New Directions. Management of. Insomnia. Balancing Pathophysiology andtherapeutics. in the. Proceedings From an Expert Roundtable Discussion

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1 New Directions in the Management of Insomnia Balancing Pathophysiology andtherapeutics Proceedings From an Expert Roundtable Discussion Release date: October 10, 2013 Expiration date: October 31, 2014 Estimated time to complete activity: 1.5 hours Jointly sponsored by Postgraduate Institute for Medicine and MedEdicus LLC This activity is supported by an educational grant from Merck & Co. Distributed with

2 2 Faculty Larry Culpepper, MD, MPH Co-Chair Professor and Chairman of Family Medicine Boston University School of Medicine Boston University Medical Center Boston, Massachusetts Tom Roth, PhD Co-Chair Director of Research Sleep Disorders and Research Center Henry Ford Hospital Detroit, Michigan Sonia Ancoli-Israel, PhD Professor Emeritus of Psychiatry and Medicine Professor of Research University of California, San Diego La Jolla, California Andrew Krystal, MD Director, Insomnia and Sleep Research Program Professor of Psychiatry and Behavioral Sciences Duke University Medical Center Durham, North Carolina Phyllis Zee, MD, PhD Benjamin and Virginia T. Boshes Professor in Neurology Director, Sleep Disorders Center Northwestern University Chicago, Illinois Target Audience This activity has been designed to meet the educational needs of physicians involved in the management of patients with insomnia disorder. Statement of Need/Program Overview An estimated 40 to 70 million Americans are affected by insomnia. According to these estimates, twice as many Americans suffer from insomnia than from major depression. However, the true prevalence of insomnia is unknown because it is underdiagnosed and underreported. Recent updates in the nosology and diagnostic criteria for insomnia have occurred as well as advances in understanding pathophysiology, which, in turn, has led to the development of potential new treatments. The burden of medical, psychiatric, interpersonal, and societal consequences that can be attributed to insomnia and the prevalence of patients with insomnia disorder treated in primary care underscore the importance of continuing medical education (CME) that improves the clinical understanding, diagnosis, and treatment of the disorder by primary care providers. This continuing education activity is based on an expert roundtable discussion and literature review and provides an update in insomnia disorder. Educational Objectives After completing this activity, the participant should be better able to: Perform a rapid assessment that leads to a diagnosis of insomnia disorder Summarize the proposed pathophysiology of insomnia disorder Evaluate current and emerging nonpharmacologic and pharmacologic therapies for insomnia disorder Appropriately select therapy for individual patients with insomnia disorder Accreditation Statement This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education through the joint sponsorship of Postgraduate Institute for Medicine and MedEdicus LLC. The Postgraduate Institute for Medicine is accredited by the ACCME to provide continuing medical education for physicians. Credit Designation The Postgraduate Institute for Medicine designates this enduring material for a maximum of 1.5 AMA PRA Category 1 Credit(s). Physicians should claim only the credit commensurate with the extent of their participation in the activity. Disclosure of Conflicts of Interest Postgraduate Institute for Medicine (PIM) requires instructors, planners, managers, and other individuals who are in a position to control the content of this activity to disclose any real or apparent conflict of interest (COI) they may have as related to the content of this activity. All identified COI are thoroughly vetted and resolved according to PIM policy. PIM is committed to providing its learners with high quality CME activities and related materials that promote improvements or quality in healthcare and not a specific proprietary business interest of a commercial interest.

3 Faculty Disclosures The faculty reported the following financial relationships or relationships to products or devices they or their spouse/life partner have with commercial interests related to the content of this CME activity: Sonia Ancoli-Israel, PhD, had a financial agreement or affiliation during the past year with the following commercial interests in the form of Consultant Fees: Ferring Pharmaceuticals; Merck & Co.; and Prudue Pharma L.P. Larry Culpepper, MD, MPH, had a financial agreement or affiliation during the past year with the following commercial interests in the form of Consultant Fees: Boehringer Ingelheim Pharmaceuticals Inc.; Forest Labs; Janssen Pharmaceuticals, Inc.; Jazz Pharmaceuticals plc; H. Lundbeck A/S; Merck & Co.; Pfizer Inc.; Reckitt Benckiser Pharmaceuticals Inc.; Sunovion Pharmaceuticals Inc.; and Takeda Pharmaceuticals Inc. Speakers Bureau: Merck & Co. Ownership Interest: M3 (My Mood Monitor). Andrew Krystal, MD, had a financial agreement or affiliation during the past year with the following commercial interests in the form of Consultant Fees: Abbott Laboratories; AstraZeneca; Bristol-Myers Squibb; Eisai Inc.; Jazz Pharmaceuticals plc; Johnson & Johnson; Merck & Co.; Neurocrine Biosciences, Inc.; Novartis; Respironics, Inc.; Roche; Sunovion Pharmaceuticals Inc.; and Teva Pharmaceutical Industries Ltd. Contracted Research: Abbott Laboratories; Astellas Pharma; Brainsway; National Institutes of Health; NeoSynch; Pfizer Inc.; St. Jude Medical (for Advanced Neuromodulation Systems [ANS]); and Teva Pharmaceutical Industries Ltd. Tom Roth, PhD, had a financial agreement or affiliation during the past year with the following commercial interests in the form of Consultant Fees: Jazz Pharmaceuticals plc; Merck & Co.; Neurocrine Biosciences, Inc.; Novartis; Pfizer Inc.; Purdue Pharma L.P.; Speakers Bureau: Purdue Pharma L.P. Contracted Research: Impax Laboratories, Inc.; Valeant Pharmaceuticals (for CeraVe). Phyllis C. Zee, MD, PhD, had a financial agreement or affiliation during the past year with the following commercial interests in the form of Consultant Fees: Ferring Pharmaceuticals; Jazz Pharmaceuticals plc; Merck & Co.; Purdue Pharma L.P.; Takeda Pharmaceuticals Inc.; Vanda Pharmaceuticals Inc.; and UCB, Inc. Contracted Research: Philips Respironics. Ownership Interest: Teva Pharmaceutical Industries Ltd. The planners and managers reported the following financial relationships or relationships to products or devices they or their spouse/life partner have with commercial interests related to the content of this CME activity: The following PIM planners and managers, Laura Excell, ND, NP, MS, MA, LPC, NCC, Trace Hutchison, PharmD, Samantha Mattiucci, PharmD, CCMEP, and Jan Schultz, RN, MSN, CCMEP, and the following MedEdicus editors and planners, Casey Covrett, PharmD, BCPS, and Cynthia Tornallyay, RD, MBA, CCMEP, hereby state that they or their spouse/life partner do not have any financial relationships or relationships to products or devices with any commercial interest related to the content of this activity of any amount during the past 12 months. Method of Participation and Request for Credit There are no fees for participating and receiving CME credit for this activity. During the period October 10, 2013, through October 31, 2014, participants must read the learning objectives and faculty disclosures and study the educational activity. PIM supports Green CME by offering your Request for Credit online. If you wish to receive acknowledgment for completing this activity, please complete the post-test and evaluation on On the navigation menu, click on Find Post-test/Evaluation by Course and search by course ID Upon registering and successfully completing the post-test with a score of 70% or better and the activity evaluation, your certificate will be made available immediately. Media Monograph Disclosure of Unlabeled Use This educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the FDA. The planners of this activity do not recommend the use of any agent outside of the labeled indications. The opinions expressed in the educational activity are those of the faculty and do not necessarily represent the views of the planners. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications, and warnings. Disclaimer Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for patient management. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by clinicians without evaluation of their patient s conditions and possible contraindications and/or dangers in use, review of any applicable manufacturer s product information, and comparison with recommendations of other authorities. 3

