Primary Psychiatry. 2006;13(8 suppl 4):1-16.
This CME is Expired
This monograph supplement is sponsored by The Chatham Institute. Funding for this monograph has been provided through an educational grant by sanofi-aventis U.S.
An Expert Review of Clinical Challenges in Primary Care and Psychiatry
The Chatham Institute is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. The Chatham Institute designates this continuing medical education activity for a maximum of 1.5 Category 1 credits toward the AMA Physician’s Recognition Award. Each physician should claim only those credits that were actually spent in the educational activity.
This activity is sponsored by The Chatham Institute and is supported by an educational grant from sanofi-aventis U.S.
Credit will be awarded upon successful completion of assessment questions (70% or better) and completion of program evaluation. If a score of 70% or better is not achieved, no credit will be awarded and the participant will be notified.
This activity is designed to meet the educational needs of psychiatrists and primary care physicians.
• Explain the comorbid relationship of insomnia and depression
• Identify risk factors for insomnia and determine appropriate screening and diagnosis of insomnia
• Review the nonpharmacologic management of insomnia
• Explain the comorbid relationship of insomnia and depression
• Describe medication treatment options for insomnia, including guidelines, targeted to type and etiology
• Illustrate specific subtopics, including the management of chronic insomnia in the elderly
To Receive Credit for this Activity
Read this monograph supplement. Then complete the posttest and evaluation form and mail or fax it to the The Chatham Institute at:
26 Main Street
Suite #350 – Program T6V22-MG Chatham, NJ 07928 Fax: 800-239-2984
To obtain credit, you should score 70% or better. The estimated time to complete this activity is 1.5 hours. Expiration date: August 1, 2007.
Faculty Affiliations and Disclosure
David N. Neubauer, MD, is assistant professor in the Department of Psychiatry at Johns Hopkins University School of Medicine and medical director of the Psychiatry Mobile Treatment Services at Johns Hopkins Bayview Medical Center in Baltimore, Maryland. He is also associate director of the Johns Hopkins Sleep Disorders Center.
Dr. Neubauer has received consulting fees from Neurocrine Bioscience Inc., Pfizer Inc., sanofi aventis U.S., and Takeda Pharmaceuticals North America.
• Insomnia remains underdiagnosed and undertreated despite a high prevalence.
• Distinguishing primary insomnia from sleep disorders that occur with comorbid conditions optimizes patient outcomes.
• Newer benzodiazepine receptor agonists are effective with fewer side effects than older benzodiazepine agonists.
• Long-term data from clinical trials lasting 6 months to 1 year have been published for hypnotics, including eszopiclone, zaleplon, and zolpidem extended-release.
Despite a high prevalence in the United States, insomnia remains underdiagnosed and undertreated. Extensive research has identified several factors that contribute to the inadequate treatment of insomnia, including the failure of patients to report insomnia to physicians, limited physician training, and physician misconceptions about the risks associated with hypnotic medications. To achieve optimal patient outcomes, physicians differentiate acute from chronic insomnia and distinguish primary insomnia from sleep disorders that occur with comorbid conditions, most notably psychiatric illnesses such as circadian rhythm disturbances. In addition, they utilize sleep hygiene measures, behavioral therapy, and/or pharmacologic medications to improve sleep problems in patients with insomnia. Newer nonbenzodiazepine receptor agonists are effective with fewer side effects than older benzodiazepine agonists; however, in 2005 a National Institutes of Health panel on chronic insomnia management indicated that clinical trials are needed to establish the long-term benefits of the newer drugs. Since 2005, data from clinical trials lasting 6 months to 1 year have been published for hypnotics including eszopiclone, zaleplon, and zolpidem extended-release. As the result of potentially altered dosing and monitoring, elderly patients require special consideration.
Chronic insomnia is a major public health concern in the United States, affecting millions of individuals, their families, and communities.1 Insomnia can be a primary or comorbid disorder with other serious conditions, including depression, medical disorders, and medications. As a result, an accurate diagnosis is critical in developing effective treatment strategies for patients.
