Select a psychoactive drug that is of pharmacological interest to you, but not one you will review as part of your Critical Review. For this paper, you may choose drugs of abuse; however, the paper mu

clinical review insomnia 927 Am J Health-Syst Pharm—Vol 65 May 15, 2008 clinical review St a c y PaS S a r e l l a , P h a r m .D., BcPS, is Clinical Pharmacist; and m i n h -tr i D u o n g , P h a r m .D., is Residency Director, Pharmacy Practice Residency Program, and Pharmacy Services Education Coordinator, Pharmacy Department, Tampa General Hospital, Tampa, FL. Address correspondence to Dr. Passarella at the Pharmacy Depart- ment, Tampa General Hospital, P.O. Box 1289, Tampa, FL 33601 ([email protected]).

Copyright © 2008, American Society of Health-System Pharma- cists, Inc. All rights reserved. 1079-2082/08/0502-0927$06.00. DOI 10.2146/ajhp060640 Diagnosis and treatment of insomnia St a c y PaS S a r e l l a a n d M i n h -t r i d u o n g Purpose. The diagnostic criteria and treat - ment of insomnia are reviewed.

Summary. Insomnia is most often de - scribed as a subjective complaint of poor sleep quality or quantity despite adequate time for sleep, resulting in daytime fatigue, irritability, and decreased concentration.

Insomnia is classified as idiopathic or comorbid. Comorbid insomnias are associ- ated with psychiatric disorders, medical disorders, substance abuse, and specific sleep disorders. Idiopathic insomnia is es- sentially a diagnosis of exclusion. A wide array of terminology exists for defining t h e d u r a t i o n o f i n s o m n i a s y m p t o m s, which may add to the confusion regarding insomnia classification. Acute insomnia refers to sleep problems lasting from one night to a few weeks, whereas chronic insomnia refers to sleep problems last - ing at least three nights weekly for at least one month. Diagnostic tools for identifying insomnia are multifacto - r i a l. N o n p h a r m a co l o gi c i n te r ve n t i o n s f o r i n s o m n i a i n c l u d e s l e e p - h y g i e n e e d u c a t i o n , s t i m u l u s - c o n t r o l t h e r a p y, relaxation therapy, and sleep-restriction therapy. The most effective pharmaco - logic therapies for insomnia are benzo - d i a z e p i n e s , b e n z o d i a z e p i n e - r e c e p t o r agonists, melatonin-receptor agonists, and antidepressants. Choice of a specific agent should be based on patient-specific factors, including age, proposed length of treatment, primar y sleep complaint, history of drug or alcohol abuse, and cost. Conclusion. Many treatment options are available for patients with insomnia. Be - havioral therapies should be initiated as first-line treatment in most patients. For p at i e nt s w h o re q u i re t h e a d d i t i o n o f pharmacologic therapy, the drugs with the most evidence for benefit include ben- zodiazepines, benzodiazepine -receptor agonists, melatonin-receptor agonists, and antidepressants. Selection of a specific agent must take into account numerous patient-specific factors.

Index terms: Antidepressants; Anxiolytics, sedatives and hypnotics; Benzodiazepines; Diagnosis; Drugs; Insomnia; Mechanism of action; Nomenclature Am J Health-Syst Pharm. 2008; 65:927-34 O ver 50 million Americans report having a sleep-related problem. 1 According to the 2005 Sleep in America Poll, 75% of people surveyed reported having a sleep problem, including difficulty falling asleep, frequent awakenings, early morning awakenings, daytime drowsiness, snoring, or sleep apnea. 2 Over 50% of respondents reported having at least one symptom of insomnia dur - ing the previous year, with one third experiencing insomnia symptoms nearly every night. The most com- mon symptoms reported included daytime drowsiness (38%) and fre- quent awakenings (32%). 2 Insomnia tends to occur more frequently in women, especially postmenopausal women, and the elderly. Additional predisposing factors for insomnia in- clude snoring and comorbid psychi- atric or medical illnesses.