4 4 Introduction An estimated 40 to 70 million Americans have insomnia. 1 According to these estimates, twice as many Americans suffer from insomnia than from major depression. 2 Patients with insomnia frequently report physical and emotional health problems, compromised social functioning, and daytime distress. Common risk factors for insomnia include female gender, advanced age, comorbid disease, and occupations involving shift work. Importantly, comorbid medical disorders are becoming more appreciated as risk factors for insomnia. Work productivity is negatively impacted by insomnia. In the 2009 US Workers America Insomnia Survey, presenteeism (low on-the-job work performance defined in the metric of lost workday equivalents) accounted for nearly 8 days of annual lost work performance per worker, equating to $2280 in individual-level human capital value. When extrapolated to the entire US workforce over the course of a year, insomnia causes million days of lost work performance, resulting in a loss of $63.2 billion. 3 The magnitude of insomnia-related problems has spurred research, resulting in an improved understanding of the disorder. Over the past decade, several changes have been made with regard to the nosology of insomnia, most notably the recent realization that insomnia is a disorder. In the past, insomnia was thought to be secondary to another medical condition. The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), has recently renamed the diagnosis as insomnia disorder, emphasizing that insomnia is a disorder in its own right even though it typically coexists with other comorbid medical conditions, including depression, anxiety, chronic pain, and cardiovascular diseases. 4 In addition, the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision, diagnostic criteria have been updated in the DSM-5 to include more stringent measures regarding the chronicity of insomnia-related symptoms. For the purpose of this monograph, the term insomnia will be used as a disorder that meets the DSM-5 criteria, which include the following: (1) difficulty falling and/or staying asleep; (2) the sleep difficulty is accompanied by next-day symptoms of distress/impairment; (3) sleep-related symptoms occur at least 3 times per week for a minimum of 3 months; and (4) symptoms persist despite adequate opportunities and circumstances to sleep. 4 Insomnia is a prevalent and costly public health concern that is associated with significant long-term effects on physical, psychological, and occupational functioning. In order to minimize the societal impact of insomnia and the burden it creates on the healthcare system, families, and patients, clinicians need to improve their recognition and treatment of insomnia as well as coexisting medical conditions. This approach starts with having an initial discussion with patients regarding the quality of their sleep. Despite its prevalence, insomnia remains undertreated and underreported. Patients are reluctant to seek medical treatment, and sleep is not commonly discussed during office visits. This continuing medical education/continuing education (CME/CE) activity is designed to update readers on the pathophysiology of insomnia, the interrelationships of insomnia and comorbid disease, and new directions in the management of insomnia. Pathophysiology of Insomnia Current research suggests that insomnia is a disorder of hyperarousal that is present 24 hours each day. The pathophysiology of insomnia is multifactorial and may be thought of in terms of dysregulation involving the following 3 components: neurophysiologic hyperactivation of the sympathetic nervous system; neuroendocrine dysregulation of hormones associated with arousal; and cognitive/behavioral responses directed toward sleep that perpetuate arousal. Expert insights on the pathophysiology of insomnia from the roundtable discussion will be presented. Figure 1 presents a schematic diagram of the 24-hour sleep-wake cycle. 5 Dr Tom Roth: For years we had this idea that insomnia is an abnormality of the sleep system. Increasingly, we have learned that insomnia is not an abnormality of the sleep system, but it is an abnormality of the wake/arousal system. Over a decade ago, Saper and colleagues proposed the flip-flop switch model of sleep-wake regulation, 6 which contains 2 sets of mutually inhibitory neural elements: wake-promoting influences on 1 side and sleep-promoting influences on the other. The monoaminergic nuclei (MN) are a major influence of the wake-promoting system, and sleep is influenced by the ventrolateral preoptic nucleus (VLPO), which is a group of cells that generate non-rapid eye movement (NREM) and rapid eye movement (REM) stages of sleep (Figure 2). 5 In patients with normal sleep, the flip-flop switch makes sudden transitions between sleep and wakefulness, which explains why a limited amount of time is spent in these transitional states throughout the course of a 24-hour day (Figure 3). 6 In patients with insomnia, however, their ability to turn off the wake-promoting influences of the flip-flop switch is weakened, resulting in extended periods of time in transitional states and a prolonged state of wake. For years we had this idea that insomnia is an abnormality of the sleep system. Increasingly, we have learned that insomnia is not an abnormality of the sleep system, but it is an abnormality of the wake/arousal system. Dr Tom Roth Dr Andrew Krystal: There are a number of objective measures that support this model of hyperarousal, including elevations in heart rate and heart rate variability. For example, Bonnet and Arand performed a 36-hour study that showed the heart rate increased and the mean heart rate variability decreased in all stages of sleep in the group of people with insomnia compared to the control group of people who have normal sleep. 7 Studies have also found that patients with insomnia, when compared to controls, have higher metabolic rates throughout the course of a 24-hour day, further suggesting arousal in the wake-promoting regions in the brain. 8 Dr Larry Culpepper: There appears to be a neuroendocrine component to this condition as well. Vgontzas and colleagues found that levels of adrenocorticotropic hormone and cortisol were significantly elevated in patients with insomnia compared to matched controls, which results in increased arousal and associated sleeplessness. In addition, patients with a higher degree of sleep disturbance secreted more cortisol compared to those with less sleep disturbance. 9

