Clinical manifestations

Presentation and course

The term insomnia indicates a stated problem with sleep initiation or sleep maintenance (despite adequate opportunity for sleep), resulting in some degree of daytime neurocognitive impairment. Some examples of daytime neurocognitive impairment include sleepiness, fatigue, poor concentration, mood lability, somatic symptoms, and excessive worry about sleep. There are also the issues of individual variation in sleep need. These may also reflect a complaint of insomnia related to a patient who desires more sleep than is physiologically needed or a difference between subjective assessment and objective measurements of sleep in a patient. These latter 2 problems, short sleep and paradoxical insomnia, respectively, may result in a patient with complaints but without measurable abnormal findings using our current evaluation tools. Lack of awareness of these problems may contribute to difficulty in diagnosis by the physician.

Insomnia contradicts the time-honored medical principle of Occams razor, which dictates that a single diagnosis is likely to account for a presenting complaint. Multiple primary and comorbid insomnia disorders may coexist in a patient who presents with complaint of insomnia. Careful history and differential diagnosis is required to sort out these disorders. Criteria for the diagnosis of insomnia disorder are shown in Table 1.

Table 1. Criteria for the Diagnosis of Insomnia Disorder

Courtesy of (03).

Prognosis and complications

The prognosis for recovery from insomnia depends on identification of possible cause(s) and an effective treatment strategy.

Insomnia is often a chronic condition, with retrospective reports indicating that about 80% of severely affected individuals have had the problem for longer than 1 year, and approximately 40% report a duration of longer than 5 years. Longitudinal studies suggest that 30% to 80% of those identified with moderate to severe insomnia show no significant remission over time. However, it is not clear whether these data relate more to the absence of recognition and treatment of insomnia in the early stages, as opposed to the difficulty treating it as a long-term problem. Strategies for detecting and diagnosing insomnia may improve sleep quality and medical benefits in the primary care practice.

Prolonged insomnia is associated with an increased risk of major depression and may be an independent risk factor for heart disease, hypertension, and diabetes, particularly when sleep time is less than 6 hours per night (31).

Complications of insomnia include impaired responses to infections, increase in inflammation, higher levels of the stress hormone cortisol, and other biomarkers related to fatigue and poor health. Pain is recognized as a cause of sleep disturbances, but a metaanalysis of several studies suggests that persons who sleep poorly may be more likely to develop a chronic pain condition with a 2- to 3-fold increase in pain problems over time (01). Further longitudinal studies are needed to determine the long-term impact of sleep on pain.

Clinical vignette

A 43-year-old woman presented to her primary care physician for a routine appointment. A screening history revealed complaints of poor nighttime sleep resulting in excessive fatigue, increased irritability, and difficulty concentrating.

A sleep questionnaire and detailed history revealed 8 years of difficulty initiating and maintaining sleep, progressively worsening. The onset of her sleep problems coincided with the birth of her first child. The patient had needed to rise several times during the night to feed her baby; however, her sleep problems did not remit when the child began sleeping through the night. The patient had attempted to treat her insomnia with sleep medication but was unable to find a drug that had tolerable side effects; many of the medications she tried left her feeling groggy and hungover the following day.

It typically took the patient about 60 to 90 minutes to fall asleep. She reported waking up spontaneously 2 to 3 times per night and, subsequently, had difficulty falling asleep; she reported spending up to 3 hours awake during the night. She had difficulty functioning at work as a schoolteacher due to increased fatigue and poor concentration.

The patient reported a history of hypothyroidism but stated that this was adequately controlled with medication. She denied any other medical conditions that could potentially interfere with sleep. Her husband described occasional soft snoring but denied any other notable nighttime behaviors.

Her sleep logs revealed a pattern consistent with psychophysiological insomnia, with extended time to fall asleep and extended awakenings throughout the night. She would attempt to nap 2 to 3 times per week but would be unable to fall asleep after lying down. Her sleep schedule was regular, but she tended to go to bed earlier on nights following a particularly bad night of sleep and attempted to sleep in on the weekends.

