Seminar Insomnia Michael J Sateia , Peter D Nowell Lancet 2004; 364: 1959–73 Effective management of insomnia begins with recognition and adequate ...

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Insomnia Michael J Sateia , Peter D Nowell

Lancet 2004; 364: 1959–73

Effective management of insomnia begins with recognition and adequate assessment. Family doctors and other health care providers such as practice nurses and psychologists should routinely enquire about sleep habits as a component of overall health assessment. Identification and treatment of primary psychiatric disorders, medical conditions, circadian disorders, or specific physiological sleep disorders—eg, sleep apnoea and periodic limb movement disorder—are essential steps in management of insomnia. Conditioned aspects of insomnia can be primary (psychophysiological insomnia) or may complicate sleep disturbance owing to other causes. Approved hypnotic drugs have clearly been shown to improve subjective and objective sleep measures in various short-term situations. Despite widespread use of standard hypnotics and sedating antidepressants for chronic insomnia, their role for this indication still remains to be further defined by research evidence. Non-pharmacological treatments, particularly stimulus control and sleep restriction, are effective for conditioned aspects of insomnia and are associated with durable long-term improvement in sleep. “Disease exists, if either sleep or watchfulness be excessive” Hippocrates, Aphorism LXXI

Doctors have recognised for millennia that disturbances of sleep constitute significant health problems. Unfortunately, recognition and treatment of abnormalities of the sleep-wake system, and complications thereof, have lagged well behind the expansion of knowledge and technical capabilities in the area of sleep medicine. For no disorder is this discrepancy more apparent than insomnia. Although much is still to be learned about the pathophysiology of the disorder, identification, systematic assessment, and appropriate treatment are clearly beneficial to patients. Here, we focus on developments in epidemiology, pathophysiology, assessment, and treatment of insomnia. More extensive discussion of fundamental clinical aspects is available from various sources.1,2

Dartmouth Medical School, Dartmouth-Hitchcock Sleep Disorders Center, Lebanon, NH 03756, USA (Prof M J Sateia MD, P D Nowell MD) Correspondence to: Prof Michael J Sateia [email protected]

ioned the interpretation that increasing age is inevitably associated with greater likelihood of sleep disturbance.4,8 Rather, progressive inactivity, dissatisfaction with social life, and presence of medical and psychiatric illness can be most predictive of insomnia in old people.9 Higher rates of insomnia are seen in women, people who are less educated or unemployed, separated or divorced individuals, medically ill patients, and those with depression, anxiety, or substance abuse.2 In many epidemiological studies, insomnia has been correlated with frequent use of medical resources,6,10–13 chronic health problems,7,13–17 perceived poor health,16 increased use of drugs,7,10 and specific medical difficulties including airways disease,18–20 hypertension,20 musculoskeletal and other painful disorders,18,19,21–23 heart disease,18,22 and prostate problems.18

Search strategy and selection criteria

Epidemiology Prevalence The reported prevalence of insomnia depends on the methods and definitions used in epidemiological studies. In early investigations,2 a prevalence of 5–35% was noted, which was dependent on descriptors used, severity, chronicity, age-group, and sampling bias. The importance of distinguishing between insomnia symptoms and genuine dissatisfaction with sleep is underscored by findings of one epidemiological study,3 which showed that 36·2% of people reported insomnia but only one in four of these described sleep dissatisfaction. Patients who have dissatisfaction with sleep have characteristics most usually associated with clinically significant insomnia. In another study,4 researchers used somewhat more stringent criteria (including a requirement of daytime consequences), which still yielded a prevalence for severe insomnia of 10–15%. Rates of insomnia with associated daytime dysfunction in attendees of general medical practices range from 10% to as high as 34%.5–7 Historically, high prevalence of insomnia has been noted in older people. Some investigators have Vol 364 November 27, 2004

A comprehensive search focused on assessment of chronic insomnia formed the basis of a previous review for the American Academy of Sleep Medicine and is described therein.2 This search was updated from 1999 to May, 2004, searching the keyword insomnia, restricted to human beings, English language, on MEDLINE and the Cochrane database of systematic reviews. The major focus was on original research related to epidemiology, evaluation, diagnosis, psychophysiological and behavioural characteristics, pharmacotherapy and non-pharmacological therapy. Articles were selected for review based on the following criteria: 1) randomised, controlled non-pharmacological and pharmacological trials; 2) controlled trials that provided relevant new information about assessment methodology or characteristics of insomnia; and 3) meta-analyses and evidencebased reviews of assessment or therapeutic modalities. Because of necessary limitations in referencing and the large number of articles, those that provided relevant new information and meta-analyses that themselves provide comprehensive reference lists were given preference for citation.



Complications Insomnia is associated with various adverse outcomes and complications. Specific daytime dysfunctions are discussed in a later section. Growing evidence shows that chronic unremitting insomnia may predispose to development of psychiatric disorders.24–26 These investigations show increased risk for new onset of depression, anxiety disorders, and substance abuse problems in people with persistent insomnia. These data alone, however, do not conclusively establish cause and effect, but must be viewed as a potentially important motivation for clinicians to identify and treat chronic insomnia problems. Demonstration of reduction of risk for psychiatric disorders in response to effective treatment of insomnia awaits further study. Individuals with clinical sleep disorders have great impairment in quality of life.6,12,27 This association seems to hold true even when comorbid conditions are adequately controlled. The degree of impairment correlates with severity of sleep disturbance and, for people with severe insomnia, rivals or exceeds the impairment noted in other chronic medical disorders such as diabetes, arthritis, or heart disease.4 Occupational adjustment, physical and social role functioning, and mental health are compromised. Affected individuals report diminished energy, concentration, and memory disturbance. Consistent with role limitations, absenteeism from work is also increased. Economic implications and use of health-care services represent important public-health aspects of insomnia. Associated costs include not only the direct costs of diagnosis and treatment (including prescription and non-prescription drugs and self-medication with alcohol) but also substantial additional indirect costs related to absenteeism, diminished productivity, accidents, and other health problems that are, at least in part, secondary to the insomnia.28–30 Health-care use is substantially greater in patients with insomnia. Increased health-care costs and raised likelihood of doctor consultation and emergency visits, laboratory tests, and prescription and over-the-counter drug use have been described in such patients.6,7

Clinical assessment In the clinical setting, insomnia is operationally defined by the patient’s subjective report of difficulty initiating or maintaining sleep, early awakening, and interrupted or non-restorative sleep. Although research studies sometimes need to apply specific quantitative definitions (eg, >30 min sleep-onset latency), in clinical practice such measures can be misleading. The subjective perception of insomnia is at least as important as the objective alterations in sleep and, therefore, the disorder is best assessed and treated with this idea in mind. Most chronic insomnia is not reported to health-care providers, who in turn do not actively elicit information 1960

Panel 1: Assessment of insomnia Initial screening Identify the nature of the complaint ● Difficulty initiating or maintaining sleep? ● Early awakening? ● Non-restorative sleep? Daytime consequences? ● Absence of consequences suggests clinical insignificance or short sleeper Frequency of complaint ● More than 2–3 nights per week in chronic insomnia Duration of complaint ● 1 month=subacute or chronic Additional history for persistent insomnia Precipitating events, course, progression Ameliorating or exacerbating factors ● Worsened by stress, medical, or psychological factors? ● Better when not trying to sleep, or away from home? ● Conditioned arousal in response to efforts to sleep? Sleep-wake schedule ● Sleep logs—evidence for delay, advance, or irregular pattern? ● Shift work? Other nocturnal symptoms or events Nightmares, terror, panic, behavioural (parasomnia), headache, pain, reflux, nocturia, night sweats, hot flash, sleep paralysis, hallucinations Associated behaviours ● Pre-bedtime rituals (eg, physical, emotional, or cognitive overactivity before sleep), nocturnal waking behaviours (eg, prolonged time in bed awake versus getting up or type of activity), food or substance ingestion Cognitions ● Negative expectations ("I’ll never get to sleep") ● Distortions ("I have to get 8 h to function"; "I should stay in bed and rest if I can’t sleep"; "I must have a pill to sleep") ● Catastrophisation ("If I can’t sleep I can’t work . . . I can’t function . . . my life will fall apart") Previous treatments—response and attitudes Assess for precipitating or causative factors Psychiatric disorder ● Mood, anxiety, other psychiatric disorders Substance misuse or medication use ● Bronchodilators, steroids, diuretics, stimulants (caffeine), antihypertensives, activating antidepressants, hypnotic rebound Medical/neurological illness ● Chronic pain, nocturnal headache, gastro-oesophageal reflux, chronic lung disease, nocturnal angina, congestive heart failure, end-stage renal disease, cancer, HIV/AIDS, menopause, dementias, stroke Sleep disorder ● Obstructive sleep apnoea—heavy snoring, reports of apnoea, daytime sleepiness ● Restless legs, periodic movement in sleep Vol 364 November 27, 2004


from patients about sleep disturbance.5,31 This omission could be attributable to the fact that most doctors receive little education about diagnosis and nonpharmacological treatment of insomnia.32 Without adequate time and a knowledge base for comprehensive assessment, the primary recourse has been use of hypnotic drugs. Most doctors have heard the message that long-term hypnotic use is not the recommended therapeutic approach, as reflected in declining rates of such prescriptions in many countries. Yet, health-care providers have not been provided with realistic alternative approaches for addressing this disorder. The essential component in assessment of chronic insomnia is a comprehensive history (panel 1). In the primary-care setting, doctors should focus on screening for treatable psychiatric disorders (eg, clinical depression or anxiety disorder), specific physiological sleep disorders such as respiratory disturbance or restless legs, and drugs or substances or medical conditions that might be contributing to insomnia. Further assessment, which can be accomplished at the primary-care or consultant level, includes careful analysis of sleep-wake schedule, more detailed identification of sleep-related symptoms, and recognition of the cognitive and behavioural factors that are usually key in the perpetuation of sleep disturbance. A history of the course of the disorder and results of previous treatment interventions are essential. Sleep medicine clinicians might use various diagnostic methods to assess insomnia. The most basic and important of these is the sleep log, which, although subjective, provides a more specific and accurate estimate of the reported sleep disturbance than global reports.2,33 Sleep questionnaires such as the Pittsburg sleep quality index can provide information about sleep quality, timing, and duration.34 Other methods assess specific aspects of insomnia, sleep-related breathing disorders, or consequences of sleep disturbance.35–39 Polysomnography (sleep study) is generally not indicated for standard clinical assessment of insomnia.40 However, evidence of true pathological sleepiness, significant snoring, and observed apnoea, or in some cases, periodic limb movement disorder, should prompt consideration of laboratory assessment. In elderly people, a high prevalence of physiological disorders that can contribute to insomnia suggests that the threshold for ordering such studies should be somewhat lower. Actigraphy, an indirect measure of sleep-wake by means of movement recording, can be a helpful adjunct in assessment of some patients with insomnia, although current practice does not call for its routine use in assessment.41

