The Future Treatment of Insomnia: Exploring the Mechanisms of Action of Current and Emerging Therapies

Release date: October 2014 | Expiration date: October 31, 2015 | Estimated time to complete activity: 2 hours The Future Treatment of Insomnia: Exploring the Mechanisms of Action of Current and Emerging Therapies

An Educational Monograph Based on an Expert Roundtable Discussion

Sonia Ancoli-Israel, PhD Allen J. Blaivas, DO David Neubauer, MD Stephen H. Sheldon, DO, FAAP Professor Emeritus of Psychiatry and Medicine Director, Sleep Clinic Associate Professor Professor of Pediatrics Professor of Research VA New Jersey Health Care Johns Hopkins Bayview Medical Northwestern University, Director, Gillin Sleep and Chronomedicine Research Center System Center Feinberg School of Medicine Deputy Director, Stein Institute for Research on Aging Director, Sleep Medicine Center Director of Education, UCSD Sleep Medicine Center Ann and Robert H. Lurie Children’s Department of Psychiatry Hospital of Chicago University of California, San Diego

This activity is jointly sponsored by the American Osteopathic Association, Connecticut Osteopathic Medical Society, Massachusetts This activity is supported Osteopathic Society, Rhode Island Society of Osteopathic Physicians & Surgeons, and Impact Education, LLC. by an educational grant from Merck & Co., Inc. The Future Treatment of Insomnia: Exploring the Mechanisms of Action of Current and Emerging Therapies

Target Audience Allen J. Blaivas, DO, Faculty, served on an advisory board for Forest Pharmaceuticals, Inc. and serves on a speakers’ bureau for Pfizer Inc. and This activity is for osteopathic physicians and other health care Boehringer Ingelheim. professionals who care for people with insomnia. David Neubauer, MD, Faculty, serves as a consultant for Novo Nordisk Statement of Need and Vanda Pharmaceuticals. The purpose of the initiative is to provide osteopathic physicians with Stephen H. Sheldon, DO, FAAP, Faculty, receives grant and research continuing medical education that offers a timely and relevant evidence- support from Dymedix Diagnostics and serves as a consultant for Purdue based update on emerging concepts underlying the neurophysiology Pharma LP. of the sleep-wake cycle and the neurobiology of sleep wakefulness. In addition, this activity will compare and contrast the mechanisms of Keith Engelke, PhD, Writer, reports no financial interest/relationship action of current and emerging insomnia therapies. relating to the topic of this activity. Steve Casebeer, MBA, Planner, reports no financial interest/relationship Educational Objectives relating to the topic of this activity. • Define the overall burden of insomnia disorder • Describe recent advances in the understanding of the underlying Method of Participation and Request for Credit pathophysiology of insomnia disorder There are no fees for participating and receiving AOA Category 1-B • Discuss emerging concepts that relate to the control of the sleep- credit for this activity. During the period October 1, 2014, through wake cycle October 31, 2015, participants must read the learning objectives and • Differentiate the mechanisms of action of current and emerging faculty disclosures and study the educational activity. If you wish to therapies for insomnia disorder receive acknowledgement for completing this activity, please complete the post-test and evaluation at http://www.osteopathic.org/docmeonline. Faculty Sonia Ancoli-Israel, PhD Media Professor Emeritus of Psychiatry and Medicine Monograph Professor of Research Director, Gillin Sleep and Chronomedicine Research Center Disclosure of Unlabeled Use Deputy Director, Stein Institute for Research on Aging This educational activity may contain discussion of published and/or Director of Education, UCSD Sleep Medicine Center investigational uses of agents that are not indicated by the FDA. The Department of Psychiatry American Osteopathic Association (AOA), Impact Education, LLC (IE), University of California, San Diego and Merck & Co., Inc. do not recommend the use of any agent outside Allen J. Blaivas, DO of the labeled indications. The opinions expressed in the educational Director, Sleep Clinic activity are those of the faculty and do not necessarily represent the VA New Jersey Health Care System views of the AOA, IE, and Merck & Co., Inc. Please refer to the official prescribing information for each product for discussion of approved David Neubauer, MD indications, contraindications, and warnings. Associate Professor Johns Hopkins Bayview Medical Center Disclaimer Stephen H. Sheldon, DO, FAAP Participants have an implied responsibility to use the newly acquired Professor of Pediatrics information to enhance patient outcomes and their own professional Northwestern University, Feinberg School of Medicine development. The information presented in this activity is not meant to Director, Sleep Medicine Center serve as a guideline for patient management. Any procedures, medications, Ann and Robert H. Lurie Children’s Hospital of Chicago or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by clinicians without evaluation of Faculty Disclosures their patient’s conditions and possible contraindications on dangers in Within the past 12 months, the following individuals in positions use, review of any applicable manufacturer’s product information, and to control the content of this program (eg, planners, faculty, content comparison with recommendations of other authorities. reviewers) reported the following financial relationships or relationships to products or devices they or their spouse/life partner have had with commercial interests related to the content of this CME activity: Sonia Ancoli-Israel, PhD, Faculty, serves as a consultant for Merck & Co., Inc., Acadia Pharmaceuticals, Inc., AstraZeneca, Ferring Pharmaceuticals, Actelion Pharmaceuticals US, Inc., Aptalis, Otsuka Pharmaceutical Co., Ltd., and Arena Pharmaceuticals, Inc.

3 The Future Treatment of Insomnia: Exploring the Mechanisms of Action of Current and Emerging Therapies

Unmet Needs in Sleep Medicine and Recent Advances in the Understanding of the Pathophysiology of Insomnia