Primary care physicians (PCPs) play a crucial role in diagnosing insomnia, which may affect as many as 69% of their patients.2 Typically, PCPs are the first physicians to see patients who seek medical advice for insomnia that affects daily function. PCPs as well as psychiatrists, who treat insomnia associated with psychiatric disorders, employ a variety of behavioral and pharmacologic approaches in managing patients with insomnia. A lack of physician training in both diagnosing and managing insomnia and misconceptions about the efficacy and risk of hypnotic medications are barriers to optimal treatment.3 Although evidence supports the efficacy of behavioral therapy, benzodiazepine (BZD) receptor agonists, and melatonin receptor agonists, more clinical trials are needed to determine the long-term benefits of these approaches. In 2005 and 2006, there were several new long-term (6 months to 1 year) clinical trials assessing efficacy of nonbenzodiazepines (non-BZDs). Despite these advances, additional education and research are crucial in providing physicians with more informed choices regarding treatment options.1
Definition of Insomnia
A common sleep disorder, insomnia affects millions of adults in the US.1 Among ~25% of people in the US who reported experiencing insomnia, 42% experienced sleep problems nearly every night and 88% have had difficulty sleeping for more than a year.4 Nearly 25% of people with insomnia experience multiple symptoms, such as difficulty falling asleep, staying asleep, and poor sleep quality (Figure 1).4
The Diagnostic and Statistical Manual of Mental Disorders defines insomnia as impairment observed in social, occupational, personal, or other important areas of function as a result of fatigue or mood disturbances resulting from disrupted sleep.5 A fourth characteristic, nonrestorative sleep, in which the individual does not feel rested upon awakening, is currently excluded from the definition because it is unclear whether people with the complaint share similar pathophysiologic mechanisms with people who experience the other complaints.1
Acute insomnia ranges from several days to a few weeks while transient insomnia occurs episodically and infrequently. Chronic insomnia occurs for at least 1 month and often lasts much longer, and typically has been refractory to treatment. Many people seek treatment when chronic insomnia affects their ability to function properly during the day. The causes of chronic insomnia may be multifactorial and may include psychiatric disorders, medical or neurological illnesses, substance abuse, environmental factors, circadian rhythm disturbances, and poor sleep hygiene. Daytime consequences of chronic insomnia may include sleepiness, fatigue, increased absence from work, diminished ability to accomplish tasks, relationship problems, nodding off during daily activities, irritability, poor concentration, and limited enjoyment of family and social life.2,4,6,7 Insomnia negatively affects vitality, social function, and mental health, with nearly the same impact as chronic conditions such as congestive heart failure or clinical depression (Figure 2).8
Insomnia and Psychiatric Illness
Although some people experience insomnia as a primary condition, the majority experience sleep problems in conjunction with comorbid conditions. Medical illnesses, psychiatric disorders, pharmacologic agents, and sleep disorders such as obstructive sleep apnea, restless legs syndrome, and periodic limb movement disorder that includes nocturnal myoclonus, may be associated with insomnia (Figure 3).1 Insomnia and comorbid conditions should be treated simultaneously to ensure optimal patient outcomes. In some cases, treatment of the comorbid condition resolves the insomnia.
A strong correlation between insomnia and psychiatric disorders has been established. In some cases, insomnia predisposes individuals to psychiatric disorders; in other cases, psychiatric illness increases the likelihood of insomnia. A survey by the National Institutes of Mental Health (NIMH), for example, revealed that 40% of people with insomnia have a comorbid psychiatric disorder.9 Breslau and colleagues10 identified insomnia as a major predictor of the subsequent development of major depressive disorder (MDD) in young Americans. Specifically, people who experience symptoms of insomnia, including trouble falling asleep, staying asleep, or waking too early, nearly every day for 2 weeks may be at increased risk for MDD. Although thoughts of suicide and psychomotor changes in people are examples of predictors of depression, insomnia may be a more useful marker because physicians may more easily recognize and document it.10
In other research establishing a link between insomnia and depression, ~90% of patients with depression reported sleep disturbances documented by electroencephalogram.9 Sleep problems in patients with depression are often typified by increased sleep latency, frequent awakenings, waking too early, and disruption of the rapid eye movement stage.9
Insomnia may be a symptom of depression or may precede the onset of a depressive episode.9 The NIMH Epidemiologic Catchment Area Study indicates that people with chronic insomnia and a psychiatric illness have an increased risk of developing a new psychiatric disorder over time.9 The study, based on interviews with 7,954 people, compared rates of psychiatric disorders and insomnia at baseline and 1-year follow up. As Figure 4 illustrates, the incidence of new cases of MDD and anxiety disorders was higher for respondents with insomnia compared with those whose insomnia resolved at the 1-year follow up (14% versus 0.6% for MDD; 25.6% versus 7.4% for anxiety disorders, respectively).11 In addition, the incidence of new cases of any psychiatric disorder was almost three times as high for respondents who still had insomnia compared with those who no longer experienced insomnia (33.6% versus 12.7%, respectively).11
Assessment and Diagnosis
As part of a routine assessment of a patient with sleep problems, physicians should consider the following risk factors for insomnia: older age; female gender, especially post- and perimenopausal women; being divorced, separated, or widowed; medical conditions, including arthritis, heart failure, and gastrointestinal disorders; psychiatric illness, including depression and anxiety; smoking cigarettes; alcohol intake; caffeine use; and use of prescription drugs that disturb sleep1 (eg, activating antidepressants, including selective serotonin reuptake inhibitors [SSRIs] and monoamine oxidase inhibitors.
