It is important that clinicians be aware of drugs that alter patients’ sleep or impair daytime alertness, which may compromise their well-being and day-to-day activities.

photoMany drugs and pharmacologically active compounds used for social purposes modify sleep. Drugs that alter sleep or impair daytime alertness may compromise the well-being and day-to-day activity of the individual; for this reason, it is important that clinicians be aware of these changes.

All of the benzodiazepines acutely increase total sleep time and sleep efficiency1 (Table 1). Slow-wave sleep is reduced and stage-2 sleep is enhanced. Rapid–eye-movement (REM) sleep time may be reduced mildly as doses go beyond recommended upper limits. All fast activities, especially sleep spindles, are enhanced.2




Zolpidem Zaleplon
Table 1. At present, sedative-hypnotics used clinically in the United States include eight benzodiazepines and two nonbenzodiazepines.

Flurazepam has a long duration of action, lasting well into the next day. It has a quick onset of action and, therefore, it works both for sleep-onset and sleep-maintenance insomnia.

Temazepam has a slow onset of action and is not well suited for sleep-onset insomnia. Its duration of action is short; therefore, next-day side effects are less evident.

Triazolam has quick onset of action and a short duration and is, therefore, unsuitable for the treatment of sleep-maintenance insomnia. Tachyphylaxis and amnesia have also been reported at the manufacturer’s recommended doses.

Zolpidem is an imidazopyridine compound with selectivity for the type 1 g-aminobutyric-acid–benzodiazepine receptor. Zolpidem has a half-life of 2.4 hours and has no active metabolites.3,4 It is useful in the treatment of sleep-onset insomnia. Residual daytime sleepiness and rebound insomnia are uncommon following therapeutic doses.5,6-8 Zolpidem has a strong hypnotic effect. Polysomnographically, it has been shown that zolpidem can increase slow-wave sleep.5,6,8 REM sleep may be reduced at higher doses. Spindle activity may be increased.6,8

Zaleplon is a pyrazolopyrimidine that binds selectively to benzodiazepine-1 receptors. It is a short-acting agent with a rapid onset of action. The half-life of zaleplon is about 1 hour. Rebound insomnia is not often seen after discontinuation of the medication.9

Modafinil is a central–nervous-system (CNS) stimulant that was approved in 1999 in the United States for the treatment of narcolepsy. Doses of 200 mg and 400 mg have resulted in significantly reduced mean scores for sleepiness, in increased wakefulness, and increased sleep latency.10 Only mild-to-moderate side effects have been reported, with headaches being the most severe. Though the specific mechanism of action of modafinil is not yet known, modafinil has a1-nonadrenergic agonist properties and may have a different mechanism of action than that of indirect sympathomimetics (such as amphetamine) (Table 2). A slight increase in slow-wave sleep and a decrease in slow-wave latency may be seen.




Table 2. Sympathomimetics.

Pemoline is a CNS stimulant that is also currently being used for the treatment of narcolepsy and daytime somnolence. Studies have shown that pemoline significantly lengthens daytime sleep-latency times,11,12 improves attention,12 improves the performance of cognitive tasks, and increases wakefulness during nocturnal sleep.12 It is less effective than methylphenidate, dextroamphetamine, or methamphetamine in controlling somnolence. Idiosyncratic and metabolic types of hepatitis have been reported as side effects of this agent. Given the potential for serious side effects, the role of pemoline13 in the treatment of sleepiness is uncertain, and the drug has been withdrawn from the market in Canada.

Dextroamphetamine may cause a dose-dependent reduction of total sleep time, REM sleep, and stage-2 sleep. Common side effects include headaches, irritability, nervousness, tremulousness, and anorexia. Insomnia, gastrointestinal complaints, and palpitations are also common complaints. Disturbed nocturnal sleep has been reported at doses above 50 to 60 mg per day.14 Amphetamines and related compounds also have high abuse potential and can cause dependency.

Drugs that Disturb Sleep and Wakefulness
Tricyclic antidepressants (TCAs) prolong REM latency and decrease REM.15 Sedation is more common with amitriptyline, doxepin, and imipramine than with desipramine, protriptyline, and nortriptyline. TCAs usually improve polysomnographic sleep (sleep efficiency) and reduce onset latency in normal subjects, as well as in some depressed patients. They may worsen periodic limb movement disorder (PLMD) during sleep and may exacerbate insomnia in some depressed patients. Doxepin has minimal effects on REM sleep.