Abstract The annual cost of insomnia disorder in the United States is estimated to range between $30 and $107 billion. This total includes Insomnia is highly prevalent in modern-day society, and sleeplessness is direct costs of $12 to $14 billion for expenses such as medical one of the most common symptoms reported by patients in the primary appointments, over-the-counter sleep aids, and prescription medication as care setting. Insomnia disorder is a risk factor for the development of well as indirect costs associated with lost productivity due to absenteeism, mental conditions but is also a potential indicator of serious mental reduced quality of life, and accidents and injuries.13 or medical issues such as depression, anxiety, congestive heart failure, The primary care physician or family physician is often the first osteoarthritis, and Parkinson’s disease. Insomnia disorder is diagnosed health care professional to hear about a patient’s sleep difficulties. It through comprehensive assessment, including a detailed patient history, is estimated that 52% to 64% of primary care patients have sleep physical examination, and questionnaires and sleep diaries. Treatments complaints, and 10% to 14% have severe insomnia that interferes with include behavioral therapies and pharmacological interventions. daytime functioning.14,15 Insomnia disorder tends not to resolve by itself, and patients often endure it for years without effective help.16 Although Introduction to Insomnia: primary care is the ideal place to treat patients with insomnia disorder, the Unmet Medical Needs diagnosis can be difficult because of frequent overlap between symptoms of insomnia and disrupted sleep due to lifestyle or environmental factors Insomnia disorder is defined as disturbed sleep in the presence of not associated with insomnia disorder. adequate opportunity and circumstance for sleep and is characterized People with sleep disorders tend to seek treatment when symptoms by difficulty initiating sleep (sleep-onset insomnia), frequent or long such as fatigue, impaired daytime functioning, and the inability to nighttime awakenings (sleep-maintenance insomnia), and waking up too concentrate become bothersome.17 The American Academy of Sleep 1,2 early without being able to return to sleep (early morning insomnia). Medicine guidelines outline treatment goals for insomnia, including A fourth characteristic, nonrestorative or poor-quality sleep, may also reduction of sleep and waking symptoms and improvement in daytime be included as part of the definition, although this is not universally functioning, and stress the importance of identifying and treating 1 accepted. comorbid conditions.18 Insomnia disorder lasts for at least 3 months and may be Patients with trouble sleeping often turn to over-the-counter precipitated by a traumatic event; emotional, personal, or work-related sleep aids and homeopathic remedies such as valerian, chamomile, stress; travel across time zones; or other events that initially disrupted and St John’s wort prior to discussing their sleep concerns with a 1 sleep habits. Insomnia disorder does not occur secondary to another health care practitioner. While widely used, few of these agents have medical condition but rather is often comorbid with medical conditions been systematically studied in clinical trials. Furthermore, the safety 3 such as chronic pain, high blood pressure, obesity or weight gain, and efficacy of these agents have not been reviewed by the Food and 4 obstructive sleep apnea, gastrointestinal problems, urinary problems, Drug Administration. Once a diagnosis of insomnia disorder has been osteoarthritis, hip impairment, fibromyalgia, peptic ulcer disease, and confirmed by a health care provider, several interventions are available, 5-8 breathing problems. including lifestyle changes, behavioral and psychological interventions, Insomnia disorder can have a negative impact on a person’s daytime and prescription medications.1 1 functioning and quality of life. In addition to fatigue, insomnia can Nonpharmacological treatments with published reports attesting 2 cause irritability, anxiety, and loss of concentration. It has also been to their efficacy include behavioral and cognitive techniques that 9 associated with increased rates of motor vehicle accidents and higher modify the precipitating and perpetuating factors that contribute to 10 rates of occupational injury. People with insomnia disorder have a lower insomnia. Several classes of prescription agents are also widely used self-reported overall health status and higher level of bodily pain, both of in the management of insomnia disorder, including benzodiazepines, 1 which contribute to reduced quality of life. nonbenzodiazepine hypnotics, and ramelteon, as well as antidepressants Determining the true prevalence of insomnia disorder is that target the serotonergic system.1 Benzodiazepines are known for their complicated because of patient underreporting and the use of different effectiveness in increasing total sleep time by reducing the time to sleep 1 definitions of insomnia. In the United States, an estimated 50 to 70 onset and the number of nighttime awakenings. However, their long- 11 million adults have chronic sleep and wakefulness disorders. Risk term use is limited by a negative effect on memory and recall and next- factors for insomnia disorder include female sex; increasing age; low day sleepiness, and continued use may increase the risk of habituation.1 income status; shift work; elevated levels of personal, emotional, and Nonbenzodiazepine hypnotics such as zolpidem tartrate, zolpidem occupational stress; and the presence of medical conditions or sleep tartrate extended-release, zaleplon, and eszopiclone have efficacy similar 2 disorders that can disrupt sleep. Although older age is associated with an to the benzodiazepines but offer more favorable safety and tolerability increased risk of insomnia disorder, the condition has been found to peak profiles. Use of nonbenzodiazepine hypnotics may also be limited by in middle age (range, 45–54 years), decrease slightly during older age an increased risk of habituation with long-term use. Antidepressants 12 (range, 65–84 years), and increase again in very old age (>85 years). and antipsychotics such as amitriptyline hydrochloride, trazodone

4 The Future Treatment of Insomnia: Exploring the Mechanisms of Action of Current and Emerging Therapies

hydrochloride, mirtazapine, and quetiapine are sometimes also used to References treat insomnia, although these are used off-label and are associated with 1. National Institutes of Health. NIH State-of-the-Science Conference: Manifestations dizziness, psychomotor impairment, and other serious adverse events. and Management of Chronic Insomnia in Adults. June 13-15, 2005. http:// The selective histamine receptor antagonist doxepin was approved for the consensus.nih.gov/2005/insomniastatement.pdf. Accessed June 17, 2014. treatment of depression in 1969, but more recently, low-dose doxepin 2. U.S. Department of Health and Human Services, National Heart, Lung, and received an indication for the treatment of insomnia characterized by Blood Institute. What is insomnia? https://www.nhlbi.nih.gov/health/health- topics/topics/inso/. Accessed June 16, 2014. 19 difficulty maintaining sleep. Furthermore, few studies have specifically 3. Van Cauter E, Knutson KL. Sleep and the epidemic of obesity in children and examined the efficacy and safety of antidepressants in the treatment of adults. Eur J Endocrinol. 2008;159(suppl 1):S59-S66. insomnia.1 4. Smith S, Sullivan K, Hopkins W, Douglas J. Frequency of insomnia report in patients with obstructive sleep apnea hypopnea syndrome (OSAHS). Sleep Med. 2004;5:449-456. Pathophysiology of Insomnia 5. Taylor DJ, Mallory LJ, Lichstein KL, Durrence HH, Riedel BW, Bush AJ. Disorder: Recent Advances Comorbidity of chronic insomnia with medical problems. Sleep. 2007;30:213-218. 6. Leigh TJ, Hindmarch I, Bird HA, Wright V. Comparison of sleep in osteoarthritic Our understanding of the neurobiology of sleep has advanced patients and age and sex matched healthy controls. Ann Rheum Dis. 1988;47:40-42. significantly in recent years with the introduction of experimental 7. Ancoli-Israel S. The impact and prevalence of chronic insomnia and other sleep disturbances associated with chronic illness. Am J Manag Care. techniques that allow access to sleep-wake centers in the brain. One such 2006;12(suppl):S221-S229. advance occurred in 1998 with the discovery of the orexin (hypocretin) 8. Katz DA, McHorney CA. Clinical correlates of insomnia in patients with chronic system.20,21 Orexins are neuropeptides synthesized predominantly in the illness. Arch Intern Med. 1998;158:1099-1107. posterior and lateral hypothalamus. Orexinergic neurons activate waking 9. National Highway Traffic Safety Administration. Traffic Safety Facts Crash Stats: Drowsy Driving. Washington, DC: Department of Transportation; 2011. DOT active monoaminergic and cholinergic neurons in the hypothalamus and HS 811 4492011. http://www.cdc.gov/Features/dsdrowsydriving/index.html. brainstem regions to maintain a long, consolidated waking period. They Accessed June 17, 2014. also receive abundant input from the limbic system.22 10. Shahly V, Berglund PA, Coulouvrat C, et al. The associations of insomnia with The clinical utility of the orexin pathway was clarified when costly workplace accidents and errors: results from the America Insomnia Survey. Arch Gen Psychiatry. 2012;69:1054-1063. 23 studies designed to disrupt the orexin pathway using orexin knockout 11. Centers for Disease Control and Prevention. Unhealthy sleep-related 24 and orexin receptor 2 gene mutation produced animals with behaviors—12 states, 2009. MMWR Morb Mortal Wkly Rep. 2011;60:233-266. narcolepsy and cataplexy. It has been reported that 90% of humans 12. Pearson NJ, Johnson LL, Nahin RL. Insomnia, trouble sleeping, and with narcolepsy and cataplexy have nearly undetectable levels of orexin complementary and alternative medicine: analysis of the 2002 National Health Interview Survey data. Arch Intern Med. 2006;166:1775-1782. in their cerebrospinal fluid.25 Furthermore, humans with narcolepsy 13. Morin CM. Insomnia: prevalence, burden, and consequences. Insomnia Rounds. 26,27 have a 90% reduction in brain orexin neurons. Of all the arousal 2012;1:1-6. systems discussed, the orexin system seems to have the most potent 14. Simon GE, VonKorff M. Prevalence, burden, and treatment of insomnia in effect on maintaining wakefulness. These experiments highlighted the primary care. Am J Psychiatry. 1997;154:1417-1423. consequence of a defective orexin system in the ability to maintain 15. Terzano MG, Parrino L, Cirignotta F, et al. Insomnia in primary care, a survey conducted on the Italian population. Sleep Med. 2004;5:67-75. wakefulness. The orexin system thus performs its critical role of 16. Morin CM, Bélanger L, LeBlanc M, et al. The natural history of insomnia: a preventing sleep by its excitatory actions on other arousal systems and population-based 3-year longitudinal study. Arch Intern Med. 2009;169:447-453. also providing excitatory input on cortical, motor, and sympathetic 17. Kraus SS, Rabin LA. Sleep America: managing the crisis of adult chronic insomnia systems.25 These new findings have provided novel targets for the and associated conditions. J Affect Disord. 2012;138:192-212. development of agents to manage clinical sleep disorders such as 18. Schutte-Rodin S, Broch L, Buysse D, et al. Clinical guideline for the evaluation and management of chronic insomnia in adults. J Clin Sleep Med. 2008;4:487-504. insomnia. 19. Silenor® [package insert]. San Diego, CA: Somaxon Pharmaceuticals, Inc.; March The first of these agents, the highly selective orexin receptor 2010. antagonist suvorexant, was approved by the Food and Drug 20. Sakurai T, Amemiya A, Ishii M, et al. Orexins and orexin receptors: a family of Administration in August 2014 for the treatment of adults with hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior. Cell. 1998;92:573-585. insomnia, characterized by difficulties with sleep onset and/or sleep 21. De Lecea L, Kilduff TS, Peyron C, et al. The hypocretins: hypothalamus-specific 28 maintenance. peptides with neuroexcitatory activity. Proc Natl Acad Sci USA. 1998;95:322-327. 22. Tsujino N, Sakurai T. Orexin/hypocretin: a neuropeptide at the interface of sleep, Summary energy homeostasis, and reward system. Pharmacol Rev. 2009;61:162-176. 23. Chemelli RM, Willie JT, Sinton CM, et al. Narcolepsy in orexin knockout mice: People with sleep disorders tend to seek treatment when symptoms molecular genetics of sleep regulation. Cell. 1999;98:437-451. such as fatigue, impaired daytime functioning, and the inability to 24. Lin L, Faraco J, Li R, et al. The sleep disorder canine narcolepsy is caused by a mutation in the hypocretin (orexin) receptor 2 gene. Cell. 1999;98:365-376. concentrate become bothersome. Once a diagnosis of insomnia 25. Lu BS, Zee PC. Neurobiology of sleep. Clin Chest Med. 2010;31:309-318. disorder is confirmed, therapeutic interventions such as behavioral 26. Mignot E, Lammers GJ, Ripley B, et al. The role of cerebrospinal fluid hypocretin and psychological interventions and prescription medications are measurement in the diagnosis of narcolepsy and other hypersomnias. Arch Neurol. available. Recent progress has elucidated more clearly the mechanisms 2002;59:1553-1562. underlying the regulation of sleep and wakefulness. Novel insomnia 27. Thannickal TC, Moore RY, Nienhuis R, et al. Reduced number of hypocretin neurons in human narcolepsy. Neuron. 2000;27:469-474. therapies are now being developed to exploit these newly discovered 28. Belsomra® [package insert]. Whitehouse Station, NJ: Merck Sharp & Dohme therapeutic targets. Corp., a subsidiary of Merck & Co., Inc.; August 2014. 5 The Future Treatment of Insomnia: Exploring the Mechanisms of Action of Current and Emerging Therapies