Direct queries regarding a patient’s sleep history are important because >50% of people who think they have chronic insomnia do not inform their physician.6 Physicians may differentiate acute from chronic insomnia by asking patients about the nature of the sleep disorder and when sleep problems began. They assess medical or psychiatric illnesses to identify comorbid conditions that may contribute to sleep problems. To identify the effects of insomnia on daily life, physicians may inquire about daytime function. To more clearly define insomnia, some physicians recommend that patients keep a sleep diary for 1 to 2 weeks to track their quality of sleep, use of sleep medications, total sleep time (TST), time to sleep onset, number of awakenings, and other factors.6
Nonpharmacologic Treatment of Insomnia
Although sleep hygiene measures may not resolve insomnia, they are typically included in a behavioral approach to insomnia treatment.3 In patients whose sleep problems are caused by poor habits, sleep hygiene may be sufficient treatment. Sleep hygiene measures include: waking at the same time every day; discontinuing caffeine 4–6 hours before bedtime and minimizing daily use; avoiding alcohol and heavy meals close to bedtime; avoiding exercise within 3–4 hours of bedtime and exercising in the late afternoon on a regular basis; minimizing disturbing light during sleep period; adjusting bedroom temperature to a comfortable level3,6; limiting time in bed to sleep and sex only (no reading, watching television, or working); and avoiding daytime napping.
In addition, physicians may start patients on sleep restriction, stimulus control therapy, or other behavioral treatments to change bedtime habits that contribute to sleep problems.6 Using the sleep restriction method, patients limit their time in bed to short periods, gradually increasing the time each day. By creating a mild form of sleep deprivation, the approach results in more rapid sleep onset and better sleep overall.6 With stimulus control therapy, patients do not go to bed at their usual bedtime but only when they feel sleepy. If patients get into bed and feel restless or agitated, they should rise, perform a relaxing activity, and return to bed when they feel drowsy. Relaxation therapy includes techniques such as progressive muscle relaxation or biofeedback to reduce somatic tensions or intrusive thoughts that interfere with sleep.6
Multi-faceted cognitive behavioral therapy (CBT) is a psychologic and behavioral approach that targets dysfunctional beliefs and attitudes toward sleep.6 In a study of 75 patients with chronic insomnia, patients treated with CBT experienced improvement in TST and middle wake after sleep onset (WASO) compared with patients treated with muscle relaxation or placebo (Figure 5).12 Despite its proven effectiveness, a best-practice model that defines the optimal number and duration of sessions has not been established.6 As a result, CBT is limited to specialists and is underutilized in primary care. Combined with behavioral treatments, however, CBT has demonstrated efficacy comparable with prescription medications for short-term treatment of insomnia.6
A Review of Pharmacologic Treatment
Approved Hypnotic Therapy
The ideal hypnotic agent has been described as one that would induce sleep within 30 minutes; maintain a normal sleep pattern for 6–8 hours without suppression of rapid eye movement; sustain minimally effective plasma drug levels without an excessively high initial dose or evidence of accumulation with repeated doses; be safe on overdose; would avoid tolerance or dependence; and would not result in withdrawal symptoms when discontinued.13,14 While no such ideal hypnotic exists, the benefit/risk profile of approved hypnotics has dramatically improved over the last 2 decades.
Older approved medications for treating insomnia include the BZDs estazolam, flurazepam, quazepam, temazepam, and triazolam. These agents act at the BZ receptor on the g-aminobutyric acid (GABA)A complex to increase sedation; however, BZDs are nonselective and bind to both the BZD receptor involved in sleep (GABAA receptor, α1 subunit) and other nonsleep mediating receptor subtypes. In addition, many of these agents have active metabolites and long half-lives (extending for days) that can lead to excessive daytime sedation. In the elderly, additional sedation often is associated with falls and injuries.15
While BZDs decrease sleep latency and increase duration of sleep, their nonselectivity and pharmacokinetic properties contribute to the adverse-event profile. Side effects include daytime sedation, cognitive impairment, lack of motor coordination, dependence and abuse, tolerance, and rebound insomnia after withdrawal.1,16,17
The non-BZDs are newer agents first introduced in the 1990s that bind preferentially to the sleep-mediating GABAA receptor, a1 subunit. As Table 1 illustrates, these drugs do not have clinically relevant active metabolites or long half-lives (range: 1–6 hours in adults). The non-BZDs available in the US are, in order of approval, zolpidem, zaleplon, eszopiclone, and zolpidem extended-release. Both their shorter half-lives and more selective binding contribute to the improved safety profile of these drugs compared with older benzodiazepines.1
The emergence of shorter half-life hypnotic drugs, such as zolpidem and zaleplon and short-to-moderate half-life hypnotic drugs, such as eszopiclone are important developments in attaining the goal of an ideal hypnotic.14 In addition to rapid absorption, the drugs offer a fast onset of action, a proven efficacy for sleep-onset latency, and rapid elimination, reducing the likelihood of residual effects.14 Eszopiclone, zolpidem extended-release, and ramelteon can be used for longer periods of time than benzodiazepines approved for short-term use by the Food and Drug Administration (FDA).
