Clinical Supplement

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Long-Term Issues in the Treatment of Sleep Disorders

Thomas Roth, PhD, Andrew D. Krystal, MD, MS, and Joseph A. Lieberman III, MD, MPH

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 Primary Psychiatry. 2007;14(7 suppl 5):1-16

This clinical supplement is supported by funding from Takeda Pharmaceuticals North America

An expert panel review of clinical challenges in psychiatry

Faculty Affiliations and Disclosures

Dr. Roth is director of the Sleep Disorders and Research Center at Henry Ford Health System in Detroit, and clinical professor of psychiatry at the University of Michigan School of Medicine in Ann Arbor.

Disclosures: Dr. Roth is a consultant to Abbott, Acadia, Acoglix, Actelion, Alchemers, Alza, Ancile, Arena, AstraZeneca, Aventis, Bristol-Myers Squibb, Cephalon, Cypress, Dove, Elan, Eli Lilly, Evotec, Forest, GlaxoSmithKline, Hyperion, Jazz, Johnson and Johnson, King, Lundbeck, McNeil, MediciNova, Merck, Neurim, Neurocrine, Neurogen, Novartis, Orexo, Organon, Orginer, Prestwick, Proctor and Gamble, Pfizer, Purdue, Resteva, Roche, sanofi-aventis, Schering-Plough, Sepracor, Servier, Shire, Somaxon, Syrex, Takeda, TransOral, Vanda, Vivometrics, Wyeth, Yamanouchi, and Xenoport; is on the speaker’s bureaus of sanofi-aventis and Takeda; and receives grant/research support from Aventis, Cephalon, GlaxoSmithKline, Neurocrine, Pfizer, sanofi-aventis, Schering-Plough, Sepracor, Somaxon, Syrex, Takeda, TransOral, Wyeth, and Xenoport.

Dr. Krystal is director of the Sleep Research and Insomnia Program at Duke University School of Medicine in North Carolina.

Disclosures: Dr. Krystal is a consultant to and/or on the advisory boards of Eli Lilly, Evotec, GlaxoSmithKline, Merck, Neurocrine, Neurogen, Novartis, Organon, Pfizer, Respironics, sanofi-aventis, Sepracor, Somaxon, Takeda, and Transoral; and receives research support from Evotec, GlaxoSmithKline, Merck, National Institutes of Health, Neurocrine, Pfizer, Respironics, sanofi-aventis, Sepracor, Somaxon, and Takeda.

Dr. Lieberman is professor of family medicine at Jefferson Medical College, Thomas Jefferson University, in Philadelphia, Pennsylvania, and speaker of the house of the Medical Society of Delaware in Newark, Delaware.

Disclosures: Dr. Lieberman is on the advisory boards of AstraZeneca, Pfizer, sanofi-aventis, and Takeda; and is on the speaker’s bureau of AstraZeneca.

Abstract

Insomnia is a disorder characterized by chronic sleep disturbance associated with daytime disability or distress, such as memory impairment and fatigue, that occurs despite adequate opportunity for sleep. Insomnia may present as difficulty falling/staying asleep or as sleep that is nonrestorative. Studies show a strong correlation between insomnia and impaired quality of life. Pain conditions and depression are commonly associated with insomnia, either as secondary or comorbid conditions. In addition, a greater incidence of anxiety, alcohol and drug dependence, and cardiovascular disease is found in people with insomnia. Data indicate insomnia results from over-engaged arousal systems. Insomnia patients experience increased metabolic rate, body temperature, and heart rate, and elevated levels of norepinephrine and catecholamines. Pharmacologic options for the treatment of insomnia include benzodiazepine hypnotics, a selective melatonin receptor agonist, and sedating antidepressants. However, insomnia may be best treated with cognitive-behavioral therapy and instruction in good sleep hygiene, either alone or in concert with pharmacologic agents. Studies on the effects of insomnia treatment use variable methodologies or do not publish negative results, and there are currently no studies of treatment focusing on morbidity. Further research is necessary to better understand the effects of insomnia therapies on medical and psychiatric disorders.

In this Clinical Information Supplement, Thomas Roth, PhD, describes the nature of insomnia and its pathophysiology. Next, Andrew D. Krystal, MD, MS, reviews morbidities associated with insomnia. Finally, Joseph A. Lieberman III, MD, MPH, provides an overview of therapeutics utilized in patients with insomnia, including behavioral therapies and pharmacologic options.

The Nature of Insomnia

Thomas Roth, PhD

Diagnostic Criteria for Insomnia

Insomnia is increasingly understood to be a disorder. A disorder is a condition  which exhibits morbidity mediated by some kind of pathophysiology. There are a variety of definitions for insomnia. The two most commonly used criteria for insomnia are those of the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition,1 and the American Academy of Sleep Medicine.2

Insomnia is a symptom-based diagnosis.3 Patients with insomnia experience one or more sleep-related complaints, including difficulty falling asleep, difficulty staying asleep, early-morning awakenings, and sleep that is nonrestorative or not adequately restorative (Slide 1). These sleep-related complaints must be associated with some kind of daytime disability or distress such as fatigue, attention/memory impairment, or sleepiness. Any one of these latter symptoms must be present with the sleep-related complaint, and must occur despite adequate opportunity for sleep. Finally, the sleep difficulty must occur at least three times per week for at least 1 month.

