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New DirectionsManagement ofin the

Balancing

TherapeuticsandPathophysiology

Proceedings From an Expert Roundtable Discussion

Insomnia

Release date: October 10, 2013Expiration date: October 31, 2014Estimated time to complete activity: 1.5 hours

Distributed with

Target AudienceThis activity has been designed to meet the educational needs of physicians involved in the management of patients withinsomnia disorder.

Statement of Need/Program OverviewAn estimated 40 to 70 million Americans are affected byinsomnia. According to these estimates, twice as many Americanssuffer from insomnia than from major depression. However, thetrue prevalence of insomnia is unknown because it isunderdiagnosed and underreported. Recent updates in thenosology and diagnostic criteria for insomnia have occurred aswell as advances in understanding pathophysiology, which, inturn, has led to the development of potential new treatments. The burden of medical, psychiatric, interpersonal, and societalconsequences that can be attributed to insomnia and theprevalence of patients with insomnia disorder treated in primarycare underscore the importance of continuing medical education(CME) that improves the clinical understanding, diagnosis, andtreatment of the disorder by primary care providers. Thiscontinuing education activity is based on an expert roundtablediscussion and literature review and provides an update ininsomnia disorder.

Educational ObjectivesAfter completing this activity, the participant should be betterable to:

• Perform a rapid assessment that leads to a diagnosis ofinsomnia disorder

• Summarize the proposed pathophysiology of insomnia disorder

• Evaluate current and emerging nonpharmacologic andpharmacologic therapies for insomnia disorder

• Appropriately select therapy for individual patients with insomnia disorder

Accreditation StatementThis activity has been planned and implemented in accordancewith the Essential Areas and policies of the Accreditation Councilfor Continuing Medical Education through the joint sponsorshipof Postgraduate Institute for Medicine and MedEdicus LLC. ThePostgraduate Institute for Medicine is accredited by the ACCMEto provide continuing medical education for physicians.

Credit DesignationThe Postgraduate Institute for Medicine designates this enduringmaterial for a maximum of 1.5 AMA PRA Category 1 Credit(s)™.Physicians should claim only the credit commensurate with theextent of their participation in the activity.

Disclosure of Conflicts of InterestPostgraduate Institute for Medicine (PIM) requires instructors,planners, managers, and other individuals who are in a position tocontrol the content of this activity to disclose any real or apparentconflict of interest (COI) they may have as related to the contentof this activity. All identified COI are thoroughly vetted andresolved according to PIM policy. PIM is committed to providingits learners with high quality CME activities and related materialsthat promote improvements or quality in healthcare and not aspecific proprietary business interest of a commercial interest.

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Larry Culpepper, MD, MPH—Co-ChairProfessor and Chairman of Family MedicineBoston University School of MedicineBoston University Medical CenterBoston, Massachusetts

Tom Roth, PhD—Co-ChairDirector of ResearchSleep Disorders and Research CenterHenry Ford HospitalDetroit, Michigan

Sonia Ancoli-Israel, PhDProfessor Emeritus of Psychiatry and MedicineProfessor of ResearchUniversity of California, San DiegoLa Jolla, California

Andrew Krystal, MDDirector, Insomnia and Sleep Research ProgramProfessor of Psychiatry and Behavioral SciencesDuke University Medical CenterDurham, North Carolina

Phyllis Zee, MD, PhDBenjamin and Virginia T. Boshes Professor in NeurologyDirector, Sleep Disorders CenterNorthwestern UniversityChicago, Illinois

Faculty

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Faculty DisclosuresThe faculty reported the following financial relationships orrelationships to products or devices they or their spouse/lifepartner have with commercial interests related to the content ofthis CME activity:

Sonia Ancoli-Israel, PhD, had a financial agreement or affiliationduring the past year with the following commercial interests inthe form of Consultant Fees: Ferring Pharmaceuticals; Merck &Co.; and Prudue Pharma L.P.

Larry Culpepper, MD, MPH, had a financial agreement oraffiliation during the past year with the following commercialinterests in the form of Consultant Fees: Boehringer IngelheimPharmaceuticals Inc.; Forest Labs; Janssen Pharmaceuticals, Inc.;Jazz Pharmaceuticals plc; H. Lundbeck A/S; Merck & Co.; Pfizer Inc.; Reckitt Benckiser Pharmaceuticals Inc.; SunovionPharmaceuticals Inc.; and Takeda Pharmaceuticals Inc. Speakers Bureau: Merck & Co. Ownership Interest: M3 (My Mood Monitor).

Andrew Krystal, MD, had a financial agreement or affiliationduring the past year with the following commercial interests inthe 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 PharmaceuticalsInc.; and Teva Pharmaceutical Industries Ltd. ContractedResearch: Abbott Laboratories; Astellas Pharma; Brainsway;National Institutes of Health; NeoSynch; Pfizer Inc.; St. JudeMedical (for Advanced Neuromodulation Systems [ANS]); andTeva Pharmaceutical Industries Ltd.

Tom Roth, PhD, had a financial agreement or affiliation duringthe past year with the following commercial interests in the formof Consultant Fees: Jazz Pharmaceuticals plc; Merck & Co.;Neurocrine Biosciences, Inc.; Novartis; Pfizer Inc.; PurduePharma L.P.; Speakers Bureau: Purdue Pharma L.P. ContractedResearch: Impax Laboratories, Inc.; Valeant Pharmaceuticals (for CeraVe).

Phyllis C. Zee, MD, PhD, had a financial agreement or affiliationduring the past year with the following commercial interests inthe form of Consultant Fees: Ferring Pharmaceuticals; JazzPharmaceuticals plc; Merck & Co.; Purdue Pharma L.P.; TakedaPharmaceuticals Inc.; Vanda Pharmaceuticals Inc.; and UCB, Inc.Contracted Research: Philips Respironics. Ownership Interest: TevaPharmaceutical Industries Ltd.

The planners and managers reported the following financialrelationships or relationships to products or devices they or theirspouse/life partner have with commercial interests related to thecontent of this CME activity:

The following PIM planners and managers, Laura Excell, ND,NP, MS, MA, LPC, NCC, Trace Hutchison, PharmD, SamanthaMattiucci, 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 partnerdo not have any financial relationships or relationships toproducts or devices with any commercial interest related to thecontent of this activity of any amount during the past 12 months.

