Drugs for the Treatment of Sleep Disorders

To understand sleep disorders, one needs to be familiar with sleep stages. Sleep can be broadly divided into two major states: rapid eye movement (REM) sleep and non-rapid eye movement (NREM) sleep. NREM sleep accounts for 75% to 80% of the total sleep period, whereas REM sleep comprises the rest of the sleep. NREM sleep is subdivided into four stages. Stage 1 is the transitional state between the wake state and sleep. Stage 2 is typically viewed as the true onset of sleep. Stages 3 and 4 are considered the “deep sleep”; based on the electroencephalogram, they are also called “slow wave sleep.” Deep sleep decreases with age, leading many elderly individuals to complain about the quality of their sleep.

Sleep disorders can be primary, secondary to psychiatric disorders, or related to pharmacologic treatment or to psychoactive substance use. Sleep disorders also become more common in persons older than 65 years, when the ability to sleep typically diminishes, especially NREM stages 3 and 4. Therefore, in evaluating sleep disorders, it is essential to complete the following:

1. A sleep history: prospective data, such as those obtained with a sleep-wake diary, can sometimes be more informative than a sleep history alone.
2. A psychiatric and medical assessment.
3. An assessment of psychoactive substance use (e.g., alcohol, caffeine, stimulants, and cocaine, especially in proximity to attempts to sleep).
4. An assessment of concomitant medications use, including antidepressants and those obtained over the counter.
5. An important diagnostic tool is polysomnography, which comprises the overnight recording of electroencephalography, eye movements, and electromyography. Polysomnography allows the determination of the characteristics and duration of the various stages of sleep and the duration of REM and NREM sleep. Additional measures include oral/nasal airflow, respiratory effort, chest and abdominal wall movement, and oxyhemoglobin saturation.
6. Another diagnostic test, commonly used to study excessive sleepiness, is the Multiple Sleep Latency Test (MSLT), in which the individual is asked to lie down in a dark room and not resist falling sleep. Sleep latency (the amount of time required to fall asleep) is assessed five times during the day to provide an index of sleepiness.

BREATHING-RELATED SLEEP DISORDER

Breathing-related sleep disorder is characterized by sleep disruption, leading to excessive daytime sleepiness, and is caused by abnormalities of ventilation during sleep, such as sleep apnea or central alveolar hypoventilation. Partial respiratory cessations are defined as hypopneas, and complete respiratory cessations are defined as apneas. Apneas and hypopneas can be classified as central, obstructive, or mixed. The number of apnea episodes per hour of sleep is the apnea index, and the number of hypopnea episodes per hour of sleep is called the hypopnea index. The total number of apnea and hypopnea episodes per hour of sleep is called the respiratory disturbance index.

Three forms of breathing-related sleep disorder have been described:

1. Obstructive sleep apnea syndrome, characterized by repeated apneas or hypopneas during sleep caused by airway obstruction. It usually occurs in overweight and obese individuals and is accompanied by normal central drive for respiration and respiratory movements. Loud snores or brief gasps alternating with episodes of silence lasting 20 to 30 seconds are common. The termination of the apneas may be associated with loud snores, gasps, or moans.
2. Central sleep apnea syndrome, characterized by apneas and hypopneas during sleep without airway obstruction. In contrast to obstructive sleep apnea syndrome, central sleep apneas are not associated with continued chest wall and abdominal breathing movements and often occur in individuals with cardiac or neurological conditions. Insomnia due to repeated awakenings is often the chief concern, and individuals may or may not report breathing difficulties. Snoring may be present, but it is usually not a prominent symptom.
3. Central alveolar hypoventilation syndrome, characterized by an impairment in ventilatory control during wake, resulting in abnormally low arterial oxygen levels that tend to worsen during sleep. It typically occurs in very obese individuals. Insomnia and excessive sleepiness are the chief concerns.

