billion more dollars of indirect economic impact due to mood disturbance, daytime drowsiness, missed days of work, impaired work performance, injuries, and car accidents.1
Primary care physicians tend to choose medication as the treatment of choice for many reasons. They receive little, if any, training in evaluation and behavioral management of sleep disorders; taking a thorough sleep history is time-consuming; and short-term sedative use is effective. The arrival of newer sedatives and widespread direct-to-consumer advertising have increased patient-initiated requests for treatment, resulting in more than $2 billion in annual sales of sleeping pills.
This update addresses several questions. What are appropriate interventions for insomnia in the primary care setting? Are nonpharmacologic approaches such as cognitive behavioral therapy effective? When should patients be referred to a sleep disorder center? When is pharmacotherapy indicated? Are the newer, costlier agents more effective and/or safer? Do they carry less risk for tolerance and dependence? In addition to the management of acute and chronic insomnia, this update reviews the latest data on the health risks of chronic sleep deprivation.
Classification of Insomnia
Acute insomnia happens on occasion in everyone, and self-imposed sleep restriction because of the hectic lives that people lead in the 21st century is almost becoming the norm. Staying up late to finish work projects, dealing with small children early in the morning, driving long distances to work, and having frequent late nights out for entertainment contribute to this phenomenon. Many of these people attempt to "make-up" sleep on the weekend.
Chronic insomnia usually is defined as persisting for at least 30 days and usually longer than 6 months. Although acute and chronic insomnia and self-imposed sleep restriction can all affect quality of life by slowing reaction times and decreasing concentration, memory, and cognitive abilities, chronic insomnia may be the harbinger of serious mood disturbances such as depression or anxiety.
The International Classification of Sleep Disorders (ICSD) first appeared in 1990, followed by a more clinician-friendly second edition in 2005.2 The three most common types of insomnia are adjustment insomnia (also known as acute insomnia), psychophysiologic insomnia, and insomnia due to a mental disorder.
Adjustment Insomnia. Also known as acute insomnia, this is more common in women and older adults and usually lasts less than 3 months. Because there often is an identified stressor that precipitates the sleep disturbance, the term adjustment insomnia is also used.
Complicated grief is an example of a common cause of acute insomnia. The patient experiences recurrent distressing emotions and intrusive thoughts after the loss of a loved one, resulting in poor sleep quality. Although a randomized controlled trial of cognitive-behavioral therapy and psychotherapy in 95 people with complicated grief showed clinical improvement, unfortunately the sleep disturbance persisted.3 The physician will have to weigh carefully the risks and benefits of using antidepressants or sedative-hypnotics in these patients.
Psychophysiologic Insomnia. Also referred to as "conditioned insomnia," psychophysiologic insomnia shares similarities with adjustment insomnia; however, it usually is of longer duration, persisting for decades in some people, and it is not associated with a specific stressor or mental disorder such as anxiety or depression. These patients experience a physiologic arousal associated with bedtime and often describe "racing thoughts," muscle tension, and an inability to relax when trying to go to sleep. Interestingly, they have less difficulty falling asleep when away from home or when not intending to fall asleep during monotonous activities.
Insomnia Due to a Mental Disorder. This is a common diagnosis among patients presenting to a sleep center. Mood and anxiety disorders are the predominant underlying conditions. The primary care physician needs to screen for affective disorders in patients with insomnia, and referral to a psychiatrist may be the most appropriate next step.
Diagnostic Criteria
Sleep difficulties can be divided into several types: delayed onset, difficulty in sleep maintenance, early morning awakening, and/or nonrestorative, restless sleep that results in daytime consequences.
Nonrestorative Sleep. Nonrestorative sleep (NRS), described as restless, fragmented, and light even though the total duration may be normal, deserves special mention because of comorbidites. More common in women, it has been associated with obesity, fibromyalgia, chronic fatigue syndrome, and obstructive sleep apnea syndromes. In middle-aged women with coronary heart disease, nonrestorative sleep may increase the risk of recurrent events.4
Ohayon,5 who has studied sleep disorders extensively, surveyed more than 25,000 individuals aged 15-100 years in 7 European countries to gain a better understanding of NRS. Overall, prevalence was 10.8%, but higher in women than in men (12.5% vs 9.0%; P < .001). NRS was associated with age younger than 55 (see Table 1 for other factors), and prevalence declined with age, which is the opposite of other types of insomnia. Daytime sleepiness occurred in one-third of the subjects; irritability and physical fatigue were the other two most common consequences, in almost 24% and 22%, respectively. (See Table 2.) When compared to other subjects with insomnia, subjects with NRS reported more impairment in daytime functioning, were more likely to consult a physician about sleep, and were more likely to take sleep medication.