Consequences A complaint of insomnia must, by definition, include a subjective report of daytime consequences. In fact, fear of daytime sequelae fuels much concern for patients Vol 364 November 27, 2004

with insomnia. Reduced total sleep time without such complications suggests that the individual may be a physiologically short sleeper. The most typical subjective reports include fatigue or diminished motivation, cognitive dysfunction (reduced concentration, vigilance, short-term memory disturbance), psychological disturbance (depression, anxiety, irritability), impaired psychomotor performance, and non-specific physical complaints such as headache, musculoskeletal problems, or gastrointestinal disturbance.42,43 Objective measures of impairment do not provide unequivocal evidence of global dysfunction. Although findings of some investigations suggest reduced vigilance, psychomotor slowing, or memory disturbance, results of studies are mixed, and the degree of dysfunction is generally mild and of uncertain functional importance.2 Although we could conclude, as most individuals with insomnia do, that the daytime difficulties experienced in association with insomnia are the direct result of sleep deprivation, current evidence suggests that this conclusion might not be entirely accurate. Rather, data indicate that hyperarousal has an important role in development of the daytime symptom profile.44 Enhanced psychophysiological arousal can give rise to both sleep disturbance and daytime consequences. From a clinical perspective, this occurrence suggests that improvement in nocturnal sleep does not guarantee corresponding improvement in daytime function and that function could improve without corresponding improvement in sleep.45 The issue of sleepiness in insomnia patients deserves further comment. Sleepiness is defined by recurrent episodes of drowsiness or involuntary dozing that arise mainly in sedentary situations. This condition should not be confused with fatigue or tiredness, which are less specific terms endorsed by many insomnia patients. Although subjective reports of sleepiness are not uncommon in people with insomnia, in many studies in which the multiple sleep latency test was used as an objective measure of sleepiness, normal or even heightened levels of daytime alertness were recorded.44,46–48 Therefore, individuals with an insomnia complaint who manifest convincing evidence of genuine sleepiness should be assessed for potential causes of sleepiness, such as sleep apnoea, periodic limb movement, or primary hypersomnolence disorders.

Psychological and psychophysiological characteristics Many psychological assessments show increased levels of depression and anxiety in patients with insomnia, including those with no diagnosable psychiatric illness.49–52 Available lines of evidence suggest that psychopathological findings are not secondary to sleep deprivation but, rather, are a primary characteristic that can have a role in the development of insomnia. 1961


Physiological assessment is consistent with a pattern of hyperarousal, which is shown by raised body temperature, heart rate, and electromyographic activity.44,53 24 h metabolic rate is consistently enhanced in primary insomnia, but not in sleep-deprived healthy individuals.44 Investigations of hypothalamic-pituitary-adrenal axis function have shown mixed results, but some findings suggest elevation of urinary free cortisol concentrations, which correlate with wake time.54 Catecholamine metabolites likewise show correlations with measures of sleep disturbance.54 Quantitative electroencephalogram analysis indicates an increase in beta frequencies at sleep onset and during non-REM (rapid eye movement) sleep. This rise in fast frequencies is correlated with, and could partly account for, the discrepancy between subjective reports and objective measures of sleep in insomnia.55,56

Evolution of the disorder Successful treatment of insomnia is dependent on accurate identification of precipitating causes and perpetuating factors. Most acute or short-term insomnias are related to situational stress, medical or psychological disorders, or circadian issues such as jet lag. In most cases, extensive assessment is not necessary to define the proximate cause. Interventions are mainly oriented to alleviation of the acute stress, patients’ education, and short-term treatment strategies emphasising sleep hygiene and, when necessary, hypnotics. Development of chronic insomnia is a more complex process. Many theoretical models of the development of chronic sleep disturbance have been proposed. The oftcited multidimensional model of chronic insomnia proposed by Spielman57 focuses on predisposing, precipitating, and perpetuating factors in the long-term evolution of insomnia. Some individuals, perhaps by virtue of psychophysiological traits that might predispose to heightened arousal or reactivity, are more prone to poor sleep than others. Specific stressors such as a medical event, psychiatric illness, time zone change, or psychological, social, or occupational stress could precipitate onset of a clinical sleep disturbance. As acute aspects of the condition evolve, patients can become increasingly anxious, frustrated, and agitated about their inability to sleep, fuelling progressive cognitive and physiological arousal that, in turn, breeds further sleep disturbance. Maladaptive strategies, such as increasing time in bed awake, result in conditioning of the bed to waking. Sometimes, unrealistic and distorted concerns about daytime consequences of the sleep disturbance contribute to additional tension. As noted, these perpetuating factors, although central in the evolution of primary insomnia, can complicate insomnia precipitated by any cause. Several models of the evolution of insomnia have been described. All tend to focus particularly on a specific aspect or starting point for the process, 1962

although they are probably best viewed as complementary to one another, rather than exclusive. Harvey58 suggests that, in the face of progressive difficulty sleeping (precipitated by any given cause), susceptible individuals are prone to focus excessively and in an exaggerated fashion on potential daytime consequences. The result of this focus is progressive autonomic and emotional arousal that triggers a cascade of problems, which worsen the disturbance. Excessive negatively toned cognitive activity (regarding the sleep deficiency) results in selective attention that serves to reinforce the perceived threats associated with the disorder. Increasing arousal fuels bodily sensations and cognitive alterations that confirm the patient’s fears about daytime consequences. Thus, chronic insomnia emanates from a cycle of progressively disturbing and distorted cognitive percepts that reinforce and escalate the sleep disturbance. Espie59 posits that the process of chronic sleep disturbance unfolds as a function of factors that interfere with the automaticity and plasticity of normal homoeostatic and circadian sleep drives. In short, he suggests that, unlike normal sleepers or noncomplaining poor sleepers, those with insomnia do not show the requisite ability to accommodate and compensate for normal variability in sleep or daytime function. Instead, they identify such changes as a function of a serious and progressive sleep disturbance (loss of plasticity). The normal process of so-called dearousal and sleep onset, which should arise in routine fashion on an established schedule, is disrupted as a result of intrusive and negatively charged cognitions that interfere with the normally automatic process of dearousal. Other models have focused mainly on disturbance in electroencephalographic patterns (eg, higher frequency at sleep onset) to account for certain aspects of chronic insomnia.60 According to this perspective, higher frequency electroencephalographic activity, which is associated with cognitive hyperarousal and that becomes conditioned to efforts at sleep initiation, results in continued sensory and information processing during the early stages of sleep. As a result, normal anterograde amnesia that accompanies the sleep initiation process does not take place and the patient with insomnia, in effect, fails to disengage from the environment. The model suggests that this occurrence accounts for the discrepancies between objective sleep recordings and subjective reports in this population. Although not stated explicitly in the theory, one would assume that such misjudgments about sleepwake state would give rise to increasing focus on the disturbance and its perceived consequences. In summary, although the pathophysiology of insomnia is not altogether clear, there seems little doubt that a self-sustaining cycle of misperception, apprehension about sleeplessness and its consequences, an exaggerated focus on sleep, and the Vol 364 November 27, 2004


concomitant physiological and cognitive processes accompanying these conditions are key components in the evolution and maintenance of many forms of the long-term condition. Specific precipitating factors in chronic insomnia include: psychiatric disorders; substance abuse; sleepwake schedule disorders; medical or neurological conditions; specific physiological sleep disorders (eg, apnoea, periodic limb movement); and primary insomnia. Although these discrete diagnostic categories are helpful to identify potential causes, we should also recognise that insomnia is typically a complex condition with many contributing factors. Psychiatric disorders, particularly depression, account for up to 40% of cases of chronic insomnia encountered in sleep centres.61 Mood disorders can be comorbid with medical conditions, substance abuse, or other sleep disorders. Insomnia complaints most often focus on sleep continuity disturbances and early awakening. Clinicians should recognise that depressed patients may focus on sleep complaints to the exclusion of mood disorder symptoms. Therefore, a high index of suspicion for underlying depression is necessary. Initial treatment is focused on pharmacological management with antidepressants, alone or in combination with hypnotic drugs. Substances that have been implicated in precipitating or perpetuating sleep disturbance include methylxanthines (caffeine and theophylline compounds) and other stimulants, steroids, certain antihypertensive drugs, and antidepressants such as bupropion. However, few, if any, systematic controlled studies of the role of these substances in chronic insomnia have been undertaken. Insomnia related to shift work is common in industrialised nations.62 Delayed sleep phase is most typical in adolescents and young adults, typically presenting as an inability to fall asleep until a very late hour, accompanied by difficulty arising at conventional times in the morning.63 Advanced sleep phase syndrome is most usually reported in older individuals and can manifest as early awakening. Blind people with non-24 h circadian rhythms normally cycle in and out of periods of poor sleep because their circadian phase fluctuates in and out of synchrony with the normal daynight cycle.64,65 Behavioural adjustments, light therapy, and melatonin are somewhat effective for insomnia associated with certain sleep-wake schedule disorders, although such treatments probably need the management skills of a sleep medicine specialist.66–71 Sleep disturbance accompanies many acute and chronic illnesses and is usually the result of multiple effects, including direct physiological disruption of sleep-wake mechanisms, pain, drug effects, or depression and anxiety in reaction to the illness. Chronic insomnia has been characterised in patients with pain,72–74 cancer,75,76 HIV/AIDS,77,78 chronic lung Vol 364 November 27, 2004

