Patient-management Strategies

An active cortex is necessary for intact cognitive function. In a sleepy individual, the cerebral cortex is to some extent deactivated; a sleep-deprived person will experience reduced physical and mental activity and productivity, more errors on the job, more risk for motor vehicle accidents, and psychosocial problems. Hormone levels can become imbalanced from excessive daytime sleepiness (EDS), and treatments for conditions unrelated to EDS can be hampered. Whether sleep restriction is voluntary or not, those who experience it habitually are at greater risk of obesity and type 2 diabetes. While an accurate history is necessary to diagnose sleep disorders, all too often a patient’s chronic daytime sleepiness is never mentioned. EDS will not show up in most blood chemistries either. It is important that primary care providers ask patients about their sleep and its quality. Other screening tools include questionnaires, which are easily administered and can be sensitive. To determine the basis of EDS, formal sleep studies may be necessary.

(Am J Manag Care. 2007;13:S140-S147)

Excessive sleepiness affects millions of Americans, taking personal, social, societal, and economic tolls. Sleepiness is reflected in deactivation of the cerebral cortex, as an active cortex is necessary for intact cognitive function.^1,2 A sleepy individual may experience reduced physical and mental activity and productivity, more errors and accidents on the job, an increased risk for motor vehicle accidents, and medical, psychiatric, and psychosocial problems. Often it is the primary care physician (PCP) who is in a position to uncover these problems and the associated excessive sleepiness. Healthcare providers can therefore avoid harm and do tremendous good for the patient, the people around the patient, and even economic productivity by taking excessive sleepiness seriously. But the problem all too often is overlooked.

In a survey of 222 consecutive general medical patients admitted to a Veterans Administration tertiary care medical center who completed a questionnaire, 28% of patients reported excessive daytime sleepiness (EDS), which was severe in 12% of these patients.3 A review of the medical records of patients reporting EDS or conditions (insomnia, snoring, leg jerks, kicking, or twitching) associated with a sleep complaint found that “no record included mention of any patient symptom related to sleep.†Such symptoms may be clinically important, but the admitting physicians failed to recognize and/or note any of them. Whether the situation has improved in the ensuing 9 years since that study was published is unknown at this time.

Potential Impact of Excessive Sleepiness on Daily Functioning

Disturbed sleep and excessive sleepiness have major impacts on many different systems in the body. The underlying conditions that cause excessive sleepiness raise the risk, for example, of diabetes, breast cancer, cardiovascular disease, immune dysfunction, and depressive disorder.^12,13 For any medical treatment to be most effective, it must be done on a background of a well-rested patient. Therapeutic failure or suboptimal effects may be the result of sleep problems. Thus, excessive sleepiness is not just a bothersome symptom, but it can be comorbid with a wide variety of conditions and complicate their treatment. Proper treatment of conditions leading to excessive sleepiness can help avoid physical disease and can make treatment of many established morbidities more effective. Since these diseases and conditions are common in the primary care setting, excessive sleepiness has taken on new meaning in this arena.

Extensive laboratory and epidemiologic evidence shows that people who sleep very little, whether because of voluntary sleep restriction or because of an organic or other cause, have an increased risk of obesity and type 2 diabetes.¹² Three of the proposed mechanisms linking sleep restriction, weight gain, and diabetes risk involve altered glucose metabolism, upregulation of appetite, and lowered energy expenditure. Hormone levels (eg, leptin, ghrelin, and insulin) and target organ response to them may be altered in conditions leading to sleeplessness.¹⁴ Obesity and diabetes in themselves increase the risk for a variety of diseases–cardiovascular diseases being the most obvious ones–affecting millions of Americans.

OSA is an independent risk factor for cardiovascular disease.¹⁵ The relationship is particularly strong for systemic arterial hypertension, and evidence is accumulating for ischemic heart disease, stroke, heart failure, atrial fibrillation, and sudden cardiac death. Although the exact mechanisms for these relationships are not known, OSA involves metabolic, inflammatory, and cellular dysfunctions related to breathing disruptions. Overactivity of the sympathetic nervous system, inflammatory pathways, endothelial dysfunction (likely related to inflammation), hypercoagulability, altered lipid metabolism, and insulin resistance are all likely direct or contributing factors.