Her self-report and her husbands report of nighttime symptoms were not consistent with obstructive sleep apnea or any other occult sleep disorder; therefore, referral for an overnight sleep study was unwarranted.

The patient was followed for 5 bi-weekly sessions of cognitive behavioral therapy for insomnia. This treatment consisted of stimulus control therapy, sleep restriction therapy, sleep hygiene education, and cognitive therapy in addition to a final session reviewing techniques to maintain treatment gains and prevent relapse. Within the first 2 weeks of treatment, the patient began sleeping more solidly and noticed improvements in daytime fatigue and alertness. Her sleep continued to improve as sleep opportunity was gradually expanded. Treatment was discontinued when the patient reported that she was getting an adequate amount of sleep and was no longer experiencing daytime symptoms. At a later follow-up appointment, the patient reported that despite occasional nights of poor sleep related to transient stressors, she could maintain the gains she made in treatment. She reported that she was falling asleep more quickly and no longer waking up during the night.

Biological basis

Etiology and pathogenesis

Various risk factors for insomnia disorder are listed in Table 2, and the model of insomnia with interaction of various factors is shown in the diagram.

Table 2. Risk Factors for Insomnia Disorder

Neurologic/psychiatric disorders with comorbid insomnia. The following are some examples of such disorders:

Alzheimer disease. Sleep disorders occur in 20% to 50% of patients, and the most common problem is difficulty in falling and staying asleep. There is increased duration and frequency of awakening during night.

Parkinson disease. Sleep disorders occur in 1% to 5% of patients, and incidence increases with age. Insomnia is due to tremors, painful dystonia, nocturia, depression, and medications.

Epilepsy. Approximately 25% of patients with epilepsy have seizures during sleep. Epileptic episodes may cause recurrent dreams, nightmares, and frequent arousals that may result in awakenings and a complaint of insomnia.

Ischemic stroke. Insomnia or excessive sleepiness and sleep disordered breathing are frequently seen in patients who have an ischemic stroke.

Major depressive disorder (MDD). Chronic insomnia disorder is a primary risk factor for depression. According to Brietzke and colleagues, sleep disturbances in major depressive disorder may be categorized as follows: (1) depressive psychopathology, (2) a sequel of rhythm disruptions, (3) major depressive disorder as a comorbidity of sleep disturbances, (4) a manifestation of the influence of sex hormones in the brain in major depressive disorder, (5) as a comorbidity of other medical conditions, and (6) a side effect of antidepressant medications (09).

Structural changes in the brain associated with insomnia. Changes in the brain in insomnia may reflect those that occur in associated neurologic disorders. A diffusion-tensor imaging study showed that white matter tracts related to regulation of sleep and wakefulness, and limbic cognitive and sensorimotor regions, are disrupted in the right brain in patients with primary insomnia, likely due to loss of myelination (21). An MRI study showed that patients with primary insomnia had enhanced connections in the left anterior cingulate cortex/insula, left posterior cingulate, and the right limbic lobe/cingulate gyrus/paracingulate gyrus with anterior cingulate cortex as compared to normal controls, whereas patients with primary insomnia and depression had weaker functional connectivity in the left corpus callosum/posterior cingulate and enhanced connectivity in the frontal and limbic lobes with anterior cingulate cortex (20). According to these authors, these differences in connectivity may be the structural basis of impairment of cognitive function due to interaction between depression and insomnia.

Molecular factors in insomnia. These include the wake-promoting chemicals like orexin, catecholamine, and histamine and sleep promoting chemicals like GABA, serotonin, adenosine, melatonin, and prostaglandin D2. The orexin-mediated increased neuronal firing in the wake-promoting area and inhibition of the sleep-promoting area is 1 of the possible mechanisms contributing to insomnia. Suvorexant, an orexin antagonist, improves sleep latency and maintenance both objectively and subjectively and also improves sleep (objective and subjective). Lemborexant binds to orexin receptors OX1R and OX2R and acts as a competitive antagonist. Daridorexant, a new dual orexin receptor antagonist tested in a clinical trial (NCT02839200), induced a dose-dependent reduction in wake time after sleep onset in subjects with insomnia disorder (10).