5 Hour 0 Hour 24 NREM REM Wake ~ 16 hrs 2/3 of Sleep-Wake Cycle Sleep~ 8 hrs 1/3 of Sleep-Wake Cycle Figure 1. A schematic diagram of the sleep-wake cycle. When transitioning into sleep, an individual begins in non-rapid eye movement (NREM) and remains in this stage for approximately 85 minutes. After this initial stage of NREM, the brain switches to rapid eye movement (REM) for approximately 5 to 10 minutes before switching back to NREM. This 90-minute pattern continues throughout the night, with REM intervals becoming longer and NREM intervals becoming shorter until wakefulness occurs. Disruptions in this defined pattern of sleep and wakefulness result in disturbances in sleep. Adapted from Rogers and Holmes, Dr Phyllis Zee: Stepanski and colleagues compared polysomnography and multiple sleep latency test data from patients seeking evaluation for chronic insomnia with data from patients without sleep problems. 11 The insomnia group slept significantly less than the control group, yet they were significantly less sleepy the next day compared with matched controls. This study found that if given the chance to sleep during the day, patients with insomnia take longer than the general population to fall asleep. Insomnia is a 24-hour disorder of hyperarousal associated with difficulty sleeping at any time of day. Insomnia is a 24-hour disorder of hyperarousal associated with difficulty sleeping at any time of day. Dr Phyllis Zee Figure 2. A schematic of the sleep-promoting and wake-promoting areas of the human brain. There are multiple cell groups in the brain that contribute to the sleep-wake system. The monoaminergic nuclei (MN) are responsible for promoting wakefulness, while the ventrolateral preoptic nucleus (VLPO) promote sleep. Monoaminergic nuclei of the arousal pathway include noradrenergic, serotonergic, dopaminergic, and histaminergic neurons located in the pedunculopontine and laterodorsal tegmental nucleus (PPT/LDT), locus coeruleus (LC), dorsal and median raphe nucleus (RN), and tuberomammillary nucleus (TMN), respectively. Every 24 hours the arousal system is overtaken by inhibitory neurons of the VLPO, resulting in the transition from wakefulness to sleep. Dr Andrew Krystal: Positron emission tomography has shown that patients with insomnia exhibit greater brain glucose metabolism during sleep and wake periods compared to people who have normal sleep, indicating the inability of patients with insomnia to appropriately transition from wake to sleep. 10 Table 1 lists elevated physiologic factors that have been observed in patients who have insomnia, which are suggestive of hyperarousal. Dr Sonia Ancoli-Israel: This inability to sleep during the day highlights why the initial assessment of sleep-related symptoms is so important. If patients indicate they re having difficulty sleeping at night but they sleep well during the day, it is less likely to be insomnia. Someone with insomnia has difficulty falling asleep during the day as much as they do at night. Someone with insomnia has difficulty falling asleep during the day as much as they do at night. Dr Sonia Ancoli-Israel Table 1. Physiologic Factors Increased During Sleep in Patients With Insomnia Body temperature Brain glucose metabolism Resting heart rate Cortisol level Electroencephalogram beta wave activity Dr Phyllis Zee: There are primarily 3 different ways to promote wakefulness: (1) blocking the sleep promoting neurons in the VLPO; (2) exciting the monoaminergic nuclei associated with the wake system; and (3) stimulation of the orexin neurons. Dr Tom Roth: I think all of you bring up a great point. When patients with insomnia get out of bed at 7 o clock in the morning, their insomnia has not gone away. For patients who have 5

6 6 24 hours a day that expresses itself periodically. The criteria for insomnia disorder specify that sleep disturbances must occur at least 3 days a week for a minimum of 3 months for us to consider a diagnosis of insomnia. 4 Dr Larry Culpepper: What do we know about the underlying brain activity or factors that contribute to this hyperarousal? Dr Andrew Krystal: I don t think we know all that much about it. We know the wake system is more active during sleep in patients with insomnia, at least to some degree. Additionally, the psychopathological and behavioral patterns of sleep appear to play a significant role in some patients with sleep problems. For example, when people experience multiple nights of bad sleep and frustration within their sleeping environment, they begin to develop the expectation of poor sleep. This expectation becomes a perpetuating factor that creates stress and increased activity of the sympathetic nervous system. In addition to the neuroendocrine and physiologic components of hyperarousal, there appears to be a behavioral/psychopathological element to this condition. Figure 3. A schematic drawing of the flip-flop switch model of sleep-wake regulation. The interaction between the ventrolateral preoptic nucleus (VLPO) and the arousal pathways (Orexin [ORX], locus coeruleus [LC], dorsal and median raphe nucleus [Raphe], and tuberomammillary nucleus [TMN]) is mutually inhibiting, functioning like an on-off (flip-flop) switch. This flip-flop switch ensures stability between sleep and wakefulness, which results in normal sleep patterns. Insomnia causes dysregulation of the switch, resulting in irregular transitioning between sleep-wake states and fragmented sleep. Reprinted with permission, Saper et al, myocardial ischemia, we find that just because they don t have angina 24 hours a day doesn t mean their cardiovascular function is normal all of a sudden. People who have insomnia are not symptomatic 24 hours a day, 7 days a week. They have insomnia Updates in the Diagnostic Criteria and Nosology of Insomnia The diagnostic criteria for insomnia have undergone recent changes with the finalization of the DSM-5, most notably with the chronicity of sleep-related disturbances, which the faculty will discuss. In addition, insomnia has been renamed insomnia disorder, emphasizing the point that while insomnia typically coexists with other medical conditions, it requires separate clinical attention. Becoming more aware of the numerous comorbid conditions associated with insomnia is important and may assist clinicians in better recognizing and managing insomnia. The following discussion provides insight into the clinical implications of recent changes in the diagnostic criteria and the significance of comorbid conditions associated with insomnia. Table 2. Insomnia Severity Index 13 Please circle the number that best describes your CURRENT severity level of sleep problem(s). Please rate this past week s severity of the following insomnia problems: None Mild Moderate Severe Very severe 1. Difficulty falling asleep Difficulty staying asleep Waking up too early How satisfied/dissatisfied are you with your current sleep pattern? 5. How noticeable to others do you think your sleep problem is in terms of impairing the quality of your life? 6. How worried/distressed are you about your current sleep problem? 7. To what extent do you consider your sleep problem to interfere with your daily functioning (mood, concentration, work)? Very satisfied Satisfied Moderately satisfied Dissatisfied Very dissatisfied Not at all A little Somewhat Much Very much Scoring: 0-7 No clinically significant insomnia; 8-14 Sub-threshold insomnia; Moderate clinical insomnia; Severe clinical insomnia. Adapted from Morin et al,

