Insomnia

What every physician needs to know:

Insomnia is the most common sleep disorder found in the general adult population, with 30 percent of adults reporting insomnia symptoms and 10 percent of adults meeting the full criteria for diagnosis of insomnia. Approximately 80-90 percent of insomnia cases are comorbid with other psychiatric or medical conditions.

Following the National Institutes of Health consensus statement in 2005, the term “comorbid insomnia” is usually preferred over “secondary insomnia” primarily because of the growing body of evidence demonstrating that insomnia follows an independent temporal course and is responsive to targeted treatment. As a comorbid condition, insomnia often requires targeted assessment and intervention concurrent with that of medical or psychiatric morbidities. Conversely, chronic insomnia is now accepted as an independent risk factor for the development of new medical and psychiatric illness.

Insomnia is characterized by difficulties initiating or maintaining sleep or an experience of nonrestorative or unrefreshing sleep that is accompanied by clinically significant distress or impairment. At this time, insomnia is a clinical diagnosis. Numerous pharmacological and psychological treatments for insomnia exist, with a large body of evidence supporting the efficacy and effectiveness of both pharmacotherapy and cognitive behavioral therapies. Poor effectiveness of any given insomnia therapy should be considered a sign of possible unrecognized etiology or an unrecognized contributing comorbidity.

Classification

The ICD-9 recognizes the two insomnia categories of organic and nonorganic disorders of initiating and maintaining sleep. Non-organic insomnia diagnoses include transient/adjustment insomnia and persistent/primary insomnia. Organic insomnia diagnoses include insomnia that is due to mental disorder, insomnia that is due to a medical condition, and insomnia that is due to a drug or substance.

Transient/Adjustment insomnia requires that symptoms have developed in response to or following an identifiable stressor andthat they persist for less than three months. Insomnia symptoms are expected to remit spontaneously upon termination of the stressor or upon the patient’s adaptation to the stressor.

Persistent/Primary insomnia requires a predominant complaint for at least one month of difficulty initiating or maintaining sleep or nonrestorative sleep. The sleep complaint must cause clinically significant distress or impairment, it must not occur exclusively in the context of another sleep disorder or other mental disorder, and it must not be due to the direct physiological effects of a substance or general medical condition.

Insomnia related to mental disorder requires the same key symptoms, exclusions, and duration as persistent insomnia, with one exception: although insomnia symptoms are judged to be related to psychiatric comorbidity, they are sufficiently severe to warrant independent clinical attention.

Insomnia that is due to medical condition requires a predominant insomnia of sufficient severity to warrant independent clinical attention and evidence that insomnia symptoms are the direct physiological consequence of the comorbid medical condition. In addition, insomnia symptoms cannot be better explained by psychiatric morbidity and do not meet the criteria for narcolepsy or obstructive sleep apnea.

Insomnia that is due to a drug or substance requires the patient to meet criteria for insomnia and to have current, ongoing drug abuse, dependence, or exposure to a drug or other substance with known sleep-disruptive properties. In addition, insomnia symptoms must be temporally correlated with intoxication, withdrawal, or exposure to the substance.

The International Classification of Sleep Disorders (ICSD-2) describes types of persistent/primary insomnia, which help to distinguish etiology and assist in treatment selection.

Psychophysiological Insomnia

Psychophysiological insomnia involves insomnia symptoms that develop in response to or following a stressful precipitating event that may or may not be clearly identifiable. Regardless of the status of the precipitating event, insomnia symptoms persist with an independent temporal course and are characterized by clear signs of behavioral conditioning. Common signs of behavioral conditioning include preoccupation with or excessive worry about sleep; experience of sudden alertness upon attempting to initiate sleep, cognitive or affective arousal in response to sleeplessness or nocturnal awakenings, and the inability to relax sufficiently to allow initiation of sleep.

Paradoxical Insomnia

Insomnia symptoms are characterized by the presence of constant or near constant awareness of environmental stimuli or ongoing cognition throughout all or most of the night while attempting to sleep. Reports of frequent nights with little to no sleep are common in this type. However, a marked mismatch exists between polysomnography or actigraphy findings and subjectively reported sleep, with objective data documenting normal or near normal sleep duration, continuity, and architecture.

Idiopathic Insomnia

In idiopathic insomnia, insomnia symptoms have been present since childhood, and they represent a general temperamental predisposition toward disturbed sleep. Idiopathic insomnia frequently presents in the context of other insomnia subtypes and may represent a vulnerability to development of psychophysiological insomnia, paradoxical insomnia, and insomnia that is due to a mental disorder or medical condition.

Inadequate Sleep Hygiene

Insomnia symptoms can be directly correlated with poor sleep hygiene behaviors, including consumption of alcohol, caffeine, nicotine, or large meals within several hours of bedtime; intentional napping or unintentional dozing within six hours of bed time; moderate or high-intensity exercise within several hours of bedtime; or the presence of an unsafe or uncomfortable bed or bedroom environment.

Behavioral Insomnia of Childhood

Insomnia symptoms can be directly attributed to the development of sleep-onset associations (i.e., somatic, environmental, or behavioral cues that must be present for sleep onset to occur) or insufficient/inappropriate limits set by caregivers. Sleep-onset associated insomnia is typically associated with difficulty initiating or reinitiating sleep in infants or very young children without the presence of a parent or repetition of often prolonged or laborious routines. Alternately, the limit-setting type typically presents in older toddlers and school age children and manifests as bedtime refusals, stalling, or “curtain calls.”