Epidemiology

In middle-aged populations, sleep-disordered breathing is present typically in 2% of women and 4% of men, whereas in older adults, the prevalence rates often increase up to 25%. Approximately one third of subjects with hypertension have sleep-disordered breathing; sleep-disordered breathing events are associated with transient elevations in blood pressure and perhaps systemic hypertension and cardiac arrhythmias. In addition, this sleep-disordered breathing has been linked to increased mortality in some studies, particularly from cardiovascular conditions. This is not surprising, given the association of sleep-disordered breathing and obesity and higher body mass index.

Alcohol, as well as sedative-hypnotics, narcotics, and barbiturates, may exacerbate respiratory problems at night and reduce the patient’s ability to wake up and breathe. Therefore, these pharmacologic agents should not be used at all or should be used with extreme caution in these patients.

Diagnosis of Obstructive and Central Sleep Apnea Syndromes

1. Symptoms of snoring and daytime sleepiness. Snoring tends to be milder in central sleep apnea, whereas it is prominent in the obstructive form. Excessive sleepiness is the chief concern of patients with both forms of sleep apnea syndrome and is due to the frequent awakenings at night. The sleepiness is most apparent during relaxing situations, such as watching television and reading. The MSLT (mentioned previously) and/or the Epworth Sleepiness Scale, a self-rating scale assessing the degree of sleepiness, are often used to evaluate daytime sleepiness. The mean sleep latency on the MSLT is often less than 10 minutes.
2. On polysomnography, an apnea index greater than 4 or a respiratory disturbance index greater than 9 and a reduction in oxyhemoglobin saturation are supportive of the diagnosis. In central sleep apnea, there may be episodes of Cheyne-Stokes respiration, characterized by a pattern of periodic breathing, with an apnea followed by hyperventilation for 10 to 60 seconds, followed by a gradual decrease in ventilation culminating in another apnea episode.
3. Imaging studies or endoscopic procedures may reveal airway obstruction, in the case of obstructive sleep apnea syndrome.

Diagnosis of Central Alveolar Hypoventilation Syndrome

On polysomnography, periods of decreased respiration lasting up to several minutes, with sustained arterial oxygen desaturation and increased carbon dioxide levels.

Sleep apnea is frequently associated with cognitive functioning problems (e.g., difficulties with memory, concentration, and attention), and some (but not all) studies have suggested a relationship between these symptoms and the degree of oxygen desaturation. Cardiac arrhythmias, such as sinus arrhythmias and premature ventricular contractions, often occur during sleep in these patients.

Treatment

Positive Airway Pressure

Nasal continuous positive airway pressure (CPAP) and bilevel positive airway pressure are probably the most commonly used nonsurgical approaches for obstructive sleep apnea. Both systems use a mask that is connected with a machine that generates positive air pressure. CPAP uses continuous pressure throughout inspiration and expiration, and bilevel positive airway pressure uses higher pressures during inspiration than expiration. Autoadjusting PAP is a variation of CPAP that incorporates various algorithms to automatically adjust air pressure based on persistence of apneas/hypopneas, snoring, and airflow limitation. It has not been found clinically superior to standard CPAP in the treatment of obstructive sleep apnea.

Surgical Interventions

Surgical interventions such as the uvulopharyngopalatoplasty and the laser-assisted uvulopalatoplasty are typically considered appropriate for those patients with anatomic abnormalities and obstructive sleep apnea.

Oral Appliances

Several dental devices are used to open the airway by holding the tongue and mandible forward. These devices are typically used with patients who have difficulties using CPAP or as a substitute for CPAP.

Weight Loss and Other Behavioral Measures

Because excess fatty tissue in the neck area may be a contributing factor, weight loss has been considered a possible treatment approach, although controlled data are lacking. In mild cases of obstructive sleep apnea, eliminating evening alcohol and sedatives, and sleeping in a lateral or prone position may help symptoms.