| Table 1. Factors Associated with Nonrestorative Sleep |
| • Younger age (< 55 years) • Alcohol intake at bedtime • Elevated room temperature ("stuffy bedroom") • Uncomfortable bed • Global dissatisfaction with sleep • Difficulty getting started in the morning • Very stressful life • Anxiety, bipolar disorder, depression Adapted from Ohayon MM. Prevalence and correlates of nonrestorative sleep complaints. Arch Intern Med 2005;165:35-41. |
| Table 2. Impaired Daytime Functioning in 2756 Subjects with Nonrestorative Sleep |
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Epidemiology of Insomnia
The National Sleep Foundation's 2005 Sleep in America poll reports that one-third of adults report difficulty with insomnia, restless leg syndrome, and/or sleep apnea. For optimal daytime functioning, men required 6.2 hours of sleep, which is less than the 6.8 hours preferred by women.6 Accordingly, insomnia is reported more often by women. There is also a higher prevalence in divorced, separated, or widowed adults as opposed to married couples.
Elderly. As people age, they tend to have more subjective complaints regarding sleep quality. Older people also tend to take medications that may have side effects or drug interactions that interfere with sleep. Even though total time in bed may not decrease, they experience frequent awakening throughout the night. They become sleepy earlier in the evening and wake up earlier in the morning (3-5 a.m.) and are unable to fall back to sleep. This shift in the sleep-wake cycle has been called an "advanced sleep-phase" (ASP). Minimal exposure to sunlight, which is an external cue for the sleep-wake cycle, also contributes to ASP. Avoiding late afternoon naps and having more illumination in nursing homes may help reset the cycle and delay sleepiness until later in the evening.7
Although melatonin, which is produced by the pineal gland, appears to enhance sleep through synchronization of circadian rhythms, its role in sleep regulation is not fully understood. In elderly people the secretion of melatonin is delayed and circulating concentrations are lower.
Haimov et al.8 looked for a correlation between melatonin and insomnia by monitoring sleep in elderly patients and measuring the urinary excretion of 6-sulphatoxymelatonin (a metabolite of melatonin). He compared four groups: elderly men and women with insomnia living independently in the community; elderly men and women without insomnia living independently in the community; elderly men and women with insomnia residing in a nursing home; and young subjects who had an average age of 24 years. All patients with insomnia had significantly lower sleep efficiency and higher activity level during sleep, and delayed onset and lower peaks of 6-sulphatoxymelatonin excretion. Interestingly, the 6-sulphatoxymelatonin peak in elderly subjects without sleep disorders did not differ significantly from that in the young control subjects. They hypothesized that lack of exposure to bright light in institutions may lead to lower 6-sulphatoxymelatonin excretion, and suggest that exposure to bright light later in the day and melatonin may be helpful for improving sleep.
Women. Reproductive hormones play a major role in sleep regulation, particularly in the perimenopause transition. In the Daily Hormone Study component of the Study of Women's Health Across the Nation (SWAN), more than 3000 women aged 43-53 in several communities throughout the United States collected morning urine samples and kept a daily bedtime diary.9 They reported answers to an 18-item questionnaire about mood, physical and vasomotor symptoms, and sleep. The odds of trouble sleeping were 29% higher in perimenopausal than in premenopausal women. For both groups the most difficulty sleeping occurred at the beginning and end of the menstrual cycle, and mood and vasomotor symptoms were strong contributors. Higher follicle-stimulating hormone (FSH) levels were significantly related to trouble sleeping in premenopausal women.
Hot flashes are a major factor for chronic insomnia in mid-life women. In a random sample of 982 California women aged 35-65, the prevalence of chronic insomnia was 36.5% in premenopause, 56.6% in perimenopause, and 50.7% in postmenopause.10 In women with severe hot flashes, the prevalence of chronic insomnia reached 80%.