musculoskeletal disorders,82 and disease,79–81 degenerative brain diseases,83 among others. Insomnia and related disturbances of sleep-wake schedule in patients with Alzheimer’s disease and other degenerative disorders are important causes of institutionalisation in this population. Treatment of insomnia associated with these disorders is typically multifactorial and should include not only attention to the primary medical problem but also associated factors such as anxiety, pain, and other somatic complications that might interfere with sleep. Fatal familial insomnia is a prion disease associated with prominent degeneration of the anterior and dorsomedial nuclei of the thalamus. It is a rare autosomal dominant disorder in which severe insomnia is an early complication. The disorder is associated with a mutation at codon 178 of the prion protein gene. The disturbance rapidly progresses to complete sleeplessness, with associated oneiric behaviour, autonomic instability, stupor, coma and death, typically within 6 months to 2 years.84–86 Obstructive sleep apnoea is most usually associated with complaints of excessive sleepiness. However, frequent awakenings due to respiratory disturbance, nocturia, or bed partner-induced arousal might give rise to an insomnia complaint.87 Central sleep apnoea has been more closely linked to insomnia symptoms, but is substantially less common than obstructive apnoea. Primary treatment should begin with appropriate therapies for the breathing abnormalities, such as nasal continuous positive airway pressure for obstructive apnoea. Likewise, periodic limb movement disorder can be associated with both daytime sleepiness and nighttime sleep disruption, although some data have cast doubt on the association between this disorder and insomnia complaints.88,89 Restless legs syndrome, often associated with periodic limb movement, is a waking dysesthesia that can result in inability to initiate sleep or return to sleep after awakening.90,91 Currently, dopaminergic drugs such as pramipexole or levodopa are most usually prescribed by sleep specialists, although other options include gabapentin, opiates, and clonazepam.92 Primary (psychophysiological) insomnia accounts for 12–15% of patients with chronic insomnia.2 Although psychophysiological insomnia is identified as a disorder in its own right, clinicians must recognise that the pathophysiological mechanisms and characteristics that define this disorder are generally seen as complications of other suspected causes of insomnia. The essential features are conditioned arousal in response to efforts to sleep and negative expectations about sleep.1,93 Patients usually become anxious and agitated in the sleep environment because they experience an increasing sense of pressure to go to sleep. Other characteristics include sleeping better when not trying to sleep (eg, watching television) or improved sleep 1963


Panel 2: Non-pharmacological treatments Stimulus control therapy Go to bed only when sleepy; maintain a regular schedule; avoid naps; use the bed only for sleep; if unable to fall asleep (or back to sleep) within 20 min, remove yourself from bed— engage in relaxing activity until drowsy then return to bed— repeat this action as necessary. Sleep restriction Maintain a sleep log; determine mean total sleep time for baseline period; initiate total time in bed=baseline mean total sleep time (not <4·5 h); for sleep efficiency (total sleep time/time in bed) >90% over 5–7 days, increase time in bed by 15 min; for sleep efficiency <80%, decrease time in bed by 15 min; repeat time in bed adjustment every 5–7 days. Sleep hygiene Maintain a regular sleep-wake schedule; do not nap, especially close to bedtime; avoid sleeping in after a poor night; avoid watching the clock; do not lie in bed for prolonged periods awake (see stimulus control); avoid excessive liquids or heavy evening meals; exercise regularly, but not within 3–4 h of bedtime; minimise or avoid caffeine (none after noon), alcohol, tobacco, stimulants. Paradoxical intention Patient is advised to deliberately attempt to remain awake, thereby reducing the performance anxiety that is believed to interfere with ability to initiate sleep. Progressive muscle relaxation A programme involving alternate tensing and relaxing of the muscles, designed to facilitate relaxation and inhibit anxietyassociated arousal that may block sleep. Biofeedback (electromyography, electroencephalography, other) Most commonly muscle biofeedback has been used, with treatment rationale similar to that of progressive muscle relaxation. Other highly specialised biofeedback techniques involving electroencephalography biofeedback (eg, theta or sleep spindle feedback) have had limited application and assessment. Cognitive therapy Also termed restructuring, cognitive therapy attempts to identify maladaptive and distorted cognitions that are common among those with insomnia (eg, "I have a chemical imbalance" or "I will never sleep without medications") and replace these with more adaptive beliefs and attitudes. Multicomponent strategies Current approaches frequently involve combinations of treatments that most usually include sleep hygiene education and stimulus control, sleep restriction therapy, or both. Progressive muscle relaxation and cognitive restructuring are typically used elements as well.


away from the patient’s own bedroom. Overestimation of time to fall asleep or time awake during the night and underestimation of total sleep time are commonplace, although the precise explanation for this occurrence is unclear. Cognitive distortions (eg, “If I don’t sleep 8 h I will be unable to function”) or rumination about inability to sleep and daytime consequences, sometimes perceived in catastrophic terms, further complicate the presentation. See above discussion on Evolution of the disorder for additional detail.

Treatment Treatments for chronic insomnia include drugs such as over-the-counter antihistamine preparations (with or without mild analgesics), benzodiazepine receptor agonists, sedating antidepressants, neuroleptics, melatonin, and herbal remedies such as valerian. The pharmacological approach has remained the most widely used for decades, despite widespread concerns about long-term effectiveness, habituation, tolerance, and potential complications, especially in elderly people. Growing evidence suggests that nonpharmacological treatments, alone or possibly in combination with drugs, produce clinically significant and durable improvement. In considering the summary data about treatments, we should note that, with some recent exceptions (see below), outcome studies of pharmacotherapy are almost entirely restricted to brief treatment duration (less than 6 weeks). Although little doubt exists about the effectiveness of hypnotic drugs for short-term treatment of acute insomnia, evidence shows that the effects of short-term pharmacotherapy trials degrade over time in patients with chronic insomnia.94 By contrast, cognitive-behavioural treatments are durable and robustly effective on longterm follow-up, and the data presented herein include many investigations with follow-up periods of 6 months or longer. In routine practice, pharmacotherapy and various non-pharmacological interventions are sometimes combined. Although clinical experience would seem to suggest that this combined approach might be effective, inadequate data exist to draw reliable conclusions about the use of this dual intervention. Further discussion of the limited data for comparison of pharmacological and non-pharmacological treatments can be found at the conclusion of the treatment section. Non-pharmacological treatments include education and sleep hygiene, stimulus control, sleep restriction, relaxation training, biofeedback (most commonly electromyography), paradoxical intention, and cognitive therapy, and less commonly used techniques such as autogenic training, guided imagery, self-hypnosis, and meditation. These methods can be used individually or in combinations, typically described under the general rubric of cognitive-behavioural therapy. Detailed descriptions of the application and effectiveness of nonpharmacological treatment are beyond the scope of this Vol 364 November 27, 2004


Seminar, but are widely available (panel 2). The following sections focus on summary information, especially that derived from meta-analyses, and reports of effectiveness, durability, application, and response predictors.

Effectiveness Initial meta-analyses of cognitive-behavioural therapy are based mainly on group design investigations with sleep logs to derive outcome measures.95,96 The included studies collectively used many treatment modalities and varying degrees of control and randomisation of patients. They suggest significant effectiveness for nonpharmacological treatments, with large effect sizes of 0·87–0·88 for reduction of sleep latency and 0·94 for improvement in sleep quality and moderate effect sizes of 0·65 for waking after sleep onset, 0·49–0·53 for frequency of awakening, and 0·42–0·49 for total sleep time. In the case of sleep-onset insomnia, effect sizes of 0·87–0·88 suggest that about 80% of treated individuals have shorter sleep latencies compared with controls. In clock terms, mean changes were: reduction of sleep latency from about 65 min to 35 min (ie, a 30 min reduction in time to fall asleep versus about 8 min reduction for controls); reduction in wake time after sleep onset from 70 min to 38 min (32 min reduction vs 10 min for controls); and increase in total sleep time of about 30 min (6·0–6·5 h) versus 4 min in controls. Ratings of sleep quality typically show the most robust improvement, with effect size of 0·94. From available data, one can reasonably conclude that subjective measures of sleep quality show greater improvement than the significant but more modest improvements in polysomnographic variables. This pattern of improvement is consistent with baseline observations that subjective complaints of insomnia patients are disproportionate to objective (polysomnographic) findings. This discrepancy suggests that polysomnography might not be the best measure for assessment of sleep disturbance in insomnia. Development of other assessment procedures awaits further research. Stimulus control treatment,97 sleep restriction,98 and multicomponent strategies that include one or both of these techniques emerge as the most effective strategies. Practice guidelines from the American Academy of Sleep Medicine,99 derived from an evidencebased review of non-pharmacological treatments including the above meta-analyses and individual studies,100 conclude that stimulus control is the standard for effective treatment. Progressive muscle relaxation and paradoxical intention also meet published criteria for well-validated effective treatments, while sleep restriction, biofeedback, and multicomponent strategies are designated as probably efficacious. The lower grading of sleep restriction, a technique widely used by sleep clinicians, might indicate the fewer available Vol 364 November 27, 2004

Morin and colleagues95 Murtagh and Greenwood108 Stimulus control SLat 0·81 WASO 0·70 TST 0·41 Sleep restriction SLat 0·98 WASO 0·76 TST –1·06 Sleep hygiene SLat 0·71 WASO ·· TST 1·16 Paradoxical intention SLat 0·63 WASO 0·81 TST 0·46 Relaxation SLat 0·83 WASO 0·06 TST 0·25 Biofeedback SLat 1·00 WASO 0·70 TST 0·38 Multicomponent SLat 1·05 WASO 0·92 TST 0·75

1·16 ·· 0·38 0·85 ·· 0·37 ·· ·· ·· 0·73 ·· 0·10 0·81 ·· 0·52 ·· ·· ·· 1·00 ·· 0·78

Data are pretreatment to post-treatment difference. SLat=time to onset of sleep. WASO=time awake after onset of sleep. TST=total sleep time.