Pharmacologic Treatment

Pharmacologic treatment has clearly a very limited role in this condition. There have been only anecdotal reports of the use of tricyclic antidepressants (TCAs) or selective serotonin reuptake inhibitors (SSRIs), such as protriptyline and fluoxetine (see Chapter 3 for a discussion of the pharmacology of TCAs and SSRIs), improving oxyhemoglobin saturation, and drugs such as theophylline, medroxyprogesterone, and acetazolamide have also been used with only very limited results. The overall evidence of efficacy for these drug treatments is lacking.

Pharmacologic Treatment of Excessive Sleepiness

In addition to treatment interventions aimed at eliminating the cause of the excessive sleepiness, it is not uncommon for clinicians to treat the excessive sleepiness pharmacologically with caffeine, psychostimulants (e.g., methylphenidate 20 to 80 mg per day), or modafinil (Provigil) (100 to 400 mg per day, usually once per day). For a discussion on the pharmacology of psychostimulants and modafinil, see Chapter 9.

PERIODIC LIMB MOVEMENTS IN SLEEP

Periodic limb movements in sleep (PLMS) consist of repeated leg movements and kicks during sleep, typically every 20 to 40 seconds, causing brief arousals from sleep.

Diagnosis

1. Symptoms of insomnia and/or daytime sleepiness.
2. Subjective reporting of leg kicks, either by the patient or by the bed partner.
3. Objective polysomnography recordings of frequent leg kicks, usually lasting 0.5 to 5 seconds. The number of leg jerks per hour of sleep is called the periodic leg movement index. An index greater than 4, with each jerk associated with arousal, is typically required for the diagnosis.

Epidemiology

The prevalence of PLMS in adults is estimated at 5% to 6%, with significant increases in prevalence (up to 30%) in older age. Iron deficiency, renal failure, peripheral neuropathy, rheumatoid arthritis, and fibromyalgia have all been associated with PLMS.

Restless legs syndrome (RLS) is a common but often underdiagnosed neurologic disorder characterized by an imperative desire to move the extremities associated with paresthesias (unpleasant sensations in legs that feel “achy,” crawly,” “tingly,” and/or “painful”), motor restlessness, worsening of symptoms at rest in the evening or at night, and, as a consequence, sleep disturbances. In addition, most patients with RLS have periodic limb movements during both sleep and relaxed wakefulness. The etiology of RLS remains unknown.

Treatment

Pharmacotherapy of PLMS

The typical approach to the pharmacologic management is the use of dopaminergic agents [e.g., levodopa/carbidopa, cabergoline, pergolide, selegiline, pramipexole (Mirapex), and ropinirole (Requip)]. Because the newer dopamine D₂ and D₃ receptor agonists are usually better tolerated than the older agents, pramipexole or ropinirole (0.25 to 2 mg q. 8 p.m.) are typically used. Most common side effects of these two dopaminergic drugs may include dizziness, drowsiness, dry mouth, insomnia, lack of appetite, memory difficulties, nausea, and fatigue. Pramipexole is available as 0.125-, 0.25-, 0.5-, 1-, and 2-mg tablets, and ropinirole is available as 0.25-, 0.5-, 1-, 2-, 3-, 4-, and 5-mg tablets. Melatonin [3 mg at bedtime (q.h.s.)], the benzodiazepine, clonazepam (0.5 to 2 mg q.h.s.) (see later in this chapter), and the anticonvulsant valproic acid (125 to 600 mg q.h.s.) have also been used with some success in the treatment of PLMS. For a discussion on the pharmacology of valproic acid, see Chapter 4.