Other conditions linked to sleep disturbances causing excessive sleepiness are stomach ulcers and depression.¹⁶ In a study of shift or daytime workers,⁵ night or rotating shift workers had a greater prevalence of ulcers compared with day workers. The greatest prevalence was for shift workers who had symptoms of insomnia or excessive sleepiness compared with those who did not. Shift work has been associated with elevated levels of gastrin and pepsinogen,¹⁷ a possible explanation for the increased risk of ulcers. However, even in daytime workers, the prevalence of ulcers was more than 3-fold higher for individuals with such symptoms versus those without symptoms.

These findings suggest that shift work and conditions leading to symptoms of excessive sleepiness interact or at least contribute to gastrointestinal ulcers in shift workers with these symptoms.⁵ Furthermore, in this study, depression was related to an alteration in sleep-wake pattern, but heart disease was related to shift work itself without regard to altered sleep. Therefore, it appears that shift work and symptoms of excessive sleepiness may be independent factors for the development of certain conditions and may each contribute to variable degrees depending on the condition and the individual.

Diagnostic Measures for Sleep Disorders. While obtaining a patient's history is critical in making the diagnosis of sleep disorders, diagnostic testing has its role, but probably less so in the primary care setting than in specialized sleep laboratories. The only potentially useful routine blood chemistries are thyroid function tests in suspected sleep apnea¹⁸ and ferritin levels in suspected cases of restless legs syndrome.¹⁹ Even these tests may be equivocal, and once a presumptive diagnosis has been made, the next stop is a sleep center for narcolepsy or to quantify sleep apnea. The physical examination is usually unremarkable, but those signs suggestive of sleep apnea should be noted (ie, crowded oropharynx, peripheral edema, hypertension, and overweight).

One way to obtain the timing, amount, and continuity of sleep is to ask the patient to record his or her sleep periods in a sleep diary or sleep log, including any naps.²⁰ A 2-week record often shows great variability in the sleep pattern, which can be important for treatment decisions. Questions for a sleep partner can focus on the patient's breathing (apnea) and limb movements while asleep. In addition, the ESS, to be completed by the patient, is a very important and useful test for excessive sleepiness. A problem with sleep diaries, however, is getting patients to complete them every day, as exemplified by patients who have been observed filling them in while in the doctor's waiting room just prior to their appointment. But for patients, the sleep diary should reveal if the patient is excessively sleepy because of sleep deprivation from willfully cutting short the time for sleep at night or from circadian rhythm disorders. Once this type of problem is ruled out, the physician has to decide if the patient may have a sleep disorder such as narcolepsy or OSA and what specialized sleep consultation or sleep studies may be indicated to reach a diagnosis.

An additional useful tool in determining the cause of sleep loss or deprivation is to use an algorithm to evaluate a patient who presents with a sleep problem. An example of one such algorithm is presented in the Figure.²¹ This algorithm can be key to determining whether the patient is more tired/fatigued or drowsy/sleepy.

Nonpharmacologic and Pharmacologic Treatments

The goal of pharmacologic treatment of sleep disturbances with a stimulant drug is to prescribe the dose, duration of action, and time of administration that relieves EDS but does not disturb nighttime sleep. Similarly, treatment of insomnia with hypnotics should help the patient sleep but not result in residual daytime sleepiness.

EDS resulting from insomnia is first treated by trying to correct the insomnia. Sleep-promoting medications include sedating antidepressants, benzodiazepines, nonbenzodiazepines (eg, zolpidem, eszopiclone, zaleplon), and a melatonin-receptor agonist, ramelteon.²⁸ The nonbenzodiazepines have largely replaced the benzodiazepines for insomnia treatment because of the nonbenzodiazepines' lower risk profile for residual effects.²⁹ Additionally, benzodiazepines are not covered under the Medicare drug benefit.

