Continuing Education

Continuing Education: Insomnia across the lifespan

Healthcare providers (HCPs) caring for women of any age will find that a substantial proportion of them have difficulty falling and/or staying asleep. When insomnia interferes with their daily life and causes distress, they may seek professional help. This article provides background information about sleep, and offers HCPs useful and up-to-date information regarding the evaluation of patients presenting with sleep problems and the wide variety of treatments that are available.

Faculty: Wendy L. Wright, DNP, ANP-BC, FNP-BC, FAANP, FAAN, FNAP, is owner of Wright & Associates Family Healthcare @ Amherst and @ Concord and is the owner of Partners in Healthcare Education, a medical education company.

Intended audience: This continuing education (CE) activity has been designed to meet the educational needs of women’s health nurse practitioners (NPs), adult NPs, family NPs, certifi ed nurse midwives (CNMs), and other healthcare providers (HCPs) who care for women.

CE approval period: Now through June 30, 2021

Estimated time to complete this activity: 1 hour

CE approval hours: 1.0 contact hour of CE credit, including 1.0 contact hour of pharmacology content

Goal statement: HCPs will increase their clinical skills in the evaluation and nonpharmacologic and pharmacologic management of patients presenting with sleep problems.

Needs assessment: Among adults in the United States, about 30% have symptoms of insomnia on occasion and 6%-10% have chronic insomnia meeting DSM-V criteria, including the all-important element of dissatisfaction with one’s sleep. HCPs who provide primary care to women need to inquire about sleep problems and understand the many treatment options available to women with impaired sleep.

Educational objectives: At the conclusion of this educational activity, participants should be able to:

  1. discuss the incidence and prevalence of insomnia across the lifespan;
  2. identify the appropriate work-up of the individual with insomnia; and
  3. describe nonpharmacologic and pharmacologic treatment options for the patient with insomnia.

Accreditation statement: This activity has been evaluated and approved by the Continuing Education Approval Program of the National Association of Nurse Practitioners in Women’s Health (NPWH), and has been approved for 1.0 contact hour of CE credit, including 1.0 contact hour of pharmacology content.

Faculty disclosures: NPWH policy requires all faculty to disclose any affiliation or relationship with a commercial interest that may cause a potential, real, or apparent conflict of interest with the content of a CE program. NPWH does not imply that the affiliation or relationship will affect the content of the CE program. Disclosure provides participants with information that may be important to their evaluation of an activity. Faculty are also asked to identify any unlabeled/unapproved uses of drugs or devices made in their presentation. Wendy L. Wright, DNP, ANP-BC, FNP-BC, FAANP, FAAN, FNAP, receives consulting fees from Merck, Pfizer, and Sanofi – vaccines.

Disclosure of unlabeled use: NPWH policy requires authors to disclose to participants when they are presenting information about unlabeled use of a commercial product or device or an investigational use of a drug or device not yet approved for any use.

Disclaimer: Participating faculty members determine the editorial content of the CE activity; this content does not necessarily represent the views of NPWH. This content has undergone blinded peer review for validation of clinical content. Although every effort has been made to ensure that the information is accurate, HCPs are responsible for evaluating this information in relation to generally accepted standards in their own communities and integrating the information in this activity with that of established recommendations of other authorities, national guidelines, FDA-approved package inserts, and individual patient characteristics.

Successful completion of the activity: Successful completion of this activity, J-19-02, requires participants to:

  1. Log on to npwh.org/courses/home/details/1266 and “Sign In” at the top right-hand corner of the page if you have any NPWH account. You must be signed in to receive credit for this course. If you do not remember your username or password, please follow the “Forgot Password” link and instructions on the sign-in page. If you do not have an account, please click on “Create an Account.”*
  2. Read the learning objectives, disclosures, and disclaimers on the next page
  3. Study the material in the learning activity during the approval period (now through June 30, 2021).
  4. Complete the post-test and evaluation. You must earn a score of 70% or better on the post-test to receive CE credit.
  5. Print out the CE certificate if successfully completed.

*If you are an NPWH member, were once a member, or have taken CE activities with NPWH in the past, you have a username and password in our system. Please do not create a new account. Creation of multiple accounts could result in loss of CE credits as well as other NPWH services. If you do not remember your username or password, please either click on the “Forgot Username” or “Forgot Password” link above or call the NPWH office at (202) 543-9693, ext. 1.

