What are the precautions for using hypnotics?😴😴😴

In today's society, many people suffer from insomnia. Insomnia is the most common sleep disorder clinically. About 10 to 15% of adults meet the criteria for a diagnosis of insomnia. Generally recommended for the treatment of insomnia psychotherapy and drug therapy. For patients with insomnia, medication is generally used on the basis of psychotherapy. Hypnotic drugs are given according to the patient's condition to relieve insomnia symptoms, improve sleep quality and improve the patient's quality of life.

What medications can be used to treat insomnia?

The principles of drug therapy should be individualized, on demand, intermittent and sufficient. The drug treatment guidelines for insomnia are generally recommended as follows: non-benzodiazepine drugs are the first choice. Short and medium-acting benzodiazepines or melatonin receptor agonists are the second choice. Antidepressants with sedative effects are optional only when necessary, but they are especially indicated for insomniacs with depression and/or anxiety. Treatment guidelines do not recommend the use of antipsychotics and antiepileptics as first-line drugs, and they are only applicable to certain special situations and special populations. 

Non-benzodiazepines: These drugs selectively activate the α subunit of the γ-aminobutyric acid receptor A (GABA_A). Their hypnotic effects are similar to those of benzodiazepines. Due to the short half-life of these drugs, their next-day residual effects are greatly reduced. They generally do not cause daytime drowsiness in patients and have a lower risk of dependence than benzodiazepines. Therefore, non-benzodiazepines can be safe and effective in the treatment of insomnia, and their long-term use has no significant adverse drug effects. Sudden discontinuation of the drug may cause transient insomnia rebound in patients. Because non-benzodiazepines are less muscle relaxant, they cause a lower risk of falls than benzodiazepines. Therefore, non-benzodiazepines are especially suitable for elderly patients with insomnia. CYP3A4 metabolizes non-benzodiazepines such as eszopiclone, zopiclone and zaleplon. Therefore, CYP3A4 inhibitors such as clarithromycin will inhibit their metabolism. It can increase blood levels of non-benzodiazepine drugs and increase the occurrence of adverse reactions. Inducers of CYP3A4, such as rifampin, lower their blood levels and reduce their efficacy. Co-administration of alcohol or other central depressants with non-benzodiazepines increases the central depressant effect. 

1. Eszopiclone: This is indicated for the treatment of trouble falling asleep or maintaining sleep. It has a peak time of 1 to 1.5 hours and a half-life of 6 hours. Adults take 1 to 3 mg orally before going to bed. Its common adverse reaction is abnormal taste. Eszopiclone was better tolerated than zopiclone.
2. Zaleplon: It is indicated for the treatment of difficulty falling asleep. It has a peak time of ≤1 hour and a half-life of 0.7 to 1.4 hours. Adults take 5 to 20 mg orally before going to bed. Its common adverse reactions are dizziness and ataxia.
3. Zopiclone: It is indicated for the treatment of trouble falling asleep or maintaining sleep. It has a peak time of 1.5 to 2 hours and a half-life of 5 hours. Adults take 3.75 to 7.5 mg orally at bedtime. Its common adverse reaction is bitter taste in mouth. 
4. Zolpidem: This is indicated for the treatment of trouble falling asleep or maintaining sleep. It has a peak time of 0.5 to 3 hours and a half-life of 0.7 to 3.5 hours. Adults take 1.75 to 10 mg orally or 6.25 to 12.5 mg sustained-release tablets before going to bed. Its common adverse effects are headache, dizziness and forgetfulness.

