Chronic Insomnia Disorder Is Among Should Take Measures to Discuss Sleep the Most Widely Reported Clinical Con- Problems and Their Impact on The

Review Article

Address correspondence to Dr Alon Y. Avidan, University of California Los Angeles, Chronic Insomnia David Geffen School of Medicine, Reed Neurological Research Center, 710 Disorder Westwood Blvd, C153, Los Angeles, CA 90095-1769, [email protected]. Alon Y. Avidan, MD, MPH, FAAN; David N. Neubauer, MD Relationship Disclosure: Dr Avidan has received personal compensation for ABSTRACT serving as a speaker for Arbor Pharmaceuticals and PERNIX Purpose of Review: Neurologists, along with all health care providers, commonly Therapeutics and receives encounter patients with insomnia, which is a condition that impacts patients’ royalties from Elsevier and underlying neurologic conditions in a bidirectional manner. While chronic insomnia UpToDate, Inc. Dr Neubauer has received personal is one of the most common sleep disturbances, only a small proportion of individuals compensation for serving on with this condition discuss their sleep problems with their providers. When insomnia is the board of directors for the described, it is more often in relationship to another medical problem, as opposed to National Sleep Foundation, as a consultant for Purdue an independent condition. In neurology practice, multiple factors including pain, Pharma LP, and as a lecturer movement disorders, sleep apnea, and medications that act on the central nervous for the American Academy of system often contribute to insomnia. An all-inclusive approach is necessary when Sleep Medicine, the American College of Chest Physicians, evaluating sleep problems in patients with insomnia. the Clayton Sleep Institute, the Recent Findings: The US Food and Drug Administration (FDA) has approved several New Jersey Sleep Society, and medications for the treatment of insomnia that target specific receptor systems in the the US Psychiatric and Mental Health Congress. brain and incorporate several unique pharmacodynamic and pharmacokinetic profiles Unlabeled Use of that can represent customized therapy for specific insomnia phenotypes. FDA-approved Products/Investigational medications for insomnia include +-aminobutyric acid (GABA)-modulating benzodiaz- Use Disclosure: epine receptor agonists, a melatonin receptor agonist, a histamine receptor antagonist, Drs Avidan and Neubauer discuss the off-label uses of and the newest approved option, a hypocretin (orexin) receptor antagonist. various central nervous Summary: This article provides an evidence-based multidisciplinary approach to the Y system acting medications treatment of insomnia, highlighting the rationale and utility of cognitive-behavioral for insomnia, which include sedating antidepressants such therapy and pharmacologic interventions. Neurologists should be proactive in assessing as amitriptyline, doxepin, the impact of underlying comorbidities on insomnia, particularly in the setting of mirtazapine, and trazodone; psychiatric conditions such as depression, sleep disorders such as circadian rhythm the antipsychotic quetiapine; antihistamine compounds disorders, and medical problems such as nocturia. such as doxylamine; medications available over-the-counter marketed as Continuum (Minneap Minn) 2017;23(4):1064–1092. sleep aids as single compounds or as a combination therapy with analgesics (acetaminophen INTRODUCTION ditions in medicine and has a signifi- or ibuprofen); and dietary Insomnia is pervasive in neurology prac- cant impact on populations treated in supplement sleep aids such as 1,2 chamomile, hops, kava kava, tice, but is often undiagnosed and neurology practices. Sleep difficulties melatonin, passionflower, tart untreated. Specific patient cohorts such often result from multiple etiologies and cherry juice, and valerian. * 2017 American Academy as older adults, patients who live in may require a multidisciplinary treat- of Neurology. nursing homes, and individuals with ment approach based on established underlying chronic comorbid medical, evaluation guidelines and evidence- neurologic, and psychiatric disorders based therapies.3 Recent evidence dem- are particularly at risk. These patients onstrates that poor sleep is associated often present with difficulties falling with a wide range of negative health asleep and maintaining sleep and expe- outcomes and that poorer quality of rience significant daytime consequences life and medical, neurologic, and psy- such as fatigue, memory problems, and chiatric comorbidities disrupt sleep. poor psychosocial function. Given this bidirectionality, neurologists Chronic insomnia disorder is among should take measures to discuss sleep the most widely reported clinical con- problems and their impact on the

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Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. KEY POINTS underlying neurologic disease and take Several classification systems offer h Recent evidence specific steps toward enhancing sleep criteria for insomnia nosologies and demonstrates that poor quantity and quality in their patients. specific insomnia phenotypes. Insom- sleep is associated with By doing so, the clinician may have a nia classification schemes are outlined a wide range of broader role in promoting wellness by the International Classification of negative health and bringing about improvements in Diseases, Tenth Revision (ICD-10) and outcomes and that some comorbid conditions as well. the Diagnostic and Statistical Manual poorer quality of life and of Mental Disorders, Fifth Edition medical, neurologic, DEFINITION OF INSOMNIA (DSM-5), which is the American Psy- and psychiatric Insomnia disorder refers to persistent chiatric Association’s 2013 update to its comorbidities disrupt difficulties falling asleep, maintaining classification and diagnostic tool.6,7 sleep. sleep, or waking up earlier than habitual Both the ICD-10 and DSM-5 assimilate h Insomnia disorder refers rise time and is associated with impair- categorizations of key sleep disorders to persistent difficulties ment of daytime functioning despite including various insomnia subtypes. falling asleep, the opportunity for sufficient sleep The 2014 American Academy of Sleep maintaining sleep, or waking up earlier than duration.4 Although patients with in- Medicine (AASM) International Classi- habitual rise time and is somnia report the chronicity of wake- fication of Sleep Disorders, Third Edi- associated with fulness during the night, insomnia tion (ICSD-3) defines general criteria impairment of daytime disorder is conceptualized to represent for chronic insomnia disorder, reviewed functioning despite a 24-hour condition reflecting a state of in Table 8-1,aswellasshort-term the opportunity for 4 hyperarousal leading to both the night- insomnia disorder. The chronic and sufficient sleep time and daytime symptomatology.5 short-term insomnia disorder criteria duration.

a TABLE 8-1 Diagnostic Criteria for Chronic Insomnia Disorder

Criteria A through F are required for a diagnosis of chronic insomnia disorder A. The patient/family members/caregiver reports or observes one or more of the following 1. Difficulties with sleep initiation 2. Difficulties with sleep maintenance 3. Waking up earlier than desired with difficulties reinitiating sleep 4. Opposition to going to bed during habitual bedtime schedule 5. Difficulties sleeping without the intervention of the parent or caregiver B. The patient/patient’s parent/caregiver report or observe one or more of the following difficulties in relationship to the nighttime sleep difficulty 1. Malaise/fatigue 2. Impairment in concentration, attention, or memory 3. Impairment in domains of social function, fulfillment of family duties, or difficulties with occupational or academic performance 4. Disturbances in mood and/or irritability 5. Excessive daytime somnolence 6. Problems with behavioral function (eg, aggression, hyperactivity, impulsivity) 7. Impairment in motivation/energy/initiative 8. Proneness for accidents and/or errors 9. Concerns about or dissatisfaction with sleep quality Continued on page 1066

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a TABLE 8-1 Diagnostic Criteria for Chronic Insomnia Disorder Continued from page 1065

C. The reported sleep/wake difficulties cannot be otherwise explained by inadequate opportunity or inadequate circumstances for sleep (ie, the patients should have sufficient allotted time for sleep and environmental conditions are conducive for sleep [safe, dark, quiet, and comfortable]). D. Frequency criteria: The sleep difficulties and associated daytime symptoms must occur at a frequency of at least 3 times per week. E. Duration criteria: The sleep disturbance and the associated daytime symptoms must be present at least 3 months. F. The sleep/wake disturbance is not attributed to or explained by another underlying primary sleep disorder (such as obstructive sleep apnea, circadian rhythm sleep-wake disorder, or a motor disorder of sleep). Notes 1. Insomnia may be observed across all age groups. Opposition to going to bed on a proper schedule and difficulty sleeping without a parent or in the absence of a caregiver intervention is seen most commonly in children and older adults who require the supervision of a caretaker due to a significant disturbance in cognitive or functional impairment (eg, patients with underlying neurodegenerative diseases such as Alzheimer dementia). 2. A unique circumstance occurs when patients suffer from insomnia and experience recurrent episodes of sleep/wake difficulties lasting several weeks at a time interval persisting for several years, but may not meet the specific duration criteria (listed in E) for any single such episode. These patients should be assigned a diagnosis of chronic insomnia disorder, given the persistence of their intermittent sleep difficulties over time. 3. Patients with chronic insomnia treated with hypnotic medications may improve and thus not meet the criteria for an insomnia disorder while using these agents. In the absence of hypnotics, however, this patient population may meet the diagnostic criteria for insomnia disorder, especially if they express concerns about their dissatisfaction with sleep continuity in the absence of hypnotics. 4. Neurologic, medical, psychiatric, and primary sleep comorbidities such as chronic pain disorders, Parkinson disease, and restless legs syndrome may induce sleep/wake complaints suggestive of insomnia. A distinct diagnosis of insomnia may not apply when these disturbances are suspected to be underlying inducers of the sleep difficulty. In many patients, however, these conditions are chronic and may not be exclusive causes of sleep difficulty. A decision to adjudicate a unique insomnia diagnosis considers: ‘‘How much of the time does the sleep difficulty arise specifically as a result of factors directly attributable to the medical/psychiatric/neurologic/sleep comorbidity?’’ or ‘‘Are there specific conditions or settings during which the sleep/wake complaints occur in the absence of these factors?’’ ‘‘Have perpetuating behavioral or cognitive issues (eg, negative expectations, conditioned arousal, and sleep-disruptive habits) arisen, indicative of an autonomous aspect occurring in parallel, but independent of the underlying insomnia?’’ A distinct diagnosis of chronic insomnia disorder may be established if there is sufficient ground to suspect that the patient’s sleep/wake complaints are not distinctly induced by the medical comorbidity. If this is indeed the case, then those sleep/wake complaints could merit the separate need to evaluate the potential for therapeutic interventions. a Modified with permission from the American Academy of Sleep Medicine.4 B 2014 American Academy of Sleep Medicine.

