Crit Care Clin 24 (2008) 477491

Pharmacology I: Eects on Sleep

of Commonly Used ICU Medications
Gerald L. Weinhouse, MD
Division of Pulmonary and Critical Care Medicine, Brigham
and Womens Hospital, 75 Francis Street, Boston, MA 02115, USA

Critically ill patients are known to have severely disrupted sleep. They
tend to have a paucity of deep sleep (slow-wave and rapid eye movement
[REM] sleep) and a predominance of light sleep and wakefulness [17].
Many of the medications commonly used in the ICU have been implicated
in this phenomenon.
Medications can aect sleep in various ways. They may aect the central
nervous system directly by penetration of the blood-brain barrier or indirectly by aecting a medical or psychiatric illness that results in altered sleep
[8]. Some medications may disrupt sleep by their eect on pre-existing sleep
disorders and others have an equally disruptive eect when withdrawn
abruptly [9]. Conversely, medications may have a benecial eect on sleep
depending on the clinical circumstance [10].
Most medications have been studied for their eect on the electroencephalogram (EEG) and thus the sleep architecture (relative percent of sleep
stages and their orderly progression through the night) of healthy volunteers
(summarized in Table 1). Well-controlled studies of the eects of medications on sleep have not been done in critically ill patients. What is known
of the eects of some commonly used ICU medications on sleep is reviewed.
Sedatives
The most commonly used ICU sedatives are those that interact with
GABA receptors in the central nervous system. Benzodiazepines and propofol bind at dierent sites on the receptor but each is able to activate this
inhibitory system to create the altered state characteristic of their clinical effect [1113]. GABA activation is part of the endogenous sleep pathway;
however, it is a late event in naturally occurring sleep leaving the early
E-mail address: gweinhouse@partners.org
0749-0704/08/$ - see front matter 2008 Elsevier Inc. All rights reserved.
doi:10.1016/j.ccc.2008.02.008
criticalcare.theclinics.com

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Table 1
Eect of commonly used ICU medications on sleep
Sedatives/hypnotics
Benzodiazepines
Propofol
a2-agonists (dexmedetomidine)
Analgesics
Opioids
NSAID
Antipsychotics
Typical (haloperidol)
Atypical (olanzapine)
Antidepressants
Tricyclics
SSRIs
Trazodone
Cardiovascular
Antihypertensives
b-antagonists
a2-agonists
Calcium antagonists
ACE inhibitors
Diuretics
Amiodarone
Antihypotensives
Epinephrine/norepinephrine
Dopamine
Respiratory
Xanthines (theophylline)
Antiepileptic
Phenytoin
Barbiturates
Carbamazepine
Valproic acid
Gabapentin

Y
[
Y
[
Y
[

W, REM, SWS, SL
TST, Stg II
W, SL
TST
SL, REM
SWS

YTST, REM, SWS

[ W, Stg II
Y TST, SE
Y
[
Y
[

W, SL
SE, Stg II
W, SL
TST, SE, SWS

Y
[
Y
[
Y
[

W, REM
TST
TST, SE, REM
W
W, SL, REM
TST, /SWS

[ W, SL
Y REM (variable, depends on lipid solubility)
Y REM
NA
No eect on sleep
NA
Nightmares
Y SWS, REM
Y SWS, REM
Y TST, SE, REM, SWS
[W
Y
[
Y
[
Y
[
Y
[
Y
[

SL
SWS
W, SL, REM
TST
SL, REM
SWS
W
TST
W
TST, REM, SWS
(continued on next page)

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479

Table 1 (continued )
H2-antagonists
Cimetidine?
Corticosteroids
Substances of abuse
Ethanol
Cannabis
Nicotine

[ SWS
Y REM, SWS
[ W, Stg II
Y
[
Y
[
Y
[

SL, REM (rst half of the night)

REM (second half of the night), nightmares
REM
SWS (if acute use; tolerance if long-term use)
TST, REM
SL

