ESSAY ON CAUSES AND EFFECTS OF INSOMNIA
I CLINICAL CROSSROADS CONFERENCES WÍTH PATIENTS AND DOCTORS Insomnia CLINICIAN'S CORNER Daniel J. Buysse, MD, Discussant DR SHIP:
MS J is a 51-year-old woman with insomnia, which began at age 35 years when her infant daughter had very disrupted sleep. By the age of 7 years, her daughter's sleep was improved but Ms J's was not. She was able to fall asleep but was unable to stay asleep after about 3 AM.
Ms J tried several medications with variable success and adverse ef- fects.
She currently takes gabapentin, which is working well.
She is very attentive to "sleep hygiene" and maintains a regu- lar bedtime and waking time. Ms J's medical history is no- table for mild depression, Raynaud syndrome, and myelo- dysplasia/myelofibrosis. Ms J works as an educational consultant. She lives with her husband and 2 teenaged chil- dren. She exercises regularly by swimming, cycling, and run- ning. She does not use tobacco and has a half glass of wine 3 nights per week. Current medications include escitalo- pram, 20 mg/d; gabapentin, 1200 mg once daily at bed- time; and sustained-release nifedipine, 60 mg/d in cold weather. Ms J has no drug allergies. On physical examina- tion, Ms J is healthy and fit. Her weight is 121 lb, blood pres- sure is 119/64 mm Hg, and pulse is 68/min.
/WSJ:
HER VIEW My insomnia began when 1 became a parent.
1 had an in- fant who never slept, nursed every hour and a half around the clock, and was just a difficult sleeper.
I never knew when she would go to sleep, when or how many times she would wake up during the night, or if she would be up at 4 o'clock in the morning. My sleep got very disrupted and that con- tinued until she was 7 years old. She finally slept, but then 1 could not sleep.
I was exhausted and could have fallen asleep standing up, but 1 could not stay asleep.
1 would wake up between 2 and 3 o'clock in the morning and that would be it for the night. Benadryl [diphenhydramine] initially worked, but over time I needed to take more and more, and then it became completely ineffective, or it would finally kick in when I needed to get up. I would be very groggy. It made me very irritable. It affected my mood.
1 tried melatonin. Trazodone was fairly effective, but 1 woke up groggy and I had really wild dreams.
Even if 1 slept through the night, I often would wake up exhausted.
1 liked being able to sleep but 1 did not like the side effects. I took Am- bien [zolpidem] once and I was up the entire night. I had severe anxiety, felt very unsettled, and just was not happy.
CME available online at www.jamaarchivescme.coni and questions on p 725.
Importance Insomnia is one of the most prevalent health con- cerns in the population and in clinical practice. Clinicians may be reluctant to address insomnia because of its many potential causes, unfamiliarity with behavioral treatments, and concerns about pharmacologie treatments.
Objective To review the assessment, diagnosis, and treat- ment of insomnia in adults.
Evidence Review Systematic review to identify and summa- rize previously published quantitative reviews (meta-analyses) of behavioral and pharmacologie treatments for insomnia.
Findings Insomnia is a common clinical condition character- ized by difficulty initiating or maintaining sleep, accompanied by symptoms such as irritability or fatigue during wakefulness.
The prevalence of insomnia disorder is approximately 10% to 20%, with approximately 50% having a chronic course.
Insom- nia is a risk factor for impaired function, development of other medical and mental disorders, and increased health care costs.
The etiology and pathophysiology of insomnia involve genetic, environmental, behavioral, and physiological factors culminat- ing in hyperarousal. The diagnosis of insomnia is established by a thorough history of sleep behaviors, medical and psychiatric problems, and medications, supplemented by a prospective rec- ord of sleep patterns (sleep diary). Quantitative literature re- views (meta-analyses) support the efficacy of behavioral, cog- nitive, and pharmacologie interventions for insomnia. Brief behavioral interventions and Internet-based cognitive- behavioral therapy both show promise for use in primary care settings. Among pharmacologie interventions, the most evi- dence exists for benzodiazepine receptor agonist drugs, al- though persistent concerns focus on their safety relative to mod- est efficacy. Behavioral treatments should be used whenever possible, and medications should be limited to the lowest nec- essary dose and shortest necessary duration.
Conclusions and Relevance Clinicians should recognize in- somnia because of its effects on function and health. A thor- ough clinical history is often sufficient to identify factors that con- tribute to insomnia. Behavioral treatments should be used when possible. Hypnotic medications are also efficacious but must be carefully monitored for adverse effects.
MMA. 2013;309(7}:706-716 www.jama.com The conference on which this article Is based look place at the Medicine Grand Rounds at Beth Israel Deaconess Medical Center, Boston, Massachusetts, on March 1,2012.
Author Affiliations:
Dr Buysse is Professor of Psychiatry and Clinical and Transla- tional Science and Director, Neuroscience Clinical and Translational Research Cen- ter, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
Corresponding Author: Daniel J. Buysse, MD, Western Psychiatric Institute and Clinic, 3811 O'Hara St, Pittsburgh.
PA 15213 ([email protected]).
Clinical Crossroads at Beth Israel Deaconess Medical Center is produced and ed- ited by Risa B.
Burns, MD, series editor; Tom Delbanco, MD, Howard Libman, MD, Eileen E.
Reynolds, MD, Marc Schermerhorn, MD, Amy N.
Ship, MD, and Anjala V. Tess, MD.
Clinical Crossroads Section Editor Edward H.
Livingston, MD, Deputy Editor.
JAMA.
706 JAMA, February 20, 2013—Vol 309, No. 7 CLINICAL CROSSROADS I was not willing to even try it a second night. Neurontin [gabapentin] has been very effective in helping me to get more sleep, but I would not say that my sleep is reliable.
Not much has made my insomnia better or worse; there haven't been stress factors, work factors, family factors.
I am not consciously thinking about things that prevent me from falling asleep, or thinking about falling asleep or stay- ing asleep and saying, oh, I wish I could sleep.
Are there other medications that I might consider, or medications in concert with the Neurontin that might help me to more con- sistently sleep?
I need a good night's sleep for emotional, intellectual, and physical consistency.
AT THE CROSSROADS:
QUESTIONS FOR DR BUYSSE What is the definition of insomnia? What are the subtypes?