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Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. KEY POINTS are similar, with key difference being mittent symptoms of insomnia, while h The insomnia the duration (fewer than 3 months about 10% meet the criteria for chronic classification by for short-term insomnia disorder and insomnia disorder associated with day- the International 3 months or more for chronic insom- time sequelae. It is common for brief Classification of Sleep nia disorder). insomnia episodes to have identifiable Disorders, Third Edition The ICSD-3 insomnia classification precipitants, such as situational crises, requires components of requires components of both night- a new medication (eg, steroids for both nighttime and time and daytime elements.4 The multiple sclerosis exacerbation), acute daytime elements. nighttime sleep symptoms consist of schedule changes (eg, neurology resi- h While patients with (1) difficulty falling asleep, (2) diffi- dent on call), or an acute neurologic chronic insomnia tend culty maintaining sleep, or (3) early problem (eg, new stroke requiring to worry about their morning awakening despite sufficient intensive care admission). inability to sleep well sleep opportunity. Subjective prob- and the negative impact lems reported by patients may include EVOLUTION OF ACUTE TO this has on their lives, a pattern of delayed sleep onset, many CHRONIC INSOMNIA they often do not describe excessive brief or protracted awakenings, and a Several models provide a rationale daytime sleepiness. sensation that sleep is fragmented and for the transformation from acute to h very light. The most likely motivation chronic insomnia. The 3P model de- In the general prompting patients with insomnia to scribes how chronic insomnia devel- population, about one-third of adults seek medical attention is related to ops as a consequence of underlying report intermittent concerns about daytime consequences. predisposing features, precipitating symptoms of insomnia, The spectrum of these daytime symp- factors, and perpetuating processes. while about 10% meet toms varies and may include poor Together these three components ele- the criteria for chronic concentration, attention, cognition, and vate a person’s insomnia risk above a insomnia associated motivation; fatigue; depressed mood; clinical threshold, as demonstrated with daytime sequelae. 8 irritability; decreased energy; and a in Figure 8-1. The figure provides a h The 3P model shows predilection to make errors. representation of Spielman and col- how chronic insomnia 8 While patients with chronic insom- leagues’ 3P model of chronic in- develops as a nia tend to worry about their inability somnia etiology. Everyone has a consequence of the to sleep well and the negative impact predetermined risk or a baseline de- underlying predisposing this has on their lives, they often do gree of vulnerability for insomnia due features, precipitating not describe excessive daytime sleep- to genetics or personality phenotypes. factors, and iness. In fact, the opposite often is People who do not express sleep perpetuating processes. observed; they report abnormal wake- disturbance at their baseline would fulness during the day and night, be below the level of clinically signifi- which could be the manifestation of cant insomnia (Figure 8-1). Acute their underlying hyperarousal process. stressors may raise patients beyond the A common daytime complaint is feel- theoretical clinical insomnia threshold ing ‘‘tired and wired.’’ to a point where they develop insomnia symptoms. Over time, perpetuating EPIDEMIOLOGY factors (eg, chronic habitual behaviors The prevalence of insomnia varies such as lying awake in bed, caffeine, significantly depending on age, gen- alcohol, daytime napping, or nighttime der, comorbidities, and the specific light from television, phone, or other population cohorts being examined.1 electronic devices) ultimately promote However, women and older adults persistent and pervasive insomnia symp- tend to express a higher risk for toms, which are responsible for propa- insomnia. In the general population, gation of the sleep disturbance. about one-third of adults report inter- Cognitive-behavioral therapy for insomnia

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8 FIGURE 8-1 3P model of insomnia etiology. The 3P (predisposing, precipitating, and perpetuating) model of insomnia etiology explains that all people express a certain vulnerability for insomnia (predisposing factors). Insomnia disorder occurs when a precipitating event pushes patients above the insomnia threshold. When the precipitating factor diminishes, the insomnia is kept above the threshold when patients develop behaviorally conditioned arousal responses associated with the bedroom environment and maladaptive behaviors that perpetuate the insomnia. These perpetuating factors are shown in the figure as use of alcohol too close to bedtime, caffeine too late during the day, and excessive light and use of television and light-emitting electronic devices. People who do not express sleep disturbance at their baseline would be below the level of clinically significant insomnia (as demarcated by the black star within the baseline period).

Modified with permission from Spielman AJ, Glovinsky P, Plenum Press.8 B 1991 Springer Science and Business Media.

(CBT-I) and pharmacotherapy addresses nights each week or each month. this third and final P as patients move Insomnia may be described as primary across a continuum from acute to chronic insomnia and conceptualized as an insomnia. independent disorder when no concomitant conditions that seem to be CHRONIC INSOMNIA contributing to the sleep disturbance For many neurology patients, insom- are present. In contrast, a patient with nia is very likely to become a chronic sleep difficulty presumably influenced nightly problem that persists for a few by the presence of another disorder, weeks, months, and even years, al- such as major depression, fibromyal- though various temporal patterns are gia, substance abuse, or obstructive possible. Patients may present with sleep apnea, may be viewed as having intermittent episodes of insomnia last- a comorbid type of insomnia. Circa- ing weeks to months interspersed dian rhythm disorders can also pre- with relatively normal sleep, or they sent with chronic insomnia. Older age may have recurrent and intermittent is associated with alteration in circadian sleep problems lasting from several rhythmicity of sleep with predisposition

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Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. KEY POINT for phase advancement of sleep tim- categorizes this as short-term insomnia h The underlying ing,referredtoasadvancedsleep- as long as the symptoms are present for mechanism of 9,10 4 wake phase disorder. Patients with fewer than 3 months. psychophysiologic Alzheimer disease frequently develop insomnia is a irregular sleep rhythms with difficulty Paradoxical Insomnia behaviorally based staying asleep for consolidated pe- Paradoxical insomnia was previously re- phenotype reflecting a riods of time, long awakenings at ferred to as sleep state misperception conditioned heightened night, and daytime sleepiness requir- and reflects a complaint of severe sleep arousal associated ing frequent naps. disturbance in the absence of corrobora- with the bed, the The ICSD-3 does not differentiate tive and objectively verifiable indicators of environment within the primary from comorbid insomnia the degree of sleep disturbance claimed bedroom (ie, clock), and maladaptive given that no apparent biological fac- by the patient. For example, a major bedtime routines. tors discriminate between possible in- mismatch may occur between a patient’s somnia subtypes, although previous misperception of complete sleepless- ICSD versions incorporated conceptu- ness during a night of in-laboratory ally useful descriptive subtypes with polysomnography that objectively re- psychophysiologic, paradoxical, and id- cords a total sleep time of 6 hours. iopathicinsomniasasexamplesof primary insomnia.4 According to the Idiopathic Insomnia ICSD-3 nosology, patients meeting a This subtype reflects persistent insom- general insomnia criteria then could be nia unrelated to an identifiable precipi- diagnosed with a specific insomnia dis- tant that begins insidiously in childhood order, including the following subtypes.4 and continues chronically in an unre- mitting pattern into adulthood. While Psychophysiologic Insomnia no consistent genetic biomarkers or The underlying mechanism of psy- neural pathology have been described chophysiologic insomnia is a be- in these patients, idiopathic insomnia is haviorally based phenotype reflecting a thought to arise from either genetically conditioned heightened arousal associ- based or congenital alterations in the ated with the bed, the environment sleep-inducing or wake-promoting sys- within the bedroom (ie, clock), and tems in the brain. maladaptive bedtime routines. Excessive focus on and worry about sleep, and Inadequate Sleep Hygiene elevated levels of cognitive and somatic Patients with this insomnia subtype arousal, particularly at bedtime, are engage in maladaptive behaviors that common. Learned sleep-preventing as- interfere with normal sleep promotion sociations perpetuate the sleep difficulty or continuity. These detrimental be- and promote this chronic form of haviors may include aberrant sleep- insomnia (Case 8-1). wake schedule problems, consumption or use of substances likely to disrupt Adjustment Insomnia sleep (eg, caffeine, tobacco, or alcohol), Adjustment insomnia occurs in temporal and engaging in evening routines that association with an identifiable stressor are not conducive to sleep. Other usually spanning a duration of fewer practices that promote this insomnia than 3 months. Sleep should improve subtype include prolonged daytime with the resolution of the stressor. In napping that is too close to bedtime, some cases, adjustment insomnia may regularly using the bedroom for activi- evolve into a chronic form and warrant a ties other than sleep, participating new insomnia diagnosis. The ICSD-3 in stimulating or emotionally upsetting

