Nonbenzodiazepine Sedative-Hypnotics for Sleep Disorders

    Learn more about Elsevier's Drug Information today! Get the drug data and decision support you need, including TRUE Daily Updates™ including every day including weekends and holidays.


    Nonbenzodiazepine Sedative-Hypnotics for Sleep Disorders


    • Non-pharmacological therapy is effective and is the standard of care for the initial treatment of insomnia.
    • When pharmacologic management is required, medication choice is based upon the individual characteristics and needs of the patient, including the type of sleep difficulty (e.g., sleep-onset insomnia, sleep maintenance insomnia, frequent awakenings, early morning awakenings, circadian rhythm disruption), treatment goals, prior treatment responses, comorbid conditions, other medications, and cost.
    • The American Academy of Sleep Medicine (AASM) guidelines for the pharmacologic treatment of chronic insomnia in adults suggest the use of ramelteon or zaleplon for sleep-onset insomnia, eszopiclone or zolpidem for sleep-onset and sleep maintenance insomnia, and doxepin or suvorexant for sleep maintenance insomnia.[62207]
    • The use of non-prescription drugs, dietary supplements, or herbal products (e.g., melatonin, tryptophan, valerian) for the treatment of chronic insomnia in adults is not recommended by the AASM guidelines.[62207]
    • Although classified as a non-prescription herbal product in the U.S., melatonin is available by prescription in Europe under the brand name Circadin as a short-term monotherapy treatment for primary insomnia characterized by poor quality of sleep in patients who are 55 years or older.[60055]
    • Patients should be re-evaluated if insomnia does not improve within 7 to 10 days after starting pharmacological therapy regardless of the medication used.

    Pharmacology/Mechanism of Action


    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]


    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][29887][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][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][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]


    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


    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, patients should be re-evaluated for a comorbid condition if insomnia has not improved in 7 to 10 days.[31451][57780][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 patients for long-term treatment with close monitoring for efficacy and safety.[30571][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. Patients should be re-evaluated 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. Diphenhydramine and doxylamine lack clinical evidence supporting safety and efficacy for the treatment of insomnia.[60018][62207][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]


    Summary of Insomnia Treatments[62207][64870][67248]

    DrugSleep onset treatmentSleep maintenance treatmentAppropriate in geriatric patients
    Zolpidem immediate release formulationsYesNoNo
    Zolpidem extended-release formulationsYesYesNo

    † Off-label use

    a Limited efficacy

    Comparative Efficacy

    Citation Design/Regimen Results Conclusion
    Dundar Y, Dodd, S, Strobl J, et al. Hum Psychopharmacol. 2004;19:305-22.[63268] Systemic review and meta-analysis of randomized controlled trials comparing zolpidem and zaleplon (6 trials).

    Sleep quality:

    Zolpidem vs. zaleplon

    Adverse events:

    Zolpidem vs. zaleplon

    Withdrawal symptoms:

    Zolpidem vs. zaleplon

    Zolpidem was more likely to improve sleep quality but also more likely to cause withdrawal symptoms compared to zaleplon (7.1% vs. 1.5%).

    No significant difference in adverse reactions between zaleplon and zolpidem.

    Staner C, Joly F, Jacquot N, et al. Curr Med Res Opin. 2010;26:1423-31.[63269] Randomized, double-blind, two-period crossover study comparing zolpidem PO 10 mg tablet and zolpidem SL 10 mg tablet in patients with primary insomnia.

    Latency to persistent sleep (LPS):

    Zolpidem SL significantly shortened LPS by 10.3 min vs. zolpidem PO.

    Sleep onset latency (SOL):

    Zolpidem SL significantly shortened SOL compared to zolpidem PO.

    Subjective sleep improvement or next-morning residual effects did not differ between the two formulations.

    Zolpidem SL is more effective in reducing sleep latency compared to zolpidem PO when given in equivalent doses.
    Ferracioli-Oda E, Qawasmi A, Bloch MH. PLoS One. 2013;8:e63773.[60018] Meta-analysis of randomized, placebo-controlled trials examining the effects of melatonin for the treatment of primary insomnia. A total of 19 trials, n = 1,683.