How is a diagnosis of insomnia made and what evaluations should be undertaken? What treatments do you recom- mend? What are the indications, contraindications, and ad- verse effects for specific medications? Can medications be used indefinitely? When should a patient with insomnia be seen by a sleep specialist? What do you recommend for Ms J?
DEFINITION OF INSOMNIA AND SUBTYPES DR BUYSSE: Insomnia is a patient-reported problem char- acterized by difficulty falling asleep or difficulty maintain- ing sleep; ie, frequent awakenings, difficulty returning to sleep after awakenings, or awakening too early with inabil- ity to return to sleep. Although nonrestorative sleep is of- ten included as a symptom of insomnia, it has different epi- demiological and functional correlates than other insomnia symptoms, including higher prevalence in young adults and a greater degree of daytime impairments such as sleepiness and fatigue.''^ The clinical disorder or syndrome of insom- nia (Box 1) additionally specifies adequate opportunity and circumstances for sleep and significant distress or symp- toms during wakefulness. Adequate opportunity for sleep distinguishes insomnia from sleep deprivation, which has different causes and consequences. Ms J clearly qualifies for an insomnia diagnosis.
Insomnia is not defined by a specific sleep amount; indi- viduals vwth other sleep disorders and voluntary sleep restric- tion may also report short sleep.
Individuals with insomnia are reliably distinguished from good sleepers by self- reported sleep symptoms, such as sleep latency (time to fall asleep) or wakefulness after sleep onset of longer than 30 minutes.' Objective sleep measures derived from polysom- nography or actigraphy show considerably more overlap between individuals with insomnia and good sleepers, mak- ing these methods less sensitive and specific than self- reports for identifying insomnia."* Furthermore, many patients with insomnia overestimate sleep latency and wakefulness after sleep onset and underestimate sleep duration in com- parison v^áth polysomnographic measures.' Thus, insom- nia often involves altered perception of sleep.
Box 1.
International Classification of Sleep Disorders, Second Edition Criteria for General Insomnia Disorder^ 1.
A report of difficulty initiating sleep, difficulty main- taining sleep, or waking up too early or sleep that is chronically nonrestorative or poor in quality.
In chil- dren, the sleep difficulty is often reported by the care- taker and may consist of observed bedtime resistance or inability to sleep independently.
2.
The above sleep difficulty occurs despite adequate op- portunity and circumstances for sleep.
3.
At least 1 of the following forms of daytime impairment related to the nighttime sleep difficulty is reported by the patient; • Fatigue or malaise • Attention, concentration, or memory impairment • Social or vocational dysfunction or poor school perfor- mance • Mood disturbance or irritability • Daytime sleepiness • Motivation, energy, or initiative reduction • Proneness for errors or accidents at work or while driving • Tension, headaches, or gastrointestinal symptoms in re- sponse to sleep loss • Concerns or worries about sleep Although insomnia is considered a sleep disorder, its pathophysiology suggests hyperarousal during sleep and wakefulness.^ Evidence of hyperarousal in insomnia includes elevated whole-body metabolic rate during sleep and wakefulness, elevated cortisol and adrenocortico- tropic hormone during the early sleep period, reduced parasympathetic tone in heart rate variability, and increased high-frequency electroencephalographic activ- ity during non-rapid eye movement sleep. Functional imaging studies demonstrate smaller wake-sleep differ- ences in regional brain metabolism in individuals with insomnia compared with good sleepers^ (eFigure 1; avail- able at bttp://www.jama.com).
Insomnia is often subtyped by tbe predominant symp- tom; ie, sleep onset vs sleep maintenance.
In epidemiologi- cal studies, sleep maintenance symptoms are most preva- lent among individuals with insomnia (approximately 50%-70%), followed by difficulty initiating sleep (35%- 60%) and nonrestorative sleep (20%-25%).^ However, mul- tiple sleep symptoms are more common than any single symptom, both cross-sectionally and longitudinally.' Insomnia disorders have also been categorized as pri- mary and secondary, depending on whether the sleep prob- lem is judged to be caused by another medical or mental disorder or medication/substance use.
In practice, it is of- ten difficult to determine whether a concurrent condition JAMA, Febraary 20, 2013—Vol 309, No. 7 707 CLINICAL CROSSROADS actually causes insomnia.'" Furthermore, insomnia is a risk factor for many of the disorders with which it coexists, in- cluding coronary heart disease and depression."''^ For these reasons, the term comorbid insomnia has been recom- mended as preferable to secondary insomnia}-^ Although sleep medicine specialists have defined subtypes of primary in- somnia,^'^ the reliability and validity of primary insomnia and its subtypes are modest at best.'^ The annual prevalence of insomnia symptoms in the gen- eral adult population ranges from 35% to 50%'^ and the prevalence of insomnia disorder ranges from 12% to 20%.®-'^ Risk factors include depression, female sex, older age, lower socioeconomic status, concurrent medical and mental dis- orders, marital status (greater risk in divorced/separated vs married or never married individuals), and race (greater risk in African American vs white race).'^ Insomnia follows a chronic course in 40% to 70% of individuals over 1 to 20 years of follow-up.'^'^^ Functional consequences of insom- nia including reduced productivity, increased absentee- ism, and increased health care costs.^'-^^ Insomnia is also a risk factor for mental disorders; the risk ratio for incident depression among individuals with insomnia is estimated at 2.10 (95% CI, 1.86-2.38).'2 Insomnia is associated with worse short- and long-term treatment outcomes in depres- sion and alcohol dependence and with increased risk of meta- bolic syndrome," hypertension,^"* and coronary heart dis- ease." Insomnia with short sleep duration may be associated with higher risk than insomnia or short sleep duration alone.
^"^ INSOMNIA DIAGNOSIS AND WORKUP The evaluation and diagnosis of insomnia are based on a care- ful clinical history of the sleep problem and relevant co- morbidities. The 3-P model (predisposing, precipitating, and perpetuating) is a useful heuristic framework for assess- ment.^^ Predisposing factors increase the risk of develop- ing insomnia and include a family history of and a lifelong propensity for s tress-related poor sleep. Precipitating fac- tors are medical, environmental, or psychosocial Stressors that initiate a pattern of poor sleep. Ms J's daughter's ir- regular sleep served as a precipitating factor for Ms J's in- somnia. Perpetuating factors are behaviors and other fac- tors that lead to a vicious circle of continued sleep disturbance. For instance, many individuals with insom- nia spend more time in bed trying to "catch up" on sleep.
