INSOMNIA

Insomnia is defined as a difficulty in falling asleep, a difficulty in staying asleep, or nonrestorative sleep (awakening feeling unrefreshed). It is usually classified as transient, short-term, or chronic, according to the duration of symptoms, although many affected individuals describe recurrent episodes of short-term insomnia, which complicates classification. It may also be classified, on the basis of the predominant insomnia complaint, as initial insomnia, sleep maintenance insomnia, or insomnia with premature terminal awakening. This division, however, is also overly simplistic, inasmuch as many patients with chronic or recurrent short-term insomnia have an evolution of symptoms over time: Initial insomnia may develop into frequent or prolonged nocturnal awakenings or a mixture of the two. Thus, etiological inferences based on the type of manifesting symptom are bound to be confounded by these symptomatic fluctuations.

Epidemiology, Consequences, and Diagnosis of Insomnia

Insomnia has also traditionally been characterized as primary or secondary on the basis of its presumed etiology. Insomnia is referred to as secondary when it is believed to be a symptom of an underlying medical, psychiatric, or sleep disorder, or when it follows medication use. This diagnosis is based on a plausible mechanism by which the underlying disorder causes insomnia (e.g., pain, shortness of breath), the occurrence of insomnia after that of the underlying condition, and a course that follows the severity of the underlying condition. According to this schema, treatment of the underlying cause should resolve the insomnia symptom. In contrast, primary insomnia is considered to be caused by physiological and cognitive hyperarousal, both within the sleep environment and during the day. The distinctions between primary and secondary insomnia have more recently been questioned, however, because of the difficulties in making this distinction, the recognition that secondary insomnia may evolve into primary insomnia, and the fact that some insomnia vulnerability factors may predispose persons with medical disorders to develop insomnia.

The point prevalence of insomnia that lasts more than a few weeks is approximately 10% to 15% of the general population.² However, because of its association with medical and psychiatric illnesses, up to 50% of individuals seen in medical practices report at least mild insomnia.³ Results of studies in individuals older than 65 suggest a 5% incidence and a 5% to 15% yearly rate of remission of insomnia.⁴,⁵ Female gender, increasing age, psychiatric and medical illnesses, substance use, low income, unemployment, and being single are all risk factors for having insomnia, although some of these may be consequences of insomnia rather than vulnerability factors.^6–8

There is increasing recognition of the adverse consequences of insomnia. Multiple studies have demonstrated that persistent insomnia is associated with a substantial increased risk of incident depression.⁹ Insomnia is also associated with globally worsened quality of life, even when psychiatric illness¹⁰ or medical comorbidity³ is accounted for. The decrements in physical functioning, general health perception, and vitality are as substantial as, or more so than, those observed with congestive heart failure.³ Furthermore, there are suggestions that insomnia is associated with an increased risk of work-related and motor vehicle accidents, as well as falls by elderly persons.¹¹ Finally, health costs in individuals with insomnia are elevated, even when comorbid medical and psychiatric illnesses are accounted for.¹²

The concept of hyperarousal is being used to unify the understanding of the pathophysiology of primary insomnia.^13–15 From a physiological perspective, individuals with insomnia have elevated evening cortisol levels,¹⁶ increased 24-hour whole body metabolic rate,¹⁷ increases in both waking and sleep-related global cerebral glucose metabolism (Fig. 15-1),¹⁸ and high-frequency electroencephalographic (EEG) activity during sleep.¹⁹ It is unclear which neural circuits are responsible for these disparate findings. Similarly, cognitive arousal is considered to be central to the generation and maintenance of insomnia. It is hypothesized that cognitive and physiological hyperarousal become paired with the sleep environment, which gradually worsens sleep and increases these arousal processes in that setting, creating a vicious cycle of insomnia.¹⁵,²⁰ Maladaptive compensatory strategies, such as spending excess time in bed, daytime napping, and alcohol and caffeine intake can then exacerbate this process.

Figure 15-1 Areas in which metabolism did not decrease from sleep to wakefulness in insomniac patients.

Rights were not granted to include this figure in electronic media. Please refer to the printed book.

(From Nofzinger EA, Buysse DJ, Germain A, et al: Functional neuroimaging evidence for hyperarousal in insomnia. Am J Psychiatry 2004; 161:2126-2168.)