An Expert Roundtable Monograph for Osteopathic Physicians

Abstract ALLEN J. BLAIVAS, DO: It is estimated that between 33% and 50% of people in the United States have some form of insomnia over the Insomnia is one of the most common symptoms reported in clinical course of 1 year.1 A recent study by the National Sleep Foundation practice. Cardinal features of insomnia include difficulty initiating reported that approximately 22% of American adults experience or maintaining sleep with impairment of daytime functioning. insomnia on a nightly basis.2 At any given time, approximately 10% of Insomnia results from a variety of genetic, environmental, behavioral, the population has a diagnosis of chronic insomnia.3 Insomnia is also and physiological factors, culminating in hyperarousal. Insomnia one of the most common sleep complaints reported to pediatric primary is associated with poor quality of life and an increased risk of other care physicians. medical and mental disorders. Current treatment options include pharmacological therapy and cognitive behavioral therapy for insomnia. STEPHEN H. SHELDON, DO, FAAP: Dr. Ancoli-Israel, can you give Behavioral treatments should be implemented whenever possible, and us some insight into the relationship between sleep and overall health? medications should be used at the lowest effective dose for the shortest How important is sleep to quality of life, productivity, and occurrence of duration possible. Among pharmacological therapies, the most evidence accidents? exists for the benzodiazepine receptor agonists, but these drugs must be carefully monitored for adverse effects. Neuropeptides arising from SONIA ANCOLI-ISRAEL, PhD: I’d like to follow up on one of the the orexin (hypocretin) system have been shown to regulate the sleep- points made by Dr. Blaivas. While he is correct about the statistics in wake cycle, leading to the development of orexin antagonists. Increased the general population, a study conducted a few years ago reported that understanding of this pathway may lead to novel therapies for insomnia nearly 50% of patients seen in a primary care office reported symptoms without the side effect profile of currently available agents. In this of insomnia.4,5 roundtable discussion, relevant data on the future treatment of insomnia To get back to your question, sleep has been increasingly recognized are discussed, specifically the mechanisms of action of current and as important to public health. The key is that when people do not emerging therapies. get enough sleep, they are sleepy during the day, even if they do not recognize it. Insufficient sleep has been linked to motor vehicle accidents, Introduction industrial disasters, and medical and other occupational errors.6,7 All of this results in decreased productivity and lower quality of life. We have STEPHEN H. SHELDON, DO, FAAP: Welcome to the roundtable to remember that insufficient sleep can be the result of two factors: (1) discussion entitled The Future Treatment of Insomnia: Exploring the sleep disorders that rob us of sleep and (2) spending too little time in Mechanisms of Action of Current and Emerging Therapies. I am Stephen bed, which is perhaps more common. I like to remind my patients that Sheldon, Professor of Pediatrics and Neurology at the Northwestern they cannot get 8 hours of sleep if they are only in bed for 5 hours each University, Feinberg School of Medicine and Director of the Sleep night, which often happens in our current 24-hour society. Medicine Center at the Ann & Robert H. Lurie Children’s Hospital of Chicago. STEPHEN H. SHELDON, DO, FAAP: Are you saying that Joining me are Dr. Sonia Ancoli-Israel, Professor Emeritus insufficient sleep is a combination of both a sleep disorder and a lifestyle? of Psychiatry and Medicine at the University of California, San Diego; Dr. Allen Blaivas, Director of the Sleep Clinic at the Veterans SONIA ANCOLI-ISRAEL, PhD: Yes, in some cases it is one or the Administration Health Care System in East Orange, New Jersey; and other, but often it is both. Dr. David Neubauer, Associate Professor at the Johns Hopkins Bayview Medical Center in Baltimore, Maryland. STEPHEN H. SHELDON, DO, FAAP: Dr. Neubauer, what is the The purpose of our discussion is to provide osteopathic physicians relationship between sleep/insomnia and chronic illness or chronic with continuing medical education that offers timely and relevant data disease? on the future treatment of insomnia, specifically the mechanisms of action of current and emerging therapies. DAVID NEUBAUER, MD: Both our clinical experience and the epidemiological research show that those who sleep less are more likely Insomnia: Defining the Problem to have chronic illness. The reverse is also true; people with more chronic STEPHEN H. SHELDON, DO, FAAP: Sleep difficulties are one of disorders tend to report disruptions in their sleep patterns, whether it is the most common symptoms reported by patients during a primary care simply the amount of sleep they get each night, the quality of sleep, or office visit. Inadequate sleep is often associated with a decline in health the experience of sleep. and behavior and can markedly impair a patient’s and their family’s A number of published reports have examined the relationship quality of life. Dr. Blaivas, how common is it for an adult presenting to a between reported sleep duration and all-cause mortality. Most of these primary care practice to report some type of sleep disorder? studies have identified a U-shaped curve, with both short-duration and long-duration sleepers at greater risk for increased all-cause mortality.8