Table 1: Mean effect sizestreatmentsleep variable

studies of this modality. Sleep hygiene education, although typically a component of treatment, has not been thoroughly investigated as an individual intervention. Those studies that have used only this approach have shown limited improvement. Table 1 shows a summary of effect size by treatment intervention. Six issues arise with respect to the efficacy data presented in these reports. First, although most published data are derived from subjective reporting in the form of sleep logs or diaries, studies that have included polysomnographic data show similar, albeit frequently more modest, improvement.100,101 Second, some caution is advised with respect to interpretation of sleep efficiency data in these treatment studies. Although sleep efficiency is greatly improved, particularly in investigations that include sleep restriction and stimulus control treatments, these interventions can accomplish this improvement mainly by reduction of time in bed, compared with actual increase in total sleep time. Nevertheless, in many studies, enhanced sleep efficiency is accompanied by improvement in sleep latency, waking, or total sleep time. Third, immediate post-treatment improvement does not ensure lasting effectiveness. Findings of metaanalyses indicate that noted improvements have lasting effect, with a mean follow-up period of about 6 months. Later investigations94,100–103 have reported robust 1965


Dose (mg)* Rapid elimination Triazolam§¶ 0·125/0·25 Zolpidem§ 5/10 Zaleplon§ 5/10 Zopiclone 3·75/7·5 Intermediate elimination Temazepam§ 15/30 Lorazepam 0·5/1·0 Slow elimination Flurazepam§ 15/30



Elimination half-life (h)†

Tmax (h)†

Active metabolites

Indications and comments‡

2–3 1·5–4 1·0 5–6

1·0 1·0–1·5 0·5–1·0 0·5–2·0

No No No *

Mainly for sleep onset and possibly sleep maintenance; less accumulation of drug over time; possibly more rebound insomnia, anterograde amnesia, untoward drug reactions described with triazolam

8–15 12–15

1·0–1·5 2·0

No No

Possibly sleep onset, may be preferred for sleep maintenance; less accumulation compared with longer-acting agents

48–120 (n-desalkylflurazepam 48–120 (n-desalkyflurazepam)



Possibly sleep onset but more typically for sleep maintenance; higher risk for daytime sedation and related complications due to drug accumulation, especially in elderly people or those with delayed metabolism



*Recommended starting dose in elderly and medically ill patients/usual recommended dose. †Elimination half-life and Tmax represent estimated averages for healthy adults. ‡All benzodiazepines carry potential for dose escalation and for psychological and physical dependence. §US Food and Drug Administration approved hypnotic. ¶Not available in Norway or the UK. *Active metabolite (S)-desmethylzopiclone currently in development as a hypnotic drug

Table 2: Hypnotic drugs

preservation of improvement with a follow-up as long as 3 years. Fourth, do specific patients’ characteristics predict success of cognitive-behavioural therapy for insomnia? Current evidence suggests that severity is not a limiting factor with respect to outcome. These data suggest that outcomes in populations with more severe sleep disturbance are equivalent, or superior, to those recorded in patients with less severe insomnia.95,103,104 In some early reports, increasing age was associated with more negative outcome of cognitive-behavioural therapy. However, further investigations have shown that this technique can produce outcomes in older groups comparable with those recorded in younger populations when the older patients have been screened for physiological disturbances that can account for their sleep disorder.95 This issue was reviewed in detail by Montgomery and Dennis.105,106 With strict inclusion criteria, they showed evidence for modest improvements with cognitive-behavioural therapy in patients age 60 years or older, although these changes were substantially less than those reported for younger populations and mixed age groups. An investigation comparing two forms of cognitive-behavioural therapy for older adults (60 years) noted significant short and long-term (6 month) improvement with both treatments compared with a waiting list control group.107 Fifth, assessments of the effect of current hypnotic drug use on outcome of cognitive-behavioural therapy show mixed results. Whereas some studies have noted less positive outcomes,108,109 others have shown effectiveness of treatment even in patients given drugs, with high rates of hypnotic discontinuation posttreatment and at follow-up.102,110 Finally, to date, most treatment trials have focused on subjective and, to a lesser extent, objective measures of change in sleep parameters. The effect of these interventions on daytime function and quality of life are sometimes 1966

overlooked, but are important measures of outcome. Such measures probably have an increasingly important role in outcomes assessment moving forward. A challenge that arises with respect to treatment of chronic insomnia is that of moving the therapy out of the rarified domain of specialised sleep clinics and into the day-to-day clinical application. Although no easy solution exists, growing evidence suggests that more routine clinical application of these techniques is at least feasible. Gains comparable with those seen in study participants can be achieved in clinical patients.103,109,111 Moreover, these treatments are effective in management of patients with so-called secondary insomnia problems—ie, insomnia attributable to medical or psychiatric illness.112,113 Cognitivebehavioural interventions can be delivered in individual treatment settings, groups, or by means of self-help programmes (written material, tapes, etc). Although findings of one meta-analysis suggested that individual treatment can be somewhat superior to group, and, likewise, group superior to self-help, the size of the differences is not clear. Group formats have been applied quite successfully with primary insomniacs, older patients, those with secondary insomnia and medical disorders, and in general practice settings.94,102,103,112,113 Although the modal number of treatment sessions is six, improvement in sleep has been reported with as few as two to three sessions.45 Irrespective of the effectiveness of these treatments, to be effective they must be conveniently accessible by most patients with chronic insomnia. Espie and colleagues103 trained health visitors (primary care or visiting nurses) to administer cognitive-behavioural therapies (eg, education, sleep hygiene, stimulus control, sleep restriction, relaxation, and cognitive therapy) to 139 chronic insomnia patients in a general Vol 364 November 27, 2004


practice setting in six group meetings at weekly intervals. Clinically meaningful improvements in sleep latency and wake time after sleep onset were noted, with more modest increases in total sleep time. The effects were sustained at 12-month follow-up. A randomised controlled trial of 209 patients applied cognitivebehavioural therapies in a general practice population of chronic insomnia patients on long-term hypnotic maintenance.114 These treatments were administered by primary care counsellors in six sessions. Analysis indicated: sustained improvements in sleep to 12-month follow-up; reductions in drug use, including discontinuation of hypnotic drugs for many; and costeffectiveness of the approach, particularly when long-term cost considerations are factored into the analysis.

Pharmacological treatment One review cannot sufficiently bridge the gap between the need for more treatment outcome data and current prescribing practices. Therefore, efforts have been made to provide extensive references to primary source material that addresses type of drug, doses, pharmacology, and applications in different populations such as elderly people. In view of the limited understanding of the pathophysiology of primary insomnia, treatments have focused mainly on symptom management. Benzodiazepine-hypnotics, zolpidem, zaleplon, and zopiclone reduce acute insomnia symptoms, but their role in the management of chronic insomnia remains unclear.115–118 In addition to questions about the effectiveness of drugs for treatment of chronic insomnia, concerns also exist about potential sideeffects of hypnotics such as daytime sedation, motor incoordination, cognitive impairments (anterograde amnesia), and related concerns about increases in the risk of motor vehicle accidents and injuries from falls. Chronic hypnotic exposure can also carry additional risks of physical or behavioural dependence, withdrawal, rebound insomnia, and increased mortality.119–123 In response to these concerns, clinicians have reduced prescriptions of traditional hypnotics and increased prescriptions of antidepressants (eg, trazodone, amitriptyline, doxepin).124,125 However, although efficacy studies of antidepressants do exist,126–130 the short-term nature of the study designs and other methodological issues leave many questions. It has also been noted that some antidepressants have serious side-effects themselves, including orthostatic hypotension, cardiac dysrhythmias, and death associated with overdoses.125 Unanimous support for the role of hypnotics in the management of chronic insomnia would be more likely if the benefits of treatment could be clearly shown to outweigh the risks of drug intervention (and the risks of no treatment). The American Academy of Sleep Medicine has published practice guidelines for Vol 364 November 27, 2004

ment of chronic insomnia and the non-pharmacological treatment of insomnia but not for pharmacological intervention.2,99,131 Many agencies have offered regulatory and advisory input about the use of drugs in the treatment of insomnia,132–136 and clinicians and researchers have outlined guidelines for pharmacological management of sleep disturbance.134–138 Most resources are cautious about the long-term prescription of hypnotic drugs. National Institutes of Health consensus conference guidelines discourage the prescription of sedative-hypnotics beyond 4–6 weeks because of concerns raised over drug misuse, dependency, withdrawal, and rebound insomnia.136 Unfortunately, studies designed to establish the effectiveness of sedative-hypnotics in chronic insomnia have several limitations.115 Inclusion and exclusion criteria vary greatly93,115,139,140 and diagnostic criteria have not been rigorously applied, particularly with respect to psychiatric syndromes.141,142 Differential diagnosis in insomnia disorders leads to different treatment recommendations.143 Outcome measures have included various global assessments, symptom checklists, and logs of night-time sleep quality, several polysomnographic measures, and, in a more limited way, measures of daytime functioning. Integration of these measures has not resulted in consensus on definitions of treatment response for use in clinical trials. Duration of treatment in studies using controlled clinical trial design has, with some exceptions, been largely limited to several nights or weeks. For example, in one meta-analysis of the available treatment literature, the median duration of treatment was 7 days and longer-term follow-up data were virtually nonexistent.115 Despite the few data supporting effectiveness with long-term use, studies have shown that patients sometimes do use hypnotics for prolonged periods (months to years).144 This off-label prescribing is presumably based, at least partly, on beliefs about the reliability of evidence from accumulated clinical practice experience and study designs other than longitudinal, controlled clinical trials.145–149 Longer-term treatment trials have begun to emerge that might lend support to the claims of sustained effectiveness and safety with chronic use, at least for some hypnotics. Krystal and colleagues150 showed no loss of effectiveness, no dosage escalation, and few side-effects with sustained use of eszopiclone (+ isomer of zopiclone) over 6 months, and a 12-month open-label extension of that study showed comparable maintenance of effectiveness and safety.151 A review of the safety and efficacy of triazolam— which has been withdrawn in several nations, including the UK, because of concerns about increased rates of CNS adverse effects—by an Institute of Medicine Committee and a task force by the US Food and Drug Administration152 indicates the current assessment procedures and recommendations for hypnotic drugs 1967