The evaluation of patients with insomnia involves identifying the scope and duration of the complaint, including its effects on daytime functioning, and searching for potential etiologies. Behaviors and cognitions relevant to sleep during both daytime and evening should be solicited from the patient. In particular, explicit focus on the period in bed both before sleep and at nocturnal awakenings may assist with determining physical or mental events that interfere with sleep. Sleep diaries may help in elucidating predictable changes in sleep quality that are based on day of the week and/or work schedules. Factors that worsen or improve sleep quality longitudinally should also be identified.

Life events that have a temporal relationship to the onset of sleep problems can frequently assist in identifying potential causes of insomnia, particularly in individuals with insomnias of shorter duration. In individuals with chronic insomnia, such events may have occurred many years in the past and may not be clear, or the insomnia may have a more insidious waxing course of severity.

Identification of potential medical, sleep-related, and psychiatric causes of insomnia is essential for optimal treatment, because treatment of such causes may at times eliminate the insomnia complaint. Insomnia in elderly persons, in whom frequent nocturnal awakenings are the most common complaint, is particularly related to medical illness,²¹ and careful attention to patients’ medical problems may provide guides to the etiology of insomnia in this group. The most common medical disorders associated with insomnia are listed in Table 15-2. In addition, all psychiatric disorders can and frequently do cause insomnia, and assessments for depression and anxiety disorders are an essential feature of the insomnia evaluation. However, it should be made clear that approximately 40% of individuals with insomnia do not have a psychiatric disorder,²² and thus the assumption that insomnia is necessarily caused by psychiatric illness is ill founded.

TABLE 15-2 Medical Disorders or Conditions Commonly Associated with Insomnia

Cardiovascular Congestive heart failure with paroxysmal nocturnal dyspnea and/or Cheyne-Stokes respiration Nocturnal angina

Pulmonary

Chronic obstructive pulmonary disease

Asthma

Nocturnal cough

Polysomnography can also assist with the assessment of insomnia in some cases. This diagnostic procedure is not recommended for most individuals with insomnia²³; however, when the clinician suspects sleep apnea or periodic limb movements of sleep (PLMSs), or when the patient reports frequent brief awakenings, polysomnography is indicated for further evaluation.

Treatment of Insomnia

The treatment of insomnia is best achieved by addressing all possible underlying contributing factors, whether they are related to medical or psychiatric causes, poor sleep habits, or counterproductive sleep-related cognitions. A combination of approaches is generally recommended. For individuals with insomnia of recent onset, an identifiable precipitant (a physical or emotional stressor) is usually present, and the duration of the complaint is often short. If, in such individuals, the insomnia is associated with substantial concern or daytime dysfunction, short-term use of a hypnotic agent is recommended so as to minimize the immediate effect of the insomnia and to prevent the development of a more chronic conditioned insomnia.

In individuals with chronic primary insomnia, and in some individuals with secondary insomnia, first-line treatments are modification of sleep-related behaviors and attitudes, called cognitive-behavioral therapy. Cognitive-behavioral therapy has a number of components: (1) limitation of time in bed (sleep restriction and stimulus control), which produces mild sleep deprivation, thus allowing shorter sleep onset and reduction in the number and duration of awakenings, and reduces the duration of time awake in bed, limiting negative associations to the sleep environment; (2) relaxation techniques, which reduce physiological and cognitive arousal in the sleep setting by use of yoga, meditation, and/or biofeedback; (3) cognitive restructuring, which addresses catastrophic beliefs and attitudes regarding sleeplessness, replacing them with more rational expectations of sleep and effects of insomnia; and (4) sleep hygiene, which refers to a variety of habits that promote good sleep such as regular bedtimes and waking times, daily exercise, avoidance of napping, careful use of alcohol and caffeine, and reduction in behaviors that promote nocturnal emotional and physical arousal (e.g., work, emotional stimulation, nighttime exercise). Cognitive-behavioral therapy has been shown to produce consistent reduction in sleep onset latency and wake time during the night, as well as smaller increases in total sleep time.²⁴,²⁵ These gains have generally been maintained over periods of up to 24 months.