Comorbid Conditions with Insomnia. Because many cases of insomnia are related to other conditions, this used to be termed "secondary insomnia." The 2005 NIH State-of-the-Science Conference11 voiced concerns that this term might promote undertreatment of insomnia and proposed that "comorbid insomnia" would be preferable. These comorbid medical problems include osteoarthritis or other painful conditions; cardiovascular, pulmonary, and gastrointestinal disorders; urinary frequency or incontinence; and neurological disease such as stroke, Parkinson's disease, and dementia. Primary sleep disorders such as sleep apnea, periodic leg movements, and restless leg syndrome invariably contribute to insomnia.
Disturbed sleep is a frequent symptom with psychiatric illnesses such as depression, anxiety, bipolar disorder, schizophrenia, and substance abuse. In the overlap of these disorders with sleep difficulties, it is not always clear whether treatment of the primary illness will lead to amelioration of the insomnia.
Studies have shown an association between sleep apnea and depression,12,13 and Peppard et al14 demonstrated in a longitudinal study that an increase of one sleep apnea category from minimal to mild was associated with almost double the risk of developing depression. This finding suggests that patients with sleep disorders should be screened for depression and vice versa.
Health Risks Related to Short Sleep Duration
Several epidemiologic surveys have shown a bidirectional relationship between sleep duration and health. That is to say, lack of sleep may lead to the development of serious illness, and many chronic diseases result in poor-quality sleep. This may explain in part why both short and long sleep durations have been associated with increased mortality rates15,16 and increased risk of coronary heart disease.17
Steptoe et al18 collected data from more than 17,000 university students aged 17-30 in 24 countries on their sleep habits and self-rated health. They found that those who slept fewer than 6 hours per night had an odds ratio of 1.99 (CI, 1.31-3.03) for poor self-rated health after adjusting for several variables such as sex, age, smoking status, physical activity, alcohol consumption, and parental education. No associations were found between health and long sleep durations (8 hours or greater per night).
Hypertension. Gangwisch and his group studied the sleep habits of 4810 adults enrolled in the first National Health and Nutrition Examination Survey (NHANES) and followed outcomes from 1982-1992.19 Adults aged 32-59 years who slept 5 hours or fewer at night were twice as likely to develop hypertension as those who slept longer (RR 2.1; 95% CI, 1.58 to 2.79). This increased risk of hypertension persisted even after controlling for other factors such as diabetes and obesity. They postulated that sleep deprivation leads to elevated sympathetic nervous system activity and increased salt retention.
Obesity. Obesity continues to rise in the United States at alarming rates, even as average sleep duration decreases. Gangwisch's group again analyzed cross-sectional and longitudinal data from NHANES 1 to determine any association between sleep duration and obesity in subjects aged 32-49 years.20 They used measured weights in 1982-1984 and self-reported weights in 1987 and 1992. Those who reported fewer than 7 hours of nightly sleep had higher average body mass indexes (BMI) and were more likely to be obese than subjects with sleep durations of 7 hours. Sleep durations of more than 7 hours showed no correlation with obesity.
A prospective study of 1001 adult patients in four primary care practices confirmed an association between obesity and sleep deprivation.21 Average BMI of these patients ages 18-91 years was 30. Overweight and obese patients slept less than patients with a normal BMI (patients reported less sleep in a nearly linear relationship from the normal through the obese group).
In a rural adult population in Iowa, Kohatsu and his group22 also found an average BMI of 30 in people reporting fewer than 6 hours of sleep on week nights. Snoring, which often is linked with obesity, was independently associated with higher BMI (p < .001).
Type 2 Diabetes Mellitus in Men. Yaggi23 reported on the long-term effects of sleep duration in middle-aged and elderly men who were followed for 15 years in the Massachusetts Male Aging Study. Of the 1139 men who were free of diabetes at baseline, those who slept 6 or fewer hours nightly had a relative risk of 1.95 for developing type 2 diabetes. This risk did not change after adjustment for age, hypertension, smoking, and waist circumference. Men who slept more than 8 hours had triple the risk of developing type 2 diabetes, as compared to men who slept 7-8 hours.
This increased risk for diabetes also was found in a random sample of middle-aged Swedish men aged 45-64 years24 who had reported short sleep duration of 5 hours or less (16% vs 5.9%). In a 12-year follow-up, men with new diabetes also were significantly more likely to have reported difficulty initiating sleep (16% vs 3.1%) and maintaining sleep (28% vs 6.3%) at baseline than the men who did not develop diabetes. Sleep duration or sleep complaints did not appear to influence the risk of new diabetes in women.