Prevalence of Insomnia

The prevalence rates of insomnia reported in the literature are inconsistent. Perhaps the best synthesis of all of the data comes from the 2005 National Institutes of Health (NIH) State-of-the-Science Consensus Conference on insomnia.4 These data, which are available on the NIH Web site,5 indicate that the prevalence of sleep disturbances  in the United States is ~30% of the population. This number is, of course, volatile. The night after a tornado, for example, a town population may have a sleep disturbance prevalence as high as 70% to 80%. However, the 30% sleep disturbance prevalence does not account for the population suffering from insomnia. When the diagnostic criteria for insomnia—such as difficulty sleeping at night and associated daytime impairment—are applied, the prevalence of insomnia is ~10% of the adult population. Finally, the prevalence of insomnia varies among medical practices in the clinical population. For example, insomnia prevalence in geriatric medicine differs from that in athletic medicine. However, across all medical specialties and all medical clinics, ~50% of patients meet diagnostic criteria for insomnia (Slide 2).

Risk Factors for Insomnia

The disparity between the prevalence in the general population and that in the clinical population may be explained by the risk factors associated with insomnia. Some of the greatest risk factors for insomnia are age and psychiatric disorders (Slide 3).

Women have more insomnia than men, and the reason for that is not well understood. On the other hand, it is very clear that shift work contributes to insomnia by causing changes in circadian rhythm. Familial aggregation is a risk factor, suggesting that there is a genetic basis for this disorder. Age and medical disorders are overlapping risk factors. Age is the greatest risk factor for insomnia; however, the reason elderly people experience increased risk of insomnia is not due to a breakdown of their sleep systems. Rather, the higher prevalence of medical disorders places elderly people at greater risk for insomnia (Slide 4).6

Ninety percent of patients with insomnia have  comorbid conditions (Slide 5). It is important for clinicians to understand that while insomnia interacts with other medical disorders, it is not necessarily caused by them. The majority of patients with medical disorders such as rheumatoid arthritis or neuropathic pain do not have insomnia. The clinical subpopulation that does have insomnia is composed of patients with a predisposition for it.

Comorbid Conditions Associated with Insomnia

Insomnia and comorbid conditions influence each other. Insomnia influences depression, for example, and depression influences insomnia. This interaction between conditions prevails in elderly patients. The more medical conditions they have, the greater the number of precipitants, and the greater their likelihood of developing insomnia. However, the fact that the incidence of insomnia is not 100% among patients who have three or four medical disorders indicates that medical disorders themselves are not responsible for causing insomnia. Rather, they precipitate, coexist with, or interact with insomnia.

Pain conditions are commonly associated with insomnia. It is now known that sleep loss and sleep fragmentation causes pain and increased inflammatory response. In turn, treating insomnia improves pain management. Other medical disorders commonly associated with insomnia include arthritis and other chronic pain syndromes, congestive heart failure, cerebral vascular disease, chronic pulmonary disease, Parkinson’s disease, dementia, gastroesophageal reflux, and renal failure (Slide 6). Virtually every medical disorder can be associated with insomnia because most medical disorders require an arousal response. Patients with a cough must wake up in order to cough. Patients with sleep apnea must wake up to re-enervate the muscles of their airways. To increase swallowing, patients must wake up.

The other major comorbidity, besides the medical conditions associated with dyspnea and pain, is depression. Several studies in the medical literature demonstrate that insomnia increases the risk of depression by a factor of 5. Patients with a history of depression are also at a greater risk of relapse if they have insomnia. As is the case with treating other comorbid conditions, treatment of insomnia diminishes illness severity and improves response to antidepressant treatment. Fava and colleagues7 demonstrated that patients with comorbid insomnia and depression experience a quicker, more effective antidepressant response when treated with a sleep agent and antidepressant combination than when treated with either a sleep agent or antidepressant alone. Clinicians must consider whether chronic treatment of insomnia can prevent the relapse of depression or other like conditions.

Pathophysiology of Hyperarousal

Although 30% of patients with a medical disorder have insomnia, one must consider the fact that 70% do not. This is likely due to the fact that insomnia does not result from sleep disturbance alone. A large amount of data now show that patients with insomnia have increased arousal. Nofzinger and colleagues8 demonstrated increased brain metabolism in the arousal centers in the brain, indicating that insomnia does not result from broken sleep systems but from over-engaged arousal systems (Slide 7).

