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Introduction to Sleep and Stress

Sleep plays a critical role in maintaining health and well-being, including cognitive performance, physiological processes, emotional regulation, physical development, and quality of life. Many biological processes occur during sleep that allow the brain to reorganize neuronal cell connections, process memories and remove waste.¹ In addition, the body uses sleep to repair cells, fight infection, restore energy, and regulate hormone production.¹ A good night’s sleep lets the mind and body wake refreshed and ready to start the day.

Appropriate sleep duration varies by age. The National Sleep Foundation recommends adults between 18 and 64 years of age get 7 to 9 hours of sleep each night.² The American Academy of Sleep Medicine and Sleep Research Society consensus statement recommends adults 18 to 60 years of age sleep 7 or more hours each night to promote optimal health.³ Infants, toddlers, and preschool-aged children need considerably more sleep. Both the National Sleep Foundation and American Academy of Sleep Medicine provide similar recommendations for sleep duration for children and adolescents.^2,4 See Table 1 for the recommended hours of sleep per night based on age group.

American adults get an average of 6.9 hours of sleep on workdays and an average of 7.6 hours of sleep on non-workdays.⁵ Work schedules, everyday stressors, a disruptive sleep environment, and medical conditions can prevent getting adequate sleep.⁶ Chronic lack of sleep may be the initial sign of a sleep disorder.⁶

Insomnia is a complaint of trouble falling or staying asleep that is associated with daytime dysfunction despite a sufficient sleep environment and adequate opportunity to sleep.⁷ Insomnia is classified as short-term (symptoms occur for < 3 months), chronic (symptoms occur ≥ 3 times per week for ≥ 3 months), or other.⁷ Short-term insomnia is estimated to affect 30% to 50% of the population, whereas chronic insomnia affects 5% to 10% of industrialized nation populations.⁷ Risk factors for insomnia include increasing age, female sex, shift work, medical conditions, and psychiatric disorders.^5,7 If short-term insomnia is not treated appropriately, it may progress into chronic insomnia.

Insomnia is associated with negative impacts on function, health, and cost to society. Increased rates of work absenteeism and motor vehicle or work-related accidents have been reported with insomnia.⁷ Drowsy driving is responsible for 886 to 6000 fatal motor vehicle accidents every year in the United States.^8,9 In addition, those with severe insomnia are 7 times more likely to have work-related accidents.⁹ Insomnia has been linked with mental health disorders (mood disorders, depression, use of alcohol) and cardiovascular disease.⁷ Insomnia imposes significant economic burden. Direct costs are estimated at $2 to $16 billion per year related to increased emergency department and healthcare office visit utilization as well as increased cost for prescription medications.⁷ Indirect costs are estimated at $75 to $100 billion per year related to work absenteeism, lost productivity, and work-related accidents.⁷

Stress and insomnia have a cyclical relationship. An increase in day-to-day stress can contribute to insomnia and lack of proper sleep can exacerbate stress. Many Americans are experiencing stress as a result of the coronavirus disease 2019 (COVID-19) pandemic. The American Psychological Association conducted an online survey to determine how individuals were coping with the stress of the pandemic. The survey found the overall stress level for adults 18 years and older in the United States was 5.4 (10-point Likert scale; 1 = little to no stress, 10 = a great deal of stress).¹⁰ This is significantly higher compared to 4.9 in 2019.¹⁰ When asked specifically about stress level related to the COVID-19 pandemic, the average was 5.9.¹⁰ Parents of children younger than 18 years of age reported a stress level of 6.7 over the past month during the pandemic.¹⁰

The COVID-19 pandemic stress also affected sleep. A meta-analysis was conducted to assess the prevalence of sleep disorders among the general population, healthcare workers, and patients with COVID-19 as a result of the pandemic. According to the review, the overall rate of sleep problems in all populations was 35.7%.¹¹ Patients with active COVID-19 were affected the most with a prevalence of 74.8%.¹¹ Healthcare workers reported rates of sleep problems of 36%, while the general public had a rate of 32.3%.¹¹