Depression. Between 50% and 75% of patients with insomnia in a clinical setting have a psychiatric disorder such as depression or anxiety.25 Insomnia may precede and predict the new onset of depression or a relapse. Sleep deprivation increases hypothalamic-pituitary-adrenal axis activity, which appears to be associated with depression.26 Compared to normal controls, patients with affective disorders have decreased slow-wave sleep and sleep continuity, but increased REM sleep.
Evaluation of the Patient
General Screening. As with any diagnosis, a thorough interview exploring the complaints of the patient, bed partner, or caregiver is crucial in the evaluation of insomnia. The patient should provide very specific answers regarding sleep habits: What time does he/she go to bed? What time does he fall asleep? Does she wake up in the middle of the night? What wakes her up? See Table 3 for components of an insomnia history.
| Table 3. Questions for Evaluating Insomnia |
| • What is the sleep difficulty (initiating, maintaining, early awakening, nonrestorative sleep)? • When did it start? Was there a precipitating factor? • What time does the patient go to bed? What time does he/she fall asleep? • Does the patient wake up in the middle of the night? • What wakes the patient? Noise, discomfort? • What time does the patient wake up? Spontaneous or with an alarm? • How long did the patient sleep? • Does the patient feel rested when he/she awakes? • Does the patient sleep better away from home? On weekends? • Does the patient take naps during the day? • Is the patient under unusual stress? Does he or she think about problems lying in bed? • Does the patient notice any restless legs at bedtime? • What are the daytime consequences of the poor sleep? • What OTC, herbal, or prescription sedatives has the patient tried? • Does the patient use caffeine, nicotine, alcohol, or other drugs? • How are the patient's relationships? Does he or she have an ctive sex life? • Does the bed partner notice any snoring, pauses in breathing, kicking? |
In addition to characterization of sleep habits, a careful history should include specific questions about pain, health habits, relationships, stress levels, and mood. Review all prescription and over-the-counter medications, including the timing of administration. Some patients may not be aware that medications such as selective serotonin reuptake inhibitors, beta-blockers, decongestants, bronchodilators, and steroids may interfere with sleep.
Although a structured questionnaire such as the Pittsburgh Sleep Quality Index can be used, most clinicians begin the evaluation with taking a history. This self-report index was recently validated in 417 community-dwelling patients older than 60 years of age.27 Scoring was based on a three-factor model of sleep efficiency, perceived sleep quality, and daily disturbances.
The physical examination will help confirm the presence of comorbid conditions such as arthritis, but is not nearly as important as a comprehensive history in the evaluation of insomnia. The history is so important because recognition of potential contributors to insomnia may lead to targeted treatment. For example, appropriate pain management often will improve sleep maintenance and quality. Diagnosing early depression or anxiety and beginning treatment of the underlying condition also may lead to resolution of the insomnia. Changing the timing of thyroid, antidepressant, or steroid administration to morning also may make a difference. Ask the patient to keep a sleep diary to track various changes he has instituted and to return for follow-up after a month.
Men. In men older than 50 years, the physician should ask about nocturia. With untreated benign prostatic hyperplasia (BPH), it is not uncommon for men to get up many times a night to urinate, which may prevent them from attaining deep, stage 4 sleep. Treating the underlying BPH usually resolves the insomnia.
Women. In women, a history of menstrual cycle sleep disturbance or vasomotor symptoms is crucial. For perimenopausal women with severe hot flashes, estrogen therapy may improve sleep by reducing awakenings and improving sleep efficiency.28 In postmenopausal women, however, the effects of hormone therapy on sleep are controversial. In a small study of postmenopausal women aged 58-72,10 hormone therapy users and 10 nonusers were compared to 11 young women.29 Polysomnography and subjective sleep quality were measured on four consecutive nights: adaptation, baseline, 40-hour sleep deprivation, and recovery. As expected, sleep in postmenopausal women was worse than in young controls at baseline and during recovery. Hormone therapy offered no significant advantage to sleep at baseline and slightly weakened the recovery response to prolonged wakefulness
Restless Leg Syndrome and Periodic Limb Movements. Restless leg syndrome (RLS), described by patients as an urge to keep the legs continually moving to get some relief, often begins around bedtime. Sometimes getting up and walking around and performing prolonged stretching of the legs for several minutes will suffice. About 80% of patients with RLS also have periodic limb movements in sleep (PLMS) throughout the night. Question the bed partner about kicking or jerking by the patient or disordered breathing, such as snoring, gasping for air, and apneic spells. Ropinirole is approved by the FDA for treatment of RLS and PLMS.