Are you sure your patient has insomnia? What should you expect to find?

Currently, insomnia remains a purely symptomatic diagnosis with no reliable objective signs. Diagnosis of insomnia requires the following symptoms, duration, and behavioral criteria be met:

• Presence of at lease one primary insomnia symptom

• Presence of at least one daytime symptom that is related to the nighttime complaint

• Clinically significant distress or impairment caused by symptoms

• Presence of symptoms for at least one month

• Adequate opportunity for sleep (i.e., more than six hours in bed per night)

Primary Symptoms of Insomnia

Complaint of difficulty initiating sleep: The patient reports an inability to initiate sleep lasting thirty minutes or more at the beginning of his or her intended sleep episode.

Complaint of difficulty maintaining sleep: The patient reports either an excessive number of nocturnal awakenings or extended periods of undesired wakefulness lasting thirty minutes or more during the intended sleep episode.

Complaint of early-morning awakening: The patient reports awakening thirty minutes to several hours prior to the desired wake time and the inability to return to sleep for the remainder of the intended sleep episode.

Complaint of nonrestorative or poor-quality sleep: The patient denies early morning awakenings, difficulty initiating sleep, and difficulty maintaining sleep and indicates adequate average total sleep time (≥ 6 hours). However, he or she describes sleep as light, unsatisfying, or otherwise poor in quality or attributes daytime complaints of fatigue or cognitive impairment to a problem with sleep.

Daytime Symptoms Related to Insomnia Complaints

Daytime symptoms related to insomnia complaints include:

• Fatigue or malaise

• Mood disturbance or irritability

• Reduced motivation, energy, or initiative

• Attention, concentration, or memory problems

• Occupational, academic, or social dysfunction

• Daytime sleepiness

• Increased likelihood of errors or accidents at work or while driving

• Tension, headaches, or gastrointestinal symptoms in response to sleep loss

• Concerns or worries about sleep

Beware: There are other conditions that can mimic insomnia:

Insomnia symptoms can be considered a barometer for general stress versus wellness. As such, acute insomnia symptoms are a common and expected associated feature of many medical and psychiatric disorders.

However, persistent symptoms of insomnia that become a prominent complaint within the context of other conditions require targeted evaluation to determine the presence or absence of an independent comorbid insomnia and its relationship to the status and management of comorbid conditions. Included in this section is a list of conditions in which the distinction between secondary and comorbid insomnia can be challenging.

Obstructive Sleep Apnea

39-59 percent of patients with obstructive sleep apnea (OSA) report symptoms of insomnia, with sleep maintenance and early morning awakenings being the most common complaints. However, the relationship between these two disorders is complex. Occult sleep apnea has been found in 29-43 percent of patients without cardinal signs of OSA.

A recent analysis of patients with OSA and insomnia found that insomnia symptoms persisted in 49 percent of patients, despite effective treatment of OSA. Accordingly, in half of cases, insomnia appears to be directly caused by OSA, while in the other half insomnia may represent an independent comorbid condition requiring targeted intervention. Conscientious follow-up is often necessary for thorough differential diagnoses of insomnia symptoms in the context of OSA. In addition, patients with chronic treatment-resistant insomnia should be considered for laboratory evaluation even in the absence of typical signs and symptoms of OSA.

Depressive and Anxiety Disorders

Insomnia is a criteria for diagnosis of almost all depressive and anxiety disorders. As such, insomnia symptoms are frequently dismissed as a symptom of the primary psychiatric disorder. However, it is well documented that insomnia commonly precedes development of anxiety and depression and is an independent risk factor for development of new depressive and anxiety disorders. In additionally, insomnia is the most frequent residual symptom in patients with major depression who are in remission.

Finally, targeted treatment of insomnia concurrent with pharmacotherapy or cognitive-behavioral treatment of anxiety or depression results in reduced insomnia symptoms and enhanced outcomes related to depression or anxiety. In combination, these data suggest that presence of comorbid insomnia be evaluated in all cases of anxiety and depressive disorders.

Circadian Rhythm Sleep Disorders

Complaints of difficulty with sleep onset or maintenance are cardinal manifestations of the Circadian Rhythm Sleep Disorders (CRSD). While neurological or sensory abnormalities may play a causal role in some cases, the most common CRSDs represent a mismatch between the endogenous circadian timing system and external clock time or social obligations. The two most common types of CRSD are the delayed type and the advanced type. In the delayed type, the internal clock is set to initiate sleep and awaken from sleep several hours later than “normal” or desired. Clinically, a delayed CRSD typically presents as moderate to severe sleep onset insomnia with difficulty awakening in the mornings and/or excessive sleepiness, lethargy, or fatigue during the morning hours.

In the advanced type, the internal clock is set to initiate sleep and awaken from sleep several hours earlier than “normal” or desired. Clinically, an advanced CRSD typically presents as moderate to severe evening sleepiness or dozing with difficulties maintaining sleep in the second half of the night. Difficulties maintaining sleep are characterized by middle-of-the-night awakenings, subjectively poor quality or non-restorative sleep, or early morning awakenings.

Because CRSDs are not a disturbance of the neurological sleep-promoting system or sleep-related cues (somatic, environmental, behavioral, etc.), they are frequently unresponsive to first-line insomnia treatments (pharmacotherapy or cognitive-behavioral therapy). Accordingly, non-response to insomnia treatment should prompt assessment for a possible CRSD.

Gastroesophageal Reflux Disease (GERD)

Compared to daytime reflux, reflux during sleep is associated with prolonged acid clearance time resulting from reduced swallowing frequency and cessation of salivary flow. Swallowing responses during sleep are associated with EEG arousal.

