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J Am Board Fam Pract: first published as 10.3122/jabfm.17.3.212 on 29 June 2004. Downloaded from

REVIEW ARTICLE Treatment of Primary

Erika N. Ringdahl, MD, Susan L. Pereira, MD, and John E. Delzell, Jr, MD, MSPH

Ten percent to 40% of adults have intermittent insomnia, and 15% have long-term difficulties. This article provides a review of the classification, , and treatment options available for insomnia. We performed a MEDLINE search using OVID and the key words “insomnia,” “sleeplessness,” “behavior modification,” “,” “medicinal,” and “pharmacologic therapy.” Articles were selected based on their relevance to the topic. Evaluation of insomnia includes a careful sleep history, review of , review of use (including over-the-counter and herbal ), family history, and screening for , , and . Treatment should be individual- ized based on the nature and severity of symptoms. Nonpharmacologic treatments are effective and have minimal side effects compared with drug therapies. Medications such as , , and can be used initially, but patients may not tolerate their side effects. Newer medications such as and have short half-lives and minimal side effects. Both are approved for short-term use in the insomniac. (J Am Board Fam Pract 2004;17:212–9.)

Many people have difficulty sleeping. A 1995 Gal- Classification lup survey found that 49% of adults were dissatis- The American Psychiatric Association’s Diagnostic and fied with their sleep at least 5 nights per month.1 Statistical Manual of Mental Disorders (DSM-IV)5 defines Population-based studies estimate that 10% to insomnia as a complaint regarding the quantity, quality, 40% of American adults have intermittent insom- or sleep timing at least 3 times a week for at least 1 nia; 10% to 15% have long-term sleep difficulties.2 month. Sleep is divided into rapid eye movement Insomnia has been associated with decreases in (REM) sleep and non-REM sleep. Non-REM sleep has work performance and increases in motor vehicle 4 stages, each progressively deeper. Stages 3 and 4, deep ␦ accidents and hospitalization rates.3 Cost estimates restorative sleep, are also called slow wave or sleep. http://www.jabfm.org/ for lost productivity and insomnia-related accidents Decreased time spent in stage 3 and 4 decreases sleep 6 exceed $100 billion per year.4 The purpose of this quality. Stage 5 sleep is REM sleep. Research studies review is to provide a current review of the classi- define insomnia as a sleep latency (time taken to fall asleep) that is greater than 30 minutes, sleep efficiency fication, the differential diagnosis, and treatment (time asleep/time in ) less than 85%, or sleep distur- options for insomnia. We performed a MEDLINE bance more than 3 times a week.7 search using OVID and the key words “insomnia,”

The International Classification of Sleep Disor- on 1 October 2021 by guest. Protected copyright. “sleeplessness,” “behavior modification,” “herbs,” ders classifies insomnia as a .8 “medicinal,” and “pharmacologic therapy.” Ab- include difficulties initiating or maintaining sleep (in- stracts were reviewed by 2 of the authors (ENR, somnia) and excessive sleep (). Several SLP). Articles were then selected based on rele- insomnia-related complaints defy categorization. Pa- vance to the topical review. tients who have sleep state misperception insomnia complain of not having slept for a long time without objective evidence of difficulty sleeping. Some pa- Submitted, revised, 24 December 2003. tients sleep less because of work or social demands From the Departments of Family and Community Med- icine (ENR) and Urgent Care (SLP) University of Missouri- (self-imposed short total sleep time) or because they Columbia School of Medicine, Columbia, and the Depart- are natural short sleepers and require less sleep.9 ment of Family Medicine, University of Tennessee College of Medicine, Memphis. Address correspondence to Erika Ringdahl, MD, Family Practice Residency Program, De- Differential Diagnosis partment of Family and Community Medicine, MA303 Medical Sciences Building, Columbia, MO 65212 (e-mail: Insomnia may be divided into extrinsic and intrin- [email protected]). sic disorders. Extrinsic disorders include problems