Abbreviations: ACE, angiotensin-converting enzyme; NA, not available; NSAID, nonsteroidal anti-inammatory drug; REM, rapid eye movement; SE, sleep eciency; SL, sleep latency;
Stg II, stage II sleep; SWS, slow wave sleep; TST, total sleep time; W, wakefulness.

events unaected [14]. The result is that sleep and conventional sedation
share similarities but also important dierences [15]. Table 2 summarizes
the similarities and dierences between sedation and naturally occurring
sleep.
At low doses, benzodiazepines and propofol suppress slow-wave sleep
(SWS) and have little eect on REM sleep [1618]. They shorten sleep latency, decrease arousals, and increase stage II and spindle activity, although
the spindles observed under the inuence of sedation are distinct from those
occurring naturally [19]. Higher doses of the medications are associated with
a characteristic slowing of the EEG and both medications can eventually

Table 2
Comparison between sedation and naturally occurring sleep
Sleep
Dierences
Spontaneous
Circadian
Essential function
Reversible with external stimuli
Associated with decreased NE release
Cyclic progression by EEG

Sedation
Not spontaneous
Not circadian
Nonessential function
Not completely reversible with external stimuli
Associated with unaected NE release
from locus ceruleus
No cyclic progression by EEG

Similarities
Altered sensorium
Overlapping neurophysiologic pathways
Muscle hypotonia
Temperature dysregulation
Respiratory depression relative
to wakefulness
Abbreviations: NE, norepinephrine; EEG, electroencephalogram.

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lead to a burst-suppression pattern [2022]. Both medications are also

associated with alteration of regional cerebral blood ow and metabolism
that may, in part, account for their electrophysiologic eect [23,24].
Investigation into the eects of any drug on sleep is limited by the
absence of reliable measures of sleep quality, especially for critically ill
patients. It is therefore unknown whether these electrophysiologic and metabolic eects correspond to important clinical eects. Some animal studies
have suggested that at least one function of sleep, the resolution of objective
measures of sleepiness, is enabled or facilitated during sedation with propofol [25,26]. Further study is necessary to conrm this eect in humans and
also to determine whether other of the functions of sleep may also occur
during sedation.
Dexmedetomidine, an a-agonist, was approved for use in patients initially
mechanically ventilated. Its relationship with sleep is dierent than that of
the GABA-agonist sedatives owing to eects closer to the onset of the naturally occurring sleep pathway in the central nervous system (CNS) [27]. Dexmedetomidine is the only parenteral form of this class of drugs available in
the United States, and is believed to inhibit norepinephrine release by locus
ceruleus thus leading to a sequence of events that more closely resembles natural sleep physiologically and clinically. It is unproven, however, whether
these theoretic advantages oer patients either clinical or outcomes benets.
Analgesics
Opioids are the mainstay of treatment for pain and discomfort in critically ill patients. They interact with the natural sleep pathway by way of
the pontothalamic arousal pathway rather than the hypothalamic pathway
most relevant to the sedatives [13,28]. Even single doses of opioids potently
suppress SWS [29,30]. REM sleep suppression by opioids is a dose-dependent phenomenon mediated by the m-receptor [31]. Opioids increase stage
II sleep but also increase wakefulness in healthy volunteers; however, if
pain is a predominant cause of disturbed sleep the overall eects of the opioids would likely be to improve sleep [32].
Even nonsteroidal anti-inammatory medications can adversely aect
sleep by decreasing sleep eciency and increasing awakenings. These eects
may be because of inhibition of prostaglandin synthesis, decreased melatonin secretion, attenuation of the normal decrease in nocturnal body temperature, or gastric irritation [33,34].
Cardiovascular drugs
Drugs to treat hypertension and arrhythmias
The use of beta-blockers in the ICU has become commonplace with an increasing list of indications for critically ill patients. They are used in the