7 Table 3. DSM-5 Insomnia Disorder Criteria (G47.00) A. A predominant complaint of dissatisfaction with sleep quantity or quality, associated with one (or more) of the following symptoms: 1. Difficulty initiating sleep. (In children, this may manifest as difficulty initiating sleep without caregiver intervention.) 2. Difficulty maintaining sleep, characterized by frequent awakenings or problems returning to sleep after awakenings. (In children, this may manifest as difficulty returning to sleep without caregiver intervention.) 3. Early-morning awakening with inability to return to sleep. B. The sleep disturbance causes clinically significant distress or impairment in social, occupational, educational, academic, behavioral, or other important areas of functioning. C. The sleep difficulty occurs at least 3 nights per week. D. The sleep difficulty is present for at least 3 months. E. The sleep difficulty occurs despite adequate opportunity for sleep. F. The insomnia is not better explained by and does not occur exclusively during the course of another sleep-wake disorder (e.g., narcolepsy, a breathing-related sleep disorder, a circadian rhythm sleep-wake disorder). G. The insomnia is not attributable to the physiological effects of a substance (e.g., a drug of abuse, a medication). H. Coexisting mental disorders and medical conditions do not adequately explain the predominant complaint of insomnia. Specify if: With non sleep disorder mental comorbidity, including substance use disorders With other medical comorbidity With other sleep disorder Coding note: The code (G47.00) applies to all three specifiers. Code also the relevant associated mental disorder, medical condition, or other sleep disorder immediately after the code for insomnia disorder in order to indicate the association. Specify if: Episodic: Symptoms last at least 1 month but less than 3 months. Persistent: Symptoms last 3 months or longer. Recurrent: Two (or more) episodes within the space of 1 year. Note: Acute and short-term insomnia (i.e., symptoms lasting less than 3 months but otherwise meeting all criteria with regard to frequency, intensity, distress, and/or impairment) should be coded as other specified insomnia disorder. Reprinted with permission from the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, (Copyright 2013). American Psychiatric Association. All Rights Reserved. Dr Larry Culpepper: In terms of how you define and diagnose insomnia, what are some key principles that primary care clinicians should know? Dr Sonia Ancoli-Israel: I think it s important for primary care clinicians to, first of all, ask their patients about sleep. Research has shown that 70% of the clinicians don t ask their patients about sleep, and more than 50% of the patients don t talk about it. 12 Thus, the first step is to determine the overall sleep-wake status of the patient. If the patient responds that he or she is experiencing sleep problems, then it takes a little more in-depth questioning regarding the specific symptoms of insomnia and their frequency and severity. There are several questionnaires including the Insomnia Severity Index (Table 2) 13 and the Epworth Sleepiness Scale that clinicians can use to facilitate sleep-related discussion with their patients. I think it s important for primary care clinicians to, first of all, ask their patients about sleep. Dr Sonia Ancoli-Israel Dr Tom Roth: I think it s also important for clinicians to differentiate sleep disturbance from insomnia because they are not the same thing. When there are inadequate opportunities or circumstances to sleep, sleep disturbances typically occur. But that is not insomnia. An insomnia diagnosis is made when a patient meets the following 4 criteria (Table 3): (1) nighttime symptoms of difficulty falling asleep and/or staying asleep; (2) next-day symptoms of distress/impairment; (3) symptoms occur at least 3 times per week for a minimum of 3 months; and (4) symptoms persist despite adequate opportunity and circumstances to sleep. 4 Comorbid Conditions Associated With Insomnia Dr Phyllis Zee: I would add that insomnia is now listed as insomnia disorder in the DSM-5 and the International Classification of Sleep Disorders, Third Edition (ICSD-3) diagnostic manuals. In the past, insomnia was labeled as primary (the absence of an adjunct comorbid condition) or secondary (insomnia arising in the context of another disorder). Although insomnia is often associated with other conditions, such as pain, depression, anxiety, and cardiovascular diseases, insomnia is its own distinct disorder (Table 4). 14 Table 4. Prevalence of People With Insomnia and Comorbid Medical Conditions 14 Comorbid condition Prevalence of insomnia In the presence of comorbid condition % In the absence of comorbid condition % Cardiovascular disease Hypertension Heart disease Musculoskeletal disease Arthritis Back or neck pain Digestive disorders Diarrhea, constipation, or gas Gastroesophageal reflux disease (GERD) Sleep disorders Sleep apnea Restless leg syndrome Emotional disorders Major depressive disorder Generalized anxiety disorder

8 8 Dr Sonia Ancoli-Israel: And since insomnia is its own disorder, you treat it once you ve made a diagnosis. And since insomnia is its own disorder, you treat it once you ve made a diagnosis. Dr Sonia Ancoli-Israel Dr Larry Culpepper: It s also important to remember that the very treatment of the comorbid condition itself may lead to insomnia-related symptoms. Respiratory stimulants, selective serotonin reuptake inhibitors, beta blockers, and many other drug classes are associated with reports of disturbed sleep (Table 5). 19 Table 5. Common Medications That Contribute to Insomnia 19 Dr Larry Culpepper: I think what Dr Ancoli-Israel mentioned is the single most important message to relay to primary care clinicians. In the past, we clinicians have been under the false impression that when an existing comorbid condition resolves for instance, depression insomnia would go away as well. And that, quite often, is not the case. Drug class Antidepressants Decongestants Cardiovascular Respiratory Stimulants Medications Selective serotonin reuptake inhibitors (fluoxetine, citalopram, sertraline, paroxetine), venlafaxine, duloxetine Pseudoephedrine, phenylephrine Beta blockers, alpha-receptor antagonists, diuretics Theophylline, albuterol Methylphenidate, ephedrine, amphetamines Dr Tom Roth: If you look at people with depression when they go into remission, the most common residual symptom is difficulty sleeping. It is important to understand that the number of residual symptoms linearly predicts time to relapse of depression. The Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial described the types and frequency of residual depressive symptoms and their relationship to depressive relapse after treatment with citalopram. 15 More than 90% of the patients with depression who went into remission had at least 1 residual depressive symptom, and the most common residual symptom domain was sleep-related disturbance (71.7%). 15 The study revealed that having a greater number of residual symptoms was associated with a higher probability of relapse. The point is that treating insomnia enables you to better manage coexisting disorders. Dr Andrew Krystal: As mentioned earlier, the error clinicians have made in the past is undertreating insomnia, expecting insomnia to get better once the symptoms of a comorbid condition improved. Moreover, clinicians should consider the possibility of underlying comorbid conditions when patients present with symptoms suggestive of insomnia. Research shows that insomnia is a known risk factor for other disorders, most notably depression and anxiety. One of the classic studies, the Johns Hopkins Precursors Study, evaluated the associations between self-reported sleep disturbances and subsequent clinical depression among medical students (classes ; mean follow-up period of 34 years). 16 Patients who reported insomnia symptoms during medical school were twice as likely to develop clinical depression compared to those without insomnia symptoms. Clinicians need to assess whether or not there are underlying comorbid conditions, such as depression, which may be intensifying the symptoms of insomnia. Dr Phyllis Zee: There is also research to suggest that insomnia may serve as a risk factor of cardiometabolic disease. A recent study that evaluated the impact of sleep on levels of fasting glucose, fasting insulin, and estimated insulin resistance showed that insomnia was associated with a 23% higher fasting glucose level and a 48% higher fasting insulin level in patients with type 2 diabetes. 