For the treatment of insomnia, how to choose between zopiclone, lorazepam and estazolam?

To know how to choose sleeping pills correctly, you must first understand them. The effects of sleeping pills vary with the dose. Low doses produce sedation, medium doses can induce physiological sleep, and high doses produce anesthesia and anticonvulsant effects.

Secondly, we need to distinguish the properties of sleep disorders. Generally, sleep disorders can be divided into difficulty falling asleep, shallow sleep and easy awakening, dreaminess and early awakening. For those who have difficulty falling asleep, drugs with fast onset and short half-life can be used; those who have shallow sleep and easy awakening can choose medium-acting sleeping pills; patients with short sleep duration such as early awakening can choose long-acting sleeping pills, etc.

Problems with the early stages of sleep refer to difficulty falling asleep; problems with the middle stages of sleep refer to difficulty maintaining sleep, which means waking up easily, having many dreams, low sleep efficiency, and poor quality; problems with the late stages of sleep refer to waking up early and having difficulty falling asleep again after waking up.

The 2017 edition of the "Guidelines for the Diagnosis and Treatment of Insomnia in Chinese Adults" recommends:

1. Non-benzodiazepines (non-BZDs) are preferred.

2. If the first-choice drug is ineffective or compliance is impossible, it can be replaced with another non-benzodiazepine drug (eszopiclone, zopiclone, zaleplon, zolpidem).

3. If the first-choice drug is ineffective or compliance is impossible, it can be directly replaced with a short- to medium-acting benzodiazepine (alprazolam, estazolam, lorazepam, triazolam).

Special reminder: Although non-benzodiazepines have clinical evidence for long-term use, considering the potential addiction problem, they should be used as short-term as possible, generally not exceeding 4 weeks. Within 4 weeks, the drug should be taken continuously.

Principles of drug treatment for insomnia

(1) Hypnotic drugs should be administered as appropriate.

(2) Individualization: Start with a small dose and do not easily adjust the drug dose once the effective dose is reached.

(3) Dosage principles: on-demand, intermittent, and sufficient:

Take the medicine 3 to 5 days a week instead of taking it every night.

Patients who require long-term drug treatment should "take medication on demand", that is, when they expect difficulty falling asleep, sedatives and hypnotics should be taken 5 to 10 minutes before going to bed.

Take it if you still cannot fall asleep 30 minutes after going to bed; take it if you wake up ≥ 5 hours earlier than your usual time and cannot fall asleep again.

(4) Treatment course: The dosage and duration of medication should be adjusted according to the patient's sleep condition:

Continuous treatment may be an option for drug interventions shorter than 4 weeks;

Drug interventions lasting more than 4 weeks require regular monthly evaluations. A comprehensive evaluation of the patient's sleep condition is required every 6 months or when the disease relapses; the treatment plan should be changed if necessary.

Drug treatment sequence

Insomnia drug treatment should follow a certain order:

(1) Short-acting and medium-acting benzodiazepine receptor agonists (BzRAs) or melatonin receptor agonists (such as ramelteon).

(2) Other BzRAs or melatonin receptor agonists.

(3) Antidepressants with sedative effects (such as trazodone, mirtazapine, fluvoxamine, doxepin) are particularly suitable for patients with insomnia accompanied by depression and/or anxiety.

(4) Combined use of BzRAs and antidepressants with sedative effects.

(5) Prescription drugs such as anti-epileptic drugs and antipsychotic drugs are not used as the first choice drugs, but are only suitable for certain special situations and populations.

(6) Although barbiturates and chloral hydrate have been approved by the FDA for the treatment of insomnia, their clinical use is not recommended.

Drug selection for different sleep disorder properties

Difficulty falling asleep

For this type of patients, drugs with a shorter half-life should be used, such as zolpidem, lorazepam, midazolam, zopiclone, etc.

Half-life refers to the time it takes for the drug concentration in the blood or the amount of drug in the body to decrease to half.

For example, if we take a 5 mg tablet of medicine, only 2.5 mg is left in the body after 2 hours, then the half-life of this drug is 2 hours.

In principle, after 7 half-lives, the dose of the drug in the body will gradually return to zero.