While most people experience a decline in body temperature at night, this is not as consistently seen among insomniacs. Bonnet and Arand9,10 demonstrated increased metabolic rate in insomnia patients. In addition,  Perlis and colleagues11 showed that these patients experience increased high-frequency electroencephalogram. Lushington and colleagues12 demonstrated that those with insomnia experience an increase in body temperature, and Stepanski and colleagues13 indicated that insomniacs also experience increased heart rate—both at night and during the day. Other studies have found that catecholamines such as norepinephrine, which are markers of hyperarousal, are elevated in patients with insomnia.14

The sleep systems in patients with insomnia are relatively normal, but the individuals are hyperaroused, as reflected in catecholamines, brain metabolism, and body metabolism. Hyperarousal overrides these normal sleep systems and causes insomnia, which then interacts with the comorbid medical and psychiatric disorders.

References

1. Diagnostic and Statistical Manual of Mental Disorders. 4th ed. Washington, DC: American Psychiatric Association; 1994.
2. American Academy of Sleep Medicine. Available at: http://www.aasmnet.org. Accessed May 30, 2007.
3. Edinger JD, Bonnet MH, Bootzin RR, et al. Derivation of Research Diagnostic Criteria for Insomnia: Report of an American Academy of Sleep Medicine Workgroup. Sleep. 2004;27:1567-1596.
4. Leshner A. National Institutes of Health State of the Science Conference statement on Manifestations and Management of Chronic Insomnia in Adults, June 13-15, 2005. Sleep. 2005;28:1049-1057.
5. US Department of Health and Human Services: National Institutes of Health. Available at: www.nih.gov. Accessed June 20, 2007.
6. Foley D, Ancoli-Israel S, Britz P, Walsh J. Sleep disturbances and chronic disease in older adults: results of the 2003 National Sleep Foundation Sleep in America Survey. J Psychosom Res. 2004;56(5):497-502.
7. Fava M, McCall WV, Krystal A, et al. Eszopiclone co-administered with fluoxetine in patients with insomnia coexisting with major depressive disorder. Biol Psychiatry. 2006;59(11):1052-1060.
8. Nofzinger EA, Buysse DJ, Germain A, Price JC, Miewald JM, Kupfer DJ. Functional neuroimaging evidence for hyperarousal in insomnia. Am J Psychiatry. 2004;161(11):2126-2128.
9. Bonnet MH, Arand DL. 24-Hour metabolic rate in insomniacs and matched normal sleepers. Sleep. 1995;18(7):581-588.
10. Bonnet MH, Arand DL. Heart rate variability in insomniacs and matched normal sleepers. Psychosom Med. 1998;60(5):610-615.
11. Perlis ML, Smith MT, Andrews PJ, Orff H, Giles DE. Beta/gamma EEG activity in patients with primary and secondary insomnia and good sleeper controls. Sleep. 2001;24:110-117.
12. Lushington K, Dawson D, Lack L. Core body temperature is elevated during constant wakefulness in elderly poor sleepers. Sleep. 2000;23(4):504-510.
13. Stepanski E, Zorick F, Roehrs T, Young D, Roth T. Daytime alertness in patients with chronic insomnia compared with asymptomatic control subjects. Sleep. 1988;11(1):54-60.
14. McClure TK, Drake CL, Roth T, Richardson GS. Sleep and endocrine responses to psychological stress in primary insomnia. Sleep. 2003;26:A311.

The Morbidity of Insomnia

Andrew D. Krystal, MD, MS

Data on the Morbidity of Insomnia

People who experience sleep difficulty often report problems with daily functioning and quality of life. While impairment and decreased quality of life are included among the criteria for the diagnosis of insomnia, the nature and degree of these impairments are difficult to ascertain. One important question is whether insomnia causes alterations in physiology or behavior that might lead to longer-term adverse consequence.

Several epidemiologic studies1-7 have used cross-sectional analysis or longitudinal data to compare people with insomnia to normal sleepers in an effort to determine the specific impairments and alterations in quality of life associated with insomnia. In another type of study, patients with insomnia receive insomnia-specific therapies and are followed to determine how their function and quality of life improve. This type of study has been the most compelling in terms of linking insomnia and morbidities.8,9

Functional Impairment and Quality of Life

Findings from cross-sectional studies show a strong correlation between insomnia and impairment. Compared to normal sleepers, people who meet insomnia criteria have impaired quality of life. They report that they do not feel as well overall, and they do not feel like they are able to function as well. In a study involving 261 insomnia patients and 101 controls, Zammit and colleagues1 employed the 36-item Short Form (SF-36) Health Survey, a well-validated epidemiologic measure of quality of life. The results demonstrated that people with insomnia differ from normal sleepers in their vitality, their emotional role, their health, and their physical role. In all of the different subscales of the survey, quality of life was diminished in the patients with insomnia (Slide 1).

An enlightening study by Katz and McHorney2 compared the SF-36 findings in a group of patients with severe insomnia to those in a group of patients with major depression and a group of patients with congestive heart failure. The striking results indicated that people with insomnia had more impairment in areas of vitality, general health, and physical ability to function than those with congestive heart failure and those with major depression. They had comparable impairments to those with congestive heart failure and major depression in other important subscales, such as emotional role and mental health. Congestive heart failure is a significant medical problem with tremendous consequences for a patient’s quality of life, and major depression is similarly devastating, yet it is becoming evident that insomnia has a comparable, and in some cases greater, impact on people’s lives than those other conditions (Slide 2).