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Case 8-1 A 62-year-old man presented to the neurology clinic complaining of insomnia that had begun 2 years ago when he had failed to obtain funding to support his research as a physics professor. He brought his sleep log to the appointment, which revealed prolonged sleep latency and that he had resorted to watching television and using alcohol to help initiate sleep. He noted that stress or sleeping in unfamiliar surroundings exacerbated his sleep problems. He reported working on his laptop until he went to bed at 10:00 PM, when he would start reading the news and doing puzzles on his tablet device in bed, until he eventually felt sleepy around midnight. His sleep diary also revealed that he resorted to drinking two to three shots of vodka to help him relax and induce sleep. He denied snoring or apneic spells anddidnotfeel‘‘restless’’orhaveanurgetomovehislegs.Hedeniedusing caffeine and did not use any medications on a daily or nightly basis. He had no chronic health issues. His body mass index was 26.5 kg/m2. His physical and neurologic examination was normal, and his upper airway examination was completely normal and was not crowded. The patient was diagnosed with psychophysiologic insomnia. He wished to avoid any pharmacotherapy, but he expressed an interest in conservative behavioral management. He was referred for cognitive-behavioral therapy for insomnia, and he was informed that mentally alerting activities, such as doing puzzles on the tablet device in bed, should be avoided, as well as limiting light sources at night to a minimum level. He was also asked to avoid the use of alcohol before bedtime. After 6 weeks of treatment, he returned to clinic reporting that his symptoms had improved. He was able to sleep for 7 hours per night without interruption and did not need to rely on any agents to induce sleep. Comment. This patient’s history and physical examination did not point to a primary medical, psychiatric, or sleep disorder and was most consistent with psychophysiologic insomnia, which is characterized by difficulties falling asleep at the desired bedtime, mental hyperarousal in bed, or heightened somatic tension interfering with sleep onset. In addition to cognitive-behavioral therapy for insomnia, appropriate nonpharmacologic suggestions for improving sleep hygiene include avoidance of mentally distracting activities, which can improve anxiety levels and keep hyperarousal from interfering with sleep onset. Another suggestion for improving sleep hygiene is to avoid spending time in bed awake and to read relaxing (or even boring) books. The light source should be limited to a small bedside lamp or book light and set ideally at the minimum level needed to allow undemanding reading. Patients should also avoid the use of alcohol before bedtime because of its adverse impact on sleep architecture.

activities too close to bedtime, or haviors that are targetable by cognitive- failing to maintain a comfortable en- behavioral therapy interventions. vironment for sleep.4 A significant degree of overlap exists between inad- Behavioral Insomnia of equate sleep hygiene and other forms Childhood of insomnia, with most patients with Behavioral insomnia of childhood is a insomnia admitting to at least one of diagnosis reserved for sleep difficulties these common maladaptive sleep be- in pediatric patients and incorporates

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Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. KEY POINTS the following three sleep-onset asso- nia episode over the clinical threshold, h A good general rule in ciation and limit-setting subtypes: and perpetuate the insomnia symp- the assessment of & The sleep-onset association type toms over time once the precipitant insomnia is to consider 3,11 reflects the child’s dependency diminishes (Figure 8-1). the potential etiology on a specific activity/behavior/ The clinical guidelines for evaluat- and likely factors that stimulation, typically objects or ing insomnia published by the AASM may predispose the settings, for initiating sleep or in 2008 highlight the key steps of the patient to develop sleep returning to sleep following an historical inventory during the clinical difficulty, precipitate an insomnia episode over awakening. When these are absent, interview, focusing on the specific the clinical threshold, sleep onset is significantly delayed. sleep-related symptoms as well as the potential contributions of psychiatric, and perpetuate the & The limit-setting type is demarcated insomnia symptoms by behaviors of stalling or refusing medical, and substance use disord- 3 over time once the going to bed that are attributable ers. When possible, a bed partner or precipitant diminishes. other family member should be inter- to an inadequate limit setting by h viewed to provide detailed informa- When possible, a bed the parent or caregiver. partner or other family tion about any apneic spells, snoring, & The mixed hybrid type is member should be characterized by features of both abnormal sleep-related movements, interviewed to provide sleep-onset association difficulties leg jerks, dream enactment, or behav- detailed information 3 and bedtime resistance. ioral abnormalities. about any apneic spells, Sleep questionnaires and sleep logs snoring, abnormal Insomnia Due to a Mental are very important in supplementing sleep-related Disorder and Insomnia Due the formal evaluation of a patient with movements, leg jerks, to a Medical Condition insomnia. A sleep diary spanning a dream enactment, period of several weeks can be quite or behavioral Diagnoses of insomnia due to a mental helpful in highlighting patterns of abnormalities. disorder or insomnia due to a medical sleep disturbance and uncovering po- h Sleep questionnaires condition presume the presence of tential circadian rhythm sleep-wake and sleep logs are comorbid psychiatric and medical con- disorders. An example of a sleep diary very important in ditions with a clear temporal association may be downloaded from the AASM supplementing the with the underlying sleep disturbance website ( yoursleep.aasmnet.org/pdf/ formal evaluation of a and generally are used where the sleepdiary.pdf ). A recently developed patient with insomnia. insomnia is severe enough to warrant consensus sleep diary provides a stan- independent treatment. dardized patient-informed sleep diary in the assessment of insomnia based Insomnia Due to a Drug or on expert consensus.12 Substance Neurologists should conduct a Insomnia due to a drug or substance general physical and neurologic exam- represents sleep problems clearly and ination, a dedicated sleep medicine temporally associated with the drug or examination, and a baseline mental substance intoxication or withdrawal status examination. Polysomnography from a wide range of medications. may be reserved for patients suspected of having a concomitant sleep disorder EVALUATION AND ASSESSMENT (eg, sleep-disordered breathing or peri- OF INSOMNIA odic limb movement disorder) that is A good general rule in the assessment likely contributing to the insomnia of insomnia is to consider the poten- symptoms, but it should not be ordered tial etiology and likely factors that may routinely in the absence of these predispose the patient to develop suspected sleep-disturbing symptoms. sleep difficulty, precipitate an insom- Home sleep apnea testing is reserved

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KEY POINT h The diversity of for patients likely to be experiencing rewarding to patients, bed partners, influences on sleep and sleep apnea. The clinician should be family members, and providers when wakefulness, extensive aware of the specific contraindica- successfully managed. Chronic insom- variability in patient tions for home sleep apnea testing, nia may result from the interplay of expectations, along with which are likely to contribute to in- numerous processes frequently occur- the wide spectrum of somnia (ie, movement disorders of ring simultaneously. Successful inter- insomnia phenotypes sleep).13,14 For more information on vention requires a multidisciplinary highlights the view that home sleep apnea testing, refer to the treatment philosophy incorporating a unitary treatment article ‘‘Sleep-Disordered Breathing’’ several concurrent strategies and, in pathway is not always by Nancy R. Foldvary-Schaefer, DO, MS, some cases, a staged approach that possible. and Tina E. Waters, MD,15 in this issue may involve further testing.3 of Continuum. The core elements of a sleep history General Recommendations should focus on the specific chronicity The diversity of influences on sleep of insomnia symptoms, impact on and wakefulness, extensive variability daytime activities and functioning, in patient expectations, along with the contribution of sleep-wake schedule wide spectrum of insomnia pheno- routines, and other sleep-related symp- types highlights the view that a uni- toms (eg, snoring, movements, behav- tary treatment pathway is not always iors). Table 8-2 provides an inventory possible. The fundamental key to man- of questions for interviewing patients aging patients with insomnia is to presenting with insomnia. creatively customize therapy for indi- vidual patients. Clinicians managing MANAGEMENT OF INSOMNIA insomnia should remember to spend Chronic insomnia is complex and sufficient time collecting the sleep often challenging, but can be very history, appreciate specific patient

TABLE 8-2 Insomnia Inventory Questionnaire

1. How long have you had symptoms of insomnia? 2. Was there a specific trigger? 3. What is the timing of the insomnia symptoms during the night? 4. Please estimate the time of sleep onset and total sleep times and the frequency and character of awakenings. 5. What is the typical rise time? 6. Is the difficulty primarily sleep onset or sleep maintenance, or is it a combination of the two? 7. Describe your evening routines and your bedroom setting. 8. Are there apparent situational or environmental variables? 9. Are you taking medications or using substances specifically for sleep? Are any of these temporally related to worsening of or improvement of sleep? 10. Describe your previous sleep difficulty and the results of any treatment approaches. 11. What specific hypnotics (if any) have you tried? (List name of medication, date of use, dose, instructions given, duration, impact, results, and side effects, if any.) 12. Have you tried cognitive-behavioral therapy? If yes, please describe.