Method of Participation and Request for CreditThere are no fees for participating and receiving CME credit forthis activity. During the period October 10, 2013, throughOctober 31, 2014, participants must read the learning objectivesand faculty disclosures and study the educational activity.

PIM supports Green CME by offering your Request for Creditonline. If you wish to receive acknowledgment for completing thisactivity, please complete the post-test and evaluation onwww.cmeuniversity.com. On the navigation menu, click on“Find Post-test/Evaluation by Course” and search by course ID9496. Upon registering and successfully completing the post-testwith a score of 70% or better and the activity evaluation, yourcertificate will be made available immediately.

Media

Monograph

Disclosure of Unlabeled UseThis educational activity may contain discussion of publishedand/or investigational uses of agents that are not indicated by theFDA. The planners of this activity do not recommend the use ofany agent outside of the labeled indications.

The opinions expressed in the educational activity are those of thefaculty and do not necessarily represent the views of the planners.Please refer to the official prescribing information for eachproduct for discussion of approved indications, contraindications,and warnings.

DisclaimerParticipants have an implied responsibility to use the newlyacquired 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 patientmanagement. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this activityshould not be used by clinicians without evaluation of theirpatient’s conditions and possible contraindications and/ordangers in use, review of any applicable manufacturer’s productinformation, and comparison with recommendations of other authorities.

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IntroductionAn estimated 40 to 70 million Americans have insomnia.1

According to these estimates, twice as many Americans suffer frominsomnia than from major depression.2 Patients with insomniafrequently report physical and emotional health problems,compromised social functioning, and daytime distress. Commonrisk factors for insomnia include female gender, advanced age,comorbid disease, and occupations involving shift work.Importantly, comorbid medical disorders are becoming moreappreciated as risk factors for insomnia.

Work productivity is negatively impacted by insomnia. In the 2009US Workers America Insomnia Survey, presenteeism (low on-the-jobwork performance defined in the metric of lost workday equivalents)accounted for nearly 8 days of annual lost work performance perworker, equating to $2280 in individual-level human capital value.When extrapolated to the entire US workforce over the course of ayear, insomnia causes 252.7 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 thepast decade, several changes have been made with regard to thenosology of insomnia, most notably the recent realization thatinsomnia is a disorder. In the past, insomnia was thought to besecondary to another medical condition. The Diagnostic andStatistical 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 eventhough it typically coexists with other comorbid medicalconditions, including depression, anxiety, chronic pain, andcardiovascular diseases.4 In addition, the Diagnostic andStatistical Manual of Mental Disorders, Fourth Edition, TextRevision, diagnostic criteria have been updated in the DSM-5 toinclude more stringent measures regarding the chronicity ofinsomnia-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 fallingand/or staying asleep; (2) the sleep difficulty is accompanied bynext-day symptoms of distress/impairment; (3) sleep-relatedsymptoms occur at least 3 times per week for a minimum of 3 months; and (4) symptoms persist despite adequateopportunities and circumstances to sleep.4

Insomnia is a prevalent and costly public health concern that isassociated with significant long-term effects on physical,psychological, and occupational functioning. In order to minimizethe societal impact of insomnia and the burden it creates on thehealthcare system, families, and patients, clinicians need toimprove their recognition and treatment of insomnia as well ascoexisting medical conditions. This approach starts with having aninitial discussion with patients regarding the quality of their sleep.

Despite its prevalence, insomnia remains undertreated andunderreported. Patients are reluctant to seek medical treatment,and sleep is not commonly discussed during office visits. Thiscontinuing medical education/continuing education (CME/CE)activity is designed to update readers on the pathophysiology ofinsomnia, the interrelationships of insomnia and comorbiddisease, 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. Thepathophysiology of insomnia is multifactorial and may be thoughtof in terms of dysregulation involving the following 3 components:neurophysiologic hyperactivation of the sympathetic nervoussystem; neuroendocrine dysregulation of hormones associated witharousal; and cognitive/behavioral responses directed toward sleepthat perpetuate arousal. Expert insights on the pathophysiology ofinsomnia from the roundtable discussion will be presented. Figure 1presents a schematic diagram of the 24-hour sleep-wake cycle.5

Dr Tom Roth: For years we had this idea that insomnia is anabnormality of the sleep system. Increasingly, we have learned thatinsomnia is not an abnormality of the sleep system, but it is anabnormality of the wake/arousal system. Over a decade ago, Saperand colleagues proposed the flip-flop switch model of sleep-wakeregulation,6 which contains 2 sets of mutually inhibitory neuralelements: wake-promoting influences on 1 side and sleep-promotinginfluences on the other. The monoaminergic nuclei (MN) are amajor influence of the wake-promoting system, and sleep isinfluenced by the ventrolateral preoptic nucleus (VLPO), which is agroup of cells that generate non-rapid eye movement (NREM) andrapid eye movement (REM) stages of sleep (Figure 2).5 In patientswith normal sleep, the flip-flop switch makes sudden transitionsbetween sleep and wakefulness, which explains why a limitedamount of time is spent in these transitional states throughout thecourse of a 24-hour day (Figure 3).6 In patients with insomnia,however, their ability to turn off the wake-promoting influences ofthe flip-flop switch is weakened, resulting in extended periods oftime in transitional states and a prolonged state of wake.

Dr Andrew Krystal: There are a number of objective measures thatsupport this model of hyperarousal, including elevations in heartrate and heart rate variability. For example, Bonnet and Arandperformed a 36-hour study that showed the heart rate increased andthe mean heart rate variability decreased in all stages of sleep in thegroup of people with insomnia compared to the control group ofpeople who have normal sleep.7 Studies have also found thatpatients with insomnia, when compared to controls, have highermetabolic rates throughout the course of a 24-hour day, furthersuggesting arousal in the wake-promoting regions in the brain.8

Dr Larry Culpepper: There appears to be a neuroendocrinecomponent to this condition as well. Vgontzas and colleaguesfound that levels of adrenocorticotropic hormone and cortisolwere significantly elevated in patients with insomnia compared tomatched controls, which results in increased arousal andassociated sleeplessness. In addition, patients with a higher degreeof sleep disturbance secreted more cortisol compared to thosewith less sleep disturbance.9

For years we had this idea that insomnia is an abnormality of the sleep system. Increasingly, wehave learned that insomnia is not an abnormalityof the sleep system, but it is an abnormality of the

wake/arousal system. —Dr Tom Roth

5

Dr Andrew Krystal: Positron emission tomography has shownthat patients with insomnia exhibit greater brain glucosemetabolism during sleep and wake periods compared to peoplewho have normal sleep, indicating the inability of patients withinsomnia to appropriately transition from wake to sleep.10 Table 1lists elevated physiologic factors that have been observed inpatients who have insomnia, which are suggestive of hyperarousal.