Increased time in bed and increased attention and effort to sleep fuel hyperarousal and perpetuate insomnia.
•^^'" Ms J's experience illustrates that insomnia often persists after reso- lution of the original Stressor.
Key elements of assessment include the patient's sleep characteristics, daytime behaviors, medical-psychiatric his- tory, symptoms of other sleep disorders, and medications (Box 2).^^ Clinicians can also use several tools to help as- sess insomnia. Most important are prospective sleep-wake diaries, which evaluate the timing and variability of sleep^^ and may identify targets for behavioral interventions (eFig- ure 2).
The differential diagnosis of insomnia includes other sleep and medical disorders (Box 2). Up to 50% of adults with obstructive sleep apnea also report insomnia. The pres- ence of loud snoring, witnessed apneas, obesity, and nar- row upper airway all suggest obstructive sleep apnea. Cir- cadian rhythm sleep disorders, such as delayed sleep- phase disorder and shift-work disorder, include symptoms of difficulty falling asleep or waking too early. Abnormal sleep timing (ie, going to bed and waking at very late times) dis- tinguishes these conditions from insomnia disorder. Rest- less legs syndrome often results in difficulty falling asleep but is accompanied by an urge to move the extremities and dysesthesias. A separate insomnia diagnosis is not needed for all patients with medical, psychiatric, or other sleep dis- orders who have insomnia symptoms, and should be made only if the symptoms are severe or constitute an indepen- dent focus of clinical attention.
TREAT/WENT OF INSOMNIA The goals of insomnia treatment are to improve quantita- tive and qualitative aspects of sleep, to reduce the distress and anxiety associated with poor sleep, and to improve day- time function.^ Insomnia treatment includes 2 broad cat- egories, cognitive-behavioral treatment and medication treat- ment. Patients often prefer nonpharmacologic approaches,-^° but two-thirds of patients taking hypnotics report at least moderate satisfaction.•*' Patients often try self-help strate- gies including reading, relaxation, and sleep hygiene and over-the-counter remedies such as alcohol, antihista- mines, and herbal preparations.^ Cognitive-Behavioral Treatment Maladaptive behaviors, thoughts, and beliefs regarding sleep can serve as perpetuating factors for insomnia disorders and are the targets of cognitive and behavioral treatments sum- marized in TABLE 1. These treatments include several com- mon elements: the use of sleep diaries to identify baseline patterns and clinical changes, the importance of patient in- vestment in changing behaviors, and the use of voluntary waking behaviors to influence sleep, which is a largely in- voluntary process. Behavioral treatments are indicated for primary and comorbid insomnia.
Cognitive-behavioral therapy for insomnia (CBT-I) is the most widely used and widely studied nondrug treatment.
The efficacy of CBT-I has been demonstrated for chronic primary and comorbid insomnia in younger and older adults; TABLE 2 summarizes meta-analyses of efficacy studies. The acute effects of CBT-1 over 6 to 10 weeks are comparable with or superior to those of hypnotic medications^" and are maintained for up to 3 years of follow-up. Behavioral treat- ments are efficacious in patients taking hypnotics^' and help patients reduce medication use." Initial combined behav- ioral therapy and pharmacotherapy, followed by CBT-I alone.
708 JAMA.
February 20, 2013—Vol 309, No. 7 CLINICAL CROSSROADS Box 2. Evaluation of Insomnia Sleep History The evaluation of insomnia rests on a careful clinical history tak- ing. The clinician should evaluate the nature, frequency, and du- ration of insomnia symptoms, their chronology, and response to treatment. The patient's symptoms should be considered across the entire 24-hour day; sleep and wakefulness affect each other in complex ways, and patients often seek treatment because of day- time symptoms and distress related to their sleep problems. Key elements of the sleep history include • Temporal aspects of sleep:
times at which the patient goes to bed, attempts to sleep, wakes up, and gets out of bed • Quantitative aspects of sleep:
sleep latency (time it takes to fall asleep); number and duration of awakenings; wakeful- ness after sleep onset; total sleep time • Qualitative aspects of sleep:
subjective sleep quality, satisfaction • Behavioral and environmental factors: nonsleep activities in bed (phone, computer, television); environment (tempera- ture, light, sound); bed partners and pets; perceived causes of awakening • Symptoms of other sleep disorders:
obstructive sleep apnea (snor- ing, breathing pauses) ; restless legs syndrome (urge to move the extremities) ; parasomnias (unusual sleep behaviors) ; circadian rhythm disorders (unusual sleep timing) • Daytime causes and consequences of disturbed sleep: nap- ping; exercise; work and activities; social and family stress- ors; use of caffeine, alcohol, and tobacco Medical and Psychiatric History Insomnia evaluation should include a medical/psychiatric history and physical examination to identify comorbid conditions that can exacerbate or be exacerbated by insomnia.
• Medical disorders: neurologic (stroke, migraine); pulmo- nary (chronic obstructive pulmonary disease, asthma); chronic pain (arthritis, fibromyalgia); endocrine (hypo- thyroidism, hyperthyroidism); gastroesophageal reflux; car- diovascular (congestive heart failure) • Psychiatric disorders: depression; bipolar disorder; anxi- ety disorders; substance use disorders • Medications: antidepressants; other sedatives; antihy- pertensives; steroids; decongestants and antihistamines; adrenergic agonists Other Tools and Tests • Sleep-wake diary: prospective record of sleep-wake tim- ing, quantity, and quality; may identify patterns that are useful targets for behavioral treatment • Wrist actigraphy: measure and store movement data for up to 28 days; rest-activity patterns correlate with sleep-wakefulness • Polysomnography (sleep study) :
not recommended for rou- tine assessment of insomnia but appropriate to evaluate suspected sleep apnea or parasomnias may produce the best long-term outcomes.'^ Cognitive- behavioral therapy for insomnia is typically delivered in 6 to 8 individual sessions, but the efficacy of brief versions^^ and Internet delivery'** have also been demonstrated.