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Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. KEY POINTS expectations, and collaborate with pa- to identify and treat other sleep disor- h When managing tients in setting clear treatment goals ders that may lead to insomnia. Exam- chronic insomnia in the specific to their nighttime and daytime ples of factors that contribute to neurology outpatient symptoms. Any patient provided with difficulty initiating sleep include anxi- setting, clinicians must hypnotics should be monitored pro- ety, excessive caffeine use, and symp- consider the specific spectively for therapeutic progress toms of restless legs syndrome (RLS). underlying neurologic and potential. A history of possible An example of RLS contributing to and psychosocial treatment-related adverse effects such sleep initiation insomnia is illustrated comorbid conditions. as complex nocturnal behaviors, amnes- in Figure 8-3. h As part of the initial tic sleep eating, or depressed mood As shown in Figure 8-2,other assessment of insomnia, should be sought by the prescribing comorbidities likely to manifest with neurologists should physician, who should then recalibrate insomnia include circadian rhythm attempt to identify and the therapeutic plan as needed. sleep-wake disorders: advanced sleep- treat other sleep wake phase disorder, manifesting with disorders that may lead Insomnia and its Comorbidities early bedtime and early morning awak- to insomnia. When managing chronic insomnia in enings, and delayed sleep-wake phase h Other comorbidities the neurology outpatient setting, cli- disorder, resulting in difficulties initiat- likely to manifest nicians must consider the specific ing sleep and difficulty awakening be- with insomnia include underlying neurologic and psychoso- fore late morning or early afternoon. circadian rhythm sleep-wake disorders: cial comorbid conditions, as illustrated Sleep apnea may contribute to sleep advanced sleep-wake in Figure 8-2. A successful outcome is maintenance insomnia, especially with phase disorder, possible when these conditions (eg, more advanced stages of Parkinson manifesting with early pain syndrome, epilepsy, Parkinson disease, where nocturia is very com- bedtime and early disease, and mental health disorders mon, making the condition difficult to morning awakenings, such as anxiety and depression) are treat. Periodic limb movement disorder and delayed sleep-wake appropriately addressed. mayalsoleadtosignificantinsomnia, phase disorder, As part of the initial assessment of especially in patients with pain syn- resulting in difficulties insomnia, neurologists should attempt dromes, Parkinson disease, narcolepsy, initiating sleep and difficulty awakening before late morning or early afternoon.

FIGURE 8-2 Differential diagnosis of insomnia according to its manner of occurrence during the night. The flow diagram depicts etiologic considerations in patients presenting with sleep initiation insomnia, sleep maintenance insomnia, and early morning awakenings.

B 2017 Alon Y. Avidan, MD, MPH. Permission remains with author.

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FIGURE 8-3 Polysomnographic depiction of a patient with restless legs syndrome (RLS). This 60-second fragment is from a diagnostic polysomnogram of a patient with chronic insomnia and reveals severe RLS, evident during video review, which showed innumerable recurrent voluntary leg movements during wakefulness. The patient experienced the severe urge to move and kick his legs (demarcated by *), which resulted in some temporary relief of the patient’s symptoms. A history of apparent RLS was not evident in this patient prior to the study. The patient took almost 3 hours to fall asleep from the period of lights out (LO) until sleep onset (SO), a difficulty which he experienced 2 to 3 times per week. Although polysomnography is not indicated in the routine evaluation of insomnia or RLS, data can help shed light on the impact insomnia has on sleep and quality of life.

B 2017 Alon Y. Avidan, MD, MPH. Permission remains with author.

KEY POINT and multiple sclerosis. Early morning potential influence of intrinsic (patient- h When managing awakening also may be a sign of a related) and extrinsic (environmental) insomnia, the initial mood disorder. The bidirectional rela- factors, the latter including noise, approach should tionship between pain, motor disorders temperature, light, radio, or television, consider the potential of sleep, as well as psychiatric condi- as shown in Figure 8-4. These factors influence of intrinsic tions such as depression and anxiety, should be targeted for patient educa- (patient-related) and extrinsic (environmental) as illustrated in Figure 8-4,iswell tion and correction during CBT-I. factors, the latter establishedintheliterature.Insomnia One key item with significant relevance including noise, and poor sleep contribute to worsened in neurology is the use of medications, temperature, light, pain, anxiety, and depression, which, in particularly antidepressants, stimulants, radio, or television. turn, worsen the underlying sleep wake-promoting agents, antiepileptic disturbances.16Y18 Interestingly, un- drugs, and dopamine agonists and healthy behaviors are also associated antagonists. Neurologists should work with insomnia symptoms in a bidirec- closely with primary care physicians and tional manner; insomnia is associated psychiatrists to provide treatment re- with heavy drinking and physical inac- garding timing and dosages with the tivity, which are also associated with lowest potential to impact sleep onset poorer sleep and insomnia symptoms.19 or maintenance. Good general advice When managing insomnia, the ini- for patients with insomnia is to avoid all tial approach should consider the stimulating drugs and substances (eg,

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Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. KEY POINT h Sleep hygiene education is a good starting point for all patients who present with chronic insomnia because it sets the fundamental ground rules that help eradicate persistent sleep difficulty.

FIGURE 8-4 Mechanism of and contribution of key comorbidities to the perpetuation of chronic insomnia. Specific intrinsic (patient-related) factors are illustrated, depicting how their bidirectional relationship with insomnia worsens insomnia. Insomnia, when poorly treated, often worsens the comorbidities (eg, pain, depression). Extrinsic factors include excessive noise, light exposure, alcohol at bedtime, nicotine, exercise, and long naps too close to bedtime.

B 2017 Alon Y. Avidan, MD, MPH. Permission remains with author. stimulating/alerting antidepressants and Education and Healthy antiepileptic drugs, bronchodilators, Sleep Habits thyroid hormones, corticosteroids, de- An inventory of healthy sleep behav- congestants, caffeine after lunchtime, iors for review with all patients who nicotine, and evening alcohol) or, when present with insomnia is provided certain activating/alerting prescription in Table 8-3.20 Sleep hygiene educa- drugs are necessary, to time adminis- tion is a good starting point for all tration earlier in the daytime with patients who present with chronic in- avoidance of nighttime dosing whenev- somnia because it sets the fundamental er possible. When possible, sedating ground rules that help eradicate persis- medications (particularly antiepileptic tent sleep difficulty. Treatment usually drugs, anxiolytics, and benzodiazepine starts with educating patients about modulators) should be taken close to the basic processes that impact sleep bedtime. However, caution should be and mechanisms to optimize the func- taken toward possible influences of tioning of the existing physiologic medications on sleep architecture, mechanisms that regulate the sleep- alteration, and suppression of upper wake cycle.3 airway muscle tone, and whether Ensure sleep-wake timing is regu- medications may precipitate or exacer- lar. Patients need to maintain regular- bate RLS. ity in their sleep and wake times and

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a TABLE 8-3 Healthy Sleep Habits

b Healthy Sleep Habits at Night Dedicate at least 30 minutes of wind-down time before bedtime in which you do something relaxing, such as read a book. Dim the lights in the house slightly for an hour or so before bed. Disconnect electronics: Stay away from light-emitting devices such as television, laptops, phones, and tablets, as the blue light from their screens can alert the brain and make it harder to fall asleep. Use the bed and bedroom for sleep and sex only. Establish a regular prebedtime routine and a regular sleep-wake schedule. Avoid alcohol or heavy meals too close to bedtime. Create a sleep-promoting environment that is dark, cool, and comfortable. Avoid disturbing noises: Consider a bedside fan or white-noise machine to block out disturbing sounds. If unable to fall asleep within 20 minutes, get up and return to another space in the house to engage in a relaxing activity, such as reading or listening to music. Lying in bed awake can create an unhealthy conditioned association between your sleeping environment and wakefulness. You want your bed to conjure sleepy thoughts and positive feelings only. Go to bed and wake up at the same time every day. Even if you have difficulties falling asleep and trouble awakening in the morning because you are tired, try to get up at the same time (weekends included). This can help adjust your body’s clock and aid in falling asleep at night. b Healthy Sleep Habits During the Day Avoid caffeine, particularly after noon. Avoid alcohol and nicotine, especially close to bedtime. Exercise regularly earlier during the day, but not within 3 hours before bedtime. Avoid naps, particularly longer than 20 minutes and outside the 1:00 PM to 3:00 PM time window. Keep a sleep diary to identify sleep habits and patterns that you can share with your doctor. a Data from the National Sleep Foundation.20 sleepfoundation.org/insomnia/content/what-do- when-you-cant-sleep.

