Chronic Insomnia

Etiology

Chronic insomnia can be primary or secondary; however, its consequences remain similar, establishing it as a clinical disorder in its own right. Despite understanding the role of hyperarousal and stress reactivity and the importance of psychological and circadian factors in producing sleep disturbances, the interaction between these elements in producing chronic insomnia remains unclear.[3] Hyperarousal may be a causal factor, an independent variable, or a secondary effect. Psychological aspects can include emotional, cognitive, and personality components. The understanding of chronic insomnia is limited by the lack of information about the interplay of neurological, endocrine, and genetic factors.[3]

A comprehensive model of chronic insomnia envisions 3 sets of factors: [4]

• Predisposing factors, including genetically determined dysfunction, neurobiological mechanisms, and personality characteristics
• Precipitating factors, such as psychosocial stressors
• Perpetuating factors, including hyperarousal, behavioral adaptation, and ensuing emotional dysregulation

This cascade is thought to lead to memory impairment, cognitive problems, and psychopathology.[4]

Epidemiology

Generally, about one-third of adults (30%-36%) report at least one symptom of insomnia. When strict ICSD-3 or Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, Text Revision diagnostic criteria are used, prevalence rates range from 6% to 10%.[5] Insomnia is more common among middle-aged and older individuals, shift workers, women, and patients with comorbid medical and psychiatric disorders.[5] Worldwide prevalence of insomnia varies widely, ranging from 79% in Brazil to 23.2% in Western Europe.[6]

Pathophysiology

Predisposing factors for chronic insomnia include genetic and epigenetic factors. Genome-wide association studies show that a large number of genes are involved. Shared genetic factors contribute to insomnia, restless legs syndrome, cardiometabolic traits, and psychiatric conditions. The brain cell types expressing insomnia genes are part of the emotion regulation circuits, not the sleep regulation circuitry.[4]

The flip-flop switch model of sleep regulation suggests a switch mechanism between sleep-promoting neuronal cell groups and wake-promoting neuronal cell groups. Wakefulness is governed by cells in the hypothalamus that activate the reticular formation of the brainstem. The sleep-inducing centers are in the ventrolateral preoptic nucleus, which activates during sleep and inhibits the wake-promoting centers with the neurotransmitters galanin and gamma-aminobutyric acid (GABA). Conversely, the ventrolateral preoptic nucleus is inhibited by the neurotransmitters noradrenaline and serotonin. Chronic insomnia may result from an imbalance between sleep-inducing and arousal-inducing mechanisms.[4][7]

This switch process also involves circadian rhythms and homeostatic sleep mechanisms (sleep drive), although research has not shown these mechanisms to be primary contributors to chronic insomnia.[4]

A third contributor to insomnia is emotion. Stressful events are a significant risk factor for sleep disruption. Early adverse childhood experiences affect the risk genes for insomnia.[4]

Chronic insomnia is likely caused by synergistic genetic and environmental factors within an epigenetic context and is a complex, polygenic stress-related disorder.[8] 

History and Physical

A clinical interview for assessing chronic insomnia should include a physical examination and a patient history, including the following: [1][9]

• Medical diagnoses, including pain
• Neurological diagnoses
• Substance use, such as caffeine, alcohol, cannabis, nicotine, medications, and illicit drugs
• Level of exercise
• Psychiatric diagnoses
• Stressors, such as work, financial, legal, and interpersonal
• Onset of sleep disturbances
• Information from the bed partner about snoring, breathing pauses, or abnormal movements or behavior
• Shift or night work
• Factors that improve or worsen sleep
• Sleep environment, such as light, noise, and temperature
• Sleep-wake patterns, including napping
• Effects on daytime function 
• Previous treatments and outcomes, including medication trials

Validated scales such as the Insomnia Severity Index (ISI) [10] or the Sleep Condition Indicator [11] can be used to gauge the severity of insomnia, and the evaluation should also include the use of a sleep diary for 7 to 14 days.[9]

Evaluation

Chronic insomnia is diagnosed based on an individual's sleep history, along with their medical, psychiatric, and substance use history. Laboratory or imaging studies are not routinely recommended for the initial evaluation, but may be considered if underlying medical comorbidities are suspected. If indicated, laboratory tests may include a complete blood count, thyroid studies, liver function, renal function, C-reactive protein, ferritin, and vitamin B12, and other studies can include electrocardiogram, electroencephalogram, brain imaging, or circadian markers, such as melatonin and core body temperature.[9]