Commercial support: This activity is supported by an educational grant from Merck.

The American Academy of Sleep Medicine (AASM) defines insomnia as a complaint of trouble initiating/ maintaining sleep that is associated with daytime consequences and that is not attributable to environmental circumstances or an inadequate opportunity to sleep.1 According to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-V), insomnia is characterized by difficulty initiating and/or maintaining sleep and/or waking earlier than desired, occurring at least 3 nights per week for at least 3 months, and causing dissatisfaction with sleep.2 Unlike in days past, when insomnia was classified as a condition secondary to another diagnosis, it is now considered an entity of its own.

The DSM-V lists insomnia among 10 other sleep–wake disorders.2 Healthcare providers (HCPs) may need to rule out other sleep–wake disorders (e.g., obstructive sleep apnea, circadian rhythm sleep–wake disorder, restless leg syndrome [RLS]) before making a definitive diagnosis of insomnia in a given patient.

Prevalence and adverse consequences

Among adults in the United States, about 30% have symptoms of insomnia on occasion and 6%-10% have chronic insomnia meeting DSM-V criteria, including the all-important element of dissatisfaction with one’s sleep.3,4 Insomnia is more common in women than in men, in older adults than in younger adults, and in persons affected by co-morbid physical or mental health conditions than in persons in the general population.1,4

Chronic insomnia, defined as insomnia lasting longer than 3 months, has many adverse effects on daily functioning, health, and quality of life.1 It is linked to increased rates of work absenteeism and occupational and motor vehicle accidents, and it has been identified as a major risk factor for developing psychiatric disorders, especially mood disorders; for relapse among persons with depression or alcoholism; for adverse effects in persons with chronic health conditions; and for development of hypertension and cardiovascular disease.1

Background information about sleep

The typical adult falls asleep within 30 minutes of going to bed. If she awakens in the middle of the night, it generally takes 30 minutes or less for her to fall back to sleep. A full night’s sleep lasts 7-8 hours. Her sleep efficiency—the amount of time asleep relative to the amount of time spent in bed—is about 85%.

The sleep-wake cycle

Wakefulness and sleep are under the control of highly complex neural circuitry consisting of neuronal populations, neurotransmitters, and pathways that form orchestrated wake- or sleep-promoting networks.5 Neurotransmitters involved in wakefulness include dopamine, norepinephrine, serotonin, acetylcholine, histamine, and orexin,6 the lattermost of which was identified in 1998 and has been found to play a critical role in maintaining wakefulness.7 Neurotransmitters involved in sleep promotion include adenosine, GABA, melatonin, and galanin.6 The role of these neurotransmitters is particularly relevant in that the medications used to treat insomnia either activate sleep-promoting neurotransmitters or suppress wakefulness-promoting neurotransmitters.

Effect of life stage on sleep

Life stages in women, including pregnancy, menopause, and older age, can have major effects on sleep quality, duration, and efficiency.

Pregnancy

Increased rhinorrhea, low back discomfort, need for an altered sleep position, fetal movements, heartburn, RLS-type symptoms, and shortness of breath can disturb sleep during pregnancy.8,9

Menopause

According to The North American Menopause Society, sleep disturbances occur mainly in women bothered by nighttime hot flashes, although a firm cause-and-effect relationship has not been established.10 Other contributors to insomnia during this life stage include general aging effects, stress, negative mood, and hormonal changes.10

Aging

Alterations in sleep architecture that occur as a part of normal aging, including a decrease in total sleep time and increases in arousals and awakenings secondary to lighter and more fragmented sleep, contribute to sleep problems such as insomnia in older persons.11 Other factors contributing to insomnia in older adults include co-morbid physical and mental health conditions and the medications used to treat them, changes in lifestyle and schedule, and altered circadian rhythm. Insomnia in older adults is typically characterized by difficulty sleeping through the night or waking up too early, as opposed to difficulty falling asleep.4

Screening

Unless HCPs specifically ask a patient about her sleep habits during a wellwoman visit or a patient broaches the topic herself—perhaps as she is about to leave the exam room— they may not learn about any sleep problems she is having. But a sleep problem such as insomnia, especially if chronic and distressful, merits a workup and treatment in many cases.

Even in a busy office setting, HCPs can start with a two-question screen: Do you experience difficulty sleeping? If so, do you have difficulty falling or staying asleep? To elicit more information, HCPs can then ask: Are you dissatisfied with your sleep? Do you suffer daytime fatigue? Affirmative answers to any or all of these questions suggest a diagnosis of insomnia, and may determine the type of treatment needed.