should allocate sufficient opportunity distracting activity (while avoiding for adequate sleep duration. work activities, light exposure, or Avoid excessive time awake in electronic devices) in another room of bed. Spending habitual time awake in the home until feeling sleepy enough the bed has the potential to perpetu- to return to the bedroom so that the ate the behavioral conditioned asso- desired association between the bed ciation of the bedroom environment and sleep is reestablished. with insomnia, which reinforces hyper- Refrain from inappropriate and arousal. The patient should be educated excessive napping behavior. For some to leave the bed after 15 to 20 sleepless people, routine regular daytime nap- minutes, getting up to pursue a quiet ping may be appropriate, but for

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Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. Y KEY POINTS patients with insomnia, naps should be noises. White noise generating de- h While some patients discouraged, especially in the late af- vices may be beneficial. have an expectation ternoon or evening. Prolonged napping Set a cooler room temperature. that their insomnia too close to the evening could facilitate To optimize sleep, the ideal tempera- management would sleep-onset difficulties. If the patient ture should be neutral to slightly cool, include a hypnotic has difficulty refraining from napping, as sleep onset is typically associated medication, data restricting naps to no longer than a 15- with the body’s temperature nadir demonstrate that the to 20-minute period earlier in the point in the evening. ideal strategy is one that afternoon and, if necessary, setting specifically incorporates alarms to limit the nap duration should Psychological and Behavioral cognitive-behavioral be suggested. Strategies therapy for insomnia. Encourage environmental condi- A wide variety of well-defined behav- h The core elements of tions conducive to sleep. A relaxing ioral approaches have been shown to cognitive-behavioral evening and bedtime routine should be effective in treating patients with therapy for insomnia facilitate sleep onset. Work projects, insomnia.21 While some patients have attend to components that regulate the watching television late in the eve- an expectation that their insomnia circadian cycle, which ning, and computer-related activities management would include a hyp- include the underlying should be strictly minimized within notic medication, data demonstrate psychological processes 2 hours of bedtime. Inappropriate that the ideal strategy is one that that can impact sleep 22 evening light exposure and device specifically incorporates CBT-I. and the maladaptive screen time (eg, laptops, video game The core elements of CBT-I are cognitive distortions devices, tablets, and phones) can outlined in Table 8-4 and attend to that fuel the perpetuation induce a circadian phase delay that components that regulate the circadian of insomnia. undermines the initiation of sleep at cycle, which include the underlying the desired time. psychological processes that can impact Minimize noise. The sleep environ- sleep and the maladaptive cognitive ment should be free of disturbing distortions that fuel the perpetuation

TABLE 8-4 Techniques and Special Goals Outlined During Cognitive-Behavioral Therapy Sessions

Technique Goal Sleep restriction Restrict actual time spent in bed to enhance and increase the homeostatic drive for sleep, enhance sleep depth and consolidation, improve sleep onset and maintenance Stimulus control therapy Associate behaviors conducive to sleep with the activity of falling asleep, imprint bed and bedroom as sleep stimulus Cognitive therapy Address dysfunctional beliefs and attitudes about sleep Relaxation training Decrease psychological and cognitive hyperarousal and anxiety Circadian rhythm entrainment Reinforce or reset biological rhythm using light and/or chronotherapy Cognitive-behavior therapy Combination of behavioral and cognitive approaches listed above

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of insomnia. CBT-I assimilates specific patients in imprinting the activity and recommendations that facilitate healthy behavior of going to bed with falling sleep routines, specifically, bedtime, asleep. It requires them to ensure a time in bed, advice on when to attempt regular morning wake-up time and to sleep, and individualized cognitive avoid daytime napping.28 The therapy psychotherapy to limit the maladaptive assumes that patients with chronic beliefs and assumptions regarding sleep insomnia have incorrectly assimilated and insomnia from hindering future maladaptive bedtime and bedroom progress. CBT-I provided as either a routines. These activities promote short-term or sustained therapy has wakefulness through cognitive condi- excellent merit.23 The basic compo- tioning, which is reinforced over time nents of CBT-I consist of a cognitive as patients remain awake in bed, component and at least one behavioral become frustrated, and experience element, such as stimulus control mental hyperarousal. Patients partici- therapy or sleep restriction therapy. pating in stimulus control therapy are While CBT-I has been investigated instructed to go to bed and attempt primarily as a formalized approach sleep when they feel sleepy and able over a series of sessions, studies have to fall asleep. If sleep fails to occur in reported the benefits of streamlined 10 minutes, they are instructed to get and more flexible schedules, including out of bed and move to another room, online CBT-I for those without access repeating the process as needed. to a provider in their area, limited Relaxation therapy. Relaxation insurance coverage, or a work/personal therapy attempts to decrease anxiety schedule that does not allow participa- and tension while awake in bed. tion in in-person CBT-I sessions.24Y27 Specific relaxation techniques may Sleep restriction. The goal of sleep include progressive relaxation, ab- restriction therapy is to increase the dominal breathing, guided imagery, homeostatic drive for sleep to promote yoga, and meditation. improved sleep onset and maintenance by reducing excessive wakeful- Pharmacologic Approaches ness in bed.11 Less wakeful time in bed Medical management of insomnia con- also should limit the continued rein- sists of four main treatment catego- forcement between being in bed and ries: (1) medications approved by the being awake. This treatment initially US Food and Drug Administration curtails patients’ time in bed to the (FDA) for the treatment of insomnia, amount of sleep they report being able (2) sedating prescription medications to achieve. Typically, the time in bed is not specifically approved by the FDA not reduced to fewer than 5 hours. for insomnia treatment, (3) over-the- Patients are required to maintain sleep counter sleep aids that are regulated diaries throughout the therapy and work by the FDA but do not require a closely with the CBT-I therapist. The prescription, and (4) an extensive list morning rise time is kept consistent of unregulated dietary supplements throughout the therapy to allow the that are commercially available, with patient to benefit from morning light claims of sleep benefits. exposureandtoentrain(resynchronize) Additionally, people often attempt the existing sleep-wake cycle with the to treat their insomnia with alcohol, circadian system and photoperiod. although this strategy is rarely recom- Stimulus control therapy. The aim mended. The sedating effect of alco- of stimulus control therapy is to assist hol may promote a shorter sleep

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Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. KEY POINTS onset, but subsequent sleep quality ceptors by GABA through its binding at h " $ Pharmacotherapy for typically is poor, with increased the - subunit interface opens the insomnia that is arousals later during the night and chloride channel, leading to an imme- approved by the ultimately with a net negative effect. diate and substantial rise in chloride US Food and Drug Insomnia medications approved conductance across the cell mem- Administration consists by the US Food and Drug Adminis- brane, rendering the neuron unable of agents with four tration. Pharmacotherapy for insomnia to raise an action potential, which leads district mechanisms of that is approved by the FDA consists of to phasic inhibition of the neuron. The actions: +-aminobutyric agents with four district mechanisms of result is membrane hyperpolarization, acid A receptor actions: +-aminobutyric acid A (GABA-A) which induces neural inhibition.33,34 modulation, melatonin receptor modulation, melatonin recep- Traditional benzodiazepine hypnotics receptor agonism, histamine 1 receptor tor agonism, histamine 1 (H )receptor (ie, temazepam, triazolam) do not 1 antagonism, and antagonism, and hypocretin/orexin an- differentiate among GABA-A receptor hypocretin/orexin tagonism. These agents have distinct subtypes. The nonbenzodiazepine re- antagonism. advantages in that both efficacy and ceptor agonist hypnotics zolpidem and h The benzodiazepine safety have been studied with appro- zaleplon act on the " GABA-A receptor 1 hypnotics are generally priate doses in unique populations of subtypes, which mediate sedation, 29 well tolerated, but patients with insomnia. Table 8-5 while eszopiclone preferentially targets because the distribution " outlines the commonly used hypnotics the 3GABA-A receptor subtype pre- of +-aminobutyric acid A based on the mechanism of action, dominantly in the reticular nucleus of receptors is widespread, pharmacodynamic profile (sleep onset, the thalamus. the side effect profile is sleep maintenance, or difficulties re- All GABA-A benzodiazepine recep- more extensive, ranging initiating sleep following an awakening), tor modulators interact with binding from drowsiness, available doses, approximate elimina- sites with different affinities to the dizziness, headache, tion half-lives, specific FDA indication, various subunits, which accounts for and lightheadedness to Drug Enforcement Administration some of the variation in their pharma- ataxia and complex schedule, and pregnancy category for cologic responses. The very broad nocturnal behaviors, such as amnestic each of these medications. The follow- distribution of GABA-A receptors sug- sleep-related eating and ing sections describe the major phar- gests that the benzodiazepine hyp- anterograde amnesia. macodynamic categories of insomnia notic action may induce a widespread medications. brain effect depending on the site of Benzodiazepine receptor modula- action.35 Thebenzodiazepinehyp- tion. GABA is the principal inhibitory notics are generally well tolerated, but neurotransmitter in the central nervous because the distribution of GABA-A system, and its receptors are defined receptors is widespread, the side effect structurally and pharmacologically as profile is more extensive, ranging from GABA-A and GABA-B. GABA-A recep- drowsiness, dizziness, headache, and tors are associated with a central chlo- lightheadedness to ataxia and complex ride channel ionophore, as illustrated nocturnal behaviors, such as amnestic in Figure 8-5.32 The benzodiazepine sleep-related eating and anterograde and nonbenzodiazepine receptor ago- amnesia.29 Patients using these agents nist hypnotics are allosteric modulators may be more likely to report rebound of GABA responses at the GABA-A insomnia on abrupt discontinuation receptor complex, a pentameric trans- following chronic use. These medica- membrane protein consisting of five tions are associated with an abuse subunits (two alpha, two beta, and one potential and therefore are designated gamma) that form a rosette around by the Drug Enforcement Agency as the chloride channel, as illustrated in Schedule IV medications. Benzodiazepine Figure 8-5. Activation of GABA-A re- hypnotics are Pregnancy Category X