Twenty-five percent of patients with a primary complaint of unrefreshing sleep and no diurnal or nocturnal heartburn have been found to have reflux events during sleep. Compared to controls, patients with a complaint of unrefreshing sleep had significantly increased acid contact time. These findings suggest that some patients with asymptomatic GERD may present in the clinic with a primary complaint of insomnia. In support of this idea, other studies have found improved subjective and polysomnographic sleep associated with proton pump inhibitor (PPI) treatment of GERD.

Behaviorally Induced Insufficient Sleep Syndrome (Voluntary Sleep Deprivation)

Insufficient opportunity for sleep is a common problem in our society. Work, family, social, and other obligations frequently intrude into the intended/necessary sleep period, resulting in reduced opportunity for sleep. Adequate sleep opportunity is a criteria for diagnosis of insomnia. Accordingly, sleep deprivation must be ruled out as the cause of insomnia complaints.

Clinically, patients with voluntary sleep deprivation typically present with a complaint of non-restorative sleep and daytime symptoms of fatigue and cognitive difficulties. However, interviews, sleep logs, or actigraphy often reveal that the patient is allowing for six or fewer hours of sleep on most or all nights.

How and/or why did the patient develop insomnia?

A number of models of insomnia exist with psychological, behavioral, neurocognitive, and neurochemical factors implicated in the development and maintenance of the disease. Most cases of chronic insomnia are comorbid and have multiple etiologies. Optimal management is often achieved by concurrent treatment of all relevant etiological factors.

The existing models may represent different perspectives on the same disease process. However, emerging evidence suggests that there are multiple distinct insomnia types, with each model potentially describing the etiology and pathophysiology of a specific type of nia type. Accordingly, the “goodness of fit” of any particular patient to any given insomnia model may indicate presence of a distinct type of insomnia.

Insomnia Models: Medical and Psychiatric Illness

Physiological and neurological symptoms of comorbid medical and psychiatric illness can be the primary causal factor in many cases of insomnia. The symptoms of comorbid conditions also frequently have a role in the perpetuation of insomnia. Accordingly, active management of comorbidities is a reasonable approach.

However, in chronic insomnia, behavioral and psychophysiological factors can develop within a matter of weeks or months, leading to development of a functionally independent insomnia with a temporal course that is independent of the comorbid condition(s). In addition, the psychosocial stress associated with having and adapting to a medical or psychiatric illness may significantly influence the development and perpetuation of insomnia. The high likelihood of the development of behavioral and psychophysiological factors suggests that targeted evaluation and management of insomnia should be considered in addition to and concurrently with treatment of comorbidities.

For example, patients with chronic pain or anxiety frequently indicate that their pain or anxiety is a primary cause of insomnia symptoms. Despite this complaint, many either refuse treatment or are simply non-adherent to prescribed therapies. In cases such as these, targeted treatment of insomnia can be expected to result in partial improvement in insomnia symptoms. However, response to insomnia treatment will likely be restricted because of the active interference of pain or anxiety symptoms on sleep. Targeted management of non-adherence, poor adherence, or non-acceptance of treatment may be indicated.

Alternately, pain or anxiety may be well managed but insomnia persists. This situation suggests the presence of behavioral, psychophysiological, or stress factors as perpetuating variables. In this case, targeted management of these variables with pharmacotherapy or cognitive-behavioral therapy is frequently effective in achieving satisfactory resolution of insomnia symptoms.

In most cases, both of these scenarios are simultaneously present to varying degrees.

Insomnia Models: Behavioral Conditioning and Hyperarousal

Behavioral conditioning and hyperarousal, which are the most widely known and accepted models of insomnia, are the foundation for most current behavioral treatments. Most cases of chronic insomnia have a clear component that is well explained by these models. Clinically, the presence of behavioral factors explained by these models is a common reason for non-response to pharmacotherapy, which makes sense given that clinical trials of hypnotic agents inherently control for these factors via procedural requirements of the study protocols. However, in the clinic setting, the behavioral restrictions of the clinical trial are rarely recommended when pharmacotherapy is prescribed.

The Stimulus Control Model proposes that insomnia is the result of conditioned arousal or activation (cognitive, affective, or somatic) that has become associated with the bed and bedroom. Under this model, non-sleep activities (e.g., work, worry, TV) experienced in the bed or bedroom become associated with the bed or bedroom. Once these associations are established, the act of attempting to initiate sleep elicits the arousal or activation associated with non-sleep activities, rather than an experience of sleepiness and a progressive decline in arousal leading to sleep onset.

The 3P Model proposes that development and maintenance of acute and chronic insomnia occurs via the interaction of Predisposing, Precipitating, and Perpetuating factors.
Predisposing factors represent a risk factor or vulnerability for the development of insomnia. Common predisposing factors include biological (e.g., basal metabolic rate, inherent neurotransmitter abnormalities), psychological (e.g., nervous or ruminative temperament), and social variables (e.g., conflicting family sleep schedules).

Precipitating factors can be any desirable or undesirable stressor, such as medical or psychiatric illness, wedding or divorce, new job or unemployment, and so forth. Precipitating and predisposing factors interact to produce initial onset of clinically significant insomnia symptoms. Once a clinically significant insomnia is present, perpetuating factors often develop.