Therefore, the shorter the half-life of a drug, the faster it will take effect, and the shorter the duration of effect. Patients who have difficulty falling asleep should choose drugs that take effect quickly, that is, drugs with a short half-life.

Difficulty maintaining sleep

For this type of patients, drugs with relatively long half-lives should be used, such as clonazepam, estazolam, diazepam, zopiclone, zaleplon, etc.

Among them, clonazepam is actually a very controversial drug in clinical practice because its half-life is very long, which can be as long as more than 20 hours.

Clonazepam is an anticonvulsant for the treatment of epilepsy in the Chinese Pharmacopoeia. It is sometimes used when some patients have persistent and severe anxiety or severe insomnia.

It is generally recommended for short-term use, and after anxiety is relieved or sleep improves, the drug can be gradually discontinued or switched to other drugs.

In addition, a drug that needs special attention is zopiclone. Some insomnia patients who take zopiclone will feel bitter and metallic taste in their mouth the next day.

Early awakening

It is generally recommended that such patients use drugs with medium to long half-lives, such as estazolam, clonazepam, zopiclone, S-zopiclone (r-zopiclone), etc. This can effectively ensure that the patient's sleep is maintained and allow the patient to sleep a full night.

Among them, compared with zopiclone, S-zopiclone (right-zopiclone) is safer and more effective. In addition to being used to treat early awakening, it can also be used to treat difficulty falling asleep or poor sleep quality.

In addition, zolpidem is a drug for treating difficulty falling asleep, but because it takes effect quickly and has a very short duration of action, when patients wake up at one or two in the morning, they can also take zolpidem to help them fall asleep again.

Precautions

Dosage: Take the medicine on demand (for example, you still can't fall asleep 30 minutes after going to bed; you have important work the next day). Intermittent treatment is recommended, 3-5 days a week, rather than using it every night.

Medication course: Use as short a period as possible, generally no more than 4 weeks. If the medication lasts longer than 4 weeks, sleep status and medication use should be evaluated every month, and the treatment plan should be changed if necessary.

Change and stop medication: Patients who use medications for a long time should avoid stopping medications suddenly, as stopping medications suddenly may cause severe withdrawal symptoms and rebound insomnia.

Do not drink alcohol when using this type of drug, because alcohol will increase the inhibition of the nervous system; during the medication treatment stage, please temporarily stop high-altitude work, fine operations, driving, etc., because taking the drug may affect concentration. After taking the drug, especially the elderly, they need to go to bed immediately to prepare for sleep. Because some sleeping pills can cause ataxia or decreased muscle tone, increasing the risk of falling.

Secondly, we should pay attention to the side effects of drugs. "All drugs are poisonous", while improving sleep, we should not ignore the contraindications of sleeping pills for special physiological and pathological groups.

Pregnant women should avoid taking sleeping pills, as some sleeping pills may cause fetal malformation, and may also cause difficulty in breastfeeding, jaundice, and drowsiness in newborns. When insomnia occurs during pregnancy, it is best to achieve the purpose of hypnosis by relaxing your mind, keeping a regular schedule, and other lifestyle adjustments;

If a breastfeeding woman takes sleeping pills, the ingredients may be transferred into breast milk, causing adverse effects on the newborn. If a mother takes sleeping pills during breastfeeding, she should avoid breastfeeding;

For patients with sleep apnea, sleeping pills can deepen central nervous system inhibition, so patients with obstructive respiratory disease or sleep apnea should not take sleeping pills.

People with acute angle-closure glaucoma and myasthenia gravis should also be aware that their symptoms may worsen dramatically when they take sleeping pills.

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References:

[1] Chinese Society of Neurology, Chinese Society of Neurology Sleep Disorders Group. Guidelines for the diagnosis and treatment of insomnia in adults in China (2017 edition)[J]. Chinese Journal of Neurology, 2018, 51(5): 324-335.

[2] Sleep Disorders Group, Neurology Branch, Chinese Medical Association. Guidelines for the diagnosis and treatment of insomnia in adults in China [J]. Chinese Journal of Neurology, 2012, 45(7): 534-540. DOI: 10.3760/cma.j.issn.1006-7876.2012.07.022.

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