Screening for Sleep-Related Breathing Disorder. Sleep-Related Breathing Disorder (SRBD), which is characterized by repetitive upper airway collapse during sleep, is a risk factor for cardiovascular disease, stroke, depression, and increased mortality.14,30-32 Patients with SRBD have an apnea-hypopnea index of 15 or more events per hour. The relationship between SRBD and insomnia is not well-understood, but both increase with advancing age. Of adults older than 65 years of age, 20% have SRBD,33 and 59.5% have insomnia complaints.34
Gooneratne et al35 compared 99 older adults with insomnia to 100 older adult controls. They found that BMI of 30 or higher, neck circumference greater than 15.5 inches, and a history of loud snoring or "stops breathing, chokes or struggles for breath" were independent predictors of SRBD in the insomnia cases. Participants who had both insomnia and SRBD had significantly lower daytime functioning and longer psychomotor reaction times.
Because of the risk for functional impairment and long-term risks in patients with concurrent illness, all elderly patients should be questioned about sleep habits, and those with insomnia should be assessed for SRBD. Often the bed partner is the instigator in bringing the patient for medical attention because of snoring or witnessed apneas. Table 4 lists symptoms and descriptions that suggest SRBD.
| Table 4. Symptoms and Signs Suggestive of Sleep-Related Breathing Disorder |
| • Loud snoring • Gasping or choking • Witnessed apneas or hypopneas by bed partner • Frequent movements that disrupt sleep • Feeling unrefreshed or tired upon morning awakening • Morning headaches • Daytime sleepiness • Obesity with a thick neck • Elevated blood pressure |
Indications for Referral to a Sleep Specialist. Patients with symptoms and signs suggestive of sleep apnea should be referred to a sleep disorder specialist.
If sleep disturbance persists for several months after sleep hygiene measures, treatment of underlying comorbidities, and a trial of sedative-hypnotics, then referral to a sleep center may be warranted. Further evaluation and testing with overnight polysomnography or actigraphy can be performed as indicated. The latter involves having the patient wear a watch-sized motion sensor to detect nighttime movement during sleep. The American Academy of Sleep Medicine does not recommend polysomnography or actigraphy for the routine evaluation of insomnia.36
Approaches to Managing Chronic Insomnia
Lifestyle Changes and Sleep Hygiene. For acute and chronic insomnia, primary care physicians should begin with teaching patients sleep hygiene and simple lifestyle changes that will improve their chances of a good night's sleep. (See Table 5.) It is surprising how many habits and behaviors people engage in that contribute to disturbed sleep, such as eating a heavy meal and drinking alcohol shortly before retiring for the night. Encourage the patient to reserve the bed for sexual activity and sleep. Eating in bed, reading an exciting novel, or discussing stressful problems before trying to sleep is not a good idea. Although explaining these tips may seem time-consuming, it will empower the patient and save time in the long run.
| Table 5. Sleep Hygiene and Stimulus Control |
| • Arise from bed at the same time every day, even on weekends. • Go to bed at the same time every day. • Avoid naps. • Eating a light snack may help since hunger may disturb sleep. • Avoid stimulants such as caffeine and nicotine. • Limit alcohol intake, especially before bedtime. • Avoid vigorous exercise after 4 p.m. • Create a comfortable sleep environment with a quiet, dark, cool room. • Institute regular sleep routines with relaxing activities, such as taking a calming bath. • Reserve the bed for sexual activity and sleep. Do not eat, read, or discuss problems while lying in bed. • If unable to fall asleep after 10 minutes, get up and go to another room. |
Cognitive Behavioral Therapy (CBT). There are several nonpharmacologic approaches to improving sleep that can be roughly grouped together under the rubric of CBT. Sleep hygiene and stimulus control can be taught by the primary care physician, but the others, such as biofeedback, guided imagery, and cognitive restructuring, usually require an experienced therapist in a sleep center. (See Table 6.) Summers37 recently published a review that discusses the evaluation of insomnia and summarizes these treatments very well.