Pathophysiology

Sleep consists of 4 progressive cycles. During a sleep cycle, there is a slow transition from the first 3 stages of sleep (known as non-rapid-eye movement [NREM] or non-REM sleep), to the fourth stage, known as rapid-eye movement (REM) sleep. The stages of sleep are differentiated by the type of brain waves measured by the electroencephalogram (EEG). Typically, an adult transitions through 4 to 6 sleep cycles per night.¹² Initial sleep cycles are shorter ranging from 70 to 100 minutes in length, while later sleep cycles are longer ranging from 90 to 120 minutes in length.¹² NREM sleep makes up about 75% to 80% of each sleep cycle.⁶ See Table 2 for a description of the stages of sleep. Failure to obtain enough of each stage of sleep may explain the adverse effects of insufficient sleep on health, emotions, and well-being.

Circadian rhythms are 24-hour cycles used by the body to regulate various processes. The most well-known is the sleep-wake cycle. Various centers in the brain balance each other to promote sleep and wakefulness using reciprocal systems in a feedback loop. Various neurotransmitters are involved in the signaling process. Excitatory neurotransmitters such as norepinephrine and dopamine promote wakefulness whereas inhibitory neurotransmitters such as gamma-aminobutyric acid (GABA) and galanin promote sleep.¹³ Serotonin regulates both sleep and wakefulness.¹³ Light is an external cue that provides the most powerful influence on the sleep-wake cycle.⁶ As darkness falls, the body produces the hormone melatonin that promotes sleep.⁶ Light suppresses the production of melatonin.⁶

Common Sleep Measures

Sleep quality is the measurement used to determine if sleep is restorative and restful. Four items are assessed to measure sleep quality. Sleep latency, or sleep onset latency, is the amount of time it takes to fall asleep. While the time it takes to fall asleep varies, the average for adults is approximately 10 to 20 minutes.¹⁴ Falling asleep within 30 minutes suggests good quality of sleep.¹⁵ Sleep waking is the number of times one wakes up during the night. Frequent wakefulness can disrupt sleep resulting in decreased sleep quality. Waking up zero to one time per night suggests good quality of sleep.¹⁵ Wakefulness, or wake after sleep onset (WASO), is the amount of time, measured in minutes, that one is awake during the night after initially going to sleep. Twenty minutes or less of wakefulness during the night suggests good quality of sleep.¹⁵ Sleep efficiency is the percent of time spent sleeping while in bed, which should be 85% or more for good quality sleep.¹⁵

Treatment of Stress and Sleep Complaints

When a patient presents with complaints of insomnia, it is important to rule out or address other potential causes such as other sleep disorders, adverse effects of medications, substance abuse, and depression before treating as insomnia. Narcolepsy is characterized by excessive daytime sleepiness combined with sudden muscle weakness.¹⁶ Restless legs syndrome (RLS) is characterized by an unpleasant sensation originating in the lower legs that is relieved by movement and often causes difficulty initiating sleep.¹⁶ Sleep apnea is characterized by brief periods in which breathing stops and starts resulting in interruptions of sleep and subsequently daytime sleepiness.¹⁶

The goals of treating insomnia are to improve the patient’s symptoms, quality of life, functional status, and sense of well-being.⁵ This is achieved through management of concomitant medical conditions, modification of medications and substances that exacerbate insomnia, and optimization of the sleeping environment. Specific treatments for insomnia are divided into two categories; nonpharmacologic (sleep hygiene and cognitive behavioral therapy) and pharmacological (nonprescription and prescription medications).

Nonpharmacologic Treatments

Sleep hygiene is the development of a consistent routine, lifestyle habits, and conducive environment to optimize uninterrupted sleep on a regular basis. See Table 3 for a list of sleep hygiene practices. Test different sleep hygiene practices to determine what helps the most. Sleep hygiene can improve sleep but may not resolve chronic insomnia or sleep disorders in which other treatments are needed. Clinical practice guidelines recommend using sleep hygiene practices in combination with other treatments rather than as stand-alone interventions because they are less effective than cognitive behavioral therapy.¹⁷

Cognitive behavioral therapy for insomnia (CBT-I) is considered first-line therapy for all patients because it has more durable benefit with less adverse effects compared to pharmacological therapy.^13,19 CBT-I addresses the dysfunctional behaviors and beliefs that contribute to insomnia.¹⁹ Components of CBT-I include sleep restriction, stimulus control, cognitive therapy, relaxation therapy, and sleep hygiene education.¹⁹