Insomnia patients may still have some residual daytime sleepiness even if medication helps their insomnia.²¹ Similarly, in SWSD, getting adequate sleep is critical, but the worker is still going to be sleepy between 2 AM and 4 AM. Pharmacologic treatment for increasing wakefulness includes 4 options. First, caffeine is the major central nervous system (CNS) drug used in the United States. Sleepy people often drink a lot of coffee and maybe in the wrong way. Rather than drinking large quantities intermittently, it may be better to sip it over several hours. Second, classical stimulants such as methylphenidate, amphetamine, and dextroamphetamine, which are dopaminergic compounds, while not US Food and Drug Administration (FDA) approved for use in insomnia patients, have been used. Third, sodium oxybate, which is specifically indicated for the treatment of sleepiness in narcolepsy patients, has been reported to be highly efficacious for the treatment of the associated cataplexy.³⁰ Another option is modafinil, which is indicatedto improve wakefulness in adult patients with excessive sleepiness associated with narcolepsy, OSA/hypopnea syndrome, and SWSD. This agent does not have major dopaminergic activity, although dopamine must be present for it to work. Its mechanism of action is not well elucidated, but it does not have much sympathomimetic activity. In shift workers with SWSD it has been shown to improve performance,²² clinical symptoms and modestly improve performance.³¹ Armodafinil, the R-enantiomer of modafinil,²² has recently been approved by the FDA. It is not yet available for use at the time of this publication.

Although dopaminergic compounds are the most potent in terms of enhancing wakefulness, these agents should be avoided in patients with sleep apnea due to their significant cardiovascular risks and CNS side effects, such as anxiety.²¹ In choosing medications, the physician needs to consider a patient's potential for abuse and cardiovascular risks. Of the various medications, modafinil has the lowest cardiovascular risk, and the Drug Enforcement Administration classifies modafinil as the one with the least abuse potential, designating it a Schedule IV controlled substance, whereas methylphenidate and the amphetamines are Schedule II.²¹ Modafinil is indicated for residual sleepiness in sleep apnea.²⁵ If this agent is prescribed for a patient with sleep apnea, the physician needs to advise the patient that the drug is not treating the condition but only any residual excessive sleepiness after more definitive treatments have been applied, often by a specialist.

Referral to a Sleep Specialist

A 40-year-old divorced mother of 2 has worked at a nursing home as a certified nurse aide for a number of years and now presents at your office complaining of tiredness and fatigue that occurs most days.

Now that her children are old enough to require less day-to-day care, she has made time to go to school, where for 9 months she has been studying to be a registered nurse. She does much of her coursework by computer, but still has to attend clinical rotations on average 3 mornings per week. As her family's sole breadwinner, she has maintained full-time work status at the nursing home, where they have accommodated her schedule as much as possible. Doing occasional day shifts, she chooses to work on average three 8- to 12-hour evening or night shifts per week to maximize waking time at home with her children. Her schedule changes weekly. She constantly juggles family, work, and school obligations and schedules.

She was motivated to seek help after nodding off at a parent-teacher conference, which was arranged because her son is manifesting behavioral problems in junior high school. The teacher expressed concern about the mother and implied that, because of the stress she appeared to be under, her parenting had been less effective this school year. Similarly, at her last work evaluation, the patient's supervisor noted a decline in her performance, including her promptness in responding to patient requests and in the accuracy of her charting.

The patient takes an oral contraceptive and occasional ibuprofen for musculoskeletal aches and pains that she feels have increased lately under the stress of her expanded commitments and demanding schedule. She says she sometimes sleeps well but often has trouble falling asleep, especially after a demanding night shift. She says that no matter how much sleep she manages to get, she's tired on waking. Around the time of her divorce, she took an antidepressant but denies being depressed now. Her weight is stable, and her sex drive is intact. She is normotensive. Her children have not complained that she snores. She reports consuming an occasional social drink of alcohol, uses no street drugs, and quit smoking years ago.

With 3 more semesters to complete before she earns her nursing degree, she wonders out loud if she's going to make it. She has been offered, once she graduates, a position as the supervising registered nurse on night shift at the nursing home where she's been working. It's what she'd like to do because then she will be home for her children every day. And previously, before school was added into the mix, she liked working nights and she feels that she did well at it.

Case Discussion. This is a case that a PCP is likely to encounter in a typical practice and raises a number of issues. The patient has an irregular sleepwake pattern because of her shift work and may be suffering from SWSD. The history of depression suggests it may still be an issue, despite the patient's denial. She reports consuming an occasional alcoholic drink, but possibly she is drinking somewhat more because of her stressful situation. SWSD and depression may coexist, and self-medication with alcohol may be an attempt to overcome any associated sleeplessness. Each and all possible factors should be considered.