A review of clinical trials of the non-BZD hypnotics demonstrates their efficacy in treating insomnia. A summary of recent clinical trials, with a focus on studies of longer duration, are summarized below.
Zolpidem and Zolpidem Extended-Release
Zolpidem is indicated for the short-term treatment of insomnia and to decrease the time to sleep onset. Zolpidem extended-release is indicated for insomnia characterized by difficulties with sleep onset and/or sleep maintenance. Zolpidem extended-release provides an immediate release followed by a prolonged release of zolpidem tartrate.18
The efficacy and safety of zolpidem extended-release was assessed in a double-blind, randomized, controlled trial. Patients (mean age 44.3 years) with primary insomnia received zolpidem extended-release 12.5 mg or placebo nightly for 3 weeks. Zolpidem extended-release resulted in improved sleep onset and sleep maintenance (reduced polysomnographic wake time after sleep onset during the first 6 hours of sleep) (Figure 6). There was no evidence of next-day residual effects. Rebound insomnia was apparent on the first night following abrupt treatment discontinuation, but did not occur on the second night.18
Researchers theorized that the extended period of elevated plasma levels, corresponding to the middle of the night, should translate into improved sleep maintenance without residual effects in patients with insomnia.19 Pharmacodynamic studies have found that compared with original zolpidem, zolpidem extended-release improved measures of sleep maintenance (eg, number of awakenings and return to sleep following awakening) in healthy volunteers with artificially created sleep difficulties (Figure 7).
Intermittent zolpidem taken as needed (3–5 days per week) was assessed in a placebo-controlled, double-blind 12-week study. The study demonstrated a significant improvement in sleep latency without development of tolerance (increase in pills per week) or evidence of rebound insomnia (Figure 8).20 Of 199 patients randomly assigned to treatment, 98 received zolpidem. Of that group of 98 patients, 7 discontinued treatment within the first 4 weeks. None of the adverse events, which included excessive sleepiness, headache, and drowsiness, were rated as severe.20 Zolpidem extended-release use on an as-needed basis has also been studied in a long-term, 24-week, double-blind trial. Adults with chronic primary insomnia took placebo or zolpidem extended-release 12.5 mg 3–7 nights per week for 24 weeks.21 Efficacy was assessed by daily morning questionnaires and Patient Global Impression (PGI) and Clinical Global Impression (CGI) scales every fourth week. Using the PGI, 89.8% and 92.3% of the zolpidem extended-release group reported the treatment helped them sleep versus 51.4% and 59.7% of placebo patients, respectively, at weeks 12 and 24. The percentage of patients who reported much or very much improved sleep according to CGI was significantly greater at each 4-week treatment interval (P<.0001, all time points) compared with placebo. For baseline adjusted analysis at 6 months, zolpidem extended-release significantly improved TST, sleep-onset latency, WASO, and number of awakenings compared with placebo. There was no observed tolerance or rebound insomnia on discontinuation. The results support the safety and efficacy of long-term use of zolpidem extended-release for managing long-term insomnia.21
In a study of the residual psychomotor and cognitive effects of hypnotic medication on 18 healthy young adults, a single dose of zolpidem extended-release and flurazepam improved falling asleep and perceived quality of sleep on subjective scales, while only flurazepam significantly impaired ease of wakening and reduced alertness. Subjects’ performance on the Critical Flicker Fusion Frequency Test, Choice Reaction Time, Immediate and Delayed Word Recall, and the Compensatory Tracking Task was significantly impaired by flurazepam (P<0.01 for each test) but not by zolpidem extended-release. Neither drug significantly affected performance on the Digit Symbol Substitution Test (DSST).22
Zaleplon is indicated for the short-term treatment of insomnia and to decrease the time to sleep onset. To determine efficacy and safety of sustained hypnotic therapy for treating insomnia, researchers conducted a 1-year, open-label extension of two randomized, double-blind trials of zaleplon. In the open-label phase, elderly patients took zaleplon 5 mg or 10 mg nightly for up to 12 months and were then followed for a 7-day, run-out period. The patients, aged 65–95 years, demonstrated significantly improved time to sleep onset (Figure 9), duration of sleep, and number of awakenings.23 They did not experience rebound insomnia on discontinuation of zaleplon.
