Nonbenzodiazepine Sedative-Hypnotics for Sleep Disorders

Pharmacology/Mechanism of Action

Antidepressants

Doxepin is a tricyclic antidepressant and is believed to exert sleep maintenance effects due to a strong binding affinity for histamine H1 receptors, which allows the use of the drug as a sedative at doses lower than those required for major depressive disorder.^{[39684][39684]}

Nonbenzodiazepine Benzodiazepine-Receptor Agonists

Zolpidem, eszopiclone, and zaleplon are thought to induce sleep by subunit modulation of the GABA-A receptor chloride channel macromolecular complex. The main site of modulatory drug action is located within the GABA-A receptor complex on the alpha-subunit, which is known as the benzodiazepine (BZ) or omega receptor. Eszopiclone has a longer half-life (6 hours) than the other drugs in the class which contributes to improving sleep maintenance.^{[30571][30571][29887][29887][57789][57789]}

Melatonin Receptor Agonists

Ramelteon and tasimelteon selectively target the melatonin receptors MT1 and MT2, which are located in the suprachiasmatic nucleus (SCN) of the hypothalamus. The SCN functions as the internal clock of the body and regulates the 24-hour sleep-wake cycle. The MT1 and MT2 receptors are believed to be involved in the promotion of sleep and the maintenance of the normal circadian rhythm (shift between day and night), respectively, when acted upon by endogenous melatonin.^{[31359][31359][56665][56665]}

Orexin Receptor Antagonists

Suvorexant, lemborexant, and daridorexant exert their therapeutic effects through antagonism of orexin receptors. These medications block the binding of wake-promoting neuropeptides orexin A and orexin B to the OX1R and OX2R receptors, subsequently suppressing the wake drive.^{[57780][57780][64870][67248]}

Dietary or herbal supplements

Melatonin is an endogenous hormone secreted by the pineal gland that interacts with melatonin receptors. Synthesis and secretion of endogenous melatonin are controlled by enzymes secreted by the hypothalamus which are activated by darkness and depressed by environmental light. The activity of melatonin at the MT1, MT2 and MT3 receptors is believed to contribute to its sleep-promoting properties, as these receptors (mainly MT1 and MT2) are involved in the regulation of circadian rhythms and sleep regulation. Commercial melatonin products are primarily synthesized because of the potential for contamination from animal-based infectious prions and viruses, which may cause serious illness.^{[60056][60056]}

Non-prescription (OTC) drugs

Diphenhydramine and doxylamine are first-generation sedating antihistamines (H1-blockers) that competitively antagonize the effects of histamine on the H1 receptor to produce their non-specific centrally-mediated sedative effects.^[63270]

Therapeutic Use

Insomnia

Short-term, prescription treatment (e.g., 7 to 10 days)

In general, short-term treatment with a sleep agent is an appropriate alternative if non-pharmacological sleep therapy has failed. Individualized pharmacotherapy is recommended and is based upon factors such as the specific sleep disturbance (e.g., delayed sleep onset, difficulty maintaining sleep), treatment goals, past treatment response and tolerability, comorbid conditions, concomitant drug therapy, and cost. Eszopiclone, lemborexant, suvorexant, daridorexant, and zolpidem controlled-release are the only prescription nonbenzodiazepine drugs shown to improve both sleep onset and sleep maintenance. Regardless of treatment selection, individuals should be re-evaluated for a comorbid condition if insomnia has not improved in 7 to 10 days.^{[31451][31451][57780][57780][30571][30571][62207][64870][67248]}

Long-term, prescription treatment

Long-term efficacy for insomnia has been established in controlled studies of eszopiclone, ramelteon, lemborexant, and suvorexant. Due to their pharmacokinetic properties, eszopiclone, lemborexant, and suvorexant are beneficial for improving both sleep onset and sleep maintenance. Clinically, other prescription sleep agents without long-term efficacy data may be appropriate in select persons for long-term treatment with close monitoring for efficacy and safety.^{[30571][30571][57780][57780][62207][64870]}

Short-term, non-prescription treatment (e.g., 7 to 10 days) with non-prescription drugs or herbal/dietary supplements