Longitudinal data demonstrate that people with insomnia experience increased absenteeism and decreased productivity in their work roles. They are also more likely to develop psychiatric disorders and medical disorders. A 1997 retrospective analysis by Simon and VonKorff3 compared a database of ~2,000 primary care patients with insomnia to controls. There were significant differences in the groups’ ratings of their social disability, ability to fulfill roles, number of days of limited activity, and number of days spent in bed. The results showed that insomnia was correlated with global impairments in patients’ ability to live their lives (Slide 3). A comparable database analysis of ~800 French employees demonstrated significantly more work absences in people who had insomnia than those with normal sleep function.4 It is not that patients with insomnia simply have more complaints; the disorder prevents them from performing the domestic, work, and recreational activities they normally would.

Insomnia as a Predictor of Psychiatric and Medical Disorders

Several studies have shown that insomnia increases the risk of depression. Breslau and colleagues5 looked at a group of patients who met insomnia criteria at baseline and a group of people without insomnia. Those groups were then assessed 3.5 years later. After that interval, there was a much greater incidence of major depression, anxiety, and alcohol and drug dependence problems in those who had insomnia. The incidence of depression had increased apprxomimately four-fold (Slide 4). While these studies do not prove causality, they show strong association, which is intriguing and worthy of further inquiry.

There are similar longitudinal data related to cardiovascular disorders. In a study by Suka and colleagues,6 4,794 male workers from one company in Japan were diagnosed with insomnia at initial evaluation and followed for 4 years. The incidence of hypertension increased in those who had difficulty initiating sleep or staying asleep compared with those who did not meet have insomnia. There was a ~40% incidence of hypertension in those with sleep problems (initiating or maintaining sleep) versus a 31% incidence in normal sleepers.

Lastly, a Swedish study conducted by Mallon and colleagues7 followed 1,870 people—both those diagnosed with insomnia and abnormal sleepers—for 12 years. In men, the risk of death due to coronary artery disease was increased by a factor of 3. Having an insomnia diagnosis was clearly correlated with this mortality (Slide 5).

Effects of Insomnia Treatment

There are limitations to our knowledge of how treatments for insomnia affect the impairments and risks associated with the disorder.8 Examinations of some measures of daytime function have produced negative findings. As there is a tendency not to publish negative findings, it is not known how often studies fail to find therapeutic effects. Another problem is that studies of daytime function, quality of life, and associated psychiatric and medical conditions have widely variable measures and methodologies. Consolidating these data in a meaningful way is consequently difficult. What is needed is a systematic series of investigations. Finally, there are no studies that have had a primary focus on morbidity; a study of the effects of insomnia therapy on morbidities must examine a group of people who have an identified set of morbidities, and then follow them in a method powered to detect those effects. However, most studies are powered to determine whether therapies include sleep and are not powered to find the effects on non-sleep outcomes.

Nonetheless, there has been a series of placebo-controlled studies with reported findings.8,9 A significant number of studies have reported ratings of insomnia patients’ restedness, alertness, ability to function, overall well-being, and quality of life. In four of these studies, people completed morning self-ratings that indicated their alertness or ability to function had significantly improved after insomnia treatment. Three studies have examined fatigue using the SF-36 or a visual analogue scale. These studies show that reported sleepiness, number of naps, and time spent napping all decreased following treatment, while ability to carry out professional activity increased. While these associations cannot be construed as hard and fast proof, it is notable that the positive findings occurred despite poor or inconsistent methodology (Slide 6). Treatment seems to improve the deficits people with insomnia experience, including those in quality of life, social role, and work performance. Effects of treatment on risks for medical and psychiatric disorders have not yet been sufficiently studied.

References

1. Zammit GK, Weiner J, Damato N, Sillup GP, McMillan CA. Quality of life in people with insomnia. Sleep. 1999;22(Suppl 2):S379-S385.
2. Katz DA, McHorney CA. The relationship between insomnia and health-related quality of life in patients with chronic illness. J Fam Pract. 2002;51(3):229-235.
3. Simon GE, VonKorff M. Prevalence, burden, and treatment of insomnia in primary care. Am J Psychiatry. 1997;154(10):1417-1423.
4. Godet-Cayre V, Pelletier-Fleury N, Le Vaillant M, Dinet J, Massuel MA, Leger D. Insomnia and absenteeism at work. Who pays the cost? Sleep. 2006;29(2):179-184.
5. Breslau N, Roth T, Rosenthal L, Andreski P. Sleep disturbance and psychiatric disorders: a longitudinal epidemiological study of young adults. Biol Psychiatry. 1996;39(6):411-418.
6. Suka M, Yoshida K, Sugimori H. Persistent insomnia is a predictor of hypertension in Japanese male workers. J Occup Health. 2003;45(6):344-350.
7. Mallon L, Broman JE, Hetta J. Sleep complaints predict coronary artery disease mortality in males: a 12-year follow-up study of a middle-aged Swedish population. J Intern Med. 2002;251(3):207-216.
8. Krystal AD. Treating the health, quality of life, and functional impairments in insomnia. J Clin Sleep Med. 2007;3:63-72.
9. Walsh JK, Krystal AD, Amato DA, et al. Nightly treatment of primary insomnia with eszopiclone for six months: Effect on sleep, quality of life and work limitations. Sleep. 2007. In Press.