Perpetuating factors, which are behaviors initiated in an attempt to compensate for insomnia or its effect on daytime function, lead to persistence of insomnia despite adaptation to or resolution of the original precipitating factor. Accordingly, in the absence of targeted treatment for the perpetuating factors, insomnia would not reasonably be expected to resolve.

Insomnia Models: Central Nervous System Stress and Disinhibition

Insomnia models have a common theme in suggesting that failure to inhibit wake-promoting regions of the brain causes abnormalities in attentional, information processing, and other mental or behavioral processes that cause disturbance of sleep quality, quantity, or continuity. These models represent a fundamental shift in perspective when compared to the behavioral and comorbid insomnia models, which posit that some form of hyperarousal or activation simply “overpowers” the homeostatic and circadian sleep-promoting neurological systems.

The Neurocognitive Model is an extension of the 3P model that proposes cortical arousal (as opposed to cognitive, affective, or somatic arousal) as a classically conditioned response that perpetuates insomnia. Specifically, repeated pairing of normal cortical arousal with sleeplessness and sleep-related cues causes altered cognitive processes that disrupt sleep or the subjective experience of sleep.

Altered cognitive processes include enhanced sensory processing, information processing, and long-term memory. Enhancement of these processes during sleep is associated with increased detection of internal and external stimuli, discrimination between stimuli, and development of short and long-term memories resulting in a discrepancy between subjectively reported and objectively measured sleep.

The Psychobiological Inhibition Model suggests that a failure to inhibit wakefulness is caused by a set of altered cognitive processes, labeled as the attention-intention-effort (A-I-E) pathway. These cognitive processes develop or take effect when, during a period of acute stress-induced insomnia, the patient becomes preoccupied or hyper-attentive to the process of initiating sleep, which is typically automatic.

This change in the attentional relationship to sleep leads to an intentional focus on sleep and insomnia symptoms and subsequent effort to actively modify them. Attention, intention, and effort are all processes of wakefulness. so when they are active, they restrict the passive and automatic process of sleep initiation.

The Cage Exchange Model is an animal model in which male rats were transferred to the soiled cage of another male rat at the peak of the sleep period. This environment change evoked a typical acute stress response characterized by an initial period of sleeplessness accompanied by autonomic and HPA axis activation. Once acute stress had dissipated, a period of disturbed sleep was observed.

Examination of Fos expression and EEG during this sleep period revealed presence of a “coactivation” of a sleep-and-wake-promoting neuronal system, resulting in a “novel intermediate state.” In this context of simultaneous activation of opposing neurological systems, the normal sleep-wake switching is destabilized.

Pharmacotherapy Effects

Any substance that crosses the blood-brain barrier has the potential to affect sleep-and-wake-promoting neuronal systems and subsequently to cause insomnia or sedation. Various antidepressant, antiepileptic, antipsychotic, cardiovascular, and respiratory medications, as well as other drugs, have been associated with onset of insomnia symptoms. The effects of various drugs on polysomnographically recorded sleep vary widely so only subjectively reported insomnia is reported here. Specific medications associated with insomnia are reviewed here.

Antidepressants

Most antidepressants have some risk of insomnia. Drugs in this category with the highest incidence of insomnia symptoms tend to cause greater increases in norepinephrine or dopamine action. All of the selective serotonin reuptake inhibitors are associated with insomnia and sedation. However, the exact mechanism by which insomnia complaints arise is uncertain because of the multiple and complex effects of these drugs on various serotonin receptors and other neurochemical systems

Antipsychotics

Antipsychotic medications are most commonly associated with sleep-enhancing or daytime sedating effects because of their primary mechanism of dopamine antagonism. However, insomnia symptoms are reported as an adverse event of these drugs by 4-25 percent of subjects.

Other drugs that may cause insomnia

Various medications used in the treatment of epilepsy, cardiovascular diseases, respiratory diseases, and allergies are also frequently associated with insomnia symptoms. The mechanism of insomnia effect varies according to the pharmacodynamic properties of each drug or drug class.

Homeostatic Abnormalities

The timing and duration of sleep are primarily controlled through the interaction of two neurobiological systems; the homeostatic sleep system and the circadian timing system. Reduced amplitude or strength of the homeostatic system has been shown to cause symptoms of insomnia. Recent research has documented 30 percent less GABA (a primary inhibitory and homeostatic neurotransmitter) in primary insomnia patients compared to normal sleepers. In the same study, GABA levels were negatively correlated with durations of wakeful episodes after sleep onset. Based on this knowledge, it is reasonable to postulate that, for some insomnia patients, insomnia symptoms are the result of a GABA insufficienty of unknown etiology.

Which individuals are at greatest risk of developing disease insomnia?

Lifestyle and Occupation: Individuals who do shift work, travel across time zones frequently, or otherwise follow an erratic or unstable sleep schedule are at increased risk for development of both insomnia and circadian rhythm sleep disorders. In addition, individuals who carry a high family, work, social, or academic load are also at higher risk for insomnia because of a high likelihood of developing poor sleep hygiene and/or maladaptive sleep-related behaviors (i.e.,, sudden transition from work/homework, parenting, etc. to attempting to initiate sleep).

Age and Gender: Insomnia occurs in 20-40 percent of older adults (> age 55), a two to four fold increase in prevalence compared to the general adult population. There is evidence to support an age-related decline in the amplitude of both homeostatic and circadian processes. However, when other factors are controlled, the role of homeostatic and circadian changes in the development of insomnia appears minimal. Accordingly, the increased rate of insomnia in older adults is best explained by increased rates of medical and psychiatric comorbidity (including other sleep disorders) and medications used to treat comorbid conditions.