| Table 6. Cognitive and Behavioral Approaches to Insomnia |
| • Sleep hygiene • Stimulus control • Sleep restriction • Relaxation therapy • Progressive muscle relaxation • Biofeedback • Guided imagery • Cognitive therapy |
In a culture that is accustomed to finding the quick fix, it is refreshing to find a randomized controlled trial demonstrating that CBT is superior to pharmacotherapy for sleep-onset insomnia in young and middle-aged adults.38 A total of 63 men and women aged 25-64 years who had a complaint of sleep-onset insomnia for at least 6 months and had at least 1 negative daytime complaint related to the insomnia were included in the study. They were randomized to receive either CBT alone, pharmacotherapy with zolpidem, a combination of CBT and zolpidem, or placebo medication. CBT alone was equal or superior to a combination of CBT and pharmacotherapy on most outcome measures, such as sleep-onset latency and sleep efficiency. Most importantly, pharmacotherapy improved sleep only moderately during the treatment phase, and sleep measures reverted toward baseline after stopping the zolpidem, whereas subjects treated with CBT maintained gains in sleep efficiency at 12-month follow-up.
Sivertsen39 replicated this finding with another randomized controlled trial in 46 adults comparing CBT with zopiclone 7.5 mg nightly or placebo. These men and women with a mean age of 60.8 all had chronic primary insomnia. CBT consisted of sleep hygiene, sleep restriction, stimulus control, cognitive therapy, and relaxation. Polysomnography and sleep diaries were used to determine wake time, sleep time, sleep efficiency, and slow-wave sleep.
Although total sleep time was similar among all three groups at 6-month follow-up, patients receiving CBT had better sleep efficiency, spent less time awake, and spent much more time in slow-wave sleep (stages 3 and 4) than those on zopiclone.
The beneficial effects of CBT may persist over time and there is no evidence of any adverse effects. Unfortunately the drawback of CBT is that it requires trained mental health professionals and has not really been adapted to the busy primary care physician's practice.
Pharmacotherapy
Before discussing the options available for managing insomnia with medication, it is important to review the risks. Glass, et al published a meta-analysis of 24 randomized controlled studies involving the use of sedative-hypnotics for insomnia in 2417 participants 60 years of age or older.40 Although total sleep time and quality improved with sedatives compared to placebo, adverse events were much higher. In people using any sedative compared with placebo, adverse cognitive events were 4.78 times more common (95% CI 1.47 to 15.47, P < 0.01), adverse psychomotor events were 2.61 times more common (1.12 to 6.09, P > 0.05), and reports of daytime fatigue were 3.82 times more common (1.88 to 7.80, P < 0.001). Because of these findings, one must use extreme caution if prescribing any sedatives to people older than the age of 60.
Over-the-Counter Medications. Most patients begin self-treatment with alcohol or antihistamines sold under several brand names. Alcohol may reduce time to sleep but can interfere with sleep quality and increases the risk of dependence over time. Diphenhydramine also is not without risk. In addition to delirium, adverse effects include dry mouth, blurred vision, urinary retention, constipation, and risk of increased intraocular pressure in individuals with narrow angle glaucoma.
Benzodiazepines. There are five of these medications that have been on the market for several years: estazolam, flurazepam, quazepam, temazepam, and triazolam. They are approved by the FDA for the short-term management (less than 35 days) of insomnia.
Adverse effects associated with these medications include residual daytime sedation, cognitive impairment, motor incoordination, dependence, and rebound insomnia. These side effects often are worse in the elderly.
Benzodiazepine Receptor Agonists. Three nonbenzodiazepine hypnotics with shorter half-lives have become available in the past decade: zaleplon, zolpidem, eszopiclone. Abuse and dependence appear to be less common than with benzodiaepines, and side effects are less pronounced, probably because of the shorter half-lives.