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a TABLE 8-5 Insomnia Medications Approved by the US Food and Drug Administration

Available Medicationb Formulations Half-life Indications Benzodiazepine immediate release Flurazepam 15 mg, 30 mg 48Y120 hours Treatment of insomnia characterized by difficulty in falling asleep, frequent nocturnal awakenings, and/or early morning awakenings Temazepam 7.5 mg, 15 mg, 8Y20 hours Short-term treatment of insomnia 22.5 mg, 30 mg Triazolam 0.125 mg, 0.25 mg 2Y4 hours Short-term treatment of insomnia

Quazepam 7.5 mg, 15 mg 48Y120 hours Treatment of insomnia characterized by difficulty in falling asleep, frequent nocturnal awakenings, and/or early morning awakenings Estazolam 1 mg, 2 mg 8Y24 hours Short-term management of insomnia characterized by difficulty in falling asleep, frequent nocturnal awakenings, and/or early morning awakenings; administered at bedtime; improved sleep induction and sleep maintenance Nonbenzodiazepine immediate release Zolpidem 5 mg, 10 mg 1.5Y2.4 hours Short-term treatment of insomnia (recommended characterized by difficulties with maximum dose sleep initiation of 5 mg for women) Zaleplon 5 mg, 10 mg 1 hour Short-term treatment of insomnia, shown to decrease the time to sleep onset Eszopiclone 1 mg, 2 mg, 3 mg 5Y7 hours Treatment of insomnia, administered at bedtime; decreased sleep latency and improved sleep maintenance Nonbenzodiazepine extended release Zolpidem extended 6.25 mg, 12.5 mg 2.8Y2.9 hours Treatment of insomnia characterized release (recommended by difficulties with sleep onset and/or maximum dose sleep maintenance (as measured by of 6.25 mg for women) wake time after sleep onset)

and nonbenzodiazepines are Pregnancy formulations: immediate release oral Category C. spray, sublingual dissolvable alterna- Benzodiazepine and nonbenzo- tive delivery formulations, and an diazepine receptor agonist hypnotics extended-release tablet. All benzodiaz- are available in various pharmacologic epine receptor agonist hypnotics are

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Dizziness, drowsiness, lightheadedness, IV X staggering, loss of coordination, falling

Drowsiness, dizziness, lightheadedness, IV X difficulty with coordination

Drowsiness, headache, dizziness, IV X lightheadedness, pins and needles feelings on the skin, difficulty with coordination Drowsiness, headache IV X

Somnolence, hypokinesia, dizziness, IV X abnormal coordination

Drowsiness, dizziness, diarrhea, IV C drugged feeling

Drowsiness, lightheadedness, dizziness, IV C pins and needles feeling on the skin, difficulty with coordination Unpleasant taste in mouth, dry mouth, IV C drowsiness, dizziness, headache, symptoms of the common cold

Headache, sleepiness, dizziness IV C

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formulated for bedtime use with one With the exception of eszopiclone and exception; the lower-dose dissolvable zolpidem extended release, for which formulation is indicated for middle- no limitation on the duration of use of-the-night insomnia provided that is implied, the formal indications for 4 hours of sleep time are available. the benzodiazepine receptor agonist

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a TABLE 8-5 Insomnia Medications Approved by the US Food and Drug Administration Continued from page 1081

Available Medicationb Formulations Half-life Indications Nonbenzodiazepine alternative delivery Zolpidem oral spray 5 mg, 10 mg Approximately Short-term treatment of insomnia characterized 2.5 hours by difficulties with sleep initiation Zolpidem sublingual 5 mg, 10 mg Approximately Short-term treatment of insomnia characterized 2.5 hours by difficulties with sleep initiation 1.75 mg, 3.5 mg Approximately As needed for the treatment of insomnia 2.5 hours when a middle-of-the-night awakening is followed by difficulty returning to sleep, provided that 4 hours of sleep time remain Selective melatonin receptor agonist Ramelteon 8 mg 1Y2.6 hours Treatment of insomnia characterized by difficulty with sleep onset Selective histamine 1 receptor antagonist Doxepin 3 mg, 6 mg 15.3 hours Treatment of insomnia characterized by difficulties with sleep maintenance Hypocretin (orexin) receptor antagonist Suvorexant 5 mg, 10 mg, 12 hours Treatment of insomnia, characterized by 15 mg, 20 mg difficulties with sleep onset or sleep maintenance a Table current as of June 25, 2017. b The authors advise readers to review the most current package inserts for each medication listed given that updates are highly dynamic and variable. c Drug Enforcement Administration Class IV refers to a lower abuse potential than schedule III drugs and limited physical and/or psychological dependence.30 d Pregnancy medication Category X refers to studies in animals or human beings that have demonstrated fetal abnormalities or where there is evidence of fetal risk. The drug is contraindicated in women who are or may become pregnant. Pregnancy medication Category C refers to animal studies that have shown risk to the fetus but where there are no controlled studies in women, or where studies in women and animals are not available.31 A new US Food and Drug Administration (FDA) pregnancy and lactation labeling rule went into effect on June 30, 2015; however, the timelines for implementing this new labeling information on drug labels and package inserts are variable. All listed pregnancy category information uses past FDA pregnancy labeling practices, as labels and package inserts for some medications have not yet been updated.

hypnotics specify that they are in- indicated for all patient subgroups in- tended for short-term therapy. cluding women and adults older than Melatonin receptor agonism. A age 65. Specific contraindications in- single melatonin receptor agonist, clude the clinical setting of severe ramelteon, is approved by the FDA hepatic disease or in patients concomi- for treating insomnia. A second ago- tantly taking fluvoxamine, a selective nist, tasimelteon, is now approved by serotonin reuptake inhibitor (SSRI) the FDA for the treatment of non- indicated for obsessive-compulsive 24-hour sleep-wake disorder. Ramelteon disorder that is a potent CYP1A2 is specifically indicated for the manage- inhibitor (a key ramelteon metabolic ment of insomnia characterized by sleep pathway). Drowsiness, tiredness, initiation difficulties. Ramelteon is avail- and dizziness are the most common able at a single dose of 8 mg, which is side effects. Ramelteon has no abuse

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Drowsiness, dizziness, diarrhea, IV C drugged feeling Drowsiness, dizziness, diarrhea, drugged IV C feeling

Headache, nausea, fatigue IV C

Drowsiness, tiredness, dizziness None C

Somnolence/sedation, nausea, None C upper respiratory tract infection

Somnolence, depression, rare but IV C possible risk of rapid eye movement (REM) intrusion phenomena

potential; hence, it is considered a attenuating the suprachiasmatic nucleus KEY POINT nonscheduled medication and is wake-promotingeffectsasopposedto h Melatonin exerts its classed as Pregnancy Category C. actively promoting sleep (Figure 8-6). activity by attenuating As a selective agonist of the mela- In this model, secretion of melatonin in the suprachiasmatic tonin types 1 and 2 (MT and MT ) the evening coincides with the peak of nucleus wake-promoting 1 2 effectsasopposedto receptors, ramelteon binds to these the suprachiasmatic nucleusYdriven actively promoting sleep. receptors with selectivity. These MT arousal cycle, ultimately inhibiting the receptors are expressed with a high mechanisms that promote evening density in the suprachiasmatic nucleus wakefulness (Figure 8-6B). The pres- of the anterior hypothalamus.36 Mela- ence of melatonin, in turn, reduces the tonin is produced by the pineal gland circadian wakeful drive and facilitates in a process regulated by the circadian activation of the sleep-promoting brain system. Melatonin exerts its activity by structures.2