Women are 1.5 times more likely than men to develop insomnia. This increased risk for insomnia in women is present throughout the lifespan, with the exception of the third decade of life. The etiology of this gender difference is unknown, but hormonal, coping, and stress exposure factors have been proposed.

Comorbid Medical or Psychiatric Illness: Any illness that is associated with increased psychosocial stress; painful or uncomfortable sensation or perception; or neurologic, metabolic, endocrine, respiratory or cardiovascular abnormalities, as well as treatments that result in these situations have the potential to cause acute insomnia. Specifically, compared to individuals without comorbidities, patients with medical and psychiatric comorbidity report markedly higher rates of insomnia.

The odds ratios of having insomnia range from 1.92 to 3.26 for individuals with hypertension, chronic pain, or breathing, urinary, or gastrointestinal problems compared to individuals without these problems. Sixty percent of patients with depression and 82 percent of patients with anxiety report development of insomnia symptoms concurrent with or following development of depression or anxiety.

What laboratory studies should you order to help make the diagnosis, and how should you interpret the results?

Overnight polysomnography is not typically indicated for the assessment of insomnia. However, it should be considered in patients with chronic treatment-resistant insomnia to rule out sleep-related breathing and movement disorders as well as paradoxical insomnia (also known as sleep state misperception).

What imaging studies will be helpful in making or excluding the diagnosis of insomnia?

None

What non-invasive pulmonary diagnostic studies will be helpful in making or excluding the diagnosis of insomnia?

None

What diagnostic procedures will be helpful in making or excluding the diagnosis of insomnia?

In some cases use of actigraphy can be helpful in diagnosing insomnia, especially in cases where the quality of self-reporting via sleep log is deemed unreliable or invalid (e.g.. by children, elderly patients, or patients with unspecified cognitive or perceptual variables). Specific applications include:

• differentiation of voluntary sleep deprivation from insomnia via documentation of adequate opportunity for sleep in patients with a primary complaint of unrefreshing or nonrestorative sleep without sleep-onset or sleep-maintenance complaints

• diferentiation of types of insomnia, especially psychophysiological versus paradoxical insomnia

• differentiating insomnia from circadian-rhythm sleep disorders

• identification of periods and patterns of unintentional dozing, of which patients are often unaware.

What pathology/cytology/genetic studies will be helpful in making or excluding the diagnosis of insomnia?

None

If you decide the patient has insomnia, how should the patient be managed?

Pharmacotherapy: Current practice of pharmacotherapy for insomnia includes FDA-indicated use of benzodiazepine (BzRA) and non-benzodiazepine (non-BzRA) hypnotic medications, the melatonin receptor (MT1) agonist ramelteon, and the tricyclic antidepressant doxepin at low doses (i.e,. 3 mg or 6 mg). Off-label use of a variety of antidepressants, atypical antipsychotics, and anticonvulsants is also widespread.

Psychological (Cognitive-Behavioral) Treatments: Psychological treatments refer to therapeutic activities aimed at changing behaviors, beliefs, or other cognitions related to insomnia. According to the American Psychological Association, there are currently five well-established psychological treatments for insomnia in adults: sleep restriction, stimulus control, relaxation, paradoxical intention, and cognitive-behavioral therapy for insomnia (CBT-I, which refers to any combination of these treatments).

For older adults, only sleep restriction, stimulus control, and CBT-I are considered well-established. These treatments are also recognized in the American Academy of Sleep Medicine Practice Parameters as either a standard (generally accepted strategy with a high degree of clinical certainty) or a guideline (a strategy with a moderate degree of clinical certainty).

Self-management: Self-management of insomnia is common with alcohol, various over-the-counter sleep aids that contain one of the non-selective antihistamines doxylamine or diphenhydramine, and melatonin, which is the most frequently used. A variety of herbal preparations (e.g., St. John’s Wort, 5-HTP) are also commonly used, with 5 percent of insomnia patients indicating use of these “alternative treatments.”

First-line Treatments for Insomnia

Pharmacotherapy with sedative or hypnotic medications and Cognitive-Behavioral Therapy for Insomnia (CBT-I) have the largest bodies of evidence to support efficacy and effectiveness as first-line treatments for insomnia. Studies that compare CBT-I and sedative/hypnotic medications have documented equivalent short-term efficacy. However, CBT-I has been found to have an advantage over pharmacotherapy in long-term efficacy, with treatment gains being maintained up to 36 months following termination of CBT-I. A two-phase combined treatment with CBT-I and pharmacotherapy, followed by continued CBT-I and concurrent medication taper appears to be most effective for achieving optimal long-term outcomes.

Non-Benzodiazipine and Benzodiazepine Hypnotics

Non-benzodiazipine and benzodiazepine hypnotics are the most frequently used first-line treatments for insomnia. Adverse events associated with all BzRA and non-BzRA hypnotics are infrequent (1 in every 10,000 doses), and hypnotics generally have a favorable risk-benefit profile compared to other medication classes (e.g., antidepressants, antipsychotics, and anticonvulsants). However, several key risks associated with hypnotic pharmacotherapy should be kept in mind.

With the exception of zaleplon, all hypnotics carry a warning or instruction that the medication should not be taken unless the patient allows opportunity for a full night (i.e., eight hours) of sleep. Residual morning sedation and possible psychomotor impairments are frequent with use of these medications, which effects can be associated with increased risk of accident or injury. The likelihood and associated severity of these effects is influenced by the dose and the elimination half-life of each specific drug.