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481

management of patients who have an acute coronary syndrome, hypertension, acute burn injuries, and for prophylaxis against dysrhythmias after
cardiothoracic surgery [3538]. Their eects on sleep are variable and depend on their lipid solubility; it is their ability to cross the blood-brain
barrier that is believed to be related to their central nervous system side
eects. The most lipid soluble (ie, propranolol) have the greatest tendency
to disrupt sleep [39]. They have been found to be associated with nightmares, insomnia, and REM suppression.
Amiodarone is a highly eective antiarrhythmic drug with neurologic
side eects occurring in up to 40% of patients on a therapeutic dose. These
neurologic eects include insomnia and nightmares in 1% to 3% of noncritically ill individuals; however, the mechanism of this eect is unknown
[40].
Angiotensin-converting enzyme inhibitors, such as captopril, have not
been found to disturb sleep, and other antihypertensives, such as calcium
antagonists, hydralazine, diuretics, and a1-antagonists such as prazosin,
have not been studied for their eects on sleep [4144]. a2-agonists, such
as clonidine and methyldopa, can increase total sleep time in healthy subjects but clonidine is REM suppressive and causes vivid dreams, and both
can cause insomnia as an adverse eect [45,46].
Drugs to treat hypotension
Adrenergic receptor agonists may cross the blood-brain barrier under
certain conditions leading to CNS side eects [47]. Septic patients and those
patients simultaneously anesthetized with propofol, for example, may be
more vulnerable to the eects of these drugs on sleep as a consequence of
this phenomenon [48,49]. Norepinephrine and epinephrine likely exert their
eects through direct a1-receptor stimulation, whereas dopamine may aect
the a1-receptor and the D2-receptor. All three agents are associated with
insomnia and the suppression of REM and SWS, although it is likely that
patients sick enough to require these drugs are also under the inuence of
other sleep-disrupting variables, such as sepsis, stress, other medications,
and attentive ICU care [9].

Respiratory medications
Patients on mechanical ventilation and those who have acute or chronic
respiratory conditions associated with symptoms are likely to receive at least
inhaled b-adrenergic receptor agonists while in the ICU. CNS stimulation
with associated restlessness and insomnia are well-known adverse eects
of these drugs. The overall eect on sleep may be positive, however, if
they alleviate dyspnea and oxyhemoglobin desaturation, which have been
demonstrated to be associated with arousals from sleep [10,50,51]. In patients with nocturnal asthma symptoms there may be a subjective

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improvement with the use of salmeterol, however it is not clear whether

these improvements correspond to objective changes in sleep architecture
[10,52].
Theophylline, a methylxanthine derivative related to caeine and once
a mainstay in the treatment of asthma and COPD exacerbations, has been
strongly associated with sleep fragmentation, poor sleep eciency, and
decreased slow-wave and REM sleep [53,54]. Although it may alleviate
nocturnal bronchospasm, the benecial eects on nocturnal breathing
may not be enough to compensate for the otherwise negative eects on sleep
[5558].
Corticosteroids
The eects of corticosteroids on sleep may depend on the clinical setting
and the type and dose of the medication administered. Corticosteroids have
been associated with REM suppression and an increase in nocturnal awakening [59]. Their CNS stimulatory adverse eects, the hypomania or steroid psychosis, can cause insomnia. Twenty-ve percent of healthy
subjects given 80 mg/d of prednisone for 5 days reported decreased sleep
[60].
Gastric acid blockers
The treatment of acute GI bleeding and prophylaxis against stress ulcers
in mechanically ventilated patients includes the use of either histamine type
2 (H2)receptor antagonists or proton pump inhibitors. The H2-antagonists
are an infrequent cause of insomnia, in part because they have limited CNS
penetrability. Cimetidine, the most blood-brain barrier permeable, is associated with insomnia in less than 2% of subjects studied, but it may also
increase SWS [61]. Proton pump inhibitors have been less well studied
and only anecdotes of sleep disturbances have been reported.
Antipsychotics
Antipsychotics have become a mainstay of the care of the agitated critically ill patient. Haloperidol, the most commonly used of the typical
antipsychotics, given to healthy volunteers in a single dose, has recently
been shown to have a tendency to increase sleep eciency and stage 2 sleep
with little eect on slow-wave activity [62]. Atypical antipsychotics, such as
olanzapine and risperidone, increase total sleep time, sleep eciency, and
SWS; data on REM eects are not consistent [62,63]. Healthy volunteers
reported improved subjective perception of sleep quality after a dose of
olanzapine and schizophrenics reported improved sleep with risperidone
compared with haloperidol [62,63]; subjective sleep quality has previously
been shown to correlate with SWS [64].