3,4 Although insomnia is a widely recognized problem across all ages, less than half of the respondents in the Sleep in America Poll were likely to discuss the problem with a physician. 2 As insomnia has gained increasing recognition as a major health issue, the number of available treatment options has also increased. There are a growing number of pharmacologic treatments available for insomnia, most of which are heavily advertised in magazines or on television. This direct-to-consumer advertising has improved the overall awareness of some of the drug treatments avail- able; unfortunately, this may dimin- ish the awareness of the benefits of behavioral therapies. Despite the high rate of insomnia and expand- ing appreciation of insomnia as a major health issue, it is still under - recognized and often inadequately treated. In this article, normal sleep architecture, the epidemiology and causes of insomnia, risk factors for clinical review insomnia 928 Am J Health-Syst Pharm—Vol 65 May 15, 2008 insomnia, pharmacologic and non- pharmacologic treatment options, and barriers to insomnia diagnosis and treatment are reviewed. In addi- tion, suggestions for future research and new sleep agents on the horizon are discussed.

Sleep basics Sleep plays a vital role in every healthy individual, although there is no overall agreement on the spe- cific functions of sleep. Potential physiological functions on sleep may include restorative functions and en- ergy conservation. 5 Current evidence suggests that there are likely multiple functions of sleep and that an indi- vidual’s sleep needs may depend on a person’s age or activity. 5 Sleep stages. Sleep can be divided into two general states: nonrapid eye movement (NREM) and rapid eye movement (REM) sleep. NREM comprises four stages of sleep, each progressing toward REM sleep. Stage 1 sleep represents a transition period between wakefulness and the early stages of sleep. 5 Stage 2 sleep, some- times known as intermediate sleep, represents the largest percentage of total sleep time. Stages 3 and 4 sleep are referred to as deep sleep and are postulated to be the restorative sleep stages. REM sleep follows NREM sleep. During REM sleep, physi- ological changes (e.g., variations in blood pressure, heart rate, and respiratory rate) and quick, irregular eye movements occur. REM sleep is also the stage in which patients recall dreaming if awakened. The specific functions of REM sleep are not fully understood, though evidence sug- gests that it may be vital for memory consolidation and, potentially, sus- taining life. 5 Normal sleep cycle. A complete sleep cycle lasts for approximately 1.5–2 hours and is repeated four to five times during the night. 5 The amount of time spent in each sleep stage changes throughout the night based on the amount of time a person has been asleep. With each sequential sleep cycle, the amount of time in stage 2 and REM sleep typically increases. Several factors contribute to alterations in normal sleep architecture, including medi- cations and sleep disorders, such as narcolepsy. Sleep architecture also changes with age. As individuals age, the amount of time spent in stages 3 and 4 sleep typically decreases while stage 1 sleep increases. 5 Sleep assessment. Objective tools for measuring sleep and sleepiness include tests such as the multiple sleep latency test (MSLT), polysom- nography, and wrist actigraphy. 5 The MSLT objectively assesses daytime sleepiness by measuring the time it takes for patients to fall asleep. These tests are not indicated for routine di- agnosis of insomnia and are required only when the patient’s history and presentation support their use.

6 In polysomnography, typically used during an overnight sleep study, elec- trodes continuously record measure- ments, including the electroencepha- logram, REMs, and muscle tone. 5 Wrist actigraphy is used adjunctively with other objective data and records movement of the wrist to determine the amount of time spent sleeping.

5 Insomnia classifications Insomnia is most often described as a subjective complaint of poor sleep quality or quantity despite adequate time for sleep, resulting in daytime fatigue, irritability, and de- creased concentration. Specific sleep complaints of patients with insomnia include delayed sleep onset, frequent awakenings, early morning awaken- ings, and waking up feeling unre- freshed. Classifications of insomnia vary by organization or specific diag- nostic criteria. Primary and comorbid insom- nias. Insomnia is classified as id- iopathic (primary) or comorbid (secondary). Comorbid insomnias are associated with psychiatric dis- orders (e.g., dementia, depression, anxiety disorders), 7,8 medical disor - ders (e.g., gastroesophageal reflux disease, chronic pain, asthma), 7 sub - stance abuse (e.g., alcoholism, abuse of prescription or nonprescription medications, illicit drug use), 7 and specific sleep disorders (e.g., periodic limb movement disorder, restless legs syndrome, circadian rhythm sleep disorders, sleep apnea). 5,7 Primary insomnia is essentially a diagnosis of exclusion. When all other potential causes have been excluded, insom- nia is classified as primary.

