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Insomnia is the most common sleep disorder, defined as a sleep disorder that occurs three or more nights per week, lasts for more than three months, and is not caused by a lack of sleep opportunities. About 10% of adults meet the criteria for insomnia, and another 15% to 20% report occasional insomnia symptoms. Long term insomnia patients are at increased risk of developing major depression, hypertension, Alzheimer’s disease, and loss of work ability.

Clinical issues

The characteristics of insomnia are unsatisfactory sleep quality or duration, accompanied by difficulty falling asleep or maintaining sleep, as well as severe mental distress or daytime dysfunction. Insomnia is a sleep disorder that occurs three or more nights a week, lasts for more than three months, and is not caused by limited sleep opportunities. Insomnia often occurs simultaneously with other physical illnesses (such as pain), mental illnesses (such as depression), and other sleep disorders (such as restless leg syndrome and sleep apnea).

Insomnia is the most common sleep disorder among the general population, and it is also one of the most commonly mentioned problems when patients seek treatment at primary medical institutions, but often goes untreated. About 10% of adults meet the criteria for insomnia, and another 15% to 20% of adults report occasional insomnia symptoms. Insomnia is more common in women and people with mental or physical problems, and its incidence rate will increase in middle age and after middle age, as well as in perimenopause and menopause. We still know very little about the pathological and physiological mechanisms of insomnia, but currently it is believed that psychological and physiological overstimulation are its core characteristics.

Insomnia may be situational or occasional, but over 50% of patients experience persistent insomnia. The first insomnia usually stems from a stressful living environment, health issues, abnormal work schedules, or traveling across multiple time zones (time difference). Although most people will return to normal sleep after adapting to triggering events, those who are prone to insomnia may experience chronic insomnia. Psychological, behavioral, or physical factors often lead to long-term sleep difficulties. Long term insomnia is accompanied by an increased risk of major depression, hypertension, Alzheimer’s disease, and loss of work ability.

The assessment and diagnosis of insomnia rely on detailed inquiry of medical history, recording symptoms, course of illness, comorbidities, and other triggering factors. 24-hour sleep wake behavior recording can identify more behavioral and environmental intervention goals. Patient reported assessment tools and sleep diaries can provide valuable information about the nature and severity of insomnia symptoms, help screen for other sleep disorders, and monitor treatment progress

Strategy and Evidence

The current methods for treating insomnia include prescription and over-the-counter drugs, psychological and behavioral therapy (also known as cognitive-behavioral therapy [CBT-I] for insomnia), and adjuvant and alternative therapies. The usual treatment trajectory for patients is to first use over-the-counter drugs and then use prescription drugs after seeking medical attention. Few patients receive CBT-I treatment, partly due to a lack of well-trained therapists.

CBTI-I
CBT-I includes a series of strategies aimed at changing behavioral patterns and psychological factors that lead to insomnia, such as excessive anxiety and negative beliefs about sleep. The core content of CBT-I includes behavioral and sleep scheduling strategies (sleep restriction and stimulus control), relaxation methods, psychological and cognitive interventions (or both) aimed at changing negative beliefs and excessive concerns about insomnia, as well as sleep hygiene education. Other psychological intervention methods such as Acceptance and Commitment Therapy and Mindfulness Based Therapy have also been used to treat insomnia, but there is limited data supporting their efficacy, and they need to be persisted for a relatively long time to benefit. CBT-I is a prescription therapy that focuses on sleep and is problem oriented. It is usually guided by a mental health therapist (such as a psychologist) for 4-8 consultations. There are various implementation methods for CBT-I, including short form and group form, with the participation of other healthcare professionals (such as practicing nurses), as well as the use of telemedicine or digital platforms.

Currently, CBT-I is recommended as a first-line therapy in clinical guidelines by multiple professional organizations. Clinical trials and meta-analyses have shown that CBT-I can significantly improve patient reported outcomes. In the meta-analysis of these trials, CBT-I was found to improve the severity of insomnia symptoms, sleep onset time, and post sleep awakening time. The improvement in daytime symptoms (such as fatigue and mood) and quality of life is relatively small, partly due to the use of generic measures not specifically developed for insomnia. Overall, about 60% to 70% of patients have a clinical response, with a decrease of 7 points in the Insomnia Severity Index (ISI), which ranges from 0 to 28 points, with higher scores indicating more severe insomnia. After 6-8 weeks of treatment, about 50% of insomnia patients experience remission (ISI total score,<8), and 40% -45% of patients achieve continuous remission for 12 months.