All hypnotics now carry a warning regarding complex sleep-related behaviors, such as driving, eating, talking on the phone, hich occur during the sleep period without the patient’s awareness or memory of the behavior. These behaviors are rare when hypnotics are used at recommended doses. However, likelihood of complex sleep-related behaviors increases with supratherapeutic doses and in the context of other sedative or hypnotic medications or CNS depressants, including alcohol.

Abuse rates for both BzRA and non-BzRA hypnotics are low (2 per 10,000 prescriptions). However, there is increased likelihood of abuse or dependence in patients who have a history of addictions, and hypnotics are typically avoided in this population.

Compared to the traditional benzodiazepines, the short half-lives of the non-BzRA hypnotics (i.e., one to six hours) are associated with reduced rates of morning sedation and other residual daytime effects, such as fatigue and cognitive impairment.

Concerns about dependence and abuse are often raised with use of these medications. However, randomized clinical trials of up to twelve months of PRN or nightly use of eszopiclone and zolpidem have found no signs of tolerance. There is no data to support the presence of a withdrawal syndrome with short or long-term use.

As noted previously, compared to other medication classes, BzRA hypnotics have low rates of abuse, infrequent adverse events, and a generally favorable risk-benefit profile. However, a clear withdrawal syndrome is associated with sudden discontinuation of the BzRA hypnotics even after only a few weeks of nightly use. With the exception of triazolam, moderate to long half-lives can be associated with increased rates of morning sedation and psychomotor impairments. For these reasons the non-BzRA hypnotics are typically preferred over the benzodiazepines.

Withdrawal symptoms may include mild unpleasant emotional or physical feelings (e.g., anxiety and nausea) and a temporary worsening of insomnia symptoms. Severe withdrawal symptoms, including vomiting, tremors, stomach/muscle cramps, and sweating. Convulsions are also possible but uncommon. Increased daytime anxiety is also a possible withdrawal symptom.

Cognitive-Behavioral Treatments

Studies of adults and older adults with primary and comorbid insomnia show that 70-80 percent of patients respond to CBT-I, with approximately 50 percent experiencing remission of insomnia. Multiple meta-analyses have demonstrated moderate to large effect sizes (d=0.42 to 1.37) for key sleep variables, including sleep-onset latency, wake-after-sleep onset, number of nocturnal awakenings, sleep quality, and total sleep time.

Effectiveness studies have shown similar rates of response and remission to CBT-I delivered in a variety of settings (e.g., primary care, sleep clinic, and behavioral sleep medicine clinic), in both individual and group formats, delivered by a variety of healthcare providers (e.g., nurse educators, psychologists, and others), and through a variety of communication mediums (e.g., face-to-face, telephone, self-help booklets, and Internet-based self-help programs).

The procedures described here include the core instructions for each treatment and do not represent the subtleties and complexities of the individual treatments or the treatment of insomnia generally. Accordingly, non-response to treatments as described here should prompt further evaluation and treatment with a certified behavioral sleep medicine specialist or other similarly trained and qualified provider.

Sleep Restriction

The objective of this treatment is to stabilize the patient’s nightly sleep schedule and duration and to produce rapid sleep onset and consolidation of sleep via the effects of reduced time in bed and a concrete sleep schedule on homeostatic and circadian sleep systems. This treatment is contraindicated in patients who are required to maintain optimal vigilance in order to avoid accident or injury (e.g., truck drivers, pilots, operators of heavy machinery, and some factory workers).

Stimulus Control

The objective of this treatment is to eliminate conditioned arousal associated with sleep and to re-establish a strong, conditioned association among sleep, the bed, and the bedroom. Changes in these conditioned responses are expected to increase the patient’s ability to initiate and re-initiate sleep quickly as needed throughout the night. This treatment is composed of a set of behavioral instructions that includes:

• Going to bed and attempting to sleep only when sleepy

• Using the bed and the bedroom for sleep and sex only

• If the patient is unable to initiate sleep within 10-15 minutes of lying down, getting up and going to another room and do something that is not mentally or physically activating

• Returning to bed when sleepy or ready to try again

• Setting the alarm and getting out of bed at the same time each day, regardless of how much sleep the patient gets

• Avoiding napping

Relaxation

Relaxation encompasses a variety of interventions that are designed to reduce somatic or cognitive arousal, including diaphragmatic breathing, biofeedback, autogenic training, meditation, and progressive muscle relaxation. Cognitive arousal seems to be most salient in the treatment of insomnia. Specific scripts for self-guided relaxation can be found online at no cost or a variety of audio recordings can be purchased at bookstores or online for patients who prefer a guided experience.

Improvements in insomnia from relaxation treatment appear to be related to the daily practice of relaxation rather than to any specific method or technique applied. Accordingly, the work of the healthcare provider is to emphasize the need for daily practice to achieve therapeutic benefit from relaxation and to work with the patient to create an explicit practice plan.

Practice is commonly recommended to be undertaken for 10-30 minutes twice per day. At least one of these practices should be unassociated with the bed, the bedroom, or attempts to sleep.

Paradoxical Intention

The objective of this treatment is to reduce sleep-related performance anxiety, worry, and preoccupation by eliminating or circumventing patients’ conscious efforts to force initiation of sleep.

On the surface, this is achieved by having the patient engage in paradoxical behavioral (i.e., trying to remain awake) while in bed. However, obtaining buy-in from the patient regarding conceptualization of insomnia as a problem of “sleep effort” and the patient’s willingness to implement this treatment can require the skill of a trained therapist. Accordingly, this intervention is recommended for implementation by trained behavioral sleep medicine specialists or others with specific training in psychological treatments.