Benzodiazepines: These drugs bind nonselectively to GABA_A receptors. They have anxiolytic, sedative, muscle relaxant and anticonvulsant properties. Therefore, this class of drugs has a better effect on patients with anxiety insomnia. Benzodiazepines commonly used in clinical practice include estazolam, flurazepam, quazepam, temazepam and triazolam. Among them, triazolam and temazepam are relatively recommended for the treatment of insomnia. Other commonly used benzodiazepines are alprazolam, diazepam, and lorazepam. These drugs are dependent. Therefore, after long-term use, patients may experience withdrawal symptoms after stopping the drug. Most benzodiazepines are contraindicated in pregnant or lactating women, patients with impaired liver and kidney function, patients with obstructive sleep apnea syndrome, and patients with severe ventilatory impairment. In addition to lorazepam and temazepam, CYP3A4 has a certain ability to metabolize benzodiazepines. Therefore, both CYP3A4 inducers and inhibitors affect their plasma concentrations. CNS depressants and alcohol also enhance the CNS depressant properties of benzodiazepines.

1. Estazolam: It is indicated for the treatment of difficulty falling asleep or maintaining sleep. The adult dosage is 1 to 2 mg orally at bedtime. It has a peak time of 3 hours and a half-life of 10 to 24 hours. Its common adverse effects include dry mouth, hangover and weakness.
2. Flurazepam: It is indicated for the treatment of trouble falling asleep or sleep maintenance. The adult dosage is 15 to 30 mg orally at bedtime. It has a peak time of 1.5 to 4.5 hours and a half-life of 48 to 120 hours. Its common adverse effects include ataxia, dizziness and hangover.
3. Quazepam: It is indicated for the treatment of difficulties falling asleep or maintaining sleep. The adult dose is 7.5 to 15 mg orally at bedtime. It has a peak time of 2 to 3 hours and a half-life of 48 to 120 hours. Its common adverse effects include dizziness, drowsiness, dry mouth, headache and unsteadiness on standing.
4. Temazepam: It is indicated for the treatment of difficulty falling asleep or maintaining sleep. The dosage for adults is 7.5 to 30 mg orally at bedtime. It has a peak time of 1.2 to 1.6 hours and a half-life of 3.5 to 18.4 hours. Its common adverse effects include ataxia and dizziness.
5. Triazolam: It is indicated for the treatment of difficulty falling asleep. The dosage for adults is 0.125 to 0.25 mg orally at bedtime. It has a peak time of 0.2 to 0.5 hours and a half-life of 1.5 to 5.5 hours. Its common adverse effects include amnesia, euphoria, upset stomach and skin tingling.

Melatonin receptor agonists: The sleep-wake cycle is regulated by melatonin. Melatonin can effectively improve symptoms caused by jet lag, delayed sleep phase syndrome, and circadian rhythm sleep disorders. Melatonin receptor agonists can be used as an alternative treatment for patients who cannot tolerate benzodiazepines or who have developed drug dependence. Melatonin and ramelteon tablets are commonly used melatonin receptor agonists.

1. Melatonin: It is indicated for patients who have difficulty falling asleep or maintaining sleep. Adults take 2 mg orally before going to bed. It has a peak time of 0.75 to 3 hours and a half-life of 6 hours. Its common side effects are dizziness, drowsiness and fatigue.
2. Ramelteon: It is indicated for patients who have trouble falling asleep. Adults take 8 mg orally before going to bed. It has a peak time of 0.75 to 1 hour and a half-life of 1 to 2.6 hours. Its common adverse reactions are dizziness, drowsiness and fatigue. It is especially effective and safe for insomniacs with sleep-disordered breathing. CYP1A2 is the main metabolic enzyme of ramelteon. CYP2C and CYP3A4 also metabolize a small amount of it. Therefore, CYP1A2 inhibitors such as ciprofloxacin will increase its plasma concentration and should not be used in combination.

Antidepressants: Serotonin and norepinephrine reuptake inhibitors (SNRIs), selective serotonin reuptake inhibitors (SSRIs), tricyclic antidepressants and other antidepressants are also used to treat insomnia.

Serotonin and norepinephrine reuptake inhibitors (SNRIs): Venlafaxine and duloxetine can be used to treat depression and anxiety to improve insomnia.

Selective serotonin reuptake inhibitors (SSRIs): Fluoxetine, fluvoxamine, paroxetine, sertraline, etc. are commonly used clinical SSRIs. They improve insomnia symptoms in patients by treating depression and anxiety disorders. Among them, fluvoxamine has a sedative effect and is a better choice for insomnia patients.