Dr Phyllis Zee: Stepanski and colleagues comparedpolysomnography and multiple sleep latency test data frompatients seeking evaluation for chronic insomnia with data frompatients without sleep problems.11 The insomnia group sleptsignificantly less than the control group, yet they weresignificantly less sleepy the next day compared with matchedcontrols. This study found that if given the chance to sleep duringthe day, patients with insomnia take longer than the generalpopulation to fall asleep. Insomnia is a 24-hour disorder ofhyperarousal associated with difficulty sleeping at any time of day.

Dr Sonia Ancoli-Israel: This inability to sleep during the dayhighlights why the initial assessment of sleep-related symptomsis so important. If patients indicate they’re having difficultysleeping at night but they sleep well during the day, it is less likely to be insomnia. Someone with insomnia has difficultyfalling asleep during the day as much as they do at night.

Dr Phyllis Zee: There are primarily 3 different ways to promotewakefulness: (1) blocking the sleep promoting neurons in theVLPO; (2) exciting the monoaminergic nuclei associated withthe wake system; and (3) stimulation of the orexin neurons.

Dr Tom Roth: I think all of you bring up a great point. Whenpatients with insomnia get out of bed at 7 o’clock in the morning,their insomnia has not gone away. For patients who have

Someone with insomnia has difficultyfalling asleep during the day as much as they

do at night. —Dr Sonia Ancoli-Israel

Figure 2. A schematic of the sleep-promoting and wake-promoting areas of thehuman brain. There are multiple cell groups in the brain that contribute to thesleep-wake system. The monoaminergic nuclei (MN) are responsible for promotingwakefulness, 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 andlaterodorsal tegmental nucleus (PPT/LDT), locus coeruleus (LC), dorsal andmedian 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.

Table 1. Physiologic Factors Increased During Sleep in Patients With Insomnia

Body temperatureBrain glucose metabolism

Resting heart rateCortisol level

Electroencephalogram beta wave activity

Insomnia is a 24-hour disorder of hyperarousal associated with difficulty sleeping

at any time of day. —Dr Phyllis Zee

Hour 0 Hour 24

Wake ~ 16 hrs2/3 of Sleep-Wake Cycle

Sleep~ 8 hrs1/3 of Sleep-Wake Cycle

NREM REM

Figure 1. A schematic diagram of the sleep-wake cycle. When transitioning into sleep, an individual begins in non-rapid eye movement (NREM) andremains in this stage for approximately 85 minutes. After this initial stage of NREM, the brain switches to rapid eye movement (REM) for approximately5 to 10 minutes before switching back to NREM. This 90-minute pattern continues throughout the night, with REM intervals becoming longer andNREM 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, 2012.5

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myocardial ischemia, we find that just because they don’t haveangina 24 hours a day doesn’t mean their cardiovascular functionis normal all of a sudden. People who have insomnia are notsymptomatic 24 hours a day, 7 days a week. They have insomnia

24 hours a day that expresses itself periodically. The criteria forinsomnia disorder specify that sleep disturbances must occur atleast 3 days a week for a minimum of 3 months for us to considera diagnosis of insomnia.4

Dr Larry Culpepper: What do we know about the underlyingbrain 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, thepsychopathological and behavioral patterns of sleep appear to play a significant role in some patients with sleep problems. Forexample, when people experience multiple nights of bad sleep andfrustration within their sleeping environment, they begin todevelop the expectation of poor sleep. This expectation becomes aperpetuating factor that creates stress and increased activity of thesympathetic nervous system. In addition to the neuroendocrineand physiologic components of hyperarousal, there appears to bea behavioral/psychopathological element to this condition.

Updates in the Diagnostic Criteria andNosology of InsomniaThe diagnostic criteria for insomnia have undergone recentchanges with the finalization of the DSM-5, most notably with thechronicity of sleep-related disturbances, which the faculty willdiscuss. In addition, insomnia has been renamed insomnia disorder,emphasizing the point that while insomnia typically coexists withother medical conditions, it requires separate clinical attention.Becoming more aware of the numerous comorbid conditionsassociated with insomnia is important and may assist clinicians inbetter recognizing and managing insomnia. The followingdiscussion provides insight into the clinical implications of recentchanges in the diagnostic criteria and the significance of comorbidconditions associated with insomnia.

Please circle the number that best describes your CURRENT severity level of sleep problem(s).

Please rate this past week’s severity of thefollowing insomnia problems:

None Mild Moderate Severe Very severe

1. Difficulty falling asleep 0 1 2 3 4

2. Difficulty staying asleep 0 1 2 3 4

3. Waking up too early 0 1 2 3 4

Verysatisfied

Satisfied Moderatelysatisfied

Dissatisfied Very dissatisfied

4. How satisfied/dissatisfied are you with yourcurrent sleep pattern?

0 1 2 3 4

Not at all A little Somewhat Much Very much

5. How noticeable to others do you think yoursleep problem is in terms of impairing the quality of your life?

0 1 2 3 4

6. How worried/distressed are you about yourcurrent sleep problem?

0 1 2 3 4

7. To what extent do you consider your sleepproblem to interfere with your daily functioning(mood, concentration, work)?

0 1 2 3 4

Table 2. Insomnia Severity Index13

Scoring: 0-7 No clinically significant insomnia; 8-14 Sub-threshold insomnia; 15-21 Moderate clinical insomnia; 22-28 Severe clinicalinsomnia. Adapted from Morin et al, 2001.13

Figure 3. A schematic drawing of the flip-flop switch model of sleep-wakeregulation. The interaction between the ventrolateral preoptic nucleus (VLPO)and the arousal pathways (Orexin [ORX], locus coeruleus [LC], dorsal and medianraphe nucleus [Raphe], and tuberomammillary nucleus [TMN]) is mutuallyinhibiting, functioning like an on-off (flip-flop) switch. This flip-flop switch ensuresstability between sleep and wakefulness, which results in normal sleep patterns.Insomnia causes dysregulation of the switch, resulting in irregular transitioningbetween sleep-wake states and fragmented sleep. Reprinted with permission, Saper et al, 2005.6

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Dr Larry Culpepper: In terms of how you define and diagnoseinsomnia, what are some key principles that primary careclinicians should know?