7 Factors associated with primary insomnia include chronic stress, poor sleep hy- giene, and learned insomnia. Primary insomnia may also be associated with a sleep-state misperception, in which patients complain of insomnia but have no objective evidence of a sleep disorder. 9 Acute and chronic insomnias. A wide array of terminology exists for defining the duration of insomnia symptoms, which may add to the confusion regarding insomnia clas- sification. Generally, insomnia is classified as either acute or chronic depending on the duration of symp- toms. Acute insomnia refers to sleep problems lasting from one night to a few weeks, whereas chronic insom- nia refers to sleep problems lasting at least three nights weekly for at least one month. 7 Acute insomnias often result from emotional or physi- cal stressors such as illness, jet lag, and environmental disturbances.

Chronic insomnias are most often associated with comorbid medical or psychological disorders. 7 Additional classification schemes and diagnosis. The Diagnostic and Statistical Manual of Mental Disor - ders, Fourth Edition, Text Revision, categorizes sleep disorders into pri- mary sleep disorders, sleep disorders related to another mental disorder, sleep disorders due to a medical disorder, and substance-induced sleep disorders. 10 The International Classification of Sleep Disorders, Re- vised, classifies sleep disorders into clinical review insomnia 929 Am J Health-Syst Pharm—Vol 65 May 15, 2008 four major categories: dyssomnias, parasomnias, sleep disorders associ- ated with comorbid diseases, and proposed sleep disorders. 11 In this scheme, insomnia is classified as a dyssomnia. As a dyssomnia, insom- nia is further characterized as an intrinsic, an extrinsic, or a circadian rhythm sleep disorder. 11 Diagnosis Diagnostic tools for identifying insomnia are multifactorial. As with any medical problem, appropriate di- agnosis must begin with a thorough medical history and physical exami- nation that addresses the patient’s sleep history. A comprehensive sleep history should include sleep habits, drug (including prescription and nonprescription medications) and alcohol consumption, nicotine and caffeine intake, comorbid illnesses, and sleep environment. A complete physical examination may help to identify potential medical conditions that may be contributing to insom- nia symptoms. Interviewing the bed partner or caregiver may also provide useful information. A one- to two- week sleep diary in which patients record bedtime, total sleep time, time to sleep onset, number of awakenings, use of medications, time of awaken- ing in the morning, and subjective feeling in the morning may provide additional insight into the patient’s sleep-related problem. 7 Direct ques- tioning about insomnia symptoms may be required, since many patients with sleep-related problems never discuss the issue with their primary care providers. 7 Some patients may require a sleep study requiring assess- ment tools such as polysomnography and the MSLT.

5,12 Effective treatments for insomnia symptoms can be iden- tified only after careful review of the patient’s sleep history and sleep stud- ies, if applicable.

Consequences of insomnia The most common outcomes of acute insomnia are sleepiness, mood changes, and impairment of daytime functioning. 7 Insomnia may interfere with interpersonal relationships and job performance and may increase health care utilization. 13-15 Further - more, chronic insomnia has been linked to increased absenteeism from work, an increased risk of psychi- atric disorders, impaired cognition, and a negative impact on quality of life. 7,16,17 Together, these effects of insomnia provide overwhelming evi- dence of the need to provide appro- priate treatment options to affected individuals. The management strategy is most likely to be affected by the length and severity of symptoms, finan - cial impact, and comorbid medical conditions. Treatment is inevitably influenced by both the clinician’s and the patient’s perceptions of each of the treatment options. Nonethe- less, the clinician and patient must discuss the treatment options avail- able and agree on the overall treat- ment plan.

Nonpharmacologic therapies Nonpharmacologic interventions include sleep-hygiene education, stimulus-control therapy, relax - ation therapy, and sleep-restriction therapy, collectively referred to as cognitive behavioral therapy (CBT).

Other treatment modalities that have been evaluated for the treatment of insomnia include yoga, light therapy, and acupuncture, though these treat- ments have not been adequately studied.

18 Education on sleep hygiene fo- cuses on environmental factors and attitudes that negatively affect sleep. 19 Sleep-hygiene recommendations include maintaining a regular sleep schedule, exercising regularly but avoiding exercise too close to bed- time, and avoiding stimulants like caffeine or nicotine right before bed- time. 12,19 Other recommendations may include ensuring a comfortable sleep environment (i.e., eliminate noises, decrease light, and maintain a comfortable room temperature) and avoiding negative thinking or focus- ing on a bedside clock. 12,19 Stimulus-control therapy focuses on eliminating maladaptive behav - iors, with the overall goal of associat- ing the bedroom with sleep. Patients are instructed to go to bed only when tired, use the bedroom only for sleeping, establish a normal sleep– wake schedule, and avoid napping. 12 Patients are also trained to leave the bedroom if unable to fall asleep within 15 minutes and to return to bed only when tired. 19 Relaxation therapy includes progressive muscle relaxation, biofeedback, and medita- tion. 12 Relaxation techniques may be especially helpful to patients for whom hyperarousal is suspected as the cause of insomnia symptoms. Re- laxation therapy may improve both sleep latency time and sleep main- tenance. Sleep-restriction therapy allows patients to improve sleep effi- ciency by temporarily inducing sleep deprivation. 20 CBT incorporates sev- eral of these behavioral techniques to improve sleep. Many studies and meta-analyses have demonstrated the effective- ness of various nonpharmacologic interventions.