Eszopiclone is indicated for the treatment of insomnia and has efficacy in treating both sleep onset and sleep maintenance. Patients with chronic primary insomnia experienced significant improvement in sleep and daytime function throughout all monthly time points in a 6-month, open-label extension study of eszopiclone in the treatment of chronic insomnia. Patients switched from placebo to eszopiclone 3 mg and patients who remained on eszopiclone showed significant and sustained improvement in WASO (Figure 10) and other parameters, including sleep latency, number of awakenings, TST, sleep quality, and daytime function.24 Patients did not develop tolerance.
Melatonin Receptor Agonists
Another newer agent, ramelteon, is a melatonin receptor agonist. Melatonin type 1 and 2 receptors (MT1 and MT2) mediate melatonin’s effect on circadian rhythms. Approved in 2005 for the treatment of sleep-onset symptoms of insomnia, this medication has no effect on the GABA receptor complex or other receptor subtypes known to be involved with addiction. Because there is no addiction, dependence, or withdrawal, ramelteon is the first nonscheduled hypnotic. Studies up to 5 weeks’ duration are available for ramelteon. For example, in a 5-week study of adults aged 18–64 years with chronic insomnia, ramelteon 8 mg significantly reduced sleep latency at weeks 1, 3, and 5 compared with placebo (Figure 11) measured by polysomnography. In addition, objective TST and sleep efficiency also were significantly improved at week 1 (P<.001), but this difference was not maintained at a statistically significant level throughout the 5 weeks. Ramelteon 8 mg was not associated with clinically relevant residual effects as assessed by DSST, memory tests, visual analogue scale, and postsleep questionnaire items. Patients aged 65 years with chronic insomnia experienced significant improvement in sleep latency measured by polysomnography (P=.005) but did not report significant differences in subjectively measured sleep latency or TST.25 In addition, ramelteon has not been associated with withdrawal syndrome or rebound insomnia. Because it lacks the potential for abuse or dependence, ramelteon is not a controlled substance.25
To date, all of the nonbenzodiazepine FDA-approved hypnotics are well tolerated, with no clinical evidence to suggest significant differences in side effects. Headache at varying rates is a side effect common to all the hypnotics. Other side effects include dry mouth and unpleasant taste with eszopiclone; fatigue and nausea with zaleplon; drowsiness and dizziness with zolpidem; dizziness with zolpidem extended-release; and dizziness and fatigue with ramelteon.26,27
For patients who have a history of insomnia and MDD or who are currently experiencing symptoms of MDD, physicians should consider a treatment strategy that includes an antidepressant. Physicians need to be aware of the importance of treating both insomnia and depression; focusing on one condition more than the other can have effects that do not benefit patients. Data show that coexisting insomnia and depression may be treated successfully when both conditions are targeted simultaneously. A study of >500 patients with insomnia and new MDD who received coadministration of fluoxetine with a dose range of 20–40 mg/day and eszopiclone 3 mg experienced significant improvement in sleep and depression symptoms.28 Patients received medication for 8 weeks, with subjective sleep and daytime function assessed weekly. The initiation of therapy with combination fluoxetine and eszopiclone significantly improved sleep latency, TST, WASO, sleep quality, sleep depth, and daytime alertness and a faster onset of antidepressant effects.28
When prescribing combination therapy, practitioners must consider the combined effects of both medications on the patient’s depression and insomnia, including the possibility of additional or more serious side effects or additive adverse effects such as daytime somnolence and drug interactions that may require dose adjustments. Overall, data show that combination therapy improves insomnia in patients with depression. In one study, nearly 200 patients whose symptoms of depression were stabilized with a SSRI (either fluoxetine [≤40 mg/day], sertraline [≤100 mg/day], or paroxetine [≤40 mg/day]) reported that they also experienced persistent insomnia. When zolpidem was prescribed for insomnia in addition to the SSRI therapy for depression, patients experienced improved sleep, longer sleep times, fewer awakenings, and better daytime functioning compared with placebo.29 There was no evidence of dependence or withdrawal associated with zolpidem use.