A systematic review and meta-analysis of randomized, controlled trials of CBT-I involving persons with insomnia without concomitant conditions found significant effects on various aspects of sleep quality. Sleep onset latency improved by 19 minutes (95% CI 14.12, 23.93).²⁰ WASO improved by 26 minutes (95% CI 15.48, 36.52).²⁰ Total sleep time improved by approximately 8 minutes (95% CI 0.51, 15.74).²⁰ Sleep efficiency improved by around 10% (95% CI 8.09%, 11.73%).²⁰

CBT-I demonstrated similar short-term efficacy when compared to benzodiazepine-receptor agonists in persons with insomnia without concomitant conditions.¹⁹ However, CBT-I was superior when assessed 6 to 12 months after treatment as the benzodiazepine-receptor agonists did not have sustained benefit after discontinuation.¹⁹ In addition, CBT-I has demonstrated efficacy for persons with insomnia with concomitant medical conditions and psychiatric disorders including, chronic pain, fibromyalgia, breast cancer, perimenopausal women with vasomotor symptoms, depression, alcohol dependence, and post- traumatic stress disorder.¹³

Despite the evidence of benefit with CBT-I, a barrier to implementation is the lack of providers with sufficient expertise. This is being addressed by the use of shorter courses of therapy and internet-based CBT-I rather than face-to-face methods.¹⁹ Although evidence is limited, brief therapies show clinically meaningful improvements in several sleep outcomes and require limited resources.¹⁷

Pharmacological Treatments

Nonprescription medications

The only nonprescription medication included in the Food and Drug Administration (FDA) over-the-counter (OTC) sleep aid monograph is diphenhydramine in the hydrochloride and citrate salt forms.²¹ Although many OTC sleep aids contain doxylamine, few studies support its efficacy.⁵ Still, the FDA has allowed the drug to remain on the OTC market. See Table 4 for a comparison of diphenhydramine and doxylamine.

Diphenhydramine

Diphenhydramine is a histamine 1 receptor antagonist. It is indicated for the relief of occasional sleeplessness in persons 12 years of age and older who have difficulty falling asleep.²¹ Tolerance to the sedative effect of diphenhydramine develops within days of repeated use; therefore, efficacy in patients with chronic insomnia is poor.²⁴ When using for short-term insomnia, patients should be counseled to have an “off” night after 3 consecutive nights of use to reduce tolerance.⁵

A limited number of studies have been conducted to assess the efficacy of diphenhydramine as a sleep aid. A systematic review identified 3 randomized controlled trials that met inclusion criteria. These studies compared use of diphenhydramine 50 mg to placebo as a single dose or multiple doses over 2 weeks.²⁴ The review data failed to demonstrate consistent positive improvements on self-reported and objective sleep measures such as sleep onset latency, sleep efficiency, and total sleep time. Although differences in objective sleep measures were recorded, each fell below the clinical and statistical significance thresholds.²⁴

The American Academy of Sleep Medicine Clinical Practice Guidelines for Treatment of Chronic Insomnia, last updated in 2017, provide a summary of the data of diphenhydramine 50 mg. This includes: sleep latency improved by 8 minutes (95% CI -17, +2) and total sleep time improved by 12 minutes (95% CI -13, +38), with no improvement in quality of sleep.⁷ The confidence intervals suggest that these improvements are not statistically significant but may be clinically significant to the patient. The American Academy for Sleep Medicine does not recommend the use of diphenhydramine as a treatment for sleep onset and sleep maintenance insomnia in adults with chronic insomnia.⁷

The most common adverse effects of diphenhydramine are sedation (indication in this case) and anticholinergic effects.²² Additive sedation may occur with concomitant use of alcohol or other CNS depressants. Patients should be counseled to avoid driving or other tasks that require full attention. Anticholinergic effects include dry eyes or blurred vision, dry mouth, urinary retention, and constipation. Additive anticholinergic effects can occur when diphenhydramine is taken with other medications having these properties.