Genetics of insomnia. Various sleep-related traits, including insomnia, are heritable. Sleep patterns and requirements vary widely among individuals, and mutations of some genes have been linked to disorders of sleep. Genome-wide association studies on soldiers in the U.S. army have shown that insomnia was linked to the occurrence of specific variants on chromosome 7 as well as differences on chromosome 9 in those of European descent (29). This study confirmed the genetic basis of insomnia and demonstrated that insomnia-associated loci may contribute to the genetic risk underlying a range of health conditions including psychiatric disorders and metabolic disease such as type 2 diabetes. Genome-wide association studies of accelerometer-derived sleep measures have identified additional loci not shown by previous self-report studies, which likely harbor causal variants associated with poor sleep and are enriched for serotonin processing genes (15). For sleep duration, these studies identified a missense variant (p.Tyr727Cys) in PDE11A as the likely causal variant.

Neuropeptide S and neuropeptide S receptor (NPSR) are associated with sleep regulation. A genotyping study has provided the evidence that the NPSR1 gene polymorphisms (rs324957, rs324981) might be susceptibility loci for primary insomnia (33).

Genetic factors seem to play a key role in why some people require less sleep. A study has reported that persons with a mutation in the β1-adrenergic receptor gene require fewer hours of sleep than most because their genetic mutation activates their adrenergic receptors more often than those without the variant (27). A missense mutation in the human DEC2 gene (BHLHE41) leads to the familial natural short sleep behavioral trait likely by regulating sleep/wake duration through modulation of the neuropeptide hormone orexin (14).

Epidemiology

Insomnia is a highly prevalent disorder in the United States. According to the polls by the National Sleep Foundation, approximately 35% of the adult population reports that they have experienced insomnia every night or almost every night within the past year. Differences in prevalence vary widely, depending on how insomnia is defined, the severity and frequency of complaints, and age and gender of the patient. For chronic insomnia, rates are higher for women and increase with age. Associated disorders, including medical and psychiatric problems, also correspond to higher frequencies of insomnia.

Prevention

Early intervention including correction of poor sleep hygiene may prevent evolution into chronic insomnia.

Acute insomnia is a nearly universal experience and presents as an occasional or infrequent event that is caused by stressful everyday activities. The evolution into secondary or chronic insomnia may be prevented by early treatment. Various types of secondary insomnia, like psychophysiological insomnia or poor sleep hygiene, may be preventable by better evaluation and intervention before well-entrenched secondary patterns develop.

Differential diagnosis

Confusing conditions

Insomnia is not confused with other neurologic or psychiatric symptoms. The key differential diagnosis components relate to obtaining a history (elicited in a systematic manner within a well-established framework) as well as attention to the presence and type of nocturnal symptoms and daytime sequelae.

Associated or underlying disorders

Associated and underlying neurologic disorders are listed below. Some of these have been discussed in subtopics of etiology and pathogenesis.

In addition, insomnia is a symptom of several medical disorders.

Other important details to inquire about include environmental noise, nightmares, partial arousal disorders, REM sleep behavior disorder, nocturnal seizures, nocturia, enuresis, sleep paralysis, and hypnagogic hallucinations.

Diagnostic workup

Partner reports. Bed partner reports are critical for obtaining information that will be helpful in directing the evaluation of chronic insomnia. Many characteristic features of sleep-related causes of insomnia occur during sleep and, hence, without the sleepers awareness. Partner information can be a critical link in confirming diagnostic suspicions. Several sleep partner questionnaires are available, making the gathering of these data more convenient.

Sleepiness questionnaires. Other tools available to gather the information necessary for directing evaluation include daytime questionnaires and methods of assessing daytime consequences. The Stanford and Epworth sleepiness scales are the most commonly used and validated questionnaires that measure daytime sleepiness.

Neuropsychological tests, sleep logs, and patient questionnaires. Neuropsychological measures of cognitive and psychomotor function (vigilance, concentration, motor speed and accuracy, memory, reasoning) have been used in research settings, although they are less clearly effective for help in the evaluation of patients in the clinical setting. Self-report assessment devices, such as sleep logs and patient questionnaires, are widely used with sufficient validation to be deemed helpful. Instruments to assess the impact of sleep on the quality of life are also available.