Guidelines recommend maintaining a sleep diary for 7 to 14 days.[9] Sleep logs or diaries are reliable and cost-effective ways to assess an individual's sleep-wake cycle. Sleep logs also include documentation of alcohol and caffeine consumption, bedtime activities, and daytime napping. Sleep logs are used to determine total sleep time, wakefulness after sleep onset, sleep efficiency, and circadian rhythm disturbances. The major limitation associated with the sleep log is establishing the reliability and validity of the diary data.[12]

Validated scales such as the ISI [10] or the Sleep Condition Indicator [11] can be used to gauge the severity of insomnia. Other widely used validated scales are the Epworth Sleepiness Scale and the Pittsburgh Sleep Quality Index.[13][14]

Polysomnography is recommended when sleep-related breathing disorders, such as obstructive sleep apnea, or sleep-related movement disorders, such as restless legs syndrome, are suspected.[8] However, it is not indicated in the initial assessment of primary insomnia [15] unless a co-existing sleep disorder is suspected.

A wrist actigraph is a noninvasive device that records gross motor activity during wakefulness and sleep. Actigraphy assesses various sleep parameters, including total sleep duration, wakefulness after sleep onset, sleep latency, and daytime naps. However, a key limitation of actigraphy is its inability to detect periodic limb movements or abnormal breathing patterns.[16] Actigraphy is recommended when circadian sleep-wake rhythm disorders are suspected.[8]

Treatment / Management

Nonpharmacological Management

Cognitive behavioral therapy for insomnia: International guidelines consistently recommend cognitive behavioral therapy for insomnia (CBT-I) as the first-line treatment for chronic insomnia, as it is effective for nighttime symptoms, daytime symptoms, and comorbid conditions.[8] CBT-I is a manualized treatment typically delivered by a trained therapist, who may be an individual or group, and consists of behavioral components and cognitive restructuring. CBT-I is based on the three-factor model of chronic insomnia—predisposing factors, precipitating factors, and perpetuating factors.[17][18](A1)

The core components of CBT-I include: [18]

• Sleep restriction therapy: This approach limits sleep opportunity to match the patient's baseline sleep ability. This therapy depends on limiting the number of sleep hours with the idea that reduced sleep time might improve the sleep drive and result in improved sleep. First, the patient's baseline sleep duration is assessed using a sleep diary. Then, the patient's prescribed time in bed (sleep window) is set to equal their average baseline sleep. The appropriate wake-up time and prescribed time to bed are set to reflect the patient's average baseline sleep. After reviewing the sleep diary each week, the prescribed time to bed is adjusted based on how consolidated the patient's sleep is.

• Stimulus control therapy: This technique is based on behavioral principles linked to conditioning. Stimuli associated with sleep, such as the bed and bedroom, are paired with sleep rather than activities such as watching television, screen time, or reading. Recommendations include only lying down to sleep when sleepy, getting out of bed if unable to fall asleep in 15 to 20 minutes, and repeating this throughout the night. Other recommendations are getting up at the same time daily and avoiding napping.

• Sleep hygiene: Although sleep hygiene is minimally effective as a stand-alone intervention, it is an essential aspect of CBT-I. Sleep hygiene includes environmental changes such as setting up a comfortable sleeping area; modifying lifestyle factors, including limiting napping or alcohol and caffeine consumption before bedtime; and exercising regularly.

Limitations of CBT-I are a shortage of trained therapists to deliver the therapy and limited financial support; however, in clinical populations under routine care, internet-based CBT-I has been shown to reduce insomnia severity compared to standard care, offering improved accessibility.[19][20](A1)

Relaxation therapy: Regular practice of deep breathing, mindfulness meditation, progressive muscle relaxation, or yoga can improve sleep quality.[18]

Pharmacological Management

Medication classes:

• Gamma-aminobutyric acid-A receptor agonists: 
  • Benzodiazepines and benzodiazepine receptor agonists act on GABA subtype A receptors (GABA_ARs) with sedative, anxiolytic, muscle relaxant, and hypnotic effects. A significant difference between the 2 groups is the receptor affinity towards different subtypes of GABA_ARs. Although all benzodiazepines have a similar affinity for various subtypes of alpha subunits, benzodiazepine receptor agonists have varying affinities for different subtypes of alpha subunits. For example, zolpidem and zaleplon have a higher affinity for the alpha-1 subunit and a lower affinity for the alpha-2 and alpha-3 subunits; however, eszopiclone has a higher affinity for the alpha-2 and alpha-3 subunits of the GABA receptor.
  • The potential advantages of benzodiazepines and benzodiazepine receptor agonists are efficacy for sleep onset and maintenance and a range of half-lives. Potential disadvantages associated with benzodiazepines and benzodiazepine receptor agonists include cognitive and motor impairment, next-day sedation, anterograde amnesia, rebound insomnia, nausea, headaches, complex sleep-related behavior, and long-term risks such as dependence, depression, falls, hip fractures, and dementia. The Beers Criteria recommend avoiding benzodiazepines and benzodiazepine receptor agonists in individuals older than 65.[1][21][22]
  • The Food and Drug Administration (FDA) has approved 4 benzodiazepines for the treatment of insomnia—temazepam, triazolam, flurazepam, and estazolam. The benzodiazepine receptor agonists approved by the FDA for the treatment of insomnia include eszopiclone, zaleplon, and zolpidem, including extended release and sublingual forms.
(A1)

• Dual Orexin Receptor Antagonists
  • Suvorexant, lemborexant, and daridorexant block the binding of wake-promoting orexin A and orexin B to OX1 and OX2 receptors, counteracting orexin/hypocretin-mediated nighttime awakening. The FDA does not recommend higher doses of these medications due to safety concerns about the increased risk of next-day driving difficulty, increased daytime somnolence, and narcolepsy-like symptoms, such as hypnogogic-hypnopompic hallucinations, cataplexy, and vivid dreams. These medications are contraindicated in patients with narcolepsy because of possible underlying mechanisms of orexin antagonism.

• Melatonin and drugs acting on melatonin receptors
  • Melatonin is a natural hormone produced by the pineal gland. The circadian system in the hypothalamus and the suprachiasmatic nucleus regulates the levels of this hormone. Melatonin is available over the counter and is approved by the FDA for the treatment of insomnia, especially in older adults. Food can delay the absorption of melatonin. Ramelteon decreases sleep latency by acting on the melatonin MT1 and MT2 receptors in the suprachiasmatic nucleus with higher affinity than melatonin. Tasimelteon is a melatonin receptor agonist effective in improving sleep initiation and maintenance in patients with Smith-Magenis syndrome and patients with non-24-hour sleep-wake disorders. Potential disadvantages include somnolence, fatigue, and dizziness.

• Antidepressants: Drugs acting as Histamine-1 receptor antagonists
  • Doxepin is a tricyclic antidepressant that, at low doses, is effective in treating sleep maintenance insomnia, including improvement in total sleep time, wakefulness after sleep onset, and sleep efficiency. At low doses, doxepin acts as a pure histamine-1 receptor antagonist. At high doses, doxepin has antihistaminic, antiserotonergic, anticholinergic, and antiadrenergic properties. The adverse effects associated with doxepin at low doses include headache and somnolence.
  • The most commonly used antidepressants for insomnia management, mainly due to their antihistaminic effects, include trazodone, mirtazapine, amitriptyline, and nortriptyline. 

• Anticonvulsant medications
  • Gabapentin may improve sleep efficiency and decrease wake time after sleep onset. This medication may also improve sleep time for patients with alcohol dependence. Pregabalin may reduce insomnia in patients with generalized anxiety disorder or fibromyalgia.[23]

• Sedating antihistamines
  • Diphenhydramine and hydroxyzine are available over the counter and are antagonists of central histamine receptors. Disadvantages include anticholinergic effects, such as dry mouth, constipation, and cognitive impairment. There is limited evidence supporting the effectiveness of antihistaminergic drugs for treating insomnia..[9]

Dosing: The 2017 American Academy of Sleep Medicine Clinical Practice Guideline for the Pharmacologic Treatment of Chronic Insomnia in Adults [24] states that pharmacological recommendations are generally weak, with moderate-to-low quality evidence. However, it provides the following dosing recommendations:(A1)

• For treating sleep-onset insomnia: Eszopiclone 2 or 3 mg at bedtime; ramelteon 8 mg at bedtime; temazepam 15 mg at bedtime; triazolam 0.25 mg at bedtime; zaleplon 5 or 10 mg at bedtime; or zolpidem 10 mg at bedtime.
• For treating sleep maintenance insomnia: Doxepin 3 or 6 mg at bedtime; eszopiclone 2 or 3 mg at bedtime; temazepam 15 mg at bedtime; suvorexant 10, 15, or 20 mg at bedtime; or zolpidem 10 mg at bedtime.