Pharmacologie Treatment Hypnotic agents approved by the US Food and Drug Admin- istration (FDA) include benzodiazepine receptor agonists (BzRAs), antihistamine drugs (eg, hydroxyzine, diphenhy- dramine), a tricyclic drug (doxepin), and a melatonin recep- tor agonist (ramelteon). Barbiturates (secobarbital, butal- bital), related drugs (ethchlorvynol), and chloral hydrate are FDA approved but are not recommended because of their potential toxicity. Physicians also prescribe a number of drugs without an FDA indication for insomnia, including anxio- lytic benzodiazepines, sedating antidepressants, sedating anti- psychotics, and anticonvulsants. Approximately 15 milhon to 20 million prescriptions are written for BzRA hypnotics annually in the United States, and approximately 6% to 10% of the population reports having used a hypnotic.^" Com- mercial claims and patient encounter data show that sev- eral of the most widely prescribed drugs are not FDA approved for treatment of insomnia.'* Hypnotics are indicated for the treatment of primary and comorbid insomnia disorder. Certain medical/psychiatric conditions constitute relative contraindications for spe- cific hypnotic agents. Conversely, specific treatment for co- morbid disorders is essential when treating patients with hyp- notics. Patients with acute or situational insomnia symptoms, such as those associated with travel or psychosocial stress, are often prescribed hypnotics as well.
Benzodiazepine Receptor Agonists. The BzRA drugs in- clude benzodiazepine (eg, temazepám, triazolam) and "non- benzodiazepine" drugs (eg, zolpidem, zaleplon, eszopi- clone) (TABLE 3).
These drugs share a common mechanism of action, binding to a specific recognition site on 7-ami- nobutyric acid type A (GABA-A) receptors. The BzRA drugs produce sedative/hypnotic, amnestic, anxiolytic, myorelax- ant, and anticonvulsant effects, but different GABA-A re- ceptor subtypes are responsible for these effects, and BzRAs vary in their specificity for these receptor subtypes.'^ For instance, zolpidem and zaleplon are relatively specific for GABA-A al receptors and have greater specificity for hyp- notic vs other effects.
The short-term efficacy of BzRA is well established in clini- cal trials that demonstrate statistically significant improve- ments in sleep quality and sleep latency; wakefulness after sleep onset, sleep time, and sleep efficiency also improve de- pending on the drug's duration of action (Table 2).^' Addi- tional double-blind, placebo-controlled studies support the JAMA, February 20, 2013—Vol 309, No. 7 709 CLINICAL CROSSROADS efficacy of BzRA for up to 6 months of nightly^° or inter- mittent*^ use and up to 12 months in open-label studies.^^ Benzodiazepine receptor agonist drugs have inconsis- tent effects on sleep stages, and the clinical relevance of sleep stage effects is uncertain. Clinically important differences between specific BzRAs result from their pharmacokinetic properties.
Most hypnotic BzRAs have rapid absorption and onset of action. More slowly absorbed BzRAs (eg, oxaz- epam, clorazepate) are less useful for insomnia. Elimina- tion half-lives of hypnotic BzRA vary widely, with predict- able clinical effects. For example, zaleplon, with a half-life of 1 hour, reduces sleep latency but has no significant ef- fect on wakefulness after sleep onset; flurazepam and its me- tabolite have half-lives up to 120 hours, resulting in re- duced wakefulness after sleep onset as well as increased daytime sleepiness.
Pharmacokinetic differences can be used to clinical advantage. Patients with sleep-onset difficulties or morning sedation from hypnotics may benefit from a drug with a short half-life and patients with sleep maintenance difficulties may benefit from one with a longer half-life.
Although some BzRAs are FDA approved for insomnia and others for anxiety, they have similar pharmacody- namic properties.
Thus, clonazepam and lorazepam are some- times used as hypnotics when they have the desired phar- macokinetic profile.
Conversely, using multiple BzRA agents (eg, lorazepam for anxiety, temazepam for insomnia) can lead to additive effects rather than distinct effects on differ- ent symptoms. Relative contraindications to BzRA use in- clude alcohol or sedative abuse/dependence, use of other sedative drugs, severe pulmonary failure or untreated sleep apnea, hepatic failure, and hypersensitivity to the drug class.
Benzodiazepine receptor agonists should be used with cau- tion in patients with depression and in older adults.
Adverse effects of BzRA hypnotics include morning se- dation, anterograde amnesia, anxiety (clearly noted by MsJ), impaired balance, increased falls and hip fractures, and Table 1. Cognitive-Behavioral Interventions for Insomnia^ Intervention General Description Specific Techniques Sleep hygiene education Recommendations promoting behaviors that help sleep, discouraging behaviors that interfere with sieep Do not try to sleep.
Avoid stimulants (caffeine, nicotine).
Limit alcohol intake.
Maintain a regular sieep schedule 7 nights per wk.
Avoid naps.
Get regular exercise at least 6 h prior to sleep.
Keep the bedroom dark and quiet.
Stimulus control Based on opérant and classical conditioning principles; nonsleep activities and the bedroom environment can serve as stimuli that interfere viiith sleep.
Treatment prescribes behaviors that strengthen associations between the environment and sleep.
Go to bed only when sleepy.
Use the bed and bedroom for sleep only.
Do not read, watch television, talk on the phone, worry, or plan activities in the bedroom.
If unable to fall asleep viflthin 10-20 min, leave the bed and the bedroom.
Retum only when feeling sleepy again.
Set the aiarm and wake up at a reguiar time every day.
Do not use the snooze button on the alarm.
Do not nap during the day.
Sleep restriction therapy Based on experimental evidence that sieep is regulated by circadian and homeostatic processes.
Treatment increases homeostatic sleep drive by reducing time in bed and maintaining a consistent wake time in the moming to reinforce circadian rhythms.
Restrict time awake in bed by setting strict bedtime and rising schedules limited to the average number of hours of actual sleep reported in 1 night.
Keep a fixed wake-up time, regardless of actual sleep duration.
If after 10 d sleep efficiency is lower that 85%, further restrict bedtime by 15-30 min.
Increase time in bed by advancing bedtime by 15-30 min when the time spent asleep is ^85% of time in bed.
Relaxation training Muscular tension and cognitive arousal are incompatible with sleep.
Relaxation decreases waking arousal and facilitates sleep at night.
Specific techniques may include progressive muscle relaxation, guided imagery, paced breathing Cognitive therapy Identify, challenge, and replace dysfunctional beliefs and attitudes regarding sleep and sleep loss.
These beliefs increase arousal and tension, which impede sleep and further reinforce the dysfunctional beliefs.