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483

Antidepressants
Although antidepressant therapy may not often be initiated in the ICU,
antidepressants are commonly prescribed in the community and many have
long half-lives; therefore, they are frequently present in critically ill patients
and a potential factor in patients care. Because a wide variety of drugs are
prescribed for depression and many patients for whom these drugs are
prescribed already have disturbed sleep, it is dicult to generalize about
the eects of antidepressants on sleep.
The tricyclic antidepressants potently suppress REM sleep but increase
total sleep time and, in general, may improve subjective sleep quality
[6568]. They increase daytime sedation but this eect lessens with time.
The selective serotonin-reuptake inhibitors (SSRIs) and the dual serotonin
and norepinephrine reuptake inhibitors (ie, venlafaxine) less potently suppress REM sleep but decrease total sleep time and may be associated with
insomnia and daytime sedation [6973].
Trazodone, a selective serotonin and norepinephrine reuptake inhibitor,
is an antidepressant sometimes used to counter the SSRI-induced insomnia.
In fact, it is often used as a hypnotic rather than an antidepressant to capitalize on its sedating side eect [65]. It has been shown to increase total
sleep time, shorten sleep latency, have only a minimal inhibitory eect on
REM sleep, and possibly increase SWS in some clinical settings [7478].
Antiepileptic medications
Most of the older antiepileptic medications, such as phenytoin, phenobarbital, valproic acid, and carbamazepine, increase total sleep time and
decrease REM sleep, and some increase SWS [79]. Dose-dependent sedation
is their most common adverse eect with an incidence of 30% to 70% [80].
One of the newer antiepileptics, gabapentin, has been used for various
o-label indications in addition to seizures. It increases total sleep time,
REM sleep, and SWS, and has a reported incidence of daytime sedation
of 5% to 15% [8183].
Sleep-related withdrawal syndromes of prescribed medications
and addictive drugs
Just as the administration of medications may disturb sleep, the abrupt
cessation of medication may also be disruptive to sleep. Withdrawal
syndromes are likely underdiagnosed; one retrospective study observed
a 32% frequency of acute withdrawal from opioids and benzodiazepines
in mechanically ventilated patients in the ICU more than 7 days [84].
Many medications taken at home are not given in the ICU because they
cannot or should not be administered to an acutely critically ill patient or
because they are believed to be nonessential. Others are given for an acute

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illness but weaned too quickly. Similarly, substances of abuse (ie, nicotine,
caeine, alcohol, heroin, cocaine) disrupt sleep both when present and
when withdrawn abruptly.
Medications that are REM suppressive, such as opioids, tricyclic antidepressants, serotonin reuptake inhibitors, and benzodiazepines, are associated
with a rebound increase in REM % when withdrawn [8]. This increase in
REM % may be associated with excessive dreaming and nightmares. REM
is also the time of greatest respiratory instability. During REM sleep,
hypoxia may be most severe in those who have COPD and obstructive sleep
apnea (OSA) and apneic events and respiratory variability are likely greater
than at other times during sleep.
Alcohol is often believed to facilitate sleep. In healthy, nonalcoholdependent people its presence shortens latency to sleep onset and decreases
REM % during the rst half of the night [85,86]. As alcohol is metabolized,
however, there is an increase in REM % during the second half of the night
and an associated increase in sleep fragmentation [87]. Withdrawal from
chronic alcohol use is well known to disrupt sleep with a decrease in total
sleep time and sleep continuity and loss of SWS and REM [88]. Alcohol
further worsens sleep-disordered breathing and snoring and may increase
parasomnias, such as nightmares and night terrors.
Cigarette smoking has been associated with sleep-onset insomnia and
nonrestorative sleep [89]. Nicotine increases alpha activity, which is
Table 3
Eect of drug withdrawal on sleep
Sedatives/hypnotics
Benzodiazepines
Analgesics
Opioids
Antipsychotics
Haloperidol
Antidepressants
Tricyclics
SSRI
Cardiovascular
a2-agonists
Antiepileptic
Barbiturates
H2-antagonists
Cimetidine
Stimulants
Amphetamines
Cocaine
Substances of abuse
Ethanol
Nicotine
Cannabis