and highlights the issues at hand. Recommendations from this committee include: development of mechanisms to improve prescribing practices and patients’ use of hypnotic drugs, with emphasis on the role of appropriate differential diagnosis in patients’ management; encouragement of primary care and other professional societies to increase members’ attention to the need for caution in prescribing hypnotic drugs at higher doses and for longer durations than those recommended; further research to identify the most valid and reliable endpoints for determination of the clinical effectiveness of hypnotic drugs; and development of trial designs that assess intermediate and long-term hypnotic effectiveness. At present, several researchers are attempting to fill the gap in our knowledge of pharmacological interventions by inclusion of multiple drugs and placebo in both acute and maintenance treatment with various outcome measures (global clinical status, subjective and polysomnographic sleep, psychological symptoms, functional status, performance, and several neurobiological and imaging measures) and by assessment of issues of adverse effects, rebound, withdrawal, and recurrence. Other workers are investigating the integration of behavioural treatments with pharmacotherapy, and include longitudinal endpoints as well. Until the results of these studies are available, opinions and debates will continue about the role of hypnotic drugs in chronic insomnia.118 In the absence of comprehensive data, meta-analyses and findings from other sources suggest that hypnotic drugs such as zolpidem and specific benzodiazepines are indicated for short-term (varying definitions, but about 2–6 weeks) treatment of acute insomnia,153,154 such as after a traumatic physical injury155 or acute emotional trauma, and in the short-term management (typically 2 weeks to 6 months) of various forms of chronic insomnia, such as primary insomnia or insomnia secondary to depression (while antidepressants are being implemented).156,157 An effort should be made to use drugs with fast onset and short half-lives for sleeponset problems, to reduce adverse daytime effects. However, the potential for rebound insomnia may be greater with hypnotics of the shortest half-life.119 Zaleplon and triazolam (see above for availability and safety concerns) are shorter-acting drugs that might be more suitable for patients whose insomnia difficulties are mostly at sleep onset. Zolpidem, zopiclone or eszopiclone, and temazepam, also appropriate for sleeponset difficulties, can be helpful for wakefulness after sleep onset because of their longer duration of activity. Table 2 presents pharmacological data for commonly prescribed hypnotics. Pharmacological differences exist between nonspecific hypnotic drugs (such as benzodiazepines) that affect GABA ( aminobutyric acid) receptors and more receptor-specific agents (such as zolpidem, zaleplon, 1968

and zopiclone) that affect a subset of GABA receptors. Theoretically, the drugs that affect a subset of GABA receptors could invoke fewer physiological effects such as muscular relaxation or antiepileptic activity seen with the benzodiazepines. This effect could also translate to reduced occurrence of pharmacological effects such as tolerance and dependence. In studies that included examination of safety and dose-escalation issues with long-term use of non-benzodiazepine hypnotics, evidence of tolerance, withdrawal, or rebound insomnia problems with nightly150,151 and non-nightly158 use was not reported. Hajak and colleagues,159 in a review of case reports and epidemiological data, concluded that evidence of dependence was comparable for zolpidem and zopiclone and substantially lower than that for benzodiazepines. Thus, evidence suggests that risk for dependence is relatively low for currently prescribed non-benzodiazepine hypnotics. However, more research is needed to better define the clinically relevant implications of the differences between drugs. Recommendations suggest that drugs should be used on an intermittent rather than regular basis, with the theoretical appeal of preserving the effectiveness over time. However, recommendations of fixed or flexible dosing strategies are unresolved. There has been some concern, based on conditioning theory, that intermittent (non-nightly) use should not be left to ‘as needed’ but rather should be prescribed as every other night or every third night to reduce the psychological factors that can maintain a focus on pill-taking in patients with chronic insomnia.119 However, several trials report treatment benefit with non-nightly schedules, including those designed with ‘as needed’ use. However, outcome assessment in some of these studies is complicated by the combined use of behavioural interventions such as stimulus control measures.160–162 On the basis of these limited data, whether the long-term, non-nightly strategies will bring about superior outcomes with fewer adverse events is uncertain, despite the commonsense appeal of the intervention. Another novel scheduling strategy includes administration of sedative-hypnotics and anxiolytics during the daytime to target 24 h hyperarousal as the underlying pathology for the primary insomnia (see above). However, results were not robustly positive in view of the specifics of that trial.163 This type of theory-driven approach might bring about more positive results in future trials. In view of the discrepancy between formal guidelines for short-term use of hypnotics and the reality of significant long-term application, several guidelines have been proposed for decision-making and documentation when clinicians choose off-label longerterm prescribing:125 that the insomnia is persistent, not secondary to a psychiatric or medical condition that can be identified and corrected, and not responsive to conservative, non-pharmacological treatments; that the Vol 364 November 27, 2004


patient is reassessed periodically to confirm continued indication for treatment, to assess whether drugs continue to be effective, to confirm that dose escalation has not occurred, to identify any late-emergent sideeffects, to assess interim medical and psychiatric comorbidities, and to continue to assess for other factors such as good sleep hygiene; and that informed consent reflects the off-label use of the hypnotic and that alternative approaches have been discussed. Various modifying circumstances can affect drug use in insomnia. These include age164 (elderly patients might be more at risk for hypnotic-related adverse events such as falls or cognitive impairment), sideeffects (risk of addiction, tolerance, rebound withdrawal),122,165 drug-drug interactions (cometabolism of some antidepressants with some benzodiazepines), cost (availability of generic drugs), patient and provider preference, and access to specialty care in sleep medicine (implementation of behavioural interventions or combined approaches of pharmacotherapy and behavioural interventions). Contraindications for use of standard hypnotic drugs include a history of a substance use disorder, pregnancy and breastfeeding, individuals whose work requires them to preserve the capacity for maximum alertness during their sleep period, and untreated obstructive sleep apnoea syndrome. Drugs have been used to treat jet lag, shift work-related sleep difficulties, and insomnia in the context of ageing,166,167 although specific indications and applications remain somewhat controversial. The role for other potential sleep-promoting drugs in primary insomnia, such as antidepressants,130 antihistamines, chronotherapies (melatonin),168,169 lowenergy emission therapy,170 and alternative therapies such as valerian171 and tryptophan, needs to be defined by outcome data. Although their use might be common, the extent and patterns are difficult to quantify. Trimipramine and doxepin have been assessed in patients with primary insomnia in double-blinded polysomnographic studies with mixed but generally beneficial results, similar to those in benzodiazepine studies. These drugs were better at sleep-continuity improvements and subjective measures than for sleeponset difficulties. In view of the widespread use of trazodone, it would be useful to have controlled clinical trial data, including longitudinal designs, for effectiveness in patients with primary insomnia. Evidence has been extrapolated from treatment trials that include people with depression for whom adjuvant trazodone has been used and generally noted to be beneficial at improving subjective sleep quality and sleep continuity.

Treatment comparisons and combined treatment Direct comparisons of cognitive-behavioural therapy and hypnotic treatments are limited, and assessments Vol 364 November 27, 2004

of the long-term outcomes associated with combined therapy are even scarcer. In a meta-analysis of 21 studies, short-term (1–8 weeks) effects of hypnotic treatment and behavioural therapy for primary insomnia were assessed.172 The two interventions both showed mean effect sizes of greater than 0·85, indicating robust therapeutic effect. Behavioural treatment indicated modest superiority for sleep initiation insomnia. However, we must recognise that the available studies of direct comparisons between pharmacological treatment and cognitive-behavioural therapy indicate that the short-term improvements recorded with drugs might not last. Morin94 noted behavioural and pharmacological (temazepam) treatments of 8 weeks’ duration to be about equally effective in the acute phase of treatment, with findings suggesting that the combined approach could be slightly more effective than either intervention alone. However, at 3, 12, and 24 months’ follow-up, the cognitive-behavioural group showed clear maintenance of improvement whereas the pharmacotherapy group did not. Results for the combined treatment group were mixed. Other direct comparisons have suggested similar outcomes with respect to the durability of cognitive-behavioural therapy versus pharmacological treatment,173 but assessments of a combined approach have been very limited. As previously noted, some studies do suggest that cognitive-behavioural interventions promote reduction in drug use for chronic insomnia patients already receiving pharmacotherapy.114,174 On the basis of the limited data available, the tentative conclusion would seem to be that both forms of treatment (individually) are reasonably effective in the short term, whereas cognitive-behavioural therapy has a clear advantage with respect to maintenance of therapeutic gains. Insufficient information is available to draw reasonable conclusions about the long-term results of combined treatment, but addition of cognitive-behavioural treatment in chronic hypnotic drug users does seem to reduce frequency of use.

Future work Many challenges remain in the characterisation, recognition, and treatment of insomnia. Future research must expand our knowledge of the biological dimensions, as well as the behavioural aspects, of the disorder. New data are emerging for pharmacological and behavioural treatments, but we have yet to achieve a clear understanding of how best to integrate these approaches for maximum effectiveness in a variety of clinical settings. Most importantly, we must educate family doctors about identification and assessment of chronic insomnia. Awareness of effective treatment strategies must be promoted and cost-effective systems for implementation of non-pharmacological treatments should be developed. 1969


Conflict of interest statement We declare that we have no conflict of interest.


Acknowledgments This work was supported in part by grant no K07-HL03646 from the National Heart, Lung, and Blood Institute (MJS). The funding source had no role in this Seminar.