212 JABFP May–June 2004 Vol. 17 No. 3 J Am Board Fam Pract: first published as 10.3122/jabfm.17.3.212 on 29 June 2004. Downloaded from with sleep , substance abuse, and situational sleep specialists have a psychiatric disorder.15 Fur- . thermore, 10% to 15% of insomniacs are substance Intrinsic disorders include psychophysiologic in- abusers.3 somnia, idiopathic or primary insomnia, obstruc- The approach to a sleep complaint begins with a tive , , thorough sleep history. Sleep-wake patterns should , and disorders. be elicited and confirmed by the patient’s bed part- Psychophysiologic insomnia occurs after an short- ner if possible. A family history may be useful. term stressor. After several nights of poor sleep, the More than 30% of insomniacs will have a family patient focuses on the inability to sleep, which history of sleep disorders, especially among first- perpetuates the problem.10 Circadian rhythm ab- degree female relatives.16 The sleep history should normalities include advanced sleep phase disorder include evaluation of underlying psychiatric disor- and delayed sleep phase disorder. Patients with ders, current medication regimens, and associated advanced sleep phase disorder, common in elderly symptoms that may coexist with the inability to persons, become sleepy in the early evening, sleep a sleep. Previous treatment attempts should also be normal amount, and then have very early morning noted. The physical examination is less useful, al- awakening. These patients may struggle to stay though physical evidence of , such as awake until a more socially acceptable evening allergies or , may be impor- time. Patients with delayed sleep phase disorder, tant. more common in adolescence, may not become is not indicated unless a sleepy until after midnight, sleep a normal length of sleep-related breathing disorder is suspected. Pa- time, and awaken very late in the morning.11 tients with daytime sleepiness, , witnessed As one ages, stage 3 and 4 sleep decreases and apneic spells, and a body mass index over 35 have a stage 1 increases, resulting in less restorative sleep. greater than 70% probability of having sleep ap- Nocturnal awakenings also increase, causing more nea.17 Patients with these symptoms, , or fragmented sleep.12 Sleep complaints are therefore should be referred for polysomnogra- more common in elderly persons.13 Although these phy. Additionally, patients who have daytime sleep- changes in sleep patterns may be responsible for iness and have such occupations as pilot or truck perceived insomnia, many sleep complaints in the driver should have sleep studies done. elderly are caused by medical conditions or medi- cation use that increases with age. Medical problems such as arthritis, allergies, Nonpharmacologic Treatment http://www.jabfm.org/ congestive , and benign prostatic hy- Treatment of insomnia should be individualized pertrophy affect sleep. Physiologic causes for sleep based on the nature and severity of symptoms and disturbances include hormonal shifts commonly af- should occur after other causes have been consid- fecting postpartum and perimenopausal women. ered, diagnosed, and treated. Nonpharmacologic Medications used to treat many common disorders, treatment is less expensive and has fewer side ef- ␤ such as decongestants, -, corticosteroids, fects compared with pharmacologic treatment. on 1 October 2021 by guest. Protected copyright. ␤-blockers, diuretics, , and H-2 Pharmacologic treatment should be used if the pa- blockers disturb sleep.11 If a medication is thought tient will benefit from the more rapid effect of drug to be the cause of a sleep disturbance, alternative therapies while pursuing the longer-lasting effects medications should be considered. If there are no of behavior modifications. alternatives, medications to treat the insomnia Nonpharmacologic treatments for insomnia are could be added to the patient’s regimen. considered effective if they decrease It can be difficult to distinguish between primary latency or increase total sleep time by 30 minutes. sleep complaints and those associated with psychi- Most treatment studies use patient-reported sleep atric disorders. Insomnia is often a symptom of diaries to measure outcome. Criteria used include underlying anxiety, depression, or . A total sleep time, sleep-onset latency, and number of survey of office-based physicians showed that 30% nocturnal awakenings. A meta-analysis of 48 indi- of patients diagnosed with insomnia were also di- vidual studies of behavioral therapy found stimulus agnosed with depression.14 Another study found control therapy to be effective and to be superior to that approximately 40% of patients presenting to progressive relaxation, imagery training, and para-