Diphenhydramine should be used with caution in patients with various medical conditions. Anticholinergic medications, including diphenhydramine, can increase intraocular pressure; therefore, patients with glaucoma should avoid diphenhydramine.^5,22 Anticholinergic agents can also cause urinary retention; therefore, patients with prostatic hyperplasia or urinary obstruction should avoid diphenhydramine.^5,22 Patients with cardiovascular disease and hyperthyroidism should be counseled to use diphenhydramine with caution as hypotension and arrhythmias can be associated with overdose.^5,22 Patients with pyloroduodenal obstruction should use diphenhydramine with caution due to reduced gastric emptying.²² In addition, patients with asthma should use diphenhydramine with caution as drying of mucus can lead to thickening of respiratory secretions and a subsequent asthma exacerbation.²²

Diphenhydramine is listed as a Potentially Inappropriate Medication for Older Adults in the 2019 American Geriatrics Society Beers Criteria.²⁵ The American Geriatrics Society recommends avoiding use of diphenhydramine and all first-generation antihistamines in older adults. Combinations of anticholinergic medication use in patients with dementia may worsen cognitive decline.

Dietary Supplements

Melatonin

Melatonin is an endogenous hormone produced by the pineal gland in the brain. Melatonin acts physiologically to regulate the circadian rhythms and sleep. Melatonin is released in response to darkness and suppressed by light. Although melatonin does not cause “sleepiness,” exogenous melatonin, used as a dietary supplement, is believed to promote sleep. A variety of doses have been studied for insomnia. This ranges from 0.1 mg to 10 mg of immediate- or sustained-release formulations taken orally within 2 hours prior to bedtime.²⁶ Common doses included in studies are 0.3 to 5 mg with 2 mg being the most frequent.^7,27

Studies on the efficacy of melatonin for the treatment of insomnia are highly variable. A meta-analysis conducted by Ferracioli-Oda et al found statistically significant improvements in objective measures of sleep with the use of melatonin.²⁸ Sleep latency improved by approximately 7 minutes (95% CI 4.37, 9.75; P < 0.001) and total sleep time increased by 8.25 minutes (95% CI 1.74, 14.75; P = 0.013) both of which were statistically significant.²⁸ Patients reported improvement in sleep quality (0.22 [95% CI: 0.12-0.32]; P < 0.001).²⁸ In this case, sleep quality was measured by standardized mean difference compared to placebo with the results being statistically significant.²⁸ The researchers considered the potential influence of dose and duration of melatonin therapy when performing the analysis. Trials with longer duration (56-126 days) and using higher doses of melatonin (5 mg) demonstrated greater effects on decreasing sleep latency and increasing total sleep time. The authors concluded that the benefit of melatonin vs placebo is small compared to other pharmacological treatments.²⁸

The American Academy of Sleep Medicine Clinical Practice Guidelines for Treatment of Chronic Insomnia provide a summary of the data for use of melatonin 2 mg in older adults (> 55 years). Meta-analysis was only achievable for sleep quality. This includes: sleep latency improvement of 9 minutes (95% CI 2, 15) with 0.21 (95% CI -0.26, +0.77) improvement in quality of sleep.⁷ The small improvement in quality of sleep was not considered statistically or clinically significant. The American Academy for Sleep Medicine does not recommend the use of melatonin as a treatment for sleep onset and sleep maintenance insomnia in adults with chronic insomnia.⁷

The most common adverse effects associated with melatonin include drowsiness, headache, daytime sleepiness, and nausea.²⁶ Drowsiness may be experienced within 30 minutes after taking melatonin and may persist for approximately 1 hour; as a result, patients should be counseled about avoiding driving or other tasks that require full attention until they know how melatonin will affect them.²⁹ Additive sedation may occur with concomitant use of alcohol or other CNS depressants.

