Somnifacient

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Somnifacient (from Latin somnus, sleep^[1]), also known as sedatives or sleeping pills, is a class of medications that induces sleep. It is mainly used for treatment of insomnia. Examples of somnifacients include benzodiazepines, barbiturates and antihistamines.

Around 2-6% of adults with insomnia use somnifacients to aid sleep.^[2] However, somnifacients only benefit transient or short-term insomnia but not chronic insomnia.^[3] It is because somnifacients lack supportive evidence for sleep aids in chronic insomnia, and chronic use of somnifacients leads to many adverse effects.^[4][5] When somnifacient is used, it should be combined with Cognitive behavioural therapy for insomnia (CBT-I) and healthy sleeping habits but not solely used due to potential severe adverse effects.^[6][7]

Somnifacients are mainly in oral formulations, including tablets, capsules, solution and suspension, with an onset time within an hour.^[8] One or two doses of somnifacients should be given for transient insomnia, while doses indicated for a week should be given for short-term insomnia.^[9]

This class includes benzodiazepines and nonbenzodiazepines that have similar mechanisms of action but different chemical structures. They both act on and enhance the actions of gamma-aminobutyric acid (GABA)-A receptors, leading to an inhibitory effect on the brain and thus inducement of sleep.^[10][11]

Benzodiazepines are somnifacients for the treatment of short-term insomnia. This class of drugs is characterized by the fusion of a diazepine ring and a benzene ring in the chemical structure. Examples of benzodiazepines are diazepam, nitrazepam, triazolam and chlordiazepoxide. Long-acting benzodiazepines, such as diazepam and chlordiazepoxide, are not recommended due to their residual effects that may precipitate the next day.^[12]

Withdrawal syndrome is a common drawback of benzodiazepines because of the development of a physical dependence on them after abrupt withdrawal. It is characterized by sleep disturbance, tremors, increased anxiety and tension, headache, muscular stiffness and pain, which may last 10–14 days.^[13] To avoid the problem, withdrawal of benzodiazepines should be carried out at a slow reduction rate, which is determined by the initial dose, duration of use and patient tolerance, but not abruptly.^[3] Three basic approaches to the taper are using the same medication for tapering, adding adjunctive medication for alleviating withdrawal symptoms, and switching to a longer-acting equivalent.^[14] One of the recommended benzodiazepine taper is to reduce the dose by 50% in the first 4 weeks, maintain the dose for 1–2 months, and then reduce the dose by 25% every 2 weeks.^[15] Other common side effects of benzodiazepines are drowsiness, dizziness, somnolence and increased risk of ataxia.

Benzodiazepines should not be taken with other central nervous system depressants, namely anticonvulsants, other types of somnifacients, antihistamines and alcohol, because it may potentially increase the toxic effects of benzodiazepines.^[16] Besides, the US Food and Drug Administration (FDA) added a boxed warning for benzodiazepines regarding the concomitant use of opioid drugs because it may increase the risk of coma, respiratory depression, general anesthesia, and death.^[17] The elderly should avoid the use of benzodiazepines due to the increased risk of cognitive impairment, falls and fractures.^[18] Benzodiazepines are also contraindicated in pregnancy and breast-feeding women since they may cause floppy infant syndrome in infants, characterized by hypotonia and CNS depression.^[16]

Nonbenzodiazepines, also known as benzodiazepine-like drugs or Z-drugs, are somnifacients indicated for short-term insomnia. Examples include zolpidem (Ambien, Stilnoct, Stilnox), zopiclone (Imovane, Zimovane), and zaleplon (Sonata).

Zolpidem (immediate release) is considered the first choice for patients with either sleep maintenance or sleep onset complaints. In cases where patients experience waking up at midnight or too early in the morning, zolpidem (extended release) or eszopiclone may be considered due to their longer actions. Zaleplon with the shortest half-life of the nonbenzodiazepines is suitable for patients who experience residual sedating effects in the morning.^[5] However, the exact medication chosen depends on the patient's tolerance, varied efficacy in individuals and drug interactions.

Nonbenzodiazepines, theoretically, are associated with greater selectivity for several subtypes of GABA-A receptors than benzodiazepines, potentially leading to a narrower range of side effects and therapeutic outcomes.^[5] However, research findings on the comparison between benzodiazepines and nonbenzodiazepines in terms of efficacy and adverse effects are conflicting. The US Agency for Healthcare Research and Quality indicates that the risk of harm from benzodiazepines is about twice as high as that from nonbenzodiazepines.^[19] Another study points out that there is no significant difference between the two classes of drugs in terms of adverse effects.^[20] Unlike benzodiazepines, nonbenzodiazepines appear to have little or no impact on sleep stages and do not lead to rapid-eye-movement (REM) sleep rebound.^[21] However, as per a review by the National Institute for Health and Clinical Excellence (NICE), inadequate evidence supports the use of Z-drugs for treating insomnia. The review noted that clinical trials inappropriately compared short-acting nonbenzodiazepines with long-acting benzodiazepines, and there is a lack of studies that compare the effects of short-acting nonbenzodiazepines to those of short-acting benzodiazepines at equivalent doses. As a result of these findings, NICE recommended taking both the patient's preferences and the product price per dose into account when prescribing a somnifacient.^[22]