Melatonin has shown efficacy in the short-term treatment of insomnia with limited adverse effects. In a meta-analysis evaluating melatonin in primary sleep disorders, melatonin demonstrated a significant benefit in reducing sleep latency, increasing total sleep time, and improving sleep quality compared to placebo. Meta-regression showed that trials using higher melatonin doses reported significantly greater effects on total sleep time, and a trend towards greater effects on sleep latency. Sleep quality was not affected by higher doses.^{[60018][60018]} Re-evaluate the individual if insomnia does not improve within 7 to 10 days after starting pharmacological therapy regardless of treatment. Based on trials of melatonin 2 mg/day PO, the American Academy of Sleep Medicine (AASM) guidelines recommend against melatonin used as a treatment for sleep onset or sleep maintenance insomnia (versus no treatment) in adults.^[62207] The Veterans Affairs/Department of Defense (VA/DoD) clinical practice guideline also recommends against melatonin for chronic insomnia following critical analysis of a systematic review that examined doses from 2 to 10 mg across 16 trials.^[73418] Diphenhydramine and doxylamine lack clinical evidence supporting safety and efficacy for the treatment of insomnia.^{[63263][63263]}

Non-24-hour sleep-wake disorder

Tasimelteon is FDA approved for the treatment of non-24-hour sleep-wake disorder. Tasimelteon significantly improved total sleep time and daytime nap duration in controlled studies. Strategically timed melatonin has also been recommended for the treatment of non-24-hour sleep-wake disorder but has weak evidence.^{[63264][63264]}

Summary of Insomnia Treatments^{[62207][64870][67248]}

† Off-label use

a Limited efficacy

Comparative Efficacy

Adverse Reactions/Toxicities

CNS Depression

Sedative-hypnotics can cause varying degrees of CNS depression. Instruct treated individuals to avoid driving or operating machinery or performing other tasks requiring mental alertness after taking their dose. Because zolpidem, eszopiclone, lemborexant, suvorexant, and daridorexant have been associated with next-day psychomotor impairment, instruct individuals to avoid driving or operating heavy machinery the day after use as per the time specifications recommended for each product by the manufacturers. Concurrent use of other CNS depressants, including ethanol, may increase the risk for next-day impairment, psychomotor impairment, or other CNS-related toxicities with these drugs. There is a potential risk for respiratory depression with nonbenzodiazepine benzodiazepine-receptor agonists (i.e., zaleplon, eszopiclone, and zolpidem) if CNS depression is severe. Most hypnotic agents should be used with caution in people with impaired/depressed respiratory function or sleep apnea since CNS depression can affect respiratory drive; however, tasimelteon and melatonin have not been precautioned for such individuals.^{[39684][30571][31359][57780][56665][29887][57789][60055][64870][67248]}

Sleep-Related Behaviors

Complex sleep behaviors (performing tasks while not fully awake and often having no memory of the event) such as making phone calls, engaging in sexual activity, eating while asleep, or sleep-driving have occurred with the use of hypnotics, such as zolpidem, eszopiclone, zaleplon, ramelteon, lemborexant, suvorexant, and daridorexant. All sedative-hypnotic medications have the potential to cause sleep-related behaviors. However, the exact incidences among various sedative products are unknown. Therefore, inform the individual of the risks prior to receiving any medication from this class. Alcohol may increase the risk of these events. Due to the risk to the patient and the general public, the sleep agent should be discontinued in people who experience a complex sleep-related behavior.^{[60088][29887][30571][57789][31359][57780][60055][64870][67248]}

Narcolepsy-like Symptoms

Symptoms consistent with narcolepsy have occurred during use of orexin receptor antagonists including lemborexant, suvorexant, and daridorexant. Symptoms include sleep paralysis (an inability to move or speak for up to several minutes during sleep-wake transitions), hypnagogic/hypnopompic hallucinations (vivid and disturbing perceptions when falling asleep or waking up), and cataplexy-like symptoms (periods of leg weakness lasting from seconds to a few minutes). Prescribers should explain the nature of these events prior to prescribing orexin receptor antagonists.^{[64870][57780][67248]}

Suicidal Ideation

Immediately evaluate patients with suicidal ideation or any new behavioral changes. A variety of abnormal thinking and behavioral changes have been reported with the use of sedative/hypnotics. These changes have included decreased inhibition, aggressiveness, bizarre behavior, agitation, hallucinations, and depersonalization. Amnesia and other neuropsychiatric symptoms may occur unpredictably. Worsening of pre-existing depression, suicidal ideation, and completed suicides have occurred in association with the use of sedative-hypnotics. The exact incidences among various sedative products are unknown. Inform treated individuals of the potential risks prior to receiving any medication from this class. Sedative-hypnotics should be prescribed in the smallest quantity consistent with good patient management to reduce the risk of overdose.^{[30571][31359][39684][57780][56665][29887][57789][67248]}

