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]

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]

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."VSports在线直播" [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.

• 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:

• 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.