Zolpidem, an imidazopyridine, is currently the most widely prescribed hypnotic in the United States. Although structurally not benzodiazepines, zaleplon and zolpidem bind differentially to the benzodiazepine type 1 site on the gamma-aminobutyric acid subtype A chloride-ion channel complex. Both are rapidly absorbed and have short onsets of action. Zalpelon has a shorter time to peak concentration (1 hour vs 2 hours) and a shorter elimination half-life (1 hour vs 1.5-3.2 hours) than zolpidem.41
Zolpidem also has an extended release formulation. Relative to placebo, zolpidem-CR 12.5 mg significantly improved sleep induction, maintenance, and total duration in a recent randomized controlled trial.42 There was no evidence of next-day residual effects as measured objectively by psychometric tests, but some rebound insomnia was noted on the first night after abrupt discontinuation following 2 weeks of therapy. This resolved the following night.
Eszopiclone is a cyclopyrrolone derivative unrelated to benzodiaepines that also enhances the actions of gamma-aminobutyric acid. It was introduced in the U.S. market in April 2005, but is the steroisomer of zopiclone, which has been available in Norway since 1988.43
A recent randomized controlled trial of eszopiclone 3 mg nightly vs. placebo in 788 adults aged 21-69 years with chronic insomnia provided evidence of sustained efficacy for 6 months for insomnia treatment.44 As early as the first week and for each subsequent month, eszopiclone produced significant improvements in sleep latency, wake time after sleep onset, number of awakenings, number of nights awakened per week, total sleep time, and quality of sleep compared with placebo (P < 0.003). Tolerance did not develop. The most common side effects were unpleasant taste, headache, infection, pain, nausea, and pharyngitis.
When the subjects in this double-blind study who were randomized to placebo were switched to an open-label 6-month extension, they also experienced significant improvement in sleep parameters compared to baseline at all monthly endpoints (P < 0.0001). The also had improved ratings of daytime functioning and well-being and no development of tolerance. The initial treatment subjects continued to report treatment gains for all sleep and daytime parameters during the 6-month extension. Unpleasant taste continued as the predominant side effect.45
Melatonin Receptor Agonist. Ramelteon, a potent agonist for the melatonin MT1 and MT2 brain receptors, has recently been granted approval by the FDA for the treatment of insomnia associated with sleep onset. The drug has not exhibited potential for abuse or dependency in laboratory tests, nor does it interact with neurotransmitter receptors most associated with these phenomena, hence it has the great advantage of being a nonscheduled drug. Few data have been published in peer-reviewed journals describing its efficacy and side effects in patients with insomnia; however, side effects noted to date appear minor. No comparison study has been performed to determine whether the recommended dose of ramelteon 8 mg has any advantage over physiologic doses of melatonin (0.3 mg), particularly for long-term use.46,47
In healthy adults (35-65 years) ramelteon doses from 4 mg to as high as 64 mg were compared to placebo.48 Mean T(max) values of 0.75 to 0.94 hours and mean elimination half-life of 0.83 to 1.90 hours remained relatively constant. Ramelteon was extensively metabolized. Besides ramelteon, four metabolites, M-I, M-II, M-III, and M-IV, were measured in serum. Metabolite M-II, which has shown weak ramelteon-like activity in vitro, was the major metabolite in serum. Digit Symbol Substitution Test and visual analog scale alertness scores were similar across all dose groups and did not differ from placebo. All adverse events were mild or moderate and resolved before study completion.
A multi-center randomized controlled trial of 829 older adults (65 years or older) with chronic insomnia compared ramelteon 4 mg or ramelteon 8 mg with placebo taken nightly for five weeks.49 Sleep data were obtained from patient diaries. Both doses of ramelteon produced statistically significant reductions in sleep latency over placebo, but the absolute differences in sleep latency time at week 5 with ramelteon 8 mg (57.7 vs 70.6 min; P < .001) do not seem to be that clinically impressive. Patient self-report on an outpatient basis also has limitations. Adverse effects were mild or moderate, and no rebound insomnia or withdrawal symptoms were noted on discontinuation. (See Table 7 for information on pharmacotherapy for insomnia.)
| Table 7. Pharmacotherapy for Insomnia |
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Melatonin. Melatonin is a natural hormone produced by the pineal gland that may be deficient in people suffering from insomnia. Melatonin is not approved by the FDA for treatment of insomnia. A small case control study comparing serially measured evening melatonin blood levels in 20 cases of primary insomnia (10 men and 10 women, average age of 53.9) found that cases had significantly lower levels of melatonin (P = 0.028) than controls.34 Their study had a few limitations. Because they only sampled subjects from 6 to 11 p.m. and not up to 3 a.m., the usual time of peak melatonin secretion, they cannot tell whether the patients with insomnia had just a delayed peak or an overall lowering of melatonin output. The lowered plasma melatonin also could be associated with insomnia-induced mild anxiety or depression rather than the insomnia itself.