6 The Future Treatment of Insomnia: Exploring the Mechanisms of Action of Current and Emerging Therapies

A meta-analysis published in Sleep in 2010 pooled data from 16 STEPHEN H. SHELDON, DO, FAAP: It appears that there may studies that included 1,382,999 male and female participants (follow- be a bidirectional cause and effect with comorbidity. What is the up range, 4 to 25 years) and 112,566 deaths. This analysis identified a recommended amount of sleep for an otherwise healthy adult? 12% greater risk of mortality among short-duration sleepers (commonly <7 hours per night, often <5 hours per night). A long duration of sleep SONIA ANCOLI-ISRAEL, PhD: We generally recommend 7 to (commonly >8 or 9 hours per night) was also associated with a 30% 8 hours of sleep per night. We work with our patients to help them greater risk of dying compared with those sleeping 7 to 8 hours per night.9 determine the amount of sleep they need to function at their optimal Other health conditions can contribute to greater morbidity and level. The challenge is that the sleepier people are, the less aware they are mortality in people who do not receive sufficient sleep. The Centers of their level of sleepiness and dysfunction. It is not uncommon for a for Disease Control and Prevention (CDC) notes on its website patient to say “I sleep 5 hours a night and I’m doing just fine.” However, that insufficient sleep is associated with increased risk of depression, if you ask the people around that patient, they will note that the patient’s obesity, type 2 diabetes mellitus, and cardiovascular disease, including performance is decreased or there are other problems. Therefore, we hypertension, stroke, coronary heart disease, and cardiac arrhythmias.10 encourage people to try to get 7 to 8 hours of sleep each night. The results of the 2009 CDC Behavioral Risk Factor Surveillance System survey indicated that approximately 33% of the 54,000 adults STEPHEN H. SHELDON, DO, FAAP: Is this related to the older than 45 years of age who completed the survey slept ≤6 hours homeostatic sleep need or circadian mechanisms? Is there a basal sleep each night (ie, “short sleepers”). On the other end of the spectrum, need? And what about sleep debt? approximately 4% reported sleeping ≥10 hours each night (ie, “long sleepers”).11 After controlling for sex, age, race, ethnicity, and education, ALLEN J. BLAIVAS, DO: The amount of sleep a person needs to be both the short sleepers and long sleepers had an increased risk of obesity, at his or her best is what we consider basal sleep time: between 7 and coronary heart disease, stroke, diabetes, and frequent mental distress.11 9 hours. There is always a competition between sleep debt and basal What is causing the excess mortality? This is difficult to measure in sleep. Most people do not sleep enough; the total average duration of larger population studies, but a number of smaller laboratory-based sleep sleep is usually less than 7 hours. A lack of sleep causes sleep debt, which deprivation studies suggest that abnormalities in hormonal, immune, is defined as the difference between our basal sleep need and the total and inflammatory processes may be driving the increased mortality. amount of sleep we lose each night. For example, the satiety hormone leptin is decreased with a short duration of sleep, leading to increased appetite and perhaps obesity.12 In a complementary manner, ghrelin, along with various inflammatory “The amount of sleep a person markers including tumor necrosis factor alpha, interleukin-6, and C-reactive protein, are all elevated with a short duration of sleep.11,12 needs to be at his or her best is Various types of cancer are associated with short duration of sleep or abnormal sleep-wake schedules, such as with shift work, including what we consider basal sleep time: breast, thyroid, prostate, and colorectal cancers.13-16 In addition, people who sleep less are of course more likely to be sleepier and inattentive between 7 and 9 hours. There is during the day, increasing the risk of various types of accidents.6 The bottom line is that sleep interfaces with nearly all aspects of our always a competition between physical and mental health, and we should encourage our patients to sleep debt and basal sleep.” make it a high priority in their lives. – Dr. Blaivas

“…a number of smaller STEPHEN H. SHELDON, DO, FAAP: Can a sleep debt be “paid back”?

laboratory-based sleep SONIA ANCOLI-ISRAEL, PhD: Yes, it can, but if a person has deprivation studies suggest that chronic partial sleep deprivation, it could take as many as 5 days of sleep beyond his or her basal needs to make up the sleep debt. Unfortunately, abnormalities in hormonal, sleeping in a few hours on Saturday or Sunday morning will not make up for sleep lost during the week. immune, and inflammatory STEPHEN H. SHELDON, DO, FAAP: Does the quality of sleep affect processes may be driving the daytime performance as much as the quantity of sleep? increased mortality.” SONIA ANCOLI-ISRAEL, PhD: Sleeping 8 to 10 hours each day can indicate the presence of a sleeping disorder, particularly if the patient – Dr. Neubauer reports feeling drowsy or fatigued during the day.

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ALLEN J. BLAIVAS, DO: I agree. If a patient who reports sleeping 8 STEPHEN H. SHELDON, DO, FAAP: Is it correct to say that to 10 hours has symptoms of tiredness, he or she should be evaluated the most important aspect of diagnosis is a clinical assessment and for a sleep disorder in the sleep laboratory to rule out the presence of evaluation of the patient? sleep apnea or another condition that might be causing the problem. SONIA ANCOLI-ISRAEL, PhD: Yes, and taking the time to listen to STEPHEN H. SHELDON, DO, FAAP: Is sleep quality assessed in the patient. the sleep laboratory? ALLEN J. BLAIVAS, DO: If you talk to patients long enough, they ALLEN J. BLAIVAS, DO: Not really. Part of the problem is that a will tell you exactly what is wrong with them. good definition of “sleep quality” cannot be found in the literature, and we depend on both subjective patient reports and objective clinical DAVID NEUBAUER, MD: If you are lucky, you can also talk to the findings to assess sleep quality. family members; they can provide valuable collateral information, A recent study attempted to assess sleep quality by investigating which is especially important for sleep problems. whether subjects who self-identified as “normal sleepers” might have disturbed sleep when evaluated using objective techniques.17 The STEPHEN H. SHELDON, DO, FAAP: Insomnia seems to be a huge results showed that several people who objectively had “normal” sleep problem, but is it often underreported or undertreated as a chronic reported always feeling tired and not sleeping well. The group that condition? reported subjective insomnia had more depression and anxiety and had dysfunctional beliefs about their sleep compared with a “normal ALLEN J. BLAIVAS, DO: By the time a sleep specialist sees these sleeper.”17 Therefore, it can be difficult to assess sleep quality because patients, it is already clear that there is a sleep problem. However, it clinical observations and self-reports often do not translate into what is not so clear in the primary care setting, because most patients have we see in laboratory studies. been dealing with fatigue for so long that they are not aware there is a problem; they just assume it is normal. In addition, there often is insufficient time during a typical office visit to ask the questions needed “…it can be difficult to assess to identify a sleep problem. sleep quality because clinical “By the time a sleep specialist sees observations and self-reports these patients, it is already clear often do not translate into what that there is a sleep problem. we see in laboratory studies.” However, it is not so clear in the – Dr. Blaivas primary care setting, because DAVID NEUBAUER, MD: I agree with Dr. Blaivas. We do not have objective criteria that clearly define sleep quality, particularly most patients have been dealing for a person reporting insomnia. Although it is hard to objectively quantify this, the bottom line is how the person feels the next day and with fatigue for so long that they how they retrospectively interpret their nighttime experience. This situation is further complicated by the fact that patients’ subjective are not aware there is a problem; descriptions frequently do not correspond to the data generated by a laboratory-based sleep study. In fact, it is not uncommon for patients they just assume it is normal.” to report that their sleep experience was poor despite being shown strong laboratory evidence indicating that their sleep quality was high. – Dr. Blaivas Conversely, the results of a sleep study may look awful, yet the patient will come in and say “that was a good night of sleep for me.” STEPHEN H. SHELDON, DO, FAAP: How is insomnia defined, and how is it assessed by the primary care physician? SONIA ANCOLI-ISRAEL, PhD: This is why we do not conduct an overnight sleep study on our patients with insomnia. A diagnosis of SONIA ANCOLI-ISRAEL, PhD: There is no doubt that insomnia insomnia is really based on what the patients perceive and what they are is underidentified. As we just heard, physicians frequently do not ask reporting; it is very subjective. about it and patients often fail to mention it. In fact, we published a paper several years ago on data from a National Sleep Foundation survey showing that of all adults with chronic insomnia, two-thirds