References 1 Morin C. Insomnia: psychological assessment and management. New York: The Guilford Press, 1993. 2 Sateia MJ, Doghramji K, Hauri PJ, Morin CM. Evaluation of chronic insomnia: an American Academy of Sleep Medicine review. Sleep 2000; 23: 243–308. 3 Ohayon MM, Caulet M, Priest RG, Guilleminault C. DSM-IV and ICSD-90 insomnia symptoms and sleep dissatisfaction. Br J Psychiatry 1997; 171: 382–88. 4 Chevalier H, Los F, Boichut D, et al. Evaluation of severe insomnia in the general population: results of a European multinational survey. J Psychopharmacol 1999; 13 (4 Suppl 1): S21–24. 5 Hohagen F, Rink K, Käppler C, et al. Prevalence and treatment of insomnia in general practice: a longitudinal study. Eur Arch Psychiatry Clin Neurosci 1993; 242: 329–36. 6 Hatoum HT, Kania CM, Kong SX, Wong JM, Mendelson WB. Prevalence of insomnia: a survey of the enrollees at five managed care organizations. Am J Manag Care 1998; 4: 79–86. 7 Simon GE, VonKorff M. Prevalence, burden, and treatment of insomnia in primary care. Am J Psychiatry 1997; 154: 1417–23. 8 Ganguli M, Reynolds CF, Gilby JE. Prevalence and persistence of sleep complaints in a rural older community sample: the MoVIES project. J Am Geriatr Soc 1996; 44: 778–84. 9 Ohayon MM, Zulley J, Guilleminault C, Smirne S, Priest RG. How age and daytime activities are related to insomnia in the general population: consequences for older people. J Am Geriatr Soc 2001; 49: 360–66. 10 Leger D, Guilleminault C, Bader G, Levy E, Paillard M. Medical and socio-professional impact of insomnia. Sleep 2002; 25: 625–29. 11 Weyerer S, Dilling H. Prevalence and treatment of insomnia in the community: results from the Upper Bavarian Field Study. Sleep 1991; 14: 392–98. 12 Hajak G. Epidemiology of severe insomnia and its consequences in Germany. Eur Arch Psychiatry Clin Neurosci 2001; 251: 49–56. 13 Ohayon M. Epidemiological study on insomnia in the general population. Sleep 1996; 19 (suppl 3): S7–15. 14 Mellinger G, Balter M, Uhlenhuth E. Insomnia and its treatment: prevalence and correlates. Arch Gen Psychiatry 1985; 42: 25–232. 15 Barbar SI, Enright PL, Boyle P, et al. Sleep disturbances and their correlates in elderly Japanese American men residing in Hawaii. J Gerontology Series A Biol Sci Med Sci 2000; 55: M406–11. 16 Foley DJ, Monjan A, Simonsick EM, Wallace RB, Blazer DG. Incidence and remission of insomnia among elderly adults: an epidemiologic study of 6,800 persons over three years. Sleep 1999; 22 (suppl 2): S366–72. 17 Roberts RE, Shema SJ, Kaplan GA. Prospective data on sleep complaints and associated risk factors in an older cohort. Psychosom Med 1999; 61: 188–96. 18 Katz DA, McHorney CA. Clinical correlates of insomnia in patients with chronic illness. Arch Intern Med 1998; 158: 1099–107. 19 Klink M, Quan S, Kaltenborn W, Lobowitz M. Risk factors associated with complaints of insomnia in a general adult population. Arch Intern Med 1992; 152: 1634–37. 20 Gislason T, Reymisdötter H, Kritbjarnarson H, Benediktsdötter B. Sleep habits and sleep disturbances among the elderly: an epidemiological survey. J Intern Med 1993; 234: 31–39. 21 Janson C, Lindberg E, Gislason T, Elmasry A, Boman G. Insomnia in men: a 10-year prospective population based study. Sleep 2001; 24: 425–30. 22 Jensen E, Dehlin O, Hagberg B, Samuelsson G, Svensson T. Insomnia in an 80-year-old population: relationship to medical, psychological and social factors. J Sleep Res 1998; 7: 183–89. 23 Gislason T, Reymisdötter H, Kritbjarnarson H, Benediktsdötter B. Sleep habits and sleep disturbances among the elderly: an epidemiological survey. J Intern Med 1993; 234: 31–39.




28 29 30 31 32 33






39 40 41

42 43

44 45



48 49



Breslau N, Roth T, Rosenthal L, Andreski P. Sleep disturbance and psychiatric disorders: a longitudinal epidemiological study of young adults. Biol Psychiatry 1996; 39: 411–18. Ford D, Kamerow D. Epidemiologic study of sleep disturbances and psychiatric disorders: an opportunity for prevention? JAMA 1989; 262: 1479–84. Weissman MM, Greenwald S, Nino-Murcia G, Dement WC. The morbidity of insomnia uncomplicated by psychiatric disorders. Gen Hosp Psychiatry 1997; 19: 245–50. Zammit GK, Weiner J, Damato N, Sillup GP, McMillan CA. Quality of life in people with insomnia. Sleep 1999; 22 (suppl 2): S379–85. Chilcott LA, Shapiro CM. The socioeconomic impact of insomnia: an overview. Pharmacoeconomics 1996; 10 (suppl 1): 1–14. Walsh JK, Engelhardt CL. The direct economic costs of insomnia in the United States for 1995. Sleep 1999; 22 (suppl 2): S386–93. Stoller MK. Economic effects of insomnia. Clin Ther 1994; 16: 873–97. Gallup Organization. Sleep in America. Princeton, NJ: Gallup Organization, 1995. Rosen R, Zozula R. Education and training in the field of sleep medicine. Curr Opin Pulm Med 2000; 6: 512–18. Babkoff H, Weller A, Lavidor M. A comparison of prospective and retrospective assessments of sleep. J Clin Epidemiol 1996; 49: 455–60. Buysse D, Reynolds C, Monk T, Berman S, Kupfer D. The Pittsburgh Sleep Quality Index: a new instrument for psychiatric practice and research. Psychiatry Res 1989; 28: 193–213. Morin C, Stone J, Trinkle D, Mercer J, Remsberg S. Dysfunctional beliefs and attitudes about sleep among older adults with and without insomnia complaints. Psychol Aging 1993; 8: 463–67. Douglass AB, Bornstein R, Nino-Murcia G, et al. The Sleep Disorders Questionnaire: I—creation and multivariate structure of SDQ. Sleep 1994; 17: 160–67. Lacks P, Rotert M. Knowledge and practice of sleep hygiene techniques in insomniacs and poor sleepers. Behav Res Ther 1986; 24: 365–68. Regestein Q, Dambrosia J, Hallett M, Murawski B, Paine M. Daytime alertness in patients with primary insomnia. Am J Psychiatry 1993; 150: 1529–34. Johns MW. A new method for measuring daytime sleepiness: the Epworth sleepiness scale. Sleep 1991; 14: 540–45. Chesson AL, Jr., Ferber RA, Fry JM, et al. The indications for polysomnography and related procedures. Sleep 1997; 20: 423–87. Littner M, Kushsida C, Anderson WM, et al. Practice parameters for the role of actigraphy in the study of sleep and circadian rhythms: an update for 2002. Sleep 2003; 26: 337–41. Zammit G. Subjective ratings of the characteristics and sequelae of good and poor sleep in normals. J Clin Psychol 1988; 44: 123–30. Stepanski E, Koshorek G, Zorick F, Glinn M, Roehrs T, Roth T. Characteristics of individuals who do or do not seek treatment for chronic insomnia. Psychosomatics 1989; 30: 421–27. Bonnet MH, Arand DL. The consequences of a week of insomnia. Sleep 1996; 19: 453–61. Means MK, Lichstein KL, Epperson MT, Johnson CT. Relaxation therapy for insomnia: nighttime and day time effects. Behav Res Ther 2000; 38: 665–78. Stepanski E, Zorick F, Roehrs T, Young D, Roth T. Daytime alertness in patients with chronic insomnia compared with asymptomatic control subjects. Sleep 1988; 11: 54–60. Sugerman J, Stern J, Walsh J. Daytime alertness in subjective and objective insomnia: some preliminary findings. Biol Psychiatry 1985; 20: 741–50. Bonnet MH, Arand DL. Physiological activation in patients with Sleep State Misperception. Psychosom Med 1997; 59: 533–40. Vgontzas AN, Kales A, Bixler EO, Manfredi RL, Vela-Bueno A. Usefulness of polysomnographic studies in the differential diagnosis of insomnia. Int J Neurosci 1995; 82: 47–60. Kales A, Caldwell A, Soldatos C, Bixler E, Kales J. Biopsychobehavioral correlates of insomnia: II—pattern specificity and consistency with the MMPI. Psychosom Med 1983; 45: 341–56. Hauri P, Fischer J. Persistent psychophysiological (learned) insomnia. Sleep 1986; 9: 38–53. Vol 364 November 27, 2004



53 54



57 58 59




63 64



67 68 69

70 71




75 76 77


Kalogjera-Sackellares D, Cartwright RD. Comparison of MMPI profiles in medically and psychologically based insomnias. Psychiatry Res 1997; 70: 49–56. Freedman R, Sattler H. Physiological and psychological factors in sleep-onset insomnia. J Abnorm Psychol 1982; 91: 380–89. Vgontzas AN, Tsigos C, Bixler EO, et al. Chronic insomnia and activity of the stress system: a preliminary study. J Psychosom Res 1998; 45: 21–31. Perlis ML, Smith MT, Andrews PJ, Orff H, Giles DE. Beta/Gamma EEG activity in patients with primary and secondary insomnia and good sleeper controls. Sleep 2001; 24: 110–17. Krystal AD, Edinger JD, Wohlgemuth WK, Marsh GR. NREM sleep EEG frequency spectral correlates of sleep complaints in primary insomnia subtypes. Sleep 2002; 25: 630–40. Spielman AJ, Caruso LS, Glovinsky PB. A behavioral perspective on insomnia treatment. Psychiatr Clin North Am 1987; 10: 541–53. Harvey AG. A cognitive model of insomnia. Behav Res Ther 2002; 40: 869–93. Espie CA. Insomnia: conceptual issues in the development, persistence, and treatment of sleep disorder in adults. Annu Rev Psychol 2002; 53: 215–43. Perlis ML, Giles DE, Mendelson WB, Bootzin RR, Wyatt JK. Psychophysiological insomnia: the behavioural model and a neurocognitive perspective. J Sleep Res 1997; 6: 179–88. Buysse DJ, Reynolds CF, 3rd, Kupfer DJ, et al. Clinical diagnoses in 216 insomnia patients using the International Classification of Sleep Disorders (ICSD), DSM-IV and ICD-10 categories: a report from the APA/NIMH DSM-IV Field Trial. Sleep 1994; 17: 630–37. Sack R. Shift work and jet lag. In: Lee-Chiong TL, Sateia MJ, Carskadon MA, eds. Sleep Medicine. Philadelphia: Hanley and Belfus, 2002: 255–63. Regestein QR, Monk TH. Delayed sleep phase syndrome: a review of its clinical aspects. Am J Psychiatry 1995; 152: 602–08. Lockley SW, Skene DJ, Butler LJ, Arendt J. Sleep and activity rhythms are related to circadian phase in the blind. Sleep 1999; 22: 616–23. Leger D, Guilleminault C, Defrance R, Domont A, Paillard M. Prevalence of sleep/wake disorders in persons with blindness. Clin Sci 1999; 97: 193–99. Skene DJ, Lockley SW, Arendt J. Use of melatonin in the treatment of phase shift and sleep disorders. Adv Exp Med Biol 1999; 467: 79–84. Skene DJ, Lockley SW, Arendt J. Melatonin in circadian sleep disorders in the blind. Biol Signals Recept 1999; 8: 90–95. Regestein QR, Pavlova M. Treatment of delayed sleep phase syndrome. Gen Hosp Psychiatry 1995; 17: 335–45. Terman M, Terman JS. Bright light therapy: side effects and benefits across the symptom spectrum. J Clin Psychiatry 1999; 60: 799–808. Cardinali DP, Brusco LI, Lloret SP, Furio AM. Melatonin in sleep disorders and jet-lag. Neuroendocrinol Lett 2002; 23 (suppl 1): 9–13. Eastman CI, Boulos Z, Terman M, Campbell SS, Dijk DJ, Lewy AJ. Light treatment for sleep disorders: consensus report: VI— shift work. J Biol Rhythms 1995; 10: 157–64. Wilson KG, Eriksson MY, D’Eon JL, Mikail SF, Emery PC. Major depression and insomnia in chronic pain. Clin J Pain 2002; 18: 77–83. Smith MT, Perlis ML, Carmody TP, Smith MS, Giles DE. Presleep cognitions in patients with insomnia secondary to chronic pain. J Behav Med 2001; 24: 93–114. Currie SR, Wilson KG, Pontefract AJ, deLaplante L. Cognitivebehavioral treatment of insomnia secondary to chronic pain. J Consult Clin Psychol 2000; 68: 407–16. Savard J, Morin CM. Insomnia in the context of cancer: a review of a neglected problem. J Clin Oncol 2001; 19: 895–908. Davidson JR, MacLean AW, Brundage MD, Schulze K. Sleep disturbance in cancer patients. Soc Sci Med 2002; 54: 1309–21. Rubinstein ML, Selwyn PA. High prevalence of insomnia in an outpatient population with HIV infection. J Acquir Immune Defic Syndr Hum Retrovirol 1998; 19: 260–65. Cohen FL, Ferrans CE, Vizgirda V, Kunkle V, Cloninger L. Sleep in men and women infected with human immunodeficiency virus. Holist Nurs Pract 1996; 10: 33–43. Vol 364 November 27, 2004