Challenge unhelpful beliefs and fears about sleep, eg:
Overestimation of numbers of hours of sleep necessary to be rested.
Apprehensive expectation that sleep cannot be controlled.
Fear of missing opportunities for sleep.
Thought joumaling to reduce rumination Design behaworal "experiments" to test beliefs about sleep.
Cognitive-behavioral therapy for insomnia Multimodal treatment combining elements of above techniques Sieep education Stimulus control techniques Sleep restriction techniques Cognitive therapy techniques May include relaxation training.
Brief behavioral treatment of Core techniques from stimulus control, sleep restriction therapies Limit time in bed to actual sleep time plus 30 min.
Establish regular wake time every day, regardless of prior night's sleep duration.
Do not go to bed until sleepy.
Do not stay in bed if awake.
^See Morin and Espíe,*' Pertis et al,** and Sateia and Buysser^ for furüier details of each therapy.
710 JAMA, February 20, 2013—Vol 309. No. 7 CLINICAL CROSSROADS Table 2.
Quantitative Reviews of Treatment Efficacy in Chronic Insomnia^ Source Studies Reviewed Major Findings Psychological and behavioral treatments Morinetal,^1994 59 Controlled studies of psychological-behavioral treatments (n = 2102) Moderate to large effect sizes (d = 0.42-0.88) for short-term outcomes of sleep latency, wake after sleep onset, riumber of awakenings, total sleep time Effects sizes maintained at follow-up Murtagh et al,^' 1995 66 Outcome studies (n = 1907) Moderate to large effect sizes (d = 0.49-0.94) for short-term outcomes of sleep latency, total sleep time, number of awakenings, sleep quality Effects maintained at long-term follow-up Pallesen et al,^ 13 Studies 1998 Participants with minimum age 50 y and group mean age >60 y (n = 388) Small to moderate effect sizes (d = 0.15-0.61) for posttreatment outcomes of sleep latency, wake after sleep onset, number of awakenings, total sleep time Moderate effect sizes (0.37-0.66) for long-term outcomes Smrth et al,^ 2002.
21 Studies 8 Pharrnacologic RCTs (n = 220 participants) 14 Behavioral RCTs (n = 250) Moderate to large effect sizes (cf = 0.46-1.44) for outcomes of sleep latency, wake after sleep onset, total sleep time, sleep quality Effect size for sleep latency was larger in behavioral than pharmacoiogic treatment studies.
Irwin etal,* 2006 23 RCTs 9f behavioral treatments for chronic insomnia Younger and older adult samples Small effect sizes for total sleep time Moderate to large effect sizes (0.50-0.79) for sleep quality, latency, efficiency, wake after sleep ohset Equivalent effects In younger and older adults except for total sleep time (smaller effect size in older adults) Montgomery et al,"' 6RCTsofCBT-l Adults agecj >60 y with primary insomnia (n = 224) Significant mean differences pre-post treatment for wake after sleep onset (self-report and polysomnography), sleep efficiency (polysomnography) Mean differences not statistically significant for sleep latency.
and polysomnography), sleep efficiency (self-report) total sleep time (self-report Van Strafen et al,"^ 10 Controlled trials of self-help 2009 interventions (eg, books, Intemef, audiofapes) vs controls and in-person treatment (n = 1000) Effect sizes small to moderate {d = 0.02-0.44) for total sleep time, sleep efficiency, sleep latency, wake after sleep onset, sleep quality in self-help vs wait-list control Effect sizes small to moderate (d = 0.02 to -0.50) favoring in-person treatment vs self-help Okajima et al,« 2011 14 RCTs of CBT-I vs control treatments (n = 958) Self-report outcomes (CBT-I vs control): effect sizes small for total sleep time (d = 0.00), moderate to large for sleep latency, wake after sleep onset, total wake time, sleep efficiency (d = 0.44 to 0.86) Objective outcomes (CBT-I vs control): effect sizes small for sleep latency, total sleep time {d = 0.13-0.24), moderate for wake after sleep onset, total wake time, sleep efficiency (cf = 0.42-0.73) Effects generally maintained with 3- to 12-mo follow-up Cheng etal," 2012 6 RCTs of computerized CBT-I vs waitlist or active control (n = 228) Small to large effect sizes (cf = 0.22-0.86) for sleep latency, number of awakenings, sleep efficiency, sleep quality. Insomnia Severity Index Nonsignificant effect size for wake after sleep onset (d = -0.18) Average number needed to treat in 4 studies ranges from 2.91 to 3.59 Pharmacoiogic treatments Nowelletal,''M997 22 RCTs of BzRA hypnotics Adults younger than 65 y (n = 1894) Moderate effect sizes (d = 0.56-0.71) for self-reported outcomes of sleep latency, total sleep time, number of awakenings, sleep quality Z scores for effect sizes range from 0.71 to 0.76 Holbrook et al,"« 2000 45 RCTs of benzodiazepine hypnotics vs placebo or other active treatments (n = 2672) Self-report outcomes: significant difference favoring benzodiazepines vs placebo for sleep latency, total sleep tirne Polysomnography outcomes: significant difference favoring benzodiazepines vs placebo for total sleep time Adverse effects (drowsiness, dizziness, lightheadedness): Significantly more likely in patients taking benzodiazepines vs placebo Smith et al,^ 2002 21 Studies 8 Phamia-cologic RCTs (n = 220 participants) 14 Behavioral RCTs (n = 250) Moderate to large effect sizes (d = 0.45-1.20) for sleep latency, wake after sleep onset, total sleep time, sleep quality Effect size for sleep latency larger in behavioral vs pharmacoiogic treatment studies Dundar et al,"' 2004 24 RCTs comparing benzodiazepine with nonbenzodiazepine BzRA drugs Total (n = 3909) Equivalent efficacy of benzodiazepine and nonbenzodiazepine hypnotics on most outcomes Shorter sleep latency for zolpidem vs temazepam or zopiclone and for zaleplon vs zolpidem Glass et al,"« 2007 24 RCTs of BzRA vs placebo Adults aged 60 or older (n = 2417) Sleep qualify:
d = 0.13, number needed to treat = 13 Total sleep time: mean difference, 25.2 min (95% CI, 12.8-37.8) No.