Dr Sonia Ancoli-Israel: I think it’s important for primary careclinicians to, first of all, ask their patients about sleep. Researchhas shown that 70% of the clinicians don’t ask their patients aboutsleep, 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 ofthe patient. If the patient responds that he or she is experiencingsleep problems, then it takes a little more in-depth questioningregarding the specific symptoms of insomnia and their frequencyand severity. There are several questionnaires—including theInsomnia Severity Index (Table 2)13 and the Epworth SleepinessScale—that clinicians can use to facilitate sleep-related discussionwith their patients.

Dr Tom Roth: I think it’s also important for clinicians todifferentiate sleep disturbance from insomnia because they arenot the same thing. When there are inadequate opportunities orcircumstances to sleep, sleep disturbances typically occur. Butthat is not insomnia. An insomnia diagnosis is made when apatient meets the following 4 criteria (Table 3): (1) nighttimesymptoms of difficulty falling asleep and/or staying asleep; (2) next-day symptoms of distress/impairment; (3) symptomsoccur at least 3 times per week for a minimum of 3 months; and(4) symptoms persist despite adequate opportunity andcircumstances to sleep.4

Comorbid Conditions Associated With InsomniaDr Phyllis Zee: I would add that insomnia is now listed asinsomnia disorder in the DSM-5 and the InternationalClassification 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). Althoughinsomnia is often associated with other conditions, such as pain,depression, anxiety, and cardiovascular diseases, insomnia is itsown distinct disorder (Table 4).14

Table 3. DSM-5 Insomnia Disorder Criteria 780.52 (G47.00)

Note: Acute and short-term insomnia (i.e., symptoms lasting less than 3 monthsbut 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 MentalDisorders, Fifth Edition, (Copyright ©2013). American Psychiatric Association. All Rights Reserved.

A. A predominant complaint of dissatisfaction with sleep quantityor quality, associated with one (or more) of the followingsymptoms: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 tosleep 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 circadianrhythm sleep-wake disorder).

G. The insomnia is not attributable to the physiological effects of asubstance (e.g., a drug of abuse, a medication).

H. Coexisting mental disorders and medical conditions do notadequately 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 780.52 (G47.00) applies to all three

specifiers. Code also the relevant associated mental disorder,medical condition, or other sleep disorder immediately afterthe code for insomnia disorder in order to indicate theassociation.

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.Comorbid condition

Prevalence of insomnia

In the presence of comorbid

condition%

In the absence ofcomorbidcondition

%

Cardiovascular disease

Hypertension 26.1 22.8

Heart disease 30.1 23.7

Musculoskeletal disease

Arthritis 30.6 21.5

Back or neck pain 34.2 17.7

Digestive disorders

Diarrhea, constipation, or gas 42.2 20.2

Gastroesophageal reflux disease(GERD)

39.2 20.7

Sleep disorders

Sleep apnea 40.9 22.0

Restless leg syndrome 50.6 22.6

Emotional disorders

Major depressive disorder 55.7 21.1

Generalized anxiety disorder 65.6 21.2

Table 4. Prevalence of People With Insomnia and Comorbid Medical Conditions14

I think it’s important for primary care clinicians to,first of all, ask their patients about sleep.

—Dr Sonia Ancoli-Israel

8 Dr Sonia Ancoli-Israel: And since insomnia is its own disorder,you treat it once you’ve made a diagnosis.

Dr Larry Culpepper: I think what Dr Ancoli-Israel mentioned isthe single most important message to relay to primary careclinicians. In the past, we clinicians have been under the falseimpression that when an existing comorbid condition resolves—for instance, depression—insomnia would go away as well. Andthat, quite often, is not the case.

Dr Tom Roth: If you look at people with depression when theygo into remission, the most common residual symptom isdifficulty sleeping. It is important to understand that the numberof residual symptoms linearly predicts time to relapse ofdepression. The Sequenced Treatment Alternatives to RelieveDepression (STAR*D) trial described the types and frequency ofresidual depressive symptoms and their relationship todepressive relapse after treatment with citalopram.15 More than90% of the patients with depression who went into remission hadat least 1 residual depressive symptom, and the most commonresidual symptom domain was sleep-related disturbance(71.7%).15 The study revealed that having a greater number ofresidual symptoms was associated with a higher probability ofrelapse. The point is that treating insomnia enables you to bettermanage coexisting disorders.

Dr Andrew Krystal: As mentioned earlier, the error clinicianshave made in the past is undertreating insomnia, expectinginsomnia to get better once the symptoms of a comorbidcondition improved. Moreover, clinicians should consider thepossibility of underlying comorbid conditions when patientspresent with symptoms suggestive of insomnia. Research showsthat insomnia is a known risk factor for other disorders, mostnotably depression and anxiety. One of the classic studies, theJohns Hopkins Precursors Study, evaluated the associationsbetween self-reported sleep disturbances and subsequent clinicaldepression among medical students (classes 1948-1964; meanfollow-up period of 34 years).16 Patients who reported insomniasymptoms during medical school were twice as likely to developclinical depression compared to those without insomniasymptoms. Clinicians need to assess whether or not there areunderlying comorbid conditions, such as depression, which maybe intensifying the symptoms of insomnia.

Dr Phyllis Zee: There is also research to suggest that insomniamay serve as a risk factor of cardiometabolic disease. A recentstudy that evaluated the impact of sleep on levels of fastingglucose, fasting insulin, and estimated insulin resistance showedthat insomnia was associated with a 23% higher fasting glucoselevel and a 48% higher fasting insulin level in patients with type 2diabetes.17 In addition, Vgontzas and colleagues evaluated thejoint effects of insomnia and short sleep duration on diabetesrisk.18 They showed that patients with insomnia and sleepduration of less than 5 hours were at significantly higher risk ofdeveloping diabetes compared to people who have normal sleep.

Dr Larry Culpepper: It’s also important to remember that thevery treatment of the comorbid condition itself may lead toinsomnia-related symptoms. Respiratory stimulants, selectiveserotonin reuptake inhibitors, beta blockers, and many other drugclasses are associated with reports of disturbed sleep (Table 5).19

Differentiating Circadian RhythmDisorders From Insomnia Insomnia is occasionally comorbid with other sleep conditions,including disorders in circadian rhythm. Table 6 lists commoncircadian rhythm sleep disorders (CRSDs) that may occur inconjunction with insomnia20; however, the effective treatmentsfor CRSDs are very different, emphasizing the importance ofdifferentiating sleep-related symptoms of CRSDs from insomnia.

