Insomnia

Insomnia

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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Seminar

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 questwww.thelancet.com 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.

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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

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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 www.thelancet.com 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

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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 www.thelancet.com Vol 364 November 27, 2004

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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 www.thelancet.com 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

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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.

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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 www.thelancet.com Vol 364 November 27, 2004

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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 www.thelancet.com 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

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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

Quazepam§

7·5/15

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)

1·0

Yes

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

2·0

Yes

*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 www.thelancet.com Vol 364 November 27, 2004

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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 assesswww.thelancet.com 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

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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 www.thelancet.com Vol 364 November 27, 2004

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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 www.thelancet.com 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

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

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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.

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