Off-label Use of Psychiatric Drugs
Off-label use of psychiatric medications to treat symptoms of insomnia is not recommended by the National Institutes of Health.1 For example, there are no studies demonstrating the effectiveness and safety of antipsychotics such as quetiapine in insomnia; therefore, these agents cannot be recommended to treat symptoms of insomnia.1
In recent years, the off-label use of antidepressant medication to treat insomnia has increased significantly, despite concerns of potentially serious side effects. Although the antidepressant medication trazodone accounts for 22% of insomnia prescription share in the US,30 a lack of efficacy data and an adverse-event profile that includes sedation, dizziness, dry mouth, psychomotor impairment, priapism, and cardiovascular events including orthostatic hypotension do not support its widespread use.31 A clinical trial comparing trazodone and the nonbenzodiazepine zolpidem found that both drugs shortened subjective sleep-onset latency after 1 week; however, the effect was not present in the trazodone group after 2 weeks of treatment (zolpidem continued to improve sleep onset after 2 weeks). While subjective sleep duration was significantly improved in both groups after 1 week, neither group was significantly different from placebo at week 2. The incidence of side effects in both treatment groups was low.32
Over-the-Counter Herbal Therapies
Patients often self-medicate with over-the-counter products (eg, diphenhydramine) or alcohol.1 Limited evidence has established the effectiveness of valerian, a popular herbal remedy thought to promote sleep.1 In addition, case reports suggest an association between valerian products and hepatotoxicity.1 Because the FDA does not regulate herbal or diet supplements, the amount of active ingredient varies among preparations. No systematic evidence supports the effectiveness of antihistamines, commonly used nonprescription agents that cause such adverse effects as daytime sleepiness and cognitive impairment.1 Melatonin, a natural hormone that may affect circadian rhythms, has not clearly demonstrated effectiveness in treating insomnia.1 Although short-term use of melatonin is considered safe, no data exist on the safety of long-term use, and it also is not regulated by the FDA.1
Managing Chronic Insomnia in the Elderly
Age-related concerns in the elderly affect treatment considerations for insomnia. As the result of impaired metabolism and excretion, elderly patients are typically prescribed lower doses of most medications. Body distribution of fat and muscle also changes in the elderly. Because psychotropics are lipophilic, they exert a more pronounced effect in the elderly, which often results in more adverse events.
A clinical concern is that use of hypnotics could increase the risk of falls in elderly patients. Among elderly patients, falls are the main cause of injury-related deaths and the leading cause of hospital admissions for trauma.15 A study of 34,163 nursing home residents with a mean age of 84±8 years (Figure 12), however, demonstrated that insomnia, rather than hypnotic medications used to treat the condition, predicted falls in elderly patients.15 The study found that untreated patients were at higher risk for falls than those treated with hypnotic medication, possibly because disturbed sleep resulted in elderly patients rising in the middle of the night, increasing their risk of falling.
Differential Diagnosis of Sleep Apnea
For patients with sleep apnea, treatment may begin with weight loss recommendations. Continuous positive airway pressure (CPAP) should be prescribed for moderate-to-severe sleep apnea. Patients who are stabilized on CPAP and have sleep problems, possibly from the appliance, may utilize nonmedication approaches and/or be prescribed a sleep aid. A preliminary trial suggests that zaleplon does not adversely affect respiratory function in patients with mild-to-moderate sleep apnea.33
Distinguishing sleep apnea from insomnia can be a challenge for physicians because the presenting symptoms may be similar. In one study, women with symptoms of sleep apnea/hypopnea syndrome and women with insomnia alone experienced overlapping symptoms.34 Patients with sleep apnea reported daytime fatigue and sleeping <6.5 hours. In addition, >40% of patients with sleep apnea reported difficulty falling asleep at bedtime, difficulty falling asleep after waking during the night, waking too early in the morning, and feeling unrefreshed on awaking,34 symptoms that also have been associated with insomnia. Symptoms suggestive of sleep apnea, including snoring, waking unable to breathe, waking with dry mouth, and daytime fatigue, indicate the need for further evaluation that may include polysomnography.
Sleep apnea has been identified as a public health concern, making its diagnosis crucial.35 In addition to drowsiness and memory loss, sleep apnea has been associated with hypertension, congestive heart failure, coronary artery disease, cardiac arrhythmias, diabetes, and stroke.34
Accurate diagnosis of insomnia is critical for effective, individualized treatment strategies (Table 2). With a thorough assessment of patients’ sleep practices and disorders, physicians can distinguish between transient and chronic insomnia, primary and comorbid insomnia related to psychiatric or other illnesses, and insomnia and suspected sleep apnea. While sleep hygiene education should be provided to all patients with sleep disturbances, cognitive behavioral therapies may benefit some patients. Pharmacologic options must be reviewed on the basis of risk/benefit ratios and the suitability of agents for individual patients based on such factors as severity of symptoms, age, or renal or hepatic impairment.