Pharmacological therapies for insomnia have evolved since the 1950s from barbiturates to long-acting benzodiazepines, then to shorter acting benzodiazepines, and, since the mid-1990s, to nonbenzodiazepine receptor agonists (BzRAs). In addition, there has been a trend away from these approved medications for insomnia and toward the use of sedating medications with original indications for other disorders (e.g., antidepressants, anticonvulsants, antipsychotics), to the point at which antidepressants constitute more than 50% of all prescription medications for insomnia.²⁶ Recommendations as to the appropriate use of hypnotics in the treatment of insomnia are evolving, and this and other treatment issues in insomnia were reviewed in a state-of-the-science National Institute of Mental Health consensus statement.²⁷

Benzodiazepines and BzRAs bind at an allosteric site on the γ-amino butyric acid A (GABA_A) receptor complex, influencing GABA binding and chloride flux. The BzRAs demonstrate relatively selective binding for GABA_A receptors that contain α₁ subunits. The α₁ subunits mediate the sedative, amnestic, and anticonvulsant properties of these agents but few of the muscle relaxant and anxiolytic aspects (Fig. 15-2).²⁸ However, it is unclear whether the relative receptor selectivity of the BzRAs have clinical significance in terms of efficacy or short- or long-term tolerability.

Figure 15-2 γ-Amino butyric acid A (GABA_A) receptor subtypes, localization and function in mouse brain.

Rights were not granted to include this figure in electronic media. Please refer to the printed book.

(From Mohler H, Fritschy J, Rudolph U: A new benzodiazepine pharmacology. J Pharmacol Exp Ther 2002; 300:2-8.)

More important than the receptor-binding characteristics of these agents are the major differences between the half-lives of these agents, which, when combined with dosage, determine the duration of the medication’s effects. Half-lives of hypnotics in this class vary from 1 to more than 100 hours (Table 15-3). Because of the variability of sleep complaints, medication choices in this class are usually based on matching the patient’s sleep complaint with an appropriate half-life agent, so as to maximize the opportunity for sleep but minimize waking hangover effects.

TABLE 15-3 Benzodiazepine Receptor Agonists Commonly Used for the Treatment of Insomnia

Benzodiazepines.

Meta-analyses have demonstrated the efficacy of benzodiazepines and BzRAs in reducing sleep onset latency, decreasing the amount of wakefulness after sleep onset, and in increasing total sleep time in patients with primary insomnia.²⁹ However, when a meta-analysis of benzodiazepines alone was performed, the absolute size of this effect for sleep onset latency was not dramatic: a reduction of 4.2 minutes when assessed by polysomnography and of 14.3 minutes by self-report. On the other hand, total sleep time was increased by a mean of 61.8 minutes.³⁰

The majority of these efficacy data come from short-duration studies. For instance, the median duration of the studies in the benzodiazepine and BzRA meta-analysis was 7 days; the common duration of insomnia complaints, in contrast, is often months to years. Studies addressing the longer term efficacy of these medications in continuous and intermittent use have been performed. Eszopiclone, the S-isomer of the commonly prescribed hypnotic zopiclone, has been shown to produce persistent benefits for sleep onset latency, wakefulness after sleep onset, total sleep time, and daytime functioning for 6 months of nightly use in comparison with placebo in patients with primary insomnia.³¹

PERIODIC LIMB MOVEMENT DISORDER

PLMSs are commonly recorded movements during sleep consisting of repetitive dorsiflexion of the foot and/or lower leg. Movements are generally subtle and may not be recognized by a bed partner, although in more severe forms, they are more obvious. PLMS may or may not be associated with arousals from sleep, and indices of the number of movements with and without arousal per hour of sleep are derived. The term periodic limb movement of sleep is derived from the strict periodicity of movements, which occur at 15- to 30-second intervals during sleep. Movements are roughly 2 seconds in duration (Fig. 15-3). When a sleep complaint occurs in the presence of PLMS, in the absence of other known causes of sleep disruption, a diagnosis of periodic limb movement disorder is given.

Figure 15-3 Periodic limb movements of sleep (PLMS) as recorded on polysomnography. EEG, electroencephalogram; EMG, electromyogram; L.A.T., left anterior tibialis; R.A.T., right anterior tibialis.