Another screening option is the BEARS Sleep Assessment Tool.12 Initial letters of the acronym stand for Bedtime problems (e.g., Does the patient have difficulty falling asleep?); Excessive daytime drowsiness; Awakenings during the night (e.g., Is the patient making frequent trips to the bathroom? Is she being interrupted by a crying baby or a sick child?); Regularity and duration of sleep; and Sleep-disordered breathing (e.g., Does the patient have obstructive sleep apnea?).

Workup: Taking a targeted history

For a patient whose screening responses suggest she may have a sleep disorder, HCPs should ask these questions (if not posed during initial screening): Do you suffer from daytime fatigue? Do you snore or have episodes where you stop breathing when you sleep (based on the report of someone sharing your bedroom or your bed)? How many hours are you in bed each night? How many hours do you sleep each night? Do you feel refreshed upon awakening and throughout the next day? Do you have restless leg symptoms? Do you ever sleepwalk or have vivid dreams?

In addition, HCPs should ask the patient about alcohol or illicit drug use, which can have profound effects on sleep. HCPs should also consider aspects of her current health that may be affecting her sleep; common offenders include overactive bladder, chronic pain, mental health disorders, fibromyalgia, hyperthyroidism, perimenopause, and RLS. In patients complaining of RLS-type symptoms, HCPs should consider checking a ferritin level. RLS can be associated with iron-deficiency anemia and ferritin levels below 50 ng/mL.13

If a patient does have ongoing health problems, HCPs should inquire about the over-the-counter (OTC) and prescription medications she is using to treat them. Commonly used medications that can disturb sleep include selective serotonin reuptake inhibitors, dopamine agonists, amphetamines, anticonvulsants, decongestants, corticosteroids, beta agonists, theophylline, antihypertensives, diuretics, and appetite suppressants.14 In addition, HCPs should ask the patient which treatments, including alcohol, marijuana, OTC preparations, and prescription drugs, she has tried to help her sleep.

Some patients may have sleepstate misperception; they believe that they are awake much of the night but are actually asleep for a normal period of time. They think that it takes them an abnormally long time to fall asleep (even though it does not) and/or they underestimate how long they remain asleep. To identify this misperception, or to better understand the nature of any patient’s sleep problem, HCPs can recommend a home sleep study.

Home sleep study

This study, conducted primarily to check for obstructive sleep apnea (OSA) with a small, portable monitor, measures oxygen saturation, heart rate, airflow, and movement in the chest and abdomen, and records time spent snoring and sleep position. The AASM recommends its use for the diagnosis of OSA in uncomplicated adult patients presenting with signs and symptoms indicating an increased risk of OSA.15 HCPs can incorporate the use of home sleep studies into their own practices.16

Sleep apnea affects 6%-17% of the general population—and not just men, obese persons, or older persons, although these are the strongest risk factors.17 One sign of OSA with which HCPs may not be aware is recurrent uvulitis. A patient who presents with frequent sore throats not ascribed to other causes and a beefy-looking uvula may in fact have OSA.18 Of note, a home sleep study does not replace polysomnography performed in a sleep laboratory. The latter is preferred if HCPs suspect that a patient has severe OSA or another type of sleep abnormality or disorder that needs to be identified.

Non-medication approaches to therapy

For a patient who meets criteria for insomnia and who wants to improve her sleep, the first step is to treat any co-morbid condition(s) that may be causing or contributing to her insomnia. At the same time, HCPs should consider the medications that the patient is already taking, including OTC/prescription medications and alcohol, to determine whether any of them may be causing or exacerbating her problem.

The next step is to evaluate the patient’s sleep hygiene and, if less than optimal, advise her to make changes. Good sleep hygiene entails19:

  • being consistent—that is, going to bed at the same time each night and getting up at the same time each morning, including on weekends;
  • making sure one’s bedroom environment is quiet, dark, cool, and relaxing;
  • removing electronic devices from the bedroom;
  • avoiding large meals, caffeine, and alcohol before bedtime;
  • getting some exercise on most days; and
  • receiving daily exposure to sunlight (if possible) and keeping lights on until bedtime.