1. Fluvoxamine: It prevents the degradation of melatonin and increases the concentration of endogenous melatonin. It is the only sedating drug among the SSRIs. The combination of doxepin and it will increase the blood concentration of the two drugs, so the dose should be reduced when used in combination. Its starting dose is 50mg or 100mg taken daily at bedtime. The commonly used effective dose is 100 mg per day.

Tricyclic antidepressants: Amitriptyline and doxepin are commonly used tricyclic antidepressants. However, because of its anticholinergic effects, amitriptyline can cause adverse reactions such as dry mouth and increased heart rate in patients, so it will not be used as the drug of choice for the treatment of insomnia.

1. Amitriptyline: It can treat anxiety and depression patients with insomnia. It has a peak time of 2 to 5 hours and a half-life of 10 to 100 hours. Adults take 10 to 25 mg orally before going to bed. Its common adverse reactions are anticholinergic effects, cardiac damage, excessive sedation, and orthostatic hypotension.
2. Doxepin: Doxepin in small doses (3 to 6 mg orally at bedtime) has a specific antihistamine mechanism. It improves insomnia symptoms in adults and elderly patients with chronic insomnia. It also can treat sleep maintenance disorders. It was clinically well tolerated and had no withdrawal effects. It has become one of the recommended drugs for the treatment of insomnia in recent years. It has a peak time of 1.5 to 4 hours and a half-life of 10 to 50 hours. Its common adverse reactions are drowsiness and headache.

Other antidepressants: Small doses of mirtazapine and trazodone can calm the patient and relieve insomnia symptoms. They are used to treat both insomnia and rebound insomnia after hypnotic drug withdrawal.

1. Mirtazapine: It can relieve symptoms of sleep disorders in depressed patients and treat anxiety and depression with insomnia. It has a peak time of 0.25 to 2 hours and a half-life of 20 to 40 hours. Adults take 3.75 to 15 mg orally at bedtime. Its common adverse effects are anticholinergic effects, appetite and weight gain, and excessive sedation.
2. Trazodone: Although its antidepressant effect is weak, it has strong hypnotic power. It can be used in patients with anxiety and depression with insomnia, sleep disturbance or severe sleep apnea syndrome. It may also be used to treat rebound insomnia after the hypnotic drug is discontinued. It has a peak time of 1 to 2 hours and a half-life of 3 to 14 hours. Adults take 25 to 150 mg orally at bedtime. Its common adverse reactions are dizziness, orthostatic hypotension, and priapism.

Orexin receptor antagonist: Orexin has a refreshing effect, also known as hypocretin.

1. Suvoresan: It is an orexin receptor antagonist. It has been approved in some countries for adults with trouble falling asleep or sleep maintenance disorders. It has a different target than other sleeping pills. Studies have shown that it has good clinical efficacy and tolerability. It has a peak time of 0.5 to 6 hours and a half-life of 9 to 13 hours. Adults take 5 to 20 mg orally before going to bed. Its common adverse reaction is residual sedation.

Non-benzodiazepines such as zolpidem and eszopiclone are generally the first choice for clinical treatment of insomnia. If the first-line drug is ineffective, melatonin receptor agonists, short- to medium-acting benzodiazepines, or orexin receptor antagonists can be replaced. Antidepressants may be added to patients with insomnia who are anxious or depressed.

When should patients use hypnotics?

1. Hypnotics may be taken 5-10 minutes before bedtime when the patient anticipates difficulty falling asleep.
2. If the patient fails to fall asleep 30 minutes after going to bed, hypnotics can be taken immediately.
3. Hypnotics can be taken immediately if the patient cannot fall asleep again after waking up at night and is more than 5 hours away from the expected time of waking up. It recommends using hypnotics with a short half-life.
4. Patients with chronic insomnia were treated intermittently with non-benzodiazepines. It will generally take the hypnotics on selected nights per week rather than on consecutive nights.