    Improved sleep onset latency:

    Melatonin vs placebo (weighted mean difference = 7.06 minutes)

    Improved sleep time:

    Melatonin vs. placebo (weighted mean difference = 8.25 minutes)

    Improved sleep quality:

    Melatonin vs. placebo (standardized mean difference = 0.22)

    No significant side effects observed.

    Melatonin significantly improved sleep latency, sleep time, and sleep quality compared to placebo. Trials with higher doses and duration of treatment were associated with greater therapeutic effect.
    Culpepper L, Wingertzahn MA. Prim Care Companion CNS Disord. 2015;17:10.4088/PCC.15r01798.[63270] Systematic review of efficacy and safety of OTC agents for the treatment of insomnia. A total of 17 publications.


    Significant positive effects were reported for sleep quality, sleep onset, and morning alertness vs. placebo. Overall, adverse effects were similar to placebo.

    Diphenhydramine and doxylamine:

    Failed to demonstrate consistent, positive improvements in objective and self-reported sleep measures.

    Melatonin demonstrated consistent positive improvements in sleep quality with limited adverse effects.


    Diphenhydramine and doxylamine lack safety and efficacy data for the treatment of insomnia.

    Adverse Reactions/Toxicities

    CNS Depression

    Sedative-hypnotics can cause varying degrees of CNS depression. Patients should be instructed 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, patients should be instructed to avoid driving or operating heavy machinery the day following a dose 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 patients with impaired/depressed respiratory function or sleep apnea since CNS depression can affect respiratory drive; however, tasimelteon and melatonin have not been precautioned in such patients.[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, patients should be informed 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 patients who experience a complex sleep 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 to patients 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; however, patients should be informed of the 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 patients 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][39684][30571][29887][57780][57789][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]



    Primary CYP Substrates

    Metabolic Drug Interactions



    Avoid use with strong CYP3A4 inhibitors

    Max dose with moderate CYP3A4 inhibitors is 25 mg/night

    Avoid use with moderate or strong CYP3A4 inducers



    Use cautiously with inducers or inhibitors of CYP2D6


    CYP2C19, CYP2D6

    Use cautiously with inducers or inhibitors of CYP2C19 or CYP2D6






    Max dose with strong CYP3A4 inhibitors is 2 mg/night

    Monitor for decreased efficacy when using strong CYP3A4 inducers



    Avoid use with moderate or strong CYP3A4 inhibitors

    Max dose with weak CYP3A4 inhibitors is 5 mg/night

    Avoid use with moderate or strong CYP3A inducers



    Use with strong CYP1A2 inducers or inhibitors not recommended



    Contraindicated with strong CYP1A2 inhibitors (e.g., fluvoxamine)

    Use cautiously with inducers or inhibitors of CYP1A2, CYP3A4, and CYP2C9



    Use with strong CYP3A4 inhibitors not recommended

    Limit dose with moderate CYP3A4 inhibitors to 5 mg/night, if efficacious

    Monitor for decreased efficacy when using strong CYP3A4 inducers


    CYP1A2, CYP3A4

    Use with strong CYP1A2 inhibitors not recommended

    Use with strong CYP3A4 inducers not recommended



    Use cautiously with strong CYP3A4 inducers or inhibitors

    Monitor for decreased efficacy when using strong CYP3A4 inducers



    Use cautiously with strong CYP3A4 inducers or inhibitors

    Monitor for decreased efficacy when using strong CYP3A4 inducers


    • 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. Sedative/hypnotics vary in their recommendations for use based upon the severity of hepatic impairment.[30571][31359][31451][39684][44125][44126][46915][57780][57789][60055][64870][67248]


    Mild hepatic impairment (Child-Pugh Class A)

    Initial dosage reductions are required in patients receiving zaleplon or zolpidem. No dose adjustments are necessary in patients receiving eszopiclone, lemborexant, ramelteon, suvorexant, daridorexant, or tasimelteon. No quantitative guidelines are available for diphenhydramine, doxylamine, or doxepin. Melatonin is generally not recommended in patients with hepatic disease.


