Official reprint from UpToDate®
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©2011 UpToDate®
Authors
Timothy Roehrs, PhD
Thomas Roth, PhD
Section Editors
Mark H Sanders, MD
Ruth Benca, MD, PhD
Deputy Editor
Kevin C Wilson, MD
The effect of drugs on sleep quality and architecture
Disclosures
Last literature review version 19.2: May 2011 | This topic last updated: June 17,
2009
INTRODUCTION — Any drug that passes the blood-brain barrier has the potential to alter
the quality and/or architecture of sleep. Effects on sleep quality include alterations in the
speed of sleep onset, the continuity of sleep, or the duration of sleep. Effects on sleep
architecture include changes in the normal age-related amount of sleep, or cycling through
non-REM and REM sleep stages. Drug-induced changes in sleep quality and/or architecture
do not necessarily imply a disturbance of sleep. In some cases, changes may be therapeutic,
while in other cases they may be benign or not well understood.
In this topic review, we discuss the effects of various types of drugs on sleep, including
drugs whose primary target is the central nervous system, the cardiovascular system, or the
respiratory system. In addition, we discuss the impact of cigarette smoking. The stages and
architecture of normal sleep are discussed in detail elsewhere. (See "Stages and
architecture of normal sleep".)
CENTRAL NERVOUS SYSTEM DRUGS — Agents acting on the central nervous system
(CNS) that may have an effect on sleep quality or architecture include benzodiazepines,
antiepileptics, antidepressants, analgesics, and CNS stimulants.
Benzodiazepine receptor agonists — The major class of CNS drugs with primary
indication as hypnotics are the benzodiazepine receptor agonists [1]. Their mechanism of
action is facilitation of gamma-aminobutyric acid (GABA)-mediated inhibition of cell firing by
occupation of subunits (ie, the benzodiazepine receptor) of the GABA receptor complex
present throughout the brain, including the ventral lateral preoptic area which controls
sleep. Some agents share the benzodiazepine chemical structure, while others are
chemically not benzodiazepines, but still act by benzodiazepine receptor occupation (eg,
zolpidem, zaleplon, eszopiclone).
All benzodiazepine receptor agonists improve sleep quality by reducing the time to sleep
onset and, depending on their duration of action, reducing wakefulness during the sleep
period, thereby increasing total sleep time. Modified release formulations of various
hypnotics (eg, zolpidem, zaleplon, indiplon) were developed or are being developed to
improve their pharmacokinetics, thereby better reducing wakefulness after initial sleep
onset.
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The following effects on sleep architecture have been found with the benzodiazepine
receptor agonists:
A reduction in the amount of light or stage 1 sleep, which is considered a therapeutic
effect.
•
Agents with a benzodiazepine structure suppress deeper, non-REM (stages 3 and 4,
also called Slow Wave Sleep) sleep, while those with a non-benzodiazepine structure
do not. The clinical significance of these stage 3-4 effects is not known.
•
Within the range of clinical doses, all the benzodiazepine agonists have little effect on
REM sleep.
•
Tolerance to the hypnotic effects of benzodiazepine receptor agonists does not develop
rapidly, as is the case with some other drugs with sedative effects. It had been suggested
that the nightly use of benzodiazepine receptor agonists be limited to two to four weeks,
although there are now data showing efficacy for one year of nightly use and a recent NIH
consensus conference concluded that chronic use is indicated for many patients with chronic
insomnia [2].
Possible effects seen with discontinuation of therapy are primarily limited to rebound
insomnia, which is usually associated with high doses. Other frequent side effects of
treatment, such as amnesia and residual daytime effects, are merely the expression of the
primary activity of the drug (ie, sedation) when the patient is awake.
Melatonin receptor agonists — Ramelteon binds to the melatonin 1 and 2 receptors,
which inhibits the wake-promoting activity of the suprachiasmatic nucleus. It reduces the
latency to sleep onset and increases sleep duration, while having no effects on sleep
architecture. It is indicated for sleep onset insomnia.