of awakenings: Mean difference, -0.63 (95% Cl, -0.48 to -0.77) All adverse events: number needed fo harm = 6 Significantly greater risk of cognitive, fatigue, performance adverse effects, but not psychomotor adverse events (dizziness, loss of balance), with active drugs vs placebo Buscemi et al,"' 2007 105 RCTs of BzRA and anfidepressanf drugs in chronic insomnia (n = 13986) Significant difference for all drugs vs placebo on polysomnographic sleep latency (weighted mean difference, -7.0 fo -12.8 min) and sleep diary sleep latency (weighted mean difference, -12.2 to -19.6 min) BzRAs: significanf effects on polysomnographic sleep efficiency; and on sleep diary wakefulness after sleep onset, sleep efficiency, total sleep time, sleep qualify Antidepressants: significarit effects on polysornnographic wake after sleep onset, sleep efficiency, total sleep time; and on-sleep diary rating of sleep quality Adverse events significantly greater for BzRA and antidepressants vs placebo Abbreviations: BzRA, benzodiazepine receptor agonist drug:
CBT-I, cognitive behavioral therapy for insomnia: RCT, randomized controlled trial.
^The studies summarized in Table 2 are the product of a systematic literature review described in the eAppendix.
JAMA, February 20, 2013—Vol 309, No.
7 711 CLINICAL CROSSROADS complex sleep-related behaviors such as sleepwalking and sleep-related eating, driving, and sexual behavior.^-* Most of these adverse effects are dose related, and some (eg, morn- ing sedation) are related to pharmacokinetic properties of specific agents. Other risk factors for adverse events in- clude increasing age, use of other sedating drugs and alco- hol, history of parasomnias, and presence of insomnia it- self.
A meta-analysis of BzRA efficacy and adverse events in older adults concluded that beneficial effects are out- weighed by adverse effects/^ Because of concerns regard- ing complex sleep-related behaviors, the FDA in 2007 re- quired additional warning language for all hypnotics. In January 2013, based on new data regarding the relation- ship between psychomotor performance and drug blood lev- els, the FDA required the manufacturers of zolpidem to lower the recommended dose for women from 10 mg to 5 mg for immediate-release products and from 12.5 mg to 6.25 mg for extended-release products. The FDA also required that manufacturers recommend the lower doses for men.
Additional concerns regarding BzRA include rebound in- somnia, withdrawal, and dependence. Rebound insomnia refers to an increase in sleep symptoms beyond baseline lev- els and is commonly observed during abrupt discontinua- tion, particularly for shorter-acting drugs." Although sev- eral early studies suggested lower potential for rebound with nonbenzodiazepine drugs compared with benzodiaz- epines, rebound can occur with both." Rebound can be mini- mized by gradual dose reduction over weeks to months. With- drawal symptoms (ie, symptoms other than the initial one after discontinuation of the drug) can last for several weeks.
Among individuals with no substance use history, BzRA self- administration represents therapy-seeking rather than drug- seeking behavior.^^ However, abuse can occur with benzo- diazepine and nonbenzodiazepine hypnotics, particularly in individuals with a history of alcohol or other sedative The BzRA hypnotics are commonly involved in drug over- doses but are rarely fatal by themselves because of a high median lethal dose. However, they are frequently taken in combination with alcohol, opiates, and other drugs, lead- ing to increased toxicity and mortality. Increased mortality risk has been associated with even therapeutic use of BzRA hypnotics,^^ although confounding by indication and the ef- fects of comorbidities may influence these findings.
Table 3. Benzodiazepine Receptor Agonist Drugs^ Class/Drug Benzodiazepines Triazolam Temazepam Estazolam Quazepam Rurazepam Alprazolam Lorazepam Clonazepam Nonbenzodiazepines Zaleplon Eszopiclone Zolpidem'^ Oral tablet Extended release Sublingual Sublingual Oral spray 1-2 1-2 1.5-2 2-3 1.5-4.5 0.6-1.4 0.7-1 1-2.5 1 (0.5-2) 1.5(0.5-2) 1.6(0.5-1.5) 1.5(1.5-2.0) 0.6 (0.6-1.3) 1.4 (0.5-3.0) 0.9 Elimination Half-Life, h'' 2-6 8-22 10-24 48-120 48-120 6-20 10-20 20-40 1(0.8-1.3) 6 (5-8) 2.5(1.4-4.5) 2.8(1.6-4.5) 2.5(1.4-3.6) 2.7 (1.5-6.7) 2.8 {1.7-8.4) Usual Hypnotic Dose, mg 0.125-0.25 15-30 1-2 7.5-15 15-30 0.25-1 0.5-3 5-20 1-3 5-10 6.25-12.5 1.75-3.5 5-10 5-10 Approved for Insomnia Yes Yes Yes Yes Yes No No No Yes Yes Yes Yes Yes Yes Yes Comments Early reports of adverse effects were likely dose-related Metabolized mainly by conjugation (no CYP-related drug interactions) Triazolo ring structure similar to triazolam Active metabolite ^-desalkytfturazepam) acojmulates with repeated dosing Active metabolite ^-desalkytflurazepam) accumulates vwth repeated dosing Often noted for significant withdrawal Metabolized by conjugation (no CYP-related drug interactions) Often used for other sleep disorders including restless legs syndrome, parasomnias Shortest-acting BzRA Approximately 30% may experience unpleasant taste or adverse effects Most widely prescribed hypnotic Higher concentrations 3-8 h postdose than traditionä zolpidem Buffer permits increased buccal absorption, lower dose Mainly absorbed via gastrointestinal tract Bioequivalent to tablets in terms of maximum plasma concentration, Tmax, elimination half-life Abbreviations: BzRA, benzodiazepine receptor agonist drug; CYP, cytochrame P-450; T^a, time to maxima] plasma concentration after daig administration.
^Sources: US Food and Dnjg Administratior>-approved prescritMng inionnation and sources.^-™ Published pharmacokinetic data are not consistently reported (or all drugs.
°Data in parentheses are observed range of values in published data.
^ In Januaiy 2013, based on new data regarding the relationship between psychomotor performance and drug blood levels, the FDA required the manufacturers of zolptdem to tower the recommended dose for women from 10 mg to 5 mg for immediate-release products and from 12.5 mg to 6.25 mg for extended-release products. The FDA also required that manu- facturers recommend the lower doses for men.
712 JAAAA, February 20, 2013—Vol 309, No. 7 CLINICAL CROSSROADS Other Medications.
Other drugs commonly used as hyp- notics are listed in TABLE 4.