If making improvements in sleep hygiene proves inadequate, a patient can try a course of psychotherapy such as cognitive-behavioral therapy for insomnia (CBT-I). CBT-I addresses sleep-disruptive beliefs, maladaptive habits, and physiologic factors and incorporates elements of cognitive therapy, stimulus control, sleep restriction, sleep hygiene, and relaxation.4,20 A systematic review and meta-analysis demonstrated that CBT-I is effective for adults with chronic insomnia.20 Two possible downsides of CBT-I, as delivered by an HCP, are that it may be difficult to access and it may be expensive. As an alternative, online CBT-I options are available and have been reported to be effective.21,22

Non-medication approaches may be particularly useful for pregnant women with insomnia because many, if not most, medications used to treat insomnia can have a potentially adverse impact on the developing fetus. A recent study of pregnant women with insomnia showed that CBT-I was preferred over drug therapy or acupuncture.8 CBT-I is also recommended as first-line treatment in healthy midlife women with insomnia and moderately bothersome vasomotor symptoms.23

Nonprescription medication options

For patients still experiencing troublesome insomnia after non-medication interventions have been tried, several OTC medications are available. Although not included in the Table, the most common nonprescription “medication” used to treat insomnia is alcohol.24 An alcoholic drink may facilitate sleep onset, but it can also cause insomnia, manifested by multiple nighttime awakenings, increased urination, and difficulty falling back to sleep.

Melatonin, valerian root, and diphenhydramine are three nonprescription medications commonly used to treat insomnia. The Table provides information about their mechanisms of action, indication(s), dosing (in most cases, women and older patients should receive only the lowest dose), appropriateness of use in pregnancy/lactation, and precautions. The Table also includes recommendations from the AASM and from the American Geriatrics Society (AGS), specifically with regard to the AGS Beers Criteria, which lists medications that can cause side effects in older adults related to the physiologic changes of aging.25

Prescription medication options

Three general categories of prescription medication options for treatment of insomnia are the benzodiazepine (BZ) hypnotics, non-BZ hypnotics, and miscellaneous hypnotics. The Table provides the same categories of information for these prescription medications as for the nonprescription medications. Again, in most cases, women and older adults should receive only the lowest dose of a given medication.

Benzodiazepine hypnotics

Five BZ receptor agonists, all Schedule IV drugs, have been approved by the FDA for short-term treatment of insomnia.26 Two drugs in this class—temazepam and triazolam— are listed in the Table; the others, which are similar to temazepam and triazolam, are estazolam, quazepam, and flurazepam. Their mechanism of action entails binding to a modulatory site on the GABAA receptor and enhancing GABA activity.27

The prescribing information for drugs in this class includes a boxed warning about administering them concurrently with an opioid, which could result in profound sedation, respiratory depression, coma, and even death. BZ hypnotics can cause complex sleep behaviors (e.g., sleep-driving, having sex or eating while asleep and having no memory of it afterward).28,29 Based on the Beers Criteria, these agents should be avoided in older adults.25 Patients who take BZ hypnotics for a prolonged period (despite the fact that they are indicated only for short-term use) and who wish to discontinue them should taper them gradually, as opposed to stopping them abruptly, to avoid withdrawal symptoms.

Nonbenzodiazepine hypnotics

These Schedule IV drugs, eszopiclone, zaleplon, and zolpidem (Table), are known as the “Z” drugs because their generic name or their predecessor’s generic name starts with “Z” (eszopiclone is the active stereoisomer of zopiclone, which is available in Japan, Brazil, and some European countries). Or perhaps these drugs are so nicknamed because they help people get their zzz’s.

Non-BZ hypnotics act through the BZ binding sites associated with GABAA receptors.30 Their effects may be slowed if they are ingested with or shortly after a meal.31-34 They should be taken only if patients can be assured of getting a full night’s sleep.31-34 Based on the Beers Criteria, these drugs should be avoided in older adults.25 Doses should be as low as possible in patients with mild to moderate hepatic impairment; in those with severe hepatic impairment, these drugs should be used at the lowest possible dose, with great caution, or avoided.31-34

Other concerns regarding the “Z” drugs include short-term effects such as complex sleep behaviors, next-day sedation, and long-term effects such as amnesia, dementia, and rebound insomnia after the drug is stopped.31-34 If these drugs are to be halted after prolonged use, they should be slowly tapered to avoid withdrawal symptoms.31-34

Miscellaneous hypnotics

These agents include ramelteon, a prescription-strength melatonin agonist; three antidepressants; and suvorexant, which inhibits the action of orexin, a neurotransmitter involved in wakefulness (Table).35-40