Over the past decade, digital CBT-I (eCBT-I) has become increasingly popular and may ultimately narrow the significant gap between CBT-I demand and accessibility. ECBT-I has a positive impact on several sleep outcomes, including severity of insomnia, sleep efficiency, subjective sleep quality, wakefulness after sleep, sleep duration, total sleep duration, and number of nighttime awakenings. These effects are similar to those observed in face-to-face CBT-I trials and are maintained for 4-48 weeks after follow-up.

Treating comorbidities such as depression and chronic pain can alleviate insomnia symptoms, but generally cannot completely solve insomnia problems. On the contrary, treating insomnia can improve the sleep of patients with comorbidities, but the effect on the comorbidities themselves is not consistent. For example, the treatment of insomnia can alleviate depressive symptoms, reduce the incidence rate and recurrence rate of depression, but has little effect on chronic pain.

The tiered treatment approach may help address the issue of insufficient resources required for traditional psychological and behavioral therapies. One mode suggests using education, monitoring, and self-help methods at the first level, digital or group psychological and behavioral therapy at the second level, individual psychological and behavioral therapy at the third level, and medication therapy as a short-term adjunct at each level.

Medication treatment
Over the past 20 years, the prescription pattern of hypnotic drugs in the United States has undergone significant changes. The prescription amount of benzodiazepine receptor agonists continues to decrease, while the prescription amount of trazodone continues to increase, although the US Food and Drug Administration (FDA) has not listed insomnia as an indication for trazodone. In addition, appetite suppressant receptor antagonists were launched in 2014 and have been widely used.

The effect size of new medication (medication duration,<4 weeks) on the primary outcome is defined through patient evaluation scales, including the Insomnia Severity Index, Pittsburgh Sleep Quality Index, Leeds Sleep Questionnaire, and Sleep Diary. An effect size of 0.2 is considered small, an effect size of 0.5 is considered moderate, and an effect size of 0.8 is considered large.

The Beers criteria (a list of drugs considered relatively unsuitable for patients aged 65 or older) recommend avoiding the use of this medication.

The drug has not been approved by the FDA for the treatment of insomnia. All drugs listed in the table are classified as Pregnancy Class C by the US FDA, except for the following drugs: Triazolam and Temazepam (Class X); Clonazepam (Class D); Diphenhydramine and docetamine (class B).
1. Benzodiazepine receptor agonist class hypnotic drugs
Benzodiazepine receptor agonists include benzodiazepine drugs and non benzodiazepine drugs (also known as Z-class drugs). Clinical trials and meta-analyses have shown that benzodiazepine receptor agonists can effectively shorten sleep time, reduce post sleep awakenings, and slightly increase total sleep duration (Table 4). According to patient reports, the side effects of benzodiazepine receptor agonists include anterograde amnesia (<5%), sedation the next day (5%~10%), and complex behaviors during sleep such as daydreaming, eating, or driving (3%~5%). The last side effect is due to the black box warning of zolpidem, zaleplon, and escitalopram. 20% to 50% of patients experience drug tolerance and physiological dependence after taking medication every night, manifested as rebound insomnia and withdrawal syndrome.

2. Sedative heterocyclic drugs
Sedative antidepressants, including tricyclic drugs such as amitriptyline, demethylamine, and doxepin, and heterocyclic drugs such as olanzapine and trazodone, are commonly prescribed drugs for treating insomnia. Only doxepin (3-6 mg daily, taken at night) has been approved by the US FDA for the treatment of insomnia. Current evidence suggests that sedative antidepressants can overall improve sleep quality, sleep efficiency, and prolong total sleep duration, but have little effect on sleep duration. Although the US FDA does not list insomnia as an indication for these drugs, clinicians and patients often prefer these drugs because they have mild side effects at low doses and clinical experience has shown their effectiveness. Side effects include sedation, dry mouth, delayed cardiac conduction, hypotension, and hypertension.