20-23 The percentage of patients responding to such therapy ranges from 50% to 80%. 20,23 One l a r g e m e t a - a n a l y s i s f o u n d t h a t nonpharmacologic treatments im- proved both sleep patterns and sub- jective reports of sleep. 21 According to the findings of another large meta- analysis, the most effective non- pharmacologic interventions for insomnia were stimulus control and sleep restriction. 22 However, sleep- hygiene education was not effective when used alone. Improvements in sleep-related problems secondary to nonpharmacologic therapies were maintained for six months or more after therapy completion. 23 Specific improvements in sleep- related problems included decreased sleep latency and improved sleep maintenance. 22 clinical review insomnia 930 Am J Health-Syst Pharm—Vol 65 May 15, 2008 Pharmacologic therapies Benzodiazepines. Benzodiaz- epines improve insomnia symptoms by binding to g-aminobutyric acid-A (GABA-A) receptors on postsynap- tic neurons in the central nervous system, thus inhibiting neuronal ex- citation through increased neuronal chloride permeability. 24 Although benzodiazepines are commonly pre- scribed for insomnia, the only benzo- diazepines with labeling for insomnia are estazolam, flurazepam, quaze - pam, temazepam, and triazolam.

These agents vary in their onset and duration of activity (Table 1). The re- sults of a meta-analysis published in 2000 revealed that benzodiazepines increased total sleep time but had no significant effect on sleep latency. 26 Potential adverse effects include day- time sleepiness or hangover effect, dizziness, and impaired memory.

27 Benzodiazepines, especially agents with short half-lives, have also been associated with anterograde amnesia.

Agents with longer half-lives (e.g., quazepam, flurazepam) increase the risk of hangover effect, thereby in- creasing risk of confusion, dizziness, and falls. 27 Benzodiazepines cause changes in the normal sleep archi- tecture, including increased stage 2 sleep and increased REM latency. 28 Moreover, no controlled studies have demonstrated the efficacy of ben- zodiazepines for relief of insomnia symptoms after 12 weeks. 27 All ben - zodiazepines are schedule IV medi- cations and have the potential for abuse. Patients taking one of these medications for just a few days can develop a physical dependence to the drug. 29 Consequently, abrupt discon- tinuation of the drug may elicit with- drawal symptoms, including anxiety, rebound insomnia, tachycardia, and diarrhea. Dosage reductions may be especially important in the elderly to decrease the risk of falls. Since triazolam and temazepam have short half-lives, tolerance to these agents may occur more rapidly than with other benzodiazepines, thus increas- ing the risk of rebound insomnia. 8,24 Estazolam and triazolam should be avoided in patients receiving cyto- chrome P-450 (CYP) isoenzyme 3A4 inhibitors because of the resulting decreased clearance of those ben- zodiazepines. 25 Additional drugs that interact with benzodiazepines include alcohol and other central nervous system depressants. Benzodiazepine-receptor agonists.

Benzodiazepine-receptor agonists ex- ert their effects on the w-receptor of the GABA-A receptor complex and inhibit neuronal excitation through increased chloride permeability. 24 Agents in this class include zolpidem, zaleplon, and eszopiclone (Table 2), all of which are schedule IV drugs.