Follow-up care

Patients and HCPs should not expect to find an effective solution for insomnia in one visit. Patients receiving any type of medication for insomnia should return for follow-up after 4-8 weeks for evaluation of efficacy, safety, and the need for ongoing treatment. The American College of Physicians guidelines suggest that patients who require medication for longer than 4-5 weeks be assessed regularly for the need to continue it.4

Conclusion

Insomnia affects millions of individuals in the U.S. Because many patients with insomnia do not mention their sleep problem at HCP visits, they should be screened for insomnia on a regular basis. Numerous treatment options, both nonpharmacologic and pharmacologic, exist. In most cases, HCPs should proceed in step-wise fashion, starting with behavioral approaches and advancing to OTC or prescription medication; the choice of medication depends on a patient’s age, health status, particular form of insomnia (problem with sleep onset, sleep maintenance, or both), and other considerations (e.g., a need to avoid drugs with addictive potential). Regardless of therapeutic choice, HCPs should follow patients with insomnia on a regular basis to ensure that treatment is effective, well tolerated, and still needed.

References

1. 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(2):307-349.

2. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 5th ed. Washington, DC: American Psychiatric Publishing; 2013.

3. American Academy of Sleep Medicine (AASM). Insomnia. 2008. aasm.org/resources/factsheets/insomnia.pdf

4. Qaseem A, Kansagara D, Forciea MA, et al; Clinical Guidelines Committee of the American College of Physicians. Management of chronic insomnia disorder in adults: a Clinical Practice Guideline from the American College of Physicians. Ann Intern Med. 2016;165(2):125-133.

5. Venner A, Fuller PM. An overview of sleep-wake circuitry: circuit nodes, pathways, and transmitters. In: Cappuccio P, Miller MA, Lockley SW, Rajaratnam SMW. Sleep, Health, and Society: From Aetiology to Public Health. Oxford Scholarship Online; 2018.

6. Guzman F. Psychopharmacology of Sleep and Wakefulness: Understanding Neurotransmitters and Pathways in Clinical Practice. Last updated February 9, 2018. psychopharmacologyinstitute.com/sleep-insomnia/psychopharmacology-sleep-wakefulness- understanding-neurotransmitters- pathways-clinical-practice/

7. Mieda M. The roles of orexins in sleep/wake regulation. Neurosci Res. 2017;118:56-65.

8. Sedov ID, Goodman SH, Tomfohr-Madsen LM. Insomnia treatment preferences during pregnancy. J Obstet Gynecol Neonatal Nurs. 2017;46(3):e95-e104.

9. Reichner CA. Insomnia and sleep deficiency during pregnancy. Obstet Med. 2015;8(4):168-171.

10. The North American Menopause Society. Sleep Problems. 2019. menopause.org/for-women/ sexual-health-menopause-online/ causes-of-sexual-problems/ sleep-problems

11. Gleason K, McCall WV. Current concepts in the diagnosis and treatment of sleep disorders in the elderly. Curr Psychiatry Rep. 2015;17(6):45.

12. Owens JA, Dalzell V. Use of the “BEARS” sleep screening tool in a pediatric residents’ community clinic: a pilot study. Sleep Med. 2005;6(1):63-69.

13. Restless legs syndrome: detection and management in primary care. National Heart, Lung, and Blood Institute Working Group on Restless Legs Syndrome. Am Fam Physician. 2000;62(1):108-114.

14. National Jewish Health. Medicines That Can Cause Insomnia. 2019. nationaljewish.org/conditions/insomnia/causes/medicines-that-can-cause-insomnia

15. Kapur VK, Auckley DH, Chowdhuri S, et al. Clinical practice guideline for diagnostic testing for adult obstructive sleep apnea: an American Academy of Sleep Medicine Clinical Practice Guideline. J Clin Sleep Med. 2017;13(3):479-504.

16. Wright WL, Dupont B, Manter B, et al. Home testing for obstructive sleep apnea. Nurse Pract Perspect. 2014;1(2):37-40. clevemed.com/ wp-content/uploads/2016/10/NPLed-Home-Sleep-Testing-for-OSAas-published-in-Nurse-PractitionerMay-issue-page-37-41.pdf

17. Senaratna CV, Perret JL, Lodge CJ, et al. Prevalence of obstructive sleep apnea in the general population: a systematic review. Sleep Med Rev. 2017;34:70-81.