Valerian

Valerian is a plant with the roots and rhizomes being used for medicinal purposes. Valerian is thought to act by binding to GABA receptors in the brain.³⁰ Doses of 400 mg to 600 mg per day taken 1 hour before bedtime for 2 to 4 weeks have been studied in clinical trials.³⁰

Limited quality evidence is available describing the efficacy of valerian in short-term insomnia. Meta-analyses have been difficult to perform because different doses and statistical measures have been used. One study found sleep latency approaching clinical significance with a reduction of 9.29 minutes (95% CI -0.27, -18.3).⁷ However, in the same study, patient-reported sleep latency increased by +3.77 minutes (95% CI -4.47, +12.01).⁷ This contradiction weakens the quality of evidence. Other studies of valerian did not find clinically significant changes in other objective sleep measures such as total sleep time, sleep efficiency, and number of awakenings.⁷ The American Academy for Sleep Medicine does not recommend the use of valerian as a treatment for sleep onset and sleep maintenance insomnia in adults with chronic insomnia.⁷

A more recent systematic review and meta-analysis of clinical studies using valerian to update available data was published in 2020.³¹ The review found data difficult to combine as the study doses, populations, concomitant health conditions, and sleep outcome measures varied greatly. The review notes that the various formulations of valerian available and the standardization of potential active ingredients within those formulations may contribute to the wide range of effectiveness data.³¹ No serious adverse events were found in this review and the authors concluded that valerian is safe for use in adult patients.³¹

The most common adverse effects associated with valerian include headache and diarrhea, and morning drowsiness is rarely reported.³⁰ Overall, data support that valerian has a wide margin of safety, with limited adverse effects. Additive sedation may occur with concomitant use of alcohol or other CNS depressants.

L-tryptophan

L-tryptophan is an essential amino acid that is a precursor to serotonin. Studies have used doses ranging from 250 mg per day to greater than 1 g per day.^7,32

A recent systematic review, meta-analysis, and meta-regression identified 18 articles for review. Overall analysis suggested that tryptophan can shorten WASO (-81.03 min/g, P = 0.017; 95% CI -1.89, -0.28).³² The meta-regression analysis found that doses of tryptophan greater than 1 gram had a reduced WASO compared to those taking less than 1 gram (56.55 vs 28.91 min, respectively, P = 0.001).³² The study authors note that other measures of sleep quality were not affected.

The American Academy for Sleep Medicine found only one study with adequate data for review therefore no meta-analysis was possible.⁷ While a couple sleep measures demonstrated improvement (total sleep time, WASO), none met criteria for clinical significance.⁷ The American Academy for Sleep Medicine does not recommend the use of L-tryptophan as a treatment for sleep onset and sleep maintenance insomnia in adults with chronic insomnia.⁷

Studies available on the use of L-tryptophan have not included reports of adverse effects.⁷ Since L-tryptophan is related to serotonin, there are concerns about increased risk of serotonin syndrome when used with serotonergic medications.

Role of the Pharmacist in Addressing Patient Stress and Sleep Complaints

When a patient presents with insomnia, it is important to complete a comprehensive sleep history to determine if the patient is a self-care candidate. The sleep history should include pertinent questions from the SCHOLAR MAC acronym.³³ See Table 5 for an explanation of the SCHOLAR MAC acronym.

Important considerations include the onset of sleep problems, medications, and lifestyle factors. The pharmacist will need to determine if the patient is experiencing short-term or chronic insomnia. Nonprescription sleep aids are not indicated for chronic insomnia; thus, medical referral would be required. The pharmacist should assess the medications the patient is currently taking—looking for those can have an impact on sleep.

In addition, the pharmacist should determine if any lifestyle factors could be considered as aggravating or remitting factors. Stimulants such as caffeine or nicotine used prior to bedtime can have an impact on sleep. Alcohol may initially improve sleep latency, but the effect wears off quickly resulting in disrupted sleep later in the night. The pharmacist can also assess and correct any sleep hygiene practices.

After obtaining a sleep history, it should be determined if the patient has any exclusions to self-care. These include: age less than 12 years, pregnancy, breast feeding, heart disease, anxiety disorders, medication-induced drowsiness, and chronic fatigue for 6 months or longer.⁵ If any exclusions to self-care are present, the patient should receive a medical referral.

Since dietary supplements are regulated differently from OTC drugs, concerns about efficacy, safety, and quality assurance are possible. When recommending dietary supplements, the pharmacist should select products from manufacturers that are reputable and employ the use of Current Good Manufacturing Practice. In addition, several organizations have developed quality assurance programs to certify dietary supplement composition. One such organization is the United States Pharmacopeia (USP). USP started a voluntary dietary supplement verification program.³⁴ The USP seal indicates to consumers that the dietary supplement product contents within the bottle match those on the label.³⁴ However, efficacy or safety of the product is not addressed by third party verification programs.