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drive unopposed. Accordingly, melatonin agonists would be expected to enhance sleep onset, as well as stabilize and possibly shift the timing of the circadian system, depending on the timing of the dose. Circadian timing, including the pronounced influence on the timing of sleep, is entrained primarily though light exposure from the photoperiod. The mechanism involves a nonvisual photochemical reaction in retinal ganglion cells with a compound called melanopsin. Light exposure information is transmitted through the relatively short retinohypo- + thalamic tract to the suprachiasmatic FIGURE 8-5 Schematic illustration of the -aminobutyric acid A (GABA-A) receptor and its associated binding nucleus, where the light/dark informa- sites. The receptor is pentameric, being tion is integrated to coordinate the composed of two alpha, two beta, and one gamma subunit. GABA-A receptors contain recognition sites for a variety of timing of the circadian clock. Note that clinically relevant drugs. The binding of GABA in two GABA artificial light, particularly the blue end binding sites at the interface between alpha and beta subunits open the receptor-associated chloride (Clj) channel. The of the visual spectrum, can alter the benzodiazepine binding site is located at the interface rhythm therapeutically (eg, evening between alpha and gamma 2 subunits. Barbiturates, ethanol, and neurosteroids bind to sites in the membrane-spanning bright light exposure to purposely de- transmembrane regions of the subunit. lay the cycle for people with abnormally advanced circadian cycles experiencing Reprinted with permission from Uusi-Oukari M, Korpi ER, Pharmacol Rev.32 B 2010 American Society for Pharmacology and Experimental Therapeutics. early morning awakening) or, much pharmrev.aspetjournals.org/content/62/1/97.long. more commonly, can cause an in- advertent delay in the circadian system with later evening sleepiness and bed- KEY POINT The evening melatonin rise and time in association with exposure to h Compared with MT1 agonist action decreases the closely held electronic screens (eg, other histaminergic suprachiasmatic nucleusYdriven wake- smartphones, tablets, and laptops). compounds, promoting stimulation that is present Histamine 1 receptor antagonism. ultraYlow-dose doxepin during the latter hours of the wake Currently, the only selective H1 re- is unusual for its very period and thereby facilitates bed- ceptor antagonist approved by the high specificity and time sleep onset, as illustrated in FDA for treatment of insomnia is selectivity for histamine 1 Y receptor antagonist Figure 8-6. The MT2 action promotes ultra low-dose doxepin. The specific activity. a circadian resynchronizing effect that FDA-approved indication is for the reinforces the circadian timing and management of sleep maintenance allows for a regular and robust daily insomnia. Compared with other hista- rhythm. The circadian system opti- minergic compounds, ultraYlow-dose mizes the ability to sleep during the doxepin is unusual for its very high nighttime and the typical alert waking specificity and selectivity for H1 re- period from the morning through the ceptor antagonist activity. Accordingly, evening hours. Melatonin and other the key pharmacodynamic action is melatonin agonists facilitate bedtime antihistamine-promoted sedation. The sleep onset by reducing the evening available doses are as high as 150 mg/d, circadian arousal, thereby leaving the and the prescribing guidelines for accumulated homeostatic sleepiness treating depression are as high as

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Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. FIGURE 8-6 The suprachiasmatic nucleus (SCN) as modulator of sleep and wakefulness. Modulation of sleep and wakefulness is a product of the interaction between several systems in the central nervous system. A, The SCN generates the alerting signals and is responsible for promoting wakefulness during the day. Throughout the daytime, melatonin levels are low, but gradually rise in the evening as a response to darkness. B, As bedtime ensues, melatonin levels continue to rise, peaking during the typical nighttime sleep hours and declining by the end of the night. The release of melatonin inhibits the wake signals generated in the SCN. As melatonin release diminishes later during the night, the wake-promoting signal from the SCN predominates and assumes control of the sleep-wake process as the night further progresses toward morning. Sunlight stimulates the SCN, maintaining arousal, while the pineal gland’s release of melatonin is suppressed, supporting wakefulness.

B 2017 Alon Y. Avidan, MD, MPH. Permission remains with author.

300 mg/d; however, the low-dose for- tial, ultraYlow-dose doxepin is consid- mulations approved for insomnia are ered a nonscheduled medication and is just3mgand6mgbeforebedtime. Pregnancy Category C. Adverse events reported include som- Hypocretin/orexin receptor antag- nolence, sedation, nausea, and upper onism. Suvorexant is a novel hypnotic respiratory tract infection. UltraYlow- and is the only insomnia medication dose doxepin should not be prescribed currently approved by the FDA that for patients with untreated narrow- works specifically by blocking the angle glaucoma or severe urinary re- wake-promoting effects of orexin/ tention or for people also taking hypocretin. The medication is clinically monoamine oxidase inhibitors. As with indicated for insomnia characterized by other tricyclic antidepressants, caution sleep onset and/or maintenance.37,38 should be exercised with use in pa- Suvorexant is a hypocretin/orexin re- tients with cardiac disease given the ceptor antagonist that promotes sleep risk for QT-interval prolongation, al- by blocking the arousal promoted by though with ultraYlow-dose doxepin, the hypocretin/orexin system, which, this is unlikely. With no abuse poten- during the daytime and evening hours,

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KEY POINTS h Several sedating helps to stabilize wakefulness. In con- broad warning targets possible abnormal antidepressant, trast to other hypnotics, suvorexant thinking and behavior following hyp- antipsychotic, blocks the binding of the neuropep- notic doses, and it notes the potential antiepileptic, tides (orexin-A and orexin-B). Suvo- for complex behaviors associated with antihypertensive, and rexant is labeled by the FDA as a amnesia, examples of which include other sedating Schedule IV controlled substance and driving, preparing and eating foods, psychotropic medications confers a slight risk of abuse.39 This talking on the telephone, and engaging are occasionally drug is contraindicated in patients in sexual behaviors when not fully prescribed by with narcolepsy and is a Pregnancy awake. Patients are advised to discon- neurologists to Category C drug. Suvorexant causes tinue the medication if these symptoms specifically treat significant somnolence in 7% to 11% of occur. Other general warnings relate to insomnia symptoms. patients, and clinically meaningful se- the potential for next-day drowsiness or h All the available dation can occur at higher doses.39 impairment and ensuring that patients over-the-counter Current recommendations advocate have sufficient time in bed following a sleep aids contain for a starting dose of 10 mg before medication dose. antihistamines, with bedtime and proceeding with either Off-label prescription insomnia most containing diphenhydramine or 15 mg or 20 mg before bedtime, if pharmacotherapy. Several sedating anti- doxylamine, which needed. The maximal FDA-labeled depressant, antipsychotic, antiepileptic, are first-generation dosage is 20 mg/d, although, in clinical antihypertensive, and other sedating antihistamines with trial development, substantially higher psychotropic medications are occa- anticholinergic and doses of 30 mg/d to 100 mg/d were sionally prescribed to treat insomnia sedative properties. also used with more carryover sedation symptoms. While sometimes helpful, and some unfavorable increases in insufficient evidence of the safety and measured reaction time. Suvorexant efficacy of these medications exists to should be used with caution in patients support their use to treat these disor- who are obese and in people taking ders, particularly in neurology patients CYP3A4 inhibitors.40 One concern who are often vulnerable to treatment- with the hypocretin/orexin antagonist related adverse effects, particularly approach to treating insomnia is the with agents that confer respiratory theoretical possibility of the intrusion depression in the setting of neuromus- of rapid eye movement (REM) phe- cular disease, amnesia, memory diffi- nomena into wakefulness. These might culty, and daytime sedation. Prescribers include sleep paralysis, hypnagogic/ should be mindful of the risk-to-benefit hypnopompic hallucinations, and ratio of these agents for insomnia. symptoms similar to cataplexy. Suvo- Specific examples include the sedating rexant is contraindicated in patients antidepressants, such as trazodone, with narcolepsy. amitriptyline, mirtazapine, and conven- General considerations when using tional clinical doses of doxepin, which hypnotic agents. While the FDA- often have been prescribed in this approved insomnia medications have manner. Quetiapine has been pre- indications for chronic insomnia, ther- scribed for insomnia; however, it can apy should be weighed carefully given increase the risk of bleeding when taken the patient phenotype, underlying concomitantly with warfarin41 and may comorbidities, and unique side effect place those with concomitant cardio- profiles and warnings. The FDA has vascular disease at higher risk of mortal- required certain warnings for all the ity because of QT-interval prolongation.42 insomnia medications. One warning re- Over-the-counter sleep aids. All lates to rare severe anaphylactic and the available over-the-counter sleep anaphylactoid reactions. The other aids contain antihistamines, with most