Benzodiazepine-receptor agonists are purported to cause less rebound in- somnia, have less potential for abuse, be associated with fewer dependency problems, and cause less of a hang- over effect compared with benzo- diazepines. 27 However, published reports have highlighted the abuse and dependency potential associated with the use of these benzodiazepine- receptor agonists. 34 Unlike benzo- diazepines, zolpidem has not been shown to have deleterious effects on the normal sleep cycle. 30 There have been reports that zolpidem causes parasomnias, including sleepwalking and sleep-related eating disorders. 35,36 Interestingly, studies have found that intermittent administration of zolpi- dem is as effective as nightly use. 37,38 Benzodiazepine-receptor agonists are more costly than benzodiazepines labeled for insomnia, most of which are available as generics. Zolpidem and eszopiclone have a relatively quick onset of action and have been shown to improve sleep- onset latency problems. 30,33 Since these agents have a longer half-life than other benzodiazepine-receptor agonists, both zolpidem and eszopic- lone improve sleep maintenance as well. Unlike other agents in this class, the dosage of eszopiclone can be adjusted based on the desired effect.

The 1- and 2-mg tablets of eszopic- lone are most often used to improve sleep latency, and the 3-mg tablets are typically reserved to address sleep maintenance problems. One of the most common adverse effects of eszopiclone is unpleasant taste.

33 Of importance, the labeling of eszopic- lone and extended-release zolpidem is not restricted to short-term use.

39 In patients already responsive to immediate-release zolpidem, the extended-release formulation may not provide additional clinical benefits. Zaleplon has a rapid onset of ac- tion and short half-life, which make it an attractive option for patients who exhibit sleep latency problems without causing hangover effects.

40 Since the duration of zaleplon’s ef- fects are so short, patients can take zaleplon in the middle of the night if at least four hours before planning to awaken. 41 Administration of any of these agents with food should gener - ally be avoided as food may delay the onset of activity and thereby dimin- ish the drugs’ effectiveness. 31-33 Melatonin-receptor agonists.

Ramelteon is the first and only agent aIncludes active metabolites Table 1.

Benzodiazepines Labeled for Treatment of Insomnia 24,25 Drug Usual Oral Dose (mg) Onset (min) Half-life (hr) Estazolam 1–2 60 10–24 Flurazepam hydrochloride 15–30 15–30 47–100 a Quazepam 7.5–15 20–45 25–84 a Temazepam 7.5–30 30–60 4–18 Triazolam 0.125–0.25 15–30 2–4 clinical review insomnia 931 Am J Health-Syst Pharm—Vol 65 May 15, 2008 aUnless otherwise noted, all agents are useful for sleep-onset and sleep-maintenance insomnia.bNot useful for sleep-maintenance insomnia.

Table 2.

Characteristics of Benzodiazepine-Receptor Agonists 30-33,a Drug Usual Oral Dose (mg) Onset (min) Half-life (hr) Zolpidem tartrate 5–10 30 1.4–4.5 Zolpidem tartrate, extended release 6.25–12.5 30 1.6–5.5 Zaleplon b 10–20 20 0.5–1 Eszopiclone 2–3 30 6 in a new class of drugs known as melatonin-receptor agonists. Ramelt- eon selectively targets the melatonin receptors MT1 and MT2 located in the hypothalamus, which are thought to be involved in the sleep–wake cycle. 42 As this agent has no affin- ity for GABA receptors, ramelteon’s adverse-effect profile differs from that of benzodiazepines and benzo- diazepine-receptor agonists. Ramelt- eon is the only sedative hypnotic not classified as a controlled substance.