Current and Emerging Treatment for InsomniaThe Role of Behavioral Treatment Interventions inInsomnia DisorderIt is widely accepted that psychological and behavioral factorsplay significant roles in hyperarousal. Interventions that targetthese factors play an important part in the management ofinsomnia disorder (Table 7).21 Several studies have reported theeffects of behavioral treatment methods administered to patientswith chronic insomnia.22 Patients reported significant increases insleep time as well as improvements in sleep latency, total waketime, and sleep efficiency after behavioral interventions. The

Irregular sleep-wake rhythm disorder (ISWD) occurs when a person’ssleep pattern is undefined, which typically includes a series of napsthroughout the 24-hour sleep-wake cycle. ISWD is common in elderlypatients with comorbid medical disorders, such as Alzheimer’s disease.

Delayed sleep phase disorder (DSPD) is a pattern of going to bed late inthe evening/early morning and sleeping until late in the afternoon. DSPDis 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 scheduledduring the normal sleep period.

Non-24-hour sleep disorder occurs when the suprachiasmatic nucleusdoes not receive light from the external environment, resulting in a sleep-wake cycle that shifts later each day. Non-24-hour disorder iscommon in patients who are totally blind.

Table 6. Circadian Rhythm Sleep Disorders20

And since insomnia is its own disorder, you treat itonce you’ve made a diagnosis. —Dr Sonia Ancoli-Israel

Drug class Medications

Antidepressants Selective serotonin reuptake inhibitors (fluoxetine, citalopram, sertraline, paroxetine),venlafaxine, duloxetine

Decongestants Pseudoephedrine, phenylephrine

Cardiovascular Beta blockers, alpha-receptor antagonists, diuretics

Respiratory Theophylline, albuterol

Stimulants Methylphenidate, ephedrine, amphetamines

Opioids Codeine, oxycodone

Table 5. Common Medications That Contribute to Insomnia19

Adapted from Sack et al, 2007.20

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following discussion addresses different types of behavioralinterventions and their impact on insomnia disorder.

Dr Sonia Ancoli-Israel: Before we discuss behavioral therapy, weshould first discuss Spielman and colleagues’ “3P” model becauseit is the basis of a lot of what we do when administering cognitivebehavioral therapies.23 The key words in the “3P” model arepredisposing, precipitating, and perpetuating (Table 8).23

Predisposing factors include conditions such as personality typeor hyperarousal. These factors predispose patients to sleep-relateddifficulties, but that does not mean they have insomnia. Thenthere are precipitating factors, such as stress, that may causepatients to lose sleep for a few nights. Getting married, having anew baby, or visiting the in-laws may cause acute sleep-relatedproblems, but those typically resolve on their own after thetriggering event has disappeared. However, some individualsexperience persistent sleep difficulties, eventually spending moretime in bed in an attempt to get more sleep, which makes theirsleep worse and leads to negative conditioning. These types ofbehaviors feed into and perpetuate insomnia, making it moredifficult to sleep. Cognitive behavioral therapies target thesenegative learned responses and essentially reteach an individualhow to sleep.

Dr Larry Culpepper: Even a short course of behavioral therapy canbe very effective. In a study involving nurse practitioners trained toprovide behavioral therapy, individuals with chronic insomniaeither received a short course of behavioral therapy, consisting of 2 intervention sessions and 2 telephone calls, or they receivedprinted educational materials.24 A total of 67% of the individualstreated with behavioral therapy showed a clinical response, comparedto 25% in the control group. In addition, 55% of those in thebehavioral 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 andcan be performed by a physician or another clinician.

Dr Tom Roth: There are some data that suggest cognitivebehavioral therapy for insomnia (CBT-I) not only improvesinsomnia symptoms but also augments the remission ofdepression. Manber and colleagues evaluated the addition ofCBT-I to escitalopram (cotherapy) in patients with coexistinginsomnia and depression, compared to escitalopram pluscontrol.25 Cotherapy resulted in a higher rate of remission fromdepression as compared to the control group (61.5% vs 33.3%,respectively) and was associated with a greater rate of remissionfrom 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 afternoonaerobic exercise program plus sleep hygiene measures in patientswith insomnia 55 years and older. The control group consisted ofpatients involved in nonaerobic activity plus sleep hygiene.26 Thephysical activity group improved significantly in sleep quality, sleeplatency, sleep duration, daytime dysfunction, and sleep efficiency.The physical activity group also had significant reductions indepressive symptoms and daytime sleepiness. Not only doesroutine long-term exercise improve sleep quality in people withinsomnia, but better sleep the night before predicts your capacityto exercise the next day.

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

Table 8. Contributing Factors to Insomnia23

Cognitive behavioral therapies target thesenegative learned responses and essentially reteach

an individual how to sleep. —Dr Sonia Ancoli-Israel

Behavioral therapy is achievable in the primarycare setting and can be performed by a physician or

another clinician. —Dr Larry Culpepper

Not only does routine long-term exercise improve sleep quality in people with insomnia, but bettersleep the night before predicts your capacity to

exercise the next day. —Dr Phyllis Zee

Sleep hygiene therapy involves teaching healthy lifestyle practices toimprove sleep. Sleep hygiene is recommended to be used in conjunctionwith other cognitive and behavioral therapies. Patients are instructed to(including but not limited to): avoid napping, maintain a regular exerciseprogram and healthy diet, sleep in a quiet, dark environment, and avoidstimulants such as caffeine and nicotine at least 6 hours before bedtime.

Stimulus control therapy is designed to re-associate the bedroom with therapid onset of sleep. Once in bed, if the patient is unable to fall asleep inwhat seems to be about 20 minutes (without looking at a clock), he or sheis instructed to leave the bedroom to engage in a relaxing activity and returnto bed when sleepy (repeat this as necessary). The objective of stimuluscontrol therapy is to limit wake time in bed. Patients should be cautionedabout the possibility of daytime sleepiness during the course of therapy.

Sleep restriction therapy limits time in bed to the amount of time actuallyspent sleeping (normally derived from a sleep log). This approach isdesigned to improve sleep continuity by using sleep restriction to enhancesleep drive (the ability to sleep). Once sleep efficiency improves, theallowed time in bed is gradually increased by 15 to 30 minutes over a periodof several weeks until optimal sleep duration is achieved. The objective ofsleep restriction therapy is to limit wake time in bed. Patients should becautioned about the possibility of daytime sleepiness during the course of therapy.