Dependence and Withdrawal

Alternatives to zolpidem, zaleplon, eszopiclone, lemborexant, suvorexant, and daridorexant should be considered in people with a history of substance abuse since these agents are controlled substances with the potential for abuse and dependence. There are postmarketing reports of abuse, dependence, and withdrawal with administration of zolpidem, zaleplon and eszopiclone. If therapy with these drugs is continued for more than 2 weeks, the possibility of a withdrawal syndrome should be considered and abrupt discontinuation of therapy avoided. Because of the potential for dependence, close monitoring is recommended. In an abuse liability study of recreational polydrug users, suvorexant produced similar subjective measures of abuse liability (e.g., drug liking) as zolpidem. In an abuse potential study of recreational sedative abusers receiving lemborexant doses of 10 mg to 30 mg, lemborexant produced similar subjective measures of abuse liability (e.g., drug liking) as zolpidem 30 mg and suvorexant 40 mg and a statistically greater response than the placebo group. A similar study conducted with daridorexant doses of 50 mg, 100 mg, and 150 mg found increased ratings of drug liking compared to placebo at the 50 mg dose and ratings of drug liking at higher doses (100 mg and 150 mg) that were similar to ratings seen with zolpidem 30 mg and suvorexant 150 mg. Prolonged use of suvorexant, lemborexant, and daridorexant did not result in physical dependence and there were no reported withdrawal symptoms after discontinuation of the drugs. Conditions that may increase the risk for prescription sedative abuse include prolonged use, a history of drug abuse or alcoholism, use of higher than recommended doses, or coadministration of the prescribed sedative with alcohol or other abused drugs.^{[57789][30571][29887][57780][64870][67248]}

Drug Interactions

CNS Depressants

Concomitant administration of sedative-hypnotics with other drugs having CNS depressant properties (e.g., psychotropics, anticonvulsants, antihistamines, narcotic analgesics, anesthetics, ethanol) is expected to produce additive CNS depressant effects and may lead to psychomotor impairment or respiratory depression. Patients should be advised not to take these medications with alcohol. Patients should not take other hypnotic agents or non-prescription/dietary supplement sleep aids concurrently. Patients should also be encouraged to confine their activities to those necessary to prepare for bed after taking their hypnotic agent. Some agents may also cause pharmacokinetic interactions; for example, doxepin increases concentrations of ramelteon and patients should be closely monitored if these medications are used concurrently.^{[31359][31359][39684][39684][30571][30571][29887][29887][57780][57780][57789][57789][56665][56665][64870][67248]}

CYP Inducers and Inhibitors

Many drugs from this class are primary CYP substrates. Concomitant administration in patients receiving CYP inhibitors or inducers may alter drug exposure, with the potential for affecting efficacy or tolerability.^{[39684][30571][31359][57780][56665][29887][57789][40912][34522][64870][67248]}

Smoking

• The exposure of tasimelteon, a primary CYP1A2 substrate, in smokers was lower than in non-smokers and therefore the efficacy of tasimelteon may be reduced in smokers. Tobacco smoking causes CYP1A2 induction.^[56665]

• Melatonin is primarily metabolized by CYP1A2. Patients who are tobacco smokers have increased melatonin clearance due to the induction of CYP1A2 by tobacco.^{[60053][60055]}

Safety Issues

Hepatic disease

All non-benzodiazepine sedative/hypnotics are extensively metabolized in the liver; recommendations for use in patients with hepatic impairment vary by medication and severity of impairment. Melatonin is generally not recommended in patients with hepatic disease, as hepatic impairment results in higher endogenous melatonin levels. There are no quantitative guidelines available for diphenhydramine or doxylamine.^{[60055][56737][52061]}

Mild hepatic impairment (Child-Pugh Class A)

Initial dosage reductions are required in patients receiving doxepin, zaleplon, or zolpidem.^{[39684][29887][57789][31451]}

Moderate hepatic impairment (Child-Pugh Class B)

Initial dosage reductions are required in patients receiving doxepin, zaleplon, or zolpidem. Maximum dose reductions are recommended in patients receiving lemborexant or daridorexant.^{[39684][29887][57789][31451][64870][67248]}

Severe hepatic impairment (Child-Pugh Class C)

Initial dosage reductions are required in patients receiving doxepin. Zaleplon and ramelteon are not recommended since systemic exposure is significantly increased. The dose of eszopiclone should not exceed 2 mg/day because systemic exposure is doubled. Suvorexant, tasimelteon, lemborexant, and daridorexant are not recommended because these drugs have not been studied in severe hepatic impairment. Avoid zolpidem since the drug may contribute to encephalopathy.^{[39684][29887][31359][30571][57780][56665][64870][67248][57789][31451]}