[ REM %, Y sleep continuity

Insomnia, [ REM %
[ REM latency, [ sleep latency, [ stage II, Y TST

Insomnia, nightmares, excessive dreaming (REM rebound)

[ REM %
[ REM %, [ sleep latency, Y sleep continuity and TST
Insomnia

[ REM %, Y sleep continuity

Insomnia
Insomnia, daytime somnolence
[ REM %, Y SWS

Abbreviations: SWS, slow-wave sleep; TST, total sleep time.

EFFECTS ON SLEEP OF COMMONLY USED ICU MEDICATIONS

485

characteristic of wakefulness, increases movement, and decreases SWS [90].

Nicotine withdrawal adversely aects sleep continuity [91,92]; however, recent data raise questions about the safety of replacement therapy in critically
ill patients [93]. See Table 3 for withdrawal syndromes associated with these
substances.
Interaction of medication with pre-existing sleep disorders
Some commonly used ICU medications may aect patients sleep by their
eect on a pre-existing sleep disorder. Obstructive sleep apnea (OSA) aects
2% to 5% of the population between 30 and 60 years old [94,95] and restless
legs syndrome (RLS) is estimated to aect 5% to 10% of adults [96]. Patients
who have these conditions, whether previously diagnosed or not, are frequently cared for in ICUs.
The relationship between certain medications and OSA is complex. The
REM suppression of such medications as antidepressants might be expected
to improve the sleep of patients who have OSA because REM is the stage
typically associated with the highest respiratory disturbance index and
greatest oxyhemoglobin desaturation. The REM suppression and poor sleep
eciency observed with these medications, however, does not seem to oer
protection against either the frequency of apneas or desaturations [97]. In
addition, some medications and alcohol are likely to increase upper airway
obstruction in non-intubated patients and should be avoided when possible

Box 1. Effect of drugs on pre-existing sleep disorders

Drugs that worsen airway obstruction in obstructive sleep
apnea
Ethanol
Narcotics
Anesthetics
? Benzodiazepines (data inconclusive at usual hypnotic doses)
? Barbiturates (data inconclusive but known to reduce tone
of the upper airway dilator muscles)
Drugs that worsen PLM/RLS
Tricyclic antidepressants
SSRIs
Lithium carbonate
Dopamine D2 receptor blockers (ie, neuroleptics)
Caffeine
Ethanol
Abbreviation: PLMS, periodic limb movements during sleep.

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Box 1 [98104]. See Box 1 for a list of some of the medications which worsen
airway obstruction in patients with OSA.
RLS and the related periodic limb movements during sleep may also be
worsened by medications and alcohol [105,106]. The therapeutic response
of the condition to dopamine agonists is consistent with the nding that
dopamine antagonists worsen it. Box 1 lists some of the medications and
substances of abuse that may worsen RLS/PLMS.
Summary
Most medications commonly used to treat critically ill patients have the
potential to aect sleep by (1) directly or indirectly interacting with the central nervous system, (2) acute withdrawal, or (3) worsening a pre-existing
sleep disorder. Poor sleep in the ICU has been linked to at least one adverse
ICU outcome measure [107111]; therefore, careful scrutiny of the medications given each patient with attention to optimizing sleep should become an
integral part of patient care.
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