Relaxation training is a technique that uses muscle relaxation, guidedimagery, and/or abdominal breathing exercises to lower arousal states thatinterfere with sleep.

Cognitive Behavioral Therapy for Insomnia (CBT-I) is a combinationof behavioral therapy (eg, sleep restriction, stimulus control) andpsychotherapeutic methods, which involve identifying dysfunctionalbeliefs about sleep and replacing them with more positive alternatives.

Table 7. Common Evidence-Based Cognitive and Behavioral Therapiesfor Insomnia21

Adapted from Schutte-Rodin et al, 2008.21

10 Dr Phyllis Zee: Some patients have tried exercising in the lateevening, but that has shown to actually phase shift (delay)circadian rhythms. Not only does exercising late in the eveningenhance 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 sleepmedicine. For example, there are several different methods totreat obesity, but they are all roads to the same outcome. Theexact same thing is true for behavioral therapy. There is no secretroad to the goal of improving sleep, and it is up to the clinician, hisor her resources, the patient’s interest, and the patient’ssophistication as to what the best road to that goal might be.

Prescription MedicationsTable 9 lists medications approved by the US Food and DrugAdministration (FDA) for the treatment of insomnia. There aremyriad medications that are used to treat insomnia, includingtricyclic antidepressants, antipsychotics, and herbal medications,which have not received regulatory approval for insomnia. Withineach medication class, there are differences in pharmacokinetic/pharmacodynamic indices, which allow clinicians to prescribepatient-specific interventions. Clinicians should consider thefollowing factors when selecting a pharmacologic agent: (1) symptom patterns; (2) comorbid conditions; (3) concurrentmedications; (4) contraindications; (5) side effects; and (6) cost.With the exception of low-dose doxepin, the most recently FDA-approved medications have short half-lives and work during thefirst few hours of sleep, without significant sleep maintenanceeffects. In contrast, emerging therapies have longer half-lives andwill presumably have improved effects on sleep maintenance.Expert guidance in the pharmacologic treatment of insomnia andsleep-related disorders will be presented.

Dr Andrew Krystal: The older sleep agents are thebenzodiazepines, which potentiate inhibition mediated byGABAA receptors through binding to a benzodiazepine site on theGABAA receptor complex. Benzodiazepines work on the sleepside of the flip-flop switch. Different subtypes of the GABAA

receptor are located throughout the central nervous system, andbenzodiazepines bind to these receptors without specificity;therefore, not only do they enhance sleep but they also shut downdifferent parts of the brain that we might not want them to,leading to unwanted side effects, including balance and memoryproblems.27 Medications that potentiate GABAA receptor activityby binding to the benzodiazepine binding site appear to havesome degree of abuse potential, but the abuse seems to be limitedto a subgroup of the population prone to substance abuse.Generally speaking, the majority of people take these medicationsfor therapeutic purposes. Compared to benzodiazepines,nonbenzodiazepines demonstrate greater selectivity in terms ofpreferential binding to a subset of GABAA receptors, affectingspecific subunits that have regional effects in brain function. Todate, 6 subunits have been identified, and, with the exception ofeszopiclone, the nonbenzodiazepines preferentially bind the alpha1 subunit, which is primarily associated with sedation.28 Becausethe mechanism of action for nonbenzodiazepines is limited to thealpha 1 subunit, they do not appear to relax muscles or provideanxiolysis to the same degree as benzodiazepines.

Dr Tom Roth: A major difference between the classicbenzodiazepines and nonbenzodiazepines relates to

pharmacokinetics. The nonbenzodiazepines tend to have muchshorter half-lives, which typically minimizes next-day sedation.However, female gender and concomitant medications, such asclarithromycin, have been shown to influence the rate at whichsome of these medications are metabolized.

Dr Andrew Krystal: There appears to be differences amongagents within the nonbenzodiazepine drug class itself. Whenescitalopram plus zolpidem controlled-release (CR) wereadministered to patients with insomnia and comorbid anxiety,sleep-related parameters improved but anxiety scores did not.29

However, when escitalopram plus eszopiclone were administeredto a similar patient population, both insomnia and anxiety scoresimproved significantly. This difference appears to be related to theeffects on additional GABAA receptor subunits, which areassociated with anxiolysis.30 The point is that these medicationsseem to differ clinically, and if you want to help people in terms ofinsomnia with comorbid anxiety, eszopiclone is probably a betteradjunctive therapy than zolpidem CR.

Dr Larry Culpepper: Studies have also found that eszopicloneimproves insomnia and depression scores when coadministeredwith fluoxetine.31 In addition to improvements in sleep parametersat each time point in the study, the eszopiclone cotherapy groupshowed significantly greater changes in 17-item Hamilton RatingScale for Depression (HAM-D-17) scores, and a significantlygreater number of patients achieved remission from depression.

Dr Phyllis Zee: There are some medications, includingeszopiclone and low-dose doxepin, that are indicated for sleepmaintenance insomnia, whereas other medications, such aszaleplon, are not (Table 9).

Dr Sonia Ancoli-Israel: I think that is a major point. Animportant aspect of selecting insomnia medications is matchingthe medication with the patient’s sleep complaint. If a patient ishaving difficulty staying asleep, but not falling asleep, you have tothink about a medication in which the action is going to bemaintained during the second half of the night, as opposed to justthe first half of the night.

Dr Tom Roth: When you look at the existing treatment options thatwork on the sleep system, none of the GABAA receptor agonistsreally have major sleep maintenance effects. They actually have sleepmaintenance effects for 3, 4, and 5 hours at the max. The reason forthat is very simple. If you have effects that last for 6, 7, and 8 hourswith medications that potentiate the GABA system, you are going tohave significant next-day impairment. This, in part, explains why alot of clinicians tend to use off-label medications, including atypicalantipsychotics and antidepressants. Among approximately 900million office visits that took place in 2006, an estimated 30 millionvisits included a prescription for insomnia without depression listedas comorbidity; nearly half of these prescriptions were forantidepressants.32 Compared to medications that work on theGABA system, the majority of off-label medications have longer

An important aspect of selecting insomniamedications is matching the medication with the

patient’s sleep complaint. —Dr Sonia Ancoli-Israel

11

half-lives, resulting in sleep maintenance effects in 6, 7, and 8 hours.These medications are effective because they target receptorsinvolved in the wake system, including histamine, dopamine, andserotonin. The wake systems are very important with regard to thepathophysiology of insomnia, and that may be why thesemedications 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 hasclearly stated that hypnotic medications should be started at thelowest possible dose and then titrated to the desired effect,provided the titration can be performed safely and the lower dosewas ineffective.