Douglas NJ. Sleep in patients with chronic obstructive pulmonary disease. Clin Chest Med 1998; 19: 115–25. 80 McNicholas WT. Impact of sleep in COPD. Chest 2000; 117 (2 suppl): 48S-53S. 81 George CF. Perspectives on the management of insomnia in patients with chronic respiratory disorders. Sleep 2000; 23 (suppl 1): S31–35. 82 Moldofsky H. Rheumatologic disorders and sleep. In: Lee-Chiong TL, Sateia MJ, Carskadon MA, eds. Sleep Medicine. Philadelphia: Hanley and Belfus, 2002: 471–76. 83 Prinz PN PJ, McCurry S. Sleep in the dementing disorders. In: Lee-Chiong TL, Sateia MJ, Carskadon MA, eds. Sleep Medicine. Philadelphia: Hanley and Belfus, 2002: 497–508. 84 Lugaresi I, Medori R, Montagna P, et al. Fatal familial insomnia and dysautonomia with selective degeneration of thalamic nuclei. N Engl J Med 1986; 315: 997–1003. 85 Lugaresi A, Baruzzi A, Cacciari E, et al. Lack of vegetative and endocrine circadian rhythms in fatal familial thalamic degeneration. Clin Endocrinol 1987; 26: 573–80. 86 Medori R, Tritschler HJ, LeBlanc A, et al. Fatal familial insomnia, a prion disease with a mutation at codon 178 of the prion protein gene. N Engl J Med 1992; 326: 444–49. 87 Krakow B, Melendrez D, Ferreira E, et al. Prevalence of insomnia symptoms in patients with sleep-disordered breathing. Chest 2001; 120: 1923–29. 88 Mendelson WB. Are periodic leg movements associated with clinical sleep disturbance? Sleep 1996; 19: 219–23. 89 Karadeniz D, Ondze B, Besset A, Billiard M. Are periodic leg movements during sleep (PLMS) responsible for sleep disruption in insomnia patients? Eur J Neurol 2000; 7: 331–36. 90 Anonymous. Restless legs syndrome: detection and management in primary care. Am Fam Physician 2000; 62: 108–14. 91 Trenkwalder C. Restless legs syndrome and periodic limb movements. Adv Neurol 2002; 89: 145–51. 92 Montplaisir J, Denesle R, Petit D. Pramipexole in the treatment of restless legs syndrome: a follow-up study. Eur J Neurol 2000; 7 (suppl 1): 27–31. 93 American Sleep Disorders Association. International Classification of Sleep Disorders, Diagnostic and Coding Manual. Rochester, MN: American Sleep Disorders Association, 1990. 94 Morin CM, Colecchi C, Stone J, Sood R, Brink D. Behavioral and pharmacological therapies for late-life insomnia: a randomized controlled trial. JAMA 1999; 281: 991–99. 95 Morin CM, Culbert JP, Schwartz SM. Nonpharmacological interventions for insomnia: a meta-analysis of treatment efficacy. Am J Psychiatry 1994; 151: 1172–80. 96 Murtagh DR, Greenwood KM. Identifying effective psychological interventions for insomnia: a meta-analysis. J Consult Clin Psychol 1995; 63: 79–89. 97 Bootzin RR, Nicassion PM. Behavioral treatments for insomnia. In: Hersen M, Eissler R, Miller P, eds. Progress in Behavior Modification. New York, NY: Academic Press, 1978: 1–45. 98 Spielman A, Saskin P, Thorpy M. Treatment of chronic insomnia by restriction of time in bed. Sleep 1987; 10: 45–56. 99 Chesson AL Jr, Anderson WM, Littner M, et al. Practice parameters for the nonpharmacologic treatment of chronic insomnia: an American Academy of Sleep Medicine report. Sleep 1999; 22: 1128–33. 100 Morin CM, Hauri PJ, Espie CA, Spielman AJ, Buysse DJ, Bootzin RR. Nonpharmacologic treatment of chronic insomnia: an American Academy of Sleep Medicine review. Sleep 1999; 22: 1134–56. 101 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: 1856–64. 102 Backhaus J, Hohagen F, Voderholzer U, Riemann D. Long-term effectiveness of a short-term cognitive-behavioral group treatment for primary insomnia. Eur Arch Psychiatry Clin Neurosci 2001; 251: 35–41.



103 Espie CA, Inglis SJ, Tessier S, Harvey L. The clinical effectiveness of cognitive behaviour therapy for chronic insomnia: implementation and evaluation of a sleep clinic in general medical practice. Behav Res Ther 2001; 39: 45–60. 104 Lacks P, Bertelson AD, Sugerman J, Kunkel J. The treatment of sleep-maintenance insomnia with stimulus-control techniques. Behav Res Ther 1983; 21: 291–95. 105 Montgomery P, Dennis J. Cognitive behavioural interventions for sleep problems in adults aged 60+ (Cochrane Review). In: The Cochrane Library, issue 2. Oxford: Update Software, 2002. 106 Montgomery P, Dennis J. A systematic review of nonpharmacological therapies for sleep problems in later life. Sleep Med Rev 2004; 8: 47–62. 107 Pallesen S, Nordhus IH, Kvale G, et al. Behavioral treatment of insomnia in older adults: an open clinical trial comparing two interventions. Behav Res Ther 2003; 41: 31–48. 108 Murtagh DR, Greenwood KM. Identifying effective psychological treatments for insomnia: a meta-analysis. J Consult Clin Psychol 1995; 63: 79–89. 109 Verbeek I, Schreuder K, Declerck G. Evaluation of short-term nonpharmacological treatment of insomnia in a clinical setting. J Psychosom Res 1999; 47: 369–83. 110 Espie CA, Inglis SJ, Harvey L. Predicting clinically significant response to cognitive behavior therapy for chronic insomnia in general medical practice: analysis of outcome data at 12 months posttreatment. J Consult Clin Psychol 2001; 69: 58–66. 111 Perlis ML, Sharpe M, Smith MT, Greenblatt D, Giles D. Behavioral treatment of insomnia: treatment outcome and the relevance of medical and psychiatric morbidity. J Behav Med 2001; 24: 281–96. 112 Lichstein KL, Wilson NM, Johnson CT. Psychological treatment of secondary insomnia. Psychol Aging 2000; 15: 232–40. 113 Davidson JR, Waisberg JL, Brundage MD, MacLean AW. Nonpharmacologic group treatment of insomnia: a preliminary study with cancer survivors. Psychooncology 2001; 10: 389–97. 114 Morgan K, Dixon S, Mathers N, Thompson JJ, Tomeny M. Psychological treatment for insomnia in the regulation of longterm drug use. Health Technol Assess 2004; 8: 1–68. 115 Nowell PD, Mazumdar S, Buysse DJ, Dew MA, Reynolds CF, Kupfer DJ. Benzodiazepines and zolpidem for chronic insomnia: a meta-analysis of treatment efficacy. JAMA 1997; 278: 2170–77. 116 Elie R, Ruther E, Farr I, Emilien G, Salinas E. Sleep latency is shortened during 4 weeks of treatment with zaleplon, a novel nonbenzodiazepine hypnotic. J Clin Psychiatry 1999; 60: 536–44. 117 Hedner J, Yaeche R, Emilien G, Farr I, Salinas E. Zaleplon shortens subjective sleep latency and improves subjective sleep quality in elderly patients with insomnia. Int J Geriatr Psychiatry 2000; 15: 704–12. 118 Holbrook AM, Crowther R, Lotter A, Cheng C, King D. Metaanalysis of benzodiazepine use in the treatment of insomnia. CMAJ 2000; 162: 225–33. 119 Roehrs T, Roth T. Hypnotics: efficacy and adverse effects. In: Kryger MH, Roth T, Dement WC, eds. Principles and Practice of Sleep Medicine. Philadelphia: W B Saunders, 2000: 414–18. 120 Kripke DF, Garfinkel L, Wingard DL, et al. Mortality associated with sleep duration and insomnia: report of the Institute of Medicine Committee on the Efficacy and Safety of Halcion. Arch Gen Psychiatry 2002; 59: 131–36. 121 Ray WA, Thapa PB, Gideon P. Benzodiazepines and the risk of falls in nursing home residents. J Am Geriatr Soc 2000; 48: 682–85. 122 Roehrs T, Merlotti L, Zorick F, Roth T. Rebound insomnia in normals and patients with insomnia after abrupt and tapered discontinuation. Psychopharmacology 1992; 108: 67–71. 123 Roth T, Roehrs TA. A review of the safety profiles of benzodiazepine hypnotics. J Clin Psychiatry 1991; 52 (suppl): 38–41. 124 Walsh JK, Schweitzer PK. Ten-year trends in the pharmacological treatment of insomnia. Sleep 1999; 22: 371–75. 125 McCall WV. Pharmacologic treatment of insomnia. In: Lee-Chiong TL, Sateia MJ, Carskadon MA, eds. Sleep Medicine. Philadelphia: Hanley and Belfus, 2002: 169–76.