PLMSs are commonly recorded on overnight polysomnography, and population estimates of the prevalence of PLMSs exceeding five per hour range from 11% to 58%.³² PLMSs are more commonly recorded in elderly persons, in patients taking antidepressants, and in a number of medical conditions (end-stage renal disease, congestive heart failure, diabetes) and neurological or sleep disorders (obstructive sleep apnea, narcolepsy, Parkinson’s disease, multiple sclerosis). Although approximately 80% of individuals with RLS demonstrate PLMS, only a small proportion of those with PLMS describe symptoms of RLS. Controversy exists regarding the clinical importance of PLMS for sleep quality or daytime alertness; some studies show a lack of correlation between PLMS index and subjective or objective sleep quality or daytime sleepiness, and others show some mild associations.³³

There is substantial evidence that PLMSs are associated with dopaminergic dysregulation at either spinal or higher central nervous system levels. Dopaminergic antagonists can produce PLMS,³⁴ whereas dopaminergic agonists are extremely effective in reducing PLMS.³⁵ Disorders characterized by dopaminergic deficiency (e.g., narcolepsy, rapid eye movement [REM] sleep behavior disorder [RBD]) are accompanied by high rates of PLMS. Functional imaging of the brain has demonstrated small but consistent reductions in dopaminergic function in PLMS. Finally, dopaminergic metabolites have been observed to be correlated with the number of PLMSs.³⁶ The presence of PLMS in quadriplegic patients suggests that the motor programs for these movements exist in the spinal cord and are somehow disinhibited in patients with excessive movements during sleep.

Clinically, periodic limb movement disorder should be suspected when an individual (or his or her bed partner) reports kicking or jerking of his or her legs during sleep and has a complaint of sleep disruption or excess daytime sleepiness that cannot be accounted for by another cause. Polysomnography is necessary to make the diagnosis of periodic limb movement disorder, both to document the PLMS but also to exclude other causes of repetitive leg movements—most prominently, obstructive sleep apnea. The differential diagnosis of nocturnal leg movements in the sleep period includes RLS (in which leg restlessness is reported before sleep onset), anxiety (in which leg movements are observed during wakefulness, not sleep), nocturnal seizures (which produce abnormal EEG changes), obstructive sleep apnea (in which characteristic respiratory abnormalities are observed), or RBD (in which movements are dream enactments, occur during REM sleep, and are not periodic).

Treatment of periodic limb movement disorder begins with an accurate diagnosis and proceeds to consideration of eliminating potential precipitating or exacerbating agents (e.g., antidepressants). PLMS can be dramatically reduced with the addition of dopaminergic agents, at least within the context of RLS. However, there is some suggestion that EEG arousals may persist even with elimination of the manifest motor activity. For this reason, coadministration of substitution of a benzodiazepine has also been advocated. Although studies of triazolam in patients with PLMS did not reveal a reduction in the periodic limb movement index, improvements in leg movements associated with arousal, sleep architecture, and daytime alertness were all demonstrated,³⁷ even after 12 weeks of nightly use.³⁸ Use of clonazepam in small numbers of patients was effective in reducing the number of PLMs, as well as improving scores on sleep continuity measures.³⁹

EXCESS DAYTIME SLEEPINESS

Excess daytime sleepiness has numerous causes. Clinical diagnostic algorithms proceed from a determination of sleep quantity to an evaluation of sleep quality and then to assessment of potential contributors to an intrinsic excess sleep drive. Insufficient sleep is the most common cause of excess daytime sleepiness among both adults and children. Because of its pervasiveness, careful attention to sleep times is required in individuals with a description of excess daytime sleepiness. Sleep quantity is determined by history, sleep logs, and if necessary, polysomnography.

Any cause of poor sleep quality can produce excess daytime sleepiness, although the most common are sleep apnea, neurological, pulmonary and cardiac diseases, and environmental sleep disruption. The underlying cause of sleep disruption is commonly discernible from the history and/or physical examination, although polysomnography may be required for some disorders (e.g., sleep apnea). Finally, if excessive daytime sleepiness is present, and if sleep quantity and quality appear to be sufficient, a primary disorder of sleepiness or a medication effect should be suspected. These are discussed as follows.