Pharmacotherapy of RLS

As in the case of PLMS, the first-line approach to the pharmacologic management is the use of dopaminergic agents; pramipexole or ropinirole (0.25 to 1 mg q. 8 p.m.) is typically used. In the event of partial response, opiates (e.g., acetaminophen with codeine 300 mg/30 mg q.h.s.) or gabapentin (Neurontin) (300 to 1,200 mg q.h.s.) is used as an augmentor. For a discussion of the pharmacology of gabapentin, see Chapter 4. In the event of persistent sleep disruption, the adjunctive use of hypnotics is common [e.g., trazodone (Desyrel) 25 to 150 mg q.h.s., zolpidem (Ambien) 5 to 10 mg q.h.s., eszopiclone (Lunesta) 2 to 3 mg q.h.s., temazepam 7.5 to 30 mg q.h.s., clonazepam 0.25 to 1 mg q.h.s., topiramate (Topamax) 100 to 300 mg q.h.s., and gabapentin 300 to 1,200 mg q.h.s.]. A discussion on the pharmacology of these hypnotics follows later in this chapter. High-dose intravenous iron is a promising, but yet rather experimental approach.

INSOMNIA

Insomnia is defined as difficulty falling asleep, staying asleep, and/or nonrestorative sleep with associated impairment or significant distress for at least 1 month. When insomnia does not occur exclusively during the course of another sleep disorder or psychiatric disorder, or as a consequence of psychoactive substance use or general medical condition, the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV), uses the term primary insomnia. The inability to initiate sleep is typically called “sleep onset insomnia,” whereas the inability to maintain sleep is termed “sleep maintenance insomnia.” Another form of insomnia is characterized by early morning awakenings and is often termed “late insomnia.” Patients who suffer from insomnia either may have only one form of insomnia or, more commonly, may experience any combination of these subtypes. Insomnia is frequently secondary to psychiatric disorders (“insomnia related to another mental disorder,” according to the DSM-IV), medical disorders (“sleep disorder due to a medical condition, insomnia type,” according to the DSM-IV), or the use of medications or psychoactive substances (“substance-induced sleep disorder, insomnia type,” according to the DSM-IV). In particular, insomnia accompanied by daytime fatigue is one of the most common manifestations of depression, being experienced by 40% to 60% of outpatients with major depressive disorder. Insomnia related to depression often encompasses both sleep initiation and maintenance difficulties and sleep architecture abnormalities. Sleep electroencephalographic recordings of patients with major depressive disorder who have sleep initiation and maintenance problems most commonly show prolonged sleep latency (sleep onset insomnia), intermittent wakefulness, sleep fragmentation, and, in some cases, early morning awakenings. Significant sleep architecture abnormalities are also detected by sleep electroencephalography, including an increase in light, stage 1 sleep, a decrease in deep, slow-wave NREM sleep in stages 3 and 4, decreased REM sleep latency, prolonged first REM sleep cycle, and an increase in total REM sleep. Overall, electroencephalographic sleep abnormalities appear to occur less frequently in depressed adolescents and children than in depressed adults.

Epidemiology

It has been estimated that approximately one third of the U.S. population has suffered from insomnia in the previous year and nearly 10% of adults suffer from chronic insomnia, defined as insomnia lasting longer than 1 month. Approximately 40% of those with insomnia have one or more psychiatric disorders, with anxiety, depressive, and substance use disorders being the most common ones. However, it appears that only a relatively small percentage of individuals who suffer from insomnia actually seek treatment for it. The prevalence of chronic insomnia markedly increases in older populations, with up to 40% of those older than 60 years reporting symptoms of insomnia. Insomnia is typically more common among women than men, and this may reflect the higher rates among women of psychiatric disorders associated with insomnia, such as anxiety and depression.

There are both substantial economic and clinical implications of untreated insomnia. It has been estimated that insomnia costs tens of billions of dollars in the United States annually. In fact, untreated insomnia is associated with decreased productivity; reduced concentration; a higher risk of accidents; and an increased risk for the emergence of psychiatric disorders, such as major depressive disorder and generalized anxiety disorder. Thus, it has been suggested that early and aggressive treatment of insomnia may be an effective means of decreasing the morbidity associated with insomnia and improving quality of life for individuals predisposed to sleep difficulties.

Diagnosis

1. Difficulty falling asleep, staying asleep, and/or nonrestorative sleep, with associated impairment or significant distress for at least 1 month.
2. Associated symptoms of depression and anxiety are common, together with diminished energy and concentration.

