Sleep disorders refer to abnormal sleep quality or certain clinical symptoms occurring during sleep, such as reduced or excessive sleep, sleep-related movement disorders, which include sleepwalking, sleep terrors, restless legs syndrome, etc. Among them, the most common and primary disorder is insomnia, characterized primarily by three main symptoms: short duration of continuous sleep, early awakening, and difficulty falling asleep. Treatments for insomnia include physical therapies (including medication and physical therapy), psychological therapies, or a combination of psychological and physical therapies. Although the American College of Physicians has identified cognitive behavioral therapy (CBT) as the first-line treatment for insomnia, due to its disadvantages such as high cost, long consultation time, lack of well-trained providers, and not being able to produce immediate results, it is difficult to implement in clinical practice. Therefore, medication remains widely used in the treatment of insomnia.
Currently, commonly recommended drugs for insomnia treatment in clinical practice include benzodiazepine receptor agonists, melatonin and melatonin receptor agonists, orexin receptor antagonists, histamine antagonists, as well as anti-anxiety and antidepressant drugs. For patients with pure insomnia, non-benzodiazepine drugs or melatonin receptor agonists are generally preferred as monotherapy. When monotherapy fails to achieve satisfactory results, combination therapy with sedative-hypnotic drugs of different mechanisms of action may be considered. For patients with comorbid emotional disorders, benzodiazepine drugs or a combination of antidepressants and antipsychotics with sedative effects should be selected based on the symptoms.
1.Benzodiazepine Receptor Agonists
Benzodiazepine receptor agonists (BzRAs), which are the most commonly used drugs for insomnia treatment in clinical practice, can be divided into benzodiazepine drugs (BZDs) and nonbenzodiazepine drugs (NBZDs).
Commonly used BZDs in clinical practice for insomnia treatment include alprazolam, estazolam, lorazepam, clonazepam, etc. They are mainly suitable for adult patients with difficulty falling asleep and sleep maintenance disorders, especially those with insomnia accompanied by anxiety. BZDs work by non-selectively binding to benzodiazepine receptors, increasing the affinity of gamma-aminobutyric acid (GABA) receptors, promoting chloride ion influx, resulting in hyperpolarization of neurons where benzodiazepine receptors are located, and exerting pharmacological effects such as sedation, hypnosis, anti-anxiety, and muscle relaxation. BZDs can shorten sleep latency, reduce nighttime awakenings, and increase total sleep time, but decrease deep sleep time. Although patients may feel improved sleep onset and prolonged sleep time after taking BZDs, sleep quality remains low. BZDs may cause daytime drowsiness, dizziness, fatigue, and cognitive decline. Elderly patients may also have an increased risk of falls and fractures. Long-term use of BZDs may lead to psychological and physical dependence, and some patients may experience severe withdrawal symptoms such as rebound insomnia and increased anxiety after discontinuation. Therefore, patients taking BZDs for a long time need to gradually withdraw the medication. The American Medical Association's insomnia medication guidelines list approved BZDs for insomnia treatment, including estazolam, flurazepam, quazepam, temazepam, and triazolam.
NBZDs selectively bind to benzodiazepine receptors, inhibiting the sleep center to produce sedative-hypnotic effects, but generally do not have anti-anxiety effects. Commonly seen NBZDs in clinical practice include zolpidem, zaleplon, zopiclone, and eszopiclone. NBZDs have a relatively short half-life, and residual daytime sedative effects are rare. Specifically, zolpidem and zaleplon are effective in improving difficulties in falling asleep, but have little effect on sleep maintenance. Zopiclone and eszopiclone, with a slightly longer half-life, are effective in treating both difficulties in falling asleep and sleep maintenance disorders.
2.Melatonin and Melatonin Receptor Agonists
Melatonin, as an important physiological sleep regulatory factor, its circadian rhythm is closely related to sleep rhythm. Melatonin is secreted by the pineal gland, showing a rhythm of less during the day and more at night, peaking at 2-3 am. It mainly acts on melatonin receptors in the hypothalamus to regulate the sleep-wake cycle. Research has found that exogenous melatonin may be effective in shortening sleep latency and increasing total sleep time, but clinical observations have found that most patients are not satisfied with the treatment effect for insomnia, which may be more suitable for insomnia patients with sleep rhythm disorders. Melatonin exerts its physiological effects mainly through two high-affinity membrane receptors, MT1 and MT2. Under the regulation of the light-dark cycle, the suprachiasmatic nucleus regulates sleep and circadian rhythm by activating MT1 and/or MT2 receptors and feeding back to the cell nucleus. Ramelteon is the first selective melatonin receptor agonist approved for marketing and has been approved by the FDA for the treatment of insomnia, primarily improving difficulty falling asleep, but it is not yet available in China. This drug can shorten sleep latency, increase total sleep time, and its adverse reactions include dizziness, drowsiness, fatigue, headache, nausea, and worsening depression symptoms and suicidal ideation in patients with primary depression. Agomelatine is the only melatonin receptor agonist available in China, with a dual mechanism of activating melatonin receptors (MT1/MT2) and antagonizing 5-HT2C receptors. Studies have found that agomelatine can improve sleep maintenance disorders, increase deep sleep and total sleep time, reduce total wake time after falling asleep, and improve sleep efficiency. Therefore, for patients with difficulty falling asleep, it is better to combine it with benzodiazepine receptor agonists. Since this drug is also an antidepressant, it can have a dual effect of improving sleep and mood for patients with insomnia accompanied by mild to moderate anxiety and depression. However, it is necessary to monitor liver function when using this drug, and it is contraindicated for patients with liver damage.