Melatonin, which binds to all three melatonin receptors, is less potent than ramelteon and
its effects on sleep quality and architecture have been inconsistent. However, melatonin is
considered a better chronobiotic, meaning that it will shift sleep phase and may be useful in
circadian rhythm disorders. A chronobiotic is especially useful for sleep phase advance
conditions such as eastward travel or establishing an earlier bedtime. (See "Physiology and
clinical use of melatonin".)
Antiepileptic agents — Classic antiepileptic drugs (eg, phenobarbital, carbamazepine, and
phenytoin) have CNS inhibitory activity, but the mechanisms of inhibition are poorly
characterized. They generally increase total sleep time and stages 3 and 4 (slow wave)
sleep, while suppressing REM sleep, with rapid tolerance to these sleep effects (ie, within a
week). Some of the new antiepileptic drugs (eg, gabapentin, tiagabine and pregabalin) act
through various mechanisms that enhance GABA activity and are being investigated as
potential hypnotics with specialized indications. While these drugs do not appear to reduce
sleep latency, they do enhance slow wave sleep and decrease wakefulness after sleep onset.
Antidepressants — Antidepressant drugs include the tricyclic agents (TCAs), monoamine
oxidase inhibitors (MAOIs), serotonin antagonist reuptake inhibitors (SARIs), and selective
serotonin reuptake inhibitors (SSRIs). Most can affect both sleep quality and sleep
architecture [3].
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Sleep quality — Antidepressant drugs have variable affect on sleep quality. As an
example, some TCAs and MAOIs are sedating, while others are stimulating. All of the SSRIs
seem to be stimulating, but the SARIs (trazodone, nefazodone) are sedating.
Sedative effects are generally due to antihistaminic and/or anticholinergic activity, although
there are exceptions to this rule. Tolerance to the sedative effects develops relatively rapidly
(usually within a week or two). As a result, the antidepressants are usually not considered
appropriate to treat insomnia, except when the insomnia is clearly associated with
depression. The efficacy and safety of antidepressants in patients with primary insomnia
have not been sufficiently confirmed, although several sleep laboratory studies have found
that low-dose doxepin improves the sleep of patients with primary insomnia [4]. The use of
antidepressants in patients with insomnia is discussed elsewhere. (See "Treatment of
insomnia", section on 'Antidepressants'.)
Sleep architecture — The effect of all antidepressants (except SARIs) on sleep
architecture is suppression of REM sleep. This is characterized by increased latency to REM
and reduction of the percentage of REM sleep. Some have argued that the REM suppressing
effects are associated with the antidepressant activity of the drugs.
Selective serotonin 2A receptor antagonists such as ritanserin, eplivanserin, and several
others are being investigated as hypnotics due to their capacity of enhance slow wave sleep.
As with the GABA agonists discussed above, these drugs have not shown strong effects on
sleep induction.
Analgesics — The impact of analgesic medications on sleep has not been thoroughly
studied. Analgesic medications include opioids (eg, codeine, morphine), antiinflammatory
and antipyretic analgesics (eg, aspirin, acetaminophen), and nonsteroidal antiinflammatory
drugs (NSAIDs). Some over-the-counter (OTC) sleeping aids and cold remedies include
analgesics, usually as a combination of acetaminophen and an antihistamine.
In healthy individuals, opioid analgesics increase wake time and reduce slow wave and REM
sleep [5]. Tolerance to these effects develops rapidly, usually within days. In a double-blind
cross-over trial of 42 healthy volunteers, both sustained-release morphine and
methadone increased the percentage of total sleep time spent in stage 2, while reducing the
percentage of total sleep time spent in stage 3 and stage 4, compared to placebo [6]. Opioid
analgesics are also associated with a high prevalence of central and complex apnea among
patients who are using them to treat chronic pain or on methadone maintenance, according
to several case series [7].
NSAIDs may impair sleep by inhibiting prostaglandin synthesis, which is believed to promote
sleep. In one study of healthy individuals, NSAIDs were associated with increased time
awake during the sleep period and unaltered sleep architecture. The net effect was modestly
decreased sleep efficiency.
Despite the adverse effects that analgesics can have on sleep in healthy individuals,
analgesics may improve sleep if pain is the cause of the sleep disturbance.