Therapeutics for the Treatment of Insomnia

Joseph A. Lieberman III, MD, MPH

National Institutes of Health Consensus Development Program Data

At the National Institutes of Health (NIH) State-of-the-Science Consensus Conference on insomnia, held in June 2005 in Washington, DC, the Federal government addressed insomnia and its associated problems for the first time in >20 years. Two of the major chronic insomnia treatment endorsements came out of that conference: First, cognitive-behavioral therapy (CBT) for insomnia is effective and should be utilized. Second, Food and Drug Administration-approved benzodiazepine receptor agonists are pharmacologically effective.1 Since that time, the FDA has approved ramelteon, a selective MT-1/MT-2 receptor agonist, as an additional hypnotic agent. Although ramelteon works by an altogether different mechanism, it is approved as a hypnotic.

Cognitive-Behavioral Therapy

Cognitive-behavioral therapy (CBT) is an important component to treatment of insomnia. The role of CBT in insomnia is to challenge the dysfunctional beliefs and misconceptions about sleep held by a person with insomnia (Slide 2).2 One of the cornerstones of CBT for insomnia is to stop the patient from focusing too much on the time. More primarily, the goal is to restructure the patient’s thinking about sleep. Although effective, the application of CBT as a wide-spread treatment is hampered by its availability (since specialized training is required) and its lack of consistent coverage by medical insurance carriers. Consequently, in some areas, there is a shortage of cognitive-behavioral therapists and an inability to access them because of insurance policies.

Other forms of behavioral treatment may be administered in the clinician’s office, however. Other CBT techniques that require less training and are thus more easily delivered include relaxation training, in which patients are taught to reduce their physiologic and cognitive arousal at bedtime. In one variation of this technique, patients are taught progressive muscular relaxation, in which they relax the muscles of their body, starting with the feet and working toward the head, until they fall asleep. Other relaxation methods may be commonly available in the community, such as relaxation sessions, transcendental meditation, yoga, and biofeedback. These therapies are available in a variety of settings and in different communities.

Sleep restriction and stimulus control are other behavioral treatments for sleep disorders. Sleep restriction centers on the belief that sleep continuity improves by limiting the time spent in bed. Patients should not lie in bed for 9 hours in hope that they will get 5 hours of sleep. If a patient has not fallen asleep within a period of time, such as half an hour, they should get out of bed and move to another setting or situation—to read a book, drink a glass of warm milk, etc.—until they are tired again. Similarly, stimulus control ensures that patients restrict their psychological associations with the bed to just sleep and sexual activity. The bed should not be used for television watching, dog grooming, stamp collecting, or any other activity executed in hopes of eventually falling asleep. Stimulus control restricts the bed to just those two activities.

Principles of Sleep Hygiene

The principles of sleep hygiene consist of largely common sense practices (Slide 3).3-5 Many patients simply do not fully understand or appreciate the various dimensions of good sleep hygiene. For example, many do not understand the importance of maintaining a regular sleep/wake cycle, in which a person goes to bed at approximately the same time and—perhaps even more importantly—wakes up at the same time, every day, 7 days a week. Patients should not try to catch up on sleep during the weekends, but rather set their own internal clock to consistently go to bed at a certain time and wake up at a certain time. People without insomnia often do not have to worry about maintaining a regular sleep/wake cycle, but for patients with insomnia it is vital to establish a regular sleep rhythm.

Exercise is another valuable part of sleep hygiene. Patients with insomnia should exercise in the morning or, at the very latest, by early afternoon. Because exercise can be stimulating, patients should not attempt to exercise vigorously in the evening in order to tire themselves. This will invigorate and stimulate them, making it more difficult to fall asleep.

Likewise, increasing exposure to bright light during the day and avoiding exposure to it during the night contribute to good sleep hygiene. Even occasional exposure to very bright light may be enough to reset a patient’s circadian clock. Exposure to a 150-watt light bulb during a nighttime lavatory visit can cause difficulty sleeping in very susceptible patients. Patients should replace a bright light with one that that has the least amount of illumination but is compatible with safety. A 4-watt nightlight, for example, might provide light sufficient to prevent injury without interfering with a patient’s ability to go back to sleep. Patients should enhance their sleep environment by reducing ambient noise, keeping the room dark, and having adequate bed covers and sleep surface.

Patients should avoid eating heavy meals or drinking alcohol within 3 hours of bedtime. They should also avoid caffeine and nicotine before going to bed. Caffeine, of course, is ubiquitous in foods and drinks. While most patients realize that coffee and cola drinks contain caffeine, many do not know that tea, many non-cola soft drinks, and chocolate do, as well. Alcohol makes people sleepy, but it has a short half-life, and as it is metabolized the body produces neurotoxins that are irritants to the central nervous system. These irritants act as stimulating agents that can overwhelm the initial sense of sedation alcohol causes. Nicotine is a stimulant as well.