The good news for this patient is that she apparently coped well with her work schedule and changing shifts until she went back to school, with those additional demands. But school has now tipped the balance. Since she has only 4 semesters to complete before getting her degree and a new position at work, a goal may be to successfully get her through this chaotic period. To do so, it is necessary to make a definitive diagnosis and not just treat symptoms. The patient appears to fit the criteria for a diagnosis of SWSD. An appropriate pharmacologic option is modafinil, but the patient should be cautioned that modafinil decreases blood levels of oral contraceptives. 32 This patient should be advised to use a barrier method of contraception if modafinil is prescribed, because an unplanned pregnancy at this point in her life would probably be quite unwelcome.

It is questionable about the validity of her not snoring based solely on her children's report. They probably have their own room(s), and children do not often report a parent's snoring unless it is excessively loud and disturbing to them. Children often sleep very soundly, so not complaining about their mother's snoring does not mean that it is not occurring. One should therefore still consider an underlying sleep disorder, such as OSA. If the patient is overweight, suspicion of OSA as a contributing factor would be heightened.

A red flag in this case is the son's new behavior problems. With 4 semesters of school left for the mother, this junior high school—aged boy could possibly harm himself in that amount of time, unless his mother's social situation is fully assessed and brought under control.

Address correspondence to: Michael J. Thorpy, MD, Professor of Neurology, Albert

2. Czisch M, Wehrle R, Kaufmann C, et al. Functional MRI during sleep: BOLD signal decreases and their electrophysiological correlates. Eur J Neurosci. 2004;20:566-574.

4. Papp KK, Stoller EP, Sage P, et al.The effects of sleep loss and fatigue on resident-physicians: a multi-institutional, mixed-method study. Acad Med. 2004;79:394-406.

6. Landrigan CP, Rothschild JM, Cronin JW, et al. Effect of reducing interns’ work hours on serious medical errors in intensive care units. N Engl J Med. 2004;351:1838-1848.

8. National Center for Sleep Disorder Research/National Highway Traffic Safety Administration Expert Panel on Driver Fatigue and Sleepiness. Drowsy Driving Automobile Crashes. http://www.nhtsa.dot.gov/PEOPLE/INJURY/drowsy_driving1/drowsy.html. Accessed October 8, 2007.

10. Gold DR, Rogacz S, Bock N, Tosteson TD, Baum TM, Speizer FE, Czeisler CA. Rotating shift work, sleep, and accidents related to sleepiness in hospital nurses. Am J Public Health. 1992;82:1011-1014.

12. Knutson KL, Spiegel K, Penev P, Van Cauter E. The metabolic consequences of sleep deprivation. Sleep Med Rev. 2007;11:163-178.

14. Campo A, Frühbeck G, Zulueta JJ, et al. Hyperleptinaemia, respiratory drive and hypercapnic response in obese patients. Eur Respir J. 2007;30:223-231.

16. McCall WV, Harding D, O’Donovan C. Correlates of depressive symptoms in patients with obstructive sleep apnea. J Clin Sleep Med. 2006;2:424-426.

18. Resta O, Pannacciulli N, Di Gioia G, Stefàno A, Barbaro MP, De Pergola G. High prevalence of previously unknown subclinical hypothyroidism in obese patients referred to a sleep clinic for sleep disordered breathing. Nutr Metab Cardiovasc Dis. 2004;14:248-253.

20. American Academy of Sleep Medicine. Two Week Sleep Diary. http://www.sleepeducation.com/pdf/sleepdiary.pdf. Accessed October 9, 2007.

22. Schwartz JR, Roth T. Shift work sleep disorder: burden of illness and approaches to management. Drugs. 2006;66:2357-2370.

24. Naismith SL, Winter VR, Hickie IB, Cistulli PA. Effect of oral appliance therapy on neurobehavioral functioning in obstructive sleep apnea: a randomized controlled trial. J Clin Sleep Med. 2005;1:374-380.

26. Morgenthaler T, Kramer M, Alessi C, et al. Practice parameters for the psychological and behavioral treatment of insomnia: an update. An American Academy of Sleep Medicine report. Sleep. 2006;29:1415-1419.

28. Ebert B,Wafford KA, Deacon S. Treating insomnia: current and investigational pharmacological approaches. Pharmacol Ther. 2006;112:612-629.

30. Thorpy MJ. Cataplexy associated with narcolepsy: epidemiology, pathophysiology and management. CNS Drugs. 2006;20:43-50.

32. Provigil [package insert]. Frazer, PA: Cephalon; 2007.

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