Central nervous system stimulants — CNS stimulant drugs have profound effects on the
quality and architecture of sleep [1]. As an example, methylphenidate and the
amphetamines increase the latency to sleep onset and increase wakefulness during the
sleep period. Effects on sleep architecture include an increased amount of stage 1 sleep, a
reduction in the amount of stage 3-4 sleep, and suppression of REM sleep. Rapid tolerance
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develops to these effects on sleep quality and staging. Upon discontinuation of the drug,
there is increased sleepiness and a rebound in REM sleep.
Some OTC decongestants contain ephedrine or pseudoephedrine, which are similar in
chemical structure to amphetamine. While these agents have not been studied, they
probably also disrupt sleep.
The methylxanthine, caffeine, disturbs sleep in a manner similar to the stimulants
mentioned above. As little as 150 mg of caffeine (equivalent to one to two cups of coffee)
has been shown to disturb the quality of sleep by increasing sleep latency and reducing
sleep time.
H3 receptor inverse agonist/antagonists are being investigated as wake-promoting drugs for
narcolepsy [8]. The histaminergic system is known to be involved in maintaining
wakefulness.
CARDIOPULMONARY DRUGS — Cardiopulmonary drugs with an effect on sleep include
the beta adrenergic blockers, centrally acting alpha adrenergic agonists, and
methylxanthines.
Beta adrenergic blockers — Beta blockers have been associated with complaints of
insomnia, hallucinations, and nightmares. Objective studies have shown that they increase
the number of awakenings and the amount of wake time during the sleep period, and they
also suppress REM sleep. These effects on sleep quality and staging seem to be limited to
lipophilic as opposed to hydrophilic beta blockers [9]. Lipophilic agents include propranolol,
pindolol, and metoprolol, while atenolol and sotalol are hydrophilic agents. Despite the
effects on nighttime sleep, the lipophilic beta adrenergic blockers increase daytime sleep
and sleepiness. The daytime effects are observed after daytime drug administration and are
not secondary to adverse effects on nighttime sleep.
Centrally acting alpha adrenergic agonists — Several studies have demonstrated that
the centrally acting alpha adrenergic receptor agonist, clonidine, disrupted the quality of
nighttime sleep by inducing more shifts to stage 1 sleep or wakefulness [10,11]. In addition,
clonidine suppressed REM sleep. Like the beta adrenergic blockers, clonidine also increases
daytime sleep and sleepiness. As with the beta blockers, the daytime effects are direct
effects.
These observations notwithstanding, the effects on daytime sleep and sleepiness of both the
alpha and beta adrenoreceptors are somewhat contradictory. Daytime sleep and sleepiness
are increased with both types of antihypertensives.
Theophylline — The methylxanthine, theophylline, disturbs sleep quality in healthy normal
individuals by delaying sleep onset and increasing wake time after sleep onset (eg, during
the sleep period). The amount of stage 1 sleep is increased, but no other effects on sleep
staging are observed [12]. In patients with COPD and asthma, the drug has no deleterious
effects on the quality and staging of sleep. It is likely in these patients that the therapeutic
effect of the drug on breathing decreases the deleterious effects of the respiratory disease
on sleep, and this improvement in breathing counteracts any direct negative effect of the
drug on sleep.
There is no consensus as to the agent of choice for the pulmonary patient with insomnia. A
variety of agents have been assessed, and an important factor may be the specific nature of
the pulmonary disease [13].
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Corticosteroids — The impact of corticosteroids on sleep has not been studied extensively.
One study found disruption of the sleep of healthy subjects treated with a corticosteroid.
The most consistent finding in another study of healthy subjects was suppression of REM
sleep [12]. Studies of self-reported sleep in patients being treated with corticosteroids have
generally found insomnia.
CIGARETTES — Cigarette smoking is associated with sleep-related complaints [14,15]. In
addition, cigarette smoking causes mild disruption of sleep architecture. In an observational
cohort study, polysomnography was performed on 2916 never smokers, 2705 former
smokers, and 779 current smokers [16]. Current smokers demonstrated the following
clinically significant differences when compared to never smokers:
• Slightly longer initial sleep latency
• Slightly less total sleep time
• Less slow wave sleep
No differences in sleep architecture were identified between former and never smokers.
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