Monoamine oxidase inhibitors can cause insomnia and daytime sedation. The most important polysomnographic finding in patients taking these agents is a marked decrease in REM sleep; total sleep time is also reduced.16,17

Selective serotonin-reuptake inhibitors (SSRIs) produce alerting effects, as compared with the sedating effects of TCAs, and can, therefore, cause insomnia. SSRIs generally do not affect daytime performance or cognitive function. Their most striking effect is increased slow eye movement in non-REM sleep. Polysomnographic studies show that fluoxetine decreases total sleep time and that it increases waking time and stage-1 sleep in both normal and depressed patients. It also worsens PLMD, and the presence of prominent slow eye movement in non-REM sleep is greatest with fluoxetine. It may induce or exacerbate REM behavior disorder.18 Paroxetine decreases REM sleep, increases REM latency, and increases slow-wave sleep.19 Total sleep time is decreased and an increase in awakenings is noted. Fluvoxamine has similar effects on the sleep architecture of depressed patients

Trazodone causes drowsiness and impairs performance in normal subjects. REM sleep may be decreased, and an increase in REM sleep may result following withdrawal.

Nefazodone is structurally related to trazodone, but has no affinity for histamine 1 receptors. It has neither stimulating nor activating effects. With its use, REM sleep increases, with no effect on REM latency or slow-wave sleep. An increase in mean sleep latency, as determined using multiple sleep latency testing, is commonly seen.

Bupropion does not usually affect sleep latency or total sleep time, but it may decrease REM latency and increase the percentage of REM.20 It also tends to have stimulating effects. Lithium prolongs REM latency, decreases REM, and increases slow-wave sleep. It can also aggravate PLMD. Buspirone has a minimal effect on sleep architecture.

Antipsychotic medications tend to enhance sleep efficiency and slow-wave sleep, but have very little effect on REM sleep. Sedation is a common side effect with older neuroleptics, chlorpromazine, and thioridazine, as compared with haloperidol.

Sedation is a more common side effect of older antiepileptic drugs (phenobarbital, carbamazepine, phenytoin, valproic acid, and primidone), and the polysomnographic studies of patients using them show shorter sleep-latency times and increased total sleep time.21-23 Newer antiepileptic drugs, such as gabapentin, may increase slow-wave sleep and REM sleep.24,25

Sleep-related complaints, including sleep disruption, have been reported in 70% of patients receiving levodopa, particularly at higher doses.26 Selegiline is reported to cause insomnia. The effects on sleep of other drugs used to treat Parkinson disease have been less studied.

Theophylline is a respiratory stimulant and bronchodilator. Disturbed sleep is a common complaint among patients using it. A prospective study27 showed that patients treated with theophylline have problems with sleep maintenance and insomnia.

Dexfenfluramine has been associated with disturbed nocturnal sleep28 and daytime drowsiness.29 In normal subjects, fenfluramine causes a dose-related decrease in sleep efficiency. Phentermine has been associated with subjective reports of insomnia.

Pseudoephedrine and phenylpropanolamine are used extensively as nasal decongestants and in over-the-counter cold preparations; both agents can cause insomnia.30

Clearly there is a wide range of disturbances of sleep and wakefulness that may arise from the use of common medications. Effects are usually characteristic of a class of medications and may be reversed on withdrawal.

Gautam Samadder, MD, is medical director, Riverside Sleep Diagnostic Center, and Eastside Sleep Diagnostic Center, both in Columbus, Ohio.

1. Siegfried K. Cognitive symptoms in late-life depression and their treatment. J Affect Disord. 1985;S1:S533-540.

2. Hirshkowitz M, Thonby JI, Karacan I. Sleep spindles: pharmacologic effects in humans. Sleep. 1982;5:85-94.

3. Hartmann PM. Drug treatment of insomnia: indications and newer agents. Clin Pharmacol. l 995;51:191-194.

4. Langtry SZ, Benfield P. Zolpidem: a review of its pharmacodynamics and pharmacokinetic properties and therapeutic potential. Drugs. 1990;40:291-313.

5. Blois R, Gaillard JM, Attali P, Coquelin JP. Effect of zolpidem on sleep in healthy subjects: a placebo controlled trial with polysomnographic recordings. Clin Ther. 1993;15:797-809.

6. Monti J. Effect of zolpidem on sleep in insomniac patients. Eur J Clin Pharmacol. 1989;36:461-466.

7. Frattola L, Maggioni M, Cesana B, Priore P. Double-blind comparison of zolpidem 20 mg versus flunitrazepam 2 mg in insomniac in-patients. Drugs Exp Clin Res. 1990;17:371-376.