Summary

If the patient is determined to have short-term insomnia and is an appropriate candidate for self-care, sleep hygiene measures and CBT-I is recommended as first-line therapy. The pharmacist can follow up in 10 days. If insomnia is not resolved, a short course of diphenhydramine 50 mg by mouth 30 to 60 minutes prior to bedtime may be recommended. The pharmacist should follow up after 3 nights. If insomnia is not resolved, medical referral is necessary.

References

1. Nunez K, Lamoreux K. What Is the Purpose of Sleep? Healthline website. Available at: https://www.healthline.com/health/why-do-we-sleep. Updated July 20, 2020. Accessed December 9, 2021.
2. Hirshkowitz M, Whiton K Albert S, et al. National Sleep Foundation’s updated sleep duration recommendations: final report. Sleep Health. 2015;1(4):233-243.
3. Watson NF, Badr MS, Belenky G, et al. Recommended amount of sleep for a healthy adult: a joint consensus statement of the American Academy of Sleep Medicine and Sleep Research Society. Sleep. 2015;38(6):843–844.
4. Paruthi S, Brooks LJ, D'Ambrosio C, et al. Recommended amount of sleep for pediatric populations: a consensus statement of the American Academy of Sleep Medicine. J Clin Sleep Med. 2016;12(6):785–786.
5. Eisenhower C. Insomnia, Drowsiness, and Fatigue. In: Krinsky DL, Ferreri SP, Hemstreet BA, Hume AL, Newton GD, Rollins CJ, Tietze KJ, eds. Handbook of Nonprescription Drugs: An Interactive Approach to Self-Care. Washington, DC: American Pharmacists Association; 2020:887-904.
6. Pacheco D. Why Do We Need Sleep? Sleep Foundation website. Available at: https://www.sleepfoundation.org/how-sleep-works/why-do-we-need-sleep. Updated November 30, 2021. Accessed December 9, 2021.
7. Sateia M, Buysse D, Krystal A, et al. Clinical practice guidelines for the pharmacologic treatment of chronic insomnia in adults: An American Academy of Sleep Medicine Clinical Practice Guideline. J Clin Sleep Med. 2017;13(2):307-349.
8. Drowsy Driving. Centers for Disease Control and Prevention website. Available at: https://www.cdc.gov/sleep/about_sleep/drowsy_driving.html. Updated March 21, 2017. Accessed November 20, 2021.
9. Suni E. Sleep Statistics. Sleep Foundation website. Available at: https://www.sleepfoundation.org/how-sleep-works/sleep-facts-statistics. Updated November 12, 2021. Accessed November 20, 2021.
10. Stress in America 2020. American Psychological Association website. Available at: https://www.apa.org/news/press/releases/stress/2020/report. Updated May 2020. Accessed November 20, 2021.
11. Jahrami H, BaHammam A, Bragazzi N, et al. Sleep problems during the COVID-19 pandemic by population: a systematic review and meta-analysis. J Clin Sleep Med. 2021;17 (2):299-313.
12. Suni E. Stages of Sleep. Sleep Foundation website. Available at: https://www.sleepfoundation.org/how-sleep-works/stages-of-sleep. Updated October 11, 2021. Accessed November 20, 2021.
13. Dopheide J. Insomnia overview: epidemiology, pathophysiology, diagnosis and monitoring, and nonpharmacologic therapy. Am J Manag Care. 2020;26 (4 Suppl):S76-S84.
14. Pacheco D. Sleep Latency. Sleep Foundation website. Available at: https://www.sleepfoundation.org/how-sleep-works/sleep-latency. Updated August 26, 2021. Accessed November 20, 2021.
15. What is Sleep Quality? National Sleep Foundation website. Available at: https://www.thensf.org/what-is-sleep-quality/. Updated October 28, 2020. Accessed November 20, 2021.
16. Key Sleep Disorders. Centers for Disease Control and Prevention website. Available at: https://www.cdc.gov/sleep/about_sleep/key_disorders.html. Updated December 10, 2014. Accessed November 20, 2021.