Patients with insomnia should engage in relaxing activities as part of their sleep preparation ritual. They should begin these activities early in the evening so that they are set for sleep at bedtime. A warm bath and socks are just two ways that patients can reduce core body temperature to predispose themselves to sleep.

Pharmacologic Options for Insomnia

Over the years, patients have used a variety of products, alone or in concert with behavioral changes and modifications, to induce sleep (Slide 4). These range from fermented or alcoholic beverages to plant preparations, including a wide variety of herbs.

Laudanum, a combination of opium and alcohol, has been around for over 100 years, and was used extensively during the American Civil War, when it was available at every corner grocery store. This may have produced more drug addicts than any other single period in history. Chloral hydrate has likewise been around for over 100 years.

Barbiturates are more recent advents. Although they are safer than some of the other substances mentioned, they still carry certain hazards and risks. Antihistamines have been—and still are—used for their sedating properties. Antihistamines are commonly found in over-the-counter (OTC) agents. However, caution is indicated in the use of such agents in elderly patients.

Benzodiazepine hypnotics are a more recent invention. These are safer than the aforementioned mentioned products, but they also have drawbacks and side effects. The nonbenzodiazepine hypnotics are agents that act at the benzodiazepine receptor sites but are not benzodiazepines. These, too, can confer some additional safety, and are still more effective than the above agents.  Importantly, these are FDA approved for the treatment of insomnia (Slide 5).

The selective melatonin receptor agonist ramelteon is a recent addition to the sleep-agent armamentarium and is also approved by the FDA for the treatment of insomnia.    

Sedating antidepressants are also widely used as hypnotics (Slide 6). These hold potential benefit for patients experiencing chronic insomnia secondary to depression.6 These agents often share the same antihistaminic action as OTC products.7 Although antidepressants have not been studied as widely as primary hypnotic agents for the treatment of primary insomnia, the hypnotic dose of a sedating antidepressant is typically less than the therapeutic effect for the treatment of depression. As with any medication, there are side effects. Caution is warranted in the elderly, since a limited number of antidepressants can cause postural hypotension8 or have cardiovascular effects.9

 

Pharmacokinetics of Benzodiazepine and Nonbenzodiazepine Hypnotics

In the process of shifting away from chloral hydrates and barbiturates and adopting more efficacious hypnotic products, doctors began prescribing long-acting benzodiazepines like flurazepam and quazepam (Slide 7).10-12 However, these medications have extremely long half-lives, meaning they have a very high risk of producing residual sedation in patients. Even the intermediate-acting agents, such as estazolam and temazepam, have half-lives long enough to cause risk of residual sedation. As a result, insomnia treatment has moved away from these agents.

The benzodiazepine with perhaps the best half-life is triazolam, which has a half-life of 1.5–5.5 hours (Slide 8).10-16 However, because of its poor side-effect profile, triazolam has never been commonly used as a hypnotic.

Many clinicians use other agents from the benzodiapine class of drugs, such as lorazepam, temazepam, and alprazolam, as hypnotics. However, this as an “off label” use of these drugs, and is accompanied by the risks associated with the use of this class of pharmaceuticals.

Conclusion

Currently, the nonbenzodiazepines and ramelteon are the newest pharmacologic treatments for insomnia patients. However, it is strongly recommended that physicians not engage only in pharmacologic treatment. Patients are best treated with the nonpharmacologic behavioral interventions outlined above, such as CBT and relaxation training. Usually, hypnotics should be prescribed only if good sleep hygiene principles and cognitive interventions are not sufficient to allow patients to get a good night’s sleep.

References

1. NIH State-of-the-Science Conference Statement on manifestations and management of chronic insomnia in adults. NIH Consens State Sci Statements. 2005;22(2):1-30.
2. Bootzin RR, Perlis ML. Nonpharmacologic treatments of insomnia. J Clin Psychiatry. 1992;53(suppl):37-41.
3. HLBI Working Group on Insomnia. 1998. NIH Publication 98-4088.
4. Kupfer DJ, Reynolds CF 3rd. Management of insomnia. N Engl J Med. 1997;336(5):341-346.
5. Lippmann S, Mazour I, Shahab H. Insomnia: therapeutic approach. South Med J. 2001;94(9):866-873.
6. National Center on Sleep Disorders Research, National Heart, Lung, and Blood Institute, National Institutes of Health. Insomnia: assessment and management in primary care. Sleep. 1999;22(suppl 2):S402-S408.
7. Mendelson WB, Caruso C. Pharmacology in sleep medicine. In: Poceta JS, Mitler MM, eds. Sleep Disorders: Diagnosis and Treatment. Totowa, NJ: Humana Press; 1998:137-160.
8. Erman MK. Insomnia. In: Poceta JS, Mitler MM, eds. Sleep Disorders: Diagnosis and Treatment. Totowa, NJ: Humana Press; 1998:21-51.
9. Jancin B. Psychotropics modestly raise cardiac arrest risk. Clin Psych News. April, 2000:28.
10. National Institutes of Health Consensus Conference. Drugs and insomnia: the use of medications to promote sleep. JAMA. 1984;251:2410-2414.
11. Physicians’ Desk Reference. 54th ed. Montvale, NJ: Medical Economics Co; 1999.
12. Physicians’ Desk Reference. 45th ed. Montvale, NJ: Medical Economics Co; 1991.
13. Lunesta [package insert]. Marlborough, MA; Sepracor, Inc.; 2005.
14. Ambien CR [package insert]. Bridgewater, NJ; sanofi-aventis; 2007.
15. Rozerem [package insert]. Deerfield, Il; Takeda Pharmaceuticals America; 2006.
16. Sonata [package insert]. Bristol, TN; King Pharmaceuticals; 2002.