Treatment of Primary Insomnia 213 J Am Board Fam Pract: first published as 10.3122/jabfm.17.3.212 on 29 June 2004. Downloaded from doxical intention. Progressive muscle relaxation is sumes that insomniacs spend more time in bed in superior to . A more recent meta-analysis an attempt to get more sleep, thereby decreasing compared the outcomes of pharmacotherapy and sleep efficiency and increasing frustration and per- behavioral therapy and found no differences be- ception of insomnia. Sleep restriction increases tween the 2 except that behavioral therapy more sleep efficiency and sleep quality.13 Patients de- significantly decreased sleep latency.18 crease the amount of time in bed to their average Stimulus control therapy, based on the premise total sleep time (the amount of time in the bed that that insomnia is a conditioned response to temporal they actually sleep), creating a mild sleep depriva- and environmental stimuli normally associated with tion and resulting in better sleep. Each week, when sleep, reassociates the bed with sleep and is espe- sleep efficiency (time asleep/time in bed ϫ 100) cially effective for sleep-onset insomnia.13,19 The exceeds 90%, the patient increases time in bed by patient is instructed to leave the if unable 20 minutes. When sleep efficiency is less than 80%, to fall asleep within 20 minutes. The patient then time in bed is decreased by 20 minutes.13 Time in returns to bed only when very sleepy, repeating the bed should not decrease to below 5 hours.19 Tem- cycle as often as needed through the night. Patients poral control therapy requires the patient to get up at avoid sleep incompatible activities when in bed the same time each day, regardless of how much (reading or watching television). they sleep, and to avoid .21 With paradoxical intention therapy, the patient Poor may worsen mild insomnia, confronts their of sleeplessness by staying but improving sleep hygiene alone is unlikely to awake. This decreases concern about the conse- impact severe insomnia. Improving sleep hygiene quences of lack of sleep and decreases performance involves giving patients a list of instructions facili- anxiety about falling asleep. Patients who undergo tating a regular sleep-wake schedule.8 Instructions cognitive therapy do not necessarily improve their include: participate in a relaxing activity until tired, sleep parameters, but they have increased satisfac- go to bed only when tired, use the bedroom only tion with their sleep patterns.13 for sleep and sexual activity, avoid naps, avoid caf- Relaxation therapies, based on the premise that feine, , and 4 to 6 hours before bed, the aroused state precludes sleep, are effective, es- avoid poor sleeping environments, decrease fluid pecially in young adults, but less so than stimulus intake before bed, avoid heavy meals, heavy exer- control or sleep restriction.13 Relaxation training cise, stimulating late-evening activities, and elimi- includes progressive muscle relaxation, where pa- nate bedroom clocks. , unless performed tients decrease muscle tension by tensing and re- immediately before , increases sleep qual- http://www.jabfm.org/ laxing different muscle groups. When using imag- ity. Moderate exercise improves sleep quality, onset ery training to decrease cognitive arousal, patients latency, and duration in older adults.22 One study focus on pleasant or neutral images or use thought- showed that exercise and (BDZs) stopping techniques. were similar in their sleep-improving abilities.23 A recent study showed cognitive behavioral ther-

apy decreased sleep latency by 54%, compared with Pharmacologic Treatment on 1 October 2021 by guest. Protected copyright. 16% with relaxation therapy and 12% with placebo Prescribing sleep agents should be based on the treatment.19 Cognitive therapy addresses dysfunc- severity of daytime symptoms and the likelihood tional beliefs; patients may have unrealistic expec- that the short-term insomnia, if untreated, could tations for sleep and misconceptions about causes progress into long-term insomnia.11 The ideal and consequences of their insomnia. Cognitive sleep agent has a quick onset of action to decrease therapy is as effective as pharmacologic therapy in sleep latency, a duration of action that prevents the elderly.20 Many insomniacs develop anxiety early morning awakenings, and minimal side ef- about going to sleep and a fear of sleeplessness, fects.11 The lowest effective dose of an agent which may perpetuate the insomnia. Others to should be used. Medications should be used for a compensate for poor nocturnal sleep, but this ag- short period (2 to 4 weeks) and intermittently, gravates the insomnia. based on the individual patient’s return to an ac- Sleep restriction and temporal control are prob- ceptable .21 ably beneficial. Sleep restriction therapy attempts to l-, though banned in 1989 because reassociate the bed with sleep. This therapy pre- of its association with eosinophilia-myalgia syn-

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Table 1. FDA-Approved Medications for the Treatment dian phase,28 so this dosing regimen could help of Insomia35 those patients who have trouble falling asleep but