These recommendations will become part of product labeling,and we have already seen this with the recent changes tozolpidem.33 For medications that are used off-label, thisinformation is not readily available because the medicationshaven’t been studied systematically.

Dr Tom Roth: The best example of this is low-dose doxepin. Inthe past, doxepin had been prescribed at doses as high as 25 mg to100 mg for the treatment of insomnia. After a dose-responsestudy was performed, the hypnotic dose of doxepin wasdetermined to range from 3 mg to 6 mg.34 It’s not whetherdoxepin is a good drug or a bad drug. The point is the drug’seffects are dose dependent. At doses higher than 6 mg, doxepinhas significant anticholinergic effects. At doses ranging from 3 mgto 6 mg, doxepin has limited anticholinergic effects and worksprimarily on the histamine receptor. So again, the problem withusing 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 MedicationsDr Larry Culpepper: Nonprescription therapies are frequentlyused by patients to treat insomnia-related symptoms, but there islimited safety and efficacy data to support these therapies. Forinstance, people occasionally use alcohol as a sleep aid, thinkingthis will improve their sleep. While alcohol has been reported tohelp people fall asleep more quickly, this effect is offset by havingmore disrupted sleep in the second half of the night.35

Dr Phyllis Zee: And then there is the issue of anticholinergic sideeffects, 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 medicationswith anticholinergic side effects only worsen many of theircoexisting conditions.

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 andthe lower dose was ineffective. —Dr Larry Culpepper

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)

Zolpidem 2.5 hrs Sleep onset 1 spray = 5 mg

Intermezzo® (Sublingual tablet)

Zolpidem 2.5 hrs Middle-of-the-night awakenings 1.75 mg, 3.5 mg

Ambien CR®(Controlled-release)

Zolpidem 2.5 hrs Sleep onsetSleep maintenance

6.25 mg, 12.5 mg

Lunesta® Eszopiclone 5-7 hrs Sleep onsetSleep maintenance

1 mg, 2 mg, 3 mg

GABAA-receptor agonists: benzodiazepines

Halcion® Triazolam 2-4 hrs Sleep onset 0.125 mg, 0.25 mg

Restoril® Temazepam 8-20 hrs Sleep onsetSleep maintenance

7.5 mg, 15 mg, 22.5 mg, 30 mg

Doral® Quazepam 39-73 hrs Sleep onsetSleep maintenance

7.5 mg, 15 mg

Table 9. Commonly Prescribed FDA-Approved Insomnia Medications

12 Dr Sonia Ancoli-Israel: These side effects need to be avoided inthis population. Diphenhydramine, for example, has increasedrebound effects in the elderly (worsening of sleep compared topretreatment symptoms).36 Yet, the elderly are some of thehighest users of OTC sleep medications.37

Dr Andrew Krystal: A significant number of OTC sleepmedications contain either diphenhydramine or doxylamine,which have substantial anticholinergic effects. Consumers whosee OTC sleep medications in the drug store frequently assumethey are safer than prescription medications, but this is notnecessarily the case.

Dr Phyllis Zee: In addition to OTC antihistamines, there arenumerous other medications that patients use to self-medicate,rather than seeking medical attention. The 2002 National HealthInterview Survey data showed that more than 1.6 million US adultsuse complementary and alternative medicine for sleep-relatedsymptoms.38 A total of 65% of those patients used biologicallybased therapies, including herbal remedies, which have limitedsafety and efficacy data and are not regulated by the FDA.

Dr Tom Roth: Falls and the risk for falling are important issueswith regard to insomnia and its treatments. The majority of dataseem to indicate that the causative factor, with regard tomedications, is total sedative load.39,40 If a patient is takingmedications with significant anticholinergic side effects while alsotaking a sleep agent, there is a risk for falling. It is not linked to anysingle medication. Additionally, there are studies that showinsomnia is more of a risk factor than sleep agents.41 If you give amedication for insomnia to patients and they sleep for 8 hoursand do not get out of bed, they do not fall. However, if you havepatients who have to get up 3 or 4 times a night because of anunderlying medical condition, then sleep agents are a risk.

Differentiating Treatments for InsomniaFrom Treatments for Circadian Rhythm DisordersCRSDs occur when the timing of the endogenous circadianrhythm and the normal 24-hour sleep-wake cycle are offset.Circadian rhythms are coordinated by the suprachiasmaticnucleus (SCN), which is reset by light through theretinohypothalamic tract.42 Although less potent than light,melatonin, which is released by the pineal gland during the darkcycle, resets circadian rhythm as well.43 Because they play keyroles in stabilizing circadian rhythm, timed exposure to melatoninand light are effective treatment methods in patients with CRSDs.

Dr Tom Roth: I would like to take a minute and have Dr Zeebriefly explain the roles of melatonin and light in CRSDs.

Dr Phyllis Zee: Light is the strongest entraining agent for thecircadian clock. Exposure to bright light in the early morninginduces phase advances, whereas light exposure in the eveningdelays the phase of circadian rhythms.44 In patients with CRSDs,the timing of light exposure (as a treatment intervention) istargeted 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 themorning. In this circumstance, increasing light exposure in the

evening (to keep them up later) and limiting light exposure in themorning (to entrain a later wake time) would be an initialintervention in this type of patient. In patients with a delayedphase disorder, the exact opposite would be prescribed. Withregard to melatonin, it has demonstrated clinical benefit inpatients with CRSDs. Melatonin does not have a major role in thetreatment of insomnia disorder45; however, in a patient who onlyhas trouble falling asleep, one should consider the possibility of adelayed circadian rhythm. If an underlying circadianmisalignment is present, a trial of low-dose melatonin may beuseful. A low dose of melatonin would be 0.3 mg to 1 mg. It’s notapproved by the FDA for the treatment of insomnia disorder.

Dr Andrew Krystal: I think it’s important to emphasize thatmelatonin should not be taken right before going to bed.