Question-and-Answer Session

Q: Is there any way to determine when insomnia is caused by depression, anxiety, or stress?

Dr. Roth: There are data showing that people with insomnia hyperarouse.1 The belief is that people who show increased norepinephrine levels during the day or show increased brain metabolism, are vulnerable to stress. Researchers in our laboratory have tested a behavioral version of this hypothesis. People without any insomnia at all were asked whether they have difficulty sleeping when they experience stress. It turns out that those people who have more disturbed sleep in stressful circumstances, in age- and sex-matched controls, have an ~11-fold increased risk of developing insomnia in the future. We cannot identify those people today, however. I think the more interesting question is how much of that hyperarousal is due to the insomnia, rather than the cause of insomnia. I suspect it is both: hyperarousal causes insomnia and insomnia causes hyperarousal. In addition, physiological hyperarousal—the increased levels of norepinephrine—is only one kind of hyperarousal. There is equally a large body of data indicating that those who suffer from insomnia also experience cognitive hyperarousal, indicating the pathophysiology is not simply biological.

Q: Are there any data in the literature on whether non-antidepressant doses, or “hypnotic doses” of non-sedating antidepressants, have any affect on sleep disorders?

Dr. Lieberman: There have been no solid studies to indicate that primary sleep disorders can be treated by treating depression. My contention has been—and I think will continue to be—that depression and primary insomnia are two separate, distinct conditions, both of which require intervention. Though primary care clinicians may seize upon the potential to use one medication to treat two different problems, the efficacy of using a solitary agent to treat these separate conditions has not been demonstrated. I think both problems must be treated based on their individual symptomatologies, and one cannot be considered secondary to the other, though this was common in the past. Therapies must be tailored to individual patients. Using one agent for both actually results in an incompletely treated patient.

Q: Most clinicians, particularly psychiatrists, are trained to think about insomnia as a symptom of another disorder. Clinicians may look very hard for an underlying psychiatric disorder or for an associated medical problem—even an acute stressor. What percentage of patients with insomnia does not have another identifiable core cause or comorbidity with the insomnia?

Dr. Roth: The most conservative estimate is about 10%, and the most liberal estimate is 25%. A minority of patients have what is euphemistically called “primary insomnia,” or insomnia with no other condition. My guess is that the number is closer to 10% to 15%. However, comorbid insomnia is very different from secondary insomnia, in which a condition or disorder is the primary cause of insomnia. And treating that primary insomnia reverses the insomnia. Most of the insomnia is comorbid with, not secondary to, other conditions. Clinicians may be trained to infer that a patient’s depression causes their insomnia. However, if insomnia is caused by depression, treating depression should, and does, alleviate sleep disruptions. This is not the case if these conditions are comorbid. Dr. Krystal presented data from Breslau and colleagues,2 which shows that in the majority of cases, insomnia precedes the depression. The data show that treating insomnia can actually improve depression. There are also data that would suggest that if you treat depression, then the more refractory symptom is insomnia. Hence, although it is clear that insomnia often is comorbid, this does not preclude the treatment of insomnia as its own distinct condition. I treat both of those conditions when they are present.
 

Q: How should clinicians determine the duration of medication use for patients with insomnia?

Dr. Roth: The National Institutes of Health (NIH) realized that insomnia is not a symptom, but rather a chronic disorder. Ever since the 2005 NIH State-of-the-Science Consensus Conference on insomnia, all drugs approved by the Food and Drug Administration have been indicated for the long-term therapy of insomnia. Equally important, the pharmaceutical companies that are trying to get drugs on the market have to provide chronic data so that those medications can be used in long-term treatment. The decision of the NIH indicates that there is a role for chronic therapy, but for whom and under what circumstances depend very much on the patient, just as in determining treatment for patients with depressive disorders. How long has the patient had insomnia, and have they relapsed? We do not have as much longitudinal data for chronic treatment of insomnia as we do for depressive disorders. These treatment options also depend on their effects on the patient. Chronic therapy has always been an option clinically, but it is now also an option in terms of regulations, both as indicated on medication labels and in terms of clinical guidelines.