Geriatric patients

Nonpharmacologic therapy, such as cognitive behavioral therapy for insomnia (CBT-I), is first line treatment for chronic insomnia in older adults.^[73432] If short term pharmacologic therapy is necessary, careful selection of drug therapy and dosage is important to reduce the risk of adverse events that geriatric adults may be particularly at risk of experiencing.^[62207] Per the Beers Criteria, nonbenzodiazepine benzodiazepine-receptor agonists (NBRAs)- including zolpidem, zaleplon, and eszopiclone- are potentially inappropriate medications (PIMs) in geriatric adults and should generally be avoided. In older adults, they can cause benzodiazepine-like adverse reactions, including syncope, falls, fractures, impaired psychomotor function, and delirium, and are associated with increased emergency department visits, hospitalizations, and motor vehicle crashes, despite only minimal improvement in sleep latency and duration. Use a lower maximum daily dose when recommended in product labeling. If an NBRA is necessary, reduce other CNS-active medications when possible and implement fall-risk reduction strategies. First-generation sedating antihistamines, such as diphenhydramine and doxylamine, are also PIMs in geriatric adults and should be avoided because of their strong anticholinergic effects.^[63923]

Orexin receptor antagonists are generally considered potentially appropriate selections for insomnia in older adults.^[62207] In clinical trials, suvorexant showed no meaningful safety or efficacy differences between geriatric and younger adults. In a pooled analysis of lemborexant, somnolence occurred more often in geriatric patients than in younger adults at the 10 mg/night dosage; caution is recommended with doses above 5 mg/night in older adults. For daridorexant, studies including geriatric patients showed increasing rates of somnolence and fatigue with age, although no age-based dosage adjustment has been recommended. Caution is advised due to the risk of falls and next-day impairment.^{[57780][57780][60017][62207][62207][64870][67248]}

During clinical trial evaluations of ramelteon, no safety or efficacy differences were observed in geriatric versus younger adults.^{[31359][62207][62207]} Tasimelteon demonstrated a higher risk of adverse effects in the geriatric population in controlled trials, which may be the result of an approximately 2-fold increase in exposure compared to younger adults.^[56665]

According to the British Association for Psychopharmacology guidelines, extended-release melatonin is the first-choice treatment when a hypnotic is indicated in older adults more than 55 years of age; there is a pharmaceutical-grade product approved for use in Europe for short-term treatment of insomnia in older adults.^{[60017][60055]} However, the American Academy of Sleep Medicine (AASM) guidelines recommend against melatonin as a treatment for primary insomnia in adults due to a lack of reliable efficacy data following an analysis of trials of melatonin 2 mg/day.^[62207] The Veterans Affairs/Department of Defense (VA/DoD) guidelines also suggest against the use of melatonin for chronic insomnia in adults based on a systematic review of studies using melatonin at doses from 2 mg/day to 10 mg/day.^[73418] There is mixed evidence that suggests a possible improvement in sleep latency (but not total sleep time or sleep efficiency) in the older adult population. Most data have not been of sufficient quality to assess for adverse events of melatonin in the geriatric adult.^{[62207][63264][62207][73432]}

Weight, gender, and ethnicity

Although systemic exposure to some sleep agents, such as zolpidem, tasimelteon, and melatonin, is higher in women than men, zolpidem is the only agent with a recommended initial dose reduction in women. Systemic exposure to zaleplon is increased in Japanese adults (and possibly other Asian populations), and is thought to be related to body weight differences or may represent differences in enzyme activities resulting from diet, environment, genetic, or other factors. Suvorexant exposure is increased in obese patients compared to non-obese patients, with obese females having the largest increase in exposure. Therefore, the risk of adverse effects from increased exposure to suvorexant, such as next-day impairment, should be considered prior to increasing the dose, particularly in obese patients who are female. When examined in clinical trials, neither gender nor ethnicity appeared to have a significant impact on the kinetics of daridorexant or lemborexant.^{[29887][31451][44125][44126][46915][57789][57780][56665][67248]}

Pregnancy

Non-pharmacologic therapy and good sleep hygiene should be used as first-line therapy for sleep disturbances during pregnancy. Pharmacologic treatment should only be used if the benefit to the mother outweighs the potential risk to the fetus, and patients should be advised not to self-treat with non-prescription drugs or supplements. Data to evaluate the use of non-benzodiazepine sleep agents during pregnancy are limited; therefore, the use of these agents is not routinely recommended during pregnancy.