18. Chang ET, Baik G, Torre C, et al. The relationship of the uvula with snoring and obstructive sleep apnea: a systematic review. Sleep Breath. 2018;22(4):955-961.

19. CDC. Sleep and Sleep Disorders. Tips for Better Sleep. Page last updated July 15, 2016. cdc.gov/sleep/ about_sleep/sleep_hygiene.html

20. Trauer JM, Qian MY, Doyle JS, et al. Cognitive behavioral therapy for chronic insomnia: a systematic review and meta-analysis. Ann Intern Med. 2015;163(3):191-204.

21. Seyffert M, Lagisetty P, Landgraf J, et al. Internet-delivered cognitive behavioral therapy to treat insomnia: a systematic review and meta-analysis. PLoS One. 2016;11(2):e01409139.

22. Ye YY, Chen NK, Chen J, et al. Internet-based cognitive behavioural therapy for insomnia (ICBT-i): a meta-analysis of randomised controlled trials. BMJ Open. 2016;6(11):e010707.

23. Guthrie KA, Larson JC, Ensrud KE, et al. Effects of pharmacologic and nonpharmacologic interventions on insomnia symptoms and self-reported sleep quality in women with hot flashes: a pooled analysis of individual participant data from four MsFLASH trials. Sleep. 2018;41(1).

24. National Sleep Foundation. How Alcohol Affects the Quality—and Quantity—of Sleep. 2018. sleepfoundation.org/articles/ how-alcohol-affects-quality- and-quantity-sleep

25. American Geriatrics Society. A Pocket Guide to the AGS 2015 Beers Criteria. ospdocs.com/resources/uploads/files/Pocket%20Guide%20 to%202015%20Beers%20Criteria.pdf

26. Medscape. Sleep Disorders Medication. Benzodiazepines. Updated January 25, 2015. emedicine.medscape.com/article/287104-medication#

27. Chawla J. What are the mechanisms of action of benzodiazepines and benzodiazepine receptor agonists for insomnia? Medscape Pharmacists. Updated September 11, 2018.

28. Restoril Prescribing Information (PI). Hazelwood, MO: Mallinckrodt Inc; September 2016. accessdata.fda.gov/drugsatfda_docs/ label/2016/018163s064lbl.pdf

29. Halcion P.I. New York, NY: Pfizer. December 2016. labeling.pfizer.com/ShowLabeling.aspx?id=586

30. Sanger DJ. The pharmacology and mechanisms of action of new generation, non-benzodiazepine hypnotic agents. CNS Drugs. 2004;(18 suppl 1):9-15.

31. Lunesta P.I. Marlborough, MA: Sunovion Pharmaceuticals Inc. 2018. lunesta.com/PostedApprovedLabelingText.pdf

32. Sonata P.I. Bristol, TN: King Pharmaceuticals, Inc. December 2007. accessdata.fda.gov/drugsatfda_docs/label/2007/020859s011lbl.pdf

33. Ambien P.I. Bridgewater, NJ. Sanofi-Aventis U.S. LLC. September 2018. products.sanofi.us/ambien/ambien.pdf

34. Ambien CR P.I. Bridgewater, NJ. Sanofi-Aventis U.S. LLC. September 2018. products.sanofi.us/ ambien_cr/ambien_cr.pdf

35. Rozerem prescribing information. Deerfield, IL: Takeda Pharmaceuticals America Inc. December 2018. general.takedapharm.com/ROZEREMPI

36. Desyrel P.I. Locust Valley, NY: Pragma Pharmaceuticals. June 2017. accessdata.fda.gov/drugsatfda_docs/label/2017/018207s032lbl.pdf

37. Epocrates. Trazodone Adult Dosing. 2019. online.epocrates.com/ drugs/8401/trazodone/Adult-Dosing

38. Silenor P.I. Morristown, NJ: Pernix Therapeutics LLC. silenor.com/Content/ pdf/prescribing-information.pdf

39. Remeron P.I. Roseland, NJ: Organon USA Inc. 2007. accessdata.fda.gov/drugsatfda_docs/label/2007/020415s019,021208s010lbl.pdf

40. Belsomra P.I. Whitehouse Station, NJ: Merck & Co., Inc. 2018. merck.com/product/usa/pi_circulars/b/belsomra/belsomra_pi.pdf

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