Dr. Krystal: When treatment is started, one does not know how long a patient will have insomnia. And after a patient starts pharmacologic treatment, one will not know if the patient still does have insomnia. Because of that ambiguity and the absence of data, I do trial tapers every couple of months. With the agreement of the patient, the agent is tapered to determine if he or she is better off with or without the medication. I find this to be a very practical approach until there are better data on how best to do this.

Dr. Lieberman: I agree. I think there are a couple of things that make this condition distinctive, one of which is that the majority of medications that we can use to treat it are scheduled. There is a natural resistance on the part of physicians to using long-term, scheduled products. However, I think psychiatrists in particular, are used to long-term drug therapy. They know that in cases like patients with recurrent episodes of depression, lifelong pharmacologic therapy is required, so I think they are more easily convinced to use chronic treatments for insomnia. Every patient is different. Some patients respond to a limited course of therapy; after a while the insomnia is ostensibly cured and the therapy can be withdrawn. Others are going to require lifelong therapy. But we can make the analogy to other treatments. For example, we treat diabetes with insulin over the course of a patient’s lifetime. However, some patients who have hypertension are treated temporarily and some require lifelong treatment. We do try to have some withdrawal from some of these medications, in some of these patients, some of the time. But the notion that we need to use some medications chronically, in patients who have severe recurring conditions, is not foreign. This is appropriate so long as we can make the association between that insomnia and some of the other conditions that these clinicians treat.

Q: Approximately 25% of the United States population is involved in shift work. Many of these shift workers have dysfunctional sleeping patterns, such as napping during the daytime and adopting a normal sleep-wake cycle on weekends. What is the impact on the morbidity for these patients, and what can we do for them?

Dr. Roth: A minority of patients with shift work—only 31%—have a sleep disorder, or difficulty sleeping at night and sleepiness in the day. There are two things that are important to understand in any patient. First, if you get them to sleep 8 hours during the day, which is itself an incredible challenge, they still will have difficulty staying awake at work and driving home because they are trying perform these activities in a downside of the circadian rhythm. These shift workers will have worse sleep hygiene, too, because their sleeping environment will be affected by daylight. Several trials have shown that wake-enhancing compounds, such as modafinil, can be helpful for people trying to stay awake during nightshifts. Second, the temptations not to maintain a regular sleep schedule are greater for shift workers, because, for example, they can attend their children’s t-ball games in the middle of the afternoon. More than anything else, people on rotating or night shifts need incredible lessons on sleep environment. Sleep disorder is defined as an inability to sleep despite adequate opportunity. Shift workers must have adequate opportunity, meaning 8 hours in bed in an appropriate environment. If they still cannot sleep—and 20% to 25% cannot—then some of the sleep agents previously discussed may be necessary. The use of light can be helpful in moving their internal clocks, though this may not be the best choice for shift workers with family or social obligations on weekends. Very clearly, use of medications can be helpful, but only after the patient’s opportunity to sleep has been maximized. Finally, it is most important to recognize that guaranteeing 8 hours of sleep will still not guarantee shift workers a safe drive home after a night of work.

Dr. Lieberman: There is a lot of variability from patient to patient. As a general rule of thumb, what we have tried to do in our practice is ensure that the patient understands what good sleep hygiene is. We use the cognitive interventions first, and then we use pharmacotherapeutic agents for awakening or increased alertness, and to help with sleep. But this is only after we have ensured that our patient is pretty well versed in what other things they need to do to help themselves.

Dr. Roth: I think your method is exactly right. One should start out with just cognitive-behavioral therapy, especially the behavioral approaches. However, before one decides that a patient has insomnia, one should make sure that the patient has adequate opportunity to sleep. That means adequate time in bed and an adequate sleep environment.

Dr. Krystal: For some people, you can institute these behavioral changes right away, but their sleep does not improve for several weeks. And there are some people whose anxiety is such that it is difficult to change their behavior. We published data showing that starting a sleep agent with behavioral therapy, with buy-in from the patient, can improve in sleep right away. And as long as there is a plan to taper that medication over the course of three weeks, before the full benefit of behavioral therapy kicks in, you still seem to get full benefit of the behavioral therapy. Some interesting data suggest that if you continue insomnia medication long term, the behavioral therapy benefits do not seem to manifest, perhaps because there is no motivation to change behavior.

Dr. Lieberman: I think you are right on the mark. There are some patients who are so afraid that they are not going to be able to sleep that they keep themselves awake. They lose sleep over the fact that they cannot get to sleep. I think a hypnotic agent, with those folks, may be the first order of business.   

References   

1. Nofzinger EA, Buysse DJ, Germain A, Price JC, Miewald JM, Kupfer DJ. Functional neuroimaging evidence for hyperarousal in insomnia. Am J Psychiatry. 2004;161(11):2126-2128.   
2. Breslau N, Roth T, Rosenthal L, Andreski P. Sleep disturbance and psychiatric disorders: a longitudinal epidemiological study of young adults. Biol Psychiatry. 1996;39(6):411-418.

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