17 In addition, Vgontzas and colleagues evaluated the joint effects of insomnia and short sleep duration on diabetes risk. 18 They showed that patients with insomnia and sleep duration of less than 5 hours were at significantly higher risk of developing diabetes compared to people who have normal sleep. Opioids Differentiating Circadian Rhythm Disorders From Insomnia Insomnia is occasionally comorbid with other sleep conditions, including disorders in circadian rhythm. Table 6 lists common circadian rhythm sleep disorders (CRSDs) that may occur in conjunction with insomnia 20 ; however, the effective treatments for CRSDs are very different, emphasizing the importance of differentiating sleep-related symptoms of CRSDs from insomnia. Table 6. Circadian Rhythm Sleep Disorders 20 Irregular sleep-wake rhythm disorder (ISWD) occurs when a person s sleep pattern is undefined, which typically includes a series of naps throughout the 24-hour sleep-wake cycle. ISWD is common in elderly patients with comorbid medical disorders, such as Alzheimer s disease. Delayed sleep phase disorder (DSPD) is a pattern of going to bed late in the evening/early morning and sleeping until late in the afternoon. DSPD is common in teenagers. Advanced sleep phase disorder (ASPD) is a pattern of early evening sleepiness and early morning awakening. ASPD is common in elderly patients. Shift work disorder occurs when a person s work hours are scheduled during the normal sleep period. Non-24-hour sleep disorder occurs when the suprachiasmatic nucleus does not receive light from the external environment, resulting in a sleep-wake cycle that shifts later each day. Non-24-hour disorder is common in patients who are totally blind. Adapted from Sack et al, Codeine, oxycodone Current and Emerging Treatment for Insomnia The Role of Behavioral Treatment Interventions in Insomnia Disorder It is widely accepted that psychological and behavioral factors play significant roles in hyperarousal. Interventions that target these factors play an important part in the management of insomnia disorder (Table 7). 21 Several studies have reported the effects of behavioral treatment methods administered to patients with chronic insomnia. 22 Patients reported significant increases in sleep time as well as improvements in sleep latency, total wake time, and sleep efficiency after behavioral interventions. The

9 Table 7. Common Evidence-Based Cognitive and Behavioral Therapies for Insomnia 21 Sleep hygiene therapy involves teaching healthy lifestyle practices to improve sleep. Sleep hygiene is recommended to be used in conjunction with other cognitive and behavioral therapies. Patients are instructed to (including but not limited to): avoid napping, maintain a regular exercise program and healthy diet, sleep in a quiet, dark environment, and avoid stimulants such as caffeine and nicotine at least 6 hours before bedtime. Stimulus control therapy is designed to re-associate the bedroom with the rapid onset of sleep. Once in bed, if the patient is unable to fall asleep in what seems to be about 20 minutes (without looking at a clock), he or she is instructed to leave the bedroom to engage in a relaxing activity and return to bed when sleepy (repeat this as necessary). The objective of stimulus control therapy is to limit wake time in bed. Patients should be cautioned about the possibility of daytime sleepiness during the course of therapy. Sleep restriction therapy limits time in bed to the amount of time actually spent sleeping (normally derived from a sleep log). This approach is designed to improve sleep continuity by using sleep restriction to enhance sleep drive (the ability to sleep). Once sleep efficiency improves, the allowed time in bed is gradually increased by 15 to 30 minutes over a period of several weeks until optimal sleep duration is achieved. The objective of sleep restriction therapy is to limit wake time in bed. Patients should be cautioned about the possibility of daytime sleepiness during the course of therapy. Relaxation training is a technique that uses muscle relaxation, guided imagery, and/or abdominal breathing exercises to lower arousal states that interfere with sleep. Cognitive Behavioral Therapy for Insomnia (CBT-I) is a combination of behavioral therapy (eg, sleep restriction, stimulus control) and psychotherapeutic methods, which involve identifying dysfunctional beliefs about sleep and replacing them with more positive alternatives. Adapted from Schutte-Rodin et al, following discussion addresses different types of behavioral interventions and their impact on insomnia disorder. Dr Sonia Ancoli-Israel: Before we discuss behavioral therapy, we should first discuss Spielman and colleagues 3P model because it is the basis of a lot of what we do when administering cognitive behavioral therapies. 23 The key words in the 3P model are predisposing, precipitating, and perpetuating (Table 8). 23 Predisposing factors include conditions such as personality type or hyperarousal. These factors predispose patients to sleep-related difficulties, but that does not mean they have insomnia. Then there are precipitating factors, such as stress, that may cause patients to lose sleep for a few nights. Getting married, having a new baby, or visiting the in-laws may cause acute sleep-related problems, but those typically resolve on their own after the triggering event has disappeared. However, some individuals experience persistent sleep difficulties, eventually spending more time in bed in an attempt to get more sleep, which makes their sleep worse and leads to negative conditioning. These types of behaviors feed into and perpetuate insomnia, making it more difficult to sleep. Cognitive behavioral therapies target these negative learned responses and essentially reteach an individual how to sleep. Table 8. Contributing Factors to Insomnia 23 Predisposing factors Precipitating factors Perpetuating factors Personality traits Arthritis pain Napping Genetic traits Psychiatric illness Excessive time in bed Social factors Stressful event Negative learned behaviors Cognitive behavioral therapies target these negative learned responses and essentially reteach an individual how to sleep. Dr Sonia Ancoli-Israel Dr Larry Culpepper: Even a short course of behavioral therapy can be very effective. In a study involving nurse practitioners trained to provide behavioral therapy, individuals with chronic insomnia either received a short course of behavioral therapy, consisting of 2 intervention sessions and 2 telephone calls, or they received printed educational materials. 24 A total of 67% of the individuals treated with behavioral therapy showed a clinical response, compared to 25% in the control group. In addition, 55% of those in the behavioral treatment group no longer met the criteria for insomnia at study completion, compared to 13% in the control group. Behavioral therapy is achievable in the primary care setting and can be performed by a physician or another clinician. Behavioral therapy is achievable in the primary care setting and can be performed by a physician or another clinician. Dr Larry Culpepper Dr Tom Roth: There are some data that suggest cognitive behavioral therapy for insomnia (CBT-I) not only improves insomnia symptoms but also augments the remission of depression. Manber and colleagues evaluated the addition of CBT-I to escitalopram (cotherapy) in patients with coexisting insomnia and depression, compared to escitalopram plus control. 25 Cotherapy resulted in a higher rate of remission from depression as compared to the control group (61.5% vs 33.3%, respectively) and was associated with a greater rate of remission from insomnia as compared to the control group (50.0% vs 7.7%, respectively). This study emphasizes the point we made earlier: Treating both disorders improves patient outcomes. Dr Phyllis Zee: We studied the impact of a 16-week afternoon aerobic exercise program plus sleep hygiene measures in patients with insomnia 55 years and older. The control group consisted of patients involved in nonaerobic activity plus sleep hygiene. 26 The physical activity group improved significantly in sleep quality, sleep latency, sleep duration, daytime dysfunction, and sleep efficiency. The physical activity group also had significant reductions in depressive symptoms and daytime sleepiness. Not only does routine long-term exercise improve sleep quality in people with insomnia, but better sleep the night before predicts your capacity to exercise the next day. Not only does routine long-term exercise improve sleep quality in people with insomnia, but better sleep the night before predicts your capacity to exercise the next day. Dr Phyllis Zee 9