The approval of newer benzodiazepine receptor agonists has established a new treatment paradigm for insomnia. The FDA has approved eszopiclone, zolpidem extended-release, and ramelteon without limiting the duration of treatment,26 broadening the scope of insomnia management. The non-BZD hypnotics have robust efficacy and a low risk of daytime somnolence, development of tolerance, dependence, withdrawal symptoms, and/or rebound insomnia.26 Clinical trials suggest that use of non-BZD hypnotics has not contributed to abuse.2
Finally, ongoing evaluation and follow up to assess the effectiveness of therapy will optimize patient outcomes.
The case study of JD illustrates a typical challenge encountered by primary care physicians (PCPs) in diagnosing and treating insomnia. JD, a woman 34 years of age, started experiencing sleep problems a few weeks earlier following separation from her husband. Her history indicated that she previously experienced sleep problems during times of stress. She generally felt down after sleeping poorly and found that over-the-counter agents left her drowsy the following day.
Although she was in good health and felt better after exercising, physical activity did not improve JD’s sleep. She had no history of depression or alcohol or drug abuse and reported enjoying activities with friends.
Because insomnia may occur as a primary condition or in association with comorbid conditions, the diagnosis was challenging. For JD, possible diagnoses include acute/transient insomnia; chronic insomnia; depression; and depression with acute/transient insomnia. Based on her history and symptoms, JD was diagnosed with acute/transient insomnia, started on nonpharmacologic interventions, including sleep hygiene measures and relaxation therapy, and scheduled for a follow-up visit.
At the follow up, JD reported continued difficulty falling asleep or maintaining sleep. Because her insomnia was unresolved, a hypnotic agent was added to her treatment.
A married 77-year-old man, AP experienced long-standing insomnia, with sleep-onset problems and sleep maintenance symptoms varying over time. His medical history included type 2 diabetes with peripheral neuropathy and breakthrough foot pain at night that exacerbated his already disturbed sleep. Although his symptoms had improved with hypnotic therapy in the past, he was concerned about long-term use of hypnotic medication.
Because hypnotic therapy previously improved his symptoms, AP was prescribed a non-BZD hypnotic with an indication for both sleep onset and sleep maintenance symptoms. He also was educated about the long-term benefits and risks of hypnotic medication, including how to use his medication appropriately.
A 52-year-old trial attorney, DR experienced long-term sleep maintenance problems that had been exacerbated by work-related stress. DR woke 4 or 5 times each night with dry mouth and the need to urinate, but easily returned to sleep. Because his snoring had worsened, his wife slept in a separate bedroom. He had gained 25 lbs during the last 3 years. He was concerned about low energy levels, worsening fatigue, memory and attention impairment, and recent tendencies toward depression. He explained that, in the past, intermittent use of a non-BZD hypnotic had been effective. The suspected diagnosis was sleep apnea. A sleep evaluation was recommended to confirm sleep apnea.
1. National Institutes of Health. National Institutes of Health state of the science conference statement on manifestations and management of chronic insomnia in adults.Sleep. 2005;28:1049-1057.
2. Shochat T, Umphress J, Ancoli-Israel S. Insomnia in primary care patients. Sleep. 1999;22(S2):359-365.
3. Benca RM. Diagnosis and treatment of chronic insomnia: A review. Psychiatr Serv. 2005;56:332-343.
4. Leger D, Poursain B. An international survey of insomnia: Under-recognition and under-treatment of a polysymptomatic condition. Curr Med Res Opin. 2005;21:1785-1792.
5. Sleep Disorders. In: Diagnostic and Statistical Manual of Mental Disorders. 4th ed, text rev. Washington, DC: American Psychiatric Association; 1994:597-662.
6. National Heart, Lung, and Blood Institute, National Institutes of Health. Insomnia: Assessment and management in primary care. www.nhlbi.nih.gov/health/prof/sleep/insom_pc.pdf. Accessed January 9, 2006.
7. Ohayon MM, Paiva T. Global sleep dissatisfaction for the assessment of insomnia severity in the general population of Portugal. Sleep Med. 2005;6:435-441.
8. Katz DA, McHorney CA. The relationship between insomnia and health-related quality of life in patients with chronic illness. J Fam Pract. 2002;51:229-235.
9. Kupfer DJ. Pathophysiology and management of insomnia during depression. Ann Clin Psychiatry. 1999;11:267-276.
10. Breslau N, Roth T, Rosenthal L, Andreski P. Sleep disturbance and psychiatric disorders: A longitudinal epidemiological study of young adults. Biol Psychiatry. 1996;39:411-418.
11. Ford, DE, Kamerow DB. Epidemiologic study of sleep disturbances and psychiatric disorders. JAMA. 1989;262:1479-1484.
12. Edinger JD, Wohlgemuth WK, Radtke RA, Marsh GR, Quillian RE. Cognitive behavioral therapy for treatment of chronic primary insomnia. A randomized controlled trial. JAMA. 2001;285:1856-1864.