Dr Phyllis Zee: I agree. Many patients with delayed sleep phasedisorder come to me indicating that they’ve tried melatonin, butit didn’t work. They usually have taken it right before bedtime,which is too late to advance the phase of circadian rhythms. Toadvance the timing of the sleep-wake cycle, the ideal time to takemelatonin is 5 to 6 hours before the patient’s natural sleep time.

Dr Sonia Ancoli-Israel: To add to what Dr. Zee was mentioning amoment ago with regard to light, the best way for the advancedphase patients to avoid morning light is by wearing sunglasseswhen they go outside because the mechanism is through the eyes.The light-dark cycle information is relayed from the retina to theSCN primarily by the retinohypothalamic tract.

Dr Tom Roth: Many elderly people are terrified of falling duringthe night, so they keep a night light on. It is very important thatelderly people keep a night light by their bathroom but outside ofthe line of vision. We need light during the day, but we also needdarkness 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 insuppressing the secretion of melatonin from the pineal gland.Short wavelength light also activates the sympathetic nervoussystem, resulting in increased arousal.46

Emerging Therapies for InsomniaTwo separate research groups discovered orexin (also referred toas hypocretin) neuropeptides, which are wake-promotingneurotransmitters produced by a cluster of neurons in thehypothalamus.47,48 Orexin peptides influence the patient’s sleep-wake cycle, appetite, and autonomic nervous system,including effects on metabolic rate and behavioral responses tostress.47 The brain contains 50,000 to 80,000 orexin producing

I think it’s important to emphasize that melatoninshould not be taken right before going to bed.

—Dr Andrew Krystal

13

neurons, which have extensive projections to many different regionsin the brain. The strongest projections appear to target wake-promoting regions that regulate arousal, including noradrenergicneurons of the locus coeruleus, histaminergic neurons of thetuberomammilary nucleus, dopaminergic neurons of the ventraltegmental area, and serotonergic neurons of the raphe nuclei.49

The orexin neurons are predominantly active during periods ofwakefulness and become less active during NREM and REMsleep. Patients who have narcolepsy experience chronic sleepinessand have an approximately 90% loss of functioning orexinneurons, further suggesting the wake-promoting role of orexinneuropeptides.50 Because orexin plays a significant role in thewake cycle, recent research has exploited the clinical benefits ofantagonizing this receptor.

In phase III clinical trials, suvorexant, a dual orexin receptorantagonist, significantly improved sleep onset and sleepmaintenance compared to placebo.51,52 However, while theefficacy of suvorexant was established, next-day impairment was a concern, warranting further evaluation of select doses. Inaddition, research has shown that antagonizing serotoninreceptors (5HT-7) significantly improves sleep maintenance,suggesting a potential role for agents with this effect in thetreatment of insomnia.53 In this final section, the roundtablepanelists discuss emerging therapies and their potential roles inthe management of insomnia.

Dr Larry Culpepper: Turning the discussion toward emergingtreatments, how do the orexin receptor antagonists and serotoninreceptor antagonists affect the sleep-wake system?

Dr Tom Roth: For the past 30 years, we’ve had medications thatwork primarily on the sleep system through GABA mechanisms.However, with the emergence of low-dose doxepin, orexinreceptor antagonists, and serotonin receptor antagonists, there aremore medications focused on reducing arousal associated withthe wake system, rather than simply pushing sleep harder. Orexinreceptor antagonists are probably the medications that are closestto the finish line, and orexin is a major transmitter system that isinvolved in the arousal system. It feeds into the noradrenergic,histaminergic, and serotonergic systems.

Dr Phyllis Zee: In addition, when orexin neurons are firing duringwakefulness, they inhibit the VLPO, which is the sleep-promotingcenter in the brain. It’s not only activating the wake promotingregions in the brain, but it’s also inhibiting the sleep center.6

Therefore, if you antagonize the orexin system, you can promotesleep by affecting both sleep and wake.

Dr Tom Roth: When you give a patient zolpidem, you want it to goto the VLPO, but it binds receptors in the cerebellum as well, whichcauses ataxia. It does these things because the GABA system is sowidespread. In contrast, orexin is produced by a small group of cellsthat are located in the lateral hypothalamus, with significantprojections to regions of the brain that promote arousal.49 Whenthese medications are administered, they cause regional effects onthe brain versus the widespread effects we typically see withmedications that potentiate the GABA system, which has a lot to dowith receptor density.

Dr Larry Culpepper: We will need to adjust our thinking withregard 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 theGABA system, the sleep side of the switch, you could not usethese medications because of the significant next-day impairment.

Dr Tom Roth: If you look at low-dose doxepin, it has profoundeffects on sleep at the end of the night. If you look at the orexinand serotonin receptor antagonists, they have profound effects onsleep at the end of the night. That is a very important timebecause in those later hours you have already slept for 4 or 5 hours, and your homeostatic drive (the increased need for sleepdue to extended periods of wakefulness) is way down. Mostpeople experience wake time in the last 3 hours of the night, andthese medications are targeting those final hours of sleep. Theother factor you have to remember is benzodiazepine receptoragonists work by simply shutting the brain down, and that makesyou fall asleep very, very quickly, which is what Dr Culpepper wasalluding to earlier. When transitioning patients frombenzodiazepine receptor agonists to these newer medications,patient education will become very important because thepharmacokinetic/pharmacodynamic indices of these medicationsare profoundly different. The onset of action of these newercompounds is not as fast as the medications that work on theGABA system; conversely, the duration of action of these neweragents appears to be longer.

Dr Sonia Ancoli-Israel: These medications may not help patientsget to sleep as fast as medications affecting the GABA systembecause orexin receptor antagonists, for example, are morefocused on extending sleep. Education will be necessary to reducethe patient’s expectation of rapidly falling asleep.

Final ThoughtsResearch suggests that insomnia is a condition of hyperarousalcaused by a relative shift in the balance of activity of the sleep-promoting and wake-promoting systems towards an increasein activity in wake-promoting systems. Insomnia is not a symptomof other disorders, but it’s comorbid with other medical conditions,requiring its own intervention. Several studies, which haveevaluated behavioral and pharmacologic therapy, support thisdirection in treatment. In addition, clinicians will not only need toinquire about insomnia when comorbid conditions are present butthey will also need to inquire about comorbid conditions wheninsomnia is present.

We will need to adjust our thinking with regard to these newer agents because they’re drastically

different, at least from a pharmacokineticperspective. —Dr Larry Culpepper

14

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New DirectionsManagement of

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Insomnia