Ramelteon is a melatonin 1 and melatonin 2 receptor agonist that has properties similar to endogenous melatonin. Chnical trials demonstrate signifi- cant effects on sleep latency and sleep duration but incon- sistent effects on wakefulness after sleep onset.*' Ramelt- eon, like melatonin, can also shift the timing of circadian rhythms, depending on the time of administration.^" Ra- melteon is generally well tolerated, with few adverse ef- fects other than sedation.
Doxepin, a tricyclic compound, is FDA approved for de- pression at doses of 100 to 200 mg and for insomnia at doses of 3 to 6 mg. At antidepressant doses, doxepin has effects on multiple central nervous system neurotransmitters (Tahle 4). At hypnotic doses, doxepin is selective for his- tamine 1 receptors, which may account for its sedative ef- Table 4. Other Drugs Commonly Used as Class/Dmg Melatonin agonist dnjgs Melatonin Ramelteon T™„h'' • 0.3-1 0.75(0.5-1.5) Hypnotics^ Harf-Life, h" .
0.6-1 1-2.6 MT,, MT,, Mechanism MT2 agonist MT2 agonist Usual Hypnotic Dose, mg 0.5-3 8 FDA-Approved Indication No FDA approval Insomnia • Comments/Adverse Effects FDA defines as a dietary supplement Main effect on sleep latency Sedating antidepressant dnjgs Doxepin 3.5(1.5-4) 15(10-30) Low dose: H, antagonist Higher doses: 5HT2, a,, M, antagonist; norepinephrine, 5HT reuptake inhibitor 3-6 Insomnia, (proprietary) depression, 10-100 anxiety (generic) 3- to 6-mg dose approved for Insomnia Adverse effects at higher doses; orthostatic hypotension, anticholinergic, cardiac conduction delay Amitriptyline Trazodone Mirtazapine Sedating antipsychotic drugs Olanzapine Quetiapine Antihistamine dnjgs Diphenhydramine Doxylamine 2-5 1-2 2(1-3) 4-6 1-2 1-4 2-3 30 (5-45) 9(7-15) 30 (20-40) 20-54 6 4-8 10 5HT2, a,, M, antagonist; norepinephrine, 5HT reuptake inhibitor 5HT2, a,, H, antagonist; 5HT reuptake inhibitor 5HT2.3, ai.2, H,,M, antagonist; 5HT reuptake inhibitor 5HT2, D,^, a,,H,, M,.5 antagonist 5HT,.2, D,.2, a,.2, H, antagonist H,, M, antagonist H,, M, antagonist 10-100 25-150 7.5-30 2.5-20 25-50 25-50 25 Depression Depression Depression Schizophrenia, bipolar disorder Schizophrenia, bipolar disorder Allergic reactions, motion sickness, parkinsonism Allergies, hypersensitivity, insomnia Adverse effects at higher doses: orthostatic hypotension, anticholinergic, cardiac conduction delay Dizziness, risk of priapism Increased appetite, weight gain, anticholinergic Hypotension, weight gain, akathisia, dizziness Dry mouth, constipation, weight gain, asthenia, headache Anticholinergic Anticholinergic; dystonic reaction Anticonvulsant dmgs Gabapentin 1.6-3 5-9 Uncertain; GABA analog but does not have activity at GABA receptors. Possible alpha2-delta receptor ligand 100-900 Postherpetic neuralgia.
epilepsy Diabetic peripheral neuropathy.
postherpetic neuralgia; adjunct for partial seizures; fibromyalgia Renal excretion, nonlinear phamnacokinetics (reduced bioavailability at higher doses).
dizziness, ataxia, fatigue Renal excretion, dizziness.
headache, weight gain.
dry mouth Pregabalin 1.5 6.3 Alpha2-delta receptor ligand.
GABA analog but does not have activity at GABA receptors.
50-300 Abbreviations: a, alpha-adrenergic receptor; D, dopamlne receptor; FDA, US Fcx)d and Drug Administration; GABA, gamma-aminobutyric acid; H, histamine receptor; 5HT, serotonin; M, muscarinic cholinergic receptor; MT, melatonin receptor; T™», time to maximal plasma concentration after drug administration.
^Sources: FDA-approved prescribing information and sources.^''^ Pubiished phamnacokinetic data are not consistently reported for all drugs.
° Data in parentheses are observed range of values in published data.
JAMA, February 20, 2013—Vol 309, No. 7 713 CLINICAL CROSSROADS feet without the typical antichohnergic adverse effects (eg, dry mouth, blurred vision, constipation) reported at higher doses.
Chnical trials demonstrate reduced wakefulness af- ter sleep onset and increased sleep efficiency and total sleep time for up to 5 weeks, with little effect on sleep la- tency."'^^ Doxepin affects wakefulness after sleep onset and sleep efficiency across the entire night, whereas BzRAs with short half-lives have limited effect in the final third of the night.
A variety of "natural" and over-the-counter drugs are used as hypnotics, despite a lack of controlled clinical trials to support their use. Melatonin is a hormone typi- cally secreted during the night, which in humans corre- sponds to the major sleep period. Melatonin has been evaluated as a hypnotic in doses of 0.3 to 80 mg, showing a small but significant effect on sleep latency but not other sleep measures." Valerian derivatives are the most widely used herbal treatments for insomnia. The heterogeneity among specific valerian preparations, doses, and study methods precludes any definitive statement regarding their efficacy.^'' Diphenhydramine, doxylamine, hydroxyzine, and other antihistamine drugs are commonly used to treat insomnia. Antihistamine drugs also antagonize muscarinic cholinergic receptors, which can lead to adverse effects including cognitive impairment and urinary retention. Few empirical data are available to support their efficacy or safety.'^ Antihistamines are frequently used in combination with analgesics in over-the-counter preparations targeted at nighttime relief of sleep and pain symptoms. Ms J's experience v^th diphenhydramine is consistent with lim- ited efficacy and the adverse effects of grogginess and irritability.