10 10 Dr Phyllis Zee: Some patients have tried exercising in the late evening, but that has shown to actually phase shift (delay) circadian rhythms. Not only does exercising late in the evening enhance symptoms of sympathetic arousal but, at the same time, you re giving the wrong signal to the circadian clock. Dr Tom Roth: I do not think these insights are unique to sleep medicine. For example, there are several different methods to treat obesity, but they are all roads to the same outcome. The exact same thing is true for behavioral therapy. There is no secret road to the goal of improving sleep, and it is up to the clinician, his or her resources, the patient s interest, and the patient s sophistication as to what the best road to that goal might be. Prescription Medications Table 9 lists medications approved by the US Food and Drug Administration (FDA) for the treatment of insomnia. There are myriad medications that are used to treat insomnia, including tricyclic antidepressants, antipsychotics, and herbal medications, which have not received regulatory approval for insomnia. Within each medication class, there are differences in pharmacokinetic/ pharmacodynamic indices, which allow clinicians to prescribe patient-specific interventions. Clinicians should consider the following factors when selecting a pharmacologic agent: (1) symptom patterns; (2) comorbid conditions; (3) concurrent medications; (4) contraindications; (5) side effects; and (6) cost. With the exception of low-dose doxepin, the most recently FDAapproved medications have short half-lives and work during the first few hours of sleep, without significant sleep maintenance effects. In contrast, emerging therapies have longer half-lives and will presumably have improved effects on sleep maintenance. Expert guidance in the pharmacologic treatment of insomnia and sleep-related disorders will be presented. Dr Andrew Krystal: The older sleep agents are the benzodiazepines, which potentiate inhibition mediated by GABAA receptors through binding to a benzodiazepine site on the GABAA receptor complex. Benzodiazepines work on the sleep side of the flip-flop switch. Different subtypes of the GABAA receptor are located throughout the central nervous system, and benzodiazepines bind to these receptors without specificity; therefore, not only do they enhance sleep but they also shut down different parts of the brain that we might not want them to, leading to unwanted side effects, including balance and memory problems. 27 Medications that potentiate GABAA receptor activity by binding to the benzodiazepine binding site appear to have some degree of abuse potential, but the abuse seems to be limited to a subgroup of the population prone to substance abuse. Generally speaking, the majority of people take these medications for therapeutic purposes. Compared to benzodiazepines, nonbenzodiazepines demonstrate greater selectivity in terms of preferential binding to a subset of GABAA receptors, affecting specific subunits that have regional effects in brain function. To date, 6 subunits have been identified, and, with the exception of eszopiclone, the nonbenzodiazepines preferentially bind the alpha 1 subunit, which is primarily associated with sedation. 28 Because the mechanism of action for nonbenzodiazepines is limited to the alpha 1 subunit, they do not appear to relax muscles or provide anxiolysis to the same degree as benzodiazepines. Dr Tom Roth: A major difference between the classic benzodiazepines and nonbenzodiazepines relates to pharmacokinetics. The nonbenzodiazepines tend to have much shorter half-lives, which typically minimizes next-day sedation. However, female gender and concomitant medications, such as clarithromycin, have been shown to influence the rate at which some of these medications are metabolized. Dr Andrew Krystal: There appears to be differences among agents within the nonbenzodiazepine drug class itself. When escitalopram plus zolpidem controlled-release (CR) were administered to patients with insomnia and comorbid anxiety, sleep-related parameters improved but anxiety scores did not. 29 However, when escitalopram plus eszopiclone were administered to a similar patient population, both insomnia and anxiety scores improved significantly. This difference appears to be related to the effects on additional GABAA receptor subunits, which are associated with anxiolysis. 30 The point is that these medications seem to differ clinically, and if you want to help people in terms of insomnia with comorbid anxiety, eszopiclone is probably a better adjunctive therapy than zolpidem CR. Dr Larry Culpepper: Studies have also found that eszopiclone improves insomnia and depression scores when coadministered with fluoxetine. 31 In addition to improvements in sleep parameters at each time point in the study, the eszopiclone cotherapy group showed significantly greater changes in 17-item Hamilton Rating Scale for Depression (HAM-D-17) scores, and a significantly greater number of patients achieved remission from depression. Dr Phyllis Zee: There are some medications, including eszopiclone and low-dose doxepin, that are indicated for sleep maintenance insomnia, whereas other medications, such as zaleplon, are not (Table 9). Dr Sonia Ancoli-Israel: I think that is a major point. An important aspect of selecting insomnia medications is matching the medication with the patient s sleep complaint. If a patient is having difficulty staying asleep, but not falling asleep, you have to think about a medication in which the action is going to be maintained during the second half of the night, as opposed to just the first half of the night. An important aspect of selecting insomnia medications is matching the medication with the patient s sleep complaint. Dr Sonia Ancoli-Israel Dr Tom Roth: When you look at the existing treatment options that work on the sleep system, none of the GABAA receptor agonists really have major sleep maintenance effects. They actually have sleep maintenance effects for 3, 4, and 5 hours at the max. The reason for that is very simple. If you have effects that last for 6, 7, and 8 hours with medications that potentiate the GABA system, you are going to have significant next-day impairment. This, in part, explains why a lot of clinicians tend to use off-label medications, including atypical antipsychotics and antidepressants. Among approximately 900 million office visits that took place in 2006, an estimated 30 million visits included a prescription for insomnia without depression listed as comorbidity; nearly half of these prescriptions were for antidepressants. 32 Compared to medications that work on the GABA system, the majority of off-label medications have longer