    Moderate hepatic impairment (Child-Pugh Class B)

    Initial dosage reductions are required in patients receiving zaleplon or zolpidem. Maximum dose reductions are recommended in patients receiving lemborexant or daridorexant. No dose adjustments are necessary in patients receiving eszopiclone, ramelteon, suvorexant, or tasimelteon. No quantitative guidelines are available for diphenhydramine, doxylamine, or doxepin. Melatonin is generally not recommended in patients with hepatic disease.


    Severe hepatic impairment (Child-Pugh Class C)

    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. Quantitative guidelines are not available for diphenhydramine, doxylamine, or doxepin; monitor for side effects and adjust the dose if needed. Melatonin is generally not recommended in patients with hepatic disease; hepatic impairment results in higher endogenous melatonin levels.

    Geriatric patients

    The geriatric adult may be particularly at risk for adverse events from some hypnotic agents, so careful selection of drug therapy and the dosage is important when treatment is indicated.[62207]


    According to the Beers Criteria, nonbenzodiazepine benzodiazepine-receptor agonists (NBRAs) (e.g., zolpidem, zaleplon, eszopiclone) are considered potentially inappropriate medications (PIMs) in geriatric adults and should be avoided. These drugs may produce adverse effects similar to benzodiazepines in older adults, such as syncope, falls, fractures, impaired psychomotor function, and delirium. There are increased risks for emergency department visits, hospitalizations, and motor vehicle crashes, as well as minimal improvement in sleep latency and duration with the use of these agents in older adults. A reduced maximum daily dose should be used if advised by the product label. If an NBRA must be used, consider reducing the use of other CNS-active medications that increase the risk of falls and fractures, and implement other strategies to reduce fall risk. First-generation sedating antihistamines (e.g., diphenhydramine and doxylamine) that are marketed for sleep are considered PIMs in the older adult according to Beers, and should be avoided because they are highly anticholinergic.[63923]


    In general, orexin receptor antagonists are considered potentially appropriate selections for insomnia in the aged adult.[62207] During clinical trial evaluations, no safety or efficacy differences were observed for suvorexant in geriatric versus younger adults. 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. In a pooled analysis of lemborexant, the incidence of somnolence was higher in geriatric patients than younger adults at the 10 mg/night dosage. Therefore, caution is recommended when using doses higher than 5 mg of lemborexant in geriatric patients. In clinical studies of daridorexant that included geriatric individuals, the risk of somnolence and fatigue increased with patient age, but no dosage adjustment has been recommended vs. younger adults; caution about risk for falls or next-day impairment.[57780][60017][62207][64870][67248]


    During clinical trial evaluations, no safety or efficacy differences were observed for ramelteon in geriatric versus younger adults.[31359][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] Based on trials of melatonin 2 mg/day, 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. 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]

    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]


    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]


    While doxylamine does not pose a significant risk to the fetus in any trimester, diphenhydramine is known to cross the placenta and should be reserved for when treatment is medically necessary. Melatonin is considered contraindicated in pregnancy because the administration of 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.[30571][31359][31451][39684][44125][44126][46915][47168][57780][57789][60055][60056][61291][64870][67248]


    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]

    [29887]Sonata (zaleplon) package insert. Bristol, TN: King Pharmaceuticals; 2019 Aug.

    [30571]Lunesta (eszopiclone) tablets package insert. Marlborough, MA: Sunovion Pharmaceuticals Inc; 2019 Aug.

    [31359]Rozerem (ramelteon) tablet package insert. Lexington, MA: Takeda Pharmaceuticals America, Inc.; 2021 Nov.

    [31451]Ambien CR (zolpidem extended-release tablets) package insert. Bridgewater, NJ: Sanofi-Aventis US, LLC; 2022 Feb.

    [33534]Centers for Disease Control and Prevention (CDC). Infant deaths associated with cough and cold medications - two states, 2005. MMWR Weekly 2007;56:1-4.

    [33689]Merenstein D, Dier-West D, Halbower AC, et al. The trial of infant response to diphenhydramine. The TIRED study - a randomized, controlled, patient-oriented trial. Arch Pediatr Adolesc Med 2006;160:707-12.

    [34522]Akutsu T, Kobayashi K, Sakurada K, et al. Identification of human cytochrome p450 isozymes involved in diphenhydramine N-demethylation. Drug Metab Dispos 2007;35:72-8.