3.Orexin Receptor Antagonists
Orexins, also known as hypocretins, are mainly secreted from the lateral, dorsal, and arcuate regions of the hypothalamus. They are considered the "wake-promoting zone" of the hypothalamus, promoting appetite and arousal, and are crucial for maintaining long-term wakefulness. A decrease in orexin production can lead to narcolepsy and irregular rapid eye movement (REM) sleep. Research has shown that the extracellular orexin A levels in the cerebrospinal fluid, lateral hypothalamus, and medial thalamus of rats exhibit significant diurnal rhythms, gradually increasing during the dark period and decreasing during the light period. This indicates that orexin regulates the sleep-wake cycle, and normal sleep control depends on the modulation of orexin in the hypothalamus.The densest projection of orexinergic neurons is to the locus coeruleus, where orexin A can promote arousal by activating noradrenergic cells. Monoaminergic and cholinergic nuclei are rich in orexin receptors. Orexinergic neurons remain quiescent during sleep, begin to discharge before awakening, and are active during wakefulness and sleep deprivation. Sleep deprivation can alter the excitability of orexin neurons through presynaptic and postsynaptic mechanisms. Orexin can induce neuronal discharge in the prefrontal cortex and promote arousal by activating histaminergic, noradrenergic, and serotonergic neurons.Orexin receptor antagonists selectively block orexin receptors. Orexin antagonists can improve insomnia and sleep quality without the adverse effects of BZDs, yet they possess stronger pharmacological activity than traditional hypnotics. Dual orexin receptor antagonists such as Suvorexant and Almorexant can increase total sleep time by promoting REM sleep, demonstrating good clinical efficacy and tolerability. They have been approved by the FDA for the treatment of insomnia.
4.Histamine Antagonists
Histamine is a neurotransmitter that promotes wakefulness and is produced in the tuberomammillary nucleus of the hypothalamus in the central nervous system. Therefore, antagonizing histamine receptors can promote sleep. Among the four histamine receptors, the H1 receptor is a key target for controlling sleep. Evidence suggests that mice with H1 receptor knockout can increase NREM (non-rapid eye movement) sleep time and episodes when given H1 receptor antagonists such as doxepin and diphenhydramine. Ketotifen, on the other hand, reduces REM (rapid eye movement) sleep and increases NREM sleep by increasing delta wave power. Based on these data, it can be inferred that the effect of histamine antagonists on sleep mainly acts on the NREM stage.
However, taking antihistamines can cause anticholinergic effects, including fever, sepsis, blurred vision, dry mouth, constipation, urinary retention, tachycardia, dystonia, and mental confusion. Currently, there is limited data on the use of histamine antagonists in treating insomnia in humans. Among histamine antagonists, doxepin is the most commonly used drug to control insomnia. It can prolong NREM sleep but reduce REM sleep, but it can also cause adverse reactions such as nausea and respiratory tract infections.
5.Anti-Anxiety and Anti-Depressant Drugs
Anti-anxiety and anti-depressant drugs are primarily partial agonists of the 5-hydroxytryptamine receptor (5-HT1A). The main representatives are buspirone and tandospirone, which belong to anti-anxiety drugs. Due to their good affinity for 5-HT1A, they can activate presynaptic 5-HT1A receptors to inhibit neuronal discharge and reduce the synthesis and release of 5-HT1A. They are primarily used to treat various anxiety disorders and accompanying anxiety symptoms. In the treatment of anxiety-related insomnia, tandospirone is more commonly used clinically. The advantages of these drugs are their mild sedative effects, minimal impact on cognitive function, no accumulation, and fewer adverse reactions compared to BZDs. However, their onset of action is relatively slow, taking 2 to 4 weeks. Clinical studies have shown that adding tandospirone to sedative-hypnotic drugs provides better therapeutic effects for insomnia patients with anxiety symptoms, and combination therapy results in better symptom improvement. The reason for the poor treatment response in most insomnia patients may be due to neglecting emotional disorders such as anxiety and depression. Although there is no direct evidence that anti-depressants and anti-anxiety drugs can directly improve insomnia, they can effectively alleviate sleep problems caused by psychological and mental factors. Therefore, when treating insomnia, it is essential to fully understand the patient's condition and consider anti-anxiety and anti-depressant therapy if necessary.
References
[1] Feng Tingyu, Xu Xiaowu. Progress in Drug Treatment for Insomnia [J]. World Journal of Sleep Medicine, 2023, 10(03): 691-696.
[2] Hu Jin, Wei Shanshan, Jiang Haizhou, et al. Research Progress in Drug Treatment for Insomnia [J]. China Journal of Chinese Materia Medica, 2023, 48(19): 5122-5130.
[3] Shen Yangyang, Zhou Junying. Drug Treatment and Progress for Insomnia [J]. Chinese Journal for Clinicians, 2023, 51(12): 1394-1397.
About the Author
Xiaomichong, a pharmaceutical quality researcher, has been committed to pharmaceutical quality research and drug analysis method validation for a long time. Currently employed by a large domestic pharmaceutical research and development company, she is engaged in drug inspection and analysis as well as method validation.
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