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Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. KEY POINT containing diphenhydramine or doxyl- compounds may be marketed as ‘‘nat- h Melatonin is a unique amine, which are first-generation ural,’’ they are not necessarily safe. member of the dietary antihistamines with anticholinergic One notable example is kava kava, supplement sleep aid and sedative properties. The over-the- which may be associated with hepatic category in the 45,46 counter sleep aids are marketed as toxicity. Because the evidence is United States, since it is single compounds or are provided as not complete, risk-benefit assessments a compound with an a combination therapy with anal- are not reliable, and much knowledge established role in gesics (ibuprofen or acetaminophen), is still lacking. sleep physiology and formulated as evening preparations. Melatonin is a unique member of demonstrated efficacy Whiletheantihistaminesedatingeffect the dietary supplement sleep aid cat- in treating circadian is the desired activity, these agents may egory in the United States, since it is a rhythm sleep-wake disorders. exert adverse and sometimes serious compound with an established role in side effects. Most concerning are the sleep physiology and demonstrated anticholinergic effects, which may con- efficacy in treating circadian rhythm tribute to delirium, confusion, dry sleep-wake disorders. It is a neurohor- mouth, constipation, and urinary reten- mone produced by the pineal gland tion. These agents should be used with that can reset sleep onset by synchroni- greater caution in older adults and pa- zation of the internal circadian clock. tients receiving other anticholinergics. With advanced age, less melatonin is Another concern is that these drugs have produced, and is often an underlying relatively long durations of action that cause contributing to advanced sleep- mayleadtonext-morningdrowsiness wake phase disorder in older age. following nighttime dosing. Tolerance Circulating melatonin levels are signifi- may develop, with chronic usage leading cantly lower in many elderly patients to inappropriate dose escalation.43 with insomnia compared to controls, Unregulated compounds. These and melatonin onset and peak times are substances are marketed as dietary sup- delayed. Melatonin replacement may be plement sleep aids and often are consid- beneficial for elderly patients experienc- ered in the realm of complementary and ing insomnia. Currently, however, more alternative medicine. These unregulated data are needed to improve our under- sleep aids are generally promoted as standing of the appropriate dosage, single or multiple compounds contain- pharmacologic properties, and indica- ing plant-derived ingredients such as tions. Melatonin is not FDA approved, chamomile, passionflower, valerian, formulations vary, and efficacy and hops, and kava kava. safety data are still needed. Tart cherry juice was found to be In the European Union, a prolonged- associated with anecdotal subjective release melatonin formulation is available reports of sleep enhancement in peo- only by prescription. Prolonged-release ple with insomnia.44 While the effect melatonin is approved in the European sizes were moderate and in some Union for the treatment of primary cases negligible, the data suggest that insomnia characterized by poor sleep a tart cherry juice blend has modest quality in patients aged 55 years and efficacy in the management of insom- older.47 nia in older adults with insomnia.44 At present, with rare exceptions, Developing an Insomnia few convincing data exist regarding Treatment Plan efficacy of these dietary supplements. The evaluation of insomnia should Patients should be warned, however, foster a patient-specific customized that while these unregulated dietary plan for management that considers

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KEY POINTS h The evaluation of the unique insomnia phenotype, chief frequent. Prescribers should pay close insomnia should foster a complaint specific to the timing and attention to the pharmacodynamic and patient-specific chronicity of the insomnia, underlying pharmacokinetic profiles and under- customized plan for comorbidities, sleep-wake pattern take therapy to address their patients’ management that symptoms, lifestyle pattern, social symptoms after carefully querying pa- considers the unique habits and routines, previously tried tients about circadian patterns, the insomnia phenotype, hypnotic therapy (specific agents, nature of the underlying sleep distur- chief complaint dose, duration, and development of bances, and potential impact on health- specific to the timing adverse effects), and any prior CBT-I.3 related quality of life. Careful attention and chronicity of the Patients should be asked to share their to sleep-wake circadian patterns is insomnia, underlying specific expectations and treatment especially important as one considers comorbidities, goals. Over time, clinicians should implementation of strategic light ex- sleep-wake pattern symptoms, lifestyle monitor symptoms regularly with pa- posure in resynchronizing the sleep- pattern, social habits tients to assess the effects of the wake pattern. and routines, previously therapeutic strategies implemented. Advanced sleep-wake phase disorder tried hypnotic therapy The cornerstone of insomnia man- is sometimes encountered among older (specific agents, agement for all patients must include patients and may be related to depressed dose, duration, and education regarding proper sleep hy- melatonin production (Case 8-2). development of adverse giene and individualized recommenda- Compared to the normal circadian effects), and any prior tions about proper sleep-enhancing rhythm demonstrated in Figure 8-7A, cognitive-behavioral behaviors. Strategies reviewed by CBT-I patients with a phase-advanced cycle therapy for insomnia. specialists should be assimilated into generally get sleepy early in the eve- h The cornerstone of the management plan and should occur ning and wake up early in the morn- insomnia management in harmony and synchronously with any ing, when they are then usually unable for all patients must pharmacotherapy intervention. to reinitiate sleep (Figure 8-7B). include education FDA-approved hypnotics may be Although the older adult may get regarding proper appropriate for initial use in treat- sleepier in the evening, he or she sleep hygiene and ing patients with insomnia, especially often still tries to remain awake until a individualized recommendations because they are generally better stud- more socially acceptable time (ie, about proper ied in populations where treatment- 10:00 PM to 11:00 PM). Then, when sleep-enhancing emergent adverse effects are more the patient awakens early and is behaviors. Case 8-2 An 82-year-old man with mild Alzheimer disease presented for evaluation of early morning awakening and the inability to return to sleep. He often became very tired around 6:00 PM and fell asleep around 8:00 PM. He had no difficulty falling asleep. However, when he woke up at around 2:30 AM to 3:00 AM, he was unable to reinitiate sleep. He then stayed awake in bed until about 7:00 AM, when he finally got out of bed and began his day. He denied any symptoms of depression other than his sleep problems. Comment. This man has insomnia in the setting of advanced sleep-wake phase disorder. The sleep-wake cycle is controlled by the circadian modulator located in the suprachiasmatic nucleus of the anterior hypothalamus. Zeitgebers, external cues (predominantly the photoperiod), synchronize the circadian cycle. Disturbances in circadian rhythms are due to a mismatch between the environmental cues and the endogenous circadian rhythms. The hypersomnolence seen in an older person may be due in part to a disintegration of the normal circadian rhythm.

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Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. FIGURE 8-7 A depiction of the sleep-wake pattern of the patient presented in Case 8-2. The patient is found to have a sleep-wake pattern suggestive of advanced sleep-wake phase disorder (ASPD). A shows normal sleep-wake patterns; B shows advanced sleep-wake phase disorder; C shows advanced sleep-wake phase disorder corrected with evening light exposure and prevention of early morning sunlight.

B 2017 Alon Y. Avidan, MD, MPH. Permission remains with author.

unable to fall back to sleep, time in comorbid neurologic conditions. All bed has not been long enough for a patients should be screened to help sufficient sleep amount, resulting in a uncover poor sleep behaviors since state of sleep deprivation. Advanced insomnia may exacerbate health prob- sleep-wake phase disorder can be lems, undermine the quality of sleep, treated with bright light therapy limit the ability to remain awake, and during the later afternoon/early eve- worsen daytime function. As with the ning timeframe, as light is one of the approach to other neurologic presen- strongest cues for synchronizing circa- tations, the neurologist should con- dian rhythms and can delay the sleep duct a careful sleep history. Insomnia cycle when given at this time. Early should be considered in every patient, morning bright light exposure should especially those who present with be avoided since it can further ad- refractory pain, headaches, seizures, vance the sleep cycle at that time, and and impaired cognition. The treat- the use of sunglasses following dawn ment approach should incorporate may be helpful. One strategy for evidence-based therapies, including bright light therapy for this disorder CBT-I and appropriately selected phar- involves exposure to at least 5000 lux macotherapies based on the timing of for 2 hours in the evening (eg, 7:00 PM sleep difficulty during the sleep cycle. to 9:00 PM) at about 1 meter eye level Even neurologists without specific (Figure 8-7C).48 training in sleep medicine should take opportunities to address the effects of CONCLUSION insomnia by integrating proper phar- Chronic insomnia in neurology prac- macologic and behavioral treatment tice represents a unique opportunity approaches, especially given the per- for clinicians to help improve the vasive nature of sleep difficulties quality of life across patients with among neurologic patients.

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