8. Maarek L, Cramer P, Attali P, et al. The safety and efficacy of zolpidem in insomniac patients: a long-term open study in general practice. J Int Med Res. 1992;20:162-170.

9. Elie R, Eckhat R, Farr I, Emilien G, Salinas E. Sleep latency is shortened during 4 weeks of treatment with Zaleplon, a novel nonbenzodiazepine hypnotic. J Clin Pharmacol. 1999;60:536-544.

10. Fry JM. Treatment modalities for narcolepsy. Neurology. 1998;50:S43-S48.

11. Mitler MM, Hajdukovic R. Relative efficacy of drugs for the treatment of sleepiness in narcolepsy. Sleep. 1991;14:218-220.

12. Nicholson AN, Pascoe PA. Dopaminergic transmission and sleep-wakefulness continuum in man. Neuropharmacology. 1990;29:411-417.

13. Mitler MM, Shafor R, Hajdukovic R, Timms RM, Browman CP. Treatment of narcolepsy: objective studies on methylphenidate, pemoline, and protriptyline. Sleep. 1986;9:260-264.

14. Jaffe JH. Drug addiction and drug abuse. In: Gilman AG, Goodman LS, Rall TW, eds. Goodman and Gilman’s the Pharmacological Basis of Therapeutics. 8th ed. New York: Pergamon Press; 1990:522-573.

15. Sharpley AL, Cowen PJ. Effect of pharmacologic treatments on the sleep of depressed patients. Biol Psychiatry. 1995;37:85-98.

16. Kupfer DJ, Bowers MB Jr. REM sleep and central monoamine oxidase inhibition. Psychopharmacologia. 1972;27:183-190.

17. Nolen WA, Haffmans PMJ, Bouvy PF, et al. Monoamine oxidase inhibitor resistant major depression: a double-blind comparison of brofaromine and tranylcypromine in patients resistant to tricyclic antidepressants. J Affect Disord. 1993;28:189-197.

18. Schenck CH, Mahowald MW, Kim SW, O’Conner K, Hurwitz T. Prominent eye movements during NREM sleep and REM sleep behavior disorder associated with fluoxetine treatment of depression and obsessive-compulsive disorder. Sleep. 1992;15:226-235.

19. Oswald I, Adam K. Effects of paroxetine on human sleep. Br J Clin Pharmacol. 1986;22:97-99.

20. Nofzinger EA, Reynolds CF, Thase ME, et al. REM sleep enhancement by bupropion in depressed men. Am J Psychiatry. 1995;152:274-276.

21. Wolf P, Roeder-Warner UU, Brede M, et al. Influences of antiepileptic drugs on sleep. In: da Silva AM, Binnie CD, Meinardi H, eds. Biorhythms and Epilepsy. New York: Raven Press; 1985:137-153.

22. Declerck AC, Wauquier A. Influence of antiepileptic drugs on sleep patients. Epilepsy Res Suppl. 1991;2:153-163.

23. Roeder-Warner UU, Noachter S, Wolf P. Response of polygraphic sleep to phenytoin treatment of epilepsy: a longitudinal study of immediate, short- and long-term effects. Acta Neurol Scand. 1987;76:157-167.

24. Rao ML, Clarenbach P, Vahlensieck M, Kratzschmar S. Gabapentin augments whole blood serotonin in healthy young men. J Neural Transm. 1988;73:129-134.

25. Placidi F, Diomedi M, Scalise A, Silvestri G, Marciani MG, Gigli GL. Effect of long term treatment with gabapentin on nocturnal sleep in epilepsy. Epilepsia. 1997;38:S179-S180.

26. Nausieda PA, Weiner WJ, Kaplan LR, et al. Sleep disruption in the course of chronic levodopa therapy: an early feature of the levodopa psychosis. Clin Neuropharmacol. 1982;5:183-194.

27. Bailey WC, Richards JM, Manzella BA, et al. Characteristics and correlates of asthma in a university clinic population. Chest. 1990;98:821-828.

28. Bever KA, Perry PJ. Dexfenfluramine hydrochloride: an anorexigenic agent. Am J Health Syst Pharm. 1997;54:2059-2072.

29. Guy-Grand B, Apfelbaum M, Crepaldi G, et al. International trial of long-term dexfenfluramine in obesity. Lancet.1989;2:1142-1145.

30. Empey DW, Meddrer KT. Nasal decongestants. Drugs. 1981;21:438-443.