The difficulty in adequately defining an acceptable diagnostic workup for the evaluation of insomnia led the American Academy of Sleep Medicine to commission several projects, resulting in multiple sets of practice parameters. A comprehensive clinical guideline for the evaluation and management of chronic insomnia in adults has been published (28). In keeping with the general format of the AASM practice parameters, this new clinical guideline paper presents recommendations based on the strength of the available evidence, using the same definitions of standard, guideline, and option that were used in the AASM practice parameters papers. In addition, this paper included consensus recommendations, based on expert opinions, for areas where practice parameters have not been developed, or for which empirical data are limited.

Table 3 summarizes the recommendations from the 2008 clinical guideline paper, with the strength of the recommendation in parentheses (ie, Standard, Guideline, Consensus, or Option).

Table 3. Clinical Guidelines for the Evaluation of Chronic Insomnia in Adults

A study, based on a questionnaire and an assessment of Insomnia Severity Index, has identified 5 novel insomnia disorder subtypes relevant to depression: 1) highly distressed; 2) moderately distressed but with intact responses to pleasurable emotions; 3) moderately distressed and insensitive to pleasurable emotions; 4) slightly distressed with high reactivity to their environment and life events; and 5) slightly distressed with low reactivity (07). This facilitates identification of the underlying causes of insomnia, development of personalized treatments, and selection of patients with the highest risk of depression for inclusion in clinical trials for prevention of depression.

Management

A correct diagnosis fostered by thorough and competent evaluation is one of the most important considerations regarding treatment. Secondary causes that need specific treatment (apnea, restless legs syndrome, etc.) must be identified and addressed directly. Treatment options for primary insomnia (excluding those due to another treatable primary problem) can be expressed in 2 broad categories of treatment: (1) nonpharmacologic treatments, and (2) pharmacologic treatments. Greater emphasis has been placed on nonpharmacological treatment options for insomnia, including evidence-based treatment in children, older adults, and patients with comorbid disorders.

Sleep hygiene. It is generally recommended that all patients with insomnia be given instructions regarding sleep hygiene, though most evidence suggests that this is not sufficient as a single intervention for most cases of insomnia. Examples of sleep hygiene instructions include limiting the variability of bedtime and risetime with a regular sleep-wake schedule, avoiding daytime naps, and avoiding caffeine and bright light exposure toward the end of the day.

Pharmacotherapy. The pharmacological principles related to the treatment of insomnia are highly complex, and voluminous literature exists on this topic. The choice of pharmacologic agents should be directed by symptom pattern, treatment goals, past treatment responses, patient preference, cost, availability of other treatments, comorbid conditions, contraindications, and side effects. Drugs used in the past as well as currently for treatment of insomnia are listed in Table 5.

Table 5. Drugs Used for Treatment of Insomnia in the Past and Present

Sedating medications should be used with caution in the elderly, due to evidence suggesting an increased risk for falls in this population. The following are recommended for use according to clinical practice guideline of AASM based on level of evidence, which is weak as compared to no treatment, for the pharmacologic treatment of chronic insomnia in adults (26):

The following are not recommended (26):

Cognitive behavioral therapy. Among nonpharmacological and behavioral interventions, cognitive behavioral therapy (CBTI) has received overwhelming support from several studies as an effective treatment for insomnia. CBTI is a multi-component intervention that addresses behavioral and psychological factors that contribute to the development and maintenance of insomnia. Two core components of CBTI are stimulus control therapy and sleep restriction therapy. Stimulus control therapy is a behavioral strategy that aims to reconnect the sleeping quarters with the act of sleeping. Patients are advised to use the bed only for sleeping or for sexual relations. If unable to sleep, the patient should get out of the bed and engage in a low-level, low-light activity (08). Sleep restriction therapy makes therapeutic use of the increased sleep pressure associated with a restricted opportunity for sleep, typically approximately 6 hours per 24-hour period. The increased end-of-day sleepiness associated with a sleep-restricted schedule allows for more effective sleep onset and can help patients with chronic hypnotic dependent insomnia. Patients should be advised that this technique is designed to enhance sleepiness and are warned to use appropriate caution to avoid accidents when undertaking this treatment plan. Education about sleep hygiene is often included as a component of CBTI. Examples of sleep hygiene instructions include limiting the variability of bedtime and risetime with a regular sleep-wake schedule, avoiding daytime naps, and avoiding caffeine and bright light exposure toward the end of the day. The cognitive component of CBTI serves to identify and modify any maladaptive beliefs or thoughts the patient has about sleep, including setting realistic expectations regarding sleep patterns and next-day consequences of sleep loss. CBTI may also include adjunctive treatments such as relaxation training or light therapy as needed.