The recommended dosage is 8 mg within 30 minutes of bedtime; no dosage reduction is necessary in the elderly. Ramelteon is metabolized by CYP1A2, so the potential for drug interactions exists. 42 Although ra- melteon is labeled only for the treat- ment of insomnias characterized by delayed sleep onset, recent studies have found that ramelteon not only significantly shortens the delay to sleep onset but also increases total sleep time. 43,44 The most common ad- verse effects reported with ramelteon include somnolence, fatigue, and diz- ziness, with no evidence of rebound insomnia. 42,45 As with eszopiclone and extended-release zolpidem, ra- melteon is not limited to short-term use. 42 Patients should be instructed not to take ramelteon with or imme- diately after a high-fat meal, which will delay absorption and beneficial effects. Although not an absolute contraindication, ramelteon should generally be avoided in patients with severe hepatic impairment. 42 Antidepressants, antipsychotics, and barbiturates. The prescribing of antidepressants for the treatment of primary insomnia is not uncommon, even though not much evidence sup- ports their efficacy or safety for this indication. Potential explanations for the increasing use of antidepressants may include physicians’ perception that antidepressants are safer than hypnotics and the prescribing re- strictions associated with other sleep agents. 27 Some antidepressants that have been used to treat insomnia in- clude trazodone, tricyclic antidepres- sants (e.g., doxepin, amitriptyline), and mirtazapine. 12,19 Of these, traz- odone hydrochloride is used most frequently at doses of 50–100 mg. 46,47 In one study of trazodone for pri- mary insomnia, trazodone was more effective in improving sleep latency and sleep maintenance compared with placebo, but zolpidem was superior to trazodone. 48 Some note- worthy adverse effects of trazodone include dizziness, sedation, hypoten- sion, headache, and priapism. 8 Some adverse effects of tricyclic antide- pressants include anticholinergic effects (e.g., sedation, constipation, dry mouth), weight gain, cardiac ar - rhythmias, lowered seizure threshold, and extrapyramidal symptoms. 12 Antidepressants are typically more beneficial in patients with comorbid depression or are reserved as alterna- tive agents for chronic treatment. Nonprescription agents. Anti- histamines. First-generation antihis- tamines, such as diphenhydramine and doxylamine, are frequent ingre- dients in nonprescription sleeping aids. The use of these drugs is not supported by much of the existing data. Common adverse effects of these agents include hangover effect, dizziness, dry mouth, and consti- pation. 18,24 Furthermore, patients quickly develop a tolerance to the sedative effects, and these agents have not been shown to improve sleep. 18 Overall, recommendations for the use of first-generation an- tihistamines should be limited to patients who experience infrequent symptoms of insomnia. Use should be cautioned in patients with comor - bid medical conditions such as glau- coma or those with an increased risk of falling, especially the elderly. 18 Melatonin. Melatonin, a hormone normally produced by the pineal gland, is a nonprescription supple- ment sold as a sleep agent. Compared with other natural remedies for sleep, melatonin has few reported adverse effects. Currently, data supporting the use of melatonin for insomnia are minimal. 18 Since the minimum effec- tive dosage of melatonin is unknown and because there is no standardiza- tion of nutraceutical ingredients in the United States, melatonin should not be recommended for routine treatment of insomnia. 18 Valerian. The mechanism of action of valerian is not fully understood but has been purported to interact with GABA receptors. 49 Currently, there is little evidence to support its use for the treatment of insomnia. 18 However, valerian currently appears on the Food and Drug Administra- tion’s (FDA’s) Generally Recognized as Safe list. Potential adverse effects include dizziness, nausea, headache, and upset stomach. 50 FDA does not strictly regulate nutritional supple- ments and herbal products sold in the United States. As a result, product ingredients are not standardized, which increases the risk of patient harm and often precludes pharma- cists from recommending nutritional supplements. clinical review insomnia 932 Am J Health-Syst Pharm—Vol 65 May 15, 2008 Choice of agent. Choice of a spe- cific sleep agent should be based on patient-specific factors, including age, proposed length of treatment, primar y sleep complaint, histor y of drug or alcohol abuse, and cost.

Similar to the benzodiazepines, dos- age reduction of the benzodiazepine- receptor agonists in the elderly may be prudent to minimize fall risk.

Agents with a quick onset of ac - tion and shorter half-lives such as temazepam and zaleplon are ideal for patients with sleep latency problems.

On the other hand, agents with lon- ger half-lives such as quazepam, zolp- idem, and eszopiclone are better for patients with sleep-maintenance is- sues. Clinicians may choose to avoid benzodiazepines in patients with a history of substance abuse. In such cases, ramelteon may be an option, since it is the only agent approved for the long-term treatment of insomnia that is not a controlled substance.

Antidepressants are a reasonable option for patients with comorbid depression and may be offered as an alternative choice for long-term treatment. Benzodiazepines and an- tidepressants may be less costly than benzodiazepine-receptor agonists and ramelteon. Typically, nonpre - scription sleep agents containing sedating antihistamines, although relatively inexpensive, should be re- served for patients with infrequent symptoms who do not have any lim- iting comorbid medical conditions.

Combining nonpharmacologic and pharmacologic therapies Studies directly comparing non- pharmacologic and pharmacologic therapies for insomnia are limited.

One small, randomized, controlled trial of 63 patients found that CBT alone or in combination with drug therapy is more effective at improv- ing delays in sleep onset than drug therapy alone or placebo. 51 In this study, CBT included sleep-restriction therapy, stimulus-control therapy, and relaxation techniques. CBT was also more efficacious at sustaining benefits after discontinuation of the intervention compared with phar - macologic therapy. Interestingly, the combination therapy provided no advantage over CBT alone for sustaining improvements in sleep onset. 51 Although these data provide additional support for nonpharma- cologic interventions as first-line therapy, the sample was small, and results may not be generalizable to patients with sleep-maintenance problems or patients with comorbid conditions. Since studies have found that nonpharmacologic therapies offer benefits with minimal adverse effects, nonpharmacologic therapies should remain a first-line option for the treatment of insomnia. Further research is needed to identify the spe- cific behavioral techniques, recom- mended length of therapy, and meth- od for delivering these techniques that provide the best outcomes.