11 Table 9. Commonly Prescribed FDA-Approved Insomnia Medications Brand name Generic name Half-life FDA-approved indications Available doses Histamine receptor antagonist (H1) Silenor Doxepin 15 hrs Sleep maintenance 3 mg, 6 mg Melatonin receptor agonist (M1 and M2) Rozerem Ramelteon 2.6 hrs Sleep onset 8 mg GABAA-receptor agonists: nonbenzodiazepines *For all zolpidem products, the lowest available dose is recommended when initiating treatment in women Sonata Zaleplon 1 hr Sleep onset 5 mg, 10 mg Edluar (Sublingual tablet) Zolpidem 2.5 hrs Sleep onset 5 mg, 10 mg Ambien Zolpidem 2.5 hrs Sleep onset 5 mg, 10 mg ZolpiMist (Oral spray) Intermezzo (Sublingual tablet) Zolpidem 2.5 hrs Sleep onset 1 spray = 5 mg Zolpidem 2.5 hrs Middle-of-the-night awakenings 1.75 mg, 3.5 mg Ambien CR (Controlled-release) Zolpidem 2.5 hrs Sleep onset Sleep maintenance 6.25 mg, 12.5 mg Lunesta Eszopiclone 5-7 hrs Sleep onset Sleep maintenance 1 mg, 2 mg, 3 mg GABAA-receptor agonists: benzodiazepines Halcion Triazolam 2-4 hrs Sleep onset mg, 0.25 mg Restoril Temazepam 8-20 hrs Sleep onset Sleep maintenance Doral Quazepam hrs Sleep onset Sleep maintenance 7.5 mg, 15 mg, 22.5 mg, 30 mg 7.5 mg, 15 mg half-lives, resulting in sleep maintenance effects in 6, 7, and 8 hours. These medications are effective because they target receptors involved in the wake system, including histamine, dopamine, and serotonin. The wake systems are very important with regard to the pathophysiology of insomnia, and that may be why these medications are frequently prescribed in practice. Dr Larry Culpepper: Since a number of clinicians prescribe off-label medications for the treatment of insomnia, the role of the FDA in the United States should be mentioned. The FDA has clearly stated that hypnotic medications should be started at the lowest possible dose and then titrated to the desired effect, provided the titration can be performed safely and the lower dose was ineffective. The FDA has clearly stated that hypnotic medications should be started at the lowest possible dose and then titrated to the desired effect, provided the titration can be performed safely and the lower dose was ineffective. Dr Larry Culpepper These recommendations will become part of product labeling, and we have already seen this with the recent changes to zolpidem. 33 For medications that are used off-label, this information is not readily available because the medications haven t been studied systematically. Dr Tom Roth: The best example of this is low-dose doxepin. In the past, doxepin had been prescribed at doses as high as 25 mg to 100 mg for the treatment of insomnia. After a dose-response study was performed, the hypnotic dose of doxepin was determined to range from 3 mg to 6 mg. 34 It s not whether doxepin is a good drug or a bad drug. The point is the drug s effects are dose dependent. At doses higher than 6 mg, doxepin has significant anticholinergic effects. At doses ranging from 3 mg to 6 mg, doxepin has limited anticholinergic effects and works primarily on the histamine receptor. So again, the problem with using off-label medications is our lack of knowledge with regard to the dose-response relationships between safety and efficacy. I think doxepin provides us with a clear example of that. Nonprescription Medications Dr Larry Culpepper: Nonprescription therapies are frequently used by patients to treat insomnia-related symptoms, but there is limited safety and efficacy data to support these therapies. For instance, people occasionally use alcohol as a sleep aid, thinking this will improve their sleep. While alcohol has been reported to help people fall asleep more quickly, this effect is offset by having more disrupted sleep in the second half of the night. 35 Dr Phyllis Zee: And then there is the issue of anticholinergic side effects, especially in the elderly, with many of the over-the-counter (OTC) sleep medications. Elderly patients may already have some cognitive impairment and balance issues, and medications with anticholinergic side effects only worsen many of their coexisting conditions. 11

12 12 Dr Sonia Ancoli-Israel: These side effects need to be avoided in this population. Diphenhydramine, for example, has increased rebound effects in the elderly (worsening of sleep compared to pretreatment symptoms). 36 Yet, the elderly are some of the highest users of OTC sleep medications. 37 Dr Andrew Krystal: A significant number of OTC sleep medications contain either diphenhydramine or doxylamine, which have substantial anticholinergic effects. Consumers who see OTC sleep medications in the drug store frequently assume they are safer than prescription medications, but this is not necessarily the case. Dr Phyllis Zee: In addition to OTC antihistamines, there are numerous other medications that patients use to self-medicate, rather than seeking medical attention. The 2002 National Health Interview Survey data showed that more than 1.6 million US adults use complementary and alternative medicine for sleep-related symptoms. 38 A total of 65% of those patients used biologically based therapies, including herbal remedies, which have limited safety and efficacy data and are not regulated by the FDA. Dr Tom Roth: Falls and the risk for falling are important issues with regard to insomnia and its treatments. The majority of data seem to indicate that the causative factor, with regard to medications, is total sedative load. 39,40 If a patient is taking medications with significant anticholinergic side effects while also taking a sleep agent, there is a risk for falling. It is not linked to any single medication. Additionally, there are studies that show insomnia is more of a risk factor than sleep agents. 41 If you give a medication for insomnia to patients and they sleep for 8 hours and do not get out of bed, they do not fall. However, if you have patients who have to get up 3 or 4 times a night because of an underlying medical condition, then sleep agents are a risk. Differentiating Treatments for Insomnia From Treatments for Circadian Rhythm Disorders CRSDs occur when the timing of the endogenous circadian rhythm and the normal 24-hour sleep-wake cycle are offset. Circadian rhythms are coordinated by the suprachiasmatic nucleus (SCN), which is reset by light through the retinohypothalamic tract. 42 Although less potent than light, melatonin, which is released by the pineal gland during the dark cycle, resets circadian rhythm as well. 43 Because they play key roles in stabilizing circadian rhythm, timed exposure to melatonin and light are effective treatment methods in patients with CRSDs. Dr Tom Roth: I would like to take a minute and have Dr Zee briefly explain the roles of melatonin and light in CRSDs. Dr Phyllis Zee: Light is the strongest entraining agent for the circadian clock. Exposure to bright light in the early morning induces phase advances, whereas light exposure in the evening delays the phase of circadian rhythms. 44 In patients with CRSDs, the timing of light exposure (as a treatment intervention) is targeted toward the patient s presenting symptoms. For example, elderly patients often present with an advanced phase disorder, which means they go to bed early at night and wake up early in the morning. In this circumstance, increasing light exposure in the evening (to keep them up later) and limiting light exposure in the morning (to entrain a later wake time) would be an initial intervention in this type of patient. In patients with a delayed phase disorder, the exact opposite would be prescribed. With regard to melatonin, it has demonstrated clinical benefit in patients with CRSDs. Melatonin does not have a major role in the treatment of insomnia disorder 45 ; however, in a patient who only has trouble falling asleep, one should consider the possibility of a delayed circadian rhythm. If an underlying circadian misalignment is present, a trial of low-dose melatonin may be useful. A low dose of melatonin would be 0.3 mg to 1 mg. It s not approved by the FDA for the treatment of insomnia disorder. Dr Andrew Krystal: I think it s important to emphasize that melatonin should not be taken right before going to bed. I think it s important to emphasize that melatonin should not be taken right before going to bed. Dr Andrew Krystal Dr Phyllis Zee: I agree. Many patients with delayed sleep phase disorder come to me indicating that they ve tried melatonin, but it didn t work. They usually have taken it right