8 The Future Treatment of Insomnia: Exploring the Mechanisms of Action of Current and Emerging Therapies

never discussed it with their physician. Furthermore, only 5% made an ALLEN J. BLAIVAS, DO: It really could be any patient who walks appointment specifically to have their sleep symptoms evaluated. Most into your office reporting difficulty falling asleep, frequent awakenings, patients only mentioned it if they happened to be in the clinic for some difficulty returning to sleep, waking too early, or just sleep that does other reason.18 not feel restorative. Older people are at increased risk, particularly older women. Patients with comorbid medical and psychiatric conditions are also at higher risk. “…data from a National Sleep In many cases, patients specifically report difficulty falling asleep or frequent awakenings. However, once you start asking questions, Foundation survey showing it becomes apparent that they are experiencing a whole constellation of sleep issues. Many patients develop maladaptive behaviors in an that of all adults with chronic attempt to solve their sleep problem, but in the end they perpetuate the anxiety that revolves around their inability to fall asleep and insomnia, two-thirds never the act of going to bed becomes anxiety provoking. For example, a patient with difficulty falling asleep stays in bed trying to get more discussed it with their physician. sleep. Some patients begin to spend time in bed even though they are Furthermore, only 5% made an not sleeping. They talk on the telephone, watch television, use their computer, eat, and even smoke. All the time they are looking at the appointment specifically to have clock and wondering why they cannot fall asleep. During the day, these people report feeling more weary than their sleep symptoms evaluated.” actually sleepy. Patients with true insomnia often are unable to fall asleep during the day no matter how tired they are. – Dr. Ancoli-Israel SONIA ANCOLI-ISRAEL, PhD: Dr. Blaivas’ point about patients STEPHEN H. SHELDON, DO, FAAP: Does the prevalence of reporting feeling weary is worth emphasizing. Many patients will insomnia vary by age, sex, and across a patient’s life cycle? say “I have insomnia and I nap 2 hours during the day”; however, a person with insomnia is typically unable to nap during the day. This is SONIA ANCOLI-ISRAEL, PhD: Yes. More women experience a clue that there is something else going on other than insomnia. insomnia than men. In older adults, the prevalence is actually quite a bit higher, closer to 25%.1 In addition, in older adults, insomnia is almost always associated with either a comorbid condition or “…we no longer use the medications used to treat the comorbidity. Insomnia is also associated with changes in the circadian clock that occur with aging as well as with terms ‘primary’ or ‘secondary’ a higher prevalence of specific sleep disorders in the older population. insomnia. The new Diagnostic STEPHEN H. SHELDON, DO, FAAP: Is there a difference between primary insomnia and secondary insomnia? and Statistical Manual of Mental Disorders (DSM-5) SONIA ANCOLI-ISRAEL, PhD: Because there is no way of knowing what is cause and what is effect, we no longer use the terms “primary” refers to the condition as or “secondary” insomnia. The new Diagnostic and Statistical Manual of Mental Disorders (DSM-5) refers to the condition as “insomnia ‘insomnia disorder.’” disorder.”19 However, we may refer to insomnia as being comorbid because it occurs at the same time as other conditions. – Dr. Ancoli-Israel The terminology is important because it can influence how we approach treatment. Referring to the condition as “insomnia disorder” STEPHEN H. SHELDON, DO, FAAP: Is there a difference between or “comorbid insomnia” suggests that all conditions should be treated insomnia, sleepiness, and fatigue? concurrently. For example, if a patient presents with depression and also reports problems sleeping, we do not treat the depression and wait SONIA ANCOLI-ISRAEL, PhD: Yes; fatigue is not the same as to see what happens to the patient’s sleep; we treat both conditions sleepiness. simultaneously. STEPHEN H. SHELDON, DO, FAAP: How do you differentiate STEPHEN H. SHELDON, DO, FAAP: Dr. Blaivas, could you fatigue from sleepiness? describe a typical patient who presents with insomnia?

9 The Future Treatment of Insomnia: Exploring the Mechanisms of Action of Current and Emerging Therapies

DAVID NEUBAUER, MD: Patients often report sleep problems including benzodiazepines, nonbenzodiazepines, a melatonin when they realize that their daytime functioning has deteriorated due agonist, and low-dose doxepin. Patients with insomnia who have to their inability to sleep well. Most often, patients say “I’m so tired,” been successfully treated with these medications are likely to report but “tired” is too ambiguous to help establish a diagnosis. The classic improvement in daytime function, better quality of life, and less patient with chronic insomnia has a decreased ability to sleep. In my comorbidity. However, the evidence base for pharmacological therapy practice, I attempt to differentiate whether the patient lacks energy, is not as robust as that for CBTI. and perhaps motivation, due to physical or mental fatigue or if he or she typically sleeps during the daytime when given the opportunity. STEPHEN H. SHELDON, DO, FAAP: Is there any evidence Most patients will provide several clues to the presence of regarding the combination of the two? insomnia when you take their history. Most will describe how, despite not sleeping during the night, it is impossible for them to nap during SONIA ANCOLI-ISRAEL, PhD: Yes. In certain patients, combining the day even though they crave sleep. Tiredness is a great starting CBTI and pharmacological therapy is very effective, particularly in point to differentiate fatigue from sleepiness. Sleepiness should have patients who find it difficult to initially comply with the behavioral the provider thinking about other disorders that might contribute intervention. I find it is effective to start with medication and then to the sleep disorder, whereas fatigue should drive the physician to slowly wean the patient off the drug while continuing with the consider a differential diagnosis, including chronic insomnia. behavioral intervention. In some cases, patients are prescribed medication before coming STEPHEN H. SHELDON, DO, FAAP: Are there any specific to our clinic. We often initiate behavioral training while they are still questions the primary practitioner can ask to differentiate fatigue taking the medication; as favorable changes in their sleeping patterns from sleepiness during the few minutes spent with the patient? occur, they often become willing to discontinue their medication.