Barriers to diagnosis and treatment Se ver al bar r iers cont r ibute to the lack of appropriate diagnosis and treatment of insomnia, includ- ing limited physician awareness or training, lack of discussion during patient consultations, patients’ be- lief that sleep problems are irrele- vant, and clinicians’ perception that current treatments are ineffective or risky.

8 Many clinicians do not receive adequate training to diagnose and treat sleep disorders. 52,53 As a result, underdiagnosis, misdiagnosis, and delayed diagnosis of sleep disorders may occur, all of which contribute to increased morbidity and increased health care utilization.

1 Two potential explanations for the lack of discussion on sleep problems during office visits include (1) the patient or physician does not view insomnia as an important medical problem and (2) the consultation time is perceived to be too short to discuss sleep habits. 8 In addition, patients with sleep-related symp- toms may fail to recognize them as problems and therefore do not report their symptoms to their clinician.

These explanations are supported by the results published in the 2005 Sleep in America Poll. 2 While 75% of respondents reported having at least one sleep-related symptom at least a few nights weekly within the previous year, only 21% of those believed they had a sleep problem. Furthermore, only 29% of respondents reported that a physician had ever questioned them about their sleep.

2 Insomnia has significant associat- ed personal and social consequences.

However, many studies evaluating the treatment of insomnia fail to assess such outcomes. As a result, clinicians may avoid treating insomnia because they believe that current treatments are ineffective in improving out- comes or quality of life. Explanations for limited outcomes data include a lack of a standardized method for documentation and a lack of effec- tive instruments for assessment. 54 Current evaluation of outcomes of insomnia treatment often relies on nonvalidated assessment tools, which may lack sensitivity and precision. 55 Clinicians may also believe that the risk of physical dependence and abuse potential outweigh any ben - efits of therapy. Treatment of insom- nia with pharmacologic agents has traditionally been recommended for only 7–10 days, despite overwhelm- ing evidence that patients often have symptoms beyond this time period.

8 Only within the past five years have studies evaluated longer-term use of sleep agents. 39 In addition, clinicians may fail to recognize the effectiveness of behavioral therapies on improving sleep-related symptoms.

Investigational agents and future research Indiplon is a nonbenzodiazepine hypnotic that binds directly to the GABA-A receptor. 56 The drug dem- onstrates preferential binding to the clinical review insomnia 933 Am J Health-Syst Pharm—Vol 65 May 15, 2008 a-subunit of GABA-A receptors. 57 Indiplon is purportedly the most potent GABA-A agonist and is 10 and 50 times more potent than zolpidem and zaleplon, respectively. 56 Cur- rently, all dosage forms of this drug remain unavailable. Eplivanserin is currently in Phase III trials for the treatment of insom- nia in adults and is a serotonin type 2A-receptor antagonist. It is current- ly being evaluated for the treatment of sleep-maintenance insomnia.

58 Further research is needed to di- rectly compare benzodiazepines to the newer hypnotic agents, including the benzodiazepine-receptor agonists and ramelteon, to determine the most cost-effective treatment. These studies should also compare hyp- notic agents with nonpharmacolgic therapies and combination therapy.

Although many studies evaluate the effectiveness of a treatment on de- creasing sleep latency or improving sleep maintenance, few have focused on the long-term outcomes of thera- py, including increased quality of life, improved job performance, and im- proved interpersonal relationships.

Conclusion Many treatment options are avail- able for patients with insomnia.

Behavioral therapies should be initi- ated as first-line treatment in most patients. For patients who require the addition of pharmacologic therapy, the drugs with the most evidence for benefit include benzodiazepines, benzodiazepine-receptor agonists, melatonin-receptor agonists, and antidepressants, and selection of a specific agent must take into account numerous patient-specific factors. References 1. National Center on Sleep Disorders Research. 2003 National sleep disorders research plan. www.nhlbi.nih.gov/health/ prof/sleep/res_plan/sleep-rplan.pdf (accessed 2008 Feb 7).

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