Other prescription medications are also used to treat insomnia, but none have been systematically evaluated for their efficacy and safety Trazodone is widely prescribed in doses of 25 to 100 mg. The largest study of trazodone showed effects comparable with zolpidem on sleep latency and sleep efficiency, but effects were nonsignificant at week U^ Although trazodone has a relatively short half-life, morning sedation is a common adverse effect, as Ms J described. Gabapentin and pregabalin are often used to treat chronic pain conditions with comorbid insomnia, including fibromyalgia. Self-reported sleep outcomes in these trials generally support positive effects on outcomes such as sleep latency and wakefulness after sleep onset, and polysomnographic studies have shown increased deep sleep.^^'^^ These effects may have contributed to Ms J's favorable response to gabapentin. Sedating antipsychotic drugs, such as olanzapine, quetiapine, and risperidone, are also used off label to treat insomnia. Self-report outcomes and a small number of polysomnographic studies suggest their efficacy but the potential for serious adverse effects, including weight gain and cardiometabolic effects, argue against their use except in patients with serious mental disorders.
714 JAAAA, February 20.
2013—Vot 309, No. 7 Referral to a Sleep Specialist Most patients with chronic insomnia are treated by pri- mary care physicians, which is appropriate given the preva- lence of insomnia and its interactions with comorbid con- ditions and medications. Evaluation and treatment by a sleep specialist are appropriate when the patient has symptoms or clinical features of another sleep disorder, such as ex- cessive daytime sleepiness (narcolepsy, apnea) loud snor- ing or witnessed apneas (sleep-related breathing disor- ders), pronounced alteration of sleep timing (circadian rhythm sleep disorder), or unusual sleep behaviors or in- jury (parasomnia). Patients seeking a formal course of CBT-I or who do not respond to hypnotic medications may also be appropriate for referral.
RECOAA/WENDATIONS FOR AAS J Ms J presents features typical of chronic insomnia, includ- ing a mix of sleep maintenance and sleep onset problems; a variety of daytime symptoms and sequelae; a precipitating factor for insomnia with persistent symptoms even after reso- lution; and trials of multiple behavioral, over-the-counter, and prescription treatments. The least typical aspect of her presentation is the absence of significant worry or cogni- tive arousal with insomnia.
More detailed information regarding sleep should be gath- ered, including symptoms of other sleep disorders such as sleep apnea, and additional history regarding sleep timing and duration.
A sleep diary and wrist actigraphy would more accurately portray day-to-day variability and time in bed.
This information could reveal additional targets for spe- cific behavioral and cognitive interventions, such as reduc- tion of time in bed to increase homeostatic sleep drive, or cognitive techniques to address arousal and unhelpful be- liefs and attitudes about sleep. Training in relaxation strat- egies may be a useful adjunct to Ms J's exercise regimen.
Additional medication strategies include a trial of dox- epin (3-6 mg), given her history of predominantly sleep main- tenance symptoms. Middle-of-the-night dosing with sub- hngual zolpidem could provide a useful as-needed treatment.
Finally, combination treatment with low doses of a short- acting BzRA (eg, zaleplon) and doxepin or trazodone could achieve some of the benefits of each drug class while mini- mizing adverse effects.
QUESTIONS AND DISCUSSION QUESTION: What do you do with patients who say they never sleep?
DR BUYSSE: Patients with insomnia generally report less sleep than we measure v^nth polysomnography, but some have an extreme degree of mismatch, called paradoxical in- somnia. The usual treatments for insomnia are indicated but may be less efficacious. One small study suggested that in- dividuals vnth extreme sleep misperception can be taught to more accurately perceive sleep by reviewing polysom- nography results.
Medications and sleep restriction may also CLINICAL CROSSROADS reduce activity in brain systems that relate to altered per- ception of sleep.
QUESTION:
What do you do with patients who take a sleeping pill every night over long periods, such as 10 years?
DR BUYSSE:
Prior to 2005, FDA labeling for hypnotics dis- couraged use for longer than 1 month; since 2005, labeling for new hypnotics does not specify a duration. This change reflects placebo-controlled data showing efficacy of hyp- notics for 6 to 12 months of nightly use.
Hypnotic medica- tions should be used in the lowest effective dose for the short- est necessary duration.
However, because insomnia is often a chronic problem, short-term use of hypnotics is unlikely to solve the problem.
I aim for intermittent, nonnightly dos- ing when possible, combined with behavioral treatment.
For some patients, long-term nightly treatment is reasonable.
Discuss the potential risks and benefits of long-term use, involve patients in decision making, and regularly reevalu- ate efficacy and adverse effects.
QUESTION:
Can you comment specifically about medica- tion alternatives in older adults?
DR BUYSSE:
Behavioral measures are particularly impor- tant in older adults with insomnia, given the potential ad- verse effects of hypnotics.
The key to behavioral treatment for sleep in elderly people is to plan activities to keep the person engaged and involved during wakefulness to reduce time in bed. There are no clear alternatives to BzRA hyp- notics for elderly patients because the alternative drugs also have significant adverse effects, including impaired cogni- tion and balance and increased falls. Try to keep medica- tion doses low, carefully monitor the patient, provide good education, and use behavioral interventions when pos- sible.
QUESTION:
DO you prescribe light therapy?
DR BUYSSE: Bright white light and blue light can help insomnia by changing the timing of the biological clock.
The effects of light depend on the time of administration.
In older adults, the biological clock is often advanced to an earlier time; light in the evening hours pushes the bio- logical clock—and sleep—to a later time. For patients who have difficulty falling asleep at night and difficulty waking up in the moming because of a delayed biological clock, bright light treatment in the morning advances sleep to an earlier time.
Conflict of Interest Disclosures:
The author has completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest.
Dr Buysse reports having served as a paid consultant on scientific advisory boards for the following companies:
Ei- sai, Merck, Pfizer, Philips Respironics, Purdue Pharma, and General Sleep Corp.
He has also spoken at single-sponsored educational meetings for Astellas and Servier.
Online-Only Material:
The eAppendix and eFigures 1 and 2 are available at http:
//www.jama.com.
Additional Contributions: We thank the patient for sharing her story and for pro- viding permission to publish it. We acknowledge Ester Saghafi, MEd, MLS, Uni- versity of Pittsburgh, and Zachary Chakan, University of Pittsburgh Medical Cen- ter, who provided invaluabie assistance and guidance with the systematic review for treatment studies; Deepa Burman, MD, University of Pittsburgh, who pro- vided valuable comments and suggestions on a draft of the manuscript; and Linda Willrich, University of Pittsburgh Medical Center, who provided administrative and technical support. No financial compensation was received.
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