DAVID NEUBAUER, MD: The patient’s ability to sleep or nap Neurobiology of Sleep is a pretty good clue. I would say that most patients with chronic STEPHEN H. SHELDON, DO, FAAP: insomnia are rarely able to sleep during the daytime. As a group, I’d like to shift gears people with insomnia maintain a higher level of arousal throughout and discuss the neurobiology of sleep. The understanding of the 24-hour cycle and their inability to sleep at nighttime likely carries neurobiological mechanisms of sleep has increased dramatically over over into the daytime, preventing them from napping as well. the past decade, driven largely by experimental techniques that allow direct access to sleep-wake centers in the brain. It is now understood that there are multiple neurochemical systems that promote “As a group, people with wakefulness and sleep. Dr. Ancoli-Israel, can you briefly describe the sleep cycle and the sleep architecture in a healthy adult? insomnia maintain a higher level SONIA ANCOLI-ISRAEL, PhD: There are 4 stages of sleep: Stage of arousal throughout the 24- (or N) 1, the very lightest stage, occurs just as a person dozes off. N2 and 3 are progressively deeper levels of sleep; N3 is the deepest level. hour cycle and their inability to The fourth stage is REM, or dream, sleep. As the night progresses, the person starts in N1 and then proceeds sleep at nighttime likely carries through N2 and N3. The first REM period generally occurs 90 to 100 minutes after falling asleep. The person continues to cycle in and out over into the daytime, preventing of these different stages of sleep throughout the night. Most of our deep sleep occurs in the first third of the night, and them from napping as well.” most of our dream sleep occurs in the last third of the night and the early morning hours. This sleep cycle is part of the circadian tendency. – Dr. Neubauer A person who takes an early morning nap is more likely to experience REM sleep. If that same person takes a late afternoon nap, he or she STEPHEN H. SHELDON, DO, FAAP: Dr. Ancoli-Israel, are there is more likely to go into deeper levels of sleep. Sleep is also controlled any current evidence-based guidelines to guide the treatment of by the homeostatic drive and the circadian drive. The combination of patients with insomnia? these 2 processes helps the body determine when to sleep and when to be awake. SONIA ANCOLI-ISRAEL, PhD: There is a large evidence base for the use of cognitive behavioral treatment for insomnia (CBTI). CBTI STEPHEN H. SHELDON, DO, FAAP: Dr. Neubauer, can you is the most effective and longest-lasting treatment available. The briefly describe the neural pathways involved in generating sleep and challenge is that the number of trained CBTI therapists is limited, so generating wakefulness? it can be difficult for patients to find a qualified practitioner. Several medications are approved for the treatment of insomnia,

10 The Future Treatment of Insomnia: Exploring the Mechanisms of Action of Current and Emerging Therapies

DAVID NEUBAUER, MD: There are several ways to model the neurotransmitter in the central nervous system. regulation of sleep and waking. One is to consider the normally The widely dispersed GABA neurons reinforce sleep on a global coordinated effects of the homeostatic and circadian factors that Dr. level within the central nervous system, but it is clear that there is a Ancoli-Israel mentioned. The homeostatic drive basically represents specific GABA action in the hypothalamus that plays a central role in the balance between wake and sleep; as humans, we are driven to promoting sleep. Consequently, GABA is considered one of the key want to sleep about one-third of the time (about 8 hours of a 24-hour neurotransmitters in the VLPO. period). If we get insufficient sleep, we become excessively sleepy, Sleep seems to be generated primarily within the preoptic which can happen either acutely or chronically. hypothalamus and the adjacent basal forebrain region. In addition to The homeostatic drive for sleep begins when we wake up and GABA, some neurotransmitters may play a role (eg, galanin). Aside increases steadily until we sleep again. During sleep, that process is from neurotransmitters, there are other substances involved. There is reversed. Whereas the homeostatic process determines how much sleep evidence that the accumulation of adenosine during wakefulness may is needed, the circadian rhythm, which is biologically synchronized promote sleepiness. Perhaps not surprisingly, we commonly use adenosine with the day-night cycle, optimizes the ability to achieve the required antagonists such as caffeine to promote wakefulness. sleep during the night. The interaction between the homeostatic and On the other side of the equation are multiple pathways and circadian systems allows us to get up in the morning and remain awake redundant neurotransmitters that promote wakefulness. There are and functioning for 16 hours and then to sleep for 8 hours at night. ascending pathways arising from nuclei in the brainstem that produce acetylcholine, serotonin, norepinephrine, and dopamine. These STEPHEN H. SHELDON, DO, FAAP: What are the particular neurotransmitters, along with histamine, which is produced in the neural pathways that control the sleep-wake cycle? hypothalamus, all have a stimulating effect. Some of these pathways pass through the thalamus, and others are wired directly into the DAVID NEUBAUER, MD: Our best understanding of the regulation hypothalamus. of sleep and waking from a neurobiological point of view is what is Current evidence suggests that the orexin system, which is housed in sometimes described as the flip-flop switch model. This model highlights the hypothalamus, ultimately coordinates these stimulatory activities via the activity of different nuclei in the hypothalamus, particularly the its widespread projections into other wake-promoting regions. ventrolateral preoptic nucleus (the VLPO), and related regions. “Current evidence suggests that “…understanding of the the orexin system, which is housed regulation of sleep and waking in the hypothalamus, ultimately from a neurobiological point of coordinates these stimulatory view is…sometimes described activities via its widespread as the flip-flop switch model… projections into other wake- (and) highlights the activity promoting regions.” of different nuclei in the – Dr. Neubauer hypothalamus, particularly the STEPHEN H. SHELDON, DO, FAAP: ventrolateral preoptic nucleus What is the role of melatonin? DAVID NEUBAUER, MD: We have already discussed the role of the (the VLPO), and related regions.” homeostatic and circadian systems and how they regulate the ability to be active 16 hours of the day and then able to sleep at night. Most people – Dr. Neubauer do not become progressively sleepy from the moment they awake until they go to sleep at night, despite the fact that there is an increase in the The flip-flop model emphasizes the role of the orexin homeostatic process. (hypocretin) system in promoting and stabilizing the waking state. The homeostatic process is offset by the increasing stimulation caused Briefly, there is a mutual inhibition between the systems that promote by circadian arousal. As bedtime approaches, the melatonin level gradually wakefulness and sleeping. Several different neurotransmitters are increases and the circadian arousal simultaneously decreases, leaving the involved in the promotion of sleep, with the best evidence for homeostatic drive for sleepiness unopposed. This explains why we can get gamma-aminobutyric acid (GABA), the most widespread inhibitory into bed and fall asleep pretty easily at bedtime.