Multi-Component Cognitive-Behavioral Treatment for Insomnia (CBT-I)

Multi-component CBT-I is arguably the most common format for delivery of cognitive-behavioral treatments. “Multi-component” refers to the use of any combination of the treatments described above, as well as other cognitive-behavioral treatments for insomnia, that have less empirical support for their efficacy or effectiveness than other treatments do. It may also include other general cognitive or behavioral interventions that are non-specific to insomnia.

Sleep Hygiene

Sleep hygiene instructions have no evidence to support them as efficacious for treatment of insomnia. Although they do support healthy optimal sleep and should be reviewed with patients, they should not be considered an active treatment. They are included here because they are the most frequent recommendations provided to insomnia patients by non-sleep specialist providers. Sleep hygiene instructions are provided to patients as follows:

• Keep a regular schedule 7 days per week.

• Avoid sleeping with pets in your bed or bedroom.

• Avoid alcohol 3-4 hours before bedtime.

• Discontinue caffeine six hours before bedtime.

• Avoid nicotine near bedtime and during night time awakenings.

• A light snack may help induce sleep, but avoid heavy meals within two hours of bedtime.

• Use of ear plugs or white noise can help reduce the effect of disruptive noises during sleep.

• Exercise regularly, but do no moderate or high-intensity exercise within three hours of bedtime.

• Make your bed and your bedroom safe and comfortable (e.g., by controlling light, noise, temperature).

Other Pharmacotherapy: Doxepin and ramelteon

Ramelteon

Ramelteon has an FDA indication for treatment of sleep-onset insomnia with demonstrated efficacy for adults and older adults. The therapeutic dose is 8 mg, which should be administered thirty minutes prior to bedtime. It is a selective melatonin agonist with a half-life of 1.4 hours and is primarily metabolized by the liver. Median time to peak plasma concentration is 0.75 hours. Ramelteon should not be taken with or immediately following a high-fat meal.

Common side effects include somnolence, headache, fatigue, and dizziness. There is no evidence to support a risk of abuse or dependence.

Ramelteon should not be used with fluvoxamine. Use with caution in the context of other CYP1A2 inhibitors and in patients with moderate hepatic impairment. It should not be used in patients with severe hepatic impairments. See the manufacturer’s prescribing information for full safety information.

Doxepin

Doxepin was initially developed as an antidepressant at recommended therapeutic doses of 150-300 mg per day. However, in 2010 doxepin received FDA approval for sleep-maintenance insomnia at lower doses, and it is currently being marketed under the trade name “Silenor.”

Recommended dosing is 6 mg for adults (3 mg for elderly patients) 30 minutes prior to bedtime. It should not be taken within three hours of a meal. It is a histamine H
₁ antagonist with median time to peak plasma concentration of 3.5 hours and half-life of 15.3 hours (31 hours for active metabolite nordoxepin).

Common side effects include somnolence, dizziness, and upper respiratory tract infection. There is no evidence to support a risk of abuse or dependence. Use with caution in patients with closed-angle glaucoma, severe urinary retention, psychiatric disorders, hepatic impairment, and in the context of CNS depressants. See the manufacturer’s prescribing information for full safety information.

Self-Management

Over-the-Counter Medications

Melatonin has evidence to support its use for sleep onset insomnia when administered thirty minutes to three hours prior to bedtime. However, the current body of research varies widely in the dose, formulation, and timing of administration. Accordingly, confidence in the efficacy of melatonin as recommended above is low. The most common side effect of melatonin is headache. There is no evidence to support risk of abuse or dependence, and no other clinically significant risk has been identified.

The antihistamines doxylamine and diphenhydramine are the primary active ingredient in almost all over-the-counter sleep aids (e.g., Tylenol PM, Simply Sleep, Unisom, Sominex). Common side effects include sedation, dizziness, psychomotor impairment, cognitive impairment, dry mouth, blurred vision, constipation, urinary retention, and weight gain. There is no evidence to support risk of abuse or dependence. Use of these drugs is contraindicated in patients with closed-angle glaucoma, decreased gastro intestinal motility, urinary retention, asthma, chronic obstructive pulmonary disease, and severe liver disease.

Alcohol

Thirteen percent of the general adult population reports using alcohol specifically as a hypnotic and 5% indicate they use alcohol in addition to sleep medications. Although alcohol does reduce sleep onset latency in a relatively reliable manner, use of alcohol for sleep should be discouraged for several reasons. First, athough it reduces sleep onset and may increase slow wave sleep during the first half of the night, it is associated with sleep fragmentation, REM rebound, and other sleep-interfering effects in the second half of the night.

Second, alcohol is known to exacerbate sleep-related breathing disorders if present. Third, some data suggests that hypnotic use of alcohol may be a risk factor for development of alcohol abuse or dependence.

Supplements – Vitamin/Mineral/Herbal

Generally, healthcare providers are apprehensive about recommending supplements because of the lack of evidence regarding the safety, efficacy, or effectiveness of available substances in this category. The two most common herbal products used for self-management of insomnia are valerian root and St. John’s Wart. A literature review of 29 trials of valerian root for insomnia concluded that valerian root does not improve polysomnographically recorded or subjectively reported sleep in insomnia patients. The FDA has released a warning that St. John’s Wart is metabolized by the cytochrome 450 system and that it may interact with other medications.