13. Greeff O. Good night—do patients really sleep well on all hypnotics? www.medpharm.co.za/safp/2001/nov/goodnight.html. Accessed November 1, 2005.
14. Greenblatt DJ. Pharmacokinetic determinants of hypnotic drug action: The art and science of controlling release. Sleep Med. 2006 May 12; [Epub ahead of print] doi:10.1016/j.sleep.2006.03.002.
15. Avidan AY, Fries BE, James ML, Szafara KL, Wright GT, Chervin RD. Insomnia and hypnotic use, recorded in the minimum data set, as predictors of falls and hip fractures in Michigan nursing homes. J Am Geriatr Soc. 2005;53:955-962.
16. Holbrook A, Crowther R, Lotter A, Cheng C, King D. Meta-analysis of benzodiazepine use in the treatment of insomnia. CMAJ. 2000;162:225-233.
17. Dawson GR, Collinson N, Atack JR. Development of subtype selective GABAA modulators. CNS Spectr. 2005;10:21-27.
18. Roth T, Soubrane C, Titeux L, Walsh J, on behalf of the zoladult study group. Efficacy and safety of zolpidem-MR: A double-blind, placebo-controlled study in adults with primary insomnia. Sleep Med. In press.
19. Weinling E, McDougall S, Andre F, Bianchetti G, Dubruc C. Pharmacokinetic profile of a new modified release formulation of zolpidem designed to improve sleep maintenance. Fundam Clin Pharmacol. 2006;20:397-403.
20. Perlis ML, McCall WV, Krystal AD, Walsh JK. Long-term, non-nightly administration of zolpidem in the treatment of patients with primary insomnia. J Clin Psychiatry. 2004;65:1128-1137.
21. Erman M, Krystal A, Zammit G, Soubrane C, Roth T, on behalf of the Zolong study group. Zolpidem extended-release 12.5-mg, taken for 24 weeks “as needed” up to 7 nights/week improves subjective measures of therapeutic global impression, sleep onset, and sleep maintenance in patients with chronic insomnia. Int J Neuropsychopharmacol. 2006;9(suppl 2):S251.
22. Blin O, Micallef J, Audebert C, Legangneux E. A double-blind, placebo- and flurazepam-controlled investigation of the residual psychomotor and cognitive effects of modified-release zolpidem in young healthy volunteers. J Clin Pharmacol. 2006;26:284-289.
23. Ancoli-Israel S, Richardson GS, Mangano RM, Jenkins L, Hall P, Jones WS. Long-term use of sedative hypnotics in older patients with insomnia. Sleep Med. 2005;6:107-113.
24. Roth T, Walsh JK, Krystal A, Wessel T, Roehrs TA. An evaluation of the efficacy and safety of eszopiclone over 12 months in patients with chronic primary insomnia. Sleep Med. 2005;6:487-495.
25. McGechan A, Wellington K. Ramelteon. CNS Drugs. 2005;19:1057-1065.
26. Physicians’ Desk Reference. 60th ed. Montvale, NJ: Thomson PDR; 2006: 1686-1690, 2867-2871, 3228-3231.
27. Moen MD, Plosker GL. Zolpidem extended-release. CNS Drugs. 2006;20:419-426.
28. Fava M, McCall WV, Krystal A, et al. Eszopiclone Co-Administered With Fluoxetine in Patients With Insomnia Coexisting With Major Depressive Disorder. Biol Psychiatry. 2006;59:1052-1060.
29. Asnis GM, Charkraburtty A, DuBoff EA, et al. Zolpidem for persistent insomnia in SSRI-treated depressed patients. J Clin Psychiatry. 1999;60:668-676.
30. Author unlisted. Health Care Sector Overview. New York, NY; Cowen and Company: April 7, 2006.
31. Mendelson W. A review of the evidence for the efficacy and safety of trazodone in insomnia. J Clin Psychiatry. 2005;66:469-476.
32. Walsh JK, Erman M, Erwin CR, et al. Subjective hypnotic efficacy of trazodone and zolpidem in DSMIII-R primary insomnia. Hum Psychopharmacol. 1998;13:191-198.
33. George CF. Perspectives on the management of insomnia in patients with chronic respiratory disorders. Sleep. 2000;23(suppl 1):S31-S35.
34. Bailes S, Baltzan M, Alapin I, Fichten C, Libman E. Diagnostic indicators of sleep apnea in older women and men: A prospective study. J Psychosom Res. 2005;59:365-373.
35. Westbrook PR, Levendowski DJ, Cvetinovic M, et al. Description and validation of the apnea risk evaluation system. A novel method to diagnose sleep apnea-hypopnea in the home. Chest. 2005;128:2166-2175.