When evaluating patients with insomnia, it is essential to complete the following:

1. A sleep history (e.g., obtaining specific details regarding the onset, duration, and time course of the insomnia and possible precipitants of the insomnia, such as environmental stress and shift work) and an assessment of sleep habits (e.g., the patient’s bedtime routine, how long the patient stays in bed awake before falling asleep, and what the patient does in the middle of the night if he or she wakes up after having been asleep).
2. A psychiatric and medical assessment.
3. A psychoactive substance use (e.g., alcohol, caffeine, stimulants, cocaine) assessment.
4. An assessment of concomitant medications use, including those over the counter.
5. An evaluation of daytime functioning.
6. When available, sleep logs or diaries are useful diagnostic tools, although subjective.

As mentioned earlier, chronic insomnia may be comorbid with a number of medical and psychiatric conditions, necessitating a proper differential diagnosis to facilitate treatment planning. These include the following:

1. Pulmonary disorders (e.g., chronic obstructive pulmonary disease and asthma) and cardiac disorders (e.g., angina).
2. Gastrointestinal conditions (e.g., gastroesophageal reflux disease).
3. Medical disorders that are associated with pain during the night (e.g., arthritis) or frequent urination at night.
4. Neurological disorders (e.g., Parkinson’s disease and dementia).
5. Psychiatric conditions (e.g., major depressive disorder, bipolar disorder, generalized anxiety disorder, panic disorder, posttraumatic stress disorder, and psychotic disorders).
6. Other sleep disorders (e.g., obstructive sleep apnea and upper airway restrictive syndrome, RLS, and periodic limb movement disorder).
7. Psychoactive drug withdrawal states (e.g., nicotine withdrawal, cocaine withdrawal, opioid withdrawal, and sedative/anxiolytic withdrawal).

Insomnia may also occur in the context of medication and psychoactive substance use, including the following:

1. Antidepressants (e.g., SSRIs, serotonin-norepinephrine reuptake inhibitors (SNRIs), bupropion)
2. Central nervous system (CNS) stimulants (e.g., methylphenidate, dextroamphetamine)
3. Corticosteroids
4. Bronchodilators
5. β-Blockers
6. Decongestants
7. Histamine H₂ blockers (e.g., cimetidine)
8. Antiparkinsonian drugs (e.g., carbidopa-levodopa, selegiline)
9. Alcohol (initial sleepiness followed by insomnia)
10. Nicotine
11. Caffeine

Finally, insomnia may be associated with major life events and lifestyle changes, high levels of chronic stress, and poor sleep hygiene practices.

Behavioral Interventions

Behavioral interventions for the treatment of insomnia are indicated when the insomnia is not secondary to another sleep disorder or to comorbid medical or psychiatric disorders and there is evidence of inadequate sleep hygiene. Inadequate sleep hygiene refers to maladaptive behaviors or attitudes that interfere with sleep onset or maintenance, such as taking daytime naps, drinking caffeine during the day, and drinking alcohol before going to bed. Caffeine increases sleep latency and sleep fragmentation and decreases total sleep time. Alcohol use is discouraged because, although it promotes sleep onset, alcohol leads to sleep fragmentation, decreased REM sleep, and early morning awakenings, thereby predisposing one to wake up frequently during the night.

Sleep Hygiene

In contrast, good sleep hygiene refers to behaviors and environmental factors that facilitate sleep onset and maintenance. Sleep hygiene may be promoted by eliminating naps, caffeine consumption, and alcohol use. Other strategies include not exercising within 5 to 6 hours of bedtime, eliminating noise or temperature extremes (i.e., being very warm or very cold while in bed), encouraging the use of window blinds (to eliminate light), and turning the clock around to avoid “clock watching,” a behavior associated with performance anxiety about sleep, which in turn might make it difficult to fall or stay asleep.