126 Riemann DV. Trimipramine in primary insomnia: results of a polysomnographic double-blind controlled study. Pharmacopsychiatry 2002; 35: 165–74. 127 Nierenberg AA, Adler LA, Peselow E, Zornberg G, Rosenthal M. Trazodone for antidepressant-associated insomnia. Am J Psychiatry 1994; 151: 1069–72. 128 Hohagen F, Montero RF, Weiss E, et al. Treatment of primary insomnia with trimipramine: an alternative to benzodiazepine hypnotics?. Eur Arch Psychiatry Clin Neurosci 1994; 244: 65–72. 129 Hajak G, Rodenbeck A, Voderholzer U, et al. Doxepin in the treatment of primary insomnia: a placebo-controlled, double-blind, polysomnographic study. J Clin Psychiatry 2001; 62: 453–63. 130 Nowell PD, Reynolds CF, Buysse DJ, Dew MA, Kupfer DJ. Paroxetine in the treatment of primary insomnia: preliminary clinical and electroencephalogram sleep data. J Clin Psychiatry 1999; 60: 89–95. 131 Chesson A Jr, Hartse K, Anderson WM, et al. Practice parameters for the evaluation of chronic insomnia: an American Academy of Sleep Medicine report. Sleep 2000; 23: 237–41. 132 Task Force of the Collegium Internationale NeuroPsychopharmacologicum (CINP). Impact of neuropharmacology in the 1990s: treatment strategies for anxiety disorders and insomnia. Eur Neuropsychopharmacol 1992; 2: 167–69. 133 US Department of Health Education and Welfare. Guidelines for the Clinical Evaluation of Hypnotic Drugs. US Department of Health Education and Welfare, 1977. 134 Borbely AA, Akerstedt T, Benoit O, Holsboer F, Oswald I. Hypnotics and sleep physiology: a consensus report. Eur Arch Psychiatry Clin Neurosci 1991; 241: 13–21. 135 National Heart Lung and Blood Institute Working Group on Insomnia. Insomnia: assessment and management in primary care. Am Fam Physician 1999; 59: 3029–38. 136 National Institute of Mental Health. Consensus Conference Report: drugs and insomnia: the use of medication to promote sleep. JAMA 1984; 251: 2410–14. 137 Nowell PD, Buysse DJ, Morin CM, Reynolds CF, Kupfer DJ, Effective treatments for selected sleep disorders. In: Nathan PE, Gorman JM, eds. A Guide to Treatments That Work. New York, NY: Oxford University Press, 2002: 593–609. 138 Kupfer DJ, Reynolds CF. Management of insomnia. N Engl J Med 1997; 336: 341–46. 139 American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders (DSM-IV). Washington DC: American Psychiatric Association, 1994. 140 WHO. International Classification of Diseases, 9th edn. Geneva: World Health Organization, 1978. 141 Nowell PD, Hall M, Buysse DJ, Reynolds CF. Psychometric and Psychiatric Evaluation. In: Kryger MH, Roth T, Dement WC, eds. Principles and Practice of Sleep Medicine. Philadelphia: W B Saunders, 2000: 1290–94. 142 Nowell PD, Buysse DJ, Reynolds CF III, et al. Clinical factors contributing to the differential diagnosis of primary insomnia and insomnia related to mental disorders. Am J Psychiatry 1997; 154: 1412–16. 143 Buysse DJ, Reynolds CF 3rd, Kupfer DJ, et al. Effects of diagnosis on treatment recommendations in chronic insomnia: a report from the APA/NIMH DSM-IV field trial. Sleep 1997; 20: 542–52. 144 Ohayon MM, Caulet M. Insomnia and psychotropic drug consumption. Prog Neuropsychopharmacol Biol Psychiatry 1995; 19: 421–31. 145 Schlich D, Heritier C, Coquelin JP, Attali P, Kryrein HJ. Longterm treatment of insomnia with zolpidem: a multicentre general practitioner study of 107 patients. J Int Med Res 1991; 19: 271–79. 146 Kummer J, Guendel L, Linden J, et al. Long-term polysomnographic study of the efficacy and safety of zolpidem in elderly psychiatric in-patients with insomnia. J Int Med Res 1993; 21: 171–84. 147 Mendelson WB. Long-term follow-up of chronic insomnia. Sleep 1995; 18: 698–701. 148 Monti JM, Monti D, Estevez F, Giusti M. Sleep in patients with chronic primary insomnia during long-term zolpidem administration and after its withdrawal. Int Clin Psychopharmacol 1996; 11: 255–63. Vol 364 November 27, 2004


149 Maarek L, Cramer P, Attali P, Coquelin JP, Morselli PL. The safety and efficacy of zolpidem in insomniac patients: a long-term open study in general practice. J Int Med Res 1992; 20: 162–70. 150 Krystal A, Walsh J, Laska E, et al. Sustained efficacy of eszopiclone over 6 months of nightly treatment: results of a randomized, double-blind, placebo-controlled study in adults with chronic insomnia. Sleep 2003; 26: 793–99. 151 Roth T, Krystal A, Walsh J, Roehrs T, Wessel T, Caron J. Twelve months of nightly eszopiclone treatment in patients with chronic insomnia: assessment of long-term efficacy and safety. Sleep 2004; 27: A260. 152 Bunney WE Jr, Azarnoff DL, Brown BW Jr, et al. Report of the Institute of Medicine Committee on the Efficacy and Safety of Halcion. Arch Gen Psychiatry 1999; 56: 349–52. 153 Monti JM, Boussard M, Olivera S, Labraga P, Alvarino F. The effect of midazolam on transient insomnia. Eur J Clin Pharmacol 1993; 44: 525–27. 154 Roth T, Roehrs T, Vogel G. Zolpidem in the treatment of transient insomnia: a double-blind, randomized comparison with placebo. Sleep 1995; 18: 246–51. 155 Lenhart SE, Buysse DJ. Treatment of insomnia in hospitalized patients. Ann Pharmacother 2001; 35: 1449–57. 156 Asnis GM, Chakraburtty A, DuBoff EA, et al. Zolpidem for persistent insomnia in SSRI-treated depressed patients. J Clin Psychiatry 1999; 60: 668–76. 157 Nierenberg AA, Adler LA, Peselow E, Zornberg G, Rosenthal M. Trazodone for antidepressant-associated insomnia. Am J Psychiatry 1994; 151: 1069–72. 158 Walsh J, Rosenberg R, Roth T, Lankford D, Jochelson P. Treatment of primary insomnia for five weeks with Indiplon-IR. Sleep 2004; 27: A259. 159 Hajak G, Muller WE, Wittchen HU, Pittrow D, Kirch W. Abuse and dependence potential for the non-benzodiazepine hypnotics zolpidem and zopiclone: a review of case reports and epidemiological data. Addiction 2003; 98: 1371–78. 160 Cluydts R, Peeters K, de Bouyalsky I, Lavoisy J. Comparison of continuous versus intermittent administration of zolpidem in chronic insomniacs: a double-blind, randomized pilot study. J Int Med Res 1998; 26: 13–24. 161 Hajak GB. “As needed” pharmacotherapy combined with stimulus control treatment in chronic insomnia: assessment of a novel intervention strategy in a primary care setting. Ann Clin Psychiatry 2002; 14: 1–7. Vol 364 November 27, 2004

162 Hajak GC. Continuous versus non-nightly use of zolpidem in chronic insomnia: results of a large-scale, double-blind, randomized, outpatient study. Int Clin Psychopharmacol 2002; 17: 9–17. 163 Bonnet MH, Arand DL. The use of lorazepam TID for chronic insomnia. Int Clin Psychopharmacol 1999; 14: 81–89. 164 Morin CM, Mimeault V, Gagne A. Nonpharmacological treatment of late-life insomnia. J Psychosom Res 1999; 46: 103–16. 165 Voderholzer U, Riemann D, Hornyak M, et al. A double-blind, randomized and placebo-controlled study on the polysomnographic withdrawal effects of zopiclone, zolpidem and triazolam in healthy subjects. Eur Arch Psychiatry Clin Neurosci 2001; 251: 117–23. 166 Roger M, Attali P, Coquelin JP. Multicenter, double-blind, controlled comparison of zolpidem and triazolam in elderly patients with insomnia. Clin Ther 1993; 15: 127–36. 167 Nakra BR, Gfeller JD, Hassan R. A double-blind comparison of the effects of temazepam and triazolam on residual, daytime performance in elderly insomniacs. Int Psychogeriatr 1992; 4: 45–53. 168 Sack RL, Hughes RJ, Edgar DM, Lewy AJ. Sleep-promoting effects of melatonin: at what dose, in whom, under what conditions, and by what mechanisms? Sleep 1997; 20: 908–15. 169 Olde RM, Rigaud AS. Melatonin in elderly patients with insomnia: a systematic review. Z Gerontol Geriatr 2001; 34: 491–97. 170 Pasche B, Erman M, Hayduk R, et al. Effects of low energy emission therapy in chronic psychophysiological insomnia. Sleep 1996; 19: 327–36. 171 Herrera-Arellano AL. Polysomnographic evaluation of the hypnotic effect of Valeriana edulis standardized extract in patients suffering from insomnia. Planta Med 2001; 67: 695–99. 172 Smith MT, Perlis ML, Park A, et al. Comparative meta-analysis of pharmacotherapy and behavior therapy for persistent insomnia. Am J Psychiatry 2002; 159: 5–11. 173 McClusky HY, Milby JB, Switzer PK, Williams V, Wooten V. Efficacy of behavioral versus triazolam treatment in persistent sleep-onset insomnia. Am J Psychiatry 1991; 148: 121–26. 174 Baillargeon L, Landreville P, Verreault R, Beauchemin JP, Gregoire JP, Morin CM. Discontinuation of benzodiazepine treatment among older insomniac adults treated with cognitivebehavioural therapy combined with gradual tapering: a randomized trial. CMAJ 2003; 169: 1015–20.