Chloral hydrate then sleep late in the morning. However, elderly Diphenhydramine patients who complain of early morning awaken- Doxylamine ings may have their sleep problem worsened by a prebedtime dose. Conversely, early morning ad- ministration of delays the circadian Trimeprazine Zaleplon phase, which might help patients who become Zolpidem sleepy earlier and awaken early. root is an over-the-counter herbal medicine used for insomnia. Valerian root, valeri- drome, has been promoted as a sleep aid. It remains ana officinalis, is a perennial plant with a volatile oil available in a low-dose (500 mg) capsule24; milk found in the rhizome in the dried form. The oil contains l-tryptophan in its natural form. The contains 3 distinct compounds, present in various safety and efficacy of the lower dose has not been amounts, but all have effects. Compared studied. with BDZs, side effects are generally less common. People with sleep disturbances may drink alco- is thought to be caused by inhibition of hol to cause drowsiness. In 1 study of insomniacs, the breakdown of either ␥-aminobutyric acid 28% used alcohol to help them sleep, and 67% (GABA) or direct metabolites that have GABA-like found it effective.25 However, alcohol can act as a properties, thus producing central sedation. Clini- central nervous system (CNS) and may cal trials using 400 mg of the aqueous extract de- increase nocturnal awakenings. Using alcohol as a creased sleep latency and increased slow wave sleep aid should be discouraged because of its abuse sleep.30 Valerian root is classified as “generally rec- potential. ognized as safe” (GRAS) in the United States for Melatonin, a neurohormone secreted by the pi- food use and is officially in the European Pharma- neal gland, has been publicized as a cure for many copoeia. A recent FDA Advisory31 has recom- sleep problems. Nocturnal secretion of melatonin mended against the use of because of liver and its suppression by bright light regulate circa- toxicity. dian rhythms and sleep.26 Sleep disturbances occur The most commonly used nonprescription when melatonin secretion is dyssynchronous from agents are the diphenhydramine and the light-dark cycle.27 Melatonin secretion de- doxylamine. Side effects include dry mouth, con- http://www.jabfm.org/ creases with age and may be partly responsible for stipation, and urinary retention. They are effective sleep disorders in the elderly.28 Tobacco, alcohol, in inducing drowsiness when taken at bedtime; and medications, such as nonsteroidal anti-inflam- however, their half-life of up to 8 hours may cause matory drugs, calcium channel blockers, BDZs, flu- residual daytime sedation. oxetine, and steroids decrease melatonin produc- BDZs are frequently prescribed for sleep distur- 27 tion. bances. BDZs shorten sleep latency, decrease noc- on 1 October 2021 by guest. Protected copyright. Melatonin is available in 0.3- to 5-mg doses.27 turnal awakenings, and increase total sleep time.32 Doses of more than 1 mg will produce supraphysi- However, they also shorten REM sleep. BDZs have ologic levels. The half-life of melatonin is only 30 , anticonvulsant, and anxiolytic to 50 minutes,27 so there is minimal residual effect properties because of their nonselective binding to the next morning. The main side effect is drowsi- BDZ2 and BDZ3 receptor subtypes.32 ness. It is unclear whether long-term use suppresses For the elderly and those with renal or hepatic endogenous production. Melatonin can interact impairment, a BDZ with a short half-life (triazo- with luteinizing and should not be given lam) and without active metabolites would be pref- to prepubertal or pregnant women. erable to avoid oversedation from an accumulation A recent study did not find any improvement in of active metabolites. A BDZ with a longer half-life sleep quality or quantity with melatonin adminis- (flurazepam) is appropriate for patients with day- tration.29 In fact, if given incorrectly, melatonin time anxiety. An intermediate agent, such as temaz- could exacerbate sleep disturbances. Melatonin epam or estazolam, may be a reasonable compro- given in the early evening will advance the circa- mise for patients with early morning awakenings.

Treatment of Primary Insomnia 215 J Am Board Fam Pract: first published as 10.3122/jabfm.17.3.212 on 29 June 2004. Downloaded from http://www.jabfm.org/ on 1 October 2021 by guest. Protected copyright.

Figure 1. Diagnostic approach to insomnia

BDZ side effects include daytime sedation, an- though unaffected by BDZ use duration.32 Gradual terograde , respiratory depression, and discontinuation can minimize rebound insomnia.32 withdrawal symptoms. Tolerance may develop Because of their addictive effects, BDZs should be within 1 to 2 weeks.8 BDZs have been associated avoided or used with caution for patients with sub- with rebound insomnia, which can occur after 1 stance abuse tendencies. night of BDZ use.32 The risk of rebound insomnia Case reports of confusion, amnesia, and behav- is greater with higher doses and short half lives, ior problems were reported with the short-acting

216 JABFP May–June 2004 Vol. 17 No. 3 J Am Board Fam Pract: first published as 10.3122/jabfm.17.3.212 on 29 June 2004. Downloaded from http://www.jabfm.org/

Figure 2. Treatment algorithm on 1 October 2021 by guest. Protected copyright.