17. Edinger JD, Arnedt JT, Bertisch SM, et al. Behavioral and psychological treatments for chronic insomnia disorder in adults: an American Academy of Sleep Medicine clinical practice guideline. J Clin Sleep Med. 2021;17(2):255-262.
18. Suni E. Sleep Hygiene. Sleep Foundation website. Available at: https://www.sleepfoundation.org/sleep-hygiene. Updated August 14, 2020. Accessed November 19, 2021.
19. Winkelman J. Insomnia disorder. N Engl J Med. 2015;373(15):1437-1444.
20. Trauer J, Qian M, Doyle J, et al. Cognitive behavioral therapy for chronic insomnia: a systematic review and meta-analysis. Ann Intern Med. 2015;163(3):191-204.
21. US Food and Drug Administration. Nighttime sleep-aid drug products for over-the-counter human use; final monograph. Code of Federal Regulations. Title 21, Part 338. Available at: https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/cfrsearch.cfm?cfrpart=338&showfr=1. Updated October 1, 2021. Accessed November 20, 201.
22. Drug facts and comparisons. Facts & Comparisons [database online]. St. Louis, MO: Wolters Kluwer Health, Inc. Updated November 11, 2021. Accessed November 20, 2021.
23. Drug facts and comparisons. Facts & Comparisons [database online]. St. Louis, MO: Wolters Kluwer Health, Inc. Updated November 15, 2021. Accessed November 20, 2021.
24. Culpepper L, Wingertzahn M. 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.
25. 2019 American Geriatrics Society Beers Criteria Update Expert Panel. American Geriatrics Society 2019 Updated AGS Beers Criteria for Potentially Inappropriate Medication Use in Older Adults. J Am Geriatr Soc. 2019;67(4):674-694.
26. Savage R, Safar N, Yohannan S, et al. Melatonin. StatPearls [internet]. Available at: https://www.ncbi.nlm.nih.gov/books/NBK534823/. Updated August 15, 2021. Accessed November 20, 2021.
27. McQueen CE, Orr KK. Natural Products. In: Krinsky DL, Ferreri SP, Hemstreet BA, Hume AL, Newton GD, Rollins CJ, Tietze KJ, eds. Handbook of Nonprescription Drugs: An Interactive Approach to Self-Care. Washington, DC: American Pharmacists Association; 2020:1001-1041.
28. Ferracioli-Oda E, Qawasmi A, Bloch M. Meta-analysis: melatonin for the treatment of primary sleep disorders. PLoS One. 2013;8(5):e63773.
29. Natural Products Database. Facts & Comparisons [database online]. St. Louis, MO: Wolters Kluwer Health, Inc. Updated September 30, 2021. Accessed November 20, 2021.
30. Natural Products Database. Facts & Comparisons [database online]. St. Louis, MO: Wolters Kluwer Health, Inc. Updated February 24, 2021. Accessed November 20, 2021.
31. Shinjyo N, Waddell G, Green J. Valerian root in treating sleep problems and associated disorders – a systematic review and meta-analysis. J Evid Based Integr Med. 2020;25:2515690X20967323.
32. Sutanto CN, Loh WW, Kim JE. The impact of tryptophan supplementation on sleep quality: a systematic review, meta-analysis, and meta-regression. Nutr Rev. 2021; nuab027.
33. Divine M, McIntosh T. Pharmacists’ patient care process in self-care. In: Krinsky DL, Ferreri SP, Hemstreet BA, Hume AL, Newton GD, Rollins CJ, Tietze KJ, eds. Handbook of Nonprescription Drugs: An Interactive Approach to Self-Care. Washington, DC: American Pharmacists Association; 2020:17-42.
34. Tsourounis C, Dennehy C. Introduction to dietary supplements. In: Krinsky DL, Ferreri SP, Hemstreet BA, Hume AL, Newton GD, Rollins CJ, Tietze KJ, eds. Handbook of Nonprescription Drugs: An Interactive Approach to Self-Care. Washington, DC: American Pharmacists Association; 2020:987-1000.

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