11 The Future Treatment of Insomnia: Exploring the Mechanisms of Action of Current and Emerging Therapies

Melatonin facilitates sleep onset; through its circadian fluctuation, the tendency to keep us awake at particular times of the day. The melatonin levels are very low throughout the daytime, gradually rise in point at which process S dominates process C has been described as a the evening, plateau through the nighttime, and then decrease in the “switch,” but a seesaw analogy might be more appropriate if the balance morning about the time we awake. eventually is tipped one way or the other. GABA is believed to be the primary inhibitory neurotransmitter, STEPHEN H. SHELDON, DO, FAAP: We all hear about patients whereas orexin is implicated in the stimulation of the wake-promoting who have a hard time unwinding at night and have difficulty falling systems and the stabilization of the sleep-wake cycle. It has been asleep. Is this a state of hyperarousal, or is there such a state of suggested that GABA is primarily driven by the homeostatic process hyperarousal that relates to insomnia? and orexins may be more driven by the circadian process. There are data suggesting that GABA release is diminished while DAVID NEUBAUER, MD: There are several reasons why people may orexin is activated in patients with insomnia.20 We know that orexin feel like they cannot sleep because their mind is racing. Perhaps they activity is compromised in people with narcolepsy,21 and it is therefore had too much coffee after dinner, or they may have a delayed circadian logical to target the orexin system for treatment of narcolepsy, but it pattern. In this situation, their programmed biological sleep onset time may also make sense to target these neurons for treatment of insomnia. might be 3:00 am but, despite that, they go to bed at 11 pm. Many In fact, there are data suggesting that blockade of the orexin receptors patients with chronic insomnia, however, have evolved into a pattern of promotes sleep in animal models and in humans.22 hyperarousal that interferes with their ability to fall asleep. Treatment of Insomnia STEPHEN H. SHELDON, DO, FAAP: Dr. Blaivas, what are the STEPHEN H. SHELDON, DO, FAAP: clinical implications for a patient like this? Advances in our understanding of the neurobiology of sleep have been accompanied by the development of novel therapies and treatment interventions “GABA is believed to be for insomnia. Dr. Ancoli-Israel, could you discuss the primary nonpharmacological interventions used and how they might elicit their the primary inhibitory clinical effects? neurotransmitter, whereas orexin SONIA ANCOLI-ISRAEL, PhD: As mentioned earlier, CBTI has been shown to be an effective nonpharmacological approach. is implicated in the stimulation CBTI reconditions people to associate the bed with sleep by using a combination of multiple behavioral therapies; the most common of the wake-promoting systems therapy is sleep restriction and stimulus control therapy, although relaxation therapy and possibly biofeedback may be incorporated and the stabilization of the sleep- as well. Sleep restriction limits the time a person spends in bed. Decreasing the amount of time in bed increases the sleep drive, making wake cycle. It has been suggested it easier to fall asleep and stay asleep. Stimulus control is used to stop the negative maladaptive behaviors that contribute to the inability to that GABA is primarily driven sleep. Essentially, CBTI teaches patients to only go to bed when they are by the homeostatic process and sleepy and to get out of bed when they begin to feel anxious and tense about not being able to sleep. In addition, CBTI trains the person to orexins may be more driven by establish a very clear wakeup time because this helps stabilize sleep and the circadian process.” the circadian rhythm. Most patients who are compliant with behavioral changes see – Dr. Blaivas significant improvements in their sleep. Perhaps as important, if a patient who has undergone CBTI begins to experience sleep problems ALLEN J. BLAIVAS, DO: As described earlier, the sleep-wake cycle again, they already have the tools to manage their insomnia. is regulated by 2 processes: process S and process C. Process S is the homeostatic process, and process C is the circadian process. The STEPHEN H. SHELDON, DO, FAAP: Dr. Blaivas, what are some of imbalance between these 2 competing processes tips the balance from the more commonly used homeopathic remedies and over-the-counter sleep to wakefulness. (OTC) treatments for insomnia? What do we know about their efficacy Throughout the course of the day, the longer a person has been and safety? awake, the homeostatic drive promotes the release of neuromodulators that activate sleep-promoting systems and inhibit wake-promoting ALLEN J. BLAIVAS, DO: A recent systematic review on this topic 23 systems. This is counteracted by the circadian process, which has was published in Sleep Medicine Reviews in 2011. The most widely

12 The Future Treatment of Insomnia: Exploring the Mechanisms of Action of Current and Emerging Therapies

studied homeopathic remedy is valerian, which is believed to target GABA neurons. Despite attempts to establish an evidence base for use “Much of the evidence for of valerian both alone and in combination with other herbal remedies such as kava and hops, the data are relatively weak. melatonin is from circadian Another commonly used herbal medication is L-tryptophan, which is an exogenous amino acid that is converted in the body into rhythm studies rather than serotonin. As is the case with valerian, the evidence of its efficacy is limited, although the weight of the evidence suggests that L-tryptophan insomnia studies. Melatonin is may produce an increase in sleepiness and a decrease in sleep probably better at regulating latency. Sarris and Byrne concluded that there is evidence to support nonpharmacological therapies such as acupressure, tai chi, and yoga.23 circadian rhythm in instances Melatonin, as discussed earlier, is a hormone secreted by the pineal gland that helps regulate circadian rhythms. Much of the evidence such as phase delay or jet lag for melatonin is from circadian rhythm studies rather than insomnia studies. Melatonin is probably better at regulating circadian rhythm than it is at directly treating in instances such as phase delay or jet lag than it is at directly treating insomnia. A recent meta-analysis of primary sleep disorders, including insomnia.” insomnia, suggested that melatonin is effective in decreasing sleep onset latency, increasing sleep duration, and improving sleep quality.24 – Dr. Blaivas However, it was less effective compared with the effect reported for benzodiazepine and nonbenzodiazepine hypnotics. A prolonged-release DAVID NEUBAUER, MD: Another issue with antihistamine-based formulation of melatonin has been shown to increase sleep quality, sleep medications is the potentially harmful interaction between decrease sleep latency, and improve quality of life without the hangover the anticholinergic sleep aids and cholinesterase inhibitors often effects sometimes seen with hypnotic agents.25 prescribed to an elderly patient to limit memory loss. It makes no Two of the most widely used OTC sleep agents are the pharmacological sense to combine these agents in older patients. antihistamines diphenhydramine and doxylamine, which are commonly found in sleep agents labeled as a “PM” formulation and are approved STEPHEN H. SHELDON, DO, FAAP: Dr. Neubauer, could you by the Food and Drug Administration (FDA) as OTC sleep aids. These talk about some of the pharmacotherapies that are approved by the agents tend to have sedating effects, particularly in older people, and FDA? can cause significant anticholinergic actions resulting in dry mouth, constipation, urinary retention, confusion and delirium, and next- DAVID NEUBAUER, MD: There are 3 broad categories of day hangover effects. Additionally, continued use of these agents can medications approved by the FDA for treating insomnia: the result in loss of response due to tolerance, leading to dose escalation to benzodiazepine and nonbenzodiazepine receptor agonist hypnotics, dangerous levels. the melatonin receptor agonists, and the selective histamine receptor antagonists. The first agents in the class of benzodiazepine STEPHEN H. SHELDON, DO, FAAP: Do OTC sleep aids have receptor agonist hypnotics were approved in the early 1970s and had other significant side effects or adverse reactions when used alone or in a benzodiazepine structure. More recent generations of these agents combination? have a different structure but similar pharmacodynamic activity. These are typically referred to as the nonbenzodiazepine hypnotics. ALLEN J. BLAIVAS, DO: Generally, herbal remedies are relatively Both the benzodiazepines and the nonbenzodiazepines are harmless with the exception of kava, which is no longer sold in many positive allosteric modulators of GABA. Normally, when GABA countries because of concerns about hepatotoxicity. None of the attaches to the GABA-A receptor, there is a central chloride channel homeopathic remedies are well regulated; the FDA does not review and that allows negative chloride ions to enter the cell, stabilizing the approve them, so despite what the packaging might say, there are no membrane and decreasing the likelihood of an action potential guarantees of purity, efficacy, or safety. occurring. These medications enhance the normal action of GABA. They are allosteric because they have a separate attachment site on SONIA ANCOLI-ISRAEL, PhD: Because OTC sleep aids are the larger GABA-A receptor complex. When a benzodiazepine-type relatively inexpensive and can be purchased in any drugstore or agonist is attached to the GABA-A receptor complex, it allows more supermarket, many people assume that they can be used without risk of negative chloride ions into the cell than when GABA alone attaches. side effects. Granted, when used appropriately, these agents are safe for This is referred to a positive allosteric modulation of GABA-A many patients, but confusion, dizziness, next-day grogginess, and the activity. potential for tolerance can make these agents dangerous, particularly for elderly people.