    [39684]Silenor (doxepin) package insert. Morristown, NJ. Currax Pharmaceuticals, LLC.; 2020 Oct.

    [40336]Pons G, Francoual C, Guillet Ph, et al. Zolpidem excretion in breast milk. Eur J Clin Pharmacol 1989;37:245-8.

    [40912]Facciola G, Hidestrand M, von Bahr C, et al: Cytochrome P450 isoforms involved in melatonin metabolism inhuman liver microsomes. Eur J Clin Pharmcol 2001;56(12):881-888.

    [44125]Edluar (zolpidem tartrate sublingual tablets) package insert. Somerset NJ: Meda Pharmaceuticals Inc.; 2019 Aug.

    [44126]Zolpimist (zolpidem tartrate) Oral Spray package insert. Englewood, CO: Aytu Bioscience, Inc.; 2019 Aug.

    [45971]Darwish M, Martin PT, Cevallos WH, et al. Rapid disappearance of zaleplon from breast milk after oral administration to lactating women. J Clin Pharmacol 1999;39:670-4.

    [46915]Intermezzo (zolpidem tartrate) sublingual tablets package insert. Stamford, CT: Purdue Pharma L.P.; 2019 Aug.

    [47168]Davis FC. Melatonin: role in development. J Biol Rhythms 1997;12:498-508.

    [56665]Hetlioz (tasimelteon) package insert. Washington, D.C.: Vanda Pharmaceuticals, Inc.; 2020 Dec.

    [56706]Russo RM, Gururaj VJ, Allen JE. The effectiveness of diphenhydramine HCl in pediatric sleep disorders. J Clin Pharmacol 1976;16:284-288.

    [57780]Belsomra (suvorexant) tablets package insert. Whitehouse Station, NJ: Merck Sharp & Dohme Corp.; 2021 Mar.

    [57789]Ambien (zolpidem immediate-release tablets) package insert. Bridgewater, NJ: Sanofi-Aventis U.S. LLC; 2022 Feb.

    [60017]Wilson SJ, Nutt DJ, Alford C et al. British Association for Psychopharmacology consensus statement on evidence-based treatment of insomnia, parasomnias and circadian rhythm disorders. J Psychopharmacol 2010;24:1577–1601.

    [60018]Ferracioli-Oda E, Qawasmi A, Bloch MH. Meta-analysis: melatonin for the treatment of primary sleep disorders. 2013. PLoS ONE 8(5): e63773. doi:10.1371/journal.pone.0063773.

    [60053]Harpsoe NG, Andersen LP, Gogenur I, et a;. Clinical pharmacokinetics of melatonin: a systematic review. Eur J Clin Pharmacol. 2015;71:901-909.

    [60055]Circadin prolonged-release tablets (oral melatonin) European Medicines Agency official product label. Dublin 2, Republic of Ireland; Flynn Pharma Ltd: 2019 Aug. Accessed April 24, 2020. Available at: www.medicines.org.uk/emc/product/2809

    [60056]Health Canada Drugs and Health Products and Natural Health Products Ingredients Database. Melatonin Monograph. First published 2012. Modified May 13, 2013. Web. Accessed August 4, 2015. Available at: webprod.hc-sc.gc.ca/nhpid-bdipsn.

    [60088]Dolder CR, Nelson MH. Hypnosedative-induced complex behaviours: incidence, mechanisms and management. CNS Drugs. 2008;22:1021-36.

    [61269]Fortinguerra F, Clavenna A, Bonati M. Psychotropic drug use during breastfeeding: a review of the evidence. Pediatrics 2009;124:547-56.

    [61291]Servey J, Chang J. Over-the-Counter Medications in Pregnancy. Am Fam Physician. 2014;90:548-555.

    [62207]Sateia MJ; Buysse DJ, Krystal AD, et al. Clinical practice guideline for the pharmacologic treatment of chronic insomnia in adults: an American Academy of Sleep Medicine clinical practice guideline. J Clin Sleep Med 2017;13:307-349.

    [63263]Culpepper L, Wingertzahn MA. Over-the-counter agents for the treatment of occasional disturbed sleep or transient insomnia: a systematic review of efficacy and safety. Prim Care Companion CNS Disord. 2015; 17(6): 10.4088/PCC.15r01798.