Whatever the cause of the lowered melatonin levels, low dose melatonin does appear to be effective for insomnia and have minimal side effects. Garfinkel50 confirmed lowered peak excretion of the main melatonin metabolite 6-sulphatoxymelatonin during the night in 12 subjects with insomnia and then randomized them in a double-blind crossover study to receive 2 mg per night of controlled-release melatonin for 3 weeks followed by 3 weeks of placebo after a one week washout period. They found that although total sleep time was not affected, sleep efficiency (83 vs 75 p < 0.001) and wake time after sleep onset (49 vs 73 min, p < 0.001) were significantly greater after melatonin than after placebo. Two patients experienced pruritus, one in the melatonin group and one in the placebo group.
Because benzodiazepines may inhibit melatonin, Garfinkel51 conducted a small randomized, double-blind, crossover study in 21 elderly subjects who were taking benzodiazepines and had low melatonin output. Subjects were treated for three weeks with 2 mg per night of controlled-release melatonin and for 3 weeks with placebo 2 hours before the desired bedtime. They assessed sleep by wrist actigraphy and found that melatonin significantly improved all aspects of sleep quality over placebo, in the presence of benzodiazepines.
In another melatonin study that included formal polysomnography,52 volunteers were given melatonin oral doses of 0.3 or 1.0 mg or placebo at 6, 8, or 9 p.m. Either dose given at any of the three time points decreased sleep onset latency and latency to stage 2 sleep. Melatonin did not suppress REM sleep or delay its onset. At either dose, subjects did not experience "hangover" effects, confirmed by mood and performance tests the morning after treatment, again suggesting its efficacy and safety.
There is little data available on long-term use in insomnia, but a review of evidence by the Agency for Healthcare Research and Quality (AHRQ) did conclude that melatonin is safe over a "period of days or weeks, at relatively high doses and in various formulations."53 Side effects include nightmares and headache.
Off-label Use of Antidepressants. Although not FDA-approved for insomnia, trazodone, doxepin, amitriptyline, paroxetine, and mirtazepine have all been prescribed for insomnia. They may be effective in the short-term but have several potential risks, and therefore cannot be recommended for non-depression uses. A recent 6-week randomized controlled trial of paroxetine in adults older than 55 years did not improve sleep efficiency.54,39
Future Directions
In June 2005, the National Institutes of Health convened a conference of many sleep experts to review the existing literature and make recommendations for future research in the management of insomnia.11 They recommended large-scale and multisite randomized controlled trials to compare effective pharmacologic agents with each other, with CBT, and with combination therapy. In addition, alternative and over-the-counter remedies should be evaluated formally. Costs and cost-effectiveness of the various treatments should be measured. Development of instruments for assessment of insomnia with attention to ease of administration and cross-cultural applicability would be a great aid to primary care physicians.
Summary
Insomnia is a common complaint of patients in primary care and can be a frustrating issue for both patient and physician. By taking a thorough sleep history, the physician can more clearly diagnosis the sleep difficulty and recommend the appropriate treatment. Encourage patients with voluntary sleep reduction to evaluate their life circumstances and make adjustments to increase sleep duration. Gaining knowledge of sleep hygiene and stimulus control measures will empower patients to make changes before resorting to medications.
- Query all perimenopausal women, patients with depression and anxiety, and older patients with comorbidities about sleep habits.
- Chronic sleep deprivation increases risks for type 2 diabetes in men, hypertension, obesity, and depression.
- Cognitive behavioral therapy is more effective than pharmacotherapy and should be the treatment of choice in chronic insomnia.
- Hypnotics should be reserved for short-term use in acute insomnia and avoided in patients older than 60 years.
- The shorter-acting nonbenzodiazepine receptor agonists probably are preferable to the older benzodiazepines because of shorter half-life and no demonstrated rebound insomnia or withdrawal symptoms.
- Melatonin and the melatonin receptor agonist appear to be safe for short-term use in older adults.
- Patients who have symptoms suggestive of sleep-related breathing disorders or chronic insomnia refractory to simple lifestyle change should be referred to a sleep disorders center.
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