13 The Future Treatment of Insomnia: Exploring the Mechanisms of Action of Current and Emerging Therapies

the early part of the night may benefit from treatment with ramelteon. “…benzodiazepines and the The third category contains the selective histamine receptor antagonist doxepin. Doxepin was initially approved for the treatment nonbenzodiazepines are positive of depression in 1969, and now low-dose doxepin is labeled for the treatment of insomnia characterized by difficulty maintaining allosteric modulators of GABA. sleep. The exact mechanism by which the medication exerts its Normally, when GABA attaches sleep maintenance effect is unknown, but it is thought to be highly selective for the histamine H1 receptors. This high degree of selectivity, to the GABA-A receptor, there is combined with a low dose, can help to minimize the adverse events frequently experienced with OTC antihistamine-based sleep aids. a central chloride channel that The approved dosing of doxepin for insomnia is 3 to 6 mg at bedtime, whereas the prescribing guidelines for major depression are as allows negative chloride ions high as 300 mg daily.28 to enter the cell, stabilizing the STEPHEN H. SHELDON, DO, FAAP: You mentioned the sedating effect of these classes of medications. Does this result in normal sleep, membrane and decreasing the or is there an effect on sleep structure architecture that is different from likelihood of an action potential normal sleep? DAVID NEUBAUER, MD: In most cases, these agents do not alter occurring.” the key indicators tracked in a polysomnographic study. There may be small changes in slow wave sleep with the benzodiazepine types of – Dr. Neubauer medications, but at the recommended doses, either with ramelteon or with low-dose doxepin, these are not significant changes. There were 5 original benzodiazepines, some of which are still available. Three newer-generation compounds, including zaleplon, STEPHEN H. SHELDON, DO, FAAP: Are these medications zolpidem, and eszopiclone, are currently available in the United appropriate for long-term use? States. These agents are differentiated by the pharmacokinetics of their formulations; zaleplon has a very short half-life, zolpidem has a DAVID NEUBAUER, MD: The label for each product clearly relatively short to intermediate half-life, and the half-life is eszopiclone indicates how long these agents can be used. For example, the labels is somewhat longer. of the benzodiazepines and the nonbenzodiazepines zolpidem and Compared with the older agents, the half-life of the zaleplon all say that they are indicated for the short-term treatment of nonbenzodiazepines is moderately short. However, zolpidem is available insomnia. in an extended-release formulation, and alternate delivery formulations With greater clinical experience and the recognition that many include a dissolving formulation that can be used at bedtime. There is patients have benefited from continued treatment without an increased also middle of the night dissolvable dosing for people with middle of number of adverse events, the FDA changed its approach to labeling the night awakenings and an oral spray version as well. some of the newer agents. For example, the label for eszopiclone does The efficacy of the benzodiazepines and nonbenzodiazepines not contain wording about short-term use. It was simply approved for depends on the individual patient and the nature of the underlying the treatment of insomnia, and there is no implied limitation on the sleep problems. The basic activity of these agents is to promote sedation. duration of use. This is also true for ramelteon and low-dose doxepin. Several safety concerns of these medications should also be mentioned. The one exception to this trend seems to be for the newer Agents with longer half-lives pose a greater risk of promoting excessive formulations of zolpidem, including the oral spray and the bedtime sleepiness or impairment lingering into the daytime. dissolvable formulation. These formulations still carry the duration The FDA has highlighted that concern and in 2013 recommended limitations in their labels because the approval of these new a reduction in the initial dose of zolpidem in women because they formulations was based on earlier efficacy studies. tend to metabolize it more slowly.26 In May 2014, the FDA decreased the recommended starting dose of eszopiclone from 2 mg to 1 mg for STEPHEN H. SHELDON, DO, FAAP: Are there other prescription both men and women. The 1-mg dose can be increased to 2 mg or 3 medications with sedating effects that are used for the treatment of mg if needed, but the higher doses are more likely to result in next-day insomnia in an off-label manner? impairment of driving and other activities that require full alertness.27 The second category consists of the melatonin receptor agonists. DAVID NEUBAUER, MD: Many agents are used off-label for the There is only one approved agent in this category, ramelteon, which is treatment of insomnia, including sedating antidepressants, other indicated for the treatment of insomnia characterized by difficulty with benzodiazepines, mood stabilizers, and sedating antipsychotics. Perhaps sleep onset. People who have difficulty falling asleep or staying asleep in the best time to use these sedating agents is when a patient has the

14 The Future Treatment of Insomnia: Exploring the Mechanisms of Action of Current and Emerging Therapies

appropriate comorbid condition such as a depressive or psychotic ALLEN J. BLAIVAS, DO: Orexin antagonists allow patients to sleep disorder. However, there are only limited efficacy and safety data on by inhibiting the excitatory input to the arousal system rather than the off-label use of these products as sleep-promoting agents in patients imposing a sedative-like effect, like the GABAergic drugs do. This is who do not present with an appropriate comorbidity. a unique mechanism of action. Orexin antagonists may selectively promote sleep without the side effects seen with the sedating agents STEPHEN H. SHELDON, DO, FAAP: Is there potential value of an such as a hangover effect, balance problems, parasomnias, and tolerance agent targeting orexins for the treatment of insomnia? with prolonged use.

DAVID NEUBAUER, MD: Because the orexin system plays a central role in the regulation of sleep and waking, it is an appealing therapeutic “Orexin antagonists may target. As we discussed earlier, there are data suggesting that the orexin system may drive the excessive arousal seen in many patients with selectively promote sleep chronic insomnia. Thus, it is appealing to consider if interventions designed to reduce orexin activity will have a positive effect on sleep. without the side effects seen with the sedating agents such “Because the orexin system plays as a hangover effect, balance a central role in the regulation problems, parasomnias, and of sleep and waking, it is an tolerance with prolonged use.” appealing therapeutic target. As – Dr. Blaivas we discussed earlier, there are It may be that many patients with treatment-resistant insomnia are data suggesting that the orexin actually overaroused and that treatment of these patients with GABA- targeted agents will continue to fail because they do not address the system may drive the excessive root cause of the insomnia. In theory, treatment of these patients with arousal system antagonists should help. arousal seen in many patients with chronic insomnia.” Summary STEPHEN H. SHELDON, DO, FAAP: This has been a fascinating – Dr. Neubauer discussion. Summarizing briefly, 7 to 8 hours of sleep each night is recommended for adults, but this is an often unattainable goal STEPHEN H. SHELDON, DO, FAAP: Dr. Ancoli-Israel, are there in people with insomnia. Although sleeplessness is one of the most any robust clinical data on the efficacy and safety of agents that target common symptoms voiced by patients during a primary care office the orexin system? visit, insomnia is often underdiagnosed. There are a number of consequences of undiagnosed and untreated insomnia, and those SONIA ANCOLI-ISRAEL, PhD: Several phase 3 studies enrolling who sleep less are more likely to have chronic illness and a low quality more than 300 patients have been conducted to investigate the long- of life. There are several nonpharmacological and pharmacological term safety and efficacy of antiorexin therapies. Specifically, these approaches to the treatment of insomnia, including cognitive studies were designed to determine the effects of orexin-targeted agents behavioral interventions, homeopathic and herbal remedies, OTC on sleep induction and sleep maintenance assessed at various time agents, FDA-approved prescription drugs indicated for the treatment points, including 1 week, 1 month, 3 months, and 1 year.29-32 of insomnia, and approved drugs used off-label for the treatment of the The results of these trials indicated that these agents are efficacious condition. Targeting the arousal system is an exciting and novel new for sleep onset and sleep maintenance in both elderly and nonelderly direction in the treatment of insomnia. We all look forward to gaining populations. The effect is observed as early as the first night the drug is clinical experience with these novel medications and more guidance taken and lasts for up to 1 year. These agents are generally safe and well about appropriate dosing and possible adverse effects. tolerated on both a short-term and long-term basis.

STEPHEN H. SHELDON, DO, FAAP: Dr. Blaivas, based on these The FDA approved BELSOMRA® (suvorexant) for adults with insomnia 33 data, how do these agents compare with currently approved insomnia who have difficulty falling asleep and/or staying asleep in August 2014. therapy?

15 The Future Treatment of Insomnia: Exploring the Mechanisms of Action of Current and Emerging Therapies

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16 The Future Treatment of Insomnia: Exploring the Mechanisms of Action of Current and Emerging Therapies

The Future Treatment of Insomnia: Exploring the Mechanisms of Action of Current and Emerging Therapies