Stimulus Control and Sleep Restriction

Following multiple failed attempts at sleeping, many people become classically conditioned to pair their bed and bedrooms with not sleeping. To break this association, patients are encouraged to engage in stimulus control, a behavioral paradigm in which patients are instructed to use their bed and bedroom only for sleep and for sex—they are not to watch television or to do work in bed, and, at night, they are to go to bed only when they are sleepy and after a set bedtime. If they have trouble falling asleep after 20 minutes, they are to exit the bed and to return again only when sleepy. Patients are encouraged to arise in the morning at the same time, regardless of the amount of sleep obtained during the previous night. Stimulus control is often used in conjunction with sleep restriction, which entails cutting average time in bed to increase sleep drive. Research supports the use of these strategies as individual behavioral interventions for insomnia.

Cognitive Restructuring, Paradoxical Intention, and Relaxation Therapy

Cognitive restructuring aims at changing and correcting maladaptive and distorted cognitions about sleep with more logical, reality-based thoughts. For example, people with insomnia often overemphasize the importance of sleep and make overly negative and catastrophic predictions about a poor night’s sleep. Cognitive therapy seeks to set more realistic expectations about sleep and to decatastrophize the consequences of sleeping fewer hours on a given night.

Paradoxical intention is another cognitive-behavioral strategy that seeks to decrease performance anxiety related to sleep. This approach is based on the following rationale: Patients with insomnia often lie awake, worrying about sleeping, thereby contributing to physiologic arousal, which in turn might make it more difficult to fall or stay asleep. To counteract this performance anxiety, patients are instructed to stay awake. By forcing themselves to stay awake, anxiety about sleep is decreased, and sleep, as a result, comes more easily.

Relaxation therapy such as progressive muscle relaxation and imagery training (e.g., imagining oneself lying on a beach listening to the sound of the waves crashing on the shore) may also be used to target and decrease the physiologic hyperarousal that is often characteristic of individuals with insomnia and may be useful adjuncts to sleep hygiene, stimulus control, sleep restriction, and cognitive therapy.

Pharmacologic Interventions

Pharmacotherapy may be indicated for the treatment of primary insomnia when behavioral interventions alone are insufficient or when a patient prefers medication to behavior therapy. Medications may also be indicated for insomnia secondary to psychiatric or medical conditions when the treatment of the underlying condition proves ineffective or when patients become sufficiently distressed or impaired by their untreated insomnia that to not treat it would lead to increased distress or dysfunction.

The currently available hypnotics are typically approved by the Food and Drug Administration (FDA) for short-term use only, and a common concern among clinicians about prescribing hypnotics is that patients will increase the dose of the hypnotic medication over time. Although tolerance can occur with almost all hypnotics, there is evidence that a substantial proportion of patients will continue to benefit from continued treatment without dosage escalation.

The benzodiazepines are often used as hypnotics, particularly given the relatively low cost of their generic formulations. Not all benzodiazepines are FDA approved for the treatment of insomnia, but off-label use is common, given the pharmacologic similarities among the compounds in this class.

Tolerance is considered to be less likely to occur in the newer, nonbenzodiazepine hypnotics zolpidem, eszopiclone, and zaleplon (Sonata), a finding consistent with recent research indicating that patients receiving intermittent dosing with zolpidem were not more likely than those administered placebo to increase the number of pills taken over time. Other studies that have examined the efficacy of intermittent dosing with zolpidem have also found sustained efficacy and a lack of rebound insomnia among patients treated for either 2 or 3 months.

Ramelteon (Rozerem) is a selective MT1/MT2 melatonin receptor agonist approved by the U.S. FDA for treatment of insomnia; its use is primarily limited to the treatment of early insomnia. The antidepressant trazodone is commonly prescribed off-label for the treatment of insomnia; however, it is not approved as a hypnotic by the FDA and limited data exist to support its efficacy as a hypnotic. The antihistamine, diphenhydramine (Benadryl), although commonly used as an over the counter sleep aid, is not a reliable treatment of insomnia because it often loses its sedative effect over time. It also exposes people to significant anticholinergic side effects.

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