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Finding better answers for sleep disorders

Vol. 5, No. 1 / January 2006

The psychopharmacology of sleep disorders is awakening from a long slumber. Before now, you might have considered sleep disorders as somewhat exotic, to be diagnosed by sleep subspecialists with fancy and expensive equipment. Other than abusable stimulants or dependence-causing hypnotics, psychopharmacologic treatments were lacking.

Today, new treatments for patients with sleep and wakefulness problems are changing assumptions about what constitutes a treatable condition, what treatments are available, and how long to treat (see “When patients can’t sleep”). As sleep’s neurobiology becomes more clear,1,2 psychopharmacologists need to become experts in diagnosing and treating sleep disorders.

‘New’ treatable conditions

Narcolepsy and cataplexy have long been recognized as important—if rare—sleep disorders. We now know that several other diagnosable and treatable conditions are much more common causes of disrupted sleep and impaired daytime wakefulness. These include:

  • shift-work sleep disorder, treatable with modafinil,3
  • obstructive sleep apnea, treatable with modafinil augmentation of continuous positive airway pressure (CPAP)3
  • chronic insomnia, treatable with chronic administration of hypnotics such as eszopiclone and others in development that do not seem to cause dependence4
  • restless legs syndrome, treatable with pramipexole and other dopamine agonists (Table 1).5

Consider these sleep disorders as the possible cause of symptoms when you evaluate a patient with treatment-resistant depression, cognitive dysfunction, insomnia, or excessive daytime sleepiness. Likewise, symptoms of nighttime wakefulness and excessive daytime sleepiness should be evaluated as possibly being secondary to another psychiatric or medical disorder, pain, or psychotropic medication.

Table 1

Psychotropic agents now used or in testing for sleep disorders

Uses

Agents

Status

Promote daytime wakefulness

Modafinil (nonamphetamine)

Approved

Armodafinil (active renantiomer of modafinil; prolonged half-life)

Late clinical testing

H3 histamine antagonists

Early clinical and preclinical testing

For chronic insomnia

Eszopiclone (active senantiomer of hypnotic zopiclone)

Approved

Indiplon (immediate- and modified-release formulas)

Late clinical testing

Zolpidem (extended-release)

Approved*

Zaleplon (modified-release)

Clinical testing

Ramelteon (selective M1/M2 receptor melatonin agonist

Approved

Obstructive sleep apnea

CPAP at night

 

Modafinil in the daytime

 

Serotonin, alpha-adrenergic antagonists

Experimental

Restless legs syndrome

Ropinirole

Approved

Pramipexole

Late clinical testing

*FDA-approved for treatment of insomnia; length of treatment not specified

CPAP: Continuous positive airway pressure

Cosmetic psychopharmacology?

For sleep deprivation caused by partying or working overtime, no one would argue that a drug—rather than a good night’s sleep—is the treatment of choice. However, the 25% of shift workers who have shift-work sleep disorder have more than a lifestyle problem. They require evaluation for treatment of sleepiness during their working hours and when they drive to and from work.

Traffic accidents have been shown to be correlated with the daily rhythm of sleepiness (Figure 1), 6 suggesting that individuals who must sleep during odd hours, work during odd hours, and drive to and from work need to be evaluated for treatment. Such treatment would include hypnotics that promote sleep when these individuals have the time to sleep and wake-promoting agents such as modafinil when they must work and drive.

Even more remarkable are data showing that a person who has been awake for 24 hours has the psychomotor performance of someone who meets the legal definition of intoxication (Figure 2).7 This finding has implications for anyone who pulls an “all-nighter,” including medical interns working in intensive care units.8

Figure 1 Timing of traffic accidents correlates with daily sleepiness rhythm

Traffic fatalities (blue bars) occur most frequently from 10 p.m. to 6 a.m. and 4 to 6 p.m., corresponding with daily sleepiness patterns (red line).

Source: Prepared from National Center on Sleep Disorder Research/National Highway Traffic Safety Administration data, reference 6

Figure 2 Moderate fatigue and alcohol intoxication
have similar effects on performance

Hand-eye coordination compared in 40 subjects kept awake for 28 hours and after consuming enough alcohol to attain a mean blood alcohol concentration of 0.10%. Results expressed as percentage of performance at start of each testing session.

Source: Adapted and used with permission from Dawson D, Reid K. Fatigue, alcohol and performance impairment. Nature 1997;388:235.

How does the clinician differentiate sleep disorders from other sleep-related problems, such as poor sleep hygiene, 24-hour consecutive overworkers, and chronic overworkers with huge sleep debts (the “I-can-sleep-when-I’m-dead” syndrome). We should not prescribe pharmacologic interventions for patients who accumulate huge sleep debts, enabling them to drive up their sleep debts even further. But shift-work sleep disorder affects many of us, at least intermittently, as our schedules change. This applies not just to classical shift workers such as police, fire, nursing, and factory workers, but also to those who:

  • commute long distances across time zones and have vital work to do in the first few days after arrival or return, while suffering “jet lag”
  • must intermittently work long hours, such as “on call” physicians and nurses, project managers, and programmers racing to meet a deadline.

By understanding the nature of true sleep disorders and their treatments, you will be in a strong position to decide whom to treat and with what.

Related resources

Drug brand names

  • Eszopiclone • Lunesta
  • Modafinil • Provigil
  • Pramipexole • Mirapex
  • Ramelteon • Rozerem
  • Ropinirole • Requip
  • Zaleplon • Sonata
  • Zolpidem • Ambien

Disclosure

Dr. Stahl receives grant/research support or serves as a consultant to Asahi, AstraZeneca, Avanir, Boehringer Ingelheim, Bristol-Myers Squibb Co., Cephalon, Cyberonics, Cypress Bioscience, Pierre Fabre, Forest Laboratories, GlaxoSmithKline, Janssen Pharmaceutica, Eli Lilly & Co., Nova Del Pharma, Otsuka, Pfizer Inc., Sanofi Synthelabo, Sepracor Inc., Shire Pharmaceuticals, Solvay Pharmaceuticals, and Wyeth.

Acknowledgement

Adapted and reprinted with permission from PsychEd Up: Psychopharmacology Educational Update 2005;1(5):6-7. Copyright 2005, NEI Press.

References

1. Wisor JP, Kilduff TS. Molecular genetic advances in sleep research and their relevance to sleep medicine. Sleep 2005;28:357-67.

2. Dement WC. The promise of sleep. New York: Delacorte Press; 1999.

3. Stahl SM. Essential psychopharmacology: the prescriber’s guide. Cambridge, UK: Cambridge University Press; 2005.

4. Krystal AD, Walsh JK, Laska E, et al. Sustained efficacy of eszopiclone over 6 months of nightly treatment: results of a randomized, double-blind, placebo-controlled study in adults with chronic insomnia. Sleep 2003;26:793-9.

5. Silber MH, Girish M, Izurieta R. Pramipexole in the management of restless legs syndrome: an extended study. Sleep 2003;26:819-21.

6. National Center on Sleep Disorder Research/National Highway Traffic Safety Administration (NCSDR/NHTSA) Expert Panel on Driver Fatigue and Sleepiness. Drowsy driving and automobile crashes: report and recommendations. Washington, DC: Department of Transportation, April 1998. Available at www.nhlbi.nih.gov/health/prof/sleep/drsy_drv.pdf.

7. Dawson D, Reid K. Fatigue, alcohol and performance impairment. Nature 1997;388:235.-

8. 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;351:1838-48.

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