Other Considerations

The European Insomnia Guideline: An update on the diagnosis and treatment of insomnia 2023 [9] recommends the following pharmacological interventions for the treatment of chronic insomnia with discussion of advantages and disadvantages on an individual basis:

• Benzodiazepines and benzodiazepine receptor agonists can be used for the short-term treatment of insomnia (less than 4 weeks); the advantages and disadvantages of longer-term treatment should be discussed with the patient.
• Sedating antidepressants at low doses can be used for short-term treatment of insomnia after consideration of contraindications; the advantages and disadvantages of longer-term treatment should be discussed with the patient.
• Orexin receptor antagonists can be used for the treatment of insomnia for up to 3 months; the advantages and disadvantages of longer-term treatment should be discussed with the patient.
• Antihistamines, antipsychotics, fast-release melatonin, and herbal remedies lack sufficient evidence to support their use in chronic insomnia and may have potential disadvantages.
• In patients older than 55, extended-release melatonin may be used for up to 3 months for the treatment of insomnia. 

Differential Diagnosis

Numerous medical, psychiatric, and neurological disorders, and certain substances may cause or contribute to chronic insomnia.[9]

Chronic insomnia is not always a symptom of another disorder; it can also be an independent risk factor for certain mental health conditions. Major comorbidities or contributing factors include: [9]

• Mental health disorders: Depressive disorder, bipolar disorder, anxiety disorders, borderline personality disorder, posttraumatic stress disorder, and schizophrenia.
• Medical conditions: Cardiovascular disorders, diabetes mellitus, chronic kidney disease, chronic obstructive pulmonary disease, rheumatic disorders, chronic pain, and malignancies.
• Sleep disorders: Obstructive sleep apnea and sleep-related breathing disorder.
• Neurological disorders: Neurodegenerative diseases, cerebrovascular diseases, traumatic brain injury, multiple sclerosis, restless legs syndrome, periodic limb movement disorder, and fatal familial insomnia.
• Substance use and prescribed medications.

Pertinent Studies and Ongoing Trials

Clinical guidelines for chronic insomnia agree that CBT-I is the treatment of choice. However, a shortage of trained therapists limits access to this modality. To address this, a stepped-care approach has been proposed, in which individuals with less severe symptoms receive the least specialized help and those with more complex and severe problems receive highly specialized help.[9] For example, CBT-I for chronic insomnia can be provided through internet-based versions such as SHUTi and Sleepio. However, participants in internet versions of CBT-I may have higher attrition rates. Researchers have developed smartphone applications (apps), such as Sleep Ninja, pro-Act-S, UnMind Night, and Calm, that deliver CBT-I in accessible formats. There is preliminary evidence that CBT-based apps can reduce insomnia symptoms.[25][26]

Further research topics include defining different insomnia phenotypes, standardizing methodologies across sleep laboratories, increasing home-based studies, developing a test for hyperarousal, developing improved hypnotics, and enhancing the understanding of the psychoneurobiological mechanisms behind insomnia. Another approach to managing chronic insomnia is prioritizing the primary prevention of mental disorders.[4]

Prognosis

According to a naturalistic study, 13.9% of good sleepers developed an insomnia syndrome during the 5-year follow-up period, and 37.5% of participants with insomnia continued to report insomnia at each annual follow-up for 5 years. The study concluded that once insomnia progresses to a disorder, it tends to persist. Women and older adults had a higher risk of persistent insomnia.[27] Currently, no externally validated models exist to predict treatment outcomes for insomnia.[28]

Complications

Chronic insomnia is often unrecognized and untreated. This disorder is a significant risk factor for future insomnia, creates a greater risk for a persistent course of insomnia, and causes increased risk for various complications, including hypertension, depression, anxiety, absenteeism, and all-cause and cardiopulmonary mortality.[27][29][27] Insomnia is also associated with an increase in inflammation. Systemic inflammation, assessed using circulating C-reactive protein levels, is independently associated with increased risk for cardiovascular disease and death.[30]