Second- and Third-line Treatments: Off-label Pharmacotherapy

Numerous non-hypnotic medications see popular use for treatment of insomnia, largely because of concerns about the abuse potential, residual morning sedation, and possible psychomotor impairments associated with benzodiazepines.

The medications listed here are considered second-line treatments because of the absence of an FDA indication for insomnia and because, depending on the specific drug, there are few or no randomized controlled trials that provide efficacy and safety data for their use in the treatment of insomnia. However, most of the drugs in this section have some evidence to support a sleep-enhancing effect in normal sleepers or in various medical or psychiatric conditions.

In terms of clinical utility, there are several situations where use of these medications for insomnia may be most appropriate. They may be preferred for treatment of insomnia that occurs in the context of comorbidities for which they are specifically indicated (e.g., quetiapine and olanzapine for insomnia in the context of psychosis or mania; pregabalin in the context of neuropathic pain or fibromyalgia). This approach may be especially relevant when single-agent treatment is preferred.

These drugs have no evidence to support a risk of abuse or dependence; they may represent an acceptable treatment in patients who have histories of substance abuse and who experience insomnia during acute and protracted abstinence.

These drugs may also be appropriate in cases of treatment resistant insomnia when multiple first-line treatments have been ineffective and other sleep disorders and direct effects of comorbidities have been ruled out.

Antidepressants

When used for insomnia, antidepressants are typically prescribed at lower doses that reduce the likelihood of adverse effects commonly associated with these medications. Doses used to treat insomnia are unlikely to have a clinically meaningful antidepressant effect. The mechanism of hypnotic effect varies with each specific drug, but it is typically through antagonism of serotonin, histamine, or norepinephrine.

Atypical Antipsychotics

The mechanism of hypnotic effect of these drugs is antagonism of histamine, norepinephrine, serotonin, and acetylcholine. Quetiapine has been studied in primary insomnia and has been found to reduce sleep-onset latency and to increase total sleep time in this population.

Quetiapine has some evidence to support its use for treatment of insomnia during acute and prolonged abstinence in patients with polysubstance abuse or dependence. Given its low risk for abuse, quetiapine may be a valid treatment option in patients with history of substance abuse or dependence.

Olanzapine and quetiapine have been studied for treatment of insomnia symptoms in the context of psychiatric conditions that include schizophrenia, bipolar disorder, and post-traumatic stress disorder. Treatment of insomnia in the context of psychiatric disorders may be the most appropriate use of the medications.

Anticonvulsants

The putative mechanism of hypnotic action for anticonvulsants is reduction of glutamate and norepinephrine release. Tiagabine and gabapentin have been shown to improve sleep in patients with primary insomnia. Gabapentin has also been found to improve subjective measures of sleep in menopausal women with hot flashes. However, the risk-benefit profile of these medications suggests that they should be used with caution in these populations.

At least two studies have shown that gabapentin is effective for treatment of persistent insomnia in abstinent alcoholic patients. Given its low risk for abuse, gabapentin may be a valid treatment option in alcoholic patients and in other patients with a history of substance abuse or dependence.

The majority of the evidence for sleep-related effects of these medications is based on assessment of sleep variables as a secondary outcome measure in clinical trials for fibromyalgia, neuropathic pain, and seizure disorders. Accordingly, use of these medications for insomnia may be most appropriate in the context of these comorbid conditions.

What is the prognosis for patients managed in the recommended ways?

The natural course of insomnia is primarily one of a persistent chronic (rather than episodic) condition. Over the course of three years, 74 percent of insomniacs will experience a year or more of persistent symptoms, with 46 percent of insomniacs’ meeting the diagnostic criteria for insomnia for the entire three-year period and 54 percent experiencing remission of insomnia symptoms at some point during the three-year period. However, 27 percent of these remitted patients will ultimately experience relapse. Female gender, age 55 years or older, and greater insomnia severity were associated with higher rates of persistence and relapse.

Prognosis Associated with BzRA and Non-BzRA Hypnotic Treatment: Response is typically seen on the first night of hypnotic administration. No effectiveness studies have been completed for these medications so response and remission rates are unknown. However, 50-80 percent of hypnotic users report significantly improved sleep and satisfaction with sleep with short- and long-term use of therapy. Recrudescence to baseline insomnia symptoms is expected upon discontinuation of non-BzRA medications. Benzodiazepines have been associated with rebound insomnia and withdrawal symptoms upon rapid discontinuation.

Cognitive-Behavioral Therapies: 70-80 percent of patients who participate in CBT-I will benefit from treatment. Fifty percent of patients can be expected to experience complete remission. It is reasonable to expect that CBT-I will result in an approximate 50 percent reduction in sleep-onset latency and the duration of episodes of waking after sleep onset. For patients who complete CBT-I, treatment gains are typically well maintained for 12-36 months following termination of treatment.

Self-Management: There are no data on the prognosis of patients who use self-management strategies.

Off-Label Pharmacotherapy: There are no data on the prognosis of patients treated with these medications.

What other considerations exist for patients with insomnia?

Excessive daytime sleepiness (EDS) and an associated increase in risk of accident and injury should be closely monitored while treating patients with insomnia. Sleep deprivation that is due to insomnia symptoms may result in EDS. Onset of EDS is also a common complaint of patients following initiation of pharmacotherapy and cognitive-behavioral therapies for insomnia.

Unsatisfactory response to insomnia treatment should always prompt futher assessment for differential diagnosis of other sleep disorders and unidentified medial or psychiatric factors and for possible medical, psychiatric, or behavioral causes of poor treatment response.