Current clinical guidelines list the use of psychological and behavioral interventions for the treatment of insomnia as a standard. Evidence suggests that, compared to pharmacotherapy, CBTI is equally effective in the short-term and more effective in the long term, making a case for initial management without medication (24). CBTI can be integrated with alternative/complementary therapies such as mindfulness meditation, yoga, acupuncture, and tai chi (36).

Although CBTI has primarily been studied in adults with primary insomnia, several publications suggest that it is an effective treatment for insomnia sufferers with comorbid psychiatric conditions (12). CBTI has been shown to be particularly effective in treating insomnia in psychiatric inpatients (13), patients with alcohol dependence (05), and patients with psychotic symptoms (23). CBTI has also been shown to be effective in treating patients with insomnia that is comorbid with medical illness (11). Research suggests that CBTI may be useful in treating insomnia associated with breast cancer (30), chronic pain (16), and fibromyalgia (22). The only limitation for wider application of CBTI is that it is time consuming.

Combination of CBTI with other therapies. CBTI can be integrated with alternative/complementary therapies such as mindfulness meditation, yoga, acupuncture, and tai chi (36). A retrospective observational study has shown that efficacy of cognitive behavioral therapy combined with eszopiclone for the treatment of sleep disorders patients transferred out of the intensive care unit was better than use of eszopiclone alone (35).

New therapeutic approaches to insomnia. There are a lack of studies specifically targeting insomnia in individuals with major depressive disorder. New therapeutic approaches including novel targets such as orexins/hypocretins and the endocannabinoid system are needed (09).

Suvorexant, an orexin antagonist, is approved for the treatment of insomnia. Results of a randomized clinical trial of daridorexant, a new dual orexin receptor antagonist, on wake after sleep onset have shown that dose-dependent improvements in wake after sleep onset and latency to persistent sleep were statistically significant in elderly people with insomnia disorder (NCT02841709) (34). It was well tolerated.

Intensive sleep retraining (ISR). Intensive sleep retraining is based on the concept that prolonged sleep deprivation leads to the accumulation of sleep pressure, which inevitably leads to sleep. It is like stimulus control therapy, which has the following components: (1) no predetermined bed time (go to bed only when sleepy); (2) to get out of bed if not asleep within 15 minutes; (3) repetition of numbers 1 and 2 until a rapid sleep onset; (4) maintaining the same wake-up time regardless of sleep length; and (5) no naps during the day (19).

The day before intensive sleep retraining, individuals are told to spend no more than 5 hours in bed. Intensive sleep retraining provides multiple short (a few minutes) sleep latencies over a 24-hour period. A randomized controlled trial has shown that intensive sleep retraining is an immediately effective and durable treatment of sleep-onset insomnia (18). Wearable devices using behavioral responses as the indicator of sleep onset enable the inexpensive, practical administration of intensive sleep retraining at home with no dependence on sleep laboratories.

Special considerations

Pregnancy

Changes during pregnancy may cause physical discomfort and sleeplessness but chronic insomnia is unusual, unless secondary patterns develop. Primary sleep disorders such as obstructive sleep apnea and restless legs syndrome can be precipitated by pregnancy and should be managed appropriately. The end of pregnancy often brings additional sleep disruption associated with a newborn, and education may be helpful in managing further difficulties in sleep.