Hypnotic benzodiazepine receptor agonists (HBRAs; e.g., eszopiclone, zaleplon, zolpidem) have been shown to cross the human placenta. Published studies of HBRAs used during pregnancy do not indicate an increased risk of congenital malformations at typical doses. However, one study has reported neural tube defects in an infant following high-dose exposure to zolpidem in the first trimester of pregnancy, suggesting that dose may play a role in the risk of these defects. In a systematic review and meta-analysis developed to assess for risks associated with use of HBRAs in pregnancy, the authors noted that pregnancy exposure to HBRAs was not associated with an increased risk of congenital malformations; however HBRA use was associated with increased risks of preterm birth, low birth weight, and being small for gestational age compared to unexposed infants. Similarly, a population-based cohort study determined that HBRA use in early pregnancy may be associated with an increased risk of infants being born small for gestational age, even after controlling for numerous confounding variables. There have been cases of respiratory depression and sedation in neonates born to mothers using hypnotics late in the third trimester of pregnancy. Moreover, neonates born to mothers who take HBRAs chronically during the latter stages of pregnancy may develop physical dependence and may be at risk of developing neonatal withdrawal symptoms in the postnatal period. Additional studies are needed to determine the true risk and incidence of these effects.^{[62207][69243][69244][69256][69257][69258][73427]}

Doxylamine has been studied in pregnancy as a combination product for the treatment of nausea and vomiting and does not appear to increase the risk for congenital malformations. However, its use for insomnia is not routinely recommended. Diphenhydramine is known to cross the placenta and should be reserved for when treatment is medically necessary. Melatonin is not recommended for use in pregnancy due to a lack of data and concerns that exogenous melatonin could potentially disrupt circadian entrainment and other pineal gland influences in the fetus. Ramelteon and tasimelteon should also be avoided due to animal studies that indicate a potential risk for fetal harm and the lack of adequate data in human pregnancy. There are no adequate or well-controlled studies of suvorexant, lemborexant, or daridorexant in pregnant women.^{[66066][73431][31359][47168][60055][60056][61291][57780][64870][67248]}

Breast-feeding

Non-benzodiazepine sleep agents are generally not recommended during breast-feeding due to the scant data available; non-pharmacologic methods for treatment should be used first. Doxepin readily distributes into breast milk, leading to potential adverse effects in the nursing infant and should be avoided during lactation. Zaleplon and zolpidem are also excreted in breast milk, but there are small studies suggesting that these two agents may be used during lactation with caution when medically necessary. It is not known if diphenhydramine, doxylamine, eszopiclone, melatonin, ramelteon, suvorexant, lemborexant, daridorexant, or tasimelteon distribute into human breast milk.^{[40336][45971][61269][62207][30571][31359][31451][39684][44125][44126][46915][57780][57789][60055][64870][67248]}

Pediatric patients

The American Academy of Sleep Medicine (AASM) pediatric insomnia guidelines indicate pharmacologic therapy is not a first-line treatment choice for pediatric patients with sleep disturbances; behavioral interventions are considered first-line therapy in pediatric patients. Most sleep disturbances in children can be successfully managed with a combination of behavior therapy and modification of sleep practices alone. Pharmacologic therapy should be patient-specific and a risk-benefit analysis should be performed before initiating therapy.^[63271]

Melatonin has reduced sleep onset and improved sleep maintenance in children with neurodevelopmental, psychiatric disorders, ADHD, and autism. In general, melatonin is considered well-tolerated and effective in pediatric patients but should be used under prescriptive authority and monitoring. The American Academy of Neurology (AAN) notes that insomnia or disrupted sleep are common in pediatric patients with autism spectrum disorder (ASD); clinicians can consider melatonin in children and adolescents with ASD if behavioral strategies have not been helpful and contributing coexisting conditions and use of concomitant medications have been addressed, starting with a low dose (e.g., 1 to 3 mg/day). Clinicians should counsel parents/caregivers regarding potential adverse effects of melatonin use and the lack of long-term safety data, including an unknown effect on pubertal development. Reported side effects in pediatric patients have included morning drowsiness, increased enuresis, headache, dizziness, diarrhea, rash, and hypothermia.^{[63272][65329]}

Safety and efficacy have not been established for doxepin, ramelteon, suvorexant, lemborexant, daridorexant, tasimelteon, eszopiclone, zaleplon, or zolpidem in pediatric patients; the use of these drugs is generally not recommended due to their safety profile and lack of convincing evidence of effectiveness. Clinical trials failed to demonstrate the efficacy of eszopiclone and zolpidem in pediatric patients with ADHD-associated insomnia.^{[30571][57789][39684][31359][57780][56665][29887][64870][67248]}

Experts recommend against the use of diphenhydramine and doxylamine for sedation in pediatric patients of any age; in clinical trials, these drugs have not been proven better than placebo and expose infants and children to side effects and toxicities, including anticholinergic effects.^{[33534][56706][33689][63272]}