before bedtime, which is too late to advance the phase of circadian rhythms. To advance the timing of the sleep-wake cycle, the ideal time to take melatonin is 5 to 6 hours before the patient s natural sleep time. Dr Sonia Ancoli-Israel: To add to what Dr. Zee was mentioning a moment ago with regard to light, the best way for the advanced phase patients to avoid morning light is by wearing sunglasses when they go outside because the mechanism is through the eyes. The light-dark cycle information is relayed from the retina to the SCN primarily by the retinohypothalamic tract. Dr Tom Roth: Many elderly people are terrified of falling during the night, so they keep a night light on. It is very important that elderly people keep a night light by their bathroom but outside of the line of vision. We need light during the day, but we also need darkness at night. Dr Phyllis Zee: If the patient needs a night light, recommend a red filter because melatonin does not get suppressed very easily with long-wavelength light, such as red. In contrast, short-wavelength light, such as blue, is more effective in suppressing the secretion of melatonin from the pineal gland. Short wavelength light also activates the sympathetic nervous system, resulting in increased arousal. 46 Emerging Therapies for Insomnia Two separate research groups discovered orexin (also referred to as hypocretin) neuropeptides, which are wake-promoting neurotransmitters produced by a cluster of neurons in the hypothalamus. 47,48 Orexin peptides influence the patient s sleep-wake cycle, appetite, and autonomic nervous system, including effects on metabolic rate and behavioral responses to stress. 47 The brain contains 50,000 to 80,000 orexin producing

13 neurons, which have extensive projections to many different regions in the brain. The strongest projections appear to target wakepromoting regions that regulate arousal, including noradrenergic neurons of the locus coeruleus, histaminergic neurons of the tuberomammilary nucleus, dopaminergic neurons of the ventral tegmental area, and serotonergic neurons of the raphe nuclei. 49 The orexin neurons are predominantly active during periods of wakefulness and become less active during NREM and REM sleep. Patients who have narcolepsy experience chronic sleepiness and have an approximately 90% loss of functioning orexin neurons, further suggesting the wake-promoting role of orexin neuropeptides. 50 Because orexin plays a significant role in the wake cycle, recent research has exploited the clinical benefits of antagonizing this receptor. In phase III clinical trials, suvorexant, a dual orexin receptor antagonist, significantly improved sleep onset and sleep maintenance compared to placebo. 51,52 However, while the efficacy of suvorexant was established, next-day impairment was a concern, warranting further evaluation of select doses. In addition, research has shown that antagonizing serotonin receptors (5HT-7) significantly improves sleep maintenance, suggesting a potential role for agents with this effect in the treatment of insomnia. 53 In this final section, the roundtable panelists discuss emerging therapies and their potential roles in the management of insomnia. Dr Larry Culpepper: Turning the discussion toward emerging treatments, how do the orexin receptor antagonists and serotonin receptor antagonists affect the sleep-wake system? Dr Tom Roth: For the past 30 years, we ve had medications that work primarily on the sleep system through GABA mechanisms. However, with the emergence of low-dose doxepin, orexin receptor antagonists, and serotonin receptor antagonists, there are more medications focused on reducing arousal associated with the wake system, rather than simply pushing sleep harder. Orexin receptor antagonists are probably the medications that are closest to the finish line, and orexin is a major transmitter system that is involved in the arousal system. It feeds into the noradrenergic, histaminergic, and serotonergic systems. Dr Phyllis Zee: In addition, when orexin neurons are firing during wakefulness, they inhibit the VLPO, which is the sleep-promoting center in the brain. It s not only activating the wake promoting regions in the brain, but it s also inhibiting the sleep center. 6 Therefore, if you antagonize the orexin system, you can promote sleep by affecting both sleep and wake. Dr Tom Roth: When you give a patient zolpidem, you want it to go to the VLPO, but it binds receptors in the cerebellum as well, which causes ataxia. It does these things because the GABA system is so widespread. In contrast, orexin is produced by a small group of cells that are located in the lateral hypothalamus, with significant projections to regions of the brain that promote arousal. 49 When these medications are administered, they cause regional effects on the brain versus the widespread effects we typically see with medications that potentiate the GABA system, which has a lot to do with receptor density. Dr Larry Culpepper: We will need to adjust our thinking with regard to these newer agents because they re drastically different, at least from a pharmacokinetic perspective. For example, suvorexant, an orexin receptor antagonist, has a half-life of 12 hours. 52 If this was a benzodiazepine that was affecting the GABA system, the sleep side of the switch, you could not use these medications because of the significant next-day impairment. We will need to adjust our thinking with regard to these newer agents because they re drastically different, at least from a pharmacokinetic perspective. Dr Larry Culpepper Dr Tom Roth: If you look at low-dose doxepin, it has profound effects on sleep at the end of the night. If you look at the orexin and serotonin receptor antagonists, they have profound effects on sleep at the end of the night. That is a very important time because in those later hours you have already slept for 4 or 5 hours, and your homeostatic drive (the increased need for sleep due to extended periods of wakefulness) is way down. Most people experience wake time in the last 3 hours of the night, and these medications are targeting those final hours of sleep. The other factor you have to remember is benzodiazepine receptor agonists work by simply shutting the brain down, and that makes you fall asleep very, very quickly, which is what Dr Culpepper was alluding to earlier. When transitioning patients from benzodiazepine receptor agonists to these newer medications, patient education will become very important because the pharmacokinetic/pharmacodynamic indices of these medications are profoundly different. The onset of action of these newer compounds is not as fast as the medications that work on the GABA system; conversely, the duration of action of these newer agents appears to be longer. Dr Sonia Ancoli-Israel: These medications may not help patients get to sleep as fast as medications affecting the GABA system because orexin receptor antagonists, for example, are more focused on extending sleep. Education will be necessary to reduce the patient s expectation of rapidly falling asleep. Final Thoughts Research suggests that insomnia is a condition of hyperarousal caused by a relative shift in the balance of activity of the sleep-promoting and wake-promoting systems towards an increase in activity in wake-promoting systems. Insomnia is not a symptom of other disorders, but it s comorbid with other medical conditions, requiring its own intervention. Several studies, which have evaluated behavioral and pharmacologic therapy, support this direction in treatment. In addition, clinicians will not only need to inquire about insomnia when comorbid conditions are present but they will also need to inquire about comorbid conditions when insomnia is present. 13

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16 New Directions in the Management of Insomnia Balancing Pathophysiology and Therapeutics