BDZ triazolam, resulting in its removal from the the nondepressed patient even though controlled market in Europe in 1991.33 Subsequently, pre- studies are lacking. Trazodone decreases the in- scriptions for BDZs decreased 30% between 1987 somnia caused by selective serotonin reuptake in- and 1991.32 hibitors and is a good choice for depressed patients In the place of BDZs, antidepressants with se- with difficulty sleeping.8 Trazodone does not affect dation as a side effect, such as , nortrip- sleep latency but does decrease REM sleep and may tyline, and trazodone, were increasingly used to treat be associated with significant rebound insomnia.11 insomnia. Amitriptyline and nortriptyline were Priapism is a potentially serious side effect of traz- previously used as sleep agents but their usage has odone and may limit its use in men. Trazodone decreased because of side effects helps depressed insomniacs more than fluoxetine and the availability of newer agents. Trazodone is during the first week of administration, but by the widely accepted for the treatment of insomnia in second week of administration, there is no signifi-

Treatment of Primary Insomnia 217 J Am Board Fam Pract: first published as 10.3122/jabfm.17.3.212 on 29 June 2004. Downloaded from cant difference.34 In direct comparison, zolpidem tives such as valerian root deserve further research. was more effective than trazodone initially, as well Tricyclic antidepressants and antihistamines should as after the first week of treatment.35 be used with caution because of their side-effect Marketed since 1993, the most commonly pre- profiles, especially when used in the elderly or with scribed sleep agents are the selective BDZ receptor other medications. Trazodone and nonselective agonists zolpidem and zaleplon. Zolpidem and BDZs can be effective insomnia treatments. Newer zaleplon are BDZ1 receptor subtype agonists and agents zolpidem and zaleplon are selective benzo- are highly selective for the GABA-chloride channel diazepine (subtype 1) receptor agonists that have a within the type I-BDZ receptors in the CNS. The rapid onset, short half-life, and minimal side ef- modulating effects on GABA produce sedation.31 fects. Consider using a short-term pharmacologic Zolpidem has a rapid onset of action and a half- agent while promoting long-term behavioral life of only 1.5 to 2.5 hours.8 These characteristics changes to improve sleep patterns. allow patients to take zolpidem later in the night when having trouble falling asleep without worry- References ing about residual cognitive impairment the next 1. The Gallup Organization. Sleep in America: a na- morning. Zolpidem decreases sleep latency and in- tional survey of US adults. Washington DC: Na- creases total sleep time; unlike nonselective BDZs, tional Sleep Foundation; 1995. zolpidem does not decrease REM or ␦ sleep.8 2. Kiley J. Insomnia research and future opportunities. The usual dose of zolpidem is 10 mg at bedtime. Sleep 1999;22 Suppl 1:S344–5. This is decreased to 5 mg in patients older than 65 3. Meyer TJ. Evaluation and management of insomnia. Hosp Pract (Off Ed) 1998;33:75–8, 83–6. or with hepatic . Common side effects in- 4. Eddy M, Walbroehl G. Insomnia. Am Fam Physi- clude drowsiness (5%), dizziness (5%), headache cian 1999;59:1911–6. (3%), and gastrointestinal symptoms (4%). Most 5. American Psychiatric Association. Diagnostic and side effects are dose-related, occurring at doses statistical manual of mental disorders. 4th ed. Wash- above 20 mg per day. One percent to 2% of pa- ington DC: American Psychiatric Association; 1994. tients taking zolpidem complain of memory prob- 6. Wagner J, Wagner M, Hening W. Beyond benzo- lems, , and confusion, and there have diazepines: alternative pharmacologic agents for the been case reports of sensory disturbances and psy- treatment of insomnia. Ann Pharmacother 1998;32: chotic symptoms.8 680–91. Zaleplon is another selective BDZ receptor ago- 7. Lacks P, Morin C. Recent advances in the assess-

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Treatment of Primary Insomnia 219