3. Appetite receptor antagonists
The neurons containing orexin in the lateral hypothalamus stimulate the nuclei in the brainstem and hypothalamus that promote wakefulness, and inhibit the nuclei in the ventral lateral and medial preoptic areas that promote sleep. On the contrary, appetite suppressants can inhibit nerve conduction, suppress wakefulness, and promote sleep. Three dual orexin receptor antagonists (sucorexant, lemborxant, and daridorexint) have been approved by the US FDA for the treatment of insomnia. Clinical trials support their efficacy in sleep onset and maintenance. Side effects include sedation, fatigue, and abnormal dreaming. Due to the deficiency of endogenous appetite hormones, which can lead to narcolepsy with cataplexy, appetite hormone antagonists are contraindicated in such patients.

4. Melatonin and melatonin receptor agonists
Melatonin is a hormone secreted by the pineal gland under dark conditions at night. Exogenous melatonin can reach blood concentrations beyond physiological levels, with varying durations depending on the specific dosage and formulation. The appropriate dosage of melatonin for treating insomnia has not been determined. Controlled trials involving adults have shown that melatonin has a minor effect on sleep onset, with almost no effect on wakefulness during sleep and total sleep duration. Medications that bind to melatonin MT1 and MT2 receptors have been approved for the treatment of refractory insomnia (ramelteon) and circadian sleep wake disorder (tasimelteon). Like melatonin, these drugs have almost no effect on wakefulness or total sleep duration after falling asleep. Sleepiness and fatigue are the most common side effects.

5. Other drugs
Antihistamines in over-the-counter drugs (diphenhydramine and docetamine) and prescription drugs (hydroxyzine) are the most commonly used insomnia treatment drugs. The data supporting its efficacy is weak, but their accessibility and perceived safety to patients may be the reasons for their popularity compared to benzodiazepine receptor agonists. Sedative antihistamines can cause excessive sedation, anticholinergic side effects, and increase the risk of dementia. Gabapentin and pregabalin are commonly used to treat chronic pain and are also first-line treatment drugs for restless leg syndrome. These drugs have a sedative effect, increase slow wave sleep, and are used to treat insomnia (beyond the indications), especially when accompanied by pain. Fatigue, drowsiness, dizziness, and ataxia are the most common side effects.

The selection of hypnotic drugs
If medication is chosen for treatment, short acting benzodiazepine receptor agonists, orexin antagonists, or low-dose heterocyclic drugs are the reasonable first choices in most clinical situations. Benzodiazepine receptor agonists may be the preferred treatment for insomnia patients with sleep onset symptoms, younger adult patients, and patients who may require short-term medication (such as insomnia due to acute or periodic stressors). When treating patients with symptoms related to maintaining sleep or early awakening, elderly individuals, and those with substance use disorders or sleep apnea, low-dose heterocyclic drugs or appetite suppressants may be the first choice.

According to the Beers criteria, the list of drugs that are relatively unsuitable for patients aged 65 or older includes benzodiazepine receptor agonists and heterocyclic drugs, but does not include doxepin, trazodone, or orexin antagonists. The initial medication usually includes taking medication every night for 2-4 weeks, and then re evaluating the effects and side effects. If long-term medication is needed, encourage intermittent medication (2-4 times a week). Patients should be guided to take medication 15-30 minutes before bedtime. After long-term medication, some patients may develop drug dependence, especially when using benzodiazepine receptor agonists. After long-term use, planned reductions (such as a 25% reduction per week) can help reduce or discontinue hypnotic drugs.

The choice between combination therapy and monotherapy
A few existing head to head comparative studies have shown that in the short term (4-8 weeks), CBT-I and hypnotic drugs (mainly Z-class drugs) have similar effects on improving sleep continuity, but drug therapy can significantly increase total sleep duration compared to CBT-I. Compared to using CBT-I alone, combination therapy can improve sleep faster, but this advantage gradually diminishes in the fourth or fifth week of treatment. Additionally, compared to medication or combination therapy, using CBT-I alone can improve sleep more persistently. If there is a more convenient alternative method of taking sleeping pills, some patients’ compliance with behavioral advice may decrease.