Like benzodiazepines, nonbenzodiazepines are contraindicated in the elderly and pregnant due to potential adverse effects. Although it is hypothesized that somnifacients may help treat depression caused by insomnia, data released by the Food and Drug Administration (FDA) shows that the use of nonbenzodiazepines including zolpidem, zaleplon and eszopiclone increased the risk of depression by over two times when compared to individuals taking placebo pills.^[23] Therefore, patients who suffer from or are at risk of depression may not be suitable for taking nonbenzodiazepines. The dose of nonbenzodiazepines should be reduced in patients with renal dysfunction due to the hepatic metabolism of the drugs.^[24]

Barbiturates are a class of sedative drugs that potentiate the action of GABA on GABA-A receptors.^[25] Their effects range from moderate sedation to total anesthesia according to the doses indicated. Due to the significant adverse effects (i.e. hallucination, agitation, confusion and hangover) and higher risk of overdose, barbiturates are now mostly replaced by benzodiazepine receptor agonists or other somnifacients in clinical practice for treating insomnia.^[21] Barbiturates are commonly used in epilepsy, acute migraines, general anesthesia, and assisted suicide.^[26] Examples of barbiturates are phenobarbital, primidone and amobarbital.

Antihistamines, also known as H₁ antagonists, are a class of drugs which inhibit action at H₁ receptors. They are clinically used to alleviate allergic reactions including allergic rhinitis, allergic conjunctivitis and urticaria mediated by histamine.^[27] First generation antihistamines such as doxylamine and diphenhydramine are accompanied by sedation as the side effect, which can be utilized to treat insomnia. Some of the antihistamines, namely promethazine and doxylamine, are available for purchase over-the-counter (OTC) and can be bought by the public in some countries for the occasional relief of insomnia.^[28] Low-dose doxepin is approved by the FDA for the treatment of insomnia.^[5] Second generation of antihistamines such as cetirizine and loratadine have a much less sedating effect than the first ones with a much lower degree of crossing the blood–brain barrier.^[29]

Common side effects of antihistamines include nausea, constipation and dry mouth.^[27] Patients with severe urinary retention or untreated angle-closure glaucoma should avoid antihistamines.^[5]

Melatonin is an endogenous hormone synthesized in the pineal gland in the brain involved in promoting sleep.^[30] It activates both melatonin receptors MT1 and MT2 to produce beneficial effects on sleep, therefore being used exogenously for mild insomnia.^[31] A small improvement in sleep onset and total sleep time by using melatonin has been shown in recent systematic reviews.^[32] Synthetic melatonin, also known as melatonin receptor agonist, is also used for sleeping disorders by mimicking the action of melatonin. Examples are tasimelteon and ramelteon.

Dual orexin receptor antagonists are drugs that block the orexin receptors OX₁ and OX₂, hence reducing the wakeful effect of the orexin system and inducing sleep.^[33] Daridorexant, lemborexant and suvorexant have been shown in studies to improve sleep onset and sleep quality.^[34][35]

• Chlorpromazine
• Olanzapine
• Zotepine
• Risperidone

• Amitriptyline
• Mirtazapine
• Trazodone

• Cannabidiol
• Tetrahydrocannabinol

Miscellaneous drugs of somnifacients show sedative effects, but they are not first-line use for insomnia or they are prescribed off-label for insomnia. When prescribing these drugs for insomnia, extra care is needed due to unexpected outcomes and benefit-risk ratios compared to approved medications for insomnia.^[39]

All somnifacients have shared risks of worsening depression, central nervous system depressant effects, abnormal thinking and behaviour changes.^[5] It is not advisable to prescribe somnifacients for routine insomnia treatment, and they should only be used for short periods in patients who are severely distressed or with transient insomnia.^[40] An important drawback of prolonged use is that it can result in rebound insomnia and withdrawal syndrome upon discontinuation.^[40] The elderly especially those with dementia should avoid somnifacients due to potential further impairment of cognitive function according to the clinical guideline, Medication Appropriateness Tool for Comorbid Health Conditions in Dementia.^[41] Most somnifacients possess Cytochrome P450 (CYP450) metabolism, a major drug metabolism pathway in the body, which may have potential drug interactions with other drugs affecting CYP450 activity, such as ketoconazole, clarithromycin and fluvoxamine.^[5] Patients with polypharmacy require extra attention due to their complex medication regimens.