    [63264]Auger RR, Burgess HJ, Emens JS et al. Clinical Practice Guideline for the Treatment of Intrinsic Circadian Rhythm Sleep-Wake Disorders: Advanced Sleep-Wake Phase Disorder (ASWPD), Delayed Sleep-Wake Phase Disorder (DSWPD), Non-24-Hour Sleep-Wake Rhythm Disorder (N24SWD), and Irregular Sleep-Wake Rhythm Disorder (ISWRD). An Update for 2015: An American Academy of Sleep Medicine Clinical Practice Guideline. J Clin Sleep Med. 2015; 11(10): 1199-236.

    [63268]Dundar Y, Dodd S, et al. Comparative efficacy of newer hypnotic drugs for the short-term management of insomnia: a systematic review and meta analysis. Hum Psychopharmacol. 2004; 19(5): 305-22.

    [63269]Staner C, Joly F, et al. Sublingual zolpidem in early onset of sleep compared to oral zolpidem: a polysomnographic study in patients with primary insomnia. Curr Med Res Opin. 2010; 26(6):1423-31.

    [63270]Culpepper L, Wingertzahn MA. Over-the-counter agents for the treatment of occasional disturbed sleep or transient insomnia: a systematic review of efficacy and safety. Prim Care Companion CNS Disord. 2015; 17(6): 10.4088/PCC.15r01798.

    [63271]Morgenthaler TI, Owens J, et al. Practice parameters for behavioral treatment of bedtime problems and night wakings in infants and young children. SLEEP. 2006; 29(10):1277-81.

    [63272]Owens JA and Moturi S. Pharmacologic treatment of pediatric insomnia. Child Adolesc Psychiatric Clin N Am. 2009; 18(4):1001-16.

    [63923]2023 American Geriatrics Society Beers Criteria Update Expert Panel. American Geriatrics Society 2023 updated AGS Beers Criteria for potentially inappropriate medication use in older adults. J Am Geriatr Soc. 2023;71:2052-2081

    [64870]Dayvigo (lemborexant) tablets package insert. Nutley, NJ: Eisai Inc.; 2023 Apr.

    [65329]Williams Buckley A, Hirtz D, Oskoui M, et al. Practice guideline: Treatment for insomnia and disrupted sleep behavior in children and adolescents with autism spectrum disorder: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology. Neurology. 2020;94:392-404. Epub 2020 Feb 12.

    [67248]Quviviq (daridorexant) tablet package insert. Radnor, PA: Idorsia Pharmaceuticals US Inc; 2023 Oct.

    [69243]Wikner BN, Kallen B. Are hypnotic benzodiazepine receptor agonists teratogenic in humans? J Clin Psychopharmacol. 2011;31(3):356-359.

    [69244]Miller MA, Mehta N, Clarak-Bilodeau C, et al. Sleep pharmacotherapy for common sleep disorders in pregnancy and lactation. Chest.2020;157(1):184-197.

    [69256]Wikner BN, Stiller CO, Bergman U, et al. Use of benzodiazepines and benzodiazepine receptor agonists during pregnancy: neonatal outcome and congenital malformations. Pharmacoepidemiol Drug Saf. 2007;16:1203-1210.

    [69257]Grigoriadis S, Alibrahim A, Mansfield JK, et al. Hypnotic benzodiazepine receptor agonist exposure during pregnancy and the risk of congenital malformations and other adverse pregnancy outcomes: A systematic review and meta-analysis. Acta Psychiatr Scand. 2022;146:312-324.

    [69258]Meng LC, Lin CW, Lin YC, et al. Association between maternal benzodiazepine or z-hypnotic use in early pregnancy and the risk of stillbirth, preterm birth, and small for gestational age: a nationwide, population-based cohort study in Taiwan. Lancet Psychiatry. 2023;10:499-508.

    Small Elsevier Logo

    Cookies are used by this site. To decline or learn more, visit our cookie notice.

    Copyright © 2024 Elsevier, its licensors, and contributors. All rights are reserved, including those for text and data mining, AI training, and similar technologies.

    Small Elsevier Logo
    RELX Group